摘要:

Russian Chemical Reviews 68 (1) 1 ± 18 (1999) Cambridge Structural Database as a tool for studies of general structural features of organic molecular crystals L N Kuleshova,MYu Antipin Contents I. Introduction II. Organisation and software of the Cambridge Structural Database III. Van der Waals atomic radii and nonbonded intermolecular distances in organic crystals IV. Principle of close packing in crystals and distribution of molecular centres in crystallographic unit cells V. Relative frequencies of occurrence of space groups VI. Why do organic crystals prefer centrosymmetrical groups? VII. Number of molecules per asymmetric unit and pseudosymmetry VIII. Supramolecular synthons and the possibility of prediction of crystal structures IX. Conclusion Abstract.The review surveys and generalises data on the use of the Cambridge Structural Database (CSD) for studying and revealing general structural features of organic molecular crystals. It is demonstrated that software and facilities of the CSD allow one to test the applicability of a number of known concepts of organic crystal chemistry (the principle of close packing, the frequency of occurrence of space groups, the preferred formation of centrosym metrical molecular crystals, etc.) on the basis of abundant statistical data. Examples of the use of the Cambridge Structural Database in engineering of molecular crystals and in the system- atic search for compounds with specified properties are given. The bibliography includes 122 references. I.Introduction Presently, the Cambridge Structural Database (CSD) is one of the most powerful information databases, which contains exhaustive data (atomic coordinates, molecular geometry and crystal sym- metry) on crystal and molecular structures of organic, bioorganic, organoelement and organometallic compounds and to a large extent coordination compounds which have been studied by X-ray diffraction and/or neutron diffraction analysis. (The term organic crystals is used to denote crystals containing at least one `organic' carbon atom, i.e., that involved in formation of C7C or C7H bonds.) Data on crystals which can hardly be called true organic molecular crystals (for example, data on inorganic alkylammo- nium salts, etc.) are also included in the CSD.Therefore, the CSD involves information on diversified organic crystals. Hence, the correct choice and rejection of compounds in the search for structural regularities in series of related and structurally similar crystals is one of the most important problems in the use of the CSD. Presently, the CSD L N Kuleshova, MYu Antipin A N Nesmeyanov Institute of Organo- element Compounds, Russian Academy of Sciences, ul. Vavilova 28, 117813 Moscow, Russian Federation. Fax (7-095) 135 50 85. Tel. (7-095) 135 93 43 (L N Kuleshova), Tel. (7-095) 135 92 15. E-mail: mishan@xray.ineos.ac.ru (M Yu Antipin) Received 23 April 1998 Uspekhi Khimii 68 (1) 3 ± 22 (1999); translated by T N Safonova #1999 Russian Academy of Sciences and Turpion Ltd UDC 548.31 13468 10 14 16 17 contains data on 181 000 crystal structures and the body of information in the CSD increases annually by 7000 ± 8000 new structures.Clearly, the availability of the sizable database gave impetus to a search for various special structural features of particular classes of compounds as well as to a search for general regularities of organic crystal structures with the use of the CSD on the basis of statistically reliable analysis of large samples. The first line of investigation began actually after the first CSD release has appeared. Studies of the general regularities of organic crystal structures using statistical analysis became possible only with the appearance of computer versions of the CSD and with the development of special programmes for statistical treatment of a large body of data.There are two approaches to the elucidation of the general rules and regularities of organisation of crystalline solids from isolated structural elements (atoms, molecules and their associates and ions). The first approach involves the use of computational methods, in particular, those used for a priori prediction of new crystal structures. In recent years, much progress in this field has been achieved.1±4 The second approach is based on the correct statistical analysis of numerous crystal-structural data accumu- lated in information databases. We dwell on the results and prospects of the second approach with the use of modern tools and facilities of the CSD.Useful new crystal-chemical information can be obtained by performing correct systematic statistical analysis of the large available body of experimental structural data. This idea appeared rather long ago. Thus many chemists and crystal chemists still use the values of the van der Waals radii which were determined by Pauling 5 and Bondi 6 based on the analysis of scarce crystal-structural and other (in particular, gas-kinetic) data available at that time. The fundamental principles of structures of organic molecular crystals (among them, the principle of close packing), which have been explicitly stated for the first time by Kitaigorodskii,7 were also established on the basis of relatively scarce statistical data.In the 1970's and in the early 1980's, these systematic studies were believed to be very promising. However, as the experimental published data on crystal structures were accumulated, these investigations became more complicated. The major obstacle (which is believed to be insurmountable) lay in the fact that non-computerised search and processing of abundant numerical data were extremely tedious procedures.2 It is worth noting that since the early days of crystallography (crystal chemistry), the researchers involved in this field have realised that data obtained in their studies are of fundamental importance and can have a wide use. Consequently, they were the first to systematically amass results of their studies. Thus as soon as 16 years after the development of the X-ray diffraction method, a beginning has been made in systematically reviewing X-ray structural data.8 In this country, results of X-ray diffraction studies of organic crystals were first surveyed by Struchkov and were reported by Kitaigorodskii 7 in 1955.More recently, the well- known handbooks by Kitaigorodskii, Zorky and Belsky were issued.9, 10 The complete bibliography concerning these sources was published by Watson.11, 12 First computer databases were compiled based on the avail- able publications. Two of them, viz., `Powder Diffraction File' 13 and `NBS Crystal Data: Database Description and Applica- tions' 14 became available totally as a computer version. These banks contain exhaustive (from the chemical standpoint) infor- mation but do not include atomic coordinates and were primarily used (and are still used) for identification and comparative studies of unit cell parameters and crystal symmetry.The compilation of structure databases which contain atomic coordinates along with crystallographic data, details of chemical structures and bibliographic description dates back to the mid- 1960's. When creating these databases, one would have to process information from current publications and to collect data on structures which have been studied previously and which are scattered over numerous literature sources. Therefore, in the initial stage, priority was given to works on the development of software for collecting, testing, processing and depositing data.Subsequently, programmes were developed for the search, selec- tion and statistical analysis of information as well as for the distribution of databases. Systematic statistical studies with the use of all the data accumulated in databases appeared only in the last decade. Presently, information on virtually all types of chemical compounds can be found in four structure databases: the Cam- bridge Structural Database (University of Cambridge, UK) contains data on 181 000 structures, the Inorganic Crystal Structure Database (University of Bonn, Germany) contains data on 41 500 structures, the Metals Data File (National Research Council of Canada, Ottawa, Canada) contains data on more than 11 000 structures and the Protein Data Bank (Broo- khaven National Laboratories, USA) contains data on more than 1500 structures.Presently, the CSD15 is the biggest database. Using the information bases of the CSD, one can perform statistically reliable systematic studies of structural data. The knowledge of precise molecular geometry is necessary for the understanding of the nature of chemical bonds and chemical structures. Therefore, early studies were devoted to the determination of mean (`typical') values of bond lengths and bond angles in various classes of chemical compounds 16, 17 and the acquisition of data on struc- tural features of particular fragments or classes of chemical compounds as a whole.18 ± 20 Systematic investigations into the mutual arrangement of molecules in crystals were begun with studies of geometrical characteristics of intermolecular interactions.In particular, stat- istical values of van der Waals atomic radii 21, 22 and geometrical characteristics of specific interactions (hydrogen bonds,23 ± 27 and the CH. . . O(N), Hal . . . Hal and some other contacts 28 ± 33) were determined. More recently, with the increase in the size of the CSD and the perfection of software for correct selection and statistical analysis of results, some researchers formulated problems based on the belief that the CSD contains, in some form, information on general regularities of molecular crystal structures. In this respect, noteworthy is the paper by Motherwell 34 in which distributions of positions of geometrical centres in molecular crystals were analysed and the preference for the realisation of L N Kuleshova,MYu Antipin the principle of close packing was statistically confirmed.Recently, some researchers have cast doubt on the firmness of this principle.35 The doubts were substantiated by the fact that the principle of close packing should contradict a tendency of molecules to form strong intermolecular hydrogen bonds and by the fact that experimental crystal structures do not necessarily correspond to the calculated global energy minima. The question of the frequency of occurrence of space groups has received the most study based on the CSD data. Numerous statistical studies were devoted to this problem.36 ± 44 Admittedly, the most detailed investigations were carried out by Belsky 42 and by Brock and Dunitz.45 The considerable attention given to this problem is quite justified because many physical properties of crystals depend on the symmetry of the molecular arrangement and hence, the a priori estimation of the crystal symmetry is an important practical problem.For example, this is of importance in the design of materials with nonlinear-optical properties, which are constructed using organic chromophore molecules.46, 47 Often, in studies using the CSD researchers attempt to establish the reasons for which compounds crystallise preferen- tially in centrosymmetrical (achiral) space groups rather than restrict themselves to simple statement of the facts (for example, about the considerable predominance of racemic crystals.48) Thus efforts to estimate the effect of molecular dipoles on the crystal packing were applied,49 a comparative analysis of densities and stabilities of compounds that crystallise in both racemic and chiral space groups was carried out 50 and the correlations between densities, calculated packing energies and some thermodynamic properties of crystals were considered for pairs of polymorphic modifications existing at room temperature.3 In recent works devoted to analysis of the frequency of occurrence of space groups,45 much attention was given to the number of formula units per asymmetric unit (Z0). Belsky and Zorky were the first to note the importance of the consideration of this parameter.51, 52 Studies of crystals with Z0>1 brought up many questions.For example: are conformations of independent molecules in the unit cell identical or not? Are independent molecules related by any symmetry transformations? What is meant by pseudosymmetry? How do pseudosymmetry elements and true symmetry of real crystals relate to each other? Do crystals with Z0>1 possess any characteristic properties? Abrahams attempted to give the answer to the last question.53 He suggested that if pseudosymmetry is present, phase transitions of the second kind can occur in crystals of a number of inorganic compounds as the temperature is increased.53 This hypothesis provided the basis for the development of a procedure for the search for new potential ferroelectrics,54 which is successfully used for predicting inorganic compounds with high-temperature phase transitions.55 Interestingly, unit cells with Z0>1 are more frequent in crystals containing molecules that can form stable associates through hydrogen bonds.56 The occurrence of unit cells with Z0>1 and the existence of pseudosymmetry are highly probable for compounds exhibiting liquid-crystal properties on melt- ing.57 ± 59 The results of studies of characteristic types of supramolecular fragments (supramolecular synthons) that formed in crystals through the strongest nonbonded intermolecular interactions for molecules of similar types or for molecules containing similar chemical functional groups may be very useful in revealing general regularities of organisation of crystal structures.60 ± 62 These studies fall within the realms of crystal engineering (a new intensively developing branch of science that appeared at the borderline between materials technology and crystal chemistry), which involves the development of procedures for the design of organic crystalline materials with predetermined properties.The crystal symmetry describes the topology of molecules in crystals and determines many physical properties of solids, namely, electrical, magnetic, linear-optical and nonlinear-optical proper- ties, electronic and ionic conductivity, etc. Therefore, the current prime objective of crystal engineering is to reveal factors thatCambridge Structural Database as a tool for studies of general structural features of organic molecular crystals affect the formation of crystal structures with a particular molecular architecture, which causes the manifestation of a desirable physical property. An important role of databases, in particular of the CSD, in the design of new materials was discussed in the review by Aakeroy.63 It was noted that the development of software of the CSD (new algorithms and statistical and cluster analyses) and the incorporation (wherever possible) of a number of thermodynamic and/or other physicochemical characteristics of compounds into the CSD will favour the directed search and design of new compounds with preset properties.Therefore, the use of the CSD has promise in the search for fundamental structural features of organic molecular crystals.However, it should be borne in mind that even very large statistical samples cannot assure automatically that statistically reliable characteristics and properties will be obtained without appropri- ate rejection and processing of the data. Therefore, when consid- ering examples of the use of the CSD, we concentrated most attention on the analysis of schemes applied in the original publications cited for creating representative statistically signifi- cant samples. Modern versions of the CSD allow one to compile and reject particular data on the basis of a series of criteria and indications, each being a subject of special discussions in the literature.The present review is the first attempt to consider the CSD as a tool in studying general structural regularities of organic molec- ular crystals. II. Organisation and software of the Cambridge Structural Database As has been mentioned above, the CSD contains results of complete three-dimensional X-ray and neutron diffraction stud- ies of organic, bioorganic, organometallic and coordination compounds. The CSD is compiled by reviewing original publica- tions in 1025 scientific journals and other sources (data as of 1988). Presently, the majority of crystal chemists and crystallog- raphers as well as many chemists consistently use the above- mentioned databases in their routine work. For example, the 1998 version of the CSD is employed by researchers at about 40 scientific institutes of Russia and Newly Independent States of the Former Soviet Union.About 150 articles were devoted to the use of the CSD. The major principles of selection and systematic numerical analysis of information in crystallographic databases were considered and analysed in detail in one of the latest papers, namely, in the review by Allen 64 `Crystallographic Data Bases: Samples and Analysis of Precise Structure Information from the Cambridge Structural Database'. Therefore, we mention only briefly the essentials of organisation and software of the CSD. The use of the CSD requires special software, namely, the programme package developed for the search, selection of required data, analysis of geometrical parameters of molecules and crystal structures and their representation with the use of computer graphics tools.The search for the required information in the CSD is performed using the QUEST programme, which specifies the query. This query can be formulated in the form of three major packages, viz., 1D, 2D and 3D. A query specified by the QUEST1D option allows one to obtain bibliography, the name of a compound, the molecular formula or the amino acid sequence, unit cell parameters, the R factor and required comments (the presence of disorder, errors, etc.).A query specified by the QUEST2D option allows one to obtain information on the atom and bond properties, the formal chemical type of the bond, tables of atom connectivities and the structural formula.A query specified by the QUEST3D option allows one to obtain the description of a crystal structure, i.e., the space group, symmetry operations, three-dimensional atomic coordinates, 3 crystallographic connectivity determined by the covalent radii and data on the correspondence between the `crystallographic' and `chemical' atoms from tables of connectivities of 2D dia- grams. Queries are specified with the use of special menus (BILD, SEARCH and QUEST). Information can be rejected by specify- ing a set of BITSCREEN indications. The QUEST3D option compiles a data file FDAT from information selected according to the query. This file serves as an input file for the GSTAT(VISTA) and(or) PLUTO pro- grammes.The GSTAT programme was originally developed for calculations of intra- and intermolecular geometry and geometry of molecular fragments.65 Presently, GSTAT is a programme package which allows one to analyse geometrical characteristics with the use of statistical and numerical methods.66 The VISTA programme (graphical supplement to GSTAT) is destined mainly for numerical, statistical and graphical analysis of the geometrical information extracted from the CSD. The PLUTO programme is applied not only by crystallogra- phers but also by chemists. This programme is destined for the preparation of various graphical illustrations, including visual- isation of both molecular structure and crystal packing based on three-dimensional coordinate data sets.The most precise data in the CSD are used in the analysis of geometrical characteristics. In the simplest case, entries containing errors and disordered structures are rejected. The CSD contains two major parameters characterising the accuracy of the crystal structure, namely, the R factor and the AS parameter. The former characterises the overall discrepancy between the diffraction data and the crystal structure solved on the basis of these data. The latter characterises the average standard deviation of bond lengths. These parameters can be used both in QUEST (for preliminary rejection in the course of the search) and GSTAT (in statistical averaging). Calculations of average molecular geometrical parameters used in statistical analysis were discussed in many papers (see, for example, Refs 67 ± 69). Generally, either an average or a weighted average is calculated.A weighted average is better suited for cases where environmental effects are insignificant (for example, for rigid parameters, such as bond lengths). If environ- mental effects are substantial (torsion angles and bond angles), simple unweighted averages should preferably be determined. It is desirable to use an unweighted average also in statistical verifica- tions of hypotheses. The absence of standard deviations of parameters for the majority of structures in the CSD does not allow one to calculate weighted averages without recourse to the original literature. However, Taylor and Kennard 69 demon- strated that an unweighted average can be sufficient even for rigid parameters provided the scatter of the experimental values is limited by the AS criterion. The authors believe that when the value of AS is 1.2, estimates of, for example, bond lengths in organic structures are quite correct.An unweighted average is used in the GSTAT programme for calculations of standard statistical characteristics. It should be noted that only selected crystal-structural data, which are obtained by X-ray diffraction analysis of single crystals, are included in the CSD. In particular, atomic anisotropic displacement parameters (previously, they were called thermal ellipsoids) cannot be analysed. These parameters contain unique information on the dynamics of crystal structures and character- istics of atomic movements and/or disorder in crystals. Unfortu- nately, these data are absent in the CSD.Trueblood and Dunitz 70 were the first to call attention to this disappointing fact. They have demonstrated how information on the dynamics of crystal structures can be used for estimating energy characteristics (for example, barriers) of slow intramolecular movements in crystals, which is important in studies of properties of organic crystals.4III. Van der Waals atomic radii and nonbonded intermolecular distances in organic crystals The atoms of elements can be, in a rather rough approximation, represented by rigid spheres with radii which are geometrical characteristics of the corresponding elements.7 The effective values of these characteristics are called van der Waals radii (WR) of elements.Needless to say these concepts are very simplified because atoms in molecules (the more so, in molecules in crystals) cannot be rigid, and their effective sizes depend also on the nearest environment as well as on the hybrid state of the atom. The first studies 71, 72 carried out with the use of the CSD have demonstrated that some bound atoms are flattened rather than spherical.73 However, the simple `rigid' spherical model appears to be a very persistent and extremely useful formalism. Frequent application of WR stems from the necessity of comparing lengths of expected nonbonded intermolecular atom ± atom contacts in crystals, which are determined as the sum of the corresponding WR, with the corresponding distances observed in crystal structures.Besides, in early work 7 WR were used for choosing force-field parameters in calculations of the energy of intermolecular interactions in crystals. Presently, the CSD is finding increasing use for choosing these parameters,1 ± 4 and the parameters of pairwise X. . .Y interactions are chosen based on the analysis of statistical distributions of bond lengths of the corresponding contacts retrieved from a large body of data in the CSD. Several systems of WR are known. They were suggested by Pauling,5 Kitaigorodskii,7 Bondi,6 Zefirov and Zorky,74 Nyburg and Faerman,75 and Batsanov.76 Bondi's system (table) ofWR6 is most commonly used in spite of the fact that it has been repeatedly criticised in more recent works.71, 74, 77 In this country, the system of radii suggested by Zefirov and Zorky 74 has gained acceptance. Rowland and Taylor performed systematic analysis of non- bonded contacts in organic molecular crystals.23 ± 26, 78 In one of their recent works, the authors decided to test the compatibility between the commonly accepted systems of WR of nonmetals H, C, N, O, F, P, S, Cl, Br and I and the observed nonbonded interatomic distances in crystals studied over a period of the last 30 years.22 Studies were carried out with the use of the 1995 version of the CSD containing 126 353 crystal structures.Only precise (R factors<5%) and ordered structures that contained exclusively the above-listed atoms were considered.Structures containing charged groups were also rejected to exclude the effect of electro- static interactions on interatomic distances. A total of 28 403 structures satisfying all the above-mentioned requirements were selected. For a pair of atoms A and B under consideration, all intermolecular distances falling within the interval (RA+RB)1.5A, where RA and RB are the corresponding WR according to Bondi, were taken into account. The broad range ensured that the sample thus obtained would not lead to results expected in advance. Distribution histograms of nonbonded distances for various atom pairs were constructed 22 with a bin size of 0.1A. Different types of histograms were obtained.Some of them showed a monotonic dependence of the number of atom pairs (n) on the distance (H . . . H). Other histograms had a well-defined peak (Cl . . . Cl). In some cases, a maximum was poorly defined (H . . . F) or absent [histograms had only a shoulder (C . . . N)] (Fig. 1). Histograms of the first type were not analysed because they gave no numerical characteristics of the distribution.{ Rowland { These histogram patterns are due to the fact that all intermolecular distances (in particular, H. . . H) are taken into consideration, among them distances that do not correspond to the real van der Waals (`reference' 7) contacts in crystals. However, the last-mentioned contacts serve as a basis for the determination of WR of atoms in crystals.Consequently, an approach used by the authors of the work 22 is of limited utility and cannot be used for estimating values of typical van der Waals H. . .H contacts. a 1075 n 1.0 0.50 3.9 3.0 2.0 c 1073 n 1.0 0.50 4 3 2 Figure 1. Distribution histograms of nonbonded intermolecular distan- ces for selected atomic pairs.22 H. . .H (a); Cl . . . Cl (b); H. . . F (c); C. . .N (d ). and Taylor 22 suggested the use of the parameter d (the distance corresponding to the histogram half peak or shoulder height; Fig. 2) as a characteristic of histograms of all the other types. The stability of this parameter is the major argument in favour of its application as a numerical characteristic. Other possible (and most commonly used) characteristics, such as the shortest con- tacts { or the position of the distribution maximum, appeared to depend strongly on the choice of the bin size and the boundaries of the distribution.Because of this, the value of d can be estimated much more reliably than the position of the maximum of the histogram or the shortest contacts. n nk nk/2 d Figure 2. Scheme for the determination of the parameter d;22 nk is the height of the maximum of the histogram. The distributions of the lengths of O. . . O, N. . .O and N. . .N nonbonded distances have a pronounced peak at short distances corresponding to typical lengths of hydrogen bonds (Fig. 3). Since only van der Waals contacts were considered in the work cited,22 all contacts of the NH and OH groups were also excluded.This restriction resulted in the removal of maxima corresponding to H bonds from all three distributions. { It is self-evident that the expression `interatomic contacts' makes sense only for the left portion of the histogram where the distances are close to the sum of WR. L N Kuleshova,MYu Antipin b 1073 n 1.0 0.50 5 4 3 d 1074 n 2.0 1.0 4.7 4.0 03.0 Distance /A Distance /ACambridge Structural Database as a tool for studies of general structural features of organic molecular crystals a 1074 n 1.0 0.50 3.0 2.2 c 1073 n 3.0 1.5 4.0 4.6 02.4 3.0 Distance /A As expected, the values of d (Table 1) for the (O,N)H . . . N(O) distances are markedly smaller than those for the (C)H .. . O(N) distances (Fig. 4). On the contrary, the values of d for (O,N)H . . . Cl(Br) are larger than those for (C)H . . . Cl(Br). This can be explained by the fact that the OH and NH groups are almost always involved in strong hydrogen bonds with oxygen or nitrogen atoms, while bonds with halogen atoms appear to be `secondary' and hence, are substantially weaker. If this assump- tion is true, the concept ofWRfor the oxygen and nitrogen atoms (at least, for the OH and NH groups) in organic crystal structures containing hydrogen bonds is meaningless. Taking into account the aforesaid, Rowland and Taylor 22 estimated the values of d for the H. . . O, H. . .N and H. . . S distributions considering only hydrogen atoms at carbon atoms.Table 1. Observed values of d (AU.22 C H Atom 3.02 2.59 3.02 2.59 3.59 3.31 3.31 3.43 3.24 3.28 3.13 3.61 3.42 3.41 2.54 2.91 2.88 2.99 3.14 HCNOFSCl Br I The authors calculated the values (ri) that characterise WR of the atom of the ith type using the values for all kinds of pairs of atom-atomic contacts (see Table 1) by minimising the following function: wijadij ¢§ Ori a rjUa2 , f a i j<i X X where dij is the value of d for the pair of atoms i and j, wij is the weighting coefficient, which is equal to 1 and 0.25 for bin sizes of 0.1 and 0.2 A, respectively. The summation was made over all types of atoms. We recall that Rowland and Taylor 22 proposed to use d as a characteristic of the distribution of intermolecular distances based on the numerical constancy of this value regardless of the choice of b 1073 n 5.0 2.50 4.0 4.5 4.0 4.5 3.0 2.2 Distance /A Figure 3.Distribution histograms of nonbonded intermolecular distances O. . .O (a), O. . .N (b) and N. . .N (c).22 Br Cl S F O N I 2.54 2.91 2.88 2.99 3.14 3.61 3.42 3.41 3.45 3.33 3.48 3.60 3.55 3.55 3.50 3.24 3.28 3.13 3.00 3.00 2.90 3.45 3.33 3.48 3.70 4.05 a 1073 n 6420 4 3 2 c 1073 n 3210 4 3 2 Figure 4. Distribution histograms of nonbonded distances (O,N)H . . .O (a), (C)H . . .O (b), (O,N)H . . .N (c) and (C)H . . .N (d).22 the bin size and boundaries of the distribution rather than on the expectation that d can be equal to the sum of WR of the corresponding atom pair.The authors only assumed that the values of ri thus determined would correlate with the values ofWR (Rw): ri=cRwi, where c is the correlation coefficient. The coefficient c appeared to be close to unity. The values of ri determined as described above as well as the values of WR determined independently are given in Table 2. It can be seen that the values of ri agree most closely with Bondi's system of radii. The authors 22 believed that this is most likely a random coincidence. It was noted that, on the whole, the radii which were determined in the work cited from a large number of interatomic distances in crystals agree well with WR determined by Bondi, yet some exceptions were observed.In particular, WR of hydrogen atoms in Bondi's system are 0.1 A larger. The calculation taking account of the distribution of the H. . .H contacts determined only by the neutron diffraction method gave a radius of 1.19 A. This value is close to that determined by Bondi. When H. . .O and H. . .N contacts were included in the consideration, the value of the radius under consideration decreased. The values of WR in Bondi's system were determined primarily from the H. . .H contacts in adamantane. It is known that covalently bound hydrogen atoms are partially positively charged in the majority of organic compounds. Therefore, H. . .H distances would be expected to be somewhat elongated due to Table 2.Van der Waals radii of selected atoms (A). Atom II I 1.17 1.72 1.57 1.36 72.02 1.78 77 1.2 71.5 1.40 1.35 1.85 1.80 1.95 2.12 HCNOFSCl Br INote. The values of Rw were determined by: I, Pauling;5 II, Kitaigorod- skii;7 III, Zefirov and Zorky;74 IV, Nyburg and Faerman;75 V, Batsanov;76 VI, Bondi;6 VII, values of ri calculated by Rowland and Taylor.22 5 b 1073 n 43210 4 3 2 d 1074 n 210 4 2 3 Distance /A VII VI IV III V 1.10 1.77 1.64 1.58 1.46 1.81 1.76 1.87 2.03 1.2 1.7 1.55 1.52 1.47 1.80 1.75 1.85 1.98 1.2 1.7 1.6 1.5 1.4 1.85 1.8 1.9 2.1 1.16 1.71 1.50 1.29 71.84 1.90 77 771.60 1.54 1.38 2.03 1.78 1.84 2.136electrostatic repulsions.On the contrary, the H. . .O distances can be somewhat shortened due to electrostatic attractions. Therefore, the radii which were determined 22 with the use of all types of H. . .X contacts based on a large body of statistical data are presumably more accurate than those determined by Bondi. Yet another noticeable difference in the values of WR was observed for the nitrogen atoms. A larger (compared to Bondi's radius) value of rN was obtained due to the unexpectedly large value of d for the N. . .N distance distribution. The authors 22 believe that the value of WR for the nitrogen atom suggested by them is more appropriate for interpreting N. . .N contacts in crystals.It should be noted that with only a few exceptions, the dispersion of the values of WR for atoms determined by different authors is small (*0.1 A). It is with this (or even narrower) accuracy that WR are generally determined in experiments.76 Therefore, the results discussed in this section can be considered as the demonstration of a new statistical approach to the estimation of these values rather than as yet another attempt to refine WR of atoms. In our opinion, a possible line of further investigation in this field with the use of the CSD can involve analysis of typical intermolecular distances in crystals at different temperatures. It is known that cooling of molecular crystals results in contraction of intermolecular contacts, which is more substantial (up to 0.2 A) than those of other contacts.Therefore, systematic analysis of these changes in crystals with a decrease in temperature (generally, from room temperature to 7100 8C and below) is of special interest. IV. Principle of close packing in crystals and distribution of molecular centres in crystallographic unit cells The major principle of organic crystal structures, namely, the principle of close packing, was stated by Kitaigorodskii in 1955.7 In recent years, several researchers concerned with computational modelling of crystal packings noted that if calculations were based on the molecular geometry of compounds, several close-packed structures were generally observed, all with packing energies within 5 kJ mol71 of the global minimum.71 The observed crystal structure is often the one found to coincide with the global minimum, but not always.1 ± 4 Some researchers believe that the principle of close packing contradicts the tendency of molecules to form stable associates in crystals through hydrogen bonds or other specific intermolecular interactions, at least in the case of polyfunctional or bulky and branched molecules.35 On the whole, the problem of a priori calculations of a crystal structure of a particular compound is far from an unambiguous solution.However, considerable progress has been observed in this field in recent years. In the recent review,4 Gavezzotti noted that nowadays the answer to the question `Are crystal structures predictable?' would have to be `Yes, sometimes'.This question was also discussed in detail in another paper.63 The major aim of a priori calculations of crystal structures is to search for optimum packings of molecules and/or their associates. In this case, the principle of close packing can provide a basis for these calculations. Therefore, the examination of its applicability with the use of abundant statistical data in the CSD is an urgent problem. Motherwell 34 attempted to find regularities of molecular arrangements in crystalline compounds. He expected to reveal preferred molecular arrangements for the purpose of using the rules found in computational modelling of crystal structures. First, the most common space groups were revealed.In the 1996 version of the CSD (160 000 structures), 82% of all organic structures encompassed by seven space groups. These are: P1 (19%), P21 (6%), P21/c (35%), C2/c (7%), P212121 (9%), Pbca (4%) and Pnma (2%). Crystal structures belonging to the above- listed groups were retrieved from the CSD with the use of the QUEST search programme. The selection was restricted to structures with one molecule per asymmetric unit (Z0=1), Disordered and polymeric structures were rejected. An exception was made for the space group Pnma, where all molecules have an inherent mirror plane coinciding with the crystallographic plane m. For this study, a selection was made with Z0=1/2. It was decided to use the coordinates of the molecular geometrical centre as the characteristics of the molecular posi- tion.These coordinates were calculated as the average of all atomic coordinates (including hydrogen atoms if present). The molecular centre coordinates were transformed as to place the molecule into the first quarter of the unit cell. The calculations were performed with the use of a modification of the standard programme PLUTO CSD. Then the data obtained were used as input parameters to the statistical display programme VISTA. The distribution patterns of the molecular centres were displayed as three-dimensional maps, which readily illustrate the cluster character of the distributions. The maps were presented as planar projections onto the coordinate planes and distribution histograms along the coordinate axes.1. Group P1 For the group P1, 967 structures that satisfy the above-mentioned requirements were selected. The results of calculations of the molecular geometrical centres are shown in Fig. 5. In the normalised distribution (i.e., with the coordinates brought into the first quarter of the unit cell; Fig. 5b), the points corresponding to clusters form a distinct cross with the following coordinates of the centre: x=0.25, y=0.25, z=0.25. As expected, in this space group the patterns are very similar for all three projections. The regions of the increased density of the distribution have the coordinates (x,y)=(0.25, 0.25). The regions of the decreased density of the distribution have the coordinates (x,y)=(x,z)=(y,z)=(0, 0), (0, 0.5), (0.5, 0), (0.5, 0.5). The y 0.75 0.250 0.75 0.25 x y 0.50 0.250 0.50 0.25 x N 360 240 120 0 0 0.25 0.50 x Figure 5.Distributions of geometrical molecular centres in the group P1;34 scattergrams for the total unit cell (a); scattergrams adjusted to bring the reference molecule to the first quarter of the unit cell (b); distribution histograms of positions of the geometrical molecular centres along the axes of coordinates of the unit cell (c). Hereinater N is the number of points. L N Kuleshova,MYu Antipin a x z 0.75 0.75 0.25 0.25 0 0 0.75 0.25 y b x z 0.50 0.50 0.25 0.25 0 0 0.25 0.50 y c N N 400 400 200 2000 0.25 0.50 y 0.75 0.25 z 0.25 0.50 z 0.25 0.50 zCambridge Structural Database as a tool for studies of general structural features of organic molecular crystals areas of low population correspond to the positions of the symmetry elements in this space group, i.e., to the centres of symmetry.Motherwell 34 suggested that this distribution pattern of the molecular centres is a graphical illustration of the principle of close packing. Clearly, the molecules cannot occupy inversion centres since asymmetrical molecules, which have no inherent centre of symmetry, were chosen. The reasons why the molecules will tend to `avoid' regions about the inversion centres are obvious if one considers the location of this molecule between two centres of symmetry at a distance d from each of them.Evidently, the best location of a `spherical' molecule is halfway between these centres. However, the shapes of real molecules are far from spherical ones and, in addition, the molecules have functional groups which can be involved in specific directional interactions (for example, hydrogen bonds). Nevertheless, judging from the results obtained, a general tendency exists according to which the molecules prefer to occupy the midpoints between centres of symmetry at a distance equal to one-quarter along each coordi- nate axis. 2. Group P21 For the group P21, 1000 structures were selected. To simplify consideration, the projection along the y axis was used as an informative projection. It was established that the molecular centres cluster predominantly halfway between the screw axes (x,z)=(0.25, 0.25) (Fig.6). In the regions (x,z)=(0, 0), (1.0, 0.5), (0.5, 0), (0.5, 0.5), i.e., on the screw axes, areas of the minimum density of the distribution are observed. This confirms the above- mentioned tendency of molecules to occupy the midpoints between symmetry elements (in this case, between screw axes). b a x N N 0.50 400 180 0.25 120 200 60 0 0 0 0.50 0.25 z 0.25 0.50 z 0.25 0.50 x Figure 6. Scattergram (a) and distribution histograms (b) of molecular centres in the group P21.34 3. Group P21/c The group P21/c contained 994 structures after elimination of structures with Z0>1. The distribution histogram (Fig. 7) shows a y x z 0.50 0.50 0.50 0.25 0.25 0.25 0 0 0 0.50 0.25 0.50 0.50 0.25 0.25 x z y b N N N 180 600 180 120 400 120 60 200 60 0 0 0 0.25 0.50 y 0.25 0.50 x 0.25 0.50 z Figure 7.Scattergrams (a) and distribution histograms (b) of molecular centres in the group P21/c.34 one narrow peak on the axis x. The histograms along the axes y and z have substantially less pronounced peaks with the coordi- nates (0.125, 0.375, 0.5) and (0.125, 0.25, 0.375). The characteristic feature of the distribution pattern in this group is a broad band of points in the plane defined by x=0.25, which corresponds to positions of molecules along the glide plane. The areas of low population in the plane (x,z) are located at the positions corre- sponding to the centres of symmetry: (0, 0), (0, 0.5), (0.5, 0), (0.5, 0.5).4. Group C2/c The sample for the group C2/c consisted of 984 structures. The distribution histograms show pronounced narrow peaks at x=0.125 and 0.375 (Fig. 8). The distribution pattern along the axis y is less distinct but the histogram has a narrow peak at y=0.25. The distribution histogram along the direction z, as well as the histogram along x, have distinct peaks at 0.125 and 0.375. The distribution patterns consist of narrow bands in the plane xy (x=0.125 and 0.375). It may be noted that there is an obvious increase in the density extending in the direction of the glide plane c and large voids in the regions (x,z)=(0, 0.25) and (0.5, 0.25), which correspond to the positions of rotation twofold axes.This is an expected result because it is obvious that molecules related by rotation axes cannot be closely packed. a x y z 0.50 0.50 0.50 0.25 0.25 0.25 0 0 0 0.50 0.25 x 0.25 0.50 y b N N N 180 250 120 120 60 0 0 400 300 200 1000 0.50 0.50 0.25 y 0.25 x Figure 8. Scattergrams (a) and distribution histograms (b) of molecular centres in the group C21/c.34 The regions of low population are also observed at the inversion centres, like in other space groups. 5. Group P212121 The sample for the group P212121 consisted of 999 structures. The histograms and the distribution densities of molecular centres in the crystal unit cell appeared to be most uniform. The only characteristic feature is the low density along the screw axis parallel to the axis z.6. Group Pbca The distribution of molecular centres for the group Pbca (999 structures) shows clear maxima on each axis at the positions 0.125 and 0.375. The points are distributed as distinct bands in all three planes with the coordinates (0.125, 0.375) along each crystal axis. The regions of low population correspond to the positions of centres of symmetry and positions of screw axes. As in the groups P1 and P212121, all three directions are equivalent. 7. Group Pnma The distributions of molecular centres for the group Pnma were constructed based on the data on 731 compounds. Since all molecules in this group have a mirror plane, the only informative7 0.25 0.50 z 0.50 0.25 z8distribution histogram is the projection (x,z).This projection has clusters of points in the regions about (0.25, 0) and (0.25, 0.5). However, these clusters are very diffuse. Regions of low popula- tion at (0, 0), (0.5, 0) and (0.5, 0.5), which correspond to the centres of symmetry, are better defined. Let us emphasise again that all the structures considered above were selected regardless of chemical atom types. The distributions of molecular centres were obtained without taking into account hydrogen bonds, electrostatic interactions and the fact that approximately 45% of all the structures under consid- eration belonged to complex organometallic molecules whose shapes are far from spherical. To exclude possible objections, the distribution patterns of molecular centres were considered for a subset of the P21/c sample consisting of hydrocarbons only (126 structures) and no significant difference could be seen in the distribution of molecular centres. With the aim of analysing the molecular environment in crystals in more detail, an extension was written for the pro- gramme PLUTO to display the molecular coordination sphere about the reference molecule according to the approaches of Kitaigorodskii 7 and Gavezzotti.79 The coordination sphere was determined based on calculations of the energy of intermolecular interactions. Only molecules whose energy of interactions with the reference molecule is not lower than 4.18 kJ mol71 were included in the calculations.The typical coordination numbers of mole- cules in the CSD were found to be 12 ± 14, which confirmed the suggestion of Kitaigorodskii.7 The potential energy was calcu- lated by summing energies of pairwise atom-atomic interactions using Gavezzotti's empirical potential.79 The electrostatic term was ignored. Analysis of several hundreds of coordination spheres determined as described above demonstrated that, almost without exception, a close-packed layer of six adjacent molecules can be observed in this coordination sphere. Needless to say that the real situation is far from simple. Many examples can be presented where the molecules form strongly bound dimers or chains. However, in these cases the molecules also tend to form a coordination sphere, which is the nearest to the closest packing of spheres.Therefore, the distribution histograms of molecular centres in the symmetry groups under consideration show peaks or clusters corresponding to the preferred positions of molecular centres in unit cells. These centres are located halfway between the inversion centres or screw axes in unit cells. The calculations of the energy of intermolecular interactions with the adjacent molecules in the coordination sphere confirmed that these assumptions are ener- getically justified. It is useful to approximate molecules by spheres to visualise the preferential formation of close-packed layers of molecules and tendencies to close packings of spheres. V. Relative frequencies of occurrence of space groups Analysis of relative frequencies of space-group occurrence for the known crystal structures is one of the most evident areas of application of the CSD in studies of general regularities of crystal structures.This analysis is of interest not only from the theoret- ical, but also from the practical standpoint, because crystal symmetry determines a number of important properties mani- fested by many crystals. Evidently, the problem of the choice of a particular space group by a molecule is thus currently the most studied. Kitaigorodskii 7 was the first to demonstrate that only a few of 230 theoretically plausible groups are of rather frequent occur- rence. Examples of crystal structures belonging to other groups are few in number, while certain space groups are `prohibited'.Among the most populated groups, centrosymmetrical space groups are by far `favourites'. Kitaigorodskii ascribed this selectivity to the difference in the packing energy of symmetric arrangements of molecules in crystals. On the whole, it was concluded that organic molecules crystallise preferentially in L N Kuleshova,MYu Antipin space groups (SG) that can ensure the close packing of spheres or tri-axial ellipsoids (which are most commonly used as approx- imations for organic molecules). In this respect, the groups P21/c and P1 were assigned to most convenient. More recently, Belsky and Zorky 40, 51, 52, 80 published a series of papers in which the most populated space groups were established based on a rather large body of data.9, 10 It appeared that there are only 9 such groups, viz., P21/c, P1, P1, P21, P212121, Pbca, C2/c, Pna21 and Pnma.They account for 79.2% of all the structures known at that time. The results obtained demonstrated that organic molecules actually crystallise preferentially in cen- trosymmetrical SG. Over 50% of all known organic structures belong to only two space groups, viz., P21/c and P1. In addition, it was noted that the inherent molecular symmetry and the number of crystallographic orbits occupied by molecules must be taken into account. More than a dozen of recent publications were devoted to studies of the relative frequencies of occurrence of SG for both organic (Wilson,36 ± 39 Padmaja et al.,41 Belsky et al.,42, 81 Mighell et al.44, 82 and Brock and Dunitz 45) and inorganic (Mackay,43 Mighell et al.44, 82 and Baur and Kassner 83) crystals based on statistically reliable data using computer databases.All authors noted the prevailing occurrence of centrosym- metrical SG. However, the frequency of occurrence of these groups for organic compounds reported in different works varies from 66% to 75%. Among inorganic compounds (Inorganic Crystal Structure Database, 1992), this frequency is, on the average, even higher (78%). Proteins and other natural polymers consisting of pure enantiomeric molecules are the exceptions, where chiral SG prevail.41 Note that the preference of a particular SG (centrosym- metrical or noncentrosymmetrical) for a molecule is of excep- tional importance from the practical standpoint to researchers involved in the design of new organic materials.In particular, compounds that can possess nonlinear-optical properties and are potentially able to generate the second harmonic of laser radiation crystallise most often in centrosymmetrical SG excluding the manifestation of the above-mentioned properties in crystals. Below we dwell on works aimed at establishing the reasons why the majority of organic molecules tend to crystallise in centrosym- metrical SG. The preferential occurrence of centrosymmetrical SG may be only indicative of the fact that organic compounds can exist as racemic mixtures of enantiomers rather than reflects the fact that these SG are energetically more favourable.Strictly speaking, to determine correctly the actual frequency of occurrence of SG it is necessary to know whether the crystals were obtained from a solution of a pure enantiomer, from a mixture of enantiomers or from a solution of an achiral compound. The great majority of crystals were grown from mixtures of enantiomers. Therefore, it is not surprising that they belong to centrosymmetrical SG. If this is the case, the problem of the preparation of noncentrosymmetrical materials can be reduced to the problem of spontaneous reso- lution of enantiomers or to the development of procedures for their forced resolution. It was noted 52 that in recent years the number of noncentrosymmetrical groups in the CSD increased somewhat, which may be indicative of an increase in the number of the natural compounds and products of the stereoselective synthesis studied.} For the crystalline compounds studied to date, virtually all 230 possible space groups are observed, except for 7 groups for inorganic compounds and 28 groups for organic and organo- metallic compounds.83 This fact can be considered as the exper- imental corroboration of the Kitaigorodskiii theory.However, as for their frequency of occurrence, only certain of space groups are } This example provides further evidence that care is required in the data rejection and sample creation. Even a very large body of structural data does not necessarily assure that the statistical characteristics or property is reliable.Cambridge Structural Database as a tool for studies of general structural features of organic molecular crystals Table 3.Distribution of organic crystals among space groups.42 m SG n (%) Number P21/c P212121 �1± 37.97 15.18 13.22 8.38 5.71 4.96 2.06 1.28 1.00 7634 3052 2658 1684 1149 998 414 257 199 P21 C2/c Pbca Pna21 Pnma Pca21 123456789Note. The following notations are used: SG is the space group; m is the number of structures belonging to a particular SG; n is the ratio between structures belonging to a particular SG and the total number of the structures under consideration. rather populated.7, 80 Only a few examples of the remaining groups are available.Thus only 18 most `popular' (according to Baur and Kass- ner 83) space groups account for 92.71% of all known structures of organic compounds. Belsky 42 has distinguished 9 most frequently occurring groups, which account for 89.8% of all compounds. The nine groups mentioned by Belsky (Tables 3 and 4) enter into 18 groups of Baur (Fig. 9). Table 4. Distribution of organic crystals among crystal systems.42 m n (%) System 14.04 55.01 27.67 1.79 1.33 0.16 2823 11061 5563 360 268 32 Triclinic Monoclinic Orthorhombic Tetragonal Hexagonal Cubic Note. The following notations are used: m is the number of structures belonging to a particular crystal system; n is the ratio between structures belonging to a particular system and the total number of structures under consideration. For inorganic compounds, Baur has also distinguished 18 most frequently occurring groups.However, these groups account for only 56.86% of all structures. The distribution histogram of space groups for inorganic compounds is more shallow than that observed for organic compounds (see Fig. 9). In the case of inorganic compounds, it is more difficult to reveal `leading' group. The dominant space groups for organic and inorganic compounds are also substantially different in spite of the above- mentioned common predominance of centrosymmetrical SG. The most substantial difference is that inorganic compounds crystal- lise in higher-symmetry space groups, namely, in trigonal, tetragonal, hexagonal and cubic systems.Thus 31.58% of the total number of inorganic compounds crystallise in groups belonging to the symmetry classes 3m, 4/mmm, 6/mmm and m3m. Only 0.63% of organic compounds belong to the above- listed groups. According to the data reported by Brock and Dunitz,45 in the case of protein and polymeric structures, the tetragonal and trigonal systems are also more abundant (13% and 16%, respectively) than in chiral crystals of organic compounds (3% and 2%, respectively). The groups C2 and C2221 in the Protein Data Bank account for 13% and 5% of structures, respectively, while these groups in the CSD (for chiral crystals) account for only 4% and 1% of structures, respectively.The populated SG of 9 a 5 10 15 20 25 30 35 n (%) 0 P1± C2/c Pbca P21/c P212121 P21 Pna21 PC1c Pnma Pbcn C2 P21/m C2/m R3± Pccn Pca21 P21212 P2/c Pc Fdd 2 I41/a P41212 C2221 b 5 10 n (%) 0 Pnma Fm3±m C2/c C2/m Fd3±m Cmcm P1± P21/c P63/mmc I4/mmm R3±m P3±m1 Pm3±m P6/mmm P21/m P63/m Pna21 F4±3m R3± Pbca R3±c P212121 P4/nmm I4/mcm Figure 9. Most populated space groups for organic (a) and inorganic (b) crystal structures (in percent of the total number of structures).83 organic compounds belong exclusively (95.38%) to triclinic, monoclinic and orthorhombic systems (Fig. 10). These crystal systems account for only 48.92% of inorganic compounds.Thus the distribution of inorganic compounds is more diversified. a Organic compounds Inorganic compounds 0 10 20 30 n (%) 0 10 20 30 40 50 1 1±mmm2 4±4±2m 422 3±3m 22/m 222 mmm 44/m 4mm 4/mm 33±6m 32 6/m 6±622 6mm 6±m2 6/mmm 23 m3± 432 4±m m3±m b Triclinic Monoclinic Orthorhombic Tetragonal Trigonal Hexagonal Cubic Figure 10. Distributions of frequencies of abundance of crystals of organic and inorganic compounds over classes of point symmetry (a) and crystal systems (b).8310 Among the above-listed 18 most frequently occurring SG of inorganic compounds, all crystal systems are present (see Fig. 10).The majority of organic molecules crystallise in low-symmetry space groups, while the majority of elements, intermetallic com- pounds and inorganic salts crystallise in high-symmetry groups. However, this does not imply that the packing rules for these compounds are diffent. The difference in structure is most likely determined by the shape of the initial structural unit as well as by the presence or absence of strong long-range electrostatic inter- actions. For inorganic compounds, the structural units are most often nearly spherical atoms or ions as well as octahedral or tetrahedral fragments. That is the reason that a large number of inorganic compounds crystallise in high-symmetry groups. The vast majority of organic compounds archived in the CSD consist of low-symmetry electroneutral molecules. Therefore, it is not surprising that organic compounds crystallise predominantly in low-symmetry groups.Presently, it is generally agreed that the molecular shape affects the symmetry of the crystal structure formed.38, 39, 45, 84 When estimating the frequency of occurrence of SG, this fact must be taken into account. Brock and Dunitz,45 like Kitaigorodskii,7 exemplified this fact by crystals of molecules possessing inherent symmetry elements, namely, a twofold rotation axis (2) and a mirror plane (m). In spite of the obvious fact that these elements are unfavourable,7 space groups containing the plane m are rather frequent, which is exclusively due to molecules possessing the inherent symmetry m.The plane m in the corresponding SG is virtually always `occupied'. If molecules possessing the inherent mirror symmetry are excluded from consideration, the distribu- tion pattern of space groups is changed (the above-mentioned group Pnma no longer belongs to abundant groups). In a half of the cases, a twofold rotation axis is occupied and in the remaining cases, it is free. In the latter case (for chiral molecules), this axis plays the same role as an inversion centre in the case of a racemic pair, namely, stable dimers are formed due to a twofold axis. Concave-shaped protein molecules often consist of such dimers, which allows them to be closely packed. Apparently, for this reason space groups containing a twofold axis occur more frequently in the Protein Data Bank than in the CSD.41 From the analysis of the frequency of occurrence of space groups for organic crystals in the CSD, Brock and Dunitz 45 found what symmetry elements are relatively more favourable.Thus it appeared that the screw axis 21 is much more favourable than the simple translation or the screw axes of higher orders. It is generally believed 7 that the axis 21 is favoured over the glide plane, which, in turn, is favoured over the translation. However, Brock and Dunitz believe that glide planes play the same role as translations in organisation of crystal structures. This conclusion is not quite without doubt, because the translation is a symmetry element of the first kind under the action of which the chirality of the molecule is retained, while the glide plane is a symmetry element of the second kind, which inverts the chirality. Therefore, it may be that comparisons were carried out based on different classes of compounds, which is not quite correct.The number of formula units per asymmetric unit (Z0) (the number of occupied orbits) is yet another important character- istics necessary for analysing the frequency of occurrence of space groups. Belsky and Zorky, who developed the concept of structural classes,51,80 were the first to note the importance of the consideration of Z0. Recently, other authors also pointed to the importance of account of this parameter. Padmaja et al.41 found that structures with Z0>1 belong predominantly to low-symme- try crystal systems (particularly often, to the group P1).Analysis of the results obtained by Brock and Dunitz with the use of the 1991 version of the CSD45 confirmed the above conclusions. It appeared that the overall number of structures with Z0>1 in the most populated chiral groups is larger than in the corresponding centrosymmetrical groups:C2 Group P1 P21 P212121 �1± P21/c C2/c Pbca L N Kuleshova,MYu Antipin 3.0 3.0 11.3 5.7 nZ0 >1 ,% 45.0 14.0 11.2 4.5 Brock and Dunitz suggested that many acentric crystals with Z0>1 are actually pseudosymmetrical structures. First sampling tests demonstrated that of 55 of a total of 256 structures with Z0>2 belonging to the group P21 can be described by the pseudogroup P21/c.The pseudosymmetry elements 1, 2, 21 and t are most often observed in the above structural type. The phenomenon of pseudosymmetry and problems associated with this effect are discussed below in more detail. VI. Why do organic crystals prefer centrosymmetrical groups? 1. The effect of molecular dipoles on the crystal-packing organisation Whitsell and coworkers 49 were among the first to perform studies aimed at elucidating the reasons for the preferential occurrence of centrosymmetrical packings with the use of the CSD. The authors attempted to verify the thesis that molecules with large dipole moments crystallise preferentially in centrosymmetrical space groups. This concept is commonly accepted by researchers involved in studies of nonlinear optics of molecular crystals.46, 47 It is based on simple inferences that the role of the electrostatic component in stabilisation of the crystal structure increases in the case of the antiparallel arrangement of molecular dipoles, which ultimately leads to the formation of centrosymmetrical crystals.As early as 1955, Kitaigorodskii 7 noted that electrostatic interactions (in the dipole ± dipole approximation) must be taken into account for crystals of strongly polar molecules. However, recent calculations performed by Gavezzotti and Filippini 85, 86 for small molecules containingC=OandN:Cgroups demonstrated that dipole-dipole interactions make only an insignificant contri- bution to the total energy of crystal stabilisation.In the estimation of the role of the molecular dipole moment in the crystal symmetry, it was suggested 49 that if the antiparallel orientation of molecules with large dipole moments is preferable, the number of crystals containing such molecules should be substantially larger among centrosymmetrical crystal structures than among noncentrosymmetrical structures. This suggestion was verified when crystal structures belonging to three space groups (P1, P1 and P21) were retrieved from the CSD (1994 version). Typical schemes of the molecular arrange- ments in these groups are shown in Fig. 11. In the group P1, all molecular dipoles are parallel to each other due to the absence of symmetry operations other than translations t.Therefore, the average dipole moment of the crystal is determined by the sum of all molecular dipole moments. In the group P1, an antiparallel neighbour corresponds to each molecular dipole and the total dipole moment is equal to zero. In the group P21, pairs of molecules are related by a combination of rotation and trans- lation operations and the value of the structural dipole should depend on the orientation of the molecular dipole relative to the screw axis (angle y). Since the experimental data on molecular dipole moments (m) are scarce, these values for a large series of c b a y Figure 11. Mutual arrangement of molecular dipole moments in crystals belonging to the space groups P1 (a), P1 (b) and P21 (c).Cambridge Structural Database as a tool for studies of general structural features of organic molecular crystals compounds were calculated using the AMPAC programme with the AM1 parameterisation.87 Crystal structures in the CSD were chosen so that the values of m could be correctly calculated within the framework of the above- mentioned approximation.Therefore, when statistical samples for the three above-listed space groups were created, the following objects were rejected: (1) compounds in which d-orbital interac- tions can occur; (2) organometallic ionic and polymeric structures; (3) structures containing molecules of solvation; (4) structures in which molecules occupy several systems of equivalent positions and (5) structures in which molecules form strong hydrogen bonds (i.e., compounds containing OH or NH groups).As a result, a Table 5. Values of the average dipole moments of organic molecules.49 n Space group m /mB m¡¾ /mB s 3.36 3.22 3.04 0.37 0.15 0.15 3.41 33 3.14 28 161 179 P1 P1¡¾ P21 Note. The following notations are used: n is the number of structures under consideration; s is the error of calculation of m; m is the value of the dipole moment for the midpoint of the distribution. total of 28, 161 (out of 1229) and 179 (out of 722) examples were selected in the groups P1, P1 and P21, respectively. The results obtained in the work 49 are presented in Table 5 and in the histograms (Fig. 12). It can be seen that the average molecular dipole moments in centrosymmetrical and noncentro- symmetrical SG are virtually identical within the rather small dispersion.No statistically reliable correlation was observed between the dipole moments of molecules and their orientations relative to the polar direction in the group P21. Hence, the molecular dipole moment is not the governing factor in choosing the space group and does not account for the observed predom- inance of racemic space groups over chiral groups. However, some effects, such as hydrogen bonds, specific interactions of polar groups and the shape of the molecule, can affect the crystal packing. Apparently, interactions of molecular dipoles play an important role at large distances. In crystals, adjacent molecules are located at distances comparable with their dimensions.More- over, dimensions of the majority of molecules are substantially larger than the shortest distances between them. Therefore, it is hardly probable that attempts to construct the molecular packing a b n (m) n (m) 40 5 200 0 8 6 4 2 8 6 4 2 m /mB c 40 200 8 6 4 2 m /mB Figure 12. Distribution histograms for molecular dipole moments in the space groups P1 (a), P1 (b), and P21 (c).49 based primarily on the consideration of total molecular dipole moments will succeed. 11 2. Density and stability of racemic crystals and their chiral counterparts The commonly accepted postulate that explains the preferrence of centrosymmetrical crystals is known as Wallach's rule.88 Accord- ing to this rule, racemic crystals tend to be denser than their chiral counterparts. The question of whether molecules in racemic crystals are packed more closely than in the corresponding chiral crystals has been a subject of speculations since 1895.88 This question has in essence two aspects:89 are racemic crystals generally more stable than their chiral counterparts and is this greater stability reflected in a larger density of racemic crystals? Wallach has deduced his rule by considering 8 chiral ¡¾ racemic pairs, and only one of these pairs was an exception.More recently, Jacques, Collet and Wilen 89 considered 12 corresponding pairs and found 4 exceptions to Wallach's rule. The improved accuracy of determination of X-ray densities (*0.15%) made it possible more correctly to verify the validity of Wallach's rule. Mason 90 was the first to perform this verification.He analysed 14 pairs of compounds and found 9 exceptions to Wallach's rule. Apparently, only statistical analysis of a large sample can provide a reliable answer to the above question. For this purpose, Brock and coworkers 50 used the CSD (1989 version). The authors created two files. The first file contained data on only noncentrosymmetrical groups (*25% instances). The second file contained data on only racemic groups (*75% instances). The data of the files were sorted according to chemical compositions of compounds and compared. The sets of structures having the same chemical composition were considered as potential objects of investigation.In several instances, com- pounds filed in the CSD under the same code turned out to be diastereomers. In this case, they were excluded from considera- tion. Particular attention was given to the problem of ambiguities of space-group determination. The space groups differing only by the presence or absence of an inversion centre were subjected to special scrutiny. For each pair, the relative differences between the densities of racemic (Dr) and chiral (Dc) crystals were calculated as follows: r a DcU . DD a 100ODr ¢§ DcU 0:5OD The final list contained 129 pairs. This number of examples was insufficient to obtain the smooth distribution (the shape of the histogram depends on the choice of the bin size and boundaries). Thus, the authors presented two variants of distributions of the values of DD, which differ by the choice of the initial boundaries (Fig.13). In spite of the differences, both distributions exhibit a pronounced bimodal character. The average value of DD for 129 n (DD) 2480 2480 +10 +5 0 75 DD (%) 710 Figure 13. Distribution histogram for the values DD for 129 chiral ¡¾ racemic pairs of the structures under study (two variants of the choice of the initial bin size are given).5012 pairs was 0.56%. However, this value is too small to confirm the rule, but it is too large to demolish it. Taking into account the bimodality of the DDdistribution, the authors attempted to divide the selected objects into two groups.One way of dividing objects is to separate pairs which are polymorphic modifications. An alternative way is to separate pairs which are not polymorphs. This separation was carried out according to the definition of polymorphs suggested by McCrone.91 According to McCrone, polymorphs are different solids that give the same liquid upon melting or dissolution. Therefore, crystal pairs of the first group (polymorphic modifica- tions) contain either achiral molecules or chiral molecules that can rapidly undergo racemisation in solutions. Crystal pairs of the second group consist of enantiomers that can be readily resolved b a n (DD) n (DD) 120 12 0 0710 75 +5 DD (%) 0 +5 DD (%) 710 75 Figure 14. Distribution histograms for the values DD for 64 pairs of structures of the first group (enantiomers that can be rapidly intercon- verted, achiral compounds) (a) and for 65 pairs of the structures of the second group (enantiomers that can be resolved) (b).50 (consequently, they are difficultly interconvertible).For 64 pairs of the objects of the first group, the average value of DD was ca. +0.20% (Fig. 14a). Consequently, a comparison of polymorphic pairs showed no noticeable difference between the packing densities of racemic and chiral crystals. The average DD value for the second group of objects consisting of 65 pairs was +0.92% (Fig. 14b). The packing densities of racemic crystals of the second group are, on the average, *1% higher than those of their chiral counterparts.Therefore, it was concluded that Wallach's rule is apparently valid only for enantiomers that can be resolved.50 It is not inconceivable that the difference in the average values of DD for the groups of crystals under consideration is due to different initial conditions of crystallisation. Compounds of the first group are always crystallised from solutions of achiral compounds or mixtures of enantiomers, while compounds of the second group are crystallised from solutions of both enantiomeric mixtures and pure enantiomers. Crystallisation of compounds of the first group from solutions depends on the relative stability of possible solid phases and sometimes affords several crystal forms. Evidently, the stabilities of these forms should be approximately equal.Enthalpies of polymorphic modifications rarely differ by more than 1 kcal - mol71. Therefore, it is hardly probable that less stable modifica- tions of compounds of the first group will be obtained. For compounds of the second group, the situation is quite different. Racemic solutions may yield racemic crystals, racemic conglomerates of chiral crystals or mixtures of both types depend- ing on their relative stability. In contrast, crystals obtained from enatiomerically pure solutions must be chiral. Therefore, chiral crystals can be obtained even if they are thermodynamically much less stable than the racemic crystals. This implies that the second group of compounds is statistically biased. Thus, pairs in which racemic crystals are energetically more favourable can be more L N Kuleshova,MYu Antipin frequent in the second group than in the first one.This is reflected in different distributions of DD. Jacques and coworkers 89 compared thermodynamic charac- teristics of the melting process for 36 pairs of chiral and racemic crystals belonging to the second group. The average values of such characteristics as DH, DS and DT are 7.54 kcal mol71, 18.5 kcal mol71 K71 and 405 K for racemic crystals and 6.28 kcal mol71, 15.7 kcal mol71 K71 and 395 K for chiral crystals. Based on these data, the authors concluded that racemic crystals are thermodynamically more stable than chiral crystals. However, it is hardly reasonable to consider this conclusion to be the general rule because the statistical data (in particular, the thermodynamic characteristics) are still scarce.It is quite probable that racemic crystals appear to be more stable because pairs in which they are less stable are absent only among compounds that have already been studied rather than among naturally occurring compounds. Therefore, statistically reliable evidence for the higher density and thermodynamic stability of racemic crystals compared to their chiral counterparts has not yet been found. 3. Comparison of thermodynamic characteristics of polymorphic modification of organic crystals The phenomenon of polymorphism in organic crystal structures has long been known. Such aspects as thermodynamic stability, pharmaceutical properties of polymorphs, conformational poly- morphism, etc.have been studied in considerable detail.4, 92 ± 98 Unfortunately, the data available in the literature are primarily descriptive and each instance of polymorphism was considered by itself. Accumulation of a large body of structural data on polymorphic modifications (PM) in the CSD brought systematic statistical studies in this field to reality. The existence of poly- morphs is still a headache problem for scientists involved in computational modelling of molecular packings. However, it is evident that due to the constancy of the chemical composition in polymorphic pairs (triads, etc.) these systems can serve as a potential source of detailed information on the struc- ture ± property relationship in organic solids because in this case the difference in the physical properties can be explained by the difference in their structural organisations.The first investigation devoted to this problem was performed by Gavezzotti and Filippini.3 The authors compared the thermo- dynamic and structural characteristics of the polymorphs avail- able in the 1993 version of the CSD. They selected only objects which were studied at room temperature, had more than one polymorphic modification and consisted of C, H, N, O, Cl and S atoms.Atotal of 163 compounds which satisfy these requirements were found, 147 of them with two, 13 with three and three with four polymorphic modifications. A total of 345 crystal structures were found.For these polymorphic modifications, thermodynamic char- acteristics of crystals were calculated according to procedures reported in the Refs 3, 86, 99 and 100. The parameters for the 6- exp potential function for intermolecular interactions were chosen 98, 100 so as to reproduce the values of thermodynamic characteristics at room temperature. Generally, the calculated values of thermodynamic characteristics agree, at best, only qualitatively with the experimental values (due to an inaccuracy of both calculated and experimental values). Nevertheless, the regularities found by the authors can be considered as justified because possible inaccuracies affect in the same manner the results of calculations for both forms, while the differences between the calculated values used by the authors are free from errors. The polymorphic pairs of compounds were placed in order of decreasing density. Therefore, the differences between the den- sities DDfor polymorphic modifications are positive by definition.The differences (%) in the other properties (P) were determined as follows:Cambridge Structural Database as a tool for studies of general structural features of organic molecular crystals DP a 100OPi ¢§ PjU , j>i . Pj The total number of points was 204. The following parameters P were calculated: D, the crystal density; V, the molecular volume; K, Kitaigorodskii's packing coefficient; E, the packing energy; S, the lattice-vibrational entropy; G, the lattice free energy, and Z0, the number of molecules per asymmetric unit.The DD, DE, DS and DZ0 distribution histograms are shown in Fig. 15. It appeared that the difference in the density between polymorphs is small and seldom exceeds a few percent. Thus 93% a n (DE) 60 40 200 3 6 DE (%) c n (DS) 40 200 4 8 DS /J K71 mol71 Figure 15. Distribution histograms for the packing energy DE (a), DD (b), DS (c), and DZ0 (d).3 of the values of DD are smaller than 5%, which confirms the results reported in the work.50 This implies that molecules can be packed in different fashions, but, apparently, not at the expense of a decrease in compactness. Cases with DD>7% occur either due to inaccuracy in determination of atomic coordinates or to large conformational differences in the molecules.Similar conclusions are drawn by examination of the DE histograms: the packing energies of PM are generally close. A few exceptions can be attributed to the structural disorder or to inaccurate positioning of some key atoms of the system. The differences in the lattice entropies DS between polymorphs in pairs are also very small (see Fig. 15). Thus the density, packing energy and lattice entropy for a polymorphic pair have close values. The results on the number of molecules per asymmetric unit (Z0) are unexpected: 62 structures (18% of the pairs selected) have Z0>1 [this value is substantially higher than the overall percentage in the CSD (8.3%)] and 46 compounds (28%) of 163 compounds selected have modifications with different values of Z0.The authors considered also possible relationships between the calculated values (bivariate statistics). The dependence of DD on DE (Fig. 16a) demonstrates that in most cases higher packing energy is accompanied by higher density. The existence of crystal structures with high energies and low packing densities can be attributed to the presence of exceptionally strong and directional hydrogen bonds in a crystal. In all cases under consideration, the differences in the free energies DG between polymorphs in pairs have the same sign as the differences in the packing energies DE (Fig. 16b). As expected, the higher the density the lower the entropy (Fig. 16c). These results demonstrate that higher crystal b n (DD) 60 40 200 8 16 DD (%) d n (DZ0) 160 80 0 1 DZ0 13 b a DG (%) DE (%) 15 20 0 100 710 715 730 745 0 DH (%) 745 730 715 720 6 4 2 0 DD (%) d c DZ0 (%) DS (%) 10 2 50 0 75 72 710 74 715 8 4 0 DE (%) 6 4 2 0 DD (%) Figure 16.Relationships between DE and densities DD (a), DG and enthalpies DH (b), DS and DD (c), and DZ0 and DE (d).3 density corresponds to higher packing energy and lower vibra- tional entropy. The dependence of DZ0 on DE is shown in Fig. 16c. The structures with Z0>1 are more stable in *50% of the occur- rences. Hence, the presence of more than one molecule per asymmetric unit dose not lead to a decrease in the stability of a crystal. Therefore, the knowledge of thermodynamic characteristics of polymorphs existing at room temperature is insufficient for explanation of their relative stability because the differences in these characteristics are generally small.Thus, it is useful to analyse molecular-packing symmetry to gain insight into the ways of formation of crystal structures in different polymorphic modifications. The space group remains the same for 28% of the polymor- phic pairs under consideration; 82% of all structures belong to the group P21/c and the remaining 18% of the structures are distributed among the groups P1, Pbca, C2/c and P212121. The greatest number of plausible arrangements of the same molecule was observed for organic crystals belonging to the group P21/c.As mentioned above, one of polymorphic forms often has Z0>1. Although a detailed analysis of such cases has not been performed, preliminary consideration of the data revealed instan- ces in which molecules in the asymmetric unit are related by pseudosymmetry operations. A detailed examination of pseudo- symmetry relations in crystals will allow one to `visualise' possible ways of formation of crystal structures, which have not been realised. The authors also noted that in 20 polymorphic pairs (24%) the molecules decide between centrosymmetrical and noncentrosym- metrical space groups. Ten pairs P21/c7P212121, six pairs P21/ c7P21, four pairs P21/c7Pc and four pairs P21/c7Pna21 were found. Comparison of thermodynamic characteristics of the poly- morphs did not allow the authors of the works cited (Refs 3, 49 and 50) to reach definite conclusions about regular- ities of organisation of crystal structures.However, although the analysis of structural regularities in polymorphic modifications did not provide answers to the problems under considerations, it doubtedlessly made it possible to mark the route and develop a strategy of further investigations in this field.14 HCO Figure 17. Molecular structure of 2,6-dimethyl-4-(diphenylmethylene)- cyclohexa-2,5-dienone (DMFUSC).101, 102 We attempted to search for PM containing chiral ± racemic partners in the 1996 version of the CSD. A total of 102 such pairs were found. The same distribution pattern of chiral and racemic modifications was observed: 45 pairs (44.1%) P21/c7P212121, 17 pairs (16.7%) P21/c7P21, 14 pairs (13.6%) P21/c7Pna21, 10 pairs (9.8%) P21/c7Pc, 3 pairs (2.9%) P21/c7P1, 7 pairs (6.9%) P17P212121, 2 pairs (2.0%) P17P21, 2 pairs (2.0%) P17Pc and 2 pairs (2.0%) P17Pna21. We hope to reveal reasons for the preferential occurrence of these chiral ± racemic pairs from a detailed analysis of structures of these polymorphic modifica- tions.Let us offer an example of a typical situation for the P21/ c ± P212121 pair. In the case of 2,6-dimethyl-4-(diphenylmethyle- ne)cyclohexa-2,5-dienone 101, 102 (DMFUSC),} the molecules adopt identical conformations in both polymorphic modifi- cations. The chirality in the molecule (Fig. 17) is determined by the difference in the rotation of the phenyl rings. In solutions, both enantiomeric forms are present due to rotation of the rings.In both crystals, molecules of one enantiomeric form are packed in identical layers (Fig. 18). The adjacent layers in the b form (P212121) are stacked in a congruent fashion, while in the a form (P21/c) the adjacent layers are related by centres of symmetry. The a ± b phase transition was observed at 383 K. Therefore, in this case two polymorphic modifications exist due to different modes of packing of layers and the enantiomeric forms readily undergo interconversion with a small consumption of energy. Analogous 0 y x HCO Figure 18. Structure of the layer in the orthorhombic modification of DMFUSC (projection onto the xy0 plane).The layer in the monoclinic modification has an analogous structure. } The reference code of the compound in the CSD. L N Kuleshova,MYu Antipin situations were observed in di(1-piperidyl) disulfide 103 (DPIPDS),} o-chlorobenzamide 104 (CLBZAM),} m-nitro- phenol 105, 106 (MNPHOL),} and bis(trimethylbenzylammonium) tetrachlorocuprate(II) 107 (MBAMCC). } These compounds can be assigned to the first group, i.e., they are enantiomers that interconvert rapidly. VII. Number of molecules per asymmetric unit and pseudosymmetry As mentioned above in the section devoted to the relative frequency of occurrence of space groups, the increasing attention is paid to crystal-chemical analysis of structures with Z0>1.Several computer programmes have already been developed for revealing pseudosymmetry in such crystal structures.108, 109 These programmes were devised originally for revealing improper symmetry in structural studies and therefore they treat pseudo- symmetry as a `negative factor'. The main purpose of these programmes is to determine deviations of atoms from certain ideal symmetry positions, which imply that some symmetry operations were missing in the course of determination of crystal symmetry. Initially, when only a few instances of crystals containing two independent molecules per asymmetric unit were known, researchers pinned hopes on comparison of their conformations and molecular geometry. This approach seemed to be very promising for studying the effect of crystal environment on molecular structure. However, expectations were not realised completely because such structures remained for long few in number.Studies of noncrystallographic (pseudosymmetrical) symme- try operations that related independent molecules in crystals have attracted growing interest as the corresponding structural data has been accumulated.45, 53, 54 Analysis of the data in the 1991 version of the CSD demonstrated that in 27% of structures with Z0>1. the molecules are related by approximate pseudosymme- try elements 1, 2, 21 and t (translation), i.e., by elements which are also present most often in space groups of crystals.{ Undoubtedly, a pseudocentre of symmetry is the most frequently occurring element.In the next stage, relationships between space groups describ- ing the crystal symmetry and pseudosymmetry transformations were searched for. The symmetry of real crystals often appeared to be a symmetry subgroup of a certain `hypothetical' crystal. It is derived by `eliminating' the corresponding symmetry element (which becomes a pseudoelement) from the symmetry group of the hypothetical crystal. Thus, Brock and Dunitz 45 found 256 crystals belonging to the group P21 with Z0=2 in the 1989 version of the CSD of which 55 crystal structures contain an inversion pseudocentre and are described by the symmetry pseudogroup P21/c. It was suggested that the great majority of structures with Z0>1 belonging to the group P1 are actually pseudosymmetrical structures.The application of the CSD made it possible to reveal also some other statistical regularities. Padmaja et al.41 noted that structures with Z0>1 are substantially more frequent in low- symmetry crystal systems (especially in the group P1). These results were confirmed.45 It was demonstrated that structures with Z0>1 are, on the whole, more abundant in chiral groups than in the corresponding centrosymmetrical groups (see Section IV). Certain preliminary conclusions were made about classes of chemical compounds for which structures with Z0>1 are most often realised. In particular, *40% of crystals of aliphatic alcohols in the CSD have Z0>1. Craven110 noted that in*50% of crystals of cholesterol derivatives, Z0>1.We performed sampling of structures of 3- and 4-hydroxy derivatives of hydropyridine in the 1996 version of the CSD. A total of 320 structures were found of which 21% instances have {R Davies and A Willer (private communication; see Ref. 45).Cambridge Structural Database as a tool for studies of general structural features of organic molecular crystals a x 0 z HCO Figure 19. Projection of the crystal structure of 3,4-dihydroxy-1-methyl-2-oxo-4-phenylpiperidine onto the x0z plane (a) and the hypothetical crystal structure obtained by shifting pseudosymmetrical chains in the crystal (b).111 Z0>1. Apparently, for all classes of compounds containing hydroxy groups there is a high probability of formation of crystals with Z0>1. It is known that compounds containing hydroxy groups form stable associates in crystals through hydro- gen bonds.It can be assumed that these associates are present even in the initial mother liquor from which crystals are grown. Thus single crystals can be formed from associates rather than from isolated molecules. The packing of associates does not necessarily lead to the optimum symmetry due to insignificant shifts required for closer packing. Let us exemplify the aforesaid by the crystal structure of 3,4- dihydroxy-1-methyl-2-oxo-4-phenylpiperidine,111 which crys- tallised in the space group Pca21, Z0=2. Two independent molecules are linked in a pseudocentrosymmetrical dimer through hydrogen bonds.These dimers are linked in infinite chains through hydrogen bonds, and the crystal structure as a whole is formed from these layers (Fig. 19a). This noncentrosym- metrical structure can be transformed into the centrosymmetrical one (symmetry Pbcn) by slightly shifting the chains with respect to each other. The shift is equal to *1.5 A. The pseudocentrosym- metrical dimers can be seen in Fig. 19a. Chains formed in the structure through hydrogen bonds are located perpendicular to the plane of the paper. The hypothetical crystal structure and the molecular arrangement are shown in Fig. 19b. It can be seen that the shift of chains in the real crystal with respect to each other leads to a closer packing. The probability of the detection of Z0>1 and consequently, of the presence of pseudosymmetry is also very high for crystals of mesogenic compounds, which are solid-crystalline precursors of liquid crystals (among them are cholesterol derivatives).110 It is known that mesogenic compounds are prone to aggregation in the liquid state, which does not necessarily occur through hydrogen bonding.For example, in four of eight crystal structures of cholesteryl benzoate derivatives, which do not form intermolecu- lar hydrogen bonds,58 Z0>1. Calculations of the energy of intermolecular interactions demonstrated that molecules are packed in crystals in a layered-stacked fashion and the strongest interactions occur between molecules related either by screw axes or by translations along the stack axis.The existence of this energy-distinguishable direction is very important because weaker interactions between layers and stacks are primarily weakened when passing to the mesophase. In this case, shifts of stacks with respect to each other as well as slight mutual rotations of adjacent molecules in stacks about stack axes become possible. Rotations result in the appearance of a supramolecular structure twisted about the stack direction. This structural feature emphasises the 15 b x0 z role of screw axes in cholesterogenic crystals. The results reported in the work 58 suggested that a genetic relationship exists between crystalline and liquid-crystalline structures and can provide the basis for further systematic studies with the use of the CSD data aimed at the design of new compounds potentially exhibiting liquid-crystalline properties.Interestingly, at least one polymorphic form often has Z0>1. The overall percentage of structures with Z0>1 in the CSD is 8.3%, while twice as many such structures are observed among polymorphic modifications (16%).3 Thus, the presence of more than one independent molecule per asymmetric unit may indicate that several different crystal packings can exist. The existence of pseudosymmetry in a particular crystal structure is an indication that a distorted higher-symmetry structure can exist. Based on this fact, Abrahams 53, 54 suggested that if this distortion is rather small, the crystal structure would be expected to become more symmetrical at higher temperature as a result of phase transition.Recall that in the cases of phase transitions of the first and second kinds, the crystal symmetry changes abruptly at the transition point. In the case of phase transitions of the first kind, a correlation between the structures of the initial and newly formed phases can be either present or absent. The characteristic feature of phase transitions of the second kind is that the symmetry group of the low-symmetry phase is a subgroup of the symmetry group of the other phase, because only some symmetry elements disappear as a result of displacements of atoms, while other elements persist. It is the latter that form a subgroup. A higher-symmetry phase corre- sponds, as a rule, to the high-temperature modification.These reasonings provided the basis for a procedure proposed by Abrahams for a search for new crystals possessing ferroelectric properties in the crystallographic databases. This method is based on the analysis of the available structural data. The ferroelectric phase transition is accompanied by loss of an inversion centre, a mirror plane m or a rotation axis 2. If H is a polar space group of the structure under study, the minimum supergroup G of the paraelectric phase can be written as follows: H , G à H á gt where the operator g(1,m, 2) represents the rotational component. In the general case, the orientation of a plane m or an axis 2 is limited by the space group H, but the translation term (t) of the equation can take any value within limits determined by the group G.To put it differently, an inversion centre, a mirror plane or a16 rotation axis that are lost can be located in any position with respect to the original one chosen for the description of the group H. Abrahams restricted the consideration to pseudocentres and mirror pseudoplanes. Polar crystal structures in which deviations (shifts) of atoms Dr with respect to hypothetical nonpolar configurations lie in the range between 0.1 and 1 A were considered as materials that will, most probably, exhibit ferro- electric ± paraelectric phase transitions. It was suggested that the maximum deviation of atoms Dr along the polar axis from the totally symmetrical position be considered as a quantitative parameter for estimating the degree of pseudosymmetry of the structure.On the basis of this parameter, the following empirical equation was derived for predicting the transition temperature: Tc=C(Dr)2 , where C&2.06104 K A72. Abrahams has cast doubt on space groups determined for structures with Dr<0.1 A. Compounds satisfying the above conditions 54 were selected in the Inorganic Crystal Structure Database (1987). For these compounds, more than 50 new ferroelectric crystals were predicted. Based on the approach developed by Abrahams, Igartua and coworkers 55 suggested a procedure for systematic studies of materials exhibiting both kinds of high-temperature phase tran- sitions. The authors suggested that compounds possessing pseu- dosymmetry under ordinary conditions would possess structural phase transitions at elevated temperatures.This was exemplified with the space group P212121. A total of 442 structures were retrieved from the Inorganic Crystal Structure Database and for 407 of them the values Dr were calculated. It appeared that in all 14 compounds, for which high-temperature phase transitions and pseudosymmetry were reported, Dr<1.5 A. About 20 structures with pseudosymmetry and Dr<1 A were additionally found for which phase transitions are highly probable. Therefore, it is evident that systematic studies of pseudosym- metrical crystals are promising for establishing structural regu- larities and for design of materials possessing desired physical properties.An analogous search for organic crystals in the CSD was not carried out. However, it is possible to trace the route to a search for compounds with the desired physical properties in the data- base based on certain crystal-structural `indications' (for example, values of Z0>1). In particular, systematic analysis of structures of long-chain molecules with Z0>1 will apparently allow one to reveal crystals of new mesogenic compounds. A successful search for new nonlinear-optical noncentrosymmetrical crystals in the CSD was carried out based on a search for molecules similar in geometry to dicyanovinylanisole (a known nonlinear-optical material).112 It appeared that the CSD already contained data on the crystal structure of p-chlorodicyanovinylbenzene,113 which possesses high ability to generate the second harmonic of laser radiation in the crystal.VIII. Supramolecular synthons and the possibility of prediction of crystal structures A governing role of intermolecular interactions, in particular of hydrogen bonds, in crystal structures of organic molecules became apparent about 40 years back.114, 115 At that time, it was already noticed that hydrogen bonds favour the formation of stable molecular associates in crystals. A series of works by Leiserowitz and coworkers in 1969 ± 1978 116 ± 118 can be considered as the first systematic study in this field. In these works, the authors attempted to derive possible molecular associates that are real- ised in some classes of chemical compounds, namely, in carboxylic acids and in primary and secondary amides.The geometrical characteristics of hydrogen bonds in crystals were determined for the first time 119 based on statistical data on the published crystal structures and the theory of graphs was applied for deducing theoretically possible fragments formed through hydrogen bonds in crystals. In addition, typical and anomalous modes of forma- L N Kuleshova,MYu Antipin tion of such molecular associates were determined based on the analysis of more than 2000 structures.120 The determination of the geometrical parameters of different types of hydrogen bonds based on more detailed statistical data became possible as the CSD data have become available. Taylor and Kennard 23 were the first to determine the geometrical parameters of CH.. .O interactions. These interactions are com- monly assigned to weak hydrogen bonds. Berkovitch-Yellin and Leiserowitz 121 noted that these weak CH. . .O interactions in crystals along with hydrogen bonds can lead to the formation of stable molecular associates. The works devoted to the consider- ation of the role of CH. . .O hydrogen bonds in the formation of crystal structures were most completely surveyed in the review.29 More recently, it was shown that the majority of functional groups form a limited number of graph-sets of associates, which are found repeatedly in different structures. Moreover, even chemically different functional groups often form associates described by the same graph-sets.122 Each type of interaction is characterised by an inherent ideal geometry of the contact.Therefore, the knowledge of functional groups of a molecule makes it possible to predict, with a high probability, associates that will be present in crystals. Etter 122 derived rules for formation of hydrogen bonds in crystals. She has supplemented Donohue's principle, according to which all `acid' hydrogen atoms in solids participate in hydrogen bonds, by the addition of the following concepts: (1) the hydro- gen-bond acceptors are used to the maximum extent if H-bond donors are available and (2) in crystals containing several potential donors and acceptors, H bonds are preferentially formed between the best donor and the best acceptor.The latter principle is very helpful in the analysis of crystal structures of polyfunctional molecules because it makes it possible to reveal a `hierarchy' of formation of hydrogen bonds. Based on this principle in the case of branched systems of H bonds in crystals, Bernstein et al.61 suggested that systems of H bonds be divided into separate subfragments with account of intermolecular dis- tances and symmetry operations of space groups. This approach allows one to unify a procedure for revealing molecular associates formed throughHbonds in all crystals listed in the CSD. Etter and Bernstein were the first to perform studies in the field of crystal engineering.61, 122 Presently, investigations in this field follow two paths.The first aim is to reveal principles of molecular aggregations in crystals based on studies of the diversity of the available crystal structures. The second line of investigation is aimed at the development of calculation procedures for crystal structures design on the basis of only the molecular geometry.1 ± 3 These two lines are `two sides of a coin' and are aimed at solving the direct and inverse problems of crystal engineering. In studies devoted to the first problem, the nature of forces owing to which molecules in crystal structures are linked in associates (hydrogen bonds, other weaker specific interactions or even usual van der Waals interactions) is first established and then one tries to reveal structural fragments consisting of most strongly bound molecules (supramolecular synthons).Works devoted to the second line of investigation are based on the molecular geometry. One tries to calculate the most favourable mutual arrangement of two molecules (dimers), of chains or planes formed by molecules and finally of a three-dimensional struc- ture.1 Alternative calculation algorithms are also available (see Ref. 31). Note that chemists involved in computation of crystal struc- tures address themselves more and more often to structural databases (most often to the CSD) primarily for choosing potential-function parameters and also for testing calculation procedures with the use of a large number of the published crystal structures.The algorithm (FlexCryst) which was developed 1 for predicting organic crystal structures was used for calculating 131 crystal structures belonging to the space group P1 and 95 crystal structures belonging to the space group P1 retrieved from theCambridge Structural Database as a tool for studies of general structural features of organic molecular crystals CSD. The agreement between the calculated and the real struc- tures was 98% and 85% for the groups P1 and P1, respectively. Needless to say that these results are very promising. However, this algorithm does not presently allow calculations for other space groups. The algorithm MOLPAK2 allows one to treat also the space groups P21, P21/c and P212121. A total of 242 crystal structures were calculated with the use of this program.The programme PROMET allows one to make rather reliable pre- dictions about realisation of a particular space group. This programme made it possible to calculate polymorphic modifica- tions of sulfathiazole, probucol and aspirin.3 IX. Conclusion Investigations with the use of the CSD as a tool in studying general regularities of organic crystal structures demonstrated that this approach produces good results. Thus the principle of close packing of organic and organometallic compounds in crystals was confirmed by statistical analysis of positions of molecular geometrical centres in crystal unit cells. The statistical values of the van der Waals radii of nonmetals were determined based on the analysis of a large sample of nonbonded interatomic distances in the published structures.The preferential types of molecular packings of organic molecules were revealed and an overwhelming predominance of centrosymmetrical space groups was noted. However, statistical analysis demonstrated no evidence that centrosymmetrical packings are energetically preferable to non- centrosymmetrical structures. Neither gain in density nor notice- able differences in the thermodynamic characteristics were revealed. Conceivably, a predominance of centrosymmetrical space groups reflects the fact that compounds can exist as racemic mixtures of enantiomers rather than the fact that they are energetically more favourable. If this is the case, then crystals belonging to noncentrosymmetrical space groups can be obtained if one establishes the reasons for spontaneous resolution of enantiomers upon crystallisation or finds a procedure for their forced resolution.It is also probable that noncentrosymmetrical crystals just have received lesser attention and, in spite of a large body of data in the CSD, a sample of compounds in this case is not yet representative. Statistical studies confirmed that molecular association in crystals through hydrogen bonds plays a governing role in the formation of crystal packings. Some structural features of crystals whose packings contain stable synthons (dimers, chains or layers) were revealed. These are, first of all, a high probability of occurrence of polymorphic modifications, structures with Z0>1 and with pseudosymmetry and cases of spontaneous resolution of isomers.These structures often possess (or can possess) useful physical properties. A procedure was developed for the search for new ferroelectrics and other materials exhibiting phase transi- tions. Analysis of the results of the first systematic statistical studies of organic crystal structures with the use of the CSD allows one to draw up a plan of further investigations in this field. Thus the first stage of studies of the reasons for spontaneous resolution of enantiomers upon crystallisation should apparently involve the establishment of types and forms of molecules that can undergo spontaneous resolution and analysis of the role of molecular association in crystals (apparently, from the initial solution). In this respect, it is very advantageous to compare crystal packings of compounds having centro- and noncentrosymmetrical polymor- phic modifications. A search for compounds exhibiting polymor- phic transformations and compounds potentially possessing liquid-crystalline and nonlinear-optical properties in the CSD can be rather simple.These are only some applications of the CSD. 17 References 1. D W M Hofmann, T Lengauer Acta Crystallogr., Sect A 53 225 (1997) 2. J R Holden, Z Du, H L Ammon J. Comput. Chem. 14 422 (1993) 3. A Gavezzotti, G Filippini J. Am. Chem. Soc. 117 12299 (1995) 4. A Gavezzotti Acc. Chem. Res. 27 309 (1994) 5.L Pauling, in The Nature of the Chemical Bond (Ithaca, New York: Cornell University Press, 1948) p. 187 6. A J Bondi J. Phys. Chem. 68 441 (1964) 7. A I Kitaigorodskii Organicheskaya Kristallokhimiya (Organic Crystal Chemistry) (Moscow: Izd. Akad. Nauk SSSR, 1955); Molekulyarnye Kristally (Molecular Crystals) (Moscow: Nauka, 1971) 8. P P Ewald, C Hermann Strukturberichte 1913 ë 1928 (Leipzig: Academische Verlagsgesellschaft, 1929) 9. A I Kitaigorodskii, P M Zorky, V K Belsky Stroenie Organi- cheskogo Veshchestva (The Structure of Organic Substance) 11. D G Watson, in CODATA Directory of Data Sources for Science and (Moscow: Nauka, 1980) Vol. 1 10. A I Kitaigorodskii, P M Zorky, V K Belsky Stroenie Organi- cheskogo Veshchestva (The Structure of Organic Substances) (Moscow: Nauka, 1982) Vol.2 Technology (Paris: CJLFNF, 1977) p. 15 12. D G Watson, in Crystallographic Data Bases (Eds F H Allen, G Bergerhoff, R Sievers) (Chester: International Union of Crystallography, 1987) p. 25 13. R Jenkins, D K Smith, in Crystallographic Data Bases (Eds F H Allen, G Bergerhoff, R Sievers) (Chester: International Union of Crystallography, 1987) p. 158 14. A D Mighell, J K Stalick, V L Himes, in Crystallographic Data Bases (Eds F H Allen, G Bergerhoff, R Sievers) (Chester: International Union of Crystallography, 1987) p. 134 15. F H Allen, O Kennard Chem. Design Autom. News 8 (1) 31 (1993) 16. F H Allen, O Kennard, D G Watson, L Brammer, A G Orpen, R Taylor J. Chem. Soc., Perkin Trans 2 S1 (1987) 17.A G Orpen, L Bramer, F H Allen, O Kennard, D G Watson, R Taylor J. Chem. Soc., Dalton Trans. 1 S1 (1989) 18. F H Allen, in Modelling of Structure and Properties of Molecules (Ed. Z B Maksic) (Chichester: Horwood-Wiley, 1987) p. 51 19. A I Yanovskii, Yu T Struchkov, in Problemy Kristallokhimii (The Problems of Crystal Chemistry) (Moscow: Nauka, 1984) p. 161 20. Yu L Slovokhotov, I V Moskaleva, V I Shilnikov, E F Valeev, Yu N Novikov, A I Yanovsky, Yu T Struchkov Mol. Mater. 8 117 (1996) 21. S C Nyburg, C H Faerman Acta Crystallogr., Sect. B 41 274 (1985) 22. R S Rowland, R Taylor J. Phys. Chem. 100 7384 (1996) 23. R Taylor, O Kennard J. Am. Chem. Soc. 104 5063 (1982) 24. R Taylor, O Kennard Acta Crystallogr., Sect.B 39 517 (1983) 25. R Taylor, O Kennard Acta Crystallogr., Sect. B 39 133 (1983) 26. R Taylor, O Kennard Acta Crystallogr., Sect A 41 85 (1985) 27. 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V K Belsky, in The XVII Congress of the International Union of Crystallography (Abstracts of Reports), Seattle, KY, 1996NT 12, p. 1 43. A Mackay Acta Crystallogr. 22 329 (1967) 44. A D Mighell, J R Rodgers Acta Crystallogr., Sect A 36 321 (1980) 45. C P Brock, J D Dunitz Chem. Mater. 6 1118 (1994)18 46. J F Nicoud, R J Twieg, in Non-Linear Optical Properties of Organic Molecules and Crystals Vol. 1 (Eds D S Chemla, J Zyss) (New York: Academic Press, 1987) p.253 47. G R Meredith ACS Symp. Ser. 233 29 (1983) 48. J Jacgues, A Collet, S H Wilen Enantiomers, Racemates and Resolutions (New York: Wiley, 1981) p. 81 49. J K Whitsell, R E Davis, L L Saunders, R J Wilson, J P Feagins J. Am. Chem. Soc. 113 3267 (1991) 50. C P Brock, W B Schwezer, J D Dunitz J. Am. Chem. Soc. 113 9811 (1991) 51. V K Belsky, P M Zorky Kristallograéya 15 704 (1970) b 52. N Yu Chernikova, V K Belsky, P M Zorky Zh. Strukt. Khim. 31 661 (1991) c 53. S C Abrahams Acta Crystallogr., Sect. B 45 228 (1989) 54. 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J Jacgues, A Collet, S H Wilen Enantiomers, Racemates and Resolutions (New York: Wiley, 1981) p. 4, 23, 94 90. S F Mason Molecular Optical Activity and the Chiral Discriminations (Cambridge: Cambridge University Press, 1982) p. 171 L N Kuleshova,MYu Antipin 91. W C McCrone, in Physics and Chemistry of the Organic Solid State Vol. II (Eds D Fox,MM Labes, A Weissberger) (New York: Interscience, 1965) p. 725 92. A Burger Pharm. Int. 3 158 (1982) 93. A Ellern, J Bernstein, J Y Becker, S Zamir, L Shahal Chem. Mater. 6 1378 (1994) 94. J D Dunitz, J Bernstein Acc. Chem. Res. 28 193 (1995) 95. J Bernstein J. Phys. D, Appl. Phys. 26 B66 (1993) 96. K Sato J. Phys. D, Appl. Phys. 26 B77 (1993) 97. L Borka J K Haleblian Acta Pharm. Yugosl. 40 71 (1990) 98. G Filippini, A Gavezzotti Chem. Phys. Lett. 231 86 (1994) 99. A Gavezzotti, G Filippini J. Chem. Soc., Perkin Trans. 2 1399 (1995) 100. G Filippini, A Gavezzotti Acta Crystallogr., Sect. B 49 868 (1993) 101. 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ISSN:0036-021X    

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Russian Chemical Reviews 68 (1) 19 ± 38 (1999) Donor ± acceptor complexes and radical ionic salts based on fullerenes D V Konarev, R N Lyubovskaya Contents I. Introduction II. Fullerenes III. Donor ± acceptor complexes and radical ionic salts of fullerenes IV. Structure and spectral characteristics of complexes and radical ionic salts of fullerenes V. Conclusion Abstract. The review generalises for the first time the published data on the synthesis and properties of donor-acceptor type of compounds based on fullerenes, various solvates and clathrates, inclusion compounds, molecular complexes and charge-transfer complexes both with inorganic donors and with organoelement donors of the tetrathiafulvalene, amine, metallocene and metal- loporphyrin series.Radical ionic salts of fullerenes with bulky cations and alkali metals obtained by intercalation or by direct synthesis in solution are discussed. Results of studies of fullerene compounds by IR, optical, ESR, X-ray photoelectron and 13C NMR spectroscopy, as well as their conducting (including super- conducting), magnetic and optical properties are discussed. The bibliography includes 208 references. I. Introduction The discovery of fullerenes, a new allotropic modification of carbon, in the mid-80's 1 confirmed the prediction of theorists 2, 3 on the possible existence of polyhedral carbon molecules with icosahedral symmetry. In the early 90's, a simple method to obtain fullerene C60 in gram amounts was found; this gave an impetus to more detailed studies of physical and chemical properties of the C60 clusters and compounds based on them.4 The number of works in this area grows steadily, and they cover an ever wider range of fundamental and applied branches of science and technology.In 1996, Kroto, Smalley and Curl were awarded the Nobel Prize in chemistry for D V Konarev, R N Lyubovskaya Institute for Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation. Fax (7-096) 515 35 88. Tel. (7-096) 517 18 52. E-mail: konarev@icp.ac.ru (D V Konarev), lyurn@icp.ac.ru (R N Lyubovskaya) Received 26 May 1998 Uspekhi Khimii 68 (1) 23 ± 44 (1999); translated by S S Veselyi #1999 Russian Academy of Sciences and Turpion Ltd UDC 593.194+547.435 19 20 21 30 35 the discovery of fullerene and for their great contribution to the development of this area.Generally, fullerenes display acceptor properties5±7 and can be regarded as p-acceptors. They can form various donor ± acceptor (D ±A) non-covalent compounds, similar to the well- known planar p-acceptors, e.g., tetracyanoquinodimethane 1 (TCNQ), tetracyanoethylene 2 (TCNE), p-quinone, etc.5, 8 NC CN CN NC NC CN CN NC 2 1 These D±A compounds are formed due to rather weak (in comparison with the standard covalent chemical bonds) van der Waals interactions and due to charge transfer from the donor to the acceptor.9 Charge transfer plays a very important role and results in qualitatively new physicochemical properties of these compounds.D±A compounds can be divided into several groups according to the degree of charge transfer (d), although there is no distinct boundary between these groups. The compounds with d close to zero can be attributed to molecular complexes. In the case of partial charge transfer from the donor to the acceptor (0<d<1), charge-transfer complexes (CTC) Dd+Ad7 are formed. For example, in the TTF ±TCNQ complex, where TTF is tetrathiafulvalene, different estimates give d=0.48 ± 0.67.8 A characteristic feature of CTC is the appearance of a new band in the absorption spectrum of the complex in the visible and near IR regions due to the transfer of an electron from the donor to the acceptor when absorption of a light quantum occurs.9 In the extreme case, i.e., in the complete charge transfer from the donor to the acceptor or in the formation of a compound from oppositely charged ions, radical ionic salts Dn+An7 are formed (in the case of radical ionic salts of fullerenes, n is an integer).The charge-transfer complexes and radical ionic salts based on planar polyconjugated heterocyclic p-donors and acceptors are being intensely studied lately. Many of them, the so-called organic metals, have unique conduction and magnetic properties.10, 11 Radical cationic salts of tetrathiafulvalene derivatives draw special attention. The majority of organic metals and super- conductors obtained to date correspond to this class of com- pounds.10, 11 The discovery of fullerene has given the researchers a new p-acceptor with a number of essential features that distinguish it from other acceptor molecules: larger size, spherical shape, unique electronic structure, high symmetry and polarisability.The resulting specific features of donor-acceptor interactions in com- pounds of the C60 fullerene enabled the design of materials with20 unusual physical properties. For example, it was found that intercalation of C60 by alkali metals results in superconductors with composition M3C60 (M=K, Rb, Cs) with rather high superconductivity transition temperatures (Tc) (184Tc4 440 K).12 ¡À 14 The salt of C60 with an organic donor, tetra- kis(dimethylamino)ethylene (TDAE), is a ferromagnetic with Tc=16.1 K,15 and apparently has superconducting properties.16 Combination of conducting polymers with fullerene enables efficient phototransfer and separation of charges with long lifetime, which increases considerably the photoconductivity of polymers and can be utilised in xerography and energy photo- transducers.17 By now, a considerable number of various D¡ÀA compounds of fullerenes have been obtained, including molecular complexes, CTC and radical ionic salts with different states of oxidation or reduction.The C60 fullerene molecule can accept up to 12 electrons13, 14, 18 and release one electron,7 i.e., the charge of the C60 molecule can vary from +1 to 712. As a result, C60 compounds manifest a broad spectrum of properties. The considerable interest of experts from different areas in fullerenes and compounds based on them is reflected in a number of books and reviews.19 ¡À 28 In particular, the reviews are devoted to chemistry,21 spectroscopy 22 ¡À 26 and magnetic properties 27 of fullerenes and compounds based on them, as well as to intercala- tion of fullerenes with alkali and alkaline-earth metals.13, 14, 28 The present review generalises for the first time the published data on the synthesis ofD¡ÀAcompounds based on fullerenes that are formed both through van der Waals interaction and charge transfer.These include solvate and clathrate compounds, inclu- sion compounds, molecular complexes, CTC and radical ionic salts of fullerenes with organic and organometallic donors and various metals.Data on IR, electronic, ESR, X-ray, photoelec- tron and 13C NMR spectroscopy are considered. The features of D¡ÀA complexes and radical ionic salts of fullerenes, including superconducting, magnetic and optical properties, are discussed. II. Fullerenes 1. Features of fullerene structure It is known that the molecule of the C60 fullerene has icosahedral symmetry (group Ih), and its surface consists of 20 six- and 12 five- membered rings.1 The molecule of the C70 fullerene consists of 25 six-membered and 12 five-membered rings. It has an elongated shape and lower symmetry (D5h). Higher fullerenes also represent polyhedral molecules and contain a larger number of hexagonal facets.25 All 60 carbon atoms in the C60 molecule are equivalent, which is confirmed by the presence of a single signal in the 13C NMR spectrum.29 The meanC7C distance in C60 (1.44 A �º ) is close to the C7C distance in graphite (1.42 A �º ).Each carbon atom in the C60 molecule is linked to three other carbon atoms by two longer 6 ¡À 5 bonds in five-membered rings and by one shortened 6 ¡À 6 bond, which is common to two fused six-membered rings. Thus, the carbon atoms in C60 have a near-sp2 hybridisation.25, 30 Usually, the symmetry axis of the p-orbital is orthol (Ysp=90 8) to the plane of the three s-bonds in the sp2 hybrid- isation. Because of the spherical shape of the C60 fullerene molecule, the four mutually linked carbon atoms do not lie in the same plane and the angle Ysp is 101.64 8 rather than 90 8.30 Thus, pyramidalisation of carbon atoms occurs in fullerenes, which results in significant strain in the fullerene molecule and changes the character of the p-orbitals; thus, there is certain contribution by a s-orbital to the p-orbitals of all fullerenes. Pyramidalisation affects strongly the electronic properties of fullerenes and prede- termines their high electron affinity, as the strain in the molecule is partially eliminated upon reduction of fullerenes.30 D V Konarev, R N Lyubovskaya 2.Donor ¡À acceptor properties and polarisability of fullerenes The ionisation potentials (IP),25 electron affinities (EA)6 and the corresponding redox potentials (EOx, ERed) 31 of the C60, C70 and C76 fullerenes are listed in Table 1.Table 1. Vertical electron affinity (EA),6 first and second reduction potentials of fullerenes (E1Red and E2Red),31 ionisation potentials (IP)25 and oxidation potentials of fullerenes (E1Ox).7 E2 IP /eV Fullerene EA/eV E1 E1Ox /Vb Red /Va Red /Va 7.58 C60 70.82 70.80 C70 +1.26 +1.20 +0.81 2.67 2.68 2.86 70.44 70.41 7 C76 aCH2Cl2, SCE, 0.05 M Bun4 NBF4; b relative to Fc/Fc+ (Fc is ferrocene). The first redox potentials of the C60 and C70 fullerenes in the polar solvents are close to each other. The redox potential of the C60/C ¡¦60. pair is70.44 V in dichloromethane and acetonitrile 5, 31 and 70.33 V in tetrahydrofuran 32 relative to the saturated calomel electrode (SCE). These values are 0.6 ¡À 0.7 V smaller than the corresponding redox potentials of TCNQ (+0.22 V) andTCNE (+0.28 V).5 Changing the polarity of the solvent shifts the redox potential of C60 insignificantly.For example, the redox potential in nonpolar benzene is70.36 V relative to SCE.32 The C60 fullerene is rather a weak acceptor. The EA of C60 in the gas phase is 2.67 eV.6 The adiabatic EA of C60 in solution (estimated from the energy of charge transfer and redox poten- tials) is much lower and equals 2.10 ¡À 2.20 eV.5 These values are comparable with the EA of such weak acceptors as 3,6-dibromo- 2,5-dimethylquinone (3) or 1,2,4,5-tetracyanobenzene (4) (2.1 eV) but are much lower than those of TCNQ (2.82 eV) and TCNE (2.90 eV).5 O Br Me CN NC Me Br CN NC 4 O3 One possible way to increase the EA is the introduction of strong acceptor substituents in fullerenes.It has been shown33, 34 that halogenated fullerenes have stronger acceptor properties than C60. For example, the theoretically calculated EA for C60Br8 is *4.0 eV.33 Fluorinated fullerenes, viz., C60F36, C60F48 and C70F54, have considerably more positive first redox potentials than the corresponding fullerenes (70.05, +0.51 and +0.76 V, respectively, relative to an Ag/Ag+ reference electrode in dichloromethane).34 The electron affinities of C60F36 and C60F48 are also higher than that of C60 (3.48 and 4.06 eV, respectively).34 Functionalisation results in significant changes in the symmetry and electron structure of the C60 fullerene.33 Fullerenes, especially C60, have high oxidation potentials.The ESR method detected the formation of the C60 radical cation in solutions containing strong oxidants,35 but individual compounds in which C60 is charged positively have not been isolated yet. Higher fullerenes possess higher electron affinities, and thus they are stronger acceptors. The C76 fullerene and other higher fullerenes undergo oxidation a little more readily than C60.7 For example, C76 is oxidised with hexabromocarboranyltris(2,4- dibromophenyl)ammonium (ERed=+1.16 V) to give a radical cationic salt with positive charge on the fullerene.7 The polarisability of the C60 fullerene molecule is high (a*85 A)36 and is several times higher than that of other p-acceptors.Therefore, polarisation van der Waals forces are essential in the formation of D¡ÀA complexes and radical ionic salts of fullerenes.Donor-acceptor complexes and radical ionic salts based on fullerenes 3. Features of the crystal structure of C60 fullerene At room temperature, C60 has a face-centred cubic (FCC) lattice.37 The shortest distance between the centres of the C60 molecules in a crystal is 10.02 A, which is smaller than the van der Waals diameter of the C60 molecule, considering the size of its p-electron cloud (10.18 A, Ref. 25), hence the p-orbitals of theC60 molecules in a crystal overlap little. The weakness of interactions between the fullerene molecules in the solid state is the reason for the fast isotropic rotation of the C60 molecules in the crystal.Below 255 K, C60 crystals undergo a phase transition from the face-centred cubic lattice to a simple cubic lattice.37 The rotation of the fullerene molecules in these crystals becomes anisotropic, it slows down, gets synchronised and occurs ratchet. In the case of such rotation, adjacent C60 molecules can be present in two different orientations relative to each other, which have different energies. In the first orientation, the shortened `double' bond of one C60 molecule is located above the electron-deficient pentago- nal facet, whereas in the second orientation, it is above the hexagonal facet of the C60 molecule. As the temperature is decreased, the number of pairs of molecules in the first orienta- tion increases and reaches 83% at 90 K.Below 90 K, the ratio of molecules in the first and second orientations remains constant, but ratchet rotation of the C60 molecules occurs in such a manner that each of two orientations is transformed only to the equivalent one.25 This results in ordering, in which the rotation of the C60 molecules in a crystal is synchronised completely. This kind of ordering can also occur in D±A complexes and radical ionic salts of fullerenes provided that the distances between the C60 mole- cules are short.38 ± 40 4. Conducting and magnetic properties of fullerenes The upper unoccupied and lower occupied levels of the C60 molecule are presented in Fig. 1. The highest occupied hu level is five times degenerate and is completely filled with ten electrons.The lowest free t1u and t1g levels are three times degenerate.25, 36 Energy, b 71 hu t1g t1u 0 hu 1 gg, hg Figure 1. Highest occupied and lowest unoccupied molecular p-orbitals of the C60 fullerene calculated by the HuÈ ckel method;36 b is resonance integral. Overlapping of p-orbitals of the adjacent C60 molecules in a crystal results in the formation of a valence band and a conduction band. The energy gap between the valence band and the con- duction band in C60 is estimated as 1.5 ± 1.8 eV,25, 36 hence crystalline fullerene is a semiconductor. The highest-energy edge of the valence band consists of the hu levels, while the lowest- energy edge of the conduction band consists of the t1u levels (see Fig.1). Magnetic measurements carried out with pure C60 and C70 fullerene specimens have shown that magnetic transitions are observed at 60 K.40 This is due to the fact that the currents of p-electrons in the six- and five-membered fullerene rings are different and create a very small but distinct magnetic moment in the fullerene molecule [for C60, m=70.3561079 A m2 (see Ref. 27)]. Cooling of specimens of pure C60 below 90 K results in the transition to ratchet synchronised rotation of the fullerene molecules. In this transition, the positions of 83% of the magnetic moments of the C60 molecules are frozen in an ordered fashion, but 17% of the magnetic moments are frozen in disorder. This results in a glassy magnetic state.40 21 When C60 specimens are placed in a magnetic field, the magnetic moments of the C60 fullerene molecules are oriented along the external magnetic field.Therefore, cooling of C60 specimens in a magnetic field below the temperature of transition to synchronised rotation of fullerene molecules results in freezing of the ordered positions of the magnetic moments of the C60 molecules and formation of the frozen glassy magnetic state. Heating of the specimens above the temperature of this transition results in violation of the synchronised rotation of fullerene molecules, and ordering of the magnetic moments of the C60 molecules disappears.40 III. Donor ± acceptor complexes and radical ionic salts of fullerenes 1. Methods of preparation Fullerene compounds are prepared using various methods: slow concentration of solutions,41 ± 43 diffusion methods,44 ± 52 cooling of saturated solutions,53, 54 precipitation with a solvent 48 ± 50, 55 and an electrochemical method.56 ± 61 Concentration of solutions containing a fullerene and a donor is the basic method for the preparation of molecular fullerene complexes.The concentration is carried out in an inert atmos- phere, as molecular oxygen can be absorbed on the surface of the fullerene molecule, which blocks the approach of the donor to the fullerene.62 As a rule, those solvents are used in which fullerenes are well soluble: carbon disulfide (7.9 mg ml71), benzene (1.5 mg ml71), toluene (2.9 mg ml71) and chlorobenzene (5.7 mg ml71).63, 64 Fullerene forms solvates of the type C60(Sol)x with many of these solvents.65 ± 74 Two competing reactions occur upon concentration in a reaction system `donor ±C60 ± solvent': Dn(C60)m(Sol)l C60+Sol+D C60(Sol)x Sol is a solvent, D is a donor; n=1 ± 6, m=1 ± 3, l=0 ± 4; x=0.4 ± 4.Shifting of the reaction equilibrium towards the formation of a complex (as the solvent is present in a considerable excess in comparison with the donor) sometimes requires a great molar excess of the donor relative to the fullerene (up to 100 : 1).75 ± 77 As the temperature is increased, the rate of displacement of the solvent by the donor from the solvent shell increases, thus the time of heating or refluxing of the reaction mixture is an essential factor.An increase in the temperature of concentration of fullerene solutions in benzene results in a decrease in the content of benzene in the crystal solvate [C60 ±C6H6], and above 40 8C the solvate is decomposed completely and virtually pure fullerene is formed.42 To avoid losses on the walls of the reaction vessel in the preparation of microquantities of complexes, special techniques for the concentration of the solvent in closed volume using a temperature gradient have been developed.41, 42 Fullerene compounds can be isolated from solutions by precipitation or cooling of saturated solutions. For example, radical anionic salts of fullerenes are isolated from solutions in pyridine and benzonitrile by precipitation with non-polar solvents (pentane or hexane).However, this results in polycrystalline specimens.48 ± 50, 55 Single crystals of the K3C60(THF)14 salt can be prepared by slow gradient cooling of a solution obtained by treatment of the C60 fullerene with potassium in tetramethylethy- lenediamine in the presence of tetrahydrofuran and diethyl ether.53 The diffusion method (in which the vessels with solutions of a fullerene and an appropriate donor are connected by a tube filled with a solvent) is most suitable for the preparation of single crystals of poorly soluble C60 compounds. Single crystals of the22 complexes (DAN)C60(C6H6)3 (DAN is dianthracene),44 the salt (TDAE)C60 [TDAE is tetrakis(dimethylamino)ethylene] 45, 46 and others have been obtained using this procedure.47 60 .anion is controlled by the exact molar ratio of the at 190 K,78 for C60[Br(CH2)3Br] at 190 K78 and for C60(Cl2C=CHCl), at 167 K.72 All these transitions are similar 60.(THF)3 is isolated from THF by precipitation with hex- to the phase transition in pure C60 at 255 K.37 The diffusion method is also used in the synthesis of fullerene radical anionic salts by cationic metathesis. The reaction is carried out in two stages. In the first stage, C60 is reduced with an excess of sodium in THF in the presence of dibenzo-18-crown-6 48 ± 50 or other crown ethers.51 The degree of reduction of the fullerene to the Cn¡ fullerene and the crown ether (1 : n). The salt [Na+(18-crown- 6)]C¡ ane.49 Similar C2¡ 60 , C360¡. and C460¡ salts are poorly soluble in THF and spontaneously precipitate from solutions.49, 51 In the second stage, the resulting sodium salts of C60 are dissolved in acetonitrile and placed in a vessel.A compound with a bulky cation, for example, bis(triphenylphosphoranylidene)ammonium chloride 5 (PPNCl), is placed in the other vessel.50, 51 Ph Ph + Ph P N P Ph Cl7 Ph Ph 5 The vessels are connected by a tube containing the pure solvent. Single crystals of (PPN)2C60 have been obtained by this method.50 Cationic metathesis of Rb3C60 with the salts Me4NCl, Et4NBr and Me4PCl in liquid ammonia can also be used; the specimens were isolated as powders.52 In the electrochemical method, the radical anions C60 ¡ .and CD can be used for medical purposes.95 Similar compounds are C70 ¡ . were obtained by reduction of neutral fullerenes in an formed upon dissolution of a mixture of fullerenes with p-tert- H-shaped cell on a platinum cathode. Compounds Ph4PCl or PPNCl with bulky cations were used as the supporting electro- lytes.56 ± 60 1,2-Dichlorobenzene or mixtures of dichloromethane with toluene and chlorobenzene with tetrahydrofuran served as the solvents. The fullerene salts crystallised on the cathode.56 ± 60 The salts MxC60(THF)y with alkali metals (M = Li, Na, K, x*0:4, y*2:2) were obtained by electrochemical reduction of C60 in the presence of a supporting electrolyte, viz., the corre- sponding tetraphenylborate. A mixture of chlorobenzene with THF served as the solvent.61 2. Solvate and clathrate compounds.Inclusion compounds Dissolution of C60 in various solvents results in formation of donor ± acceptor compounds.65, 66 The interaction of the solvent with C60 occurs basically through polarisation van der Waals forces. In fact, the solubility of fullerenes in solvents with high polarisability, especially in benzene (a*10 A3) and naphthalene derivatives (a*20 A3) is the highest.63, 64 Most of the complexes with solvents are unstable, but in some cases C60 solvates can be isolated as crystals by slow concentration of the solutions.67 ± 74 The interaction with the solvent molecules results in the orientational ordering of molecules compared to crystalline C60; in certain cases, this allows one to perform X-ray diffraction studies of these compounds.Solvate compounds have diverse crystal structures: C60(C6H6)CH2I2 has lamellar packing,67 C60(C6H6)4 forms a cage with hexagonal channels,68, 69 while C60(C6H12)2 70 and C60(1,2-Me2C6H4)2 71 have hexagonal layered packing. The crystal cells of the solvates have lower symmetry than that of pure C60. However, the crystal structure could not be determined for many solvates, such as C60(Cl2C=CHCl),72 C60(CS2) 73 and C60(CCl4)10,74 because of significant orienta- tional and structural disorder. The solvent molecules in clathrate compounds are located in the cavities between the bulky fullerene molecules. Clathrate compounds of C60 are obtained by precipitation of the fullerene from toluene with a large excess of the other solvent, viz., n-pentane, 1,3-dibromopropane, butanone, diethyl ether, ace- tone,78 n-heptane,79 etc.80, 81 The composition of the clathrates is C60(Sol)x.For solvents with small molecules, x=1. As the size of solvent molecules increases, x decreases. Precipitation of fullerene with isobutane results in pure C60.78 Clathrate compounds have D V Konarev, R N Lyubovskaya been obtained basically with the solvents in which the solubility of fullerene is very small; this suggests that the interaction between the molecules of the solvent and fullerene is weak.78 ± 81 Solvate and clathrate compounds are characterised by phase transitions related to orientational ordering of the fullerene molecule.For instance, phase transitions for C60(Me2CO) occur at 240 K,78 for C60(CS2)x at 230 K,78 for (TSeT)xC60(CS2)y (TSeT is tetraselenatetracene) at 203 ± 240 K,82 for C60(C5H12) Compound (TSeT)xC60(CS2)y contains up to 26% of carbon disulfide and only traces of the donor.82 The high content of the solvent probably results in orientational disorder and separates the C60 molecules from each other to such an extent that upon complete removal of carbon disulfide the fullerene is completely sublimed at *520 8C, whereas the maximum sublimation rate of pure C60 is reached only at 700 8C.82 Inclusion compounds of fullerenes are obtained by refluxing aqueous solutions of g-cyclodextrin 6 (g-CD) with finely dispersed fullerene.83 ± 85 There are two types of complexes of g-CD withC60: one C60 molecule forms van der Waals contacts with two g-CD molecules, or a van der Waals aggregate of several C60 molecules forms short contacts with several g-CD molecules.83 ± 85 The unique property of these compounds is their solubility in water, therefore such complexes can be utilised in reactions that occur in the presence of water.In particular, complexes of fullerene with g- butylcalix[8]arene (7) in toluene.86 Complexation with calixarenes has been proposed for efficient separation of fullerene mix- tures.86, 87 It is possible to isolate C60 of 99.5% purity by multiple recrystallisation of a mixture containing 85% C60 and 15% C70.86 It was shown that fullerene molecules are separated from each other C60 ± in crystal structures of compounds p-iodocalix[4]arene 88 and C60 ± p-iodocalix[5]arene.89 But OH O O HO 8 8 OH OH 6 7 3.Complexes with inorganic compounds Complexes of fullerenes with S8,41, 90 ± 92 P4,93 I2,94 S4N4 75, 95 and a number of other small molecules have the composition C60X2 or C60X(Sol). The crown-shaped S8 molecule is very flexible, and molecular sulfur readily forms complexes with fullerenes. The structures of compounds C60(S8)2 and C60S8(CS2) are cage lattices of the fullerene molecules with channels filled with the sulfur molecules.90, 91 In compounds C70(S8)6 and C76(S8)6, the fullerene molecules form loose corrugated hexagonal layers with distances between the fullerene molecules 10.2 ± 10.5 A.41, 92 All S8 ± fullerene compounds contain shortened S7C contacts [3.13 ± 3.52 A, which is shorter than the sum of the van der Waals radii of sulfur and carbon (3.7 A)].As a result of this strong interaction, the rotation of fullerene molecules ceases almost completely. This made it possible to establish the structure of the fullerenes C70 (see Ref. 92) and C76 (see Ref. 36) more precisely. The complex C60(P4)2 has a laminar structure.93 In compound C60I2(C6H5Me), iodine can act as an acceptor with respect to C60, as its EA (3.06 eV) is higher than that of fullerene (2.65 eV). This compound has a donor ± acceptor sandwich structure, in which the iodine molecules are located between the fullerene and toluene molecules.94 Tetrasulfur tetranitride S4N4 (8), like S8, has a crown shape and forms a number of molecular complexes with the C60 fullerene.Donor-acceptor complexes and radical ionic salts based on fullerenes S S S S N N N N 8 The following compounds were isolated from toluene: C60 .S4N4 and C60(S4N4)2.75 The similarity of the sizes of the S4N4 and benzene molecules results in their mutual replacements in the crystal lattice of the complex. For this reason, compounds of the series C60(S4N4)27x(C6H6)x were isolated from benzene, where x<2.75, 95 This replacement has a random character, and the use of an excess of the donor yields compounds with a higher content of S4N4. In the crystal structure of the complex C60(S4N4)1.33(C6H6)0.67, the densely packed layers of fullerene molecules alternate with layers of tetrasulfur tetranitride and benzene molecules.95 cluster and C60 The Pd6Cl12 form a complex C60(Pd6Cl12)2(C6H6)3 with cage structure, in which each fullerene molecule is surrounded by eight Pd6Cl12 molecules.96 4.Complexes with organic donors The interest in complexes of fullerenes with donors of the tetrachalcogenafulvalene class (9 ± 17) is primarily related to the fact that both tetrathiafulvalene and its derivatives are the main components in the production of organic metals and supercon- ductors.10 It is known97 that tetrachalcogenafulvalenes are strong donors with IPs ranging from 6.3 to 7.4 eV. The molecular polarisability of these donors is 15 ± 38 A.97 Tetrathiafulvalenes have planar structures, sometimes with a small deviation of the terminal groups from the conjugation plane.10 This structure allows arrangement of their salts in regular stacks or layers.A partial charge transfer (0.254d 41) from the donor to the acceptor is a prerequisite for the appearance of conductivity.8 Tetrathia(selena,tellura)fulvalenes 9 ± 17 are widely used as donors for the preparation of complexes with fullerenes. S S S S S S S S 9 (BEDT ± TTF) Table 2. Fullerene complexes with tetrachalcogenafulvalenes. Donor Bis(ethylenedithio)tetrathiafulvalene Octamethylenetetrathiafulvalene Dibenzotetrathiafulvalene Bis(ethylenethio)tetrathiafulvalene Hexamethylenetetratellurafulvalene Bis(dimethylthieno)tetratellurafulvalene Tetramethylenedithiodimethyltetrathiafulvalene Bis(methylthio)ethylenedithiotetrathiafulvalene Tetramethyltetraselenafulvalene a For the C70 fullerene. S S S S 10 (OM ± TTF) Abbreviation BEDT± TTF (9) OM±TTF (10) DB± TTF (11) BET ± TTF (12) HM± TTeF (13) BDM± TTeF (14) TMDTDM± TTF (15) C1TET ± TTF (16) TM± TSeF (17) SS 11 (DB ± TTF) Te Te 13 (HM± TTeF) Me SS Me 15 (TMDTDM± TTF) Me Se Se Me (TM ± TSeF) The (BEDT ± TTF)2C60 complex was the first to be obtained.98 Subsequently, about a dozen compounds of full- erenes with tetrachalcogenafulvalene derivatives have been syn- thesised (Table 2).It was found that the degree of charge transfer in these compounds is insignificant.5, 98, 103 ± 106 This is due both to the weak acceptor properties of fullerene and the steric factors unfavourable for charge transfer from the p-orbitals of the initially flat donors to the spherical t1u orbital of C60.106 The formation of complexes with spherical fullerene molecules results in strong distortion of the flat tetrachalcogenafulvalene mole- cules, which assume boat conformations: the dihedral angles between the flat central fragment E4C2 and the terminal groups of tetrachalcogenafulvalene derivatives are 20 ± 30 8,98, 101, 103, 105, 107 which results in some violation of p-conjugation in these molecules.108 The packing of fullerene molecules in the crystals of these complexes can be diverse: dense 5, 89, 100 or rather loose 107, 108 layers of C60 molecules,98, 100 double chains of C60 mole- cules 98, 102, 110 as well as island motifs with isolated C60 mole- Solvent without solvent C6H6 C6H6 C5H5N C6H6 C6H5Me C6H5Cl without solvent CS2 CS2 without solvent CS2 C6H6 SS Te Te S SS SMe Se Se Me 17 Donor : fullerene : solvent ratio 2 : 1 1 : 1 : 1 1 : 1 : 1 1 : 1 : 1 1 : 1 : 1 a 1 : 1 : 1 1 : 1 : 1 1 : 1 1 : 1 : 1 2 : 1 : 3 2 : 1 1 : 1 : 2 1 : 1 : 0.5 23 S S S S S S 12 (BET ± TTF) Me Me Te Te S S Te Te Me Me 14 (BDMT± TTeF) SMe S S SS S SMe S 16 (C1TET ± TTF) Ref.Structural type 98, 99 chain 5 100 100 100 101 101 102 layered island 77layered "" 103 104, 105 106 107 102 island layered double chains layered "24 Table 3.Complexes of C60 with organic donors. Solvent Abbreviation Donor TPDP (18) twin-TDAS (19) 2,20,6,60-Tetraphenyldipyranylidene 3,30,4,40-Tetrathiabis(1,2,5-thiadiazole) twin-BEDT ± TTF (20) CS2 without solvent CS2 CTV (21) BTX (22) DAN (23) C6H5Me CS2 C6H6 Bis(ethylenedithiotetrathiafulvaleno)[b,h]- 1,4,7,10-tetrathiacyclododeca-2,8-diene Cyclotriveratrylene 9,90-trans-Bi(telluraxanthenyl) (9,10,90,100)-Bi(9,10-dihydroanthrylene) (dianthracene) 2,3,6,7,10,11-Hexamethoxytriphenylene HMT (24) SbPh3 Au(PPh3)Cl Hydroquinone without solvent the same "" 23 (DAN) cules.101, 105, 111 The donor-acceptor interaction of tetrathiafulva- lene molecules with C60 occurs both by the n ± p type (the n-orbitals of the sulfur atom of the central E4C2 donor fragment are directed to the centre of the six-membered ring of one C60 molecule) and by the p ± p type (the central E4C2 donor fragment is almost parallel to the six-membered ring of the other C60 molecule).98, 105 The distance between heteroatoms of the donor and atoms of the C60 molecule is somewhat shorter than the sum of the van der Waals radii of the corresponding heteroatoms and carbon atoms.98 ± 107 Syntheses of tetrathiafulvalene complexes with halogenated fullerenes have been described. As halogenated fullerenes are stronger acceptors than the C60 fullerene, the oxidation of tetrathiafulvalenes with the formation of radical cationic salts is possible.33, 119 In addition to compounds of fullerenes with tetrachalcogena- fulvalene derivatives, compounds with donor molecules of other classes (Table 3) have also been obtained.S S N N O O S S N N S S 19 (twin-TDAS) 18 (TPDP) The molecules of compounds 21 (CTV),114 22 (BTX) 54, 111 and 23 (DAN)44 have three-dimensional shapes (BTX and DAN, of the `double butterfly' type, and CTV, of the hemisphere type). The structures of these molecules match well the spherical surface of the C60 molecule, which forms molecular complexes with them owing to numerous van der Waals contacts. DAN has a unique ability to undergo cocrystallisation with C60 almost quantitatively even from dilute solutions in benzene; this can be utilised for the isolation of C60 from various mixtures.44 The C70 fullerene matches less the spatial shape of such molecules as CTV and DAN and does not form complexes with these donors.44, 114 However, it forms complexes with composition 1 : 1 : 0.5 with BTX and CS2.119 Isolated packing of C60 molecules is character- istic of complexes with other donors, such as HMT,115 SbPh3,116 Au(PPh3)Cl 117 and hydroquinone118 (see Table 3).S S S S S S S S All of the complexes described above are dielectrics with a conductivity of*1076 S cm71 and less.5, 100, 103, 104 S S S S S S S 5. Composites of conducting polymers with the C60 fullerene S 20 (twin-BEDT ± TTF) MeO OMe Te MeO OMe The discovery of the photoinduced charge transfer in polyvinyl- carbazole ±C60 composites 17 stimulated the intense development of studies in this field.Composites with a dozen of different polymers have been studied by now.120 Films of polymer ±C60 composites are prepared by concentration of solutions of a polymer and a small amount of a fullerene (from 1% to 3% of the polymer weight) in aromatic hydrocarbons on a sub- strate.17, 120 ± 122 Te MeO 22 (BTX) OMe 21 (CTV) Only weak charge transfer from the polymer to the fullerene is observed in these composites in the ground state.121,122 For tration of C60 ¡ . (2.361018 spins g71) was detected in a composite example, an ESR signal corresponding to an insignificant concen- polyvinylpyrrolidone ±C60.122 The polymer photoexcitation occurs at energies higher than the difference between the HOMO and LUMO levels of the polymer.This is accompanied by fast transfer of an electron Donor : fullerene : solvent ratio 1 : 2 : 4 4 : 3 1 : 1 : 1 1 : 3 : 1 1 : 1 : 1 1 : 1 : 3 2 : 1 6 : 1 2 : 1 3 : 1 MeO MeO D V Konarev, R N Lyubovskaya Ref. Structural type 43, 109 113 layered cage 110 chain 114 54, 111 44 island "layered 115 island 116 117 118 """ OMeOMe OMe MeO24 (HMT)Donor-acceptor complexes and radical ionic salts based on fullerenes (<10712 s) from the photoexcited polymer molecule to the C60 molecule with formation of a complex (polymer+) ±C¡60. in excited state.Transition to the state with free separate charge carriers is now possible from this state.121 Charge separation in the excited state of CTC results in the generation of charge carriers and a strong increase in the photoconductivity of the polymer.121 The involvement of a fullerene in efficient charge separation in these composites is reduced to two factors. On the one hand, as an acceptor, the fullerene accepts electrons occupying the LUMO of the polymer upon photoexcitation with formation of vacancies (`holes') on the polymer. On the other hand, the recombination of photoexcited electrons and `holes' is considerably inhibited due to their spatial separation upon delocalisation of charges on the bulky fullerene molecule.121 As the rate of electron transfer is high and the rate of carrier recombination is relatively low, the quantum yield of formation of charge carriers increases consid- erably in the presence of a fullerene.121, 122 The possibility of using these composites in xerography, in solar energy phototransducers and in other devices is being studied.120, 121 6.Complexes and radical ionic salts of fullerenes with amines. Magnetic properties of the (TDAE)C60 salt 60. at 1070 nm in the complicates the study of these compounds and results in signifi- cant differences in the estimation of their magnetic properties. The compound (TDAE)C60 has been studied by IR,133 The detection of ferromagnetic transition with the highest temper- ature known for organic materials (Table 4) 15 in the salt formed by the C60 fullerene and tetrakis(dimethylamino)ethylene (25) (TDAE)C60 has stimulated strong interest in compounds of C60 with amines.Polycrystalline specimens of fullerene compounds with amines are obtained by precipitation of a fullerene solution in toluene with an excess of amine.15, 123 ± 128 Single crystals of (TDAE)C60 have been obtained by mutual diffusion of solutions of tetrakis(dimethylamino)ethylene 25 and C60 in toluene.45, 46 Other unsaturated amines, e.g., 26 and 27, react with fullerenes to give radical anionic salts having unusual magnetic properties (see Table 4).123 ± 128 Saturated amines, such as N,N,N0,N0-tetramethyl-p-phenyl- enediamine (TMPD) or triphenylamine (TPA) (see Table 4), possess weaker donor properties than the amine 25, and form only weak charge-transfer complexes.76, 77, 129 These compounds are obtained by concentrating solutions of fullerenes in chloro- benzene with a large excess of the donor (100 : 1).The existence of charge transfer in compounds of C60 with TMPD is confirmed by the presence of an absorption band of C¡ optical spectrum and a shift of the absorption band of the T1u(4) vibration of C60, which is sensitive to charge transfer onto the fullerene molecule, in the IR spectrum.76 Table 4. Donor-acceptor complexes and radical ionic salts of C60 with amines. Abbreviation Donor D:C60 ratio 1 : 1 Tetrakis(dimethylamino)ethylene Tetrakis(pyrrolidino)ethylene TDAE (25) TPYE (26) 1 : 1 TMBI (27) 2,2-Bi(1,3-dimethylimidazolidin-2-ylidene) 2,20-Bi(1,3-dimethylhexahydropyrimidin-2-yl) TMBH (28) 1,5-Diazabicyclo[4.3.0]non-5-ene 1,8-Diazabicyclo[5.4.0]undec-7-ene 72 : 1 2 : 1 DBN (29) DBU (30) 1 : 1 1 : 1 N,N,N0,N0-Tetramethyl-p-phenylenediamine TMPD TPA Triphenylamine 3 : 1 DAP 1,5-Diaminopentane a Number of spins per formula unit determined by ESR; b addition of amine to fullerene is possible.25 N N Me N Me N Me2N NMe2 N N NMe2 Me2N NMe Me N 27 26 25 Me N Me N N N N N Me N Me N 30 29 28 Amines with sterically unhindered nitrogen atoms add to fullerenes.132 Some amines with strong donor properties, such as 27, 29 or 30, reduce fullerene and add to it. The reaction of C60 with these amines in solution 123, 127, 128 can occur in two steps: k2 k1 Am+[C60] [Am+] [C 60 ¡ .] salt [Am+C60 ¡ . ] zwitter-ion Am is an amine. If the first reaction step is sufficiently fast (k1 is high) and the resulting salt is poorly soluble in the solvent (as in the case of TDAE), the reaction stops in the first step, and the salts [Am+][C ¡60.] can be isolated. If k1 is small and the formation of salts occurs slowly (as in the case of amines 29, and, especially, 27 and 30), and the resulting salts are rather soluble in the solvent, the amine adds to C60 in this stage to give diamagnetic zwitter- ions.123, 127, 128 These reactions are accompanied by recombina- tion of radicals, which results in a gradual decrease in the signal of the radical anionC¡60.. The addition products that are precipitated from the solution contain a small amount of the radical anion C60 ¡ .[4% and 2% for (DBU)C60 and (TMBI)C60, respec- tively 123, 128]. Fullerene mixed addition and reduction products are perhaps formed in the reaction. If the salt is rapidly precipi- tated from benzene, the addition cannot go to completion. In this case, the reaction product, viz., (DBN)C60, contains a large percentage of reduced C¡60. (14%) and manifests strong magnetic fluctuations down to 80 K.127 The addition of amines to C60 Raman,134 ESR,135 ± 137 NMR138 and X-ray photoelectron 139 spectroscopies. The temperature of ferromagnetic transition in (TDAE)C60 is 16.1 K. It has been shown39, 43, 135 that the onset of Ref.Magnetic properties Compound Sa type 1 15 125 salt 7 0.02 123 124 126 127 128 CTC see note b 7CTCb CTCb 0.14 0.04 ferromagnetic (Tc=16.1 K) superposition of paramagnetic and ferromagnetic phases weak paramagnetic ferromagnetic (Tc<140 K) antiferromagnetic weak antiferromagnetic only near magnetic order observed 77 76, 129 77 130, 131 CTC molecular complex 7 726 the ferromagnetic state in (TDAE)C60 specimens requires that they were kept for several days at 20 ± 100 8C (constant temper- ature). Without this procedure, the (TDAE)C60 specimens man- ifest only antiferromagnetic properties.39, 43, 135 Several mechanisms for the origin of the ferromagnetic state in (TDAE)C60 have been discussed.38, 140, 141 It has been shown by ESR137, 142 that in (TDAE)C60 complete charge transfer from the donor to the fullerene occurs.It was assumed that ferromagnetism is due to the presence of the radical anion C¡60.. However, other temperature.39,138 salts with the radical anion C60 ¡ . do not manifest any ferromag- netism.38, 141 It was suggested 38, 39 that ferromagnetism in (TDAE)C60 is also determined by the presence of the radical cation TDAE+.. The ESR spectrum of (TDAE)C60 contains only one line with g=2.0008, which is an average value between those for TDAE+. (g=2.0035) and C60 ¡ . (g=1.9960).38, 142 This is probably due to sphere, as is the case in C¡60. (see Ref.143). the strong exchange interaction between TDAE+. and C¡60. . The C60 molecules in crystalline (TDAE)C60 are packed in one- dimensional chains along the crystallographic axis c 7with short- ened distances between the centres (9.98 A)15, 45 (Fig. 2). The presence of shortened contacts between the C60 molecules allows the slowing down of the rotation of these molecules on cooling, with transition to synchronised ratchet rotation, as in crystals of pure C60 cooled below 90 K. In fact, the rotation of the C60 fullerene molecules in (TDAE)C60 slows down at temperatures below 150 K, as confirmed by broadening of the 13C NMR signal.38, 138 According to theoretical calculations, the negative charge of the radical anion C60 ¡ . is mostly concentrated in the by slowing down of the rotation of C60 molecules in this salt.45 equatorial area of the fullerene sphere.Because of this, long-range magnetic order can be formed in this salt upon transition to synchronised rotation of C60 molecules.38, 39 In this case, the spins of C60 ¡ . in the fullerene chain along the crystallographic axis c 7are superconducting phase with Tc=17.4 K may be present in Measurements on a SQUID magnetometer have shown that a ordered antiferromagnetically. The antiferromagnetic interaction can be transferred between the fullerene chains through the radical cation TDAE+. (see Refs 38 and 39). a 1 C60 C60 C60 c TDAE TDAE 2 C60 C60 C60 TDAE TDAE C60 C60 C60 Figure 2. Scheme for formation of ferromagnetic order in the salt (TDAE)C60 by the spin polarisation mechanism;38, 39 (1) is ferromagnetic interaction; (2) is antiferromagnetic interaction. According to theory,39 distortion of the radical cation TDAE+.may result in inhomogeneous spin density distribution on TDAE+. (Fig. 2). In fact, after keeping of the salt (TDAE)C60 at constant temperature,39 the 1H NMR spectrum displays two sets of lines (A and B) from the methyl groups of TDAE+. (see Ref. 138). This implies an asymmetrical spin density distribution in the radical cation TDAE+. . Asymmetrical spin density distribution results in violation of the antiferromagnetic order of the C¡60. spins (Fig. 2) and the onset of ferromagnetic transition highly symmetrical cationic environment. The phenyl substituents D V Konarev, R N Lyubovskaya below 16.1 K.Ferromagnetic ordering of the C¡60. spins is observed in the plane ab normal to the crystallographic axis c 7 (Fig. 2). Compound (TDAE)C60 manifests only antiferromagnetic properties without preliminary keeping at constant temperature. In this case, the spin density is uniformly distributed on TDAE+. , and the intensity ratio of linesAand B in the 1HNMRspectrum of (TDAE)C60 differs from that of the specimens kept at constant No ferromagnetic properties have been found for compounds of TDAE with higher fullerenes (C70±C96). This is apparently due to differences in the electronic structures of C¡60. and radical anions of higher fullerenes, as the negative charge in the mono- anions of higher fullerenes was found to be delocalised over the entire anion surface rather than in the equatorial area of the The conducting properties of some compounds of fullerenes with amines have been studied.45, 46, 123 The antiferromagnetic phase of the salt (TDAE)C60 displays semiconductor properties with a conductivity of about 1075 S cm71 and an activation energy (Ea) of 0.4 ± 0.8 eV.46 The conductivity of the ferromag- netic phase of (TDAE)C60 at room temperature is of the same order of magnitude (561075 S cm71).It is also of activated character and is due to tunnelling of electrons between the fullerene molecules. Electron transfer is largely affected by the rotation of fullerene molecules; for this reason, the decrease in the activation energy at 150 K from 0.3 to 0.14 eV is explained It was shown123 that the conductivity of (TMBI)C60 is 561074 S cm71.(TDAE)C60.16 The volume of the superconducting phase increases if the sample is cooled very slowly at *150 K, which temperature corresponds to the transition to hindered and synchronised rotation of the C60 molecules. 7. Complexes and radical ionic salts of C60 with metallocenes Table 5 lists the compounds of C60 with metallocenes. The donor properties of metallocenes vary over a wide range, and they can form compounds with different degrees of charge transfer with fullerenes (from molecular complexes to radical ionic salts containing C60 3¡.).50, 151 The cyclopentadienyl rings of metallo- cenes coordinated with fullerenes are parallel to the five-mem- bered fullerene rings.For example, the deviation from this plane in the structure [(C5Me5)2Ni]C60(CS2) is only 0.3 8 (see Ref. 149). Such a coordination ensures the maximum overlapping of the metallocene and fullerene p-orbitals and efficient charge transfer. Two types of structures are characteristic of compounds of metallocenes with fullerenes. In compounds of C60 with ferrocene and cobaltocene, dense layers of fullerene molecules alternate with layers of the metallocene molecules.47, 145 The layers of the fullerene molecules in compounds with substituted metallocenes are looser and also alternate with the layers of the donor.149 The physical properties of these compounds are little studied.It is known that the ESR spectra of compounds of C60 with nickelo- cene and decamethylferrocene contain a signal corresponding to C¡60. (see Ref. 147). The complexes [(C5H5)2Ni]C60 and [(C5H5)2Co]C60 display magnetic properties with an S-shaped magnetisation curve which has a hysteresis. However, these properties disappear on exposure of the specimens to air,140 which indicates that the radical anions C¡60. in these complexes are sensitive to oxygen. It has been shown that the conductivity of [(C5Me5)2Ni]C60(CS2) is rather high (1072 S cm71).149 8. Fullerene salts with bulky cations Radical anionic salts of C60 ¡ . and C¡70. with bulky cations, such as Ph4P+, PPN+ and others,56 ± 58, 152 ± 154 are stable in air (Table 6).Each radical anion of C60 in these ionic compounds is located in aDonor-acceptor complexes and radical ionic salts based on fullerenes Table 5. Compounds of C60 fullerene with metallocenes. Donor (C5H5)4Fe4(CO)4 (C5H5)2Fe (C5Me5)2Fe Biferrocenyl (C5H5)2Ni (C5Me5)2Mn (C5Me5)2Ni (C5H5)2Co (C6H6)2Cr (C5Me5)2Co (C5H5)(C6Me6)Fe a The compound gives a signal corresponding to C60 7. in ESR spectra; b the compound gives an S-shaped magnetisation curve with hysteresis.147 Table 6. Salts of fullerenes with bulky cations. Cation Ph4P+ Ph4As+ PPN+ (5) Ru(biPy)2á 3 of the cations are drawn together to the six-membered rings of the fullerene in such a manner that the phenyl groups surround completely the C¡ fullerene molecule is surrounded by 22 phenyl groups of the cations, which efficiently shield the charge of the C2¡ 60 anion.According to X-ray diffraction data, there are no shortened distances between the fullerene anions in the crystal; the shortest distance between the centres of fullerene molecules is *12.5 A.152, 153, 155 A study of the magnetic susceptibility of these salts 49 showed that they are paramagnetic.49, 50 Apparently, the bulky cations surrounding the C60 fullerene radical anions interfere with their magnetic interaction. The magnetic susceptibility is determined by the spin ground state of fullerene radical anions. The magnetic moment of salts containing the C¡60. and C360¡ anions is 1.8 mB at room temperature, which corresponds to the singlet ground state with S=1/2.At low temperatures, the magnetic susceptibility in C60 ¡ . salts decreases because of the weak antiferromagnetic a. Conducting properties of fullerene salts. Superconductivity interaction between the neighbouring fullerene molecules. The magnetic moment of C2¡ be 2.5 mB.49, 50 A study of the conductivity of these salts showed that all of them are semiconductors. The conductivity of the salt [Ru(bipy)3](C60)2 (Table 6) is 1072 S cm71, and this salt is a semiconductor with an activation energy of 0.15 eV.59 It has been shown56,153 that the conductivity of the salts of C60 ¡ . with the the degree of reduction x=1, the saltsM.C60 can display metallic strongly depending on the degree of the fullerene reduction.At Ph4P+ cation is from 1077 to 1074 S cm71. The low conductivity is apparently due to the large distances between the fullerene anions in these compounds.Solvent D:C60 : Sol ratio 1 : 1 : 0.3 C6H6 2 : 1 2 : 1 0.8 : 1 : 0.7 without solvent the same MeCN 1 : 1 1 : 2 1 : 1 : 1 1 : 1 : 1 1 : 1 : 1 1 : 1 1 : 1 : 1 without solvent the same CS2 PhCN CS2 without solvent PhCN Charge on the fullerene Composition (Ph4P)C60(Ph4PCl) (Ph4P)C60(Ph4PCl)2 (Ph4P)2C60(Ph4PBr) (Ph4P)2C60Ix (0<x<1) (Ph4P)C70(Ph4PI) 71 71 71 71 71 (Ph4As)C60(Ph4AsCl) 71 (PPN)C60(C6H5Cl) (PPN)2C60 (PPN)2C60(PPNCl)MeCN (PPN)3C60(MeCN)2 71 72 72 73 [Ru(biPy)3](C60)2 71 60.radical anion. In the salt C60(PPN)2,155 one to use them for the reduction of fullerenes. For example, The redox properties of metalloporphyrins also make it possible 60 . salts at room temperature was found to levels, which can be populated with up to six electrons.25, 36 Reduction of fullerene results in the population of the t1u energy 27 Ref. Magnetic properties Compound type 144 77 molecular complex the same CTCa, b CTC 145 146 147 superposition of paramagnetic and ferromagnetic phases displays magnetic properties b CTCa, b CTC CTCa s=1072 S cm71 displays magnetic properties b the same CTCa, b CTC salt Cn¡ 60 (n=1, 2, 3) 146 148 149 48 47 150 50 151 salt Cn¡ 60 (n=1, 2, 3) Ref. Method of synthesis 57 56 152 153 154 electrocrystallisation """" 152 " 48 50, 155 49 49 "diffusion cationic metathesis the same 59 electrocrystallisation 9.Salts of the C60 fullerene with metalloporphyrins compound Cr(II)(TPP), where TPP is tetraphenylporphyrin, has strong donor properties (EOx=70.86 V)156 and reduces full- erene in tetrahydrofuran to C¡60. to give the [Cr(TPP)]C60(THF)3 salt.156 The reaction is reversible; the addition of toluene shifts the equilibrium towards the formation of neutralC60. In pure toluene, the reduction of C60 does not occur. The [Cr(TPP)]C60(THF)3 salt is a paramagnetic with S=1/2.156 The Sn(I)(TpTP) complex, where TpTP is tetra-p-tolylpor- phyrin (EOx=71.17 V), in the presence of N-methylimidazole (N-MeIm) forms a salt with C60 with composition [Sn(TpTP)](N- MeIm)2(C60)2.N-Methylimidazole stabilises the Sn(TpTP)2+ cation and hence facilitates the formation of the complex.48 10. Metal salts of fullerenes Therefore, the compounds obtained can display conducting and superconducting properties if the degree of reduction x of the C60 fullerene ranges from 0 to 6.13, 14, 25 The character of conductivity in the salts Mx .C60 varies conductivity.61, 157 ± 159 The compounds M3C60 have higher conductivity (e.g., the conductivity of K3C60 at room temperature was shown to be28 2.561073 S cm71) than the compounds MxC60 with different stoichiometry. At low temperatures, the salts M3C60 display metallic conductivity and can pass into the superconducting state.The density of energy states at the Fermi level N(EF) (number of states eV71) is an important parameter determining the super- conductivity transition temperature (Tc). Because of the small overlapping of the p-molecular orbitals of the neighbouring C60 molecules in the compounds M3C60, the conduction band is half occupied and has a width of 0.2 ± 0.3 eV. At a small band width, the density of states at the Fermi level is rather high (25 states eV71 for K3C60 and 35 states eV71 for Rb3C60, see Ref. 25). It is this fact that explains higher Tc values in fullerene salts with alkali metals in comparison with other known organic superconduc- tors.10 In the compounds M3C60 with face-centred cubic (FCC) lattice, an increase in the size of the alkali metal atom results in an increase in the distance (d) between the fullerene molecules in the crystal cell and a linear increase in Tc.The explanation for the latter phenomenon is that the increase in d(C607C60) in M3C60 decreases the overlapping of the p-molecular orbitals of the neighbouring fullerene molecules and, accordingly, the width of the conduction band. The narrowing of the conduction band increases the density of states at the Fermi level (as the number of states at the Fermi level does not depend on the band width and is constant) and increases the temperature of superconductivity transition (Tc).13, 14, 28 However, if the distance between the centres of fullerene molecules in the crystal cell is more than 10.3 A, the compound becomes a Mott dielectric.161 It was found that theM2C60 andM4C60 salts, in which the C60 molecule accepts two or four electrons, display only semiconduc- tor properties with an activation energy of about 0.5 eV.160 The significant difference of these phases from the M3C60 phase may be due to a decrease in the symmetry of the fullerene molecule in these compounds.Partial removal of the degeneracy of the t1u orbital and splitting of the conduction band into two bands (completely filled and vacant) with an energy difference between them of*0.5 eV occurs inM2C60 andM4C60.160 At x=6, the conduction band is filled completely, andM6C60 compounds are dielectrics.13 If more than six electrons are introduced in a C60 molecule, filling of the t1g level starts; this level can accept six electrons. Therefore, metallic conductivity is displayed again and transition to the superconducting condition is possible at a degree of reduction of fullerenes, x, in C60 compounds from 6 to 12.13, 18 The conductivity of C70 fullerene salts is little studied.Calculations show that MxC70 phases, where M is an alkali metal and x=4, can have metallic conductivity, while at x=1.8 they can be semiconductors. For example, the K4C70 phase actually has metallic conductivity but is not a superconductor down to 1.35 K.13 b. Intercalation of fullerenes The crystals of the C60 fullerene have a densely packed FCC lattice 37 with relatively weak intermolecular bonds between separate molecules. This lattice contains two tetrahedral and one octahedral cavities per molecule with radii 1.10 A and 2.06 A, respectively, hence fullerene is a convenient object for intercala- tion.If the cavities are completely filled with the metal atoms, the composition of the compounds obtained has the formula M3C60. As the dopant size or the number of its atoms are increased (to n=6), the densely packed FCC-lattice is transformed to a less dense volume-centred cubic (VCC) lattice with six equivalent tetrahedral cavities per C60 molecule.13, 14, 28 Diverse methods for the intercalation of fullerenes have been developed. In the most popular procedure for the synthesis of MxC60 compounds, a fullerene and x equivalents of an alkali metal are placed in a quartz tube evacuated to 1072 ± 1075 Torr, which is then sealed and heated at 200 ± 500 8C.162 The intercala- tion of the C60 fullerene with alkali metal hydrides, borohydrides and azides and other reagents has also been described.13, 14 D V Konarev, R N Lyubovskaya The gas-phase intercalation of the C60 fullerene suffers certain drawbacks.In this case, it is difficult to control the degree of reduction of the fullerene; the formation of a mixture of MxC60 phases with different content of the metal is possible (for example, M3C60 contains the M6C60 phase, which is a dielectric). An inevitable heterogeneity of the specimens formed complicates the study of the crystal and electronic structure of these materials.with C60 ¡ . and C360¡. radical anions in solutions.153, 154 Single crystals of these compounds are obtained by syntheses Refluxing a fullerene solution with a 90-fold excess ofKor Rb in toluene results in a precipitate containing 1% of a super- conducting K3C60 phase and 7% of a superconducting Rb3C60 phase.163 The addition of 5%± 30% of benzonitrile to toluene favours the electron transfer from the alkali metal to the fullerene and interferes with the precipitation of intermediate compounds with the C60 ¡ . and C260¡. anions, which allows one to obtain specimens with high content (up to *50%) of the superconduct- ing M3C60 phase. Reduction of fullerene with an alkali metal in pure benzonitrile results inMxC60 compounds, where x=4, 5 and 6.162 A drawback of the method is the presence of an unconsumed alkali metal among the reaction products. Heating and stirring of a suspension of fullerene in Cu, Zn) resulted in the corresponding salts of C60 ¡ .and C260¡. . The N-methylimidazole with a high excess of a metal (Li, Na, Ba, Fe, and compounds have the formulas: [M(N-MeIm)x]C60 [M(N-MeIm)x]2C60, where x=4 ± 6.148 A series of compounds MxC60(THF)y, where x=0.4 ± 3 and y=1 ± 14, have been obtained by the reaction of C60 with alkali metals in THF in the presence of 1-methylnaphthalene,55 by cooling a C60 solution reduced with potassium in tetramethyle- thylenediamine 55 or by the reaction of C60 with K[Mn(C5Me5)2] in THF.164 Salts with small x (*0.4) and y (*2.2) values have been obtained by electrochemical reduction of fullerene in the presence of an alkali metal tetraphenylborate.61 60 .in the structure of K3C60(THF)14 are packed The anions C3¡ in linear chains;53 one of the K+ ions is coordinated with a five- membered ring of C60 and serves as a bridge between two fullerene radical anions. The other two K+ cations are located above and below the C3¡ 60 . anion, forming contacts with six-membered rings of C60. TheK+ cations are also coordinated with THF molecules. Judging by the arrangement pattern of the C3¡ 60 . anions, the structure of K3C60(THF)14 is similar to that of M3C60 super- conductors with an FCC lattice. However, the distance between theC3¡ 60 .ions is large, and this compound does not display metallic properties.53 A compound with a different stoichiometry, viz., MxC60(THF)y, where x*0.4 and y*2.2, has a conductivity of 50 S cm71 at room temperature, which increases with a decrease in temperature and is about 1000 S cm71 at 100 K. This is probably due to incomplete charge transfer to the fullerene (d=0.4) and the presence of small distances between C60 molecule centres along the crystallographic axis c (9.93 A) in the crystal.61 After removal of tetrahydrofuran from the salt K3C60(THF)7 by evacuation, keeping at constant temperature at 300 8C for 12 h and subsequent cooling to 103 8C, heat evolution in the sample is observed, which is explained by a transition to a more stable phase with an FCC lattice.As a result, the sample becomes a super- conductor containing 31% of the superconducting K3C60 phase.164 c. Fullerene polymerisation in MC60 andM3C60 salts The intercalation of C60 fullerene with alkali metals in stoichio- metric ratio (1 : 1) gave the radical anionic salts KC60, RbC60 and CsC60.157 ± 159 On slow cooling of the intercalation products, [2+2]-cycloaddition of the neighbouring fullerene molecules occurs, which results in the polymerisation of C¡60. into linear chains. The distance between the centres of fullerene molecules decreases to 9.11 ± 9.13 A.157 Polymeric compounds are stable in air,157 insoluble in tetrahydrofuran and depolymerise only on heating above 320 8C. A study of the conductivity of the resultingDonor-acceptor complexes and radical ionic salts based on fullerenes polymeric specimens showed that [KC60]n is a three-dimensional metal the conductivity of which slowly increases on decreasing the temperature to 4 K.158 Magnetic measurements also show159 that [KC60]n behaves as a three-dimensional metal down to liquid- helium temperatures.Unlike [KC60]n, the [RbC60]n and [CsC60]n polymers are one-dimensional metals and pass to the dielectric state at 50 K and 40 K, respectively. At 25 K, the [RbC60]n and [CsC60]n polymers undergo magnetic transition with antiferro- magnetic ordering of spins in the polymeric chain. The interaction between antiferromagnetic polymeric chains occurs through alkali metal atoms, which results in three-dimensional magnetic ordering of spins.159 The nature of conductivity in these compounds is not clear yet.It is possible that polymerisation of fullerenes results in p-conjugated bonds between the molecules and the conduction electrons can move through them along the fullerene chain. Another possible mechanism assumes that the carbon atoms that are not bound directly and correspond to the neighbouring fullerene skeletons approach each other with overlapping of the t1u orbitals of these skeletons, and the conduction electrons move through these orbitals.13 The second variant is more likely, as it has been shown158 that the decrease in the ionic radius of the metal on going from rubidium to potassium results in overlapping of the t1u orbitals of fullerenes belonging to different polymeric chains and to a change from one-dimensional to three-dimensional conductivity.If C60 doped by alkali metals is rapidly cooled by liquid nitrogen, polymerisation cannot occur and monomeric radical anionic salts are obtained, such as KC60, RbC60 and CsC60.157 Heating of monomeric KC60 above 77 K, or RbC60 and CsC60 above 160 K, results in dimerisation; the dimeric phaseK2(C60)2 is a dielectric.157 It has been shown that the radical anion C360¡. in compounds state is observed at different populations of the conduction band, M3C60 can polymerise as well.165 Na2CsC60 polymerises with transition to an orthorhombic phase at a pressure of 3 kbar; the resulting polymer maintains superconducting properties.165 d.Superconducting compounds of C60 To date, about thirty superconductors have been obtained based on C60. Their superconducting transition temperatures range within 2 ± 40 K (Fig. 3). Compounds with compositionM3C60, whereM=K, Rb or a combination of K, Rb and Cs, with an FCC lattice (Fig. 3, 1) have been studied in most detail.12 ± 14, 28 It was found for this series of compounds that Tc increases linearly with the size of the alkali metal atom and the distance between the centres of fullerene molecules, d(C607C60), in the crystal cell.13, 14, 28, 166 An increase in Tc is also observed in the reaction of the M3C60 salts with ammonia. For example, the intercalation of Na2CsC60 with Tc /K 5 40 metal 1 Mott dielectric 20 semiconductor dielectric 2 superconductor 3 4 0 10.5 10.3 9.7 d /A 10.1 9.9 Figure 3.Phase diagram for the salts M3C60. Dependence of Tc on the closest distance (d) between the centres of C60 molecules in crystalline state at room temperature:14 (1), experimental data for M3C60 (K3C60, K2RbC60, K2CsC60, KRb2C60, Rb3C60, Rb2CsC60 and RbCs2C60) with FCC lattice; (2), experimental data for the series Na2(RbxCs17x)C60 with simple cubic lattice; (3), Li2RbC60; (4), Li2CsC60; (5), Cs3C60 with A15 structure, which has superconductor properties under 15 kbar. 29 ammonia results in (NH3)4Na2CsC60 with a similar crystal lattice, while the distance between the C3¡ 60 . radical anions increases from 9.99 A to 10.23 A.This is accompanied by an increase in Tc from 10.5 K in Na2CsC60 to 29.6 K in (NH3)4Na2CsC60.166 However, it was found160 that the com- pound Cs3C60 with the A15-type structure and distances between the fullerenes molecule *10.35 A is the Mott dielectric and becomes a superconductor with Tc=40 K only at a pressure of 15 kbar.160 The salts MxC60 have the highest temperature of supercon- ductivity transition for x=3.28 If the stoichiometry deviates from this value in either direction, Tc starts to decrease, and at x42 and x54 the compounds no longer pass into the superconducting state. On transition from one crystal lattice type to the other, the character of interaction between the neighbouring fullerene molecules changes.Therefore, the compounds Na2MC60, where M=K, Rb and Cs, with simple cubic lattice have a different dependence of Tc on the distance between the fullerene molecules than the compoundsM3C60 with FCC lattice. A minor increase in this distance in compounds with a simple cubic lattice strongly increases the Tc (Fig. 3, 2).14 A weak covalent interaction Li7C in compounds Li2MC60 (Fig. 3, 3, 4) changes their electronic structure, and these com- pounds do not display superconducting properties.14 A group of superconductors AxC60 obtained by intercalation of C60 with alkaline-earth metals, i.e., Ca, Sr and Ba, is of interest.13, 18 Unlike M3C60 (M=K, Rb, Cs), in which the population of the t1u orbital occurs, the superconductivity in these compounds is due to the population of the t1g orbital.The Tc of compounds AxC60 ranges within 4 ± 8.5 Kand depends little on the distance between the fullerene ions.13 The superconducting but it is rather difficult to determine the exact extent of charge transfer (d) to the fullerene. In the series of compounds CaxC60 with x=3 ± 6, Ca5C60 has the maximum conductivity (the degree of charge transfer to C60 d equals 10) and passes in the super- conducting state at 8.4 K.13, 18 The compounds Ca3C60 (d=6) and Ca6C60 (d=12) (the conduction band is completely popu- lated) do not display metallic properties.13, 18 As opposed to Ca3C60 and Ca6C60, a weak covalent interaction of Ba and Sr with fullerene in Ba3C60, Ba6C60, Sr3C60 and Sr6C60 is possible because of the larger ionic radii of these metals.This results in a decrease in the actual charge transfer to the fullerene and in only partial population of the conduction band at x=3 and x=6.18 Therefore, Ba3C60 and Sr3C60 display metallic properties, and Ba4C60, Sr6C60 and Ba6C60 have superconducting properties at Tc=4, 7 and 4 K, respectively.13, 18 It has been shown166 that C60 fullerene intercalated with lanthanides can also be a superconductor (for example, Yb2.75C60 has Tc=6 K). e. Intercalation of molecular complexes of C60 with alkali metals Structural diversity of organic molecules allows one to create C60 compounds with different packing of the C60 molecules in the crystal, viz., one-dimensional chains, two-dimensional layers or three-dimensional arrangement of the C60 molecules.Fullerene compounds with one-dimensional and two-dimensional packing of the C60 molecules are of special interest for the study of conducting and superconducting properties. In addition, by using different donor molecules, it is possible to control the distance between the fullerene molecules in the crystal lattice in order to obtain materials with high Tc. This stimulated studies of the intercalation of C60 complexes with alkali metals. The intercalation of molecular complexes of C60 is accompanied by reduction of the fullerene according to the scheme: Red D(C n¡ 60 n Red+)Sol Dd+Cd¡ 60 Sol Red is reducing agent.30 The intercalation of C60 complexes with octamethylenetetra- thiafulvalene (10) (OM± TTF)C60(C6H6) or bis(ethylenedioxy)- tetrathiafulvalene [(BEDO ± TTF)*C60] with potassium and rubidium is carried out at 1074 ± 1075 Torr and 55 and 67 8C, respectively, as in the case of pure C60.168, 169 The intercalation of (OM± TTF)C60(C6H6) gave compounds with composition Kx(OM± TTF)C60(C6H6), where x41:8.Apparently, the sol- vent is retained in the compound.168 Because of their small radii, the alkali metal atoms occupy the cavities in the structure of the starting molecular complex; this increases somewhat the param- eters of its crystal cell.169 The intercalation of (OM± TTF)C60(C6H6) with potassium gives a superconducting phase with a transition temperature of 17 ± 18.8 K, and that with rubidium gives a superconducting phase with Tc=23 ± 26 K.The intercalation of [(BEDO ± TTF)*C60] with potassium yields a superconducting phase with Tc=15 K.168, 169 f. Intercalation of fullerenes and their complexes with halogens The intercalation of fullerenes with molecular iodine (I2) and interhalides, viz., IBr and ICl, gives the complexes (Hal2)xC60. The reaction is carried out at 100 ± 250 8C in evacuated tubes.40, 170, 171 The content (x) of the halogen in the sample can vary from 0.2 to 2,170 ± 172 depending on the conditions and duration of intercala- tion. A study of the structure of the (I2)2C60 complex has shown that it has a layered structure; the C7I distances (3.6 ± 4.0 A) are smaller than the sum of the van der Waals radii of carbon and iodine.170 There is no charge transfer from the fullerene to iodine in these compounds.Iodine is weakly bound to the fullerene and is removed from the compound at 200 8C.170 (I2)2C60 is a dielectric the conductivity of which is less than 1079 S cm71 (Ref. 170). A study of the magnetic properties of C60 complexes obtained by intercalation of fullerene with I2, ICl and IBr revealed magnetic transitions 40, 171 at 60 K, 30 K and 30 K, respectively. For pure C60 and C70 fullerenes, these are also are observed at 60 K.38 Apparently, these magnetic transitions, like those in the case of pure fullerenes, are due to transition of the specimens to the frozen glassy magnetic state,38 because synchronisation of rotation of the C60 molecules is also possible in the presence of shortened contacts between the C60 molecules in the crystals of these molecular complexes at low temperatures.Cooling of these specimens in a magnetic field below this temperature results in freezing of a completely ordered orientation of the magnetic moments of the fullerene molecules. The intercalation of the complexes (DB ± TTF)C60(C6H6), (TMDTDM± TTF)2C60(CS2)3 and TPDP(C60)2(CS2)4 with iodine results in compounds with a high content of iodine, viz., (DB ± TTF)C60I9, (TMDTDM± TTF)2C60I7.5 and TPDP. .(C60)2I10 .173, 174 The intercalation of C60 complexes with iodine is based on the solid-phase oxidation of the donor component of these complexes with the formation of a radical cation. The solvent, for example, CS2, is displaced by iodine.174 Ox (D n+ n Ox7)C60 Dd+Cd¡ 60 Sol Ox is oxidant.The intercalation is accompanied by noticeable changes in the ESR spectra due to the oxidation of the donor.173 The optical absorption spectra display a shift (up to 10 nm) of the absorption bands of the basic electron transition e0 at l=260 and 350 nm and an increase in absorption intensity in the region of 450 ± 620 nm.173 These changes can be due to the formation of a radical cation by the donor.173 The position of the absorption band of the T1u(4) vibrations of C60 (1429 cm71) in the IR spectrum of intercalated specimens is not changed, which indi- cates the absence of charge transfer to the fullerene molecule. The starting complexes are dielectrics. Intercalation results in an insignificant increase in the conductivity of the complexes (by a D V Konarev, R N Lyubovskaya factor of less than 100), which is apparently due to the large distances between the donor molecules in these complexes.174 IV.Structure and spectral characteristics of complexes and radical ionic salts of fullerenes 1. Specific features of the crystal structure The position of the C60 molecules in a crystal and the number of direct van der Waals contacts between the fullerene molecules make it possible to distinguish several structural types of fullerene compounds.175 1. Three-dimensional packing of the C60 fullerene molecules with distances between the centres of the molecules ranging from 9.8 to 10.3 A is observed in fullerene salts MxC60 (x=1 ± 6) with alkali and alkaline-earth metals.Simple cubic, cubic face-centred, cubic volume-centred and rhombic lattices with the number of closest neighbouringC60 molecules from 8 to 12 correspond to this type of packing.13, 14 2. Layered packing, in which two-dimensional dense or loose hexagonal layers of C60 molecules are formed. The number of closest neighbouring fullerene molecules ranges from 4 to 6. The layers of donor molecules in these structures also alternate with layers of C60 molecules. In the donor layer, e.g., in the (TMDTDM± TTF)2C60(CS2)3 complex,103 there are also short- ened contacts between theTMDTDM±TTF molecules.Ashift of hexagonal layers relative to each other with transition to simple hexagonal packing of layers can be observed in compounds with small donors.This refers to compounds of C60 with such molecules as I2,170 S4N4,95 P4,93 TMPD,129 OM± TTF,5 TPDP109 or DAN.44 The structure of the (DAN)C60(C6H6)3 complex with layered packing of C60 molecules is shown in Fig. 4. Each C60 molecule in this complex is surrounded by four fullerene molecules with a distance of 10.07 A between the centres. a c Figure 4. Projection of the crystal structure of the complex with grey spheres) along the crystallographic axis b 744 (schematic repre- (DAN)C60(C6H6)3 (the positions of the fullerene molecules are indicated sentation). The solvate benzene molecules (not shown) are located in the dianthracene layer.44 3. Cage packing: the fullerene molecules form various cavities or channels, in particular, hexagonal channels, which are filled with donor molecules. The number of the closest neighbouring fullerene molecules can vary from 4 to 8.This structure is represented by compounds of C60 with twin-TDAS,113 C6H6 68, 69 and S8.90, 91 4. Chain packing: the fullerene molecules form densely packed chains (with two closest neighbouring fullerene mole- cules) or double chains (with three closest neighbouring fullereneDonor-acceptor complexes and radical ionic salts based on fullerenes molecules). This structure is characteristic of complexes of full- erene with BEDT± TTF,98, 99 twin-BEDT ± TTF102 and C1TET ± TTF.110 5. Island mode of packing: in this case, there are no direct van der Waals contacts between the fullerene molecules, and all distances between the centres of C60 molecules are *12 A.This type of packing is observed in compounds with large donor molecules (HMT,115 Ph3Sb116) or cations (Ph4P+ (see Refs 57, 136 and 153) and PPN+ (see Refs 58 and 155). The structures of some fullerene complexes, for example with such donors as DBTTF105 and BTX, are intermediate between the cage and island structures.111 Figure 5 presents the structure of the DBTTF.C60 .C6H6 complex. It is characterised by isolated packing of C60 molecules, in which each of them is surrounded by six closest neighbouring fullerene molecules with a distance of 10.4 ± 10.5 A between the centres. This distance is larger than the van der Waals diameter of fullerene (10.18 A) but smaller than the distance characteristic of island structures (*12 A).Figure 5. Crystal packing of the complex (DB ± TTF)C60 .C6H6 (posi- tions of fullerene molecules are indicated by grey spheres; crystallographic axes are shown by straight lines).100 Table 7 lists the mean bond lengths of the C60 fullerene molecule in its compounds. It is evident that the bond lengths in C60 change with an increase in the degree of charge transfer to the fullerene molecule; in this case, the 6 ± 5 bonds shorten while the 6 ± 6 bonds elongate. The direction of changes in the bond lengths upon reduction of fullerene is due to the nature of the t1u orbital, which is anti-bonding with respect to the 6 ± 6 bonds and bonding with respect to the 6 ± 5 bonds.13 This results in elongation of the fullerene molecule, and the C60 sphere is distorted to become an ellipsoid.Table 7. Lengths of 6 ± 5 and 6 ± 6 bonds for D±A complexes and radical ionic salts of C60. Ref. Compound 6 ± 6 Bond length/A Charge 6 ± 5 Bond on C60 length/A C60 176 116 98 145 109 90 149 47 155 1.355(9) 1.383(4) 1.389(7) 1.387(6) 1.381(6) 1.340(8) 1.389(3) 1.384(8) 1.399(2) 1.400(4) 1.445(3) 1.467(2) 1.452(5) 1.452(1) 1.450(5) 1.451(6) 1.448(8) 1.449(3) 1.453(4) 1.446(2) 1.452(1) 1.432(1) C60(SbPh3)6 C60(BEDT ± TTF)2 C60[(C5H5)2Fe]2 (C60)2TPDP(CS2)4 C60(S8)2 C60[Ni(C5Me5)2]CS2 C60[Co(C6H5)2]CS2 C60(PPN)2 K3C60 K6C60 000000 71 71 72 73 76 13 13 31 2. Stability The stability of fullerenes with respect to atmospheric oxygen differs from the stability of their compounds.In solid state, fullerenes can adsorb oxygen on their surface.62 In solution, they can add oxygen under illumination to give epoxides C60On, where n=1, 2 and 3 (therefore, it is preferable to carry out reactions with fullerenes in the dark).19 Anionic fullerene compounds are particularly sensitive to oxygen because of the possible reaction Cn¡ C60+nO¡ 60 +nO2 2 . This reaction can also yield addition products C60O¡2 . at the 60. 70., is 70.4 V.31 With these values of redox potentials, 2 . couple becomes more positive due to stabilisation of fullerene 6 ± 6 or 6 ± 5 bonds.177 In aprotic media, the redox potential of the O2/O¡2 .couple is 70.8 V,48 while the first redox potential of fullerenes, C60/C ¡ and C70/C ¡ oxidation of fullerene radical anions C60 ¡ . and C¡70. is thermody- namically unfavourable, and hence radical monoanionic fullerene compounds should be stable when exposed to air. This is actually observed for salts containing theC¡60. radical anion (KC60, RbC60, CsC60) and salts with bulky cations.56 ± 58, 152 ± 154, 157 The insta- bility of salts ofC¡60. with metalloporphyrins,48 metallocenes 48, 147 and amines 15, 134 in the air can be due to the fact that protons or metal cations can stabilise the charge on O¡2 . . The redox potential of theO2/O¡ the O2¡.radical anion, which enables the oxidation of C¡60. . The second redox potential of fullerenes C¡60./C260¡ and C70 ¡ ./C270¡ is *70.8 V,31 hence the oxidation of fullerene di- anions with oxygen is thermodynamically favourable. Therefore, radical anionic salts containing fullerene dianions or Cn¡ 60 anions in higher degrees of reduction are very sensitive with respect to oxygen.82 3. Thermogravimetry Derivatography is generally used to study the thermal stability of both pure fullerene and its compounds.43, 44, 54, 75, 101, 104, 178 Heat- ing in air causes complete combustion of fullerene at 650 8C. In nitrogen, fullerene starts to sublime at 600 8C, and the maximum sublimation rate is reached at 700 ± 800 8C.178 It is possible to determine the content and the strength of binding of a solvent in a complex from derivatograms of molecular complexes of fullerenes.43, 44, 54, 75, 101, 104 Thermogravi- metric studies of fullerene complexes show that partial decom- position of donors occurs in these compounds.The decomposition temperatures of donors in complexes are close to those of the pure donors. In certain instances, the decomposition temperature of a donor increases owing to its stabilisation because of the donor-acceptor interaction with the fullerene.44, 54, 75 The presence of a large amount of a solvent in a molecular complex separates the fullerene molecules from each other. Therefore, the sublimation temperature of the fullerene in such complexes even after complete removal of the solvent is lower 43, 50, 103 than that of pure C60.178 4.Spectroscopy of compounds based on fullerenes A significant number of publications deal with the study of fullerenes and their compounds by spectroscopic methods (see, for example, Refs 5, 22 ± 26, 36 and 179 ± 195). a. Electronic spectroscopy Optical spectroscopy is a convenient method for the study of changes in the electronic structure of fullerenes upon formation of donor ± acceptor compounds.5, 9, 181 ± 185 The optical absorption spectrum of the C60 fullerene in solid state (Fig. 6) has been studied in detail.25, 66 In the ultra-violet region (250 ± 400 nm), two intense bands corresponding to sym- metry-allowed electronic transitions are observed.There is a rather strong band in the visible region (l=420 ± 540 nm) with a maximum at l=450 nm (2.7 eV), the origin of which is not quite clear. This band is absent in the absorption spectra of C60 solutions,25 but appears, for example, upon aggregation of several32 D 2.6 1.8 1.0 0.2240 800 600 400 l /nm Figure 6. The absorption spectrum of C60 in a KBr matrix.181 C60 molecules in a complex with g-cyclodextrin in aqueous solution.84 Therefore, this band is sometimes 179 related to intermolecular transfer of an electron from the HOMO of the C60 molecule to theLUMOof the neighbouringC60 molecule. The absorption at l=540 ± 620 nm (2.2 ± 2.0 eV) has low intensity and corresponds to the symmetry-forbidden hu?t1u transition from HOMO to LUMO of one C60 molecule (see Fig.1).25 The manifestation of this forbidden transition both in liquid and in solid phase is explained by a deviation of the symmetry of C60 molecules from Ih.25 The absorption edge of fullerene in optical spectra is in the region of 1.95 ± 1.75 eV, which corresponds to 640 ± 700 nm, and it is basically related to exciton transitions.180 The formation of molecular complexes does not induce considerable changes in the electronic system of fullerenes.181 Irrespective of the solvent, the absorption edge of fullerene in fullerene solvates shifts by 0.1 eV upfield in comparison with pure fullerene,180 which is explained 185 by separation of fullerene molecules from each other by the solvent.The spectra of complexes both in solution and in solid state display charge-transfer bands (CTB) from the donor to the fullerene. The process of charge transfer for complexes with an uncharged ground state upon absorption of a light quantum is described by the scheme: hn D(1+d)+A(1+d)7. Dd+Ad7 The dependence of the charge transfer energy (hnCT) on the donor IP for complexes of one acceptor with a series of donors is linear. This dependence is described by the equation:5, 9 hnCT=a(IP7EA)7EC, where a is a constant, IP is the ionisation potential of the donor, EA is the electron affinity of the acceptor, and EC is the energy of electrostatic interaction between the donor and acceptor radical ions in the excited state of the complex.Such a dependence for complexes of the C60 fullerene with substituted anilines 182 and naphthalenes 183 (IP=7.2 ± 8.13 eV) in toluene is shown in Fig. 7 and can be described by the expression: hnCT=0.91IP74.34 (eV). Table 8 lists the energies corresponding to the maximum of the charge-transfer band for a number of C60 complexes in the solid state. It is evident that hnCT decreases with a decrease in the redox potential (ERed/Ox) of the donors.5 Irradiation of a crystalline complex (TMPD)C60 with visible solvates,187, 188 violation of symmetry of the environment of the C60 fullerene molecules is observed, which results in partial light (He ± Ne laser) was found to cause a strong increase in the modification of symmetry-forbidden vibrations, hence they absorption at 1070 nm.76 This is related to the formation of a long-lived radical anion C60 ¡ .upon transfer of an electron from dislocations, admixtures or solvent molecules in the crystal appear in the IR spectra. This is due to the presence of defects, TMPD to C60. The lifetime of the C60 ¡ . radical anion in a crystal is structure of C60 and in crystal solvates. about 1 h, which is several orders larger than the lifetime in the case of similar electron transfer in solution.76 D V Konarev, R N Lyubovskaya hnCT /eV 9 3.0 7 8 4 5 6 2.6 2 3 1 2.2 IP /eV 8.0 7.8 7.4 7.2 7.6 Figure 7. Dependence of charge transfer energy hnCT on ionisation potentials of donors in CTC of C60 in toluene: (1), N,N-diethylaniline;182 (2), N,N-dimethylaniline;182 (3), N-methylaniline;182 (4), 1-methoxynaph- thalene;183 (5), 2,6-dimethylaniline;182 (6), o-toluidine;182 (7), 1-methyl- naphthalene;183 (8), aniline;182 (9), 1-chloronaphthalene.183 Table 8.Position of the charge-transfer band maximum in electronic absorption spectra of C60 complexes in solid state. Ref. CTC ERed/Ox of hnCT /eV the donor /V 70.086 +0.29 +0.39 +0.42 7+0.52 7 1475 1045 101 98 110 [(C5Me5)2Fe]2C60 (OM± TTF)C60(C6H6) (TMDTDM± TTF)2C60(CS2)3 (BEDO ± TTF)*C60 a (BET ± TTF)C60(C6H5Me) (BEDT ± TTF)2C60 (twin-BEDT ± TTF)C60(CS2) 1.13 1.35 1.38 1.51 1.55 1.65 1.65 a The exact complex composition has not been determined. Charge transfer from the donor to the fullerene in the ground state is related to the population of the t1u orbital of the C60 fullerene.This enables electronic transitions from the t1u orbital to vacant molecular orbitals with higher energies (see Fig. 1), which results in the appearance of new absorption bands in the near IR region. Their position corresponds to definite charge of the fullerene molecule: . C270¡ C460¡ C360¡ C260¡ C70 ¡ . Fullerene C60 ¡ . 1070 1165 1370 950 n (nm) 730 1195 88 780 1380 35 35 35 35, 48, 184 50 Ref. b. IR spectroscopy The change in the symmetry and redistribution of the electron density upon formation ofD±A complexes and radical ionic salts of fullerenes is reflected in their IR spectra.9, 25, 26, 184 ± 195 Due to its high symmetry (Ih), the C60 molecule has 46 characteristic normal vibrations.Four of these are active in the IR spectra [T1u(1 ± 4) vibrations with absorption bands at 527, 577, 1183 and 1429 cm71, respectively] and ten in Raman spectra; 32 normal vibrations in the C60 molecule are symmetry-forbidden in the dipole approximation.25, 26, 186 In the crystalline C60 fullerene 186 and some of its crystal At room temperature, the molecules of the C60 fullerene in crystals rotate quickly and isotropically, occupying positions with the Th symmetry.188 The T1u vibrations, which are active in IRDonor-acceptor complexes and radical ionic salts based on fullerenes spectra of theC60 fullerene, are threefold degenerate and appear as single bands.Cooling C60 crystals below 255 K results in an orientational-type phase transfer with freezing of the rotation of the fullerene molecules and a decrease in its position symmetry to S6.189 The degeneration of the T1u(4) vibration of C60 at 1429 cm71 is eliminated, and at 8 K it is split into three bands with wave numbers 1424.5, 1427.9 and 1431.2 cm71. The T1u(3) vibration at 1183 cm71 remains unsplit.189 Similar splitting of the T1u(4) vibration of C60 into three bands (Table 9) has been reported in compounds of C60 with amines, viz., (TMPD)C60 and (TPA)C60.190 This splitting is due to freezing of rotation of the C60 molecules in the crystal of the complex due to the intermo- lecular interaction with molecules of the donor and a decrease in the positional symmetry of the C60 molecules (in comparison with pure fullerene above 255 K).190 Table 9.Position of the T1u(4) vibration band of fullerene (n) and degree of charge transfer (d) estimated from Eqn (2) in donor ¡¾ acceptor complexes and radical ionic salts of C60. Ref. Compound n /cm71 Compound d type 189 C60 1424, 1428, 1431,a, b 1429 c 1429 75 S4N4C60 molecular 0 complex the same 077 (S8)2C60(C6H5Cl)0.5 (TPA)C60 (TMPD)C60 (C5H5)2CoC60(CS2) *1 1429 1425, 1428, 1433 b " 1422, 1425, 1427 b CTC 1411 (C5H5)2CoC60(C6H5CN) 1413 1407 1395 1394 1394 1392 (C6H6)2CrC60 [Na(18-C-6)]C60(THF)3 (Ph4P)C60(Ph4PCl) (Ph4P)C60(Ph4PI) RbC60 d CTC CTC CTC salt """ *1 1390 " (Ph4As)C60(Ph4AsCl) 194 190 190 *0.5 47 *0.5 48 *0.7 150 48 *1 184 *1 195 26, 191 *1 184 a Measured at 8 K; b splitting of the T1u(4) band of fullerene on freezing the rotation in the crystal; c measured at 293 K; d film.The transfer of electron density from the donor to the C60 fullerene in the ground state results in a shift of some of its bands in the IR and Raman spectra.26, 191, 192 This is caused by the population of the t1u orbital of the fullerene and interaction of the T1u vibrations with virtual electronic transitions from the t1u orbital to the higher t1g orbital.191 Figure 8 shows the charge dependence of the position of absorption bands (n) of C60 vibrations active in the IR spectrum.26, 191 The T1u(4) and T1u(2) vibrations are most sensitive to charge transfer: they are charac- terised by a linear increase in np and an almost linear shift of n.The A1g(2) vibration active at 1469 cm71 in the Raman spectrum also has a linear dependence of n on the degree of reduction of the fullerene molecule.26, 192 This relationship may be used for the determination of the degree of C60 reduction in salts,26 including that occurring during intercalation. The plasma frequency (op) (square root of the oscillator force) also changes linearly with the charge on the fullerene molecule (Fig. 9). The change in frequency of absorption bands in the IR spectrum of C60 vibrations in D¡¾A complexes makes it possible to estimate even a small degree of charge transfer (0<d<1).This method has already been used previously for the estimation of charge transfer in organic CTC.9, 193 degree of charge transfer (d), as the transition from C60 to the C60 ¢§ . The T1u(4) vibration is most suitable for determination of the radical anionic salts is accompanied by a strong shift of the absorption band of this vibration from 1429 cm71 to 1390 ¡¾ 1395 cm71 (see Refs 26, 48, 184, 191 and 195) (Table 9). 33 n /cm71 1480 1460 5 1440 1400 1360 43 1180 2 580 540 500 1 460 6 x 5 4 3 2 1 0 Figure 8. Wave numbers (n) for different degrees of reduction (x) of the C60 fullerene molecule.191 (1), T1u(1) vibrations; (2), T1u(2) vibrations; (3), T1u(3) vibrations; (4), T1u(4) vibrations; (5), A1g(2) vibrations.op /cm71 600 500 400 300 200 100 x 5 4 3 2 1 0 Figure 9. Plasma frequency (op) for different degrees of reduction (x) of the C60 fullerene molecule.191 (1), T1u(2) vibrations; (2), T1u(4) vibrations. The change in the positions of absorption bands of three other T1u vibrations active in the IR region on transition from C60 to C¢§60. is less marked.26, 192 Taking into account the linear dependence of the position of the absorption band of the T1u(4) vibrations on the degree of reduction of the fullerene molecule, it is possible to use Eqn (1) for the estimation of the degree of charge transfer in complexes:9, 193 (1) 2Dn d a n0O1 ¢§ n21 =n20 U , where n0 is the position of the absorption band of the T1u(4) C60 ¢§ .salts [1392.52.5 cm71, depending on the crystal structure vibration in neutral C60 (1429 cm71); n1 is its average position in (Table 9)], and Dn is the difference between the positions of absorption bands of T1u(4) vibrations in neutral C60 and in the corresponding complex. The use of these values in Eqn (1) gives Eqn (2): (2) d%0.03 Dn. The accuracy of estimation of charge transfer d, which is 0.03, depends on the accuracy of measurement of the positions of absorption bands in IR spectra (1 cm71). One can see from Table 9, which lists the positions of the T1u(4) vibration bands and the degree of charge transfer in C60 compounds estimated from Eqn (2), that the degree of charge transfer is close to zero (molecular complexes) for the majority of C60 compounds with organic donors.In radical ionic salts, the34 degree of charge transfer is close to unity. Only the complexes of C60 with TMPD,190 cobaltocene 47, 48 and dibenzenechromium 150 have intermediate degrees of charge transfer. c. ESR spectra The g-factors and DH of ESR signals of fullerenes and their compounds are listed in Table 10. In a discussion of the ESR spectra of C60 compounds, it is necessary to emphasise the presence of two ESR signals at room temperature in specimens of the initial, `pure' fullerene, one with g=2.0025 ± 2.0021 and DH=2 G196, 197 and the other with g=2.0006 ± 2.0012 and DH=0.5 ± 2 G;196 their widths virtually do not change down to liquid-helium temperatures.These signals originate from defects, i.e., paramagnetic admixtures formed upon oxidation of fullerene with oxygen.177, 196 The intensity of the former signal increases by an order of magnitude on heating the specimen in air at 623 K for 2 h and by two orders on heating for 24 h.196 The intensity of this signal changes considerably depending on the way the fullerene has been obtained or stored. Unlike the signals related to the oxidation of fullerenes, the ESR signals of the Cn¡ 60 anions have a considerably larger line width (DH=20 ± 60 G), which depends strongly on temperature. The ground state of the radical anion C¡60. is a singlet (S = 1/2) with g=1.997 ± 1.999. This value is smaller than the g-factor of a free electron.56, 56, 61, 153 Larger g-factors (2.0008) are observed only in salts of C60 with amines.38,142 The C2¡ 60 anion displays a signal with g=2.0010 and DH=10 ± 30 G at room temperature.This corresponds to the triplet state (S=1) with forbidden splitting D%0: two electrons with parallel spins are so distant from each other that they behave similarly to electrons with independent spins, therefore their interaction is not displayed in the ESR spectra.50 The radical anion C3¡ 60 . is in a singlet basic state (S=1/2) at room temperature, and its g-factor equals 2.0012 ± 2.0017, and DH=10 ± 30 G.49 In the compounds M3C60, the ESR parameters (the g-factor and DH) of the C3¡ radical anion depend on the nature of the metal.13, 14 The ESR signals of all of the Cn¡ 60 anions become much narrower as the temperature is decreased.58, 153, 154 Due to the Jahn ± Teller effect, the presence of fullerene radical anions in C60 salts with bulky counter-ions results in violation of the Ih symmetry of C60.48 ± 50, 149 The effect can be both dynamic Table 10.g-Factors and line widths (DH) for ESR signals in D-A complexes and radical ionic fullerene salts. Compound C60 C60 (Ph4P)C60(Ph4PCl)2 (PPN)C60(C6H5Cl) (Ph4P)2C60I0.35 KC60(THF)5 Na0.4C60(THF)2.2 (TDAE)C60 (TDAE)C70 (TDAE)C84, C90, C96 (DBU, DBN)C60 [(C5H5)2Co]C60(C6H5CN) (Ph4P)C70(Ph4PI) SbCl3+C60 (CB11H6Br6)C76 154 357 a The signal is observed below the temperature T; b the ESR signal was measured at two different temperatures T(T1); c the signal is observed above the temperature T; d ESR signal after transition of the compound to ferromagnetic state.Charge on fullerene 00 71 71 71 70.4 71 71 71 71 71 71 +1 +1 60 . g-Factor 2.0021 2.0023 2.0006 ± 2.0012 1.9991 1.9992 2.0007 1.9979 1.9987 1.999 2.0008 2.0017 ± 2.0030 2.0022 2.0020 ± 2.0022 71.9969 2.000 2.047 2.0029 2.0030 and static on the ESR time scale.198 At room temperature, a dynamic effect with fast transition from one static Jahn ± Teller configuration to the other is observed. Based on the ESR data, the frequency of this pseudo-rotation is estimated as*1012 Hz.198 If the temperature is decreased, pseudo-rotation is hindered, the ESR signal narrows, and transition to the static Jahn ± Teller effect is observed.In the salt (Ph4P)C60(Ph4PCl)2, this transition occurs when the temperature is decreased to 70 K;199 this is accompanied by abrupt narrowing of the signal. On further decreasing the temperature, its width almost does not change. The static Jahn ± Teller effect at low temperatures (4 ± 70 K) results in transformation of the isotropic ESR signal to aniso- tropic. For instance, the Na(18-crown-6)C60(THF)3 salt displays an anisotropy of the g-factor: g\ =1.9968, gk=2.0023.48 60. radical anion decreases from Ih to As the symmetry of the C¡ D5d, the T1u state splits into two states, viz., E1u and A2u (Fig. 10). The difference between the energies of the E1u and A2u states is small and equals 1 kcal, therefore thermal population of the over- laying A2u state can occur, and an additional `high-temperature' signal with g=2.000 appears in the ESR spectrum of C¡ 2T1u C60 7.(Ih) Figure 10.Scheme of partial removal of degeneration of the t1u orbital in the C60 7. radical anion upon lowering the symmetry from Ih to D5d.48 The radical anion C¡70. in the (Ph4P)2C70I salt gives a broad ESR signal with g=2.047,154 as does that in the salt (TDAE)C70, with g=2.0022.136, 137 Higher fullerenes display a narrow signal with g=2.0023,143 which is close to the g-factor for the free electron. 60. radical anion in some fullerene The ESR signal of the C¡ complexes has been used to determine the degree of charge T /K <300 a <300 a <300 a 300 300(77) b >50 c 300(113) b 300 300 300 <16 a, d <300 a <300 a 300(5) b 130(4.5) b >24 c 300(4.2) b 300 300 D V Konarev, R N Lyubovskaya 60..48 2A2u 1 kcal 2E1u C60 7.(D5d) Ref. DH /G 196 197 56 58 153 55 61 38, 142 136, 137 143 127, 128 48 0.3 ± 1.0 0.5 ± 2.0 0.5 ± 2.0 45 35(5) 1 ± 2 50(14) 34 30 22 30 10 1.85 ± 2.40 40(5) 24(6) 3600(1.5) 1.5 0.5Donor-acceptor complexes and radical ionic salts based on fullerenes transfer from the donor to C60 (based on the number of C¡60. spins per formula unit).123, 127, 128 d. X-ray photoelectron spectroscopy X-Ray photoelectron spectroscopy (XPS) is a sensitive method for the determination of the valence state of elements in thin (0.5 ± 4.0 nm) surface layers.Based on the position of lines corresponding to internal electronic shells of heteroatoms of the donors contained in the complex and their shift relative to the lines of the individual donor, it is possible to estimate the redistribution of the electron density upon formation of a D±A compound and the atomic composition of the compound.200 ± 205 The C(1s) X-ray photoelectron spectrum of the C60 fullerene consists of the main singlet peak with an energy of 285 eV. The higher energy region contains a satellite shifted by 5.9 eV from the main C(1s) peak. It originates from excitation of a p-plasmon, i.e., coordinated vibrations of p-electrons of the C60 molecules in a crystal.206 The density of valence electrons is determined from the electron energy loss spectra (EELS).The loss function has two peaks in the case of the C60 fullerene,203, 206 which correspond to the p-plasmon with a maximum at 5.8 eV originating from excitation of plasma vibrations of p-electrons and the (p+s)- plasmon with a maximum at 26.1 eV originating from excitation of all valence electrons in C60.203, 206 The position of the C(1s) peak in the XPS spectra of molecular C60 complexes and salts of fullerenes remains unchanged, but some changes in its satellite structure occur.44, 205 The disappearance of p ± p* transitions of phenyl substituents of the donors in the compounds, e.g., satellite in structure of (DAN)C60(C6H6)3 44 and in salts with bulky cations,205 has been reported.This is due to the strong interaction of the phenyl substituents of the donor with the fullerene or to the fact that, upon formation of a compound with fullerene, the p ± p* tran- sitions in the donor molecule become less favourable than the excitation of plasma vibrations of p-electrons of the fullerene itself.44, 205 In many compounds, a decrease in the energy of the p+s-plasmon is observed: 24.0 eV in (S8)2C60,203 25.2 eV in (BTX)C60(CS2) 54, 119 and 25.5 eV in TPDP(C60)2(CS2)4.43 The shift in the position of the S(2p), N(1s) and Te (3d5/2) lines of the donor heteroatoms in various fullerene complexes by 0.1 ± 1.0 eV towards higher energies can be caused 200, 201, 204 by the electron density shift from the donor to the fullerene.However, in some cases a similar shift in fullerene complexes in comparison with the individual donors can also be due to the calibration of spectra of the complex and the donor with respect to the C(1s) line, as the exact position of this line in the spectra of the donor and C60 can differ.200 A shift in the position of the S(2p) peak in compound (S8)2C60 towards lower energies by 0.4 eV has been reported.203 60 e. 13C NMR spectroscopy The 13C NMR spectrum of crystalline C60 fullerene at room temperature contains a narrow singlet at d 143.29 This is caused by fast rotation of the C60 molecule and isotropic averaging of the signal.As the temperature is decreased, the rotation of fullerene molecules is hindered, and broadening of the signal is observed.22 The observed phase transitions in fullerene at 255 and 90 K result in stepwise changes in the line width. The formation of molecular complexes does not change the position of the 13CNMR signal of the fullerene.93, 98, 114 The formation of fullerene anions, Cn¡ (n=1, 2, 3), causes a shift of the 13C NMR signal towards lower magnetic field, which can be due to the paramagnetic state of these 60 ions.50, 207, 208 However, the salts containing the C60 ¡ . and C260¡. anions have close chemical shifts of signals in the 13C NMR spectra (d 187 and 183, respectively), though their magnetic susceptibilities differ strongly.207, 208 A shift of the 13C NMR signal to d 156 is also observed in the diamagnetic state of the C6¡ anion.208 35 V.Conclusion Based on the survey of the most important results concerning the synthesis and properties of the D±A complexes and radical ionic salts of fullerenes obtained over the last years, one can distinguish the most important directions of the development in this field and evaluate some possibilities of using fullerene compounds, both for obtaining new materials and for solving fundamental problems. The ability of molecules of the C60 fullerene, its molecular complexes and salts to synchronise their rotation in crystals results in the appearance of unusual magnetic properties in these compounds. The existence of the frozen glassy magnetic state of fullerenes and molecular complexes of fullerenes with halogens has been established; radical anionic salts of C¡60.with unsatu- rated amines possess ferromagnetic properties with the highest Tc among organic materials; various magnetic properties are dis- played by complexes of C60 with metallocenes. Obviously, syn- thesis of D±A complexes of fullerenes with strong organic and organometallic donors, viz., unsaturated amines, metallocenes and metalloporphyrins, and the study of their structure and properties will lead to new interesting results. Another important direction includes the synthesis of con- ducting and superconducting materials based on fullerene com- pounds. By now, several dozens of superconductors with Tc440 K have already been obtained based on C60 and some specific features of their superconductivity have been rationalised.Superconducting phases can exist in fullerene compounds with alkali or alkaline-earth metals, lanthanides, and in salts of C60 with strong organic donors: they can be obtained both by direct chemical synthesis and by intercalation in the gas phase. Fullerenes are weak acceptors, and the range of donors capable of reducing them to radical anions is limited. In addi- tion, the essential drawback of both superconducting and ferro- magnetic compounds of fullerenes is their instability in air. This restricts considerably the possibilities of obtaining and applying the fullerene-based materials with specific conducting and mag- netic properties.One possible way to solve these problems is the synthesis of three-component systems. The systems `organic donor ± fullerene radical anion ± alkali metal cation' include a wider range of ionic compounds of fullerenes. In some of them, the fullerene radical anion can be stabilised because the bulky organic donor sterically hinders the approach of oxygen molecules to the fullerene radical anion. In the majority of fullerene complexes that have been obtained, in particular in the complexes with tetrathiafulvalenes, charge transfer is insignificant because of the weak acceptor properties of C60 and C70. However, in a three-component system `donor radical cation ± neutral fullerene ± halide anion', fullerene compounds with radical cations of the donors can be obtained.Similar compounds can also possess conducting and magnetic properties. Three-component systems can be obtained by intercalation of fullerene complexes (with either alkali metals or halogens) or by direct synthesis in solution. In the latter case, it is probably possible to obtain single crystals of these compounds. Synthesis of complexes of chemically modified fullerenes, in particular, brominated, chlorinated and fluorinated ones, seems to be a promising direction. Unlike the C60 and C70 molecules, these derivatives have strong acceptor properties and can appa- rently yield molecular complexes and radical ionic salts with strong organic donors (e.g., tetrathiafulvalenes).The significant delocalisation of electrons in C60 upon photo- induced electron transfer results in the formation of free charge carriers and high photoconductivity. In the near future, this phenomenon can find application for the development of energy phototransducers and other devices that use photoconductivity. Therefore, the study of electron photoconduction in fullerene compounds is an important direction. 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Commun. 267 (1994) 208. J Chen, Z Huang, R Cai, Q Shao, H Ye Solid State Commun. 95 233 (1995) a�Dokl. Chem. Technol., Dokl. Chem. (Engl. Transl.) b�Russ. Chem. Bull. (Engl. Transl.) c�Physics-Uspekhi (Engl. Transl.) d�Russ. J. Phys. Chem. (Engl. Transl.) e�Russ. Crystallography (Engl. Transl.) f�Russ. J. Gen. Chem. (En

ISSN:0036-021X    

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Russian Chemical Reviews 68 (1) 39 ± 53 (1999) Recyclisation of carbo- and heterocyclic compounds involving malononitrile and its derivatives { V P Litvinov Contents I. Introduction II. Recyclisation of three- and four-membered rings III. Recyclisation of five-membered rings IV. Recyclisation of six-membered rings V. Conclusion Abstract. Published data on recyclisation reactions of carbo- and heterocycles with participation of malononitrile and recyclisation of compounds containing a malononitrile fragment or fragments with malononitrile as a synthon are surveyed, described system- atically and analysed. The bibliography includes 206 references. I. Introduction Recyclisation of carbo- and especially heterocyclic compounds occupies an important place in organic chemistry.Recyclisation in the presence of various nucleophilic, electrophilic or dipolar reagents occurs as opening of the ring in the initial molecule and its subsequent closure. This process is often accompanied by ring expansion or contraction, introduction of a heteroatom in the ring or its replacement by another heteroatom, etc. Nevertheless, from the preparative viewpoint, all these complex transformations occur during a one-stage reaction, which makes possible relatively easy synthesis of compounds that are difficult to obtain by other methods or modification of heterocyclic fragments in complex, including natural, molecules. The latter is fairly important for the synthesis of new biologically active products.At present, a large number of transformations of this type are known; they include name reactions, for example, the Yur'ev, Zincke ± Konig and Hafner reactions, the Dimroth, Boulton ± Katritzky, Cornforth and Kost ± Sagitullin rearrangements, etc. The problem of recyc- lisation is considered in numerous publications and reviews (see, for example, Refs 1 ± 24). Malononitrile 1, containing highly reactive methylene and cyano groups,25 is of special interest as a reagent for recyclisation of carbo- and heterocyclic compounds. In this review, we consider recyclisation reactions with participation of malononitrile and its derivatives including carbo- and heterocyclic compounds with vicinal cyano groups. Primary attention is paid to the synthetic potential of these reactions and less space is given to the reaction mechanisms, because the data on the mechanisms are quite limited and often contradictory.V P Litvinov N D Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 117913 Moscow, Russian Federation. Fax (7-095) 135 53 28. Tel. (7-095) 135 88 37 Received 12 March 1998 Uspekhi Khimii 68 (1) 45 ± 60 (1999); translated by Z P Bobkova #1999 Russian Academy of Sciences and Turpion Ltd UDC 547.7/8 39 39 41 45 50 II. Recyclisation of three- and four-membered rings In 1983, a group of German scientists found that cyclopropene derivatives 2 react with the malononitrile anion, generated by treatment of malononitrile with sodium methoxide in methanol, to give functionally substituted cyclopentadienes 3.Bicyclic derivatives 4 were postulated as intermediates in this reaction.26 NC NH Ph CO2But MeONa Ph CO2But MeOH + CH2(CN)2 1 R R 2 R R4 NC NH2 Ph CO2But R R 3 (49% ± 64%) R=Me, Ph. Cycloaddition of N-cyclohexenylpyrrolidine 5 to 2,2- dimethyl-1,1-cyclopropanedicarbonitrile 6 has been reported.27 The reaction follows an SN2 mechanism and yields adduct 7. On partial hydrolysis, this product rearranges into spiro compound 8, which is further hydrolysed to give 5-(4,4-dimethyl-2-oxocyclo- pentyl)pentanoic acid 9. Me N Me C6H4Me2 95% EtOH N + D, 19 h CNCNMe 150 8C, 31 h NC CN Me 6 5 7 (47%) O O Me (CH2)4CO2H H3O+ Me Me CN Me H2N 9 (83%) 8 (91%) The reactivity of substituted tetracyanocyclopropanes has attracted considerable attention of researchers in recent years.Thus it was found that treatment of 3,3-phthaloylcyclopropane- 1,1,2,2-tetracarbonitrile 10 with nucleophiles (alcohols or ketox- { This review is dedicated to the memory of Professor Yu A Sharanin.40 imes) induces recyclisation of the cyclopropane fragment in 10 and results in the formation of 2-alkoxy-2-(2-alkoxycarbonylphenyl)- 5-amino-4-cyano-3-dicyanomethylene-2,3-dihydrofurans 11.28,29 NC CN CN O NC NC OR RO7 NC H2N CN O ORO2C 11 10 . R=Me, Et, (CH2)2OH, N=CMe2, N Unlike the cyclopropane 10, 3,3-diacetylcyclopropane- 1,1,2,2-tetracarbonitrile 12 reacts with alcohols or ketoximes in the presence of catalytic amounts of the corresponding sodium alkoxides or oximates with retention of the cyclopropane ring to give substituted 3-oxabicyclo[3.1.0]hexane-1,6,6-tricarbonitriles 13.28,30 However, when a twofold excess of the catalyst is used, 2,3-dihydrofuran derivatives 14 are formed under similar con- ditions. NC CNCOMe NC RO Me CN O NC OR H2N Me RO7 O13 Me NC NC CN NC CN O 12 Me H2N OR O14 R=Me, Et, N=CMe2, N=CMeEt, N=CMeBu, (CH2)2OH, ., N N The cyclopropane ring is also retained when substituted pyrazoline-4-spirocyclopropanetetracarbonitriles 15 are treated with alcohols and ketoximes under the same conditions; this reaction affords adducts 16.31 CN O OR0 CNO CN NC NR R0O NR R0O7 +R0OH N N N NC Me CN Me 15 ., N H2N16 R=Pri, Ph; R0 =Me, Et, N=CMe2, N=CMeEt, N When ethyl pentacyanocyclopropanecarboxylate 17 is made to react with alcohols in the presence of an equimolar amount of the corresponding alkoxide, it undergoes recyclisation to give 5,5- dialkoxy-2-amino-4-dicyanomethylene-2-pyrroline-3-carboni- triles 18. The formation of a stable intermediate, sodium penta- cyanopropenide 19, was noted.32 CN CN 7 NC CN CN RO7 +RO7Na+ CO2Et NC Na+ NC CN NC CN 19 17 NC NC Na+ 7 NC NC CN CN H2SO4 OR OR H2N H2N N OR OR NH18 R=Me, Et. V P Litvinov 2H-Pyrazolo[3,4-b]pyridines 21 have been prepared by recyc- lisation of tetracyanocyclopropanes 20 involving phenylhydra- zine.33 R NC R NH2 CNCN PhNHNH2, MeOH 125 8C, 24 h BuOH D, 8 h NH NCH2N NC CN 21 NPh R NH2 NC NPh N H2N N20 R=Me, Et, Ph, 4-ClC6H4, 4-NO2C6H4.The reaction of 3-dicyanomethylene-1,2-diphenylcycloprop- 1-ene 22 with 3,4-dihydroisoquinolines 23 in ethanol is accom- panied by recyclisation giving rise to 4-dicyanomethylene-2,3- diphenyl-4H-2,3,6,7-tetrahydropyrido[2,1-a]isoquinolines 24 in 73%± 78% yields.34 Refluxing of the compound 22 with isoni- triles 25 in acetonitrile results in the formation of 4-dicyano- methylene-4H-cyclopenta[2,3-b]imidazole derivatives 26 in 43%± 58% yields.35 CN Ph Ph N CN N + Ph R CN NC CH2R 23 22 Ph 24 R=H, Me, Ph. CH2RR Ph N N Ph 22+RCH2N=C 25 CN NC 26 R=Ph, CO2Et.Various three-membered heterocycles, oxiranes,1,36 thiir- anes 1,36 ± 38 and aziridines,38,39 can also undergo recyclisation on treatment with nucleophiles. Thus it was found that the reaction of oxiranes 27 with malononitrile in the presence of sodium ethoxide in ethanol occurs as recyclisation yielding 2-amino-4,5- dihydrofuran-3-carbonitrile 28.40 ± 42 CN R3 R3 EtONa R2 R1 R2 EtOH NH2 + CH2(CN)2 1 R1 O27 O28 R1=H, Me, Et, Ph; R2, R3=H, Me. In the case of oxiranes 29, recyclisation proceeds via acyclic intermediates 30, which were treated with malononitrile after isolation. This afforded 2-amino-4-nitromethyl-4,5-dihydro- furan-3-carbonitrile 31 in yields of up to 60%.43 ± 45 R CH2NO2 RCHCH CHNO2 Et3N 1 MeOH OH O 30 29 NC CH2NO2 R H2N O31 R=H, Me.2-Methoxy-2,3-diphenyloxirane 32 recyclises in the presence of sodium malononitrile giving rise to 2-amino-4,5-diphenyl- furan-3-carbonitrile 33.46Recyclisation of carbo- and heterocyclic compounds involving malononitrile and its derivatives CN Ph Ph PhOMe O Ph NH2 32 O33 H NC CH2Br The g-iminolactone 35 has been synthesised by treatment of the oxirane 34 with potassium malononitrile in tert-butyl alco- hol.47Me Me Me HN Me O34 O35 It has also been reported48, 49 that recyclisation of 2,2-dicya- nooxiranes 36 in the presence of amidines 37 affords 4-amino- imidazole-5-carbonitriles 38. R CN NH NPh R CNCN + R0 NH O O PhN NH2 36 37 R0 HN H2N N N NC R0 NC R0 N N RHC Ph 38 OH Ph Thiiranes also enter into recyclisation reactions.1, 38, 42, 50 ± 52 For example, thiiranes 39a ± c react with malononitrile in the presence of sodium hydride in DMSO giving 2-amino-4,5-dihy- drothiophene-3-carbonitriles 40a ± c in 50%± 62% yields. Note that in the case of the thiiranes 39a,b, ring opening occurs in conformity with Krasuskii's rule, while in the case of 39c, the ring opens against this rule.38,50 CN R2 R2 R1 1, NaH DMSO R1 NH2 S 39a ± c S 40a ± c R1=H: R2=H (a), Me (b), Ph (c).Recyclisation reactions for three-membered nitrogen-contain- ing heterocycles have been reported.42, 52 ± 54 The reaction of aziridines 41 with malononitrile in the presence of sodium hydride affords different products depending on the reaction conditions and the ratio of the reactants.42 When the compounds 1 and 41 are taken in equimolar amounts, 2-amino-1-(toluene-p-sulfonyl)-4,5- dihydropyrrole-3-carbonitrile 42 is formed.The reaction with a twofold excess of the initial aziridine 41 (ButOK, 10 8C) yields spiro compound 43, whereas the use of a twofold excess of malononitrile and an increase in the reaction temperature to 100 8C results in the formation of 2,3-dihydropyrrolo[2,3-b]pyr- idine 44. CN NaH 710 8C NH2 NTs 42 HN Ts N 1 N N ButOK 10 8C Ts 43 NH Ts 41 NH2 NC ButOK 100 8C N H2N Ts N44 41 Recyclisation of four-membered heterocycles with participa- tion of malononitrile is also known.Thus the reaction of 2-oxe- tanone 45 with malononitrile in the presence of sodium hydride affords 2-amino-3-cyano-6-methyl-4-pyrone 46.55 O O CN 1, NaH O H2C Me NH2 45 O46 Treatment of 1-ethoxycarbonyl-5-oxo-4-oxaspiro[2.3]hexane 47 with malononitrile under similar conditions gives rise to a mixture of cyclopentenone 48 and 2-amino-4-pyrone 49 (yields 49% and 24%, respectively).56 1-Dimethoxyphosphoryl-1- methyl-5-oxo-4-oxaspiro[2.3]hexane 50 reacts with malononitrile under the same conditions to afford 2-amino-3-cyano-6-(2-dime- thoxyphosphorylpropyl)-4-pyrone 51 in 58% yield.56 CO2Et O HO NC 1, NaH CO2EtO + THF O HH H O CO2Et H2N 49 47 O48 O O NC Me 1, NaH Me P(OMe)2 O THF O P(OMe)2 H2N O O 51 50 III.Recyclisation of five-membered rings Recyclisation of tetracyanocyclopentanes 52 has been reported.57, 58 Depending on the reaction conditions, they are transformed into 2-dicyanomethylenepyrrolidines 53 or tetracya- nopiperidones 54. R1 CN NC PriOH Et3N R1 CN 2 NC NNR2 53 NHNR22 R1 CN NCNC CN 52 KMnO4 HCl, H2O O N CN CN CN 2 NR2 54 R1=Me: R2=Me, Et; R1=Pr, R2=Me. A scheme for the transformation of 2-dicyanomethylenein- dane-1,3-dione 55 into salts 56 has been proposed.59 The trans- formation is attained by refluxing 55 in acetonitrile in the presence of lithium iodide or methyltriphenylphosphonium iodide or by stirring it in dry THF with finely divided sodium. The reaction scheme includes a single-electron transfer in the indanedione 55 resulting in symmetrical radical anion 57, which cyclises to give spirocyclopropane intermediate 58.The rearrangement of the compound 58, accompanied by cyclopropane ring opening, and subsequent cyclisation result in the formation of cyclopropane intermediate 59. This compound also recyclises to afford salts 56. Treatment of the lithium or methyltriphenylphosphonium salt 56 with concentrated hydrochloric acid gives 2,3-dicyano-1,4-naph- thoquinone 60 in 65% and 40% yields, respectively.59V P Litvinov 42 O O CN a or b 7 under similar conditions being thus converted into 2-acetyl-5- amino-3-methylcyclopentadiene-1,1,4-tricarbonitrile 70 in 60% yield.67 C N .CN Me CN MeOC 57 O N O 55 H+ NC 1, NaOH N O O N7 Me Me EtOH 7 C Me Me CN (CN)2CH O O67 N . .Me Me 7 CN CN NHCOMe NC NC NH2 O59 O 58 O O7 Me Me N (CN)2HC (CN)2HC CN CN N68 HCl Me NC NH2 CN CN . 60 56 O O NC Me HN (a)M+I7, MeCN, D,M =Li, Ph3PMe; (b) Na, THF, 20 8C, 48 h. CN Me NC Me N COMe MeOC Me H2N CN NC O69 70 The review on molecular rearrangements of five-membered heterocycles11 published in 1984 presents virtually no data on recyclisation with participation of malononitrile or recyclisation of heterocyclic systems containing malononitrile fragments. Meanwhile, an original pathway to aminoazulenes 61 consisting in recyclisation of lactones or iminolactones, 2H-cyclohepta[b]- furan derivatives 62, on treatment with methylene active nitriles, including malononitrile, had been reported in the litera- ture.36, 60 ± 63 R R 1, EtONa or X NH2 1, ButNH2 It has been noted 68 ± 71 that isoxazoles 71 recyclise to give 2-amino-4H-pyran-3,5-dicarbonitriles 72.Opening of the isoxa- zole ring in the compound 71 under the action of an aldehyde and EtONa in ethanol gives rise to substituted nitriles 73. The subsequent nucleophilic attack on the compounds 73 by malono- nitrile followed by cyclisation of the Michael adducts 74 affords aminopyrans 72.69 O 62 61 CN R2 R2 CN X=O, NAc; R =CO2Et, COMe. CN NC 1 R2CHO N R1 HN NC O 71 R1 O R1 O74 73 R2 CN NC 2,5-Disubstituted pyrrolidine-3,3,4,4-tetracarbonitriles 63 react with aromatic amines to give 2-aminopyrrole-3,4-dicarboni- triles 64.64 Depending on the ratio of the reactants, the reactions of the compounds 63 with primary alcohols in the presence of KOH yield either 3,4-dicyanopyrroles 65 or substituted 3H-pyrro- lo[2,3-d]pyrimidines 66.65, 66 R1 O H2N CN NC NC CN NC CN 72 NC CN R0NH2 NC 140 8C 7HCN R NH2 R R R NH2 R1=Me: R2=Ph, 4-MeC6H4, 4-MeOC6H4, But; R1=Ph: R2=Pri, But, CHEt2.NR0 HN NR0 63 64 R=Ph; R0 =Ph, 3-MeC6H4. CN NC In turn, when fused isoxazoles 75 and 76 are made to react with malononitrile in the presence of triethylamine, the corre- sponding annelated 2-amino-3-cyanopyridine 1-oxides 77 and 78 are formed in high yields.70 ± 72 O O N CHR R0O Me CN Me NH N N 1, Et3N 65 O 63 R0OH KOH NH2 N CN N O N N O NH2 RH2CN O OR0 Me 75 Me77 N R R3 R3 N66 CN R2 R2 1, Et3N ; R0 =Me, Et, Pr.R=Ph, 4-BrC6H4, 4-FC6H4, 4-MeC6H4, O O N N NH2 R1 O R176 78 R1=H, Me; R2=H, NO2; R3=H, Cl, NO2. 4-Acetyl-2,5-dimethyloxazole 67 also reacts with malononi- trile with recyclisation of the oxazole ring. This reaction results in the formation of 3-amino-6-dicyanomethyl-2,4-dimethylpyridine- 5-carbonitrile 68 in 33% yield. 5-Acetyl-2,4-dimethyloxazole 69, which is an isomer of the compound 67, reacts with malononitrileRecyclisation of carbo- and heterocyclic compounds involving malononitrile and its derivatives Recyclisation of 4-aminothiazolin-2-ylidenemalononitriles 79, prepared from 4-aminothiazoline-2-thiones 80, in the presence of sodium ethoxide in ethanol giving substituted 3,5-diaminothio- phene-2,4-carbonitriles 81 has been described.73 H2N H2N NR2 Me2SO4 NR2 MeSO74+ 1, Et3N MeOH MeCN S R1OC SMe R1OC S S 80 CN H2N H2N NR2 EtONa CN EtOH R1OC NHR2 NC CN S79 S 81 (30% ± 64%) R1=OEt, NH2; R2=Me, Ph, Bn, CH2CH=CH2.Substituted 4-dicyanomethylenethiazolidin-5-ones 82 form complexes 83 with morpholine. Hydrolysis of these complexes with hydrochloric acid affords pyrrolo[3,4-c]pyridine derivatives 84, whereas their interaction with NaOHfollowed by acidification gives rise to furo[3,4-c]pyridine derivatives 85.74 CN CN R2 7 O HN O NC O H NC R2 S H +N O S O RN1 R1 N O 82 83 R2 S HN H+ NR1 O O CN84 O H H2N O CN O N OH7 H+ NaO CN NaO S HO S HO NR1 R2 R2 NHR1 H2N H O O N O NR1 R2 85 S R1=Ph, 4-MeC6H4, 4-MeOC6H4; R2=Ph, 4-MeC6H4.It was also shown that 2-methylthio-5,7-diphenyl-1,3,4-oxa- diazolo[3,2-a]pyridinium iodide 86 reacts with malononitrile in ethanol in the presence of triethylamine to give 2-amino-5,7- diphenylpyrazolo[1,5-a]pyridine-3-carbonitrile 87.75 Ph Ph 1, Et3N CN EtOH N Ph O Ph N + I7 N N SMe NH2 87 (72%) 86 2-Methylthio-5-phenyl-1,3,4-thiadiazolo[3,2-c]-4-quinazoli- nium iodide 88 reacts with malononitrile in a similar way, with elimination of one heteroatom from the five-membered ring. Thus it was shown that the salt 88 reacts with malononitrile in dry 43 acetonitrile in the presence of triethylamine to give 2-amino-3- cyanopyrazolo[1,5-c]quinazoline 89.76 When potassium triethyl- amine is replaced by potassium tert-butoxide, a mixture of the pyrazoloquinazoline 89 and 3,4-dihydroquinazoline 90 is formed.76 Ph N 1, Et3N MeCN N N Ph N I7 NH2 N+N NC 89 (56%) N Ph SMe S 88 1, ButOK NH + 89 (54%) MeCN NC CN 90 (24%) Recyclisation of 1,3-oxathiolium salts 91 on treatment with malononitrile has been used successfully in the synthesis of func- tionally substituted thiophenes 92.36, 77 ± 81 In the general form, the mechanism of this reaction includes the attack on the 2-position of the salt 91 by the malononitrile anion to give adduct 93.The subsequent cleavage of the ring at the C(2) ± S(3) bond in the compound 93 gives intermediate 94, which then cyclises according to the Thorpe reaction pathway to give imine 95; this product isomerises into more stable 3-aminothiophene 92.S 7 S X7 CH(CN)2 + CH(CN)2 R2 R1 R1 O O 91 R2 93 NC CN NH NC COR1 R2 R2 R1COCH2S S 95 94 NC NH2 COR1 R2 S 92 ; R1=Ph, 4-BrC6H4, 4-ClC6H4,O O R2=Ph, 4-MeOC6H4, 4-Me2NC6H4. 1,3-Oxathiolidene-2-immonium salts recyclise in a similar way to give functionally substituted thiophenes.81,82 The reaction of 3-methylthio-1,2-dithiolium iodides 96 with ylidenemalononitriles 97 in dichloromethane in the presence of triethylamine has been shown83 to afford dithiolylidenenitriles 98 and recyclisation products � 2-iminothieno[3,2-b]thiopyran-3- carbonitriles 99.R2 SMe R3 CN Et3N + + CH2Cl2 S R1 CN Me I7 S 96 97 R3 R3 NC S S S CN R1 + R1 HN CN R2 R2 S99 98 R1=Ph, SMe, 4-MeOC6H4; R2=H, 4-MeC6H4; R3=Ph, 4-MeOC6H4.44 The reaction of iodide 100 with malononitrile in the presence of triethylamine in chloroform is also accompanied by recyclisa- tion of the dithiole fragment. Simultaneously, ring expansion occurs and 2-imino-4-(N-methylanilino)-2H-[1,4]dithiapino- [2,3-b]indole-3-carbonitrile 101 is formed in 83% yield.84 NMePh + S NMePh S 1, Et3N I7 CN CHCl3 S S NH NHNH 101 100 1,3,4-Dithiazolium perchlorates 102 react with malononitrile in the presence of a base (Et3N, NaH, pyridine, g-picoline) in EtOH, THF, CH2Cl2 or MeCN.Depending on the substituent at the C(5) atom, the base used and the ratio of the reactants, this gives 4-amino-2-(1-cyano-2-dialkylamino-2-sulfanylvinyl)-6-phe- nylpyrimidine-5-carbonitriles 103, 2-dicyanomethylene-5-phenyl- 1,3,4-dithiazole 104 or substituted 1,3-butadiene 105.85HS H2N R N R=NMe2, NEt2 NC CN N103 Ph ClO7 Ph Ph 4 CN S S + R 1, B R=NMe2, SMe 7RH N N CN S104 S 102 CN R CN R=NEt2 HS 7PhCN,7S8 CN H2N105 B is a base. The pathway of the reactions of 1,3-dithiolium perchlorates with malononitrile also depends substantially on the nature of the substituents in the heterocycle and the solvent used. For example, the reaction of 2-diethylamino-4-phenyl-1,3-dithiolium perchlo- rate 106a with malononitrile in the presence of a weak base (g-picoline) results in the formation of 2-dicyanomethylene-4- phenyl-1,3-dithiole 107, whereas in the presence of a strong base (triethylamine), 3-amino-5-diethylamino-2-thiobenzoylthio- phene-4-carbonitrile 108a is formed.85 Ph CN S CN Ph S S107 1, B + CN H2N S 4 R ClO7 106a,b PhC R S S 108a R=NEt2 (a), NMe2 (b).However, when 2-dimethylamino-derivative 106b is used as the substrate, 1,3-dithiole 107 is formed in the presence of the strong base, triethylamine. Similarly, the final products formed in the reaction of 4,5- diphenyl-1,3-dithiolium perchlorates 109 with malononitrile depend on the reaction conditions; this reaction can yield (in various proportions) 2-dicyanomethylene-4,5-diphenyl-1,3- dithiole 110, 2-amino-5,6-diphenyl-1,4-dithiine-3-carbonitrile 111 and 4-amino-2-dicyanomethylene-5,6-diphenyl-2H-thiine-3- carbonitrile 112.85 V P Litvinov Ph Ph CN S S + + NR2 1, B 20 8C CN Ph ClO7 Ph 4 S110 S 109 NH2 CN Ph Ph S NH2 + + CN S Ph CN Ph S 111 CN 112 O.NR2=NEt2, N The reaction of 3,5-diphenyl-1,2,4-dithiazolium perchlorate 113 with malononitrile on refluxing in THF in the presence of sodium hydride is accompanied by recyclisation and gives 2,6- diphenyl-4-sulfanylpyrimidine-5-carbonitrile 114 in 92% yield.86 Ph CN S S + N 1, NaH Ph THF N Ph ClO7 SH Ph 4 N 114 113 2-(2-Hydroxyphenyl)-4-dicyanomethylene-4H-1,3-benzox- azine 116 and 5-imino-2-(2-hydroxyphenyl)-1-benzopyrano- [4,3-d]pyrimidine-4-thione 117 have been synthesised by recyclisa- tion of 1,2,4-dithiazolidine 115 involving malononitrile in the presence of NaF (refluxing for 2 min in a 1 : 1 DMSO: Pr2O mixture).87 NC O S S CNS 1, NaF NH NH O 115 OH HO CN NC N N OH + OH NH O O 116 (45%) 117 (4%) NH S On fusion with malononitrile (15 min, 90 8C), 2-butylbenzoi- midazo[1,2-d][1,2,4]thiadiazol-3(2H)-one 118 undergoes recycli- sation with elimination of isocyanate to give 3-imino-2,3- dihydrobenzoimidazo[2,1-b][1,3]thiazole-2-carbonitrile 119.88, 89 NH O 1 N N 90 8C, 15 min NBu CN N S S 119 (46%) N118 In a series of studies,90 ± 93 it has been found that benzofurox- ans recyclise on treatment with malononitrile giving rise to substituted 2-amino-3-cyanoquinoxaline N,N-dioxides.Recycli- sation of benzofuroxan-15-crown-5 120 during the reaction with malononitrile in DMF in the presence of triethylamine, resulting in the formation of 2-amino-3-cyanoquinoxaline N,N-dioxide 121,93 can be cited as an example. O O O N NH2 N O O 1, Et3N O O O DMF O O N CN N O O O 120 121 ORecyclisation of carbo- and heterocyclic compounds involving malononitrile and its derivatives IV. Recyclisation of six-membered rings For six-membered carbocycles containing a malononitrile frag- ment, base-induced recyclisation of 1-amino-1,3-cyclohexadiene- 2,6,6-tricarbonitriles 122, resulting from dimerisation of alkylide- nemalononitriles, has been reported.This reaction yields 2-dicya- nomethylene-1,2-dihydropyridine-3-carbonitriles 123 and involves intermediate formation of cis(trans)-2-amino-1,3,5-hex- atriene-1,1,3-tricarbonitriles 124.94 ± 101 CN H2N R1 NH2CN NC CN NC Et3N CN CN CN H R2 R1 R2 R1 NH 122 CN R2 123 H124 R1=Ph, 4-MeC6H4; R2=Ph, 4-FC6H4, 4-ClC6H4, cyclo-C3H5. The formation of acetylaminothiophene 125 in a low yield in the recyclisation of hexa-1,3-diene 126 upon refluxing with morpholine polysulfide in ethanol for 4 h has been described.102 NH2CN CN Me NC O HNS8, D NHCOMe EtO2C EtO2CH2C CN CN CN S 125 (1.5%) 126 Recyclisation of six-membered heterocycles with participa- tion of malononitrile possesses a substantially greater synthetic potential.First of all, mention should be made of recyclisation of heterocyclic compounds to carbocyclic compounds. For example, recyclisation of 2,4,6-triphenylpyrylium salt 127 during its reac- tion with malononitrile in tert-butyl alcohol in the presence of potassium tert-butoxide affords 2-amino-3-cyano-4,6-diphenyl- benzophenone 128, which is difficult to obtain by other methods, in a high yield.103 ± 106 O Ph Ph PhC 1, ButOK BF74ButOH Ph Ph O +Ph H2N CN 127 128 Later, this reaction was used to prepare 2-amino-3-cyano-4- methyl(or phenyl)-6-piperidylaceto(or benzo)phenones 129 107 and 2,4,6-triphenylbenzonitrile 130 108 from pyrylium salts 131 and 2,4,6-triphenylthiapyrylium perchlorate 132. R R 1, ButOK + CN N O N ButOH R NH2 4 ROC129 ClO7 131 R=Me, Ph.Ph Ph 1, Pri2NEt ClO74+ EtOH Ph Ph Ph Ph S 132 CN 130 The synthesis of 4-amino-2-benzoyl-1-phenylfluorene-3-car- bonitrile 133 in 89% yield by the reaction of 2,4-diphenyl-5H- indeno[2,1-b]pyrylium perchlorate 134 with malononitrile in ace- tonitrile in the presence of piperidine has been reported.109 45 Ph Ph PhOC 1, HN MeCN NC Ph O + ClO74133 134 NH2 2-Benzopyrylium salt 135 undergoes similar recyclisation on treatment with malononitrile in the presence of sodium tert- butoxide in tert-butyl alcohol. This gives 2-amino-1-(3,4-di- methoxybenzoyl)-4-methyl-6,7-dimethoxynaphthalene-3-carbo- nitrile 136 in 33% yield.110 COR MeO MeO R NH2 + 1, ButONa ButOH CN MeO MeO OClO74135 136 Me Me R=3,4-(MeO)2C6H3. Of other examples of recyclisation of six-membered oxygen- containing heterocycles with malononitrile, the formation of (2- amino-3-cyano-4H-1-benzopyran-4-yl)acetamide 138 from cou- marin 137 should be mentioned.111 CH2CONH2 CN 1, NH3 O O NH2 138 O 137 It has been reported 112 that 2-formyldimedone 139 reacts with malononitrile in the presence of piperidine in methanol or ethanol to give 2-amino-4-dicyanomethyl-7,7-dimethyl-5-oxo-5,6,7,8-tet- rahydrobenzopyran-3-carbonitrile 140 in 78% yield and 3-cyano- 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-2(1H)-quinolone 141 in 20% yield.Me O 1, HN Me H CHO 139 O Me Me O HN O NH2 Me Me + CN CN O O CH(CN)2 141 140 A new method for the synthesis of comunds of the ben- zo[h]quinoline series 142 has been proposed.113 The method is based on the Michael addition of malononitrile to 2-arylidene-1- tetralones 143 in the presence of sodium methoxide in methanol.The reaction mechanism was confirmed by isolation of the reaction intermediate, 4H-naphtho[1,2-b]pyran 144. NC CN O C6H4R-4 O 1, MeONa C6H4R-4 MeOH 143 OR0 NH2 CN CN N O R0O7 C6H4R-4 C6H4R-4 144 142 (73% ± 92%) R=H, Me, Cl, OMe, NO2; R 0 =Me, Et.46 The condensation of pyrazolinone 145 with malononitrile in the presence of ammonium acetate and methyl ethyl ketone on refluxing in ethanol for 3 h gives rise to substituted nicotinonitrile 146.114,115 Me CHO N O OH NC6H4NO2-4 145 MeN O NC6H4NO2-4 MeN O NC6H4NO2-4 The reaction of 4H-pyrans 147, incorporating a dicyano- methylene fragment, with amines is accompanied by recyclisation and results in the formation of 4-dicyanomethylene-1,4-dihydro- pyridines 148.116 ± 118 R NC NC RNH2 O NC NC R 147 R=Alk, Ar.However, the reactions of 4-dicyanomethylene-2-phenyl-4H- benzo[b]pyran 149a and the corresponding thiopyran 149b with malononitrile in methanol in the presence of KOH gives 5-ami- no-4-cyano-2-phenylbenzo[b]pyrano[4,3,2-de][1,6]naphthiridine 150a or the corresponding thiopyranonaphthiridine 150b.119 CN NC 1, KOH MeOH Ph X 149a,b X=O (a), S (b). The benzopyran 149a reacts with primary amines under mild conditions giving rise to 4-amino-5-R-imino-2-phenyl-4H-[1]ben- zopyrano[3,4-c]pyridines 151.120 Ph RNH2 149a O 151 R=Ph, Bn, PhNH. In order to synthesise analogues of the antitumour antibiotic streptonigrin, recyclisation of 4-dicyanomethylene-2-(2-qui- nolyl)-4H-[1]benzopyran 152 in pyridine in the presence of NH4OH has been studied.This reaction gave 4-amino-5-imino- 2-(2-quinolyl)-4H-[1]benzopyrano[3,4-c]pyridine 153 in 91% yield.121 1 CN MeEtCO O NH Me Me N NH2 CN OH 146 (60%) RNR 148 R PhN CN X NH2 N 150a,b N NH2 NR NC R=Recyclisation of 4-dicyanomethylene-2-(2-hydrophenyl)-4H- [1,3]benzoxazine 154 induced by various nucleophiles follows a similar pathway. Thus refluxing of the benzoxazine 154 in 2-methoxyethanol in the presence of ammonium acetate affords 2-(2-hydroxyphenyl)-4,5-diimino-3,4-dihydro-5H-[1]benzopyra- no[4,3-d]pyrimidine 155a in 91% yield.122 The thiazine 155b was prepared by treatment of the benzoxazine 154 with hydrogen sulfide in the presence of triethylamine, and the 1,3-oxazine 155c was synthesised by treatment of the compound 154 with hydro- chloric acid in 2-methoxyethanol.It was noted that adducts 156a ± c are formed as intermediates in this reaction; in the case of the thiazine 155b and oxazine 155c, the Dimroth rearrangement occurs under the reaction conditions, yielding 2-(2-hydroxy- phenyl)-5-imino-4-thio-3,4-dihydro-5H-[1]benzopyrano[4,3-d]p- y-rimidine 157 and 2-(2-hydroxyphenyl)-4,5-dioxo-3,4-dihydro- 5H-[1]benzopyranopyrimidine 158.122 NC 155b 155c X=NH (a), S (b), O (c).When isatic anhydride [2H-3,1-benzoxazine-2,4(1H)-dione] and its substituted derivatives 159 react with malononitrile in DMF in the presence of triethylamine and then the reaction mixture is hydrolysed with 48% HBr or 6N KOH, they are converted into 2-amino-4-hydroxyquinolines 160.123, 124 Com- pounds 161 and 162 were identified as reaction intermediates. R R O NH4OH, Py O CN 153 152 . NO C6H4OH-2H2X N HONC CN 154 C6H4OH-2 N X O 155a ± c NHN NHC6H4OH-2 NH S O 157 (79%) NH N C6H4OH-2 NH O O 158 (45%) O O R O 1, Et3N DMF O HN 159 V P Litvinov RNNH2 NH HN C6H4OH-2 X CN 156a ± c OH CN+ NH2 N 161Recyclisation of carbo- and heterocyclic compounds involving malononitrile and its derivatives OH O R R CCH(CN)2 + NH2 NH2 N 160 (73% ± 86%) 162 R=H, Cl, Me, OMe.Recyclisation of pyrimidines involving malononitrile has been studied comprehensively.19, 125 ± 136 For the reaction of 1,4,6- trimethylpyrimidinium iodide 163, it was found that first the 4(6)-position of the pyrimidine nucleus in the compound 163 is attacked by the malononitrile anion, which gives adduct 164. Then the pyrimidine ring in the compound 164 is cleaved at the N(3) ± C(4) bond. Due to the presence of both nucleophilic [the N(1) atom] and electrophilic [the nitrile group carbon atom] reaction sites, the intermediates 165 and 166 thus formed cyclise to give pyridine 167.The latter is stabilised by being converted into aminopyridine 168 upon abstraction of an aminomethylene frag- ment as methylamine and formic acid.125 Me Me Me N N N 1, Et3N Me I7 Me 7H+ NC N 7N Me N + (CN)2HC Me CN Me 165 Me 163 164 Me Me7 NCH NMe H+ NCH NMe H2O C N Me N7 Me 167 166 CN CN MeN +MeNH2+HCO2H Me NH2 CN 168 Recyclisation of 2,3-disubstituted 4(1H)-pyrimidinethiones 169 on treatment with malononitrile in ethanol in the presence of sodium ethoxide affords pyridinethiones 170 in 78% ±93% yields.128 S S S NC NC 1, EtONa R2N C 7 EtOH N HN N N R1 N 169 NR2 R1 R1 NR2 S NC N H2N NR2 R1 170 R1=Ph: R2=Ph, 3-MeC6H4, 4-MeC6H4; R1=R2=4-MeC6H4.Recyclisation of 2(1H)-pyrimidinediones 129 and fused pyri- midines, such as quinazolines,132 1H-pyrazolo[3,4-d]pyrimi- dines 131 and their 3-oxides 130 occurs in a similar way. The scheme for the recyclisation of pyrimidinediones can be represented in relation to the interaction of 5-cyano-1,3-dimethyluracil 171 with malononitrile.134, 135 47 O O CN Me CN Me N N 1, EtONa H EtOH HCN N O O N C CN Me 171 Me H O O CN Me CN Me N N CN C O N 7N O N N Me Me . . C H NH O CN Me N N N O NH2 Me Recyclisation of 1-thia-2a,5a-diazaacenaphthene system 172 on treatment with malononitrile in ethanol in the presence of sodium ethoxide giving fused tetracyclic heterocyclic compound 173 in 88% yield has been described.136 +NH2Cl7 NH2 S S N N CH(CN)2 1, EtONa EtOH, 25 8C N N CN CN 172 O Me O Me NH NH S S N N N NH2 NH2CN N N CN CN 173 Me O Me O The recyclisation of 1-phenylphthalazine 3-oxide 174 during its reaction with malononitrile in methanol in the presence of sodium methoxide is accompanied by the loss of two nitrogen atoms and gives 3-phenylindene-2-carbonitrile 175.137 Ph Ph N 1, MeONa CN MeOH N O 175 174 The recyclisation of 2,3-diphenyl-5,6-dihydropyrazine 176 occurring on refluxing with malononitrile in ethanol over a period of 1 h follows a peculiar pathway and affords 2,6-diamino-4,10- diphenyl-1,7-diazatricyclo[5.2.1.04,10]deca-2,5-diene-3,5-dicarbo- nitrile 177 in 70% yield.138 7 (CN)2C (CN)2HC N Ph HN HN 1, EtOH Ph Ph Ph Ph Ph N N + H N 176 Ph Ph CN NC NH 1 HN N Ph NC Ph HN NH48 Ph CN NC N N NH2 H2N Ph 177 Recyclisation of 1,3,5-oxadiazinium salts 178 with participa- tion of malononitrile carried out in acetonitrile in the presence of triethylamine has been reported.2-Amino-6-aryl-4-carbamido- pyrimidines 179 were obtained in this way in 65%± 83% yields.139 NR2R3 NR2R3 1, Et3N N N NHCONR2R3 N + MeCN CN X7 NR2R3 R1 R1 O 178 CN NR2R3 N N NHCONR2R3 R1 CN 179 R1=Ph: R2=Me, R3=Me; R2,R3=(CH2)5, (CH2)2O(CH2)2. When reacting with malononitrile, 1,3,5-triazine undergoes recyclisation, similar to the transformation of pyrimidines into pyridines.This gives 4-aminopyrimidine-5-carbonitrile in 80% yield.140, 141 Recyclisation of 4H-1,2,4,6-thiatriazine 1,1-dioxide 180 yielding 3-amino-4-cyano-1,2,6-thiadiazine 1,1-dioxide 181 should be classified as the same type of reaction.142 HN NH CH(CN)2 (NC)2HC 1 HN HN NH NH S S O O O O 180 CN CN HN CH(CN)2 NC N HN C. . NH2 NH HN S S O O O O CN NH2 HN N S O O 181 3-Cyanopyridin-2(1H)-ones, -thiones, -selenones and their derivatives represent an important class of heterocyclic com- pounds because of the diversity of their chemical transformations and the possible practical applications.36, 76, 143 ± 154 These bifunc- tional compounds, which contain the nitrile and the oxo ± hydroxy, thione ± thiol or selenone ± selenol functional groups in the vicinal positions, proved to be promising starting compounds in the preparation of annelated heterocyclic systems difficult to obtain by other methods.143, 144 The strategy of the synthesis of 3-cyano-2-pyridinones, -thiones and -selenones and their hydro- genated analogues is based, first of all, on cyclisation of function- ally substituted carbonyl compounds or their derivatives with malononitrile or other derivatives of cyanoacetic acid.155 ± 164 During these studies it was found that thio(seleno)pyrans 182a,b are formed in the reactions of arylidenemalononitriles 183 with cyanothio(or seleno)acetamides 184a,b, or in a one-step procedure involving aromatic aldehydes, malononitrile, and the amides 184a,b, or in the reactions of arylidenecyanothio(or seleno)- acetamides 185a,b with malononitrile.The compounds 182a,b readily recyclise to give the corresponding pyridinethiones (or selenones) 186a,b.143, 144, 155, 157, 159, 161, 164 ± 179 NC X + NCCH2CNH2 Ar NC 183 184a,b ArCHO+184a,b NC Ar H2NCX 185a,b Ar CN NC C 7X NH2 N Ar CN NC X H2N HN 186a,b X=S (a), Se (b). According to the results of physicochemical studies, including X-ray diffraction analysis, the thio(or seleno)pyran ring in the compounds 182a,b occurs in the flattened boat conformation in which the aryl substituent at the 4-position is equato- rial.159, 168, 180 ± 183 The steric overcrowding of the thio(or seleno)- pyran molecules 182a,b with bulky electron-withdrawing substituents hampers the bond inversion in the ring and inversion of the substituents and thus makes impossible the conformational transitions in the heterocycle at higher temperatures.Therefore, on heating, ring cleavage at the weakest bond occurs (it is denoted by a dashed line in the scheme) and the compounds 182a,b are then converted into pyridinethiones(or selenones) 186a,b. In some studies,165, 184 ± 186 faulty data on the structures of the thiopyrans 182a and the pyridinethiones 186a are presented. The structure of the thiopyrans 182a (Ar = 4-ClC6H4, 4-MeOC6H4) was attrib- uted to the corresponding pyridinethiones 186a.165, 168 The struc- tures of 5-acetyl-2-amino-4-(4-methoxyphenyl)-6-methyl-4H- thiopyran-3-carbonitrile and 2,4-diamino-5-cyano-3-(2-furyl)- methylene-3,6-dihydropyridine-6-thione reported in the litera- ture 185, 186 are also erroneous.In addition, it has been found that the thiopyrans 182a recyclise on treatment with dimedone 187 to give 2-amino-4H-pyran-3-carbonitriles 188, whereas on treatment with ketones, 182a are converted into pyridinethiones 189.187 O 182a + O 187 R1 182a+R1CH2COR2 R2 An original pathway to substituted pyridinethiones 190 has been proposed.188 The reaction of b-enaminothioamides 191 with malononitrile under kinetically controlled conditions gives sub- stituted thiopyrans 192; on heating with a base under thermody- namically controlled conditions, these products are converted into pyridinethiones 190, their yields being more than 80%.V P Litvinov Ar CN NC 1 C 7 X N H N 1 H Ar CN NC D X NH2 H2N 182a,b O Ar CN NH2 O 188 Ar CN S HN 18949 Recyclisation of carbo- and heterocyclic compounds involving malononitrile and its derivatives Ph Ph NC NaOH 1 N ArHNC EtOH S NAr H2N O S 192 191 Ph NC NHAr S HN 190 Ar=Ph, 4-MeC6H4, 4-ClC6H4, 4-BrC6H4, 4-MeOC6H4. Yet another convenient route to substituted 3-cyanopyridine- 2(1H)-thiones is recyclisation of enamino nitriles of the 1,3- dithiacyclohexene series.191 ± 202 In particular, it was found that 2,2-dialkyl-6-aryl-1,3-dithiacyclohex-4-enes are converted into 3-cyanopyridine-2(1H)-thiones 189 in high yields.25, 144,193, 194 This reaction is formally accompanied by elimination of a hydro- gen sulfide molecule and two hydrogen atoms, the subsequent transformations being determined by the structure of the initial substrate.The reaction conditions also have a substantial influ- ence on its course. For example, recyclisation of 1,3-dithiacyclo- hex-4-ene 199 carried out in the presence of an organic base in methanol at 20 ± 25 8C yields pyridinethione 200, whereas heating of the compound 199 in DMF at 150 ± 160 8C gives a mixture of the pyridinethiones 200 and 201. Ar CN Me MeOH NH2 20 ± 25 8C Recyclisation of 6-amino-3,4-tetramethylene-2-thiothio- pyran-5-carbonitrile 193 involving organic bases affords substi- 3-cyano-4,5-tetramethylene-1,2-dihydropyridine-2(1H)- S Me CN HN S R1=R2=Me tuted thiones 194.189 H2N S R1H2C 200 Ar S Ar S NH R2 CN S NC X N NC 199 DMF +HN X +200 7H2S 150 ± 160 8C S Et NH194 193 201 X=O, CH2.The ylidene-derivatives of 6-amino-2H-thiopyran-5-carbon- itrile 195, prepared from thiopyrylium salts, are converted into 2,6-dicyano-3-sulfanylanilines 196; this reaction is similar to the reactions of pyrylium salts with nucleophiles.187 R3 R3 CN R2 CN R2 MeONa MeOH R1OC SHCN S NH2 H NC COR1 CN 195 To elucidate the recyclisation mechanism, 4-amino-6-phenyl- 2-cyclohexanespiro-1,3-dithiacyclohex-4-ene-5-carbonitrile 199 [Ar = Ph, R1,R2 = (CH2)4] was studied by X-ray diffraction analysis.198 The results led to the conclusion that the molecules of 1,3-dithiacyclohex-4-enes 199 contain a conformationally rigid intramolecular system. Therefore, energy supplied from the out- side causes rupture of the weakest bonds, S(1) ± C(6) and S(3) ± C(2), (shown by a dashed line in the scheme), which results in the formation of cyclohexanethione or acyclic thioketones 202 and arylidenecyanothioacetamides 203 as intermediates.The com- pounds 202 and 203 are finally converted into 3-cyanopyridine- 2(1H)-thiones 189.25, 144, 194, 198 R3 R3 NH2 CN R2 CN R2 CN NC R1H2C S 7MeOCOR1 HS NH2 R1H2C HS Ar NH COR1 Ar NC R2 S +H2NSC203 S 199 R2 202 CN 196 R1=OMe, NH2: R2=Me, R3=Et; R2,R3=(CH2)4. Ar Ar CN R1 CN R1 7H2S CSNH2 In turn, piperidone 197, containing a cyanothioacetamide fragment, recyclises on refluxing in ethanol in the presence of a catalytic amount of piperidine to give 2,7-naphthiridine 198.190 S R2 S R2 HN O Ar CN Me HN CN R1 EtOH CSNH2 Me N S R2 HN 197 Me Me 189 Me CN Me MeN N CN Me EtO2C CSNH2 EtO2C Me CSNH2 CN CN S Me S Me 7H2 NH MeN MeN NH MeO MeO 198 (74%) The mechanism of recyclisation of 4H-thiopyrans and 1,3- dithiacyclohex-4-enes 199 was confirmed by studying their cross- recyclisation with various CH acids, a-methylene ketones, 1,3- dicarbonyl compounds and their enamines, ethyl cyanoacetate and malononitrile.25, 143, 144, 181 ± 183 Under thermodynamically controlled conditions, cycloelimination of heterocyclic com- pounds 182 and 199 occurs, yielding arylidenecyanothioacet- amides 203 and either malononitrile or thioketones, respectively.The subsequent competing transformations of the amides 203 involving malononitrile or carbonyl compounds give rise to substituted pyridinethiones 204 or 186a.50 Ar CN NC 7CH2(CN)2 NH2 H2N XCH2COY D [203] S 182a NH2 [or CH2(CN)2] CN S CH2R1 R1H2C 7S Ar R2 R2 S 199 Ar Ar NC CN CN X or S S H2N Y NH NH 204 186a X=Alk, OAlk; Y=Alk. To elucidate the mechanism and stereochemistry of trans- formations of the heterocyclic compounds 182a and 199, their reactions with pyridinium ylides have been studied.144, 156, 181, 182 It was found that in this case, too, arylidenecyanothioacetamides 203 are formed as intermediates; they react stereoselectively with pyridinium ylides to give 3,4-trans-1,2,3,4-tetrahydropyridine-2- thiolates 205.The latter are converted into pyridinethiones 206 on heating with ammonium acetate in acetic acid. + Ar H N 7 AcONH4 CN 203+ +NCHCOR AcOH R HO S7 R HN 205 Ar CN S R NH206 The results obtained demonstrated that the stereochemistry and the electronic structures of heterocyclic compounds 182a and 199 have similar features, namely, (1) both molecules contain a planar enaminonitrile fragment with a well-developed system of p,p-conjugation; (2) they are partially hydrogenated; (3) they contain a nonplanar ring sterically overcrowded with alkyl and aryl substituents; (4) they contain one or several electron-with- drawing groups as substituents. Due to these features, when the enthalpy increases, the compounds 182a and 199 cannot decrease their energy upon conformational transitions; instead, they undergo cycloelimination involving the weakest bonds.The reactions of arylidenecyanothioacetamides 203 with dimedone afford substituted pyrans 207, which recyclise in the presence of bases to give intermediates 208 and then quinoline- thiolates 209.203 ± 206 Ar O O CSNH2 B : 25 8C 203+ O NH2 O 207 187 Ar O Ar O CN CN D BH+ S7 CSNH2 O7BH+ N 209 208 V P Litvinov V. 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Yu A Sharanin, V P Litvinov, A M Shestopalov, V N Nesterov, Yu T Struchkov, V E Shklover, V K Promonenkov, V Yu Mortikov Izv. Akad. Nauk SSSR, Ser. Khim. 1768 (1985) f 199. Yu A Sharanin, V K Promonenkov, V P Litvinov, A M Shestopalov, in Novoe v Khimii Azinov (Tez. Dokl.), Sverdlovsk, 1985 [New in the Chemistry of Azines (Abstracts of Reports), Sverdlovsk, 1985] p. 75 200. V K Promonenkov, Yu A Sharanin, V P Litvinov, A M Shestopalov, Yu T Struchkov, V E Shklover, V N Nesterov, in Khimiya i Tekhnologiya Geterokumulenov dlya Proizvodstva Khimicheskikh Sredstv Zashchity Rastenii (Tez. Dokl. Vsesoyuz. Soveshch.), Moscow, 1985 [The Chemistry and Technology of Heterocumulenes for Production of Chemical Means for Plant Protection (Abstracts of Reports of the All-Union Meeting), Mos- cow, 1985] p. 44 201. Yu A Sharanin, V K Promonenkov, A M Shestopalov, in Vsesoyuz. Soveshch. po Khimii i Tekhnologii Piridinovykh Osnovanii dlya Proizvodstva Khimicheskikh Sredstv Zashchity Rastenii (Tez. Dokl.), Moscow, 1983 [The All-Union Meeting on the Chemistry and Technology of Pyridine Bases for Production of Chemical Means for Plant Protection (Abstracts of Reports), Moscow, 1983] p. 40 202. A M Shestopalov, Yu A Sharanin, V P Litvinov, V K Promonenkov Zh. Obshch. Khim. 59 2395 (1989) d 203. V K Promonenkov, Yu A Sharanin, M P Goncharenko, A M Shestopalov, S N Melenchuk, in Khimiya i Tekhnologiya Geterokumulenov dlya Proizvodstva Khimicheskikh Sredstv Zashchity Rastenii (Tez. Dokl. Vsesoyuz. Soveshch.), Moscow, 1985 [The Chemistry and Technology of Heterocumulenes for Produc- tion of Chemical Means for Plant Protection (Abstracts of Reports of the All-Union Meeting), Moscow, 1985] p. 57 204. M P Goncharenko, V K Promonenkov, Yu A Sharanin, in Khimiya i Tekhnologiya Piridinsoderzhashchikh Pestitsidov (Tez. Dokl. Vsesoyuz. Konf.), Chernogolovka, 1988 [The Chemistry and Technology of Pyridine-Containing Pesticides (Abstracts of Reports of the All-Union Conference), Chernogolovka, 1988] p. 125 205. Yu A Sharanin,M P Goncharenko Zh. Org. Khim. 24 460 (1988) b 206. M P Goncharenko, Candidate Thesis in Chemical Sciences, Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 1993 a�Chem. Heterocycl. Compd. (Engl. Transl.) b�Russ. J. Org. Chem. (Engl. Transl.) c�Mendeleev Chem. J. (Engl. Transl.) d�Russ. J. Gen. Chem. (Engl. Transl.) e�Dokl. Chem. Technol., Dokl. Chem. (Engl. Transl.) f�Russ. Chem. Bull. (Engl.

ISSN:0036-021X    

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Russian Chemical Reviews 68 (1) 55± 72 (1999) Reductive amination of oxygen-containing organic compounds VATarasevich,NGKozlov Contents I. Introduction 55 II. Reductive amination of carbonyl compounds with ammonia and amines 55 III. Reductive amination of alcohols with ammonia and amines 60 IV. Reductive amination of aldehydes and ketones with nitro compounds and pyridine bases 62 V. Reductive amination of aldehydes, ketones and alcohols with nitriles and oximes 63 VI. Conclusion 69 Abstract. The data dealing with reductive amination of oxygen- containing organic compounds of different classes are systema- tised. New data on the amination agents and the catalysts used are presented. The dependence of the reactivity of reagents on their structures is considered.The bibliography includes 249 references. I. Introduction Reductive amination or hydroamination is widely used for the synthesis of amines. This method is based on the reaction between oxygen- and nitrogen-containing compounds on the surface of a catalyst under a hydrogen atmosphere or in solution in the presence of hydrogen donors. In the literature, this reaction is often referred to as `reductive alkylation', which does not reflect exactly its chemical essence. It has beenshowninnumerous studies that during the reaction with oxygen-containing compounds in the presence of hydrogen donors, some nitrogen-containing compounds, namely, nitro and nitroso compounds, nitriles and oximes, are first reduced to amines, and then the latter react with oxygen-containing com- pounds.Thus, this reaction occurs successfully when an amino group is present; therefore, it is more correct to call this reaction `reductive amination' or `hydroamination' rather than `reductive alkylation'. This reviewdeals withreductive aminationreactions involving hydrogen or hydrogen donors; the reaction conditions and the catalysts used are discussed. II. Reductive amination of carbonyl compounds with ammonia and amines The ability of ammonia and amines to formimines with aldehydes and ketones and the fact that imines can be reduced relatively easily to the corresponding amines permitted the synthesis of amines by direct amination of carbonyl-containing compounds V A Tarasevich Centre for Chemical Technology, Belarus Academy of Sciences, ul.Zhodinskaya 16, 220141 Minsk, Republic of Belarus. Fax (7-017) 263 19 23. Tel. (7-017) 264 11 16 NGKozlov Institute of Physical Organic Chemistry, Belarus Academy of Sciences, ul. Surganova 13, 220072 Minsk, Republic of Belarus, Fax (7-017) 268 46 79. Tel. (7-017) 268 53 70 Received 2 July 1998 Uspekhi Khimii 68 (1) 61 ±79 (1999); translated by Z P Bobkova #1999 Russian Academy of Sciences and Turpion Ltd UDC 547.233 with ammonia or amines. Hydrogen (in the presence of a catalyst) or formic acid and its derivatives are used most often as the reducing agents in this process. This reaction is widely employed to prepare amines fromvarious aldehydes and ketones. Mignonac 1, 2 was the first tocarry out the reductive amination of aldehydes and ketones with ammonia.Mixtures of the corre- sponding primary, secondary and tertiary amines were obtained from aliphatic aldehydes and ammonia in the presence of nickel catalysts. Inthe first stage of the reaction, ammonia adds tothe carbonyl compound (Scheme 1, pathway a); this is followed by the reduction of either the product of nucleophilic addition itself, a-amino alcohol 1 (pathway d), or the product of its dehydration, imine 2 (pathways b and c).3 In some cases, the imines formed in the condensation of carbonyl compounds with ammonia can be isolated, whereas the a-amino alcohol 1 could not be isolated.4 As the primary amine is accumulated in the reaction mixture, it enters intoreactionwiththe initial carbonyl compoundsimilarly to ammonia (Scheme 1, pathway e).The imine 3, which is formed upon dehydration of the condensation product, is converted into secondary amine (pathways f and g). In addition, primary amine canreact withthe imine 2 to give addition product 4, the reduction of which also gives a secondary amine (pathways h± j). Secondary amines also can enter into this type of reactions (pathways k± n); this gives tertiary amines. Thus, the process occurs as a set of consecutive and parallel reactions yielding a mixture of primary, secondary and tertiary amines. To suppress the formation of secondary and tertiary amines, the reductive amination of carbonyl compounds is carried out in the presence of ammonium salts.5 Under these conditions, only primary amines are formed.Apparently, an excess of ammonium salts shifts equilibrium towards primary amines; in addition, the formation of secondary amines is suppressed because primary amines lose their nucleophilic properties upon transformation into alkylammoniumions + + H H H H Cl7 N H . Cl7+ H N H R N H R N + H H H H For example, the introduction of ammonium chloride into the reaction mixture during hydroamination of 1-(2,5-dimethoxyphe- nyl)propan-2-one 5 with ammonia in methanol in the presence of Raney nickel permitted the synthesis of 2-amino-1-(2,5-dimethox- yphenyl)propane 6 in 95%yield.656 MeO O CH2CMe OMe 5 Most often, hydroamination of carbonyl-containing com- pounds with ammonia is carried out in the presence of nickel catalysts.7 ± 9 When metallic rhenium and rhodium supported on alumina are used as the catalysts, the total yield of primary and secondary amines reaches 93%± 95%.10 In order to direct the process at the formation of secondary amines, catalysts are often modified by various oxides.Thus the reaction of cyclohexanone 7 with ammonia catalysed by the 0.35% PdO/SiO2 catalyst modi- fied by Ag, Mn, K, Na and Al oxides gives dicyclohexylamine 8 in 97% yield.11 NH3 O PdO/SiO2 7 Synthesis of 2,2-disubstituted 1,5-diaminopentane derivatives by the reaction of the corresponding aldehydes containing a terminal nitrile group with excess ammonia over acid catalysts has been reported.12, 13 The imino nitrile formed in the first stage is hydrogenated over catalysts based on Co, Ni, Ru and other noble metals at 60 ± 150 8C and 5 ± 15 MPa.The yields of diamines amount to 50% ± 72%. The use of reduced promoted fused iron catalysts (RPFIC) in various reactions, most of all, in reductive amination of carbonyl- containing compounds, has been described in a review.14 Among other reactions, the reductive amination of octan-2-one with ammonia has been studied in detail.15 ± 18 The kinetic isotope effect observed after replacement of H2 by D2 made it possible to propose a stepwise mechanism of reductive amination of carbonyl compounds, the addition of hydrogen to ketimine being the rate- determining step. Hydroamination of 3,5,5-trimethylcyclohex-2-enone (iso- phorone, 9) with ammonia in the presence of a copper ± zinc ± aluminium catalyst (SNM-1) and RPFIC at 160 ± 230 8C has been reported.19, 20 The yield of 3,3,5-trimethylcyclohexylamine 10 reaches 90%± 95%.RR0CHNH CR0R OH f 7H2O RR0CHN CR0R 3 g H2 RR0CHNH CHR0R RR0C O k (RR0CH)2N CR0R OH MeO NH3, H2 NH 8 RR0CHNH2 RR0C O NH3 a e H2 RR0CHN CR0R j 7NH3 i 2 (RR0CH)2N CR0R m H2 H2 NH2 7NH3 n (RR0CH)3N 7H2O l NH2 CH2CHMe OMe 6 3-Aminomethyl-3,5,5-trimethylcyclohexylamine 11 is pre- pared by reductive amination of 1,3,3-trimethyl-5-oxocyclohex- anecarbonitrile 12 with ammonia with simultaneous reduction of the cyano group at 50 ± 150 8C on Raney nickel or cobalt using anhydrous Ni, Co, Y, and La halides as co-catalysts.The yield of the amine 11 was 83%.21 Transformation of aldehydes and ammonia into secondary amines was attained 22 by using a three-component catalyst based on Cu, a metal of the series Cr, Mn, Fe and Zn and a platinum group metal (Pt, Pd, Ru, Rh). The predominant formation of either primary or secondary amines from ketones and ammonia can depend significantly on the procedure used to prepare the catalysts and on the catalyst composition, all other factors being the same. Study of hydroamination of cyclohexanone 7 with ammonia in the presence of various catalysts has demonstrated 23 that in the presence of a nickel catalyst, the primary amine, cyclohexylamine 13, is formed predominantly, whereas the use of colloidal platinum results in the secondary amine 8 being formed as the major product.However, later,24 it was found that in the presence of plati- nated silica gel, the ketone 7 is readily converted into the primary amine 13 rather than into the secondary amine 8, as noted in the study 23 cited above. Thus, depending on the method for the preparation of the platinum catalyst, either secondary or primary amines can be synthesised. Hydroamination of alicyclic ketones with aromatic amines in the presence of catalysts containing Ru, Rh, Pd or Ni supported on g-Al2O3 yields, depending on the temperature conditions, either cycloaliphatic or aromatic secon- V A Tarasevich, N G Kozlov Scheme 1 H2 RR0C OH RR0CHNH2 7H2O d NH2 1 H2O H2 7H2O b RR0C NH c 2 2 RR0CHNH CR0R h 4 NH2 Me Me NH3, H2 Me Me 7H2O O H2N Me Me 10 9 Me CN Me CH2NH2 NH3, H2 Me Me 7H2O O H2N Me Me 11 12 7, H2 NH3, H2 NH O NH2 Cat 7H2O 8 13 7Reductive amination of oxygen-containing organic compounds dary amines.For example, at 180 8C and pH2=5 MPa,25 dicy- clohexylamine was obtained from cyclohexanone 7 and aniline 14a over a nickel catalyst, whereas the reaction between the same compounds or their para-substituted derivatives at temperatures of dehydration of alicyclic compounds (above 300 8C) gives 26 only the corresponding diarylamines. R R0 O +H2N 14a ± c 180 8C, H2 NH 7H2O 8 (R=R0=H, 74%) 350 8C NH R R0 7H2,7H2O R, R 0 =H (a), Hal (b), Alk (c).The reductive amination of arylaliphatic aldehydes and ketones with ammonia results in the formation of primary aliphatic-aromatic amines. 9, 27, 28 The reaction is complicated by the reduction of the corresponding carbonyl compounds to hydrocarbons. The yield of the amination products is influenced by the location of the carbonyl group with respect to the aromatic ring of the initial aldehyde or ketone. The yields of amines produced from aromatic aldehydes or alkyl aryl ketones are much lower than the yields of amines formed upon hydroamina- tion of ketones in which the carbonyl group is removed from the aromatic nucleus. Thus over a nickel catalyst at 150 8C and 8 MPa, acetophenone is converted into 1-phenylethylamine 16 in 50% yield.28 O NH2 NH3, H2 CHMe CMe Cat 16 15 NH2 NH3, H2 CH2 CH2CHMe Cat Under the same conditions, benzylideneacetone 17 gives 2-amino-4-phenylbutane in 84% yield.29 O CH CHCMe 17 18 In this case, it should be borne in mind that the reaction starts with hydrogenation of the alkene double bond.This eliminates the conjugation between the carbonyl group and the aromatic nucleus. Thus it has been shown 30 that hydrogenation of 3-phe- nylacrolein 19 at 80 8C and pH2=2 MPa gives initially aldehyde 20 and then alcohol 21. OH O O 21 20 19 A method has been proposed 31, 32 for the synthesis of dia- mines 22 from aliphatic dialdehydes containing four to ten carbon atoms; according to this method, they are treated with excess ammonia and hydrogen in the presence of Ni, Co, Pd or Ru catalysts at 40 ± 1508 C and a pressure of 10 MPa.NH3, H2 H2NCH2(CH2)nCH2NH2 CHO(CH2)nCHO Cat 22 (78% ± 90%) n=4 ± 10. In order to prevent the formation of secondary amines and possible intramolecular cyclisation giving a heterocyclic deriva- 57 tive, excess ammonia is used (the ammonia : aldehyde molar ratio is 5 : 1). Conversely, an excess of the initial dicarbonyl compound is favourable for the formation of heterocyclic systems. Thus the reaction of acetonylacetone 23 with ammonia [the diketone : am- monia molar ratio is (2 ± 3) : 1] in the presence of Raney nickel at pH2=15 MPa resulted in the synthesis of a mixture of 2,5- dimethylpyrrole 24 and 2,5-dimethylpyrrolidine 25, i.e.amination and cyclisation were accompanied by hydrogenation of the pyrrole ring.33 Esters of 4-oxo acids behave in a similar way. O NH O O NH3 MeCCH2CH2CMe MeCCH2CH2CMe Cat 23 Me Me O NH2 NH + NH MeCH CHCH2CMe 7H2O Me Me 25 (28%) 24 (59%) Hydroamination with primary amines, like hydroamination with ammonia, involves evidently the intermediate formation of addition product 26, which is either hydrogenated to amine 27 or is converted initially into imine 28 and then into the amine.34 OH R00NH2 RR0C O RR0C NHR00 26 RR0C NR00 +H2O 28H2 H2 RR0CHNHR00 27 A kinetic study of the catalytic reductive amination of acetone 29 with isopropylamine 30 in aqueous alcohol over a platinum catalyst at 29 8C has demonstrated 35 that the reaction consists of two steps: the formation of imine 31 and its subsequent hydro- genation, giving rise to diisopropylamine 32.PriNH2 (30) H2 Pri2NH Cat Cat Me2C NPri 31 Me2CO 29 32 This pathway to secondary amines, which includes the for- mation of imines, has also been confirmed in studies dealing with hydroamination of furfural 33 with aromatic amines. It was shown that the reaction over palladium catalysts includes the initial formation of the corresponding imines, which are then hydrogenated, in particular, in the furan ring.36 ± 38 The yields of substituted N-(2-tetrahydrofurylmethyl)anilines 34 vary from 10% (for o-bromoaniline) to 85% (for aniline).When palladium immobilised in the polymeric matrix of the AB-17-8 or AN-1 anion exchanger is used, the yield of N-(2-tetrahydrofurylmethy- l)aniline reaches 100%. R H2, Cat CHO + H2N 7H2O O33 R R H2 NH CH N Cat O O CH234 R=H, m-Me, p-Me, o-Me, m-Hal, p-Hal, o-Hal. The reductive amination of furfural 33 with cyclohexylamine over the same catalysts at 20 ± 60 8C and pH2=0.98 ± 1.03 MPa in a solvent (an alcohol or a hydrocarbon) affords N-(2-tetrahydro- furylmethyl)cyclohexylamine 35 in a high yield.58 H2, Cat CHO + H2N 7H2O 13 O33 H2 NH CH N CH2 Cat O O 35 (99%) Palladium catalysts immobilised in an anion-exchanger poly- meric matrix are inferior to Pd/C regarding the rate of formation of the amine 35 but are superior regarding the selectivity and the service stability.The rate of reductive amination of the aldehyde 33 was found 39 to be directly proportional to the dielectric constant of the solvent. N,N-Diethylaminophenols are prepared 40 in high yields by reductive amination of acetaldehyde with o-, m- and p-amino- phenols at 150 8C and pH2=2 MPa in the presence of Pt, Pd or Ni catalysts in the medium of an aliphatic alcohol (MeOH, EtOH, PrnOH). For example, in the case of m-aminophenol, the yield of N,N-diethyl-m-aminophenol was 98.4%. In a study of reductive amination of aliphatic ketones with primary amines, it has been found 41 ± 43 that the product yield is substantially influenced by steric factors caused by the structures of both the ketone and the initial amine.Steric restrictions were considered 44 to be the only reason for the fact that the yields of amines upon the hydro- amination of ketones with cyclohexylamine 13 decrease in the sequence acetone>methyl ethyl ketone>diethyl ketone. When ethanolamine is used instead of cyclohexylamine, steric hindrance markedly diminishes, and the yields of hydroamination products obtained from acetone and diethyl ketone 36 become almost identical. Study of the influence of steric factors on the reductive amination of acetone with aniline and 2,4,6-trimethylaniline 37 45 has shown that the sterically hindered amine 37 is converted into secondary amine, N-isopropyl-2,4,6-trimethylaniline 38, in 36% yield (when aniline is used, the yield of the corresponding secondary amine increases to 98%).Me Me Me2CO, H2 Me NHPri Me NH2 Cat Me Me 38 37 The yield of the product of reductive amination of benzylide- neacetone 17 and benzylideneacetophenone 39 with toluidines 46 Me 300 8C 3 4 R R H2 H2 5 2 Me(CH2)2CCH2CHCHR0 CH2CHCHR0 Pt Pt O1O NHR00 46 NHR00 47 200 8C Me R=R0 =H, Me, Et; R00 =H, Me. V A Tarasevich, N G Kozlov varies as a function of the position of the methyl substituent in the aromatic amine. The yields of secondary amines 40 in the hydro- amination of the ketone 17 were 14.0, 35.0 and 52.4% for o-, m- and p-toluidine, respectively. Meanwhile, it was found that the yields of secondary amines formed from aliphatic amines increase with an increase in the basicity of the amine used. O Me H2 CH CHCR+H2N 7H2O 17, 39 R Me CH2 CH2CHNH 40 R=Me (17), Ph (39).Secondary amines of the aliphatic series have been prepared in two stages from primary amines and aldehydes.47 In the first stage, imines were synthesised; after isolation, they were hydrogenated over a platinum catalyst in anhydrous EtOH. The total yields of the imines 41 and the amines 42 were 40%± 63%.48 R0CHO H2 R NH2 Pt 7H2O RN CHR0 41 RNHCH2R0 42 R=R0 =Et, Prn, Pri, Bun, Bui. Reductive amination of carbonyl compounds of the furan series has been studied only occasionally. Reductive amination of unsaturated ketones 43 with ammonia has been reported.49 ± 51 The reaction was carried out in methanol saturated with ammonia over skeletal nickel ± aluminium catalyst and under a hydrogen pressure of 12 ± 14 MPa.52 O NH2 NH3, H2 Cat (CH CH)nCR (CH2 CH2)nCHR O O 43 n=1, 2; R=Alk.The synthesis of pyrrole (44) and pyrrolidine (45) homologues from furan derivatives 46, containing an amino group in the alkyl substituent, over platinum catalysts should be regarded as a peculiar intramolecular reductive amination reaction (Scheme 2). The reaction consists of two stages: hydrogenolysis of the furan ring at the O(1) ± C(5) bond to give amino ketones 47 and amino alcohols 48 and their intramolecular hydroamination leading to the formation of a heterocycle.53 ± 55 Selective hydrogenolysis at the O(1) ± C(5) bond is possible only with platinum catalysts R Scheme 2 R0 NR00 44 R Me(CH2)2CHCH2CHCHR0 OH NHR00 48 R R0 NR00 45Reductive amination of oxygen-containing organic compounds (Pt/C, Pt/asbestos); in this case, the mixture of reaction products contains pyrrolidines and pyrroles with a propyl radical at the 5-position.Pyrrolidine homologues are formed at 200 ± 220 8C, their yields being 85%± 90%, whereas pyrrole homologues are produced at 300 8C in *85% yield. The yields of N-methyl- substituted pyrrolidines and pyrroles are somewhat lower (70% and 73%± 75%). High-boiling nitrogen-containing compounds (2% ± 3%) and the recovered amine (*23%) were also detected in the product mixture.55 The structure of the pyrrolidines and pyrroles formed is determined by the structure of the aminoalkyl side chain.54, 55 The influence of the structure of alkyl and aminoalkyl groups in the molecules of the furan derivatives 49 on the course of hydro- genolysis and the formation of pyrrole and pyrrolidine trialkyl derivatives was studied.55 3 4 R 2 5 Me CH R00 C CH2 O1NH2 R0 49a ± c R=R0=R00=H (a); R=Me, R0=R00=H (b); R=R0=R00=Me (c).When the substituents R and R0 at the carbon atom attached directly to the furan ring in 49 are methyl groups, hydrogenolysis of the furan ring is more selective, due to the shielding effect, and involves the O(1) ± C(5) bond. In addition, in the presence of these substituents, the formation of the pyrrole ring is impossible. As a result, catalytic hydrogenation of 2-(3-amino-1,1-dimethylbutyl)- 5-methylfuran 49c over platinum catalysts at 250 8C resulted in the synthesis of 2-n-butyl-3,3,5-trimethylpyrrolidine 51.56 3 4 Me H2 2 5 Pt Me C CH2CHMe O1NH2 Me Me 49c 2 3 Me Me H2 Me(CH2)3C C CH2CHMe 4 NH 7H2O 5 O Me NH2 Me 50 51 Whereas the reaction on platinum catalysts gives only one series of pyrrolidine homologues owing to the selective rupture of the C(5) ± O(1) bond at 200 ± 220 8C, in the presence of skeletal nickel ± aluminium catalysts, three series of pyrrolidine homo- logues containing methyl, ethyl or n-propyl groups at the 2-posi- tion can be obtained (Scheme 3).57 Scheme 3 3 4 R 2 5 CH2 CH CH2 O1NH2 b c a R R R MeCCH2CHCH2 MeCH2CCH2CHCH2 Me(CH2)2CCH2CHCH2 O O NH2 NH2 NH2 O R R R NH NH HN (a) rupture of the O(1) ± C(5) bond; (b) rupture of the O(1) ± C(5) and C(4) ± C(5) bonds; (c) rupture of the O(1) ± C(5) and C(3) ± C(4) bonds.59 The yield of pyrrolidines in the hydrogenolysis products was, on the average, 70%± 75% based on the consumed amine. The pyrrolidines formed contained 35% of 2-methyl-4-R-pyrrolidines, 20% of 2-ethyl-4-R-pyrrolidines and 45% of 2-n-propyl-4-R- pyrrolidines. The formation of a particular pyrrolidine homo- logue depends substantially on the reaction temperature. For example, when the temperature is raised to 270 8C, the proportion of 2-methyl-4-R-pyrrolidines increases to approximately 50%± 60%; however, the overall content of pyrrolidines in the reaction products diminishes to 30%± 40%.The synthesis of pyrrole homologues over skeletal nickel ± aluminium catalyst is carried out at 300 8C;58 in this case, the mixture of pyrroles contains 30% of 2-methyl-5-R-pyrroles, 25% of 2-ethyl-5-R-pyrroles and 45% of 2-n-propyl-5-R-pyrroles (Scheme 4). 3 4 Scheme 4 2 5 CH R CH2 CH2 O1NH2 b c a R R R MeC(CH2)2CH MeCH2C(CH2)2CH MeCH2CH2C(CH2)2CH O O O H2N H2N H2N R R R HN NH HN (a) rupture of the O(1)7C(5) bonds; (b) rupture of the O(1)7C(5) and C(4)7C(5) bonds; (c) rupture of the O(1)7C(5) and C(3)7C(4) bonds. Hydroamination of cyclohexanone 7 and cyclopentanone 52 was performed 59 using azobenzene 53, 1,2-diphenylhydrazine 54 and cyclohexanone phenylhydrazone 55.It is known that hydra- zines are able to undergo hydrogenolysis over nickel ± alumina or copper ± alumina catalysts at 250 8C to give primary amines.60 It was found that in all cases, hydrogenolysis of the N±N bond and the formation of secondary cycloalkylamines (in 18% to 75% yields) is a typical reaction pathway. Since the N=N bond in azobenzene 53 is relatively stable, it can undergo hydrogenolyis only after saturation; therefore, the use of the hydrazine 54 results in higher yields of the reductive amination products; for example, the yields of N-cyclohexylaniline 56 obtained upon hydroamina- tion of cyclohexanone with azobenzene and 1,2-diphenylhydra- zine are 45% and 75%, respectively. H2 NH NH N N 54 53 7, H2 H2 N NH2 7H2O 14a NH 56 Several studies,14, 61 ± 70 `generically' related to hydroamina- tion, deserve special attention.They describe the synthesis of various amines in the presence of RPFIC in the Fischer ± Tropsch synthesis. These catalysts are used to prepare various hydro- carbons and oxygen-containing organic compounds from CO and H2.71, 72 The use of the modified Fischer ± Tropsch reaction for the synthesis of oxygen-containing compounds and their reductive amination with ammonia, alkylamines and piperidine 57 have led to the development of a number of one-step proce-60 dures for the synthesis of various amines. Thus hydrogenation of CO at 169 ± 195 8C, 10 ± 12 MPa and at an H2 :CO ratio of (2 ± 6) : 1 in the presence of HNMe2 (1 vol.%±10 vol.%) over RPFIC gives rise to dimethylalkylamines.70 The yield of liquid amines reaches 73%. The use of piperidine and RPFIC in the modified Fischer ± Tropsch synthesis permitted the preparation of N-alkyl- piperidines with alkyl substituents consisting of one to fifteen C atoms at the nitrogen atom (the selectivity of the reaction with respect to amines reaches 97%).64 ± 69 The highest activity was found for RPFIC containing V2O5, Al2O3 or Cr2O3 and CuO.68 Two pathways to N-alkyldimethylamines are possible: (1) hydro- amination of a surface oxygen-containing intermediate, precursor of an aldehyde, ketone or alcohol; (2) direct hydroamination of alkanals or alkyl methyl ketones, primary components of the Fischer ± Tropsch synthesis.Synthesis of alkylamines from CO, H2 and N2 in the presence of RPFIC has been carried out. The process included two alternating reactions performed in one catalytic area: first NH3 was obtained from H2 and N2 and then it was used to aminate the oxygen-containing or olefinic products of the Fischer ± Tropsch synthesis, formed after the introduction of CO. Primary terminal C4 ±C9 amines were the major reaction products.73, 74 Reductive amination of aldehydes and ketones is usually carried out at high (up to 50 MPa) pressures of hydrogen.75 Various solvents have been used in this process, MeOH, EtOH, PriOH, ButOH, THF and cyclohexanol.76 ± 78 Nickel or cobalt catalysts 34, 77,79 ± 81 and platinum group metals (Pt, Pd) supported on activated carbon 79, 82 ± 85 are used most often. Some metals (Ni, Pt, Ru, Rh) supported on an active material, for example, on alumina or kieselguhr, are also employed.77,86 ± 88 Catalysts based on copper and chromium oxide mixtures have been patented.89 Rhenium and palladium sulfides (Re2S7, PdS) as well as Fe, Co, Ni,Wand Mo sulfides supported on alumina proved to be highly active catalysts of reductive amination.90, 91 In some studies, catalysts modified with sulfur or other organic or inorganic sulfur-containing compounds have been considered.Thus reduc- tive amination of 4-methylpentan-2-one 58 with N-phenyl-1,4- phenylenediamine 59 over nickel supported on kieselguhr (63% Ni) at 165 8C and a hydrogen pressure of 5.2 ± 7.0 MPa gave N-phenyl-N0-(1,3-dimethylbutyl)-1,4-phenylenediamine 60 in 58% yield.The addition of But2S increased the yield of the diamine 60 to 97%.88 H2 MeCCH2CHMe2+H2N NH Ni 59 58 O NH NH MeCHCH2CHMe2 60 Sulfoxides, thiols and sulfur-containing heterocycles have also been used to modify the catalysts.92 The influence of the nature of the catalyst on the yield of the final product can be followed in relation to the reductive amination of camphor 61 with methyl- amine 62. Thus when Raney nickel is used as the catalyst, N- methylbornan-2-imine 63 (yield 82.8%) is formed predominantly, whereas the reaction over 5% Pd/C yields a mixture of the imine 63 and N-methylbornan-2-ylamine 64 (30.4% and 65.7%, respec- tively). H2 MeNH2 (62) 7H2O NHMe NMe O 64 61 63 H If platinum oxide is used as the catalyst, the yield of the amine 64 reaches 92.7%.82 High stereoselectivity of RPFIC, unusual for metallic heterogeneous catalysts, has been noted.93 ± 95 Thus the V A Tarasevich, N G Kozlov degree of transformation of d,l-camphor into endo- (65) and exo- bornan-2-ylamines (64) during hydroamination reaches 92%, the endo to exo ratio being (1.4 ± 1.8) : 1.Apparently, this stereo- selectivity is due to the `imine ± enamine' tautomerisation occur- ring on the acid ± base sites of the catalyst. RNH2, H2 + 7H2O H NHR O 65 64 61 H NHR R=H, Alk. Highly effective and selective catalysts for hydroamination of aldehydes and ketones with ammonia, amines and nitro com- pounds have been developed.These catalysts, which make it possible to conduct this reaction under mild conditions (20 ± 60 8C, and pH2=0.1 MPa), are Pd, Pt, Rh, Co, Fe, Ni and Cu complexes with dimethyl- and dibenzylglyoximes and with poly- meric macroligands such as polyacrylic acid, polyethyleneimine, copolymers, anion exchangers, cation exchangers, etc.96 ± 106 The rate of hydroamination in the presence of these catalysts depends appreciably on the nature of the polymeric matrix. The major contribution to the activity is made by the rigidity of those sections of the macromolecule which bear the active metal sites. The activity and selectivity of these catalysts can be controlled by changing the `local rigidity;' this can be attained by increasing the temperature, by using a different solvent or exchangeable ion, by varying the particle size of the support, by irradiating the polymeric matrix or by introducing microadditives of another solvent.99, 106 III.Reductive amination of alcohols with ammonia and amines The reaction of ammonia with alcohols results in the formation of mixtures of primary, secondary and tertiary amines. In the vast majority of cases, alcohols react with ammonia or amines only in the presence of catalysts. Heterogeneous acidic catalysts have found wide application in industry. In the presence of these catalysts, the process is carried out in the gas phase at 350 ± 450 8C. Their influence consists in the activation of the C±OH bond due to adsorption of the alcohol on the catalyst acid sites.The reactions between ammonia and alcohols are carried out using dehydrating catalysts (copper, nickel and cobalt on alumina, fused iron, copper chromites) 107 ± 111 and hydrogen. In this case, the reaction follows a mechanism other than the acid ± base one. First, the alcohol is dehydrogenated to give aldehyde, and then the aldehyde condenses with ammonia, and the imine thus formed undergoes hydrogenation coupled with dehydration. NH3 H2 RCHO RCH2OH 7H2 7H2O RCH NH Cat RCH NH RCH2NH2 (RCH2)2NH RCH NH (RCH2)3N 7NH3 7NH3 The mechanism of dehydration of alcohols followed by amination has been comprehensively studied by Bashkirov et al.112 ± 117 Secondary and tertiary amines are formed upon the reactions of primary and secondary amines with aldimines.RPFIC modified with various oxides have been successfully used in reactions with amines. For example, hydroamination of a number of alcohols (2-ethylhexan-1-ol, octan-1-ol, octan-2-ol, heptan-4-ol) with dimethylamine at 210 ± 240 8C gave the corre- sponding N,N-dimethylalkylamines in *80% yields. The highest yield of tertiary amine was observed in the presence of RPFIC promoted by 10% Al2O3+1% CuO.118 The same catalyst was used in the reductive amination of borneols 66 with ammonia, which afforded bornylamines 67 and 68, mostly as endo-iso- mers.119Reductive amination of oxygen-containing organic compounds NH3, H2 + 7H2O H NH2 OH 67 68 66 H NH2 Copper-containing catalysts exhibit high activity in the ami- nation of various alcohols with ammonia and amines. When bifunctional catalysts, Cu/Al2O3 or Ni/Al2O3, were used in hydro- amination of alicyclic alcohols, the yields of primary amines reached 80%. To suppress cyclisation and isomerisation, lithium and potassium hydroxides were introduced into the alumina.120 Hydroamination of cyclohex-2-enol 69 in the presence of Cu/ Al2O3, Ni/Al2O3 and Pt/Al2O3 has been studied.121 In the case of the copper catalysts, cyclohexylamine is mostly formed (yield 65%), whereas the reaction carried out at 310 8C over active dehydrating Pt and Ni catalysts containing 10%, 15% and 20% of the metal gives aniline.In the presence of copper and nickel catalysts at 310 8C, pyridine bases are formed, mostly 2-methyl- pyridine (60% ± 62% of the total amount of pyridine bases). Presumably, in the latter case, the reaction passes through the formation of an unstable bicyclic compound resulting from insertion of the nitrogen atom of the amino group into the ring with the simultaneous rupture of the carbon ± carbon bond.NH2 OH NH2 7H2 14a NH3 Cat HN NH3 69 7H2 Cat N When alkanols are hydroaminated with dimethylamine, 2-eth- ylhexylamine and cyclohexylamine over the industrial copper ± zinc ±aluminium oxide-type catalyst (SNM-1) and over RPFIC,122 ± 125 the highest yields of non-symmetrical secondary and tertiary amines (up to 90%) are attained at 175 ± 195 8C and at an amine : alcohol molar ratio of 0.2.Secondary amines con- taining an alkyl radical (C10 ±C22) are prepared by hydroamina- tion of alcohols with primary amines at pH2=0.3 ± 0.5 MPa in the presence of the Ni or Ni ± Cu catalyst containing someK2CO3; the yields of non-symmetrical secondary alkylamines can be as high as 85%. H2 RNHR0 +RNR0 RNH2+R0OH 2 Ni, K2CO3 R=C10H21 ±C22H45, R0 =CH3 ±C8H17. When K2CO3 is not added, the content of secondary amine in the amination products is 17%, and the content of tertiary amine is 45%.126 To increase the yield of amines, nickel catalysts are modified with various additives. Thus the activity of nickel oxides prepared by various methods and their mechanical mixtures with titanium dioxide, quartz and Aerosil has been studied in the vapour-phase amination of n-butanol in the presence of hydrogen under atmospheric pressure.127 Synergism of nickel ±titanium and nickel ± silicon binary oxide catalysts in this reaction was found.It is noteworthy that in some cases, in order to attain higher yields of amines, two-stage synthetic procedures are used, which include a separate a stage of dehydration of alcohols to aldehydes.111 Non-symmetrical dialkylamines are prepared in 75% ±90% yields 112 by the reaction of a primary amine with an alcohol in the presence of a catalyst containing copper chromite at 180 ± 210 8C and pH2=4.0 ± 12.0 MPa. When copper catalysts are used, the reaction between ethanol and ammonia at pH2=15.0 MPa affords triethylamine (yield 90%).128 Unlike hydroamination of primary and secondary aliphatic alcohols with ammonia, which mainly yields primary amines, hydroamination of tetrtahydrofurfuryl alcohol 70 gives rise to a 61 heterocyclic compound, piperidine 57.This reaction, which is of interest from the practical viewpoint, has been studied in detail.129 ± 135 Scheme 5 shows the possible pathways to the main products (57, 71 ± 74) formed from the alcohol 70, ammonia and hydrogen. It was found that, irrespective of the catalyst used, the reaction products contain piperidine, tetrahydrofurfurylamine 71, N-(n-pentyl)piperidine 72, N-(tetrahydrofurfuryl)piperidine 73 and bis(tetrahydrofurfuryl)amine 74. Scheme 5 NH3, H2 7H2O HN OH 57 O 70 NH3 NH2 7H2O O71 H2 H2 70 OH HO 7H2O 75 57 N OH 7H2O 72 76 70+57 N CH2 7H2O O 73 70+71 CH2NHCH2 7H2O O O 74 When this reaction is carried out in the presence of the SNM-1 catalyst, the yield of the amine 71 reaches 62% at a virtually complete conversion of tetrahydrofurfuryl alcohol. When Co- and Ni-based catalysts are used, the formation of piperidine is the predominant reaction route (its yield reaches 51%).The com- pounds 73 and 74 result from intermolecular amination of the alcohol 70 with piperidine and with the amine 71, respectively. The presence of N-(n-pentyl)piperidine 72 among the reaction prod- ucts was explained 135 by hydrogenolysis of the alcohol 70 at the intracyclic C±O bond with the intermediate formation of pen- tane-1,5-diol 75, its partial hydrodeoxygenation to n-pentan-1-ol 76 and subsequent interaction of the alcohol 76 with piperidine.Nitrogen-containing five-, six- and seven-membered hetero- cyclic compounds have been prepared by hydroamination of the corresponding diols with ammonia over the industrial SNM-1 catalysts and RPFIC.136 ± 139 The formation of the heterocycle in the reaction of butane-1,4-diol 77 with a mixture of NH3 and H2 (Scheme 6) occurs in two stages. First, the initial diol 77 is aminated to give 4-aminobutan-1-ol 78, and then this product undergoes intramolecular amination (cyclisation) to give pyrroli- dine 79. Scheme 6 NH3 OH O HO HO 7H2O 7H2 77 NH2 NH HO 7H2O 78 79 NH2 H2 78+79 N N 7NH3 81 80 N N N N 77+797H2O 7H2 82 8362 The yield of the compound 79 on the SNM-1 catalyst at 220 8C reaches 85.5%.139 The appearance of N-4-aminobutylpyr- rolidine 80 in the product mixture can be interpreted as being due to the reaction between 4-aminobutan-1-ol 78 and pyrrolidine.Partial hydrodeazotisation of the compound 80 affords N-(n- butyl)pyrrolidine 81. 1,4-Dipyrrolidinobutane 82 is formed upon exhaustive amination of butanediol with pyrrolidine. The highest yield of the compound 82 (22.5%) was attained with RPFIC. Dehydrogenation of one heterocycle in the molecule of 82 gives rise to N-(4-pyrrolidinobutyl)pyrrole 83. The reaction of hexane-2,5-diol 84 with a mixture of NH3 and H2 is highly selective. The yield of 2,5-dimethylpyrrolidine 25 over RPFIC at 200 8C amounts to 93%.139 The subsequent dehydro- genation of pyrrolidine 25 yields 2,5-dimethylpyrrole 24.OH NH3 72H2O 7H2 HN HN OH 84 24 25 Hydroamination of pentane-1,5-diol 75 and hexane-1,6-diol 85 with ammonia follows a similar route, resulting in the for- mation of piperidine 57 and perhydroazepine 86, respectively. (CH2)m NH3 HO(CH2)nNH2 HO(CH2)nOH 7H2O 7H2O 75, 85 NH 57, 86 n=5 (75), 6 (85); m=1 (57), 2 (86). The main pathways of the catalytic transformations of the diol 75 during its interaction with NH3 and H2 can be illustrated by Scheme 7. The presence of N-(n-pentyl)piperidine 72 in the reaction products is due to the alkylation of piperidine 57 with the diol 75 involving the intermediate formation of N-(5-hydrox- ypentyl)piperidine 87 and its subsequent hydrodeoxygenation. Hydrogenolysis of the C±C bond in the alkyl substituent of the compound 72 accompanied by elimination of an n-butane mole- cule gives rise to N-methylpiperidine 88.Scheme 7 H2 NH+HO(CH2)5OH N(CH2)5OH 7H2O 7H2O 75 87 57 H2 NMe N(CH2)4Me 7BunH 88 72 A typical feature of the transformation of the diol 85 139 (Scheme 8) is relatively high yields of N-alkyl-substituted perhy- droazepines 89 ± 91 and secondary and tertiary alkylamines 92 ± 94. For example, when the diol 85 is hydroaminated over the SNM-1 catalyst at 1808C, the total contents of perhydroazepines 89 and 91 in the reaction products reaches 22%. Piperazine and 1-alkyl- and 1,4-dialkyl-piperazines have been synthesised by hydroamination of diethanolamine or N-alkyldie- thanolamines in the presence of RPFIC.140 Cyclisation of ethyl- enediamine 95 with propane-1,2-diol 96 giving 2-methylpyrazine 97 over a catalyst containing 1% of Pd supported on a mixture of zinc and chromium oxides (Zn : Cr = 3 : 1) has been studied.141 The highest selectivity of this process is observed at 388C.N HNH2 H2N(CH2)2NH2+MeCHCH2OH Pd 7H2 Me Me 95 96 OH NH N97 V A Tarasevich, N G Kozlov Scheme 8 NH3 NH3 Me(CH2)5NH2 72H2O 72H2O HO(CH2)6OH 85 HN 86 H2 N(CH2)5Me 85+86 7MeH 89 H2 N Me N(CH2)4Me 7BunH 90 91 {Me(CH2)5}2NH Me(CH2)5NH2 7NH3 7H2 Me(CH2)5NH(CH2)4CH CH2 92 H2 Me(CH2)5 3N Me(CH2)5 2N(CH2)4Me 7NH3 7CH4 93 94 IV.Reductive amination of aldehydes and ketones with nitro compounds and pyridine bases Reduction of nitro compounds, which is carried out in a variety of ways (catalytic hydrogenation; reduction with iron in the presence of hydrochloric acid, with metal sulfides, zinc or iron in a strongly alkaline medium, lithium aluminium hydride and hydrazine; and electrochemical reduction) is among the methods used most widely for the synthesis of amines. These reactions occur via several intermediate stages; for most of the reducing agents listed above, they include the formation of nitroso compounds and hydroxylamines. H2 H2 H2 R2CHNO R2CHNO2 R2CHNHOH 7H2O 7H2O R2CHNH2 R2C NOH Catalytic hydrogenation has found wide application in indus- try. Most often, it is used to convert aromatic nitro compounds into the corresponding amines.142, 143 The ability of nitro compounds to be reduced to amines under the conditions of reductive amination has permitted the use of this ample class of nitrogen-containing organic compounds for direct amination of aldehydes and ketones.This reaction was first performed by Emerson.144 A mixture of acetone 29 and nitro- benzene 98 was reduced by hydrogen in an autoclave over platinum oxide; the yield of N-isopropylaniline 99 reached 59%.144±147 H2 NHPri NO2 PtO2 Me2CO+ 29 99 98 Subsequently this reaction has been widely used to synthesise secondary amines. Hydroamination by nitro compounds is nor- mally carried out in autoclaves over platinum catalysts under a pressure of hydrogen.86,148 Thus reductive amination of acetone by 4-nitrodiphenylamine at 120 8C and pH2=2.0 ±2.5 MPa on the Pt/C catalyst gave N-phenyl-N0-isopropyl-p-phenylenediamine in 95% yield.149 To increase the yield of secondary amines the catalysts are modified by various additives. For example, the reaction catalysed by platinum supported on carbon containing phosphorous acid gives amines in preparative yields.78 Other acids or acidic compounds�H3BO3, organic acids or anhydrides, CO2Reductive amination of oxygen-containing organic compounds � are also used as modifying agents.Acidic additives form salts with primary amines and thus prevent side reactions. Apart from platinum, nickel catalysts are also widely used in this reaction.The use of a catalyst containing 63% of Ni supported on kieselguhr permits preparation of secondary amines from nitro compounds and ketones in yields of up to 57%. Modification of this catalyst by sulfur-containing compounds (sulfides, disulfides, sulfoxides, thiols) made it possible to increase the yields of amines to 75%.87 Hydroamination carried out with aromatic nitro compounds is accompanied in some cases by hydrogenation of the aromatic ring.150,151 To prevent this process, mixtures otones with aromatic nitro compounds are reduced over various catalysts containing Pt, Pd, Ni, Rh, Os, Sr or Co on silica or alumina in the presence of SO2.150 The same can be attained by using metal sulfides.Amines can be obtained in preparative yields by conducting the reaction at 250 8C at a pressure of hydrogen of up to 10.0 MPa in the presence of cobalt, nickel or molybdenum selenide or telluride as the catalyst.152 Palladium-containing anion exchangers are efficient catalysts of hydroamination of aldehydes and ketones by nitro compounds (mostly, aromatic ones).99,106 A study of the influence of the substrate structure on the rates of hydroamination of oxygen- containing compounds by nitro compounds of the aromatic series has shown that the reaction rate decreases following an increase in the magnitude of the Hammett constant.153 Several studies 151, 154 ± 156 have been devoted to hydroamina- tion of alicyclic and heterocyclic ketones by nitro compounds of aliphatic and aromatic series over nickel± and copper ± alumina catalysts.It was found 151 that hydroamination of alicyclic ketones 99 with nitrobenzene at 250 8C and at pH2=2.0 MPa over nickel catalysts gives rise to N-cycloalkylcyclohexylamines in yields of up to 82%. In the presence of copper catalysts, N-cyclo- alkylanilines are formed in this reaction (yields 40%± 80%). H2 O NH (CH2)n Ni/Al2O3 (CH2)n NO2+ H2 NH 98 99 (CH2)n Cu/Al2O3 n=2 ± 4. The capability of pyridine and its alkyl-substituted derivatives to be reduced to piperidines permits the use of these nitrogen- containing heterocycles in the reductive amination of ketones. Thus reductive amination of aliphatic and alicyclic ketones with pyridine and its monomethyl derivatives over nickel catalysts under a pressure of hydrogen has been studied.157, 158 The reac- tions of pyridine 100 and a-, b- and g-picolines 101a ± c with ketones afford the corresponding N-substituted piperidines as the major products.R R0R00CO N CHR0R00 R H2 O N Ni/Al2O3 (CH2)n R N (CH2)n 100, 101a ± c R=H (100), 2-Me (101a), 3-Me (101b), 4-Me (101c); R0 =Me, Et, But; R00 =Me, Et; n=2, 3. It was assumed 157, 158 that this reaction can follow two path- ways. One of them includes simultaneous reduction of the ketone to the corresponding secondary alcohol and hydrogenation of pyridine 100 to piperidine 57. The subsequent interaction of the alcohol with piperidine accompanied by dehydration affords N- substituted piperidine derivatives.In the second pathway, pyr- idine is reduced to piperidine and the latter reacts directly with the ketone, without its intermediate transformation into the alcohol. This pathway, like the first one, affords N-substituted piperidine as the final product. 63 The use of a-picoline as the aminating agent demonstrated that the methyl group located in the vicinity of nitrogen has a substantial influence on the reaction route. For example, hydro- amination of methyl ethyl ketone 102 with this compound, in addition to the expected product 103 (yield 4%), gave the products resulting from elimination of the methyl group from the pyridine ring (104, 9%) and elimination of the methyl group from the N-substituent (105, 5%).Me CH Et N 103 Me Me H2 +O C Et N CH Et N Me 104 Me 102 101a Et N CH2 105 The course of hydroamination of aliphatic ketones with pyridine bases depends substantially on the ketone structure. Thus the highest yield of the final reaction products is achieved when pyridine is made to react with alkyl methyl ketones; for example, the yield of N-butan-2-ylpiperidine in the reaction with methyl ethyl ketone amounts to 50%. When pyridine reacts with diethyl ketone 36 and propyl ethyl ketone 106, the yields of the target reaction products sharply decrease (32%, for the ketone 36) due to the substantial steric hindrance created by the two alkyl radicals attached to the carbonyl group. tert-Butyl methyl ketone does not enter into hydroamination at all.158 The optimum conditions for the synthesis of N-alkylpiperidines are the follow- ing: temperature 220 ± 230 8C, pH2=2.0 MPa; v=0.3 h71, cata- lyst�20% Ni/Al2O3.158 V.Reductive amination of aldehydes, ketones and alcohols with nitriles and oximes 1. Nitriles and oximes as aminating agents Owing to the progress in the chemistry of nitrogen-containing organic compounds achieved in recent years, nitriles can be considered to be readily available starting compounds for the synthesis of diverse and valuable organic products. Methods of catalytic ammonolysis occupy a special place in the synthesis of nitriles. They include, first of all, oxidative ammonolysis of saturated and unsaturated hydrocarbons, meth- ylbenzenes, naphthalene and pyridine.Linear hydrocarbons, for example, butane and butenes, can be converted by ammonolysis into saturated and unsaturated mono- and dinitriles.159 ± 167 Thus oxidative ammonolysis of butadiene gives rise to a mixture of nitriles of fumaric and maleic acids (total yield 67%).168 Oxidative ammonolysis of toluene, xylenes, mesitylene or dimethylnaphtha- lenes can be used to synthesise nitriles of the corresponding mono- , di-, and tri-carboxylic acids, their yields being 70%± 95%.169, 170 Halotoluenes, toluidines and cresols can also be introduced into ammonolysis; this gives rise to the corresponding benzonitrile. Methylpyridines are converted into the nitriles of pyridinecarbox- ylic acids in 70%± 95% yields.171 ± 175 At present, ammonolysis is employed in industry to produce acrylonitrile, benzonitrile and nitriles of methacrylic, terephthalic, and nicotinic acids. These processes have been patented and considered in several reviews (see, for example, Refs 176 ±179).Thus, the development of this line of research has extended substantially the range of raw materials used for the production of diverse amines. Hydrogenation of carbonitriles has been studied in detail, because the products of their reduction are important for practical purposes. Nitriles are converted into primary amines upon the64 addition of two hydrogen molecules. However, the first molecule is added faster than the second one. Therefore, the reduction intermediately gives aldimines, which are converted into primary amines during subsequent hydrogenation.In some cases aldi- mines can be isolated in a pure state. The general pattern of hydrogenation of nitriles can be written as follows: H2 H2 RC N RCH NH RCH2NH2. Cat Cat Aldimines are highly reactive and are able to react with the resulting primary amines; this gives rise to secondary and tertiary amines. Therefore, hydrogenation of nitriles can yield different products, depending on the reaction conditions.180 Catalytic reduction of nitriles with molecular hydrogen is the most interesting process. A fairly broad range of catalysts have found practical application in the nitrile hydrogenation�mono- metallic (Pt, Pd, Ni, Co, etc.) and bimetallic (Ni ± Co, Co ± Cr, etc.) catalysts; bifunctional metallic catalysts supported on vari- ous materials (Al2O3, TiO2, SiO2, MgO) modified with various additives (acids, alkalis); and metals (Pt, Pd, Ni, Co) immobilised on polymers.For example, synthesis of 3-amino-5-aminomethyl- 2-methyl-4-methoxymethylpyridine by coupled hydrogenation and dehalogenation of 6-chloro-2-methyl-4-methoxymethyl-3- nitropyridine-5-carbonitrile over palladium-containing anion exchanger AB-17-8 has been described.181 The yield of the target product (20 ± 60 8C, pH2=0.98 ± 1.03 MPa, EtOH as the solvent) reaches 99%. The catalyst proposed for this reaction proved to be much more stable and active than Pd/C. Data on the liquid-phase hydrogenation of hexanenitrile to amines have been reported.182 Reduced metals (Ni, Co, Ru, Pd, Pt, Os, Cu) on g-Al2O3 were used as the catalysts in this reaction.In terms of their activity in hydrogenation, the studied catalysts can be arranged in the sequence Ru>Ni>Os>Co>Pd>Pt >Cu; the selectivities of these catalysts were also dissimilar. Thus the cobalt catalyst exhibited the highest selectivity (91%) with respect to primary amine (hexylamine). The highselectivity with respect to secondary amine was found for Ru and Pt catalysts (81% ± 89%). In the presence of the Pd catalyst, the yields of di- and tri-hexylamines are 65.4% and 34.6%, respectively. Hydro- genation of hexanenitrile over the industrial nickel ± chromium catalyst at 120 ± 140 8C and pH2=5.0 MPa gave a mixture of amines containing 64% of the secondary amine and 36% of the primary and tertiary amines (the total yield).By varying the reaction temperature, the pressure of hydrogen and the chemical composition of the catalyst, the ratio of the reaction products can be controlled. Thus at 145 8C and pH2=0.35 ± 0.50 MPa, 100% conversion of acetonitrile was attained; the reaction products were found to contain 3.1% of primary amines, 45.4% of secondary amines and 51.5% of tertiary amines. At higher temperatures, the yield of secondary amines increases.180 The use of Pd, Pt and Ru catalysts supported on lithium aluminium spinel in this reaction permits the preparation of an amine mixture containing 99.7% of tertiary amine.183 Numerous studies dealing with hydrogenation of acetonitrile 107 and acrylonitrile 108 over a series of copper and copper ± nickel catalysts with various metal contents (5% Cu; 8%Cu+2%Ni; 15%Cu+2%Ni, etc.) have been carried out.Gumbrin was used as the support. Some catalyst specimens were modified with NaOH (3%). Hydrogenation was carried out at 100 ± 200 8C under atmospheric pressure. The reduction of the nitriles 107 and 108 affords mixtures of the corresponding primary, secondary and tertiary amines. The copper ± nickel catalyst (8% Cu+2%Ni) annealed at 900 8C proved to be the most active towards hydrogenation of acrylonitrile; the total yield of amines on this catalyst was 69.7%. The modification of the Cu ± Ni catalyst with alkali increases its stability.184 The nitrile 108 was converted into dipropylamine in two stages with a high yield.185 In the first stage, acrylonitrile was hydrogenated to propionitrile 109 in the presence of a catalyst containing Pd, Bi and K on silica gel, and in the second stage, the resulting V A Tarasevich, N G Kozlov propionitrile was converted into dipropylamine using 50%± 56% Ni supported on kieselguhr at pH2=0.1 ± 2.0 MPa and 140 ± 200 8C.H2 H2 (CH3CH2CH2)2NH CHCN CH2CH2CN CH2 109 108 To increase the yield of primary amines, hydrogenation is carried out in the presence of ammonia. The role of ammonia or alkali is to retard the reaction of aldimines with amines and deamination.186 ± 188 The addition of ammonia markedly increases the yields of higher primary amines (C8 ±C24) produced in the hydrogenation of the corresponding individual nitriles or their mixtures.189 ± 191 The introduction of LiOH, NaOH, KOH or Na2CO3 (0.1 mass %± 2.0 mass % relative to the catalyst) leads to higher yields of primary amines.Thus hydrogenation of phenylacetonitrile 110 over Raney nickel gave 2-phenylethyl- amine 111 in 51.2% yield, the yield of the corresponding secon- dary amine 112 being 37.5%. When 2.0 mass % NaOH was introduced into the catalyst, the yield of the primary amine became 92.5% ±95.5%.192, 193 H2 CH2CN Cat 110 CH2CH2NH2+ CH2CH2 2NH 111 112 Since benzylamine 113 is a valuable compound for fine organic synthesis, a large number of studies dealing with catalytic hydrogenation of benzonitrile have been carried out.Hydrogena- tion of benzonitrile in dioxane in the presence of ammonia at 70 ± 80 8C has been studied.194 Nickel supported on kieselguhr was used as the catalyst. The benzene ring was not hydrogenated under these conditions; the yield of benzylamine was 76% ±79% and the selectivity was 82.5%. Interesting results have been obtained in a study of hydrogenation of benzonitrile on the Pt/C, Pd/C and Ru/ C catalysts.195 The reaction rate was found to increase on increasing the pressure of hydrogen; however, the yield of toluene also increased (from 0.3% ± 3.0% to 8%± 9%). Hydrogenation of nitriles and dinitriles in methanol or cyclo- hexane 196 is carried out on cobalt catalysts supported on Fe, Co, Mnor Cr metal powders at 80 ± 120 8C and pH2=25.0 ± 35.0 MPa in the presence of ammonia.The yields of the corresponding primary amines were 90%± 95%. It was noted that the service life of metal-supported catalysts is longer than those of catalysts supported on oxides. Dinitriles of the aliphatic and aromatic series are hydro- genated under the same conditions as mononitriles. For example, octamethylenediamine (yield 91%) is prepared by catalytic reduc- tion of the dinitrile of the corresponding acid in the presence of a ruthenium catalyst in an inert solvent containing an additive of NH3, at pH2=3.0 MPa.197 By varying the reaction conditions, the reduction of dinitriles can be terminated at the stage of formation of amino nitrile as the major reaction product.Thus the dinitriles CN(CH2)nCN (where n = 1 ± 10) can be converted on a rhodium catalyst into the corresponding amino nitriles, formed in high yields.198, 199 Data on the conditions and the mechanism of this reaction and various factors that influence its course have been described systematically.200 The mechanisms of the formation of primary, secondary and tertiary amines were described in detail. In terms of their activity in this reaction, known catalysts can be arranged in the following sequence: Pt>Pd>Ni>Co>Fe> Cu. The reduction of aliphatic dinitriles containing CN groups at the 1,2-, 1,3- and 1,4-positions, in addition to the corresponding diamines, yields five-, six- and seven-membered saturated hetero- cyclic compounds, resulting from intramolecular heterocyclisa-Reductive amination of oxygen-containing organic compounds tion.For example, succinodinitrile 115 is converted into pyrroli- dine 79. H2 H2N(CH2)4NH2 +NH3 NC(CH2)2CN 115 HN 79 Data on the hydrogenation of nitriles in the presence of homogeneous or heterogeneous catalysts in the liquid phase have been described systematically.201 The reaction mechanisms and the pathways to side products were considered. The effects of the solvent, temperature, the pressure of hydrogen and the nature of the catalyst on the course of this reaction carried out over heterogeneous catalysts were studied. Oximes are also hydrogenated using nickel catalysts.Thus hydrogenation of acetone oxime gives a mixture of amines in which the secondary amine predominates.202 H2 Me2CHNH2+(Me2CH)2NH Me2C NOH Hydrogenation of a number of alkylaromatic oximes has been studied.203 It was found that the formation of primary amines is preceded by the intermediate formation of imines 116; in some cases, they can be isolated from the reaction mixture (Scheme 9). The reaction products contain primary, secondary and tertiary amines.204 ± 207 Secondary amines result from interaction of the imine 116 with primary amines. They can also arise upon deamination of primary amines in the presence of a catalyst.208 Scheme 9 H2 H2 116 NH PhC PhC NOH PhCHNH2 Alk Alk 116 Alk NH2 H2 C N CHPh Ph NH CHPh PhC 7NH3 Alk Alk Alk Alk PhCH NH Alk 2 Rosenmund et al.209 were the first to use an oxime acetate for preventing the formation of a secondary amine.Hydrogenation of the benzaldehyde oxime acetate 117 gave a primary amine (formed as acetate 118) in 91% yield. + H2 CH NOAc AcO7 CH2NH3 117 118 Primary amines are also prepared by hydrogenation of oximes in acetic anhydride. Thus hydrogenation of benzaldehyde oxime under these conditions resulted in the synthesis of N-benzylaceta- mide; hydrogenation of acetone oxime gave N-(1-phenylethyl)a- cetamide.204 Free amines are obtained by hydrolysis of these amides. Good yields of primary amines, formed as hydrochlor- ides, are attained when oximes are hydrogenated on a palladium catalyst in anhydrous ethanol with three equivalents of HCl.210 Hydrogenation of oximes in the presence of ammonia,211 which increases the yield of primary amines, has found a wider practical application.In the case of catalytic hydrogenation of oximes, nickel, cobalt and rhodium supported on alumina are used most often as the catalysts.204 In the reduction of oximes of a,b-unsaturated ketones, platinum dioxide is used as the catalyst and MeOH is used as the solvent.205 The solvent has a substantial influence on the composition of the products of oxime reduction in the liquid phase. For example, when a more polar solvent was used, aziridine was obtained from benzylideneacetone oxime, in addition to the corresponding amine.212 Study of hydrogenation of cyclohexa- 65 none oxime in various solvents in the presence of Pt, Pd, Rh and Ru supported on finely dispersed carbon made it possible to elucidate the influence of the solvent and the catalyst on the reaction rate and the product composition.The reaction does not occur in dioxane; the reaction in methanol proceeds in the presence of the rhodium catalyst, while in acetic acid, it proceeds over a platinum catalyst. When the reaction is carried out in water, cyclohexanol is produced as the major product.212 Apart from the platinum Group metals listed above, cobalt is also used to catalyse hydrogenation of oximes. In some cases Raney cobalt is more active than the nickel catalyst.213 Alumina is usually employed as the support.204, 214 When oximes are reduced over copper catalysts, together with amines, side products are formed, in particular, the Beckmann rearrangement product, the corresponding ketones, aldehydes, nitriles and imines.215 Apart from molecular hydrogen, the hydrazine ± Raney nickel system is also widely used as the reducing agent in the hydro- genation of oximes.208, 216 This system permits easy and selective reduction of oximes to primary amines. 2.Reductive amination of oxygen-containing compounds with nitriles and oximes Significant progress in the development of new methods for the synthesis of amines was associated with the use in the reductive amination of nitriles and oximes, which had not been used previously as direct aminating agents. Hydroamination of oxy- gen-containing compounds with nitriles extends still further the potential of this reaction.The ability of nitriles to be reduced to amines under the conditions of catalytic hydrogenation made it possible to aminate various ketones and aldehydes in one stage.217 ± 221 The reaction is carried out in the vapour phase over a heterogeneous catalyst in a flow-type setup operating under a pressure of hydrogen. The process of hydroamination of oxygen-containing compounds with nitriles includes several successive coupled reactions resulting in the formation of secondary amines. In the carbonyl compound ± nitrile ±hydrogen system, this reactions occurs in accordance with the following scheme:218, 219 H2 RCN RCH2NH2, Cat R0 H2O RCH2NHCOH RCH2NH2+R0R00CO 7H2O R00 H2 RCH2NHCHR0R00 RCH2N CR0R00 R, R0 =H, Alk, Ar; R00 =Alk, Ar.Under the reaction conditions, carbonyl compounds are partly reduced to the corresponding alcohols. The possibility of hydroamination of alcohols with nitriles, as shown below, also cannot be ruled out. H2 RCN RCH2NH2, CatH2 R0R00CHOH, R0R00CO Cat RCH2NH2+R0R00CHOH RCH2NHCHR0R00 7H2O R=H, Alk, Ar; R0 =H, Alk, Ar; R00 =Alk, Ar. The reaction pathway depends on the structures of the reactants and on the rate of each particular stage. The above reactions might also occur simultaneously. Hydroamination of cyclic ketones by aliphatic nitriles under a pressure of hydrogen has been studied.218, 219 Nickel ± alumina and copper ± alumina catalysts with a metal content of 15%± 20%, both non-modified and modified by the addition of Li, Na66 and K, were used.The main reaction pathway is the formation of alicyclic secondary amines 119. O NHCH2R H2 +RCN (CH2)n (CH2)n Cat 107 ± 109, 120 7, 52 R=Me (107), CH=CH2 (108), Et (109), Prn (120); n=3 (7, 8), 2 (52, 121). The yields of the corresponding amines 119 with the 15% Cu/ Al2O3 catalyst at 240 8C and pH2=1.5 MPa reaches 75%. The introduction of alkaline additives (Li, Na, K) in the copper ± alumina catalyst increases the total yield of amines by 5%± 12%. The di(cycloalkyl)amines 8 and 121 are formed as side products. It was assumed 218 that the main reason for the formation of the amines 8 and 121 is the low stability of N-alkylcycloalkylamines 119 under the conditions employed.In fact, when N-ethylcyclo- hexylamine is passed over the catalyst under the conditions of hydroamination, it partly decomposes to give a mixture of cyclo- hexylamine 13 and dicyclohexylamine 8 (up to 30%). Study of the reductive amination of the alicyclic ketones 7 and 52 with aceto- (107), acrylo- (108), propio- (109) and butyro-nitriles (120) showed that the yield of N-alkylcycloalkylamines 119 decreases following an increase in the number of the carbon atoms in the nitrile molecule. N-Alkylcyclohexylamines 123 have been prepared in good yields (up to 73%) by hydroamination of phenols 122 with nitriles on nickel ± alumina catalysts. In this case, amination is accom- panied by hydrogenation of the aromatic ring.222 R0 R0 RCN, H2 OH Ni/Al2O3 122 R=Me, Et, Pr; R0 =H, o-Me, m-Me, p-Me.Table 1. Synthesis of aliphatic-aromatic secondary amines by hydroamination of ketones and aldehydes with nitriles Nitrile Ketone, aldehyde T=220 8C, pH2=1.5 MPa, v=0.25 h71 acetonitrile " Acetophenone Benzophenone Benzyl methyl ketone " Benzylidenacetone Acetone Methyl ethyl ketone Diethyl ketone Cyclopentanone Cyclohexanone "benzonitrile """" T=230 8C, pH2=1.5 MPa, v=0.20 h71 Benzylidenacetone acrylonitrile butyronitrile isobutyronitrile benzonitrile acetonitrile " p-Methoxybenzyl- idenacetone 1-Phenylpent- 1-en-3-one T=220 8C, pH2=1.0 MPa, v=0.30 h71 phenylacetonitrile " Acetone Diethyl ketone Methyl propyl ketone " Cyclohexanone " (CH2)n NH + (CH2)n 119 8, 121 NH CH2R 123 Catalyst 15% Cu/Al2O3+2% LiOH 15% Cu/Al2O3+2% LiOH 20% Cu/Al2O3 36% Cu/MgO 20% Cu/Al2O3 20% Cu/Al2O3 20% Cu/Al2O3 20% Cu/Al2O3 20% Cu/Al2O3 36% Cu/MgO 36% Cu/MgO 15% Cu/Al2O3+6% LiOH 36% Cu/MgO 15% Cu/Al2O3+6% LiOH 15% Cu/Al2O3+6% LiOH 20% Cu/MgO 20% Cu/Al2O3 20% Cu/MgO 20% Cu/MgO V A Tarasevich, N G Kozlov In order to synthesise aromatic amines which contain the amino group in the side chain and form a number of important biologically active compounds, hydroamination of acetophenone 15, benzophenone 124 and benzyl methyl ketone 125 with nitriles has been carried out.223 In the presence of copper ± alumina catalysts, the highest yields (31% ± 72%) of secondary amines were attained with 20%Cu/Al2O3 at 220 8C, pH2=1.5 ± 2.0 MPa.The reactivity of ketones in the amination by nitriles decreases in the order 125 > 15 > 124.223 The conjugated system of bonds present in acetophenone results in a lower positive charge on the carbonyl carbon atom; this accounts for the decrease in the reactivity of the ketone 15. In the case of hydroamination of benzophenone with acetonitrile, the yield of N-ethylbenzhydryl- amine is influenced not only by conjugation but also by steric factors. Ethylbenzene and diphenylmethane were isolated as side products upon hydroamination of aceto- and benzophenone. Virtually no propylbenzene is formed on hydroamination of benzyl methyl ketone.NHCH2R O R0CN, H2 CH R0 C R 15, 124 R=Me, Ph; R0 =Me, Et, Prn. O RCN, H2 C Me CH2125 R=Me, Et, Prn. Unsaturated ketones, aliphatic nitriles, phenylacetonitrile, aliphatic and alicyclic ketones, benzonitrile and aldehydes have been used successfully for the synthesis of aliphatic-aromatic amines 219, 223 ± 227 (Table 1). N-Alkylbornan-2-ylamines were synthesized in 45%± 55% yields by hydroamination of camphor 61 by aliphatic nitriles.228 The resulting amine N-ethyl-a-phenylethylamine N-ethylbenzhydrylamine N-ethyl-a-methyl-b-phenylethylamine N-ethyl-1-methyl-3-phenylpropylamine N-isopropylbenzylamine N-(butan-2-yl)benzylamine N-(pentan-3-yl)benzylamine N-cyclopentylbenzylamine N-cyclohexylbenzylamine N-propyl-1-methyl-3-phenylpropylamine N-butyl-1-methyl-3-phenylpropylamine N-isobutyl-1-methyl-3-phenylpropylamine N-benzyl-1-methyl-3-phenylpropylamine N-ethyl-1-methyl-3-(p-methoxyphenyl)- propylamine N-ethyl-3-phenyl-1-ethylpropylamine N-isopropyl-2-phenylethylamine N-(pentan-3-yl)-2-phenylethylamine N-(pentan-2-yl)-2-phenylethylamine N-cyclohexyl-2-phenylethylamine NHCH2R CH Me CH2 Yield (%) Ref.223 223 223 224 219 219 219 219 219 58 28 72 65 58 42 46 36 54 224, 225 224, 225 224, 225 224, 225 224 70 75 60 70 60 224 60 226 226 226 226 61 36 50 52Reductive amination of oxygen-containing organic compounds RCN, H2 7H2O O NHCH2R 61 R=Me, Et, Prn.Systematic study of the reductive amination of carbonyl- containing compounds and secondary alcohols of the terpene series resulted in the development of preparative and selective methods for the synthesis of both unsaturated and completely hydrogenated amines with diverse structures (aliphatic; mono- bi- and tricyclic; containing three-, four, five- and six-membered rings) 229 ± 239 (Table 2). A series of 3-(1-alkylaminoethyl)- and 3-(arylmethylami- noethyl)-pyridines have been synthesised in 50%± 65% yields by hydroamination of 3-acetylpyridine 126 with aliphatic and aro- matic nitriles.240O NHCH2R RCN, H2 C CH Cu/Al2O3 N N Me Me 126 R=Me, Et, Prn, Ar. Hydroamination of an a,b-unsaturated heterocyclic ketone� 4-(2-furyl)but-3-en-2-one 127�which has an additional reaction site, the oxygen atom of the furan ring, has been studied.This process can follow several alternative pathways depending on the catalyst used (Scheme 10). In the presence of a copper ± magne- sium catalyst, the reaction stops at the stage of formation of a Table 2. Reductive amination of carbonyl-containing compounds and alcohols of the terpene series. Nitrile, oxime Ketone, alcohol T=220 8C, pH2=1.5 MPa, v=0.25 h71 acetonitrile L-Camphor " 1,3,3-Trimethylbicyclo- [2.2.1]heptan-2-one (+)-S-Carvone " Acetone (+)-S-carvone oxime acetonitrile L-Menthol benzonitrile acetonitrile cis-3,7,7-Trimethylbicyclo- " [4.1.0]heptan-2-ol Hexahydropseudoionone 1-Ethylbicyclo[2.2.1]- heptan-2-one T=250 8C, pH2=1.5 MPa, v=0.25 h71 acetonitrile propionitrile acetonitrile Isocamphanone, isocamphanol Isofenchol 1-Ethyltricyclo- [2.2.1.02.6]heptan-3-one Citronellal propionitrile T=240 ± 260 8C, pH2=1.5 MPa, v=0.20 h71 acetonitrile 2-Acetylbicyclo- [2.2.1]hept-5-ene a The total yield is given.secondary amine of the furan series, namely, 2-(3-alkylaminobu- tyl)furan 128 (yield 45%± 48%); the use of copper ± alumina catalyst results in hydrogenolysis of the furan ring at the O(1) ± C(5) bond and cyclisation of the intermediate amino ketone. In this case, N-alkyl-2-methyl-5-propylpyrrolidine 129 is the main product (yield 42%± 46%).241 In addition, the reaction products contain a small amount of pyrrole derivatives 130 (5%), which result from the direct replacement of the oxygen atom of the furan ring by an amino group accompanied by hydrogenation of the carbonyl group and the double bond in the side chain.RCN 4 5 O1 Cu/MgO Cu/Al2O3 Catalyst 15% Cu/Al2O3+(2 ± 6)% LiOH 15% Cu/Al2O3+(2 ± 6)% LiOH 15% Cu/Al2O3+(2 ± 6)% LiOH 15% Cu/Al2O3+(2 ± 6)% LiOH 15% Cu/Al2O3+(2 ± 6)% LiOH; N-ethylmenthyl-, neomenthyl-, 36% Cu/MgO 15% Cu/Al2O3+(2 ± 6)% LiOH; N-ethyl-5-isopropyl-2-methylcyclo- 36% Cu/MgO 15% Cu/Al2O3+(2 ± 6)% LiOH 15% Cu/Al2O3+(2 ± 6)% LiOH 15% Cu/Al2O3+(2 ± 6)% LiOH 15% Cu/Al2O3+6% LiOH 15% Cu/Al2O3+(2 ± 6)% LiOH 15% Cu/Al2O3+(2 ± 6)% LiOH 36% Cu/MgO 67 Scheme 10 RCH2NH2, H2 Cat 3 O 2 CH CHCMe +RCH2NH2 127 NHCH2R + (CH2)2CHMe (CH2)3Me N O 128 130 CH2R Me Me(CH2)2C(CH2)2CHMe NCH2R+130 O NHCH2R (CH2)2Me 129 Ref.The resulting amine Yield (%) 229 60 a N-ethylbornylamines (exo- and endo-isomers) the same 230 80 60 ± 70 a 231 232 60 N-ethylcarvo-, isocarvo-, neocarvo- and neoisocarvomenthylamines N-isopropyl-5-isopropyl-2-methyl- cyclohexylamine 233, 234 70 a isomenthyl- and neoisomenthylamines 235 60 236 237 85 69 a hexylamine N-benzyl-1,5,9-trimethyldecylamine N-ethyl-1-ethylbicyclo[2.2.1]hept-2-yl- amines (exo- and endo-isomers) 238 80 N-ethylisocamphylamines 238 238 60 75 238 N-propylisofenchylamine N-ethyl-1-ethyltricyclo[2.2.1.02.6]- hept-3-ylamine N-propyl-3,7-dimethyloctylamine, N-propyl-3,7-dimethyloct-6-enylamine 35 30 239 70 2-(a-ethylaminoethyl)bicyclo- [2.2.1]heptane68 Several studies have been devoted to the interaction of nitriles with bifunctional oxygen-containing compounds in which both reaction sites can be involved in hydroamination. In particular, reactions of hydroxy ketones, diketones and diols were inves- tigated.242 ± 244 OH O RCCH2CHMe RCN Secondary amines, heterocyclic compounds O O RC(CH2)nCR or RCN Secondary amines, diamines, heterocyclic compounds RCH(OH)(CH2)nCH(OH)R a-Diketones and a-glycols react with nitriles according to similar patterns.Thus the reaction of diacetyl with nitriles yields the same products as the reaction of ethylene glycol, namely, mono- and diamines.243, 244 Acetylacetone (b-diketone) 131 is unstable under the reaction conditions, products of its decom- position being involved in reductive amination.The reaction of the diketone 131 and benzonitrile 114 over the 15% Cu/MgO catalyst at 240 8C and pH2=1.5 MPa gives rise to N-ethylbenzyl- amine 132 (yield 29%), N-isopropylbenzylamine 133 (yield 19%) and N,N-diethylbenzylamine (yield 18%) (Scheme 11). Scheme 11 O O 114, H2 Me2CO+MeCHO CMe MeCCH2 131 CH2NEt2 CH2NHEt CH2NHCHMe2 + + 134 133 132 Reactions of dinitriles with carbonyl compounds have been studied. It was found 221 that hydroamination of acetone and butanal with adiponitrile 135 can follow two pathways, one yielding a heterocycle and one yielding aliphatic amines.The nitrile groups in the adiponitrile molecule behave under the hydrogenation conditions as if they possessed different reactiv- ities. This fact has been explained by the formation of unstable cyclic systems.245 A pseudo-ring forms upon interaction of nitro- gen of one nitrile group with the hydrogen located at the a-position relative to the second nitrile group. Therefore, reduc- tive amination occurs as preferential reduction of one nitrile group rather than simultaneous reduction of both of them and yields 6-aminohexanenitrile 136. H2 CN CN NC (CH2)4 Cat H2N (CH2)5 136 135 The amino nitrile 136 can undergo two types of transforma- tion. The first of them is hydrogenation of the secondCNgroup to give hexamethylenediamine 137 and subsequent hydroamination of a carbonyl compound, for example, acetone 29.The second route includes hydrogenation of the amino nitrile 136 accompa- nied by cyclisation and gives rise to perhydroazepine 86. The crucial factor which determines the reaction route is temperature. Thus at 190 8C, the yields of N-isopropylperhydro- azepine 138 and N,N0-diisopropylhexamethylenediamine 139 are 25% and 84%, respectively, whereas at 240 8C they are 22% and 3%. H2 H2 H2N(CH2)5CH NH Cat Cat H2N(CH2)5CN 136 V A Tarasevich, N G Kozlov Me2CO, H2 NH NHCHMe2 Cat 86 138 Me2CO, H2 H2N(CH2)6NH2 Cat Me2CHNH(CH2)6NHCHMe2 139 137 The good results attained in hydroamination of oxygen- containing compounds, together with the theoretical fundamen- tals and the published data concerning reduction of oximes to primary amines under conditions similar to those used in hydro- amination, permitted oximes to be employed for the first time for reductive amination of various ketones and aldehydes.246 ± 249 Analysis of the ability of oximes to be reduced over heterogeneous catalysts led to the conclusion that, in addition to the traditional catalysts used to reduce oximes to primary amines (platinum Group metals and nickel), copper catalysts are also active in this process.Hydroamination of carbonyl compounds with various oximes includes several consecutive coupled reactions, resembling those involved in hydroamination of carbonyl compounds with nitriles.The necessity of a high degree of coupling between separate stages becomes evident if one examines the processes occurring in the `oxime ± carbonyl compound ± hydrogen' ternary systems over a heterogeneous catalyst. Initially, the oxime is reduced on the hydrogenating sites of the catalyst to give a primary amine (Scheme 12).247, 248 Scheme 12 H2 H2 RR0C NH RR0C NOH RR0CHNH2 Cat Cat R=Alk, Ar; R0 =H, Alk, Ar. The resultinimary amine can participate in many thermo- dynamically allowed reactions. Within the scope of our review, condensation of the primary amine with the carbonyl compound is of interest (Scheme 13).247, 248 Scheme 13 R00 H2 RR0CHNH C R000 RR0CHNH2+R00R000C O Cat 7H2O OH H2 RR0CHNHCHR00R000 RR0CHN CR00R000 Cat R, R00 =Alk, Ar; R0, R000 =H, Alk, Ar.The reaction of the primary amine with the imine, resulting from incomplete reduction of the oxime, is a competing process (Scheme 14).247, 248 Scheme 14 H2 RR0CH NHCHRR0 RR0C NH+RR0CHNH2 Cat 7NH3 NH2 H2 NHCHRR0 RR0C (RR0CH)2NH Cat Thus, when there is no coupling between the formation of primary amine and its condensation with the carbonyl compound (see Schemes 12 and 13), the overall process can be substantially influenced by the reaction of the primary amine with the nitrogen analogue of the carbonyl compound, i.e. imine (see Scheme 14). The formation of symmetrical secondary amines markedly decreases the selectivity of the main reaction.247, 248 The attainment of coupling depends appreciably on the catalyst. The carbonyl compound should be activated towards condensation (see Scheme 13) to an extent that its reactivity inReductive amination of oxygen-containing organic compounds Table 3.Reductive amination of ketones, aldehydes and alcohols with oximes. Oxime Ketone, aldehyde, alcohol T=210 8C, pH2=1.5 MPa, v=0.25 h71 Pentan-2-one Cyclohexanone Acetaldehyde Propanal Butanal 2-Methylpropanal cyclohexanone cyclopentanone cyclohexanone ""cyclopentanone " T=210 8C, pH2=1.0 MPa, v=0.30 h71 Acetaldehyde Propanal Pentanal 3-Methylbutanal benzaldehyde """ T=240 8C, pH2=1.5 MPa, v=0.25 h71 Cyclohexylmethanol 3-methylbutanal " relation to the nucleophile be higher than that of the imine.This activation occurs on the acid sites of the catalyst.248 The con- densation proceeds via intermediate formation of the addition product, which is converted into imine upon dehydration. This stage is followed by hydrogenation of the C=N double bond on the hydrogenating sites of the catalyst and by the formation of a secondary amine, which is the final reaction product. The data on the methods of synthesis of secondary amines from oximes, ketones, aldehydes and alcohols are presented in Table 3. VI. Conclusion The data considered in the review convincingly demonstrate the substantial progress achieved in the development of catalytic methods for the synthesis of amines based on reductive amination of various oxygen-containing organic compounds.The most significant achievements are the use of nitriles and oximes, which had not been used previously for these purposes, as aminating agents; elaboration and use of complex catalysts for reductive amination, which allow the processes to be conducted under mild conditions with high selectivity; and the use of reduced promoted fused iron catalysts in the synthesis of nitrogen-containing hetero- cycles. The assimilation of new reactions of oxidative ammonolysis and oxo synthesis made it possible to synthesise numerous nitriles, carbonyl compounds and oximes, needed for the production of amines of various structures and compositions. Thus, there are strong grounds for believing that in the near future, the reaction in question would become one of the most significant methods for the preparation of amines.References 1. G Mignonac, C Moureu C. R. Hebd. Seances Acad. Sci. 169 237 (1919) 2. G Mignonac C. R. Hebd. Seances Acad. Sci. 171 223 (1921) 3. M V Klyuev, M L Khidekel' Usp. Khim. 49 28 (1980) [Russ. Chem. Rev. 49 14 (1980)] 4. R Layer Chem. Rev. 63 489 (1963) 5. Jpn. P. 54-10 384; Ref. Zh. Khim. 12 N 69P (1980) 6. US P. 3 187 047; Chem. Abstr. 63 9873 (1965) 7. M A Popov, N I Shuikin Dokl. Akad. Nauk SSSR 101 273 (1955) a 8. M A Popov, N I Shuikin Izv. Akad. Nauk SSSR, Otd. Khim. 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USSR P. 620 477; Byull. Izobret. (31) 57 (1978). 226. N S Kozlov, L V Gladkikh, S I Kozintsev, T K Efimova Dokl. Akad. Navuk BSSR 23 713 (1979) 227. N S Kozlov, L I Moiseenok, N N Gladkikh, S I Kozintsev, L V Gladkikh Dokl. Akad. Navuk BSSR 27 532 (1983) 228. USSR P. 517580; Byull. Izobret. (22) 72 (1976) 229. I I Bardyshev, N G Kozlov, T I Pekhk, T K Vyalimyae Vestsi Akad. Navuk BSSR, Ser. Khim. Navuk (4) 71 (1980) 230. N G Kozlov, G V Kalechits, T K Vyalimyae Khim. Prir. Soedin. 480 (1983) g 231. USSR P. 765 257; Byull. Izobret. (35) 141 (1980) 232. I I Bardyshev, N G Kozlov, T K Vyalimyae, T I Pekhk Khim. Prir. Soedin. 546 (1980) g 233. USSR P. 825 504; Byull. Izobret. (16) 95 (1981) 234. N G Kozlov, T I Pekhk, T K Vyalimyae Khim. Prir. Soedin. 312 (1981) g 235. G V Kalechits, N G Kozlov, T I Pekhk, T K Vyalimyae Zh. Obshch. Khim. 53 203 (1983) h 236. N G Kozlov, T K Vyalimyae, L A Popova, S A Makhnach, T E Kozlova Zh. Obshch. Khim. 57 2739 (1987) h 237. N G Kozlov, G V Kalechits, N A Belikova, M D Ordubadi, T K Vyalimyae Zh. Org. Khim. 21 535 (1985) d 238. N G Kozlov, Doctoral Thesis in Chemical Sciences, Institute of Physical Organic Chemistry, Academy of Sciences of Bel. SSR, Minsk, 1990 239. T S Raikova,N G Kozlov, T K Vyalimyae Zh. Org. Khim. 17 1468 (1981) d 240. USSR P. 535 298; Byull. Izobret. (42) 69 (1976) 241. N S Kozlov, L I Moiseenok, S I Kozintsev Dokl. Akad. Nauk SSSR 252 1132 (1980) a 242. N S Kozlov, L I Moiseenok, S I Kozintsev Dokl. Akad. Navuk BSSR 28 1002 (1984) 243. N S Kozlov, L I Moiseenok, S I Kozintsev Dokl. Akad. Navuk BSSR 24 917 (1980) 244. N S Kozlov, L I Moiseenok, S I Kozintsev Vestsi Akad. Navuk BSSR, Ser. Khim. Navuk (6) 25 (1980) 245. A P Tomilov, S K Smirnov Adiponitril i Geksametilendiamin (Adi- ponitrile and Hexamethylenediamine) (Moscow: Khimiya, 1974) 246. USSR P. 650 994; Byull. Izobret. (9) 119 (1979) 247. N S Kozlov, V A Tarasevich, S I Kozintsev, L V Gladkikh Dokl. Akad. Nauk SSSR 244 1130 (1979) a 248. N S Kozlov, V A Tarasevich, S I Kozintsev Dokl. Akad. Navuk BSSR 23 910 (1979) 249. N S Kozlov, A S Zhavrid, L V Gladkikh, S I Kozintsev, V A Tarasevich Vestsi Akad. Navuk BSSR, Ser. Khim. Navuk (3) 57 (1983) a�Dokl. Chem. Technol., Dokl. Chem. (Engl. Transl.) b�Russ. Chem. Bull. (Engl. Transl.) c� Catal. (Engl. Transl.) d�Russ. J. Org. Chem. (Engl. Transl.) e�Russ. J. Appl. Chem. (Engl. Transl.) f�Russ. J. Phys. Chem. (Engl. Transl.) g�Chem. Nat. Compd. (Engl. Transl.) h�Russ. J. Gen. Chem. (Engl

ISSN:0036-021X    

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Russian Chemical Reviews 68 (1) 73 ± 84 (1999) Levulinic acid in organic synthesis B V Timokhin, V A Baransky, G D Eliseeva Contents I. Introduction II. Physicochemical characteristics III. Preparation IV. Reactions involving the carboxy group V. Reactions involving the carbonyl group VI. Reactions involving the methyl and the methylene groups VII. Oxidation and reduction reactions VIII. Conclusion Abstract. Data concerning the methods of synthesis, chemical transformations and application of levulinic acid are analysed and generalised. The wide synthetic potential of levulinic acid, partic- ularly as a key compound in the synthesis of various heterocyclic systems, saturated and unsaturated ketones and diketones, diffi- cultly accessible acids and other compounds is demonstrated.The accessibility of levulinic acid from hexose-containing wood-proc- essing and agricultural wastes is noted. The bibliography includes 260 references. I. Introduction At present, the use of organic synthesis on an industrial scale is so extensive that the problem of limited natural resources, such as petroleum and gas employed in this process comes to the fore- ground.1 This generates a need for timely measures aimed at elaboration of alternative strategies of fine organic synthesis on the basis of alternative sources of raw materials. In this context, the synthesis of key compounds from wood processing products holds great promise. The most common cellulose-derived prod- ucts include glucose, xylose, ethanol, polyhydric alcohols and furfural.Their use in industrial organic synthesis has been documented in numerous publications. Much less attention has been given to such cellulose hydrolysis products as organic acids, first of all, 4-oxopentanoic or levulinic acid (LA). The molecule of LA contains two highly reactive functional groups providing a great number of synthetic transformations. LA has been used to obtain various heterocyclic compounds, saturated and unsatu- rated ketones and diketones, difficultly accessible acids, alcohols and so on. We have analysed publications devoted to LA and found that despite the great number of these studies, their results have virtually not been generalised. Some reviews on the subject (see Refs 2 and 3) are not sufficiently comprehensive and outdated.B V Timokhin, V A Baransky, G D Eliseeva Irkutsk State University, ul. Karla Marksa 1, 664003 Irkutsk, Russian Federation. Fax (7-395) 233 22 38. Tel. (7-395) 246 47 62 (B V Timokhin) Received 28 April 1997 Uspekhi Khimii 68 (1) 80 ± 93 (1999); translated by R L Birnova #1999 Russian Academy of Sciences and Turpion Ltd UDC 547.484.451 73 73 74 75 76 81 81 82 In our opinion, the synthetic potentialities of LA are far from being exhausted, although the attention of investigators has now switched to starting compounds from other natural sources. Our desire to fill the information gap in this field, on the one hand, and to attract the attention of investigators and practitioners in synthetic chemistry to the high synthetic potentialities of LA manufactured from wood-processing and agricultural wastes on an industrial scale, on the other hand, was the incentive to write this review.II. Physicochemical characteristics Under normal conditions, LA is a colourless crystalline com- pound with a melting point of 37 8C, its boiling point (with decomposition) is 246 8C. The main physical constants for LA are as follows: d 20 4 1.140, d 25 4 1.1447; n 20 d 1.4796, n 25 d 1.441; sur- face tension 39.7 dyne cm71 (25 8C); heat of vaporisation (150 8C) 0.58 kJ mol71 and heat of fusion 79.8 J mol71 (see Ref. 4). Levulinic acid is readily soluble in water, ethanol, diethyl ether, acetone and many other organic solvents.The temperature dependence of solubility ofLAin water has been studied in detail.5 In water, LA is fairly well dissociated, its pKa (25 8C) is 4.59, see Ref. 6. In other words, the acidity of LA is comparable with that of the majority of lower alkane carboxylic acids. For comparison of gas-phase acidity ofLAwith those of other carboxylic acids, see Ref. 7. The analysis of 1H and 13C NMR spectra of LA allowed a correct assignment of signals,2 which demonstrated that the protons of the b-methylene group at position 3 are more `acidic': (d=2.71 ppm) than those of the a-methylene group (d=2.47 ppm). The rate of oxygen exchange of LA with water was studied using mass spectrometry. It was found 8 that the exchange of the carbonyl group oxygen occurs 10 times faster than that of the carboxy group.The approximate values of the pseudo-first-order constants in excess of H218O are kCO = 761073 s71 and kCOOH = 561074 s71, respectively. As expected, the carbon atom of the carbonyl group of LA is more susceptible to nucleophilic attack than that of the carboxy group. The first ionisation potential of LA (9.7 eV according to photoelectron spectroscopic data 8) corresponds to withdrawal of an electron from the orbital for which the main contribution is given by the unshared electron pair of the carbonyl oxygen atom.74 H2SO4 Me O Me OH HO1 O Me O COOH Me HO O3 H2SO4 O H2C OH HO2 The knowledge of the specific characteristics of the keto ± enol equilibrium of LA is substantial for the understanding of mech- anisms of its reactions; for the equilibrium constants of LA derivatives see Refs 9 and 10.It was found 10 that the content of the enolic forms of LA, viz., 4-hydroxypent-3-enoic (1) and 4-hydroxypent-4-enoic acids (2), in diethyl ether is as low as 1.961072%. The concentration of the LA enolic forms 1 and 2 in D2O solutions is negligible, which followed from the absence of deuterium exchange at C(3) and C(4) (13C NMRspectral data). A similar conclusion was made from the analysis of UV spectra of aqueous solutions of LA.11 Apparently, the ease of intramolecular transfer of the proton from the carboxy group to the carbonyl atom of oxygen is the reason for the predominant formation of 5-hydroxy-g-valerolactone (3) rather than the enolic forms.On the other hand, in acidic media (D2O with addition of D2SO4) rapid H/D exchange occurred 2 resulting in the formation of C(3)D2, C(5)D3-pentadeuteriolevulinic acid. Thus under con- ditions of acid catalysis the concentration of the enolic forms 1 and 2 increases substantially. Apparently, the structures 1 and 2 are the intermediates in the cyclisation of LA into the lactones 4 and 5 (Scheme 1).8 Thus, the generally accepted viewpoint that LA is at equili- brium with the unsaturated lactones 4 and 5 (see, e.g., Ref. 12) is not quite correct, since an appreciable concentration of these lactones is observed only in the presence of strong mineral acids. As expected, removal of water shifts the reaction towards the formation of the cyclic product.Thus the lactone 4 can be easily prepared by boiling LA in the presence of sulfuric or phosphoric acids using a Dean ± Stark trap.13 It should be noted that the lactone 5 is thermodynamically more stable and is formed from the lactone 4 upon heating or treatment of the latter with a base.14 Enolisation of the lactone 4 into 2-hydroxy-5-methylfuran is theoretically possible. However, compound 4 does not manifest any enolic properties and its O-alkylation cannot be carried out despite the evolution of 0.3 equiv. of methane in the determina- tion of mobile hydrogen according to the Tserivitinov proce- dure.15 The chemical behaviour of furanones is rather specific and its consideration is beyond the scope of this review.Different aspects of furanone chemistry have been described in a compre- hensive review.16 Thio derivatives of LA manifest an even greater trend for intramolecular cyclisation. Thus the reaction of LA with P2S5 or H2S gives only cyclic products, such as the dihydrothiophenones 6 and 7 containing traces of 5-mercapto-5-methyltetrahydro- thiophen-2-one.17, 18 O Me O Me S 6 S 7 III. Preparation On an industrial scale, LA is produced from wood-processing and agricultural wastes. The basis of industrial methods for the preparation of LA is transformation of hexoses in acidic media. This is usually considered as a combination of dehydration OH OH O OH H2C OH O resulting in the formation of 5-hydroxymethylfurfural (8) and its subsequent hydration resulting in LA.The formation of 5-hydroxymethylfurfural 8 occurs through a series of consecutive reactions, which has been established by numerous studies aimed at identification of intermediate products and analysis of path- ways of their further transformations (Scheme 2).19, 20 The ene- diol 12 obtained upon enolisation of D-glucose (9), D-mannose (10) or D-fructose (11) in acidic media is the key compound in the formation of 5-hydroxymethylfurfural 8. Its dehydration results in compound 13, which represents the enol form of 3-deoxyhex- osulose (14). Compound 13 yields 3,4-dideoxyglycosulosene-3 (15). The latter is readily converted into the dienediol 16, which eventually results in 5-hydroxymethylfurfural via the intermediate cyclic compound (17).Humin compounds are the side products of this reaction.20 CHOOH HO OH OH CH2OH 9 CHO HO HO OH OH CH2OH 10 CHO C O CH2OH OH CH2OH 14 CHO C OH CH CH C OH CH2OH 16 B V Timokhin, V A Baransky, G D Eliseeva Scheme 1 7H2O O O Me Me O5 O4 Scheme 2 HC OH CH2OH C OH C O HO HO OH OH OH OH CH2OH 12 CH2OH 11 7H2O CHO CHO C O C OH CH CH 7H2O OH CH OH OH CH2OH CH2OH 15 13 HOH2C CHOH HO 17O7H2OCHO HOH2C O8Levulinic acid in organic synthesis OH 7H2O H2O2 CHO Me Me Me CH O O22 OOH COOH Me H2O O Me O O Me COOH H HOO H2O2 Me OH O OH The conversion of 5-hydroxymethylfurfural 8 into LA is a result of addition of a molecule of water to the C(2)=C(3) bond of the furan ring.19, 20 This leads to ring opening with formation of an unstable tricarbonyl intermediate 18.The latter is decomposed into the final products, viz., LA and formic acid. H2O, H+ OH 8 OH CHO H2C CHO HOH2C O O OH OH Me CHO OH CHO Me O O O Me CHO 7HCOOH O O 18 COOH Me Me CH(OH)2 O O There are several assumptions about the nature of intermedi- ates involved in the conversion of compound 8 into LA. The above scheme has been proposed in a recent study 21 devoted to the analysis of this reaction (the formation of humin compounds is not shown). The sequence of transformations was proposed by Horvat et al.21, 22 on the basis of analysis of 13C NMR spectra of the reaction mixture formed in the hydration of compound 8.Acid treatment of plant raw materials containing up to 75% of polysaccharides in the form of cellulose and hemicelluloses results in the hydrolysis of polysaccharides to monosaccharides.23 The rate of wood pulp hydrolysis depends on the acid concentration, temperature, pressure and particle size.24 Hydrolysis of cellulose to hexoses at atmospheric pressure is usually performed with strong acids (HCl, H2SO4) at 100 8C. The resulting hydrolysate is heated up to 110 8C with 20% HCl and kept at this temperature for 24 ± 28 h. The reaction is accelerated by free halogens, tran- sition metals, anion-exchange resins and other compounds.2 After termination of the one-pot reaction, the reaction mixture is filtered to separate humin compounds and concentrated.LA is isolated from the mixture by distillation at reduced pressure or extraction with ether, ethyl acetate or ethyl methyl ketone. The yield of LA is about 40% with respect to the hexose content.2 The reaction performed at 190 8C under pressure gives a considerable gain in time.25 Preparation of LA from hexoses in supercritical reactors (34.5 MPa, 200 ± 385 8C) has been described in many papers over the last decade.26, 27 In the absence of acidic or basic catalysts, the dehydration reaction is more selective. Currently, degradation of hexoses under hydrothermal conditions 28, 29 or using alcohols in the presence of strong acids at 180 ± 200 8C30 is being devel- oped.This permits one to reduce the reaction time to several minutes at sufficiently high yields of LA.Asearch for new efficient catalysts is currently under way. Thus zeolites were found to 75 Scheme 3 H2O OCHO Me OH O O 7HCOOH Me COOH H2O2 O 23 manifest high catalytic activity in the preparation of LA from glucose and fructose.31 Furfuryl alcohol (19), another product of wood pulp chemical processing, is an alternative source of LA. Its heating in aqueous organic acids (Ka=1076 ± 1074) in the presence of hydrochloric acid affords LA in more than 80% yield. When this reaction is performed in boiling ethyl methyl ketone in the presence of HCl, LA is formed in 90%± 93% yield.33, 34 The hydroxy derivatives 20 and 21 were shown (13C NMR) to be the key intermediates in this reaction.21, 22 H+, H2O 7H2O HOH2C HOH2C OH O19 O20Me COOH H2O H2C OH O O21 Levulinic acid is also formed upon oxidation of 5-methylfur- fural (22) with 28% H2O2 at 60 8C in the presence of HCOOH.This reaction gives a mixture of levulinic and 4-oxopent-2-enoic (23) acids (Scheme 3).35, 36 It was shown 37 that LA is formed in high yield in the reaction of 4-(diphenylmethylsilyl)butyrolactone (24) with MeMgI. MeMgI Ph2MeSiCl O O Ph2MeSi O 24 O Me COOH H2O O Me O O LA can also be obtained in satisfactory yields 38 upon con- jugate addition of nitroethane to acrolein in the presence of Al2O3 with subsequent oxidation of 4-nitropentanal (25) with an H2O2 ±K2CO3 system. Al2O3 CHO CH EtNO2+H2C COOH Me Me CHO H2O2, K2CO3 O 25 NO2 Despite the high yield of LA in the above reactions, they still cannot compete on an industrial scale with the simple and inexpensive procedures used in the preparation of LA from plant raw material.IV. Reactions involving the carboxy group Of reactions involving the carboxy group of LA, special mention should be made of esterification which yields useful levulinates. The reaction of LA with primary alcohols, which is a first-order reaction with respect to both reactants,39 occurs in solutions ofLA in respective alcohols even at room temperature.40 In order to76 obtain esters in nearly quantitative yields, the reaction is carried out in the presence of typical dehydrating agents, such as sulfuric,41, 42 polyphosphoric 43 or p-toluenesulfonic acid.44, 45 The use of anion-exchange resins 46 or 2-halogenopyridinium salts 47 also gives good results.The increase in the size of the hydrocarbon fragment of the primary alcohol does not impede its esterification.48 Since primary alcohols are easily and selectively acylated under these conditions, LA is used as a protective group in the synthesis of oligonucleotides 49 and oligosaccharides.50 ± 52 Deprotection can be achieved using sodium borohydride 53 or sulfite anion donors.54 However, hydrazinolysis is the most efficient method for deprotection.55, 56 Under mild conditions, LA esters quantitatively react with hydrazine and its derivatives, which results in the regeneration of the original alcohol and the formation of the corresponding dihydropyridazinone, as a result of which the acid is completely eliminated from subsequent reaction.The formation of dihydropyridazinones and their reac- tivities are discussed in Section V. The synthesis of LA esters with tertiary alcohols in good yields usually involves other reactions than esterification. For example, tert-butyl levulinate is obtained by the reaction of LA with dimethylformamide tert-butyl acetal57 or tert-butyltrichloroaceti- midate.58 Me COOBut O a or b COOH Me O (a) (ButO)2CHNMe2; (b) CCl3C( NH)OBut. Substituted benzyl and aryl esters of LA can be obtained using other classical methods for ester synthesis, e.g., acylation of alcoholates with levulinoyl chloride 2, 59 ± 61 or alkylation of LA salts with alkyl halides under conditions of phase-transfer catal- ysis.62 O +ROM COCl Me O R=CH2Ph, Me2C6H3, C10H7; M=Na, K.COOR Me O a +RBr R=CH2Ph COOK Me (a) KOH, H2O, CHCl3, Bu4NBr. In addition to the methods described above, there are some other ways to obtain LA esters. Levulinates are formed by the reaction of LA with diazomethane derivatives,63 upon photo- oxidation of cyclopentenone derivatives,64 from the correspond- ing nitro compounds by the Nef reaction 65 or catalytic carbonylation of 4-alkoxybutan-2-one on rhodium catalysts.66 O RCHN2 R=Et, Pri3Si COOH Me OR O photooxidation R=Me O Me COOR Me KMnO4 COOR Me R=Alk NO2 Me OR [RhCl(CO)2]2 +CO R=Me, Et O LA thio esters are obtained in high yields by the reaction of thiols with a pyridinium salt of LA formed in situ from the free acid and 2-fluoro-1-methylpyridinium tosylate.67 B V Timokhin, V A Baransky, G D Eliseeva Decarboxylation of LA in the gaseous phase occurs with difficulty.68 Attempts to perform this reaction in a flow of hydro- gen over Ni- and Pd-catalysts at 180 ± 330 8C or over zeolites containing group I, II and VIII metals were more successful.69 Thus heating of the lactone 4 up to 570 8C in the presence of SiO2 gave up to 80% of ethyl methyl ketone.70 A method for decar- boxylation proposed recently using xenon fluoride was applied successfully to LA.Such fluorodecarboxylation occurs at room temperature 71 via intermediate fluoroxenon esters 26.COXeF Me COOH Me +XeF2 7F7 O 26 Me O F+CO2+Xe+F7 O Studies of anodic electrolytic decarboxylation of LA under conditions of the Kolbe reaction have established interesting synthetic possibilities. In methanol, at a potential difference of 80 ± 129 V and 2 ± 3 A in the presence of sodium methoxide, LA was converted into octane-2,7-dione (27).72 Cross-decarboxy- lation in the presence of other carboxylic acids results in unsatur- ated ketones 28 73 and higher aliphatic oxo acid esters 29.74, 75 O a Me Me O 27 COOH Me Me Me b O O 28 MeC(CH2)n+2COOMe c 29 O; (c) HOOC(CH2)nCOOMe, COOH (a) MeOH, MeONa; (b) Me n=4, 8, 12.In addition to the above reactions involving the carboxy group of LA, of note is its nucleophilic addition to alkoxyacetylenes.76 The addition product 30 is unstable and is easily rearranged into the lactone 31 which ultimately yields 3-methylhex-3-enedioic acid (32). Me COOH MeCOOH, CH2Cl2 +EtOC CH 780 8C O OEt O 1. KOH 2. H2SO4 Me Me O O EtOOCCH2 30 31 O O COOH HOOC 32 Me V. Reactions involving the carbonyl group 1. Reactions with N-nucleophiles The presence of two highly reactive functional groups in the LA molecule determines its specific properties. Reactions of LA with nitrogen-containing nucleophiles provide an illustrative example. As a rule, reactions of LA with such nucleophiles are not terminated by their addition to the carbonyl group or the formation of the corresponding amide but result in heterocyclisa- tion.For example, the carbonyl group of LA undergoes the Knoop ± Oesterlin reductive amination.77 This reaction is cata- lysed by Co, Ni and Pd and gives either the corresponding amino acids 33,78 or 5-methyl-2-pyrrolidone derivatives 34 as a result of cyclodehydration, depending on whether the carboxy group of LA is protected or not.79, 80Levulinic acid in organic synthesis COOR1 Me O R1=H, Et; R2=H, Me, Ar. The amides formed by the reaction of LA with various amines are attractive not only because of their biological activity,81 but also because of their ability for cyclisation. Thus the amide 35 formed in the reaction of phenethylamine with a-angelicalactone (4) is unstable and is at equilibrium with the corresponding pyrrolidone 36 (the 35 : 36 ratio is 1 : 2).82, 83 4+ Ph NH2 HO Me36 Reactions of anilines with LA or the lactone 4 in acidic media yield reactive benzoazepinone derivatives 37 rather than ani- lides.84, 85 The direction of their hydrogenation depends on the nature of the reagent used.Thus hydrogenation with hydrogen over PtO2 results in saturation of the C(4)=C(5) bond of the azepine ring, whereas treatment of the benzoazepinones 37 with LiAlH4 results in the reduction of the oxo group to the methylene group. Treatment of compound 37 with POCl3 gives the chloro- substituted benzoazepine 38. R2 +Me O NHR1 Me R2 NR1 37 R2=H, Me, MeO. The result of the reaction of LA with pyrrole derivatives containing the 2-aminoethyl group depends on its position in the ring.Thus the reaction of LA with 2-(2-aminoethyl)pyrrole gives the 1H-pyrrolo[3,2-c]pyridine derivatives 39.86 A similar reaction of LA with 3-(2-aminoethyl)indole (tryptamine) or N-(2-amino- ethyl)indole leads to the formation of fused heterocyclic systems 40 and 41, respectively.87, 88 Me COOH O R1=Et H2, cat., R2NH2 R1=H O Me O 35 O N Ph H+ COOHH2, PtO2 R2 LiAlH4 O R2 POCl3 R2 COOEt Me NHR2 33 R2 N Me O 34 Ph NH Me O RN1 Me NR1 Me Cl 38 RN1 77 Me COOH NH2 NH NH39 NH NH2 NH N O NH 40 Me N NH2 Me N N O 41 The reaction of LAwith 5-aminopyrazoles gives substituted 4- methyl-6H-7,8-dihydropyrazole[3,4-b]azepin-7-ones.89 R Me COOH + N O NH2 NRMe RN O NRHN The reaction of LA with o-phenylenediamine derivatives results in the formation of the benzoimidazole ring and yields isomeric pyrrolobenzoimidazolones 42 and 43.90 NH2 Me COOH + O R NH2 O O R N N + Me Me R NH NH 43 42 R=Cl, Me.Substitution of an amide group for an amino group in the aromatic component of this reaction affords other types of heterocyclic derivatives. Thus anthranilic acid and its amides react with LA to give fused heterocyclic systems, e.g., 2,3,3a,4- tetrahydropyrrole[1,2-a]quinazoline-1,5-diones 44 from anthra- nilamides.91, 92 R Me COOH COXH + O NH2 O R R X H+ Me COXH O N Me NHO O 44 R=H, Cl; X=O, NH, NMe, NPh.As noted above, LA and its esters readily react with hydrazine and its derivatives to give the corresponding hydrazones. Dihy- dropyridazinones 93 ± 96 possessing analgesic and diuretic activities are formed from hydrazine and its monosubstituted hydrazones upon cyclodehydration.9778 Me COOCH2R O Me N NHR R=H, Alk, Ph, p-MeC6H4, p-EtOC6H4. Dihydropyridazinones are highly reactive compounds and can be used in organic synthesis. Using compound 45 as an example, it was demonstrated that dihydropyridazinones are easily oxidised with bromine or SeO2 to the corresponding pyridazinones 93, 94 and reduced with LiAlH4 first to tetrahydropyridazines 95 and then to hexahydro derivatives.98 Pyridazinones undergo alkyla- tion, nitration and chlorination.99 Compound 45 was also used to obtain glutamic acid via the intermediate pyridazinone-3-carbox- ylic acid.100 MeN SeO2 or Br2 NH AcOH O45 Cl Cl2 Cl HNO3 O2N LiAlH4 45 10% HNO3 The formation of the dihydropyridazinone ring upon treat- ment of levulinamide with hydrazine illustrates the possibility of nonenzymic hydrolysis of the peptide bond.This is exemplified by reaction of N-levulinoyl-L-phenylalanine (46) with hydrazine.101 COOH O Me NHO 46 LA reacts very easily with 2,4-dinitrophenylhydrazine. This circumstance was used in the development of a semi-quantitative colorimetric procedure for determination of hydrazones. This method is based on the ability of LA to serve as an acceptor of 2,4-dinitrophenylhydrazine and to regenerate the ketone from the corresponding hydrazone as a result of the exchange reaction.102 It was noted also that treatment of the oximes 47 with LA recovers carbonyl derivatives.103 R1 Me O NOH+ 47 R2 +H2NNHR 7H2O Me COOCH2R NNR 7RCH2OH O Me MeN MeI NNMe NH O O MeNNMe MeNNMe O Me Me LiAlH4 NH NH NNH COOH HO2CCH(CH2)2CO2H H2/Ni NNH NH2 O PhCH2CHCOOH NH2 NH2 Ph 45+ NH2 COOH B V Timokhin, V A Baransky, G D Eliseeva R1 Me COOH O+ NOH R2 R1=Me, R2=Ph; R1=Ph, R2=H; R1=R2=Ph.LA hydrazones manifest noticeable antibacterial activi- ty.104 ± 106 They also serve as a source of N-subsituted pyrroli- dones.The reaction between LA and hydrazides of nicotinic or isonicotinic acids demonstrates an approach to the synthesis of N-acyl pyrrolidones 48.107 Me COOH +RCONHNH2Me COOH COOH OMe HCl H2, PtO2 N NHC(O)R NHNHC(O)R Me RCONH NO 48 R=3-pyridyl, 4-pyridyl. Unlike acylhydrazines, their thio analogues react with LA or its esters to give the 1,3,4-thiadiazole derivatives 49.107, 108 O N N Me COOH+RCNHNH2 R 7H2O S O S 49 Me The hydrazones 50 prepared from LA and 3-aryl-2-hydrazi- noquinazolinones are thermally unstable and undergo the Dim- roth rearrangement at melting temperature with simultaneous cleavage of the imine bond, eventually resulting in 3-amino-2- anilinoquinazolinones 51.109 R O O NH2 N N R Me N N N N HN (CH2)2COOH 51 50 The role of LA arylhydrazones in the Fischer indole synthesis has been studied in most detail, since this reaction gives an access to not only heteroauxin analogues manifesting growth-regulating activity 110 but also to a broad range of antiinflammatory drugs, such as indometacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl- indol-3-ylacetic acid].111 Halogen-, alkyl- and alkoxy-substituted arylhydrazines,112, 113 1-naphthylhydrazine 114 and various N-acyl-N-arylhydrazines enter into this reaction.115 ± 120 Sodium arylhydrazinesulfonate can be used instead of phenylhydrazine hydrochloride which is unstable on storage.121, 122 The mechanism of this reaction was studied with LA as an example. It was found that hydrazone rearrangement, which is probably similar to the Claisen rearrangement of allyl phenyl ethers, is the key stage.The key intermediate of the imine type, viz., compound 52, which gives the intermediate 53 upon hetero- cyclisation, was studied by 13C NMR spectroscopy.123 COOH Me + X NNH2 R OMe COOH N X NRLevulinic acid in organic synthesisMe H+ COOH X HN NR CH2COOH X CH2COOH X Me NH2 Me NR NH NHR 53 52 X CH2COOH Me NR 2. Reactions with O- and S-nucleophiles Under conditions of acid catalysis, LA esters react easily with alcohols and thiols to give the corresponding dialkylacetals and dialkyldithioacetals in more than 90% yields.124 Special mention should be made of compound 54 formed in the reaction of LA with 3-mercaptopropionic acid, which can selectively extract some metal cations.125 S(CH2)2COOH Me C(CH2)2COOH S(CH2)2COOH 54 The reaction of LA with thiazolyl- and indolylethanols gives the fused tetrahydropyrans 55 and 56.126, 127 COOR Me O OH HN O COOR NHMe 55 N N OH O Ar S S Ar COOR Me 56 The reaction of LA or its esters with 1,2-diols or dithiols gives dioxolanes and dithiolanes.128, 129 As is known, the formation of such structures is often used to protect the carbonyl group.This approach is also used in multistage syntheses involving LA. Thus the 1,2-dioxolane (57) and 1,3-dioxolane (58) derivatives of LA were used to protect its carbonyl group in the syntheses of a natural pheromone,130 Z-jasmone and dihydrojasmone.131 ± 133 Me COOH COOH Me S S O O 58 57 The presence of an amino group in the a-position with respect to the hydroxy or the mercapto group in amino alcohols or amino thiols makes it possible to carry out heterocyclisation on their reactions with LA134, 135 to give the bicyclic lactams 59.Me XH X Me N COOH+R NH2 O R O 59 R=COOH, CHMe2; X=O, S. 79 3. Reactions with organoelement compounds The carbonyl group is capable of nucleophilic addition of organo- metallic compounds. However, this reaction is often complicated due to involvement of the carboxy group. g-Valerolactone deriv- atives 136 ± 140 are formed instead of the expected hydroxy acid derivatives even in reactions of organometallic derivatives of group I and II elements with levulinates with the protected carboxy group.Thus the reaction of LA with allylzinc bromide gives 5-allyl-g-valerolactone (60) in 80% yield.139 Me THF, 0 8C COOH+ ZnBr O Me O O 60 The allyl carbanion formed in situ as a result of hydrolysis and scission of the Si7C bond in allyltrimethylsilane under the action of tetrabutylammonium fluoride adds to LA to give the g-valer- olactone 60 following hydrolysis of the intermediate product.141 Bu4NF Me3Si 7Me3SiF +7 MeCO(CH2)2COOH 60 [Bu4NC3H5] Nevertheless, allylation of LAand its esters to the correspond- ing derivatives of 4-hydroxyvaleric acid can be achieved with allyl bromide in the presence of metallic Zn, Sn and Al 142, 143 as well as alkyl complexes of transition metals.144 The pseudo-Barbier reaction involving ethyl levulinate and alkyl halides in the presence of samarium cyclopentadienyl complexes is also possible.145 The reaction of LA with metal cyanides and hydrocyanic acid gives the cyanohydrin 61.146 The latter yields 5-cyano-g-valero- lactone (62) under the action of dehydrating reagents; its hydrol- ysis gives 2-hydroxy-2-methylglutaric acid (63).The lactone 62 can also be converted into 2-methylglutamic acid.147 OH COOH Me COOH Me HCN or NaCN O CN 61 Me Me P2O5 HOOC COOH O CN NH2 O62Me HOOC COOH H+ OH 63 The reaction of the cyanohydrin 61 with hydrazine followed by oxidation gave the azo compound 64, which is an initiator of radical reactions.148, 149 COOH Me NaCN, HCl 1.NH2NH2, 30 8C; 2. Cl2, 5 8C 61 O Me HOOC N CN 2 64 The carbonyl group of LA or its esters reacts with phos- phorus-substituted carbanions 150, 151 in the Wittig and Horner ± - Emmons reactions to give compounds 65 and 66. COOR Me O80 +7 COOH HOOC Ph3PCHCH2COOH R=H Me 65 ButO 7 P(O)(OEt)2 COOMe Me CN R=Me ButO CN66 R=H, Me. Hydrides of group IV and V elements also easily add to the carbonyl group of LA. Hydrosilylation in the presence of rhodium complexes with chiral ligands occurs as enantioselective reduc- tion.152, 153 However, unlike diethylsilane, which gives a stable silylation product,154 hydride derivatives of arsenic and phospho- rus yield unstable addition products that easily undergo intra- molecular cyclisation.155, 156 Me COOH O Me COOSiHEt2 Et2SiH2 OSiHEt2 O H2N N AsH2 HAs Me O O (EtO)2P(O)H (EtO)2P(O) Me The result of the reaction of halides of group V elements with LA depends on the nature of the halide.As would be expected, bismuth and antimony halides yield predominantly acyl deri- vatives,157, 158 whereas the reaction with MeNbCl4 results in the chlorination of the carbonyl group of LA.159 The same result is observed in the interaction of LA with phosphorus penta- chloride.160 However, the reaction of PCl5 with a-angelicalactone (4) leads to phosphorylation of the multiple bond.161 + Cl2(O)P Cl3P PCl5 7PCl6 O Me O Me O O Me O O4 4.Condensation reactions Aldol condensation of LA with aromatic and heterocyclic alde- hydes under conditions of the Claisen reaction gives a,b-unsatu- rated carbonyl compounds and their derivatives. Benzaldehyde and its analogues easily enter into the condensation reaction to give 6-aryl-4-oxohex-5-enoic acid (67),162 ± 164 while the reaction of LA esters with 2-hydroxyacetophenone yields the 2-substituted chromone 68.165 ± 167 It is believed 168 that this reaction proceeds via the lactone intermediate by the Stobbe condensation. Me COOR O p-AlkC6H4CHO COOH p-AlkC6H4 R=H 67 O O o-HOC6H4COMe Me R=Alk COOAlk O68 Since the unsaturated acids 67 thus formed are g-oxo acids, they retain ability to form pyridazinones on reaction with hydra- B V Timokhin, V A Baransky, G D Eliseeva zine.Pyridazinones can undergo bromination and yield pyrida- zines.169 Condensation of LA with furfural offered even broader possibilities for the synthesis.170 ± 175 This reaction can yield diverse furancarboxylic acids. 5-Furfurylidenelevulinic acid (69) is the main reaction product at room temperature. However, at a temperature above 50 8C, the proportion of 3-furfurylidene- (70) and 3,5-difurfurylidenelevulinic acids (71) increases.173 COOH Me CHO + O O HOOCCH2 + COO COOH+ Me O O O 69 O 70 HOOCCH2 + O O 71 O Acid treatment of the acid 69, i.e., the main reaction product, gives dilevulinic acid 72; its reduction on a Raney nickel catalyst yields sebacic acid,171 and its cyclisation results in the dicarboxylic acid 73, which served as the starting compound in the synthesis of prostaglandins.174 O HOOC 69 COOH O 72 O HO7 CH2COOH (CH2)2COOH 73 H2, Ni HOOC(CH2)8COOH Condensation of LA or its esters with cyanoacetic acid under conditions of the Knoevenagel reaction yields the nitriles 74.The latter were used to obtain 3-methyladipic acid by reduction of the double bond and acid hydrolysis.176 NH3 COOR+NC COOH Me O Me Me H2O, H+ H2 NC NC COOR COOR 74Me HOOC COOH R=H, Me, Et, CH2Ph. Like aldehydes and ketones, LA undergoes acid-catalysed condensation with phenols and naphthols to give the 4,4-diaryl- substituted valeric acids 75.177 ± 180 H+ OH Me COOH+ O R (CH2)2COOH Me R RHO 75 OH R=H, Me.Levulinic acid in organic synthesis Furan and its derivatives react analogously.181 ± 183 Conjugate condensation of furan with acetone and LA or its esters makes it possible to obtain macrocycles of the type 76, which can selectively extract metal ions similarly to crown ethers.Me Me Me O (CH2)2COOEt O O O Me Me Me (H2C)2 76 EtOOC The reaction of LA with resorcinol occurs in a different way and gives the arylated g-valerolactone 77.184 Me COOH 1,3-(HO)2C6H4 3 O Me O 1,3-(HO)2H3C6 77 O In the reaction of LA esters with enol silyl ethers in the presence of equivalent quantities of TiCl4, cross-aldol condensa- tion occurs smoothly to yield esters of 4-hydroxy- 4,5-dimethyl-6- oxocarboxylic acids 78.185 R TiCl4 Me COOEt+Me OSiMe3 O MeMe R COOEt O 78 OH R=Alk.A similar reaction takes place in the condensation of LA with chlorodifluoromethyl ketones.186 VI. Reactions involving the methyl and the methylene groups The carbonyl and the carboxy groups of LA activate the neigh- bouring carbon atoms. Therefore, LA undergoes easy chlorina- tion and bromination. These reactions yield organic halides which represent valuable `building blocks'. Chlorination of LA with chlorine at moderate temperatures results in 3,5-dichlorolevulinic acid (79).187 With a rise in temper- ature or in the presence of Lewis acids, more profound chlorina- tion takes place to give 2,3,5,5,5-pentachloro-4-oxopentenoic acid (80),188 ± 191 which can be used as defoliant.Cl Cl2, 70 ± 80 8C COOH ClCH2 COOH Me 79 OCl O Cl2, 200 8C COOH Cl3C O 80 Cl The result of bromination of LA strongly depends on the medium in which the reaction is performed. By varying the solvent, one can obtain different bromo derivatives of LA with sufficiently high selectivity. Thus bromination in the presence of concentrated HCl gives predominantly 2-bromolevulinic acid (81),191 whereas in acetic acid 3,5-dibromo-derivative 82 is obtained.192 In methanol, the reaction results in regioselective bromination of LA at the methyl group to give 5-bromolevulinic acid (83).193 81 COOH Me Br2, HCl conc. 81 O Br Br COOH Me Br2, AcOH COOH BrCH2 O 82 O COOH BrCH2 Br2, MeOH 83 O Combination of halogenation and dehydrohalogenation of LA affords halogen-containing hydroxyfuranones 84a,b.194, 195 COOH Me 1.X2 2. Et3N HO XH2C O O O 84a,b X=Cl (a), Br (b). Sulfur tetrafluoride 196 ± 198 and its derivatives 199 are the most effective fluorinating agents for LA. However, this does not involve the methyl and the methylene groups. It was shown that the lactone 3, which is always present in a solution of LA, is the first to undergo fluorination. The latter is converted into 1,1,1,4,4- pentafluoropentane through the intermediate 85. COOH Me HF SF4 3 Me F 20 8C, 12 h O O O85 SF4 MeCF2(CH2)2COOH 100 8C, 7 h SF4, HF MeCF2(CH2)2CF3 MeCF2(CH2)2C(O)F 20 8C, 12 h Ethyl levulinate undergoes fluorination only at the carbon atom of the carbonyl group under these conditions.200 The methyl group of LA is active in the metallation reaction.Thus treatment of LA with lithium diisopropylamide gives the organolithium compound 86 which, in turn, yields 6-phenyl-4,6- dioxohexanoic acid (87) in the reaction with benzoyl chloride.201 COOH COOH Me LiCH2 PhCOCl Pri2NLi O O 86 Ph COOH O 87 O VII. Oxidation and reduction reactions The result of oxidation of LA strongly depends on the type of the oxidant. High-temperature oxidation of LA with oxygen over V2O5 gives succinic acid 202 and oxidation of LA with selenium dioxide under conditions of the Riley reaction results in 2-oxo- glutaric acid.203 O2, V2O5 COOH HOOC COOH Me HOOC COOH SeO2 O O Oxidation ofLAand its derivatives with peroxy compounds in the Baeyer ± Williger reaction has been studied.204 ± 207 The first step of this reaction yields hydroxyperoxyvaleric acid derivatives 88, which rapidly cyclise to peroxyvalero-g-lactones 89.If the carboxy group is protected, succinates are formed. COX Me COX Me +R1OOH R1OO O OH 8882 X=OR2 COOR2 MeOOC Me X=Cl, OH O R1OO O 89 Reduction of LA can be carried out by various methods. First, mention should be made of catalytic hydrogenation of LA and its esters on Raney nickel. The free acid is quantitatively converted into g-valerolactone,208 while its esters are reduced to 4-hydrox- yvaleroates.209 Analogous products are obtained upon hydro- genation of LA and its esters on a copper ± chromium catalyst (CuO, 80%; Cr2O3, 20%).210 Modification of hydrogenation catalysts with optically active substances (L-alanine, L-phenyl- alanine, L-glutamic acid, D-tartaric acid) allowed one to accom- plish asymmetric synthesis of g-valerolactone from LA.211 ± 213 Under conditions of reductive cyclisation, LA and its esters serve as starting compounds in the synthesis of different saturated lactones, e.g., 5-substituted butyrolactones.214 ± 216 Thus the opti- cally active g-valerolactone is obtained in good yield by reduction of LA with silanes in the presence of rhodium catalysts with chiral ligands.217 The reaction of LA with SOCl2 gives the saturated lactone 90 in addition to levulinoyl chloride.This reaction is believed to occur according to the mechanism depicted in the scheme given below.218 The yield of compound 90 can reach 100%.219 Appa- rently, the formation of 5-methoxy-g-valerolactone in the reaction of LA with methyl chloroformate occurs in a similar way.220 The halogen atom in compound 90 is rather mobile. Thus the reaction of the lactone 90 with equimolar amount of 90% tert-butyl hydroxyperoxide gives compound 89 (R1 = But).221 O COOH Me S Cl +SOCl2 O 7HCl O Me O O Me COCl Cl7 O 7SO2 O Me Cl O 90 The reaction of LA with sodium dithionite in boiling aqueous dioxane also gives g-valerolactone. It is believed 222 that this reaction occurs through the formation of a-hydroxysulfinates.For catalytic hydrogenation of the oxo group of LA catalysed by ruthenium and rhodium complexes see Refs 223 and 224. More profound reduction of LA derivatives to diol or valeric acid is also possible. Thus reduction of LA with lithium alumi- nium hydride gives racemic pentane-1,4-diol,225 while electro- chemical reduction of LA under conditions of catholyte recirculation and membrane separation of anolyte gives valeric acid.226 Bakers yeast reduce LA esters to 4-hydroxyvalerates in good yields and then to (R)-g-valerolactone and (S)-pentane-1,4- diol.227 VIII. Conclusion Thus, easy access to LA from natural renewable raw materials makes this acid a readily available starting compound for the synthesis of 1,4-dicarbonyl systems the synthetic approaches to which are limited.228 On the one hand, LA enter into miscellaneous reactions of nucleophilic addition of N-, O-, S- and C-centred nucleophiles at the oxo group; on the other hand, it undergoes classical trans- formations characteristic of carboxylic acids. Moreover, LA as a typical representative of g-oxo carboxylic acids reacts with involvement of both functional groups at once.This permits the B V Timokhin, V A Baransky, G D Eliseeva synthesis of various types of heterocyclic compounds on the basis of LA, e.g., pyrrolidone, benzoazepinone, indole and chromone derivatives. It is noteworthy that the presence of an electron-acceptor carbonyl group in the LA molecule strongly increases the acidity of the protons at C(3).Their mobility favours the alkylation and halogenation of the LA molecule as well as its lactonisation. Owing to the accessibility of LA, the methods for synthesis of various compounds based on it efficiently compete with alter- native synthetic approaches. In addition, both LA and its derivatives possess various useful properties which significantly expand the range of their ever increasing synthetic applications. Thus levulinic acid is used to control plant growth.229 Being an inhibitor of choline photoly- sis,230 LA can inhibit or stimulate chlorophyll synthesis.231 It is used as a modifying additive to resins based on furfuryl alcohol,232 modifies the surface of aminoaerosils,233 confers radiation-pro- tective properties to polymers234 and is used for scheelite flota- tion.235 Its esters and salts are used in the food industry 236 ± 240 as preservatives, stabilising and flavouring agents as well as in the manufacture of cosmetics 241 ± 246 and in medicinal practice.247 ± 250 LA esters as additives increase thermal stability of poly(vinyl chloride) 251 and improve the characteristics of motor fuels,252 while glycol esters are perfect plasticisers.41, 61, 253 Compounds synthesised from LA are used as corrosion inhibitors,254 initiators of radical polymerisation,148, 149, 255 ± 257 cross-linking reagents 258 and components of liquid crystals.259, 260 There is no doubt that LA may be used as one of the components in the elaboration of an alternative source of raw materials in organic synthesis.References 7. 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年代:1999

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