ORGANIC CHEMISTRY1. INTRODUCTIONA NOTEWORTHY feature of the theoretical section is t'he discussion, for thefirst time in these Reports, of electrophilic substitution at a saturated (singlybonded) carbon atom. Also careful consideration is given to acidity func-tions, to isotope effects, and to solvent effects ; nuclear magnetic resonancestudies now show every sign of becoming a matter of routine. Only verybrief consideration of free-radical chemistry has been possible this year forlack of space. The section on quantum organic chemistry covers theperiod 1959-61, which has been marked by much publication centred onintensive work on fundamental problems, and by the study of electron-spinresonance and nuclear magnetic resonance spectra, but without majoradvances in quantum organic chemistry itself.Among general methods, interest in hydroboronation is undiminished,and the Wittig olefin synthesis and related methods find valuable applica-tion.Vinyl-lithium has been successfully made and exploited, and photo-chemical preparative methods continue to show valuable developments.In the field of stereochemistry the greatest interest attaches to the studyand use of optical rotatory dispersion for establishing the stereochemicalenvironment of appropriate chromophores. A claim1 to have obtained the" first example of an optically active Grignard reagent " is also noteworthy,and studies of conformational problems continue to be very fruitful.Much work has been done on aliphatic unsaturated compounds. Im-proved methods are applied to the synthesis of long-chain olefinic acids;natural acetylenic acids continue to attract attention ; and various simpleacetylenes having functional groups directly attached to triply linkedcarbon are described. Carbenic intermediates have been used in synthesesof allenes, and the absolute configuration of mevalonolactone has beenestablished.There have been important developments in the catalytic trimerisationof acetylenic to benzene derivatives.Highly strained poly-t-butylbenzeneshave been prepared and found to have interesting properties, as has a newcyclic system, radialene (hexamethylenecyclohexane) , Xylylenes (quino-dimethanes) receive important consideration, as do cyclic polyenes withboth few, e.g., four, and many, e.g., twenty, carbon atoms.Activity in the field of alicyclic compounds is unabated, ranging fromthe preparation and study of stable di- and tri-arylcyclopropenium saltsand other cyclopropane derivatives to larger rings, especially fused-ringsystems; where complexities continue to be unravelled, and to sesqui- andtri-terpenes.In the terpene area the combination of classical organicchemical studies with physical methods (X-ray crystallography, nuclearmagnetic resonance spectroscopy, optical rotatory dispersion studies) hasyielded valuable results very expeditiously. Much has been done on theestablishment of relative and absolute stereochemical configurations.1 H. M. Walborsky and A. E. Young, J . Amer. Chem. SOC., 1961, 83, 2595McWEENY: QUANTUM ORGANIC CHEMISTRY 137There has been a great abundance of work on every aspect of hetero-cyclic chemistry, with theoretical and physicochemical studies playing animportant r6le.Some fascinating novel sulphur heterocyclic compoundsare reported : e.g., the 1,2-dithiolium cation, and 1,2,4,6-tetraphenylthia-benzene. Interest in the biogenesis of alkaloids continues ; the detailedchemistry of the yohimbine group receives attention; the structure ofechitamine chloride has been established by X-ray and chemical methods ;and an elegant synthesis of conessine has been achieved.There have been valuable developments in the study of the mechanismof reaction of simple members of the carbohydrate group, and the firstcrystalline 3-ketoseY ~~-xylo-3-hexulose has been prepared.Sugar sulphateshave received important attention and sugars with a sulphur atom in thering, e.g., D-xylothiapyranose, are reported for the first time. Methods ofisolating starch fractions without degradation have been notably improved,giving, for example, an amylose with molecular weight >106.The importance of physicochemical methods to the steroid field has beenincreased by the successful application of optical rotatory dispersionmeasurements ; and intramolecular radical reactions, especially photolyticreactions, are now important in this field. A total synthesis of (&)-cestroneby a group of Russian workers is reported, and steroid lactones continue toattract attention.The section on amino-acids, peptides, and proteins, covering a two-yearperiod, is rich in notable advances.A few examples are: the applicationof mass spectrometry to the analysis of protein hydrolysates; the use ofI , 1 ’- carbonyldi-imidazole and 2 -ethyl- 5-phenylisoxazolium-3-sulphonate forforming peptide bonds ; the synthesis of biologically active peptides andclose analogues, and the correlation of their structure with biological activity ;the synthesis of bradykinin; the elucidation of the chain sequence of bovineACTH, and ribonuclease, and of the complete sequences of the ct- andp-chains of human hEmoglobin.T. S. S.N. B. C.2. QUANTUM ORGANIC CHEMISTRYTms report is concerned with the three-year period 1959-61. During thistime, many aspects of molecular quantum mechanics have received atten-tion and several thousand papers have appeared: but the number of out-standing advances in what may properly be called “quantum organicchemistry ” has been comparatively small.This situation is not likely topersist and major developments may be expected during the next few years.It should be seen rather as a sign of even more intensive work on funda-mental problems, with a return of emphasis to small molecules and evensingle atoms. When the forging of new theoretical tools is complete, thereis little doubt that organic chemistry will claim some of the first rewards.The present situation in molecular quantum mechanics was nicelysummed up by Coulson, a t the 1959 Boulder Conference.1 QuantumConference on Molecular Quantum Mechanics,476.Rev.Mod. Phys., 1960, 32, 169138 ORGANIC CHEMISTRYchemistry is over thirty years old and “ it is not surprising that many of theplums have now been picked and really interesting and novel fruit is harderto come by.” Although there was a steady development of basic theory,really original applications appeared to be taking place in only four fields:(i) the interpretation of vibronic spectra, and related topics connectedwith equilibrium shapes of molecules and complexes; (ii) the electronicspectra of aromatic radicals and ions, including more especially electron-spin resonance (ESR) spectra ; (iii) the interpretation of nuclear magneticresonance (NMR) effects in terms of spin coupling through the electron dis-tribution; and (ivj ligand field theory, including, for example, the magneticproperties of complex ions.The “plums~’ in n-electron theory-which used to be dealt with inperhaps four of every five theoretical papers-have indeed been picked :the harvest is useful because it helps us to understand other molecularproperties, particularly those uncovered by radio-frequency and microwavespectroscopy ; but sophisticated calculations of n-electron wave functions,and their use in discussing resonance energies and reactivities, are no longerthe main preoccupation of the theoretical chemist. This feeling is reflectedin a number of recent reviews, by Kotani et u Z . , ~ LO~din,~ Hall,4 Pople,5and Preuss.6Selection from the many hundreds of papers with a direct bearing onorganic chemistry has been made to illustrate major developments, mainlyin three areas where progress is steady and a connected survey possible.Basic Theory.-GeneruZ.Until recently, quantum chemistry dependedalmost entirely on the molecular-orbital (MO) and the valence-bond (VB)method. In MO theory the electrons occupied molecular orbitals; invalence-bond theory they . occupied atomic orbitals (AO’s) with spinscoupled in such a way as to describe localized electron pairs (“ bonds ”).It was generally recognized that either approach, carried to conclusion,would yield the same exact wave function (see, for example, McWeeny ’)but that the molecular-orbital method was more practical in non-empiricalcalculations. Consequently, nearly all rigorous work was based uponmolecular-orbital wave functions of the form(1) = IZ“wlw2 * - * vN1,where yl, y2 .. . yN are molecular spin-orbitals (Le., molecular orbitals with aspin factor a or to describe positive spin or negative spin), $Zl indicates theoperation of making the orbital product antisymmetric, as required by thePauli principle. Most normal molecules have “ closed-shell ” ground statesin which each molecular orbital appears twice, once with an a- and oncewith a b-factor, and the ground state is then described by a single configura-tion of type (1) and indicated in the usual way, e.g., [ ls22s2] for the berylliumatom. This approximation is transcended by setting up functions of type2 M. Kotani, Y. Mizuno, K. Kayama, and H.Yoshizumi, Ann. Rev. Phys. Chem.,1958, 9, 245.P. 0. Lowdin, Ann. Rev. Phys. Chem., 1960, 11, 107.G. G. Hall, Reports Progr. Phys., 1959, 22, 1.J . A. Pople, Ann. Rev. Phys. Chem., 1959, 10, 331.6H. Preuss, Natumuiss., 1960, 4’7, 241.‘R. McWeeny, Proc. Roy. SOC., 1955, A, 227, 288McWEENY: QUANTUM ORGANIC CHEMISTRY 139(1) for " excited " configurations (e.g., [ls22s13s1] for the beryllium atom)and allowing them to mix with the one-codguration approximation.Many-configuration calculations continue on simple systems (useful surveyshave been given by McLean et d.,* and by Allen and Karog), but theyare slowly convergent and of somewhat academic interest to the organicchemist. In fact, as Coulson, Craig, and others first showed lo the applica-tions to organic molecules are on the whole disappointing.Non-empiricalcalculations along these lines have been concentrated, for obvious reasons,upon small molecules. Examples of interest to the organic chemist aremethane,ll acetylene,l2 methylene and methyl, l3 carbon monoxide,14 form-aldehyde,l5, water,16 nitric oxide,17 ammonia,18 CH3-, NH3, and OH3+,19CH, NH, OH,20 BH, CH, OH, FH, 21carbon dioxide and. acetylene,22C3, N3-, NO,+, HF,-. 23 Such calculations are important largely becausethey raise, and go some way towards answering, a variety of fundamentalquestions: what approximations will it be safe to make in discussing largermolecules? what form should a semi-empirical theory take? and what is thebest way of describing the electronic structure of a complicated molecule?One approximation of over-riding importance, essential when dealingwith large organic molecules, is that of " neglecting the inner shells "-moreprecisely, assuming that the nuclei and inner shells merely provide aneffective potential field for the valency electrons (or for a particular " group "such as the n-electrons).The Grst reasonably comprehensive discussion ofthis approximation was given by Parr and his c o - ~ o r k e r s . ~ ~ They showedthat if the wave function is written as an antisymmetrized product of twofactors, namely,in which @A is a wave function for the inner shell (the A shell) and aBdescribes the electrons of interest (the B shell), then it is mathematicallylegitimate to treat the B shell electrons alone, provided the field in whichthey move is properly determined from @*. The product form (2) is still* A.D. McLean, A. Weiss, and M. Yoshimine, Rev. Mod. Phys., 1960, 32, 211.sL. C. Allen and A. M. Karo, Rev. Mod. Phys., 1960, 32, 275.lo D. P. Craig, Proc. Roy. SOC., 1950, A , 200,474; 1950, A , 202,498; C. A. Coulsonand J. Jacobs, ibid., 1951, A , 206, 287; C. A. Coulson, J. Jacobs, and D. P. Craig, ibid.,p. 297; R. G. Parr, D. P. Craig, and I. G. Ross, J . Chem. Phys., 1950, 18, 1561.l1 R. K. Nesbet, J . Chem. Phys., 1960,32,1114; E. L. Albasiny and J. R. A. Cooper,Mol. Phys., 1961, 4, 353.l2 L. Burnelle, J . Chem. Phys., 1961, 35, 311; G. W. King, Canad. J . Chem., 1960,33, 365.l3 A. Padgett and M. Krauss, J . Chem.Phys., 1960,32, 189; G. W. King and G. L.Malli, Canad. J . Chem., 1961, 1652.B. J. Ransil, Rev. Mod. Phys., 1960, 32, 245; A. C. Hurley, ibid., p. 400.l5 J. M. Foster and S. F. Boys, Rev. Mod. Phys., 1960, 32, 303; P. L. Goodfriend,F. W. Birss, and A. B. F. Duncan, ibid., p. 307.IsR. McWeeny and K. Ohno, Proc. Roy. SOC., 1960, A , 255, 367.17H. Brion and C. Moser, Phys. Rev., 1960, 118, 675.l*H. Kaplan, J . Chem. Phys., 1957, 26, 1704.19H. Hartmann and G. Gliemann, 2. phys. Chem., 1959, 19, 29.2o M. Krauss and J. F. Wehner, J. Chem. Phys., 1958, 29, 1287.21 A. C. Hurley, Proc. Roy. SOC., 1959, A , 249, 402.22 A. D. McLean, J . Chem. Phys., 1960,32, 1595; A. D. McLean, B. J. Ransil, and23 E. Clementi, J . Amer. Chem. Soc., 1961,83,4501; J .Chem. Phys., 1961, 34, 1468.24 R. G. Parr, F. 0. Ellison, and P. G. Lykos, J . Chem. Phys., 1956, 24, 1106.= g[@A@BI, (2)R. S. Mulliken, ibid., p. 1873140 ORGANIC CHEMISTRYan approximation, but it is much less severe than an orbital form such as(1) since each factor may be a many-electrop function of high accuracy.Only calculation can reveal the limitations of this kind of approach butavailable results l6 do suggest that the inner shells can be (‘ separated off”in a rather satisfactory way and that they may be assumed to be virtuallyunchanged when the atoms form molecules. These are, of course, basicpremises of qualitative valence theory, but a convincing demonstration oftheir validity is a major problem of quantum mechanics. Here, as always,the task is to formulate the theory so that it recognizes qualitativelyestablished features of real molecules : the existence of “ loosely coupled ”electronic groups is such a feature and is succinctly and generally recognizedby wave functions such as (2).In later work along these lines, Lykos andParr 25 have analysed the basis of n-electron theory, providing considerablejustification for the usual practice of discussing the n-electrons by themselves.Since this work of Lykos and Parr, the validity of separating wave func-tions according to expression (2) has been examined more generally by Arai 26and by LO~din;~’ and the effective field for one group of electrons in thepresence of any number of other groups has been represented 2* in terms ofdensity operators, which allow a generalization of the Coulomb and exchangepotentials of simple molecular-orbital theory. Parks and Pam z9 havedeveloped the special case of separated electron pairs (e.g., localized bonds)in some detail: their theory is then closely connected with the earlier workof Hurley, Lennard-Jones, and Pople,30 though Parks and Parr are more*concerned with developing practical semi-empirical methods and have gonesome way in this direction in an application to formaldehyde.31 Theyillustrate the importance of introducing self-consistency by discussing thereorganization of the o-electrons when a n-electron is excited and, inparticular, its bearing on the n + n* transition energies.The results areof preliminary nature, and the calculations of it ‘much more empirical char-acter than those mentioned previously,l5 but further developments areexpected. As Boys 32 has remarked, an important feature of all suchwork is the search for “ molecular invariants ”-quantities (e.g., suitablydefined electronegativities, “ bond functions,” etc.) which vary little frommolecule to molecule and can ultimately be adopted as semi-empiricalparameters or “units of structure.” Further work with wave functionsof the product form (2) may be expected to shed light on the stereochemistryof organic molecules, including, for example, the classic problem of theethane potential barrier, referred to in some detail by Wils0n.3~ It canbe shown 28 that, although the primary interactions of different electronicgroups are electrostatic, there are also “ polarization ” and “ dispersion ”25P.G. Lykos and R. G. Parr, J . Chem. Phys., 1956, 24, 1166.26 T. Arai, J . Chem. Phys., 1960, 33, 95.27P.-0. Lowdin, J . Chem. Phys., 1961, 35, 78.28 R. McWeeny, Proc. Roy. SOC., 1959, A , 253, 242; Rev. Mod. Phys., 1960,32,335.29 J. M. Parks and R. G. Parr, J . Chem. Phys., 1958, 28, 335.3oA. C. Hurley, J. Lennard-Jones, and J. A. Pople, Proc. Roy. A~OC., 1953, A , 220,31 J. M. Parks and R. G. Pam, J . Chem. Phys., 1960, 32, 1657.3aS. F. Boys, Rev. Mod. Phys., 1960, 32, 296.a3E. B. Wilson, Adv. Chem. Phys., 1959, 2, 367.446McWEENY: QUANTUM ORQANIC CHEMISTRY 141effects, just like those appearing in the theory of intermolecular forces. Areview by Pitzer 34 is of interest in this connexion.A basic difficulty in constructing accurate wavefunctions of any kind (for a whole molecule or even for single bond) is thedescription of electron correlation, a subject thoroughly reviewed byLowdin.35 For example, the two electrons in a a-bond are not restrained, inmolecular-orbital description, from coming arbitrarily close together in spiteof their strong mutual repulsion.A method of admitting some degree of cor-relation which is now gathering ground is that of " splitting " each molecularorbital. Instead of both electrons being placed in the same orbital (k,describing the pair by [y(l)y(2)] x [spin function], they are allowed to occupydifferent orbitals, y and y', which tend to keep them apart : symmetry isrestored by using a wave function [y(1)y1(2) + y'(l)y(Z)] x [spin function]." Split-orbital " functions were introduced independently by Hylleraas 36and by E ~ k a r t , 3 ~ ~ who replaced the closed-shell helium configuration ls2 bythe " open shell " ls'ls'', bringing one electron closer to the nucleus (con-tracted 1s' orbital) and sending one further away (expanded 1s" orbital).Similar treatments of the two-electron bond go back to Coulson and F i ~ c h e r , ~ ~Lennard-Jones and P ~ p l e , ~ ~ ~ and Mueller and E~ring,~'' and have beenutilized recently by O-ohata 38 and Kotani et ~ 2 .3 8 ~ In essence, a generalsplit-orbital wave function may be written in the form (2) with an " a factor "and a ' ' P factor," determining respectively the density of a electrons(spin, +&) andThe usual (doubly occupied) molecular-orbital function, written in this way,gives identical a and #? densities : but for radicals and systems in non-singletstates this is not so, and it is the difference of the a and the #? density whichyields the (resultant) spin density observed in electron-spin resonanceexperiments.I n general, the single antisymmetrized product (3) is not aspin eigenfunction (as it is for a configuration of doubly occupied molecularorbitals, with zero total spin) but represents a mixture of states of variousmultiplicity. To describe a singlet ground state (S = 0) the " contamina-tion " by functions with 8 ;t 0 should be removed by means of a suitableprojection operator,39 but the calculations then become very heavy: theymay, however, be performed in certain cases.The first n-electron applica-tion, by Itoh and Yoshi~umi,~~ yielded a benzene ground-state energy veryclose to that obtained by Parr, Craig, and Ross l o who used extensiveconfiguration interaction. Dearman and Lefebvre 41 recently applied thismethod of “ different-orbitals-for-different-spins ” to the ally1 radical, withexceedingly satisfactory results. Similar calculations on naphthalene andits ions have been made by Hoyland and Goodman,42 and the general theoryhas been further developed by Pauncz, de Heer and LO~din.~3 Recentwork by Linnett and Dewar and their co-workers 449 45 depends on the samegeneral principles. We return to these topics in discussing calculations ofspin density in electron spin resonance applications.In dealing with increasingly elaborate wave func-tions for molecules it must be remembered that the function itself has nodirect physical or chemical interest : the significant quantities 46 are the elec-tron density and (to a smaller degree) the “ pair function ” which describeshow the motions of two electrons are correlated.In n-electron theory theelectron density is described in LCAO approximation by the well-knownmatrix of “charges ” and “bond orders,’’ whose elements indicate theamounts of (n) charge in the various atomic orbitals and the weights of the“ overlap densities ” which describe the bonds. This special example ofilr “ density matrix ” provides the basis of ‘‘ electron population analysis,”which originated some ten years agoY47 was further developed by M~lliken,~~and is now a standard feature of most non-empirical LCAO calculations onsystems of all kinds.In general, the elements of an LCAO density matrixindicate the electron “ populations ” of orbital and overlap regions definedby the atomic orbitals and yield a clear physical picture of the electrondistribution and the origin of various molecular properties (e.g., dipolemoments, bond polarities, chemical reactivities) . Various examples ofpopulation analysis have been published.49 Density matrix theory andsome of its applications were reviewed by McWeeny 28 at the BoulderConference.Finally, although openly empirical in its approach,the method of atoms in molecules 50 and its many variants deserve mentionunder this heading.The situation in 1958 was summarized in theseReports;51 since then a comprehensive review by Arai 52 has appeared. Arecent paper by Stewart 53 gives a particularly clear and simple expositionof the method and a useful commentary on its applicability.Semi-empirical Molecular-orbital Theory.-Under this heading we con-sider various approximate forms of n-electron theory, from crude HiickelPopulution analysis.Atom in molecules.theory to approximate configuration interaction 54 and self-consistent field 5 5(SCF) methods, and still rougher approximate work on the c-electrons ofsaturated molecules. Applications involving magnetic effects (electron-spinand nuclear magnetic resonance) appear in the next section.Notablereviews of recent developments have been given by L~nguet-Higgins,~~Hall,4 Pople,5 Hartmam~,~’ PreussY6 and F ~ e n o . ~ ~Perhaps the most ambitious effort to give a criticalevaluation of approximation methods in n-electron theory has been madeby Ruedenberg in six long papers.59 This is the culmination of othercareful comparisons of various methods, applied to polycyclic systems (frombenzene to ovalene) by Ham and RuedenbergY6O which do much to strengthenconfidence in the value of less sophisticated work with relatively old-fashioned tools. It has long been recognized that the success of varioussimple theories (e.g., free-electron model and Huckel inolecular-orbitalBheory), and their surprising measure of agreement, is a consequence ofmolecular “ geometry.” More precisely, Ruedenberg traces this back toit “ topological matrix ” with unit elements corresponding to nearest-neighbour links and zeros elsewhere.This describes the way in whichthe atoms are connected, and it determines the essential form of the molecu-lar orbitals, while the actual geometry (which is changed by distorting thesystem ; e.g., trans- to cis-butadiene) is introduced only through distant-neighbour interactions and is of secondary importance. The eigenvectorsof the topological matrix are the Huckel molecular orbitals which surviveso many theoretical refinements with so little change of form and usefulness.This work helps to provide a sound basis for models of the type developedby Pariser and Parr 54 and P ~ p l e .~ ~ Recent investigations of currentapproximations have also been made by Parr, Stewart, Lykos, Coulson andSchaad, and others.61The value of simplemolecular-orbital theory has again been strikingly demonstrated in work onthe precise equilibrium forms of conjugated systems, in particular on thepossible alternation of bond lengths in long polyenes. The observed ultra-violet spectra of long-chain polyenes cannot be reconciled with equivalenceof the bonds (Kuhn,62 Dewar 63) and, following O o ~ h i k i t , ~ ~ Longuet-Higginsand Salem 6 5 have now shown, by allowing properly for o-bond strain,144 ORGANIC CHEMISTRYthat a marked alternation of bond lengths is inevitable even in the infinitepolyene.In later papers the latter authors considered cyclic polyenes,66where alternation was again established, and long polyacenes,67 wherealternation was found to be unlikely. Anno and Coulson 68 have extendedsuch work fo graphite, finding that alternation does not occur for anyplausible parameter values. Such studies are important in connexion withthe contention by Clar et ~ 1 . ~ ~ that the benzenoid rings in polynuclear con-densed hydrocarbons often appear to be joined by single bonds. Aninteresting case of low-order connecting bonds occurs in biphenylene andsimilar compounds : in such cases it is again important, as Ali and Coulson 70show, to admit dependence of the resonance integral upon bond length (andhence order) and to carry the calculation to self-consistency.The correla-tion of bond lengths and bond orders seems to be receiving less attention, butCruickshank and Sparks have made a careful study of naphthalene, andaccurate electron-diffraction measurements are discussed by Bak and Hansen-N ~ g a a r d . ~ ~ It is now generally accepted that, as Coulson 7 3 first suggested,there is no single length-order curve and that hybridization is an importantfactor; the situation has been discussed by Trotter 74 and by Mu1liken;TsDewar and Schmeising 76 have also discussed the length-order relationship.With the appearance of Vol. 111, Pt. 2, of the “ Dictionary of Values ofMolecular Constants,” 77 Hiickel molecular orbitals and bond orders arenow available for all the commoner conjugated hydrocarbons and manyradicals : in many cases, polarizabilities and localization energies are alsotabulated. Huckel calculations on less common non-classical aromaticcompounds continue to be made 78 alongside the more refined calculations(e.g., by Mataga et ~ 1 .~ ~ on naphthalene and anthracene). However, whenappreciable charge shifts occur, as in non-alternant and substituted hydro-carbons and in heterocyclic compounds, simple molecular-orbital theorybecomes unreliable and it is desirable to use self-consistent-field or configura-tion-interaction methods. This raises certain difficulties in fixing an in-creased number of parameters, and work with this aim has continuedin a wide field and a t various levels. Brown and Heffernan 8o have useda form of self-consistent-field theory (developed in previous papers 81) onolleagues have made Pariser-Parrtype calculations on chloroazines 82 and self-consistent field calculations onformic acid.83 To cite still more representative examples, Julg andBonnett 84 have employed an improved LCAO method 85 to discuss fulveneand the carbonyl group.Other papers have dealt with o-quinones,86phenol,87 aromatic methylpyridines,89 purines, monochloro-pyridine~,~~ various nitrogen- heterocycle^,^^ carb~lines,~~ and furan, pyrrole,and thiophen.94 It is important in such calculations to show that a varietyof properties are satisfactorily accounted for by using the same parametervalues (cf. Amos and Hallg5).An apparently declining interest in hyperconjugation was to someextent revived by the Indiana (1958) C0nference,~6 at which notable con-tributions were made by Sutton, Dewar, Turner, and Streitwieser.Semi-empirical calculations (see, e.g., Pauncz et d 9 7 ) continue.There has been a great deal of work, which cannot be fully reported, inconnexion with ultraviolet spectra of aromatic compounds. forinstance, cites over 500 papers (many of them semi-theoretical), almostentirely from one year (1958), and gives a commentary on the work ofMoffitt and of Sidman and a list of their publications: their regular andbrilliant contributions in this field will be sadly missed. Other reviewshave been given by Porter 99 on triplet states, Herzberg loo on free radicalspectra, Mason ll1 on molecular spectra in general, Murrell 112 on charge-transfer spectra, Ramsay on molecular spectra,l13 and Brocklehurst et ~ 1 .1 1 4Very useful work by Mason 115 on nitrogen-heterocyclic compounds con-tinues. Progress in this field, by use of Pariser-Parr theory (along the linesof earlier work 116) is reported by Anno;l17 and most of the work citedin the last paragraph makes some reference to spectra. Considerable atten-tion has been devoted to n+n* transitions involving the lone pair ofa heterocyclic nitrogen atom; for example, Anno,lf7 and Goodman and hisco-workers, 118 have used a variety of semi-empirical methods. Perturbationmethods for dealing with the effect of substituents have also been developedby Petruska.llg Simple molecular-orbital theory has been applied to aceta-nilide by Baba and Suzuki,120 and to ketyls and related (ionic) compoundsby McClelland;121 Peacock 122 has discussed aniline, using a self-consistent-field method and allowing for bond-length variations.Larger molecules have also received attention, e.g., porphyrins byG ~ u t e r m a n , ~ ~ ~ and porphin by Kobayashi.12* Notable efforts at a deeperand less empirical level have been made by Green and Linnett 125 and byMcEwen ; 126 they consider a variety of nitrogen-oxygen compounds, includ-ing nitromethane, nitrogen dioxide, nitrosomethane, and nitrosamines.127Careful calculations on ethylene, also taking into the account the a-electrons,are reported by I'Haya 128 whose work is based on that of Lykos andPam.Environmental eEects were the subject of a Royal Society DiscussionMeeting,129 and the electronic spectra of radicals and ions in solution havereceived considerable attention.Murrell has considered molecular com-plexes 130 in a series of papers (as well as in his review 112) and also theeffects of protonation in acid solution l31 (see also Mataga and Mataga 92).Basic strengths (of purines, etc.) have been discussed by Nakajima andP ~ l l m a n , l ~ ~ and acidity by S t r e i t ~ i e s e r . ~ ~ ~ Removal of " forbiddenness "of singlet-triplet transitions by environmental effects (presence of a para-magnetic molecule) has been explained in two ways, by Hoijtink 134 andby Murrell, 135 severally. Solid-state applications also include notablework on the Davydow spectra of molecular ~rysta1s.l~~Aromaticity and reactivity.Valuable efforts have been made to clarifythe concept of aromaticity and its relation to chemical reactivity. Therecent book ‘‘ Non-benzenoid Aromatic Compounds ” 137 contains a valuablesurvey by Craig, and the concept has also been re-examined by P e t e r ~ , l ~ ~by Fukui et a1.,139 and by Vol’pin.140 There is much to be said 138 for areturn to the ‘‘ old-fashioned ” view, in which aromaticity is directly linkedwith reactivity, particularly in view of the uncertain experimental signifi-cance of the theoretical resonance energy. Unfortunately, the variousindices of reactivity-though they often show a convincing correlationwith chemical data-also have a somewhat obscure significance, since thefundamental theory of chemical reactions is still in a singularly primitivestate.Atom localization energies (Wheland 141) which relate to the “ locali-zation ” of 0,1, or 2 n-electrons OG a particular centre in a transition complex(and corresponding bond localization energies) are commonly used as reac-tivity indices, and methods of calculating these quantities have been dis-cussed by Koutecky 142 and by Baba.143 Simonetta 144 has discussed thenature of the activated complex, particularly in nucleophilic substitution,and Morita Onthe other hand, perturbation methods which make no reference to a transi-tion-state “ model ” (the reagent merely being regarded as perturbingthe molecule) still enjoy considerable popularity.Greenwood and Hay-ward 146 have shown how the-atom and bond polarizabilities may be calcu-lated in self-consistent-field approximation, obtaining results qualitativelysimilar to those obtained from Hiicbel theory. Perturbation methods havealso been developed by Das et ~ 1 . l ~ ’ and by Fukui et ~ ~ 1 . ~ ~ 8 One majordevelopment in this field is due to B r ~ w n , l ~ ~ who proposes developing earliersuggestions by Nagakura and Tanaka 150 for a new mechanism of aromaticsubstitution. Brown considers the initial steps in electrophilic substitutionto beE Ehas made elaborate calculations on the benzenium ion.attached tetrahedrally to a ring-carbon atom). * The theory is very flexible,different steps being rate-determining in dieerent cirbumstances.In hissecond paper, 149 molecular-orbital calculations are described and a new re-activity index (a “ Z value ”) is proposed. It turns out that the 2 valuesare related to the “ frontier ” densities introduced by Fukui et &.151 andseverely criticized by other workers. 152 On the other hand, Nagakuraand Tanaka 153 defend the use of the “ free valency,” not only for thenormal molecule (radical reactions), but also for its cation (electrophilicreactions) and anion (nucleophilic reactions), assuming that electron transfermay be the important step. Recent work in this field has been surveyed,with special reference to the extensive Japanese literature, by F ~ e n o , ~ ~ andPullman and Pullman have reviewed the application in bi01ogy.l~~ Itmust be confessed that the whole field is in a somewhat confused and unsatis-factory state, largely owing to our ignorance of the rate-determiningmechanisms.The difficult problems associated withthe theoretical treatment of saturated molecules still resist solution, butsome progress has been made.In addition to the more formal theory alreadyreported, much work has been done in the Japanese school. O-ohata 38has studied the electron-pair bond, using essentially a “ covalent-plus-ionic ”wave function in discussing the bond polarity and its relation to Mulliken-type electronegativities ; Nagahara 155 has discussed the carbon-carbon bondin particular; and Hnmano 156 has treated $he polarity of the C-H bond.Fukui et ~ 1 .l ~ ~ have used a general, but very primitive, molecular-orbitaltheory of saturated molecules along the lines proposed by Sandorfy 158 andlater Y0shizumi;~~9 a good correlation with experimental quantities isobtained but a considerable number of empirical parameters are required.The use of simplified models is also illustrated in the work of Franklin andLampel60 on C-H bonds in ionized hydrocarbons. The nature of theelectron-pair bond has been examined from a less empirical standpoint byShull. l6With the realization 162 that localized bond orbitals (BO’s) may beobtained by appropriate mixing of molecular orbitals, and with the decliningpopularity of valence- bond theory, the status of hybridization becomes lessclear and its introduction largely unnecessa.ry (except in simple pictorialdiscussions of structure).Nevertheless the traditional method of pointinghybrids along the bonds and setting up suitable electron-pair functions hasTheory of sccturated molecules.McWEENY: QUANTUM ORGANIC CHEMISTRY 149been used, not only in semi-empirical discussions, but also to obtain wavefunctions of high accuracy.16 It now seems probable that there will be somerevival of interest in hybridization. Murrell,la3 Gilbert and Lyk0s,16~ andGolebiewski 165 have recently given simple recipes for constructing hybridsby an alternative criterion, that of maximum overlapping, and the depen-dence of bond properties on hybridization (particularly in the light ofquadrupole-coupling data) has been discussed by Wilmhurst 166 and manyothers.Interpretation of Nucleax Magnetic and Electron Resonance EX€ects.-Impressive advances in this area continue and useful reviews have appearedrecently.Pople 5 has discussed recent work on electric and magnetic effectsin general, a field also reported by Buckingham.le7 Karplus has reviewedthe use of nuclear magnetic resonance in obtaining information onmolecular wave functions 16s and the general theory of weak interactions,l69and Brownstein 170 and Corio 171 deal with more chemical applications. Theinterpretation of the spin Hamiltonian has been discussed by Bersohn ;I72Weissmanf73 has also reviewed the uses of both nuclear magnetic andelectron-spin resonance spectroscopy. The underlying theory of electron-spin resonance is nicely illustrated in a review by Carrington and Longuet-Higgin~,17~ while Grechiskin 175 has made a useful survey of the experimentala,nd theoretical literature on nuclear quadrupole resonance.The excellenttextbook on high-resolution nuclear magnetic resonance by Pople, Schneider,and Bernstein 176 deserves special mention, two chapters being devoted tothe quantum-mechanical discussion of coupling constants and chemical shifts.The coupling of nuclear spins in a moleculeis usually described by a " spin Hamiltonian " which contains only nuclear-spin operators, with certain coefficients (the various coupling constants).The energies of different nuclear-spin states then appear as eigenvalues ofthe spin Hamiltonian (operating on a nuclear-spin function), just as the elec-tronic energies appear as eigenvalues of a Schrodinger Hamiltonian (operatingon an electronic wave function).It is now recognized that the couplingconstants are in fact determined by the ordinary electronic wave function(i.e., that nuclear spins are coupled via the electron distribution) and thatmuch information about the electronic structure can be obtained fromobserved values of coupling constants. The same is true in electron-spinresonance, where the operat'ors for the total (non-zero) electronic spin alsoNuclear magnetic reSonance.Magnetic Resonance," McGraw-Hill Book Co., Inc., New York, 1959150 ORGANIC CHEMISTRYoccur, along with electron-nuclear-spin coupling constants. Conversely,the prediction of coupling constants provides a sensitive test of theoreticalmodels and approximate wave functions.Calculations ab initio, along thelines followed by R a m ~ a y , l ~ ~ are usually prohibitively difficult but havebeen made for simple systems. For organic molecules it is usual to adopta semi-empirical approach such as that of McC0nnell,17~ which shows inparticular that proton-proton coupling constants are proportional toformal H-H bond orders: this result has been used with some success byWilliams and G u t o ~ s k y , l ~ ~ but, in the absence of precise wave functions,H-H bond orders cannot be estimated very reliably and the approach seemsbetter adapted to qualitative discussions. Another way of describing thepresence of H-H bond orders is to say that there is an appreciable deviationfrom the approximation of perfect pairing and it is natural that the valence-bond theory should be revived in this new context.This has been done byKarplus and Anderson la0 who discuss the H-H, H-F, and F-F couplingsin fluorinated ethanes and ethylenes. Karplus has also given a valence-bond interpretation of proton-spin coupling through the n-electron distribu-tion of conjugated molecules,lsl while McConnell la2 has used the method toinfer that coupling constants for protons separated by an even number ofC-C bonds are negative. The valence-bond theory has also been developedby Hiroike la3 and by Alexander.la4 A study of the molecular-orbital ap-proximation led to the conjecture by Pople, Schneider, and Bernstein 176that nuclear spin-spin coupling was dependent on a correlation of electronicspins. I f an electron of spin +Q is at one nucleus, the probability of find-ing a second electron at the other nucleus depends on whether its spin isalso +$ or -8; the '' contact " coupling of each electron spin with its nucleusthen transmits the effect to the two nuclei.This result has been establishedunder very general conditions by McWeeny and Mizuno 185 and makes ituseful to d e h e a '' spin-coupling density "-adding to the list of densities(electron density, " pair " density, spin density) which are, in principle,observable and have a greater intuitive appeal than the wave function itself.Apart from its fine structure, due to nuclear spin-spincoupling, the position of a resonance peak depends on the magnetic fieldat the nucleus: this differs from the applied field, owing to induced diamag-netic currents in the electron distribution, and the peak may therefore beshifted bodily according to electronic environment.This " chemical shift "is another source of useful information about the electron distribution.Ramsay's original work,186 again, does not lend itself to semi-empiricaldevelopment; but the theory due to Pople 187 gives some promise of dealingChemicaZ shifts.p. 11McWEENY: QUANTUM ORGANIC CHEMISTRY 151with shiffs in terms of local “ atomic ” contributions. Work along suchlines has been pursued by Karplus and Das 188 and by Fi~man.18~ Alter-native treatments, in which second-order perturbation theory is avoided,have been developed by Stephen190 and by Sinha and Mukherjee,191 andhave been used in non-empirical calculations by Das and Bers0hn.1~~Among many other, more empirical applications are those by Fraenkelet al.,193 which suggest a proportionality between C-H proton shift andthe charge on the carbon atom, and also those by Katayama et al.forstilbenes. lg4Effects arising from nuclear quadrupole momentsshed light on the field gradient at the nucleus, arising from the electrondistribution. The subject has been reported on briefly by Buckingham,l67reviewed by G r e ~ h i s k i n , ~ ~ ~ and surveyed in the book by Das and Hahn.195Since the early work of Townes and Dailey Ig6 many papers have appearedon the relationship of quadrupole coupling constants to bond polarity andhybridization parameters ; some recent attempts are due to Wilmhurst,l66Karnan0,1~~ and 0-0hata.3~ Recent work on specific molecules includesthat of Hooper and Bray lg7 on various substituted hydrocarbons (bothsaturated and conjugated); that of Dailey 198 on alkyl halides; and a usefulsurvey by Bersohn 199 of deuteron coupling constants.Efforts have beenmade (e.g., by Brion and Moser,200 and by Kato 201) to calculate couplingconstants non-empirically from molecular-orbital wave functions ; but, asthe work of Brion and Moser 2oo and of Richardson 202 shows, it is exceed-ingly difficult to get reliable information about the field at the nucleus, andagreement with experiment may often be largely fortuitous.One most satisfactory development in the lastfew years has been the interpretation of electron-spin resonance experimentsby using the concept of spin density.This is mostly simply defined 2% 185in terms of the densities, Pa and Ps, of electrons of spin ++ and spin -4.The electron (i-e., charge) density is Pa + Ps, while the spin density isPa - Ps and is proportional to the x-component (M,) of total spin (vanish-ing in a singlet state): the normalized spin density, p,, introduced byM~Connell,~O~ results when (Pa - Ps) is multiplied by 1/(2Ms). The couplingQuadrupole coupling.Electron-spin resonance.152 ORGANIC CHEMISTRYof electron and nuclear spins is completely determined by py, mainly by itsvalue at the nuclei (the isotropic, " contact " coupling) and near the nuclei(the anisotropic, dipole-dipole coupling, which averages to zero for rapidlytumbling molecules).When the spin density, p,, at a point is negative thelocal spin angular momentum is in opposition to the overall spin, M,. Inthe simple molecular-orbital description of a radical, p, is everywhere posi-tive, indicating the odd-electron density which may vanish on certainatoms ; negative densities then arise at these points when configurationinteraction is 204 With an LCAO approximation the spindensity appears as a weighted sum of atomic-orbital contributions, and thecorresponding " spin populations " (cf. " electron populations ") give asimple picture of the distribution of unpaired spins and of the origin of thehyperfine couplings.The kind of information obtained from electron-spinresonance experiments is well illustrated by the work of Gordy and hisschool on N-acetylglycine 205 and glycylglycine. 208 Calculations of spindensity in aromatic radicals and ions are rapidly becoming standard, simplemolecular-orbital theory with configuration interaction giving a fair pictureeven of the negative densities. Since a single antisymmetrized ' function,with an cc-factor and a #?-factor (e.g., different orbitals for diflFerent spins),does not represent a pure spin state, its use in predicting spin propertiesis open to criticism. On the other hand, the one-determinant wave function(to which the orbital form is equivalent) is much more convenient than theprojected function which would ideally be used. Efforts have been made 207to justify the one-determinant form and work with functions of this kindcontinues,2o8 but there is still some controversy as to the most reliablemethods.Examples of recent calculations are provided by Lefebvre et aL209(perinaphthenyl, triphenylmethyl), Hoij tink et aiL210 (pyrene negative ion),and Vincow and Fraenkel 2J1 (semi-quinone ions). Semi-empirical self-consistent-field theory has been developed for this purpose by McLachlan 212who also succeeds in explaining the general similarity in electron-spinresonance spectra of positive and negative alternant ions.213 The valence-bond theory has also proved useful in spin density calculations, notablyin the hands of Gutowsky and his collaborators.214 Anisotropic hyperfinecouplings, inferred from single-crystal spectra, are obtained by averaging thedipole-dipole operator over the spin-density function and have been suc-cessfully treated by McConnell and Strathdee.215 The general theory ofboth isotropic and anisotropic electron-nuclear coupling effects has also beendiscussed by McWeeny and Mizuno.lg5 Accurate numerical calculationsRIDD: THEORETICAL ORGANIC CHEMISTRY 153have been attempted with some success, notably by Brion and Moser,200Lin et aZ.,216 and Yamazaki et aZ.217 (NO molecule).Finally, the work reported in this section has many ramifications ofmore specialized interest. As a closing example, there is a growing interestin the " zero-field splitting " of molecular Zeeman levels due to electron-electron spin-dipole coupling.This effect, first observed by Hutchison andMangum 218 for the phosphorescent triplet state of naphthalene, has nowbeen widely discu~sed.21~ I n this way it is possible to obtain detailedinformation about the electron distribution in individual molecules inexcited states-a remarkable feat. Indeed, the quantum theory of electronand nuclear resonance efTects is advancing at a rate reminiscent of the earlythirties, making sense of a vast amount of detailed information and shed-ding new light on the electronic structure of organic molecules and radicals.R. McW.3. THEORETICAL ORGANIC CHEMISTRYPart IIT is convenient to outline first some developments concerning acidityfunctions and isotope effects, for these have a bearing on many mechanisticproblems.Acidity Functions.-This subject was last reviewed in 1959. Manystudies of indicator equilibria have since been reported, relating to theH0,2 and J , (= HR = C,) functions.However, probably the mostsignificant development comes from the increasing evidence that indicatorsof the same charge type can show large differences in the acidity dependenceof protonation equilibria. Thus the protonation of secondary and tertiaryamine~,~ of 1,3,5-trimetho~ybenzene,~ and of some azulenes 7 has beenshown to deviate from predictions based on the conventional H , acidityfunction. Related discrepancies involving the H- function in aqueoushydrochloric acid are apparent from recentThe effects of medium on the protonation of amines have been discussedin terms of the hydrogen bonds formed by the conjugate acids but, ingeneral, the structural features that cause deviations from typical " H ,behaviour " do not seem to be understood.Over the same range of acidity,the protonation of 1 -nitroazulene varies with the acid concentration ina different way from that of 1,3,5-trimetho~ybenzene;~ it therefore seemsimpracticable to define an acidity function in terms of the protonation ofaromatic rings.The deviation of the rates of acid-catalysed reactions from a simpledependence on the H , function has been often taken as evidence for thepresence of a water molecule in the transition state.On this matter, theoriginal Zucker-Mammett hypothesis has been extended by Bunnett 9 ina way that attempts to distinguish between the r6le of water as a nucleophileand as a proton-transfer agent; this mechanistic distinction is based on theslope of a plot of log (k + H,) against log aHz0 (see p. 164). However, anysuch approach implies that the acidity-function measurements are appro-priate for the substrate used. It is therefore not surprising that thesearguments break down when applied to proton transfers to aromatic rings;several examples are now known where such proton-transfer reactions showa simple H,-dependence under conditions where it seems very probablethat a water molecule is involved in the transition state.6, 10 The enolisa-tion of acetone was recently considered 11 to show an No-dependence, butredetermination l2 of the basicity of acetone makes this conclusion improb-able.Further measurements of the H , function in basic media have beenreported.13 The strongly basic properties attributed to aqueous hydrazineand aqueous ethylenediamine are not reflected in the rate of hydrogen-exchange between molecular hydrogen and the medium.l4Isotope Effects involving Deuterium.-These can be divided into threeclasses : primary effects derived mainly from changes in the vibrational fre-quencies of a hydrogen nucleus during transference to another centre ;secondary effects associated with the substitution of deuterium for hydrogena t a position not undergoing the reaction studied; and solvent effects arisingfrom differences between water and deuterium oxide as reaction media.In kinetic studies, all three types of isotope effect sometimes combine toproduce the observed result; the last two effects also influence equilibria.These have been reviewed by Westheimer,15with special reference to the interpretation of low kE/kD ratios.Interestcontinues in the possible contribution from proton tunnelling,16 and theunexpectedly large isotope effect on the activation energy of one eliminationreaction has been interpreted in that way.17 Swain and his co-workers 18, Ishave pointed out that the kH/E, ratios for hydride-ion transfers appearto be much less sensitive to substituent effects than those for proton trans-fers; this has been suggested as a mechanistic criterion and has been appliedto the oxidation of alcohols 18 by bromine, and to the decarboxylation ofsubstituted benzoylacetic acids.l9Secondary isotope effects. It has been clear for some time that severalfactors must be involved in determining the direction and magnitude ofsecondary isotope effects.20 Halevi's arguments 21 concerning the greaterinductive electron-donation by deuterium are supported by recent evi-dence 22 that the ring deuteration of benzoic acid and phenol lowers theacidity of these molecules; in the same way, deuteration increases the extentof ionisation of triphenylmethyl chloride.23 However, deuteration of themethyl group of acetophenone lowers the basicity of the molecule;24 a resultthat corresponds to the decrease in the rate of some solvolyses when p-hydrogen atoms are replaced by deuterium.25 This has generally beenattributed to the greater hyperconjugative electron donation of p-hydrogenatoms compared with #&deuterium a t o m ~ , 2 ~ ~ but an alternative explanationconcerning the lower non-bonded repulsions of deuterium atoms has alsobeen put forward.26 The importance of such non-bonding interactionsreceives support from evidence that some /?-deuterium isotope effects arisefrom a difference in the entropy of activation;27 this is interpreted in termsof the relative potential barriers for rotation of CH, and CD3 groups.27 Insome solvolyses, y -deuterium isotope effects are of similar magnitude butopposite direction (E&, < 1) to those for the p-position;28 these havealso been discussed in terms of molecular vibrations.28The inductive contribution to the isotope effect is considered to arise fromthe difference in the lengths of the C-H and C-D bonds resulting from theanharmonicity of the potential curve.21 However, the contribution fromnon-bonding interaction has been attributed 26 to the difference in the ampli-tudes of vibration of C-H and C-D bonds; to a first approximation, this isindependent of the anharmonic shift in bond length.Sotvent isotope evffects. A simple set of rules for predicting the solventisotope effect on acid-baae equilibria involving oxygen acids has been putforward by Bunton and Shiner.29bic The calculations are based on a struc-tural treatment of solvation and involve the number and stretching fre-quencies of the hydrogen bonds arising from the solvation of the reactantsand the products.to the kineticisotope effects expected for certain model transition states ; nucleophilicsubstitution by hydroxide ions, 29b reactions at ca'rbonyl groups,29b and pro-ton transfers from hydroxonium ions have been treated in this ~ a y . 2 ~ ~Primary isotope effects should also be important in the last reaction, butfrom a consideration of the solvent isotope effect, it is estimated that themaximum value of JcH,o/kDIo should be about 3 ~ 6 . ~ ~ ~ The solvent isotopeeffect for proton transfers to olehs has also been discussed by Willi.30The dependence of reaction rates and equilibria on the fraction ofdeuterium oxide in its mixtures with water presents a more complex prob-lem, and the relative importance of the factors concerned do not yet seemto be clearly established.31 However, considerable attention has beengiven to the type of variation expected for different kinds of transitionstate.32 Other studies of solvent isotope effects in solvolyses concern thetemperature dependence 33 and the influence of neighbouring gr0ups.3~ Thebase-catalysed loss of tritium from phenylacetylene in water and deuteriumoxide has also been studied 35 (cf. p. 170).Aromatic and Pseudo-aromatic Compounds.-Pseudoaromaticity. Hept-alene 36 (1) illustrates clearly the instability of pseudo-aromatic systems 37This approach has been extended 2 9 b 3although the conjugate acid (2) appears to contain an aromatic ring.36 Thisinstability contrasts with the significant aromatic stability of the relatedcompound (3), as indicated by reactions of a dimethyl derivative.38 Theproperties of this conjugated system, and the less stable pentalene derivative(4) have been discussed by Asgar Ali and Coulson.39 From valence-bondcalculations, they conclude that structure (3) should have a symmetricalground state and thus be aromatic, while structure (4) should be pseudo-aromatic.This type of tricyclic compound appears to offer some difficultiesto the simple rules for distinguishing between aromatic and pseudo-aromaticsystems, essentially because of the significant contribution of structurestypified by ( 5 ) to the ground state of the molecule (cf.ref. 37, footnote,p. 3179). The nuclear magnetic resonance spectrum of a dimethyl derivativeof compound (3) does not suggest tt completely aromatic str~cture.38~The recent evidence that the organic ringsin dibenzenechromiuin contain alternate single and double bonds 4O has ledto some discussion concerning the ease of rotation of the r i n g ~ . ~ l The firstsubstitution has been effected with this compoundY42 giving the diester (6),as a result of metallation, reaction with carbon dioxide, and esterification.The text 42 hints that the product may be a mixture of isomers as a resultof the restricted rotation of the rings. From the solvolysis of such com-pounds as methylferrocenylmethyl acetate (7), it appears that the metallo-cene group greatly facilitates SN 1 substitution a t adjacent centres ;43 -45this has been explained by considering the resulting carbonium ion as ametallocene derived from a cyclopentadienyl radical and a fulvene positiveion (8) .44 Stereochemical studies indicate that the facilitation of ionisationis greatest when the leaving group is trans to the metal in the transition~tate.~3, 45Nuclear nzagnetic resonance measurements 01% aromatic systems ; chemicalshifts. Two important factors in determining the chemical shift are theinduced ring current in the aromatic system and the local electron density.The first factor has been used as an estimate of the aromaticity of the ring;in this way it has been suggested that 2-pyridones have about 35% of thearomaticity of benzene.46 Proton chemical shifts and more recently 13C-chemical shifts have also been used to obta,in information on n-electrondensities.Nuclear magnetic resonance measurements on the symmetrical mono-cyclic systems C7H,+, C,H6, C5H5-, and C8Hg2- have shown4' that theIH- and 13C-chemical shifts are related approximately linearly to the n-elec-tron density.However, other factors can modify the relative chemicalshifts observed in more complex molecules. In bicyclic systems the chemicalshifts in one ring are influenced by the induced ring current in the other,and in monosubstituted benzenes the 13C- and IK-chemical shifts at theortho-positions (and the 13C-chemical shift at the l-position) are influencedby the magnetic anisotropy of the s u b s t i t ~ e n t .~ ~ The proton chemicalshifts can also show large and inexplicable solvent effects.49Nevertheless, the recent measurements of 13C-chemical shifts are suffi-cient to show that this may be the most sensitive way of probing the n-elec-tron densities in isolated aromatic molecules. As expected, the range ofchemical shifts in alternant aromatic hydrocarbons is ~Iight,~O but a muchgreater variation occurs with azulene 4 7 9 50 and this has led to a set ofn-electron densities in good agreement with recent calculations.51, 52 Inmonosubstituted benzenes the 13C-chemical shifts are small at the rneta-position, and generally as expected at the para-positi~n;~~, 53 at the ortho-position some apparent anomalies occur; thus the n-electron density at theortho-position in nitrobenzene appears to be greater than 53 Themost recent calculations suggest that the n-electron density in this positionshould be a little less than unity.54Related studies of proton chemical shifts have concerned a~ulene,~7 thepyridine ring and trisubstituted benzenes.56 In a general reviewof o-values, Taft 57 has discussed the variation of the lgF-chemical shiftswith the inductive (oI) and resonance (a,) parameters of other substituents.Electrophilic Aromatic Substitution.-Probably the most rapidly develop-ing section of aromatic substitution concerns the electrophilic replacementof atoms or groups by hydrogen, and this subject, together with nitrationand halogenation, is discussed separately below.On the theoretical side,the concepts of frontier electron density and superdelocalisability have beenapplied to non-alternant hydrocarbons by Fukui and his collaborators 68and a critical comparison of the different reactivity indices has been pub-lished. Empirical approaches to the influence of substituents continueto be developed, usually on the basis of the Hammett equation 57, 6o but inone case with a different mathematical form 61 that reflects the earlierqualitative division into polarisation and polarisability effects.Further mechanistic studies have been published on sulphonation, 62 andthe partial rate factors for the sulphonation of toluene have been redeter-mined.63 Kinetic studies have been reported on the acetylation of anisoleby acetic acid in the presence of boron trifluoride 64 (this reaction may in-volve Ac+ ions), and on the further isopropylation of isopropylbenzene.65Engelsma and Kooyman 66 have discussed some interesting orientationalproblems involved in the gas-phase chlorination of aromatic compounds,including the extensive meta-substitution in diphenyl ether.Mechanistic studies, mainly by W.N. White and his co-workers, havebeen carried out on the O r t ~ n , ~ ~ Claisen,68 benzidine,Gg and nitramine 7urearrangements. Substituent effects on the Claisen rearrangement lead toa rather complex picture of the transition state, involving many different,kinds of contributing structure.68 There appear to be two independentacid-catalysed mechanisms for the benzidine rearrangement of N-methyl-hydrazobenzene:6g one is of the fist order in hydrogen ions and the otheris of the second order.solutions in aqueous methanol.I n the nitramine rearrangement deuteratioriof the ortho-positions does not change the ortho : para ratio.70 This resultand the kinetic effects of substituents are considered MeIrepresented by structure (9), together with other con- A r " *1H tributing structures, including further electron transferto the nitro-group. In the Reporter's view it is also (9)possible to interpret the new results in terms of the earlier mechanism forthis reaction.71Kresge and Chiang lo have shown that theprotodetritiation of 1,3,5-trimethoxy-Z-tritiobenzene in aqueous acids isgeneral acid-catalysed and obeys the Bronsted relationship over an unusu -ally wide range of acidity, including the acids H30+, H*CO,H, and H,O.There is no evidence of base-catalysis.Since the overall reaction path mustbe symmetrical these results indicate that the transfer of a proton by aBronsted acid and the acceptance of the tritium nucleus by a Bronsted baseare not synchronous; the intermediate (10) is apparently formed and takesThis conclusion applies to feebly acidic ([H+] Mto provide evidence for a radical-ion intermediate aspart in the forward and the reverse reactions as shown. In related reac-tions, Olsson 72 has discussed how the rate-coefficient ratio ( L 1 / k 2 ) dependson the point of substitution and on the nature of the isotopes being ex-changed; he concludes that there is a significant isotope effect on the orienta-tion of hydrogen-isotope exchange.A logarithmic plot of the rate of protodetritiation of 1,3,5-trimethoxy-2-tritiobenzene against Ho has a slope of unityY6 but the general acid-catalysis observed at lower acidities makes it difficult to believe that theunit slope arises from a pre-equilibrium proton transfer to the substrate.This throws further doubt on some of the arguments used to support the A-1mechanism of hydrogen isotope exchangeY73 and there now seems no firmevidence for this reaction path. However, Melander has given some reasonswhy the A-1 mechanism may operate for substitution in the less reactiveand Gold has emphasised that, at high acidities, there arestill some difficulties over the mechanism illustrated ab0ve.7~Eaborn and Taylor 75 have determined the partial rate factors for thedisplacement of tritium by hydrogen a t the aromatic carbon atoms oftoluene, t-butylbenzene, biphenyl, naphthalene, and the halogenobenzenes.Their results indicate that the activating effects pf methyl and t-butyl groupsin the para-position can lie in either the inductive or the hyperconjugativeorder, depending on the medium,75a and that the variation in the ortho : pararatios in different media should be attributed to the reactivity of the reagent,not to different degrees of steric hindrance at the ~rtho-position.~~Other studies on acid-catalysed hydrogen-isotope exchange concern thereactions of substituted azulenes 7 and the effect of stannic chloride on reac-tions involving carboxylic acids.76Partial rate factors have been measured for the base-catalysed hydrogen-isotope reactions of dimethylaniline with amide ions in liquid ammonia.77In these and related reactions the most important factor appears to be theinductive effect of the substituent in modifying the acidity of the C-Hb0nds.7~ Base-catalysed hydrogen-isotope exchange in azulene appears tooccur most easily at the 1- and the 3-position 78-a somewhat unexpectedresult, since these are positions of high electron density.These reactions, togetherwith hydrogen-isotope exchange, have been recently reviewed.79 Kuivilaand Nahabedian have given further details of the protodeboronation of suchcompounds as p-methoxyphenylboronic acid ;loa, 80 the results support theearlier conclusion 81 that the reaction occurs by a slow proton transfer toReplacement of other substituents by hydrogen.the aromatic ring, followed by fission of the C-B bond.However, thedependence of the reaction rate on acidity, together with other evidence,indicates that two paths are involved, namely, directA-XE2 reaction at low acidities, and prior attachmentof a bisulphate ion to the boron (structure 11) atEaborn and his co-workers 82p 83 have studied theeffect of substituents in the aryl group on the rate ofcleavage of aryl-metal compounds by aqueous perchloric acid containingsome methanol or ethanol. These reactions are represented (in a slightlysimplified form) by the equation:where X = Ge, Sn, or Pb, and R = Me, Et, or cyclohexyl. For the ger-manium compounds,82a a logarithmic plot of the rate coefficient against thea+-values for the substituents is linear, but this is not true for the relatedcompounds of tin 83 and lead.8Zb The rates of cleavage of the tin and leadcompounds give linear plots when the function o + 0*4(0+ - G) is used asthe o-value of the substituent (cf.ref. 6Oa). This deviation from the con-ventional o-values for electrophilic substitution indicates that cleavage ofthe tin and lead compounds makes a relatively slight demand on the electron-donating properties of the substituents. Eaborn and Pande 82b point outthat these reactions clearly proceed by electrophilic attack at the carbonatom of the metal-aryl bond and thus the relative ease of cleavage is nota measure of the relative electronegativity of the organic fragment.Protodeiodination of p-iodoaniline loa in dilute aqueous acids appearsto involve slow addition of a proton to the aromatic ring, followed by a fastreaction in which the I+ ion is lost.The reaction is not catalysed by iodideions and the rate follows the h, acidity function.Olah, Kuhn, and Flood 84 have obtained some very interest-ing results on the nitration of the alkylbenzenes and the halogenobenzenesby nitronium tetrafluoroborate in tetrahydrothiophen dioxide. Under theseconditions the relative reactivities of the alkylbenzenes are surprisinglysimilar, and toluene is only 1.6 times more reactive than benzene, comparedwith the usual factor of about 25.However, this lack of discriminationbetween different molecules is not attended by a lack of discriminationbetween the individual positions of substitution ; thus the proportion ofmeta-substitution in toluene (2.8%) is about normal. These results make itvery difficult to believe that the carbon atoms are competing individuallyfor the nitronium ion, particularly since the partial rate factor for meta-substitution in toluene is far below unity (0.14). It is therefore suggested s4that the formation of a n-complex between the aromatic rings and thenitronium ion is rate-determining, and in support of this it is pointed outthat the rates of nitration can be correlated with the relative stability ofNitration.162 ORGANIC CHEMISTRYn-complexes.The orientation of substitution is considered to be deter-mined by the position of the nitronium ion in the n-cornple~,~~ but theresults do not seem to exclude the possibility that t,he rate-determining stepis followed by a second, product-determining step in which the orientationis determined only by the relative stability of the a-complexes a t the differentcarbon atoms.The results for the halogenobenzenes are in general agreement with thosegiven above, although the differences from normal nitration procedure areless marked. Deuteration of benzene, toluene, and fluorobenzene has beenobserved 84 to increase the rate of nitration under the same conditions; fordeuteration and nitration a t the para-position in fluorobenzene, E,/k, = 1.22.The work of Norman and his co-workers 85-87 has considerably increasedthe information on the orientation and partial rate factors of aromaticnitration and has clarified some of the factors determining ortho :pararatios.They have also confirmed that the rates of para-nitration of tolueneand t-butylbenzene lie in the inductive order.88Nitration of methyl 2-phenylethyl ether is of particular interest becausethe orientation varies with the conditions ;85a the amount of ortho-substitu-tion is 2S*9y0 with a mixture of nitric acid and sulphuric acid, and 66%with acetyl nitrate in acetonitrile. The greater amount of ortho-substitutionunder the latter conditions is attributed to the action of dinitrogen pent-oxide in forming the oxonium salt (12); this is considered to undergo theintramolecular rearrangement (12+ 13).The same authors 85b have shown that the high ortho :para ratiosobserved in the nitration of benzene derivatives with --M substituents (e.g.,nitrobenzene) are paralleled in chlorination by positive chlorine ; this sup-ports the view g9 that an electronic effect on the aromatic ring is involved,rather than rearrangement from a side chain. Other recent papers concernthe nzeta-directing effect of the P+O group in triphenylphosphine oxideand the possible formation of the mixed anhydride NO,*O*SO,H in mixturesof nitric acid and sulphuric a ~ i d . ~ l There is some evidence that nitroniumacetate can act as an acetoxylating reagent;92 the reaction of o-xylenewith nitric acid in acetic anhydride gives about 50% of 3,4-xylyl acetate.Kupinskaya and Shilov93 have shown that the rate ofchlorination of anisole by hypochlorous acid can be determined by a slow,acid-catalysed reaction between the acid and dissolved silver chloride (about10 -5w) ; this reaction presumably forms molecular chlorine which rapidlychlorinates the anisole.The zero-order reaction reported by de la Mare,Ketley, and Vernon has been interpreted in the same way, and the r61eof halogen cations (e.g., C1+) a t low acidities has been recon~idered.~~ How-ever, a t these very low concentrations, silver chloride is probably completelyionised into silver and chloride ions, and so the reaction studied by Kupin-skaya and Shilov 93 probably involves chloride ions and hypochlorous acid.This is unlikely to apply to the zero-order reactions studied by de la Mareet ~ 1 .~ ~ since the rate was not very sensitive to the silver ion concentration.Aromatic chlorination by t-butyl hypochlorite does not appear to be afree-radical reaction; the ortho : para ratios are consistent with reactionthrough either positive chlorine or molecular chlorine, depending on thecondition^.^^ Other recent papers have concerned the effects of variouscatalysts (CF,*CO,H ; ZnCl, ; IBr) on halogenation in organic solvents ;the influence of solvent composition on the chlorination of toluene andt-butylbenzene has also been studied. 98 The chlorina-tion of biphenyl by molecular chlorine in acetic acidgives about 14% of an adduct containing four chlorineatoms:99 the greater part of this product is believedto have the stereochemistry shown in structure (14) ;the extensive formation of the adduct suggests thatsuch additions are more important than is generally realised.Although many aryloxide ions appear to react with molecular brominein aqueous media a t about the encounter rate, this is not true for the 2,4-di-nitrophenoxide ion or for anisole derivatives.100 Partial rate factors havebeen measured for the bromination of biphenyl and naphthalene by molecularbromine in acetic acid.lO1 The acidity dependence of the ortho : para ratioin the bromination of biphenyl by hypobromous acid in aqueous acetic acidhas been explained lo2 in terms of two brominating agents, BrOH,+ andBrOAc; the former appears to give a +o : p ratio of about 0.59, and thelatt,er one of about 0.17.Nucleophilic Aromatic Substitution.-A new view of the S,l transitionstate in the decomposition of arenediazoninm ions has been put forward byHalogenation.Taft.103 The accelerating effect of meta-substituents being greater thanthat expected from the Hammett equation, he suggests that the transitionstate has a high degree of radical-ion character in that during the heterolysisa n-electron of the aromatic ring moves “ with concerted uncoupling ” intothe sp2-orbital involved in the C-N bond.This is considered to give riseto a triplet aryl cation (15) which derives some stabilisation from the inter-action of the lone n-electron with the substituent.lo4Some very large solvent effects in the bimolecular mechanism of nucleo-philic aromatic substitution have been considered to arise from differencesin relative solvation of the attacking anions,lo5 and a general account ofthese solvation effects is given on p. 171. The relative reaction rates ofsubstituted phenoxide ions with 1 -chloro-2,4-dinitrobenzene suggest Io6 thatthe transition state is very similar to the completely localised Whelandstructure; for the substituent effects are similar to those on the acidity ofphenols.lo6 Other recent kinetic studies on the displacement of chlorideions from 1 -chloro-2,4-dinitrobenzene concern the reaction withamines 1079 108 and with methoxide ions.logBunnett and Buncell10 have studied the rate of displacement of themethoxyl group from the azonaphthyl ether (16) in aqueous acid.Fromthe dependence of the reaction rate on the activity of water (after allowancefor the protonation of the azo-group) they conclude that the slow stepinvolves proton-transfer to the incipient methoxide ion (17). It is a littledisturbing that the medium-dependence for the reaction of the analogousphenyl ether is sufficiently different to suggest nucleophilic attack by wateron the carbon atom of the methyl group. If the implied difference in thepoint of bond fission is borne out by isotopic studies, these results will bea notable success for Bunnett’s treatment of medium effects in strongacids (cf.p. 154).J. F. Bunnett and E. Buncel, J. Amer. Chem. SOC., 1961, 83, 1117RIDD: THEORETICAL ORGANIC CHEMISTRY 165The nucleophilic displacement of chloride ions from cyanuric chloride(2,4,6-trichloro-l,3,5-triazine) by aniline in benzene has been studied byBitter and Zollinger.111 Both acids and bases catalyse the reaction andthere is evidence that 2-pyridone, but not 4-pyridone, can act as a bifunc-tional catalyst.The reaction of 1,3$-trinitrobenzene with bases has sometimes beenconsidered to involve proton-loss,ll2 but the work of Miller and Wynne-Jones 113 makes it more probable that electron-transfer is involved. How-ever, the problem is complicated by the fact that, in pyridine solution, theresulting charge-transfer complex is largely dissociated into ions ;I1 3b refer-ence is made to an earlier suggestion me that the pyridine cation (C,H,N+)can be stabilised by the formation of a three-electron N-N bond with anotherpyridine molecule.By using an acetone-ether solvent at low temperatures,Allen, Brook, and Caldin have measured 114 the rate of formation of a charge-transfer complex between 1,3,5-trinitrobenzene and a dimer of diethyl-amine. The ‘reaction of the trinitrobenzene with hydroxide ions is complexand light-sensitive.Homolytic Aromatic Substitution.-A redetermination of the relativerates of phenylation of benzene and nitrobenzene 116 has necessitated minorchanges in the partial rate factors for the phenylation of many substitutedbenzenes. 116 Previous work on the arylation of benzotrichloride requiresmore serious correction.The report that only me&-substitution is observedin the reaction with p-nitrophenyl radicals 117 is incorrect: the productsare 118 o- > 3%, m- - 64%, p- - 32%. The reaction with phenyl radicalsgives less meta-substitution (o- 12%, m- asyo, p - 39y0), in accord with presentviews on the polarity of substituted phenyl radi~a1s.l~~ Other work con-cerns the nucleophilicity of methyl and p-methylphenyl radicals 119 rela-tive to phenyl radicals; and arylation of naphthalene has been studiedfurther.121 There is some evidence for steric effects in the reaction ofo-chlorophenyl radicals with o-dichlorobenzene.122Other aspects of free-radical chemistry are not being considered in thisyear’s Report, but the following references may be useful.Homolyticoxidation has been reviewed by Waters,123 and reactions of alkyl compoundsby Kerr and Trotman-Dickenson.l2* Part of the latter review overlapsthe discussion of hydrogen abstraction from aliphatic compounds byTedder.125 Bartlett and his co-workers have published a series of paperson the concerted fission of two or more bonds in the decomposition of peroxy-compounds.126 A review of free-radical chemistry by Williams is mainlyconcerned with substitution.127 Developments in the physical chemistryof free radicals are described in the report of the International Symposiuma t Uppsala.12sHeteroaromatic Compounds.-Heats of combustion are now availablefor a number of a z o l e ~ , ~ ~ ~ but their interpretation in terms of resonanceenergies is complicated by uncertainties in the energy of the classical struc-tures ; nevertheless, it appears probable that the resonance stabilisation isappreciable.Microwave studies of isotopically substituted thiophens havegiven considerable information on the molecular structure ; 130 the double-bond character of the C-S bond in thiophen is considered to be much greaterthan that of the C-0 bonds in furan.130At low acidities, the conjugate acid of quinazoline has been recognisedfor some time to have the abnormal structure (18), resulting from the addi-tion of a water molecule. The first effect of increasing the acidity has nowH OH(‘8) (‘9) (20)been shown 131 to be dehydration, so that the normal cation (19) is the pre-dominant form in sulphuric acid at Ho -4.3.At still higher acidities thedi-cation (20) becomes the main component. However, from considerationsof relative reactivity the abnormal cation may still determine the orienta-tion of electrophilic substitution, even in strongly acidic media.132 Otherstudies of acid-base equilibria concern pyrazine l33 and substitutedimidazoles. 134By isotopic labelling with 15N, D. J. Brown has proved 135 that the re-arrangement of the methyl group, shown in structures (21) and (22), isaccompanied by a shift of the indicated nitrogen atom; it appears that ringopening occurs, followed by rotation about one C-N bond and ring closure.Eaborn and Sperry 136 have measured the acid-catalysed displacement oftrimethylsilyl groups at different positions in several heteroaromatic com-pounds, including dibenzofuran and dibenzothiophen. For dibenzofuran,the partial rate factors are lower than for nitration but show that there isa much greater preference for substitution para to the oxygen atom.Thisdifference in the orientational pattern of protodesilyla,tion and nitrationmakes it probable that neither reaction follows the order of n-electrondensities in the isolated dibenzofuran molecule. The orientation of carb-oxymethylation of dibenzofuran has also been measured ;I3' 1 -substitutionpredominates, and the reaction appears to be homolytic.Other recent work includes the unexpectedly easy chlorination of 2,5-di-methylpyra~ine,~~~ and the bromination of pyridine l-oxide both by positivebromine at high acidities 139 and by what appears to be an addition-elimina-tion mechanism.140 Dewar and his co-workers have given further considera-tion to the reactivity 141 and aromaticity 142 of " borazarenes "; compoundswith a boron atom between two ring nitrogen atoms do not appear to havesignificant aromatic stability.143 The diazapentalene (23) has been pre-pared 144; its basic properties are very slight.J.H. R.Part IIElectrophilic Substitution at a Saturated Carbon Atom.-Metallic leavinggroups. This subject has not previously been reviewed. Three main typesof reaction have been studied: (i) halogenation, (ii) acidolysis, and (iii) ex-change. The reacting group R retains its configuration in all cases wherethe reactions are bimolecular in mechanism, in contrast to nucleophilicsubstitution where inversion is more general.Possible mechanisms, and the problems involved in the study of theexchange reactions, are set out by Charman, Hughes, and 1ngold.l" Thethree possible exchange reactions are one-alkyl (iiia), two-alkyl (iiib), andthree-alkyl (iiic) :(i) R-HgX + X, + RX + HgX,(ii) R-HgR + HX f RH + RHgX(iiia) R-HgX + HgX, + R-HgX + HgX,(iiib) RzHg + HgX, + ZRHgX(iiic) R,Hg + RHgX + RHgX + R,Hg136C. Eaborn and J.A. Sperry, J., 1961, 4921.13' P. L. Southwick, M. W. Munsell, and E. A. Bartkus, J . Amer. Chem. SOC., 1961,138A. Hirschberg and P. E. Spoerri, J . Org. Chem., 1961, 26, 2356; H. Gainer, M.139 H.C. von der Plas, H. J. den Hertog, M. van h e r s , and B. Haase, Tetrahedron140 M. Hamana and M. Ya.mazaki, Chem. and Pharm. Bull. (Japan), 1961, 9, 414.141 M. J. S. Dewar and V. P. Kubba, J . Amer. Chem. SOC., 1961, 83, 1757.142M. J. S . Dewar and R. Dietz, Tetrahedron, 1961, 15, 26.143 S. S. Chissick, M. J. S. Dewar, and P. M. Maitlis, J . Amer. Chem. SOC., 1961, 85,144 W. Treibs, Naturwiss., 1961, 48, 130.H. B. Charman, E. D. Hughes, and C. K. Ingold, J., 1959, (a) 2523, (b) 2530.83, 1358.Kokorudz, and W. K. Langdon, J . Org. Chem., 1961, 26, 2360.Letters, 1961, 32.2708168 ORGANIC CHEMISTRYReaction (iiib) was the earliest studied because the products are different&om the reactants. Retention of configuration was first indicated by thework of Nesmeyanov et who used a displaced group with more than oneasymmetric centre, and this, together with the bimolecular character ofthe reaction, was confirmed by using di-( - )-s-butylmercury where themolecular dissymmetry is due to single asymmetric centres bound directlyto mercury.lb The SEl mechanism was thus excluded.The rate ofexchange increased as the ionicity of the salt increased, indicating the XE2rather than the SEi mechanism. Similar conclusions have been drawnmore recently from three-alkyl and uncatalysed one-alkyl exchange re-actions by the use of double labelling with 203Hg and (-)-s-butyl groups.This type of 8E2 mechanism in which the attacking and leaving groupsare on the same side of the reacting centre is supported for the one-alkylexchange by observations that neopentylmercury compounds react at asimilar rate to ethylmercury compounds.Reutov et al.interpret their results on the two- ti and three-alkyl 7exchange as involving a four-centre transition state (1). A similar four-centre transition state has been postulated by Dessy and Lee,8 but asthe exchange of ethylphenylmercury with mercuric halide involves equalamounts of cleavage of phenyl and ethyl groups9 they suggest that thetransition state must be symmetrical with respect to the two mercuryatoms (2). Other symmetrical transition states have been ruled O U ~ . ~ ~ ,CIThe proposed transition state is compatible with the obtuse angle betweencarbon-mercury bonds in ethylphenylmercury 9b and with the effect ofsubstituents in the phenyl ring, but the possibility of different mechanismsof attack at sp2- and sp3-carbon atoms has not yet been ruled out.Cat-alysis of the one-alkyl reaction by one or two anions has been attributed toeasy reaction by the 8,; mechanism.1°The XEl mechanism has also been demonstrated;11 the rate of the one-alkyl exchange between ethyl a-bromomercuri-a-phenylacetate and 203HgBr22A. N. Nesmeyanov, 0. A. Reutov, and S. S. Poddubnaya, Izvest. Akad. NaukH. B. Charman, E. D. Hughes, C. K. Ingold, and F. G. Thorpe, J., 1961, 1121.E. D. Hughes, C. K. Ingold, F. G. Thorpe, and H. C. Volger, J., 1961, 1133.0. A. Reutov, T. P. Karpov, E. V. Uglova, and V. A. Malysnov, Tetrahedron( a ) R. E. Dessy, Y. K. Lee, and J-Y.Kim, J . Amer. Chem. SOC., 1961,83,1163 ;lo H. B. Charman, E. D. Hughes, C. K. Ingold, and H. C. Volger, J., 1961, 1142.0. A. Reutov, W. I. Sokolov, and I. P. Reletskaya, Izvest. Akad. Naulc S.S.S.R.,S.S.S.R., Otdel. khim. Nauk, 1953, 649.6E. D. Hughes and H. C. Volger, J., 1961, 2359-* O . A. Reutov, Angew. Chem., 1960, 72, 198.*R. E. Dessy and Y. K. Lee, J . Amer. Chem. SOC., 1960, 82, 689.Letters, 1960, No. 16, 6.(b) H. Sawatsky and G. Wright, Canad. J . Chem., 1958, 36, 1555.Oldel. khirn. Nauk, 1961, 1217JOHNSON: THEORETICAL ORGABIC CHEMISTRY 169in 70% aqueous dioxan is independent of the mercuric bromide concentra-tion. The effect of substituents in the phenyl group is also consistent withthe unimolecular mechanism. Two-alkyl exchange does not occur betweenR,M and MBr, where M = Cd, Be, or Mg (R = Et or Ph) because thecorresponding compounds R-MBr do not exist .I 2 The disproportionation ofalkyltrimethylsilanes 13 in benzene in the presence of aluminium bromidehas been postulated as a displacement on carbon and nucleophilic attack onsilicon, also involving the X,i mechanism, with steric effects dominant incontrolling the rate.Retention of configuration and second-order kinetics are characteristicof acidolysis, though the demonstration of retention of configuration is lessclear-cut because of side reactions.14 Four-centre transition etates,15 andXE2 attack by the hydronium ion 16 in which C-H bond formation is rate-determining, have been proposed. Solvent isotope effects (k@, = 1.7 & 0.3and 1.0 for the acidolysis of cyclopropyl- and methyl-mercuric bromide,respectively) are considered to support the latter mechanism.In general,the rate increases from t-butyl to methyl and with increasing s-characterof the C-metal bond.17 The rate sequence Ph,Hg > Ph2Pb > Ph,Sn foracidolysis is manifested mainly in the activation energy. 0 bservations thatsome acidolyses, e.g., that of isopropyl- but not of cyclopropyl-mercuricbromide, are greatly accelerated by oxygen 18 may invalidate some of theearlier conclusions.The halogenation of a dialkylmercury is also bimolecular, with stereo-specific retention at the displaced carbon.lg In non-polar solvents the re-action involves free-radicals, but in polar solvents it is ionic.In some casesoxygen has little effect on the rate,lg but in others the rate is reducedS2*The fate of carbanions in solu-tion depends upon their structure, the nature of the leaving group, thesolvent, and the counter-ion. A carbanion capable of attaining a con-figuration with a plane of symmetry, e.g., (3; X = H,21 Et,22ay NMe2,23OMe 22b), generally tends to give a completely racemic product in dimethylsulphoxide, and one with partial retention of configuration in t-butylalcohol (or propanol), but there is net inversion in ethylene glycol. Theresults have been attributed to different amounts of asymmetric solvationand, by use of deuterated solvents,21 it was shown that the product is gener-ally formed by proton abstraction from the solvent.When the carbanion170 ORGANIC CHEMISTRYcontains an internal proton source 23 (3; X = OH or NH,), there is netretention in both t-butyl alcohol and ethylene glycol. The carbanions(3 and 4; X = CN ,*) with carbon as the leaving group are more susceptibleto racemisation, particularly in less acidic solvents, because of their ambi-dentate nature. The dependence of steric course on the counter-ion (NR,+or K+) is shown by the net retention of configuration for (3; X = CN) int-butyl alcohol with NR;, whereas only racemisation occurs with K+. Thecarbanions (3 and 4; X = CN, CO*NH, or C02Et), with hydrogen as the leav-ing are completely racemised in all solvents, the amount of deu-terium exchange in a deuterated solvent being equivalent to the amount ofracemisation.When the free carbanion might be expected to be non-planar,hydrogen exchange is much faster than racemisation 25a, and some reten-tion is found in all solvents. This has been explained for the compound (5)by assuming that asymmetry arises by overlap of empty sulphur d-orbitalswith either the lone pair in .sp3 hybridised, or the p-orbital in the rehybridised(sp2-p) carbanion. The latter type of overlap is less likely because of thelack of any through-conjugation effect when some a-sulphonyl-carbanionsare forced into this configuration.26a Cram et 1 3 1 . ~ ~ ~ observed small isotopeeffects in the racemisation and deuterium exchange of compound (5), butunder other conditions 25b no isotope effects were observed in the racemisa-tion.&Orbital overlap has also been suggested as the main factor contri-buting to the faster hydrogen exchange of tri(thioethoxy)methane than oftriethoxymet hane. 6b.The rate of deuterium exchange in CF,*CD(Hal), is much greater thanthe rate of elimination of DF 27a and it has been suggested that the tri-fluoromethyl group is equal to, or better than, the fluorine atom in facilitatingformation of a carbanion. Factors that favour the carbanion (relative tothe concerted E-2) mechanism of elimination have been discussed,27b andthe generalisation that the absence of a kinetic isotope effect implies thathydrogen is not transferred in the rate-determining step has been criti-~ised.27~ The rates of base-catalysed tritium exchange of phenyltritio-acetylene 28 have been measured in H,O and D,O; the isotope effect(EoD-/kOR- = 1-34) is consistent with hydroxide ion’s acting as a base ornucleophile. Calculations show that the reactions of the phenylacetyleneanion with water and with H,O+ have E, M los and E, rn loll 1.mole-lJOHNSON: THEORETICAL ORGANIC CHEMISTRY 171sec.-1, respectively. The pK,'s of a number of cyanocarbon compounds 29are remarkably low; e.g., cyanoform has pK, -5.13 in perchloric acid and-5-00 in sulphuric acid. Carbanions have also been postulated as possibleintermediates in the base-catalysed elimination of nitrous acid from benzylnitrate,3OU in the solvolysis of nitrostyreneY3Ob and in the Hofmann elimina-tion of ethylene from triethylsulphonium halides 30c by triphenylmethyl-sodium.The complete stereospecificity of rearrange-ment of ally1 ethers to cis-propenyl ethers has been ascribed to the partialbonding of the metal ion to both ends of the intermediate carbanion in thetransition state.31, A similar transition state, but with specific participa-tion of the solvent, has also been postulated.31b Benzyl migration in 2,2,3-triphenylpropyl-lithium 32a is faster at 0" than phenyl migration in 2,2,2-triphenylethyl-lithi~m,~~~ and phenyl migration is faster than p-tolylmigration in 2-phenyl-2-p-tolylpropyl-lithium.32C This is in accord witha carbanion intermediate for which it has been calculated that the ion withthe half-migrated phenyl group has lower energy than the free unbridgedcarbanion.Z,%Diphenylpropylmagnesium does not rearrange, the cor-responding lithium compound rearranges only above 0", and the potassiumcompound can be prepared only in the rearranged form.32c The isomerisa-tion of lithiobenzyl s-butyl ether in aprotic solvents to the lithium salt ofcc-s-butylbenzyl alcohol proceeds with some retention of configuration, theamount of retention decreasing with increasing solvation of the cation.33Dehydrochlorination of 2-chloro-1 , l-diphenylethylene in di-n-butyl ether 34involves phenyl migration in the free carbanion or a concerted carbanion-migration mechanism. A concerted cyclic mechanism may also be involvedin the exchange of alkyl and aryl groups between triaryl-sulphonium or-telluronium ions and alkyl l i t h i ~ m s , ~ ~ " and in the reaction between ethyl-lithium and benzyl chloride for which a lithium kinetic isotope effect hasbeen 0bserved.35~Nucleophilicity and Basicity of Anions. -Much attention has beenpaid to the fact that many reactions are greatly accelerated in dipolaraprotic solvents or by traces of dipolar aprotic solvents in other solvents.For example, the rate enhancement in ion-dipole reactions is up tolo5 for bimolecular nucleophilic aromatic substitution 36 and up to 107for bimolecular nucleophilic aliphatic substitution 37, 38 and carbanion172 ORGANIC CHEMISTRYformation.24b Since conductivity studies 39 show that most electrolytesare completely dissociated a t low concentration in dipolar aprotic solvents,studies of these reactions have shed light on the concepts of nucleophilicityand basicity of ions.Rate enhancement for an ion-dipole reaction on goingfrom a protic to a pure aprotic solvent is generally due to a large decreasein the solvation of anions (particularly small anions), coupled with smallerchanges in the solvation of cations and of large, negatively charged, polaris-able transition states. 36Cavell has shown that the marked decrease in the rate of reaction betweeniodide ion and butyl bromide 40a or iodide in acetone caused by theaddition of small amounts of water cannot be accounted for in terms ofchanges in dielectric constant alone. Evidence has been presented for anequilibrium of the type (iv) (R = H, Me) which decreases the concentrationof the reactive anions in'solution.The addition of small amounts of methanolto acetonitrile 41 causes only negligible changes in dielectric constant, butstill there is a large decrease in the rate of halogen exchange; this decreasewas used in calculating an association constant (K,) for reaction (iv). Thevalues of K, which were obtained when phenols were added in place ofmethanol were proportional to the integrated intensity of the O-H stretchingfrequencies of the phenols.41The effect of solvent change from pure water, methanol, or ethanol topure dimethyl sulphoxide on the alkaline hydrolysis or alcoholysis of methyliodide 38 has been studied. For water, log k2 ( E , = second-order rate con-stant) is an almost linear function of the mole fraction (%) of dimethyl sulph-oxide.This is due to an initial linear decrease in activation energy down to x 0-5, followed by a levelling-off, coupled with an initial decrease in log Adown to x w 0.5, followed by a subsequent increase. Although dimethylsulphoxide 42a and dimethylformamide 42b can form compounds with methyliodide and dimethyl sulphate, respectively, the trimethylsulphoxidiumsalt 42a is not an intermediate in this reaction. The addition of 10 moles yoof dimethyl sulphoxide to methanol 24a causes a much larger increase(18-fold) than the addition of any but the final 10 moles yo of dimethylsulphoxide (>35-fold) in the rate of carbanion formation from (+)-a-methyl-j3-phenylpropionitrile and methoxide ion. The effect of smallamounts of dimethyl sulphoxide has been ascribed to specific solvation ofthe transition state, whereas a t very high concentration dimethyl sulphoxidecompetes effectively with methoxide ion for the remaining methanol, thusleaving methoxide ions relatively unsolvated and reactive.The rate in-crease in the reaction of butyl bromide with carbani0ns,~3 on addition offrom 5% to 95% of dimethylformamide to the benzene solvent, is a linearunction of the dimethylformamide concentration and has been ascribed tosolvation of the cation associated with the carbanion.These changes in the solvation of anions are such that aprotic solventstend to level, and protic solvents tend to differentiate, the nucleophilictendencies of halide and halogenoid ions,37 whereas, conversely, aproticsolvents tend to differentiate, and protic solvents to level, the carbonbasicity 44 and hydrogen basicity aQa of such ions.Rates of solvolysis arescarcely changed on going to dipolar aprotic s01vents,3~, 45 but concomitantfirst- and second-order exchange of chloride ion with diphenylmethylchloride in dimethylformamide has been reported. 48 The reaction betweenpyridine and butyl bromide 47 is not appreciably influenced by change toa dipolar aprotic solvent,, suggesting that dipole-dipole reactions may notbe influenced as much as ion-dipole reactions; however, this may be a for-tuitous cancellation of effects because small amounts of dimethyl sulphoxideaccelerate the reaction between allylamine and 1 -chloro-2,4-dinitrobenzene 48in 2-phenylethanol .Of importance to the interpretation of rates of SN3 reactions in aqueous-a'lcoholic solution are explanations 49 of rate changes observed when smallamounts of water are added to alcohol solvents.With methanol there isan initial increase, with ethanol (except in the presence of the stronglynucleophilic, but weakly basic, thiophenoxide ions) there is a decrease, inrate. The difference in behaviour has been ascribed to the surprisinglyhigh concentration of the less reactive hydroxide ion in ethanol containingsmall amounts of water, whereas corresponding methanol solutions containmainly methoxide ion.Carbonium Ions.-Non-chsical carbonium ions. Acetolysis of cis-bicyclo[3,1 ,O]hexan-3-y1 toluene-p-sulphonate (6) is subject to a special salteffect and anchimeric ac~eleration,~~" and the 3-deuterated toluene-p-sul-phonate gives the cis-acetate in which the deuterium is equally distributedamongst positions 1, 3, and 5;50b these facts are uniquely consistent withthe intervention of the trishomocyclopropenyl cation (7).Acetolysis ofthe trans-isomer involves little deuterium redistribution, special salt effectsor anchimeric acceleration, indicating little interconversion between classicaland non-classical ions. The structure and implications of homoaromaticand homoallylic carbonium ions have been discussed. 5~ The exact structureof the homoallylic carbonium ion derived from cholesteryl compounds isdescribed as (8) rather than (9) because the same products are obtainedfrom cholest er y 1 and 3p - h y dr ox y met hyl-4-norc holest - 5 -ene toluene -p - sul-phonate (10) on acet~lysis.The products of solvolysis of alliylmercurysalts are characteristic of normal solvolytic reactions.59 The reaction inacetic acid is slow, but on addition of perchloric acid, an instantaneous reac-tion (v) occurs, which is then followed by a slower reaction yielding mercury,perchloric acid, and solvolysis products.The product composition is inde-pendent of the anion; e.g., cyclohexylmercury salts give 89.5 & 1.3% ofolefin and 10-5 &- 1.3% of a cyclohexyl derivative. The most probablemechanism involves scheme (via, b).(v)(via)(vib)GeneraE solvolytic reactions.R*HgX + HCLO, -+ RHgCIO, + HXR-HgX + RHg+ + X-R.Hg+ -F HgO + R+ + ProductsSlowThe very large difference (+ 17.5 kcal./mole) in free energy of activationbetween methyl and t-butyl salts, 59b when compared with the previoushighest value (<S kcal./mole), implies that the reaction involves a transi-tion state which is highly charged in relation to the initial state.The formation of +4y0 of methane on treatment of methyl bromide ina hydrocarbon solvent with aluminium bromide has been ascribed to theformation of the methyl cation which abstracts a hydride ion from thesolvent.60 The spectrum of a number of allylic compounds in sulphuricacid has been reported to be due to allylic carbonium ions.61 The fadingof solutions of the triphenylmethyl ions in, for example, acetic anhydrideor nitromethane containing small amounts of ether has been ascribed tothe formation of a 1 : 1 complex between the ether and the carboniumion.62a I n chloroform, the tri(methoxypheny1)methyl ion is fairly stable,but the colour of the tri(to1uene-p-sulphonylpheny1)methyl and triphenyl-methyl ions fades much more rapidly, particularly in " wet " ch1oroform.6zbThe first-order reaction of 2-chloroethyltrimethylsilane to give ethyleneis dependent upon the ionising power, but not the nucleophilicity, of thesolvent. 63a Intervention of the trimethylsilyl cation has been postulated,and the suggestion made that such ions may be as accessible as carbo-nium ions, but that alternative reaction paths may be more favoured withsilicon compounds. Deamination of trimethylsilylmethylamine 63b involves,not the trimethylsilylmethyl cation, but loss of the elements of diazo-methane, probably by nucleophilic attack on silicon.A study of the stereo-chemistry of a number of reactions of alkylsilyl halides, alcohols, ethers,and esters 63c in solvents of low ionising power, shows that " good " leavinggroups such as chloro or acyloxy lead to predominant inversion, but withpoorer " leaving groups other stereochemical paths are available. Re-actions involving nitrosation, diazotisation and deamination have beenreviewed.64The upper limit of exchange of [35S]thiocyanate ion with diphenyl-methyl thiocyanate 65a is less than one-third of the rate of isomerisationto the isothiocyanate, indicating the intervention of ion-pairs, even in aceto-nitrile as solvent. Ion-pairs are also indicated in the solvolysis of diphenyl-methyl p-nitro[ 180]benzoate 65b (where the rate of carboxyl- 1 8 0 scram-bling is three times the solvolysis rate) and in the chloride ion exchangewith an optically active diarylmethyl chloride 65c (where, even in the presenceof a highly dissociated inorganic chloride, the rate of racemisation exceedsthe rate of exchange). In the presence of mercuric chloride,66 the ratioof the rate of racemisation to the rate of exchange is reduced to 1-50 & 0-03,though both racemisation and exchange rates are greatly enhanced.Thissuggests that all exchange occurs by regeneration of RC1 from RfHgC1,-ion-pairs which have become racemic and have lost all distinction betweenthe three chlorine atoms.The solvolysis and rearrangement of propylbromide in the presence of mercuric salts in aqueous formic acid has alsobeen disc~ssed.~'Methyl 2-deoxy-~-glucopyranosides,~~~ like most alkyl glycosides, under-go acid-catalysed hydrolysis by the A- 1 mechanism with hexose-oxygenfission, but hydrolysis of t - butyl ,k?-D-glucopyranoside involves alkyl-oxygenfission. The observation of an O-isotope effect (k16/k18 = 1.03) in theacid-catalysed hydrolysis of methyl a-D-glucopyranoside and the predom-inant inversion on hydrolysis of phenyl 2,3,4,6- tetra- O-met hyl-P-D- gluco -pyranoside and of phenyl a- and p-D-glucopyranosides indicate that suchsolvolyses do not involve ring opening. X-Phenyl 2 , 3,4,6- te tra-O-met hyl-P-D-thioghcopyranoside resists acid-catalysed methanolysis.Acid-catalysedhydrolysis of a series of phenyl a-~-glycosides,~~" unlike that of the cor-responding ~ - ~ - g ~ y c o s i d e s , ~ ~ ~ is unaffected by substituents in the phenylgroup. This has been attributed to easier elimination of phenol via an anti-periplanar transition state [scheme (vii)] which is accessible from the a-con-figuration only. Comparison of relative rates for the p-isomer and thecorresponding methyl glycosides suggests that this may not be a generalreaction. The rates of acid-catalysed hydrolysis of glucose and mannoseare decreased by both primary and secondary deuterium isotope effects.70The secondary effect is due almost entirely to deuterium in position 1 andis almost unaffected by deuterium in other positions. In the acid-catalysedanomerisation of 1,3,4,6-tet;ra-O-acetyl-2-deoxy-~-glucopyranoside the rateof l-acetoxy-exchange is greater than the rate of inversion (k,/ki = 1-8-3.7)indicating an X,l type of mechanism.The fission of arylalkyl ethers inconcentrated sulphuric acid is a normal A-1 reaction, but alkyl ethersundergo attack by sulphur trioxide on the oxonium salt 72 to give theintermediate [R1R20.S0,H] + which slowly decomposes ; the extent of forma-tion of this intermediate is critically dependent on the solvent concentration.Solvolysis of adamantan- 1 -yl derivatives (1 9) 73a is easier than mightbe expected, being only 1000 times slower than that of t-butyl, but lo5and 1011 times faster than that of bicyclo[2,2,2]octan-l-yl and bicyclo-[ 2,2,2]heptan-l-y1 derivatives, respectively.The difference from t-butyl isascribed to angle strain in a somewhat flattened, but not planar, transitionstate, and there is no evidence to suggest that inhibition of bridgeheadhyperconjugation can alter the rate significantly. The acetolysis of adam-antan-2-yl toluene-p-sulphonate (20) 73b is 15 times slower than that ofcyclohexyl toluene-p-sulphonate, but lo6 times faster than that of 7-norbornyltoluene-p-sulphonate. The formation of oxazolines 74a from 2-benzamido-4-t- butylcyclohexyl and from 2-benzamidocyclohexylmethyl sulphonate, whichrequire the anti-periplanar conformation in the transition state, has beenused to show that the anchimeric driving force in the reaction must be .greater than 5.5 kcal./mole, quite sufficient to allow all or part of the reac-tion to proceed through the boat conformation where necessary.Theassisted pyrolysis of the all-equatorial 2-hydroxy-NNN-trimethyl-5-t-butylcyclohexylammonium hydroxide 74b also proceeds through the boatconformation.The ratio AC*/AS$ in aqueous acetone may be diagnostic of the SN1mechanism 76a in cases where other methods fail. Thus in SNl reactionsthe ratio has a value >2-77, whereas much smaller values occur for 8,Zand mixed-mechanism reactions. The use of this criterion of mechanism178 ORGANIC CHEMISTRYhas also been discussed by Robertson and Sc0tt.~6~ The volume change ofactivation in the reaction between ethyl iodide and tripropylamine inmethanol ( - A V = 24 c.c./mole) 77a is much less than the overall volumechange during reaction (-AV = 56-6 c.c./mole); this result is difficult toreconcile with the view that the transition state resembles the solvatedproduct.The corresponding value for the reaction between methyl iodideand N-ethyl-N-methylaniline is 20 c . ~ . / m o l e , ~ ~ ~ and that for the reversereaction is -45 c.c./mole. The difference between these values is inreasonable agreement with the value (-AV, = 55.8 c.c./mole) for theoverall volume change a t 25". Discrepancies with previous work havebeen put down to the variation of A V with pressure.Carbenes.-This subject has been reviewed.78 The kinetics of thethermal decomposition of diazodiphenylmethane have been st~died.79~3Precise measurements on the decomposition of 2,2'-azodi-(a-mefhylpropio-nitrile) in several solvents show that the rate and activation parameters varyconsiderably with the solvent and calculations indicate that plots of A&'$against AH2 may well be linear because of systematic errors in their computa-tion.Reaction of photochemically produced methylene with allenes andbutadiene involves competitive addition to double bonds and insertionin C-H bonds ; the excited cyclopropane derivatives thereby produced areunstable unless deactivited by collision. The spectroscopic states of methyl-ene in solution and in the gas phase have been discussed.81 Methylenereacts with the carbon-halogen bond in simple alkyl halides,82 the reac-tivity order being primary > secondary > tertiary.The reactions arecompetitive with reaction a t the C-H bond and, for primary and secondaryhalides, the intermediate (21) has been postulated. Dichlorocarbene (fromchloroform and base) has been inserted by cleavage of mercury-halogenbonds,83 to give trichloromethylmercury compounds, as in (viii) :Rearrangements occur with carbenes derived from neopentyl and relatedhalides. Labelling with deuterium was used to show that methyl migrationand intramolecular C-H insertion can occur in neopentylcarbene. 84a,Thermally produced carbene from 2-methyl-2-phenyl-2-diazopropane 85undergoes phenyl migration, methyl migration, and C-H insertion in theratio 10 : 1 : 8.3, which is a much greater proportion of methyl migrationthan is observed with the corresponding carbonium ion.Isobutene isformed from an n-butyl or isobutyl halide and a strong base by predominanta-elimination to give the intermediate carbene,84cs 86 except in the case ofisobutyl iodide ; 84' no a-elimination occurs with s-butyl chloride or isobutylmethyl ether or sulphide.86 Cyclic carbenes derived from five- or six-membered rings give lOOyo of 0lefin,~7 but those from larger rings givemixtures of olefins and products derived by 1,3-, lJ5-, and 1,6-transannularalk ylation.There is kinetic evidence for the occurrence of dibromocarbene on brom-ination of tribromomethane by hypobromite ion,88 and for occurrence ofp-nitrophenylcarbene. 89 Methylene and mono- and di-methoxycarbonyl-carbene react with increasing discrimination with C-H bonds (in the ordertertiary > secondary > primary C-H), owing to the smaller reactivity ofthe substituted carbenes ; polar structures in the transition state areIsoelectronic nitrogen analogues of carbenes, i.e., R-N:, have beenpostulated as intermediates in the photochemical decomposition of alkyl,gla~vinyl,91c and acyl 91d azides.Consideration of the volume change of activa-tion in the Curtius rearrangement 92 and the kinetic form of the alkalinedecomposition of N-chloroacetanilide g3 are also consistent with acyl- andaryl-azenes, respectively. However, spectrophotometric studies on thephotolysis of methyl azide gave no indication of the presence of methylazene,only for that of a ~ i n i d i n e .~ ~Carbonyl and Related ReactiollS.-Conformation. Studies of the rela-tion between reaction rates and conformation continue. Acid-catalysedhydrolyses of methyl cyclohexane-mono- and -di-carboxylates and of methyl4-t-butylcyclohexanecarboxylates have been studied in detail 95a and theresults compared with those of the corresponding alkaline hydrolysis.g5bNo firm conclusions could be drawn from the rates of reaction about theimplicated. ..conformations of the trans-ly2-mono- and di-carboxylate, but they areprobably diequatorial, because, contrary to previous belief, the tr~ns-1~2-diacid and its monoanion are diequatorial. 96 The conformational equili-brium constant for the ethoxycarbonyl group has been estimated from theequilibration of ethyl cis- and trans-4-t-butylcyclohexanecarboxylate 97(AF - 1.2 kcal./mole), and the alkaline hydrolysis of ethyl cis-4-methyl-cyclohexanecarboxylate (AF - 1.0 to - l.2).97u These values are supportedby the equilibration of ethyl cyclohexane- 1,3-dicarboxylate 97b.and by acomparison of the rates of hydrolysis of ethyl cis- and trans-4-t-butylcyclo-hexanecarboxylate g70 (AF -1.O), but the latter agreement may be for-tuitous in view of several cases where a cyclohexane derivative reacts fasterthan the all-equatorial trans-4-t-butylcyclohexane derivative.95a, b , 98 Thecorresponding free-energy difference for the carboxyl group, calculated fromacid dissociation constants, is slightly larger [AF =' - 1 ~ 7 9 ~ ~ (corr., - 1-4 97(7,-l.6,99b -1.6 kcal./mole 99cJ.An 8 - 9-fold acceleration hasbeen demonstrated for alkaline hydrolysis of some alicyclic acetates at 25"where hydroxyl groups are on carbon atoms adjacent to the acetoxylgroup.100 Much greater accelerations have been observed at 78" by intro-duction of cis- and trans-hydroxyl groups adjacent to the acetoxyl group ofcyclopentyl acetate.lol The rate differences are markedly affected by tem-perature.The acceleration in the case of the trans-diol monoacetate (22)rules out previous suggestions that hydrogen bonding of the hydroxyl groupto the ether-oxygen atoms of the acetoxyl group in the transition state isresponsible for the acceleration, and indicates that hydrogen bonding tothe carbonyl oxygen in the transition state (23) and/or a microscopic mediumeffect are responsible, Facilitation of alkaline hydrolysis of methoxy-carbonyl groups by vicinal hydroxyl groups in some indole alkaloids has alsoIntramolecular facilitation of hydrolysis.Types I-V specific polysaccharides of Pasteurella psezdotuberculosiscontain a number of different 3,6-dideoxyaldohexoses comprising 3,6-dideoxy-D-xyb- (abequose), -D-arabino- (tyvelose), -L-arabino- (ascarylose),and -D-ribo-hexose ( p a r a t ~ s e ) .~ ~Acid degradation of the antibiotic chalcomycin yields chalcose, a 4,6-dideoxy-3-O-methylaldohexose. 52Several deoxy-sugars, including di-, tri-, and tetra-saccharides, havebeen detected in the hydrolysed glycosides from the nodules of Raphiommeburkei.53Cyclic derivatives. The importance of hydrogen- bonding on acetalformation is discussed in a paper in which the methylene groups of thetri-0-meth ylene acetal of D -g&ycero-D -glum- heptitol (p- sedoheptitol) areshown to be in the 1,3 : 2,4 : 5,7-p0sitions.~4Phenylboronic acid reacts with methyl OI-D-glucopyranoside to give the 4,6-cyclic ester, con-p h 1 3 < ~ ~ . o & verted by more of the acid into the 2,3-(diphenyl0 pyroboronate) (4). Similarly, methyl CC-D-man-nopyranoside is converted by an excess of theacid into the 2,3 : 4,6-die~ter.~~ These estergroups are readily removed by water or alcohols.Unlike p-D-glucopyranose 2,3,4,6-tetra-acetate 1-nitrate, the pentanitrate does not easily undergo anomeriza-tion, presumably because the 2-nitrate group, unlike the acetate, does notparticipate in the displacement.As expected, treatment of the penta-nitrate with methanol gives methyl a-D-glucopyranoside tetranitrate, butunfortunately the reactivity of this compound is too low for the method tobe of value for preparation of disaccharides. However, condensing 3,4,6-tri-O-acety~-$-D-glucopyranosy~ chloride 2-nitrate with p-D-glucopyranose1,2,3,4-tetra-acetate gives a good yield of the isomaltose derivative, togetherwith a small proportion of genti~biose.~~The ester group of a number of aldose 1-(2,4,6-trirnethylbenzoates) hasbeen displaced by treatment with methanol containing methanesulphonicIn a typical example, p-D-glucopyranose 1 -(2,4,6-trimethylbenzoate)is converted into methyl a-D-glucopyranoside.Study of anomerization and exchange reactions at position 1 of the2-deoxy-~-g~ucopyranose tetra-actetates 58 where no neighbouring groupeffect is possible has shown that the reactions proceed by-the XNl mechan-ism.59 In such reactions in acetic acid, acetic anhydride, and sulphuricacid there is a pronounced acceleration due to an isotope effect when theacids contain deuterium.6oTreatment of 2-acetamido-2-deoxy-~-ribose or D-arabinose with aqueousammonia gives an equilibrium mixture of the two containing twice as muchof the arabinose compound. The amount of each epimer in the mixturedepends on the relative stabilities of the chair conformations Gf the pyranosering.61 Prolonged treatment of D-glucosamine with aqueous ammonialeads to the production of 2 -met h y 1- 6 -D -arabino- tetrahydroxybut yl- , 2 -methyl-5 -D -arabino-tetrah ydroxybutyl, 3- D -erythro- trihydroxypropyl- , and2,5- bis- (~-arab~no-tetrahydroxybutyl) -pyrazine.Several anomeric pairs of N-aryglycosylamines have been prepared bydeacetylation of their acetates by sodium in methanol, in which mutarota-tion is arrested.63 N-Arylaldosylamines undergo true transglycosylationin ethanol containing hydrogen chloride and another arylamine.64When a sugar o-chloro- or o-iodo-phenylosazone is heated with aqueouscopper sulphate the phenylosotriazole is obtained, dehalogenation occur-ring.65 Osotriazoles are stoicheiometrically oxidized by ceric salts, to give2-phenyl-l,2,3,triazole-4-carboxylic acid.66N-Beizzyloxycarbonyl-amino-acids condense readily with sugarsin pyridine in the presence of dicyclohexylcarbodi-imide, esterificationinvolving mainly the primary alcoholCrystalline arsenites that are readily hydrolysed have been preparedfrom alditols and arsenic trioxide.68In the nitration of D-fructose the product obtained depends on the acidityof the esterifying solution.It has now been found that use of nitroniumsulphate gives a compound, C,H,,07, with pyruvaldehyde joined by anacetal-type linkage to an anhydro-D-fructose. 69N-Alkyl- and N-aryl-carbamates are readily obtained by treating sugarsand derivatives with isocyanates. 70Treatment of D-ghCOSe in cold concentrated sulphuric acid with phos-phorus oxychloride is claimed to give excellent yields of D -glucose 6-phosphate(as the barium salt) which is believed to exist in the acyclic form.71 Thephosphate groups of a number of partially substituted myoinositol phos-,phates have been shown to undergo migration in acid solutions.72 Attemptsto prepare phosphate esters of sugars by treating deoxy-halogeno-derivativeswith silver phosphate 7 3 or silver diphenyl phosphate 74 sometimes lead toanhydro-sugars. The preparation is described of 5,6-, 3,6-, and 3,5-cyclichydrogen phosphates of D-glucose. 75D-Glucose 6-sulphate, isolated as the crystalline potassium salt, is pre-pared by treating D-glucose with pyridine-sulphuric anhydride in dimethyl-formamide 76 or with chlorosulphonic acid in cold concentrated sulphuricacid.77 Direct esterification is also found to occur mainly at c(6) in D-galaC-tose, but by using suitably substituted derivatives other monosulphates ofD-glucose and D-galaCtOSe have been prepared.78 Oxidation of sugar sul-phates with sodium periodate is complex but gives valuable information forcharacterizing unknown esters. 79 Acid hydrolysis of the methyl glycosidemonosulphates shows that the sulphate group stabilizes the glycosidic linkand that the 6-sulphate is more effective than the 3-sulphate. The parentsugar is the only one isolated, showing that no inversion of configurationoccurs. These experiments show that acid hydrolysis of sulphated polysac-charides should give some sulphated mono- and oligo-saccharides.80 Reduc-tion of sugar sulphates with lithium aluminium hydride leads to the parentsugar only, with no trace of deoxy-sugar.81 Solutions of hydrazine are onlypartially successful for removing sulphate groups.82Amino-sugars.D-Gulosamine is obtained from D-xylose by successivereaction with nitromethane, methanolic ammonia, and hydrochloric acid.83A general method by which all 2-amino-2-deoxy-~-aldohexoses have beenmade involves treatment of the D-pentose with hydrogen cyanide and9-aminofluorene, followed by removal of the fluorenyl substituent by cata-lytic hydrogenation. Methyl 2-ace tamido-4,6 -0-benzylidene-2 -deoxy-a- D -idopyranoside 3-methanesulphonate is converted by sodium acetate into the2 -amino-2-deoxy-~-talose derivative, and the 3-amino-%deoxy-~ -gulosederivative is obtained similarly from the D-idoside.86 Oxidative degrada-tion of the diethyl dithioacetal of 3-acetamido-3-deoxy-~-altrose gives2-acetamido-2-deoxy-~-ribose.~~ Crystalline 5-acetamido-5-deoxy-~-xyZo-hexulose is made by the oxidative action of Acetobucter suboxydum on2-acetamido-2-deoxy-~-glucitol.~~ A definitive synthesis of muramic acidis described.89 The structure of neosamine C, 2,6-diamino-2,6-dideoxy-~-glucose, obtained from the antibiotic complex, zygomycin A, has beenconfirmed by synthesis.g0Mycosamine is shown by synthesis to be 3-amino-3,6-dideoxy-~-man-nose,91 and mycaminose to be 3,6-dideoxy-3-dimethylamino-~-glucose. 92Two new arnino-sugars from an antigenic polysaccharide of Pneumococcushave been tentatively identified as 2-amino-2,6-dideoxy-talose and -L-galactose.93A method for purifying amino-sugars involves the preparation andhydrogenolysis of a suitable SchWs base.94 Amino-sugars are convertedinto the N-acyl derivative by treatment with the acid in the presence ofdicyclohexylcarbodi-imide. 95When a mixture of D-glucosamine hydrochloride and D-mannose isheated on paper a small quantity of N-mannosyl-D-glucosamine is formed. 96Under more drastic conditions disaccharides are produced ; 6-O-mannosyl-~-glucosamine has been isolated.Polyamides , including a tetrahydroxy-Nylon 6,10, have been preparedby the interfacial reaction of sebacoyl dichloride and suitably substitutedlY6-diamino- 1 -6-dideoxyhexitols. 98The presence of the acetamido-group of3-acetamido-3-deoxy-~-allose diethyl dithioacetal favours the formation of2-acetamido-~-ribose by oxidation with peroxypropionic acid.The pentoseis not obtained directly by similar oxidation of D-altrose diethyl dithio-a ~ e t a l . ~ ~Controlled oxidation of a number of sugar dithioacetals gives monosul-phoxides; these are stable to alkali, but they are readily converted by dilutemineral acid into the parent sugar and a dialkyl disulphide and by methanolichydrogen chloride into methyl furanosides and pyranosides. Also obtainedwere a number of disulphoxides that are stable to acid at room temperaturebut readily degraded to the next lower aldose by dilute ammonia.loOTetra-0-acetyl-D-ribofuranosyl bromide is obtained by treating alkyl1 -deoxy-1 -thio-a-D-ribofuranosides with acetic anhydride followed bybromine.lo1 Treatment of analogous compounds with mercuric acetate orsilver benzoate results in the replacement of the alkylthio- by the acyloxy-radical.1°2 The action of Raney nickel on aldose dithioacetals gives the1-deoxyalditols ; partial desulphurization has been found to be a reasonablemethod for making 1 -deoxy-1 -thioethylalditols. 1°3Sugars with a sulphur atom in the ring have been reported for the firsttime. Successive treatments of 1,2-O-isopropy~idene-~-xylofuranose 5-folu-ene-psulphonate with sodium thiocyanate and sodium sulphide, or sodiumthiosulphate and potassium borohydride, lo4 orpotassium thiolacetate and sodium in methanol lo5yield crystalline 5 -deox y - 1,2 - O-isopropylidene- 5 -mercapto-D-xylose, hydrolysis of which gives 1 4 0D-xylothiapyranose (5).The pyranose ring isextremely stable and mutarotation is slow evenwhen catalysed by ammonia.Reagents: 1, (a) CS,-NEt,, (b) MeI, (c) Me*SO,Cl. 2, Boiling C,H,N.3, Al-Hg. 4, HC1 (to remove CHPh:), then HgCl,. 5 , H,S.In another sequence the amino-group is formed by reducing theazido-residue introduced by treating a toluene-p-sulphonate with sodiumazide, and the thiol group is obtained by debenzylating the benzylthio-derivative produced by opening an epoxide ring with sodium benzyl sulphide.Methyl 2-amino-4,6 - 0- benzylidene- 2,3 -dideox y - 3-mer capto-/3-~ -alloside hasbeen made from methyl 2-amino-4,6-0-benzylidene-2-deoxy-/3-~-glucoside inrather a similar manner.Di- and Oligo-saccharides.-Columns containing a mixture of carbon andaluminium oxide have been successfully used for separating mono-, di-, andloSL.D. Hall, L. Hough, and R. A. Pritchard, J., 1961, 1537.C. Jamieson and R. K. Brown, Canad. J . Chern., 1961, 39, 1765.lo* For a review see D. R. Kalkwarf, Nucleonics, 1960, 18 (No. 5), 76.log L. Goodman and J. E. Christensen, J . Amer. Chem. SOC., 1961, 83, 3823.J. E. Christensen and L. Goodman, J . Amer. Chem. SOC., 1961, 83, 3827.l l l W . Meyer zu Reckendorf and W. A. Bonner, PTOC. Chem. SOC., 1961, 429HO'NEYMAN : CARBOHYDRATES 345tri-saccharides. In this way p-gentiobiose has been isolated from the mix-ture obtained by treating D-glucose with emulsin.l12Sophorose, which has been found to have a remarkable stimulatingeffect on the cellulase production of a strain of Trichoderma viride,l13 hasbeen synthesized by a simple method,l14 which modifies the conditionsdescribed earlier : 115 methyl 4,6-O-benzylidene-a-~-glucoside reacts withacetobromoglucose to give a sophorose derivative from which the free sugaris isolated by acetolysis followed by deacetylation.Crystalline or-ko jibiose (2- O-a-D-glucopyranosyl-a-D -glucopyranose) hasbeen obtained by the action of lactase on a branched trisaccharide result-ing from the action of Leuconostoc mesenteroides on a mixture of sucroseand lactose.l16The 1,6-glycosidic link in polysaccharides is the most stable to acidhydrolysis, but the least stable to acetolysis.This has enabled kojibioseand nigerose to be isolated 11' from the acetolysis of the dextran, known tobe unusually rich in 1,2 linkages,lls from Leuconostoc mesenteroides NRRLB-1299. From another strain, B-421, nigerose is isolated in particularlygood yield.117Treatment of a mixture of maltose and D-xylose with a transglycosylasefrom Penicillium lilacinum gives 3-O-~-~-glucopyranosyl-~-xylose.~~~Sodium hypochlorite degrades maltose and lactose to crystalline 3-0-a-~-glucopyranosyl- and 3-O-~-~-galactopyranosy1-~-D-arabinose, respectively, inyields of about 35y0.120Leucrose (5-O-a-~-glucopyranosyl-~-fructopyranose) is the main sugarisolated from the product formed by dextran-producing cultures of Strepto-coccus bovis acting on sucrose.121Several novel disaccharides have been obtained by treating chondroitinsulphate A, B, or D with a chondroitinase preparation from Proteus vulgaris.A and B both give the A49 5-~-g~ucuronido-~-acety~-~-ga~actosamine4-(hydrogen sulphate) (€9, whereas Dgives the isomeric 6-( hydrogen sulphate).HC*OHF H ----Another except that disaccharide it is a di(hydrogen from D is sulphate) similar H O .; g HC.0I-I 1 O . d H liJD-galactose part and the other probablyH0,S.O. CHICHI1co CH,*OH Iwith one sulphate residue on c(6) of theon or C(3) of the uronic acid part.A similar but distinct disaccharide di-sulphate is also obtained from B.122 COlH (8,Crystalline stachyose tetrahydrate has been prepared from the tubers112V.D. Stefanovid, J . Chromatog., 1961, 5, 453.113M. Mandels and E. T. Reese, Biochem. Biophys. Res. Comm., 1959, 1, 338.114B. Coxon and H. G. Fletcher, jun., J. Org. Chem., 1961, 26, 2892.115 K. Freudenberg, H. Toepffer, and C. C. Andersen, Ber., 1928, 61, 1750.l l s F . Yamauchi and K. Aso, Nature, 1961, 189, 753.117 K. Matsuda, H. Watanabe, K. Fujimoto, and K. Aso, Nature, 1961, 191, 278.118 T. A. Scott, N. N. Hellman, and F. R. Senti, J . Amer. Chem. SOC., 1957, 79, 1178.119 S. A. Barker, M. Stacey, and D. B. E. Stroud, Nature, 1961, 189, 138.laoR. L. Whistler and K. Yagi, J. Org. Chem., 1961, 26, 1050.121E. J. Bourne, D. H. Hutson, and H. Weigel, Biochem. J., 1961, 79, 549.122S. Suzuki, J . Biol. Chem., 1960, 235, 3580346 ORGANIC CHEMISTRYof the Japanese artichoke (Stuchys sieboldii, Stachys tuberi,fera).l23 A largenumber of oligosaccharides containing D-galactose and sucrose have beenisolated from the roots of Cucubulus b u ~ c i f e r .~ ~ ~A monosodio-sucrose has been obtained free from ammonia,125 anda crystalline sucrose monoacetate has been prepared by treating sucrose withacetic anhydride in pyridine.126 Hydrogenolysis of sucrose in ethanol ordioxan at 180 gives 2,6-anhydro-~-~-fructofuranose (2,5-anhydrO-B-D-hctopyranose), a new type of anhydro-ketose in which the 2,6-ring is inthe boat form and is very sensitive to acid.I27When maltose in ethanol is treated with piperidine, acetic acid, and tri-ethylamine the Amadori rearrangement product, 1 -deoxy- 1 -piperidino-maltulose, is obtained. With lactose, however, the reaction goes furtherand U-D-galactosylisomaltitol is produced.Hydrolysis or pyrolysis of thisgives isomaltitol, which may be 2-acetyl-3-hydroxyfuran but is still beinginvestigated. 128Exposure of polysaccharides to y-radiationleads to degradation. Dextran is more rapidly attacked if oxygen is presentbut the primary reaction under any conditions appears to be the formationof free radi~a1s.l~~Further separations have been made by using gel filtration throughSephadex, a cross-linked dextran. Fractionation is according to molecularsize and a number of dextrans of low molecular weight have been examinedin this way.130Reaction with iodine in calcium chloride solution has been suggested forprecipitating linear polysaccharides from mixtures containing also branchedmolecules.By this method ivory-nut mannan is shown to be composed oflinear molecules only. 131The Weerman reaction has been applied to oxidized polysaccharides 132and shown to confirm the structural information obtained by the Barrydegradation. 133The molecular weights, determined by the light-scattering method, ofthe polysaccharides made by heating lzvoglucosan in the presence of acidrange from 2600 to 310,000. About 55% of the glucosidic linkages involveC(s), 35% are at C(2) or C(4), and 10% at C(3) This is in reasonable agree-ment with the known reactivities of the different positions.134 Polymeri-zation of 1,6-anhydro-~-~-galactose also yields branched-chain polysaccha-rides but with a rather lower proportion (43%) of the glycosidic linkagesinvolving C(6).135 Branched molecules have also been obtained by heatingPolysaccharides.-General.D-glucose with phosphoric anhydride or sulphuric acid,136 and from a varietyof sugars, including disaccharides, by heating them in dimethyl sulphoxidecontaining acid. l 3 7A xylanase-free transglucosylase from Penicillium Zilcccinum has been usedto make a glucoxylan by transferring glucosyl units from maltose to esparto-grass xylan.138Cellulose.When a solution of a cellulose triacetate in nitromethane wassupercooled crystallization occurred slowly. The resulting crystals, whichwere visible under the microscope, were square and of lamellar structure,the chain molecules being normal to the planes of the lamellae. Deacetyla-tion was achieved without affecting the shape of the crystals or the orienta-tion of the resulting cellulose I1 molecules.139A comparative study of the methods available for obtaining the homo-logous series of oligosaccharides from cellulose has shown that best yieldsresult from direct acid hydrolysis.In addition to all members up to cello-hexaose a small amount of celloheptaose was obtained, together with indi-cations for the first time of the presence of the octaose and n0na0se.l~~Etherification of cellulose with ethylene oxide to give O-hydroxyethyl-celluloses leads to progressive modification of the structure of the fibres inthe manner typical of a topochemical r e a ~ t i 0 n .l ~ ~ Random substitution ofthe products occurs with toluene-p- sulphonyl chloride. 1 *2Treatment of acetylated triphenylmethyl ethers of cellulose with hydro-gen bromide in anhydrous acetic acid at 0" gives cellulose acetates having anunusually high proportion (87 %) of the free hydroxyl groups attached toc(6). By acetylating a partially hydrolysed cellulose acetate with aceticanhydride a t room temperature the product was almost completely substi-tuted a t c(6). A range of cellulose acetates differing only in the positionsof the substituents is now available.143Several classes of dye are known which react with cellulose during dye-ing.* These include derivatives of dichloro- and monochloro-l,3,5-tri-a ~ i n e , l ~ ~ , lP5 of vinyl sulphone and the hydrogen sulphates of 2-hydroxyethyls u l p h o n e ~ , ~ ~ ~ and of chlor~pyrimidines.~~~ In mild alkali only one of thechlorine atoms of the dichloro-l,3,5-triazine derivatives reacts, whereasunder more drastic conditions both react to give a cross-linked cellulose136T.Nakamura, J . Chem. SOC. Japan, Ind. Chem. Sect., 1960, 63, 1769.la? F. Micheel, A. Bockmann, and W. Meckstroth, Makromol. Chem., 1961, 48, 1;F. Micheel and R. Puchta, ibid., p. 17; F. Micheel and D. Mempel, ibid., p. 24; F.Micheel and H. Alfes, ibid., p. 33.lseS. A. Barker, M. Stacey, and D. B. E. Stroud, J., 1961, 3995.la9R. St. J. Manley, Nature, 1961, 189, 390.140 G. L. Miller, J. Dean, and R. Blum, Arch. Biochem. Biophys., 1960, 91, 21.Ia1M. Oberlin and J.Quinchon, MakromoE. Chem., 1960, 41, 218.142 J. Quinchon, Bull. SOC. chim. France, 1960, 2071, 2073.143 W. R. D. Leigh, J . , 1961, 754.144 Imperial Chemical Industries Limited, B.P. 772,030, 774,925, 781,930.lQ5 Ciba Ltd., B.P.775,308, 780,591 ; Imperial Chemical Industries Limited, Belgian146 Farbwerke Hoechst A.-G., B.P. 733,471; German P. 953,103.14? Imperial Chemical Industries Limited, French P. 1,182,006; Bayer A.-G.,P. 543,071.Belgian P. 572,973.*For a review of the chemistry of reactive dyes see H. Zollinger, Angew. Chem.,1961, 73, 125348 ORGANIC CHEMISTRYderivative.14* The presence of a covalent link between cellulose and dyehas been shown by isolating a coloured D-glucose derivative from the prod-ucts obtained by the microbiological degradation of the dyed cellulose.149Many cross-linking agents for cellulose have been examined in attemptsto obtain cotton fabrics with resistance to creasing.The compounds whichreact in this way include 1,3-dichloropropanol, 150 derivatives of divinylsulphone,151 tris-aziridin-l-ylphosphine 0Xide,152 and di-epoxides.153Cellulose acetate crotonates have been cross-linked by treatment withamines, and the reactions of unsaturated esters in the presence of peroxideshave been studied. 15* Supporting investigations on D-glucose derivativesare described.155Still milder methods are being sought for isolatingstarch and its fractions without degradation. One method 156 depends onleaching starch with hot water in the absence of oxygen and is good on asmall scale, giving an amylose which has a weight-average molecularweight >1 x 106.This amylose is hydrolysed to the extent of 95% by/I-amylase. Unfortunately this method is difficult to use on a larger scale.157Another small-scale method employs prolonged contact at room tempera-ture with dimethyl sulphoxide, to give a solution from which both amyloseand amylopectin are precipitated with butanol. The precipitate is thenredissolved by heating it briefly in oxygen-free water at 70" and the amyloseis precipitated with butanol. After one recrystallization the amylose hasa weight-average molecular weight of 1.9 x lo6 and is attacked to the extentof more than 95% by p-amylase. The yield is essentially quantitative andthe chemical modification is negligible.Evidence is presented for believing that in amylose the D-glucose ringsexist in chair (Cl) and boat (3B) conformations in equilibrium.In theamylose-iodine complex the chair form predominates but the units ofretrograded amylose are mainly in the boat form.158The or-amylolysis of potato starch gives maltotetraose 63-phosphate 159as Limit dextrin. This structure is elucidated by a method depending onover-oxidation with sodium periodate.160 Although most of the phosphateof starches is attached to amylopectin it is possible that small amountspresent as ester groups on amylose may account for the incomplete hydro-Starch and gZycogen.149 T. L. Dawson, A. S. Fern, and C. Preston, J . SOC. Dyers and Coburists, 1960, 76,149 0.Stamm, H. Zollinger, H. Zahner, and E. Giiumann, HeZv. Chim. Acta, 1961,160 Fothergill and Harvey Ltd., B.P. 696,282; Deering Milliken Research Corp.,161G. C. Tesoro, P. Linden, and S. R. Sello, Teztile Res. J., 1961, 31, 283.163 G. L. Drake and J. D. Guthrie, Textile Res. J . , 1959, 29, 155.16s C. W. Schroeder and F. E. Condo, Textile Res. J., 1957, 27, 134; R. Steele, ibid.,164W. M. Corbett and J. E. McKay, J . SOC. Dyers and Colourists, 1961, 77, 543;W. M. Corbett, J., 1961, 2926; W. M. Corbett and J. E. McKay, ibid., p. 2930.210.44, 1123.B.P. 855,547.1961, 31, 257.J. E. McKay and W. Taylor, ibid., p. 547.166 G. A. Gilbert, Sturke, 1958, 10, 95.157P. J. Killion and J. F. Foster, J. Polymer Sci., 1960, 46, 65.158 J.Holl6, J. Szejtli, and M. T6th, Sturke, 1961, 13, 222.lasThe nomenclature is that of W. J. Whelan, Ann. Rev. Biochem., 1960, 29, 105.laoF. W. Parrish and W. J. Whelan, Biochem. J.: 1961, '49, 19PHONEPMAN : CARBOHYDRATES 349lysis of some amyloses by p-amylases. Potato and wheat amyloses weretreated with phosphatase in conjunction with ,&amylase without any changein the amount of hydrolysis; the small amount of phosphate in the amylosesmay be attached to the reducing end or may be present as a diester which isnot attacked by phosphatase.161Starches from commercial maize and from high-amylose maize have afraction amounting to 4-9% which has molecules intermediate in shapebetween amylose and amylopectin. This material is less highly branchedthan amylopectin, is stained blue by iodine, and absorbs iodine to theextent of 60 mg.per g.lS2 The amyloses from high-amylose maize starcheshave molecular weights and iodine affinities similar to those of ordinaryamyloses, but the amylopectins have molecules with longer outer branches.163Theseare the cyclic molecules containing from six to twelve glucose ~ n i t s . 1 ~ ~Some of them readily form crystalline inclusion complexes with aliphaticacids.Examination166 of the absorption spectra of the iodine complexes ofa number of different amylopectins and glycogens shows that for amylopec-tins the maximum absorption is at about 540 mp whereas for glycogens it isa t about 460 mp. This and other data have revealed that Floridean starchfrom the fronds of Dilsea edulis is an amylopectin rather than a glycogen.le7The aggregated complex formed in alkaline solution from amylopectinand cetylpyridinium chloride is pictured as being a matrix of negativelycharged amylopectin molecules cross-linked by positively charged cetyl-pyridinium micelles.16*Four different methods based on oxidation with sodium periodate forthe end-group assay of glycogens have been critically examined. 169 Onlyone 170 of them is as reliable as the use of potassium periodate, but anotherwhich allows over-oxidation to proceed and then involves extrapolation tozero-time is also acceptable. 171 Glycogen, isolated from animal tissue bymethods which avoid the use of alkali, had a higher molecular weight(100 x lo6) than that isolated by alkaline extraction (1-8 x lO6).172All the products obtained from polysaccharides by periodate oxidationare rapidly degraded by alkali, but those from starches may be convertedinto alkali-resistant methyl acetals.173 No reaction has been found thatconfers similar alkali-resistance on the oxycelluloses.174Seven different Schardinger dextrins have now been isolated.161W. Banks and C. T. Greenwood, Chem. and Ind., 1961, 21, 714.162R. L. Whistler and W. M. Doane, Cereal Chem., 1961, 38, 251.lG3E. M. Montgomery, K. R. SBXSOP, and F. R. Senti, Starke, 1961, 13, 215.1'54A. 0. Pulley and D. French, Biochem. Biophys. Rea. Comm., 1961, 5, 11.l'35H. Schlenk and D. M. Sand, J . Amer. Chem. Soc., 1961, 83, 2312.166 A. R. Archibald, I.D. Fleming, A. M. Liddle, D. J. Manners, G. A. Mercer, and16'C. T. Greenwood and J. Thomson, J., 1961, 1534.lB8 M. M. Fishman and I. Freud, J . Colloid Sci., 1961, 16, 392.leeD. J. Manners and A. Wright, J., 1961, 2681.170D. J. Manners and (in part) A. R. Archibald, J., 1957, 2205.171A. S. Perlin, J . Amer. Chern. SOC., 1954, 76, 4101.172 M. R. Stetten and H. M. Katzen, J . Amer. Chem. SOC., 1961, 83, 2912.1731. J. Goldstein and F. Smith, Chem. and Ind., 1961, 1081.I74 J, Honeyman and J. R. Holker, Textil-Randachaz, 1961, 16, 561.A. Wright, J . , 1961, 1183350 ORGANIC CHEMISTRYPolysaccharides from bacteria, fuwi, and a2p. Further informationabout the amino-sugars present in bacterial cell-walls has been published.175The extracellular polysaccharides from several species of agrobacteriahave been shown to be composed mainly of p-D-glucopyranose units with1 +2-linkages.The polysaccharides are difficult to methylate completely,especially at C(3).176The highly branched mannan from baker’s yeast gives, on acid hydrolysis,a homologous series of 1+ 6-linked or-D-mannopyranose oligosaccharides.~77Acetolysis affords adztionally the l+2-linked di~accharide.17~The fresh-water green alga, Nitella translucens, contains 4% of astarch-like polysaccharide which has been found to consist of amylose(12%) and an amylopectin having an average chain-length of 19 glucoseunits. 179The cell-wall of Hydrodictyon africanum Yaman consists mainly of an‘‘ or-cellulose,” built up from equimolecular amounts of D-glucose andD-mannose, and a hemicellulose which is also a glucomannan.180The alkali-soluble polysaccharides of Chlorellct ppyrenoidosa include onewhich has similarities to starch, another which is a branched p-linked galac-torhamnan containing also arabinose, xylose, mannose, and glucose, and athird which contains mainly galactose,.glucose, and rhamnose but also 20y0of an unknown sugar.181The water-soluble polysaccharides from Caulerpa $Ziformis harvested inNovember have been hydrolysed to arabinose, xylose, galactose, and man-nose and are essentially similar to those of C . racemosa and C. sertuZurioides.ls2Laminarin from the brown algz is composed mainly of 1+3-linkedD-glucopyranose units but a few are 1+6-linked. The molecule also con-tains D-mannitol and probably has one branch-point. Chrysolaminarinfrom diatoms is of a similar molecular weight and has similarly linked glucoseunits (although a somewhat higher proportion are 1+6-linked) but containsno mannitol.183Measurements of pH have confirmed that alginic acids isolated from dif-€erent sources differ in structure.184Agarose, an agar polysaccharide from Gelidium Amansii, is composedof 1+3-linked units of agarobiose, 4-O-~-~-galactopyranosyl-3,6-anhydro-~-galactose.l8~ In the case of porphyran from Porphyra umbilicalis there isstrong evidence that the 3,6-anhydro-~-galactose units are formed in Naturefrom L-galactose 6-~ulphate,18~ which has also been obtained by hydrolysis1 7 5 5. M. Ghuysen, Ind. Chim. belge, 1960, 25, 1077; M. R. J. Salton, Biochim.Biophys. Acta, 1960, 45, 364; M. R. J. Salton and J. M. Ghuysen, ibid., p. 355.1 7 6 P. A. J. Gorin, J. F. T. Spencer, and D. W. S. Westlake, Canad. J . Chem., 1961,39, 1067.17’s. Peat, W. J. Whelan, and T. E. Edwards, J., 1961, 29.1 7 8 s . Peat, J. R. Turvey, and D. Doyle, J., 1961, 3918.l 7 O D . M. W. Anderson and N. J. King, J., 1961, 2914.l S o D. H. Northcote, K. J. Goulding, and R. W. Horne, Biochem. J., 1960, 77, 603.lE21. M. Mackie and E. Percival, J., 1961, 3010.ls3A. Beattie, E. L. Hirst, and E. Percival, Biochem. J., 1961, 79, 531.ls4A. Haug, Acta Chem. Scand., 1961, 15, 950.lE5 C. Araki and 5. Hiram, Bull. Chem. SOC. Japan,, 1960, 33, 597.186D. A. Rees, Biochem. J., 1961, 78, 25P.S. A. Olaitan and D. H. Northcote, Bwchem. J., 1961, 81, 7PH O N E Y M A N : CARBOHYDRATES 35 1of the p01ysaccharide.l~~ Porphyran1879 and the agar of CerumiumboydeniiTwo polysaccharides from carrageenin differ in that one contains galac-tose 6-sulphate whereas the other, probably formed from the first, incor-porates 3,6 - anhydrogalact ose . OA water-soluble polysaccharide of Enteromorphu compressa contains ahigher proportion of rhamnose with ester sulphate groups attached.lglInfrared spectroscopy suggests that the sulphate groups are axial 192 andtherefore attached to C(2) of rhamnose.lglIsolichenin, a food reserve polysaccharide of Iceland moss, Cetrariccislandica, is shown by partial acid hydrolysis to be made up of equal amountjsof a-D-gIUCOpyI’anOSe units linked 1+3 and 1+4, probably without anybranching.193 It is, however, different from nigeran which has an alternat-ing sequence of 1 +3- and 1 +4-a-~-glucopyranose units. Lichenin fromthe same moss contains @-D-glucopyranose units of which 70% are 1+4-and 30% 1 +-3-linked. Degradations of lichenin with laminarinase prep-arations show that this enzyme attacks either a 1+3- or a 1-+4-linkage of,8-D-glucopyranose which is attached throughHemiceZZuZoses.-The use of esterification with phenyl isocyanate forblocking free hydroxyl groups in carbohydrate acetates has been developedand applied to a glucuronoxylan from birch. About 24% of the xylose unitsare acetylated at 12% at C(2), and 6% at both. Migration of thephenylcarbamate group can occur, however.lg5Essentially linear glucomannans have been obtained from the wood ofEastern white pine (Pinus strobus, L.) lg6 and of Ginkgo biloba, L.197In an arabinogalactan of the Western larch some of the galactopyranoseunits are hydrolysed at about the same rate as the arabinofuranose ones;there is no evidence for the presence of galactofuranose ~nits.1~8 Anarabogalactan from maple-tree sap has been shown by gas-liquid chromat-ography to contain about 5% of rhamnose.199Acid-hydrolysis of the hemicelldoses of the wood of Landes maritimepine gives a number of uronic acids related to mono-, di-, and tri-saccharides,including a novel one, 2 -0- (4-O-methyl-a-~ -glucuronopyranosyl) -~-lyxo-pyranose . 200A low-molecular-weight xylan from tamarack has a main chain of about16 D-xylopyranose units linked 1+3, with possibly one 1+4, 3 single unitcontain 6 - 0- methyl- D - galactose.to another such unit.branches of 4-O-methyl-~-glucuronic acid linked 1+2, and a branch of anL-arabinofuranose unit.201The weight-average molecular weights of a number of 4-O-methyl-glucuronoxylans of woods correspond with degrees of polymerizations of450-500 units.202 The structures of a number of such xylans have beendiscussed.203Many galactomannans have been isolated from legume seeds and now agalactan, containing minor amounts (8%) of mannose and arabinose, hasbeen obtained from Centrosemu plumuri. The links are mainly 1-+4 butabout 15% are 1+3.204The gum exuded by Fqara xanthoxyloides gives, on gradedhydrolysis, a 4-O-(4-0-methy~-a-~-g~ucuronosyl)-D-ga~ac~ose 205 which hasalso been obtained from the gum of myrrh. Gum asafoetida has a highlybranched molecule with a backbone of (mainly) 1+3-linked @-D-galacto-pyranose units with side chains of residues of L-arabinofuranose, D-galacto-pyranose, D-glUCUrOniC acid, and 4-O-methyl-~-glucuonic acid.206 Thegums of Khaya senegalensis include one with a main chain consisting largelyof 1+4-linked D-galacturonic acid and of 1 +2-linked L-rhamnopyranoseunits.207 The gum from Albixxia xygia (Macbride) is unique in containingboth D-glUCUrOniC acid and its 4-O-methyl ether.208MisceEluneous. D-Glucuronic acid is the uronic acid present in heparin.209D-Glucosamine is the only sugar in chitin.210Simultaneous dialysis and partial acid hydrolysis of mucopolysaccharidesproceed without appreciable N-deacetylation and give additional oligosac-charides. Much new structural information is being obtained by use ofthis technique.211Plunt gums.