ISSN:0306-0012    

DOI:10.1039/CS97201FX005

出版商:RSC    

年代:1972

数据来源: RSC

ISSN:0306-0012    

DOI:10.1039/CS97201BX007

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

The Chemistry of Dyeing By I. D. Rattee DEPARTMENT OF COLOUR CHEMISTRY, THE UNIVERSITY, LEEDS, LS2 9JT 1 Introduction Fermentation, cooking, and dyeing are probably the most venerable of man’s ventures into applied chemistry. All three may well have originated at the same point in man’s activities, the cooking pot. Each involves processes of consider-able complexity and, in the modern context, provides the basis for academic and industrial research frequently crossing classical interdisciplinary boundaries. In each case, also, the development of scientific attitudes has involved clearing away centuries of entrenched empiricism, although it. must be agreed that previous experience has often provided the clues for scientific explanation of particular phenomena.In modem terms dyeing involves the synthesis of complex, coloured organic compounds with solubility in appropriate solvents (almost universally water), which are capable of becoming adsorbed on to molecular ‘surfaces’ of appro- priate substrates in a controllable manner, and of diffusing within those sub- strates. Thus the chemistry of dyeing covers aspects of the organic chemistry of aromatic compounds, the nature of solutions of complex molecules, polymer chemistry, adsorption and related interfacial phenomena, diffusion, and polymer physics. Since the interaction of complex aromatic molecules with substrates extends beyond the obvious topic of textile colouration into histology and bio- chemistry, the chemistry of dyeing provides a meeting point for investigators with apparently disparate interests.This is further emphasized by the fact that in textile dyeing the concern of the chemist does not end with the colouration process, since the consumer demands that the dyed material be fast to wet treat- ments, e.g. washing, and to light. Thus photochemical degradation of dyes is a relevant topic in dyestuff and dye application research. The year 1856 saw the chance discovery of mauveine by W. H. Perkin and the beginning of the synthetic dyestuff industry, for many years the major part of the organic chemicals industry in Britain and Germany. Its inevitable con- cern with the many aspects of dyes and dyeing created within the industry a favourable environment, particularly in Britain, for the development of other branches of industrial chemistry, e.g.pharmaceuticals. Important contribu- tions were also made to the industrial chemistry of fibrous polymers and surfactant compounds. It is clear that a comprehensive review of activities in the sphere of the chemistry of dyeing could run to considerable length, or discuss matters so briefly as to provide little useful information. Therefore, for the purposes of the present treatment, attention will be confined as closely as The Chemistry of Dyeing possible to the chemistry of the dyeing process itself, and other aspects will be left for other occasions. 2 Natural Colouring Matters Until the second half of the last century dyers universally used materials ex- tracted from roots, leaves, insects, etc.for the colouration of materials. These were not always obtained in their directly usable coloured form: frequently the colouring matters had to be released from their glucosides by fermentation. One of the oldest dyes, indigo, is obtained from the woad plant Isatis tinctoria as its glucoside indican, which interacts with plant yeasts in water to give the water- soluble leuco indigo. Air oxidation then yields the blue indigo pigment. Two other ancient natural dyes, (1) and (2), have the structures shown. Of these two, Kermesic acid (2) is possibly the oldest dye so far identified, being known in the time of Moses. 1-10 OH Curcumin (the colotrriizg mutter from turmeric root) Kermesic acid (the coloiirilzg matter from the i!isec[ Quercus coccifera) Dyers showed great initiative in devising means of obtaining and applying colouring matters to textiles, and over the centuries experience was accumulated and passed on through traditional means such as guilds.In addition, manuals came to be written which often contain early publications of general interest in applied chemistry. For example, the PZictho of Gioanventura Rosetti, published Rattee in 1548, contains the first known reference to a method for manufacturing hydrochloric acid. Despite the limitations of natural colouring matters dyers produced a wide range of shades. The Plictho contains some hundred recipes for colouring different textiles. Another important contribution to early chemistry was the technique of mordanting which anticipated organometallic- complex chemistry. The discovery arose from the fact that the dyes which gave a desired colour often exhibited no affinity for the material to be dyed.It was found that pretreatment of the material with either a tannin or a solution of certain mineral salts, e.g. alum or iron salts, conferred upon it affinity (‘teeth’) for the dye. The use of different mordanting compounds gave different shades with the same dye and led to a further extension of the available shade choice. In practice, the exact shade produced using natural dyes depended on the contribution of traces of secondary colouring matters, as well as other factors. The composition of the coloured extract of a plant depends upon climatic, seasonal, and regional factors, as might be expected.In addition, the ease with which mordants may be used is accompanied by an inevitable sensitivity of the shade towards trace metals present in the water used for dyeing. This is also a factor subject to regional and seasonal variations. As a consequence the shades produced by ancient dyers were highly individual, and the emergence of dyeing as a ‘mystery’ is not surprising. The methods used by early dyers were not capable of producing results of the highest quality, and while this might often be a disadvantage astute business men were able to turn it to advantage, as in the case of Persian carpets. Here much of the unique character of the carpets depends upon the lack of penetration of the wool fibres by natural colouring matters, which gives a special interest to the appearance of the pile.This effect is extremely difficult, if not impossible, to achieve with synthetic dyes available. 3 The Appearance of Synthetic Dyes Affairs remained virtually unchanged over centuries until synthetic dyes were produced in quantity during the second half of the last century. Thus were provided standardized products covering a wider range of shades than was accessible previously, and generally at a lower price. The major natural dyes of high quality, indigo and madder (alizarin) were rapidly replaced by their syn- thetic equivalents. The discoveries of Griess in diazo chemistry in 1861 were soon put to good use to develop the azo colouring matters virtually unknown in nature and generally superior to natural dyes in almost every way.The early discovery of sulphonation opened the way to producing dyes of any desired solubility. The first developments occurred at a time when structural organic chemistry was in its infancy, and bulk manufacture of organic chemicals like aniline, or simple substances like sodium nitrite, had to be specially developed. The rapid development of structural organic chemistry, stimulated at least in part by interest in dye chemistry, provided the basis for a systematic explanation of some of the factors determining dyeing behaviour, and the observation of correlations between chemical structure and properties.The first manifestation of this new approach was the work of Bottiger, who achieved the objective of The Chemistry of Dyeing producing sulphonated azo dyes applicable to cellulose fibres directly, without a mordant. This was not possible prior to Bottiger’s work in the 1880’s, although the direct application of dyes to wool and silk were well known. Bottiger showed that linear bis- and tris-azo dyes bearing sulphonic acid groups were suitable for direct cotton dyeing in the presence of salt, and the first ‘direct dye’, Congo Red (3), was marketed in 1888. Congo Red (Bottiger, 1884) (3) Further systematic studies were encouraged by this progress and led to the classification of dyes according to their behaviour as acid dyes (sulphonated dye anions), basic dyes (dye cations), direct dyes (selected acid dyes for cotton dye- ing), acid milling dyes (selected acid dyes giving high fastness on wool), etc.It was from this time that the chemistry of the dyeing process began to be regarded as a matter for investigation, albeit in a crude way. Further investigations were directed towards finding improved dyes giving fastness to light and washing, and also improved ease of application. As a consequence of these efforts further dye classes came to be developed, and also an understanding of the processes involved in their adsorption and retention by the fibre. 4 The Search for Washing Fastness The need to produce dyeings which resisted washing processes and did not fade in sunlight has always been accepted.The dyers of France were organized from the early sixteenth century into two guilds: the teinturier du gratzd teint and the teinturier du petit teint, the former producing relatively fast dyeings. From the early eighteenth century onwards the post of Inspector General of the Dyeing Industry was held by a succession of eminent French chemists, whose respon- sibility it was to devise and improve chemical methods of distinguishing between fast and fugitive dyes. In the progress of their work the concepts of the afhity of dyes for fibres and their diffusion into fibres came to be developed in a rudi- mentary way. In addition, concepts of physical entrapment came to be developed to explain the fastness of some dyes. Progress was naturally limited because these efforts predated chemistry in the modern sense.Nevertheless, the necessary approaches towards the achievement of fast dyeing were tentatively indicated by the eighteenth century, although little could be done until synthetic dyes be- came available and the beginning of systematic structural organic chemistry. Ruttee The lack of fastness in dyeing arises from the essential reversibility of the dyeing process. In short, the washing process is a desorption procedure which reverses the adsorption process of the dyeing. The production of a fast dyeing thus becomes a problem of making the dyeing process either fully irrevers- ible or at least not reversible during washing procedures. This objective is achieved to some extent during the application of dyes on to mordanted materials.On wool a chrome mordant provides a basis for dyeings of very high fastness. The shades produced by mordanting are in all cases dull, however, owing to the electronic interaction of the metal atom with the main chromogenic system. An alternative approach is based on the fact that it is possible to dye wool at 100 "Cwhile washing is normally carried out at 40 "C. The rate of diffusion of dyes is much greater at the higher temperature so that high molecular weight dyes may be adsorbed rapidly in dyeing but desorbed slowly in washing. Neither of these lines of attack was fruitful in cotton dyeing, partly because the chemical differences between proteins and cellulose make fast mordanting impossible in the latter case, and partly because cotton goods are washed very much more severely than wool goods.The most successful approach was based on the dyeing behaviour of indigo, which is applied as a substantive leuco dye from solution and then oxidized to the pigment form within the fibre. Mechanical entrapment provides the fastness in this case. RenC Bohn discovered in 1902 that anthraquinonoid compounds could be prepared which were not only better dyes than indigo but also more stable, thus giving rise to the modern vat dyes which remain the fastest class of dyes for cellulose. The approach taken in developing fast-to-washing acid dyes was applied to dyes for the man-made fibres, although in this case very high temperature dyeing methods had to be developed.The most recent approach has been with the fibre-reactive dyes which achieve a non-reversible dyeing process by chemical reaction with the fibre. The concept of chemically reacting dyes and substrates originated in the same period as Bohn's discoveries, but its translation into practice took many years. The production of fast-to-washing dyes produced many problems in dye application. Consequently, some thirty years ago serious attempts began to be made to explain the dyeing process in physico-chemical terms. The objective was partly to obtain a clearer idea of what kinds of dye would be fast, and partly to provide a means of developing better dyeing methods. The effort made took place almost entirely in industrial laboratories and was directed very largely by industrial attitudes.Although great progress was made and indeed a new academic subject established, the theoretical developments reflect their 0rigins.l In the recent period, a unifying approach to the somewhat diverse body of information has become possible, and it is on this basis, rather than chrono- logical development, that the topic will be considered here. T.Vickerstaff, 'The Physical Chemistry of Dyeing', Oliver and Boyd, London, 2nd edn., 1954. 149 The Chemistry of Dyeirig 5 Binding Forces in Dyeing The process of dyeing involves adsorption of dye molecules by a substrate, normally a textile polymer, from an external phase which initially contains all the dye.An equilibrium is eventually established whereby a new external phase concentration and a dyed material result. This differs from imbibition of the initial dye solution by the material by virtue of the concentration changes. The loss of dye by the external solution is normally termed exhaustion and this reflects the affinityor substantivity of the dye for the substrate. The existence of the affinity factor was clear to Berthollet and is described in his work ‘Element de I’art de la teinture’ of 1791. However, chemical knowledge of that time, or indeed for many years after, was not able to deal usefully with such concepts. Today such effects are considered in energetic terms and the concentration changes are seen as gains in free energy.The desorption of the dye from the substrate in these terms requires the input of energy, so that the free energy change measures the constraint upon desorption or the binding force between the dye and the sub- strate. The binding forces between interacting molecular systems are now extensively studied in a much wider area of interest than colouration, and current ideas are reviewed in detail elsewhere.2 Nevertheless, for the present purpose some brief description is valuable. It should be stated at the outset that the dyeing process, reflecting as it does a competition between substrate and external phases, may be considered in terms of negative as well as positive effects in the dye-substrate interaction, Five general kinds of binding forces are believed to influence dye adsorption.The simplest forces which require consideration are the coulombic interactions between ionic charge centres in dye ions and in substrates. Clearly they may be attractive or repulsive according to circumstances. Their mode of action is simply electrostatic, and consequently they should not be affected by environmental factors of a non-ionic character. Coulombic interactions have been very ex- tensively studied in relation to the adsorption of dye ions and their role will be considered at a later stage. Both dyes and substrates are frequently of a significantly polar character, quite apart from their propensities for ionization. Dipolar effects are present, and direct or induced dipolar interactions are to be expected.These will be subject to slightly different influences compared with ionic (coulombic) inter- actions and can be more generally effective. By reason of their necessary structural features dye molecules have low-lying electronically-excited states which interact with visible light, and also may participate readily in adsorption interactions through dispersion forces. These forces, according to classical theory, fall off very rapidly with distance and it would be expected that with large molecules interacting thermal effects would readily lead to bond rupture. However, McLachlan has shown recently that in the ‘three body’ situation, e.g. dye-solvent-substrate susceptibility factors en- ‘H. C. Longuet-Higgins, Discuss. Faruduy SOC.No.40 ‘Intermolecular Forces’, 1965, 7. Rartee able the perturbational effects giving rise to dispersion forces to be transmitted through the ~olvent.~ An important and common induced binding force is the hydrogen bond. Care must be taken in proposing hydrogen-bond mechanisms in dye binding owing to the often forgotten presence of water, which can act as a competing species for binding positions in the dye or the substrate. On purely energetic grounds hydrogen-bond-dye binding is improbable in aqueous systems unless special statistical factors are operating. The last form of binding force which needs to be considered is the so-called hydrophobic interaction, which arises from the disturbance caused by non-polar solutes or residues of the water structure.Such solutes or residues promote water structuring in their vicinity, and there is a consequent entropic driving force for association to limit the ordering effect on the water.4 All of the above kinds of binding force can be expected in the consideration of dye binding, but this is no less true in relation to the properties of the poly- meric substrates with which the dye is to interact. The physical structure of the polymer into which it is proposed the dye will enter and become adsorbed, depends upon the cohesive forces between polymer molecules. Cellulose is insoluble, for example, entirely because of the cohesive effect of multiple hydrogen bonding. When cellulose is immersed in water, the water can compete for some of the hydrogen bonding centres, leading to some swelling of the cellulose, but solution cannot be achieved without special methods.Polyamide fibres such as Nylon 66, acrylic fibres such as Orlon, and polyester fibres are all dependent entirely upon internal cohesive forces for their solution and melting properties. Special chemically cross-linked polyamides and wool keratin supple- ment regular cohesive forces with covalent bonding between polymer chains, providing additional stabilization. The centres for the action of cohesive forces in polymers are not essentially different from those involved in dye binding. Thus wool keratin exhibits coulombic cross-links between -NH,+ and -COO-groups as well as the general forces discussed. In acrylic fibres the presence of -SO,-, in some cases --COO-, and other ionic groups, has an anti-cohesive effect offset by general forces.As a consequence, in these and in all other cases it must be expected that dye binding by the substrate is not a simple case of adsorption on to an active surface. The above considerations are well exemplified by the behaviour of small molecules such as phenols. Phenolic compounds are readily taken up by proteins and polyamides from aqueous solution. Where phenol itself is used, it possesses sufficientIy high aqueous solubility and affinity for considerable amounts to become adsorbed. Binding is thought to be due to a combination of induced dipole effects and hydrophobic interaction, together with dispersion forces.In the case of polyamides, the extent to which phenol molecules can compete with the internal cohesive forces in the polymer is sufficient to lead to disruption A. D. McLachlan, Discuss. Furuduy Soc. No. 40 ‘Intermolecular Forces’, 1965, 239.‘A. K. Covington and P. Jones, ‘Hydrogen Bonded Solvent Systems’, Taylor and Francis, London, 1968. TIe Chemistry of Dyeing of the polymer structure, swelling of the fibres, and eventually dissolution. The affinity of the adsorbate can be increased by substituting the phenol with alkyl groups. However, these reduce the aqueous solubility because of their water structuring influence and limit the external concentration. The swelling per mole adsorbed remains the same but the adsorption is reduced.Jf 0-phenyl phenol is used, the limitation upon uptake imposed by low aqueous solubility is consider-able, and all that occurs is some swelling and a lowering of the glass transition temperature. These observations are quite general so that the physical structure of all textile polymers is readily modified by appropriate simple compounds with adequate solubility. Thus cellulose acetate is swollen by phenols or aniline, cotton cellulose by morpholine, acrylic fibres by furfural, nylon by phenols, pyridine, or aromatic amines, polyester fibres by aryl phenols, etc. None of the above adsorbates are dyes of course, and in order for compounds to be made which absorb visible electronic energy, their population of delocalized electrons must be greatly increased by extending the resonance system.Dyes have inevitably larger molecular size and weight, compared with the compounds already discussed, but no other new principle is involved. For example, aniline and the dye p-phenylazoaniline behave in the same way with only quantitative difierences. The subject of dye binding requires a consideration of the participa- tion of both the dye and the substrate in the interaction. In the same way as cohesive forces operate in polymers, dye molecules designed to show ready adsorption on to polymers frequently exhibit dye-dye interactions, either in the external solution phase or on the adsorbing surface itself. Such interactions may favour or disfavour adsorption according to circumstances. In addition, the dye-substrate interaction involving large and frequently flexible molecules can lead to configurational changes in either or both components.These may favour or disfavour further adsorption. They may also lead to metastable molecular configurations of a different colour from that expected. Every instance of dye-substrate interactions involves a complex balance of these several effects. The outcome of the resolution has sometimes apparently unrelated consequences. Some particular examples provide a basis for a consideration of how the various factors may operate. A useful example of the interplay of effects is provided by the dyeing of polyester fibre with disperse dyes.6 This substrate cannot be dyed from aqueous solvents with dye ions, owing to coulombic repulsion effects and the hydro- phobic nature of the polymer.On the other hand, it cannot be dyed with in- soluble non-polar materials owing to the need for a molecular dispersion in order to permit diffusion through the polymer matrix. Consequently, disperse dyes which are weakly polar and sparingly soluble in water are used. If the dyes are too polar they are fairly water soluble but have low affinity. Dyeing is most readily carried out using fairly low molecular weight dyes of low solubility and which diffuse rapidly within the fibre. However, such dyes possess a signi-T. Vickerstaff, ref. 1, p. 484; I. M. S. Walls, J. Textile Inst., 1954, 45, 258; E. Merian, J. Carbonell, U. Lerch, and V. Sanahuja, J. SOC.Dyers and Colourists, 1963, 79, 505; J.Thompson, Ph.D. Thesis, University of Leeds, 1970. ficant vapour pressure due to their relative lack of cohesive energy in the solid state; when the polymer is heat-treated some dye volatilizes. The vapour pressure may be reduced either by making the dye more polar or by increasing the cohesive energy in the solid state through an increase in molecular size. The first solution leads to a lower affinity for the fibre while the second leads to slower diffusion. Since the problems arising from the second solution are the more readily overcome, this is the one adopted by dyestuff chemists. To solve the diffusion problem a quantity of a second compound with affinity but which is not coloured, e.g. a phenol, may be added to the dyebath.When this is adsorbed it disrupts the cohesive forces in the polymer and leads to swelling and conse- quently a more ready diffusion of the dye, Alternatively, the polymer may be rendered more permeable by heat alone. As a consequence, dyeing at tem- peratures above 100°C under pressure has bxome commonplace. It is found that disperse dyes are displaced by water even from hydrophobic fibres. Thus the maximurn adsorption observed when the system is saturated with water may be as little as one third of the value observed when the dye is taken up from the dry vapo~r.~ Whether the competition is isosteric, i.e. com-petition of water and dye molecules for the same adsorption sites, or allosteric, i.e. water adsorption leading to configurational changes in the polymer un- favourable to dye adsorption, is not known.The effect of water is so marked as to suggest that the latter explanation may prove the correct one. However, the competitive effect explains why uptake of disperse dyes by relatively hydrophilic substrates such as wool keratin or cotton cellulose is small. In order to achieve a satisfactory level of uptake it is necessary in these cases to use larger molecules of higher intrinsic affinity, and at the same time make them soluble enough by the introduction of polar groups such as -S02NHa or SO,-. This introduces the factor of coulombic forces in the latter case. In wool keratin both carboxy and ammonium groups are present, so that in the presence of increasing amounts of acid the fibre develops an increasingly positive potential, owing to the back-titration of the carboxy-groups.The uptake of dye anions does not lead to any unfavourable coulombic effects until the adsorbed ion concentration exceeds the concentration of ammonium groups. Since this is a very large value, greatly exceeding any practical requirement, no real limitation is experienced. However, with polyamide fibres, e.g. Nylon 66, the concentration of fixed positive and negative charges is quite small, and unfavourable coulombic effects manifest themselves at depths of shade of practical interest.6 With very small ions such as chloride, or even small dye ions, the coulombic repulsion effect is sufficient to produce a ‘saturation’ effect when the adsorbed ion concentration is equal to the fixed charge concentration of opposite sign.However, when dye ions of higher affinity are used the saturation value may exceed the fixed charge value. With very high affinity ions it is difficult to detect any significant electrostatic saturation level. This coulombic effect is an example of dye-dye interaction on the adsorbing surface. At the point of T. Vickerstaff, ref. 1, p. 439; H. Brody, Textile Res. J., 1965,35, 844. The Chemistry of’Dyeing electrostatic saturation the fibre surface has zero charge, and any further adsorp- tion will lead, in the case of dye anions, to a negative potential and consequently an increasing potential energy in the surface. On the other hand, adsorption occurs because free energy is gained.The two effects are in opposition and adsorption stops when the two are equal. This will only happen when the potential energy exceeds zero in the case where the free energy gain is very small. The situation of electrostatic saturation observed with polyamides is found ab initio when cellulose is dyed with anions. Cellulose contains few fixed positive charges with the consequence that the adsorption of ions leads immediately to coulombic repulsion effects. This effect can be offset by increasing the ionic strength of the external solution to lower the surface potential, but for simple anionic dyes the effect is not great enough for practical interest. Dyes of high affinity must be built up by extending conjugation so as to provide a balancing free energy gain.This is precisely what was done by Bottiger in developing the direct cotton dyes. However, one undesirable consequence is that the extended conjugation systems which are necessary contain many interacting centres for the absorption of electronic energy, leading to dull shades. This problem is overcome and the level of fastness raised to a quite new level with fibre reactive dyes.’ The dyes in this case are generally of lower affinity than direct cotton dyes and hence of brighter shade. The exhaustion equilibrium is, however, con- tinually displaced by virtue of the chemical reaction between the dye and the fibre. This results in a satisfactory level of dyebath exhaustion despite the lower affinity, and provides very high fastness to washing since affinity factors are no longer determinate in this respect.Coulombic effects may be generally regarded as disfavouring dye adsorption more than favouring it. Other interaction effects between adsorbed dyes may, however, assist adsorption. An extensively studied example of this is provided by Acridine Orange adsorbed by soluble protein molecules. In solution Acridine Orange tends to form dimers, and the electronic interaction of the two chromo- gens causes a marked colour change. In very dilute solution moll-I) the dye exists in the monomer form, but if a small amount of a soluble protein is added to such a solution there is an immediate colour change consistent with dimeriza- tion.In fact what has occurred is the adsorption of the Acridine Orange on to the protein with a simultaneous interaction between the adsorbed dye molecules. This phenomenon is termed stacking of the adsorbed dye.s The free energy gain of dimerization of Acridine Orange is considerable (-5.7 kcal mol-l) and the stacking effect adds a free energy gain comparable to that of the actual dye- substrate interaction. The formation of stacks appears to be very dependent upon steric factors and it is likely that the dye-dye interactions can produce new configurational forms of flexible proteins. Thus rigid proteins give rise to low ’W. F. Beech, ‘Fibre Reactive Dyes’, Logos Press, London, 1970; I. D. Rattee, J. SOC.Dyers and Colourists, 1969, 85, 23.D. F. Bradley and M. K. Wolf, Proc. Nut. Acud. Scf. U.S.A., 1959, 45, 944; R. F. Beers, J. Bucteriol., 1964, 88, 1249; R. F. Beers and G. Armilei, Nafure, 1965, 208, 466 Rurtee probabilities of stacking, whereas with flexible systems the probability is high. If the probability is defined as probability of dye existing in stacks K= probability of dye adsorbed as monomer then the correlations shown (Table) are obtained. Table Protein General description of configuration K DNA Rigid two-stranded configuration 1.96 Polyadenylic acid pH > 7, single-stranded flexible coil N 100 pH < 5, rigid two-stranded helix -5 Heparin Flexible single-stranded coil 600 The steric factor is not likely to be the only one determining the stacking prob- ability, but it is undoubtedly of considerable importance.Stacking or adsorption in aggregates is by no means uncommon, although on insoluble substrates it has been little studied. Since a protein in solution will normally adopt a configuration of lowest energy, interaction with a dye molecule can produce new configurations which may be more or less stable to hydrolytic attack. Glazer has shown that 01-chymotrypsin is rendered unstable by the dye Evan’s Blue.Qa This dye was able to produce some 70% autolysis in 3 h at ambient temperatures. Just how steric- ally dependent the effect is can be seen from the fact that the isomeric dye Trypan Blue produces very little autolysis under otherwise identical conditions. The two dye structures are shown [(4) and (5)]. Evan’s Blue brings about no autolysis with other proteins.Glazer believes that the dye-protein interaction stabilises least folded conforms of the protein in such a manner as to increase the probability of hydrolysis. The opposite effect, i.e. stabilization, has also been observed. Bound methyl orange ions have been observed to stabilize serum albument.Ob Another interesting example of a conformational effect is provided by the work of Merian et aZ.l0who applied an azo dye in the trans-configuration to polyester fibres. Irradiation with U.V. light converted the dye into the cis-configu- ration with shrinkage of the polymer fibres. The effect was reversible and did not occur in the absence of dye.The effect serves to demonstrate the closeness of the conformation of the adsorbate and adsorbant in this case. 6 Adsorption Isotherms and the Application of Thermodynamics to Dye Binding Thus far, discussion has been concerned with the molecular mechanisms involved in dye-binding interactions. Much of our theorising in this regard is based on the study of the energetics of adsorption and the pursuit of clues provided by (a) A. N. Glazer, Proc. Nat. Acad. Sci. U.S.A., 1969, 64, 235; (b) G. Markus, ibid., 1965, 54, 253. lo H. Husy, E. Merian, and G. Schetty, Textile Res. J., 1966, 36, 615; 1969,39, 94. 155 TCre Chemistry of Dyeiig NH, OH Oti NH,-03swN=N=Me N=Nws03-SO, -)I e so, -Evan’s Blue (C.T. Direct Blue 53) (3) Trypan Blue (C.I.Direct Blue 14) (5) general thermodynamic considerations. The general description of adsorption phenomena, i.e. the generalization of experimental data, takes the form of isotherms, isobars, and isosteres. These are derived from the postulate for the adsorption of an ideal gas on to a homogeneous adsorbing surface when no interaction occurs between adsorbed molecules : where r represents the surface concentration, p the external pressure, T the temperature, Q the activation energy of the adsorption interaction, R the gas constaiit, and k a constant relating to the gas itself. By creating conditions in which T,p, and rrespectively are kept constant, isotherms, isobars, and isosteres relating to the adsorption can be derived. The isotherm expressed in equation 1 is a simple proportionality between randp; it is known as thepartition isotherm.It is not necessarily the case that the manifestation of a partition isotherm demonstrates the ideality of the adsorbate or the homogeneity of the adsorbing surface. It can be shown that this kind of isotherm is observed in ideal mixing situations, i.e. where the interactions between non-adsorbed molecules away from the surface are comparable with that between the adsorbed molecules and the surface. This can be shown as follows: the adsorption interaction may be represented as the transformation of two interacting pairs of dissimilar molecules Ruttee into two similar pairs. Designating the adsorbate as 1 and the adsorbant mole- cules as 2 this gives 1-1 1-2-2-2 1-2 The change in potential energy (dUo)will be, as a consequence, 2n12 -<n,,+ n22) = duo (2) For ideal mixing to occur d Uomust be zero so that and it is not necessary to postulate ideality (i.e.n,,= 0) for the non-adsorbed molecules.Partition isotherms are exhibited by disperse dyes on all textile substrates. The measurement of isosteric heats of adsorption at different values of r has shown that the adsorbing surfaces act homogeneously.ll The values of the isosteric heats compare closely with the heat of solution of the dyes when dyeing is carried out in the presence of water, or with the heat of sublimation for dye- ings from the vapour phase. There is some evidence, however, which suggests that these effects may be fortuitous.It is clear that if an adsorbed molecule occupies some particular binding site on a surface, then an unadsorbed molecule arriving at that site cannot be adsorbed. In other words, a probability factor needs to be considered when there is a limited number of adsorption sites. This is the problem considered by Langmuir in producing his classical isotherm equation in which rand p have their earlier significance, Sis the concentration of adsorp- tion sites, and K is the equilibrium constant for the interaction. When S 9 r, equation 4 revers to a partition isotherm equation. This condition can arise when S is so large that convenient experimental concentrations keep r < S, or when the saturated vapour pressure or solubility of the adsorbate is very low, imposing an upper limit on r consistent with a given value of K.Thus the partition isotherm shown with disperse dyes on substrates may be more due to the solubility characteristics of the dye than any property of the adsorbing surface.This example serves to show the shortcoming of isothermal or isosteric generalizations in explaining molecular mechanisms. It is rare that they provide just a single explanation for any phenomenon. The adsorption of dye ions on surfaces (inevitably charged) tends to follow the Langmuir isotherm equation except where stacking may occur or extensive l1 F. Jones and R. Seddon, Textile Res. J., 1964, 34, 373; 1965, 35, 334. me Chemistry of Dyeing configurational changes, such as fibre swelling, take place.Again the obedience of the equation by the adsorption equilibrium does not mean that the adsorbing fibre bears a relatively limited number of sites, although this is not precluded. The surface potential energy effect previously discussed in relation to the adsorp- tion of ions can equally well provide an explanation, with each adsorbed dye molecule treated as an ‘anti-site’ repelling approaching molecules. This approach has been shown to apply in dye-ion adsorption by celldosela and to be theoretic- ally quite gene~a1.l~ Nevertheless, much useful information is provided by isothermal or isosteric generalizations from the point of view of demonstrating likely molecular factors. These arise from consideration of the energy factors in dye adsorption and the application of thermodynamic concepts. Assuming a stable polymeric substrate and a stable dye, then at equilibrium the chemical potentials of the dye in the solution and fibre phases, ps and pp respectively, must be equal.Since pus= pos+ RTln As and p~= pof + RTln Af (5) in which pos,frepresent standard state chemical potentials and &AP are activities in the solution and fibre phases respectively, then the standard affnity, Ap0 (or pop -pas) is given by Avo= RTln Af/As (6) In dilute solution, neglecting aggregation effects, As may be equated with the dye concentration. The value of APis more difficult to define and much discussion h~sraged among dyeing theoreticians on this point.This renders absolute affinity values doubtful, although they nevertheless are useful numerical general- izations of isothermal data. However, useful information can be drawn from the isosteric data, If for a given dye experimental conditions ensure that at different temperatures the concentration of bound dye is a constant, then since Af = f(Of) where (Of) is the bound dye concentration in appropriate units, APwill be constant if f(Df) is temperature independent. This enables the activation energy of adsorption to be calculated from equation 6 and the classical relationship between affinity, enthalpy, and entropy. Thus -AHO 1InAs= -.-As + In f(Df) (7)R Tf% Several assumptions have to be made if equation 7 is to be used to calculate the isosteric heat of adsorption. Firstly, it must be assumed that the temperature change affects only the state of the dye adsorption equilibrium directly so that no other changes, e.g. transitions, in the polymer due to temperature, indirectly l1 S.R. Sivarajan, G. Srinivasan,G. T. Baddi, and M. R. Ravidrishnan, Textile Res. J., 1964, 34, 807; S. R. Sivaraja Iyer and N. T. Baddi, ‘Contributions to the Chemistry of SyntheticDyes and the Mechanism of Dyeing’, Symposium Proceeding, 36, Centre of Advanced Study, U.D.C.T., University of Bombay, 1968. la M. A. V. Devanathan, Proc. Roy. SOC.,1962, 267,256. Rattee cause a change in the equilibrium adsorption situation through entropic or other effects. Secondly, in the absence of direct knowledge of the activity coefficient of the dye at the different temperatures, molar concentrations are employed.This is not a problem providing the change, if any, in the activity coefficient of the dye in solution is small enough over the temperature range. An additional problem arises because several substrates of interest, such as wool keratin, polyamides, and polyesters, are unstable to dyebath conditions especially where achievement of adsorption equilibrium is required. The reactions involved are various but naturally enough all are temperature dependent and the desorbed decomposition products can affect ‘equilibria’ considerably. From the point of view of ‘absolute’ measurements the situation is clearly impossible. Nevertheless, progress can be made provided the many aspects of non-ideality are borne in mind.Cellulose is a very stable substrate from the point of view of dye adsorp- tion studies, and very useful data have been obtained14 which show that the isosteric heat of adsorption of direct cotton dyes on cellulose is concentration dependent and shows a sharp break at a surface concentration equivalent to saturation. Adsorption continues beyond this point due to multilayer formation. In protein investigations heat of adsorption studies have suggested the contribu- tion of hydrophobic interaction to dye binding. This is possible because unlike other dye-binding interactions, hydrophobic interactions are endothermic. Some of the problems presented by the properties of dye-substrate systems, in attempted applications of thermodynamic analysis, will not be unfamiliar to chemists working in comparably complex fields such as polymer, surface, or biological chemistry.In all these fields experience is being gained increasingly in the use of flexible theoretical models which provide greater insight in relation to molecular mechanisms. At the same time in dye-adsorption work, attempts to gain information about the adsorption system which are thermodynamically meaningful are beginning to reveal new problems as well as solutions. Some of these will be discussed at a later stage. However, at a more practical level the cautious application of classical theoretical concepts to dye adsorption has proved, and is proving, fruitful.7 The Dyeing Process Thus far, discussion has been directed towards the dye-binding equilibrium in so far as such a term may be employed with metastable and complex polymeric substrates. However, in practice even an apparent equilibrium is rarely attained, and the concern of those whose business is to dye materials rather than physical chemistry is generally with the kinetics of the dyeing process. These are subject to many variable factors relating particularly to diffusion, and in dyeing machines to mass-transfer factors. Diffusion may occur owing solely to a simple entropic driving force leading to an equalization of distribution of some species in a system, or this may be combined with a free-energy-gain factor. Broadly speaking, the uniform dis- l4 E.H. Daruwalla and A. D’Silva, Textile Res. J., 1963, 33,40. TAe Chemistry of Dyeing tribution of a soluble dye in solution arises from the first factor. The proviso is necessary because dye solutions are frequently non-ideal but any errors that are made due to such approximations are small. In an adsorption process, however, free-energy-gain effects provide the driving force and are involved in the diffusion process. The substrates in which there is any interest are less permeable than water to a moving dye molecule or ion, and consequently diffusional processes in substrates are slower and generally rate determining. However, they are subject to diffusion in the external phase because of mass-transfer effects. The dye adsorption process consists initially of the adsorption on to the sur- face of the polymer of dye from adjacent solution.This sets up a concentration gradient within the polymer leading to diffusion. This process in turn depletes the polymer surface of dye and disturbs the surface equilibrium. Provided that dye replenishes the adjacent solution rapidly, the diffusion rate within the fibre determines the rate of uptake of dye. However, the replenishment of the surface solution depends upon the admittedly rapid diffusional properties of the dye in the water, and in the absence of enforced circulation this can be slow enough in practice to make the rate of dye uptake dependent upon the concentration gradient in the liquor near the surface.Circulation of the liquor introduces a new parameter and the rate of dyeing may be seen to be dependent upon stirring rates. The dyebath is most conveniently considered, as a consequence, in terms of three components : (i) the general solution (ii) the hydrodynamic boundary layer (iii) the adsorbing substrate The thinner the hydrodynamic boundary layer the less effect it can have on the diffusional processes, and this is achieved by increasing the rate of liquor flow past the surface. In the following discussion of diffusional factors, attention will be confined to a situation of optimum flow so that only the effect of dye-sub- strate interaction need to be considered. The chemical engineering aspects of dye adsorption are extensively reviewed e1~ewhere.l~ The initial adsorption at the surface of a polymer substrate phase involves a free-energy gain, and if no diffusion occurred then an equilibrium would be very rapidly established.However, minimization of the free energy of the system is achieved by diffusion of the adsorbed dye into the polymer to find unoccupied adsorption sites and creating unoccupied sites at the polymer solution interface. Since the adsorption interaction on a molecular scale is specific rather than general, the moving dye molecules must negotiate a path through the polymer system from one interaction point to the next. The diffusional process is conse-quently subject to two constraints : firstly, the general physical constraint pro- vided by the probability of ‘diffusional space’ being created in front of the molecule as a consequence of the thermal motion of polymer chains; secondly, there is the specific constraint presented by unoccupied adsorption sites which will tend to hold the diffusing molecule in one place.l6 R. McGregor and R. H. Peters, J. SOC.Dyers and Colourists, 1965, 81, 393; R. McGregor, ibid., 1965, 81, 429. Kattee The constraint offered in the first of the above instances will depend upon the size and shape of the diffusing molecule and the polymer structure. For small ions, e.g. chloride, diffusing through a polyamide, it has been shown that this kind of constraint is not an important consideration.16 However, as the popula- tion of diffusing ions or molecules increases crowding effects become signi- ficant.l6 An increase in the size of the molecules may have the same effect.General physical constraints of this kind are of great importance in dyeing kinetics. They are responsible for many of the problems of dyeing polyester fibres, wool keratin, and polyamides. An increase in the thermal agitation of the polymer chains by raising the temperature of the system, or the addition of swelling agents which disrupt cohesive bonds in the polymer by competitive action, are the means normally adopted to achieve adequately rapid dyeing in such cases. The constraint presented by the adsorption interaction is frequently difficult to distinguish froin the general physical constraint offered by the molecular network of the polymer. This is because larger dye molecules generally exhibit higher affinity, so that both constraints increase with size.However, with small ions only adsorption constraints occur and the diffusional behaviour can be described satisfactorily in terms of the probability of a diffusing ion becoming trapped by an adsorption site. With dye molecules and ions complications arise since adsorption itself involves probability factors due to size. The relationship between probability of site trapping and concentration may be rendered more complicated as a consequence. Constraints on diffusion due to adsorption effects are normally dependent upon the concentrations of adsorption sites and the adsorbed dye because of the probability factor involved in adsorption.The diffusional behaviour of the dye is consequently described by Ficks equation in which the rate of change of adsorbed concentration (&/at) is related to the concentration gradient (&/ax) by the diffusion coefficient (D). It has been shown that the nature of the concentration dependence of D relates to the adsorption, so that if the concentration gradient is replaced by the chemical potential gradient it more closely approaches a ~0nstant.l~ If various values of D are determined so that a limiting value Do is calculated for c -0, then this represents a measure of the physical constraint and the maximum adsorption constraint. It is not possible to arrive at any meaningful value by extrapolation to a maximum value of D which should equal the physical constraint factor alone because of crowding effects at high concentration. Diffusional studies of dyes in polymers have attracted much detailed attention and many difficult technical situations have been e~p1ained.l~ Recent attempts l6 G.Chantrey and I. D. Rattee, J. SOC.Dyers and Colourists, 1969, 85, 618; G. Chantrey,Ph.D. Thesis, University of Leeds, 1971. R. H. Peters, J. H. Petropoulos, and R. McGregor, J. SOC.Dyers and Colourists, 1961, 77, 704; R. H. Peters in ‘Diffusion in Polymers’, ed. J. Crank and G. S. Park, Academic Press, London, 1968. The Chemistry of Dyeing to combine concepts of dyeing kinetics with theories of the equilibrium have been made through the application of the theory of the thermodynamics of irreversible processes.An idealized model can be constructedla which has some limited applicability. As with other refined quantitative theoretical approaches, further progress is held up by relative lack of knowledge with regard to all the factors operating in the system. 8 Possible Future Trends As in many other complex fields, attempts to determine scientific explanations of the dyeing process create more questions than they answer. Nevertheless, this process is paradoxically accompanied by a clearer understanding. The introduc- tion of fibre-reactive dyes in 1956 and their rapid development was greatly facilitated by the state of knowledge of dyeing chemistry. To a large extent, developments in this field have resulted more from scientific analysis of the dyeing situation than chance (the traditional method).In the recent period it has begun to be appreciated that, like polymers, dyes exhibit an interesting physical chemistry of their own. This affects important parameters such as ease and extent of solution, precipitation in manufacture, drying, and bulk handling properties. As man-made substrates become increas- ingly important, the disperse dyes which are used to dye them will dominate the dyestuff scene. It is in this connection that solid-state studies are important and in the coming period are likely to provide a growth point in the study of the chemistry of dyes and dyeing. Much remains to be done, however, in further elucidating molecular mechanisms of adsorption, particularly in relation to the chemical structure of the dye since the accuracy with which the behaviour of a dye structure can be predicted leaves much to be desired. B. Milicevic and R. McGregor, Helv. Chim. Ada, 1966, 49, 1302; ibid., p. 1319; ibid., p. 2098.

ISSN:0306-0012    

DOI:10.1039/CS9720100145

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

Isotope Effect Studies of Elimination Reactions By A. Fry DEPARTMENT OF CHEMISTRY, UNIVERSITY OF ARKANSAS, FAYETTEVILLE, ARKANSAS, U.S.A. ;and DEPARTMENT OF CHEMISTRY, UNIVERSITY OF AUCKLAND, AUCKLAND, NEW ZEALAND ‘Reaction mechanisms iri general ure eluciduted in successive approximations. The relative timing of concerted bond changes should represent the ne.yt major stage in the study of several general reactions, of which elimination is one of the simplest. Up to the present only reconnaissance work on it has been done.’ 1 Introduction The above quotation’ is the last paragraph of Sir Christopher Ingold‘s 1962 Faraday Lecture on the mechanism of the elimination reaction. In the past ten years substantial progress has been made in elucidating the timing of bonding changes in elimination reactions, and one of the most powerful tools in such studies has been the kinetic isotope effect.However, in many respects exploita- tion of this unique tool for activated coniplex study has barely scratched the surface of the possibilities. It is the purpose of this work to review what has been done in this area, and to attempt to show how the technique could be used in helping to answer some of the remaining questions about mechanisms of elimination reactions. With a few minor exceptions and limitations, kinetic isotope effects, i.e. differences in rates of reaction for isotopic isomers, are to be expected $and only if there are bonding changes at the labelled atom in proceeding from reactants to the activated complex.2 Relative magnitudes of isotope effects are related to the extent and type of bonding change.Using modern computer techniques and programs for evaluating vibrational frequencies of isotopic isomer^,^^^ it is now possible to make highly sophisticated calculations of the isotope effects to be expected from different activated-complex models. The results for these different models can be tested against experimental data, and the incorrect ones rejected. Two very powerful techniques which can greatly expand the usefulness of this approach are: (1) the measurement and calculation of isotope effects for re- actants successively labelled at different positions in the m~lecule,~ and (2) the measurement and calculation of isotope effects for reactions involving substrates C.K. Ingold, Proc. Chem. SOC.,1962, 265. a J. Bigeleisen, J. Chem. Phys., 1949, 17, 675; J. Bigeleisen and M. Wolfsberg, Ah. Chem. Phys., 1958,1, 15; M. J. Stern and M. Wolfsberg,J. Chew. Phys., 1966,45,4105; L.Melander, ‘Isotope Effects on Reaction Rates’, Ronald Press Co., New York, 1960. M. Wolfsberg and M. J. Stern, Pure Appl. Chem., 1964,8,225, 325; J. H. Schachtschneider and R. G. Snyder, Spectrochim. Acta, 1963, 19, 117. A. Fry, Pure Appl. Chem., 1964, 8,409. containing aromatic rings with various substituents.6 Agreement between experiment and qualitative theory or calculated results may be obtained for many activated complex models when isotope effect results for a substrate labelled at only one position must be fitted, but when isotope effect results for a substrate labelled successively at several positions must agree with qualitative theory or calculated results, the number of acceptable activated complex models decreases dramatically.Further refinements in the activated complex model may be made by correlating changes in isotope effects with changing reaction mechanisms (changes in relative bonding or timing) as substituents on aromatic rings in the reacting system are changed. In view of the many atomic positions at which bonding changes take place, mechanisms of elimination reactions are particularly susceptible to attack by these two techniques but, as yet, neither has been exploited fully. 2 Primary Elimination Reaction Mechanisms-Isotope Effect Predictions The primary mechanisms of elimination reactions are conveniently and tradi- tionally considered in three broad mechanistic classes,1ss-8 El, E2, and Elcb.In principle, the various mechanisms are susceptible to distinction on the basis of isotope effect experimentati~n.~ The questions of whether there are clear-cut dividing lines between the mechanistic classes can perhaps be best answered by isotope effect research. Mechanistic subtleties within the broad classes can be studied effectively using relative magnitudes of isotope effects for closely related compounds. For one charge type, the three primary mechanistic classes (other elimination reaction mechanisms will be considered in later sections) and their predicted isotope effect consequences are depicted below.The predictions are qualitative and are based on the assumption that isotopic substitution at (but not that ‘remote’ from) atomic positions undergoing bonding changes in the activation process will result in isotope effects. This assumption is solidly based on theorya (with some reservation about the definition of ‘remote’) but can also be utilized successfully on a more or less empirical bask4 For more precise predictions, recourse should be made to the type of detailed calculations men- tioned above. For a recent application of this time honoured technique to isotope effect experiments, see B. W. Palmer and A. Fry, J. Amer. Chem. SOC.,1970,92,2580.* W.H. Saunders, jun., ‘Elimination Reactions in Solution’, in ‘The Chemistry of Alkenes’, D.V. Banthorp, ‘Elimination Reactions’, Elsevier Publishing Co., London, 1963. ed. S. Patai, Interscience Publishers, New York, 1964, p. 149. 8J. F. Bunnett, Angew. Chem., 1962, 74, 731 (Angew. Chem. Internat. Edn., 1962, 1, 225); Surv. Progr. Chem., 1969, 5, 53.* Review sources which the author has found particularly useful in considering applications of isotope effect research in elimination (and other) reaction mechanism studies include references 1,2,6-8 and E. A. Halevi, Progr. Phys. Org. Chem., 1963,1,109; W. H. Saunders, jun., ‘Kinetic Isotope Effects’, in S. L. Friess, E. S. Lewis, and A. Weissberger ‘Investigation of Rates and Mechanisms of Reactions’, 2nd edn., Interscience Publishers, New York, 1961, Vol.8, Part 1, p. 389; W. 14. Saunders, jun., Surv. Progr. Chem., 1966,3, 109; H. Simon and D. Palm, Angew. Chem. Internat. Edn., 1966,5,920; A. Streitwieser, jun., ‘Solvolytic Displace- ment Reactions’, McGraw-Hill Book Co., New York, 1962; E. R. Thornton, ‘Solvolysis Mechanisms’, Ronald Press Co., New York, 1964; and K. B. Wiberg, Chem. Rev., 1955, 55, 713. In addition, appropriate sections in Ann. Reports and Ann. Rev. Phys. Chem. are very helpful. A. Carbonium Ion Mechanism, El.-Primarylo kinetic isotope effects would be + Pc=%I I1 (11 expected for labelled X and a-carbon, but not for labelled p-carbon or for a-or p-hydrogens. SecondarylO hydrogen isotope effects would be expected for a-hydrogens and for properly oriented ,&hydrogens. Carbonium ion (1) is a reactive intermediate, and there should be no measurable /%carbon or a-or p-hydrogen isotope effect on the overall rate in its decomposition to the elimina- tion product.ll In the event that reaction of (1) with Y-has an appreciable activation energy, there should be an isotope effect (small, or perhaps even inverse since bond formation is involved) for labelled Y-.B. Concerted Mechanism, E2.-Primary kinetic isotope effects would be ex- pected for labelled Y--, /%carbon, a-carbon, X, and the eliminated /%hydro- gen. Secondary isotope effects might be found for the a-hydrogens and the non-eliminated p-hydrogens. C. Carbanion Mechanism, E1cb.-For the Elcb mechanism, two limiting types Primary isotope effects are those observed for cases where a bond to the labelled atom is being broken or formed in the rate-determining step.Secondary isotope effects are those observed for cases where formal bond rupture or bond formation at the labelled position is not involved, but where bonding at the labelled atom is altered (as by hybridization changes, hyperconjugation, non-bonded steric interaction changes, etc.) in the rate-determining step. As we shall see, it is difficult to distinguish between certain primary and secondary isotope effects, especially for some 8-hydrogen isotope effects in elimination reactions. l1 Any isotope effects involved in further reactions of a reactive intermediate would not affect the overall rate of an irreversible reaction since, by definition, such an intermeaiate can only decompose to products.However, if there is a partition of a reactive intermediate among paths (including internal return) having different isotope effects, the product ratios will be altered by the presence of the isotope or, in a competitive experiment, some products will be enriched and others depleted in the isotope. For an example of such an E14~1 partition see G. J. Frisone and E. R. Thornton, J. Amer. Gem. SOC.,1968,90, 1211. Isotope Efect Studies of Elimination Reactions should be considered. If formation of carbanion (3) is rate-determining (type A), primary kinetic isotope effects would be expected for labelled Y-, /3-carbon, and /?-hydrogens.Whether secondary isotope effects are to be expected for the non-eliminated /?-hydrogens or the a-hydrogens would probably depend on the change in /?-carbon hybridization. There should be no measurable iso- tope effects on the overall rate for labelled a-carbon or X as reactive inter- mediate (3) is converted to products.ll Alternatively, if formation of carbanion (3) is rapid and reversible and its conversion to products is rate-determin- ing (type B), primary kinetic isotope effects should be observed for labelled X, a-carbon, and p-carbon, and equilibrium isotope effects could be measured for labelled Y-and the ,%hydrogens. Again, a secondary isotope effect might be observed for labelled a-hydrogens. The fact that the E2 ‘mechanism’ is really a whole spectrum of mechanisms with varying degrees of fractional bonding among X, a-C, /?-C,Y-, and /?-H has been pointed out in a particularly clear fashion by Bunnett.8 It is easy to visualize a version of (2) which would look very much like (3) and which would be the most Elcb-like of the E2 mechanisms.Similarly, one could visualize bonding in (2) which would place its structure very close to that of (1) (assuming placement of X-near a-C and of Y-or a nucleophilic solvent near the /?-H). The isotope eRect technique, using substrates labelled successively in various positions, is probably the most effective tool available for placing the mechanism of a particular reaction at a given point in the mechanistic spectrum. In the discussion below, particular attention will be given to what can be learned about the borderline mechanistic areas by isotope effect techniques.The isotope effect results available for reactions occurring by the various primary mechanisms will be taken up in the order El, Elcb, E2. All elimination reactions are accompanied, to a greater or lesser degree, by competing substitution (and sometimes other) reactions, and this can give rise to serious problems in isotope effect studies, especially for labelled a-C and X. A changed isotopic composition of a substrate due to an isotope effect in a competing reaction may give a ‘false’ isotope effect in the elimination reaction. For instance, if an elimination reaction were to go by the Elcb mechanism with rate-determining carbanion formation (type A) no isotope effect should be observed for labelled a-C.But if there is a normal isotope effect for labelled a-C in a competing sN2 reaction, the substrate will be enriched in the heavy a-C isotope during the initial stages of the reaction and this fractionation should be reflected in an enrichment of the heavy a-C isotope in the elimination products giving a ‘false’ normal isotope effect if the calculation is based on recovered starting material, or a 'false' inverse isotope effect if the calculation is based on elimination products (see also reference note 11). 3 Isotope Effect Studies of El Reactions A. Labelled P-Carbon.-The most critical isotope-effect distinction at the borderline between the El and E2 mechanisms is whether or not there is an isotope effect for a compound with P-C labelled; for the E2 mechanism there should be an isotope effect, whereas for the El mechanism there should not.Unfortunately, no such experiment has been carried out on a compound for which the mechanism is thought to be El or on the borderline between El and E2. The only isotope effect study of an elimination reaction in which P-C is labelled is that of Simon and Mullhofer12 who found k12/k1* = 1.036 for the pyrolysis at 51 "C of n-pr0py1-[2-~~C]-trimethylammoniumhydroxide. Clearly, as expected, this is an E2 and not an El reaction. It would be interesting to search for possible isotope effects in the elimination reactions of p-C-labelled 1-p hen yle t h yl (4), 2-phen yl-2-pr op y l (5), 2-phen y l-2-meth y l-2-p rop yl (6),t -but yl (7), etc., halides or toluene-p-sulphonates, where El or El42 borderline reac- tions might be expected.Variation of the substituent Z might well influence the mechanisms of the reactions and the magnitudes of any isotope effects found. a-and/or fl-hydrogen isotope effect measurements have been carried out on all of the above systems (see below). B. Labelled X.-In principle, almost all the kinetic and kinetic isotope-effect research in solvolytic reactions which have been suggested to have carbonium ion intermediates is pertinent to the study of the El elimination reaction. In practice, in a large fraction of such studies, the products are not identified, and even when they are the emphasis is most frequently placed on the substitution products.In a qualitative sense, isotope effects are to be expected for both the El and E2 mechanisms for compounds labelled at X, a-C,or Y-. Quantitatively, for labelled X, larger isotope effects are to be expected for El (complete %-X bond rupture) than for E2 mechanisms (T-X bond weakening). The few available studies give results in line with this conclusion, but much remains to be done before detailed mechanistic conclusions can be drawn. In the reaction H. Simon and G. Mullhofer, Chem. Ber., 1963, 96, 3167; ihid., 1964,97, 2202; Pure Appf. Chem., 1964, 8, 379. Isotope Effect Studies of Elimination Reactions of t-butyl chloride with alcoholic silver nitrate,13 the chlorine isotope effect, k36/k37= 1.0075, is in the SN~range (1-0075--1.0081) rather than the SN~ range (1 .0057-1.0058), established by Hill and Fry14 for displacement reactions of substituted benzyl chlorides.Saunders and Zimmerman15 compared the sulphur isotope effect for the uncatalysed, ka2/kS4 = 1.0103, and ethoxide ion catalysed, k32/k34= 14072, decomposition of t-butyldimethylsulphonium iodide in ethanol. Presumably, there is complete rupture of the %-S bond to form a carbonium ion intermediate in the uncatalysed case, but in the E2 reaction catalysed by ethoxide ion the aC-S bond is weakened but not broken. However, there may be some question about whether a carbonium ion is formed in the former case, since t-butyldimethylsulphoniumiodide had earlier givenl6 a substantially higher sulphur isotope effect, k32/k34 = 1.0177, in a reaction with hydroxide ion in water.If the aC-S bond were completely broken in both cases, why should the isotope effects be different? Perhaps the answer lies in rupture of stronger sulphur-solvent solvation bonds in water than in ethanol on going from the positively charged sulphur in the ion to neutral dimethyl sulphide. Saunders and KaW7 have reported some calculations of sulphur, nitrogen, and deuterium isotope effects for various mechanistic models. Measurements of chlorine and/or sulphur isotope effects for elimination reactions of a series of p-substituted 1-phenylethyl chlorides or dimethylsulphonium salts might provide valuable information about the El-E2 mechanistic borderline region.C. Labelled a-Carbon or Y-.-Predictions about differences in magnitudes of isotope effects for a-C and Y-labelled compounds reacting by El or E2 mech-anisms are less clear and experimental data are very sparse. No experimental isotope effect measurements for labelled Y in elimination reactions of any kind have been reported. Several quite large (k12/k14 = 1-05-1.08) isotope effects for labelled a-C compounds reacting by the E2 mechanism have been reported (see below). Solvolysis isotope effects for a-C labelled t-butyl chloride,18 k12/k14= 1.027, and p-substituted-1-phenylethylbromide,ls k12/k13 = 0.9995-1.0127, are uniformly lower than those for SN2 reactions of the same compounds (k12/k13= 1.036 for the 1-phenylethyl bromides). All the measurements were made on substitution rather than elimination products, but it is quite probable that the elimination reaction trend would be the same.If so, measurement of isotope effects for a-C labelled compounds in suitable systems such as (4), (3, and (6) above could serve as a powerful probe for the El42 mechanistic border- line. R. M. Bartholomew, F. Brown, and M. Lounsbufy, Nature, 1954, 174,133; Canad. 3. Chem., 1954,32,979. J. W. Hill and A. Fry,J. Amer. Chem. SOC.,1962,84,2763. loW. H. Saunders, jun., and S. E. Zimmerman, J. Amer. Chem. SOC.,1964, 86, 3789. l6 W. H. Saunders, jun., and S. Asperger, J. Amer. Chem. SOC.,1957, 79, 1612. l7 W. H. Saunders, jun., Chem.Ind. (London), 1963, 1661; A. M. Katz and W. H. Saunders, jun., J. Amer. Chem. SOC.,1969,91,4469. M. L. Bender and G. J. Buist, J. Amer. Chem. SOC.,1958,80,4304. J. Bron and J. B. Stothers, Canad.J. Chem., 1969,47,2506, and earlier papers in the series cited there. D. Labelled a-Hydrogen.-The magnitude of the a-hydrogen isotope effect may be a very useful criterion of the degree to which a-C has changed from sp3 to spe hybridization in carbonium ion formation in the E1-4~1 mechanism or in incipient double bond formation in the E2 mechanism. The generally accepted@ origin of the a-hydrogen isotope effect is the relaxation of bonding (mainly involving H-"C bending frequencies) in going from the sp3hybridized reactant to the near spa hybridized transition state.An ingenious demonstration of this concept is provided by Belanic-Lipovac, Borcic, and Sunkoeoin their studies on isomeric allylic chlorides : 4-Me,CCl-CH=CD, -Me,C-CH=CD, no C -D hybridization change, kH/ = kD = 1:OO I f Me,C=CH-CD,CI Me,C=CH-CD, C-D hybridization change, kH/ kD = 1-20 In recent reviews21v23 of the many reports on a-hydrogen isotope effects in solvolysis and other substitution reactions, s~1-Elreactions are shown to have large (kH/kD 1.15 at 25 "C) a-hydrogen isotope effects, characteristic of N significant weakening of the "C-H bonding in the activation process. sN2 reactions (and solvolysis reactions of primary halides or tosylates), on the other hand, showed a-hydrogen isotope effects ranging from small 'inverse' (kH/kD < 1, strengthened "C-H bonding in a 'tight' activated complex) to small 'normal' values (kH/kD > 1, weakened "C-H bonding in a 'loose' activated complex).On the basis of recent work,23 which demonstrates that the main differences in a-hydrogen isotope effects in limiting s~l-Elreactions are due to differences in HQCXbending force constants in the reactants, it is now possible to say with considerable assurance that elimination (or substitution) reactions which have a-hydrogen isotope effects significantly different from the limiting values (at 25 "C,kH/kD N 1-22for X = F; N 1.15 for X = Cl; N 1.125 N Nfor X = Br; 1.09for X = I; and 1.22for X = OTP) must have, at least in part, mechanisms different from El (or Sxl).In order to use these data in an effective manner in investigating the relationship between the El and E2 mech-anisms, information on the magnitude of a-hydrogen isotope effects to be V. Belanic-Lipovac, S. Borcic, and D. E. Sunko, Croat. Chem. Acta, 1965,37, 61. S. Seltzer and A. A. Zavitas, Canad. J. Chem., 1967,45, 2023. e4 V. J. Shiner, jun., W. E. Buddenbaum, B. L. Murr, and G. Lamaty, J. Amer. Chem. Soc., 1968,90, 418. es V. J. Shiner, jun., M. W. Rapp, E. A. Halevi, and M. Wolfsberg, J. Amer. Chem. Soc., 1968,90,7171. 24 A. Streitwieser, jun., and A. G. Dafforn, Tetrahedron Letters, 1969, 1263. 1 69 Isotope Efleect Studies of Elimination Reactions expected in E2 reactions must be available.On the basis of the few measure- ments which have been made, it appears that E2 a-hydrogen isotope effects are small but perhaps suf€iciently variable so as to serve as a useful mechanistic criterion. Using sodium ethoxide in alcohol, the following a-deuterium isotope effects have been reported: for isopropyl bromide,26 no effect; for 2-phenyl- ethyldimethylsulphonium bromide,2s no effect (there was extensive exchange) ; for 2-phenylethyltrimethylammoniumiodide,26 a very small effect (kH/kD > 1); for 2-phenylethyl bromide,2s kH/kD = 1.17 (1.08 per deuterium); and for cyclohexyl t~sylate,~~ kH/kD = 1.14 (using potassium t-butoxide in t-butyl kH/kD = 1.15). In this last case the E2 a-hydrogen isotope effects are substantially smaller than that observed2* in acetolysis of cyclohexyl toluene-p- sulphonate, where kH/kD = 1.22.For the decomposition of n-pr~pyl-[l-~H]- trimethylammonium hydroxide in vacuum at 50 "C, the a-tritium isotope effect was foundll to be small, kH/kT= 1-10. Clearly, large a-hydrogen isotope effects are to be expected for El reactions. On the basis of the above limited data it is tempting to speculate that the reduction in the size of the a-hydrogen isotope effect from the El limiting value might be useful in evaluating the extent to which the aC-X bond is still intact at the E2 activated complex. But the situa- tion is perhaps more complex in that a substantial a-hydrogen isotope effect would probably be expected for a reaction with a mechanism near the centre of the E2 range, where there is considerable double bond formation, as well as for an E2 reaction with a mechanism near the El border.More data on closely related E2 reactions, such as those of various p-substituted 2-phenethyl or 1,2-diphenylpr~pyl~~derivatives, would be very useful in evaluating the usefulness of the a-hydrogen isotope effect as a criterion of elimination-reaction mechanism. It is also of interest to note that magnitudes of a-hydrogen isotope effects may be of considerable value in estimating the type and degree of neighbouring group participation in SNl-El solvolytic reactions. Such backside bonding is expected to lead to more restricted %-H bending motions in the activated complex than in the reactants, and thus to reduced a-hydrogen isotope E.Labelled fi-Hydrogen.-By far the greatest number of isotope effect studies of elimination reactions have utilized compounds with the /%hydrogens labelled; a large fraction of these studies has been concerned with solvolytic Sxl-El reactions, often under conditions where there is little or no elimination, and often without specific attention to the elimination aspects of the overall reaction. 25 V. J. Shiner, jun., J. Amer. Chem. SOC.,1952, 74, 5285. 26 S. Asperger, N. Ilakovac, and D. Pavlovic, J. Amer. Chem. SOC.,1961, 83, 5032; Croat. Chem. Acta, 1962, 34,7; S. Asperger, L. Klasinc, and D. Pavlovic, ibid., 1964, 36, 159. K. T. Finley and W. H. Saunders, jun., J. Amer. Chem. SOC.,1967, 89, 898. E8 W. H. Saunders, jun., and K.T. Finley, J. Amer. Chem. Soc., 1965. 87, 1384. 29 See the discussion in ref. 8 (i.e. Surv. Progr. Chem., 1969,5, 81). 30 For leading references see ref. 9, A. Streitwieser, 'Solvolytic Displacement Reactions'; S. L. Loukas, M. R. Velkou, and G. A. Gregoriou, Chem. Comm., 1970,251; C. C. Lee and L. Noszko, Cunad. J. Chern., 1966,44, 2491 ; C. C. Lee and E. W. C. Wong, J. Amer. Chenr. SOC.,1964, 86, 2752. As far as primary isotope effects are concerned, /%hydrogen labelling should provide a clear distinction between the El (no primary effect) and E2 (definite primary effect) mechanisms. But since there are substantial secondary /?-hydrogen isotope effects in E~-SNI reactions (see below), and since E2 primary p-hydrogen isotope effects change smoothly from small to large to small again as the degree of transfer of the /?-hydrogen from p-C to Y-increases,31 it is impossible to use with assurance the magnitude of the /%hydrogen isotope effect as a distinctive criterion of mechanism at either the El42 or the E2-Elcb borderline.In solvolytic reactions of aliphatic tertiary and many secondary substrates, replacement of /?-CH, by p-CD3 causes a rate depression of about a third, P/kD 1~33.~~~~~ For solvolysis ofN The effects are generally ~umulative.~~~~~ other secondary and primary substrates the /%hydrogen isotope effects are much For instance, for solvolysis in water, for the series ethyl bromide, isopropyl bromide, t-butyl chloride the kH/kD per CD, group values are 1.03 (60 "C), 1.15 (60"C), and 1.37 (2 0C).36This reduction is thought to stem from increasing nucleophilic solvent involvement (Sri2-like) as the branching decreases, and points to carbonium ion character at a-C as being the important reason for the secondary ,&hydrogen isotope effect .36 The main mechanism through which the carbonium ion centre exerts its influence is almost certainly hyperconjugation (delocalization of the sp3-s BC-H o-bond electrons into the developing a-C p orbital), resulting in 'looser' BC-H bonding in the activated complex than in the reactants, and thus an isotope effect in the 'normal' direc- ti~n.~'The BC-H a-orbital and the developing p-orbital on a-C must be 31 F.H. Westheimer, Chem. Rev., 1961, 61,265; for more extensive calculations and leading references to recent work see R.A.More O'Ferrall, J. Chem. SOC.(B), 1970,785. 3a Shiner and Lewis have summarised the notable early work of their research groups in this area, V. J. Shiner, jun., Tetrahedron, 1959, 5, 243; E. S. Lewis, ibid., 1959,5, 143. The early work of Streitwieser's group also deserves special mention, see A. Streitwieser, jun., R. H. Jagow, R. C. Fahey, and S. Suzuki, J. Amer. Chem. SOC.,1958,80,2326. Halevi's penetrating and critical review (ref. 9) is excellent. A frequently used and useful form for expressing such results on a per-hydrogen basis is d(dFt) = (RT/n)log kH/kD; alternatively, kH/kD for a substrate having n hydrogens replaced by deuteriums may be raised to the I/n power.IP V. J. Shiner, jun., B. L. Murr, and G. Heinemann, J. Amer. Chern. SOC.,1963, 85, 2413, and references cited therein. 85 K. T. Leffek, J. A. Llewellyn, and R. E. Robertson, Cunad. J. Chem., 1960,38,2171, and other earlier papers in the series cited there. In line with this, for some cases such as t-butyl chloride (ref. 1I), these isotope effects are remarkably independent of solvent; for other cases, such as isopropyl tosylate, the nucleo- philic involvement of the solvent shows up clearly: kH/kD = 1.55 (1.24 per CD,) cf. kH/kD = 2.12 (1.45 per CD,) for solvolysis in water (ref. 35) and trifluoroacetic acid (ref. 24). The low, kH/kD = 1.25 (for the 8-D5 molecule), 8-hydrogen isotope effect for solvolysis of t- amyldimethylsulphonium iodide is probably best explained by an activated complex with comparatively little carbonium ion character at a-C, with most of the positive charge still being on sulphur; S.Asperger and N. Ilakovac, Chem. Znd.(London), 1960,1191 s7 A decrease in non-bonded interactions involving the 8-hydrogens as the carbonium ion centre develops has been suggested (see, for example, H. C. Brown, M. E. Azzaro, J. G. Kelling, and G. J. McDonald, J. Amer. Chem. Soc., 1966, 88, 2520, for leading references) as the main cause for the 8-hydrogen isotope effect. In the opinion of the author, the pro- ponents of hyperconjugation have much the better of the argument, but, fundamentally, any detailed models from which calculations are made for comparison with experiment neces- sarily involve both molecular geometries and force constants, so, in a way, the question becomes moot (or perhaps better, subject to 'computer experiment' test).Isotope Efect Studies of Elimination Reactions parallel for maximum overlap (electron delocalisation), which leads to the conclusion that there should be conformational requirements for the /?-hydrogen isotope effect. That this is indeed the case has been demonstrated in a most convincing manner by Shiner and ~o-workers.~~~~~ Compound (8) undergoes EI-SN~solvolysis with kH/kD = 1.14, while its isotopic isomer (9), in which there can be no overlap of the BC-D o-orbitaI with the developing a-Cp-orbital, has a kH/kD value of 0.986. It was even possible to tabulate contributions to the D isotope effect by /3-hydrogens in various different conformations relative to the C-Cp-orbital.s8 The existence of isotope effects for the El-s~lsolvolysis of compounds labelled in positions remote from a-C but conjugated with it by a benzene ring3a or triple bond3B also strongly supports the hyperconjugation explanation for /%hydrogen isotope effects.c1 kH/kD = 1.08 kH/kD = 1.09 It might be expected that hyperconjugative stabilization of the developing positive charge on a-C would be less important, leading to a reduced /?-hydrogen isotope effect, for a case where the positive centre is conjugated with a benzene ring, especially one containing an electron donating group. Such a study has been reported from Shiner’s laboratory:2a X kHlkD CHsO 1.113 CHII 1 -200 H 1 -224 NOa 1.151 s8 V.J. Shiner, jun., and J. S. Humphrey, ju.,J. Amer. Chem. SOC.,1963, 85, 2416. sp V, J. Shiner, jun., and G. S. Kriz, jun., J. Amer. Chem. Soc., 1964, 86,2643. 172 The 'standard' /%hydrogen isotope effect per CD, group (t-butyl cNoride data34) is kH/kD = 1.33. All the above values are substantially lower, that for the strongly conjugated p-methoxy-compound being especially low, in accord- ance with the above suggestion. All the reactions, except that of the p-nitro compound, are SNI-E~ on the basis of the a-hydrogen isotope effect classifica- tion given above.aa Both the a-and /%isotope effects are decreased for the p-nitro-compound because of the incursion of substantial nucleophilic attack by the solvent on a-C.Neighbouring phenyl participation in E1-3~1solvolysis reactions may also be studied by /?-deuterium isotope effects. To the extent that neighbouring phenyl can supply electrons to the developing positive charge, a reduced isotope effect would be expected as described above. Furthermore, a bridged ion would freeze the molecule in a conformation unfav~urable~~ for hyperconjugation (dihedral angles of 60" between the a-C p-orbital and the PC-H bonds). For a sym- metrical phenonium ion, to a first approximation at least, the a-and /%hydrogen isotope effects would be expected to be the same. On the basis of about normal a-and very low /?-hydrogen isotope effects in the E14~1 solvolysis of 2-phenyl- ethyl tosylates, Saunders and co-worker~~~ concluded that neighbouring phenyl participation did take place, but that the activated complex resembles reactant much more than a symmetrical phenonium ion.From the results of recent Ph,' \. 4-' 8' not CD;----~H, TsO-a-and fl-hydrogen isotope-effect research by Loukas, Velkou, and Gregoriou3" it appears that neighbouring phenyl participation in the 3-phenyl-2-butyl system may be very solvent dependent. At any rate, this is quite a complex system, and isotope effect research has excellent potential for making a meaning- ful mechanistic contribution. In several E14~1 the idea of @-hydrogen participa- soIvolysis rea~tions,~l-*~ tion has been invoked to rationalize /?-hydrogen isotope effects larger than those expected from the standard cumulative approach mentioned ab~ve.~~.~~ For 40 W.H. Saunders, jun., and R. Glaser, J. Amer. Chem. SOC.,1960,82, 3586 and earlier work cited there; see also R. A. Sneen, R. W. Jenkins, jun., and F. L. Riddle, jun., ibid., 1962,84, 1598. 41 V. J. Shiner, jun., and J. G. Jewett, J. Amer. Chem. SOC.,1965, 87, 1382, 1383; 1964, 86, 945; V. J. Shiner, jun., and J. 0.Stoffer, ibid., 1970,92, 3191. D. J. Cram and J. Tadanier, J. Amer. Chem Soc.. 1959, 81, 2737. S. Winstein and J. Takahashi, Tetrakdron, 1958, 2, 316. 173 Isotope Eflect Studies of Elinrincttion Reactions instance, Shiner and Jewett,*l in studying the solvolysis of cis-4-t-butylcyclohexyl brosylate, found that kH/kD = 2.565 for the 2-equatorial-2,6-diaxial-D3-compound, which is considerably larger than the expected value of 2.260 based on the monoequatorial-D (1 -096)and monoaxial-D (1 -436) values.The authors attribute the discrepancy to non-equivalence of the two axial hydrogens, one of them being involved in normal hyperconjugation with the positive centre, and the other forming an unsymmetrical hydrogen-bridge : 6-QBsk -ItBut D ID The neighbouring hydrogen participation is viewed 'as an extreme manifestation of a type of electronic interaction also associated with hyperconjugation'. The elimination reaction predominates in the above reactions, and an alternative view which may have merit in some cases is to think of these solvolytic reactions as occupying the El42 border with some small amount of PC-H bond extension being caused by nucleophilic solvent attack on the p-hydrogen.This should give rise to a small primary isotope effect. In effect, as the /%hydrogen becomes more positive by hyperconjugative electron withdrawal from the BC-H o-bond, the role of a nearby solvent molecule would be changed from general solvation to specific weak covalent interaction. If an ion-pair inter- mediate is formed, the covalently bound solvent molecule would still be present; in any event, the next step of the reaction, the elimination proper, must involve such an interaction since the /%hydrogen must eventually be removed to the solvent. The geometry of the activated complex for such a mechanism need not be greatly different from that for neighbouring hydrogen participation.Indeed. steric factors permitting, the /%hydrogen would be expected to shift toward a-C, responding to the electron shift represented by hyperconjugation. It would seem that a good test for such a mechanism would be to study the /%hydrogen isotope effect in systems such as these as a function of the nucleophilicity of the solvent. In the solvolysis reactions of erythro-and threo-3-cyclohexyl-2-butyl toluene-p-sulphonates, Cram and Tadax~ier*~ found substantially higher 18-hydrogen isotope effects in acetic acid than in the less nucleophilic formic acid, as would be expected for the suggested mechanism. A more extensive study of solvent effects on isotope effects for such systems might provide the definitive data needed.CH3COZH HCOzH C-CsHn erythro liH/kD 2.10 1 -73 CHS-C-CHCHsI1 threo kHlkD 1 -87 1 -54 D OTs Another similar but somewhat more conventional alternative view of E1-s~ solvolytic reactions with 'abnormally high' /%hydrogen isotope effects is to consider them to involve recombination of the carbonium-ion-anion ion pair to \/ I/x--JC-"C, + -k,-ruc& x-/ .\ \++S-D \ ?S+ i I sst Ton pair reactants, in kinetically significant competition with p-hydrogen abstraction by solvent to form olefin. The latter process would, of course, involve a primary p-hydrogen isotope effect, and this, in the usual steady-state treatment of such a system, would be reflected back into an overall reaction rate showing an 'abnormally high' isotope effect.Such ion pair recombination can sometimes be detected by common-ion rate depression or, better, by isotopic or other exchange experiments. A proposal of this sort has been made by Shiner's group (and discounted by to explain the high value of the isotope effect in the EI-SN~solvolysis of [2Hg]t-butyl chloride in trifluoroethanol. Similarly, Smith and Good6 have interpreted their p-hydrogen isotope effect results in the 44 V. J. Shiner, jun., W. Dowd, R. D. Fisher, S. R. Hartshorn, M. A. Kessick, L. Milakofsky,and M. W. Rapp, J. Amer. Chem. SOC.,1969,91,4348; (and the contrary view) D. J. Raber, R. C. Bingham, J. M. Harris, J. L. Fry, and P.v.R. Schleyer, ibid., 1970,92, 5977. 46 S. G. Smith and D. J. W. Goon, J. Org. Chem., 1969, 34, 3127. 175 2 Isotope Efect Studies of Elimiriution Reactions solvolysis of phenyldimethylcarbinyl chloride, p-nitrobenzoate, and thiono- benzoate in this way. This idea may be conveniently examined using the usual mechanistic formulation : Neglecting substitution for simplification of illustration (assuming a case where olefh formation predominates greatly, kE 9 ks) and using the usual steady- state treatment on the unlabelled compound, it is found that Applying the same treatment to the labelled compound, defining the ratio of ion recombination to olefin formation for the unlabelled compound as /C-~H/~EH= c (similar to the solvolysis mass-law constant a),and dividing one equation by the other leads to equation (1): The ratio klH/klDfor a limiting solvolysis reaction of phenyldimethylmethyl- CD, derivatives is probably not much different from that of 1-phenethyl-CD, compounds,22N 1-22at 25 "C.The value of k~~/k~~may be evaluated directly by olefin analysis to determine the ratio of elimination into the CH, branch [to give PhC(CD,)=CH,] to elimination into the CD3 branch [to give PhC(CH,)=CD,]. Values of kEH/kEDranging from 1-7to 2.9 were determined by Smith and If E(X-)is very small, corresponding to the usual irre- versible El reaction, kobsH/kobsD = klH/klD. By the nature of the bonding in-volved ('looser' bonding for PC-H in the carbonium ion than in the reactants), it can be concluded that k,H/klD will always be greater than IC-~H/~-~D,which will have a lower limit of unity.For illustrative purposes, results of a few calculations using equation (1) are presented below. The following values were used for the various isotopic ratios: klH/klD = 1-22, k~~= 2-00, ~~ k--,H/k-,D = 1.11, (X,)/ (xs)= 1. /k 4X-) Possible E :(X-) values kobsH/kobsD 0 Irreversible for E = 0 1 *22 0.01 1 :0-01,or 0.1 :0-1, or 0.01 :1, etc. 1 -23 0.1 10:0.01,or 1 :0.1,or 0.1:1, etc. 1.31 0-5 50:0-01, or 5 :0*1,or 0.5 :1, etc. 1-55 1 100:0.01,or 10:0.1,or 1 :1, etc. 1*77 10 lOOo:O.Ol,or 100:0.1,or lO:l, etc. 2-01 100 10,000:0~01,or lOOO:O.l, or 100:1, etc. 2.19 Under the usual reaction conditions used for isotope effect measurements, e.g.OeOlM-RX, it is apparent that external X-salt would have to be added, or else E would have to be quite large before an appreciable increase in kobsH/kobsD would be observed. Ion recombination is a kind of substitution reaction and, just as is the case for k-,H/k-lD, other competing substitution reactions would be expected to have small values for ksH/ksD.The net effect of such competing substitution reactions under these reversible conditions would be to use up the labelled substrate more rapidly than if it had to undergo an elimination reaction, thus increasing kobsD, which causes kobsH/kobsD to decrease. In the limit, only substitution takes place, and the value of kobsH/kobsD is that characteristic of the solvolytic substitution reaction alone.The kH/kDresults of Smith and with different leaving groups follow this pattern : X k~~/ kH/kD(D3) kH/kD(D6) (olefin/ether)(D,)k~~ Chloride 2.9 1-22 1 -42 0-13 p-Nitrobenzoate 2.4 1.32 1 -76 1.0 Thionobenzoate 1 -7 1 *34 1 a94 16 As far as p-hydrogen isotope effects go, reaction of the chloride, giving mostly substitution products, is a nearly normal sN1 solvolysis reaction (the degree of ion recombination is unknown and is not necessarily very small); and reaction of the thionobenzoate is primarily a solvolytic elimination reaction, probably somewhat complicated by ion recombination. Using 1.22 for k,H/k,D and 1.1 1 for k-lH/k-lD, the observed 1.34 for kobsH/kobsD, and the observed 1.7 for 177 Isotope Eflect Studies of Elimination Reactions ~EH/~E~,the value of E(X-) can be calculated from equation (1) to be 0.23, probably indicating a value of 50 or more for E.It would be interesting to see if added X-would have the predicted effect of increasing kobsH/kobsD for this case. Although a few other measurements or estimates have been made11f4* of the /%hydrogen isotope effect in the conversion of carbonium ions to elefins in the second step of EI-SNI solvolysis reactions, no useful correlations seem to have emerged. The technique, involving isotopic measurements on the olefinic reac- tion products, is straightforward and relatively simple, and this area of research merits more attention. A whole spectrum of mechanisms might be revealed, with kH/kDvalues varying through a maximum for symmetrical bonding of the abstracted proton to /?-Cand the solvent.Noyce and co-workersQ7 studied the primary and secondary /?-hydrogen isotope effects in the acid-catalysed racemization and dehydration of 2-phenyl-2-hydroxypropionic acid and 1,2-diphenylethanol. A normal secondary /?-hydrogen D +H,O 4-DH,O+ isotope effect was found for the racemization reaction, and fairly large (kH/kD = 1-72, 1-83) /?-hydrogen isotope effects were found for the overall dehydration reactions. By an analysis similar to that used in developing equation (1) above, Noyce and co-workers concluded that the observed kH/kD arose from a com- bination of primary and secondary isotope effects, that the carbonium ion was formed rapidly and reversibly, and that the rate determining step was abstraction of the p-hydrogen by solvent.48 It would be of interest to study the P-C carbon-14 isotope effect in a reaction such as this.In concluding this section on @-hydrogen isotope effects in solvolytic reac- tions, it is of interest to review briefly the contributions made to the question of participation by the C(l)-C(6) electrons in solvolysis of norbornyl derivatives by isotope effect research. As pointed out above,22~30~40 delocalization of a develop- ing positive charge at a-C in an E14~1 reaction by conjugation or neighbouring group participation reduces both the a-and /?-hydrogen isotope effects. For acetolysisof exo- and end0-[2-~H]norbornyl brosylates at 50 "C,Lee and Wong30 found a-hydrogen isotope effects of (kH/kD)exo= 1.07 and (kH/kD)endo = 1.20.The isotope effect for the endo-compound is about normal, but that for the exo- compound is very low, consistent with extensive backside attack in the rate- 46 M. s. Silver, J. Amer. Chem. Soc., 1961, 83, 3487, and references cited there. D. S. Noyce, D. R. Hartter, and R. M. Pollack,J. Amer. Chem. Soc., 1968,90,3791; D. S. Noyce and C. A. Lane, ibid., 1962,84, 1641. 48 It might be noted that this reversible carbonium ion mechanism formally bears the same relationship to the ordinary El-SN 1 mechanism as the reversible and irreversible carbanioa mechanisms bear to each other. Fry determining step. The same type conclusions were drawn from solvolysis data f for /%hydrogenisotope effects for em- and end0-[2-~H]- or -[2,2-2HH]-norborny1 broniide~~~ Finally, and perhaps providing the strongest and bro~ylates.~~~~~ I’ kg J.P. Schaefer and D. S. Weinberg, TetrahedronLetters, 1965, 2491 ;J. P. Schaefer, M. J. Dagani, and D. S. Weinberg, J. Amer. Chem. SOC.,1967, 89, 6938. 6o J. M. Jerkunica, S. Borcic, and D. E. Sunko, Chem. Conrm., 1967, 1302. b1 B. L. Murr and J. A. Conkling, J. Amer. Cliem. SOC.,1970, 92, 3464. Isotope Eflect Studies of Elimination Reactions evidence for the indicated participation, ex0-[6-~H]-norbornyI brosylates show substantial y-hydrogen isotope effects, while end0-[6-~H]-norbornyI brosylates show none.62 L H(k /kD)? exo = 1.09 -1.15 4 Isotope Effect Studies of Elcb ReactionP A.Labelled Y-, a-C,8-C, or X.-Almost no heavy-atom isotope effect research has been carried out on reactions thought to proceed by the Elcb mechanism. For reactions which might have carbanion formation as the rate-determining step (type A, Section 2) probably the most critical test that could be applied is whether or not an isotope effect is observed if either a-C or leaving group X is labelled. The prediction is that there would be no isotope effect for either a-Cor X labelled substrate for rate-determining formation of a carbanion, whereas there would be isotope effects for either the E2 or reversibly formed carbanion (type B, Section 2) mechanism. The only four a-C carbon-14 labelled cases examined,12e5* decomposition of ethyl-, n-propyl-, t-butyl-, and 2-(p-nitro- J.M. Jerkunica, S. Borcic, and D. E. Sunko, J. Amer. Chem. SOC.,1967, 89, 1732; B. L. Murr, A. Nickon, T. D. Swartz, and N. H. Werstiuk, ibid., 1967, 89, 1730, and earlier papers cited there. 53 An excellent critical review of the carbanion mechanism for olefin-forming eliminations appeared recently, D. J. McLennan, Quarr. Rev., 1967, 21,490. 51 E. M. Hodnett and W. J. Dunn, tert., J. Org. Chem., 1967,32, 4116. 180 pheny1)et h y1t r ime t hylammon ium salts , have all shown sizeable isotope effects (kla/k14= 1.026-1.075). A nitrogen isotope effect, k14/k15= 1.024 at 98 "C, was also with the latter compound. Clearly, rate-determining car- banion formation cannot be the elimination reaction mechanism in these cases.Furthermore, the /%hydrogens of 2-p-(nitrophenyl)ethyltrimethylammonium iodide did not undergo exchange when heated with tritiated water at 100 "C for one elimination reaction half-life,56 so the reversible Elcb mechanism is also inconsistent with the experimental results. It appears that all the above- mentioned compounds react by the E2 mechanism (see the next section). 14C: k12/k14= 1.078; 15N: k14/k1'= 1.024; no a 0-H exchange with HTO Mechanism: E2, not Elcb Although a few more leaving-group (X), nitrogen, and sulphur isotope-effects have been measured (see the E2 Section below) only one other case is of interest in searching for the E2-Elcb mechanistic border. For the decomposition of cis-2-phenylcyclohexyltrimethylammoniumiodide, which is thought to undergo an E2 unrielimination, a normal nitrogen isotope effect, k14/k16 = 1.012, was found by Ayrey, Buncel, and Bo~s.~~For the isomeric trans-compound, which can react to give the conjugated olefin only by a syn-elimination (related deu- terium tracer research had ruled out an ylide mechanism), a very small nitrogen isotope effect, k14/k15= 1.002, was measured.57 The @-deuterium labelled compound did not exchange with solvent hydrogen under elimination reaction Q-g-Q Ph NMe,+ Ph H NMe,I- 16N: ~?'~/k''= 1-002 syn-E2 or Elcb conditions, so the reversible carbanion mechanism is ruled out.If the small nitrogen isotope effect is real (error limits were not specified), its very existence rules out an Elcb mechanism involving rate-determining carbanion formation ; but if this is an E2 reaction, it must certainly lie near the Elcb border.It would L5 E. M. Hodnett and J. J. Sparapany, Pure Appl. Chem., 1964,8, 385. E. M. Hodnett and J. J. Flynn, jun.,J. Amer. Chem. SOC.,1957, 79, 2300. b7 G. Ayrey, E. Buncel, and A. N.Bourns, Proc. Chem. Soc., 1961,458. hotope Eflect Stirdies of Elintiriutiori Reacrioiis be interesting to have comparative /%deuterium and a-carbon-14 isotope-effect data on these two isomeric compounds. No isotope effect measurements have been made for compounds thought to react by either of the Elcb mechanisms using reactants labelled at p-C, but since all bimolecular elimination mechanisms would be predicted to show P-C isotope effects, no qualitative mechanistic distinction is possible.The magnitudes of such effects would, however, be useful in placing the mechanism of a given reaction at a certain position within the E2 mechanistic spectrum, a matter which will be dealt with more fully in the next section. For a reactant labelled at incoming nucleophile Y, a primary kinetic isotope effect (perhaps low because bond formation is involved) should be observed for reaction by the E2 or the type A Elcb mechanism, whereas for the type B Elcb mechanism only an equilibrium (probably very low and capable of independent calibration) isotope effect would be expected. No such experiment has been carried out, but it merits serious consideration. B.Labelled p-Hydrogen.-The presence of isotopic exchange between the /%hydrogens of an elimination reaction substrate and the deuterium (or tritium) labelled solvent/base system (or vice versa) serves to identify reversible carbanion formation. It is usually considered that this identification of a carbanion in such a system indicates the existence of an Elcb rather than an E2 reaction mechanism. However, this does not necessarily follow, since, as was pointed out by Hine, Wiesboeck, and Ramsay5' in 1961, and later more clearly by Bre~low,~~ the elimination reaction mechanism might be E2 with carbanion formation being simply an irrelevant side reaction. This possibility has been widely dis-~0~nted~s~~1~~*~~on various grounds, but remains a viable criticism.As pointed out above, heavy-atom isotope effect research might possibly settle this question. Evidence on this point may also be obtained from /$hydrogen isotope effect studies. For both the E2 and type A Elcb mechanisms, primary p-hydrogen isotope effects are to be expected, so no qualitative mechanistic distinction is possible. Given sufficient calibration data, some mechanistic use might be made of relative magnitudes of isotope effects. For type B Elcb reactions, the situa- tion is rather complex, but has mechanistic promise. For the frequently encoun- tered case where Y-is the conjugate base of the solvent and both labelled and unlabelled substrates are allowed to react in the presence of excess unlabelled solvent, no useful isotope effect data can be obtained, since the labelled sub- strate quickly loses its label, and thus will show no isotope effect in the elimina- tion reaction, regardless of the mechanism.For cases where an aprotic solvent is used, and the labelled and unlabelled substrates are separately allowed to react with Y-,the carbanion from each isotopic isomer can only return to its own isotopic precursor. The E2 and type A Elcb mechanisms will thus proceed with their characteristic normal primary isotope effects, whereas the type B Elcb 08 J. Hine, K.Wiesboeck, and 0.B. Ramsay, J. Amer. Chem. SOC.,1961, 83, 1222. bB R. Breslow, Tetrahedron Letters, 1964, 399. 60 H. M. R. Hoffmann, Tetrahedron Letters, 1967 4393.mechanism will show only a small equilibrium isotope effect, reflecting the different equilibrium concentrations of the carbanion. By comparing the rate of reaction of the unlabelled substrate in the un- labelled protic solvent to that of the labelled substrate in the labelled protic solvent, an equivalent analysis is possible. A normal primary isotope effect will be obtained if reaction takes place by the E2 or type A Elcb mechanism, whereas an equilibrium (solvent) isotope effect will be obtained if the reaction mechanism is type B Elcb. A general formulation of the Elcb mechanisms for such a case may be developed using the usual steady-state treatment : The rate of olefin formation for the unlabelled compound in the unlabelled solvent will be: kEHklHIRH][Y-1rateH = hH[RH] = ~E;H+ k-,*[YH] Utilizing a similar expression for reaction of the labelled compound in the labelled solvent, and recognizing that R-is the same carbanion whether gener- = hD,ated from RH or RD so that k~,~ and defining 8 = k-lHIYH]/k~H, general equation (2) is obtained: For an Elcb reaction involving rapid and reversible carbanion formation (type B), 6 > 1, the overall rate will usually be second-order, first-order each in RH and YE (or RD and YE), so that kobsH -k,Hk-,D[YD] -K"[YD] kobsD kIDk-lH[YH] KnTyH] If, as is frequently the case, YH and YD are solvent, then their concentrations are effectively constant and equal and kobsH/kobsD = KH/KD,the ratio of the isotopic equilibrium constants.Depending on the strength of bonding in RH vs. Isotope Ezict Studies of Elimination Reactions BH this ratio may range from somewhat smaller (the usual case) to somewhat larger than unity. In Skell and Hauser's first investigations1 of possible exchange of p-hydrogens under elimination reaction conditions, 2-phenylethyl bromide did not accumulate deuterium from the labelled basic aqueous-alcoholic solvent. The type B Elcb (reversible carbanion formation) mechanism was thus ruled out. Since that time, many investigations with similar results have been carried out.sz Several casess3 are now known where exchange does take place in such experiments and, for some of these, isotope effects have been determined as well. Isotope effects on exchange reactions themselves were found to range from very high:* klH/klD-12 for toluene and ethylbenzene, to very low, klH/klD = 1.3-10.5-1 -5 for 2-octyl phenyl ~ulphone,~~ -4for 2,2-dihalogeno-l,1 ,l-trifluoro- ethanes,6s and 1.76 for cis-2-methoxycyclohexyl p-tolyl ~ulphone.~~ The low values of klH/klD were attributeds5 to rapid internal return to R-of the particular H (or D) originally abstracted by Y-, so that the real rate process is one of diffusion exchange of YH and YD.Alternatively, the low values might arise from either very slight or very extensive transfer of H from R to Y at the activated A plot6* of log kH/kDvs. the difference in acid dissociation constants for a wide variety of YH and RH cases goes through a maximum as might be In recent interesting research,6g triptycene showed a normal isotope effect in the exchange reaction, klD/klT= 2-24 (equivalent to klH/klD z 6.16) showing the stability of a bridgehead carbanion.For the Elcb type B elimination of 4-methoxy-2-butanone to 3-buten-&one and of 4-met hoxy-4-me t hyl-2-pen tanone to 4-me thyl-3-pen ten-2-0ne,~ O exchange of the /%hydrogens (those a to the carbonyl group) with D,O-OD-was fast, and the overall isotope effects were 0.87 and 0.77 (kobsH/kobsD in the above equation). Similarly, Crosby and Stirling71 observed rapid exchange and kobsH/kobsD = 0.66 and 0.78 for the elimination of phenoxide from 2-phenoxy- 61 P. S. Skell and C. R. Hauser, J. Amer. Chem. SOC.,1945,67, 1661. 62 A partial list of such studies includes W.H. Saunders, jun., and M. R. Schreiber, Chem. Comm., 1966, 145; V. J. Shiner, jun., and M. L. Smith, J. Amer. Chem. SOC.,1958,80,4095; P. J. Smith and A. N. Bourns, Canad. J. Chem., 1970,48, 125; J. L. Coke, M. P. Cooke, jun., and M. C. Mourning, Tetrahedron Letters, 1968, 2247; J. L. Coke and M. P. Cooke, jun., ibid., 1968, 2253; J. L. Coke and M. C. Mourning, J. Amer. Chem. SOC.,1968, 90, 5561; J. L. Coke and M. P. Cooke, jun., ibid., 1967, 89, 6701; N. A. LeBel, P D. Beirne, E. R. Karger, J. C. Powers, and P. M. Subramanian, ibid., 1963, 85, 3199; J. Weinstock, J. L. Bernardi, and R G. Pearson, !bid., 1958, 80, 4961; T. I. Crowell, R. T. Kemp, R. E. Lutz, and A. A. Wall, ibid., 1968, 90, 4638; J. Hine and P.B. Langford, J. Org. Chem., 1962, 27, 4149; and ref. 56. 6a F. G. Bordwell, M. M. Vestling, and K. C. Yee, J. Amer. Chem. SOC.,1970, 92, 5950; see also refs. 58 and 59 for earlier examples. 64 A. Streitwieser, jun., W. C. Langworthy, and D. E. Van Sickle, J. Amer. Chem. SOC.,1962, 84, 25 1. 66 D. J. Cram, D. A. Scott, and W. D. Nielson, J. Amer. Chem. SOC.,1961,83,3696. 86 J. Hine, R. Wiesboeck, and R. G. Ghirardelli, J. Amer. Chem. SOC.,1961,83, 1219. 67 J. Hine and 0. B. Ramsay, J. Amer. Chem. SOC., 1962,84,973. R. P. Bell and D. M. Goodall, Proc. Roy. SOC.,1966,294, 273. O9 A. Streitwieser, jun., and G. R. Ziegler, J. Amer. Chem. SOC., 1969, 91, 5081. 'O L. R. Fedor, J. Amer. Chem. SOC.,1969, 91, 908. J. Crosby and C. J. M. Stirling,J.Chem. SOC.(B), 1970,679. 184 ethyldimethylsulphonium iodide and 2-phenoxyethyl methyl sulphone, in full agreement with the Elcb type B mechanism. Such inverse isotope effects could .>PhSOfCH$CH2 OPh OD.--PhS02CDCH, OPh -OPh, PhS02CD=CH2 D2 0 also be possible for reaction by an E2 mechanism if the primary isotope effects were small (unsymmetrical transfer3' of H from p-C to Y)and the H,O-OH-vs. D20-OD-isotope effects on E2 reactions were less than unity. Steffa and Thornt~n~~studied such solvent-base isotope effects for the E2 reactions of a series of /?-phenethyl derivatives, and found kH/kD values of 0.56-0.63 at 80.45 "C.It seems likely that the above reactions are in fact Elcb and not E2. Additional evidence on this point, which also bears on the details of the slow phenoxide elimination step is provided by Redman and Stirlir~g.'~ Substitution of phenyl for one of the hydrogens on a-C has very small effect (a factor of 1.3) on the overall rate of the reaction, whereas a similar substitution for a typical E2 reaction, dehydrobromination of ethyl bromide, increases the rate by a factor of 50.Thus, the activated complex for elimination from the sulphone must have very little double bond character (either E2 or the second step of Elcb), and also very little "C-X bond rupture. Isotope effect studies with a-C carbon-14 labelled sulphones having various p-substituted phenyl groups at a-C should reveal very nicely any trends in the double bond character of the activated complex.Use of thiophenoxy instead of phenoxy sulphones increases the double bond character of the elimination reactions,73 and comparative a-C carbon-14 isotope-effect studies could go a long way in calibrating the degree of double bond character in activated complexes of various mechanisms. This reaction might also serve as a useful vehicle for the study of secondary hydrogen isotope effects in Elcb reactions. Would the overall rate of the reac- tion be affected by substituting deuterium for hydrogen at a-C? This would correspond to a /?-hydrogen isotope effect in solvolytic reactions, and has been very little studied. Streitwieser and Van Sickle74 have measured secondary a-and /?-hydrogen isotope effects in hydrogen exchange reactions of ethylbenzene.Referring again to equation (2), for an Elcb reaction with rate-determining carbanion formation (type A), 6 < 1, the overall rate will be first-order each in RH and YH (or RD and YE),so kobsH/kobsD = kIH/klD.This is the same kinetic expression as for the E2 reaction and variable kH/kD ratios would be expected in both cases, depending on the degree of hydrogen transfer between Y-and Is-C at the activated complex, a maximum being observed for the sym- metrical case.31 As mentioned above, isotope effect studies with a-C or X labelled compounds would provide a critical test for distinguishing between the E2 and Elcb type A mechanisms. 7e L. J. Steffa and E. R. Thornton, J. Amer. Chem. SOC.,1967, 89, 6149. R. P. Redman and C.J. M. Stirling, Chem. Comm., 1970,633. "A. Streitwieser, jun., and D. E. Van Sickle, J. Amer. Chem. SOC.,1962, 84, 254. Bordwell and co-~orkers~~~~~ have presented persuasive arguments that an Elcb type A mechanism is followed in the elimination af acetic acid from 2- phenyl-2-acetoxy-1 -nitrocyclohexanes and cyclopentanes and of methanol from 2-phenyl-trans-2-methoxynitrocyclopentane.Large (kobsH/kobsD = 4.9-8.1) ,&deuterium isotope effects are observed in all of the reactions, as would be expected for the Elcb type A mechanism for more or less symmetrical transfer of the /%hydrogen from P-C to X-. A reaction such as this might be very useful +---[QqB' QPll NO;--Bfi NO, B koYsJk2s MeO-/MeOH 8.0 piperidine 4.9 in investigating the possibility of changing the relative BC-H YS. Y-H bonding in the activated complex (and thus the magnitude of kobsH/kobSD) by changing the strength of the base used to abstract the /%deuterium.If the change in kobsH/kobsD of 8.0 to 4.9 when the base is changed from methoxide ion to piperidine is caused by a difference of this type, a more extensive investigation of other bases would appear to have merit. It would also be of interest to inves- tigate the possibility of a secondary isotope effect for a compound such as this labelled with deuterium at the 6-position. In what is suggested to be another carbanion elimination reaction of type A (no exchange could be detected) Cram and Wingrove found a low /3-deuterium isotope effect of kobsH/kobsD = 1.2 in the reaction of 2-methyl-3-phenyl-l,1,1-trifluoropropane with potassium t-butoxide in t-butyl A check for an isotope effect with the a-C or X labelled material would be of interest to see if this might be an E2 reaction.Another variant of the Elcb mechanism has been suggested by Rappoport 76 F. G. Bordwell, R. L. Arnold, and J. B. Biranowski, J. Org. Chem., 1963, 28, 2496. 78 D. J. Cram and A. S. Wingrove, J. Amer. Chem. SOC.,1964, 86, 5490. Fry and co-w~rkers~~ and supported by Bordwell’s If effectively all the substrate is converted by the base to the carbanion in a rapid reaction, additional base will not increase the concentration of the carbanion further, and the reaction will become pseudo-iirst-order. As defined, /%hydrogen isotopic isomers would both be converted completely to carbanion, and there would be no isotope effect since the isotopically substituted atom is no longer in the molecule in the following rate-determining step.In such a reaction Rappoport and Schohamy7’ found kH/kD= 0.93 for the elimination of HCN from 2,6-dimethyl-4-(1,1,2,2-tetracyanoethyl)aniIine in the presence of triethyl- or tri-n- butyl-amine. Bordwell, Yee, and Kni~e~~ found kH/kD= 1.7 for the overall elimination of methanol from 2-phenyl-trans-2-methoxy-l-nitrocyclopentane using sodium methoxide in methanol. The value of kH/kD for the first step (carbanion formation) was a normal 7.5, the same as that for carbanion formation from l-phenyl-Znitropropane using potassium t-butoxide in t-butyl alcohol.More O’Ferrall and Slae79 have carried out an extensive isotope effect study of a reaction thought to occupy the Elcb-E2 mechanistic border. The p-elimina- tion of water from 9-fluorenylmethanol to form dibenzofulvene was investigated in water, methanol, t-butyl alcohol, and mixtures of the latter two alcohols in the presence of the respective solvent conjugate bases. This substrate is charac-terized by a very poor leaving group, OH, and a p-hydrogen which is very acidic by virtue of the aromatic nature of the carbanion formed by its loss. Both factors favour an Elcb mechanism, and for all solvent systems the primary mechanism appears to be Elcb, with carbanion formation being rate-determining in t-butyl alcohol (type A mechanism) and carbanion decomposition being rate- determining in the other solvents (type B mechanism).Various amounts of simultaneous competitive reaction by an E2 mechanism are also proposed. 2 OH In water and methanol, exchange was rapid compared to elimination. In agreement with most of the work mentioned above, the exchange reaction isotope effects were large, with kH/kDg 7. For solvent water, the overall ’I7 Z. Rappoport, Tetrahedron Letters, 1968, 3601 ;Z. Rappoport and E. Shohany, Israel J. Chem. Proc., 1968,6, 15. 78 F. G. Bordwell, K. C. Yee, and A. C. Knipe, J. Amer. Chcm. SOC.,1970,92, 5945. 7p R. A. More O’Ferrall and S. Slae, J. Chem. SOC.(B), 1970, 260; R. A. More O’Ferrall, ibid., 1970, 268. Isotope Eflect Studies of Elimination Reactions (solvent) isotope effect was kH/kD= 0.92 (comparing the rate of the unlabelled compound in unlabelled water with the rate of the labelled compound in labelled water).The corresponding value for solvent methanol was 0-36. These are reasonable values for solvent isotope effects on the substrate-carbanion equilibria in type B Elcb reactions. Again, it is unlikely that a combination of a primary and solvent isotope effect on an E2 mechanism could give such low overall values for kH/kD.However, on the basis of detailed analyses of the initial rates of reaction of the labelled substrate in unlabelled solvent and of the unlabelled substrate in labelled solvent, the authors concluded79 that a small fraction of the reaction proceeds by a competitive E2 mechanism.In pure t-butyl alcohol or in its mixtures with 1.6 or 1.84% methanol the overall rate of the reaction became much greater and no exchange was detected. The overall isotope effect in the pure t-butyl alcohol was large, kH/kD = 7.5, but when 1-2% methanol was added it dropped to ca. 3.3 (with still no ex- change). More O’Ferrall’s favoured interpretati~n~~ of these results is that the rate-determining step of the elimination reaction in pure t-butyl alcohol is carbanion formation (Elcb type A mechanism), and that addition of small amounts of methanol results in the incursion of a slower competitive reaction by an E2 mechanism which has a small value for kH/kD.When more methanol is added, carbanion formation becomes reversible (Elcb type B mechanism) and kH/kD falls to less than unity. Presumably the competitive E2 reaction retains some, but not major, importance. The alternative interpretation that the elimina- tion reactions observed in some or all of these solvent-base systems are due to E2 reactions with different isotope effects owing to different degrees of transfer of H from P-C to the base, could be investigated by looking for isotope effects with a-C or X labelled compounds.Such studies would be especially valuable in comparing the results in pure t-butyl alcohol with those in t-butyl alcohol with 1-2% of methanol added. It would also be of interest to investigate more thoroughly the /%hydrogen isotope effects in t-butyl alcohol containing slightly more than 2% methanol where 6 values in equation (2) might be expected to be neither very large nor very small, leading to intermediate values for kH/kD. C.Labelled a-Hydrogen.-The above studies of More O’Farrell and Slae7 provide the only definitive data available on a-hydrogen isotope effects in Elcb elimination reactions. /%Tritium exchange was measured for the aa-2H2,P-3Hand ~za-H,,p-~H compounds in water, kH/kD= 1.02, and in methanol, kH/kD = 1.10: The corresponding value found by Streitwieser and Van Sickle7* in the forma- tion of the carbanion from ethylbenzene in the presence of lithium cyclohexyl- amide was kH/kD =1-11. These a-effects correspond to &effects in solvolytic reactions, but the cause of the effects is not as well understood.More O’Ferrall suggests that the difference between water and methanol may reflect an important contribution from carbon-oxygen bond breaking in the E lcb transition state (presumably in the elimination step). It would be interesting to compare the above results with the corresponding one for reaction in pure t-butyl alcohol where, supposedly, carbanion formation is rate-determining. There may be unrealised potential for Elcb-E2 borderline mechanistic discrimination in the use of a-hydrogen isotope effects. 5 Isotope Effect Studies of E2 Reactions A. Introduction-A General Reaction Scheme.-Of all the ways of representing the variety of activated complexes for the E2 spectrum of mechanisms, that suggested by More O’Ferrall*O seems to this author to be the most useful generally.It is well suited to discussions of variations of isotope effects with structures in elimination reaction systems. Figure 1 is a schematic representation A El I Y-+€1-c-c-x *YH +-C-C-X II Elcb’ II Reactant Carbanion Figure 1 E2 mechanistic spectrum of various E2 mechanisms, adapted from the potential surface diagrams of More 8o R.A. More O’Ferrall, J. Chem. SOC.(B), 1970, 274. Isotope Efect Studies of Elimination Reactions O’Ferrall.81 Each letter (actually, each spot) within the diagram represents a different activated complex, each with its own separate potential surface, and the positions of the letters relative to the species at the corners of the diagram indicate the structural relationships of the various activated complexes and their positions along the reaction co-ordinate.Thus, activated complex A would be described as ‘reactant like,’ with only slight weakening of the 42-H and “C-X bonds and with only slight /C-”C double bond character. This activated complex, in accordance with the Hammond would be for a reaction giving a very stable olefin. Activated complex F would be described as ‘car- bonium-ion like’ and ‘olefin like’, with very weak T-X bonding, much lC--aC double bond character, and extensive transfer of H from p-C to X-. It is a rela-tively simple matter to make qualitative predictions of isotope effects for the various possible labelled molecules from the strengths of the various bonds as analysed above.The procedure also lends itself to quantitative isotope effect calculations of the type mentioned in the Introduction. For instance, in a qualitative sense, for activated complex F, a large isotope effect would be pre- dicted for the X labelled compound and a small isotope effect (on the Y-H side of the maximum) would be predicted for the /%hydrogen labelled compound. It is also easy to see how substrate structural changes will affect the position and bonding of the activated complex and, hence, how the isotope effects will change with structural changes. For instance, if the elimination of ,!3-phenethyl chloride had a ‘central’ activated complex represented by B, substitution of a nitro-group in the para position of the ring would make the reaction more ‘carbanion like’, and the new activated complex would shift toward H with an accompanying increase in transfer of H from p-C to Y giving a smaller ,!3-hydrogen isotope effect (assuming a near symmetrical case for the unsubstituted compound), a decrease in the BC--“C double bond character, and an increase in the “C-X bond strength, giving a smaller isotope effect for the X labelled compound.It is to be noted that this change from F to H results in the activated complex becoming mure ‘carbanion like’ as the structural change results in greater carbanion stability. This is opposite to the Hammond postulate prediction because the effect of the structural change is applied in a fashion perpendicular rather than parallel to the primary reaction co-ordinate.This appears to be a general phenomenon, and is discussed in considerable detail by More O’Ferrall,*” following the earlier work of Thornton and co-~~orkers.~~~~~ B. Isotope Effects in the /?-Phenethyl System.-The /?-phenethyl system (10) seems ideally suited to the application of isotope effect studies in identifying In More O’Ferrall’s procedure, a potential surface is constructed with the reactant, product, carbanion, and carbonium ion occuping potential wells at the four corners of a square.Potential energy contour lines are drawn in the usual fashion to show saddle points (activated complexes) between various pairs of species at the four corners of the diagram, etc.The position of the reaction co-ordinate and the activated complex for a given reaction will depend on the relationship of the structure of the activated complex to the structures and energies of the four species at the corners of the potential surface. G. S. Hammond, J. Amer. Chem. Soc., 1955,77, 334. E. R. Thornton, J. Amer. Chem. SOC.,1967, 89, 2915. changes in the nature of activated complexes caused by changes in substrate structure or the reaction medium. Changes in X, Y-, Z, R1 and R2 can be expected to shift the activated complex in all directions from that for a reference ‘central’ mechanism represented by B in Figure 1. No systematic study of this type has been carried out, but most of the scattered data available seem to be consistent with analyses of the types mentioned in the introduction to this section.For instance, in the decomposition of ethyltrimethylammonium iodide in ethanol-ethoxide ion at 60 “C, the nitrogen isotope effect k14/k15is 1.0173s4 and the #?-deuterium isotope effect kH/kD is -6 (estimated from higher tem- perat ure data85). For p-phene thy1 trime t hylammonium bromide, the corre-sponding values are kI4/kl5= 1409484 and kH/kD N 3.88 If ethyltrimethyl- ammonium ion is taken to have an activated complex near B in Figure 1 with the /?-hydrogen about equally bonded to p-C and Y,replacement of a /3-hydrogen by phenyl would make the remaining /%hydrogens more acidic, shifting the activated complex toward H. This would give a more carbanion-like activated complex, with greater transfer of H from /?-Cto Y,with an accompanying reduction in the p-hydrogen isotope effect.There should also be less weakening of the “C-N bond, with an accompanying reduction in the nitrogen isotope effect. These are exactly the results observed. Another similar example is provided by Saunders and Edison’ss6 /%deuterium isotope effect data for different leaving groups. For (10; Z = R1 = R2 = H),+ + with X = Br, OTs, SMe,, and NMe,, kH/kD = 7.11, 5.66, 5-07, and 2-98. The order given would correspond to increasing carbanion character in the activated complex, and would be represented by a shift from near B toward H in Figure 1. These changes should be accompanied by increasing transfer of H from /?-C to H, and thus by decreasing /%deuterium isotope effects, as observed.Consistent with this, Saunders, Bushman, and Cockeril18‘ concluded that there was less carbanion character in the activated complex for the decomposition of /3-phen- ethyltrimethylammonium bromide in t-butyl alcohol-t-butoxide than in ethanol- ethoxide, on the basis of higher /?-deuterium isotope effe~ts~~?~~ and lower Hammet p values in the former solvent system. Jt is surprising that no one seems to have measured /%deuterium isotope effects in (10) with R1, R2, and X constant and 2 varying, say from CH30 to 84 G. Ayrey, A. N. Bourns, and V. A. Vyas, Canad. J. Chem., 1963, 41, 1759. V. J. Shiner, jun., and M. L. Smith, J. Amer. Chem. SOC.,1958,80,4095. 86 W. H. Saunders, jun., and D.H. Edison, J. Amer. Chem. SOC.,1960, 82, 138. 87 W. H. Saunders,jun., D. G. Bushman, and A. F. Cockerill, J. Amer. Chem. SOC.,1968,90, 1775. Isotope Efect Studies of Elimination Reactions CH, to H to C1 to NO2. Hammett p values for such reactions all seem to be positive,ss so it is quite likely that the activated complexes will all lie on the carbanion side (the ‘H side of B’) in Figure 1. Thus, for the substituent series suggested, the p-deuterium isotope effects should decrease regularly (or perhaps increase to a maximum and then decrease). By changing R2in (10) to methyl or phenyl, the whole series should be transferred toward the carbanion side of Figure 1, so that the expected maximum in the p-deuterium isotope effect could surely be found.The a-deuterium isotope effect data of Cockeril18@ support the argument that electron-withdrawing substituents on the ring in these systems shift the mech- anism away from the carbonium ion or olefin-like area toward the carbanion side of Figure 1. He found a-deuterium isotope effects of kH/kD = 1.047, 1.043, and 1.017 in (10; R1= R2 = H, X = OTs) for Z = CH20,H, and C1, respec-tively, indicating decreasing spacharacter for a-C in the order listed. McFarlaneQO found low, kH/kD= 2-3-24, /%deuterium isotope effects for such toluene-p- sulphonates, and interpreted his results in terms of a carbonium-ion-like E2 reaction, with the /$hydrogen less than half transferred from /3-C to Y-.If such is the case, large and decreasing isotope effects would be expected for X labelled compounds as the substituent Z becomes more electron withdrawing.Such experiments have not yet been carried out. However, in closely related work, the nitrogen isotope effects measured by Bourns and Smithg1 for Z = CH30,+ H, and CI in (10; R1= Ra = H, X = NMe,) were k14/k16= 1.014, 1,015,and 1-011, respectively. This again would correspond to more carbanion character for the activated complex of the chloro-compound, with an accompanying decreased weakening of the T-N bond and a lower isotope effect. Especially interesting studies of changing isotope effects with changing reacton media have been reported by Saunders, Cockerill, and co-workersg2 in their work with p-phenethyldimethylsulphoniumsalts, (10; Z = R1= Ra = + H, Xi = SMe,).In the reaction of hydroxide ion with the sulphonium bromide in water-dimethyl sulphoxide mixtures the rate increased sharply with increasing DMSO content and the sulphur isotope effect decreased from k32/k34= 1.0074 in pure water to 1.0011 in ~20%DMSO. The p-deuterium isotope effect did not change very much in this solvent range, but when the DMSO content was increased further, kH/kD increased to a maximum and then decreased again. The effect of adding DMSO was interpreted in terms of an increase in the effec- tive base strength of hydroxide ion due to solvation changes, thus shifting the activated complex toward the carbanion-like side of the E2 spectrum (from near B toward H or G in Figure 1).This should result in decreased weakening C. H. DePuy and C. A. Bishop, J. Amer. Chem. SOC.,1960,82,2532, and earlier research cited there. 8B A. F. Cockerill, Tetrahedron Letters, 1969, 4913; see also ref. 26 for other a-deuterium isotope effects in the /I-phenylethyl system. 9o F. E. McFarlane, Dim. Abs. (B), 1969, 2358. 91 A. N. Bourns and P. J. Smith, Proc. Chem. Soc., 1964,366. ea A. F. Cockerill, J. Chem. SOC.(B), 1967, 964; A. F. Cockerill and W. H. Saunders, jun., J. Amer. Chem. SOC.,1967, 89,4985, and earlier papers in the series cited there. 192 of the aC-S bond, giving decreased sulphur isotope effects, as observed. As the DMSO content is increased even further, the carbanion becomes even more stable and, now in accordance with the Hammond postulate,s2 the activated complex becomes increasingly more reactant-like (corresponding to a shift from the G-H area toward A in Figure 1).Assuming that the transfer of H from P-C to Y was more than half complete at the saddle point in the 20% DMSO solution, adding DMSO and making the activated complex more reactant-like should result first in having H symmetrically bonded to Y and p-C (maximum kH/kD),and then to having H less than half transferred from /3-C to Y (decreasing kH/kD) as observed. Thus, as the DSMO content is in- creased, the E2 saddle points on the potential surfaces represented in Figure 1 would move from somewhere near B toward the area between G and H, and then back toward A. The onIy labelled carbon isotope effect studies in /?-phenethyl systems were carried out on p-nitrophenethyltrimethylammoniumsalts (10; Z = NOz, R’= f R2 = H, X = NMe,), and in that case widely divergent values were reported for the same effect from two different laboratories.For the a-C labelled com- pound, Hodnett and D~nn~~ found klZ/kl4= 1.078, whereas Simon and Mull- hofer’s value for the same effect was 1.026. The reason for the discrepancy is not known and, in any event, comparative data for related compounds are needed before useful mechanistic conclusions can be drawn. and amino-nitr~gen~~ isotope effects were also reported for this compound, but again lack of comparative data precludes mechanistic speculation, except for the very important point that these studies confirm that the mechanism is E2, and not Elcb.Other /%deuterium isotope-effect studies of E2 reactions which seem to have substantial carbanion character are those of England and McLennan on DDT,03 Yano and Oae on p-phenylsulphonylethyl toluene-p-s~lphonate,~~ and Baker and Spillett on /3-phenethyl methyl sulph~xide.~~ A particularly interesting and readable account of the use of tracer and isotope-effect data in eliminating all other mechanisms than E2 for the bimolecular elimination reaction of /!?-phen- ethyltrimethylammonium derivatives is given by Smith and Bourns. 96 Other /%deuterium isotope effect studies of p-phenethyl derivatives which appear to react by central E2 mechanisms include those of Burton and de la Mare on 1,l,2,3,4-pentachlorotetraling7(their a-deuterium isotope effect measurements provide additional support for a central mechanism where a-C has considerable spz character), Willi on various 2,2-diphenethyl benzene- ~ulphonates,~~ and Shiner Bethel1 and Cockerill on 9-brom0-9,9’-bifluorenyl,~~ @aB.D. England and D. J. McLennan, J. Chem. SOC.(B), 1966,696. Y. Yano and S. Oae, Tetrahedron, 1970, 26, 27. B6 R. Baker and M. J. Spillett, J. Chem. SOC.(B), 1969, 481. 96 P. J. Smith and A. N. Bourns, Canad.J. Chem., 1970,48, 125. @’G. W. Burton and P. B. D. de la Mare, J. Chem. SOC.(B), 1970,897. A. V. Willi, J. Phys. Chem., 1966,70, 2705; Helv. Chim. Acta, 1966,49, 1725. @O D. Bethel1 and A. F. Cockerill, J. Chem. SOC.(B), 1969,917. Isotope Efiect Studies of Eliminatiorr Reactions and De Puy and their co-workers on 2-aryl-1-propyl derivatives.loO Bunnett, Davis, and Tanida have reportedlOl low (kR/kD= 2-4 and 2.6) &deuterium isotope effects for the EtSNa- and MeONa-catalysed elimination reactions of l-phenyl-2-methyl-2-~chloro[l,l-~H,]propane,(10; Z = R1 = H, R2 = Me, X = CI).They interpret these results in terms of a carbonium-ion-like E2 reaction. Presumably the @hydrogen is less than half transferred from P-C to Yin the activated complex. It would be of interest to examine /%deuterium and leaving group X isotope effects as a function of changing substituent 2 in such a system. As Z becomes more electron withdrawing the mechanism would probably move toward the central E2 area, resulting in increasing /%deuterium and decreasing X isotope effects.C. Isotope Effectsin Other E2 Systems-syn vs. anti Elimination.-Almost all of the isotope-effect research in the p-phenethyl system has involved rneasure- ments of leaving group and /%deuterium effects. The possibilities for obtaining useful mechanistic data from a-C or p-C labelled compounds have not been exploited and there are not enough reported results on other systems to provide a solid base for mechanistic conclusions or extrapolation. Simon and Mullhofer12 found little variation in isotope effects for elimination reactions of a-C carbon-14 labelled ethyl-, n-propyl-, and t-butyl-trimethylammonium salts (k12/k14 N 1.06-1*07 at 40 "C). Their value for a-C carbon-14 labelled 2-(pnitrophenyl)- ethyltrimethylammonium salt decomposition was significantly lower, kf2/k14 = 1-026 at 100 "C,but as mentioned above, Hodnett and Dunn's value for the same effect at the same temperature was 1*078.54 The discrepancy has not been resolved.Generally, these reactions all appear to have activated complexes with a good deal of carbanion character, implying relatively little "C-X bond weakening. All of the reported a-C-isotope effects seem quite high for such an activated-complex model. More extensive data are clearly needed. In the only #LC labelled isotope effect study reported, Simon and Mullhofer12 found k12/k14 =1.036 for the decomposition of n-propyltrimethylammonium salts at 51 "C. Again, comparative data for other compounds would be very useful.Shiner's initial report25 of a large primary @deuterium isotope effect, kH/kD = 6-7 at 25 "C, in the E2 elimination reaction of isopropyl bromide in ethanol- sodium ethoxide made it clear that the presence of an isotope effect could be diagnostic of mechanism. In recent years, this presence or absence of a primary 19-deuterium isotope effect has been used extensively to help decide whether elimination in an E2 reaction takes place by a syn or an anti mechanism. For instance, in the decomposition of the threo quaternary ammonium salt (lla and d), large /3-deuterium isotope effects were found by Pankova, Sicher, and Zavadalo2 for both cis-and trans-olefin formation. For the isomeric erythro- looV.J. Shiner, jun., and B. Martin, Pure Appl. Chem., 1964, 8, 371; V. J. Shiner, jun., and M. L. Smith,J. Amer. Chem. Soc., 1961,83,593; C. H. De Puy, D. L. Storm, J. T. Frey, and C. G. Naylor, J. Org. Chem., 1970, 35, 2746. lol J. F. Bunnett, G. T. Davis, and H. Tanida, J. Amer. Chem. Soc., 1962, 84, 1606. lornM. Pankova, J. Sicher, and J. Zavada, Chem. Comm., 1967, 394 CH2But HH ariti \/C-CI1 1E expected-I \Bu" CH2Bu'NMe,+ cis (kH/kD)cis= 3.1 -4.7, i.e. cis-olefin is formed by unti elimination il CH, €311' uii ti 1[ c1i*1311t \/ 110 IE expected* /c=c \ Bun trans Bun H\ ,CH,Bu'syn c=c1E expected, /\ Bun H NMe,+ tram (kH/kD)trans= 2.3 -492, i.e. trans-oleh is formed by syit elimination compound (1 1band c), no isotope effect was found in the formation of either the cis-or trans-olefin.Clearly, the cis-olefin is being formed by the 'normal' anti elimination mechanism, whereas the trans-olefin is being formed by syn elimin- Isotope Efect Studies of Elimirratioti Reactions ation. Similar isotope-effect results had been obtained early by Zavada,Svoboda, and Sicherlo3 in their study of the decomposition of cyclodecyl quaternary ammonium salts. Since that time, similar isotope-effect or tracer studies have led to identification of the syn elimination mechanism as an exclusive or important path for formation of trans-olefins in a number of other ~ystems.~~~-~~~ On the other hand, the same isotope-effect tool has been used to show that the elimination react ions of threo-1-met hyl-2-deuter ioprop yltrimet hyl-am- monium ion (12), to both cis- and trans-2-butene proceed by anti mech- anisms.loS Similarly, both cis-and trans-Zbutene are formed from erythro-3- D Me*:Me‘ NMe+ (1 2a) Me I> anti \I + c=cD kH/kD = 1.0 / \ H H deuterio-Zbromobutane by anti mechanisms, the trans-olefin giving kH/k” values of 34-46, and the cis-olefin giving kH/kDvalues of 1.0-l.1.109 erythro and threo-3-deuterio-Zbutyl tosylates also undergo anti elimination only.11o The remarkable difference in the mechanism of trans-olefin formation between quaternary ammonium salts (11) and (12) is almost certainly due to the differ- ences in the steric environment about the /?-hydrogen being removed in the elimination reaction.lo5 Staggered conformations (1 la) and (12a) give cis-olefin by normal anti elimination mechanisms; conformation (1lb) is much more Io3 J.Zavada, M. Svoboda, and J. Sicher, Tetrahedron Letters, 1966, 1627;Coll.Czech. Chem. Comm., 1968,33,4027. lo4J. L. Coke and M. C. Mourning, J. Amer. Chem. SOC.,1968,90,5561. lo6 D. S. Bailey and W. H. Saunders, jun., Chem. Comm.,1968, 1598; J. Amer. Chem. SOC. 1970,92, 6904. M. Svoboda, J. Zavada, and J. Sicher, Coll. Czech. Chem. Comm., 1967,32, 2104; 1968 33, 1415. lo’ M. Pankova, J. Zavada, and J. Sicher, Chem. Comm., 1968, 1142; J. Zavada, M. Pankova, and J. Sicher, ibid., 1968, 1145. lo8D. H. Froemsdorf, H. R. Pinnick,jun., and S. Meyerson, Chem. Comm., 1968, 1600.logR. A. Bartsch, Tetrahedron Letters, 1970, 297. 110 D. H. Froemsdorf, W. Dowd, and W. A. Gifford, Chem. Comm., 1968,449. crowded. Conformation (12b) is relatively uncrowded, leading to normal anti elimination, but in its counterpart (1 lc) the large trimethylamino-group forces the carbon chains on both the a-and p-carbons back so as to ‘surround’ the anti-,8-hydrogen, thus reducing its accessibility to the incoming base. In the alternate eclipsed conformation (1Id) the /%hydrogen is ‘surrounded‘ only on one side, and if the alpha and beta alkyl groups are large enough, this steric effect will overcome the natural tendency toward anti elimination through a staggered conformation. These steric effects should become worse as the com- plexity of (i) the a-and ,8-alkyl groups, and (ii) the base becomes greater, leading to a greater preference for the syn rather than the anti mechanism for trans-olefin formation.Bailey and Saunders105 have found results corresponding to both such effects in their studies of the reactions of 2- and 3-hexyltrimethyl- ammonium ions with various solvent-base systems. Increased base strength also results in a greater tendency toward syn elimina-tion.lo5 All of these reactions seem to have a great deal of carbanion character; the very low nitrogen isotope effect, k1*/k15 = 1.002, in the syn elimination of trans-2-phenylcyclohexyltrimethylammonium iodide5’ was cited earlier as evidence of this. Accordingly, it is quite likely that the ,8-hydrogen is more than half transferred from 13-Cto Y in all cases now being considered. Referring again to Figure 1, an increase in the base strength will cause the reaction to become even more carbanion-like, moving the activated complex even farther from the central B area toward H and G.This motion, being ‘perpendicular’ to the primary reaction co-ordinate, will cause even greater transfer of H from ,8-Cto Y,thus reducing the isotope effect. An alternate viewlo5 is that increasing the base strength leads to less stretching of both the carbon-hydrogen and carbon-carbon bonds. In fact, the isotope effects for syn elimination, kH/kD = 1.9-2-3, seem to be smaller than those for anti elimination, kH/kD = 2-6-3.4, in almost all cases.102J04J05 In norbornyl and bicyclo[2,2,2]octyl derivatives, syn elimination is the pre- dominant or exclusive path, as shown by deuterium tracer and isotope-effect studie~.~~l-ll~In these compounds also, (kH/kD),,tt > (kH/kD)8,,.hH bD+“’n UtIfh+ Formed H Not formed kH/k = 1-86 for X = NMe, ll1H.Kwart, T.Takeshita, and J.L. Nyce,J. Amer. Chem. SOC.,1964,86,2606. 11* N. A. LeBel, P. D. Beirne, E. R. Karger, J. C. Powers, and P. M. Subramanian, J. Amer. Chem. SOC.,1963, 85, 3199; N. A. LeBel, P. D. Beirne, and P. M. Subramanian, ibid., 1964, 86,4144. llaJ. L.Coke and M. P. Cooke, jun., J. Amer. Chern. Soc., 1967,89,2779, 6701. 197 Isotope Eflect Studies of Elimination Reactions Coke and co-workers114 have shown that syn elimination is an important (sometimes predominant) path for the Hofmann elimination in 4-, 5-, 6-, and 7-membered rings, where only cis-olefins can be formed.They used tracer and isotope effect techniques similar to those mentioned above. Brown and SaunderP extended the above research on 3,3-dirnethyIcyclopentyltrimethyl-Me Me MeQ*@ Me Me Me I-I H. I) NMe,+ D If kH/kD=1-71 ammonium salts to other base systems, and found that the amount of syn elimination varied widely (from 10% to 72% as the basicity of the medium increased). The values for kH/kD also varied somewhat with base (1 -62-1 ~92) but no clear, mechanistically useful pattern is apparent. For cyclopentyltri- methylammonium ion, Brown and Saunders determined that = 4-75 under conditions where (kH/kD)Byn= 1-85 for the dimethylcyclopentyl compound.Under conditions where only anti elimination is important, Saundem and Ashe116 measured intramolecular /%deuterium isotope effects of kH/kD = 4-33, 3.99, and 3.22 at 191 "C in aqueous base for cyclohexyl, cyclopentyl-, and 3-pentyl-trimethylammonium toluene-p-sulphonates. The results are interpreted in terms of increasing carbanionic character for the compounds in the order listed, resulting in increasing transfer of H from P-C to Y and thus decreasing values for kH/kD. Their stated plan to see if, as predicted, the nitrogen isotope effect will decrease in the order listed should provide a valuable test of these mechanistic ideas . Finley and Saunders2' have carried out an extensive study of primary 18-and secondary a-and /%deuterium isotope effects in the E2 elimination reactions of cyclohexyl toluene-p-sulphonate in ethanol-sodium ethoxide and t-butyl alcohol-potassium t-butoxide.Both the a and 18 secondary isotope effects were large, kH/kD = 1.14-1.15 and 1.36-1-51, and the primary /%effect was larger in t-butyl alcohol, kH/kD = 7.53, than in ethanol, kH/kD = 4.47. Although other interpretations of these data might be given, it is interesting to speculate that the activated complexes for these reactions might be near 'central' with much double bond character (near B in Figure 1). Both secondary isotope effects llJM.P. Cooke, jun., and J. L. Coke, J. Amer. Chem. SOC.,1968,90, 5556; J. L. Coke and M. P. Cooke, jun., Tetrahedron Letters, 1968,2253; J. L.Coke, M. P. Cooke, jun., and M. C. Mourning, ibid., 1968, 2247. 115 K. C. Brown and W. H. Saunders,jun., J. Amer. Chem. SOC.,1970, 92, 4292. 116 W. H. Saunders,jun.,and T. A. Ashe, J. Amer. Chem. SOC.,1969,91, 4473. 198 are large, consistent with much sp2 character for both a-C and p-C. If this were the case, the primary p-deuterium isotope effect in ethanol might correspond to slightly less than half transfer of H from P-C to Y. The result in t-butyl alcohol would then be shifted toward more carbanion character in the activated complex, corresponding to near symmetrical bonding of H to p-C and Y.It would be interesting to have primary and secondary ,&deuterium isotope effect results for 1-methyl-or l-phenyl-cyclohexyl toluene-p-sulphonate for comparative purposes.Such substitution should shift the activated complex toward the carbonium ion side of Figure 1. 6 Other Elimination Reactions and Mechanisms A. Merged Elimination-Substitution Reaction Mechanisms.-The pioneering research of de la Mare and Vernon117 demonstrated the greater effectiveness of the weaker base thiophenoxide ion than of the stronger base ethoxide ion in promoting elimination reactions. Since that time, elimination reactions have been shown to be induced with great facility by other weak bases, especially halide ions in dipolar aprotic so1vents.8J18-121 It is contended by sorne8Jz1 that these reactions are more or less normal E2 eliminations, but the E2H-E2C spectrum of mechanisms proposed by Parker, Ruane, Biale, and WinsteinlZ2 is supported by others, notably Parker's research group.lz0 In the E2H-E2C proposal, removal of the /%hydrogen in elimination reactions is supposed to be accompanied by and aided to a greater or lesser extent by backside attack of Y on the "C-X bond, as shown in activated-complex models (13)--(15).To H ---Y HY I I II x A x (1 3) E2H (14) (15) E2C' date, very little isotope effect research has been reported on reactions of this type, and it is not clear whether this mechanistic scheme can be distinguished 117 P. B. D. de la Mare and C. A. Vernen, J. Chem. SOC.,1956,41. 118 S. Winstein, D. Darwish, and N. J. Holness, J. Amer. Chem. SOC.,1956, 78, 2915.llg R. A. Bartsch, J. Org. Chem., 1970, 35, 1023, and earlier work cited there. l80 G. Biale, A. J. Parker, S. C. Smith, I. D. R. Stevens, and S. Winstein, J. Amer. Chem. SOC.,1970,92, 115; D. Cook and A. J. Parker, Tetrahedron Letters, 1969,4901, and earlier work cited there. la1 J. F. Bunnett and E. Baciocchi, J. Org. Chem., 1970, 35, 76; D. Eck and J. F. Bunnett, J. Amer. Chem. SOC.,1969,91, 3099, and earlier work cited there. lZ2A. J. Parker, M. Ruane, G. Biale, and S. Winstein, Tetruhrdron Letters, 1968, 2113. Isotope Eflect Studies of Eliminuriori Reactions from the usual E2 spectrum of mechanisms (Figure 1 above) on the basis of isotope effect measurements. It would appear that there is little if any difference between (13) and a 'central' or 'carbanion-like' E2 activated complex.For (14) and (15), the obvious difference from the E2 counterparts is in the inter- action of Y with a-C. To the extent that this interaction is important, the a-C and secondary a-deuterium isotope effects should be shifted away from those characteristic of a carbonium-ion-like activated complex toward those charac- teristic of sN2 reactions, that is toward higher a-C, and lower secondary a-deuterium isotope effects (see the analysis in the El section above). To the extent that this Y-"C interaction is not important, the mechanisms become part of the normal spectrum of E2 mechanisms. No a-C or a-deuterium isotope effect studies have been reported for these systems. There is some question in the author's mind as to whether such results would be considered to be useful by the proponents of the scheme since Parker's group contends120 that in the E2C activated complex, P-C is virtually sp2 hybridized and there is a well developed double bond between a-C and p-C.' It seems that two substituents and a well developed double bond at a-C leave little room for bonding between a-C and Y (or X).The small to medium-sized &deuterium isotope effects in such reactions seem to be more or less normal for E2 reactions which are carbonium-ion-like and product-like (near F on Figure l), where H is more than half transferred from P-C to Y-. An E2 reaction with an activated complex between B and E in Figure 1, with the transfer of H from p-C to Y- less than half complete, would also be consistent with the data.Comparative studies on structurally similar substrates would be needed for distinction. In the tetraethylammonium fluoride catalysed elimination reaction of /3-phenethyl the P-deuterium isotope effect was kH/kD= 3.99 at 25 "C.The corresponding value for the tetraethyl- ammonium chloride catalysed elimination reaction of t-butyl chloride in aceto- nitrile at 45 "C was kH/kD = 3~81.l~~It is also easy to visualize an activated complex in the E2H-E2C spectrum which would be expected to give such results. More O'Ferrall has made a few model isotope effect calculations for such Kevill, Cromwell, and co-w~rkers~~~ proposed a somewhat different kind of SN-E merged mechanism for the halide-ion-promoted elimination of 2-bromo-2- benzyl-1-indanone and its 3,3-dimethyl derivative in acetonitrile.In their scheme, attacking nucleophile Y-is oriented near the back side of the "C-X bond by Ia3 J. Hayami, N. Ono,and A. Kaji, Tetrahedron Letters, 1970, 2727. la4D. N. Kevill and J. E. Dorsey, J. Org. Chem., 1969,34, 1985. D. N. Kevill, E. D. Weiler, and N. H. Cromwell,J. Amer. Chem. SOC.,1966,83,4489, and earlier papers in the series cited there. association with the nearby relatively positive carbonyl carbon. /3-Deuterium isotope effects for the two compounds were kH/kD = 3.3 and 2-5 at 74 "C. * Br 6-These results are consistent with an activated complex which is very carbonium- ion-like so that there is little weakening of the BC-H bond and a low isotope effect.Introduction of the two methyl groups enhances the carbonium ion nature of the reaction (movement of the activated complex further toward E from B on Figure l), reducing the transfer of H from P-C to Y, and reducing the isotope effect. Although such measurements have not been made, if this is the correct interpretation of the mechanism of the reaction, it would be pre- dicted that the a-Cisotope effect would decrease and the X isotope effect would increase when the two methyl groups are introduced. Another interesting conse- quence of this mechanism is that an isotope effect would be expected for the carbonyl carbon carbon-14 labelled compound. (But since the developing double bond is conjugated with the carbonyl group in any mechanism, at least a kind of secondary carbon-14 isotope effect for the carbonyl carbon labelled compound might be expected.) The Hammett plot of the rate data for various Z groups is curved, indicating a mechanism changing with Z.It would be interesting to see if there are corresponding changes in kH/kD,etc. A third type of merging of substitution and elimination reaction mechanisms has been proposed by Sneen and Robbins,lZ6 but no attempt has been made as yet to study its isotope effect ramifications. The iodide-promoted elimination of bromine from 1,1,2,2-tetrabromo[l ,2-2H,]- ethane may also have a S-E merged mechanism of some sort. Lee and Miller a secondary deuterium isotope effect of kH/kD z 1.28 at 81-1 11 "C, which is consistent with considerable double bond character in the activated complex.B. The Ylide Mechanism.-The ylidemechanismfor the decomposition of quatern- ary ammonium salts and related compounds is a special case of the carbanion mechanism, and much of the isotope effect discussion in the Elcb section above is pertinent to the ylide case as well. Cope and MehtalZ8 showed that quaternary lZ8 R. A. Sneen and H. M. Robbins, J. Amer. Chem. SOC.,1969,91,3100. 12' W. G. Lee and S. I. Miller, J. Phys. Chem., 1962, 66, 655; see also C. S. T. Lee, I. M. Mathai, and S. I. Miller, J. Amer. Chem. SOC.,1970,92,4602. A. C. Cope and A. S. Mehta, J. Amer. Chem. SOC.,1963,85,1949. Isotope Effect Studies of Elimination Reactions ammonium hydroxide (16) decomposed to 1,l-di-t-butylethylene with nearly complete transfer of the p-deuterium atom to the trimethylamine evolved, indicating predominant reaction through ylide (1 7).No methyl-deuterium or +NMe, D +NMe, (16) methyl-carbon-14 isotope effect studies appear to have been carried out on such reactions. Isotope effects would be expected for such labelled compounds, subject to the usual carbanion isotope effect considerations (see the Elcb section above), and for the nitrogen, “C,BC, and a-and ,&hydrogen labelled compounds as well, if conversion of (17) to olefin is rate determining. On the other hand, if formation of (17) is rate determining, no isotope effects would be expected for the nitrogen, a-C,P-C, or a-or /%hydrogen labelled compounds.Using the tracer technique illustrated above, the ylide mechanism has been excluded for a number of elimination reactions.57~100~102~105~113~129 In the decomposition of 5a-cholestan-6fi-yl trimethylammonium iodide and its tris-trideuteriomethyl isotopic isomer in ethanol at 70 “C, Cooper and McKenna130 found kH/kD= 1.6. The authors suggest that this high ‘secondary’ isotope effect has a steric origin, in that there is more steric compression to be relieved in the unlabelled than the labelled compound. It is interesting to specu-late about the possible alternative explanation that the reaction might be proceed- ing, at least in part, by an iodide ion-promoted ylide mechanism with an accom- panying primary isotope effect.C. Pyrolytic Elimination Reaction~.~~~---Several /%deuterium isotope effect studies of syn eliminations in the pyrolyses of esters have been re~0rted.l~~ In all cases the kH/kD values are quite large, and the results are interpreted in terms of a concerted reaction involving a six-membered cyclic activated complex in which there is considerable BC-H bond rupture. No systematic comparisons of kH/kD values for closely related compounds have been carried out, nor have isotope effects been measured for any a-C or P-C labelled com- 129 W. H. Saunders, jun., and D. Pavlovic, Chem. Znd. (London), 1962, 180. lSo G. H. Cooper and J. McKenna, Chem. Comm., 1966,734. 13l C. H. DePuy and R. W. King, Chem. Rev., 1960, 60, 431; A. Maccoll, ‘Olefin-forming Eliminatjons in the Gas Phase’, in ‘The Chemistry of Alkenes’, ed.S. Patai, Interscience Publishers, New York, 1964, p. 203. 138 D. Y. Curtin and D. B. Kellom, J. Amer. Chem. SOC.,1953,75,6011; P. S. Skell and W. L. Hall, ibid., 1964, 86, 1557; C. H. DePuy, R. W. King, and D. H. Froemsdorf, Tetrahedron, 1959,7, 123; A. T. Blades and P. W. Gilderson, Canad.J. Chem., 1960,38, 1401, 1407, 1412. (18.) pounds. Considerable kinetic information is available133 on system (18), and it would be interesting to examine the primary isotope effects for a-C, P-C, and #&hydrogen labelled compounds as a function of Z and M. Similar secondary isotope effect studies with the a-hydrogen labelled compounds would also be of interest. Blades, Gilderson, and Wallbridge13* have also observed large deuterium isotope effects in the thermal elimination reactions of ethyl chloride and bromide.The results are interpreted in terms of a four-centre activated complex with considerable PC-H bond rupture. Studies of the variation of carbon, halogen, and deuterium isotope effects in the corresponding thermal decompositions of a series of p-substituted a-and/or j3-phenethyl halides would be of interest. In a recent study of a rather unusual reaction, Egge~l~~ measured the 18-deuterium isotope effect in the thermal decomposition of 2-deuteriotri-isobutyl- aluminium. The isotope effect is large, kH/kD = 3.7 (extrapolated to 25 "C from higher temperature data), and is interpreted in terms of a four-membered cyclic activated complex.But RU' Bu' CHZI I BU~--AI-CH, BU'-AL----CH, Bd-Al + C-Me I--+ ! I I I I!I -I II D-:-Me I>----. C-Me D Me I IM t Me The isotope effect study of the Chugaev reaction by Bader and is a classic example of the use of the successive labelling approach. They were able to distinguish between two suggested syn elimination mechanisms, repre- sented by activated complexes (19) and (20), for the pyrolysis of 5-methyl-tran.s- 2-methyl-1-indanyl xanthate on the basis of *C, a-S and P-S isotope effect 133 G. G. Smith, F. D. Bagley, and R. Taylor, J. Amer. Chem. SOC.,1961,84,3647; R. Taylor,J. Chem. SOC.,1962,4881. la4 A. T. Blades, P. W. Gilderson, and M. G. H. Wallbridge, Canad.J. Chem., 1962,40,1526, 1533; A.T. Blades, ibid., 1958, 36, 1043. labK. W. Egger, Internat. J. Chem. Kinetics, 1969, 1, 459. Ia4 R. F. W. Bader and A. N. Bourns, Canad. J. Chem., 1961,39, 348. Isotope Eflect Studies of Elimination Reactions studies. The observed *C, a-S,and /3-S isotope effects were k12/k13= 1-0004i-0.0006, 1.0086 i-0.0016, and 1.0021 k 0.0007.These values are consistent with a large bonding change at a-S,a small bonding change at fl-S, and little or no total bonding change at *C, in going from reactant to activated complex. Inspection of (19) and (20) clearly reveals the superiority of the latter, especially as far as the a-Sisotope effect is concerned. The size of the p-S isotope effect is a bit disturbing for reaction through (20); perhaps there is also considerable *C-PS bond stretching at the saddle point (that bond must eventually break in forming the final products).In related work, Briggs and Djerassi found137 the expected normal /&deuterium isotope effects in the syn elimination reactions of 2-methylcyclohexyl-S-methyl xanthates and acetates. However, some anti elimination was also found and, for the xanthates, this reaction proceeded without any detectable /%deuterium isotope effect. The authors interpreted this unusual result in terms of an El type reaction, where "(2-0bond rupture, unassisted by ,B-hydrogen bond extension, was the rate-determining step, For the anti elimination of the acetate, the /3-deuterium isotope effect found was interpreted in terms of a similar carbonium- ion-like activated complex but, in this case, with neighbouring hydrogen assistance.D. Eliminations to Form Carbon-Oxygen and Carbon-Sulphur Double Bonds.-Several isotope effect studies have been carried out on elimination reactions which result in the formation of carbonyl or thiocarbonyl groups or of sulphenes. The experimental approaches, mechanistic tests and conclusions, and general results are much the same as in olefin-forming eliminations. Buncel and found a large nitrogen isotope effect, k14/k15 = 1.0196 at 30 "C,in the con- version of benzyl nitrate to benzaldehyde in an ethanol-ethoxide ion system. 6-07 Y-I1PhCH-O-NOZ----+ PhCH + NO, lS7 W. S. Briggs and C.Djerassi, J. Org. Chem., 1968,33, 1625. 13* E.Buncel and A. N. Bourns, Cunad. J. Chem., 1960,38,2457. No deuterium was incorporated into the recovered reactant which was carried out in C2H50D,so it is clear that a carbanion is not formed reversibly. The results are consistent with an EZlike concerted elimination. In a similar study, Smith and found large nitrogen, k14/k16= 1.0091--1.013, and /3-deuterium isotope effects, kH/kD= 4.25, in the conversion of 9-fluorenyl nitrate to fluorenone, again consistent with a concerted EZlike mechanism. A much smaller ,&deuterium isotope effect, kH/kDE 1-1 at 430 "C,was measured by Cookson and Wallis140 in the pyrolysis of allyl diphenylmethyl ether to form benzophenone and propene. The low value was thought to be r 6-l* accounted for by an activated complex with much carbonium ion character at the allylic carbon and little stretching of the benzhydryl C-D bond.An excellent check on the mechanism of this reaction would be to measure carbon-14 isotope effects for compounds successively labelled at the benzhydryl carbon and the three carbons of the allyl group. Malonic esters and related compounds containing easily cleaved -0Ar groups may hydrolyse by carbonyl-forming elimination reactions to produce keten intermediates. Several solvent deuterium isotope effect give OH Y!II I Y-ArO--C--C'--C02Et~ ArO-C=C--CO,Et -Ar, c)=C=<--C'O,EtI YH I IK K R results consistent with a type B Elcb mechanism (reversible carbanion forma- tion). Thiocarbonyl groups are formed in elimination reactions of Ar-S- from disulphides.The p-deuterium isotope effect for such an elimination reaction from ~(biphenyl-4-y1)benzyl p-tolyl disulphide in isopropyl alcohol-sodium 139 P. J. Smith and A. N. Bourns, Canad. J. Chem., 1966,44,2553. 140 R. C. Cookson and S. R. Wallis, J. Chem. Soc. (B), 1966, 1245. 141 For leading references, see R. F. Pratt and T. C. Bruice, J. Amer. Chem. SOC.,1970, 92, 5956. Isotope EffectStudies of Elimination Reactions isopropoxide at 30 "C was found14* to be large, kH/kD = 6-1, consistent with an activated complex with H about equally bonded to p-C and Y. The corresponding elimination of HCN(DCN) from 4-phenyldiphenylmethyl Ph Ph Ph y-[ n]rPhCbH4-k 1 -S-CN .111, PhCsHb -C=S---CN PhC, H,-C=SI 1zf H*--Y 6-thiocyanate had a much smaller isotope effect,143 kH/kD= 3-0, at 20 "C.This was interpreted in terms of greater transfer of H from p-C to Y in the activated complex than for the above disulphide case.Sulphur, P-C, and cyanide carbon isotope effect data would be helpful in further placing these reactions at their proper positions within their E2-like mechanistic spectrum. In related research, alkane sulphonyl chlorides were found to undergo base- catalysed elimination reactions to give ~u1phenes.l~~ The /i?-deuterium isotope Y-PhCH2SO2C1 PhCFiX SO2 + I-ICl effects were low, kH/kD = 2.0-4-0, consistent with extensive transfer of H from P-C to Y in the activated complex. E. Elimination to Form Triple Bonds.-Several deuterium isotope effect studies have been carried out on elimination reactions of olefinic substrates, leading to the formation of acetylenic compounds.Prichard and B~thner-Byl~~ concluded that the elimination-rearrangement reaction of l-bromo-2,2-diphenylethylene to diphenylacetylene takes place by a type B (pre-equilibrium) Elcb mechanism. The solvent isotope effect was kH/kD= 033, consistent with that conclusion (see the discussion in the Elcb section above). In a rather unusual reaction, Schlosser and Ladenberge~l~~ found large, kH/kD -7-3-15.3, a-deuterium isotope effects and small, kH/kD-1-00-144, /%deuterium isotope effects in the dehydrochlorination of cis-and trans-l-chloro-2-phenyl styrenes with phenyl-lithium. The mechanism proposed for this reaction involves rate-determining abstraction of the a-hydrogen by the phenyl-lithium, followed by fast elimination of HCI from the lithium compound.,D PhLi 'Li PhLi PhC=C Li\c1 slow' PhO 14a U. Miotti, U. Tonellato, and A. Ceccon,J. Chem. SOC.(B), 1970, 325. 143 A. Ceccon, U. Moitti, U. Tonellato, and M. Padovan,J. Chem. SOC.(B), 1969, 1084, and earlier papers in the series cited there. 144 J. F. King and T. W. S. Lee, J. Amer. Chem. SOC.,1969,91,6524. 1*5 J. G. Pritchard and A. A. Bothner-By, J. Phys. Chem., 1960, 64, 1271. 140 M, Schlosser and V. Ladenberger, Chem. Ber., 1967, 100, 3877. 206 The isotope effect results are in accord with such a mechanism. In the triethylamine-catalysed dehydrobromination of ci~-[~H,]dibromo-ethylene to bromoacetylene, Kwok, Lee, and MillerlP7 found no deuterium exchange with solvent, and no isotope effect, kH/kD = 1-00.From their overall analysis of the reaction, they concluded that the reaction took place by an Elcb mechanism in which the R-YH+ ion pairs which were formed rapidly and reversibly did not dissociate before undergoing loss of bromide ion at an isotope independent rate to give products (see the discussion above in the Elcb section). In contrast to the above carbanionic reactions, Hargrove, Dueber, and Stang148 have shown that certain ethylenic compounds can also undergo El reactions to give acetylenes. In the solvolysis of p-styryl trifluoromethanesulphonate, the secondary p-deuterium isotope effect is kH/kD = 1.42.Approximately 35 % Ph I EtOH BCDB=C-OSOzCFs +CDz=C-Ph DCEC-Ph+ of the product was phenylacetylene, the remainder being acetophenone. The secondary isotope effect for this reaction is larger than the corresponding effect for El-s~lreactions of saturated substrates. The authors suggest that this is because the developing p-orbital on a-C is exactly lined up with the BC-H bond, making hyperconjugative delocalization of the developing positive charge especially effective; and that the BC-H bond in this unsaturated system is closer to a-C and shorter than a corresponding saturated BC-H bond. No isotope effect studies of elimination reactions to form carbon-nitrogen triple bonds appear to have been carried out, but would be of interest.F. Eliminations to Form Cyclic Compounds.14s-Most cyclization reactions might be classified as eliminations, and many isotope effect studies have been carried out on such systems. Such reactions are taken to be beyond the scope A x of this review, but the general considerations of establishing whether a reaction is concerted or stepwise, and of determining the degree of bonding changes at various positions by isotope effect techniques are the same as those discussed here. Two examples will be considered. 147 W. K. Kwok, W. G. Lee, and S. I. Miller, J. Amer. Chem. SOC.,1969, 91, 468. R. J. Hargrove, T. E. Dueber, and P. J. Stang, Chem. Comm., 1970, 1614. 149 An interesting review of early work in one aspect of this field is given by V.Prelog, Rec. Chem. Progr., 1957, 18,247. 207 1'0 Isotope Efect Studies of Eliminution Reactions In studying the cyclization of 3-chlor0-1,l -dideuteriopropyl p-tolyl sulphone in ButOD-KOBut, Bird and Stirlir~gl~~ found an inverse solvent isotope effect, kH/kD = 0-5. The unlabelled substrate underwent rapid exchange of the y- hydrogens with labelled solvent. These results are incompatible with an E2 DI To-SOZ-CD-CH~To-SO,-YCD\ -Cl_/ \/(3-32 mechanism, for which a larger, normal y-deuterium isotope effect would be expected (using labelled substrate in labelled solvent) ;but they are completely consistent with a type B (pre-equilibrium) Elcb mechanism (see the detailed discussion of such systems in the Elcb section above). Crawford and Cameron151 concluded that the symmetrical trimethylene- methane (21) was an intermediate in the elimination of nitrogen from 4-methylene- 1-pyrazoline to form methylene cyclopropane on the basis of isotope effect studies.When the 3,3-dideuteriopyrazoline was used, more of the label was found in the ring than in the em-methylene group, indicating an intramolecular isotope effect (kH/kD = 1.37) in the conversion of (21) to product. When combined with the data on decomposition of the 3,3-dideuterio-exo-dideuterio-pyrazoline, this result led the authors to conclude that (21) was indeed an inter- mediate, and that an alternative concerted mechanism for product formation was excluded. An important contribution to the observed large secondary isotope effect was thought to be the greater ponderal effect for rotation of CD2 than of CH2.110 R. Bird and C. J. M. Stirling,J. Chem. Soc. (B),1968,111. lS1 R. J. Crawford and D. M. Cameron,J. Amer. Chem. Soc., 1966,88,2589. G. a-Elimination Reactions.-Isotope effect studies have been carried out on numerous reactions involving carbene or carbenoid intermediates, and many of these reactions can be classified as aeliminations. Most such research is con- sidered to be beyond the scope of this review, but, as before, isotope effect data can provide valuable mechanistic information.152 Two examples will be discussed briefly. Skell and Plo~ika~~~ generated carbene (22) by co-condensing carbon vapour and the labelled acetone on to a liquid nitrogen cooled surface under high vacuum.The intramolecular isotope effect in the conversion of (22) to propene was kH/kD= 1.7 at -170 "C (estimated to be 1.1 at 25 "0.The authors take CH,=CH-CD3 CH3COCD3 + C. -170°C CO + CH3--e-CD3,____+ the low value of to indicate that a free carbene is involved, as contrasted with higher isotope effect values reported for complexed carbenes or carbenoid reactions. Swain and Thornton have a sulphur isotope effect of kS2/k3*= 1.0066 in the hydroxide ion catalysed conversion of p-nitrobenzyldimethyl- sulphonium toluene-p-sulphonate to pp'-dinitrostilbene. The reaction was first-order with respect to hydroxide ion and the sulphonium salt, and + fastArm 3. (23)5RCHCHSMe, ArCH=CHAr + Me,S I Ar carbanion (23) was formed reversibly as shown by deuterium exchange.A large sulphur isotope effect (k32/k34-1.018) would be expected for conversion of (23) to the carbene, so the cogent argument is made (indirectly) that the lower observed value must require an additional dimethyl-sulphide-producingstep which proceeds without an isotope effect. The last step in the indicated mech- anism provides such a path, since the second dimethyl sulphide will have the same isotopic composition as the then existing reactive intermediatell (23) usFor a few such applications, see H. Kwart and H. G. Ling, Chem. Comm., 1969, 302; W. Kirmse, H. D. von Scholz, and H. hold, Annalen, 1968, 711, 22; J. R. Jones, Trans. Faraday SOC.,1965,61,95; S. Seltzer, J. Amer. Chem. SOC.,1961, 83, 2625; J.Hine, R. J. Rosscup, and D. C. Duffey, ibid., 1960,82,6120. 16a P. S. Skell and J. H. Plonka, Tefruhedrun Letters, 1970, 2603. lWC. G. Swain and E. R. Thornton,J. Amer. Chern. SOC.,1961,83,4033. 205, Isotope Efect Studies of Elimination Reactions (which will be somewhat enriched in the heavy isotope, but which will not show further fractionation in the last step). The isotopic composition of the measured dimethyl sulphide will be the average of that formed in the rate-determining and last steps. The kind hospitality of Professor de la Mare and his colleagues during the author’s visit at the University of Auckland, where this review was initiated, is gratefully acknowledged.

ISSN:0306-0012    

DOI:10.1039/CS9720100163

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

Quantum Mechanical Tunnelling in Chemistry By M. D. Harmony UNIVERSITY CHEMICAL LABORATORY, CAMBRIDGE, CB2 1EW* 1 Introduction and Scope One of the most unusual and interesting results of quantum mechanics is the prediction of tunnelling, i.e. the ability of a particle (or system of particles) to exist in, or pass through, a region of space where its total energy is less than its potential energy. According to classical mechanics, such a phenomenon is impossible, but in quantum mechanics it is a natural result of the probabilistic interpretation of wavefunctions, by which the states (position, momentum, energy, etc.) of atomic and molecular systems are specified. In view of this non- classical wave nature ascribed to particles, there is a certain logical inconsistency in using the classical word 'tunnelling' to describe the above phenomenon.The usage is universal, however, and seems to be entirely sensible in a probabilistic sense. The physical importance and consequences of tunnelling have been recognized since the very earliest days of quantum mechanics. Hundl discussed the prob- ability of intramolecular rearrangements via tunnelling in 1927, and the follow- ing year the importance of tunnelling in the decay of radioactive nuclei was described.2As early as 1932, Wigner3 discussed tunnelling with a view aimed at chemical kinetics; in the same year, the tunnelling mechanism responsible for the doubling of certain spectral bands of ammonia was ~larified.~ Since these earliest days numerous experimental and theoretical studies have been performed to describe quantitatively the mechanisms and consequences of tunnelling in chemical systems. In this article, we will review some of the areas in which tunnelling has been of significance over the years since its recognition.Several reviews and dis- cussions of particular areas have appeared in the past. For example, Johnstons and Caldin6 have provided reviews of various aspects of proton tunnelling in ordinary chemical reactions, and the significance of tunnelling to the under- standing of the hydrogen bond has been well-described.' The theory and certain *Present address : Department of Chemistry, The University of Kansas, Lawrence, Kansas, 66044, U.S.A. F. Hund,Z. Physik, 1927,43, 805. G.Gamow, 2.Physik, 1928, 51,204. E. P. Wigner, Z. phys. Chem. (Leipzig), 1932, B19, 203. D. M. Dennison and G. E. Uhlenbeck, Phys. Rev., 1932, 41, 313. H. S. Johnston, Adv. Chem. Phys., 1961, 3, 131. E. F. Caldin, Chem. Rev., 1969, 69, 135. 'See, for example, C. Haas and D. F. Hornig, J. Chem. Phys., 1960, 32, 1763; D. Hadzi, J. Chem. Phys., 1961, 34, 1445; G. M. Barrow, Spectrochim. Acta, 1960, 16, 799. 211 Quantum Mechcmical Tunnelling in Chemistry experimental aspects of tunnelling methyl groups have been reviewed,* and Lowdins has discussed tunnelling from a biological viewpoint. The view pre- sented here will be less specific, with the aim toward stressing the unity of the phenomena together with the differences.In order that the general features will be understood, we present in the next section an elementary theoretical discussion of tunnelling. Following this we shall move directly to a consideration of some chemical applications. We shall avoid tunnelling phenomena which lie principally in the realm of physics research, such as electron tunnelling through superconductor junctions.1° 2 Theoretical Characteristics of Tunnelling A. Free Particle Incident upon a Potential Barrier.-As a simple illustration we consider a particle of mass rn moving in one dimension from left to right through a rectangular potential barrier. Two cases may be distinguished [see Figures l(a) and l(b)], depending upon whether the potential energy to the right I I I 1 I Oa Oa X-X-I I I I I 0 -a +U X-X-Figure 1 Simple one-dimensional potential barriers.Incident particle has energy E * C. C. Lin and J. D.Swalen, Rev. Mod. Phys., 1959, 31, 841.* P. 0.LoGdin, Adu. Quantum Chem., 1965,2,213. loJ. Bardean. Phys. Rev. Letters, 1961, 6, 57. 212 Harmony of the barrier is the same as, or different from, the potential energy on the left. These cases are termed symmetrical and unsymmetrical, respectively. The solutions yt of Schrodinger's equation ZY=E??' for either case are well-known,ll and may be obtained by joining up functions for each of the regions I, 11, and III so that Yt and yt' are continuous at x = 0 and x = a. Solutionsyt exist for both Et > V, and Et -= V,. If the transmission coefficient Tis defined as the probability that a particle will tunnel through the barrier, the result is found to bell for the symmetrical case with E < V,, 4k12k2'T= (k12 + k22)2sinh2ak2+ 4k12kz2 In equation 2, kl = 1/2mE/hand k, = ,/2m(Vo -E)/h. For E > V,,equation (2) applies if we replace kZ2 by -k,'' = 2m(E -V,)/h2 and sinh by sin.To get some idea how the transmission coefficient depends upon the physical para- meters we have plotted Tin Figure 2 as a function of E for both a proton and deuteron incident upon a barrier of height 20 kcal mol-l, and width 1 A. This Figure indicates clearly that (a) tunnelling decreases markedly as V,/E becomes large, and (b) that tunnelling decreases rapidly as the mass of the tunnelling particle increases.Further computations show a final feature, namely that tunnelling decreases rapidly as the width of the barrier increases. These are the chief characteristics of tunnelling which are expected to occur for all systems, even those having smoothed potential barriers rather than the square type in this example. While it is not shown in Figure 2, the transmission coefficient for particles having E > V, is not always unity, that is, there is a small probability of reflection above the barrier. For the unsymmetrical case of Figure l(b) an expression similar to equation (2) may be derived. As a first approximation equation (2) may be applied if it is multiplied by k3/k1 where k3 = 1/2rn(E -Vl)/h. Thus as Vl becomes more negative (for a fixed incident energy) the transmission coefficient increases.If Vlis positive on the other hand, T decreases until eventually (when E -Vl < 0) it goes to zero, that is, the probability of escaping to x 3 u vanishes. These effects of the unsymmetrical barrier have often been overlooked in the past, but their importance has been particularly emphasized by Johnston et al.l2 In general, tunnelling may be of significance in chemical phenomena when the wavefunction describing the tunnelling particle has a significant amplitude across the barrier region. Thus the de Broglie wavelength A = h/p provides a suitable qualitative measure for predicting relative tunnelling efficiencies. For particles of atomic mass 1, 2, 5, 10, 20, 50, and 100 having identical energies of 20 kcal mol-l, the de Broglie wavelengths are 0.31, 0-22, 0-14, 0.097,0.068, l1 (u) L.Landau and E. Lifshitz, 'Quantum Mechanics', Addison-Wesley, Reading, Mass., 1958; (b)H. Eyring, J. Walter, and G. E. Kimball, 'Quantum Chemistry', John Wiley, New York, 1944; (c) D. Park, 'Quantum Theory', McGraw-Hall, New York, 1964. l8H. S. Johnston and J. Heicklen, J. Phys, Chem., 1962.66, 532. 213 Quantum Mechanical Tunnelling in Chemistry 0 8 12 16 20 -1 i(kca1 mol ) -Figure 2 Transmission coefficient as a function of particle energy. Curves a and b are for deuteron and proton, respectively, incident upon rectangular barrier 20 kcal mol-' high and 1 A wide. Curve c is for proton incident upon parabolic barrier of same height and base width 0.044,and 0.031 A respectively. From these values it is clear that only the very lightest particles have a de Broglie wavelength comparable to the width of barriers in molecular systems (&-1 A).Nevertheless, tunnelling of heavier particles may still be observable if the barrier height is sufficiently low, or the barrier width sufficiently small. Since the sharp-edged rectangular barrier is not a very realistic one for physical situations, other functional forms have been investigated. Figures l(c) and l(d) show two of those for which exact equations for the transmission coefficient exist. In Figure l(c), the functional form is Y(x) = Vo/cosh2ax (3) and the transmission coefficient is given bylS l* See ref.11 (a), p. 77. Harmony T= sinh2(nk/a) sinh2(nk/a) + cosh2[(.rr/2)1/(8rnV,/h2a2) --_-11 when, as is typical, the square root term is greater than zero. In equation (4) k = ,/m/fiand E < V,. This symmetrical potential function is a special case of a more complicated function first investigated by Eckart.14 The potential in Figure l(d) is an inverted parabola for -a < x < + a, V(X) = Vo(l -5) and V(x) = 0 otherwise. An exact calculation for the transmission coefficient yield^^^--^^ for this case ___._ for all values of E> 0, where y = 1 -E/V, and = 27r2a42mV0/h. Each of the latter two potential functions of Figure 1 has been used rather extensively in practical applications. The potential of equation (5) has been par- ticularly appealing because of its simplicity and the simple resulting expression for Tgiven in equation (6).In Figure 2, equation (6) has been plotted for a proton incident upon a barrier having V, = 20 kcal mol-l and 2a = 1 A. The simplified Eckart potential of equation (3) and Figure l(c) is undoubtedly more realistic than the parabolic form, however, particularly because of the absence of the discontinuities present at x = 2 a in the latter function. Both of the barrier functions yield transmission coefficients having the same strong dependence upon E, V,, and barrier width, although the details differ quantitatively. B. Bound Particle Tunnelling through Potential Barriers.-Here we consider bound particles which may exist in two or more potential energy minima separated by potential maxima.We show in Figure 3 one of the common poten- tial functions of this form. Numerous types are encountered in physical problems, including functions having non-equivalent maxima and minima. In this section we shall merely consider the behaviour of a single particle of mass rn moving in the double-minimum potential of Figure 3, but it is perhaps useful to mention that this potential is applicable to the inversion motion of the protons of ammonia. The principal quantum mechanical feature of systems such as this is that all particle energies are not now available, i.e. Schrodinger's equation (equation 1) permits only certain energy states. For the double-minimum potential, the qualitative appearance of the lower-energy states has been shown in Figure 3.l4 C.Eekart, Phys. Rev., 1930, 35, 1303. lS See ref. 11 (a), pp. 177-178. l' R.P. Bell, Proc. Roy. SOC.,1935, A148, 241. l7 R. P. Bell, Trans. Furuduy SOC.,1959, 55, 1 . 215 Qtuntum Mechanical 7bnnelling in Chemistry I t V -a +a X-Figure 3 (a) Typical double-minimum potential; (b) qualitative forms of wavefunctions of lowest states The characteristic feature is that below the barrier top the states occur as closely- spaced doublets. As the top of the barrier is approached the doublet spacing increases, and above the barrier the doublet structure finally disappears. Also shown in Figure 3 are the qualitative appearances of the eigenfunctions for the two lowest pairs of states. Note that the probability distribution (y2)is identical in the two equivalent wells, and is non-zero in the region of the barrier.The question which must now be considered is what is meant precisely by tunneZZing in such a system. Suppose we found by some measurement that at a certain time the particle existing in the potential of Figure 3 had an energy of E$(v = 0, + symmetry), and were asked where the particle was located. The acceptable answer is that there is a 50% probability that the particle existed in the region x < 0 at the time of the measurement; somewhat more approxi- mately we might state that the particle has an equal probability of existing in either well. This answer is the proper one according to the interpretation of stationary states.Suppose instead, that a measurement of position made at some time t = 0 showed positively that the particle was in the left-hand well with an energy of Napproximately EZ E,. We ask now where the particle might be found at 216 Harmony t > 0. To answer this question it is necessary to utilize the concept of non-stationary states, since the certain presence of the particle in the left-hand well means it is not in any of the stationary states. Berryls has described some of the general principles that must be considered. The simplest resulting view is that non-stationary states may be experimentally observed if the average lifetime of the state is long compared to the characteristic time involved in the particular measuring technique being used.For the particular case considered bere, the most elementary theory19 leads to the conclusion that the particle tunnels between the left and right wells, represented by the non-stationary states y6 + y, and yi -Y;, respectively, at a frequency 2(E, -Eif)v: = h (7) Thus at the time t = l/vt the particle is in the right well, while at t = 2/vt it is again back in the left well. It is clear that the doublet separations provide a direct measure of the tunnel- ling rate or average lifetime of a non-stationary state of the particle. Much more sophisticated analyses have been performed,20p21 but this simple result is satis-factory for symmetrical barriers of the double-minimum type when the doublet spacings are small compared to the separation between states of different v.For the free particle case it was found that the tunnelling probability might increase or decrease when the potential became unsymmetrical, depending upon whether the right-hand potential decreased or increased. For the bound particle case, the tunnelling rate usually decreases very markedly when any small asym- metry is introduced in the right-hand well. If, for example, the right-hand well is deepened by an amount equal to 1% of Yo,the tunnelling rate may decrease by as much as a factor of 100. As shown by the computations of Somorjai and Hornig,22 this effect is caused not by any major change in the structure of the energy levels, but by the localization of the stationary state wavefunctions in either the left or right well.Thus in the case above, the lowest energy state yo represents a particle largely localized in the slightly deeper right well, while in the next-lowest state ylthe particle is largely localized in the left-hand well. Then a particle definitely known to be in the left well at t = 0 will have a non-stationary state function of the form yl+ cy0 where c2 < 1. This particle willeventually appear in the right well (state yo+ but it will take a time longer by a factor on the order of c2 than that of the symmetrical case. This problem has been treated quantitatively by Brickmann and Zimmermann,21v23 who show, for example, that an offset of the minima of only 20 cm-l in a double-minimum potential with a barrier of N 6000 cm-l leads to a decrease in R.S. Berry, Rev. Mod. Phys., 1960, 32, 447. See, for example, C. H. Townes and A. L. Schawlow, ‘Microwave Spectroscopy’, McGraw- Hill, New York, 1955, Chap. 12. xo P. 0. Lowdin, Biopolymers Symp., 1964, 1, 161. x1 J. Brickmann and H. Zimmermann,J. Chem. Phys., 1969,50, 1608. R. L. Somojai and D. F. Hornig, J. Chem. Phys., 1962,36, 1980. laJ. Brickmann and H. Zimmermann, Ber. Bunsengesellschafr Phys. Chem., 1966, 70, 157. Quantum Mechanical Tunnelling in Chemistry vt of a factor of ca. 100. An expression for vt which is equivalent to Brickmann and Zimmermann's result in the limit of small asymmetry and small tunnelling is24 where vto is the tunnelling rate for the limiting symmetrical potential, 2dE = hvto and d Y is the difference in the energy of the minima.As an example, vto might be 2 x 1O1O s-l, which means dE N 1 cal mol-l. If the minima differ by 1 kcal nio1-l (dV = 1000 cal mol-l), the tunnelling rate is decreased by a factor of ca. 1 x It is evident that very serious errors may arise if a symmetrical function is utilized to approximate an unsymmetrical one in tunnelling calculations. From the foregoing it is seen that the tunnelling properties in bound systems are adequately described if the energy level doublet separations are known. In principle these energy levels are obtained by solving equation (1) using an appro- priate potential function V(x) as in Figure 3. Very few exact analytic solutions are available, however, for realistic potentials.The best known is probably the symmetrical Manning potential26 XV(x) = A sech4-X -B sech2-2P 2P where A, Byand p fix the precise size and shape of the function. Although an exact formal solution of equation (1) has been obtained using this function, no simple expression for the doublet spacing results. Most attempts at relating the doublet spacings, dE,, to the physical para- meters (mass, barrier height, shape, and width) have used approximation methods of some The most commonly used method is the WKB approxi- mation which was first applied to the double-minimum system by Dennison and Uhlenbe~k.~The general result given by this treatment is AEv = hv-exp( -P,,dx)7r where Po = 42m(V -Eu), v is the (harmonic) oscillation frequency within each well, and x1 is the value of x for which Ev = Yin the barrier region.This method shows clearly that dEv is determined primarily by the area under the barrier, but is not greatly affected by its precise shape. The integral in equation (10) has been evaluated analytically for a few simple barrier but in general the problem has been treated numerically. Recently we suggested an approximate expression27 for the symmetric double- *' M. D. Harmony, to be published. M. F. Manning, J. Chem. Phys., 1935, 3, 136. ae N. Rosen and P. M. Morse, Phys. Rev., 1932,42,210; F. T. Wall and G. Glocker, J. Chem. Phys., 1937, 5, 314. ITM. D. Harmony, Chem. Phys. Letters, 1971, 10, 337. 218 Harmony minimum potential which shows clearly the dependence of dE, upon the physical parameters, and which is expected to be valid for cases of small tunnelling (small dEo) when each well is more or less parabolic (harmonic) in character.This equation aha3IaAEo/h = xp( -aa2)2mnJ is independent of the precise shape and height of the barrier, but depends strongly upon the separation of the minima (2a),the mass (m),and the oscillator frequency (v) in each well (a = 27~vm/fi).Also, a maximum barrier height of 2n2v2a2mis implied. Corrections to equation (11) to account for the barrier shape and height have been derivedYa7 but the equation itself provides a useful semi- quantitative means for predicting dEo.In Figure 4 we have shown the variation of vt (=2AE,/h)for both a proton and a deuteron as a function of the separation of the minima for a fixed value of the well force constants (k = 47r2v2m).t -16 1 \ 0.4 0.8 1.2 1.6 2 .o Figure 4 Dependence of tunnelling frequency upon the separation of the potential well minima (computed from equation 11) for a proton and a deuteron. k = 3 x lo6 Quantum Mechanical Tunnelling in Chemistry Finally we should mention that numerical solutions for the energy level splittings may be obtained to any desired accuracy by using the matrix mechanics technique.22s28There is, of course, a loss of simplicity in this type of computation, but it is recommended when the experimental data are sufficiently good to warrant the computational effort. C.The ReIationship between Bound- and Free-particle Tunnelling Cases.-The discussion in Section 2A was couched in terms of transmission probability, T, while that in Section 2B was in terms of tunnelling frequency, vt. We can, in fact, also state the properties of free-particle tunnelling in terms of a tunnelling frequency. This is done merely by multiplying T by the rate at which particles strike the barrier. Thus if vi particles/second strike the barrier (or equivalently, if a single oscillating particle strikes the barrier vi timeslsecond), the tunnelling frequency is vt = vi T. This suggests that bound-particle tunnelling might be treated by performing a free-particle tunnelling calculation using equations (4) or (6), for example, and then multiplying this by the oscillator frequency v which is appropriate for the potential wells of interest.Although this seems a reasonable approach, it will generally lead to a serious underestimation of vt, particularly for symmetric potentials. In simple terms this is because for bound particles there is a kind of resonance between the two wells, so that each time the bound, oscillating particles in the left well strike the barrier they transmit a certain probability amplitude to the right well. This probability then builds up, since the particles are not free to escape to x = + co. On the other hand, this mechanism is not operable for the free particle, since once through the barrier the particles con- tinue to x = + co.A more detailed discussion of this matter has been given recently.23 3 Tunnelling in the Real World In the real world of molecules and chemistry, the tunnelling of a single particle along a one-dimensional co-ordinate may seem a highly unlikely model to apply. Indeed, the real potential surfaces of molecules and molecule-aggregates are complicated and many-dimensional, and all the nuclei in the system are undergoing at least small oscillations. In many cases several nuclei must be undergoing large displacement motions. Still, it has proved to be possible to treat many real systems as judiciously selected one-dimensional problems. The validity of such one-dimensional models is normally judged by the extent of agreement with available experimental data.Unfortunately, since the many- dimensional problems are still impractical from a computational viewpoint, there has been little work performed for more than one-dimensional problems.2a A few examples should show how real systems are turned into one-dimensional cases. An intra- or inter-molecularly hydrogen-bonded proton is a rather simple case.' It clearly has stable equilibrium positions (wells) about which it under- J. D. Swalen and J. A. Ibers, J. Chem. Phys., 1962, 36, 1914. yoT.R. Singh and J. L. Wood, J. Chern. Phys., 1968,48,4567. Harmony goes small oscillations. To get from one stable well to another it must tunnel through a potential barrier following a path not really known in most cases, but assumed to be more or less along the lines representing the hydrogen bonds.Because, in general, the tunnelling proton is much lighter than the remainder of the system, only the motion of this single particle need be considered. In many cases it is clear that several nuclei undergo simultaneous tunnelling. The umbrella inversion motion of the ammonia molecule provides a good illustration: The protons move along a path similar to, but not identical with, the normal co-ordinate for the symmetrical (v2) bending mode. The potential energy as a function of the height of the pyramid is of the form of Figure 3, with the maxi- mum corresponding to the planar configuration. Although all three protons move during the tunnelling motion (the nitrogen moves also to ensure that the centre of mass remains constant), the kinetic energy may be represented correctly by the motion of a single particle of reduced mass, p.28Calculations show that 3(14)(1) or more approximately, p -3.‘ 14 + 3(1)’ As a final example, consider the ordinary chemical reaction involving proton or hydrogen atom transfer. The potential surface here is indeed not simple, since even the most elementary treatment indicates that the energy surfaces must be considered to be a function of two bond distances, the one being broken and the other being formed. But according to ordinary transition state theory, there does exist a low-energy pathway, known as the classical reaction path, along which the proton may be considered to move. Actually this view is much too naIve, of course, and one should investigate other possible paths over the saddle point region which are energetically feasible.30 Nevertheless we see again how, in an approximate way, a complicated motion is reduced to a simple one- dimensional problem.We will have more to say about the reaction path later. 4 Experimental Observation of Tunnelling A. General Considerations.-As for most molecular phenomena, the existence of tunnelling is best detected by its effects upon various macroscopic or micro- scopic equilibrium and non-equilibrium properties which are measureable in the laboratory. The most direct and quantitative method is the spectroscopic observation of the doublet splitting of the stationary-state energy levels in a bound system such as ammonia.Thus the splittings of the v = 0, 1, and 2 states of NH3 (and its various deuteriated forms) have been observed by microwave *O H. S. Johnston and D. Rapp, J. Amer. Chem. SOC.,1961, 83, 1. Quantum Mechanical Tunnelling in Chemistry and i.r. spectroscopy, and the agreement of the observations with the double- minimum model2* leads one to conclude that ammonia is indeed a tunnelling system. One might argue that these observations have nothing whatever to do with tunnelling, which is true in the sense that no rate phenomena were being observed, but unless some other quantum mechanical explanation of the doublet splittings can be deduced, the tunnelling conclusion is inevitable. In fact, there is other evidence for tunnelling in ammonia which is of a rate nature.The shifts of the rotation-inversion states of ammonia in a static electric field (Stark effect) are found to be second-order in the field strength (ccE2),which implies that the dipole moment of the molecule is effectively This is reasonable only if the molecule is inverting very rapidly, as indeed it is (kz lofos-l). In contrast, phosphine inverts by tunnelling very slowly (the doubling of z lod s-l has been too small to observe spectroscopically) and should exhibit a first-order Stark effect characteristic of a rigid non-planar symmetric rotor. One of the earliest studies providing evidence for tunnelling involved the determination of thermodynamic functions (particularly the entropy) of mole- cules.Thus a calorimetric determination of the entropy of a molecule must agree with that evaluated by statistical mechanical means. It was found, for example, that agreement was possible for ethane only if, in the statistical theory, the torsional (harmonic vibrational) mode was replaced by a large amplitude mode which permitted tunnelling of methyl protons between three equivalent minima.32 As with ammonia, the characteristic feature of the energy levels for ethane is the presence of closely-spaced pairs of doublets below the barrier maxima. For chemical reactions involving transfer of light nuclei such as protons or deuterons, the effects of tunnelling are shown by the reaction rate constants. Usually it is necessary to measure either the isotope effect (k~/k~)or the temper- ature dependence of the rate constant. The presence of appreciable tunnelling will usually lead to (a) greatly enhanced isotope effect^,^^^^ (b) non-linear Arrhenius plots,6 and (c) unexpectedly large differences in effective activation energies for H and D species6 In practical cases, one or more of these pheno- mena may be observed, depending on the accuracy of the data, the temperature range studied, and, of course, the magnitude of the tunnelling.Other measurements having the potential for detecting tunnelling include electron diffraction and n.m.r. The latter technique has particular advantages, since it has the possibility of distinguishing, via temperature-dependence studies, the rate at which molecules undergo intramolecular conversions.As an example, the n.m.r. spectrum of aziridine shows the ring protons to be all equivalent (even at low temperatures), indicating that the amino-proton is inverting fast on the n.m.r. time-scale. On the other hand, the spectrum of tetramethyla~iridine~~ shows two pairs of non-equivalent methyl groups, indicating slow inversion. 31 D. K. Coles and W. E. Good, Phys. Rev., 1946,70,979; J. M. Jauch, Phys. Rev., 1947,72, 715. 8a J. D. Kemp and K. S. Pitzer, J. Chem. Phys., 1936,4,749. 3a A. Warshel and A. Bromberg, J. Chem.Phys., 1970,52,1262; A. Bromberg and A. Warshel, J. Chem. Phys., 1970,52, 5952. T. J. Bardos, C. Szantay, and C. K. Navada, J. Amer. Chem. SOC.,1965, 87, 5796. Harmony The difficult problem is knowing whether the inversion is influenced by tunnelling or whether it is simply a classical process involving transfer over the barrier.As with the proton-transfer reactions, the isotope effect and temperature depend- ence should, in principle, permit tunnelling to be detected. In fact, in the tetra- methylaziridine case, the reported value of Eu(H) -&@) = -3.3 kcal is considerably larger than expected from zero-point energy differences, and consequently it seems likely that tunnelling is involved. B. Intramolecular Tunnelling.-For a macroscopic sample of a substance A, which converts unimolecularly via a double-minimum potential to a substance B, the effective rate constant may be written3s keii = Cf(i)vA--+B(i) I where vA&) is the reaction (isomerization) rate for species of energy ~t, andf(i) is the fraction of all molecules in any state ~t as given by Boltimann’s energy distribution. The summation for all states above the top of the bar- rier reduces approximately to a single term of the classical Arrhenius form, A exp(-Eu/kT),where A is essentially one-half the classical vibrational fre- quency and Eu is the energy difference between the lowest state (v = 0) and the first state above the barrier.For states below the barrier top, YA+B is replaced by the tunnelling frequency, vt, calculated by the methods of Section 2B, and the summation is carried out for all states v below the barrier maximum. In general it is clear that equation (12) does not lead to Arrhenius-type behaviour (linear Ink vs.l/T). In particular, if the ground-state tunnelling rate [vt(O)] is large enough, keffwill be essentially temperature independent at low temperature. To illustrate equation (12) we have computed kerf for N-H-and N-D-aziridine. The potential barrier V, is taken as 5000 cm-l ( NN 14 kcal mol-l), and the other input data are: vt(0) = 180 s-l, v = 1200 cm-l, A = 1013s-l, and Eu = 4800 cm-l for the (CH,),NH species; vt(0) = 1.8 x v = 850, A = 0.7 x 1013 and Ea = 5100 for the (CH2),ND species. The vt(0) values were obtained by using equation (1l),,’ and the vibrational energy levels are assumed to be harmonic in behaviour. Tunnelling rates for the other states below the barrier top are obtained from the vt(0) values by assuming a factor of 30 increase for each succeeding state.Figure 5 shows the results of this computation. Note in par- ticular the different high- and low-temperature behaviour. There is considerable uncertainty in these calculations, but the results do indicate that the (CH,),NH species probably inverts too fast to observe on the n.m.r. time scale, in agree- ment with experimental results. On the other hand, the (CH2),ND species rate should be observable by n.m.r., and perhaps the transition region between the low-and high-temperature behaviour may be accessible. In the past several years a number of authors have discussed intramolecular conversions from both the classical Arrhenius and the tunnelling points of view.ab R. E.Weston, J. Amer. Chem. SOC.,1954, 76, 2645. 223 Quantum Mechanical llmnelling in Chemhtry 4 *t‘ a -00 I I021 I 2. 5 3.5 4.5 5.5 Figure 5 Efective rate constant for ariridine inversion as a function of temperature. Curve (a) is for (CH2)aNH species, (b) for (CHa),ND species. See text for input data West~n~~and Koeppl et aLa6considered the rate of inversion of XY3-type species (including XY,Y2Y3forms) similar to ammonia. Using a method first devised by Costain and S~therland~~ for obtaining an approximate double-minimum potential, these workers predicted the inversion rates for many pyramidal species. One of the principal interests was in ascertaining whether the asym- metric forms converted sufficiently slowly to show optical activity experimentally.From these studies it was shown that when X =P or As, the conversions would be slow by either tunnelling through, or passage over, the barrier for a variety of Y groups, and hence the observed3* optical activity in molecules of this type was verified. Another interesting series of studies was provided by the experimental observa- tion of the fluorine equivalence of PF5in n.m.r. Berry40 first postulated so G. W. Koeppl, D. S. Sagatys, and G. S. Krishnamurthy, J. Amer. Chem. Soc., 1967, 89, 3396. C.C.Costain and G. B. B. M. Sutherland, J. Pliys. Chem., 1952,56, 321. H. S. Gutowsky, A. D. McCall, and C. P. Slichter, J. Chem. Phys., 1953,21, 279. s8 K. Mislow, ‘Introduction to Stereochemistry’, Benjamin, New York, 1965.‘CI R. S. Berry, J. Chem. Phys., 1960, 32, 936. Harmony a suitable mechanism for this involving a large amplitude internal motion following more or less the E normal vibrational mode of this Dsh species. Later Holmes41 performed more extensive theoretical studies of a variety of related phosphorus species. The most startling result was that the tunnelling mechanism for PF, was found to be about as favourable as the classical over-the-top mech- anism at room temperature even though the tunnelling particles (fluorine nuclei) are relatively heavy. The reasons for this seemingly anomalous result are that the barrier is not too high or wide, but more importantly the number of states below the barrier top is large (w21).The latter fact permits a net tunnelling (summed over all the levels) which is appreciable, even though the ground state tunnelling frequency (x s-l) is quite small. M~etterties~~ has reviewed much of the recent experimental work on fluxional motions of the type shown for PFs. In view of the PF5 results, it seems likely that tunnelling motions may be responsible for some of the observations of large amplitude intramolecular motions. However, it must be remembered that for suf€iciently low and wide barriers the motions will most likely be dominated by passage over the barrier via the excited vibrational states. As a final example, the molecular beam study of IF, by Kaiser et is interesting. These workers found this species to be effectively non-polar at high temperatures and polar at low temperatures. One proposed explanation of this is that IF, undergoes a large amplitude motion of the double-minimum type, with only a few states below the barrier. At low temperature, the beam deflection measurements are dominated by the lowest states, which are polar, whereas at high temperature they are dominated by the states near to or above the barrier, which are effectively non-polar. Tunnelling may be playing a role here, but the data are not conclusive with respect to the detailed dynamical processes.C. Intermolecular Tunnelling, Proton Transfer Reactions, etc.-In the simplest version of ordinary transition state theory of chemical kinetics, bimolecular reactions are postulated to occur by the passage of the reactants through some high energy transition state and then on to products.In this view, reactants must pass over a potential barrier to produce products. If tunnelling through the barrier is permitted, the true quantum mechanical rate constant is obtained by applying a correction factor, r,to the classical rate constant calculated with neglect of tunnelling: kQM = I'k To calculate r,one normally assumes that the reactants exist with a two-dimensional Maxwellian energy distribution, P(E) = (l/kT)exp(-E/kT).Then the quantum tunnelling correction for the one-dimensional reaction path is simply the sum over all energies of the transmission probabilities, T(E)[weighted by P(E)],divided by the net transmission probability for the classical process : 41 R.R.Holmes, Inorg. Chem., 1968, 7,2229. 4n E. L. Muetterties, Accounts Chem. Res., 1970, 3, 266. 4s E. W. Kaiser, J. S. Muenter, and W. Klemperer, J. Chem. Phys., 1970, 53,53. Quantum Mechanical Tunnelling in Chemistry The denominator achieves the simple form because in the classical process the transmission probability vanishes unless E > Vo,when it is unity. The zero of energy in equation (14) is that of the reactants, and T(E)is an expression of the form of equations (2), (4), or (6). In general, does not have a simple temperature dependence, but is expected to approach unity at high tempera- tures. It is clear also that In ~QMvs. 1/T will not, in general, produce a linear Arrhenius plot, although the quantum contribution to the slope (dln r/d[l/Tl) will often not be large.Equations (13) and (14) and the theory as outlined have been applied to a variety of chemical problems over the years, using primarily the parabolic and Eckart barriers for evaluation of T(E).Two general approaches have been used: in the first method, experimental isotope effects [k~/k~,Ea(D) -Ea(H), for example] are used to determine the height and width of the potential bairierYs usually using the parabolic barrier because of its simplicity; in the second approach, the potential energy surface for the reacting system is determined by some independent theoretical method, such as that of sat^,^^ or a more sophisticated method such as used by Shavitt et ~21.~~for H + H2.A one-dimen- sional barrier (usually of the Eckart-type) is then fit to the computed reaction path, the tunnelling contributions are calculated, and the results are compared with experimental rate constants, activation energies, and isotope effects. Caldin’ss recent review provides good coverage of the former method with respect to proton transfer reactions in liquid solution. Although the parabolic barrier is not very reasonable physically, and the interpretation of the width parameter (2a in equation 5) is not entirely clear, the method has been useful in describing and correlating trends in barrier parameters for related reactions. It should be pointed out that in studies of this type it is usually assumed, either explicitly or implicitly, that the tunnelling co-ordinate and the parabolic barrier extend from reactant to product; that is, x c -a corresponds to reactant and x > a to product in Figure l(d).Furthermore, the tunnelling mass has usually been taken to be 1, 2, or 3 a.u. for H, D, or T, respectively. Except for these assumptions (which will be discussed shortly), the principal objections one might have to these studies is the use of the parabolic barrier. It would be interesting to have some of these studies repeated using an Eckart barrier for comparison purposes. Studies of the second type above have most often been concentrated on simple reactions such as H + H2,30p46or CH3 + H, -CH, + H.6 More recently, however, Warshel and Br~mberg~~ have applied the method to both the initiation and propagation steps of the oxidation of dihydrophenanthrene. These studies 44 S.Sato, J. Chem. Phys., 1955, 23, 2465. 45 1. Shavitt, R. M. Stephens, F. L. Minn, and M. Karplus, J. Chem. Phys., 1968, 48,2700. 46 1. Shavitt,J. Chem. Phys., 1968, 49,4048; R.E. Weston, J. Chem. Phys., 1959,31, 892. Harmony have left little doubt as to the necessity for tunnelling corrections, and in most cases the theoretical results have been in semi-quantitative agreement with experiment, although they are strongly dependent upon the detailed model. Considering the many uncertainties which exist, it was interesting that WarsheP3 was able to explain quantitatively a very large isotope effect by a large quantum tunnelling isotope effect of r(H)/r(D) = 11.84.In all of these studies, the principal uncertainties in determining r are caused by uncertainties in (a) proper barrier shape, (6) proper path for tunnelling, and (c) proper reduced mass. The most common assumptions of m = 1a.u. for proton transfer, and that a single one-dimensional tunnelling path exists which leads from reactants to products, are undoubtedly too naive. Some years ago, Johnston and Rapp30 discussed the difficulties in separating out exactly such a path for even a collinear reaction of the form AH + B. ShavitP has commented on this for the H + H2case also. Johnston and Rapp have suggested that the more proper tunnelling paths should be along lines of slope -45" on the usual AH vs.HB contour diagrams. These paths correspond essentially to H motion with the end groups motionless. Paths of this kind do not lead from reactant to product, and indeed it is usually found that these paths have potential energy minima far above those for reactants and products. These workers have sug- gested further that the tunnelling factors should be summed over all paths in the vicinity of the saddle point, which lends a two-dimensional character to the evaluation of r.Nevertheless, this modified method is still only an approxima- tion of the real problem. The proper reduced mass to use in the tunnelling calculations is intimately related to the tunnelling path. For proton transfer between infinitely heavy groups along the -45" paths, the proper reduced mass is & a.u.*' For the H + H, case, the corresponding asymmetrical stretching normal mode of linear H3would have a reduced mass of & a.u.Most of the simple tunnelling comp~tations~~on H + H2(and isotopic variations) have used a reduced mass which corresponds to a path for which the kinetic energy of the three-particle system is diagonal from reactants to products. For this path the reduced mass for the H + H, reaction is a.u. In any real paths it is probably true that the reduced mass is not strictly constant over any extended range of reaction co- ordinate. Recently there have been a number of papers describing the dynamics of the simple H + Ha reactions in a detailed way.** These theoretical studies have pointed out clearly many of the inadequacies of the simple treatments, including the problems involving reaction paths and the one-dimensional assumption.This recent work has also avoided the arbitrary assumption of particular barrier shapes (such as Eckart or parabolic barriers) by using numerical solutions of 47 T. E. Sharp and H. S. Johnston, J. Chem. Phys., 1962,37, 1541. '* D. J. Diestler and V. McKoy, J. Chem. Phys., 1968,48,2951; D. G. Truhlar and A. Kupper-mann, J. Amer. Chem. Sac., 1971, 93, 1840; R. A. Marcus, J. Chem. Phys., 1966, 45, 4493; E. M. Mortensen, J. Chem.Phys., 1968,48,4029. Quantum Mechanical Tunnelling in Chemistry Schrodinger’s equation to obtain transmission probabilities for the ‘real’ potential barrier. Encouragement of this work by Professor A. D. Buckingham is greatly appre- ciated, as is partial support from a N.S.F. grant.

ISSN:0306-0012    

DOI:10.1039/CS9720100211

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

Reactivity of Organic Molecules at Phase Boundaries By F. M. Menger DEPARTMENT OF CHEMISTRY, EMORY UNIVERSITY, ATLANTA, GEORGIA 30322, U.S.A. 1 Introduction Interfaces are regions where two immiscible homogeneous phases come into contact. An organic molecule which is adsorbed from a bulk phase on to an interface often experiences a profound environmental change. For example, the dielectric constant and the concentration of reactants at an interface may differ substantially from those of the adjacent phases. Boundary state molecules would, therefore, be expected to exhibit interesting chemical properties, and the nature of these properties is the subject of this review. Probably the outstanding boundary state property is molecular order. While the orientation of reactant species in solution is usually random, molecules at interfaces often have well-defined orientations.In certain cases, described later, the orientation of organic molecules at an interface can be measured and altered at will. The importance of the chemistry of ‘arranged‘ molecules is seen, for example, in biological systems where the majority of reactions involve specific adsorption at surfaces of proteins, membranes, and cellular particles. Indeed, one may regard biochemistry as the organic chemistry of ordered molecules. Despite the relevance of interfacial organic chemistry to bio- chemistry (and to pharmacology, polymer chemistry, organic synthesis, etc.), there are few recent detailed investigations in the area.This is reflected in the fact that some of the most intriguing examples of boundary state reactions cited in this article are many years old. One final point may be made by way of introduction. I have chosen to neglect theoretical considerations in favour of a more qualitative approach; perhaps the purpose of the present review is not so much to inform as to stimulate interest in a rather unique field of research. 2 Solid Surfaces Adsorption of light by a complex comprised of an electron donor D and an electron acceptor A gives rise to electron transfer, as in equation (1). Return to the ground state is rapid in homogeneous solutions. When the donor and hv DA +D+A-acceptor are solids in close contact with each other, the lifetime of the charge- transferred state is prolonged.An electron which moves across the interface can wander from one acceptor molecule to another; a ‘hole’ in the donor layer can Reactivity of Organic Molecules at Phase Boundaries similarly migrate among neighbouring molecules. The resulting separation of oxidized and reduced species enhances their lifetimes. Kearns and Calvin1 investigated the behaviour of solid donor-acceptor systems (see Figure). Violanthrene (a polynuclear aromatic hydrocarbon) was vacuum sublimed on to a glass slide plated with thin metal electrodes. A solution of a quinone, o-chloranil, was then sprayed on to the violanthrene surface. An e.s.r. signal and a new absorption band at 7200A were produced by the intimately- associated donor and acceptor compounds.Moreover, coating the violanthrene with the acceptor increased the dark current by almost lo6.Illumination of the cell caused another current increase of about lo5which decayed exponentially with time when exposure to the light was terminated. These results may be \ ,0.02cm spacing / -0 -Chtoranil -Violanthrene (-5 xldirn thick) Electrodes ‘Glass slide Figure rationalized in terms of an interfacial electron transfer. Once the positive and negative charges move several molecular diameters into their respective layers, they are relatively free to migrate and to carry a current. The photoconductivity is probably caused by mobile positive charges in the donor layer, because illum- ination of the donor surface generates larger photocurrents than acceptor-face illumination.Upon removal of the light, the electrons and holes drift back to the interface where the ground state is reestablished. Not surprisingly, biological organelles involved in electron transport, such as chloroplasts, are characterized by highly-organized laminated structures. If a multifunctional molecule positions itself at an interface so that one of the reactive groups is more exposed to an external reagent than the others, then a high degree of reaction selectivity is possible. One of the few examples of this type of selectivity was reported by Den0 et aL2 who studied the homogeneous and heterogeneous photochemical chlorinations of n-octanoic acid. Homo- geneous chlorination in CC14 resulted in a mixture of monochlorinated isomers containing 17% 8-chloro-n-octanoic acid.When n-octanoic acid was first adsorbed on to alumina and then reacted heterogeneously with chlorine in CC14, the product mixture contained much more of the 8-isomer (33%). Apparently, the carboxy-groups of the n-octanoic acid adsorb on to the alumina surface such that the hydrocarbon tails are aligned more or less perpendicular to the surface. The methyl groups become the most accessible point of attack by the l D. R. Kearns and M. Calvin, J. Amer. Chem. SOC.,1960,83,2110.*N.C. Deno, R. Fishbein, and C. Pierson, J. Amer. Chem. SOC.,1970,92,1451. Menger chlorine free radical (particularly if the chains are tightly packed), and the amount of terminal chlorination increases substantially.Cheer and Johnson3 described another selective reaction carried out on an alumina surface [equation (2)]. Two products [(l)and (2)] are possible for this Me OH (11 (21 (aryl migration ) (methylene migration) (2) acid-catalysed rearrangement, depending upon whether the aryl or methylene group migrates. In a homogeneous reaction (boron trifluoride etherate in methylene chloride), erythro-epoxide gave (1):(2) = 77 :23 and threo-epoxide gave (1) :(2) = 90 :10. The predominance of (1) in both cases was attributed to a greater migratory aptitude of the aryl group relative to that of the alkyl group. The heterogeneous rearrangement catalysed by alumina behaved quite differently: erythro led to >90% (2) and threo led to >90% (1).This remarkable stereoselectivity was explained by conformationally-immobile transition states in which both the epoxide and alcohol oxygen atoms of the substrate are fixed to the alumina surface [equations (3) and (4)]. II) 8rythlb thno (3) (4) Papain, a water-soluble proteolytic enzyme, was found by Katchalski and co- workers* to function heterogeneously when embedded in a collodion membrane.* C. J. Cheer and C. R. Johnson, J. Amer. Chem. Soc., 1968,90,178. R. Goldman, 0.Kedem, I. H. Silman, S. R. Caplan, and E. Katchalski, Biochemistry, 1968, 7,486. Reactivity of Organic Molecules at Phase Boundaries A 400 pm thick collodion film was immersed in an aqueous solution of papain and impregnated with enzyme.The membrane was then treated with a reagent which cross-linked the adsorbed enzyme molecules and prevented leaching from the membrane. (Cross-linking did not appear to affect enzymic activity.) A rate vs. pH profile for the ‘enzyme-membrane’, determined by adding membrane slices to solutions of benzoyl-L-arginine ethyl ester, showed a gradual rate increase from pH 6.0 to 9-6.On the other hand, native enzyme displayed a bell-shaped profile with a maximum rate of ester hydrolysis at pH 6.5-7-0. The fact that the optimal pH of the embedded papain is not reached even at pH 9.6 suggests that the acidity within the membrane microenvironment is 2-4 pH units lower than the external pH. One reason for this difference may be that the local pH at the membrane is decreased by the protons generated from the enzyme-catalysed hydrolysis [equation (S)].Another explanation for the dis- papain RCOtR +RCOZ-+ HOR + H+ (5) torted pH profile of the heterogeneous reaction is that a diminished enzymic activity, which normally results from an increase in pH above the pH maximum, is compensated by a subsequent increase in the steady-state concentration of the substrate within the membrane. The bell-shaped curve is thereby flattened. Interestingly, the enzyme-membrane hydrolyses gelatin much more exten- sively than does native enzyme. Perhaps the gelatin molecules adsorb on to the membrane surface, unfold, and expose a large number of peptide linkages to the hydrolytic action of the bound enzyme.Clearly, systems such as this are complex. Nevertheless, their study is necessary if we are ever to understand how enzymes function in vivo on the surfaces of membranes and subcellular particles.s The investigation by Kornblum and Luriee of the homogeneous and hetero- geneous alkylations of phenol deserves mention since the results illustrate certain constraints imposed on a reaction proceeding on the surface of a crystal lattice. Homogeneous alkylation of sodium phenoxide by allyl bromide in ethylene glycol dimethyl ether (in which both reactants are soluble) gave 99% allyl phenyl ether [equation (6)]. Heterogeneous alkylation of sodium phenoxide (carried out by adding allyl bromide to a suspension of the phenoxide in ethyl ether) gave o-allylphenol as the major product [equation (7)].There was also some ether formation in the latter reaction, but this was shown to arise from a competing homogeneous process. The difference in the reaction sites [equations (6) and (7)] is not a solvent effect, because homogeneous alkylation of p-t- octylphenoxide in diethyl ether yielded only ether product. Therefore, some feature of the surface reaction leads to a strong preference for attack at an ortho carbon of the benzene ring. The absence of oxygen alkylation at the crystal surface [equation (S)] may have two causes. First, a halide ion departing into an aprotic solvent would be 6 For additional examples of matrix-bound enzymes, see K. Mosbach, Ada Chem.Scund., 1970,24,2084; K. Mosbach and B. Mattiasson, ibid., 1970, 24,2093. 0 N. Kornblum and A. P. Lurie, J. Amer. Chem. SOC.,1959,81,2705. 232 Menger 0' Na* OCH2CHmCH2 homoqeneous-0+ CH2==CHCH2Br (99Oh) 0' Na' OH t CH2=C HCH,B r heterogeneous bcH2cH=cH2 poorly solvated. Second, covalent bonding to the oxygen nucleophile would dissipate charge on the oxygen, thereby depriving the sodium ions in the proximity of the oxygen of one of their counterions. Since ion migration in a solid is less ready than in solution, the resulting coulombic repulsion between the sodium ions could not be easily relieved. OCH,RI0 -0/ / (8) The above difficulties do not apply to carbon alkylation at the solid phenoxide surface [equation (9)]. The incipient bromide ion is stabilized by ion-pair forma- tion with one of the sodium ions which presumably clusters about the oxygen anion.Since 'removal' of a sodium ion occurs concomitantIy with loss of charge on the oxygen, there is little accumulation of unfavourable coulombic repulsion. 233 Reactivity of Organic Molecules at Phase Boundaries From a practical standpoint, a reaction at a solid surface may have an advan- tage over its homogeneous counterpart in the ease of product isolation. Thus, Leermakers and James’ used small pieces of polyvinyl phenyl ketone as a sensitizer in the photolytic conversion of norbornadiene into quadricyclene. Removal of the sensitizer after the reaction was a simple matter. Another example is the Merrifield8 solid-state synthesis of polypeptides.A polypeptide is con- structed stepwise while the chain is attached to an insoluble resin. After each reaction, the system is freed of side products and excess reagents by thorough washing of the resin. Patchornik and Kraus@ acylated phenylacetic acid by ‘immobilizing’ the acid on an insoluble polymeric carrier. Phenylacetic acid was treated with chloromethylated polystyrene [equation (10); P = polymer], and the resulting ester was acylated with an acid chloride and trityl-lithium. The derived polymer was isolated by filtration, washed, dried, and treated with HBr in trifluoroacetic acid to give the desired ketone. By immobilizing the ester on the polymer surface and by running the acylation heterogeneously, self condensation of the ester (an important side reaction in homogeneous acylations) was avoided.P-CHzCl+ PhCH2C02H P-CH20COCH2Ph PhjCLi IRCOCt --“c“d, IRCOCH2Ph P-CHZOCOCHPh COR 3 Films Many water-insoluble organic substances having both hydrophilic and hydro- phobic moieties can be readily spread on a water surface to form films one molecule thick. Valuable information concerning the reactivity of oriented molecules in such monomolecular films has been secured using an instrument known as a surface balance. The surface balance confines a film within a rect-angular area bounded on two opposite sides by a movable barrier and by a float attached to a torsion wire arrangement. The surface pressure of the film, measured directly by means of the float system, may be increased by adjusting the movable barrier such that the area of the film is decreased.A decrease in area may have the effect of forcing molecules lying flat on the water surface into vertical posi- P. A. Leemakers and F. C. James, J. Org. Chem., 1967,32,2898 ;see also G. R. De Mare, M. C. Fontaine, and P. Goldfinger, ibid., 1968, 33,2528. * S. Wang and R. B. Merrifield, J. Amer. Chem. SOC.,1969,91,6488. *A. Patchornik and M. A. Kraus, J. Amer. Chem. Soc., 1970,92,7587. Menger tions where they require less room. Therefore, the capability is available of manipulating the orientation of molecules and of determining their orientation by comparing the area per molecule in the film with the actual molecular area.Over thirty years ago MitchelllO studied the light-induced hydrolysis of stearic anilide monolayers spread on 5N-HCI subphases [equation (1l)]. He showed that the apparent quantum yield depended on the molecular area of the film. When the film compression was increased, the area per molecule decreased, and the quantum efficiency increased up to a point where it levelled off. This be- haviour was ascribed to a change in angle between the dipole axis of the stearic anilide chromophore and the direction of the incident light. Shah and Schulmanll injected cobra venom into the water phase beneath a dipalmitoyl lecithin film and measured the change in potential across the mono- layer caused by an enzyme-catalysed ester hydrolysis [equation (1211.The CH OCO(CH2)14 Me II I CHOCO (CH2),4Me CHOH II ?-I p-+ CH 2-OP- OCH 2CH 2 NMe3It 0 0 surface pressure remained nearly constant throughout the reaction, indicating that the hydrolysis products did not leave the monolayer. Although the reaction proceeded rapidly at applied surface pressures of 5-15 x N cm-l, there was virtually no ester hydrolysis at pressures greater than 20 x N cm-l. In other words, the reaction could be mechanically ‘switched off’. Compression of the monolayer decreases the intermolecular spacing of the film and hence impedes the ability of the active site of the enzyme to penetrate the monolayer. This rationale is consistent with the finding that dioleoyl lecithin monolayers are subject to enzyme-catalysed hydrolysis even at pressures near 40 x N cm-l.The rigid olefinic linkages in the oleic acid side chains lead to a loosely- packed arrangement of molecules that is difficult to compress. Marsden and RideaP showed that the double bonds of unsaturated fatty 10 J. S. Mitchell, Proc. Roy. Soc., 1936, A155, 696. l1 D. 0. Shah and J. H. Schulman, J. Colloid Interface Sci., 1967, 25, 107. lgJ. Marsden and E. K. Rideal, J. Chem. Suc., 1938, 1163. 235 Reactivity of Organic Molecules ut Phase Boundaries acid films are oxidized by aqueous subphases containing KMnO,. The rate of oxidation of a monolayer of the cis-isomer of the fatty acid in equation (13) was found to decrease only 25% when the applied pressure was increased from 2 to 8 x N cm-l.An identical pressure increase on a monolayer of the corre- Me(CHa),CH=CH(CH2)llCOaHMe(CHa),CH-CH(CHJllC02H (1 3)I1 OH OH sponding trans-isomer led to 100-fold rate decrease. A reasonable explanation for this large difference follows. At low compressions, both the cis-and trans- compounds lie flat along the water surface where the double bonds, being in close proximity to the KMnO,, are readily oxidized. When the trans-isomer is subjected to 8 x N cm-l pressure, the hydrocarbon chains are forced to stand vertically out of the water. Since most of the olefinic linkages are then no longer in contact with the aqueous KMn04, the reaction rate drops 100-fold. The cis-fatty acid resists a 90”change in orientation at 8 x N cm-l because the ‘bent’ chains fit less easily into a vertical array.Consequently, the pressure increase has only a small effect on the rate. The oxidation rate of double bonds in films of unsaturated steroids depends on the position of the double bond and on the stereochemistry of the steroid.la Unfortunately, very little is known about the regioselectivity and stereoselec- tivity of reactions of complex natural products at phase boundaries. The photochemical decomposition of a monolayer of 4hydroxystearic acid on 500 ml of 0.01-NH,SO, is sensitized by trace quantities (3 pg) of nickel ion in the subphase.14 Such an effect is reminiscent of the sensitivity of living systems to drugs and inhibitors. Langmuir and Schaefer15 were able to detect the presence of 2 x 10-sM aluminium ion in water by utilizing the efficient adsorption of cations by monomolecular films of fatty acids.Monolayers of stearic acid above metal solutions were crushed and skimmed off; the ‘monoskims’ were melted and their cooling observed under a polarizing microscope. Skims from mono- layers lying upon 2 x 10-*M aluminium ion gave distinctly-different crystal patterns from those lying upon pure water. Daviesls and Gainesl’ have cited further examples of monolayer reactions. 4 Liquid-Liquid Interfaces The formation of nylon is one of the most vivid examples of an organic reaction which occurs rapidly at a liquid-liquid interface. When an aqueous solution of hexamethylenediamine is placed upon a solution of sebacoyl chloride in carbon tetrachloride, a milky film of polymer appears at the juncture of the two im- J.F. Danielli and N. K. Adam, Biochem. J., 1934, 28, 1583. l4 J. S. Mitchell, E. K. Rideal, and J. H. Schulman, Nature, 1937, 139, 625. l5 I. Langmuir and V. J. Schaefer, J. Amer. Chem. Soc., 1937,59,2400. l6 J. T. Davies, Adv. Catalysis, 1954, 6, 1. l7 G. L. Gaines, ‘Insoluble Monolayers at Liquid-Gas Interfaces’, Interscience, New York, 1966, chap. 7. Menger miscible liquids. A long thread of nylon may be slowly withdrawn from the film until one of the reagents is exhausted. In 1928 Be1P published his work on the physical organic chemistry of re- actions at liquid-liquid interfaces. Only a few papers on the subject have appeared since then.Bell treated benzoyl-o-toluidine in benzene with KMnO, in water to produce benzoylanthranilic acid [equation (14)]. The benzene and water solu- tions were allowed to remain in two layers, each of which was stirred separately. Oxidation was assumed to take place exclusively at the horizontal boundary. The reaction rate was found to be independent of the stirring speed, first-order with respect to KMn04, and independent of the benzoyl-o-toluidine concentra- tion above a certain level. There was also an amazing 13-fold rate increase with a 10 "C temperature rise. Bell concluded from these results that the interfacial reaction is caused by permanganate ions striking an adsorbed layer of benzoyl-o- toluidine. Highly-approximate calculations showed that at 25 "C only one in lo7of the permanganate ions reaching the interface manages to react success- fully with a substrate molecule. Mansoori and Maddenl9 oxidized tetrachlorohydroquinone [equation (193 by stirring solutions of the material (15-90 ml, 50% cC14-50% 2-octanone) with 1500 ml aqueous CeIV.The rate was zeroth-order with respect to CeIV but directly proportional to the hydroquinone concentration in the organic phase. The reaction was believed to be homogeneous in nature (taking place either in an aqueous zone adjacent to the interface or throughout the aqueous phase). This requires that the tetrachlorohydroquinone moIecuIes cross the interface prior to their oxidation. Since the reaction is zeroth-order in CeIV, the transfer of the substrate from the organic solvent into the water is probably rate-determining.The mechanism of an imidazole-catalysed ester hydrolysis at a water-heptane R. P. Bell, J. Phys. Chem., 1928, 32, 882. lo G. A. Mansooriand A. J. Madden, Amer. Inst. Chem. Engineers J., 1969,15,245. Reactivity of Organic Molecules at Phase Boundaries boundary was elucidated here at Emory.20 Aqueous imidazole solutions were stirred rapidly under carefully-controlled conditions with hep tane solutions of p-nitrophenyl laurate, and the rate of the resulting ester hydrolysis was deter- mined as a function of the following reaction variables: stirring speed, concen- tration of reactants, temperature, viscosity of the hydrocarbon phase, volume of the heptane and water solutions, deuterium and salt content of the water, lauroylimidazole content of the heptane, presence of surfactant, and structure of the catalyst.Without going into details, the results of these experiments strongly support a true boundary reaction rather than a homogeneous process occurring in either the bulk water phase or the bulk heptane phase. The inter- facial hydrolysis was found to be first-order in imidazole from 0.03 to 0.26M. A plot of the rate vs. concentration of ester in the heptane displayed a pronounced saturation effect above 3 x 10-3M. There was no observable rate increase when the temperature was elevated from 15 to 30 "C. These results point to a diffusion-controlled process. Remarkably small concentrations of laurate ion in the water phase (6 x 10-5M) were found to impede significantly the interfacial ester hydrolysis.The surfactant adsorbs at the interface (according to a Freundlich isotherm) and inhibits the reaction by competing for adsorption sites and/or by perturbing the structure of the interfacial region. The laurate experiments were informative because they showed that the reaction between imidazole and ester at the inter- face involves nucleophilic attack [equation (16)] rather than general base catalysis. The latter mode of catalysis would produce laurate ion directly. Consequently, if general base catalysis were operative, a product inhibition should have been observed, and this was not the case. On the other hand, the interfacial hydrolysis catalysed by hydroxide ion did indeed exhibit product inhibition.One would expect this behaviour here because laurate ion is definitely a reaction product. + HOC, H, NO, Synthetic organic chemists might be able to use reactions at liquid-liquid interfaces to good advantage, particularly with regard to controlling or altering stereochemistry. Some credence to this idea arises from preliminary experiments21 on the oxidation of borneol and isoborneol to camphor [equation (17)]. Homo-geneously, isoborneol is oxidized by aqueous chromic acid twice as fast as borneo1.22 In contrast, the two epimers are oxidized at virtually identical rates when the reactions are carried out heterogeneously (by stirring the alcohols in heptane with aqueous chromic acid).While no evidence exists which proves so F. M. Menger, J. Amer. Chem. SOC.,1970, 92, 5956. W. P. Bradley, unpublished results. Is H. Kwart and P. S. Francis, J. Amer. Chern. SOC.,1959, 81, 2116. Menger that these latter reactions are in fact completely interfacial, the fast borneol oxidation may result from a favourable adsorption of the borneol at the heptane- water boundary prior to formation and collapse of the chromate ester inter- mediate. This is reasonable because borneol has a less hindered alcohol group than isoborneol. borneol camphor isobsrneol stark^^^ found that stirring octyl halides with aqueous solutions of in-organic anions did not lead to sN2 substitution unless a quaternary salt was present in the organic phase.Thus, a mixture of 100 g 1-chloro-octane in 25 ml decane and 100 g NaCN in 25 ml water at 105 "Cgave no I-cyano-octane after 3 h. However, addition of 5 g hexadecyltributylphosphonium bromide resulted in a 95 % yield of 1-cyano-octane after 1-8 h at 105 "C.The effect of the quaternary salt was termed 'phase-transfer catalysis' because cyanide ion must migrate from the aqueous phase into the organic phase and exchange with bromide ion before reaction with the alkyl halide. The cyanide-bromide exchange is remi- niscent of an ion exchange resin. As cyanide is consumed in the organic phase, it is replenished by material in the aqueous cyanide pool. Although the sub- stitution reaction is probably not interfacial, movement across the interface is an essential part of the mechanism.Starks also showed that quaternary salts which are soluble in non-polar solvents catalyse many other two-phase reactions involving anions such as the heterogeneous oxidation of olefins by aqueous perinanganate and the reduction of ketones by aqueous sodium borohydride. The concentration of reactants at a liquid-liquid interface may differ sub- stantially from the concentration in the adjoining phases. An outstanding example was published by Fry and Reed24 who electrochemically reduced 2'2-dichloronorborane [equation (1 8)] in DMF containing tetraethylammonium bromide. They obtained endo-norbornyl chloride (38 %) and nortricyclene (62 x)which were shown to arise from a common carbanion intermediate [equation (18)].When one mole of water was added to the DMF, the ratio of products changed from 38 :62 to 80 :20. Addition of water, a proton donor, increased the relative amount of norbornyl chloride because proton capture by the carbanion competes more effectively with loss of chloride ion. In contrast to water, acetic acid and phenol hardly affected the ratio of 38: 62. Furthermore, when both tetraethyl-ammonium bromide (0.1M) and phenol (I-OM) were present in the DMF, the former provided the protons required for norbornyl chloride formation 23C.M. Starks, J. Amer. Chem. SOC.,1971, 93, 195. z4 A. J. Fry and R. G. Reed, J. Amer. Chem. SOC.,1971,93, 553. 239 4 Reactivity of Organic Molecules at Phase Boundaries (as shown by ethylene production). Apparently, lack of adsorption of phenol at the mercury-DMF interface, where the carbanion forms and reacts, causes an enormous apparent reversal in acidity. 4-CI For reasons of brevity, the present review contains no discussion of emulsion polymerization and other applications of reactions of molecules at phase boundaries. This is unfortunate since the great practical importance of the subject should be emphasized. The world will be a better place when scientists- and nations-solve their respective boundary problems.

ISSN:0306-0012    

DOI:10.1039/CS9720100229

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

The Photochemistry of Transition=metalColordination Compounds -A Survey By W. L. Waltz and R. G. Sutherland DEPARTMENT OF CHEMISTRY AND CHEMICAL ENGINEERING, UNIVERSITY OF SASKATCHEWAN, SASKATOON, SASKATCHEWAN, CANADA 1 Introduction In recent years, there has been a rapid and expanding interest in the photo- chemistry of transition-metal co-ordination compounds. This has been due not only to the resurgent interest in the chemistry of these systems, but also to the extensive progress that has been made both in the interpretation of their elec- tronic spectra and in the photochemistry of organic systems. The purpose of this article is to present a systematic survey of the diverse behaviour manifested by co-ordination complexes upon exposure to visible and near-u.v.light. The material has been chosen to indicate areas of active interest and to illustrate the interdisciplinary dependence between this and related fields such as absorp- tion and emission spectroscopy. This aim has necessitated a rather restricted choice of citations; however, a number of recent and comprehensive review articles on the photochemistry1-6 and the photoluminescences of transition-metal complexes as well as an excellent monograph’ are available. 2 Nature of the Excited State The absorption of electromagnetic radiation is a quantized phenomenon, and for radiation in the visible and U.V. regions sufficient energy is available to bring about change in the electronic state of a system as well as changes in its vibra- tional and rotational motion.The relationship between this energy of transition, E, and the frequency of the exciting radiation is given by equation 1 and thus E. L. Wehry, Quart. Rev., 1967,21,213. (a)V.Balzani, L. Moggi, F. Scandola, and V. Carassiti, Inorg. Chim. Acta, Rev., 1967, 1,7; (b) V. Balzani, L. Moggi,and V. Carassiti, Ber. Bunsengesellschaft Phys. Chem., 1968, 72, 288; (c) L. Moggi, V. Balzani, and V. Carassiti, ibid., p. 293. D. H. Valentine, jun., Adv. Photochem., 1968, 6, 124; Ann. Survey Photochem., 1969, 1, 457; ibid., 1970, 2, 341. (a)A. W. Adamson, W. L. Waltz,E. Zinato, D. W. Watts, P. D. Fleischauer, and R. D. Lindholm, Chem. Rev., 1968,68, 541; (b) A. W. Adamson, Co-ordination Chem. Rev., 1968, 3,169; (c)A. W. Adamson, Rec.Chem. Prop., 1968,29,191; (d)A. W. Adamson,Pure Appl. Chem., 1969,20,25. J. F. Endicott, IsraelJ. Chem., 1970, 8, 209. * (a) P. D. FIeischauer and P. meischauer, Chem. Rev., 1970, 70, 199; (b) F. E. Lytle, Appl.Spectroscopy, 1970,24, 319.’V. BaIzani and V. Carassiti, ‘Photochemistry of Co-ordination Compounds’, Academic Press, London, 1970. The Photochemistry of Transition-metal Co-ordinatiort Compounds -A Survey E = Nhv = Nhclh = (2.859 x 104)/hkcal mol-1 (1) where N = Avogadro's number h = Planck's constant v = frequency of the radiation h = wavelength of absorbed radiation in nanometres c = velocity of light the energy which is available for photochemical processes. For the regions of interest, 200-800 nm, this represents energies between values of ca.143 and 36 kcal mol-1 respectively. For co-ordination compounds, sufficient energy is available to cause homolytic and heterolytic bond cleavage and in some instances photoionization. It is important to realize that chemical reaction by an energetically enriched system represents only one of several potential modes of energy dissipation available to the system. In general, the energy dissipation scheme can be quite complex, as shown in Figure 1. The energy level diagram is representative of 60 --50 -40 P 1 dE"-30-E Y F 20-6, c 10-0-Figure 1 Energy level diagram for CrIII complexes in octahedral symmetry, Oh. (a) Transitions: 1, 1', 1": absorption. 2,2', 2": emission-2 and 2',fluorescence; 2",phosphorescence. 3, 3', 3'f: non-radiative deactivation.4, 4': non-radiative crossing-4 (and also 3, 3'), internal conversion; 4' (and 37, intersystem crossing. 5, 5', 5": thermal equilibration of vibrational and rotational levels. 6, 6', 6": chemical reaction. (b) Capital letters designate the terms or energy states, and the superscripts indicate the spin multiplicities of the states. (c) Lower-case letters symbolize electronic configurations in the strong-field approximation of ligand-field theory, and from these configurations arise the various energy states. (d) In some instances, the 4Tzelevel may be below that of the %Eqstate. (e) After A. W. Adamson, J. Phys. Chem., 1967,71, 798. Waltz and Sutherland CrIII complexes of octahedral microsymmetry (Oh symmetry).The overall symmetry of the complex will generally be lower than octahedral, but in the first approximation, the six identical atoms bonded directly to the CrlI1 centre and octahedrally situated about it determine the form of the energy-level diagram for the ligand-field states of Figure 1. For the sake of clarity, only the lower excited energy states (4T1g, and 2Eg)and the ground state (4A2g)4T2g, are shown. Other states higher in energy exist and may be of importance to the photo- processes of CrIII systems.gv8 In connection with Figure 1, several general points warrant particular attention. The absorption of light (transitions 1, l’, and 1”) leads to electronically excited states that are generally vibrationally and rotationally excited by virtue of the Franck-Condon Principle.The latter modes equilibrate rapidly with their surroundings (transitions 5, 5’, and 5”) to give a vibrationally and rotationally equilibrated system, but the system is still in an electronically excited state from which both radiative and non-radiative processes may occur as well as chemical ones. The radiative and non-radiative processes can be classified on the basis of whether the transitions occur between states having the same spin multi- plicity, such as the quartet states, or between states having diflerent spin multi- plicities, such as quartet-doublet crossings.t A radiative transition between states of the same spin multiplicity (2 and 2’ of Figure 1) is termed fluorescence whereas a non-radiative one (3, 3’, and 4) is called internal conversion.Like- wise, between states differing in their spin multiplicities, the radiative and non- radiative crossings are referred to as phosphorescence (2’)and intersystem crossing (3” and 4’) respectively. In solutions at room temperature, most transition-metal complexes do not luminesce but in the solid state and in low-temperature media, luminescence (usually phosphorescence) is more prevalent .6p The non-radiative transitions are not observed directly, but their relative importance is inferred from the ab- sence or presence of luminescence and/or photochemical reaction. From luminescence and photochemical studies of transition-metal complexes (and also those of organic systems), it is generally inferred that the non-radiative transi- tions between excited states of a given spin multiplicity, e.g.4T1g---4T2g of Figure 1, are very fast, with first-order rate constants of the order of 10l1s-l. Similarly, intersystem crossings between excited states, such as 4T2g---2Eg, appear to be fast even though they are formally spin-forbidden owing to the change in spin multiplicities accompanying such crossings.6 -9 Luminescence from higher excited states of transition-metal complexes apparently has not been observed; this implies that the non-radiative processes are favoured over the radiative ones. In contrast, both the radiative and non-radiative transitions from the lowest excited states of a given spin multiplicity to the ground state appear to be relatively slow.For CrlI1 complexes, the first-order rate constants for transitions from the lowest quartet and doublet states to the ground state t Spin multiplicity = 2s + 1, where S is the spin quantum number. L. S. Forster, TransitionMetal Chem., 1969,5, 1. J. N. Demas and G. A. Crosby, J. Amer. Chem. SOC.,1970,92, 7262. 243 The Photochemistry of Transition-metal Co-ordination Compounds -A Survey appear to bc in the range of 104-10B s-l and of 101-106 s-l respectively?-lo Although information on photophysical events is still quite meagre, several general conclusions can be drawn in regard to the effects of these photophysical processes on the photochemical ones.Owing to the relative time scales involved, it is more probable that photochemical reactions will occur from the lowest excited state of a given spin multiplicity. Since the lowest excited state differing in spin multiplicity from that of the ground state is generally expected to have a longer lifetime than that of the lowest excited state having the same spin multi- plicity as that of the ground state, photochemical reaction from the former may be more probable than from the latter one. There is, however, mounting theoret- icalll and experimental evidence (see Section 3A) that, at least for CrIII systems, and can be photochemically active, and both of the low-lying states (*TSg indeed can show a difference in their photochemical behaviour. In any event, for photochemical reactions to be competitive with the relatively fast photo- physical ones, the activation energies for the former must be small (Gca.10 kcal mol-I} in comparison to the activation energies encountered in the thermal chemistry of transition-metal complexes. Crystal-field calculations suggest activation energies of the order of zero for photosubstitutional reactions in CrIII complexes occurring from either or 4T2g;the situation for CoIII complexes appears to be less favourable.ll In addition to characterizing photoevents in terms of the associated rate constants, it is more common to describe the efficiency of such events relative to the amount of absorbed light because these are usually more readily obtainable experimentally. The efficiency for a particular photochemical or physical process such as those shown in Figure 1 is expressed in terms of the quantum yield, 4, (equation 2).rate of change of the process of interest (2) '= rate of absorption of light quanta of a specified wavelength The totality of all such events, excluding possible secondary thermal ones, must be unity. Thus a chemical quantum yield less than one indicates the occurrence of other competing processes. An energy level diagram, such as Figure 1, provides a convenient represen- tation of possible excited-state events, but does not adequately convey one very important point; that is, the change in electron density upon excitation. Such change is not only the source of the non-equilibrium condition of the excited state but also determines the nature of the excited state and thus has a strong bearing on the subsequent course of events.This change in electron density on excitation is better portrayed by a molecular orbital energy diagram, such as that for ferrocyanide, Fe(CN),4-, shown in Figure 2, where the relative positions lo Schoen-nan Chen and G. B. Porter,J. Amer. Chem. SOC.,1970,92,2189. l1 A. W. Adamson, J. Phys. Chem., 1967,71,798. l2 H. L. Schlaefer, J. Phys. Chem., 1965, 69,2201; 2.Chem., 1970, 199 (Chem. Ah., 1970, 72, 72 6392). Waltz and Sutherland of the metal and ligand orbitals contributing to a given molecular energy con-figuration provide a measure of the electron distribution. Fe M.O. CN Qrbitals I I Ii I +50 301, I \ I I Qrbitals - ‘E 0- u 0 0 0.-- -50- F>r a8 c W -100 ---150 1 ’a,, Figure 2 Molecular orbital energy diagram for ferrocyanide ion.(a) Electrons fill the levels completely up to and including the 2tZg level. (b) The d-d or ligand-field excitations correlate with the 2t,, to 3eg transition whereas a charge-transfer band, CT, arises from the 2tSo to 4tlu transition. (c) After J. J. Alexander and H. B. Gray, J. Amer. Chem. SOC.,1968,90,4260. From such quantum mechanical descriptions and from the spectral properties of absorption and emission bands, there has arisen an oversimplified, but useful, classification of electronic transitions as d-d or charge-transfer, CT.7113~1d Transitions of the d-d or ligand-field type are essentially localized on the central metal and represent an angular redistribution of electronic charge.Since these absorption transitions occur from bonding or non-bonding orbitals to anti- bonding orbitals, they are generally characterized by weakening of the metal- ligand bonds. They frequently fall into the category of symmetry-forbidden transitions (Laporte forbidden) for centrosymmetric complexes such as octa- hedral ones. This results in low values for the molar extinction coefficients, typically 1-1 50 1mol-1 cm-l for octahedral complexes and smaller if the transi- tions are also spin-forbidden, e.g. aEpt4A2g,Figure 1. These restrictions are * J. J. Alexander and H. B. Gray, J. Amer. Chem.SOC.,1968,90,4260. ‘.See for example, T. M. Dun, in ‘Modern Cosrdination Chemistry’, ed. J. Lewis and R. G. Wilkins Interscience Publishers Inc., New York, 1960, Chapter 4. The Photochemistry of Transition-metal Co-ordination Compounds -A Survey also applicable to the radiative transitions. Although the spin rule is also valid for non-radiative processes, these processes are now symmetry-allowed ones (see ref. 7). In contrast to the ligand-field case, CT transitions are generally symmetry- allowed, and consequently the extinction coefficients are frequently much larger in magnitude, ca. lo41 mol-1 cm-l. They represent a much more extensive re- distribution of electron density and one of a more radial nature. In a limiting sense, they can represent changes in the formal oxidation numbers of the atoms involved.In addition, they are generally observed at higher energies (but not always) than those for d-d transitions, and in fact may mask the higher-energy, ligand-field ones. Within the CT classification, one can further subdivide the transitions into ones involving movement of charge from the metal to the ligand(s) (CTTL) or to the solvent (CTTS), from the ligand(s) to the metal (CTTM), or from one ligand-centred orbital to another one (L-L). 3 Photochemical Reaction Modes Three fundamental types of photochemical reaction are known for co-ordina- tion compounds : substitution, rearrangement, and redox rea~tions.l-~~~ In a number of instances more than one mode is observed for a given system.A. Photosubstitution.-A large number of metal complexes undergo photo- substitution, involving solvation, anation, or ligand (solvent) exchange. Of the systems studied, those of chromium(m) complexes have provided the greatest amount of information on this type of reaction, generally one of photoaquation. For complexes possessing octahedral microsymmetry, e.g. Cr111L6, photo- substitution, shown as photoaquation in equation 3, occurs on irradiation of the hv CrIIIL, + H20-+ Cr1I1L5(H2O)+ L (3) quartet and doublet d-d bands (see Figure l), and the reaction is believed to involve heterolytic cleavage of the Cr-L bond. The quantum yields range from ca. 0-01-ca. 0.5, and the values are nearly independent of the particular d-d band irradiated.113s4$7 A similar situation is encountered for non-Oh systems, i.e.those with mixed ligands; however, there is now a greater variation in the quantum yields with wavelengths, and several aquation modes are possible (see below).* There is also some evidence that U.V. irradiation of the CT bands may give rise to redox proce~ses.~~~~~~J~ For Oh systems, the constancy of the photochemical quantum yield whether the quartet bands or doublet band were irradiated led to the early proposal that the lowest energy doublet state, is responsible for chemical rea~tion.~~?~~ * The term system shown in Figure 1 is not strictly applicable to non-Oh complexes although the designation of a state as a doublet or quartet remains valid. l6 (a) P.Riccieri and H. L. Schlgfer, Inorg. Chem., 1970, 9, 727; (b) H. F. Wasgestian and H. L. Schllifer, 2.phys. Chem. (Frankfurt), 1968, 62, 127. l6 P. D. Fleischauer, Ph.D. Thesis, University of Southern California, 1968. l7 (a) M. R. Edelson and R. A. Plane, Znorg. Chem., 1964, 3, 231 ; (b) R. A. Plane and J. P. Hunt, J. Amer. Chem. Soc., 1957, 79, 3343. Waltz and Sutherlatid Support for this proposal comes from the relatively long lifetime of this state as determined by emission studies, where lifetimes in the range 10-6-10-1 s are observed, usually in low-temperature media or in the solid state (see also ref. 18). Of recent interest is the possible photochemical activity of the quartet states and the lowest energy one in particular (see Figure 1).Central to this issue are the lifetimes of the quartet states, especially the 4T2gstate, and certain photo- physical features germane to this point warrant mentioning. Where fluorescence is observed from the lowest quartet level, it is found at considerably lower energies than that for absorption,ss8 suggesting considerable distortion of this level relative to the ground state, and as such the quartet’s lifetime may be longer than otherwise expected. This interpretation finds support from recent low-temperature measurements of fluorescence and phosphorescence lifetimes for several CrIII complexes where the ratio of the 2Eglifetime to that of 4T28 varied from ca. 10 :1 to ca. 500 :1.l0An allied point is that in their pure elec- tronic states (zeroth vibrational levels), the 2Egand 4Tzgmay in a number of systems be close in energy, with the latter possibly being below the doublet one where fluorescence is observed.When the two levels are energetically reasonably close, thermal repopulation of the 4T2gfrom the 2Eg(the reverse of processes 5” and 4 of Figure 1) can be significant in the energy degradation ~cheme.~~~-~~~~~~7~~lS-~~Other aspects of this subject have also been dis-cussed.ll~22 -24 Photochemical studies of non-Oh CrIII complexes that can exhibit two different photoaquation modes have helped to clarify the photochemical role of the quartet state(s). A number of such studies have been carried out.497915924-26 The extensive investigations of Cr(NH3)5(NCS)2+ in aqueous O-1N-H2S04 by Adanison and co-w~rkers~~ will be discussed in some detail as the results illus- trate some features of general occurrence. For this complex, two aquation modes occur, equations 4 and 5.Both aquation reactions occur upon irradiation hv Cr(NH3)5(NCS)2++ H20-+ Cr(NH,),(H,0)3+ + NCS-(4) hv Cr(NH,)5(NCS)2i+ H,O +Cr(NH3)4(H20)(NCS)2++ NH3 (5) of the quartet and doublet bands and the quantum yields progressively decrease with increasing wavelength of radiation. However, if the doublet state is not l8 T. Ohno and S. Kato, Bull. Chem. SOC.Japan, 1970, 43, 8. lS (a) G. B. Porter, Schoen-nan Chen, H. L. Schlafer, and H. Gausmann, Theor. Chim. Acta, 1971, 20, 81; (b) Schoen-nan Chen and G. B. Porter, J. Amer.Chem. SOC.,1970,92, 3196. ao F. D. Camassei and L. S. Forster, J. Chem. Phys., 1969, 50, 2603. a1 J. L. Laver and P. W. Smith, Chem. Comm., 1970, 1497. a*V.Balzani, R. Ballardini, M. T. Gandolfi, and L. Moggi, J. Amer. Chem. SOC.,1971, 93, 339. a3 A. D. Kirk, K. C. Moss, and J. G. Valentin, Canad. J. Chem., 1971, 49, 375. a4 (a)J. E. Martin and A. W. Adamson, Theor. Chim. Acta, 1971,20, 119; (6) A. W. Adamson, J. E. Martin, and F. D. Camessei, J. Amer. Chem. SOC.,1969, 91, 7530; (c) E. Zinato, R. D. Lindholm, and A. W Adamson, ibid., 1969, 91, 1076. 4L M. F. Manfrin, L. Moggi, and V. Balzani, Znorg. Chem., 1971, 10, 207. asA. D. Kirk, J. Amer. Chem. SOC.,1971, 93, 283. 247 5 The Photochemistry of Transition-metal Co-ordination Compounds -A Survey solely responsible for photoaquation, the ratio of $NH3 :$NCS-should be dependent upon wavelength.Indeed, this ratio varies with wavelength, being 15.3 :1 (373 nm radiation; quartet band), 22.1 :1 (492 nm; quartet band), and 8.2 :1 (652 nm; doublet band). This lends strong support to the idea that both the lowest quartet state and the doublet one can be involved in chemical reaction. Furthermore, the preferred mode of photoaquation (ammonia release) differs from the thermal one, where thiocyanate release predominates. This illustrates the important point that the photosubstitution mode need not necessarily be an acceleration of the thermal process. Another generally encountered feature exhibited by Cr(NH3)5(NCS)2+ is that the apparent activation energies for both photoreactions are small, being about 1-2 kcal mol-l, compared to that for the thermal release of thiocyanate (ca.25 kcal mol-l). For the product of reaction (3,Cr(NH3)a(H20)(NCS)2+,both cis- and trans-isomers could occur. Evidence has been presented that suggests the photo- product is the trans-isomer: this is in accord with the empirical rules proposed by Adamson for predicting the photochemical product(s) of non-Oh chromium(m) complexes.ll The general validity of these rules has recently been challenged principally upon the grounds that the stereochemical products arising from Cr(NH3),(C1)2+ or (Br) and trans-dichlorobis(ethy1enediamine)-chromium(m) are in the cis-rather than the expected trans-configurations.7~1s~zs~z6 However, as Kirkzs has suggested, these discrepancies may be a manifestation of the stereomobility in the photosubstitutional reactions of chromium(m), and if this proves to be general, it would be somewhat in contrast to the thermal behaviour of these A final point concerns the interaction of CrIII systems with electronically excited organic or inorganic species.The effect of complex ions in quenching triplet states of organic compounds is well known,28 and recently such studies have been extended to inorganic systems, such as CrIII complexes, both in ~~~~ ~~solution and in the solid ~tate. The results, while so~far limited ~~ to a few systems, do indicate that the interaction involves collisional processes accompanied at least in part by intermolecular energy transfer.There is, however, some evidence that other processes, such as quenching without energy transfer, may also be imp~rtant,~~~~~~~~~~~ and more detailed discussions of energy transfer mechanisms can be found else~here.~.~~ 27 R. D. Archer, Co-ordinationChem. Rev., 1969, 4, 243. (a) J. G. Calvert and J. N. Pitts, jun., ‘Photochemistry’, John Wiley and Sons, Inc., New York, 1966, Chapter 4; (b) H. F. Wasgestian and G. S. Hammond, Theor. Chim. Acta, 1971, 20, 186. 29 D. J. Binet, E. L. Goldberg, and L. S. Forster, J. Phys. Chem., 1968, 72, 3017. 30 (a) H. Gausmann and H. L. Schlafer, J. Chem. Phys., 1968, 48, 4056; (b) A. D. Kirk, A. Ludi, and H. L. Schlafer, Ber. Bunsengesellschaft Phys.Chem., 1969, 73, 669; (c) H. L. Schlafer, H. Gausmann, and C. H. Mobius, Znorg. Chem., 1969, 8, 11 37. 3L G. B. Porter, J. Amer. Chem. SOC.,1969, 91, 3980. 32 (a) V. S. Shastri and C. H. Langford, J. Amer. Chem. Soc., 1969, 91, 7533; (b) J. N. Demas and A. W. Adamson, ibid., 1971, 93, 1800. 33 I. Fujita and H. Kobayashi, J. Chem. Phys., 1970,52,4904. nz F. Wilkinson, Adv. Pliotochem., 1964, 3, 241. 248 Waltz atid Sutherland The methodology of such studies has in general been to observe the quenching of emission from the energy-donor by the CrIII energy-acceptor, and the subse- quent sensitization of phosphorescence and/or photoaquation from the CrlI1 entity. The intermolecular energy transfer reactions between Cr(NH3),(NCS)2f and excited biacetyl molecules or acridinium ions in aqueous 0.1N-H2S04 exemplify this te~hnique.~* In the presence of Cr(NH3)5(NCS)2+, the phos- phorescence from the lowest triplet state of biacetyl is quenched, whereas the fluorescence from the lowest singlet state is not affected.That energy transfer has occurred from the biacetyl triplet level is shown by the release of ammonia, with no apparent chemical degradation of the biacetyl. When acridinium ion is the sensitizer, the quenching of the acridinium ion’s fluorescence is accompanied by release of both ammonia and thiocyanate, with the former predominating. Although the phosphorescence of acridinium ion is not observed, the quantum yield of thiocyanate release decreases in the presence of oxygen.This suggests that the triplet state of acridinium ion may be sensitizing the release of thio- cyanate. For both sensitizers, the4~~~ is about half of the value resulting from direct excitation of the lowest quartet band. Of particular importance is the comparison of the ratio $m3:~NCS-for the sensitized reactions and those for direct photolysis of the lowest quartet and doublet states, these being > 100 :1 (biacetyl), 33.3 :1 (acridinium ion), 22-2:1 (quartet), and 8-2:1 (doublet). This comparison strongly suggests that ammonia release occurs primarily from the lowest quartet level whereas thiocyanate loss originates within the doublet level. Furthermore, from considerations of the variations in the quantum yields themselves as well as those of the ratios, it has been postulated that the method of population of a given excited state (direct excitation versus sensi-tization) may be vital to the subsequent course of excited-state events (see also ref.22). This powerful tool of photosensitization has also been applied to the substitution reactions of CO(CN)~~-(ref. 31) and PtC142- (ref. 32), as well as to the photoredox decomposition of cobalt(1u) acido-ammines (see Section 3C). B.Photorearrangements.-Within this classification occur geometrical isomeriza- tion, racemization, linkage isomerization, and ligand rearrangement. Square- planar complexes of platinum(@ afford examples of geometrical photoisomeriza- tion, i.e. cis-trans isorneri~ation.~~~~~~ The cis-bis(glycinato)platinum(n), upon irradiation of the d-d type bands in the near-u.v., rearranges to the trans-isomer with a value of $isom of ca.0*13.35The reverse reaction, that is trans to cis isomerization, does not occur, although prolonged irradiation of the CT band (254 nm) for the trans-isomer leads to decomposition. In contrast to thermal isomerization, where the presence of unco-ordinated glycine is required, photo- isomerization does not lead to incorporation of free, radioactive glycine into either isomer. These features suggest that the photoprocess involves an intra- molecular twist mechanism (one without bond cleavage) whereas the thermal 35 (a) V. Balzani and V. Carassiti,J. Phys. Chem., 1968,72,383; (b) F. Scandola, 0.Traverso, V. Balzani, G.L. Zucchini, and V. Carassiti, Inorg. Chim. Acta, 1967, 1, 76; (c) V. Balzani, V. Carassiti, L. Moggi,and F. Scandola, Znorg. Chem., 1965, 4, 1243. The Photochemistry of Transition-metal Co-ordination Compounds -A Survey reaction proceeds via an intermolecular path. The constancy of $isom, the intra- molecular character of the photoreaction, and the spectroscopic-theoretical evidence for excited triplet states of tetrahedral conformation for square-planar PtC14a-,36 have led to the suggestion that the reactive intermediate is a triplet state of pseudo-tetrahedral geometry, as shown in equation 6, where NnO designates the glycinato ligand.36 Further support for a tetrahedral intermediate cis, singlet tetrahedra 1 trans, singletground state inter med iate, ground state triplet state comes from symmetry considerations where the square-planar-tetrahedral in-terconversion is photochemically allowed but thermally disallowed, and from a recent semi-quantitative theoretical study.*’ A tetrahedral intermediate has also been postulated in an attempt to explain the photoisomerization of Pt(Et,P),CI, in organic solvents, where both cis to trans and trans to cis re-actions occur and a photostationary equilibrium, different from the thermal equi- 1ibrium, is encountered. * A number of metal systems have been reported to photoracemize, with that of aqueous tris(oxalato)chromium(m), Cr(C,04)33-, having been studied in detai1.1~4~7~39*40The photoracemization mechanism appears to be an intra-molecular one involving cleavage of a Cr-0 bond in the primary step, as shown in equation 7, followed by the reaction leading to inversion, equation 8.39 0 36 D.S. Martin, jun., M. A. Tucker, and A. J. Kassman, Inorg. Chem., 1965, 4, 1682. (a)T. H. Whitesides, J. Amer. Chem. SOC.,1969, 91,2395; (b)D. R. Eaton, J. Amer. Chem. SOC.,1968, 90, 4272; (c) F. S. Richardson, D. D. Shillady, and A. Waldrop, Znorg. C‘him. Actu., 1971,5, 279. 38 P. Haake and T. A. Hylton, J. Amer. Chem. SOC.,1962, 84, 3774. 39 S. T. Spees and A. W. Adamson, Znorg. Chem., 1962, 1, 531. 40 V. S. Sastri and C. H. Langford, J. Phys. Chem., 1970, 74, 3945. Wuitz arid Sutherlaiid 0 II 0 -ce I0-Cr'-OH, __c0---H204 O,O The incorporation of water into the free carboxy-group at least some of the time (equation 7) is shown by the fact that photoexchange of solvent oxygen accom- panies the racemization reaction to some extent.The +recem of cd. 0.1 is essentially independent of the nature of the d-d bands irradiated (Figure 1) and of temperature, but sensitive to the composition of the solvent: D20 or aqueous acetone, alcohols, and dimethyl sulphoxide mixtures depress The photoreaction is reported to be sensitive to acidity in 0.2 M dimethyl sul- phoxide40 but not so in water.39 The solvent sensitivity of the photoreaction may well be a reflection of the extent to which hydrogen-bonding to water favours distortion of the excited state and thus to the bond cleavage reaction.40 Solvent effects are also observed in the thermal racemization and aquation reactions of Cr(C204),3-, and these reactions appear to be mechanistically similar to the phot~reaction.~~ An interesting observation about a racemic mixture of Cr(C20,)33- is that preferential racemization of one enantiomer can be induced using circularly polarized light (A > 500 nm).42 Finally, U.V.photo-lysis of the CT band leads to photoredox decomposition similar to that observed for other metal(rI1) oxalates such as ferri~xalate.~~~~~ For linkage photoisomerization, the isomerization of the nitro-group (-NO,) to the nitrito-form (-ONO) isrepresentative, the case of CO(NH~)~(NO~)~+ being well doc~mented.~~~~~~~~~~-~~While the photochemistry of CO(NH~)~(NO~)~ appears to be complex (redox decomposition, aquation, and linkage iso- merization being reported under various conditions), the results obtained by Balzani and co-workers provide a reasonably coherent picture of the photo- lytic behaviour of this This complex exhibits CT bands of ClTM character at 239 and 325 nm and a ligand-field band at 458 nm.Upon irradiation of the CT and d-d bands, aqueous 0.1N-HC104 solutions of CO(NH,),(NO,)~+ exhibit, as the primary photoprocesses, both redox decomposition (the major process) and nitro to nitrito isomerization. The quantum yields decrease signi- ficantly with increasing wavelengths'of radiation; however, the ratio of : changes only slightly, being 3-9:1 (254 nm radiation; CT band), 3-7:1 (313 nm; CT),5-6:1 (365nm; between CT and dd),and 3.4 :1 (442 nm; d-~l).~~ These features suggest that both photoreactions may originate from the same '* K.V. Krishnamurty and G. M. Harris, Chem. Rev., 1961, 61, 213. '* B. NordCn, Acta Chem. Scand., 1970, 24,349. V. Balzani, R. Ballardini, N. Sabbatini, and L. Moggi,Inorg. Chem., 1968,7, 1398. B. Adell, Z. anorg. Chem., 1955, 279, 219. "W. W. Wendlandt and J. H. Woodlock, J. Inorg. Nuclear Chem., 1965, 27, 259. 25 1 The Photochemistry of Transition-metal Co-ordination Compounds -A Survey excited state, probably the lowest energy CT one, although in light of recent studies for cobalt(n1) systems (see Section 3C), the participation of states that are lower in energy and that differ from the nascent excited state in their spin multiplicities cannot be discounted.While the absorption maximum of this CT state lies at a higher energy than that of the ligand-field one, the order of the pure electronic states could be reversed owing to distortion in the CT state, as portrayed in Figure 3. Thus, excitation of the d-d band could populate the CT I t charge-transf er excited state c critical co-ord inate Figure 3 Schematic representation of a possible relation of CT and d-d excited states for CO(NH,)~(NO,)~+.(a) Order of excited states: energy of absorption maximum, CT > d-d: pure electronic energy, d-d > CT. (b) After V. Balzani, R. Ballardini, N. Sabbatini, and L. Moggi, Inorg. Chem., 1968, 7, 1398. state via a subsequent non-radiative transition.In any event, the reaction mech- anism appears to involve the homolytic bond cleavage of the Co-NO, bond, giving rise to a radical-ion pair intermediate as depicted in equation 9, Subse-quent separation of NO, from the cobalt(@ entity by thermal diffusion from CO(NH,),(ONO)~+ CO(NH~)~(NO,)~+h', CO(NH,),~+-NO,/ (9)II Co2++ 5NH3 + NO, the solvent cage leads to the redox products. In competition with this are the cage recombination reactions leading to formation of the original starting Waltz and Sutherland material and of the nitrito-product, which itself rearranges to the thermally more stable nitro-form. In contrast to its solution behaviour, irradiation in the solid state results primarily in linkage i~omerism.~~-~~ An interesting example of ligand photorearrangement occurs in the photo- chromism of primary metal dithiz~nates.~~ With radiation above ca.400 nm, non-aqueous solutions of these compounds undergo striking colour changes, ranging from yellow, orange, or green to blue or violet. The transitions respon- sible for these changes appear to be of an intraligand character (L-Ltype): the nature of the metal centre does not greatly affect the colour changes. The thermal return reactions involved in the photochromic effect are fast ;however, the rates are very sensitive to the nature of the metal atom, to the presence of acids and bases, and to the polarity of the solvent. These features plus the absence of free radicals and of net photochemical reaction lend support to an overall photomechanism involving a cis-trans isomerization of an azomethine group coupled with a proton shift, as shown in equation 10 for the square- Ph \N-H / \\ N C ' Ph S N '\ =N Ph\ N-H / \\N C N -H \ N N S \I ph I -C \\N /H-i A N 'Ph C \ -N /TJ ,Ph \ Ph orange blue planar mercury compound. The rate-determining step in the thermal return appears to involve the proton shift.Owing to their ease of preparation, metal dithizonates readily lend themselves to a series of interesting laboratory experi- ments based on their photochromic beha~iout.~' It should not be concluded from this example that irradiation of L-L bands necessarily leads to ligand rearrangement, as other systems are known to exhibit different types of photo-chemical processes such as photoredox decomposition (see below).46 (a) L. S. Meriwether, E. C. Breitner, and C. L. Sloan, J. Amer. Chem. Suc., 1965, 87,4441 ; (b) L. S. Meriwether, E. C. Breitner, and N. B. Colthup, ibid., 1965, 87, 4448; (c) W. H. Foster, jun., J. M. Dowd, jun., and R. A. Coleman, U.S.P. 3 475 339/1969 (Chem. Abs., 1970, 72, 56 633n). 'I A. W. Adamson, personal communication. The Photochemistry of Trarisitiort-metal Co-ordinatiori Conipounds -A Survey C. Photo-oxidation-Reduction.-These processes can involve either intra- or inter-molecular transfer of electronic charge, and can be further distinguished on the basis of whether the central metal undergoes oxidation or reduction.Considering intramolecular ones first, few examples involving the oxidation of the central metal atom are known;' however, numerous examples of photo-reduction of the metal and oxidation of the ligand(s) can be cited, with the photochemistry of cobalt(m) complexes being noteworthy. The general photo- lytic features of acidic aqueous solutions of cobalt(1rr) acido-ammines of the type Co111(NH3),X, where X can be H20, NH3, halide (and pseudohalide), NO2-, carboxylato, or -O,CO~~~(NH,),, will be discussed;48-54 their behaviour is somewhat representative of other cobalt(m) system~.~-~~~ The spectra of acido-ammines consist of one or two d-d bands in the visible-near-u.v. regions, with the lower energy one sometimes split into two band^.^^^^^^ The higher energy band is obscured in some cases by the first of generally two CT bands at shorter wavelengths of CTTM (or L-L) character.Irradiation of the CT bands leads to the formation of CoI1 with quantum yields ranging from ca. 0.1 upwards of 1, and exceeding one for X = I-. When the first CT band is energetically close to the d-d bands, as for the easily oxidized X groups, e.g. I-and Br-, ligand-field excitation also leads to cobalt(r1) production but in lesser amounts. The CT situation is frequently complicated by the simultaneous occurrence of photo- aquation [or linkage isomerism as for CO(NH,),(NO,)~+]. The redox process involves the homolytic fission of the Co-X bond (or Co-N in some cases), as shown in equation 11.The overall fate of X depends upon its chemical nature. hv (H~N)~CO"'-X __+ CO" + 5NH4f + X H+ Halogen transients have been observed in flash photolysis studies for X = I-or Br-,48b whereas for X = C1-, nitrogeneous radicals appear to predominate.50a The presence of X has been inferred by scavenging techniques in other cases,50t52 and the free-radical character of the reactions has been used to initiate poly- merization of vinyl material^.^^ (a) A. W. Adamson, A. Vogler, and I. Lantzke, 1. Php. Chem., 1969, 73, 4183; (6) S. A. Penkett and A. W. Adamson, J. Amer. Chem. SOC.,1965, 87, 2514; (c) A. .W. Adamson, Discuss. Faraday SOC.,1960, No. 29, p. 163; (d)A. W. Adamson and A. H. Sporer, J. Amer. Chem. SOC.,1958, 80, 3865. 4D (a) M. F.Manfrin, G. Varani, L. Moggi, and V. Balzani, Mol. Photochem., 1969. 1, 387; (b) L. Moggi, N. Sabbatini, and V. Balzani, Gazzetta, 1967, 97, 980. (a) G. Caspari, R. G. Hughes, J. F. Endicott, and M. Z. Hoffman, J. Amer. Chem. SOC., 1970,92, 6801 ;(b)E. R. Kantrowitz, J. F. Endicott, and M. Z. Hoffman, ibid., p. 1776; (c) J. F. Endicott, M. Z. Hoffman and L. S. Beres, J. Phys. Chem., 1970, 74, 1021; (d) J. F. Endicott and M. Z. Hoffman, J. Amer. Chem. SOC.,1965,87, 3348. H. Way and N. Filipescu, Inorg. Chem., 1969, 8, 1609. J. E. Barnes, J. Barrett, R. W. Brett, and J. Brown, J. Inorg. Nuclear Chern., 1967,30, 2207. J. S. Valentine and D. Valentine, jun., J. Amer. Chem. SOC..1971, 93, 11 11. O4 N. Shinozuka and S. Kikuchi, Nippon Kaguku Zasshi, 1966, 87, 97; 1966, 87, 1413.sL R. A. D. Wentworth and T. S. Piper, Inorg. Chem., 1965, 4,709. La (a) L. V. Natarajan and M. Santappa, J. Polymer Sci., Part A-1, Polymer Chem., 1968, 6, 3245; (b) G. A. Delzenne, J. Polymer Sci., Part C, Polymer Symposia, 1967, 16, 1027; (c) Gevaert Photo-Production N.V., Belg. P. 647 442/1964 (Chem. Ah., 1965, 62, 24006). Waltz and Sutherland The overall sequence of events leading to the final products is not completely understood. The situation is complicated by the simultaneous occurrence of photosubstitutional processes, by secondary thermal and photochemical reactions, and by the participation of excited states lower in energy than those populated directly by absorption of light (see below).An early mechanism pro- posed by Adamson and co-workers focused on the formation and subsequent reactions of a radical-ion pair intermediate [similar to that in equation 91 to account for the occurrence of both photoredox and photoaquation reaction^.^^^^ Others have stressed the importance and possible natures of the excited states involved, and discussed various alternative mechanisms.1-3~5~7~43~4g~so~s3~s7 Emission studies have not helped in these investigations as cobalt(m) complexes have generally not been found to luminesce. Recent photosensitization studies do indicate, however, that not only can the nascent singlet states be photo- chemically active but so also can non-spectroscopic, lower energy triplet states, probably of CT chara~ter.~~~~~~~~~The occurrence of excited species differing from the nascent ones has also been inferred from scavenging experiments with alc~hols.~~~~The photochemistry of the longer-wavelength, ligand-field bands is primarily one of substitutional reactions.The quantum yields, in contrast to those of the CT bands, are invariably small, e.g. cu. and the mechanism may now be one of heterolytic bond ~leavage.~~~~~~~~ Finally, a set of empirical rules has been given that summarizes many of the features of the photochemistry of these and other cobalt(m) complexes.6o The fairly recent recognition of photoelectron production for transition-metal complexes serves to illustrate intermolecular photoredox, where the central metal (or more appropriately the complex) undergoes oxidation.Studies of photoelectron production have centred on aqueous solutions of cyanide com- plexes, in particular ferrocyanide, Fe(CN)64-, for which the overall reaction is that shown in equation 12, where elq represents the solvated electron. Identi- In Fe(CN)64-__+ Fe(Oe3-+ eLq fication of the electron has been accomplished directly by flash photolysi~~l-~~ and by electron spin resonance measurements on low-temperature alkali glass,65 br Z. Simon, Canad. J. Chem., 1960,38,2373. “(a) M. A. Scandola and F. Scandola, J. Amer. Chem. SOC., 1970, 92, 7278; (b) M. A. Scandola, F. Scandola, and V. Carassiti, Mol. Photochem., 1969, 1, 403. A. Vogler and A. W. Adamson, J. Amer. Chem. SOC.,1968, 90,5933. A. Vogler and A.W. Adamson, J. Phys. Chem., 1970,74,67. *I M. S. Matheson, W. A. Mulac, and J. Rabani, J. Phys. Chem., 1963, 67, 2613. *I (a) M. Ottolenghi and J. Rabani, J. Phys. Chem., 1968, 72, 593; (b) G. Czapski and M. Ottolenghi, Israel J. Chem., 1968, 6, 75. **(a) W. L. Waltz and A. W. Adamson, J. Phys. Chem., 1969, 73, 4250; (6) W. L. Waltz, A. W. Adamson, and P. D. Fleischauer, J. Amer. Chem. SOC., 1967, 89, 3923. R. Devonshire and J. J. Weiss, J. Phys. Chem., 1968, 72, 3815. as P. B. Ayscough, R. G. Collins, and F. S. Dainton, Nature, 1965,205, 965. 255 The Photochemistry of Transition-metal Co-ordination Compouiids -A Survey and indirectly but quantitatively by chemical scavenging technique^.^^,^^ The spectrum of ferrocyanide consists of d-d bands in the blue and near-u.v.regions and C"bands in the U.V. The ligand-field bands arise from the 3egt2tto transition (see Figure 2), and their photochemistry is one of aquation rather than electron produ~tion.~~~~~~-~~ Electron production originates upon irradia- tion of the CT band^,^^*^^-^^ and appears to be accompanied to a lesser extent by photoaquation.87-6e Some dispute exists as to the assignment of the CT state involved in electron production. Ohnoe7has assigned this to one arising from a CTTL transition, in agreement with the molecular orbital interpretati~nl~ (see Figure 2). Others contend that the photoactive state correlates with a CITS band.66e68 Both interpretations nevertheless involve movement of electron density from the metal centre to the periphery of the complex, followed by solvation of the electron.The quantum yields for both photoionization and photoaquation tend to be higher than those normally found for transit ion-metal compounds, ranging from ca. 0.l-ca. 0.9; however, they appear to be sensitive to experimental conditions such as pH.407163p66-6gAt low pH's, the photoreactions are now probably those of HFe(CN)63-, a weak acid.66-68 Although photoelectron production has been observed for only a few ~y~tem~,4~~~~~~~~~~~ it may prove to be a fairly widespread reaction mode for transition-metal compounds. Examples of photo-oxidation-reduction reactions of an intermolecular type involving reduction of the metal centre appear to be relatively s~arce.~~~~~~~ Ion-pair complexes of the type CO(NH,),~+*X-,where X-is I- or C1-, which exist at high concentrations of aqueous Co(NH3)@,+and X-, can be considered y.~~~~~~~in this ~teg~~ The near-u.v.spectra'l of the ion-pairs differ ~~ from that of the sum of the components, CO(NH3)e3+and X-: the difference is generally one of higher level of absorption and, for X = I-, the partial masking of the higher energy d-d band of CO(NH,),,~+.Irradiation at 254 nm of the chloride ion-pair leads to yields of cobalt(n) in the range ca. 0.3-ca. 0~8.484~60d~ss~ Formation of chlorine as a product does not occur;60d however, a transient, presumably C12-, has been reported in flash photolysis studies.soa The photo- sensitization of what could be the ion-pair by naphthalene in a 50% water-ethanol mixture gives rise to a higher cobalt@) yield than does direct photo- lysis.68b Exposure of the iodide ion-pair to 370 nm light gives rise to iodine (41, = 0.77)and presumably cobalt(Ir), although it was not reported as such.'*d The general reaction mechanism appears to be that of equation 13, which bears P.D. Airey and F. S. Dainton, Proc. Roy. SOC.,1966, A291,340,479. *7 S. Ohno, Bull. Chem. Sac. Japan, 1967, 40, 1765, 1770, 1776, 1779. *e (a) G. Stein, Israel J. Chem., 1970, 8, 691; (b) M. Shirom and G. Stein, ibid., 1969. 7,405; (c) G. Stein, in 'Solvated Electron', ed.R. F. Gould, American Chemical Society, Washington, D.C., 1965, pp. 230-241 ;(d)M. Shirom and G. Stein, Nature, 1964,204, 778; (e) M.Shirom and G. Stein, J. Chem. Phys., 1971.55, 3372.3379. G. Emschwiller and J. Legros, Compt. rend., 1965, 261, 1535. 7O G. V. Bwton, F. S. Ddnton, and J. Kalencinski, Internut. J. Radiation Phys. Chem., 1969, 1, 87. (a) M. G. Evans and G. H. Nancollas, Trans. Faraday Soc., 1953, 49, 363; (b)N. Tanaka, Y. Kobavashi. and M. Kamada. Bull. Chem. SOC.Japan, 1967,40,2839. Waltz and Sutherland hv Co(NH3)e3+.X-+Co2++ 6NH4' + X H+ a formal resemblance to that for the cobalt(nr) acido-ammines (equation 11). An additional feature concerns the irradiation of the lower-energy ligand-field band of CO(NH&~+(peak at 475 nm) in the presence of I-. While the spectral characteristics of this band are not affected by ion-pair formation, irradiation of this band, that is photochemically ina~tive~~d in the absence of I-, leads to formation of iodine from the ion-pair.This feature suggests the possibility that the excited Co(NH&'+ entity may be a stronger oxidizing agent than the ground-state species. Such photoredox reactions of ion-pairs may prove to be a fairly common reaction mode for transition-metal complex ions in the presence of easily oxidized counter-ions and in solvents where the ion-pair formation constants are considerably greater than those found in aqueous media. 4 Discussion For a number of these photoreactions, there are similar thermal processes. It is apparent, however, that the chemistry of the excited state does represent a situa-tion different from that of the thermal one and not merely an acceleration of thermal reactions.In this regard, the inclusion into the photochemistry of these systems of vibrationally excited ground-state species does not at this time appear to be necessary, although the occurrence of such reactions remains a distinct possibility. In general, the quantum yields for photochemical reactions of transition-metal complexes are less than unity and in many instances much less. This indicates that to understand the chemistry of the excited states not only must the photo- chemical aspects be investigated but also the competing photophysical ones. While the general absence of luminescence for these systems in solution at room temperatures has hindered such studies, the recent introduction of the technique of photosensitization into this field has contributed substantially to the under- standing of photo-processes, and particularly to the recognition of the impor- tance of various excited states, both spectroscopic and non-spectroscopic ones, to the course of excited-state events. In a number of cases, some correlation appears to exist between the nature of the band irradiated and the mode of the resulting photochemical reaction. Thus, irradiation of ligand-field bands frequently results in substitutional or related processes whereas irradiation of @r bands gives rise to oxidation- reduction modes.This generalization can be a useful one, but it presupposes, aside from the restricted nomenclature of designating transitions as d-d or CT, certain conditions that may not always be met in practice.It suggests a certain level of incommutability between d-d and CT states, and such a condition may not always exist; such may be the case with some cobalt(m) acido-ammines. The participation of states lower in energy than those populated directly by light absorption, and particularly those differing in their spin multiplicities, may complicate the situation. This may not always involve a change in the type of The Photochemistry of Transitiort-metal Co-ordination Compounds -A Survey photochemical reaction, but rather a change in the pathway of reaction as exemplified by Cr(NH,),(NCS)*+. The extent to which this type of generaliza- tion is fulfilled and the possible development of other relationships requires further detailed investigations.Finally, since sustained interest in a field can result from both its fundamental and applied importance, it is well to inquire briefly into some of the applications of the photochemistry of transition-metal co-ordination compounds (see also refs. 4a and 7). Substantial use is made of these types of compounds in the imaging industry, e.g. iron cyanides in the blueprinting field.72 Systems such as ferrioxalate and Reinecke's salt find widespread use as u.v.-visible chemical actinometers.qa~7The employment of the photochemistry of transition-metal complexes occurs in other areas such as polymerization,66 generation of reagents in analytical chemistry,7s and synthetic inorganic chemistry.7P Although atten- tion in this article has been confined mostly to the liquid phase, the photo- chemical and photophysical processes of transition-metal systems in the solid state are receiving increased attenti~n.~~~~ Such great diversity in the photo- behaviour of transition-metal co-ordination compounds suggests a continuing and expanding interest in these systems both from applied and fundamental viewpoints.J. Kosar, 'Light-Sensitive Systems', John Wiley and Sons, Inc., New York,1965. 73 See for example (a) C. E. Bricker and S. S. Schonberg, Analyr. Chem., 1958, 30,922; (6) A. A. Nemodruk and E. V. Bezrogova, J. Analyt. Chem. (U.S.S.R.), 1969,24,239.''(a) R. A. Bauer and F. Basolo, J. Amer. Chem. SOC.,1968, 90, 2437; (6) J. A. Broomhead and W. Crumley, Chem. Comm., 1968, 1211; (c) L. H. Berka and G. E. Philippon, J. Inorg. Nuclear Chem., 1970, 32, 3355; (d) S. H. Mastin and P. Haake, Chem. Comm., 1970, 202; (e) S. J. Lippard and B. J. Russ, Inorg. Chem., 1967, 6, 1943. E. L. Simmons and W. W. Wendlandt, Co-ordination Chem. Rev., 1971, 7, 11.

ISSN:0306-0012    

DOI:10.1039/CS9720100241

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

The Biosynthesis of Sterols By L. J. Mulheirn SHELL RESEARCH LTD., MILSTEAD LABORATORY OF CHEMICAL ENZYMOLOGY, SITTINGBOURNE, KENT and P. J. Ram* DYSON PERRINS LABORATORY, SOUTH PARKS ROAD, OXFORD OX1 3QY 1 Introduction The discovery of the intermediates and the stereochemistry of the enzymic processes by which squalene is biosynthesized from mevalonic acid has been described in a previous Quarterly Review’ and in other re~iews.~~~ Application of these results to studies of the Iater stages of triterpene and sterol biosynthesis has proceeded rapidly over the past six years and, together with improved methods of enzyme isolation and chemical synthesis, is providing a detailed picture of the complex reactions involved. This review describes the main areas of recent investigation, with particular reference to the mechanistic and stereo- chemical results which have been obtained.Some properties of the enzymes mediating various stages of the biosynthetic sequence are also outlined. Although many investigations have been concerned with cholesterol biosynthesis in animals, parallel studies on other organisms have also been reported. Some interesting variations of reaction sequence and mechanism are observed in different species and are summarized here. However, this aspect has been more fully reviewed el~ewhere.~ The uses and limitations of radioactive compounds in the study of biosynthetic sequences have also been discussed in depth else- where.3a Literature received in England after April 1971 has not been included in the Review, although, for the sake of completion, important recent results have been appended in footnotes.2 The Conversion of Farnesyl Pyrophosphate to Squalene A. Stereochemistry.-The work of Cornforth, PopjBk, and co-workers1e2 has established the stereochemistry of the processes by which mevalonic acid (MVA) is converted to squalene. In particular, the use of specifically deuteriated and tritiated farnesyl pyrophosphate has revealed the stereochemical result of the * Present address: Research Department, Roussel Laboratories Ltd., Covingham, Swindon, Wilts SN2 4BE. R. B. Clayton, Quart. Rev., 1965, 19, 168, and references therein. * (a)J. W. Cornforth and G. Popjhk, Biochem. J., 1966, 101, 553; (b)J.W. Cornforth, Quart. Rev., 1969, 23, 125. (a) I. D. Frantz and G. J. Schroepfer, jun., Ann. Rev. Biochem., 1967, 36, 691 ;(6) C. J. Sih and H. W. Whitlock, Ann. Rev. Biochem., 1968, 37, 661. * L. J. Goad in ‘Natural substances formed biologically from mevalonic acid’, ed. T. W. Goodwin, Academic Press, London and New York, 1969, p. 45. The Biosynthesis of Sterols tail-to-tail linkage of farnesyl units by the enzymes of a rat-liver homogenate (Scheme 1). The process produces an overall inversion of stereochemistry of the hydrogen atoms attached to the prochirali- carbon atom C-1 of one farnesyl Scheme 1 It Squaiene G= Scheme 2 @=Phosphate t For general definition see K. R. Hanson,J. Amer. Chern. SOC.,1966, 88, 2731. Mulheirn and Ramm residue and retention of stereochemistry of HR attached to C-1 of the second farnesyl group, while Hs is lost and stereospecifically replaced by a hydrogen atom (HB) from the coenzyme NADPH.Thus, the symmetrical molecule squalene is formed by an asymmetric process.$ Two main mechanisms were proposed to explain this coupling process in the light of the stereochemical features outlined above. The first (Scheme 2)Sa involved isomerization of one farnesyl residue to a nerolidyl derivative, genera- ting a terminal methylene group capable of nucleophilic addition to the second farnesyl moiety with inversion of stereochemistry. The pyrophosphate group (or an analogous sulphonium groupKa) could then be removed by reductive H-S I. hl EnzymeEnzyme x3 GJyTG-G&*G S:i EnzymeEnzyme G+YG ---+Squalene Gs+ G= WbV-Enzyme @= Phosphate Scheme 3 t trans-Farnesyl pyrophosphate-squalene synthetase has now been isolated and purified 45-fold (I.Schechter and K. Bloch, J. Biol. Chem., 1971, 246,7690). c(u) G. Popjhk, Dew. S. Goodman, J. W. Cornforth, R. H. Cornforth, and R. Ryhage. J. Biol. Chem., 1961, 236, 1934; (b) J. W. Cornforth, R. H. Cornforth, C. Donninger, and G. Popjiik, Proc. Roy. Soc., 1966, B 163, 492. 261 The Biosynthesis of Sterols cleavage with hydride transfer from NADPH. This mechanism resembles that by which isopentenyl pyrophosphate reacts with dimethylallyl pyrophosphate and geranyl pyrophosphate to give farnesyl pyrophosphate.The second mech- anism (Scheme 3) postulated displacement of the pyrophosphate group of one farnesyl unit by an enzymic sulphydryl group with inversion of stereochemistry.bb Addition of the second unit could then be followed by rearrangement to form the central carbon-carbon bond and reductive cleavage of the squalene-sulphur bond. The feasibility of the latter type of mechanism has been demonstrated by the chemical synthesis of squalene from farnesol by Stevens’ rearrangement of a sulphonium ylide followed by reduction of the resulting sulphide.s However, subsequent work suggests that neither mechanism is operative in rat and yeast enzymes in vitro. B. Presqualene Pyrophosphate.-It has been demonstrated‘ that free nerolidyl pyrophosphate is not an intermediate in the coupling of farnesyl units to give squalene in yeast, contrary to the predictions of Scheme 2 outlined above.In the absence of the cofactor NADPH a new intermediate is formed. This com-pound, ‘presqualene pyrophosphate’, was first isolated from a yeast microsomal preparation by Rilling,*a who showed the presence of two fifteen-carbon units and one pyrophosphate group. The intermediate retained only three of the four C-1 hydrogens of the initial farnesyl groups (as does squalene) and could be converted to squalene, in the same enzyme system, on addition of NADPH. The compound has since been isolated from a rat-liver microsomal preparationsb P8‘0s (a)G. M. Blackburn, W. D. Ollis, C. Smith, and 3.0. Sutherland, Chem.Comm., 1969, 99; (b)J. E. Baldwin, R. E. Hackler, and D. P. Kelly, J. Amer. Cltern. Sac., 1968,90,4758.’S. S. Sofer and H. C. Rilling, J. Lipid. Res., 1969, 10, 183. *(a)H. C. Rilling, J. Biol. Chem., 1966, 241, 3233; (6) H. C. Rilling, J. Lipid. Res., 1970, 11, 480. Mulheirn and Ramm and is converted to squalene by either enzyme system in the presence of NADPH. The structure originally proposedsa for presqualene pyrophosphate (1) was shown to be incorrect by synthesi~.~ More detailed physical data were subse- quently interpreted in terms of (2).1° A chromatographically identical compound was isolated in a similar way by Popjak et aZ.,ll who interpreted their data (in particular the reported retention of all four farnesyl C-1 hydrogens) in terms of structure (3).Subsequently, Wasner and Lynenla reported the isolation of an intermediate which retained only three farnesyl C-1 hydrogen atoms and which, when labelled with [1J4CC]-farnesyl pyrophosphate, gave [W]malondialdehyde on ozonolysis. The com- pound was formulated as (4). Both (3) and (4) had been proposed5 as possible intermediates in squalene formation (Scheme 2). Recently, the structure (2) proposed by RillinglO for presqualene pyrophos- phate has been confirmed by degradation and by unambiguous synthesis.13* Of the eight possible isomers [(5)--(8) and optical antipodes] only one is bio- logically active. The absolute stereochemistry of this compound has been defined as (5). Although (5) has not been obtained in pure form by synthesis, incorporation of various mixtures of isomeric pyrophosphates into yeast homo- genates containing NADPH results in efficient conversion of the active isomer * The degradation results have recently been confirmed and extended (J.Edmond, G. PopjAk,S. Wong, and V. P. Williams, J. Biol. Chem., 1971, 246, 6254). E. J. Corey and P. R. Ortiz de Montellano, Tetrahedron Letters, 1968, 5113. loW. W. Epstein and H. C. Rilling, J. Biol. Chem., 1970, 245, 4597. l1 G. PopjAk, J. Edmond, K. Clifford, and V. Williams, J. Biol. Chem., 1969, 244, 1897. l1 H. Wasner and F. Lynen, F.E.B.S. Letters, 1970, 12, 54. I* (a) R. V. M. Campbell, L. Crombie, and G. Pattenden, Chem. Comm., 1971, 218; (b) L. J. Altman, R. C. Kowerski, and H.C. Rilling, J. Amer. Chem. Soc., 1971, 93, 1782; (c) H. C. Rilling, C. D. Poulter, W. W. Epstein, and B. Larsen, ibid., p. 1783; (d) R. M. Coates and W. H. Robinson, ibid., p. 1785. 263 6 The Biosynthesis of Sterols to squalene. In the light of these results, Scheme 4 has been proposed to explain the conversion of farnesyl pyrophosphate, via (9,to squalene.l3C C. Investigationof Reaction Sequence.-As described above, the conversion of farnesyl pyrophosphate to the symmetrical molecule squalene is an asymmetric process in which a hydrogen atom is lost from one farnesyl residue and replaced @ HR G+G HS HR G= &&/-Scheme 4 Mulheirn and Ramm by a hydrogen from NADPH. In many organisms the next step is the conversion of squalene to 2,3-epoxysqualene (see Section 3).Since in rat liver the micro- soma1 fraction contains the enzymes responsible for both the coupling of farnesyl groups and the epoxidation of squalene, it has been suggested2*~14 that an ordered arrangement of enzymes in the microsomes could result (Scheme 5) in a geometrically controlled transfer of the coupled squalene molecules [containing a hydrogen from NADPH (HB) in one half of the molecule] to the epoxidase. This could occur either directly (path ia) or by means of a carrier protein (path ib) in such a way that HB would be located specifically at either a or 18 during epoxidation. However, if squalene were first liberated into a metabolic pool (path ii), detachment from the enzymic environment would randomize the orientation of the molecules and subsequent transfer to the epoxidase would distribute HBequally between a and p.Thus by using tritiated NADPH these two pathways should be distinguishable. The distribution of radioactivity at a and 16 can be measured by conversion of labelled 2,3-epoxy- squalene (9) to lanosterol (10) or cholesterol (11) followed by specific oxidation at C-11 or C-12. An experiment in which squalene was formed anaerobically from farnesyl pyrophosphate and [3mNADPH by a rat-liver microsome preparation and subsequently converted aerobically to showed equal distribution of radioactivity at C-11 and C-12. However, the possibility that anaerobic incubation promoted liberation of free squalene (path ii) by blocking the action of the epoxidase cast doubt on this result. A study using I3H]NADPH in a continuous incubation of farnesyl pyrophosphate with pig liver homogenafelqa gave lanosterol having a ratio of tritium activity at C-11: C-12 of 1.28: 1.This small difference, together with the presence of some radioactivity at unknown positions in the molecule, did not allow a decision to be made between the operation of paths i and ii. Also, the presence of free squalene in the homo- genate suggested2b that the enzyme systems may have been disrupted and the microsomal order lost during preparation, since intact liver contains very little squalene, and what free squalene is found is not in equilibrium with newly bio- synthesized squalene.ls Studies on intact cells are more likely to provide a definite answer on this point. A similar experiment on incorporation of [l-3H2]farnesyl pyrophosphate into eburicoic acid (12) in the fungus Polyporus suZph~reus~~showed equal distribu- tion of activity at C-11 and C-12.It is noteworthy, however, that recent studies of the squalene epoxidase from yeastlS have shown it to be a soluble enzyme, in contrast to the rat liver epoxidase which is microsomal. This variation of enzyme properties suggests the possibility that reactions which appear to be IrA.H. Etemadi, G. Popjbk, and J. W. Cornforth, Biochem. J., 1969,111,445. l.5 B. Samuelson and Dew. S. Goodman, J. Bid. Chem., 1964,239,98. (a)G. Popjik, Arch. Biochern. Biophys., 1945,48,102; (b)A.V. Loud and N. R. L. Bucher, J. Biol. Chem., 1958, 233, 37. W. Lawrie, J. McLean, P. L. Pauson, and J. Watson, Chem. Cornrn., 1965, 623. I. Schechter, F. W. Sweat, and K. Bloch, Biochim. Biophys. Acra, 1970, 220,463. 265 The Biosynthesis of Sterols @ HA @ONH2 1 - Couplins Epoxidase enzyme Scheme 5 Free squalene pool Mulheirn and Ramm chemically identical in various organisms may occur by different processes at the enzymic level. 3 Conversion of Squalene to Triterpenes A. Oxidative Route; 2,3-Epoxysqualene.-The central role of squalene in the biosynthesis of sterols and triterpeneslg has been verified by extensive tracer studies. Tchen and Bloch 2o observed that cyclization in a rat liver homogenate containing D20or H2180 gave lanosterol (10) devoid of deuterium or l80while incubation in the presence of 1802resulted in incorporation of the isotope.The oxidation-cyclization process was shown to require NADPH and oxygen to- gether with both microsomal and supernatant fractions of the homogenate. In 1966, Corey et a1.21 and van Tamelen et al.z2 showed that this conversion involves a new intermediate, 2,3-epoxysqualene (13a). This compound could be cyclized to lanosterol anaerobically and, as expected, [180]-2,3-epoxysqualene gave [1s0]lan~~tero1.22b Examination of the enzymes mediating this conversion, squalene epoxidase and epoxysqualene cyclase, showed that both are located in the microsomes of liver. The ep~xidase,~~ which has not been obtained in soluble form (in contrast to the epoxidase in yeast18), requires NADPH and oxygen together with a supernatant fraction.The cyclase, which has been solubilized and purified, appears to require no cofactor~.~~ It is inhibited by the analogue 2,3-iminosqualene (13b).21b The widespread role of 2,3-epoxysqualene in the conversion of squalene to triterpenes has been rapidly established. In higher plants, cycloartenol (14) replaces lanosterol as the principal triterpene* and its formation from 2,3- epoxysqualene has been demonstrated in a cell-free preparation from bean leaves25 and in the microsomal fraction of cultured tobacco cells.26 A similar pathway is known to operate in Euphorbia latex2' and in several other species4 Cycloartenol also appears to be the key triterpene in algae since the brown alga Fucus spiralis28and the phytoflagellate Ochrumunas malhamensisaD incorporate MVA and 2,3-epoxysqualene into this triterpene rather than into lanosterol.l8 (a) R. B. Woodward and K. Bloch, J. Amer. Chem. SOC.,1953, 75,2023; (b) A. Eschen-moser, L. Ruzicka, 0.Jeger, and D. Arigoni, Hefv. Chim. Acta, 1955,38, 1890. ao T. T. Tchen and K. Bloch, J. Biof. Chem., 1957,226,931. I1 (a)E. J. Corey, W. E. Russey, and P. R. Ortiz de Montellano, J. Amer. Gem. Sac., 1966, 88, 4750; (b) E. J. Corey, P. R. Ortiz de Montellano, K. Lin, and P. D. G. Dean, J. Amer. Chem. Soc., 1967, 89, 2797. aa (a) E. E. van Tamelen, J. D. Willett, R. B. Clayton, and K. E. Lord, J.Amer. Chem. SOC., 1966, 88,4752; (6) E. E. van Tamelen, J. D. Willett, and R. B. Clayton, J. Amer. Chem. Soc., 1967, 89, 3371. as S. Yamamoto and K. Bloch, ref. 4, page 35. a4 (a) P. D. G. Dean, P. R. Ortiz de Montellano, K. Bloch, and E. J. Corey, J. Biol. Chem., 1967, 242, 3014; (6) J. D. Willett, K. B. Sharpless, K. E. Lord, E. E. van Tamelen, and R. B. Clayton, J. Biol. Chem., 1967, 242, 4182. 25 H. H. Rees, L. J. Goad, and T. W. Goodwin, Tetrahedron Letters, 1968, 723. a6 (a) U. Eppenberger, L. Hirth, and G. Ourisson, European J. Biochem., 1969, 8, 180; (b)R. Heinz and P. Benveniste, Phytochemistry, 1970, 9, 1499. G. Ponsinet and G. Ourisson, Phytochemistry, 1968, 7, 757. L. J. Goad and T. W. Goodwin, European J. Biochem., 1969,7,502.ae H. H. Rees, L. J. Goad, and T. W. Goodwin, Biochim. Biophys. Acta, 1969,176, 892. The Biosynthesis of Sterols (b) X=NH The cyclase enzyme of 0.malhamensis appears to be partially ~~Iuble,~~ in contrast to that in rat liver, which is located in the micro~ornes.~~ A cell-free system from peas causes cyclization of 2,3-epoxysqualene to /3-amyrin (1 5), a process which, as in the rat liver enzyme system, is inhibited by 2,3-imino-squalene.so In yeast the epoxide is efficiently cyclized to lanoster01~~ while the fungus Fusidium coc~ineum~~ converts it to the protosterol fusidic acid (16) and related tri terpenes. B. Non-oxidative Route of Squalene Cyclization.-"he intermediacy of 2,3-epoxysqualene is not, however, universal.While the protozoan Tetrahymena pyriformis does not produce sterols, the pentacyclic triterpene tetrahymanol(l7) *O E. J. Corey and P. R. Ortiz de Montellano, J. Amer. Chem. SOC.,1967,89,3362. a1D. H. R. Barton, A. F. Gosden, G. Mellows, and D. A. Widdowson, Chem. Comm., 1968, 1067. 3a W. 0.Godtfredsen,H. Lorck, E. E. van Tamelen, J. D. Willett, and R. B. Clayton, J. Amer. Chem. SOC.,1968,90,208. Mulheirn and Ramm has been isolated.33 Simultaneous feeding of [3H]-2,3-epoxysqualene and ['*C]-squalene resulted in incorporation of only 14Cactivity into tetrahymanol, using either whole cells or a soluble enzyme preparati~n.~~ Further, anaerobic cycliza- tion of squalene in media containing D20or H21*0gave tetrahymanol contain- ing deuterium (probably at C-3) and l80 (at C-21).These results are consistent with the theory that the triterpene is formed by proton-initiated cyclization of ~qualene,~~terminating in acquisition of a hydroxide ion from the medium. H A similar non-oxidative pathway for squalene cyclization appears to be operative in the fern Polypodium v~lgare~~where squalene is converted to the triterpene fern-9-ene (18) while 2,3-epoxysqualene is not incorporated. It is significant that this organism does convert 2,3-epoxysqualene to p-sitosterol (19) and other This is the only demonstration to date of the operation as (a) F. B. Mallory, J. T. Gordon, and R. L. Conner, J. Amer. Chern. SOC.,1963, 85, 1362; (6) Y. Tsuda, A. Morimoto, T. Sano, Y.Inubushi, F.B. Mallory, and J. T. Gordon, Tetra-hedron Letters, 1965, 1427. (a) E. Caspi, J. M. Zander, J. B. Greig, F. B. Mallory, R. L. Conner, and J. R. Landrey,J. Amer. Chem. SOC.,1968, 90, 3563, 3564; (b) E. Caspi, J. B. Greig, J. M. Zander, and A. Mandelbaum, Chem. Comm., 1969, 28; (c) J. M. Zander, J. B. Greig, and E. Caspi, J. Biol. Chem., 1970,245, 1247. *O (a) D. H. R. Barton, A. F. Gosden, G. Mellows, and D. A. Widdowson, Chem. Comm., 1969,184; (b) D. H. R. Barton, G. Mellows, and D. A. Widdowson, J. Chem. SOC.(0,1971, 110. The Biosynthesis of Sterols of both the oxidative and non-oxidative pathways of squalene cyclization in a single organism. 4 Mechanisms of Formation of Tetracyclic Triterpenes The processes involved in the cyclization of 2,3-epoxysqualene have been studied most intensively in the context of lanosterol formation by rat liver enzymes.It has been postulated that cyclization proceeds (Scheme 6) to give the protosterol carbonium ion (20a)lg6 or its stabilized equivalent (20b)3s followed by a con- certed series of hydrogen and methyl migrations terminating in the loss of the 9B hydrogen of (20) to give lanosterol (21). The demonstration that squalene containing six 4-p0-R protons of MVA gives lanosterol retaining only five of HO (b) Z =nucleophilic group I HU' HO (22) Scheme 6 J. W. Cornforth, Angew. Chem. Internut. Edn., 1968, 7, 903. 270 Mulheirn and Ramm these hydrogenss7 supported this scheme. Also, the protons at C-17a and C-20/3 of lanosterol were shown to have originated from C-13 and C-17 of (20) by degradation of cholesterol (22).3793saThe process was also shown to involve two 1:2 migrations rather than a single 1 :3 migration.38bThis result has since been confirmed by direct degradation of lanosterol biosynthesized in a yeast enzyme system.s8C Migration of the C-8 and C-14 methyl groups of (20) had previously been shown to involve two 1 :2 migrations by the use of 13C-labelled substrates.l Indirect support for the involvement of a protosterol inter- mediate has been obtained by studies on the fungal protosterol fusidic acid (23).The hydrogens at C-9P and C-13a were shown to be derived from the 4-pro-R position of MYA as predicted for the unrearranged protosterol @ = hydrogen originating from the 4-pro-R position of MVA Scheme 7 * A possible protosterol intermediate (20b; Z = OH) has recently been synthesized. How-ever, on incubation with a rat liver homogenate no incorporation into lanosterol could be demonstrated (H.Immer and K. Huber, Helv. Chim. Actu, 1971, 54, 1346).*'J. W. Cornforth, R. H. Cornforth, C. Donninger, G. PopjBk, Y. Shimizu, S. Ichii, E. Forchielli, and E. Caspi, J. Amer. Chem. SOC.,1965, 87, 3224. 38 (a)E. Caspi and L. J. Mulheirn, Chem. Comm., 1969, 1423; (6)M. Jayme, P. C. Schaefer, and J. H. Richards, J. Amer. Chem. SOC.,1970, 92, 2059; (c) D. H. R. Barton, G. Mellows, D. A. Widdowson, and J. J. Wright, J. Chem. SOC.(C), 1971, 1142. E. Caspi and L. J. Mulheirn, J.Amer. Chem. SOC.,1970, 92,404. 37te Biosynthesis of Sterols While lanosterol appears to be the primary product of cyclization of 2,3-epoxysqualene in animals and fungi, the equivalent compound in higher plants and algae appears to be cycloartenol (14).4 It has been postulated that this triterpene is formed via a protosterol intermediate similar to that envisaged for lanoster01.~~Following a backbone rearrangement, the carbonium ion could be stabilized at C-9 by addition of an enzymic nucleophile to give (24) (Scheme 7). Elimination of this group would then allow formation of the cyclopropane ring.41 This scheme is supported by the demonstration that all 4-pro-R protons of MVA are retained in cy~loartenol.~~ The enzyme-stabilized moiety (24) may be invoked as a common intermediate in the formation of several triterpene~~v~~ since, in addition to cycloartenol formation in plants, lanosterol (21) could be derived (in animals and fungi) by loss of the C-SP hydrogen from (24).Also, the cucurbitacins [e.g. cucurbitacin B (25)] may be produced by further back- bone rearrangement of (24), a route which is consistent with preliminary IabeI- ling studie~.*~t 5 The Action of 2,3-Epoxysqualene Cyclase on Synthetic Substrates A. Factors ARecting Cyc1ization.-In two series of papers by Corey et aZ.4a-4s and van Tamelen et al.*7-soa number of synthetic analogues of 2,3-epoxy- squalene have been investigated as substrates for rat liver epoxysqualene cyclase and the structures of the enzymically generated products compared with those resulting from chemical cyclization of the epoxides.These investigations have provided information on (a) the basic structural features of 2,3-epoxy- squalene which are essential for acceptance and cyclization by the enzyme, (6) the factors which enable the cyclase to control the conformation of the epoxide t However, formation of Ianosta-7,24-dien-3/3-01 in rat skin has recently been shown to occur by a pathway which may not involve lanosterol since all six 4-pro-R protons of MVA are retained in this triterpene (G. M. Hornby and G. S. Boyd, Biochem. J., 1971 124, 831).J. H. Richards and J. B. Hendrickson, ‘Biosynthesis of Sterols, Terpenes and Aceto- genins’, Benjamin, New York, 1964, p.274. 41 H. H. Rees, L. J. Goad, and T. W. Goodwin, Biochem. J., 1968, 107,417. J. M. Zander and D. C. Wigfield, Chem. Comm., 1970, 1599. 43 (a)E. J. Corey and S. K. Gross, J. Amer. Chem. SOC.,1967, 89, 4561; (6) E. J. Corey and W. E. Russey, ibid., 1966, 88, 4751. 44 E. J. Corey, K. Lin, and M. Jautelat, J. Amer. Chem. SOC.,1968,90,2724. 45 (a)E. J. Corey, A. Krief, and H. Yamamoto, J. Amer. Chem. SOC.,1971, 93, 1493; (b) E. J. Corey, P. R. Ortiz de Montellano, and H. Yamamoto, ibid., 1968, 90, 6254; (c) E. J. Corey, K. Lin, and H. Yamamoto, ibid., 1969,91,2132. 46 E. J. Corey and H. Yamamoto, Tetrahedron Letters, 1970, 2385. 47 (a)R. J. Anderson, R. P. Hanzlik, K. B. Sharpless, E. E. van Tamelen, and R. B. Clayton, Chem. Comm.,1969, 53, and refs.therein; (b)E. E. van Tamelen, K. B. Sharpless, R. Hanzlik, R. B. Clayton, A. L. Burlingame, and P. C. Wszolek, J. Amer. Chem. SOC.,1967, 89, 7150; (c)E. E. van Tamelen, J. D. Willett, M. Schwartz, and R. Nadeau, J. Amer. Chem. SOC.,1966, 88, 5937. 48 (a) R. B. Clayton, E. E. van Tamelen, and R. G. Nadeau, J. Amer. Chem. Soc., 1968,90, 820; (b) L. 0.Crosby, E. E. van Tamelen, and R. B. Clayton, Chem. Comm., 1969, 532. 49 (a) E. E. van Tamelen, R. P. Hanzlik, R. B. Clayton, and A. L. Burlingame, J.Amer. Chem. SOC.,1970,92, 2137; (b) E. E. van Tamelen, R. P. Hanzlik, K.B. Sharpless, R. B. Clayton, W. J. Richter, and A. L. Burlingame, ibid., 1968, 90, 3284. E. E. van Tamelen and J. H. Freed, J. Amer. Chem. Soc., 1970, 92, 7206, and preceding papers.Mulhsirn and Rumm and hence the configuration of the putative protosterol intermediate, and (c) the enzymic and thermodynamic factors involved in the conversion of the pro tosterol to lanos tero I. The LPdouble bond and the terminal isopentenyl unit of the epoxide do not play an essential part in cyclization, since the analogues (26a-4 are converted efficiently to the corresponding lanosterol derivatives (27a-c).43147a 18,19-Dihydr0-2~3-epoxysqualene(28) is accepted by the enzyme but is cyclized to give the tricyclic compound (29), which is structurally related to that obtained by chemical cyclization, differing only in stereochemistry at one or more un- defined positions47b (a dehydro-analogue was obtained on chemical cyclization of 2,3-epoxysqualene i tselP7c).10,ll-Dihydrosqualene is epoxidized randomly at either end but is not cy~lized.~~b R (27)Ia)R=H (bl R= T (c) R=-(c) R=& I The Biosynthesis of Sterols The role of the terminal methyl groups adjacent to the oxiran ring of 2,3-epoxysqualene has been shown to be important for the acceptance and orienta- tion of the substrate by the cycla~e.~~~~~ When either methyl group is removed the efficiency of cyclization is greatly reduced. The epoxide (30a) is converted in 1-1.5 % yield (6 % of 2,3-epoxysqualene efficiency) to 4a,l4a-dimethylcholesta-8,24-dienol(3 la), while the isomeric epoxide (30b) and the bis-demethyl epoxide (3Oc) are not ~yclized.~~a In these cases the major products (15% and 95% respectively) are the corresponding glycols formed by enzymic hydrati~n.~*~~*~ The homologue (3Od) is cyclized (45% of 2,3-epoxysqualene efficiency) to 4a-ethyl4&14a-dimethylcholesta-8,24-dienol(31 b).48* (30)(a) R' = CH,; R2=H (b) R'=H; R2=CH3 (c) R~=R*=H id) R'=C,H,;R*=CH, B.Factors Affecting Rearrangement of Protosterol Intermediates.-The import-ance of the central methyl groups at (2-6, C-10, and C-15 of 2,3-epoxysqualene has been investigated by synthesis of demethyl analogues and their cyclization by rat liver homogenate~.~~g~~ The 6-, lo-, and 15-mono-demethyl compounds (32a-c) are efficiently cyclized and rearranged to the lanosterol derivatives (33a) (61 'A,(33b) (18-24'A, and (33c) (40-50 'Arespe~tively.~~a~~~However, the 10,15-bis-demethyl epoxide (32d), which is accepted by the cyclase (38 % con-version), gave a compound having an unrearranged ~keleton~~b and formulated as (34).Inhibition of this process by 2,3-iminosqualene indicated that the product was formed by the normal cyclase system. Similarly, 20-dehydro-2,3-epoxy- squalene (35) is ~onverted*~C into a compound thought to be the protosterol (36). Again the normal enzyme system was implicated by the inhibitory effect of Mulheirn and Ramm (32)(a) R'=H ;R2=R3= CH3 (33)(a) R'=H ;R2=R3=CH3 (b) R2=H; R'=R3=CH3 (b) R2=H; R1=R3=CH3 (c) R3=H; R'=R2=CH3 ( C) R3=H;R'= R2=CH3 (d) R1=CH3; R2= R3= H / H HO \ \ (34) 0 OH (36)Oh at one (37)position The Biosynthesis of Sterols 2,3-iminosqualene and by suppression of conversion of 2,3-epoxysqualene to lanosterol in the presence of the synthetic epoxide. The failure of these two compounds to rearrange suggests that the repulsive forces generated by the presence of the two central methyl groups in the natural protosterol intermediate greatly facilitate the rearrangement process. Removal of only one methyl group does not reduce the strain sufficiently to prevent re- arrangement.However, even when all methyl groups are present, rearrangement can be prevented and the protosterol skeleton stabilized by conjugation of the C-20 electron-deficient centre with double bonds in the side-chain. This thermo- dynamic interpretation of the results is supported by the observed conversion of the protosterol (37) to dihydrolanosterol by acidic treatment.46 However, the Mulheirn and Ramm failure of these unnatural substrates to rearrange could be due to conformational changes which they may introduce within the enzyme.It has also been suggested that the cyclization and rearrangement process may occur on two different enzyme the initial cyclization product being stabilized by an enzymic or other nucleophile followed by transfer to the second site and rearrangement. The failure of the analogues (34) and (36) to rearrange could then result from their rejection by the second enzyme. The role of the enzyme in termination of the protosterol rearrangement by introduction of the d* double bond of lanosterol has been studied by comparison of the products of enzymic and chemical reaction of certain synthetic substrates.60 The epoxide (38) was cyclized chemically to give, among other products, the iso-euphenol analogue (39), resulting from cyclization in the all-chair conforma- tion.However, in the presence of a liver cyclase system, this substrate was converted, in low yield, to the lanosterol analogue (40). Similarly, the epoxide (41) was cyclized chemically to 9p-d7-lanostenol but (42) enzymically to HO@-’’ ’\ (43) H 217 The Biosynthesis of Sterols lanosterol (21). It was suggested that the enzymic cyclizations generate carbonium ions (44) and (45) which are intermediates in conversion of the protosterol carbonium ion (43) to lanosterol. The results demonstrate the role of the enzyme in inducing loss of the 9p-hydrogen of (43) to give the d8double bond rather than the thermodynamically more stable 4’isomer, and are compatible with the proposed mechanism of lanosterol formation described in Section 4.The information obtained with modified substrates has been collated in terms of the apparent role of the various parts of 2,3-epoxysqualene (46) during con- version to lanostero1.60 The portion (a)-(y) is the basic structure required for lanosterol formation, although (a)constitutes the minimum requirement for cyclase action. (p) appears to be involved in the enzyme control necessary to form a six-membered ring c rather than the chemically preferred five-membered ring.Finally, the methyl groups at C-10 and C-15 are implicated in rearrange- ment of the protosterol, while further enzymic participation may be required to stabilize the protosterol intermediate and to direct the termination of backbone rearrangement to give lanostero1.60 6 Uses of MVA in Studies on Later Stages of Sterol Biosynthesis The three methylene groups at C-2, C-4, and C-5 of WA each carry two pro-chiral hydrogen atoms. Replacement of individual hydrogens by an isotope gives six isomeric compounds. Five of the mono-tritiated isomers were syn- thesized by Cornforth and Popjhk using chemical and enzymatic methods, and these compounds were used to elucidate the stereochemical changes involved in conversion of MVA to squalene.2 The remaining 5s-isomer has recently been prepared.51 Incorporation of these isomers into squalene proceeds in a stereo- chemically defined manner.Therefore, following folding and cyclization of 2,3- epoxysqualene, the position and stereochemistry of the hydrogens which were labelled in MVA can be predicted in lanosterol (Scheme 8). Although little direct proof has been obtained by degradation of lanosterol itself, studies on cholesterol and other sterols fully support this scheme. Similar predictions on the mode of incorporation of hydrogens of MVA into other triterpenes, such as cycloartenol (14), tetrahymanol (17), fusidic acid (16), and others, have also received experiment a1 verification. The use of tritiated species of MVA in studies of triterpene and sterol forma- tion is facilitated by the technique of ‘double labelling’.Feeding a mixture of 14Cand 3Hspecies having a known ratio of specific activities enables the number of tritium atoms in the produced sterol to be determined by measuring changes in this 3H:14Cratio. The 14Cactivity acts as an internal standard provided that allowance is made for the loss of any carbon atoms in the biosynthetic sequence. The position of incorporation of tritium can then be defined by specific degrada- tions of the sterol and measurement of the resulting changes in 3H:14C ratio. In addition, any unexpected changes in tritium content occurring during the 61 (a) P. Blattmann and J. Retey, Chem. Comm., 1970, 1394; (b) J. W. Cornforth and F.P. Ross, ibid., p. 1395; (c) A. I. Scott, G. T. Phillips, P. B. Reichardt, and J. G. Sweeney, ibid., p. 1396. Mulhrirn and Ram H02C The Biosynthesis of Sterols biosynthesis can be detected. These may be caused by equilibration (e.g. the loss of tritium from 2R-[2-3H]MVA due to the reversibility of the isopentenyl pyro- phosphate-dimethylallyl pyrophosphate isomerism in some organisms4) or from isotope effects causing preferential removal of the lighter hydrogen isotope. It is also important to note that, in most experiments, the synthetic MVA used is a mixture of 3R and 3s isomeric species; thus ‘2R’-tritiated MVA is actually a mixture of (2R, 3R)-[2-3H]and (2S, 3S)-[2-3H]isomers. However, in the few cases examined it has been shown that the 35’-isomer is not phosph~rylated~~ and that hence only the 3R-isomer is metabolized, a result which is now assumed to be general.The technique of ratio counting has been used extensively in studies on the conversion of variously labelled species of lanosterol to cholesterol in rat liver enzyme systems. Such investigations have given detailed information of the processes involved in the loss of the three methyl groups of lanosterol, the migration of the As double bond to A5, and the saturation of the AZ4double bond. The following sections include a summary of these results and an outline of the progress which has been made recently in the application of this tech- nique to studies of sterol biosynthesis in other organisms.7 Demethylations of Lanosterol in Cholesterol Biosynthesis A. Loss of the C-4 Methyl Groups.-Bloch and co-worker~~~ demonstrated that the demethylations of lanosterol at C-4 and C-14 in rat liver result in the release of stoicheiometric amounts of CO,. The sequence of reactions was thought to involve hydroxylation followed by oxidation to the corresponding aldehyde and acid with subsequent decarboxylation. Recent studies have pro- vided support for this route and have established that, contrary to an earlier the 4a-methyl is eliminated before the 4P-methyl. A rat liver preparation rapidly converts 4u-hydroxymethyl-4~-methyl c holes tanol (47a) and 4 a-hydr ox yme t hy lcholes tan01 (47 b) to cholestan01,55 while the 4/%hydroxymethyI analogue (47c) is not metabolized.The initial hy- droxylation of the methyl groups was shown to require molecular oxygen and NADPH, although the nature of the hydroxylating enzyme is still uncertain.5s Oxidation of the alcohols occurs anaerobically and the microsomal enzyme involved could be replaced adequately by crystalline liver alcohol dehydro- gena~e.~’The final stages of oxidation and decarboxylation have recently been sa (a) F. Lynen and M. Grass], 2.physiol. Chem., 1958, 313,291 ;(6) R. H. Cornforth, J. W. Cornforth, and G. PopjBk, Tetrahedron, 1962, 18, 1351; (c) D. Arigoni, Pure Appl. Chem., 1968, 17,331. 63 (a) J. A. Olson, M. Lindberg, and K. Bloch, J. Biol. Chem., 1957, 226,941 ;(b) F. Gautschi and K. Bloch, J. Amer. Chem.SOC.,1957, 79, 684; J. Biol. Chem., 1958, 233, 1343; (c) K. Bloch, Ciba Symposium on The Biosynthesis of Terpenes andsterols, ed. G. E. W. Wolstenholme and M. O’Connor, 1959. s4 J. L. Gaylor and C. V. Delwiche, Steroids, 1964, 4, 207. ssK. B. Sharpless, T. E. Snyder, T. A. Spencer, K.K. Maheshwari, G. Guhn, and R. B. Clayton, J. Amer. Chem. SOC.,1968, 90, 6874. (a) J. L. Gaylor and H. S. Mason, J. Biol. Chem., 1968, 243,4966;(b) A.C.Swindell and J. L. Gaylor, ibid., p. 5546. s7 N. J. Moir, W. L. Miller, and J. L. Gaylor, Biochem. Biophys. Res. Comm., 1968, 33,916. Mulheirn and Ramm shown to require the cofactor NADf,and, by using rat liver microsomes deficient in this cofactor, 4,4-dimethylcholest-7-en-3~-ol(48a) and 4a-methylcholest- 7-en-318-01(48b) were converted to the 4a-carboxylic acids (48c) and (48d) respec-tively.68 Decarboxylation was completed on reincubation in the presence of NADf,indicating that the cofactor is required to oxidize the 318-hydroxy-group I C02 H 1 HO Scheme 9 (a) W.L. Miller and J. L. Gaylor, J. Biol. Chem., 1970, 245, 5369,5375; (b) G. M. Hornbyand G. S. Boyd, Biochem. Biophys. Res. Comm., 1970,40, 1452. 281 The Biosynthesis of Sterols to a ketone either prior to, or concomitant with, decarboxylation. The cofactor NADPH has also been implicated in reduction of the ketone to a 3~-alcohol following decarboxylation.66b The results of several studies indicate that, follow- ing the loss of the 4a-methyl group, the remaining 4p-methyl equilibrates to the 4a-position (Scheme 9) prior to oxidation and elimination, probably by the same enzyme ~ystem.~*~~~ The sequence of reactions summarized in Scheme 9 is supported by studies on the biosynthetic origin of the 4a- and 4p-methyl groups.It has been demon- strated, both by n.m.r. spectroscopyso and by chemical degradation,s1 that 3S-2,3-epoxysqualene is the precursor of lanosterol and that the 4a-methyl group of lanosterol is derived exclusively from C-2 of MVA, while the 4p-methyl originates from C-3’. With this information at hand, [2-14C]MVA was incubated with a rat liver enzyme preparations2 and several precursors of cholesterol were isolated. While lanosterol and related compounds contained six 14C atoms, 4a-methylcholest-7-en-3~-olretained only five labelled atoms, confirming the loss of the original 4a-methyl group and epimerization of the 4p-methyl to the 4a-position. This scheme is also supported indirectly by the isolation of 4p- methylcholesta-8,24-dien-3~-olfrom rat skin.63 B.Loss of the 14a-Methyl Group of Lanosterol.-The initial experiments of Bloch and co-worker~~~ suggested that C-14 demethylation involves oxidation to the carboxylic acid followed by loss of CO, and that this process precedes those at C-4. The oxidative sequence has been supported by the demonstration that the 14a-hydroxymethyl and 14a-formyl compounds (49a) and (49b) are K. B. Sharpless, T. E. Snyder, T. A. Spencer, K. K. Maheshwari, J. A. Nelson, and R.B. Clayton, J. Amer. Chem. SOC.,1969, 91, 3394. 6o K. J. Stone, W. R. Roeske, R. B. Clayton, and E. E. van Tamelen, Chem. Comm., 1969,530. G. P. Moss and S. A. Nicolaides, Chem. Comm., 1969, 1072, 1077. R. Rahman, K. B. Sharpless, T. A. Spencer, and R. B. Clayton, J. Biol. Chem., 1970,245, 2667. (a) A. Sanghvi, D. Balasubramunian, and A. Moskowitz, Biochemistry, 1967, 6, 869; (b)A. Sanghvi, J. Lipid. Res., 1970, 11, 124. Mulheirn and Ramm efficiently converted to cholesterol by liver micros~rnes.~~~ However, these compounds are probably not true intermediates since demethylation is thought to occur before migration of the nuclear dmble bond to the d7position (see below). It was also postulated that decarboxylation is accompanied by migration of the d double bond to the d 8(14) position (Scheme 10, path a).40953c 8 Migration of the d Double Band to d in Cholesterol Formation A.Double-bond Migrations Associated with Loss of the 14a-Methyl Group.- The observation that neither 4,4,14-trimethyl~holestanol~~nor 4,4,14-trimethyl- cholest-7-en-3/3-01~~is metabolized by rat liver homogenates suggested the participation of the As double bond of lanosterol in the loss of the 14a-methyl group. In addition, the conversion of cholest-8(14)-en-3/3-01 (50a) and its 4,4- dimethyl analogue (50b) to cholesterol was demonstrated.64@ This process was (50)(a) R=H (51)(a) R= H (b) R=CH3 (b) R=CH3 shown to require molecular oxygen since no conversion was obtained anaerobic- ally.This suggested a decarboxylation mechanism as outlined in Scheme 10 (path a). The use of lanosterol derived from 2R-and 2s-tritiated MVA provided more information on the reactions associated with C-14 dernethylati~n.~~~~~ Conver-sion of lanosterol to cholesterol was shown to proceed with loss of the 2-pro-S hydrogen of MVA located at the C-15a-position of lanosterol, while the 15p- hydrogen is retained. This result implicated the 15a-hydrogen in the C-14 demethylation sequence, and two mechanisms have been proposed to account for this observation. t Evidence has recently been obtained from studies with a microsomal enzyms system that C-14 demethylation occurs not by decarbuxylation but by release of formic asid at the al- dehyde level of oxidation (K.Alexander, M. Akhtar, R. B. Boar, J. F. McGhie, and D. H. R. Barton, Chem. Comm., 1972, 383).J. Fried, A. Dudowitz, and J. W. Brown, Biochem. Biophys. Res. Comm., 1968, 32, 568. J. L. Gaylor, C. V. Delwiche, and A. C. Swindell, Steroids, 1966, 8, 353. *6 W. H. Lee and G. J. Schroepfer, Biochem. Biophys. Res. Comm., 1968, 32, 635. L. Canonica, A. Fiecchi, M. G. Kienle, A. Scala, G. Galli, E. G. Paoletti, and R. Paoletti, J. Amer. Chem. SOC.,1968, 90, 3597; Steroids, 1968, 12, 445. G. F. Gibbons, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1968. 1458. 283 The Biosynthesis of Sterds The involvement of a d*,l4 diene intermediate formed as in Scheme 10 (path 6) was supported by the fact that cholesta-8,14-dienol (51a) and its 4,4-dimethyl s R ac7 R R Scheme 10 (53)ta) R'=H, R~=OH (b) R'=OH, R2=H Mulheirn and Ram analogue (51b) are metabolized in liver enzyme preparati~ns~~-~l and that the latter compound became labelled when non-radioactive material was added to an incubation in which tritiated dihydrolanosterol was being metabolized to The group X may represent an enzymic or nucleophilic moiety cholester01.~~b or simply a hydrogen atom removed enzymatically as a hydride ion.The enzymic conversion of one of the epimeric diols (52) to cholester01~~ is consistent with path 6, although the stereochemistry of the active isomer is, as yet, unknown. An alternative mechanism consistent with the stereospecific loss of the 15a- hydrogen atom is represented by Scheme 10 (path c).In this case the f18(14) intermediate, formed as in patha, is subsequentlydehydrogenatedto cholesta-8,14-dienol. Reduction of the flI4 bond would then give the d intermediate. Such an indirect process might be necessary to achieve the thermodynamically unfavour- able d8(14)-+ dsmigration. Here again several types of X group can be en- visaged. In this connection, the diols (53a) and (53b) have been converted to cholesterol enzymically in high yield.73* Reduction of the d8~14diene to the d intermediate has been shown to involve addition of hydrogen from NADPH at C-14a and a proton from the medium at C-15.74The 15p-hydrogen of lanosterol, which is retained during conversion to the d8914 diene, occupies the 15a-position in cholester01,~~ indicating that reduction of the d14 bond involves addition of a proton at the 15P-position, giving an overall trans reduction.B. Transposition of the d8Double Bond to d5.-The isomerization of the d double bond to A7 involves stereospecific loss of the 7P-hydrogen since lanosterol derived from (2S)-[2-3H]MVA (and thus containing tritium at the 7P-position) gives cholesterol devoid of tritium at C-7, while the 7a-hydrogen of lanosterol is retained. An intramolecular migration of hydrogen from C-7 * However, a recent detailed investigation by means of incorporation and trapping experi- ments provides strong evidence that a intermediate is not involved and that the bio- synthetic sequence is, in fact, as outlined in Scheme 10 path b (K.T. W. Alexander, M. Akhtar, R. B. Boar, J. F. McGhie, and D. H. R. Barton, Chem. Comm., 1971, 1479). OD (a) B. N. Lutsky and G. J. Schroepfer, Biochem. Biophys. Res. Comm., 1968, 33, 492; (b)M. Akhtar, A. D. Rahimtula, I. A. Watkinson, D. C. Wilton, and K. A. Munday, Chem. Comm., 1968, 1406. 70 L. Canonica, A. Fiecchi, M. G. Kienle, A. Scala, G. Galli, E. G. Paoletti, and R. Paoletti, J. Amer. Chem. SOC., 1968, 90, 6532. 71 (a) M. Akhtar, I. A. Watkinson, A. D. Rahimtula, D. C. Wilton, and K. A. Munday,Biochem. J., 1969, 111, 757; (b) I. A. Watkinson and M. Akhtar, Chem. Comm., 1969, 206. J. A. Martin, S. Huntoon, and G. J. Schroepfer, Biochem. Biophys. Res. Comm., 1970, 39, 1170. 73 S. Huntoon and G. J. Schroepfer, Biochem.Biophys. Res. Comm., 1970,40,476. 74 M. Akhtar, A. D. Rahimtula, I. A. Watkinson, D. C. WiIton, and K. A. Munday, Chem. Comm., 1969, 149. 76 (a) E. Caspi, P. J. Ramm, and R. E. Gain, J. Arner. Chem. SOC.,1969, 91, 4012; (6) P. J. Ramm and E. Caspi, J. Biol. Chem., 1969,244,6064. 7* (a) L. Canonica, A. Fiecchi, M. G. Kienle, A. Scala, G. Galli, E. G. Paoletti, and R. Paoletti, Steroids, 1968, 11, 749; (6) E. Caspi, J. B. Greig, P. J. Ramm, and K. R. Varma, Tetrahedron Letters, 1968, 3829; (c) G. F. Gibbons, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1968, 1212. 285 The Biosynthesis of Sterols to C-9 is not involved since the 9a-hydrogen originates from the medium.77 The reversibility of this isomerization has recently been demonstrated by incor- poration of radioactivity at C-9 of cholest-7-en-3/3-ol re-isolated after incu- bation with liver microsomes in tritiated water.78 The conversion of cholest-7-en-3/3-01 (54a) to cholesta-5,7-dien-3/3-01 (55) results in stereospecific removal of the 5a-and 6a-hydrogen The dehydrogenation process requires molecular oxygenso and a requirement for the cofactor NADP+has been detectedaS1 Attempts to demonstrate a hydroxyla-tion-dehydration mechanism for this step have been unsuccessful.Such a route should involve an aerobic hydroxylation followed by an anaerobic dehydration of the intermediate alcohol. While both 6a-and 6/3-hydroxycholest-7-en-3/3-ol (55) (54)(a)R1=R2=R3=H (b) R1=R3=H; R2=OH (c)R’= R~=H;R~=OH (d) R’=OH; R2=R3=H Scheme 11 ’? (a) M.Akhtar and A. D. Rahimtula, Chem. Comm., 1968,259; (b) L. Canonica, A. Fiecchi, M. G. Kienle, A. Scala, G. Galli, E. G. Paoletti, and R. Paoletti, Steroids, 1968, 11, 287; (c) W. H. Lee, R. Kammereck, B. N. Lutsky, J. A. McCloskey, and G. J. Schroepfer, J. Biol. Chem., 1969, 244,2033. 78 D. C. Wilton, A. D. Rahimtula, and M. Akhtar, Biochem. J., 1969,114,71. 79 (a) A. M. Paliokas and G.J. Schroepfer, jun., J. Biol. Chem., 1968,243,453; (b) M. Akhtar and S. Marsh, Biochem. J., 1967, 102,462. M. E. Dempsey, J. Biol. Chem., 1965, 240,4176. *IT. J. Scallen and M. W. Schuster, Steroids,1968, 12, 683. Mulheirn and Ramm (54b and c) are converted to cholesterol by rat liver enzymes in the presence of oxygen, anaerobic incubation of these compounds results in conversion to cholest-7-en-3/3-ol (54a) rather than cholesterol, indicating that they are not true intermediates in the dehydrogenation process.82 Similar investigations on the metabolism of 5a-hydroxycholest-7-en-3/3-ol(54d) have also led to the conclusion that this diol is not an intermediate in cholesterol biosynthesis.The failure to detect hydroxylated intermediates in the C-5 dehydrogenation step has led to the s~ggestion~~~~* that this and other cis dehydrogenations may be accomplished by an enzyme-oxygen complex (Scheme 1 l), similar to that postu- lated for analogous reactions in fatty acid biosynthesis.85* HO Scheme 12 * It has now been shown that the 6a-hydrogen is not transferred to the cofactor, NAD" and is, therefore, probably removed as a proton (D.J. Aberhart and E. Caspi, J. Biol. Chem., 1971, 246, 1387). as M. Slaytor and K. Bloch, J. Biol. Chem., 1965, 240, 4598. 8s S. M. Dewhurst and M. Akhtar, Biochem. J., 1967, 105, 1187. 84(u)D. C. Wilton and M. Akhtar, Biochem. J., 1970, 116, 337; (b) J. M. Zander and E. Caspi, J. Biol. Chem., 1970, 245, 1682. (a) G. 3. Schroepfer and K. Bloch, J. Biol. Chem., 1965, 240, 54; (6) W. Stoffel and H. G. Schiefer, 2.physiol. Chem., 1966, 345, 41. The Biosynthesis of Sterols The final reaction of this sequence is the saturation of the d7double bond of the 5,7-diene intermediate. This involves the addition of a proton from the medium at C-8p and a hydride from NADPH at C-7a (Scheme 12).86 The assignment of orientation at C-7 follows from the observation that the 7a- hydrogen of lanosterol, which is retained in the 5,7-diene intermediate, occupies the 7p-position in chole~terol.~~~~c Again, reduction of the double bond involves a trans addition of hydrogens.9 Stereochemistry of Hydrogenation of 424of Lanosterol Although it is still uncertain at which point saturation of the ~l~~double bond of lanosterol occurs in the overall process of conversion to cholesterol, the stereo- chemistry of the process has been elucidated. The addition of hydrogen at C-24 was studied by the use of cholesterol (56) biosynthesized from (4R)-[2-14C, 4-3H]MVA.87 The side-chain was cleaved by a bovine adrenal enzyme prepara- tion, giving 4-methylpentanoic acid (57) which was subsequently degraded to 2-methylpropanol (58) containing one tritium atom as predicted.37 Oxidation to 2-methylpropionic acid resulted in loss of tritium activity and thus located the tritium at C-24 of cholesterol.Oxidation of 2-methylpropanol with yeast alcohol dehydrogenase, which removes only the l-pro-R proton of aliphatic primary alcohols, gave 2-methylpropanal (59) with retention of tritium. This established the tritium atom at the 24-pro-R position of cholesterol (56) and in- dicated that reduction of Az4 of lanosterol involved addition of a hydrogen at the 24-pro-S position. 87 The stereochemistry of hydrogen addition at C-25 followed from two pieces of evidence. Firstly, it was shown by X-ray diffraction that cholesterol is con- verted by the organism Mycobacterium smegmatis to (25S)-26-hydroxycholes- tenone (60a)88a [rather than the (25R)-isomer as previously reporteds8b].Secondly, when cholesterol biosynthesized from [2-14C]MVA in a rat liver enzyme system is oxidized by this organism, the 14C-labelled terminal methyl group is hydroxylated. This was shown by oxidation of (60a) to the aldehyde (60b) followed by decarbonylation to (60c). Since it is known that in the da4-double bond of lanosterol (21) the labelled carbon atom is cis to the C-24 hydrogen, it follows that the double bond is saturated by cis addition of two hydrogens to C-24 and C-25. The cofactor NADPH is involved in the reduction and the process has been shown to result in addition of a proton from the medium at C-24 and a hydride ion at C-25.89This cis reduction involving NADPH contrasts with the trans reductions of the A14 and 4' double bonds of other intermediates in cholesterol biosynthesis which have been described above.86D. C. Wilton, K. A. Munday, S. J. M. Skinner, and M. Akhtar, Biochem. J., 1968, 106, 803. 8' (a) E. Caspi, K. R.Varma, and J. B. Greig, Chem. Comm., 1969, 45; (b) J. B. Greig, K. R. Varma, and E. Caspi, J. Amer. Chem. Soc., 1971, 93, 760. 88 (a) D. J. Duchamp, C. G. Chidester, J. A. F. Wickramasinghe, E. Caspi, and B. Yagen, J. Amer. Chem. Soc., 1971, 93, 6283; (b) E. Caspi, M. G. Kienle, K. R.Varma, and L.J. Mulheirn, J. Amer. Chem. SOC.,1970, 92, 2161. in M.Akhtar, K. A. Munday, A. D. Rahimtula, I. A. Watkinson, and D. C. Wilton, Chern. Comm.,1969, 1287. Mulheirn and Ram H R 10 Sterol Formation in Other Organisms The investigations of cholesterol biosynthesis reported above have stimulated similar investigations in other species. The structures of the sterols of pIants, fungi, and algae suggest a biosynthetic route parallel to that of cholesterol. However, while the overall process appears to be common to all organisms, some unexpected variations of sequence and mechanism have been detected. As mentioned previously, the triterpene cycIoartenol(14) is known to replace lanosterol as the product of cyclization of 2,3-epoxysqualene in higher plants The Biosynthesis of Sterols and some algae.4s26-29However, lanosterol, although it is not a true inter-mediate, can be metabolized to phytosterols in some plants.g0This result has been attributed to a lack of specificity of certain enzymes for the natural sub-strate.Incorporation of [2-14C]MVAinto the triterpenes and sterols of various plants indicates that, as in lanosterol demethylation in animals, loss of the 4a-methyl group is followed by epimerization of the 46-methyl to the 4a-position before The isolation of many plant triterpenes lacking a methyl group at C-4 indicates that the overall demethylation sequence in plants may be C-4a 3 C-14a ---f C-48 (after epimeri~ation),~rather than that believed to be operating in rat-liver homogenates; C-14a -+ C-4a -C-46 (after epimer-ization).In contrast, the fungal triterpene fusidic acid (16) retains all six labelled atoms when biosynthesized in the presence of [2-14C]MvA,indicating that this compound has resulted from direct elimination of the 4p-methyl group of the original triterpene and retention of the 4a-methyl group. 92 Few investigations have yet been reported on the nuclear double-bond migra-tions associated with C-14 demethylation of the triterpenes of lower organisms. In the formation of poriferasterol (61) by the phytoflagellate Ochromonm maIhamensis the 7p-hydrogen is lost during d8-d7isomeri~ation,~~while in both this organism and the leaves of the larch, Larix decidua, the 6a-hydrogen atom is lost on introduction of A5~nsat~ration.~~Both processes are identical to those observed in cholesterol biosynthesis.In contrast, the d 8-d7isomeriza-tion occurring during the biosynthesis of ergosterol (62) and related sterols in H IH / H I (a)J. Hall, A. R. H. Smith, L. J. Goad, and T. W. Goodwin, Biochem. J., 1969, 112, 129; (b) M. J. E. Hewlins, J. D. Ehrhardt, L. Hirth, and G. Ourisson, European J. Biochem., 1969, 8, 184; (c) Ref. 4, p. 65. O1 (a) E. L. Ghisalberti, N. J. de Souza, H. H. Rees, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1969,1403; (b) F. F. Knapp and H. J. Nicholas, ibid., 1970,399; (c) F. F. Knapp and H. J. Nicholas, Phytochemistry, 1971, 10, 97. Oa (a) D. Arigoni, ‘Conference on the Biogenesis of Natural Products’, Academia Nazionale dei Lincei, Rome, 1964; (6) G.Visconte di Modrone, Ph.D. Thesis, E. T. H. Zurich, 1968. 83 A. R. H. Smith, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1968,926. 94 (a) A. R. H. Smith, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1968, 1259; (b) L. J. Goad and T. W. Goodwin, European J. Biochem., 1969,7, 502. Mulheirn and Ramm yeast results in elimination of the 7a-hydrogen atom,O6 although introduction of the d6double bond again proceeds by loss of the 5a-and 6a-hydrogen atoms.g6 The presence of a trans daa-double bond is a feature of many sterols produced by plants, fungi, and algae. Here again, variations have been observed in the stereochemical course of dehydrogenation. The fungus Aspergillus fumigatus produces ergosterol (62) by elimination of the 22-pro-S and 23-pro-Sprotons,06b while the alga Ochromonas malhamensis produces poriferasterol (61) by loss of the 22-pro-R and 23-pro-R protons.039 g4a Similar results in reIated species4# g6C suggest that all fungi and algae may show this divergence of hydrogen elimina- tion at C-22 and C-23.Finally, the alkylation at C-24 of phytosterols, which has been shown to involve transfer of methyl groups from S-adenosylmethionine, also appears to occur by a variety of mechanisms. The principal routes have been reviewed elsewhere. g7* O8 However, more detailed investigations will be needed before the extent and significance of these variations can be assessed. 11 Conclusion The identification of the component reactions of sterol biosynthesis, described in this review, has been achieved by the application of three main lines of investigation.Detailed knowledge of the biosynthesis of squalene from MVA has been utilized to study individual demethylation, migration, and elimination processes occurring at later stages of the sequence. The chemical synthesis of putative intermediates has allowed the feasibility of various hypotheses to be examined, while investigation of the enzymes and cofactors involved in in- dividual reactions is proving to be a powerful tool for the analysis of reaction sequences in cell homogenates. The results obtained from these studies give a detailed picture of the biosynthesis of cholesterol from MVA in rat liver homo- genates. Parallel investigations are now being conducted with other organisms.However, the principal remaining question concerns the absolute sequence of these reactions, if indeed there is one. Such investigations will probably involve the application of current techniques to intact cells and organisms, The reported identification of proteins capable of solubilizing squalene and other sterol pre- cursors, and which catalyse several stages of sterol biosynthesis in rat liver enzyme has added a further dimension for future investigation. 95 (a)E. Caspi and P. J. Ramm, Tetrahedron Letters, 1969, 181 ;(b) M. Akhtar, A. D. Rahim-tula, and D. C. Wilton, Biochem. J., 1970, 117, 539. 96 (a) M. Akhtar and M. A. Parvez, Biochem. J., 1968, 108,527; (b)T. Bimpson, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1969,297; (c) M.Akhtar, M. A. Parvez, and P. F. Hunt, Biochem. J., 1968, 106, 623. O7 E. Lederer. Quart. Rev., 1969, 23, 453. (a)Y. Tomita, A. Uomori, and E. Sakutai, Plzytochemistry, 1971,10,573; (6)H. C. Malhotra and W. R. Nes, J. Biol. Chem., 1971, 246, 4934. (a) M. C. Ritter and M. E. Dempsey, Biochem. Biophys. Res. Comm., 1970, 38, 921 ;(b)T. J. Scallen, M. W. Schuster, and A. K. Dhar, J. Biol. Chem., 1971,246,224; (c) M. C. Ritter and M. E. Dempsey, J. Biof. Chem., 1971,246, 1536,

ISSN:0306-0012    

DOI:10.1039/CS9720100259

出版商:RSC    

年代:1972

数据来源: RSC