摘要:

~~ QUARTERLY REVIEWS VAPOURS OF THE ELEMENTS By BERNARD SIEGEL (AEROSPACE CORPORATION EL SEGUNDO CALIFORNIA) THIS Review is of the bonding in those homonuclear molecules that are only observed at high temperatures the condensed state of the element being the stable form at room temperature. Most of the elements fall into this category. Emphasis is placed on the significance of the bond strength as exemplified by the bond dissociation energy in correlating the various types of vapour molecules. However it should be noted that a comparison of chemical stabilities in terms of Doo the bond dissociation energy at O'K is only meaningful if the molecules are compared at a specific pressure. Because of the different pressure-temperature relationships for the various non-volatile elements their equilibrium vapour pressures at any given temperature vary widely and this affects strongly the degree of dissociation at any specific temperature.Often the magnitudes of the degrees of dissocia- tion for two molecules are in apparent conflict with their respective bond dissociation energies as is the case for Li and Cs, shown in Fig. 1. As will be discussed Doo is appreciably larger for Li,. The larger mole frac- tions of Cs, in relation to Cs atoms reflects merely the higher vapour pressures of caesium than of lithium. A second point can be made from Fig. 1. The normal boiling point of lithium is 1 6 2 0 " ~ ~ but the mole fractions of Liz in the saturated lithium vapour have been computed to 3000"K with the equilibrium vapour pressure rising to 1 14 atm. at that temperature. It is seen that the mole fractions of Li, in relation to Li atoms rise to a maximum at 3000"~.Thus despite the fact that the Doo for Li is below that of any permanent homonuclear gas molecule Li is quite stable in the saturated vapour at 3000"~. Comparison is made in Fig. 1 with the dissoci- ation of F and C1 under identical conditions of temperature and pressure. It is seen that these gases exhibit similar behaviour except that association is very much greater for Cl because of its considerably higher bond strength. It should also be noted that at atmospheric pressure lithium is virtually monatomic at 3000"~.* Unless is it specified otherwise our discussion is for the saturated vapours of the elements i.e. those vapours which are at the equilibrium vapour pressure of the element at any given temperature.*A more detailed discussion which will be published elsewhere of the effect of the volatility-bond strength relationship in determining the degree of dissociation of homo- nuclear molecules has been prepared by the writer. 77 1 78 QUARTERLY REVIEWS Temperature O K FIG. 1. Saturated and non-saturated lithium vapour. A comparison with fluorine and Chlorine under identical conditions of temperature and pressure. The circles are for the saturated lithium vapour above the normal boiling point; the squares are for the unsaturated vapour at atmospheric pressure. The thermodynamic data required to compute the data in this Figure were obtained from refs. 16 and 64. Group IA and IIA elements Each of these elements forms diatomic molecules which are more weakly bonded than are any of the permanent gas molecules.The Group IIA elements must form normal diatomic molecules from atoms which have the ns2 valence shell configuration in the ground state. Molecules of this type having as many electrons in antibonding as in bonding molecular orbitals do not have much chemical binding energy.l The latter are thus of the secondary or van der Waals type and one would expect the bond dissociation energy to be less than 10 kcal./mole the approximate lower limit for normal sigma bonds. The Mg molecule has been observed by absorption spectroscopy in the rapid non-equilibrium sublimation of Mg,N at 1200-14Oo0c but only monatomic Mg(g) was found when the sublimation was carried in an equilibrium manner; the calculated bond dissociation energy Doo for Mg from this study was 7.2 kcal./mole.It G. Herzberg “Spectra of Diatomic Molecules” 2nd edn. D. Van Nostrand Princeton 1950. a J. R. Soulen P. Sthapitanonda and J. L. Margrave J. Phys. Chem. 1955,59,132. SIEGEL VAPOURS OF THE ELEMENTS 79 was concluded that Mg is formed in an early step in the sublimation procedure but that only Mg(g) is stable when equilibrium is attained. Similarly in a mass spectrometric study of the saturated vapour over strontium at 500-650°c only monatomic Sr was found,3 and in mass spectrometric studies of the beryllium vapour in the range 1137-1347"~ only monatomic beryllium was found.* A Doo of 16 kcal./mole has been estimated5 for Be but this value seems high for the type of bonding that is undoubtedly involved. The above discussion is for the normal diatomic molecule.However it is conceivable that metastable molecules might form from excited states of the alkaline earth atoms. Such a situation exists for the metastable He molecule which is in a triplet sigma state and has6 a Doo of at least 1.76 ev. However the excited states must be created by electronic excitation and metastable He has only been observed to form in the emission spectrum of excited helium at low pressures. Therefore metastable He is not actually a high-temperature species since the overall thermodynamic temperature at which it is formed is quite low. Since the IA atoms have the nsl valence shell ground-state configurations diatomic molecules can form simply by formation of a sigma bond by overlap of the s atomic orbitals. The homonuclear diatomic molecules of the IA elements should therefore be more strongly bonded than those of the IIA elements.This is in fact the case and each of the former have been studied in some detaiL7-l0 The Doo values are given in Table 1. However TABLE 1. Bond dissociation energies at O'K of diatomic Group IA molecules Molecule Liz Na2 K2 Rb2 cs2 Doo (kcal./mole)* 25.8 17.5 11.9 11.3 10.4 * Data from Ref. 7. the overlap between single electrons in the spherically symmetrical s atomic orbitals of the alkali-metal atoms does not lead to very strong bonding as compared with most of the molecules to be discussed in subsequent sections. An interesting hypothesis regarding the nature of this weak bonding has been advanced. This involves a repulsion between the valence and non-bonding electrons and was suggested because of the significantly weaker bondingll in Li than in Li,+ (similarly Na,+ is more strongly bonded1 than is Na,).A. J. H. Boerboom H. W. Reyn and J. Kistemaker Physica 1964,30,254. 0. T. Nikitin and L. N. Gorokhov Zhur. neorg. Khim. 1961,6,224. J. Drowart and R. E. Honig J. Phys. Chem. 1957,61,980. P. N. Reagan J. C. Browne and F. A. Matsen Phys. Rev. 1963,132,304. W. H. Evans R. Jacobson T. R. Munson and D. D. Wagman J. Res. Nut. Bur. T. A. Coultas J. Chem. Eng. Data 1963 8 527. Stand. 1955,55,83. a R. J. Thorn and G. H. Winslow J. Phys. Chem. 1961,65,1297. lo M. M. Makansi W. A. Selke and C. F. Bonilla J. Chem. Eng. Data 1960,5,441. l1 E. W. Robertson and R. F. Barrow Proc. Chem. Soc. 1961,329. l2 R. F. Barrow N. Travis and C. V. Wright Nature 1960 187 141. 80 QUARTERLY REVIEWS Although the diatomic homonuclear molecules of the alkali metals have been deduced by other means they have not yet been observed mass spectrometrically.In fact one such study reports the absence of Na and K at temperatures above and below 1OOO"c by non-equilibrium heating from a fi1a~ent.l~ Group IIIB elements Boron.-The Group IIIB elements have the ns2np1 valence shell configura- tions in the ground-state atoms but bond formation in their homonuclear diatomic molecules does not apparently involve only the simple overlap of thep electrons. The B molecule in the ground state has a triplet sigma electronic configuration indicating that the molecule has a double b0nd.l Nevertheless this double bond is not very strong (probably because of repulsions from the non-bonding valence electrons) since Doo is undoub- tedly less than 70 kcal./mole.A value of 69 & 11.5 kcal./mole has been reported from spectroscopic data,14 while 65.5 & 5.5 kcal./mole has been obtained from mass spe~trometry.~~ The B found by the latter method was observed in the sublimation of boron at 2330"~ although it was shown to be present in extremely small amounts in comparison with B(g) at that temperature. However boron is similar to the alkali metals in that the mole fraction of B increases substantially with temperature in the saturated boron vapour. From data in the JANAF Tables on B(g) and B,(g) the mole fraction of the latter increases from 7.3 x to 3.7 x in the temperature range 2500-3900"~.~~ Accordingly the observed absence of B in a mass spectrometric study of boron vapour at 2 1 0 0 " ~ ~ ~ should not be surprising since at that temperature the mole fraction of B would be probably below the detection limits of mass spectrometers.Recent studies of the vapour of boron carbide by the torsion-effusionfs and Knudsen- celPg techniques at temperatures up to 2522 and 261 5°K reported only B(g). Heavier Diatomic Molecules.-Very little is known about Al,. In a mass spectrometric study of the equilibrium vapour over aluminium carbide at 210O0K a trace mass peak was noted20 for A12+ but it is not clear whether the latter is due to ionisation of A12 or fragmentation of gaseous aluminium carbide upon electron impact. Since the aluminium vapour pressure at 2100"~ has the appreciable valuela of 0.0188 atm. the A12 molecule should be observable at this temperature if its bond strength is at all appreciable.l3 T. Yuasa Bull. Chem. SOC. Japan 1962 35 211. l4 A. G. Gaydon "Dissociation Energies" 2nd edn. Chapman and Hall London l6 G. Verhaegen and J. Drowart J. Chem. Phys. 1962,37,1367. l6 JANAF Thermochemical Tables Dow Chem. Co. Midland Michigan 1963. l7 P. A. Akishin 0. T. Nikitin and L. N. Gorokhov Doklady Akad. Nauk S.S.S.R. lS D. L. Hildenbrand and W. F. Hall J. Phys. Chem. 1964,68,989. l9 H. E. Robson and P. W. Gilles J . Phys. Chem. 1964,68,983. 2o W. A. Chupka J. Berkowitz C. F. Giese and M. G. Inghram J. Phys. Chem. 1953. 1959,129,1077. 1958 62 611. SIEGEL VAPOURS OF THE ELEMENTS 81 A value for the Doo of this molecule has been estimated5 as 39 kcal./mole. Under these conditions fluorine which has a comparable dissociation energy would have a mole fraction of F of 0.001 a value which is detect- able by mass spectrometry.A mass spectrometric studyZ1 of gallium vapour at 865-1025"~ pro- duced the mass spectral ions Ga+ and Ga2+ in the ratio of 100 to 1. However Ga,O+ was also found and the ratio of the latter to Ga2+ was constant as both species decreased with time leading to the conclusion that the Ga2+ was probably formed by fragmentation of the oxide impurity rather than from a primary Ga molecule. A Ga,+ mass peak was also found in the vapour over gallium carbideZo at 1600"~ the ratio Ga+/Ga2+ being 1890. Here also there is no assurance that the Ga$ is attributable to Ga since it could have arisen from fragmentation of gaseous gallium carbide. An upper limit of 32-34.5 kcal./mole has been estimated5e20 for the Do" of Ga,.Values of 22.4 & 2 ~ 5 ~ and 30 & 14 kcal./mo1eZ3 have been calculated for the Doo of In on the basis of mass spectrometric data. From data on the saturated vapour over indium antimonides it was shown that the mole fraction of In relative to In(g) rises with increasing temperature in the range 1220-1381"~ although at 1381"~ the mole fraction of In is2 only 4.5 x since this temperature is almost 1000" below the normal boiling point of indium. TABLE 2. Dissociation energies at 0 OK for the Group IIIB diatomic molecules Molecule B2 A12 Ga2 In T1 Do" (kcal./mole)* -6615 (39)5 (< 32 to 3 4 ~ 5 ) ~ ~ ~ ~ 2222 (14)5 * Data in parentheses are estimated values. The dimeric ion TI2+ has been found at 429-700"~ in the saturated vapour of thallium,24 the ratio T1+/T12+ being 100.However the TI2+ was attributed to fragmentation of a thallium oxide film on the metal rather than as indicative of Tl, for reasons similar to those described above for Ga,. An estimated Doo of 14 kcal./mole has been advanced5 for TI,. The generally decreasing Doo values with molecular weight for the Group IIIB homonuclear diatomic molecules are given in Table 2. Group IVB elements The change from ns2np1 to ns2np2 valence shell ground-state configura- tions of the elements makes a substantial difference in the types of homo- nuclear molecules formed in the vapours of these elements. The diatomic molecules of the Group IVB elements are appreciably more strongly bonded 21 S. Antkiv and V. H. Dibeler J. Chem. Phys. 1953,21 1890. za G. DeMaria J. Drowart and M. G. Inghram J.Chem. Phys. 1959,31,1076. 23 E. G. Shvidkovskii Doklady Akad. Nauk S.S.S.R. 1963,149,816. 24 S. A. Shchukarev G. A. Semenov and I. A. Ratkovskii Zhur. neorg. Khim. 1962 7 469. 82 QUARTERLY REVIEWS than the corresponding Group IIIB diatomic molecules of the same period. Further the Group IVB elements (with the exception of lead) form higher polymeric molecules of variable chain lengths a behaviour not observed with the elements considered heretofore. Diatomic Molecules.-The diatomic C molecule is listed in Herzberg’s compilation1 as having a triplet pi ground electronic configuration but it has been shown that the latter is a low-lying excited state and that the actual ground state is a singlet sigma Accordingly the ground state C molecule has a double bond as is evidenced by its re of 1.312 A which is considerably shorter than the 1.54 A bond distance of the typical C-C single bond.26 A number of values ranging from 140-150 kcal./mole have been rep~rted~*~’-~l in recent years for the Doo of C, but the preferred value is about 144 kcal./mole.It has been claimed that the probable ground state of the Si molecule is a triplet sigma If so Si is different from C2 in that Si has a single rather than a double bond in the ground-state molecule. This is reflected in the very much weaker bonding in Si,. A value of about 75 kcal./mole has been reported in several places5-31p33 for the Doo of Si, as well as 69 kcal./m01e.~~ The overlap is within the experimental uncertainties and the actual value is probably near 75 kcal./mole. Values of about 64 kcal./m01e,~~~~ 46 k c a l ./ m ~ I e ~ ~ ~ ~ and 23 kcal./mole5 have been computed for the Doo of Ge, Sn, and Pb, respectively. The Doo values for the Group IVB homonuclear diatomic molecules are given in Table 3. Higher Molecules.-With the exception of lead the vapours of each of the elements in this Group have been reported to consist not only of atoms and diatomic molecules but a number of higher polymers as well. These will be discussed in turn commencing with the lightest element carbon. A linear triatomic C3 molecule has been found spectroscopically in 26 E. A. Ballik and D. A. Ramsay J. Chem. Phys. 1959,31,1128. 26 T. L. Cottrell “Strengths of Chemical Bonds” Butterworths London 1958. S. M. Reed and J. T. Vanderslice J. Chem. Phys. 1962,36,2366. 28 L. Brewer W. T. Hicks and 0. H. Krikorian J.Chem. Phys. 1962 36 182. 2B D. Steele Spectrochim. Acta 1963,19,411. 30 W. A. Chupka and M. G. Inghram J. Phys. Chern. 1955,59,100. 31 J. Drowart G. DeMaria and M. G. Inghram J. Chem. Phys. 1958,29,1015. 32 R. D. Verma and P. A. Warsop Canad. J. Phys. 1963,41 152. 33 R. E. Honig J. Chem. Phys. 1954 22 1610. 34 J. Drowart G. DeMaria A. J. H. Boerboom and M. G. Inghram J. Chem. Phys. 35 M. Ackerman J. Drowart F. E. Stafford and G. Verhaegen J. Chem. Phys. 1962 1959 30 308. 36 1557. SIEGEL VAPOURS OF THE ELEMENTS a3 carbon v a ~ o u r . ~ ~ - ~ Trapping out of such vapours generated at 2300- 2600"~ in inert-gas matrices at very low temperatures has also shown the presence of C3 by spectros~opy.~~ In early mass spectrometric studies of carbon vapour C C, and C3 gases were found at about 2400"~ with C the most a b ~ n d a n t .~ ~ ~ ~ In a later mass spectrometric study C4 and C were identified in this vapour along with C C2 and C3;41 however at 4100"~ C4 and C5 were reported to be less abundant than C, C, or C. Based on heats of f o r m a t i ~ n ~ ~ ~ ~ $ * ~ y ~ ~ th e AH,,," of the reaction C,(g) +C,(g) + C(g) is - 182 kcal./mole a value substantially higher than that for the simple dissociation of C2(g) to 2C(g). The corresponding value for C,(g) -+ C,(g) + C(g) is - 124 kcal./mole making C3 more stable than C,. However C5 is somewhat more stable thermodynamically than C4. This increased stability of the odd-numbered molecules as compared with the even-numbered molecules has been found by mass spectrometry41 and by a theoretical molecular orbital In the former only trace amounts of the higher polymeric molecules (26 and C were observed but the latter42 predicts that C6 and C7 should be more abundant.At 2000"~ this analysis predicts C5 to be the most abundant species in the saturated carbon vapour with C becoming comparably abundant in the 2500-3000"~ range and even higher polymers important at higher temperaturcs. Thus at 2000°K the average numbers of atoms per molecule is 4.8 while at 3000" it is 8.1 and at 4000" it is 13.5. These polymeric molecules are predicted to be linear rather than ring-shaped and bonded solely through double bond^.^^^^^ In the vapour over silicon at 1660"~ mass spectral peaks ranging from Si+(g) to Si,+(g) were found ;33 these may each represent neutral molecules especially in view of the fact that carbon is known to form such polymers.From reported data16p34 the dissociation energies at 298 OK for the reactions Si,(g) -+ Si,(g) + Si(g) and Si,(g) -+ Si2(g) + Si(g) are about 95 and 104 kcal./mole. As was found for C3 and C2 the primary dissociation of Sis to Si + Si is considerably more endothermic than that for Si + 2Si(g). The shape of the Si molecule is unknown but it has been assumed to be linear by analogy31 with C,. Mass spectral peaks ranging from Gef to Ge,+ has also been f ~ ~ n d ~ ~ for germanium vapour with the polymeric species accounting for about 20% of the vapour at 1370"~. The polymeric ions have been attributed to parent At 1800"~ the relative partial pressures of the poly- meric molecules decrease with increasing molecular weight the vapour 38 K. Clusius and A.E. Douglas J. Chem. Phys. 1954,32,319. 37 W. R. S. Garton Proc. Phys. SOC. 1953 A 66,848. 38 L. Brewer and J. L. Engelke J. Chem. Phys. 1962 36,992. 39 W. Weltner jun. P. N. Walsh and C. L. Angell J. Chem. Phys. 1964,40,1299. 40 R. Honig J. Chem. Phys. 1954 22 126. 41 J. Drowart R. P. Burns G. DeMaria and M. G. Inghram J. Chem. Phys. 1959 42 K. S. Pitzer and E. Clementi J. Amer. Chem. SOC. 1959,81,4477. 43 E. Clementi J. Amer. Chem. SOC. 1961,83,4501. 44 R. E. Honig J. Chem. Phys. 1953 21 573. 31 1131. 84 QUARTERLY REVIEWS being predominantly atomic germanium. The AH," for Ge,(g) + Ge,(g) + Ge(g) is - 89 kcal./m01e,~~ maintaining the trend established for carbon and silicon. At about 1200"~ clusters of Sn mass peaks up to Sn,+ have been found,44 but the fraction of molecules is much smaller than for germanium actually less than 1 %.In the tin vapour the relative abundances of polymeric species decrease with increasing molecular weight. The evaporation of lead at 8 0 0 " ~ has been studied mass spectrometric- ally.44 No molecule higher than Pb was found and at this temperature even the Pbz molecules are in very small concentration the Pb,+/Pb+ ratio being 3 x Group VB elements The one additional electron in N as compared with C drastically changes the bonding in the homonuclear molecules of these elements so the gaseous N is the stable form of nitrogen at ordinary temperatures in contrast to crystalline diamond or graphite. This extra electron permits the formation of a triple bond in N as compared with the weaker double bond in C,. Furthermore it prevents the nitrogen atom from forming hybridised orbitals only with bonding electrons.The repulsions due to the non-bonding electron pair which must be associated with each nitrogen atom in higher nitrogen molecules or stable crystalline configurations based on bonds other than van der Waals forces reduces the strength of N-N bonds are compared with C-C bonds. Thus the dissociation energy for N is 225 kcal./mole while the N-N and N=N bond energies are 39 and I00 kcal./mole; the dissociation energy for C is 144 kcal./mole while the C-C and C=C bond energies are 82.6 and 145.8 kcal./mole.26 It is easily seen from these data that there is a far smaller difference in bond energy for the carbon system between the C molecule and individual bonds in diamond or the conjugated graphite structure than is character- istic of nitrogen.This prevents the formation of a stable condensed state of tervalent nitrogen at ordinary temperatures. However as Table 4 shows the strengths of the bonds in the homopolar TABLE 4. Dissociation energies at O'K of Group VB diatomic molecules Molecule N P As Sb Biz Dissociation energy (kcal./moIe) 22514 1 1614 9114 7Ol4s2 4747948 diatomic molecules of the heavier Group VB elements progressively dimin- ish with increasing weight the most significant drop occurring between N and P,. This very much alters the relative bond strengths between the dia- tomic molecules and the elements in condensed states. Further although N cannot make appreciable use of its high-lying 2d orbitals the heavier group VB elements have lower-lying d orbitals which can be used for sig- nificant increase in bond strength of individual bonds.These factors contribute to making phosphorus and the other Group VB elements form SIEGEL VAPOURS OF THE ELEMENTS 85 stable crystalline modifications at normal temperatures. Thus the gaseous molecules of these elements are only observed at elevated temperatures. However the crystalline states of the Group IVB elements relative to their gaseous molecules are more firmly bound than are the corresponding Group VB solids as is evidenced by the generally higher boiling points and sublimation energies of the Group IVB elements. This leads to volatili- sation of the Group VB homonuclear elements at considerably lower temperatures than is characteristic of the Group IVB elements. At such lower temperatures one might expect to find molecules more complex than simply diatomic molecules especially since P As and Sb in tervalent states can conceivably form tetra-atomic molecules with each atom at the corner of a regular tetrahedron; it should be noted that such molecules require distortion from the mutually perpendicular pi orbitals of the ele- ments in their ground states since the bond angles in the tetrahedral molecules would be each 60°.It should also be noted that this tetrahedron is different from that based on quadrivalent carbon in which the latter is at the centre of the tetrahedron forming bond angles of 109" 28' with four atoms at the corners of the tetrahedron. The conditions of temperature and type of sublimation procedure which permit observation of Group VB homonuclear gaseous molecules that are more complex than diatomic molecules are discussed below after the discussion of bonding in the dia- tomic molecules.Diatomic Molecules.-The emission spectra of the diatomic molecules of this group have long been kn0wn.l The dissociation energies for N, P, and As, given in Table 4 were obtained from such data14 and appear to be quite reliable. The approximate validity of the spectroscopic value of 69 kcal./molel* for Sb has been confirmed by a value of 70.6 kcal./mole obtained by mass spectrometry.22 The value of 70 kcal./mole is selected for Table 4. The dissociation energy for Bi is somewhat more controversial. A spectroscopic value of 39 kcal./mole is recommended by Gaydon but this value is questionable in view of more recent work. By combining vapour-pressure data obtained by effusion with the degree of dissociation of the vapour obtained from the molecular beam velocity spectrum Ko*~ deduced the relative abundances of Bi and Bi in the temperature range 1100-1220"K.This led to a dissociation energy of Bi of 77.1 kcal./mole. By a combined Knudsen and torsion-effusion technique at 913-971"~ Yo~iyarna~~ obtained a value of 70 kcal./mole. However a more recent recalculation of KO's and Yosiyama's data by Brackett and Brewer4' has reduced the value to 47 -+ 1 kcal./mole. Furthermore a recent combined Knudsen-torsion effusion study4* of bismuth vapour at 45 C. C. KO J. Franklin Znst. 1934 217 173. 46 M. Yosiyama J. Chem. SOC. Japan 1941 62,204. 47 E. Brackett and L. Brewer U.S.A.E.C. UCRL-3712 (1957). 4R A. T. Alred and J. N.Pratt J. Chem. P/z-Ys. 1963 38 1085. 86 QUARTERLY REVIEWS 824-970"~ has led to a D,, of 47.9 & 2.7 kcal./mole. Accordingly the value of 47 kcal./mole is given in Table 4. Each of the diatomic molecules in the normal ground state is in a singlet sigma electronic state,l indicating that the bonding is by a triple bond. However the bond strengths of these triple bonds fall markedly with in- creasing molecular weight. Tetra-atomic Molecules.-Most data indicate that phosphorus arsenic and antimony evaporate under equilibrium conditions at temperatures below about 1OOO"c to form the corresponding P, As, and Sb4 molecules with a virtual absence of the corresponding diatomic molecules under these conditions. This has been shown for phosphorus by vapour density meas~rements~~ and mass spe~trometry;~~ for arsenic by vapour density,51 torsion and mass spectrometry;53 and similarly for anti- m ~ n y .~ * - ~ ~ In the case of phosphorus it was shown mass spectr~metrically~~ that mass peaks attributable to both P2+ and P,+ could be found but that the former originated by collisions of P molecules with the hot spectro- meter filament. Studies with cadmium arsenide in the temperature range 220-280"~~' and 434-695"~~~ have also demonstrated that As is the only appreciable gaseous molecule containing arsenic in the vapour. The latter study was by dew point measurements combined with direct pressure measurements while the former was by mass spectrometry. It was concluded that the As,+ and AS,+ mass peaks were fragments from As ionisation although a small amount of As could not be ruled out.Despite the virtual absence of diatomic molecules in the equilibrium vapour of phosphorus arsenic and antimony at moderately high tempera- tures these diatomic molecules have been found at such temperatures when the evaporations were carried out in a non-equilibrium manner. Under such conditions mass spectrometric s t ~ d i e s ~ ~ ~ of the sublimation of alloys of P As and Sb with indium and gallium at temperatures to 1200"~ demonstrated that P, As, and Sb, were formed along with P, As, and Sb,. This was proved by the observed variation of the ion- intensity ratios corresponding to tetrameric and dimeric molecules as a function of temperature the tetramers increasing with temperature. Simi- larly it has been shown5 by torsion momentum data that whereas As is 49 D.P. Stevenson and D. M. Yo-' J. Chem. Phys. 1941 9,403. 6o J. S. Kane and J. H. Reynolds J . Chem. Phys. 1956,25,342. 61 P. J. McGonigal and A. V. Grosse J. Phys. Chem. 1963 67 924. 62 F. Metzger Helv. Phys. Acta 1943 16 323. 63 L. Brewer and J. S. Kane J. Phys. Chem. 1955,59 105. 54 P. Goldhger and M. Jeunehomme "Advances in Mass Spectrometry," ed. J. D. 66 V. V. Illarionov and A. S. Cherepanova Doklady Akad. Nauk S.S.S.R. 1960,133 56 G. M. Rosenblatt and C. E. Birchenall J. Chem. Phys. 1961 35 788. 67 J. B. Westmore K. H. Mann and A. W. Tickner J . Phys. Chem. 1964 68 606. 68 V. J. Lyons and V. J. Silvestri J. Phys. Chem. 1960,64,266. 6 9 J. Drowart and P. Goldfinger J. Chim. phys. 1958,55,721. Waldron Pergamon Press pp. 534-546 New York 1959. 1086. SIEGEL VAPOURS OF THE ELEMENTS 87 the only significant species in the equilibrium arsenic vapour non-equilib- rium evaporation leads to mainly As,.Clearly in this temperature range the equilibrium between the tetra-atomic and diatomic molecules favours the tetra-atomic molecules. This has been disputed by a mass spectro- metric study of phosphorus vapour which was interpreted,60 on the basis of ionisation curves at various electron energies as forming P and P3 in addition to P,. While the latter study used an alumina crucible with a 0.5 mm. hole the puzzling conclusions may have been due to non-equilibrium conditions. Another conclusion of this sort has been advanced22 regarding the presence of Sb as well as Sb in the equilibrium vapour over indium antimonide at 800-1150"~. In the latter it was claimed that the relative amounts of Sb as compared with Sbp increase with increasing temperature.The formation of P, As, and Sb when non-equilibrium conditions were employed strongly implies that these diatomic molecules are the primary species evaporating from the condensed states. Although at equilibrium the tetra-atomic molecules appear to be favoured energetically in the temperature range below 1 OOO"c these tetra-atomic species con- ceivably could result from precursor diatomic molecules which would then be observed if measurements were made before sufficient time was allowed for equilibrium to be attained. In this connection it should prove informative to inquire into the structure of red phosphorus which is the form generally used in the phosphorus experiments. Although the structure of red phosphorus is not known definitely Pauling and SimonettaG1 have suggested that it is formed thermally from white phosphorus which is believed to consist of weakly joined tetrahedral P units by the rupture of one P-P bond in each P unit giving chain structures with opened tetra- hedra.Sublimation of the latter need not result in primary P molecules but might possibly sublime as P molecules. As for arsenic and antimony these elements form metastable crystalline forms which contain tetra- hedral units but heating of the latter converts them into metallic modifica- tions in which each atom is tervalent but specific units such as As and Sbp are not present.62 Electron diffraction studiesG3 of phosphorus and arsenic vapours have delineated the structures of P and As,. These molecules are tetrahedral with three 60" bond angles per atom; presumably Sb is also tetrahedral.These short bond angles are quite unusual for these elements and reflect considerable steric strain. In view of the tervalences of these elements in the tetra-atomic molecules the bonds should be essentially single bonds rather than the triple bonds characteristic of the diatomic molecules. This is indicated by the bond distances in P4 and P, 63 2.21 A in P4; 1.894 A in P,. Accordingly the bond dissociation energies of the diatomic molecules 6o J. Carette and L. Kerwin Canad. J. Phys. 1961,39 1300. 61 L. Pauling and M. Simonetta J. Chem. Phys. 1952,20,29. 62 A. F. Wells "Structural Inorganic Chemistry," 3rd edn. Oxford Univ. Press 6a L. R. Maxwell S. B. Hendricks and V. M. Mosley J.Chem. Phy3.. 1935 3 699. London 1962. 88 QUARTERLY REVEWS of this group should be far greater than those for individual bonds in the tetrahedral molecules. The dissociation energies for the reactions X4(g) -+ 2X,(g) are given in Table 5; these data were obtained by mass spectro- In dissociation X to 2X2 six single bonds are broken to form two triple bonds. It can be seen from Table 5 that the heavier X4 molecules TABLE 5. Dissociation energies of Group VB tetra-atomic to diatomic molectrles at 2 9 8 ” ~ A Hzg8’ (kcal./mole) 55.754 69*654 62-422 63.454 are somewhat more stable relative to 2X2 than is P,. In view of the weakness of the “triple” bond in Bi the single bonds in Bi would be weaker still and it should not be surprising that Bi has not been reported as a stable gaseous molecule.This is especially true in view of the 1832”~ boiling point for bismuth.s4 Higher Molecules.-Without specifying temperatures Kenvines found that the evaporation of red phosphorus leads to a small P,+ mass peak with a ratio of ion intensities P4+/P8+ of 200. In a more detailed study Carette and KerwinG0 again reported the presence of P8+ in the vapour above red phosphorus with an ion-intensity ratio Pt+/P8+ of 500 at 320”c. This indicates the formation of small amounts of P8. Kane and Reynolds50 were unable to detect such a P8 species but did find traces of As8 in arsenic vapour. Carette and Kerwin report that the thermal treatment of the sample prior to mass spectral analysis plays a role in this phenomenon.60 Group VIB elements The first of the Group VIB elements resembles nitrogen in that oxygen forms a permanent diatomic gas.However the resemblance between the Group VB and VIB elements stops here. Whereas phosphorus arsenic and antimony form equilibrium vapours at temperatures below 1000°c consisting primarily of tetrahedral molecules under comparable condi- tions sulphur and selenium form complex vapours of ring-shaped molecleus with an entire spectrum of ring sizes. Moreover the distribution of mole- cules of various ring sizes is different for sulphur than for selenium. Whereas antimony forms a stable tetrahedral molecule there is no evidence that the comparable Group VIB element tellurium forms polymeric rings. At much higher temperatures however sulphur and selenium resemble the corresponding Group VB elements in that they form predominantly diatomic molecules.64D. R. Stull and G. C. Sinke “Thermodynamic Properties of the Elements,” American Chem. SOC. ,Washington D.C. 1956. 6s L. Kerwin Canad. J. Phys. 1954,32,757. SIEGEL VAPOURS OF THE ELEMENTS 89 Diatomic Molecules.-It has been difficult to definitively assign a dis- sociation energy for the S molecule from spectroscopic data; values of 3-3 3.6 and 4.4 ev are cited by Gaydon,14 who recommends the highest value of 101 kcal./mole while Cottrel126 has recommended the middle value of 83 kcal./mole. However the preponderance of evidence now favours 101 kcal./mole. This has been proved by mass spectrometry6G-68 and by recalculated vapour-pressure data.69 The spectroscopic value for the dissociation energy of Se is 65 kcal./rn01e,~~ but a higher value of 75 kcal./mole has also been reported from a mass spectrometric The spectroscopic value foi the dissociation energy of Te is 53 kcal./m01e,~* in good agreement with a value of 52.0 kcal./mole obtained mass spectro- metri~ally.~~ These values are given in Table 6 along with the spectro- TABLE 6.Dissociation energies at O'K of Group VIB diatomic molecules Dissociation energy (kcal./mole) 1 1 8.014 10166-69 6515(75)70 52-514*71 scopic value for 0,. The mass spectrometric value for Se is given in parentheses while the value for Te as given in Table 6 is the average be- tween the two values cited above. The ground-state diatomic 0 and S molecules are known to be in triplet sigma electronic states and are thus diradicals. Although this assignment is less certain for Se it is probable that this molecule resembles O2 and S in its bonding.14 That S is a diradical has been proven by its magnetic s~sceptibility.~~ One can also assume that these Group VIB diatomic molecules have the double bond characteristic of oxygen.As can be seen from Table 6 the bond strengths decrease regularly with in- creasing weight in this group of molecules reflecting the fact that in the unsaturated vapours the heavier molecules dissociate to the atoms at lower temperatures than do the lighter molecules. Since S and Se are present only as minor constituents in the equilib- rium vapours of these elements at temperatures below 700-800"~ investigations of the properties of these diatomic molecules have usually been carried out at temperatures exceeding 10oO"~. Thus an electron- diffraction study of the molecular parameters of s has been carried at 1123"~ the equilibrium reaction between S and SO has been at 1523"~ while the thermodynamics of S have been studied by the sublimation of sulphides that give S2 at numerous temperatures over Molecule 0 2 s 2 Se2 Te2 1000 "Km54,66-68 66 J.Berkowitz and J. R. Marquart J. Chem. Phys. 1963,39,275. 67 R. Colin P. Goldfinger and M. Jeunehomme Nature 1960,187,408. 68 R. Colin P. Goldfinger and M. Jeunehomme Trans. Faraday Soc. 1964 60 306. 6 9 L. Brewer J. Chem. Phys. 1959,31 1143. 70 D. Detry Ind. Chim. belge 1963 28,752. 71 R. F. Porter J. Chem. Phys. 1961 34 583. 72 J. A. Paulis C. H. Massen and P. v. d. Leeden Trans. Faraday SOC. 1962,58 52. 73 L. R. Maxwell S. B. Hendricks and V. M. Mosley Phys. Rev. 1931,49 199. 74 E. W. Dewing and F.D. Richardson Trans. Faraday SOC. 1958,54,679. 90 QUARTERLY REVIEWS Unlike sulphur and selenium tellurium apparently does not form ring- shaped molecules even at lower temperatures. The only gaseous molecule thus far observed for tellurium is Te,. The latter has been observed mass spectrometrically by sublimation of germanium telluride75 and lead t e l l ~ r i d e ~ ~ and by its absorption spectrum from the sublimation of tin and lead tellurides. 76 Ring-shaped Molecules.-A number of vapour-density studies for sulphur covering the temperature range 300-1000"c have clearly indicated that the vapour is complex in this temperature range and that the composi- tion varies with temperature. Mixtures of s8 s69 and s2,77-79 and also Sq,80 were deduced from the data. Electron diffraction studies81,82 have established that the S8 molecule is a puckered ring with S-S bond distances of 2-07-2.08 A a value considerably longer than the 1-889 AZs double bond distance in S B .In the electron diffraction study by Maxwell et aZ.73 it was observed that the S-S bond distance increased with decreasing tem- perature representing increased polymerisation of S to higher ring-shaped molecules as the temperature was lowered. The complex equilibrium vapour of sulphur has been elucidated most completely by mass spectrometry.6s Berkowitz and Marquart's equilibrium data are shown in Fig. 2. It can be seen that at 350"~ the preponderant I 1 1 I I T.'K FIG. 2. Saturated sulphur vapour below 700°K. Reproduced with permission from J. Berkowitz and J. R. Marquart J. Chem. Phys. 1963 39 275.76 R. Colin and J. Drowart J. Phys. Chem. 1964,68,428. 76 R. F. Brebrick and A. J. Strauss J. Chem. Phys. 1964,41 197; 1964,40,3230. 77 G. Preuner and W. Schupp Z . phys. Chem. 1909,68,219. 78 G. Preuner and I. Brockmoller Z . phys. Chem. 1912,81,129. 79 W. Klemm and H. Kilian Z. phys. Chem. 1941,49 B 279. 80 H. Braune S. Peter and V. Nevelhg 2. Naturfousch. 1951 6a 32. J. D. Howe and K. Lark-Horovitz Phys. Rev. 1937 51 380. 82 Chiu-Li Lu and J. Donohue J. Amer. Chem. Soc. 1944,66,818. SIEGEL VAPOURS OF THE ELEMENTS 91 species is s8 with some s6 and s7. At somewhat higher temperatures ss becomes a minor constituent of the vapour with S4 and S doing so at even higher temperatures. Traces of S and Sl0 have also been observed. These S molecules appear to be ring-shaped rather than linear.83 Bond energy data for the polyatomic sulphur molecules are given in Table 7.It can be seen that these sulphur-sulphur single bonds are not particularly strong. TABLE 7 . Bond energies for polyatomic sulphur molecules Molecule Energy per bond Molecule Energy per bond (kcal./mole)* (kcal./mole)* s3 55.5 s 7 62.2 s 4 58.0 s8 62.8 s 5 60.2 SQ 62.2 s6 61.7 SIO 62.8 * Data taken from ref. 66. In free-evaporation studies at slightly elevated temperatures it has been shown by mass spectrometry that the actual vapour species subliming from the surface of sulphur is s8(g) from rhombic sulphur which consists of s8 units in the crystal and s&) from an allotropic form of sulphur which is known to consist of s6 units in the crystal.84 This demonstrates the importance of ascertaining whether equilibrium is obtained.Un- doubtedly the S,(g) species will equilibrate to form mainly s&) at these temperatures if sufficient time is allowed for the attainment of equilibrium. The molecular weight of the equilibrium vapour over selenium at about 200"~ has been shown to be nearly Se by vapour-pressurestudies.85~86 At 550-800"c both Se and Se have been interpreted from vapour- pressure studies as the principal gas species in selenium vap~ur.'~ Electron diffraction patterns of selenium vapour best fit a Se model.81 There has only been an incomplete mass spectometric study of this v a p o ~ r . ~ ~ In the latter carried out at 177-237"~ Se$ was by far the principal ion formed mass spectrometrically and Se is clearly the principal gaseous species in this temperature range.However ions ranging from Se$ to Se8+ were also found and it may be assumed that the vapour is as complex as that of sulphur. The bond energy per bond for Se6(g) at 298"~ as calculated from data in Stull and Sinke's c~mpilation,~~ is 43.5 kcal./mole. This reflects weaker bonding than in the analogous s6 or s8 molecules. 83 L. Pauling Proc. Nat. Acad. Sci. 1949 35 495. 85 K. Neumann and E. Lichtenberg 2. phys. Chem. 1939,184 A 89. J. Berkowitz and W. A. Chupka J. Chem. Phys. 1964,40,287. A. A. Kuliev and M. G. Shakhtakhtiaskii Dokkady Akad. Nauk S.S.S.R. 1958 120 1284. 92 QUARTERLY REVIEWS Transition metals The IB elements form homonuclear diatomic molecules which are more strongly bonded than those of the IA elements. The ground state of Cu has been identified as a singlet sigma state with a rather short bond distance.87 This was attributed to the greater binding energy obtainable via hybridisation.Mass spectrometric values for Doo of Cu ranging from 46 to 51 kcal./mole have been rep0rted,8~-~O while the value obtained by the Birge-Sponer extrapolation of spectroscopic data is 48 kcal./m~le.~~ Ackerman et aL8* have compared these data with common heats of vapor- isation of the elements and free energy functions and have found that the agreement is thereby improved the Doo being about 46 kcal./mole. For Ag the Doo obtained from mass spectrometry is about 38 kcal./ m ~ l e ; ~ ~ ~ ~ ~ ~ ~ ~ a higher value of 41.4 kcal./mole was obtained spectro- sc~pically.~~ For Au the mass spectrometric Doo is 50-53 kcal./mole,8*-90 with the preferred value being about 52 kcal./mole;88 the Doo obtained by the Birge-Sponer extrapolationsg is very much higher and is probably in error.The data for copper vapour between 1440 and 1730°~88189 indicate a generally rising mole fraction of Cu, as compared with Cu with increasing temperature as is characteristic of the IA molecules. This is also the case for Ag and Au,. While the mole fractions of diatomic molecules in the saturated vapours of the alkali metals are considerably higher than those of Cu, Ag, or Au, it must be remembered that the normal boiling points of the IB elements are much higher than those of the alkali metals and thus the total vapour pressures are considerably higher for the latter elements. For example the mole fraction of Cu in copper vapour is only about 3 x at 1700”~ but the total copper vapour pressure at this tempera- ture is only 1.3 x atm.;64 at this temperature each of the alkali metals has a saturated vapour pressure in excess of one atm.There has been a reportg2 of even higher molecules in the vapour of silver with Ag and Ag being present in appreciable amounts at tem- peratures below 1500”~. However this has not been observed in any of the studies described above or indeed in other mass spectrometric studies of silver v a p o ~ r ~ ~ ~ ~ ~ and probably must be discounted. The diatomic molecules of the IIB elements Zn, Cd, and Hg have been observed spectroscopically. The Doo values for these molecules are even lower than those for the ITA elements. Gaydon cites 6 2 and 1.4 kcal./mole for Zn, Cd, and Hg, respectively with the value for D.N. Travis and R. F. Barrow Proc. Chem. Soc. 1962,64. M. Ackerman F. E. Stafford and J. Drowart J. Chem. Phys. 1960 33 1784. J. Drowart and R. E. Honig J . Chem. Phys. 1956,25 581. P. Schissel J. Chem. Phys. 1957 26 1276. 9 1 D. White A. Sommer P. N. Walsh and H. W. Goldstein “Advances in Mass g2 A. W. Searcy R. D. Freeman and M. C. Michel J. Amer. Chem. Soc. 1954 76 93 M. B. Panish J. Chem. Eng. Data 1961,6 592. Spectrometry,” Proc. Second Cod. ed. R. M. Elliott Macmillan Co. N.Y. 1963. 4050. SIEGEL VAPOURS OF THE ELEMENTS 93 Zn very much in doubt.14 A somewhat smaller value of 0.6 & 0.2 kcal./ mole has recently also been found for Cd,.g4 In view of the extreme weakness of these bonds it is not surprising that these molecules have not been observed mass spectrometrically despite efforts to find such mole- c u l e ~ .~ ~ There is no known diatomic molecule for the transition metals of Groups I11 to VII despite several mass spectrometric searches for such molecules (for example scandium yttrium lanthanumg6 and tantalumQ7)*. The problem is particularly complicated for metals with very high boiling points such as tantalum because studies carried out at temperatures even as high as 3000”~~~ are still very far from the normal boiling point (5700”~). Even at 3000”~ the vapour pressure of tantalum is less than atm.64 and it would take a very strong bond indeed to form a stable molecule at this very high temperature and very low pressure. Among the Group VIII metals a homonuclear diatomic molecule is known presently only for nickel. This Ni molecule was observed mass spectrometrically and a Doo of - 54-5 kcal./mole was computed from the data.g8 Since cobalt and iron have normal boiling points very close to that of nickel,64 the Co and Fe molecules will probably also be found.? Dia- tomic molecules in the vapours of rhodium iridium osmium and ruthen- ium could not be found however in mass spectrometric ~ t u d i e s .~ ~ ~ ~ In these cases the metals have considerably higher boiling points than Fe Co or Ni. Thus the calculated vapour pressures at which the vapours were studied are as follows 2.5 x mm. at 2353”~ for R u ~ ~ 8-5 x mm. at 2205”~ for Rh,loO and 3-8 x mm. at 2630”~ for Ir.loO At these temperatures and pressures the Doo required for the stable existence of the respective diatomic mole- cules would probably be in excess of that found for Ni, and it is thus unlikely that the diatomic molecules will be observed for these heavier mm.at 2715”~ for O S ~ ~ 3-05 x *It has come to the attention of the writer that the molecules Sc, Y, and La have been recently identified mass spectrometrically in the vapours above the corresponding metals. The reported Doo values are 25.9 f 5 37.3 f 5 and 57.6 f 5 kcal./mole for Sc, Y and La, respectively. (G. Verhaegen S. Smoes and J. Drowart U.S. Atomic Energy Commission Report WADD-TR-60-782 1963). [Note Added in Proof:-Since this review was prepared there has been a reported mass spectrometric observation of Co (A. Kant and B. Straws J. Gem. Phys. 1964 41 3806). The Doo obtained in that study was 39 f 6 kcal./mole. Although Ti, Cr and Mn could not be actually obtained upper limits were set for their Doo values.Some more recent data will shortly be available on the composition of the sulphur vapour. These data however are only slightly different than those in Fig. 2 (J. Berkowitz Molecular Composition of Sdfur Vapor in “Elemental Sulfur” ed. C. B. Meyer John Wiley and Sons New York in the press)]. O4 B. L. Bruner and J. D. Corbett J. Phys. Chem. 1964,68 1115. 95 K. H. Mann and A. W. Tickner J . Phys. Chem. 1960,64,251. O6 R. J. Ackermann and E. G . Rauh J. Chem. Phys. 1962,36,448. 97 T. P. Babeliowsky and A. J. H. Boerboom “Advances in Mass Spectrometry,” Proc. Second Conf. ed. R. M. Elliott Macmillan Co. N.Y. 1963. O * A. Kant J. Chem. Phys. 1964 41 1872. O0 M. B. Panish and L. Reif J. Chem. Phys. 1962,37 128. loo M. B. Panish and L. Reif J.Chem. Phys. 1961,54 191 5 . 94 QUARTERLY REVIEWS Group VIII metals at such temperatures. The possibility of observing such molecules is enhanced if the temperatures are nearer the boiling points of the metals. If the bond strengths of such molecules are not sufficiently high to withstand dissociation at temperatures exceeding 4000"~ and pressures below one atm. these molecules might exist in significant concentrations only at temperatures considerably in excess of the normal boiling points in their saturated vapours. The Doo values for the homonuclear diatomic molecules of transition metals are given in Table 8. TABLE 8. Bond dissociution energies at O'K for the diatomic molecules of transition metals Molecule Doo (kcal./mole) Molecule Doo (kcal./mole) 4688-90 2% 614 3888,89,91 Cd2 0~6'~ 214 5288-90 Hg2 1 ~ 4 ' ~ Ni -54.598 cu2 Ag2 Au2

ISSN:0009-2681    

DOI:10.1039/QR9651900077

出版商:RSC    

年代:1965

数据来源: RSC

摘要:

COPPER-PROMOTED REACTIONS IN AROMATIC CHEMISTRY By R. G. R. BACON (DEPARTMENT OF ORGANIC CHEMISTRY QUEEN'S UNIVERSITY BELFAST NORTHERN IRELAND) and H. A. 0. HILL (INORGANIC CHEMISTRY LABORATORY OXFORD) General features COPPER and its compounds are outstanding within the transition series for the variety and value of their applications as reagents or catalysts for organic reactions. The development of these processes has been largely empirical and their mechanisms are not well understood. This Review is confined to aspects of copper chemistry encountered in aromatic reactions and is particularly concerned with recent observations in this area. Less attention is paid to long-established features which have been described in other reviews; these include accounts of the Ullmann method of biaryl synthesis,l the Sandmeyer r e a ~ t i o n ~ ~ and some other applications in nucleophilic aromatic substitution proce~ses.~ To systematise the diverse effects of copper described in the recent literature they are grouped in accordance with the change undergone by the aromatic compound i.e.as reduction oxidation substitution or ring-enlargement processes. The following are examples Reductions 2ArHal + 2Cu -+ Ar-Ar + 2Cu+ + 2Hal- 2ArN,+ + 2Cu+ -+ AraAr + 2Cu2+ + 2N ArHal + XH -+ ArH + HHal + X CU' Oxidations 2Ar-MgX+ + 2Cu2+ -f Ar.Ar + 2Cu+ + 2MgX+ ArNHeNH + 2Cu2+ -+ ArH + 2Cu+ + 2H+ + N CU" ArH + 0 -+ ArOH etc. 2ArH + Xu3+ -f Ar-Ar + 2Cu2+ + 2H+ ArH + Br- + 2Cu2+ -+ ArBr + 2Cu+ + H+ Replacements ArHal + CuX -+ ArX + CuHal CU' ArHal + HX -+ ArX + HHal CU' ArN,+ + X- -+ ArX + ArX + N P.E. Fanta Chem. Rev. 1946,38 139; 1964,64 613. 2 W. A. Cowdrey and D. S. Davies Quart. Rev. 1952 6 358. 8 K H. Saunders "The Aromatic Diazo-compounds and their Technical Applica- 4 J. F. Bunnett and R. E. Zahler Chem. Rev. 1951,49 273. tions," Edward Arnold and Co. London 1949. 95 96 QUARTERLY REVIEWS It will be seen that in some cases the copper species undergoes cheimcal change and in other cases its function is catalytic. Thus some aromatic reductions involve electron loss in the copper Cue+ CuI or CuI -+ CuII and some oxidations involve electron gain CulI -f CuI or occasionally CuIII + CuII. In other instances a copper species catalyses processes in which e.g. oxygen is the oxidant or an alcohol or alkoxide is the reduct- ant. Likewise in substitution processes copper species may undergo ligand exchange with the substrate whilst in other cases a copper catalyst and a nucleophil are separate components of the reaction system.These are essentially practical distinctions since catalysis may in fact involve tran- sient chemical change in the copper e.g. by the formation of intermediate complexes or by the operation of oxidation-reduction cycles Cu' - e -+ Cu" -f CuI + e Before particular reactions are discussed attention is drawn to the following general features of aromatic reactions involving copper species (a) The literature is largely concerned with chemical changes in organic molecules and there is a dearth of information qualitative or quantitative concerning changes in the copper. To a varying extent copper is likely to be present at more than one oxidation level proportions of which may alter during reaction.This could be due to initial heterogeneity to oxida- tion-reduction processes or to disproportionation 2Cu' + cu + CU" (b) The copper ions undergo complex-formation with molecules or anions in the reaction system. It is therefore understandable that copper- assisted reactions are frequently very variable in rate and are sometimes completely inhibited depending e.g. upon what anions reagent or solvent molecules or specific complexing agents are present in the system to compete as ligands for the metal. (c) Copper species are effective towards a limited range of atoms or groups in aromatic molecules ; these are mainly halogen atoms diazonium- salt groups and some sulphur-containing functional groups. There is in addition increasing evidence that copper has a marked capacity for facilitating hydrogen transfer from a wide range of donor molecules to specific acceptors.( d ) Substituent effects in copper-promoted aromatic reactions may differ from those in related reactions not involving copper; this needs further elucidation. When e.g. the group Y in a substrate C,H4XY is an unsatur- ated function such as NOz or CO,H the response of X is often high particularly if it is in an ortho-position to Y. (e) Both heterolytic and homolytic mechanisms have been suggested but it is often difficult to establish that a reaction is of one form or the other. A complication is the possibility of interconversion between organic BACON AND HILL COPPER-PROMOTED REACTIONS 97 intermediates of ionic and radical type by processes such as R* + Cu2+ -+ R+ + Cu+ (.f) Special problems arise when reactions occur at interfaces between solid copper species and liquid organic media.In such heterogeneous systems reaction rates or yields of products tend to be rather poorly reproducible and to be affected by changes in agitation conditions and changes in the physical or chemical character of the surface. The commonest reagents thus employed are copper metal and cuprous oxide. The former whether employed e.g. as “copper bronze” or as the powder precipitated from a copper(r1) salt solution may be contaminated with other metals oxygen anions or organic material. For various purposes e.g. Ullmann syntheses,l metal from prescribed sources has been recommended or preliminary treatments have been advocated such as washing with organic solvents or activation of the surface with iodine.In the case of cuprous oxide the Cu20 content of a sample of typical laboratory-grade reagent may be no higher than about 90%; it will probably also contain substantial amounts of CuO and may be con- taminated with small amounts of moisture cationic and anionic species and organic material. A precipitation method has been used by some in- vestigators to prepare cuprous oxide used in diazonium-salt reaction^.^ Samples of the oxide prepared from the pure elements prove to be non- stoicheiometric with an excess of oxygen atoms in the l a t t i ~ e . ~ There are large departures from the stoicheiometric proportion in surface layers of oxide made by reaction of oxygen with copper films.s The consequences of these lattice irregularities for the catalysis of reactions in the gaseous phase have still to be clarified and their effects on liquid-phase reactions are even more obscure.The relative energies of the oxidation states of the metal and the type and stability of the complexes which it forms in its different oxidation states are highly relevant to copper-promoted aromatic reactions. These features of the inorganic chemistry of the element are briefly surveyed in the next section. Inorganic chemistry of copper Thermodynamics.-Copper atomic number 29 has the electronic configuration KL 3 ~ ~ 3 ~ ~ 3 d ~ ~ 4 ~ 1 . The first three ionisation potentials are 7.72 20.29 and 36.83ev. The relatively high ionisation potential together with a large sublimation energy contribute to the “noble” character and resistance to oxidation of the metal.The principal oxidation states are +1 and 3-2 with the 3.3 state known for a few complexes e.g. K&UF6. The second ionisation potential of copper is large compared with that of any element in the same Period from calcium (1 1-87) to nickel (1 8-1 5ev) and M. O’Keeffe and F. S. Stone Proc. Roy. Soc. 1962 A 267,501. C. M. Quinn and M. W. Roberts Trans. Faraday Soc. 1964,60,899. 98 QUARTERLY REVIEWS for this reason copper(1) is more stable to oxidation than the other transi- tion metals of the Period in their +1 oxidation states. The relative stability of the first three oxidation states 0 +1 and +2 is very sensitive to change in environment. The standard electrode poten- tials of copper in aqueous solution are Cu/CuI +0.522v; Cu/CuII 3-0.345~; the large heat of hydration of copper(II) -507kcal.compared with that of copper(I) - 139kcal. compensates for the higher second ionisa- tion potential to make the hydrated copper(I1) ion the more stable state in aqueous solution. All soluble simple copper(1) salts disproportionate in water by the reaction 2Curaq -+ Cuo + CuIraq with the disproportionation constant K = 1.2 x lo6 at 25”. In the presence of ligands for which the metal in its two oxidation states has different affinities the disproportion- ation constant varies greatly; thus in aqueous 1,2-diaminoethane which can chelate copper(r1) but not copper(I) K = lo5 but in aqueous ammonia K = 2 x lod2. The latter relationship is reflected in the reaction CU(NH,),~+ + Cu -f 2Cu(NH,),+ Copper(1) tends to form thermodynamically stable complexes with polarisable ligands or z-accepting ligands.The stability of copper(1) halide complexes in aqueous solution increases with increasing atomic number of the halogen and copper(1) is therefore a so-called “class b” ion.’ Copper(I1) halides have the reverse order of stability and copper(I1) is a “class a” ion. Copper(1) forms complexes with carbon monoxide cyanide ion alkenes,8 alkyne~,~ and in special circumstances aromatic nuclei,1° all these ligands having empty n*-orbitals capable of taking part in synergic bonding i.e. a-donation from the ligand to the metal ion and n-donation from the d-orbitals of the metal to the n*-orbitals of the ligand. It has been suggested’ that similar bonding is involved in the “class b” halide com- plexes with the empty d-orbitals of the halide ions as n*-orbitals but it also has been suggestedll that polarisation by the electronegative copper(1) is moreimportant.Such discussions tend to obscure the fact that the “class b” metal-halide bond strengths in the gas phase increase with decreasing atomic number of the halogen. However the increase is much less than in “class a” metal halides and so in aqueous solution the free energy of hydra- tion of for example the chloride ion dominates and reverses the usual “class a” stability order. The stability of copper(1) complexes has been little studied either in aqueous or non-aqueous solution and would repay investi- gation. Copper(rI) on the other hand has been extensively studied and it is evident that of all bivalent ions of the first transition Period copper(I1) usually forms the most thermodynamically stable complexes.This has been S. Ahrland J. Chatt and N. R. Davies Quart. Rev. 1958 12 265. R. M. Keefer and L. J. Andrews J. Amer. Chem. SOC. 1949 71 1723. G. E. Coates “Organo-metallic Compounds,” Methuen and Co. London 2nd R. J. P. Williams Proc. Chem. Soc. 1960 20. edn. 1960 p. 352. lo R. W. Turner and E. L. Amma J. Amer. Chem. Suc. 1963,85,4046. BACON AND HILL COPPER-PROMOTED REACTIONS 99 expressed12 in the Irving-Williams series of complex-ion stabilities Mn2+ < Fe2+ < Co2+ < Ni2+ < Cu2+> Zn2+. The interpretation of this sequence is still open to question. Stereochemistry.-When associated with ligands of low polarisability or ligands which have no empty r-orbitals copper(1) usually has the co- ordination number two as in Cu(NH,)$ and forms two linear bonds which can be described in terms of either sp- or sd-hybrid 0rbita1s.l~ With n-bonding or polarisable ligands the co-ordination number is variable though usually four and tetrahedral stereochemistry is observed.Copper(n) on the other hand has either (a) a co-ordination number of six with a distorted octahedral arrangement usually with four short bonds and two long bonds owing to either Jahn-Teller distortion or lack of spherical symmetry of the d9 ion or (b) a co-ordination number of four with a square-planar arrangement which can be considered as an extreme case of a tetragonally distorted octahedron involving complete removal of two trans ligands. Copper(r1) is only tetrahedral in a few complexes e.g.K,CuCl,. The difference in stereochemistry displayed by the two oxidation states often affects the Cul/CuII redox potential. This is illustrated by some observation^^^ on complexes of copper(1) and (11) with bipyridyls and o- phenanthrolines. Substituents in the 6,6’-positions in the 2,2’-bipyridyls increase the oxidation potential i.e. increase the relative stability of the copper(r) state thereby reflecting the smaller sensitivity of tetrahedral copper(1) to steric interaction as compared with that of square-planar copper(I1). Kinetics.-It might be expected that the kinetic stability of copper@ complexes like other d10-~~mple~e~,15 would approximately follow their order of thermodynamic stability. Even so these complexes are labile perhaps because of the spherically symmetric ion resulting from the filled d-subshell.The rate of the reaction16 between the species Cu(CN) and *CN- was such that exchange was complete in 2 minutes even though the assocation constant /I2 of Cu(CN) is The rates of formation and the exchange rates of complex copper(r1) ion with most ligands are very fast. Thus the rate of exchange of water with the aquated ion has1’ a first-order rate constant of lo8 sec.-l and even exchange with a chelating ligand exemplified by reaction of the species C~(en),~+ with isotopically labelled 1 ,2-diaminoethane,18 is 90 % complete in 3 seconds at 0”. The lability of most copper(11) complexes results from l2 H. Irving and R. J. P. Williams J. 1953 3192. l3 L. E. Orgel “Introduction to Transition-Metal Chemistry,” Methuen and Co. l4 B. R. James and R. J.P. Williams J. 1961 2007. l5 H. G. Hertz 2. Electrochem. 1961 65 36. l6 A. C. MacDiarmid and N. F. Hall J. Amer. Chem. SOC. 1954,76,4222. London 1960 p. 66. M. Eigen J. Pure Appl. Chem. 1963 6 97; R. E. Connick and E. D. Stover D. G. Popplewell and R. G. Wilkins J. 1955 4098. J . Phys. Chem. 1961 65 2075. 100 QUARTERLY REVIEWS the weak bonding and ease of replacement of the two axial ligands. Electron exchange between copper([) and copper(n)19 is very fast with a rate constant 5 x lo7 M-lsec.-l at least in the presence of halide ions which form a bridge between the two cations thereby facilitating electron transfer. Catalysis by Copper Compounds.-Copper(r) by forming complexes with aromatic nuclei alkenes alkynes and aryl halides may so perturb the molecule that a different rate of reaction or distribution of products from that observed in the absence of the metal ion may result.Similarly perturbation by metal ions such as copper(rI) functioning as Lewis acids has been used to explain their catalysis20 of e.g. the bromination of /3-diketones. The small differences in energy between the first three oxida- tion states 0 + 1 and +2 has an important effect in the use of copper and its compounds as catalysts. Thus when the metal has been converted into a particular oxidation state some oxidant or reductant may cause rever- sion of the metal ion to its initial oxidation state and so the active ion may be continuously regenerated. Both copper(1) and copper(I1) are suited to catalyse numerous organic reactions because of their ability to form complexes with a wide variety of ligands and because formation and dissociation of the complexes can occur very rapidly.Reduction processes The reactions to be discussed are (i) additive hydrogenations X + H -f XH2 (ii) reductive coupling 2ArX -+ Ar.Ar (iii) substitutive reduction ArX -+ ArH. Examples of copper-promoted reactions of types (ii) and (iii) are found among halides certain sulphur compounds and diazonium salts. (a) Additive Hydrogenation.-For heterolytic gas-phase hydrogenation the catalytic activity of copper is much inferior to that of many other transition metals.21 On the other hand the study of homogeneous hydro- genation in the liquid phase22 arises from Calvin’s that solutions of some copper(1) salts activated molecular hydrogen as a reductant for some inorganic species and for p-benzoquinone ; e.g.the latter absorbed about 1 mol. of hydrogen at 100” in quinoline containing copper(1) a ~ e t a t e . ~ ~ . ~ Silver and mercury were also catalysts for some homogeneous hydrogenations and the utility of copper with respect to organic substrates is now known to be greatly exceeded by that of certain complexes of other l9 H. M. McConnell and H. E. Weaver J. Chem. Phys. 1956 25 307. 2o F. Basolo and R. G. Pearson “Mechanism of Inorganic Reactions,” John Wiley 21 C. G. Bond “Catalysis by Metals,” Academic Press New York 1962. 22 J. Halpern Quart. Rev. 1956 10 463; Adv. Catalysis 1959 11 301. 23 M. Calvin Trans. Furaday SOC. 1938,34,1181; J. Amer. Chem. SOC. 1939,61,2230. 24 S. Weller and G. A. Mills J. Amer. Chem. Soc. 1953 75 709; L. W. Wright and and Sons New York 1958 p.333. S. Weller ibid. 1954 76 3345. BACON AND HILL COPPER-PROMOTED REACTIONS 101 transition Indeed p-benzoquinone appears to be the only organic compound for which copper has been demonstrated to function as a homogeneous-hydrogenation catalyst; even tetrachloro-p-benzoquinone failed to be reduced owing it was suggested to strong bonding with copper preventing access of hydrogen to the In spite of this severe limitation the reduction of benzoquinone is of interest for this Review as an example of copper-catalysed hydrogen transfer discussed in Sections (e) and(f). In this respect it represents an extremecase molecular hydrogen being a donor of low activity and high specificity compared with some of those donors which are highly effective for substitutive reduction processes of type (iii) discussed in later Sections.Moreover present experience suggests26 that donors which are effective for these copper-catalysed substitutive reductions are not assisted by copper catalysis in the additive reduction of unsaturated compounds such as quinones. Homogeneous hydrogenation also provides a good example of some of the generalisations which were made (p. 96) concerning copper-promoted reactions. Thus reduction systems may contain the species copper(rI) dimeric or monomeric copper(I) and copper(o) among which copper(1) species appear to be the most effective; the rate of reaction is highly de- pendent upon the nature of anions solvent or complexing agents in the system; reduction is considered to proceed by a heterolytic or homolytic route depending on circum~tances.~~,~~ The following representation of the heterolytic process shows transfer of hydride ion to copper and assistance by an organic basic solvent which combines with a proton Cu2+ + H + B + CuHf + BHf CuHf + Cu2+ + B + 2Cuf + BH+ Cu+ + H + B + CuH + BHf O:C,H,:O + CUH + BHf -+ HOC,H,*OH + CU+ + B (b) Reductive Coupling of Halides.-The production of biarylsl by the Ullmann coupling process 2ArHal + 2Cu -+ Ar-Ar + 2CuHal dates from F.Ullmann’s investigations in 1901. The term “Ullmann reaction” is also applied to copper-catalysed condensations of aryl halides with phenols or amines (p. 122) which he investigated later. The coupling reaction is frequently a good method for preparing symmetrical biaryls and is sometimes successful for conversions of mixed halides into unsymmetrical biaryls; it has been applied to some hundreds of mono- 26 J.Halpern J. F. Harrod and B. R. James J. Amer. Chem. SOC. 1961 83 753; J. Kwiatek I. L. Mador and J. K. Seyler ibid. 1962 84 304; R. D. Gillard J. A. Osborn P. B. Stockwell and G. Wilkinson Proc. Chem. SOC. 1964 284. R. G. R. Bacon S. C. Rennison and 0. J. Stewart unpublished investigations. 27 M. Parris and R. J. P. Williams Discuss. Faraday Soc. 1960,29,240; W. J. Dun- ning and P. E. Potter Proc. Chem. SOC. 1960,244. 102 QUARTERLY REVIEWS cyclic or polycyclic aryl halides and heteroaromatic ha1ides.l It can be used in the ferrocene series.28 All these preparations constitute a subdivision of the broader area of halide-metal interactions which have often been discussed as examples of hornolytic processes; on the other hand it has long been recognised that ionic intermediates may also be involved.29 There have been advocates both of a homolytic inte~pretation~~g~l of the Ullmann coupling reaction and of a heterolytic interpretati~n.lt~~ Several features of the process were discussed by who examined substituent effects for normal and abnormal courses of reaction in symmetrical and unsymmetrical Ullmann coupling.One of his inve~tigations~~f concerned the relative ease of forma- tion of symmetrical or unsymmetrical biaryls Ar.Ar or Ar.Ar‘ in mix- tures containing a reactive halide ArHal and a less reactive halide Ar’Hal; he considered that the results were best explained by a heterolytic react ion mechanism. If depicted as in discussions of reactions of gaseous alkyl halides on metal decomposition of liquid aryl halide on a copper surface would follow the path (a) shown in the annexed scheme; chemisorption here involves association with the metal through the halogen atom and accession of two electrons from the lattice giving a copper halide and copper aryl.The latter might then react heterolytically with further aryl halide as in ( d ) to give the biaryl. The copper(1) can serve to activate the halogen of the aryl halide as in copper-catalysed substitutions. Altema- tively the bond-breaking process occurring in chemisorption might involve successive accession of single electrons as in (b) and (c) giving an inter- mediate aryl radical; the pairing of radicals might then also give the biaryl as in (e). 3‘ H:I Ar-Hal (a) .1 -+ I 1 cu cu /CU cu /(4 \(4 (+ ArHal) \ ( b ) l I (pairing of cu cu radicals) Ar.Hal/ I -+ Ar-Ar + 2CuHal (4 This mechanistic distinction may however be too rigid since the postul- ated copper aryl is a thermally unstable species and can be regarded as a source of either aryl radicals or ions Ar. + Cu + Ar-Cu + Ar-Cu+ 28 M. D. Rauscli J. Org. Chem. 1961 26 1802. 29 W. A. Waters “The Chemistry of Free Radicals,” Clarendon Press Oxford 1948. 30 W. S. Rapson and R. G. Shuttleworth Nature 1941 147 675. 31 H. E. Nursten J. 1955 3081. 32 M. Nilsson Acta Chem. Scund. 1958 12 537; Svensk. Kern. Tidskr. 1961 73 9. 33 J. Forrest J. 1960 (a) 566 (b) 574 (c) 581 (d) 589 (e) 592 (f) 594. J. S. Campbell and C. Kemball Trans. Furuday Soc. 1961,57,809; 1963,59,2583. BACON AND HILL COPPER-PROMOTED REACTIONS 103 Within the broader area of halide-metal reactions those of the alkali metals are the most extensively studied.Sodium alkyls and aryls are well- known as end products or intermediates but the first step in the reaction is a single-electron transfer to give a radical as was shown more than 30 years ago by Paneth's sodium-flame experiment^^^ and recently by a trapped-radical technique35 at liquid-nitrogen temperature which was effective not only for alkyl halides but also for iodobenzene Phl + Na + Ph. + Na+ + I- There has been no similar demonstration of radical production in reactions of copper with halides. Phenylcopper(~)~~ results from the reaction PhMgBr + CuI -+ CuPh + MgBrI and is reported to be spontaneously oxidised to biphenyl and copper oxide by air. Good yields of biphenyl or bi- l-naphthyl were obtained by heating the appropriate copper(1) aryls (made from lithium aryls) in toluene under nitr~gen.~' This decomposition may proceed through aryl radicals CuAr + Cu + Ar.but if the solvent is not attacked these cannot have much freedom in the system. The reactivity of copper(1) aryls towards aryl halides needs investigation the reaction with alkyl halides CuPh + AlkBr -+ PhAlk + CuBr was reported36 to be moderately successful with ally1 bromide but unsuccessful with n-butyl bromide. The temperature needed for Ullmann coupling reactionsf is commonly around 200" though depending on the reactivity of the halide it may be as low as 100" or as high as 300". High-boiling and relatively inert solvents such as nitrobenzene have sometimes been employed as diluents and dimethylformamide (b.p.153 ") has recently been recommended3* for the more reactive halides such as iodonaphthalene halides of the type C6H4X.Hal (X = NO2 CO,Me Me),38 and iodides of the type O-C,H,ICOR;~~ its value may be due at least partly to its capacity to dissolve copper(1) halide from the surface of the metal. Solvents however are not invariably beneficial since as described in Section (e) they may participate in halide reductions. Comparisons of the reactivity of different aryl halides in Ullmann coupling are available only from yield data and these are rather poorly reproducible. For example yields q ~ ~ t e d ~ ~ ~ ~ for the halides o- m- and p-C6H4Hal.N02 vary by up to 20-30 % and do not always show the same order of reactivity among members of the series. With respect to the nature of the halogen the general trend of halide reactivity is ArI > ArBr > ArCl though there may be a little difference between bromides or 36 J.E. Bennett and A. Thomas Nature 1962 195 995; 6th Symposium on Free 38 H. Gilman and J. M. Straley Rec. Trav. chim. 1936 55 821. 37 R. G. R. Bacon and H. A. 0. Hill unpublished investigations. 38 N. KornblumandD. L. Kendall J. Amer. Chem. Soc. 1952,74,5782. 39 R. G. R. Bacon and W. S. Lindsay J. 1958 1375 1382. 40 W. Davey and R. W. Latter J. 1948 264. 41 P. H. Gore and G. K. Hughes J. 1959 1615. Radicals Cambridge 1963. 104 QUARTERLY REVIEWS iodides of the more reactive types; coupling of aryl fluorides is unknown. The strong activating effect of an electron-attracting group in an ortho- position has long been known; e.g.potassium o-bromobenzoate under- went Ullmann coupling in water at 90-100°.42 In a study of 26 sub- stituted ha loge no benzene^,^^^ Forrest observed that NOz or C0,Me groups were strongly activating in the ortho-position but not in meta- or para-positions ; this was also found with more weakly electron-attracting groups such as CN; moderate activation occurred with the electron- donating OMe group and also with CH3 and C1 and in all three cases these effects were similar in ortho- meta- and para-positions. Such obser- vations illustrate the marked differences in substituent effects which are generally observed between copper-promoted replacements of aryl halides and e.g. their reactions with alkali-metal salts or other nucleophils ; distinctive reaction mechanisms are thus indicated.It is conceivable that the particularly strong effect of some ortho-substituents may be due to their capacity to associate with the metal and thus to facilitate reaction with neighbouring halogen i.e. there may be a resemblance to the “built- in solvation” effect discussed by B ~ n n e t t ~ ~ for other reactions of aryl halides with ortho-NO or -CO,R substituents. Although in favourable cases the yields of symmetrical biaryls may attain 70-90% in Ullmann coupling they are frequently much lower owing to incomplete reaction or to the formation of identifiable or resinous by- products. The most important side reaction is the substitutive reduction ArHal -+ ArH discussion of which is deferred until Section (e). A second type of reaction is substitution between the halide and a suitable aromatic compound which may be present ArHal + Ar’H + Ar-Ar’ This result was attributed30 to attack by aryl radicals in the case of iodo- benzene and ethyl benzoate which formed some ethyl 2- and 4-biphenyl- carboxylate.More complicated substitutions have been o b ~ e r v e d ~ ~ ~ between iodobenzene or substituted iodobenzene and rneta-dinitro- compounds which thereby became linked at the position between the nitro-groups giving biaryls of types (I) and (11) here shown for the simplest members of the series each being obtained in yields of up to 12% PhI + 42 W. R. H. Hurtley J. 1929 1870. 43 J. F. Bunnett Quart. Rev. 1958 12 1. BACON AND HILL COPPER-PROMOTED REACTIONS 105 The compound (11) presumably results from copper-catalysed reduction of NOz to NH2 by hydrogen from an organic donor or hydrogen iodide followed by catalysed arylation of the amino-function.A third variety of side reaction may occur if more than one kind of halogen atom is present in the system. This is a halogen-transfer (see p. 120) between an aryl halide and a copper(1) halide produced in the coupling; nuclear bromine may thus be replaced by chlorine nuclear iodine by bromine or chlorine. In one example the side-reaction o-C6H4ClI + o-C6H,C12 only to the extent of 5 % but replacement of iodine by bromine has been observed33d in yields of up to 50% from mixtures of substituted halides of the types C,H,XBr and C6H4YI. Fourthly there may be side reactions such as copper-induced decarboxyla- tion of C0,I-I groups and condensation of a halide with compounds con- taining phenolic or amino-groups.More obscure in origin are the di- benzofurans which have been detected as by-products in reactions of o-chloroi~dobenzene~~ and of l-bromo-2-iodo-4,5-dimethoxybenzene,45e though they could be formed by internal condensation of halogenohy- droxybiphenyls water being the source of the phenolic group. Copper([) salts produced in the Ullmann coupling appear to be ineffective in the further reaction 2ArHal + 2Cuf -+ Ar.Ar + 2Cu2+ + 2Hal- There is a method of coupling salts of iodosulphonic acids with aqueous copper sulphate and copper,44 which could conceivably involve CuI species but the chemistry of this system has not been investigated. With reactive types of aryl halides coupling to the extent of 5-15% has lately been effected with cuprous oxide.26 The most important application of this oxide as a coupling agent is in the preparation of biphenylenes.These difficultly accessible compounds are obtained e.g. in 10-40% yield by briefly heating oo'-di-iodobiaryls with a large excess of the oxide at about 350". The final stages of a synthesis of the parent compound (111) are as follows This process has been developed by Baker McOmie and their co- w o r k e r ~ ~ ~ and by Cava and his co-w~rkers,~~ following an earlier investiga- 44 H. J. Barber and S. Smiles J. 1928 1141 ; W. M. Cumming and G. D. Muir J. Roy. Tech. Coil. Glasgow 1937 4 61. 46 W. Baker J. F. W. McOmie et al. J. (a) 1954 1476; (b) 1958 2658; (c) 1961 3986; (d) 1963 922. 46 M. P. Cava and J. F. Stucker J. Amer. Chem. SOC. 1955,77,6022. 106 QUARTERLY REVIEWS tion by Lothrop4' who found copper metal to be ineffective.However analogous cyclisations giving a biphenylene or triphenylene have been detected as side reactions between copper and certain o - d i h a l i d e ~ ~ ~ ~ ~ and have been attributed to the polymerisation of benzyne intermediates. The Ullmann coupling reaction is remarkably specific to compounds in which the halogen is attached to a benzenoid or aromatic-type heterocyclic nucleus and appears to have little applicability to alkyl or monoarylalkyl halides. On the other hand diarylalkyl halides are highly responsive. Recent investigations2* show that the reaction 2Ph2CHBr -+ Ph,CHCHPh is effected practically quantitatively with many metals and particularly readily with copper or silver and that it also succeeds with copper(1) compounds.Similarly a diarylalkyl dihalide gives the olefinic coupled compound with copper as in the reaction49 2Ph,CC12 -+ Ph,C:CPh,. ( c ) Reductive Coupling of Organosulphur Compounds.-The coupling of aromatic compounds containing bivalent sulphur functions has been less investigated than the coupling of halides but it appears to proceed much less readily. The following four e~arnples~O-~~ show the reaction of copper with XS- substituted aryl compounds of suitable structure and also with aryl compounds containing a-thio-groups ArS-SAr or Ar.SCN -+ Ar-Ar (Ar = 1-anthraquinonyl) Ar-SH -+ Ar*Ar(60%) + ArH(250/b) + Cu,S + H (Ar = 9-acridyl) (ArCHS) -f ArCH:CHAr (20-700/;) (Ar = C6H5 C6H,X CloH7 etC.) Ar,CS + Ar,C:CAr (75-90%) (Ar = C,H5 C,H,X etc.) Closely related to these intermolecular reactions are the intramolecular ring-contractions which occur with extrusion of sulphur when certain polycyclic compounds are heated with copper e.g.in boiling quinoline or diethyl phthalate. The following examples (partial structures shown) from the papers of Loudon and his c o - ~ o r k e r s ~ ~ show the formation of a phenanthrene (IV) and a phenanthridine derivative (V) 47 W. C. Lothrop J. Amer. Chem. SOC. 1941 63 1187. 49 Org. Synth. 1951 31 104. 6o E. Kopetschni G. P. 360,419 and 362,984. 61 K. Lehmstedt and H. Hundertmark Ber. 1930,63 1229. 52 J. H. Wood J. A. Bacon A. W. Meibohm W. H. Throckmorton and G. P. Turner 63 A. Schonberg 0. Shutz and S. Nickel Ber. 1928,61 1375. 64 I. D. Loudon et al. .I. 1957 3814 3818; 1958 1588; 1959 885. E. R. Ward and B. D. Pearson J. 1961 515.J. Amer. Chem. SOC. 1941 63 1334. BACON AND HILL COPPER-PROMOTED REACTIONS 107 Partial extrusion of sulphur from a disulphide bridge55 may give a Reaction of sulphur compounds in quite different circumstances is thiophen derivative (VI) recorded5s for the coupling process with sulphonyl chlorides which is effected by heating and is regarded as homolytic in character; copper(1) salts are catalysts. ArS0,CI + ArH -+ Ar.Ar’ + SOz + HCI (d) Reductive Coupling of Diazonium Salts.-Diazonium salts are highly susceptible to Sandmeyer-type substitution reactions,2 promoted by copper or copper(1) compounds in aqueous solution. Reductive coupling is also a copper-promoted reaction but requires closely defined experi- mental conditions since it is subject to competition from substitution.It is further complicated by the possibility that the loss of nitrogen is either complete or partial leading to a biaryl or an azo-compound respectively. The result in summary is that ArN2+ may give Ar-Ar ArN:NAr ArX or ArH. Observations on the coupling reactions213 were first made in the 19th century. The preferred technique originating with Vorlander and Meyer and developed by Atkinson and his co-w~rkers,~~ consists in treating the diazonium salt solution according to a prescribed mixing procedure with a suitable copper reagent. The latter may consist of an equimolar quantity of freshly precipitated copper(1) oxide suspended in aqueous ammonia or an aqueous solution presumably containing Cu(NH3) 2+ ions prepared by reducing a copper(r1) salt in the presence of ammonia with hydroxylamine sulphur dioxide or a ferrous salt; an ammoniacal suspension of copper is an alternative reagent.57 Little is known concerning reaction mechansims or changes occurring in the copper species.It is considered that the latter functions reductively ; i.e. the overall change is theoretically 2ArN,+ + 2Cu+ -+ Ar.Ar + 2CuZ+ + 2N Known substituent effects are similar to those discussed for the coupling of halides in the sense that an electron-attracting substituent particularly in an ortho-position favours biaryl production. The reaction has been most successful (40-90 % yields) with diazotised o-amino-carboxylic acids of the benzene series,57 and with corresponding ~ r t h o - ~ * or 1 ,8-compounds2 of the naphthalene series. An o-SO,H group has led to a biaryl; 0- m- or p-NO gave mainly a biaryl but also an azo-compound; with no sub- stituents or with substituent CH,- OH- or NHAc-groups only azo- compounds have been obtained.57 By-products ArC1 ArOH ArOAr 6s P.J. Bain E. J. Blackman W. Cummings S. A. Hughes E. R. Lynch E. B. McCall and R. J. Roberts Proc. Chem. Soc. 1962 186. 67 E. R. Atkinson et al. J. Amer. Chem. Soc. 1940,62 1704; 1941,63,730; 1943,65 476; 1945,67,1513; 1950,72,1397. 68 R. G. R. Bacon and R. Bankhead J. 1963 839. W. L. F. Armarego J. 1960,433. 108 QUARTERLY REVIEWS A r m 2 or Ar,NH may result from competitive substitutions. Un- symmetrical biaryls have been obtained from mixtures of diazotised o-aminocarboxylic and azo-linked polymers are preparable from tetrazo-c~mpounds.~~ A variation on biaryl formation is displayed when copper metal acts as an electron donor for both ArN2+ and Hg2+ in the addition compound of a diazonium chloride and mercury(r1) chlorides ;60 this produces a mercury diaryl 2ArN,+ + 2Hg2+ + 6Cu + Ar.Hg.Ar + Hg + ZN + 6Cu+ (e) Substitutive Reduction of Halides.-Processes described in the literature for effecting reductions of the type ArHal -+ ArH usually involve metal hydrides or various hydrogen donors in association with metal catalysts.Biaryl formation is sometimes a competing reaction. On the other hand when the Ullmann coupling method is used to prepare biaryls substitutive reduction is sometimes a side reaction; this is also the case in preparations of diaryl ethers or diarylamines by the Ullmann method (p. 122). Recent investigations have shown26*61*62 that when hydrogen donors and experimental conditions are suitably chosen copper- catalysed substitutive reduction of halides becomes a major reaction.For specific acceptors hydrogen transfer i s thus emerging as an important feature of copper chemistry. Aryl halides and certain other types of halides constitute the main group of acceptors but some sulphur compounds and diazonium salts are also responsive. Individual ary 1 halides differ very widely in their capacity for reduction and this feature needs further investigation. When the response of acceptors to catalysed reduction is being assessed control experiments are necessary in view of the possibility of some degree of non-catalysed donor-acceptor interaction which is not always predictable from the literature. A great variety of donors may be used; the following sub-sections deal with three types which have been investigated.Carboxylic acids and their derivatives as donors. This was first exempli- fiedg3 by the conversion of ortho-nitro-halides into the corresponding dehalogenated nitro-compounds with copper as catalyst in molten benzoic acid or in hexanoic acid at 150-200"; the carboxyl group was assumed to be the source of hydrogen. A later in~estigation~~ showed that a less reactive halide such as bromonaphthalene was reduced by a mixture of cuprous oxide acetic anhydride and pyridine ; carboxylic hydrogen was again thought to be involved but its source was not obvious. This process 68 A. A. Berljn V. I. Liogonkii and V. P. Parini J. PuZymer Sci. 1961,55 675. 8o E.g. Urg. Synth. Coll. Vol. 11 381. 61 R. G. R. Bacon S.C. Rennison and 0. J. Stewart Pruc. Chem. SOC. 1964 409. e2 R. G. R. Bacon and H. A 0. Hill J. 1964 1112. 63 W. T. Smith J. Amer. Chem. SOC. 1949,71,2855; W. T. Smith and L. Campanaro 84 W. G. H. Edwards and R. G . Stewart Chem. and Ind. 1952,472; W. G. H. Edwards ibid. 1953 75 3602. and G. K. McIndoe ibid. 1953 1091. BACON AND HILL COPPER-PROMOTED REACTIONS 109 has proved useful in a ~ynthesis.~~ In a recent study,62 1-bromonaphthalene was converted into naphthalene in pyridine with copper@ acetate or with a reacting mixture of cuprous oxide with acetic acid monofluoroacetic acid acetic anhydride or hexadeuteroacetic anhydride. Since with the last- named reagent about 70 % of the product was deuteronaphthalene the major source of the transferred hydrogen is clearly an a-carbon atom.Decarboxylation simultaneously occurs and the process has tentatively been represented as involving transfer of hydride ion by a cyclic process within a halide-copper(1) salt complex; the carbene postulated as a decomposition product may be the precursor of the tars which are pro- minent in these reactions r( Ar - Br-Cu H -%-CO’ \J 1 20 Formic acid undergoes catalysed Ar CuBr H :CH2 CO - I decarboxylation at a low temperature and is ineffective as a reductant but formate ion has moderate activity as a donors1 and can plausibly be considered to function by copper-catalysed hydride-ion transfer ArHal + H-CO,- + ArH + Hal- + CO The observationg2 that benzoic anhydride also caused reduction suggests that aromatic nuclear hydrogen can be transferred to an acceptor. With o-chlorobenzoic anhydride or a-chlorinated acetic acid derivatives bromo- naphthalene was converted into chloronaphthalene.This suggests that chlorine may likewise be transferred but the results are ambiguous because any copper@ chloride produced by decomposition of these acid derivatives would cause the same substitution (p. 120). Alcohols amines and alkoxides. An old patented processgg for reducing picryl chloride to 1,3,5-trinitrobenzene included the use of copper and an aliphatic alcohol. This is an exceptional case and recent experiences1 suggests that an easily dehydrogenated alcohol such as diphenylmethanol is needed for the reduction of moderately reactive halides such as l-bromo- naphthalene and the yield even so is low. Amines appear to be a good deal more effective than alcohols,g7 and with cuprous oxide e.g.in boiling collidine they effect reduction in competition with substitution e.g. -+ Ar-NHCH,R (CU20) ArHal + RCH2.NHz - -+ ArH + HHal + RCH:NH J- (W) RCHO + NH 86 R. D. Topsom and J. Vaughan J. 1957 2842. 68 J. Meyer German P. 234,726. 87 R. G. R. Bacon and 0. J. Stewart J. 1965 in the press. 2 110 QUARTERLY REVIEWS Alkoxides are much more effective than alcohols in catalysed hydrogen transfer. An example appearede8 in an examination of the reaction system l-CloH7Br-NaOMe-Cu20-H*CO~NMe2(solvent) which produced both naphthalene and the expected 1-methoxynaphthalene. Further investigation28,81 has shown reduction of aryl halides to be a general reaction of primary or secondary alkoxides occurring e.g. in refluxing collidine or dirnethylacetamide in the presence of cuprous oxide or copper.With alcohols or amines as donors there is uncertainty concerning whether the reaction is homolytic or heterolytic but reduction by an alkoxide can reasonably be represented as transfer of a hydride ion to the halide which may be activated by association with the copper f v Ar Hal-Cu Ar- Hal - Cu’ +I - I H - CRR’ H CRR’ I II C0- 0 Proof of the transfer of a-hydrogen requires deuterium or tritium labelling as has already been doneeQ for the related uncatalysed reaction ArN,+ + CHRR’sOH -+ ArH + H+ + CORR’ The observations1 that t-butoxide ion is a reductant indicates that P-C-H bonds may also be utilised. These results have prompted examination of copper@ hydride as a reductant. It is an unstable even at room temperature and has proved ineffective with aryl halides,62 probably because of loss of hydrogen before the temperature needed for reduction had been attained.Nevertheless its existence suggests that interactions of the type CU+ H- + CU-H + CU H. are significant in copper-catalysed hydrogen transfer. Aromatic compounds as donors. Observations reported from time to time that dehalogenated compounds are by-products of Ullmann coupling reactions indicate that some of the aromatic halide molecules are acting as hydrogen donors for other halide molecules. For example reduction has been found to varying extents with o-bromobenzoic acid,’* o-iodo- carbonyl compounds,39 1 -iodo-2-methylnaphthalene and methyl 1-bromo- 2-na~hthoate.~~ Reduction has also been observed when tetralin was used as s~lvent,’~ and when catechol or resorcinol were presents1 in Ullmann coupling reactions.Extensive reduction occurred in Ullmann-type 68 R. G. R. Bacon and H. A. 0. Hill J. 1964 1108. 69 L. Melander Arkiv Kemi 1951 3 525; A. F. Rekasheva and G. P. Miklukhin 7 0 E. Wiberg and W. Henle 2. Naturforsch. 1952,76 250. 71 R. W. Hardacre and A. G. Perkin J. 1929 180; M. S . Lesslie and E. E. Turner Doklady Akad. Nauk S.S.S.R. 1951,80,22l;Zhur. obshchei Khim. 1954,24,96. J. 1932,281. BACON AND HILL 1 COPPER-PROMOTED REACTIONS 1 1 1 preparations of complex diary1 ethers containing carboxyl groups,72 and also when phenols containing nitro or carboxyl groups were used in reac- tions with aryl halides and cuprous There are numerous cases of reduction occurring as a side reaction in Ullmann amination processes used in syntheses of acrid one^'^ (p.123). Recent investigations26~s1 reveal a widespread capacity of aromatic species to act as donors for halides e.g. in refluxing collidine or dimethyl- acetamide containing a suspension of cuprous oxide or copper. Depending on the activities of the donor and acceptor molecules reduction may vary from less than 10 % to more than 80 %. Donors include phenols quinones amines hydrazino-compounds hydrazo-compounds and nitro-com- pounds and the source of hydrogen may be either the nucleus or a sub- stituent group. This is illustrated by the following examples in which the origin of the transferred hydrogen atoms is shown by the nature of the isolated dehydrogenated products ; these are detected particularly readily when an active acceptor such as o-bromonitrobenzene is employed.The products (VII) and (VIII) are the result of the oxidative coupling of phenols hydrogen having been lost from a para-nuclear position and a para- methyl group respectively; the other two cases show the loss of hydrogen from a hydrazo- or hydrazino-group. PhNH-NHPh -2H_ PhN:NPh These dehydrogenation products are identical with those obtained when the donors participate in oxidations e.g. by transition-metal ions which are regarded as homolytic in character. Hence it is possible that these copper-catalysed hydrogen transfers involve atoms rather than ions. Observed side reactions are production of the biaryl ArSAr catalysed substitution of the halide by a nucleophilic donor and catalysed oxidation of the donor if air is present. There are indications that molecules contain- ing pyridine rings may also serve as donors; this may complicate their use (a) H.King J. 1939 1157; (b) W. M. Whaley L. Starker and M. Meadow J. Org. Chem. 1953 18 833. 73 R. M. Acheson “Acridines,” Interscience Publishers New York 1956 p. 148. 112 QUARTERLY REVIEWS as ~ o l v e n t s . ~ ~ g ~ ~ Indeed it appears that very numerous variations may be made in the nature of the reductant. In one example,7s a redox reaction between a copper(I1) salt and ascorbic acid or inorganic reductants resulted in conversion of o-iodobenzoic acid into benzoic acid. cf) Substitutive Reduction of Other Types of Aromatic Compounds.- Apart from halides diazonium salts provide the chief class of aromatic compounds for which copper species are known to catalyse substitutive reduction ArN,+ -+ ArH.This is a much easier process than reduction of halides and several methods for effecting it have been discussed in R e v i e ~ s . ~ t ~ ~ Alcohols particularly ethanol have a long history of applica- tion as reductants but suffer from the important defect that the production of an ether is a competitive and often dominant reaction -+Ar.OC,H + Hf + N (C2H6.0 H) ArN,+ -+ArH + CH,CHO + Hf + N The best examples of reduction with ethanol generally involve diazonium salts containing nitro- carboxylic or halogeno-substituents. The reactions can be aided by copper species and about 20% of the reductions by ethanol tabulated by K ~ r n b l u m ~ ~ were effected in the presence of copper powder cuprous oxide or copper sulphate. The most generally satis- factory reductant for diazonium salts is hypophosphorous acid." Its reaction was found to be catalysed by several inorganic species including copper metal and copper(@ salts; a free-radical chain mechanism was p~stulated.'~ There is very little information about the copper-promoted reduction of nitrogen-containing compounds other than diazonium salts.Dissolution of cuprous oxide in concentrated sulphuric acid containing p-chloronitro- benzene gave a good yield of p-~hloroaniline.~~ This method which prob- ably involves copper(1) sulphate has also been used for the substitutive reduction of diazonium Little is known also concerning the response of sulphur-containing functional groups. When 2,6-dimethylphenol was examined as a hydrogen donor for 1 -nitr0-2-thiocyanatobenzene,*~ in conjunction with cuprous oxide (as for aryl halides) the following reactions were observed 2Ar.SCN -+ ArS-SAr -+ ArSAr 74 R.G. R. Bacon and H. A. 0. Hill J. 1964 1097. 7s M. Anbar S. Guttmann and C. Friedman Proc. Chem. SOC. 1963,lO. 76 N. Kornblum Org. Reactions 1944 2 262. 77 N. Kornblum and A. E. Kelly Science 1953,117,379; N. Kornblum G. D. Cooper 7a G. C. Finger and R. H. White J . Org. Chem. 1958 23 1612. 7 9 H. H. Hodgson and H. S. Turner J. 1942 748; H. H. Hodgson and S. Birtwell and J. E. Taylor J. Arner. Chern. Suc. 1950,72 3013. J. 1943 433. BACON AND HILL COPPER-PROMOTED REACTIONS 113 Oxidation processes Oxidation of aromatic compounds can be effected by copper(I1) com- pounds occasionally by copper(m) and often by copper(1) or copper(i1) acting in conjunction with various oxidants.As in other aromatic oxidation processes the substrate may undergo dehydrogenation dehydrogenative coupling and various kinds of oxygenation and a mixture of products often results. The classification of reactions used below is therefore some- what arbitrary. The discussion does not include such side-chain reactions as the dehydrogenation of benzoin to benzil,sO or the coupling of phenyl- acetylene to diphenyldiacetylene,sl exemplifying characteristic effects of copper which are not confined to the aromatic series. Biaryl- or Polyaryl-formation by Oxidative Coupling.-The following are coupling reactions of diverse type in which the use of copper compounds is a common feature. (a) Salts of copper(r1) and of some other transition metals oxidise solutions of Grignard reagents causing a coupling of the aryl group; biaryls may then be obtained in 80-90 % yield.82 This effect can plausibly be represented as a single-electron transfer to the aryl carbanion followed by pairing of the resulting radicals Ph-MgBr+ + Cu2+ -f Ph.+ MgBr+ + Cu+; 2Ph. -+ Ph-Ph (6) When no other reagents are present an aqueous copper(r1) salt solution is an inadequate oxidant for the aromatic ring even for com- pounds as reactive as phenols. Under more drastic conditions i.e. by employing a copper@) salt in an excess of a molten phenol at 180-220” smooth oxidation occurss3 giving good yields of nuclear-linked dimers and trimers provided that one or two of the reactive positions are blocked by alkyl groups. Thus p-cresol gave the dimer (IX) and the trimer (X) together with Pummerer’s ketone.These are well-known effects of phenol oxidations by transition-metal ions and occur through phenoxy-radical~.~~ m m Me Me (IX) Me Me Me. (X) (c) A special facility for displacement is found in a boronic acid group attached to a benzene ring. Oxidation by copper@) acetates5 gives a biaryl Org. Synth. Coll. Vol. I 80. G. Eglinton and A. R. Galbraith J. 1959 889. 82 M.,,S. Kharasch and 0. Reinmuth “Grignard Reactions of Nonmetallic Sub- stances Constable and Co. London 1954 ch. 5; E. Sakellarios and T. Kyrimis Ber. 1924 57 322. 83 W. W. Kaeding J. Org. Chem. 1963 28 1063. W. A. Waters “Mechanisms of Oxidation of Organic Compounds,” Methuen and Co. London 1963. 2. Holzbecher Chern. Listy 1952,46 17. 114 QUARTERLY REVIEWS by coupling whilst phenol-formation by oxygenation is a competing process ; the overall reactions are 2Ar*B(OH) + ~CU(OAC) + 3H,O Ar.B(OH) + 2Cu(OAc) + 3HaO 4- Ar.OH + 4AcOH + CU,O + B(OH) Ar-Ar + 4AcOH + Cu,O + 2B(OH) The following mechanism may be suggested Ar- Ar .f (coupling) Ar.+ B(OH) + Cu+ + H+ Ar-B(OH),,H,O + Cu2++ 5. Pa+) J. (HP) Arf + Cu+ ArOH + Hf Similar results are founds6 with ferroceneboronic acid. (d) Progressive nuclear coupling probably giving larger polymers than trimers such as (X) can be achieved8' by treating benzene with the mixed reagent A1C13-H20-CuCl, in which the Lewis acid is believed to cause cationic additive polymerisation and the copper(I1) causes de- hydrogenation giving a para-polyphenyl AICI + H,O 3 AICI,(OH)- H+ (followed by similar steps and terminated by loss of H+) In connection with this reaction the existence of the complexlo C,H,,AlCl,,CuCl is of interest.(e) Another method of polyrnerisations8 involves treatment of a 2,6- disubstituted phenol with a mixture of oxygen and copper([) chloride in a heterocyclic base such as pyridine. This process yields polyethers by seA. N. Nesmeyanov V. A. Sazonova and V. N. Drozd Doklady Akad. Nauk. P. Kovacic and A. Kyriakis J. Amer. Chem. SOC. 1963 85 454; P. Ksvacic and A. S. Hay J. Polymer Sci. 1962 58 581 ; G. F. Endres and J. Kwiatek ibid. S.S.S.R. 1959 126 1004. J. Oziomek J. Urg. Chem. 1964,29 100. p. 593; G. F. Endres A. S. Hay and J. W. Eustance J. Urg. Chm. 1963,28,1300. BACON AND HILL COPPER-PROMOTED REACTIONS 115 C-0 coupling in competition with formation of the dimeric dipheno- quinone by C-C coupling C-0 coupling is favoured by high base:copper ratios by lower tempera- tures and by avoidance of sterically hindered bases.It was considered that equilibria in the co-ordination of solvent ligands on a CuII-oxidant species determine these differences in catalyst behaviour CuI*L + L f cu"L,+l A r o w Y O H ) C-C-I in ked product C-0-1 in ked product An investigationS9 of related reactions has suggested that copper- oxygen interaction involves electron-transfer processes such as Such species presumably convert the phenol into phenoxy-radicals which lead to C-C- or C-0-linked products as has been discussed else~here.~* Dehydrogenation Processes.-The following examples illustrate the oxidative action of copper species causing the loss of different kinds of labile hydrogen. (a) Dehydrogenation of a hydroaromatic to an aromatic ring occurred in the case of 9 lO-dihydroanthra~ene,~~ which gave anthracene with copper(r1) chloride or bromide in boiling benzene (cf.p. 119). Under the same conditions toluene underwent dehydrogenative coupling to bibenzyl. (b) A substituent hydrazino-group undergoes the following degrada- tion through a presumed di-imide type of intermediate when treated with hot aqueous copper sulphate ~ C U + + 2nL + 0 + (L,Cu2+),0,2- + 2LnCua+O- 2CG+ ArNH.NH,-ArN:NH + 2Cu+ + 2H+ J. ArH + N Thus the overall effect if the hydrazine derivative is derived as is commonly the case from a reactive halide or diazonium salt is to cause substitutive reduction of the starting material. This process began to be used in the 89 E. Ochiai Tetrahedron 1964 20 1831.D. C. Nonhebel J. 1963 1216. 116 QUARTERLY REVIEWS 19th century76 and there are numerous recent examples in aromatic and heterocyclic chemistry which demonstrate its utility. The results of a studys1 of the oxidation of phenylhydrazine by silver or mercuric oxide suggested that the di-imide intermediate breaks down to aryl radicals. (c) Bradley’s studies of indanthrone chemistryg2 provide several examples of effects of copper and its compounds in catalysing substitutions and substitutive reduction and in causing dehydrogenation of methyl- amino-groups. These oxidations were effected e.g. with copper or copper(r1) acetate in boiling nitrobenzene and led to demethylation and to production of formaldehyde and of a formamidine derivative (XI) which was obtained as a copper(1) complex.The sequence of reactions is suggested in the following simplified scheme t cH20 (d) A complicated reaction has been described for cyanide synthesis 93 which in essence appears to involve the dehydrogenation of an intermediate imine. An aldehyde e.g. benzaldehyde mixed with ammonia in methanol solution is treated with oxygen in the presence of copper@) chloride. The following reaction scheme in which an imine radical is an inter- mediate was suggested PhCHO + NH + PhCH:NH + H,O J. (Cua+) PhCiN + PhCH:NH (DisProPofiionation) PhCH:N. + Cu+ + H+ J. (02) (Cut) PhC iN + HO2. -+ HOZ- + CU’+ Oxygenation Processes.-These are illustrated by reactions occurring (a) in aqueous copper-salt solutions and (b) in the thermal decomposition of copper salts of carboxylic acids. (a) A typical result of an oxidation effected by transition-metal ions in aqueous solution is the conversion of 2,6-dimethylphenol into a mixture of the coupled product (VII) the corresponding diphenoquinone (XII) and the quinone (XIII) n 91 R.L. Hardie and R. H. Thompson J. 1957 2512. 92 W. Bradley J. 1951 2129 2147 2158 2163 2170 2177. 93 W. Brackman and P. J. Smit Rec. Trav. chim. 1963 82 757. BACON AND HILL COPPER-PROMOTED REACTIONS 117 The product (XII) is the result of further dehydrogenation of (VII) formed by dehydrogenative coupling of the phenol and the quinone (XIII) is presumably a similar secondary oxidation product formed from 2,6- dimethylhydroquinone which has arisen by para-hydroxylation of the phenol. Hydroxylation of an aromatic nucleus by an aqueous solution of suitable transition-metal ions Mn+ can be accounted for by a reaction sequence such as ArH + Mn+ -+ Ar.+ M(n-l)+ + H+ Arm + Ma+ -+ Ar+ + M(n-1)' Ar+ + H 2 0 -f ArOH + H+ Aqueous copper sulphate is without action on 2,6-dimethylphenol but the products (XII) and (XIII) result if other oxidants such as sodium persulphate sodium hypochlorite hydrogen peroxide or oxygen are also present.94 It is knowng5 in the case of persulphate and hypochlorite at least that these oxidants convert CuII into CuUI since tervalent copper complexes with the formulae Na,Cu(IO,), 16H,O and Na,Cu(TeO,), 2OH,O are precipitated if the reaction is performed in the presence of sodium periodate or sodium tellurate respectively. In the absence of such complexing agents reactive Cu3+ ions probably effect hydroxylation of 2,6-dimethylphenol as suggested above for the generalised case of transi- tion-metal ions Mn ; they could arise e.g.by the electron-transfer process cu2+ + s,o,2- -f CU3f + so,=- + so*2- Copper(Ir1) is greatly stabilised by periodate ligands and the isolated complex is less active than mixtures of copper@) salts and appropriate oxidants; however it converts 2,6-dimethylphenol into the diphenoquinone (XII)94 and has been used as an analytical reagent for dihydric Oxidation of phenols by CuILO systems are of interest in connection with biological oxidations of the following typeg7 effected by copper- containing oxidases Brackman and Havingags have demonstrated similar effects in the labora- tory by stirring methanolic solutions containing copper(r1) acetate a monohydric or dihydric phenol and a primary or secondary amine such Q4 R.G. R. Bacon and Alia Izzat unpublished investigations. Q6 L. Malatesta Gazzetta 1941 71 467 580; M. W. Lister Canad. J. Chem. 1953 g6 G. Beck Mikruchemie 1951 38 152; cf. D. A. Keyworth and K. G. Stone 97 E.g. J. M. Nelson and C. R. Dawson Adv. Enzymology 1946,4,99; A. B. Lerner g8 W. Brackman and E. Havinga Rec. Trav. chim. 1955 74 937 1021 1070 1100 31 638. Analyt. Chem. 1955 27,833. ibid. 1953 14 73. 1107. 118 QUARTERLY REVIEWS as morpholine in an oxygen atmosphere. Phenol was thus converted into ortho-benzoquinone which then reacted further with the base and oxidant. Details of the Cu11-02 interaction are uncertain (cf. p. 115) but hydrogen peroxide is involved in the suggested reaction sequence which is briefly summarised in the following scheme.Here MH represents morpholine ; one of its functions is to provide ligands in reversible association with copper ions. In the case of similar experiments with naphthols nuclear coupling competed with the oxygenation sequence. The same method of oxidation has been applied to aromatic a~nines.~~ (b) Old observations on the effect of heat on copper salts of aromatic acids have recently been extended in industrial laboratories resulting in a process which in overall effect converts the acid into a phenol.lOOslO1 The acid reacts with an inorganic copper(rr) salt or with copper(r1) oxide at 200-300" the solvent being water or excess of the acid. Carbon dioxide is lost and an ester remains from which the phenol is obtained by hydrolysis. Alternative mechanistic possibilities have been discussed,1o1 but it is agreed that a cyclic bond-breaking process is involved and that the copper(r1) acts oxidatively as in the following representation of the con- version of copper(rr) benzoate into phenyl benzoate and thence into phenol 0 The hydroxyl group enters the ortho-position to the lost carboxyl group; thus o-toluic acid gives rn-cresol whilst rn-toluic acid gives o- and p-cresol.The overall effect on the inorganic material may be to produce a copper(r) salt by the reaction Cu + CuII 3 2CuI. A variation on the process102 consists in heating basic copper(rr) benzoate e.g. in nitrobenzene at 2OO0 G. Engelsma and E. Havinga Tetrahedron 1958 2 289. loo W. W. Kaeding J. Org. Chem. 1961,26,3144; W. W. Kaeding R. 0. Lindblom 101 W. G. Toland J. Arner.Chem. SOC. 1961,83,2507. loa W. W. Kaeding and A. T. Shulgin J. Org. Chern. 1962,27,3551. and R. G. Temple Znd. Eng. Chem. 1961 53 805. BACON AND HILL COPPER-PROMOTED REACTIONS 119 whereby hydroxylation occurs without loss of carbon dioxide giving salicylic acid 0 0 Halogenation by Copper(1r) Chloride or Bromide.-Chlorination or bromination by copper(r1) halides has some affinity with other reactions discussed in this Section since a reduction of the inorganic halide occurs ArH + ZCuHal -+ ArHal -j- HHal + 2CuHal Unlike copper(u) iodide the bromide and chloride dissociate to the copper@ halide and halogen only at high ternperature~.~~~ In solution however they serve as halogenating agents for phenols under mild condi- t i o n ~ ~ ~ ~ and for aromatic hydrocarbons under more drastic condi- tions.Complicating features have been noted; e.g. addition of copper(1) bromide removes an induction period and the presence of traces of water causes halogenation to occur in the side chains of alkylbenzenes instead of in the nucleus. The process is clearly complicated and factors contributing to it may be dissociation of the halide in the solvent 2CuBr + 2CuBr + Br,; heterolytic or homolytic substitution by the halogen with catalysis by copper salts ; complex-formation between the aromatic nucleus and the copper@ halide; and the production of inter- mediate radicals and ions by electron-transfer processes ArH + Cu2+ + Ar. + H+ + Cu+ Are + Cu2+ -+ Ar+ -+ Cu+ and Substitution processes Substitution Reactions of Aryl Halides.-Applications of copper are of two kinds (a) Exchange reactions of the type ArHal + CuX -+ ArX + CuHal occur between the halide and a copper(1) salt in which the ion X may be halide cyanide thiocyanate or organic species such as SAIL SAr or CrCAr.(b) Copper cuprous oxide or other copper compound catalyses reactions of an aryl halide with a nucleophil i.e. ArHal + X-(or HX) -+ ArX + Hal- (or HHal). In processes of type (b) alkali- metal alkoxides phenoxides halides cyanide or other salts may provide the anion X- whilst amines and phenols are the main examples of non- ionic nucleophils HX. These are generally heterogeneous processes loS S. A. Shchukarev and M. A. Oranskaya J. Gen. Chem. U.S.S.R. 1954,24,1889; P. Barret and N. Guenebaut-Thevenot Bull. SOC. Chim. France 1957,409. lo* A. W. Fort,J. Org. Chem. 1961,26 765; E.M. Kosower W. J. Cole G.-S. Wu D. E. Cardy and G. Meisters J. Org. Chem. 1963,28,630. lo6 J. C. Ware and E. E. Borchart J. Org. Chem. 1961,26,2263 2267. 1 20 QUARTERLY REVIEWS though the catalyst commonly goes into solution as reaction proceeds when HX is the nucleophil. It may be supposed that catalysis involves the joint association of the aryl halide and the nucleophil with the surface of the cuprous oxide or other species employed. Haiide exchange. This has been noted as a side reaction in Ullmann coupling p r o c e ~ s e s . ~ ~ ~ ~ ~ It was used preparativelylo6 for obtaining chloro- derivatives of polycyclic quinones from the corresponding bromo- compounds ; reaction with copper(1) chloride was carried out in a-picoline. A of the reaction 1-CloH7Br + CuCl+ 1-Cl0H,C1 + CuBr showed it to occur rapidly and nearly quantitatively in suitable organic solvents at temperatures of the order of 1 10-1 50".It was a second-order reaction and the rate was solvent-dependent 105k at 110" being 0-2 for the heterocyclic bases or benzonitrile 10 for dimethylacetamide 12 for dimethylformamide and 25 for dimethyl sulphoxide. It occurred only with copper salts. It was inhibited by chloride ion by pyridine and more strongly by 2,2'-bipyridyl. It was reversible but with the equilibrium well in favour of formation of aryl chloride. The aryl fluoride did not react and the ease of displacement of the other halogens was ArI > ArBr > ArCl whilst the order of entry of halide from the salt was CuCl > CuBr > CuI. When applied to sub- stituted bromobenzenes XC,H,Br the reaction with copper@ chloride was remarkably insensitive to the substituent X.The p-methoxy- and o- or p-methyl-derivatives reacted at about the same rate as the unsubstituted bromide; the rates with the m- and p-nitro-compounds were respectively only 3 or 5 times as great but a nitro-group in the ortho-position had the substantial effect of increasing the rate about 400-fold. These results are in marked contrast to those from substitutions not involving copper cata- lysis which may show rates increased by lo6 or more when nitro-substi- tuents are present; they often show however similar enhancement of activity by ~rtho-nitro-~~ as compared with para-nitro-groups (cf. p. 104). Discussion of the mechanism is handicapped by lack of information concerning the nature of the solute species in organic solutions of copper(1) salts.It may be supposed that dissolved copper(1) chloride is essentially monomeric and that un-ionised CuCl is associated with up to three solvent- molecule ligands in tetrahedral co-ordination ; solvated ions Cu+L,Cl- may also be present in equilibrium with other species. The preference of copper(1) for polarisable ligands suggests the formation of a complex ArHal+CuClL preceding the substitution reaction. Similar intermediates the formation constants of which should increase in the order ArCl ArBr ArI have been suggested elsewhere for CuX-aryl halide interaction^^^^^^ and for copper-catalysed reactions of amines and aryl halides.73 As in the analogous case of the Sandmeyer reaction,2 views may vary concerning representations of the transition state in the exchange process.Possibilities are a four-centre concerted process (XIV) without definable 106 W. B. Hardy and R. B. Fortenbaugh J. Arner. Chem. SOC. 1958,80,1716. lo7 C. F. Koelsch and A. G. Whitney J. Org. Chem. 1941 6,795. BACON AND HILL COPPER-PROMOTED REACTIONS 121 intermediates; an intermediate iorlisation step (XV) (alternatively the copper halide may already be ionised) followed by nucleophilic displace- ment; and intermediate radical formation (XVI) with the metal alternat- ing between the CuI and CuII state. Br /I /cuLx ArBr + CuCIL + Ar CI Br + CuL / \ or Ar Br Br Br \ + Ar CuL + ArCl + CuBrL ‘af An objection to the intermediate-radical view is that in a reaction with an aryl iodide formation of an iodine-containing bivalent copper species CuIHal is unlikely.The ionic mechanism is attractive in that a positive charge on a substituent is known to increase its lability to nucleophilic attack.los The observed effects of inhibitions and in part at least effects due to solvent molecules are attributed to their competing with the halide ligands for the copper(r) salt. An alternative method of effecting halogen exchangea8 is to treat the aryl halide with an alkali-metal halide or tetra- alkylammonium halide in e.g. boiling dimethylformamide containing a suspension of cuprous oxide; the observed order of halogen reactivity is the same as that noted above. Cyanide formation. The use of copper(1) cyanide in substitutions of the type ArHal + CuCN -+ ArCN + CuHal is a well-established method of preparing aryl and other cyanides ;log early studies of the process were made by Rosenmund and by von Braun.Traditionally a mixture of the re- agents is heated either without solvent or in a heterocyclic base but the method has recently been improved by the use of dimethylformamide or N-methylpyrrolidone as solvents.110 Likewise 1 -cyanonaphthalene was quantitatively obtained74 from l-bromonaphthalene in dimethyl sulph- oxide in 2 hours at 180° as comparedlll with a 90% yield being obtained in quinoline in 15 hours at 215”. The reaction with bromonaphthalene lo8 B. A. Bolto and J. Miller Austral. J . Chem. 1956,9,74. lo@ P. Kurtz in Houben-Weyl “Methoden der Organischen Chemie,” 4th edn. 1952 vol. 8 Part 111 p. 302; D. T. Mowry Chem. Rev. 1948,42,189. M. S. Newman and D. K. Phillips J. Amer. Chem. Soc. 1959 81 3667; M.S. Newman and H. Boden J. Org. Chem. 1961 26 2525; L. Friedman and H. Boden ibid. p. 2522. Org. Synth. Coll. VoI. 111 631. 122 QUARTERLY REVIEWS was slower than the corresponding reaction of the bromo-compound with copper(1) halides. This is in harmony with what has been stated concerning the halide-exchange reactions since the stability constants of copper(1) complexes with cyanide are higher than those with the halides. Ullmann and his co-workers112 found that the reaction ArHal + KOAr' -+ ArOAr' + KHal was catalysed by copper and they described numerous examples of the process; the halide phenol potassium hydroxide and copper ( 4 . 0 2 g.-atom per mole) were heated at -200". The more recent literature113 reports yields of 55-65% with unsubstituted or methyl- or methoxy-substituted reagents and higher yields at lower temperatures when the halide is activated by a nitro- group.The method has given poor results72 when applied to the synthesis of more complex naturally occurring diary1 ethers containing carboxyl groups. In one such in~estigation~~" improvements were made by using copper in the proportion of -1 g.-atom per mole; cuprous oxide also proved effective. Another variation,l14 used for a kinetic investigation consisted in using a small amount of a copper(1r) halide with the aryl halide phenol and potassium hydroxide in diethylene glycol dimethyl ether as solvent; the effective catalyst was considered to be copper@. In a general investigations8 of cuprous oxide as a catalyst for nucleo- philic substitutions of aryl halides this method was found to be effective with either phenol or sodium phenoxide; a suspension of the oxide (1-2 mol.) in boiling collidine or dimethylformamide was used.This process has found application in studies of alkaloid synthesis.115 An evaluation of the methods7 has shown its utility with a wide range of halides and phenols except when the latter are substituted by nitro- or carboxyl groups; under suitable conditions it gives better yields than the traditional Ullmann method. Copper copper(1) oxide and copper@) oxide catalyse the reaction and when phenols are used the catalyst goes into solution as reaction proceeds producing inactive copper halides. Reaction occurs more easily with sodium phenoxides than with phenols. There is a large solvent effect which is not related to the basicity of the solvent.Substitutive reduction is an important side reaction and de- carboxylation also occurs. An example of reductions7 was the partial conversion of o-bromoni trobenzene into nitrobenzene by p-cresol which thus gave the coupled dimer (IX) (p. 11 3) isolated as its di-o-nitrophenyl ether formed by catalysed reaction with the aryl halide. Amination processes. There are only occasional examples in the literaturells of copper-catalysed substitution of the type shorn on p. 109 Formation of diaryl ethers. 11* F. Ullmann and P. Sponagel Ber. 1905 38 2211; F. Ullmann and A. Stein 113 Org. Synth. Coll. Vol. 11,445 Coll. Vol. 111 566; P. A. Sartoretto and F. J. Sowa 11( H. Weingarten J. Org. Chem. 1964 29 977 3624. 116 J. R. Crowder E. E. Glover M. F. Grundon and H. X. Kaempfen J.1963,4578. 118 Keg. J. M. McManus and R. Herbst J. Org. Chem. 1959 24 1042. Ber. 1906 39 622; Annalen 1906 350 83. J. Amer. Chem. SOC. 1937 59 603. BACON AND HILL COPPER-PROMOTED REACTIONS 123 in which the nucleophil is an aliphatic amine. The best-known applica- tions are industrial as in the preparation of N-methylaniline from chloro- benzene for which copper(1) chloride is the best of various catalysts examined.l17 More important in the laboratory are the applications arising from Ulhann's discovery118 that small amounts of copper catalyse the condensation of aniline with o-chlorobenzoic acid giving diphenylamine- 2-carboxylic acid from which acridone can be prepared n The process is carried out in the presence of a base usually potassium carbonate and can alternatively be applied to mixtures of o-amino- carboxylic acids and aryl halides.This provides a standard route to acridine compounds and has been reviewed in detail by A c h e s ~ n ; ~ ~ side reactions are reduction or coupling of the halide and tar formation. Analogous processes have been developed for the synthesis of pheno- thiazines and phenoxazines.llD Copper-catalysed condensation of an aryl halide with an N-acetylarylamine is known but has been little investigated; oxygen may be involved at some stage in this reaction.120 Other substitutions of halides. Apart from the Ullmann-type prepara- tion of diary1 ethers other examples of substitution by oxygen-containing groups have occasionally been reported. Acetate ion for example reacts with o-halogenobenzoic acids in the presence of coppeT"12J21 giving after hydrolysis salicylic acid.The use of sodium alkoxidess8 and copper catalysts to introduce alkoxy-groups is limited by the marked tendency of reduction to occur (p. 109). It is relevant to refer here also to observations of catalysis by copper salts in decompositions of iodonium salts such as Ar21+ + H,O 3 ArOH + Arl + H+ which have been extensively studied. One of the mechanisms discussed for this catalysis122 involves an oxidation-reduction cycle in the copper ion somewhat similar to that shown in (XVI). As would be expected from the strong bonding of sulphur-containing ions to copper the exchange reactions of copper(1) thiocyanate or thio- phenoxide with bromonaphthalene in organic solvents are slower than those of copper(1) halides.74 Good yields of organic sulphides have been 117 E.C. Hughes F. Veatch and V. Elersich Ind. Eng. Chem. 1950,42,787. 118 F. Ullmann Ber. 1903 36 2382. llS H. Gilman et al. J. Amer. Chem. SOC. 1944 66 888; J. Org. Chem. 1958 23 1903; A. J. Saggiomo P. N. Craig and M. Gordon ibid. p. 1906; G. E. Bonvicino L. H. Yogodzinshi and R. A. Hardy ibid. 1961,26,2793. 1x1 1'. E. Weston and H. Atkins J . Amer. Chem. SOC. 1928,50,859. 121 K. W. Rosenmund and H. Harms Ber. 1920,53,2226. 122 M. C. Caserio D. L. Glusker and J. D. Roberts J. Amer. Chem. SOC. 1959 81 337; F. M. Beringer E. M. Gindler M. Rapoport and R. J. Taylor ibid. p. 351. 124 QUARTERLY REVIEWS obtained however e.g. at 200" in quinoline by reaction of aryl halides with copper(r) salts of alkane- or arene-thiol~,~~~ or by reaction of the halides with sodium salts of thiols in dirnethylfonnamide in the presence of cuprous oxide.74 Another variation in procedure involves the generation of copper(r) salts by the reaction RS3R + 2Cu + 2RSCu in dimethyl- acetamide in the presence of the aryl halide.124 The copper-catalysed formation of C-C bonds was exemplified again in the case of the very reactive halide o-bromobenzoic by its con- densation with sodium derivatives of p-dicarbonyl compounds in the presence of copper bronze.Acetylene derivatives in good yield have recently been prepared in refluxing ~ y r i d i n e l ~ ~ by the reaction Arl + CuC ICPh + Arc iCPh When reactive ortho-substituents such as C02H OH or NH2 are present in the halide cyclisation with the acetylenic bond also occurs giving isocoumarin benzofuran or indole derivatives respectively Other Copper-catalysed Substitutions.-In view of limitations of space and of the existence of an earlier Review,2 the Sandmeyer and related substitution reactions of diazonium salts will not be discussed.Since that Review was written neither practical nor theoretical aspects of the reaction have greatly altered. It resembles halide-replacement reactions by involving solutions of complexes of copper(1) with the reacting species. Similarly different views may be held concerning mechanisms of decomposition of these complexes. The observation126 of polymerisation of a vinyl monomer initiated by aryl radicals from the reaction lends support to the view that it may occur homolytically. Reference must also be made to a recent detailed ReviewlZ7 of the Meerwein reaction in which an aryl group from decomposition of a diazonium salt adds to olefinic compounds.The reaction is copper-catalysed is closely related to the Sandmeyer reaction and has likewise been interpreted by both homolytic and hetero- I ytic mechanisms. Also available are accounts of two well-established processes in which copper catalysis is observed in replacement of nuclear hydrogen with formation of a C-C linkage; the result is carbonylation in the Gatter- man-Koch reaction128 and cyclisation in the Pschorr ~eacti0n.l~~ 123 R. Adams and A. Ferretti J. Amer. Chem. Soc. 1959 81 4927. 12* J. R. Campbell J. Org. Chem. 1962 27 2207. 125 R. D. Stephens and C. E. Castro J. Org. Chem. 1963 28 3313. 126 D. C. Nonhebel and W. A. Waters Proc. Roy. SOC. 1957 A 242 16. 12' C. S. Rondestvedt Org.Reactions 1960 11 189. 128 N. N. Crounse Org. Reactions 1949 5 290. lZ9 De L. F. DeTar Qrg. Reactions 1957 9,409. BACON AND HILL COPPER-PROMOTED REACTIONS 125 Ring enlargement Copper and its salts catalyse the decomposition of diazomethane to carbene which readily polymerises to polymethylene In the presence of an olefin the carbene is largely consumed by addition to the double bond giving a cyclopropane derivative. A similar addition reaction occurs with benzene but is accompanied by ring opening the product being cycloheptatriene (XVII). This method of preparation was independently discovered in three l a b o r a t o r i e ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ and CH,N -f :CH + N ; n:CH -+ (CH,) represented130 as involving the following sequence in which complex is an intermediate.has been a copper CuHal + :?H2-6iN - Hal-CuUi,-h i N-N2+ Hol-~u-& Yields of up to 85% result130 with the catalytic species CuBr CuCl or CuC12 the last-named apparently being reduced to CuCl; and yields of 10-20 % result with CuI Cu or CuSO,. This copper-catalysed reaction has advantages over an earlier method of converting benzene into cyclo- heptatriene in which photochemically initiated decomposition of diazo- methane was used. It enables pure 7,7-dideuterocycloheptatriene to be prepared.132 When applied to alkyl- halogeno- or methoxy-substituted benzene it affords the corresponding cycloheptatriene derivatives in yields of 35-75 %.133 We wish to thank Dr. Barbara Auret for much help in the preparation of the manuscript. 130 E. Muller and H. Fricke Annalen 1963 661 38. 131 G. Wittig and K. Schwarzenbach Annalen 1961 650 1. 133 E. Muller H. Fricke and H. Kessler Tetrahedron Letters 1963 1501. W. von E. Doering and W. R. Roth Tetrahedron 1963 19 715.

ISSN:0009-2681    

DOI:10.1039/QR9651900095

出版商:RSC    

年代:1965

数据来源: RSC

摘要:

THE REACTIONS OF METAL HALIDES WITH ALKYL CYANIDES By R. A. WALTON (DEPARTMENT OF CHEMISTRY THE UNIVERSITY MANCHESTER 13) 1. Introduction INTERE~T in the chemistry of the transition metals has resulted in the study of the complexes formed by transition metal halides with a large variety of donor molecules e.g. amines phosphines etc? Alkyl cyanides (or nitriles) in particular form a large number of compounds with metal halides and the recent interest in their preparation and structure has prompted this Review. The alkyl cyanides particularly methyl cyanide are also widely used as solvents in inorganic chemistry for preparative work and the measurement of the physical properties of compounds. The aim of this Review is to show the versatility of the alkyl cyanides in inorganic chemistry. In addition to the above points which will be dealt with in detail the complexes formed between metal carbonyls and alkyl cyanides and metal halides and phenyl cyanide are also discussed.2. Properties and structure of alkyl cyanides Before considering the complexes of alkyl cyanides with metal halides we will first discuss the properties and structure of the alkyl cyanides themselves. They are colourless highly toxic liquids which are generally stable in air and although stable aromatic nitrile oxides R-C=N-+O are known,2 where R is a bulky group the corresponding aliphatic nitrile oxides are very unstable. Methyl cyanide is a considerably stronger base than ~ a t e r ~ and con- sequently a weaker acid. The physical constants4 of the lower alkyl cyanides RCN where R = Me Et or Pry indicate their favourable solvent properties (see Section 6).The infrared and Raman spectra of the lower alkyl cyanides have been investigated in great detail.5 The spectral data for methyl cyanide is con- sistent with a pseudo-tetrahedral structure (C3* ~yrnmetry)~ and a linear C-CEEN system. Ethyl cyanide as expected has a lower (Cs) symmetry.8 The vibrations associated with the cyanide group are of particular interest. In liquid methyl cyanide the C-N stretching (v2) and C-C-N bending (v8) See e.g. C. K. Jsrgensen “Inorganic Complexes” Academic Press London and C. Grundmann and J. M. Dean Angew. Chem. 1964 76 682; Y. Iwakura M. A. Weissberger “Technique in Organic Chemistry” vol. VII Organic Solvents See e.g. G. Herzberg “Infrared and Raman Spectra” Van Nostrand New York New York 1963.Akiyaman and K. Nagakubo Bull. Chem. SOC. Japan 1964,37,767. * W. S. Muney and J. F. Coetzee J. Phys. Chem. 1962 66 89. Interscience Publ. Inc. New York p. 224. 1945 p. 332. * N. E. Duncan and G. J. Janz J. Chem. Phys. 1955,23,434. 126 WALTON THE REACTIONS OF METAL HALIDES WITH ALKYL CYANIDES 127 modes are observed at 2250 and 380 cm.-’ respectively.’ Similar bands are observed for the other alkyl cyanides. A band of medium intensity at 2290 cm.-l in methyl cyanide very close to the C-N stretching vibration is believed to arise from a combination of the symmetric CH deformation and C-C stretching vibrations.’ Low-temperature spectroscopy of the aliphatic dinitriles* shows the presence of trans and gauche isomers; the amounts of each depend upon temperaturs. N Isomers of succinonitrile (a) trans (b) gauche.Electron-diffraction investigations of methyl cyanide have been carried out by several worker^,^ and a C-N bond length of 1.155 & 0.03 A is close to the value expected for a C-N triple bond. The C-C bond length (1.465 and force constantlo are consistent with sp-sp3 bond character. It is clear that the Lewis base character of the alkyl cyanides can arise either by donation of the T electrons from the C-N triple bond or from the “lone pair” localised on the nitrogen atom. In all the complexes of metal halides and alkyl cyanide so far isolated the bonding is believed to be of the latter type. We shall now discuss these complexes with emphasis on their structure and type of bonding involved. 3. Reactions of metal halides with unidentate alkyl cyanides (a) Halides of Non-transition Metals.-The trihalides of boron and aluminium and the tetrahalides of tin form well characterised complexes with alkyl cyanides.These and other complexes of the non-transition metal halides are summarised in Table l.11-23 P. Venkateswarlu J. Chem. Phys. 1951,19,293; 1952,20,923. See e.g. W. E. Fitzgerald and G. J. Jam J. Mol. Spectroscopy 1957 1,49. L. Pauling H. D. Springall and K. J. Palmer J. Amer. Chem. SOC. 1939,61 927; M. D. Danford and R. L. Livingston ibid. 1955,77,2944. lo J. W. Linnett J. Chern. Phys. 1940 8 91. l1 R. Fricke and F. Ruschhaupt 2. anorg. Chem. 1925 146 103. l a H. Bowlus and J. A. Nieuwland J. Amer. Chern. SOC. 1931 53,3835. l3 H. J. Coever and C. Curran J. Amer. Chem. SOC. 1958,80,3522. l4 W. Gerrard M. F. Lappert and J.W. Wallis J. 1960 2178. l5 S. Geller and 0. N. Salmon Acta Cryst. 1951 4 379. l6 E. L. Muetterties J. Inorg. Nuclear Chern. 1960 15 182. l7 A. K. Holliday F. J. Marsden and A. G. Massey J. 1961 3348. l9 A. I. Popov and F. B. Stute J. Amer. Chem. Soc. 1956,78,5737. 2o R. C. Aggarwal and M. Onyszchuk Proc. Chem. Soc. 1962,20. 22 P. Pfeiffer and 0. Halperin 2. anorg. Chem. 1914 87 335. 23 N. A. Pushin M. Ristic I. Parchomenko and J. Ubovic Annalen 1942 553,278. C. D. Schmulbach J. Znorg. Nuclear Chem. 1964,26 745 and references therein. A. A. Woolf J. Inorg. Nuclear Chem. 1956,3 285. 128 Halide BeCl BF3 BCl BBr BI3 BQ4 AlCl AIBr GeF SnF SnCI SnBr QUARTERLY REVIEWS TABLE 1. Complexes of non-transition metal halides Alkyl cyanide R = Me Et Ph Me Et Pr Me Et Pr Bu Ph Me Me Me Me Me Me Me Me Et Pr Ph Me Et Ph HalidelRCN mole ratio 1:2 1:l 1:l 1:l 1:2 1:2 1:1 2:3 and 1 :2 1:2 1:l and 1:2 1:2 1:2 1:2 Comments Ref.11 Dissociated in vapour 12 13 phase 13 14 15 Complex “impure” 16 Decomposes above 130” to BCI,.MeCN 17 Hygroscopic 18 Decomposes - 85” 19 Thermally stable and non-volatile 20 Sparingly soluble in excess MeCN 21 In benzene dissociates to 1 1 adduct 13 22,23 The boron(rr1) iodide complex is of uncertain stoicheiometry as are several alkyl cyanide adducts of magnesium bromide which have been Silicon(1v) bromide has been described as forming a white 1 2 complex with methyl cyanide,25 but recent work shows that no reaction occurs under anhydrous conditions.26 Germanium(1v) chloride also fails to react with alkyl cyanides,13s2’ as do silicon(1v) chloride and tin(1v) iodide.26 This behaviour is in keeping with the usual acceptor order of the tetrahalides of Group I V B ~ ~ i.e.F>CI>Br>I and Sn$Ge>Si. It is noteworthy that the phosphorus and antimony pentahalides dissolve in methyl cyanide. In the case of PCI, the usual ionic dissociation PCl + PCl$ + PC16- occurs,28 and there is no evidence for the formation of solvated species of the type [PCI,(MeCN),]+. With SbCl a solid solvate of composition SbCI,,MeCN (m.p. 175”) has been isolated.29 This was formulated as the heteropolar compound [SbCIJ [SbC16],2MeCN,29 but recent infrared spectra studies28 on this system indicate that the octahedral species trans- [SbCl,(MeCN),]+ and [SbClJ- predominate. Because the alkyl cyanide complexes of the boron aluminium and tin halides have been the most thoroughly investigated we will now consider them in more detail.24 B. N. Menschutkin 2. anorg. Chem. 1909,61 11 1. 25 J. E. Reynolds J. 1909 25 512. 26 I. R. Beattie Quart. Rev. 1963 17 382. 27 V. V. Udovenko and Yu. Ya Fialkov Zhur. neorg. Khim. 1957,2,2126. 28 I. R. Beattie and M. Webster J. 1963 38. 29 L. Kolditz and H. Preiss 2. anorg. Chem. 1961,310,242. WALTON THE REACTIONS OF METAL HALIDES WITH ALKYL CYANIDES 129 (i) Boron(111) halides. A wide variety of alkyl cyanides form 1 1 adducts with boron(I1r) halides and these are generally stable at room temperature in the absence of moisture.14 They are readily hydrolysed by cold water and ligand-exchange experiments of the type BCl,,MeCN + L + BC13,L + MeCN have been carried This gives the donor order pyridine>tetrahydro- furan>BuntS>MeCN>acylic ethers for BCl as acceptor.Vapour-pressure meas~rements~~ on BX,,MeCN (X = F or C1) show these complexes to be completely dissociated in the vapour phase whereas in dilute benzene solutions no appreciable dissociation occurs.13 This dissociation of the complexes in the vapour phase has been used as a method of purifying boron(Ir1) fluoride via the complex BF,,PhCN.,I The crystal structure of BF,,MeCN has been determined3 and the bond parameters are shown below. The most important conclusions from this 103' Bond parameters for BF,,MeCN (C3v symmetry). structure determination is that the C-C-N-B system is linear. This is of particular significance since in all alkyl cyanide complexes of metal halides investigated the linearity of this system is apparently maintained,* and this is expected for donation from the lone-pair on the nitrogen atom.Both the C-C and C-N bond lengths in this complex are slightly shorter than in free methyl ~yanide,~ and this would imply a slight increase in the C-N bond order in the complex. The analogous chloride and bromide com- plexes are isomorphous but no structural details have been reported for these molecule^.^^ In the series BF,,L where L = MeNH, MeCN NH3 and Me,N the methyl cyanide adduct has the longest and weakest B-N bond.33 These structural data correlate well with the relative stabilities of these addition compounds. Thus BF,,MeCN is completely dissociated in the vapour phase at 50"c whereas BF,,MeNH is stable. The infrared active C-N stretching frequency increases by 70-1 10 cm.-l upon complex f ~ r m a t i o n ~ ~ ~ ~ and this increase is diagnostic of complex formation via the lone-pair on the nitrogen atom.The intensity * There is some evidence for a bent C-N-Cu bond in Cu,Cl,(MeCN) and Cu,CI (MeCN)s (see p. 136). A. W. Laubengayer and D. S. Sears J. Amer. Chem. SOC. 1945,67,164. s1 H. C. Brown and R. B. Johannesen J. Amer. Chem. SOC. 1950,72,2934. 32 J. L. Hoard T. B. Owen A. Buzzell and 0. N. Salmon Actu Cryst. 1950,3 130. 33 J. L. Hoard S. Geller and T. B. Owen Actu Cryst. 1951,4,405. 130 QUARTERLY REVIEWS of the C-N stretching vibration in the complexes is very much greater than in the free nit rile^,^^,^^ and this is attributed to an increase in the polarity of the C-N bond. Beattie and G i l ~ o n ~ ~ have recently discussed the increase in the C-N stretching frequency in terms of (a) coupling of the C-N and B-N stretching frequencies and (b) some increase in the C-N force con- stant.For BX,,MeCN the C-N stretching frequency is insensitive to variations of the mass of X and the B-N force constant. An alternative explanation of this frequency increase involves the postulation of structures with different bond m~ltiplicities.~~ The infrared spectrum of these com- plexes is further dealt with in Section 5. (ii) AZuminium(r1r) halides. A recent phase study1* has confirmed the existence of AlC13,2MeCN19g36 and AlCI,,MeCN,37 but earlier reports of 2A1C13,MeCN38 could not be substantiated. The complex 2A1C13,3MeCN is also known,18 and melting point data suggest it is more stable than A1C13,2MeCN. The above compounds and A1Br3,2MeCNlQ are white generally hygroscopic solids.The chloride complexes are believed to be of the type Al,Cl,,nMeCN where n = 2 3 or 4. Molecular weight and Raman spectra studies have been used1* to de- termine the nature of the solute species present in dilute solutions of aluminium(rI1) chloride in methyl cyanide. The cationic species [A12C1, nMeCN]+ have been proposed on the basis of the dissociation 2nMeCN + 3A12C1 + 2[Al,C15,nMeCN]+ + 2AlC14- The presence of AlC14- in the system was shown by its characteristic Raman spectrum. (iii) Tin(rv) halides. The 1 1 and 1 2 alkyl cyanide and phenyl cyanide adducts of tin(1v) chloride have been extensively i n ~ e s t i g a t e d . ~ ~ ~ ~ ~ Dipole moment and molecular weight data show that in benzene solution SnC14,2RCN dissociate to form the corresponding 1 1 a d d ~ c t s .~ ~ ~ ~ Brown and Kubota30 have also studied the dissociation of SnCI4,2PhCN from infrared spectra studies. Using this together with dielectric constants they conclude that SnCl,,PhCN has a dipole moment of 8 . 4 ~ (i.e. Clv or CPv symmetry possible).* Other workers however obtained no spectro- scopic evidence for the presence of 1 1 adducts.13 No reliable moment could be calculated for the 1 2 addition although earlier studies by Ulich and his co-w~rkers~~ suggest that the moment for SnC14,2EtCN is high thus favouring a cis-octahedral configuration. * In this and subsequent symmetry classifications we shall assume that R in RCN is a 34 W. Gerrard M. F. Lappert H. Pyszora and J. W. Wallis J. 1960,2182. a5 I. R. Beattie and T.Gilson J. 1964 2292. 36 W. L. Groeneveld and A. P. Zuur Rec. Trav. chim. 1957 76 1005. 37 G. Perrier Compt. rend. 1895 120 1424. 38 G. Perrier Bull. SOC. chim. France 1895 13 1031. T. L. Brown and M. Kubota J. Amer. Chem. Soc. 1961 83 331. 40 T. L. Brown and M. Kubota J. Amer. Chem. SOC. 1961 83,4175. 41 H. Ulich E. Hertel and W. Nespital 2. phys. Chem. 1932 B 17 21. point. If dissociation does occur in solution it can give rise to the possibility of cis-SnC14,2MeCN + SnCl,,MeCN + MeCN + ?rans-SnCl4,2MeCN and this must be generally true for soluble species of the type MX4,2L. Both the frequency and intensity of the C-N stretching vibration show characteristic increases in the c o m p l e ~ e s . ~ ~ ~ ~ ~ ~ ~ A simplified normal co- ordinate analysis for the methyl cyanide complex SnC14,2MeCN indicates that a kinematic coupling should give rise to a small increase in frequency.,O The far infrared and Raman spectra of SnC1,,2RCN have been examined in the solid and s ~ l u t i o n .~ ~ ~ ~ ~ ~ ~ The number of metal-halogen stretching vibrations in the infrared spectrum is consistent with a cis-c~nfiguration,~~ and bands previously assigned to Sn-N vibrations40 have been shown to be associated with the Sn-Cl stretching ~ i b r a t i o n s . ~ ~ ~ ~ ~ Solution spectra below 400 cm.-l have confirmed the presence of the 1 :l adducts SnCl, RCN., Since the alkyl cyanides contain the linear C-C-N group steric hindrance is unlikely to force a trans-configuration as is found with other complexes of the type SnC14,2L,45 where L is a fairly bulky ligand such as EtoO or Me,N.For cis-SnC14,2RCN a splitting of the C-N stretching frequency might be expected as has been observed for cis-complexes containing co- ordinated phosphoryl molecules where the P=O stretching frequency is a However if the coupling through the central metal atom is cis-trans isomerization Some possible stereochemistries for SnCI4,2RCN (a) cis (&) (b) trans (D4h) and SnCI,,RCN (c) trigonal bipyramid (&) (d) square pyramid (C,"). weak this splitting may not be observed.* Brune and Zei14 measured the Raman spectra of SnC1,,2RCN and suggested that these molecules pos- sessed a trans-configuration. Their observation of a band at 340 cm.-l which is also observed in the infrared spectrum at 339 cm.-l is consistent with the cis-configuration since molecules possessing a centre of symmetry (i.e.trans D,J cannot have vibrations which are both infrared and Raman * The configuration of cis-SnC14,2POC13 has been confirmed by a crystal structure determination; see C. I. Branden Acta Chem. Scand. 1963 17 759. The splitting of the P=O (or C=N) stretching frequency could also arise from the presence of non- equivalent POCla or RCN molecules or from solid state effects. 42 H. A. Brune and W. Zeil 2. Naturforsch. 1961 16a 1251. 43 H. A. Brune and W. Zeil 2. phys. Chem. (Frankfurt) 1962,32 384. 44 I. R. Beattie G. P. McQuillan L. Rule and M. Webster J. 1963 1514. 45 I. R. Beattie and L. Rule J. 1964 3267. 46 J. C. Sheldon and S. Y . Tyree J. Amer. Chem. SOC. 1958,80,4775. 132 QUARTERLY REVIEWS active. This is a consequence of the well-known mutual-exclusion prin- ~iple.~’ A normal co-ordinate analysis of SnC1,,MeCNP8 shows this molecule to have a trigonal-bipyramidal (C2J structure.This is only one of several possible structures for this molecule two of which are shown above. (b) Halides of Transition Metals.-Transition-metal halides have been by far the most extensively investigated and in some cases they form complexes in several metal oxidation states. Complexes of alkyl cyanides with transition-metal halides were first reported as long ago as 1858,49 but few detailed studies have been carried out until recently. We shall divide this section according to the solvolytic nature of the metal halides i.e. Group A being complexes formed by the scandium titanium vanadium and chromium sub-groups and Group B by the remaining transition metals.(i) Group A . The crystalline c o i n p l e ~ e s ~ ~ - ~ ~ formed by these metal halides are readily hydrolysed and consequently they can only be handled under rigorously anhydrous conditions. These experimental difficulties have until recently impeded the study of several of these complexes. In several instances complexes of differing stoicheiometry and oxidation state can be obtained by altering the experimental conditions. Thus vanadium(1v) chloride reacts with alkyl cyanides to form complexes of the types VC14,2RCN or VC13,3RCN depending upon the presence or ab- sence of an inert solvent.56 In addition to the complexes shown in Table 2 several other systems have been investigated. The complexes TiC14,3RCN reported by Hertel and Demmer53 could not be isolated by and from the reactions of zirconium(1v) and vanadium@) chloride6’ with alkyl cyanides 47 See e.g.K. Nakamoto “Infrared Spectra of Inorganic and Co-ordination Compounds” J. Wiley and Sons Inc. New York 1963 p. 24. 48 W. Zeil and C. Dietrich Z . phys. Chem. (Frankfurt) 1963,38,36. 49 W. Henke Annalen 1858,106,280. 5 0 H. Funk and B. Koehler Z. anorg. Chem. 1963,67 325. 51 H. J. EmelCus and G. S. Rao J. 1958,4245. 52 E. L. Muetterties J. Amer. Chem. Soc. 1960 82 1082. 53 E. Hertel and A. Demmer Annalen 1932 499 134. 54 R. S. Kern J. Inorg. Nuclear Chem. 1963 25 5 . 55 R. J. H. Clark J. Lewis D. J. Machin and R. S. Nyholm J. 1963 379. 56 M. W. Duckworth G. W. A. Fowles and R. A. Hoodless J. 1963 5665. 57 G. W. A. Fowles and R. A. Walton J. 1964,4953. 58 E. M. Larsen and L. E. Trevorron J.Inorg. Nuclear Chem. 1956 2,254. 59 H. Funk G. Mohaupt and A. Paul 2. anorg. Chem. 1959,302 199. 6o H. Funk W. Weiss and M. Zeising 2. anorg. Chem. 1958 296 36. 61 K. Feenan and G. W. A. Fowles J. 1964,2842. 61u J. P. Fackler personal communication. 62 H. L. Krauss and W. Huber Ber. 1961,94,2864. 63 E. A. Allen B. J. Brisdon and G. W. A. Fowles J. 1964,4531. 64 D. A. Edwards J. Inorg. Nuclear Chem. 1965 27 303. 65 E. A. Allen K. Feenan and G. W. A. Fowles J. 1965 1636. 66 H. Funk and G. Mohaupt Z. anorg. Chem. 1962,315,204; G. W. A. Fowles and 67 R. A. Walton unpublished observations. J. Frost unpublished observations. WALTON THE REACTIONS OF METAL HALIDES WITH ALKYL CYANlDES 133 TABLE 2. Complexes of Group A transition-metal halides Halide Alkyl cyanide R = Me Ph Me Et Ph Halide/RCN mole ratio 1:3 1:l Comments Ref.ScCl TiF 50 Soluble in MeCN to give 1 :2 adduct 51 52 13 51 53 Soluble in parent RCN 51 51 X=Cl and Br. Also pre- pared from TiX3,2NMe 54-57 X = C1 and Br. Soluble in parent RCN 51 Only investigated by phase study 58 Sublimes in vacuo; soluble in benzene 56,59 X = C1 and Br 55,56 Prepared in “inert” solvent 60 X = Cl or Br. Soluble in 61 excess RCN and in non- polar solvents 61 X = C1 Br or I. Com- plexes octahedral 61a 62 MoC1,,2RCN isolated 63 Emerald-green crystalline solids 64 MoBr3,3PrCN soluble in benzene 65 WC1,,2RCN isolated 63 WC1,,2RCN isolated 63 WBr4,2RCN isolated 63 66 Purple-back solid 54 TiCl Me Et Ph Me Et Ph Me Me Et Pr 1:l and 1:2 1:2 1:2 1:3 TiBr TiI TiX ZrX Me Et Pr Ph 1:2 HfCl4 Me 1:2 VCl Me Et 1:2 vx3 VOCl NbX Me Et Me Ph Me Et Pr 1:3 and 1:4 1:2 1:l Me Et Pr Et Me 1:l 1:3 1:2 Tax CrCl CrX MoO,Cl MoCl MoOCl Me Ph Me Et Pr Me Et Pr 1:2 1:2 1:2 MoBr Me Et Pr 1:3 WCl WCl WBr5 WOCl Me Et Pr Me Me Et Pr Me Et Pr Ph 1:2 1:2 1:2 1:l no complex has been isolated.Also of some interest are several mixed- ligand complexes of the type MX3,nL,2RCN where n = 1 or 2 and L = 2,2’-bipyridyl triphenylphosphine or triphenylarsine. These are formed by the reaction of titanium(m) chloride6* or molybdenum(II1) bromide65 with the donor ligand L in alkyl cyanide solutions. We shall now discuss the stoicheiometry properties and stereo- chemistry of several of these complexes. Stoicheiometry. Reaction of the halides with a large excess of alkyl cyanide invariably leads to the formation of complexes of empirical formula MX,,RCN MX,,RCN or MX3,3RCN depending upon the 88 G.W. A. Fowles R. A. Hoodless and R. A. Walton J. Inorg. Nuclear Chem. 1965,27 391. 134 QUARTERLY REVIEWS halide used. The niobium(v) and tantalum(v) complexes are the only examples known of the first type and they have been shown to be non- ionic six-co-ordinate monomers.61 In the case of MX4,2RCN available evidence points to six co-ordinate species in the solid state although in solution some are believed to dis- sociate to yield the 1 1 adducts. VC14,2RCN for example,56 dissociates in benzene solution but VCl,,RCN has not been isolated from the solution. Titanium(1v) chloride forms both the 1 :1 and 1 2 a d d u ~ t s ~ ~ ~ ~ whereas titanium(rv) fluoride forms only the 1 :I a d d ~ c t ~ ~ ~ ~ ~ and this is probably dimeric in the solid52 and consequently six co-ordinate.Only in case of MoBr3,3PrCN has a complex of type MX3,3RCN been shown to be monomeric in but those of titanium and vanadium- (111) halides are non-ionic in the parent alkyl cyanide and almost certainly contain the discrete six-co-ordinate species [MX3,3RCN].55~5s The com- plexes of composition VX3,4MeCN probably contain one mol. of alkyl cyanide in the crystal lattice since in the case of the chloride complex washing with a non-polar solvent leaves only VC13,3MeCN.58 Reduction reactions. In several instances alkyl cyanides behave as strong reducing agents with transition-metal halides. Thus only com- plexes of quadrivalent molybdenum and tungsten can be isolated when alkyl cyanides react with the hexa- and penta-halides of these element^.^^ This is very similar to the behaviour of these halides with pyridine and other base^.^^^^^ Vanadium(1v) chloride reacts with alkyl cyanides in carbon tetrachloride solution to give VCI 4,2RCN,56y59 but direct reaction in the absence of a solvent results in reduction of vanadium to the tervalent state and formation of VC13,3RCN.56 In no cases have oxidation products been isolated although HC1 has been detected in some With other halides (e.g.TiCl,,NbC15) no reduction occurs even under forcing conditions. Solubility studies. All the cyanide complexes described in this section are soluble to some extent in the parent alkyl cyanide. VCl,,ZRCN dissociates in benzene56 and in this respect resembles the analogous tin(1v) chloride complexes. This is in contrast to the behaviour of the corresponding molybdenum and tungsten compounds which are monomeric in this solvent.63 Ulich Hertel and Nespita141 have reported a similar dissociation of TiC1,,2EtCN in benzene but other workersG7 find little evidence for this from molecular-weight studies.The above dissociations may well be dependent upon the experimental conditions and a trace of moisture in the system could lead to an apparent dissociation owing to a small amount of hydrolysis. Feltz’l has investigated the species present when TiC1,,2MeCN is dissolved in “slightly moist” methyl cyanide and isolated a crystalline 69 R. E. McCarley and T. M. Brown Inorg. Chem. 1964,3 1232. 70 G. W. A. Fowles unpublished observations. A. Feltz 2. anorg. Chem. 1963 323 35. WALTON THE REACTIONS OF METAL HALIDES WITH ALKYL CYANIDES 135 product of composition Ti2C1,0,4MeCN.This again emphasises the need to work under rigorously anhydrous conditions when studying these complexes since hydrolysis often results in misleading analytical and structural data. Magnetic and spectral properties. The magnetic moments of the para- magnetic complexes of the first-row transition-metal halides are as expected diagnostic of valency state and close to the “spin-only” moment^.^^^^ TiC1,,3MeCN is the only example where the variation of magnetic susceptibility with temperature has been in~estigated.~~ The magnetic data fit72 a ground state distortion in which the 2T,g term is split by - 600 cm.-? In the case of MoC14,2RCN ( p - 2.5 B.M.) and WX4,2RCN ( p - 1-7-2.0 B.M.),63 the low moments (pBpin only = 2.83 B.M.) presumably arise from the larger values of the spin-orbit coupling constants found for second- the third-row transition For MoBr3,3RCN the magnetic moments occur in the range 3-5-34 B.M.,65 and these values are typical of octahedral molybdenum(u1). From a study of the spectral properties of a variety of complexes of titanium(II1) ~ h l o r i d e ~ ~ ~ ~ alkyl cyanides would appear to occupy a high position in the spectrochemical series. A comparison of Dq values leads to the order RCN > H20 > R,CO > dioxan > tetrahydrofuran > C1 > Br. With the complexes of molybdenum(1v) and tungsten(1v) halides,63 the spectra are complicated by the presence of intense charge-transfer bands which obscure the weak spin-forbidden d-d transitions. The ultraviolet spectra7* of the titanium@) and zirconium(1v) do complexes show intense bands which have been assigned to transitions of the types RCN(n) --f dc and halogen (T) -+ de.The infrared spectra of the complexes show the expected characteristic increase in the C-N stretching frequency. The complexity of the spectra of several complexes of the type MX4,2RCN (M = Ti or Zr and X = C1 or Br) favours a cis-~onfiguration,~~ and the Raman spectrums7 of ZrCI4,2RCN seems to confirm this. A previous assignment of the stereo- chemistry of the titanium and zirconium complexes from the splitting of the C-N stretching frequency76 is questionable (see p. 131). Further evi- dence for the cis-configuration is provided by the 19F magnetic resonance spectrum of TiF,,MeCN in methyl cyanide;52 the cis-1 2 adduct is believed to be present in solution.72 B. N. Figgis Trans. Faraday SOC. 1961 57 198. 7s See e.g. B. N. Figgis and J. Lewis “Modern Co-ordination Chemistry,” Inter- 74 G. W. A. Fowles and R. A. Walton J. 1964 2840. 75 I. R. Beattie and M. Webster J. 1364 3507. s6 G. S. Rao Z. anorg. Chem. 1960,304 351. science Publ. Inc. New York 1960 p. 428. 136 QUARTERLY REVIEWS (ii) Group B. The diamagnetic colourless crystalline complexes CuX,MeCN where X = C1 or Br and CuN03,4MeCN were first reported by Morgan in 1923.77 More recently several complexes of the type CuX,4RCN where X = BF4 ClO or NO, have been prepared by re- duction of solutions of copper(I1) salts in methyl cyanide,78 or by the reaction of copper(1) oxide with a boron(II1) fluoride-ether solution in the appropriate alkyl cyanide.79 Conductivity data7* in methyl cyanide show that these complexes behave as 1 :1 electrolytes in this solvent.The cor- responding silver and gold complexes [MI(RCN),]X where X = BF4 or ClO are also k n o ~ n ~ ~ ~ ~ ~ and the stable zinc complexs1 has been isolated as its perchlorate and tetrafluoroborate salts. Although the complex ions [CuCl(MeCN),]+ [CuCl,(MeCN),] [CuCl,(MeCN)]- and [CUC~,]~- are believed to be present in a copper(r1) chloride solution in methyl cyanide,82 reduction occurs in the copper(I1) bromide systema3 and bromine is liberated. The orange-yellow gold(II1) complexes AuCl,,RCN have been pre- pared,49v84 and the chloride is also capable of aurating several aryl cyan- ides AuCl + (AH)-CN -+ AuClz-A-CN + HCl where (AH)-CN represents the original aryl cyanide.Naumanns5 has described the preparation of the light blue and yellow- brown complexes CuC1,,2MeCN and CuCl,,MeCN respectively. Willett and Rundles6 have recently prepared a third complex CuCl,,$MeCN and determined the crystal structure of this complex and of CuCl,,MeCN. These two complexes were shown to be a trimer and dimer respectively with an essentially planar arrangement of the ligands about the copper atoms and the alkyl cyanide molecules in terminal positions trans to one another. Although the methyl cyanide molecules were linear in the com- plexes the Cu-N-C angle was significantly less than 180". This is the first example known where the linearity of the M-N-C system in alkyl cyanide complexes is not maintained and Willett and Rundle concludedss that the bonding nitrogen atom uses orbitals with partial sp2 character.Whether this is unique will require a more exhaustive structural investigation of these and similar systems. 77 H. H. Morgan J. 1923 2901. 78 B. J. Hathaway D. G. Holah and J. D. Postlethwaite J. 1961 3215. 7 9 H. Meerwein V. Hederich and K. Wunderlich Arch. Pharm. 1958 291 541 G. Bergerhoff 2. anorg. Chem. 1964,327 139. B. J. Hathaway and A. E. Underhill J. 1960,3705; B. J. Hathaway D. G. Holah (Chem. Abs. 1960,54 5427). and A. E. Underhill J. 1962,2444. 82 C. Furlani A. Sgamellanti and G. Ciullo Ric. Sci. Rend. Sez. 1964 A 4 49. 83 W. Schneider and A. V. Zelewsky Helv. Chim. Acta. 1963,46,1848 85 A. Naumann Ber. 1914 47 247. 86 R. D. Willett and R. E. Rundle J. Chem. Phys. 1964 40 838. M. S . Kharasch and T. M. Beck J. Amer. Chem. Soc.1934,56,2057. WALTON THE REACTIONS OF METAL HALIDES WITH ALKYL CYANIDES 137 (a) Cu2C1,,2MeCN (b) Cu3C1,,2MeCN Chlorine-bridged methyl cyanide complexes of copper(n) chloride. A single-crystal X-ray analysis of ZnC1,,2MeCN8’ has confirmed a distorted tetrahedral arrangement of bonds about the zinc atom. The linearity of the C-C-N bond was again confirmed and the Zn-N bond length is 2.0 A. This bond length is similar to that found for the copper(r1) complexes described above but is appreciably longer than the B-N bond in BF,,MeCN.32 Until recently few of the alkyl cyanide complexes of manganese iron cobalt or nickel had been studied in any detail. The complexes COX, nRCN where X = C1 or Br and n = 2 or 3 were isolated many years a g ~ ~ ~ ~ ~ ~ and solution studies on the COX,-MeCN system have received attention.89 Spectral and conductivity data in methyl cyanide suggest that in solution a series of equilibria occur involving the tetrahedral species [CoX,(MeCN),] [CoX,(MeCN)]- and [Cox4],- and the octahedral ion [ Co(MeCN)J2+.Janz and his ~o-workers~~ isolated the crystalline com- plexes [CoX2,3MeCN] from these systems which they formulated as ionic [CO(M~CN),~+] COX,^]. Their conductivity data however were in- consistent with this ionic structure and later workg0 has shown the “complexes” [CoX2,3MeCN] to be tetrahedral CoX2,2MeCN with a further mol. of methyl cyanide held in the crystal lattice. Hathaway and Holahgo have recently investigated in great detail the methyl cyanide complexes of manganese iron cobalt and nickel. The crystalline complexes were investigated by conductivity spectral and magnetic studies and the presence of tetrahedral and/or octahedral species was established.Most complexes are of the general formula MX,,nMeCN where n = 2,3,4 or 6 but the complexes FeC13,2MeCN and Fe,X8,6MeCN can also be isolated. The latter complex (X = Cl or Br) is interesting since it was shown to be the mixed iron(II)-iron(m) complex [Fe(MeCN),2+] [FeX4-I, containing octahedral iron(@ and tetrahedral iron(u1). It was I. V. Isakov and Z. V. Zvonkova Doklady Akad. Nauk S.S.S.R. 1962,145,801. A. Hantzsch 2. anorg. Chem.. 1927 159 273. W. Libus Roczniki Chem. 1962 36 999; G. J. Janz A. E. Marcinkowsky and H. V. Venkatasetty Electrochim. Acta 1963 8 867. O 0 B. J. Hathaway and D. G. Holah J. 1964,2400,2408. 138 QUARTERLY REVIEWS suggestedso that the formation of the chloride and bromide complexes was probably associated with the stability of the tetrachloro- and tetrabromo- ferrate(rI1) anions.These workersgo also concluded that the spectrochemical series MeCN > HzO > Ethyl acetate x MeNO holds and we may compare this with the similar series derived for com- plexes of titanium(n1) chloride (see p. 135). The nickel@) complexes NiXz,2RCN and NiX2,4RCN where R = Me Et or Ph have also been reportedg1 by Russian workers. Few structural data are available although the structures which were suggested differ from those of Hathaway and H~lah.~O A series of aquocyanide and amino- cyanide complexes of nickel can also be prepared.g1 Of the platinum metals only the complexes of platinum(I1) with alkyl cyanides have been investigated in any detail.The rhodium(I1x) and iridium(@ complexes (NH,),(MCI,,MeCN),H,O are said to and a partial crystal structure of PdC12,2PhCN showsg3 the molecule to have a trans-planar configuration. In 1907 Hofmann and Bugge reportedg4 the pale yellow complexes PtC12,2RCN where R = Me or Ph and on the basis of their chemical reactions Lebedinskii and his co-workersg5 assigned a cis-planar configura- tion to these complexes. The splitting of the C-N stretching vibration in PtC12,2MeCN has been interpreteds6 as being consistent with this cis- configuration ; this cannot however be regarded as unambiguous (see p. 13 1). Oxidationg7 of the bis(alky1cyanide) complexes yields deriva- tives of platinum(1v) of the types PtX4,2RCN where X = Cl or Br or trans-PtC1,Br2,2RCN.The above platinum complexes were “normal” in that they show the characteristic increase in the C-N stretching frequency. The so-called “anomalous” ammine-alkyl cyanide complexesQs of platinum(I1) form another class of complexes which have recently aroused i n t e r e ~ t . ~ ~ ~ ~ ~ ~ They are of general formula [Ptn(RCN),(A),]X where A = NH3 or a primary amine X = PtCl or CI, and n = 1-4. In all cases the infrared spectrum shows absence of the C,N frequency but 91 A. V. Babaeva and Kh. U. Ikramov Zhur. neorg. Khim. 1964,9 591 596. 92 V. V. Lebedinskii and P. V. Simanovskii Zzvest. Sekt. Plutiny 1939,16,53 (Chem. Abs. 1940 34 4685); V. V. Lebedinskii and I. A. Fedorov ibid. 1935 12 87 (Chem. Abs. 1935 29 3254). O3 J. R. Holden and N. C. Baenziger Actu Cryst. 1956,9 194. 94 K. A. Hofmann and G.Bugge Ber. 1907,40,1772. 9s V. V. Lebedinskii and V. A. Golovnya Izvest. Sekt. Plutiny 1945 18 38 (Chem. Abs. 1947,41,6187); 1948,21 32 (Chem. A h . 1950,44 10566). 96 R. D. Gillard and G. Wilkinson J. 1964 2835. O7 V. A. Golovnya and Chia-Chien Ni Zhur. neorg. Khim. 1959,3 1954. V. V. Lebendinskii and V. A. Golovnya Izvest. Sekt. Plutiny 1939,16,57 (Chem. 9g Yu. Ya Kharitonov Chia-Chien Ni and A. V. Babaeva Zhur. neorg. Khim. loo Yu Ya Kharitonov Chia-Chien Ni and A. V. Babaeva Dokludy Akud. Nuuk A h . 1940 34 4685). 1961,6,131; 1962,7,997; 1963,8,34. S.S.S.R. 1961 141 645. WALTON THE REACTIONS OF METAL HALIDES WITH ALKYL CYANlDES 139 presence of a C=N stretching frequency at - 1600 cm.-’. It was con- cluded99~100 that in the complexes the “free” alkyl cyanide was not co- ordinated as in [Pt(RCN),(R‘NH,),]X, but that the complexes were in fact amidine derivatives [Pt{ RC(NH) =NHR’ },( R’NH ,) ,]X,.Harris and StephensonlOl had previously carried out an X-ray analysis on “ [Pt(MeCN),(NH,),]Cl,,H,O” and assigned a trans-octahedral con- figuration in which the methyl cyanide molecules were bonded from the T electrons of the C-N triple bond. This they found was also consistent with the absence of the C=N stretching frequency. However a recent redetermination of the crystal structure of this complex has confirmedlo2 the amidine structure. The platinum is square planar with two ammonia molecules trans to one another. Diammine bis(acetamidine) platinum(I1) ion. (iii) Metal Carbony1s.-Several metal carbonyls form complexes with alkyl cyanides.One two or three carbonyl groups are replaced in chrom- ium molybdenum or tungsten hexacarbonyl for example to yield (RCN)M(CO), (RCN) ,M( CO) 4 or (RCN),M( CO) 3. These complexes can be prepared photochemically103~104 or by direct reaction.lo5 The latter method gives (RCN),M(CO) and these complexes are excellent inter- mediates in the formation of new compounds not available by other routes.lo5 Spectroscopic studieslos have shown that complexes of the type (MeCN)M(CO), (MeCN),M(CO), and (MeCN),M(CO), have C4?) C,.(cis) and C,v(cis) symmetry respectively. In all these complexes bond- ing is via the lone pair on the nitrogen atoms.lo7 4. Reactions of metal halides with bidentate alkyl cyanides So far we have only considered complexes formed by the unidentate alkyl cyanides RCN. The bidentate cyanides NC-(CH,),.CN have also lol C.M. Harris and N. C. Stephenson Chem. and Znd. 1957 426. lo2 N. C. Stephenson J. Znorg. Nuclear Chern. 1962,24,801. loS W. Strohmeier and K. Gerlach Z. Nuturforsch 1960 15 b 622; W. Strohmeier lo* G. R. Dobson M. F. Amr El Sayed I. W. Stolz and R. K. Sheline Inorg. lo6 D. P. Tate W. R. Knipple and J. M. Augl Znorg. Chem. 1962 1 433. lo6 B. L. Ross J. G. Grasselli W. M. Ritchey and 2-1. D. Kaesz Inorg. Chern. 1963 lo7 I. W. Stolz G. R. Dobson and R. K. Sheline Inorg. Chern. 1963,2 323. and G. Schonauer Ber. 1961,94,1346. Chem. 1962 1 526. 2 1023. 140 QUARTERLY REVIEWS been studied and in particular some interesting low-temperature spectro- scopic studies carried out. It has previously been shown that for BF3,MeCN3 and other com- plexes donation from the lone pair on the nitrogen atom results in an essentially linear C-CrN+M system.Thus formation of chelate com- plexes by bidentate cyanides will not be favoured for short chains unless n bonding occurs from the C-N triple bond. Since no example of the latter type has been reported the formation of chelates is unlikely Although Morgan" suggested that { Cul[ C,H,(CN),] )NO3 contained chelating cyanide molecules later work has shown this to be incorrect. The vibrational spectrum8~lo8 of liquid and solid succinonitrile NC. [CH,I,.CN shows that the trans(C,)-gauche (C,,) ratio depends upon temperature and that in the solid (-44") the molecules exist in the pure gauche configuration. This trans-gauche isomerisation has proved in- valuable in determining the configurations of the bidentate alkyl cyanides and their complexes with copper@ nitrate.The complex { Cu(NC. [CH JnCN) )NO3 has been shown by X-ray analysisloQ and low-temperature spectroscopy1l0 to consist of nitrate ions and polymeric chains with bridging alkyl cyanide molecules. The copper atoms are tetrahedrally surrounded by four nitrogen atoms with Cu-N distances of about 2.0 A. The Cu-N-C-C grouping is essentially linear and the succinonitrile molecules take a gauche configuration. Similar structural analyses have been carried out on glutaronitrile adiponitrile and their copper(1) nitrate complexes.111 Jain and Rivest112 have found that the bidentate alkyl cyanides react with tin(rv) titanium(iv) and zirconium(1v) to give complexes of the type 2MX4,B MX4,B or MX4,2B where B = NC*[CH,I,.CN depending upon the experimental conditions and alkyl cyanide used.Few structural studies were carried out on these complexes although the 2 1 and 1 1 adducts were believed to be polymeric. The presence of free and co- ordinated cyanide groups was inferred from the infrared spectra of the 1 2 adducts. It was concluded that these complexes were six-co-ordinate addition compounds with only one CN group of each alkyl cyanide mole- cule co-ordinated. Kubota and Schulzell3 have also prepared several of the 1 1 adducts with lo* T. Fujiyama K. Tokumaru and T. Shimanouchi Spectrochim. Acta 1964 20 lo9 Y . Kinoshita I. Matsubara and Y . Saito Bull. Chem. SOC. Japan 1959,32 741. I. Matsubara Bull. Chem. SOC. Japan 1961 34 1710. ll1 Y. Kinoshita I. Matsubara and Y . Saito Bull. Chem.SOC. Japan 1959,32,1216; lla S . C. Jain and R. Rivest Carrad. J. Chem. 1963,41,2130. 113 M. Kubota and S . R. Schulze Inorg. Chem. 1964,3,853. 415. I. Matsubara ibid. 1961,34,1719; 1962,35,27. WALTON THE REACTIONS OF METAL HALIDES WITH ALKYL CYANIDES 141 tin(iv) and titanium(1v) chloride which they suggested were polymers with cyanide bridging. Unlike the stable low-temperature conformer of succinonitrile which is gauche,* this ligand assumes the trans form in these complexes. The C-N stretching frequency increases by 30-60 cm.-l in the com- plexes again ruling out T bonding from the C-N triple bond. 5. Infrared spectra of alkyl cyanide complexes As emphasised in the preceding sections alkyl cyanides co-ordinate to metal halides and carbonyls via the lone pair on the nitrogen atom.It seems to be worth correlating the C-N stretching frequency in the com- plexes with the bond type. The shift of the C-N stretching frequency upon co-ordination is in the opposite sense to that observed with co-ordinated phosphine oxides sulphoxides ketones and other donor groups and clearly an explanation is required. Two factors seem important in explaining this increase and both will now be discussed. (a) Kinematic Coupling.-A simple valence-field calculation for the linear system R-C-N-M s h o w ~ ~ ~ J ~ * that coupling of the C-N and M-N stretching vibrations should give rise to a small increase in the C-N stretching frequency although the C-N force constant may be unchanged from that in the free ligand. The larger increase (70-110 cm.-l) for the complexes BX,,RCN arises from the higher frequency of the B-N stretch- ing vibration than with other M-N vibrations.It is of interest that a similar increase in frequency is observed for the nitrile (b) Ionic Contribution to the C-N Bond.-There appears to be some evidence for a slight increase in the C-N force constant35 in BX,,RCN and this cannot be explained in terms of kinematic coupling. It has recently been suggested116 that the force constant of the C-H bond depends to a large extent on the ionic character of the bond. A small percentage of ionic character in the bond would increase its force constant whereas larger amounts would decrease it. Considering the C-N bond then a small increase in the polar nature of the bond may well give a shorter stronger bond. Evidence for this is provided by the intensity increase of the C-N stretching frequency on complex formation.This concept of ionic character has also been used to explain the C-N stretching frequencies of inorganic and organic cyanides.l" 11* E. R. Nightingale Proc. 7th Internat. Conf. Co-ordination Chemistry Stockholm 1962 p. 217. 115 S. Califano R. Moccia R. Scarpati and G. Speroni J. Chem. Phys. 1957,26,1770. 116 R. G. Jones J. A. Ladd and W. J. Orville-Thomas Spectrochim. Acta 1964 20 1697. 11' M. F. Amr El-Sayed and R. K. Sheline J. Inorg. Nuclear Chem. 1958,6,187. 142 QUARTERLY REVIEWS It must be emphasised that the strength of the C-N bond may depend critically upon the percentage of ionic character and this in turn determines the sense of the frequency shift. Although kinematic coupling and ionic character of the C-N bond contribute to the frequency increase neither is solely responsible for it.6. Use of methyl cyanide as a solvent The boiling point (81.6" at 760 mm.) freezing point (-45.7") dielectric constant (37-5 at 20") and other physical properties* of methyl cyanide make it a potentially useful solvent for inorganic chemists. It has con- sequently found wide application as a solvent for inorganic preparations and the measurement of physical properties of compounds. These uses are now discussed and illustrated with suitable examples. (a) Preparative Medium.-Addison and his co-workers118 have found that the rates of reaction of copper zinc and uranium with dinitrogen tetroxide are greatly increased in the presence of methyl cyanide. Reactions of this type in methyl cyanide invariably lead to the formation of methyl cyanide complexes of the corresponding nitrate.l19 In several cases the co-ordinated methyl cyanide can be removed by pumping in vacuo or heating and this may provide a route to the anhydrous nitrates.For example12* MeCN pump in Ni + N,04 -4 Ni(NO3),,3MeCN -.+ Ni(N0d2,2MeCN vacuo 170" in vacuo .+ Ni(N03)2. Alkyl cyanide adducts are useful intermediates in the preparation of complex halides of transition metals. Nyholm and Schaife121 have prepared the interesting tetrahedral species [VXJ- where X = C1 or Br by reaction of vanadium(m) halides with RX where R = Et,N or Ph,MeAs in methyl cyanide. The octahedral complex anions [VX4,2MeCN]- were first isolated and these when heated to 80" decomposed to give the tetrahedral halogeno-vanadate(111) anions.Other complex halides of the type [MX,I2- where M = Ti Zr V or Mo and X = C1 or Br are formed122 when the alkyl cyanide adducts MX4,2RCN react with amine hydrohalide in chloroform. Reaction of MoC14,2RCN and MoBr3,3RCN with a variety of uni- dentate and bidentate ligands results in the replacement of co-ordinated alkyl cyanide and the formation of new complexes.s5 The 2,2'-bipyridyl and 1,lO-phenanthroline adducts MX4,B where M = Ti Zr Nb or Ta 118 C. C. Addison J. C. Sheldon and N. Hodge J. 1956 3906. C. C. Addison and N. Logan "Preparative Inorganic Reactions" ed. W. L. C. C. Addison and B. F. G. Johnson unpublished observations. lZ1 D. E. Schaife 5th Internat. Conf. Co-ordination Chemistry London 1959 laa G. W. A. Fowles and R. A. Walton Inorg. Synth. 1965 in the press.Jolly Vol. 1 p. 141. p. 152; R. S. Nyholm Croat. Chern. Acta 1961,33,157. WALTON THE REACTIONS OF METAL HALIDES WITH ALKYL CYANIDES 143 and X = C1 or Br can be prepared123 by reaction of the metal halide with the ligand in alkyl cyanide solution the halide dissolving as its alkyl cyanide adduct. Many other preparative uses of methyl cyanide are known in which complex formation with the solvent does not appear to occur. For example it is a good solvent for the preparation of complex nitrates124 of the type [M(N0,),I2- where M = MnII CoII Ni" or Cu". (b) Solvent for Physical Measurements.-As a result of its appreciable dielectric constant many salts behave as strong electrolytes in methyl cyanide.125 1 1 and 1 2 electrolytes usually have molar conductivities in the ranges 120-1 60 and 220-280 ohm-1cm.2 respectively for solutions containing about Electrolytes generally have higher conductivities in methyl cyanide than in nitrobenzene or nitromethane and the former solvent is therefore to be preferred.All three solvents however suffer from the disadvantage that they may cause solvolysis which could lead to spurious conductivity data. For example small conductivity values ( A - 30 ohm-1cm.2) in methyl cyanide are usually indicative of an equilibrium of the type123 MX,,L + MeCN + [MX,-,-L,MeCN]+X- As a solvent for spectral measurements methyl cyanide again suffers from its tendency to cause solvolysis. The tetrahedral ions [NiXJ2- and [CuBr,12- for example,12s are very sensitive to solvolysis but this can usually be reversed by addition of halide ions.The spectra of a variety of complex halides MXsn- where M = UIv NpIv PuIv Wv and X = C1 BI or I have been in methyl cyanide and there is no evidence for reaction with the solvent. Except for a band at 380 cm.-l which is infrared and Raman active methyl cyanide is transparent below 400 cm.-l and is thus a particularly useful solvent for far infrared spectro~copy.~~ In conclusion it may be noted that the alkyl cyanides can'be polymerised to the linear conjugated polymers (-CR=N-) by heating many of the alkyl cyanide complexes of metal halides.128 I thank Professor J. Lewis and Drs. B. F. G. Johnson J. R. Miller and A. Thompson who kindly read the manuscript and made many helpful suggestions and Professor J. P. Fackler and Drs. D. A. Edwards and G. W. A. Fowles for making results available prior to publication.las M. Allbutt K. Feenan and G. W. A. Fowles J. Less-Common Metals 1964 6 299; G. W. A. Fowles and R. A. Walton ibid. 1963,5 510. lZ4 D. K. Straub R. S. Drago and J. T. Donoghue Znorg. Chem. 1962,1,848. lZ5 P. Walden 2. phys. Chem. 1906 54 182; P. Walden and E. J. Birr ibid. 1929 144,269. lZ6 D. M. L. Goodgame M. Goodgame and F. A. Cotton J. Amer. Chem. SOC. 1961,83,4161; J. C. Barnes and D. N. Hume Znorg. Chem. 1963,2,444. lZ7 See e.g. R. L. Ryan and C. K. Jmgensen Mol. Phys. 1964 7 17; B. J. Brisdon and R. A. Walton J. 1965 2274. lZ8V. A. Kargin V. A. Kabanov V. P. Zubov and A. B. Zezin Doklady Akad. Nauk S.S.S.R. 1961,139,605 E. Oikawa and S. Kambara J. Polymer Sci. B Polymer Letters 1964 2 649. mole of solute per litre.

ISSN:0009-2681    

DOI:10.1039/QR9651900126

出版商:RSC    

年代:1965

数据来源: RSC

摘要:

CARBON-13 NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY By J. B. STOTHERS (UNIVERSITY OF WESTERN ONTARIO LONDON CANADA) IN 1957 the first of successful determinations of nuclear magnetic resonance of 13C nuclei in natural abundance appeared and since then although relatively few investigators have pursued n.m.r. studies of this nucleus sufficient work has been done to indicate several features which offer new approaches to problems of chemical interest. It is the purpose of this Review to examine the present state of knowledge in this field to draw attention to some of the major problems and to indicate potential areas in which the technique should provide rewarding information. The Review is not intended to provide an introduction to n.m.r. spectroscopy in general since several excellent sources are a~ailable.~ The results which can be obtained directly from carbon spectra are our prime consideration.Consequently we are concerned for the most part with the chemical shift which has been called “the most important single parameter to be derived from the n.m.r. ~pectrum”.~~ Two earlier reviews of this field have ap- peared. 9 4 1. Introduction Many of the chemical applications of n.m.r. spectroscopy have become routine and several reviews of these have been published although most are concerned primarily if not entirely with the spectra of lH and 19F n ~ c l e i . ~ ~ It is therefore appropriate to compare the techniques of 13C spectroscopy and the data therefrom with those of the more familiar cases. Compared with protons the major differences for 13C are its low natural abundance (1.1 %) and smaller magnetic moment.These factors make direct measurements by n.m.r. difficult since at constant field the signal strength for 13C is 1.76 x relative to unity for lH. Nevertheless (a) P. C. Lauterbur J. Chem. Phys. 1957 26 217; (b) Ann. New York Acad. Sci. 1958,70 841. (a) J. A. Pople W. G. Schnieder and H. J. Bernstein “High Resolution Nuclear Magnetic Resonance” McGraw-Hill Book Co. Inc. New York 1959; (6) L. M. Jack- man “Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chem- istry” Pergamon New York 1959; (c) H. S. Gutowsky “Nuclear Magnetic Resonance” in Technique of Organic Chemistry vol. I Part IV 3rd edn. Interscience New York 1960; (d) W. D. Phillips “High Resolution H1 and Fl9 Magnetic Resonance Spectra of Organic Molecules” Ch.6 in “ Determination of Organic Structures By Physical Methods” ed. F. C. Nachod and W. D. Phillips Academic Press New York 1962; (e) C. P. Slichter “Principles of Magnetic Resonance” Harper and Row New York 1963. P. C. Lauterbur “Nuclear Magnetic Resonance Spectra of Elements Other Than Hydrogen and Fluorine” Ch. 7 in “Determination of Organic Structures by Physical Methods” ed. F. C. Nachod and W. D. Phillips Academic Press New York 1962. J. B. Stothers “Applications of n.m.r. Spectroscopy” Ch. IV in “Elucidation of Structures by Physical and Chemical Methods” ed. K. W. Bentley vol. XI Technique of Organic Chemistry Interscience New York 1963. 144 a C. H. Holm J. Chem. Phys. 1957,26,707. STOTHERS 13C N.M.R. SPECTROSCOPY 145 this is within the capabilities of present spectrometers and future develop- ments will no doubt improve the situation.Because of the low sensitivity and long relaxation times Tl relatively large samples are required to ob- tain maximum signa1:noise (S/N) ratios and thus the attainable field homogeneity is less than that obtained with lH and 19F. On the favourable side there are features which tend to compensate for some of the difficul- ties. Since its nuclear spin I is 3 the 13C nucleus has no nuclear quadru- pole moment and sharp signals are expected if spin-couplings with other nuclei are resolved While this is indeed the case for spectra of 13C- enriched compounds in general only direct one-bond interactions (e.g. C-H C-F etc.) are resolved in natural abundance spectra. These coupling constants are in the range 120-350 c./sec.The observed bands are broadened by longer range interactions which are usually <10 c./sec. There are no complications due to 13C-13C interactions since the proba- bility of molecules having two adjacent 13C nuclei is very small The total variation in 13C chemical shifts (including ionic compounds) is known to be at least 450 p.p.m. (ca. 7 kc./sec. at 15.1 Mc./sec.) and spectra consisting of easily identifiable multiplets are obtained. The spectrum of butenone (Fig. 1) provides an example having each of the common multiplets. p;c H-+ c.0 m I “h n Y Me FIG. 1. 15.085 Mc./sec. 18C spectra of butenone CHa=CHCOCH3. 2. Experimental techniqaes (a) Determination of Spectra.-Up to the present rapid-passage dispersion mode conditions using liquid samples have been employed for most studies of natural abundance 13C n.m.r.spectra. In general conven- tional high resolution absorption mode operation leads to saturation of the absorbing nuclei because of the high radiofrequency power required 146 QUARTERLY REVIEWS for detection of weak signals. Typical results and the basic features of the dispersion mode technique have been discussed* and Fig. 1 illustrates these. In particular it is important to note that the multiplets tend to be skewed and it is essential that measurements be made in both sweep direc- tions and averaged to obtain the true peak positions and relative intensi- ties. The skewing of the multiplets is attributed to “magnetisation transfer” during the period of the ~ c a n . ~ ~ ~ As an example of this effect consider the four bands assigned to the methyl carbon in Fig.1. The first transitions recorded in each scan are more intense than the others. When the two traces are combined it can be seen that the total intensity for each transition very closely approaches the expected 1 3 3 1 binomial ratio. The fact that skewed multiplets are often produced can be helpful for spectral analysis. For practical purposes an approximate limit can be placed on the sensitivity of rapid passage dispersion mode operation at 15.1 Mc./sec. In 15 mm. diameter cells a carbon nucleus giving rise to a narrow singlet can be detected at a concentration of ca. 1 gram-atom per litre for which case a signal intensity having a SIN ratio of ca. 3 can be expected. In general therefore molar solutions are required to detect the presence of a specific carbon nucleus.If the nucleus is strongly spin-coupled to other nuclei more concentrated solutions are of course necessary. As a specific example of the lower limit for detection the absorption of a fully sub- stituted nucleus such as a ketonic carbonyl carbon in a molecule of molecular weight 250 can be measured by use of a 250 mg. sample. These figures are approximate however and will vary with the particular spectro- meter employed and the breadth of a particular signal but the values may be used to estimate the applicability of the technique for specific cases. Certain modifications of the usual method directed at improving the SIN ratio have been developed. One interesting albeit limited means of over- coming difficulties associated with saturation due to inefficient reIaxation of the absorbing nuclei was reported by Forsh and Rupprecht.’ They employed a flow method whereby the liquid sample contained in a large reservoir in the magnetic field was continuously pumped through the resonance coil.A signal enhancement of ca. three-fold relative to that ob- tained for a stationary sample was realised. While specific applications of this approach may be envisaged its practical limitations are too restric- tive for general use. Shoolery* demonstrated that better resolution can be observed in the absorption mode using spinning samples and a specially constructed receiver insert but the sensitivity is not enhanced. Much more generally useful improvements have arisen from recent developments in double resonance techniques whereby more than one nucleus is excited simultaneously through the use of two (or more) radio- frequencies.If an observed nucleus is spin-coupled to a second nucleus H. M. McConnell and D. D. Thompson J. Chem. Phys. 1957 26 958; 1959 31 85; A. Patterson and R. Ettinger Z. Elektrochem. 1960,64,98. S . Fordn and A. Rupprecht J. Chem. Phys. 1960,33 1888. J. N. Shoolery 3rd Conf. Exptl. n.m.r. Pittsburgh March 1962. STOTHERS 13C N.M.R. SPECTROSCOPY I47 which is irradiated simultaneously the spectrum is perturbed the effects of the perturbation depending on the relative power level for the second radiofrequency. In 1955 Bloom and Shooleryg described the effects of such perturbing radiofrequency fields in some simple systems and the subject has been reviewed recsntly.1° Lauterbur demonstrated the poten- tial of the method for 13C spectroscopy several years employing a field sweep technique whereby the 13C spectrum is observed in the normal way while protons spin-coupled to the carbons are irradiated at their resonance frequencies.If the power level for proton irradiation is suffici- ently large the 13C-lH interactions are effectively eliminated and the multiplets collapse to form singlets. An additional benefit in these “spin- decoupling” experiments is the occurrence of a positive nuclear Over- hauser effectlo which tends to increase the intensity of the observed singlets over that expected for simple collapse of the multiplet. Very often the enhancement is more than two-fold for normal dispersion mode operation representing a substantial aid for the study of natural abundance spectra. For maximum effect the perturbing radiofrequency field must be at the resonance frequency of the second nucleus but partial collapse of the original multiplet results if it is close thereto.To illustrate a typical result for a simple system the 13C spectra of pyridine obtained at three different settings of the proton radiofrequency field are given in Fig. 2(b-d). Enhancement due to an Overhauser effect is clearly apparent. In practice complete decoupling cannot be achieved merely by using a sufficiently large radiofrequency field and a residual coupling effect may be observed.ll This can be largely eliminated however by frequency modulation of the second radiofrequency field.12 An elegant application of the double resonance method for observing weak spectra has been developed by Baker,13 employing two frequency synthesisers in combination with a proton-stabilised frequency-sweep spectrometer.In effect one source supplying low radiofrequency power is held on the peak of a sharp absorption line of nucleus A while the second source at higher radiofrequency power output is used to sweep the frequency through the spectrum of nucleus X. If A and X are spin- coupled the intensity of the A transition will change as the resonance frequencies of X are traversed. If the power level in the X spectrum is suitably adjusted these intensity changes of the A line will duplicate the actual X spectrum. The method termed i.n.d.0.r. (internuclear double resonance) spectroscopy is without doubt an important advance but un- fortunately the cost of the instrumentation required will hinder its general application.A. L. Bloom and J. N. Shoolery Phys. Rev. 1955,97,1261. lo J. D. Baldeschwieler and E. W. Randall Chem. Rev. 1963,63,81. l1 W. A. Anderson and R. Freeman J. Chem. Phys. 1962,37,85. l2 W. A. Anderson and F. A. Nelson J. Chem. Phys. 1963,39,183. l3 E. B. Baker J. Chem. Phys. 1962 37 91 1 ; R. Freeman and W. A. Anderson ibid. 1963 39 806. 148 b) QUARTERLY REVIEWS I I I I H- FIG. 2. 15.085 Mc./sec. 13C spectra ofpyridrite showing efects of simultaneous irrdiatwn at 60 Mc./sec. (a) Normal spectrum (6) with u-protons decoupled (c) with y-proton decoupled and (6) with F-protons decoupled. A more easily realised approach for both improved resolution and sen- sitivity is that described by Paul and Grant,l4J6 utilising absorption- mode operation and proton spin-decoupling with or without sample spinning.An additional benefit of much more accurate chemical shift data can be realised if the two irradiating frequencies are measured accurately (1 in lo6) at the instant of maximum decoupling. At present their tech- nique appears to offer the best approach for n.m.r. study of 13C in natural abundance. It should be emphasised that conventional high resolution absorption mode conditions are entirely adequate for the study of 13C-enriched compounds and several examples have been published (e.g. see refs. 16 17). (b) CalibratioD.-Audio side-band modulation is the usual means of calibration for a 13C spectrum with the exception of the newer methods mentioned above. For internal referencing a strong signal (often a solvent band) may be chosen and the positions of the remaining bands measured relative to it by interpolation.Otherwise an external reference preferably l4 €2. G. Paul and D. M. Grant 14th Cod. Anal. Chem. Appl. Spec. Pittsburgh March 1963. l6 E. G. Paul and D. M. Grant J. Amer. Chem. SOC. 1964,86,2977. l6 K. Frei and H. J. Bernstein J. Chem. Phys. 1963,38,1216. D. M. Graham and C. E. Holloway Canad. J. Chem. 1963,41,2114. STOTHERS 13C N.M.R. SPECTROSCOPY 149 enriched in 13C can be employed. In the latter case bulk susceptibility corrections are required for the most precise work unless specially con- structed cells are used.1s If the sample and external reference are con- tained in concentric spherical cavities centred in the detector coil bulk susceptibility differences are eliminated. More commonly 13C spectra have been obtained using test-tubes (15 mm.diameter) containing several cm. height of liquid to approximate the infinite-length criterion for cylindrical samples3a and bulk susceptibility corrections are often neglected because of their small effects on the relatively large chemical shift difference for 13C nuclei. In general the precision of measurement of the line positions is ca. 5 c./sec. at 15.1 Mc./sec. and the accuracy of the chemical shift data is of the order 0.3-0-5 p.p.m. for dispersion-mode operation. As noted earlier a marked improvement can be realised by using the optimum conditions described by Paul and GranP for which the shift error is &0.07 p.p.m. at 15.1 Mc./sec. with the resolution approaching 1.5 c./sec. The problem of choosing a suitable reference compound has been discussed* and it appears that carbon disulphide offers the best compromise for this purpose.Since 13C-enriched CS2 is not readily available however extensive use has been made of secondary reference compounds containing excess of 13C e.g. methyl iodide sodium acetate dimethyl carbonate and sodium carbonate. The observed data are subsequently converted to a more common scale having either C6H6 or CS as an arbitrary zero point. The latter is employed throughout this Review. (c) Spectral Analysis.-As mentioned earlier first-order patterns generally arise in these spectra and their multiplicities and relative in- tensities (averaging both sweep directions) provide the primary evidence for the analysis. The first problem is to distinguish the transitions which belong to each of the various multiplets.Spin-decoupling experiments are a valuable aid for this sorting process particularly for cases in which there are several overlapping multiplets. In the ideal case one can transform a complex spectrum into a series of singlets one band for each chemically shifted carbon nucleus and so reduce th6 poblem to a measurement of these peak positions i.e. the relative chemical shifts. The second stage in the analysis is the assignment of a particular band to a specific carbon nucleus. Again the observed multiplicities and intensi- ties are helpful combined with a knowledge of chemical shifts for suitable model compounds. The problem of band assignment is simplified con- siderably by the fact that the effects of substituents on chemical shifts are very often additive.Unequivocal assignments can be made by a comparison of the 13C spectrum of a compound containing deuterium at a specific position with that of the unlabelled material. The effect of substitution of lH by 2H (I = 1) is a greatly increased spin-lattice relaxation time TI for the substituted carbon nucleus with the result that under the usual ex- perimental conditions these nuclei are so easily saturated that their signals H. Spiesecke and W. G. Schneider J. Chem. Phys. 1961,35 722. 150 QUARTERLY REVIEWS are not ordinarily observed. Spiesecke and Schneider19 have demonstrated the utility of this approach and have given some typical spectra. 3. Survey of Results In the main the available data have been obtained for relatively simple molecules (< 16 carbon atoms) but several examinations of homologous series and series of closely related compounds have revealed certain general trends exhibited by the 13C chemical shifts and 13C-X coupling constants.Sufficient progress has been made to allow an assessment of the principal factors contributing to the shielding of 13C nuclei and to permit one to suggest possible applications. To illustrate the general behaviour of 13C nuclei in various organic molecules some specific results are outlined in this section after which a discussion of the findings and applications of these is presented. For the common functional groups 13C nuclei absorb over the range -25 to +200 p.p.m. (relative to CS2) as illustrated in Fig. 3. alkenes a I ka nes 8 RGR - - - ;c=c= -c=c- oryl C-0 aryl C mtm RCH lxxa - fs 0 Q n>3 n=3 7 2 C6H6 CH,OH C6H, CH 0 I00 2 0 0 p.p.m.H- 1 I I I I I 1 I I I I 1 FIG. 3. Range of lSC chemical shijh for common organic carbon nuclei. (a) Chemical Shift Results.-@ Aromatic hydrocarbons. One of the first surveys of a specific family of compounds was that carried out by Lauterbur2* at 8.5 Mc./sec. for the series benzene methylbenzenes biphenyl naphthalene phenanthrene pyrene acenaphthylene fluoran- 19 H. Spiesecke and W. G. Schnieder J. Chem. Phys. 1961,35 731. 20 P. C . Lautexbur J. Amer. Chem. Soc. 1961 83 1838. STOTHERS 13C N.M.R. SPECTROSCOPY 151 thene and azulene. For the alternant hydrocarbons the carbon shieldings for the nuclei bonded to two other carbons only differ very slightly (<l p.p.m.) from that of benzene 65.0 p.p.m. while the carbon nuclei at ring junctions absorb at appreciably lower field (55-61 p.p.m.).For the non- alternant hydrocarbons the aromatic nuclei absorb over a much wider range (52-74 p.p.m.) and even though definitive assignments were not possible the two types of hydrocarbon exhibit clear differences. Since theoretically the sigdicant distinction between the alternant and non- alternant hydrocarbons is that for the former the n-electron density qc at each carbon is very close to unity while for the latter large differ- ences may result at various positions it follows that 13C shifts in aromatic systems may be governed by the n-electron distribution. For azulene a more complete assignment of the signals to specific nuclei was accom- plished by comparing spectra of some substituted (CH and 2H) derivatives.From this analysis the 13C shielding of a specific carbon A uA was shown to correlate approximately with the n-electron density q A . The “best fit” was given by the results of a v.e.s.c.f. treatment. This result led to an expression for the chemical shift (relative to benzene) AuA of the form ACT = u (qA - I) (1) where u is a positive constant of ca. 200 p.p.m. Lauterbur21 obtained another estimate a w 160 p.p.m. indirectly from a comparison of the data for several aromatic derivatives (see p. 162). Shortly afterwards Spiesecke and SchneiderZ2 published results bearing on this relation and the azulene problem. They measured the 13C shifts for C,H,- C,Hg C,H,+ and CsHs2- for which the n-electron densities are taken as known and obtained the value u M 160 p.p.m. It is clear therefore that aromatic carbon shieldings are strongly dependent on local 7-r-electron densities.The results for the methyl-substituted benzene series indicated two general features of aromatic I3C shieldings. The more distinctive of these is a pronounced deshielding of ca. 9 p.p.m. at an aromatic carbon upon replacement of hydrogen by methyl. The origin of this change is as yet unexplained but it cannot be attributed entirely or even substantially to a neighbour-anisotropy effect although this has been suggested. It is par- ticularly interesting that this deshielding influence is approximately constant for a large variety of aromatic derivatives and only for cases in which there is substantial steric interference with the methyl group are marked changes in its magnitude found. The second feature which was recognised although the differences are small was that the indirect effects of a methyl group on the other aryl carbons are additive with successive methyl substitution on the ring provided the methyl groups are in meta or para orientations.(ii) OZefinic hydrocarbons. Although the early 13C results showed that 21 P. C. Lauterbur Tetrahedron Letters 1961 No. 8 274. 22 H. Spiesecke and W. G. Schneider Tetrahedron Letters 1961 No. 14 468. 152 QUARTERLY REVIEWS olefinic carbon nuclei absorb in the same region as aromatic carbon,2 a systematic study of olefins has only recently been reported.23 Friedel and Retcofsky determined the 13C spectra of several pentenes hexenes and heptenes as well as some dienes. Their results demonstrated additional general features of 13C shieldings.From the data for twenty-two mono- olefins which exhibit absorption over the range 40-87 p.p.m. it was apparent that the effects of methyl substitution on or close to the olefinic carbons are approximately additive. Replacement of an olefinic hydrogen tends to deshield the substituted carbon and to shield its doubly-bonded neighbour. These changes were invariably found although their magnitude depends on the location of the double bond in the carbon skeleton. Examples are given in Table 1 together with those for an aromatic system benzene -+ toluene,ls and certain aliphatic systems discussed below. Friedel and Retcofsky’s results have been analysed recently in another way,Z4 to show that for simple hydrocarbons the 13C chemical shift TABLE 1. Efect of methyl substitution on 13C shieldings in various hydro- carbon skeletons (in p.p.rn.relative to parent compound) Parent Cpd Shift due to CH substitution at C(,) at C(a) -9.1 -10 f 0*5* -6.6 f 1*4* - - 7.2 - 9.35 -9.19 -9.88 +7.6 f 1*2* - + l a 1 f 1.0* - - + 1-6 + 4.4 - -9.51 + 2.45 -9.47 + 2-49 - 9-98 $2-10 * Figures represent ranges observed for several examples. C(d) + 2.8 - - + 0.2 - -0.51 -0.35 - 0.50 Ref. 19 23 27 2s R. A. Friedel and H. L. Retcofsky J. Amer. Chem. SOC. 1963 SS 1300. 24 G. B. Savitsky and K. Namikawa J. Phys. Chem. 1964,68,1956. STOTHERS 13C N.M.R. SPECTROSCOPY 153 may be a constitutive property largely dependent on the immediate chemical environment of a specific nucleus. From the data for olefins including values for some cycloalkenes and simple alkanes,le a set of ten empirical bond parameters- was determined from which 70 reported shifts for sp3 and sp2 carbons were calculated to within 2 p.p.m.In contrast to other spectroscopic methods 13C shieldings are not sensitive to double-bond conjugation in simple dienes. The carbon shifts for buta-1,3-diene are close to those found for the olefinic carbons in pent-1-ene hex-1-ene and styrene,25 with the larger deviation exhibited by the terminal carbons (ca. -3-5 p.p.m.) a difference which is absent from a comparison with penta-l,4-diene and hexa-l,5-diene. A most interesting observation was made for the allenic dienes for which the central carbon [e.g. C(2) in buta-1,2-diene] absorbs at 4 0 p.p.m. to lower field than any other unsaturated nucleus in the hydrocarbon series in the range -16.7 to -13.4 p.p.m.An explanation for this remarkable shift has been offered (see p. 161). (iii) Acetylenic hydrocarbons. A few alkynes have been exarnined4J6,23 and the shifts for the sp-hybridised carbon atoms were found in the range 104-129 p.p.m. This region is virtually free from other 13C signals and thus acetylenes are readily identifiable. Until very recently the reported 13C spectra of alkanes19 included only those for CH, C,H6 C3H8 CH(CH3), and C(CH,) since the chemical-shift differences for saturated carbon nuclei are relatively small in the higher homologues and the signals are not resolved sufficiently by the usual pxocedures. Using their improved method15 described earlier Paul and Grant carefully measured the 13C shieldings for the linear alkanes up to C, and showed26 the existence of additive substituent effects such that the observed chemical shifts were described by a linear relation.26 From the results of these spectra and those of the branched hydrocarbons up to cg these authors suggested a slightly modified linear expression of the form (iv) Aliphatic and alicyclic hydrocarbons.to account for the n-alkane In equation (2) the shift of the kth carbon (relative to C6H6) is given by the sum of the products of the number of carbons in the lth position (i.e. Q 16 y 6 or E relative to C,) and a factor A which is an additive parameter for that position plus a constant 13 1.26 which is very close to the shift difference between C6H6 and CHI 130.8 p.p.m. To apply equation 2 five variables were evaluated; the standard deviation of the fit for 30 observed n-alkane shifts was 0.21 P.P.m.For the branched compounds eqn. (2) does not give satisfactory 26 K. S. Dhami and J. B. Stothers Canad. J. Chem. 1965,43 510. 26 E. G. Paul and D. M. Grant J. Amer. Chem. SOC. 1963,85 1701. 27 D. M. Grant and E. G. Paul J. Amer. Chem. SOC. 1964 86 2984. 154 QUARTERLY REVIEWS results unless eight additional variables are used. To account for the effects of neighbouring groups on the carbon shieldings an analysis of the neighbour-anisotropy effects of the C-C bonds was attempted using the simple point-dipole model.2a While it is interesting that a linear relation of the form expected was obtained the required value for the anisotropy of the magnetic susceptibility of a C-C single bond dxc-c was 416 x lo-* ~m.~/mole a figure which is ca.lo2 larger than all previous e~tirnates.~~ The last entries in Table 1 illustrate the effect of methyl substitution at the various carbon nuclei in a hydrocarbon chain for comparison with the unsaturated systems. The cycloalkanes C3 to C17 have been examined by 13C n.m.r. spectro- copy^^ and the most striking feature of these data is the remarkably high field position for cyclopropane 196-3 p.p.m. Its position is virtually the same as that for methane 195.8 p.p.m.la The other members of this series exhibit absorption over the range 164-170 p.p.m. (Fig. 4) varia- tions within which have been ascribed to conformational effects. The shieldings for the medium rings C 2-C17 closely approach the values for long-chain linear alkanes but do not overlap. To explain the high-field position of the cyclopropyl signals Burke and L a ~ t e r b u r ~ ~ using a ring- current model found that a satisfactory accounting for the observed shielding required a current due to 3.5 electrons flowing in a ring of radius 1-10 A.No suitable method is available for estimating a ring-current contribution in the larger rings. (v) AZiphatic derivatives. In 1958 LauterbuP published the results of a survey of several series of methane derivatives to show that within a group of closely-related compounds the 13C chemical shifts followed a strikingly regular variation. As examples a plot of the data for the series (CH3),Z where Z = N C Si Sn against the Pauling electronegativity of Z gives a straight line as does the plot for the series with Z = Cl Br I but the slopes are different. Nearly linear variations of shift with composi- tion were also found for several other series [such as Me,H(,-,,CZ and Z,CH(3-Z) for x == 1,2,3] although again the slopes differ for each.Spiesecke and SchneideP later attacked the problem of 13C shieldings in simple alkyl derivatives through an examination of the lH and 13C shifts in several CH3X and CH,-CH,X molecules and found that all values do not correlate with substituent electronegativity. The greatest deviations were exhibited by compounds having X = I Br C1 S while the others X = F 0 N C Si H showed reasonably linear changes. The deviations were attributed to neighbour-anisotropy contributions of the C-X bonds and the authors concluded that the observations were adequately explained by the interplay of these two factors. Savitsky and Namikawa31 have 28 J.A. Pople Proc. Roy. SOC. 1957 A 239,550; H. M. McConnell J. Chem. Phys. 1957 27 226. 29 A. G. Moritz and N. Sheppard Mol. Phys. 1962,5,361. 90 J. J. Burke and P. C. Lauterbur J. Amer. Chem. SOC. 1964,86 1870. 31 G. B. Savitsky and K. Namikawa J. Phys. Chem. 1963,67,2430. STOTHERS 13C N.M.R. SPECTROSCOPY 155 recently analysed the figures for the series RZ with R = Me Et Pri But; Z = F 0 N C C1 Br I C,H, C02H and found that for each 2 except OH it was apparent that there is a regular change with increasing bulk of the Z group in addition to the trends previously noted. These authors concluded that the additive effects of successive methyl substitution on the a-carbon are related to the C-2 bond distance suggesting a contribution due to bond hybridisation in addition to the other factors.(vi) Aromatic derivatives. Much attention has been focused on the 13C shieldings in aromatic systems since the first reportlb of their dependence on substituent polarity. For the monosubstituted benzenes Lauterbur2' noted a correlation with the Hammett (T parameter and compared the variations with those previously found for 19F and lH resonances in similar c o m p o ~ n d s . ~ ~ ~ ~ ~ The p-carbon shifts display the best linear behaviour and it was suggested that the 13C shieldings may be more simply related to ground-state electron distributions than either those for 19F or lH. Unequivocal proof for the assignmets of the aryl shieldings was provided by Spiesecke and SchneiderlS by a comparison of the spectra of specifically deuterated derivatives with those of the normal monosubstituted benzenes C,HSX [X = F C1 Br I CH, OCH, NH2 N(CH3)2 CHO C02CCl, NO2].A total range of 60 p.p.m. is found for the aryl shieldings with the largest variation shown by the C(l) nucleus. The 18 p.p.m. variation for the C(4) shifts exhibits a good linear dependence on the Hammett 0 parameter while the meta-carbon atoms (C(,) and C(51) are little affected by the substituent appearing over a total range of only 2-6 p.p.m. As noted above 19F shieldings appear to depend on the (T parameter and are correlated by an expression3* M a 1 + @R (3) @ara = Taft has found that except for + R groups eqn. (3) is applicable to 13C data by using the constants o( = 6.0 18 = 23-0 both of which differ somewhat from those required for 19F data. La~terbur,~,~ has systematic- ally examined the 13C aryl shifts for a variety of methyl-substituted benzene derivatives (CH3),C6H4-,X [X = OH OCH, I NH2 N(CH3)2 NO2] and found that successive substitution of methyl groups on the aromatic ring causes additive variations in the aryl shieldings.Thus if the substitu- ents are not ortho the aromatic 13C shifts in polysubstituted cases are given by the algebraic sum of the effects observed for the monosubstituted benzenes. In these cases and the agreement between observed and calculated values is often -1 p.p.m. and generally the deviations are less than 2 p.p.m. If the substituents are ortho larger deviations are usually 32 R. W. Taft J. Phys. Chenz. 1960 64 1805 and earlier references. 33 R. R. Fraser Canad. J. Chem. 1960 38 2226. 34 R. W. Taft 3rd Ann. Conf.SOC. App. Spect. Cleveland Sept. 1964. 35 P. C. Lauterbur J. Amer. Chem. Soc. 1961 83 1846. 36 P. C. Lauterbur J. Chem. Phys. 1963 38 1406 1415 1432. 37 G. B. Savitsky J. Phys. Chem. 1963 67 2723. 156 QUARTERLY REVIEWS found. Lauterbur has refined the treatment of substituent effects in the polysubstituted cases to account for the various patterns exhibited in an effort to extract more information from the available data although inter- pretations of small deviations from additivity in terms of n-electron dis- tributions are questionable before solvent effects are better under~tood.~' For structural analysis however the simple additivity relation should prove useful on its own. Since the carbonyl carbon nucleus absorbs at low-field in a region relatively free of other signals this grouping is well suited for n.m.r.study. In the usual conditions a singlet is observed for all carbonyl carbons except that of the formyl group for which a well defined doublet arises JC-H = 165-205 c./sec. Surveys of carbonyl resonance positions have been r e p ~ r t e d ~ ~ ~ ~ ~ to show that these signals are found over a range of ca. 70 p.p.m. and that some of the effects encountered in the infrared and ultraviolet spectra for this grouping are manifest in their 13C spectra. These results indicated that 13C carbonyl data would prove to be useful adjuncts to other physical measurements. The normal absorption regions for the common carbonyl groups are included in Fig. 3. From the available data interfering signals in this portion of the 13C spectrum are restricted to those of some olefinic carbon^,^^^^^^^ the central allenic nucleus,23 oxime~,~ and CS2.For reasons noted below it seems probable that solvent effects could be used to dis- tinguish carbonyl signals from these others although in any case the presence of a carbonyl group may be confirmed by the infrared spectrum. The major factors contributing to carbonyl shieldings include substitu- tion conjugation hydrogen-bonding and ring size in cyclic Alkyl groups on or near C, the carbonyl carbon produce changes direc- tionally similar to those found for the hydrocarbons although the magni- tude is much reduced ca. -5 p.p.m. Clearly a neighbour-anisotropy effect cannot be the sole reason for this general trend but its origin is not obvious. Substitution by an electronegative atom on the carbonyl carbon gives the opposite effect.For example replacing a directly bonded carbon or hydrogen by oxygen nitrogen or chlorine invariably produces a high field shift of the carbonyl peak. One possible explanation of this change is that the substituent alters the electronic configuration of the C=O bond such that a net increase in n-electron density at the carbonyl carbon results. Simple HMO calculations support this.41 To judge from the data for several aliphatic polychlorinated compounds further substitution at the cc-posi- tion enhances this effect. The changes due to increased chlorine substitution have been examined39 in several carbonyl series and have been found to be qualitatively similar although there are quantitative differences. Not (vii) Carbonyl compounds. 38 P. C. Lauterbur Abst.138th Meeting Amer. Chem. SOC. New York 1960 p. 22B. 38 J. B. Stothers and P. C. Lauterbur Canad. .I. Chem. 1964,42 1563. 40 D. H. Marr and J. B. Stothers Canad. J. Chem. 1965,43,596. 41 S ForsCn Spectrochim. Acta 1962 18 595. STOTHERS I3C N.M.R. SPECTROSCOPY 157 unexpectedly the a-hydroxyl group does not give the same result because of hydrogen-bonding. The very pronounced deshielding caused by intra- molecular hydrogen bonding was first noted in the study of substituted methyl benzoateslb and has been found to be quite general for carbonyl arbo on.^^^^^ Note that meta- and para-substituents in aromatic carbonyl compounds do not affect the carbonyl shieldings appreciably (see Table 2). TABLE 2. Substituent effects on carbonyl shieldings in various comp0und.r (in p.p.m.Jrom CS,) R R-CHO R*CO*CH3 R.C02H R.C02*CH3 H- - - 6.8 27.0 (33*0)* CH3- - 6.8 - 12.3 15.6 23.0 CH,=CH- 0.4 - 4.4 20-5 29.2 1-8 - 3.2 20.2 26.7 - 27.6 - 27.2 C,H€D- .Q-NO&,H,- (4.017 - 3.3 4-MeO-C,H4- 2.6 - 2.9 * Value for ethyl ester. t m-NOz derivative. Perhaps the most interesting trend is that exhibited by conjugated systems relative to the corresponding saturated analogues. In general conjugated carbonyl carbons absorb at the higher field. This difference has been observed for all types of carbonyl function examined although its magnitude differs somewhat in each series. In addition the results show that although not precisely the same the effects of a double bond and an aryl ring are comparable. The data for a few carbonyl functions are given in Table 2 to illustrate these points.In alicyclic systems the carbonyl carbon shielding depends on the ring size but does not follow the behaviour displayed by the cycloalkanes (see Fig. 4). An interpretation of the results illustrated in Fig. 4 presents a difficult problem. The most puzzling feature is the remarkably low-field position of cyclopentanone and other five-membered ring carbonyl compounds.39 A similar difference is found for certain ketonic derivatives including dimethyl ketals dioxolans and dithi~lans.~~ Significant although lesser differences from the others are exhibited by the eight- and nine- membered rings as well. Minor contributions due to conformational effects may account for the relatively small changes in the remaining examples the behaviour of which is analogous to the hydrocarbons except that the observed shifts are comparable to those found for acyclic ketones.(viii) Carbonium ions. lH and 19F n.m.r. spectra have proved to be valuable for the positive identification of aliphatic carbonium ions44 42 G. E. Maciel and G. B. Savitsky J. Phys. Chem. 1964 68,437. 43 M. Anteunis D. A. Ross and J. B. Stothers unpublished observations. 44 N. C. Deno Chem. Eng. News 1964 Oct. 5 p. 88; N. C. Deno C. V. Pittman and M. J. Wisotsky J. Amer. Chem. Soc. 1964 86 4370; D. M. Brouwer and E. L. Mackor Proc. Chem. SOC. 1964 147. 158 185- 175 ma QUARTERLY REVIEWS at 196.3 - - Cycloa I kanes Ring size FIG. 4. Variation of lSC shieldings with ring size for cyclohexanes (upper) and carbonyl and more recently 13C spectroscopy has been utilised as well.45 For example the 13C spectrum of CH,.CO+SbF,- shows clearly that a partial positive charge is located on the carbonyl carbon.Employing the i.n.d.0.r. method (see p. 147) and 13C-enriched the carbonyl carbon signal was found at -45.4 p.p.m. relative to that in CH,COF. Larger low-field 13C shifts have been observed for other cations including (CH-),C+ (-273 p.p.m. from B u ~ C ~ ) ~ ~ ~ and (C,H5)3C+ (-129.6 p.p.m. from Ph3C.0H).45c Although some of these changes may be due to solvent effects (these alkyl cations were examined in SbF and H,S04 solutions respectively) the pronounced deshielding in the cations clearly indicates a concentration of positive charge on carbon and an effect of delocalisation over the aromatic rings is apparent. It is unfortunate that the low concen- tration of these ionic complexes precluded measurements of the other shieldings which must await technical advances.(b) Coupling Constants.-Since the prime aim of this Review is an examination of 13C shielding results only the important features of 13C 45 (a) G . A. Olah W. S. Tolgyesi S. J. Kuhn M. E. Moffatt I. J. Bastein and E. B. Baker J. Amer. Chem. Soc. 1963,85 1328; (b) G. A. Olah E. B. Baker J. C. Evans W. S. Tolgyesi J. S. McIntyre and I. J. Bastein ibid. 1964 86 1360; (c) G. A. Olah E. B. Baker and M. B. Comisarow ibid. p. 1265. carbon nuclei in cycloalkanones (lower.) STOTHERS "C N.M.R. SPECTROSCOPY 159 spin-coupling interactions are noted in this section to acquaint the reader with current developments and to provide key references. Normally direct one-bond 13C-X coupling interactions are well-resolved in natural abund- ance spectra but the precision of measurement is low (- &3 c.[sec.).Thus better data (- 5 1 c./sec.) are obtainable from 13C satellite In addition longer-range interactions are resolved in the latter. The Jzac-lx parameter shows promise for both practical and theoretical prob- lems particularly the relatively large one bond J's (120-250 c./sec.). For these Muller and Pritchard4' first noted that JiaC-iH values correlate with bond properties specifically the hybridisation of the C-H bond and hence the bond length. They suggested equation (3) to account for their observations for several hydrocarbons where p C-H is the percentage of s character of the bonding C orbital. Their results indicated that bond polarity is relatively unimportant. Later Malin~wski~~ showed that the effects of substituents on JiaC-iH in several substituted methanes are very nearly additive and a theoretical interpreta- tion was For the halogenomethanes an evaluation by the maximum overlap orbital treatment has been given.5o Since eqn.(3) was suggested several reports of the apparent linearity of pc-H with JCeH have appeared and some workers have assigned values for the s character of specific bonds in various structures. The latter step seems premature in view of the steadily increasing number of exceptions found re~ently.~' It is clear that more study is essential and some pertinent suggestions have been made.51 A more detailed review citing major references should be consulted for further details.52 The question of the signs of coupling constants has attracted interest and on the assumption (now known to be true) that 13C-H interactions are positive the relative signs of other coupling constants were d e d u ~ e d .~ ~ ~ ~ Direct I3C-l3C couplings have received only limited attenti0n~~91~ since such studies require doubly labelled compounds to obtain satisfactory SIN ratios for 13C spectra. A detailed study of several examples has revealed1' that there is no simple general correlation with bond distance except for C-C single bonds but Jc-c is proportional to the product of the s charac- 46 N. Sheppard and J. J. Turner Proc. Roy. SOC. 1959 A 252,506. 47 N. Muller and D. E. Pritchard J. Chem. Phys. 1959 31 768 1471; N. Muller 48 E. R. Malinowski J. Amer. Chem. SOC. 1961 83,4479. H. S. Gutowsky and C. S. Juan J. Amer. Chem.Soc. 1962,84 307. so J. H. Goldstein and R. T. Hobgood J. Chem. Phys. 1964,40 3592. 61 (a) N. Mulier and P. I. Rose J. Amer. Chem. Soc. 1962 84 3975; (6) G. J. Kara- batsos and C. E. Orzech ibid. 1964,86,3574; 1965,67 560. s2 D. M. Grant Ann. Rev. Phys. Chem. 1964,15,489. 6a P. C. Lauterbur and R. J. Kurland J. Amer. Chern. Soc. 1962,84 3405; F. A. L. Anet ibid. 1962 84 3767; S. S. Danyluk ibid. 1964 86 4504; G. V. D. Tiers J. Phys. Chem. 1963,67,928; K. A. McLauchlan Chem. Comm. 1965,105. ibid. 1962,36 359. 1 60 QUARTERLY REVIEWS ters of the carbon atoms forming the various types of C-C bonds and appreciable r-bond contributions to .Ic- are indicated. 4. Discussion of results (a) General Considerations.-Before considering specific applications of 13C techniques to problems of chemical interest the general features of 13C shieldings can be examined in terms of current theory of nuclear screening.For a specific nucleus A the chemical shift depends on the field HA experienced at that nucleus and which is given by HA = Ho (1 - uA) where Ho is the applied field. Following Saika and Sli~hter,~* we may write the total screening constant aA as the sum of three separate quantities (i) (Td a diamagnetic contribution due to local electron currents; (ii) up a local paramagnetic term involving mixing of electronic states by H,; and (iii) a term u‘ for contributions by circulations on all other atoms of the molecule including the effects of neighbouring anisotropic atoms bonds or ring structures. For all nuclei except protons u’ is relatively unimportant. Neighbour- anisotropy effects appear to be of the older of a few p.p.m.for 13C shieldings. Od is given by the well-known Lamb formula and depends on the electron density about A. With Slater atomic orbitals the increase in Ud caused by the addition of a 2p electron is 14 p.p.m. Because of the large differences observed therefore the paramagnetic term up is the dominant contribution to 13C shieldings. It is also related to the electron density at A. The first attempts to correlate 13C shieldings with substituent electro- negativity or polarity have been described above and it is clear that electron-density changes at a particular carbon are reflected by its chemical shift. A linear relation might be expected within a series of compounds for which the ad and up contributions change regularly while 0’ remains constant.The simple aromatic derivatives in which the substituent is well removed from the centre of interest apparently afford suitable systems to judge from the p-carbon shielding results. In aliphatic compounds sub- stituents must be much closer to exert appreciable effects and it seems likely that variable up and u‘ contributions owing to the substituent group are responsible for deviations. As noted before linear changes are observed in closely related aliphatic series with different substituents producing different slopes in the various series. Attempts to rationalise deviations from linearity for “8 against electro- negativity” plots in terms of neighbour-anisotropy effects seem likely to fail since unduly large values for the Ax term in the point-dipole model are required.Even though the model is oversimplified very appreciable effects should be observed for the proton shifts in these molecules since anisotropic contributions would only be slightly modified by the geometric factors. A suitable model is yet to be suggested which will account for the 54 A. Saika and C. P. Slichter J. Chem. Phys. 1954 22 26. STOTHERS 13C N.M.R. SPECTROSCOPY 161 observations. The general trends found in both aromatic and aliphatic derivatives however indicate that the local electron density at a specific carbon nucleus has a major influence on the resonance position of that carbon atom. Inability to account for the trends quantitatively is com- pensated by the general observation of additivity of substituent effects in related compounds. (b) Applications.-In this section several chemical applications of 13C n.m.r.spectroscopy are described but the published results represent only the preliminary stages. In no case can it be said that the method has been fdly developed and consequently some of the following comments are conjectural. Certain areas appear to warrant detailed study and some suggestions have been advanced on the basis of the limited data presently available. (i) Theory of chemical shifts. Because of the large shift differences 13C shieldings offer an excellent means of examining the factors contribut- ing to nuclear shielding. Compared with proton results for which the major factors a d and up exert quantitatively similar but opposite effects and hence the calculated shieldings represent a small difference between two approximate quantities the observed differences for 13C nuclei allow one to separate the variables more successfully.Although there are apparent anomalies one can unravel the major influences in a qualitative manner. Pople has developed55 an approach based on molecular orbital theory of the diamagnetic currents induced in a molecule by an external magnetic field. He showed that the up term must be a major contributing factor to 13C shieldings and as a first approximation was able to estimate up contributions for carbon-carbon multiple bonds and the carbonyl group. The calculated effects are less than those observed by a factor of ca. 2-3. It is interesting that this method predicts a marked low-field shift for the central carbon in an allene as observed (see p. 153). More recently Karplus and P ~ p l e ~ ~ have examined the problem of 13C shifts in conjugated molecules and formulated a molecular orbital theory giving reasonable agreement with experiment but clearly illustrating the need for further studies both experimental and theoretical.They showed that up must be the dominant factor and developed a general expression (6) for the shielding of a carbon A (relative to C6H,) having a charge density qA close to unity and free valence FA close to the benzene value of 0.399; (TA = (86.7 + 46.0 AJ(qa -1) + 46.0 (FA -0.399) (6) where A = 0 for carbon bonded to three other carbons. Equation (6) was obtained from expressions of the form (7) developed for the up term 66 J. A. Pople Discuss. Faraduy SOC. 1962,34,7; Mol. Phys. 1964,7 301. 66 M. Karplus and J.A. Pople J. Chem. Phys. 1963 38 2803. 162 QUARTERLY REVIEWS From (7) it is evident that the paramagnetic term depends on the T- electron density only through the polarity term A for C-H bonds but three other factors enter as well (i) the mean excitation energy for the molecule dE (ii) the dimensions of the 2p orbital r and (iii) the free valence. These factors were discussed in detail and the method was illus- trated with four alternant hydrocarbons and buta-l,3-diene. Further refinements can be anticipated with the appearance of more 13C results. (ii) Estimations of n-electron distributions. As noted earlier remarkably good agreement between experiment and theoretical calculations is given by equation (1) for the correlation of 13C shieldings with =-electron densi- ties.Several examples are discussed by L a u t e r b ~ r ~ ~ and at present the approach appears to be capable of providing as reasonable estimates as those obtained by various theoretical calculations. It has been however that (34 cannot be the major factor responsible for this charge dependence but rather the main contribution must arise from changes in the up term in agreement with a similar conclusion drawn by Saika and Slichter for 19F ~hieldings.~~ Wu and Dailey5' have concluded that observed substituent effects result from the combined effect of at least two separate additive mechanisms one of which is =-electron variation both contribut- ing to the shielding to an approximately equal extent. For organic chemists one of the most important applications of 13C spectroscopy is to provide direct evidence for ground-state electron distri- butions which have previously been surmised on the basis of chemical reactivity only.As an example we may consider cyclohex-2-enone for which it is generally assumed that a polarised form makes a significant contribution to the ground state. Comparison of its carbonyl and olefinic shieldings with those for cyclohexanone and cyclohexene (Fig. 5a) bears A - 4 ' 8 FIG. 5 . lsC shieldings of olefinic and carbonyl carbon nuclei in (a) alicyclic cases and (b) acyclic examples. Values given in p.p.m. from CS,. 67 T. K. Wu and B. P. Dailey J. Chem. Phys. 1964,41,2796. STOTHERS 13C N.M.R. SPECTROSCOPY 163 out the general assumption clearly. The /3-carbon is significantly de- shielded while the carbonyl carbon is shielded as expected for an appreci- able polarisation of the r-electron system by the electron-attracting oxygen atom.The analogous comparison for the acylic series illustrated in Fig. 5(b) leads to a similar conclusion. It is significant that the diene shieldings do not differ greatly from those of the mono-olefin but the effect of the oxygen atom in the conjugated system is pronounced. Both observations are in complete agreement with current conclusions regarding the struc- tures of these molecules. Thus the variation of 19C shieldings with n- electron distributions may be employed qualitatively although the quanti- tative inter-relation of these is not yet known with certainty. (iii) Stereochemical problems. The first indication that 13C data might be useful for stereochemical studies was the fact that substituent effects on aromatic shieldings in ortho-substituted derivatives are not additive.L a ~ t e r b u r ~ ~ noted this for substituted dimethylanilines nitrobenzenes and iodobenzenes and attributed it to steric inhibition of resonance. Support for the interpretation was provided by the changes in para-carbon shield- ings and their correlation with other measures of steric interference. Analogous results have been observed for side-chain carbon nuclei and a detailed study of aromatic ketones has been pre~ented.~~J~ In contrast to those of aromatic nuclei the shieldings of carbon atoms bonded directly to aromatic rings are not dependent on the nature of the sub- stituents. For many examples of meta- and para-substitution the shieldings of the a-carbon atom of toluenes,l b735p36 ace top hen one^,^^^^^ alkyl phenyl ketones,so methyl benzoates?' benzaldehydesY6l and styrenes,25 are virtually unaffected ; apparently conjugative interactions dominate.Appreciable deviations from the small range of shifts exhibited by the above derivatives are found however for the ortho-substituted cases and these deviations show a dependence on the size of the substituent5' rather than its polarity strongly suggesting the existence of steric interactions. From the spectra of more than fifty acetophenones an empirical expression relating the observed carbonyl shielding with the angle of twist 8 of the carbonyl grouping was and tested.59 Without exception reasonable values of 6' were obtained some of which are listed in Table 3 together with estimates obtained by analyses of other results.The 13C method seems to have certain advantages over the others not the least of which is the absence of grossly abnormal estimates. An extension of the method to other aromatic ketones has also been presented.s0 While refinements are no doubt required the problems involved are not insignifi~ant.~~.~~ In aliphatic conjugated systems it appears that 13C carbonyl shieldings also depend on the planarity of the system and a clear distinction between planar S-cis and non-planar conformations is possi ble,40 although these 58 K. S. Dhami and J. B. Stothers Tetrahedron Letters 1964 No. 12 631. 5 9 K. S. Dhami and J. B. Stothers Canad. J. Chem. 1965 43,479. bo K. S. Dhami and J. B. Stothers Canad. J. Chem. 1965 43,498. K. S. Dhami Ph.D. thesis Univ. of Western Ontario 1964.164 QUARTERLY REVIEWS TABLE 3. Angles of twist in some hindered acetophenones as estimated by various physical methods Subs t i tuen t s 13C n.m.r.* 28 O 32" 25 O 25 50" 51 O 57 O Ultraviolet Dipole Kerr spectra? momentst constant2 40" 34" - 24" - - 35 O - - 55 O - - 63 O 62" 90" - 90" - - - - * Ref. 59. t E. A. Braude and F. Sondheimer J. 1955 3754 # M. J. Aroney M. G. Corfield and R. J. W. Le Fevre J. 1964 698. systems do not exhibit large differences by other physical measurements. Since the basis for employing carbonyl shifts to measure steric inter- ference rests on the absence of polar effects further support for the sim- plified if not naive interpretation of the results was required. Originally it was suggested that the carbonyl shielding is independent of substituent polarity because of its non-terminal position in the resonance ~ystem.~S To confirm this point a study of the vinyl carbon shieldings in several substituted styrenes was made.25 It was found that while the ,%carbon shieldings are strongly dependent on substituent polarity the a-carbon shifts are not in accord with the simple model.(iv) Solvent efects. It has been recognised for some time1* that sig- nificant effects on 13C shieldings are exerted by various solvents but only a few preliminary reports have been p r e ~ e n t e d . ~ ~ ~ ~ ~ ~ ~ ~ - ~ ~ Most of these have been concerned with carbonyl and hydroxylic solutes in hydrogen-bonding solvents. The effects while pronounced at the carbon bearing oxygen are rapidly attenuated along the carbon skeleton as some typical results listed in Table 4 show.Undoubtedly the polarisation of the solute is changed by these interactions but shielding changes which would reflect this are small e.g. at C(4) in acetophenone and phenol. It follows therefore that the local electronic environment at the carbonyl is altered appreciably and it is pertinent that the solvent effects correlate with the changes in energy of the n -+ T* transition.61 Attempts to correlate the solvent shifts with the common solvent polarity scales reveal a reasonably linear relation with Y-values . The use of 13C spectroscopy for structural elucidations may be anticipated although little has appeared in the formal literature. As more experimental results become available the potential areas of application multiply. At present it is clear that carbonyl reson- 62 (a) G.E. Maciel and G. C. Rubin J. Amer. Chem. SOC. 1963 85 3903; (b) G. E. Maciel and R. V. James ibid. 1964,86,3893. (v) Potential applications. P TABLE 4. Efect of solvent on I3C chemical shifis (given in p.p.m. from CS,) Solvents C6H6 C4H80,* CHa-OH DMSOt Ref. - 35.2 62b *; Compound Carbon Nil CCl C6H12 Phenol C-1 - 38.0 38.1 37.1 36.1 C-4 - 71-9 72.9 74.4 - Ace top henone c=o - 3.2 -2.1 - 2.9 -3.1 - 6.3 c-1 56.7 55-4 - 56.4 55.8 55.9 C-4 61.2 60.4 - 61.2 61-5 59.7 - 167.9 167.4 - 167.4 167-8 167.5 - CH C-2 64.4 63.1 - - 63.8 - c-3 43.0 43.7 - - 41.0 - 73-9 6 39 z k P - Acetone c=o - 12.3 -11.0 - 9.3 -11.5 - 12.3 - 16.0 - 62a Cyclohex-2-enone C = 0 -4.3 - 3.6 - 2 8 * 1,4-Dioxan. 3 - - - 7.0 - 40 t Dimethyl sulphoxide. 166 QUARTERLY REVIEWS ances may be particularly valuable.A rich potential field is the character- isation of organic compounds lacking H or F and of fully substituted groups. Another interesting facet is the study of bond parameters via 13C coupling interactions and several workers have attacked this problem showing that while the approach is promising certain features require careful study (see p. 159). Throughout this Review several outstanding problems as well as poten- tial avenues of investigation have been mentioned and the results of more detailed studies some of which are under way may be awaited with interest. There seems little doubt that 13C spectra should improve our insight into the theory of chemical shifts and spin-coupling interactions as well as a number of aspects of molecular structure.There is a clear need for more experimental data from which to build but even the limited available evidence points to the fact that 13C spectroscopy can be helpful for many problems through the use of empirical correlations in a manner similar to that of optical spectroscopy. Kinetic studies are a natural extension of 13C methods and since the chemical shifts are relatively large the study of moderately rapid reaction rates represents an area awaiting attention. Temperature effects on 13C spectra are virtually unexplored although several interesting possibilities are apparent from the foregoing discussion and by analogy with the results of n.rn.r. studies of more abundant nuclei. Both of these aspects become even more inviting if one considers the use of suitably labelled reactants.A valuable and exciting practical application of 13C techniques will be isotopic tracer studies since a compound enriched in 13C could be followed throughout a reaction or reaction series without disturbing the system. Substances which are unstable or not easly isolable could be readily detected degradations to isolate the labelled centre would be unnecessary in many cases and an “instantaneous” record of the progress of a reaction would be available. These represent distinct advantages over conventional studies with radioactive tracers. Although no reports of such studies have appeared there is activity in this direction in several laboratories. A particu- larly interesting application is the study of biological processes by use of 13C techniques. Biogenetic problems appear to offer an excellent means for an evaluation of the method.An important feature for tracer studies is that enrichment of a few percent. would suffice for many systems. If highly enriched material were used conventional high-resolution n.m.r. tech- niques could be employed and the variety of applications now common- place for lH and 19F nuclei would be possible. 5. Conclusions Without question the major obstacle to widespread use of 13C spectro- scopy is the need for increased sensitivity. Hence a most eagerly awaited technical development is that of magnets with superconducting coils, STOTHERS 13C N.M.R. SPECTROSCOPY 167 suitable for high resolution work. For 13C studies higher magnetic fields would make accessible the spectra of a much wider range of substances. Fortunately present developmentse3 indicate that in the not too distant future homogeneous fields much higher than those presently employed will be available. On the basis of recent reports it appears that the limit of detectability for I3C in natural abundance may be lowered by an order of magnitude (see p. 146). Thus the future of 13C spectroscopy is assured and the technique should provide valuable assistance for the expansion and refinement of both theoretical and practical considerations. 63 Chern. Eng. News. 1964 June 8 55.

ISSN:0009-2681    

DOI:10.1039/QR9651900144

出版商:RSC    

年代:1965

数据来源: RSC

摘要:

BIOSYNTHESIS OF STEROLS STEROIDS AND TERPENOIDS. PART I. BIOGENESIS OF CHOLESTEROL AND THE FUNDAMENTAL STEPS IN TERPENOID BIOSYNTHESIS By R. B. CLAYTON (DEPARTMENT OF PSYCHIATRY STANFORD UNIVERSITY SCHOOL OF MEDICINE PALO ALTO CALIFORNIA) Introduction THE principal aim of this and the following Review (Part 11) will be to survey the work relating to the biosynthesis of sterols and to some major aspects of the conversion of cholesterol into steroid hormones and bile acids. Intensive studies of cholesterol biosynthesis particularly those conducted in the 1950s in the laboratories of Bloch Cornforth and Popjiik and Lynen have elucidated most of the essential features of the bio- genesis not only of cholesterol and related sterols but of terpenoid com- pounds in general. The resulting advances in knowledge have covered a front far too broad for detailed treatment in these Reviews and the salient results in several areas of terpene biochemistry will be dealt with only briefly in Part 11.So far as possible detailed discussion will be reserved for more recent work but for coherence it seems unavoidable to reiterate much older material although it has been covered extensively in several earlier Reviews. An excellent concise discussion of the chemical principles involved in most of the steps in cholesterol biosynthesis will be found in the Review by Cornforth.’ Fieser and Fieser2 present a valuable outline of the biosynthetic pathway with emphasis on the chemical techniques (degradative procedures etc.) used in the biochemical studies up to 1958 and CrabbC3 has reviewed cholesterol biosynthesis in the broader context of the biogenesis of terpenes.The most comprehensive recent Review of sterol biosynthesis covering both enzymology and chemical mechanisms is that of Popjhk and Cornforth4 and earlier work has been discussed in detail by B l o ~ h . ~ ~ ~ Other valuable surveys are those of Tchen’ and Wright.8 Many important contributions to the field were published in a CIBA Foundation Symposium in 1959.9 A single volume contains excellent recent l Cornforth J. Lbid Res. 1959 1 3. Fieser and Fieser “Steroids” Reinhold New York 1959 Ch. 13. CrabM Rec. Chem. Progr. 1959,20 189. Popjak and Cornforth in “Advances in Enzymology” ed. Nord Interscience 1960 Bloch Harvey Lectures 1952,48,68. * Bloch “Vitamins and Hormones,” eds. Harris Marrian and Thimann Academic Tchen “Metabolic Pathways,” ed.Greenberg Academic Press New York 1960 Wright “Annual Review of Biochemistry,” ed. Luck Annual Reviews Palo Alto CIBA Foundation Symposium Biosynthesis of Terpenes and Sterols ed. Wolsten- vol. 22 281. Press New York 1957 vol. 15 p. 119. p. 389. 1961 30 p. 525. holme and O’Connor Little Brown and Co. Boston 1959. 168 CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 1 69 reviews of both the chemistrylO and biochemistryll of the adrenal steroids. The biochemistry of the steroid hormones has also been reviewed by Samuels12 and by Engel and Langer,13 and that of the bile acids by Bergstrom Danielsson and Samuelsson14 and by Danie1s~on.l~ The Major Features of the Pathway of Cholestrol Biosynthesis.-Isotope studies by Bloch and his co-workers revealed the origins of the individual carbon atoms of the side chain of cholesterol in either C(l) or C(z) of acetate and in the light of suggestions made by Bonner and ArreguiP concerning the biogenesis of the isoprene units of rubber in which a similar pattern of distribution of acetate carbons was postulated these results led to a revivalof a hypothesis originally due to Heilbron Kamm and 0wensl7 and stated more specifically by Robinson,l* that the triterpene hydro- carbon squalene was a biological precursor of cholesterol.This early work including the first direct demonstration of the biosynthesis of squalene in mammalian tissue and its conversion into chole~ter01~~ has been reviewed by B10ch.~ A crucial contribution to proper understanding of the role of squalene in sterol biogenesis was the structural elucidation of lanosterol a non-saponifiable component of wool wax which was shown by Ruzicka and Jeger and their associates20 to be 4,4’,14a-trimethyl- cholesta-8,24-dien-3/?-01.In consideration of this structure Woodward and Bloch21 suggested a pattern of cyclisation of squalene (Fig. 1 I) which could account for the biological derivation of both lanosterol (11) and cholesterol (111) from this hydrocarbon the 4,4’-gem-dimethyl structure of lanosterol being derived from a terminal isopropylidene group of squalene. They pointed out that the departure from the strict “iso- prenoid” arrangement of methyl groups at C(13) and C(la) of lanosterol would have to be accounted for in terms of a shift of methyl groups of squalene in the course of cyclisation. The squalene cyclisation scheme of Woodward and Bloch differed from that suggested earlier by Robinson1* in which the central bond of squalene corresponded to that between C(s) and C(7) of cholesterol.Assuming that the distribution of acetate carbon atoms in the isoprene units throughout the squalene molecule conformed to the pattern found in the cholesterol side chain the labelling pattern in lo Moore and Heftmann “Handbuch Experimentellen Pharmakologie,” ed. Deane Springer Berlin 1962 vol. 14 pt. 1 p. 186. l1 Dorfman ref. 10 p. 511. l2 Samuels ref. 7 p. 471. l3 Engel and Langer ref. 8 p. 499. l4 Bergstrom Danielsson and Samuelsson “Lipid Metabolism,” ed. Bloch Wiley Sons New York 1960 p. 291. l6 Danielsson “Advances in Lipid Research,” ed. Paoletti and Kritchevsky Acade- mic Press 1963 vol.1 p. 335. l6 Bonner and Arreguin Arch. Biochem. Biophys. 1949 21 109. l7 Heilbron Kamm and Owens J. 1926 1630. l8 Robinson Chem. and Znd. 1934 53 1062. lS Langdon and Bloch J. Biol. Chem. 1953 200 129. 2o Voser Mijovic Heusser Jeger and Ruzicka Helv. Chim. Acta 1952,35,2414. 21 Woodward and Bloch J. Amer. Chem. SOC. 1953,75,2023. 170 QUARTERLY REVIEWS o \ / \ / I FIG. 1. Biogenetic relationship between squalene lanosterol and cholesterol. the cholesterol nucleus must differ depending upon which scheme was valid. In support of their hypothesis Woodward and Bloch21 gave evidence that the mixed C(lo) and C(13) of cholesterol contained methyl carbon of acetate and Bloch22 later showed that C(7) was also derived from the methyl carbon of acetate. Further confirmation came from the demonstra- tion that lanosterol was synthesised in rat tissue both in ~ i t t - 0 ~ ~ and in V ~ V O ~ ~ and in turn was efficiently metabolised to cholesterol.Finally the total degradation of ~qualene~~ and of biosynthesised from labelled acetate with identification of the origin of each carbon atom of both structures from either C(l) or C(z) of acetate gave results (I and 111) in total agreement with the postulated biogenetic relationship. Intermediate reactions between acetate and squalene The incorporation of acetate into squalene can best be discussed as four sequential phases (1) conversion of acetate into mevalonate ; (2) conver- sion of mevalonate into isopentenyl pyrophosphate which is probably the immediate precursor of the isoprene unit in all living systems; (3) the head-to-tail condensation of three isopentenyl pyrophosphate molecules yielding farnesyl pyrophosphate; and (4) the tail-to-tail union of two of these farnesyl residues to give the symmetrical structure of squalene.The essential biochemical mechanisms of phases (2) and (3) were clarified before 1960 and have been reviewed in detai1.1,4*7 Some new proposals concerning phase (1) have been put forward and the stereochemical aspects of phases (2)-(4) have recently been the subject of a penetrating analysis. zz Bloch Helv. Chim. Acta 1953 36 161 1. z3 Clayton and Bloch J. B i d Chem. 1956 218 305 319. 24 Schneider Clayton and Bloch J. Biol. Chem. 1957 224 175. 25 Cornforth and Popjhk Biochem. J. 1954,58,403. ze Cornforth Hunter and PopjBk Biochem. J. 1953,54 590 597; Cornforth Gore and PopjPk ibid.1957,65,94. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 171 The Conversion of Acetate into MeValonate.-In the early 1950s the search for the biological equivalent of the isoprene unit conducted in several laboratories followed along lines that were related to a mechanism suggested for the biogenesis of the isoprene units of rubber by Bonner and A r r e g ~ i n . ~ ~ ~ ~ The five-carbon branched chain acid radicals isovalerate /3-hydroxyisovalerate /3/3-dimethylacrylate as well as the six-carbon acid radical p-hydroxymethylglutarate were all utilised as precursors of cholesterol but with extensive randomisation of their carbon atoms. /3-Hydroxymethylglutarate was suggested as a precursor of sterols by Bloch5 but although the synthesis of hydroxymethylglutaryl-CoA (VI) (CoA = coenzyme A) from acetyl-CoA (IV) and acetoacetyl-CoA (V) by enzyme extracts of both liver and yeast was d e m ~ n s t r a t e d ~ ~ ~ ~ (Fig.2 (a) 2 CH,.CO- SCoA -f CH,-COCH,CO- SCoA + CoASH (IV) (V) CH,*COw SCoA + CoASH I I (V’) (b) CH,CON SCOA + CH,CO*CH,COW SCOA -+ CH3-C-OH CH,-CO,H CH,CO- SCOA CH,CO- SEnz NADPH __f 1 1 Em-SH ---+ CHS-C-OH (4 C H,CO,H I CH,C02H CH2*CH,0H 1 I NADPH CH,-C-OH SEnz _If CH,-C-OH + EnzSH CH,*CO,H CH,-CO,H (VII) (VIII) (d) CH,*CHO CH,.CH,OH NADPH I (or NADH) I -+ CH3-C-OH I I CHS-C-OH CH2*C02H CH2*CO2H (1X) (VIII) FIG. 2. Synthesis of mevalonic acid from acetate. a b) further insight into the pathway between acetate and the terpenoid compounds finally came from the fortuitous discovery of mevalonic acid 27 Arreguin and Bonner Arch.Biockem. Biophys. 1950 26 178. 28 Rudney ref. 9 p. 75. 28 Lynen Henning Bublitz Sorbo and Kroplin-Rueff Biochem. Z. 1958 330 269. 172 QUARTERLY REVIEWS (VIII) by Folkers and his a ~ s o c i a t e s . ~ ~ ~ ~ The structural relationship of this compound to hydroxymethylglutarate prompted a study of its possible r61e as a cholesterol precursor,32 which showed that one enantio- morph of racemic mevalonic acid was almost quantitatively converted into the isoprene unit with concomitant loss of the carboxyl group.= The pattern of labelling in s q ~ a l e n e ~ ~ ~ ~ ~ and cholester01~~ biosynthesized from [2J4C]mevalonate conformed to this mode of utilisation of mevalon- ate. Moreover labelled mevalonic acid was isolated from a liver enzyme system by a trapping technique in which unlabelled mevalonic acid was added to the system during synthesis of squalene from [14C]acetate.37 The pathway outlined in Fig.2 (a)-(c) has become generally accepted as the route of biosynthesis of mevalonic acid in yeast and mammalian ~ ~ s s u ~ s . ~ ~ ~ ~ ~ ~ ~ It has been fully discussed by Popjak and Cornforth4 and set forth in more or less detail by numerous other reviewers (see e.g. ref. 43). The evidence points to a reduction of hydroxymethylglutarate to mevalonate which is only reversible with difficulty thus accounting for the efficient utilisation of mevalonate for sterol synthesis in contrast to the poor utilisation of hydroxymethylglutaryl-CoA which is subject to cleavage to acetyl-CoA and acetoacetate. Mevaldic acid (IX) although reduced by a specific reductase to mevalonic acid (Fig.26) and hence made available for sterol synthesis,30~39~41~44-446 is probably not a normal intermedi- ate.ss,40,42,45 An enzyme-bound intermediate (VII) of equivalent oxidation state has been postulated (Fig. 2 ~ ) . ~ A different view of the origin of mevalonic acid has recently been put forward by Brodie et aZ.47 (Fig. 3) who have studied an avian liver enzyme preparation that was active in fatty acid synthesis with a view to testing the intermediates in that process for their availability as precursors of mevalonic acid. Attention was dire~ted~*-~O primarily to the utilisation of 30 Folkers Shunk Linn Robinson Wittreich Huff Gilfillan and Skeggs ref. 9 p. 20. 31 Wolf Hoffman Aldrich Skeggs Wright and Folkers J. Amer. Chem. SOC. 1956 78,4499; 1957 79 1486.34 Tavormina Gibbs and Huff J. Amer. Chem. SOC. 1956 78,4498. 33 Tavormina and Gibbs J. Amer. Chem. SOC. 1956,78,6210. 34 Dituri Gurin and Rabinowitz J. Amer. Chern. Soc. 1957 79 2650. 35 Cornforth Cornforth Popjiik and Gore Biochem. J. 1958 69 146. 36 Isler Ruegg Wursch Gey and Pletscher Helv. Chim. Acta 1957 40 2369. 37 Knauss Porter and Wasson J. Biol. Chem. 1959 234 2835. 38 Durr and Rudney J. Biol. Chem. 1960 235,2572. 39 Lynen ref. 9 p. 95. 40 Knappe Ringelmam and Lynen Biochem. Z. 1959,332 195. 41 Coon Kupiecki Dekker Schlesinger and del Campillo ref. 9 p. 62. 48 Brodie and Porter Biochem. Biophys. Res. Comm. 1960 3 173. 43 Bernfeld “The Biogenesis of Natural Compounds,” Pergamon Press New York 44 Wright Cleland Dutta and Norton J. Amer. Chem. SOC. 1957 79 6572. 45 Schlesinger and Coon J.Biol. Chem. 1961 236,2421. 46 Knauss Brodie and Porter J. Lipid Res. 1962 3 197. 47 Brodie Wasson and Porter J. Biol. Chem. 1963 238 1294. 48 Brady Proc. Nat. Acad. Sci. US. 1958 44 993. 49 Wakil and Ganguly J. Amer. Chem. SOC. 1959 81 2597. Lynen J. Cell. Cow. Physiol. 1959 54 (Suppl. l) 33. 1963. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 173 (a) HO,CCH,-CO~ SCoA + Enz-SH -+ HO,CCH,CO- SEnz + CoASH (XI (XI) (b) HO,C.CH,-CO- SEnz + CH,-CO- SCoA -+ CH3COCH,CO- SEnz + CoASH + CO (IV) ow OH I I CH (c) CH,-COCH,CO- SEnz + CH,CO- SCoA -f HO,C-CH,CCH,CO- SEnz + CoASH OH NADPH 1 - I I CH3 I I CH3 (VIII) + HO,C.CH,.CCH,CHO Enz - (d) HO,CCH,-CCH,-CO- SEnz ~ OH HO,CCH,C.CH,CH,OH + EnzSH i OH NADPH I I CH3 FIG. 3. Alternative scheme for mevalonic acid biosynthesis involving enzyme-bound intermediate^.^^^^^ acetyl-CoA and malonyl-CoA (X) each of which was found to enhance the incorporation of the other into hydroxymethylglutarate in the absence of reduced nicotinamide adenine dinucleotide phosphate (NADPH).How- ever the initial condensation-decarboxylation reaction between these two compounds apparently led to acetoacetyl units that were firmly bound to the enzyme (XII) since addition of an unlabelled pool of acetoacetyl-CoA had little effect on the efficiency of incorporation of labelled acetyl-CoA or malonyl-CoA into hydroxymethylglutaryl-CoA. In the presence of NADPH the product was mevalonic acid (VIII). The authors interpret their results to support the alternative reaction pathway (Fig. 3 a-d) in which malonyl-enzyme (XI) yields acetoacetyl-enzyme (XU) as a key intermediate common to both fatty acid and sterol synthesis.They sug- gest that acetoacetyl-enzyme may be a focal point for mechanisms controlling the relation between these two processes. According to this view the previously observed reactions (Fig. 2) are due to slow exchange of reactants between their coenzyme A and enzyme-bound forms. These results have so far not been confirmed by other workers but whereas Porter and his co-workers have extended them51 and have recently claimed52 to have obtained results with rat liver preparations that were consonant with their earlier findings with avian liver systems one attempt to test their findings in a rat liver preparation was reported to be unsuccessful.53 51 Brodie Wasson and Porter J. Biol. Chern. 1964 239 1346.62 Porter Guchhast and Vadlamundi 6th International Congress of Biochemistry 63 Fimognari and Rodwell 6th International Congress of Biochemistry New York New York 1964 Abstracts p. 590. 1964 Abstracts p. 573. 4 1 74 QUARTERLY REVIEWS The Conversion of Mevalonate into Isopentenyl Pyropbosphate.-The first clue to the mechanism whereby mevalonic acid provides the isoprene unit for the biosynthesis of terpenoid compounds was the observation that a dialysed enzyme system from yeast catalysed the conversion of mevalonic acid into squalene only on addition of adenosinetriphosphate (ATP) Mg++ and pyridine nucle~tides.~~ The formation of a monophosphorylated derivative of mevalonic acid which served as an efficient precursor of squalene was shown by T ~ h e n ~ ~ 9 ~ ~ to be catalysed by a mevalonic kinase of yeast.Similar enzymic activity was also observed in mammalian On the basis of its elementary analysis stability to both acid and alkaline hydrolysis and its failure to undergo lactone formation,58 the new com- pound was suspected to be mevalonic acid 5-phosphate (XIII) and was identified as such by chemical ~ynthesis.~~s~~ Subsequent intensive work in the laboratories of B l o ~ h ~ ~ ~ ~ ~ P ~ p j h k ~ s ~ * and L ~ n e n ~ ~ s ~ l showed that mevalonic acid monophosphate underwent a second ATP-dependent phosphorylation to the 5-pyrophosphate (XIV)G2963 followed by a con- certed dehydration and decarboxylation reaction which required a third molecule of ATP. The product of these reactions (Fig. 4a) was identified by Bloch and his c o - ~ o r k e r s ~ ~ as isopentenyl pyrophosphate (XV).The transformation entailed the loss of the carboxyl carbon of mevalonic acid phosphate but retention of its original phosphate group and acquisition of a second phosphate from ATP. The diphosphate was readily hydrolysed in acid in keeping with its proposed pyrophosphate structure. The structure of the isopentenyl moiety was demonstrated by phosphatase hydrolysis followed by steam distillation in the presence of carrier isopentenol and the formation of isopentenyl 3,5-dinitrobenzoate. The structure of the com- pound has also been confirmed by organic ~ynthesis.~~~~* Several mechanisms for the dehydration-decarboxylation reaction which constitutes the last step in isopentenyl pyrophosphate formation have been considered by Bloch and his co-workersB2 who have purified the enzyme involved 120-f0ld from yeast autolysates.The strict stoicheiometry between ATP and mevalonic pyrophosphate consumed and isopentenyl pyrophosyhate ADP and CO produced argue in favour of a concerted process involving a 3-phosphorylated intermediate (XVI) as shown (Fig. 4b). Such an intermediate has however never been isolated and may well be incapable of more than transient existence. 64 Amdur Rilling and Bloch J. Amer. Chem. SOC. 1957 79 2646. 66 Tchen J. Amer. Chem. SOC. 1957 79 6344. 66 Tchen J. Biol. Chem. 1958,233 1100. 67 Popjhk ref. 9 p. 148. 68 DeWaard and Popjak Biochem. J. 1959 73,410. 59 Chaykin Law Phillips Tchen and Bloch Proc. Naf. Acad. Sci. U.S.A. 1958 60 DeWaard Phillips and Bloch J. Amer. Chern. SOC. 1959 81,2913. 61 Lynen Eggerer Henning and Kessel Angew.Chem. 1958 70,738. 6s Henning Moslein and Lynen Arch. Biochem. Biophys. 1959,83,259. 64 Yuan and Bloch J. Biol. Chem. 1959,234,2605. 44,998. Bloch Chaykin Phillips and DeWaard J. Biol. Chem. 1959 234 2595. CLAYTON CHOLESTEROL AND TERPENBID BIOSYNTHESIS 175 CH20H I I I CH,*CB,H CH ATP Mn++ -+ __ (a) CH,C-OH (VIII) F I ? CH,-0- 7-0-k-0- I OH OH CH,OP CH,OP*P I CH2 I I ATP Mn++ I I I --+ ATP CH __- Mn++ CH,.C-OH C H ,C-0 H CH,C02H CH,CO,H + ADP (XIII) 4- ADP (XIV) CH,O P. P I CH2 I C / \ CH CH (XV) -+ CO + ADP + PO,- B Q ' & O H y 2 CH,-O-P-O-f'-O- FIG. 4. Conversion of mevalonic acid into iropentenyl pyrophosphate. The Conversion of Isopentenyl Pyaophosphate into Farnesyl Pyrophos- phate)-Lynen and his collaborators identified farnesyl pyrophosphate (Fig.5 XIX) as a precursor of squalene61 in yeast and it was later showns5 that farnesyl pyrophosphate was preceded in the biosynthetic sequence by geranyl pyrophosphate (XVIII). The first step in the conversion of iso- pentenyl pyrophosphate into farnesyl pyrophosphate was the enzymic isomerisation of isopentenyl pyrophosphate (XV) to dimethylallyl pyro- phosphate (XVII) Fig. 5a).66967 The mechanism of formation of the terminal isopropylidene groups of squalene from the isomeric isopentenyl structure was thus clarified since each terminal isoprene unit of squalene arises from a molecule of dimethylallyl pyrophosphate. Dimethylallyl pyrophosphate is converted into geranyl pyrophosphate (XVIII) and the latter in turn to trans-trans-farnesyl pyrophosphate (XIX) by sequential reactions involving isopentenyl pyrophosphate (Fig.5b c). Thus one half of the symmetrical carbon skeleton of squalene is assembled. This pathway has been shown to operate in mammalian liver by Popjak and his co- w o r k e r ~ ~ ~ ~ ~ who have also established the trans-trans-structure for the 65 Lynen Agranoff Eggerer Henning and Moslein Angew. Chem. 1959 71 657. 66 Agranoff Eggerer Henning and Lynen J. Arner. Chem. Soc. 1959 81 1254. 67 Agranoff Eggerer Henning and Lynen J . Biol. Chem. 1960 235 326. 88 PopjBk Tetrahedron Letters 1959 19 19. 6 v Goodman and PopjBk J . Lipid Res. 1961 1 286. 4. 176 QUARTERLY REVIEWS farnesyl pyrophosphate and demonstrated the biosynthesis of squalene from farnesyl pyrophosphate that had been prepared by organic synthe- sis.70p71 Some important advances in knowledge of the stereochemistry of these reaction are discussed below.CH,OPP I CH2 I / \ (XV) C CH3 CH HC*CH,*OPP c / \ (XVII) CH3 CH CH8 CH3 \ I / C=CHCHzCH2~CHz~C=CH.CHz*OPP + PP + H+ CH3< (XVI I I) CH3 CH3 I I C=C H-C H 2-C H ,-C=CH-C Hz-C H z-C=C H-CHZ-OPP + PP + Hi- \ / CH3 CH3 ow __L_ a .7-0- OH + Ht + -0-t-0-k-0- ? F R*C\H2 H OH OH ,c=c ,c=c’ B Q H,C ‘cH,o*p-o-p-o- H3C CHiC,H ti (W O H O H (R=Di methylallyl) FIG. 5. Synthesis of farnesyl pyrophosphate and general mechanism of condensation of isopentenyl pyrophosphate with ally1 pyrophosphates. ‘O Popjak Cornforth Cornforth Ryhage and Goodman Biochem. Biuphys. Rcs. Popjiik Cornforth Cornforth Ryhage and Goodnian J. Biol. Chern. 1962 237 Cornrn. 1961 I 204. 56. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 177 In the process of the formation of the new carbon-carbon bond in each of these condensation reactions an allylic pyrophosphate group is eliminated.While it seems most probable that the enzymic condensation takes place in concerted fashion as shown in Fig. 5d it may formally be considered as a two-stage process of which the first stage consists of an elimination of the allylic pyrophosphate group as the inorganic anion with the formation of a cation that is subject to resonance stabi1isation.l The situation becomes energetically favourable when a new nucleophilic group [i.e. the methylene group of isopentenyl pyrophosphate (XVI)] is available for attack by the carbonium ion and the resulting structure is stabilised by ejection of a proton with the formation of a new ally1 pyro- phosphate.The essential characteristics of this mechanism were discussed on a theoretical basis by Rilling and Blo~h'~ and by Lynen et aLS1 before completely substantiating experimental data were available and were elaborated by Cornforth and P ~ p j a k ~ ~ in an early attempt to account for the formation of squalene. There is now evidence from work with a variety of biological systems that the same mechanism applies generally to the head-to-tail linkage of isoprene units in terpenoid compounds. Although it does not appear to have been confirmed at an enzymic level the same principle of attack upon a neighbouring double bond by a resonance- stabilised carbonium ion derived from an allylic pyrophosphate is probably the basis of formation of a wide variety of cyclic terpenoid compounds.An interesting non-enzymic analogy with the postulated biochemical mechanism has recently been described74 (Fig. 6) in which an ethereal 6 (XXIV) Y CH,-O-y-OPh (XXI I I) OPh FIG. 6. solution of geranyl diphenyl phosphate (XX) was partially transformed on prolonged standing into a mixture of myrcene (XXI) and ocimene (XXII) while neryl diphenyl phosphate (XXIII) with a cis-allylic double bond gave a 45% yield of limonene (XXIV) under the same conditions. 73 Rilling and Bloch J. Biof. Chem. 1959 234 1424. 73 Cornforth and Popjhk Tetrahedron Letters 1959 19 29. '* Miller and Wood Angew. Chem. Internat. Edn. 1964 3 310. 178 QUARTERLY REVIEWS The Conversion of Farnesyl Pyrophosphate into Squalene and the Stereo- chemistry of Squalene Biosynthesis.-The mechanism of condensation of two molecules of farnesyl pyrophosphate with the formation of squalene remains to be fully elucidated though many features of the transformation may now be described in extraordinary detail primarily as a result of the brilliant contributions of Cornforth and Popjik and their collaborators.When squalene is synthesised from [5,5-2H,]mevalonate by a rat liver enzyme system 11 of the theoretically possible 12 deuterium atoms are retained.75 The deuterium atom which is lost is detached from one of the two centre carbon atoms of the squalene molecule and in a reaction medium in which all other components are unlabelled is replaced by a normal hydrogen atom. This conclusion was based on a detailed mass- spectrometric examination of the succinic acid fragment derived from the ozonolysis of squalene representing the four central carbon atoms of the molecule.In the mass spectrometer the anhydride of this succinic acid gave peaks with masslcharge ratios of 3 1 corresponding to trideutero- ethylene ion; 44 and 43 corresponding to the ketene fragments CD,CO and CHDCO; and most significantly a peak at rnass/charge ratio 59 corresponding to (CHDCD,CO) in high abundance. Confirmatory results were obtained in the mass spectrometric analysis of the succinate dimethyl ester which yielded peaks with mass/charge ratios of 90 (CH,OCOCHDCD,) and 1 18 (CH,OCOCHDCD,CO). The inter- pretation of these results was based on a careful comparison with the mass spectra of normal (unlabelled) succinate tetradeuterosuccinate and sym- metrical dideutero- and asymmetrical dideutero-succinates all of which were prepared by organic synthesis.The origin of the hydrogen which displaces a deuterium atom from one of the centre carbon atoms of squalene was examined by experiments in which [14C]farnesyl pyrophosphate was incubated with microsomes in the absence of oxygen and in a medium containing either 3HH0 or NADP3H. In the former case only 0.01 3-0-01 5 pg.-atom 3H per pmole of squalene was incorporated whereas in the latter 0-55-0.82 pg.-atom per pmole was incorporated leaving no doubt that NADPH is the source of the entering hydrogen atom. On the other hand in a more complex enzyme system (microsomes + supernatant fraction) containing "HO and [14C]mevalonate was shown to be incorporated into farnesol with an up- take of 0.38-0.49 pg.-atom 3H per pinole and into squalene with an uptake of 1.48-1 -16 pg.-atom 3H per pmole.The enhanced incorporation of 3H from 3HH0 which evidently accompanied the condensation of the farnesyl pyrophosphate molecules under these conditions was attributed to the possibility of labelling the NADPH from ,HHO by concurrent side reactions in the less pure enzyme preparation and was offered as an explanation of the earlier findings of Rilling and Blo~h.'~ These authors 75 Popjdk Goodman Cornforth Cornforth and Ryhage J. Biol. Chern. 1961 236 1934. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 179 in experiments similar to those of Popjak et al. but using instead of the rat liver enzyme system a crude autolysate of yeast had concluded that two atoms of hydrogen from the water of the incubation medium were intro- duced into the centre of squalene during its biosynthesis.In a re-examina- tion of the problem with the use of purer enzyme preparations from yeast and employing mass spectrometric analysis of the 4-carbon centre fragment of squalene in the form of 1,4-propanediol rather than succinic acid Childs and B l o ~ h ~ ~ obtained results that were in essential agreement with those of Popjkk et al. In a further detailed study of the formation of squalene from farnesyl pyrophosphate (Fig. 7) Popjtik et aL71 were able CH D I 1 I R*C H ,*C=C H-C-0 P P D CH NADPH Microsornal enzyme system -+ I I I (XXV) + PPO*C-CH=C-CH,-R - D CH D H CH I I I I I I (XXVI) R*C H ,*C===C H-C-C-CHd*C H 2-R D D (R=G e ran y I) FIG. 7. Loss of deuterium from [l,l-2H2]farnesyl pyrophosphate in coupling to form squalene.to show that synthetic all-trans- [2-14C; 1 l-2H2]farnesyl pyrophosphate (XXV) yielded squalene in which the centre two carbon atoms retained only three of the four possible deuterium atoms (XXVI). Similarly when the corresponding [2J4C; 1 1-3H ,]-labelled substrate was used the 3H/14C ratio in squalene was 75 % of that in the farnesyl pyrophosphate. The incorporation of [,H,]farnesyl pyrophosphate into squalene took place without any measurable isotope effect suggesting that the enzymic process was stereospecific. This interpretation was confirmed unambigu- ously by experiments which involved (1) a demonstration that the hydrogen transferred from NADPH to one of the centre carbons of squalene was removed from the “B” face77 of the pyridine ring of the n~cleotide,~~ and (2) the isolation of the four centre carbons of squalene (Fig.8a XXVII) synthesised from [2-14C; 5,5-2H2]mevalonate in the form of optically active succinate (XXVIII) containing three atoms of deuterium and one of normal hydrogen per molecule.79 The structure of the succinic acid ob- tained in this experiment was deduced from its behaviour in the mass 76 Childs and Bloch J. Bioi. Chem. 1962 237 62. 77 Cornforth Ryback Popj Ak Donninger and Schroepfer Biochem. Biophys. Res. 78 PopjAk Schroepfer and Cornforth Biochenz. Biophys. Res. Comm. 1961/62 6 70 Cornforth Cornforth Donninger Popjak Ryback and Schroepfer Biochem. Comm. 1962,9 371. 438. Biophys. Res. Comm. 1963 11 129. 4** 180 QUARTERLY REVIEWS n (XXVI I) CHCH~W (XIX) D' 'D &i3 L D' 'D (S)- Succinic acid (XXVIII) (XXIX) FIG.8. (a) Absolute stereochemistry at the centre of squalene formed from [l ,I -2H,] farnesyl pyrophosphate or [5,5-2H2]mevalonate.7g (b) The experiment of Samuelsson and Goodman.81 spectrometer and from the finding that the optical rotatory dispersion curve for this material was the mirror image of that of a synthetic sample of [2-2Hl]succinic acid of known absolute configuration it was con- cluded that the absolute configuration of the trideuterosuccinic acid (XXVIII) and hence of the asymmetric carbon at the centre of the squalene synthesised in this experiment was S. It was pointed out by Cornforth et ~ 2 . ' ~ that the foregoing observations permit the prediction that tritium introduced into squalene in the course of biosynthesis from farnesyl pyrophosphate in the presence of NADP3H should appear in either the 1 la or 12/3 position in the steroid nucleus depending upon the direction of cyclisation of the squalene molecule.This expectation was confirmed independently by Samuelsson and Goodmans1 (Fig. 8b) who prepared cholesterol biosynthetically labelled from [14C]farnesyl pyro- phosphate (XIX) and NADPH and injected it into a rat from which both cholic and chenodeoxycholic acids were recovered Vid a bile fistula with ap- proximately equal 3H/14C ratios. The cholic acid (XXIX) was converted into the 3a,7rx-diacetoxy-methyl ester and this in turn was oxidised under non-enolising conditions to yield the 12-ketone in which approximately 8o Cahn Ingold and Prelog Experientia 1956 12 81. Samuelsson and Goodman Biuchem. Biuphys. Res. Cumm. 1963 11 125; J.Biol. Chem. 1963 239 98. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 181 one half of the tritium content of the cholic acid had been lost. On enolisa- tion to labilise the hydrogen atom at C(ll) all but 2-9 % of the tritium was displaced. The results thus indicate approximately equal distribution of tritium between C(ll) and C(12) with all of the label in the latter position in the /3-configuration. In view of the accumulated evidence that hydroxy- lations in the steroid nucleus take place without i n v e r ~ i o n * ~ ~ ~ ~ the con- figuration of tritium at C(lz) in the precursor cholesterol must also be pre- sumed to be 12p and while no evidence was available for that at C(ll) it is reasonable to assume that it is in the a-position. Information concerning the stereochemistry of hydrogen exchange at C(l) of fariiesyl pyrophosphate during squalene biosynthesis was obtained84 by the use of mevalonate (Fig.9a XXX) stereospecifically labelled by CH,.CO H C% % .,H NADH* (xxxrr) R'.c%- c= CH- c - 'OPP cH3 I (XXXIII) (R' = Geranyl) FIG. 9. (a) Preparation of 5-R-[5-2H]mevalonic acid and its incorporation (b) into farnesyl pyrophosphate and (c) into squalene. The hydrogen atom derived from NADH in the last step is designated H* reduction of mevaldic acid (IX) with mevaldic reductase and 4-R- [4-2H;1- reduced nicotinamide adenine dinucleotide (NADH) or 4-R- [4-3Hl] NADPH (XXXI). [5-3Hl]-Mevalonate prepared in this way was mixed with [4-14C]mevalonate so that loss or retention of tritium atoms in the course of enzymic conversions could be assessed in terms of 3H/14C-ratios.Thus the 3H/14C ratio in farnesol biosynthesised from 82 Bergstrom Lindstedt Samuelsson Corey and Gregoriou J. Amer. Chem. SOC. 83 Hayano Gut Dorfnian Sebek and Peterson J. Amer. Chem. Sac. 1958 $0 1958,80,2337. 2336. _ _ _ - _ 84 PopjBk 6th International Congress of Biochemistry New York 1964 Abstract p. 545. 182 QUARTERLY REVIEWS this material was assumed to represent a value of 3 atoms 3H/3 atoms 14C. The absolute configuration of C(l) of farnesyl pyrophosphate (XXXII) was presumed to be unchanged from that of C(5) of the precursor [3H,]mevalonate (Fig. 8b). It was also assumed that this configuration was R since liver alcohol dehydrogenase removed the labelled hydrogen atom from Q1) of farnesol biosynthesised from the enzymically labelled meval~nate.~~ (That this assumption was correct was supportedSg by the results of other experiments in which geraniol stereo-specifically labelled by a non-enzymic method was oxidised by liver alcohol de- hydrogenase in the presence of NAD.) When 1-R- [l ,5,9-2H3]-farnesyl pyrophosphate formed from 5-R- [5-2Hl]mevalonate was converted enzymically into squalene (XXXIII) no loss of deuterium could be de- tected.The conclusion that both centre carbon atoms of squalene retained the labelled hydrogens present in farnesyl pyrophosphate was confirmed by ozonolysis of the squalene and gas-radiochromatographic analysis of the fragments. From these results it was concluded that the hydrogen atom removed from C(l) of farnesyl pyrophosphate in the course of con- densation to squalene is epimeric to that removed from farnesol by alcohol dehydrogenase and that during the formation of squalene there is either no inversion at C(l) of the farnesyl pyrophosphate molecule involved in the hydrogen exchange reaction or there is an even number of inversions resulting in an apparent retention of configuration.There is no evidence yet available that distinguishes between these two possibilities. These results define the stereochemical outcome of the changes taking place at C(l) of one farnesyl pyrophosphate molecule in the course of squalene formation but they shed no light on the stereochemistry of the concomitant changes that occur at C(l) of the other. Further experimentss4 have given evidence on this point and also on the stereochemistry of the changes involving the C(I) carbon atoms of dimethylallyl pyrophosphate and geranyl pyrophosphate in the course of their respective condensations with isopentenyl pyrophosphate (Fig.10). 5-R- [5-2Hl]Mevalonate prepared from mevaldate and A-deutero NADH was converted into squalene (XXXIV) in a rat liver homogenate and the squalene isolated and de- graded by ozonolysis to yield succinic (XXV) and levulinic (XXXVI) acids. The dideutero-succinic acid representing the four middle carbon atoms of squalene may be of two kinds depending upon whether retention of configuration occurs at both or only one of the farnesyl pyrophosphate C(l) centres. The succinate should be optically active -SSin the former case and optically inactive (meso) -RS in the latter and in fact was found to be optically inactive. Thus the overall process of the union of two farnesyl pyrophosphate molecules to yield squalene results in retention of con- figuration at C(l) of one molecule and inversion at the other.From the same experiment evidence was obtained for inversion of configuration at C(l) in 85 Donninger and Popjak Eiochem. J. 1964 91 lop. 86 Donninger and Ryback Eiochem. J. 1964,91 1 1 ~ . CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 183 both dimethylallyl pyrophosphate and geranyl pyrophosphate in their reactions with isopentenyl pyrophosphate. The two carbon atoms in question appear as C(2) of levulinic acid (XXXVI) and must be asymmetric since they are linked to one deuterium and one hydrogen atom. By hypoiodite oxidation the levulinic acid was converted into succinic acid (XXXVII) in which the asymmetric carbon atom retained its configuration.The optical rotation of the succinic acid indicated a configuration of R which can only arise if inversion takes place at C(l) of the precursor pyrophosphates in the course of addition to the double bond of isopentenyl pyrophosphate. Such a result is consistent with a bimolecular nucleophilic substitution mechanism. fH3 \ ,,Y / (xxxv') (R)-Succinic acid (xxxvr I) (R)-Succinic acid (XXXVlI) FIG. 10. Further analysis of stereochemistry of incorporation of 5-R-[5-2H,Jrnevalonic acid into geranyl and farnesyl pyrophosphates and into squalene. 184 QUARTERLY REVIEWS In more recent studies by Cornforth and Popjiik and their co-workers8* the loss of the hydrogen atom from C(z) of isopentenyl pyrophosphate in the course of its condensation to form trans-trans-farnesyl pyrophosphate has been examined with the use of mevalonic acid stereospecifically labelled at C(4) with deuterium in either the S or R configuration.C(4) of mevalonate becomes C(2) of isopentenyl pyrophosphate and hence the formation of the trans-double bonds of farnesol involves the loss of hydro- gen atoms originally present at C(4) of mevalonate. No label was retained in farnesyl pyrophosphate when the precursor was 4 -S- [4-2H,]mevalonate and 4-S- [4-3H ;2-14C]mevalonate yielded squalene that contained only 14C whereas squalene formed from the 4-R-isomer (Fig. 1 1 XXXVIII) retained the 3H/14C ratio of the starting material. The stereochemistry of labelling of farnesyl pyrophosphate (XXXIX) from 4-R- [4-3H ; 2-14C]mevalonate (XXXVIII) must therefore be as shown (Fig.11). FIG. 11. Absolute stereochemistry of proton eliminations at C-2 of isopentenyl pyrophosphate during biosynthesis of farnesyl pyrophosphate. The unprecedented detail which these studies have revealed with respect to the stereochemistry of squalene biosynthesis still leaves unanswered the question of exactly how the two halves of the molecule become united and clearly the answer must ultimately come from studies of the enzyme system involved. Two general mechanisms have been suggested which are consistent with all of the experimental data. Two variants of the first type of mechanism75 are shown in Fig. 12. The assumption in each case is that one of the reacting molecules of farnesyl pyrophosphate undergoes prior isomerisa- tion to nerolidyl pyrophosphate (XL)68*74 thus making of this molecule a methylene carbon capable of entering into an S,2 type of interaction CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 185 with C(l) of the second farnesyl pyrophosphate molecule (XIX) in a manner analogous to the interaction between isopentenyl pyrophosphate and dimethylallyl pyrophosphate.This second farnesyl residue might be expected to undergo inversion at C(l) again by analogy with what is known of the reactions involving isopentenyl pyrophosphate. The positive charge imparted to the carbon chain by the leaving phosphate group may be neutralised either in the formation of a cyclic phosphate (XLI) (Scheme 1) or in the formation of a sulphonium compound (XLII) through reaction with a methionine residue (Scheme 2). In either case a final reductive cleavage is envisaged which results in the liberation of squalene and entails t PP + @- I SCHEME 1.H SCHEME 2. (R = Geranyl) FIG. 12. Hypothetical schemes for squalene pyrop hosp hate. biosynthesis involving nerolidol 186 QUARTERLY REVIEWS the insertion of a new hydrogen atom at the carbon (originally C(l) of nerolidyl pyrophosphate) from which one hydrogen has been removed as a proton. On the basis of the evidence that has been cited this exchange involves no change in configuration. The second type of mechanism,87 which may also be subject to modifica- tion of detail is outlined in Fig. 13. The initial step is the displacement of pyrophosphate from one farnesyl pyrophosphate molecule by a sulph- hydryl group of the enzyme (Fig. 13a). A reaction of the farnesy1-S- enzyme complex (XLIII) with a second farnesyl pyrophosphate could then yield a difarnesyl-enzyme complex (XLIV) which may undergo a Stevens rearrangement leading to the formation of the central carbon-carbon bond R*C+ f i R*C\H2 ,C=CH-Cl-L-OFF - ,C=CH-CH,-S-Enz + PP -k Ht t (a) CH3 H3-Enz CH3 (XLIII) R.C+ R*C\H2 + ,C=CHCH2-S-Enz ____c ,C= CHCH,-S- Enz (b) CH3 C,,H=$- CH,.R cH3 ‘dF? CH3 (XLIV) ,C%R f t ‘ CH3 CH CH =C R*C\H* /a3 ,C=CHC~CHiCH=C CH,R S-Enz (XLVII) (XLVI I I) (R = geranyl; B = proton acceptor possibly part of active site of enzyme) Stevens rearrangement. FIG. 13. Hypothetical mechanism for coupling of farnesyl pyrophosphate involving 87 PopjBk NATO-sponsored symposium; Metabolism and Physiological Significance of Lipids ed. Dawson and Rhodes Wiley and Son London 1964 p. 45. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 187 of squalene (Fig.13c). The product at this stage is a squalyl-S-enzyme complex (XLV). From the known characteristics of the Stevens rearrange- ments8 it seems likely that it would be assisted by an appropriately situated proton-accepting group (B) at the active site. According to a suggestion put forward by Woodward (cited in ref. 87) the reductive liberation of squalene from the enzyme complex might be facilitated by prior reaction (Fig. 13d) with a third farnesyl pyrophosphate molecule to yield a new sulphonium complex (XLVI). The products of reductive cleavage (Fig. 13e) would now be squalene (XLVII) and farnesyl-S-enzyme (XLVIII). As pointed out by PopjBk Woodward’s suggestion should be amenable to experimental testing since it implies that the enzyme in its resting state should always accommodate a farnesyl residue.There have as yet been few detailed reports of experiments specifically designed to isolate and study the possible intermediates in the conversion of farnesyl pyrophosphate into squalene but those that have appeared suggest a complex sequence of events and do not exclude either type of mechanism outlined above. Thus Gosselinss reported that when labelled farnesyl pyrophosphate was incubated with a microsomal preparation in the absence of NADPH which is an essential requirement for squalene formation it was in part converted into a material bound to microsomal protein from which a labelled hydrocarbon could be liberated by acid hydrolysis. The hydrocarbon behaved similarly to squalene on chromato- graphy but failed to form a hexahydrochloride that co-crystallised with that of squalene.These observations have been confirmed and extended by Krishna et al. in experiments performed with a “solublised” squalene synthetase preparation from beef liver microsomes. 91 These workers showed that the protein-bound hydrocarbon after liberation by acid hydrolysis behaved on gas-liquid chromatography like a C, hydrocarbon somewhat more polar than squalene. They also presented evidence for the transformation of this unidentified material into squalene when it was incubated further (in the protein-bound state) in the presence of NADPH. Gosselin and Lyneng2 have recently described experiments in which a rat liver preparation was incubated with labelled mevalonic acid under conditions which should carry the transformation of mevalonic acid as far as farnesyl pyrophosphate followed by the addition of the microsomal enzyme components normally responsible for coupling the two farnesyl groups to produce squalene but without addition of NADPH.This pro- cedure resulted in the formation of a labelled substance having the characteristics of a phospholipid from which acid hydrolysis liberated a hydrocarbon similar to but not identical with squalene. The phospholipid- like material did not behave as a precursor of squalene but no datum was 88 Thompson and Stevens J. 1932 55 69. 89 Gosselin Arch. Internat. Physiol. Biochem. 1962 70 89. 91 Anderson Rice and Porter Biochem. Biophys. Res. Comm. 1960,3 591. ga Gosselin and Lynen Biocheni. Z . 1964,340 186. Krishna Feldbruegge and Porter Biochem.Biophys. Res. Comm. 1964 14 363. 188 QUARTERLY REVIEWS presented with reference to either the structure or the metabolic potential of the hydrocarbon released from it by acid hydrolysis. The relationship between this hydrocarbon and that described in earlier brief reportsSgs therefore remains unclear. It is possible that these observations foreshadow further important advances in the understanding of squalene formation. However there is considerable evidence (discussed by Popjkk and Corn- forth4) for alternative pathways of metabolism of farnesyl pyrophosphate and some of these may be accentuated when the normal pathway to squa- lene is obstructed as in the work described above. The Biological Conversion of Squalene into Lanosterol.-The scheme of cyclisation of squalene put forward by Woodward and Bloch21 implied that lanosterol or some closely related compound should be an intermediate in the biosynthetic pathway between squalene and cholesterol.After this intermediate r81e of lanosterol had been clearly e~tablished~~-~~ a major aspect of subsequent investigations became the elucidation of the mechan- ism of conversion of squalene into lanosterol. Experimental work in this area was preceded by the extensive development of the theoretical concepts of Ruzicka Eschenmoser and their collaborators 93s 94 according to which squalene was visualised as a common biological precursor not only of lanosterol and related tetracyclic triterpenes but also of the pentacyclic triterpenes such as the amyrins and lupeol. In this theoretical treatment the cyclisation of squalene was considered as a steroelectronically controlled concerted process initiated by electrophilic attack of a cationic species such as Hf or OH+ and involving a series of transient carbonium ion intermediates.Stabilisation of the final cyclisation product was presumed to take place either by loss of a proton or neutralisation of the positive charge by OH-; some examples of the suggested biogenetic relationship are shown in Fig. 14. The biogenesis of the different classes of cyclic triterpene was rationalised in terms of several alternative conformations of the squalene chain and various carbonium ion rearrangements to which they should lead. Thus an essential r61e of the enzyme catalysing such a cyclisation must be to impose the appropriate conformation upon the squalene chain.The conformation of squalene and the sequence of rear- rangements suggested for its conversion into lanosterol by a concerted cyclisation initiated by OH+ are depicted in Fig. 14a. This scheme accounts for the presence of the 1 4 ~ and 13p methyl groups in lanosterol in terms of two 1,2 shifts of methyl groups of squalene. Eschenmoser et aLg4 pointed out that with ring B initially present in the boat conformation this mechanism was more consistent with a non-stop cyclisation process than the 1,3 shift of a methyl group from C(s) to C(13). The hypothesis of the central r61e of squalene as a biological precursor of polycyclic triterpenes in both animals and plants is now supported by various experiments some of which will be discussed below. The bio- g3 Ruzicka Experientia 1953 9 357 362.94 Eschenmoser Ruzicka Jeger and Arigoni Helv. Chim. Ada. 1955 38 1890. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 189 HO HO Euphol Dammarenediol FIG. 14. Derivation of some tetracyclic and pentacyclic triterpenes from squalene. FIG. 14a. Stereochemical course of cyclisation of squalene to form lanosterol. 190 QUARTERLY REVIEWS synthesis of squalene from labelled mevalonate and its active turnover have recently been demonstrated to take place in higher plant tissuesg5 with incorporation of the label according to the same pattern as is found in squalene of animal tissues. 96 Moreover a pentacyclic triterpene of animal origin has recently been isolated. 97 The first experiments designed to test the postulated mechanism of squalene cyclisation were those of Tchen and B l o ~ h ~ * ~ ~ ~ who showed that the enzymic cyclisation of squalene in the presence of D,O yielded lanos- terol into which no measurable amount of deuterium had been incorpor- ated a result that is consistent with a concerted process without stable intermediates.Moreover ISO was incorporated into lanosterol when the incubation was carried out in an atmosphere enriched in ISOz but not when the medium contained Hz1*O. These and other observations strongly support the concept that the cationic species which initiates the cyclisation is either enzymically “activated” oxygen or OH+ derived from it. The cyclisation reaction requires NADPH and enzymic factors from both the microsomal and soluble fractions of a liver homogenate.lOO Its character- istics are therefore those of a “mixed function oxidase” reaction.lol Many such reactions are now known in the oxidative metabolism of the steroids and other examples will be discussed in a later section.The possibility that squalene cyclisation may be initiated by the attack of OH+ has prompted attempts to inhibit cholesterol formation by the use of catalase which would be expected to reduce the OH+ concentration of tissues or tissue homogenates and results have been reportedlo2 which seem to support this concept. However a closer study of the effect shows that it is due not to the enzyme (hepatocatalase) per se but to an impurity of low molecular weight which inhibits the conversion of mevalonate into squalene. O3 The rearrangement of the methyl groups at the centre of the squalene molecule leading to the 13p 14a-dimethyl structure of lanosterol has been shown by two differently designed experiments to take place by 1,2-shifts of the methyl groups as postulated by Eschenmoser et aLg4 Maudgal Tchen and Blochlo4 synthesised 13C-labelled all-trans-squalene by the method of Dicker and Whitinglo5 using as an intermediate a mixture of geranylacetones one of which contained 13C in the carbonyl carbon and 95 Nicholas J.Biol. Chem. 1962 237 1485. 96 Nes and Rosin 6th International Congress of Biochemistry New York 1964 p. 97 Mallory Gordon and Conner J. Amer. Chem. Sac. 1963 85 1362. Q8 Tchen and Bloch J. Biol. Chem. 1957 226,931. 9Q Tchen and Bloch J. Amer. Chem. Soc. 1956,78 1516. loo Tchen and Bloch J. Bid. Chem. 1957 226 921. lol Mason Adv. Enzymol. 1957 19 79. O 2 Puig-Muset Martin and Fernande International Symposium.Drugs Affecting lo3 Caravaca May and Dimond Biochem. Biophys. Res. Comm. 1963,10 1S9. lo4 Maudgal Tchen and Bloch J. Amer. Chem. Soc. 1958 80 2589. Io5 Dicker and Whiting J. 1958 1994. 588. Lipid Metabolism Milan 1960. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 191 the other contained 13C in the methyl group attached to the carbonyl carbon. A mixture of three types of squalene as shown (Fig. 15 I 11,111) was obtained and subjected to enzymic cyclisation to lanosterol. The species I11 would be expected to yield two patterns of labelling in lanos- terol depending upon which end of the molecule became involved in the initiation of the cyclisation process. Moreover the pattern of lanosterol labelling would be expected to be different depending upon whether species (111) were to cyclise with a 1,2- or 1,3-rearrangement of methyl groups.Squalene species (III) when cyclised in one of the two possible directions with 1 ,Zrearrangement of methyl groups will yield one molecule of acetic acid (that from C, + C3,J as indicated in Fig. 15 which is labelled in both carbons with 13C. Under no circumstances would such a doubly labelled acetic acid be obtained by a 1,3 shift of a methyl group. The lanosterol derived from the mixed synthetic squalenes was oxidised by a modified Kuhn-Roth procedure to acetic acid which repre- sented the various methyl groups of the lanosterol molecule together with the carbons to which they were attached. The acetic acid obtained from the oxidation was converted into ethylene and analysed by mass spectro- metry with the identification of a peak corresponding to the doubly labelled molecules in approximately the expected abundance.The 1,2-shift mechanism was thus supported. Further evidence for this mechanism was provided by the experiment of Cornforth and his co-workers106 similar in principal to that of Maudgal et al. but utilising mevalonolactone labelled with 13C. In the mevalonolactone (I) used for the experiment some molecules were labelled in the methyl group and in C(*) others were labelled in only one or the other of these positions and others were unlabelled. Squalene biosynthesised from this mixture would consist of many differently labelled -species of which two (Fig. yield cholesterols with different labelling distributions fiyTwol,2-\ (a) - HU & \ i g LQ-J FIG.15. Different 13C- labelled squalenes used by Maudgal Tchen and Bloch to Cornforth Cornforth Pelter Horning and Popjak Tetrahedron 1959 5 31 1 demonstrate the 1 &shift of methyl groups in cyclisation to lanosterol. I92 QUARTERLY REVIEWS FIG. 16. Distribution of label (e) at centre of squalene and in cholesterol derived from [3',4-13C,]mevalonolactone. depending upon whether the C(la) methyl group became attached to C(13) by a 1,2 or 1,3 rearrangement. Cholesterol biosynthesised from this mixture was oxidised to acetic acid which was analysed by mass spectrometry to determine the proportion of doubly labelled molecules. These appeared with an abundance that could only be accounted for if a 1,2-methyl group migration were to occur during cyclisation.Proof that the methyl carbons in the terminal isopropylidene groups of squalene retain their individual identity in the course of cyclisation has been presented by Arigoni.lo7 Soya-bean seedlings were supplied with [2-14C]mevalonate and the labelled soya-sapogenols subsequently isolated. The 1,3-glycol structure in ring A (Fig. 17 IL) was oxidised to give the HO *d3 CH,OH @-om *& CO,H - 0 0 3 *CH 3 (I L) (0 Q-1) FIG. 17. Labelling of 4a-methyl group of soyasapogenol from [2-14C]mevalonate. unstable 3-0x0-24-carboxylic acid (L) which was readily decarboxylated to the ketone (LI) giving CO that contained no 14C. Hence in the forma- tion of this pentacyclic triterpene the axially oriented hydroxymethyl group at C(4) was derived from the methyl carbon of mevalonic acid. There is also retention of individual identity by the corresponding gem.- disubstituted carbon atoms in gibberellic acid (LIII)lo8 and rosenono- lactone (LIV),1079108 and by the gem.-dimethyl groups of the isopropylidene structure of the terpenoid chain of mycelianamide (LII).loS The evidence in the latter case is considered in more detail in a later section.The stereospecific fate of the two apparently identical methyl carbons of the isopropylidene group of squalene is entirely consistent with the stereo- specificity noted above for the loss of hydrogen from C(2) of isopentenyl lo' Arigoni ref. 9 p. 231. lo8 Birch and Smith ref. 9 p. 245. lo9 Birch Kocor Sheppard and Winter J. 1962 1502. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 193 pyrophosphate during establishment of the allylic double bond.It is also clearly a further example of the now well established phenomenon of dissymmetric reactivity of a symmetrical substrate in association with an enzymic site. OH The Conversion of Lanosterol into Cholesterol.-The conversion of lanosterol into cholesterol entails the following changes (1) Replacement of the methyl groups at C(4) and C(14) with hydrogen atoms; (2) shift of the d8 bond to d5; (3) saturation of the side chain. While much information has been obtained concerning the biochemical conditions necessary for these various changes individually it has proved much more difficult to determine whether in a given tissue these reactions must always take place in a definite sequence and if so what that sequence is. In particular the stage (or stages) at which the saturation of the side chain takes place remains inadequately defined.Some of the studies bearing on this point are considered in further detail below but for the moment it is sufficient to note that ample evidence has been obtained for the conversion of various d 24-deri~ati~e~24p11 0-113 and 24,25-di hydro-derivative~~~~~~ O 9 ll1 7 lI3-ll7 into cholesterol. Evidence for the sequence in which the three methyl groups attached to C(4) and C(14) are removed from lanosterol (11) (Fig. 18) has been presented by Bloch and his co-workers. A material slightly more polar than lanosterol was isolated from the tissues in trace amounts but with high specific activity at short time intervals after the injection of 14C-acetate into rats. This material was further converted into cholesterol by a liver homogen- ate.lls By experiments with trace amounts of the labelled compound its individual structural features were characterised and it was tentatively Johnston and Bloch J.Amer. Chem. SOC. 1957 79 1145. ll1 Lindberg Gautschi and Bloch J. Biol. Chem. 1963 238 1661. 112 Steinberg and Avigan J. Biol. Chem. 1960 235 3127. 113 Schroepfer J. Biol. Chem. 1961 236 1668. 114 Frantz Davidson Dulit and Mobberley J. Biol. Chem. 1959 234 2290. Schroepfer and Frantz J. Biol. Chem. 1961 236 3137. 116 Kandutsch and Russell J. Biol. Chem. 1960 235 2256. 117 Wells and Lorah J. Biol. Chem. 1960 235 978. 118 Gautschi and Bloch J. Amer. Chem. SOC. 1957 79,684. 194 QUARTERLY REVIEWS identified as 4,4’-dimethylcholesta-8,24-dien-3~-01 (LVIII) with some doubt remaining as to the exact position of the nuclear double bond.This sterol and its 4’- and d8(14)-isomers were subsequently prepared by partial synthesis.llg The radioactive material easily separated from the compound on crystallisation but was inseparable from the d8(g)-isomer even HO HO + CO (LVIII) CH + CO steps HO (LXVI I) (LXVI I I) (Lw FIG. 18. Conversion of lanosterol into cholesterol via dZ4-intermediates. ll9 Gautschi and Bloch J . B i d Chem. 1958,233 1343. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 195 during reduction to the 24,25-dihydro-derivative and oxidative fission of the ~ l ~ ~ ~ - b o n d . The derivative of the d7-isomer was separated from the radio- active material by this procedure With this confirmation of the structure it was concluded that the C(,,)-methyl group was the first to be removed from lanosterol.When incubated with rat liver honiogenates 4,4'- dimethylcholesta-8,24-dien-3/3-o1118 or lanosterol (II),lz0 that had been labelled biologically with [2-14C]acetate yielded 14C0 squivalent to the CH,*CH2 )N-CH CH,- 0Q"-".H2+ 0 (LW C%CH CH methyl groups removed. No labelled formaldehyde could be detected. The demethylating enzyme system was present in the microsomal fraction and required both oxygen and NADPH. Semicarbazide added to the incuba- tion medium inhibited the conversion of lanosterol into both cholesterol and CO and caused the accumulation of unidentified polar metabolites which could be converted in turn into cholesterol. These results were in- terpreted120 to suggest that each methyl group at C(,) and C(la) of lanos- terol was oxidised through the sequence CH + CH,OH + CHO + CO,H (e.g.LV-LVIT) to be eliminated finally as CO,. Up to the present time however none of the hypothetical intermediates with partially oxidised methyl groups has been identified and no separation of the enzymes involved in these oxidative steps has been reported. While the prior removal of the C(,,)-methyl group seems to be reasonably well established for the mammalian pathways of sterol synthesis the fact that this may not hold in plants is suggested by the structure of macdougal- lin (LXXI) isolated121 from the cactus Perziocereus nzacdougalli. This compound presumably arises from lanosterol by a route involving removal of the 4,4'-methyl groups without attack on that at C(14). The presence of one methyl group at C(4) together with the one in the 14a-position is found122 in cycloewcalenol (LXXII) and in the closely 120 Olson Lindberg and Bloch J.Biol. Chem. 1957 226 94. 121 Djerassi Knight and Wilkinson J . Arner. Chem. SOC. 1963 85 835. 12* Cox King and King J . 1959 514. 196 QUARTERLY REVIEWS related alkaloid cyclobuxine (LXXIII).123 Both of these structures imply removal of a 4-substituted methyl group before attack on the C(,,)-methyl group in the cyclopropano-steroid series. Indeed the C(,,)-methyl group is unattacked in all of the cyclopropano-steroids so far isolated suggesting that this structural feature is for some reason (possibly the absence of a As-bond) incompatible with oxidative attack on the methyl group at The removal of the two methyl groups at C(4) of 4,4’-dimethylcholesta- 8,24-dien-3P-ol (LVIII) probably takes place in stepwise fashion with oxidation of the 316-hydroxyl group to the ketone (LIX and LXII).lll Thus the 3a3H label is lost from lanosterol 4,4,-dimethyl-da-cholestenol 4a-methyl-d 7-cholestenol and 4a-methyl-d *-cholestenol when these com- pounds are metabolised to cholesterol and the metabolism of lanosta- 8,24-diene-3-one and 4,4’-dimethylcholest-8-enone to cholesterol has been demonstrated.On the other hand zymosterol (LXVI) previously shown by Alexander and Schwenk12 and by Johnston and BlochllO to be converted into cholesterol by mammalian enzymes retained the 3a3H in the process. It has been pointed out by B l o ~ h l ~ ~ that decarboxylation at C(,) of the intermediates LX and LXIV would be facilitated by the C(,)-keto-group and the extreme lability of a 3-0x0-4-carboxylic acid has been noted by Britt Scheuerbrandt and Bloch (unpublished observation quoted in ref.111). Facilitation of the decarboxylation at C(14) by the As-bond (LVII) has also been suggested by Bloch. That the oxidation and elimination of one methyl substituent at C(4) must be completed before the other is attacked has not been unambigu- ously established but it seems probable since 4a-methyl-d 7-cholestenol (LXXIV) (methostenol or lophenol) has been identified in both anima112s-12a c(14)* and plant and its ds-isomer has also been isolated from animal tissues.130 As noted abovelll these compounds are metabolised to choles- terol and a putative partially oxidised intermediate (LXXV) in the conc lZ3 Brown and Kupchan J . Amer. Chem. Suc. 1962 84,4590,4592.124 Alexander and Schwenk Arch. Biochem. Biophys. 1957 66 381. lZ6 Bloch ref. 9 p. 4. lZ6 Frantz Davidson and Dulit Fed. Pruc. 1956 15 255. lZ7 Wells and Neiderhiser J . Amer. Chem. Soc. 1957 79 6569. lt8 Neiderhiser and Wells Arch. Biochem. Biophys. 1959 81 300. lZ9 Djerassi Krakower Lemin Liu Mills and Villotti J . Amer. Chem. Suc. 1958 130 Kandutsch and Russell J. Biol. Chem. 1960 235 2253. 89 6284. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 197 version of lophenol into cholesterol is also metabolised to It has been pointed out by Popjhk and Cornforth4 that the a-orientation of the remaining methyl group at C(4) in lophenol cannot be taken as evidence that this is the original orientation of the last methyl group of lanosterol to be removed since an enol form of the ketone (LXI) would probably be involved in elimination of the first carboxyl group from C(4) and on reversion to the keto-form (LXII) the remaining C(,)-methyl group would assume the less hindered a-configuration.Gaylor and D e l w i ~ h e l ~ ~ used 4a-methyl-d8-cholestenol as a trapping agent during enzymic de- methylation of 24,25-dihydrolanosterol that had been labelled from [2-14C]mevalonate and concluded from their results that the stereo- specific identity of the 4,4'-methyl groups in lanosterol was the same as that demonstrated in soya-sapogenols (IL) by Arigoni.lo7 The several arguments used by these authors to support their conclusion do not however circumvent the difficulty of interpretation alluded to by Popjhk and C ~ r n f o r t h . ~ The Final Steps in Cholesterol Biosynthesis.-The C,,-sterol resulting from demethylation of lanosterol if no reduction occurred in the side chain would be zymosterol (cholesta-8,24-dieno1) (LXVI).In the studies by Johnston and Blochllo of the in vitro conversion of this sterol into choles- terol liver homogenates prepared under the gentle conditions of B u ~ h e r l ~ ~ converted both zymosterol (LXVI) and d8-cholestenol (24-dihydro-zymos- terol) into cholesterol but a homogenate prepared by the more disruptive Waring Blendor procedure metabolised only the first of these two com- pounds. On the basis of these observations and the report by Stokes et ~ 1 . l ~ ~ of the isolation of desmosterol (d5~24-cholestadienol LXIX) from chick embryos with evidence for its r61e as an intermediate in cholesterol s y n t h e s i ~ ~ ~ ~ ~ ~ ~ it was argued1l0~llZ that as indicated in Fig.18 the reduc- tion of the dZ4-bond probably occurred as the final reaction in cholesterol biosynthesis and that the conversion of various 24-25-dihydro-sterols into cholesterol represented deviations from the normal pathway. (For full discussion see Bloch.6) However it is now evident that all of the nuclear transformations between lanosterol and cholesterol can take place equally well in the 24,25-dihydro-series as in the dZ4-series and since they are more accessible than their ~l~~-analogues many 24-25-dihydro-compounds have been used in studies of the changes taking place in the nucleus. Johnston and BlochllO found that the conversion of zymosterol into cholesterol required oxygen and assumed that the oxidative step was in- volved in the shift of the nuclear double bond.It was suggested that the d"Y6-bond might arise by hydroxylation followed by dehydration in ring B with the possible formation of a 5,7-diene structure such as (LXVIII) Pudles and Bloch J . Bid. Chem. 1960 235 3417. 132 Gaylor and Delwiche Steroids 1964 4 207. Bucher J. Amer. Chem. SOC. 1953 75 498. lR4 Stokes Fish and Hickey J. Biol. Chem. 1956 220,415. 135 Stokes Hickey and Fish J. Biol. Chem. 1958 232 347. 198 QUARTERLY REVIEWS as an intermediate.6 It has subsequently been shown that the conversion of d 7-cholestenol into cholesterol requires oxygen114 but that the conversion of 7-dehydrocholesterol into cholesterol does not.115J36 7-Dehydrocholes- terol is formed during conversion of LI ‘-cholestenol into cholesterol137 and the sequence d8 3 d7 -+ A5s7 -3 d5 is therefore supported.Moreover convincing evidence for the irreversibility of the last two of these steps in mammalian tissues has been presented by Frantz et a?.138 in contrast to the finding of Glover and his c o - w o r k e r ~ ~ ~ ~ J ~ ~ whose data suggest that they may to some extent be reversible. Evidence such as that of Fagerlund and 1dlerlP1 for the conversion of cholesterol into d 7-cholestenol in starfish probably has little relevance to the mammalian biosynthetic pathway since there is evidence that the invertebrates have special mechanisnis for the modification of ring B in the preformed sterol nucleus as for example in the conversion of cholestanol into d 7-cholestenol in insects.lP2 Though the intermediate r6le of d 7-cholestenol and 7-dehydrocholes- terol in the conversion of da-cholestenol into cholesterol seems to be reasonably well established the biochemical mechanisms involved require further clarification.Nothing is known of the enzymic mechanism of the shift of the double bond from the 8(9) position though some results relevant to this problem are discussed in the following section. While the overall conversion of d 7-cholestenol into cholesterol requires both oxygen and NADPH the latter appears to be necessary only for the reduction of the double bond of 7-dehydrocholesterol but not for the oxygen-requiring step from d7-cholestenol to 7-dehydro~holesterol.~~~ If the A7 -+ d5y7- transformation involved a hydroxylated intermediate such as a 6-hydroxy- d7-cholestenol it would be expected that this hydroxylation in common with other steroid hydroxylations would require both oxygen and NADPH.In this connection it may be noted that Harvey and B l o ~ h l ~ ~ failed to demonstrate a conversion of d7-3/3-6/3-dihydroxycholestenol into cholesterol under anaerobic conditions. Reduction of the d2cbond and the effects of triparanol The question of the stage in the biosynthetic sequence at which reduction of the dZ4-bond takes place has given rise to much discussion usually on the basis of inadequate evidence and it is only recently that serious at- tempts have been made to approach this difficult problem by means of appropriate experiments. 138 Kandutsch .I. Biol. Chem. 1962 237 358. 137 Dempsey Seaton Schroepfer and Trockman J. Biol. Chem. 1964 239 1381. 138 Frantz Sanghvi and Schroepfer J.Biol. Chem. 1964 239 1007. 139 Mercer and Glover Biocheni. J. 1961 80 552. I4O Glover and Stainer Biochern. J. 1959 72 79. I 4 l Fagerlund and Idler Canad. J. Biochem. Physiol. 1960. 38 997. 142 Clayton and Edwards J. Biol. Chem. 1963 238 1966. 143 Harvey and Bloch Chem. and Ind. 1961. 595. CLAYTON CHOLESTEROL AND TERPENOID BIOSYNTHESIS 199 The ob~ervationl~~-~*~ that triparanol { MER-29 l-[LC(diethylamino- ethoxy)phenyl ]-l-(p-tolyl)-2-(p-chlorophenyl)ethanol (LXX) > an inhibitor of cholesterol synthesis caused accumulation of desmosterol (LXIX) in vivo and in vitro at first seemed to strengthen the view that the reduction of the ~ l ~ ~ - b o n d occurred principally if not exclusively as the last step. However it is now clear that triparanol does not inhibit the conversion of desmosterol into cholesterol specifically.In various systems it can also prevent reduction of the ~ I ~ ~ - b o n d of zymosterol (LXVI),l13 d7,24-~holes- tadienol ( LXVII),14' d 5~7~24-cholestatrienol (LXVIII),148 and lanosterol (II),la9 and probably in many other c o r n p o ~ n d s . ~ ~ ~ J ~ ~ Desmosterol probably accumulates as the major sterol of liver during triparanol treat- ment because of the high efficiency of the liver enzymes responsible for the various nuclear transformations. Under normal conditions the liver con- tains the intermediates between squalene and cholesterol only in fractions of a percent of the cholesterol concentration. It was pointed out by Blochs that this situation does not hold for mammalian skin and there is also evidence that it does not hold for intestinal tissues.Rodent skin normally contains measurable amounts of several 313-monohydroxy- sterols representative of intermediate stages in cholesterol biosynthesis. It has been possible to achieve a complete resolution of this mixture of sterols which with the exception of lanosterol were found to occur in the normal animal almost exclusively as the 24,25-dihydro-derivatives. The major effect of triparanol was to cause their accumulation as the d24- analogues15o and all possible 3-monohydroxy-sterol intermediates of both the A 24- and 24,25-dihydro-series between squalene and cholesterol were chromatographically identified several of them for the first time. The enzymes responsible for reduction of the AN-bond in both des- moster01~~~ and lanoster01~~~ are similar with respect to their intracellular distribution (in the microsomal fraction) co-factor requirements (NADPH but not NADH) and their response to various inhibitors and Avigan et ~ 1 .l ~ ~ suggest that the same enzyme could carry out the reduction of the side chain independently of the structure of the nucleus. This would certainly be consistent with the various findings discussed above but as the authors point out it cannot be regarded as proven on the basis of the limited data available. Goodman et al.153 studied the time-course of incorporation of [14C]- mevalonate in vivo into rat liver sterols which were separated into fractions 144 Blohm and Mackenzie Arch. Biochem. Biophys. 1959 85,245. 145 Blohm Kariya and Laughlin Arch. Biochem. Biophys. 1959 85 250. 146 Avigan Steinberg Vroman Thompson and Mosettig J.Biol. Chem. 1960 147 Frantz and Mobberley Fed. Proc. 1961 20 285. Frantz Sanghvi and Clayton J. Biol. Chem. 1962,237 3381. 149 Avigan Goodman and Steinberg J. Biol. Chem. 1963 238 1283. 150 Clayton Nelson and Frantz J. Lipid Res. 1963 4 166. lS1 Horlick and Avigan J. Lipid Res. 1963 4 160. 152 Avigan and Steinberg J. Biol. Chem. 1961 236 2898. 153 Goodman Avigan and Steinberg J. Biol. Chem. 1963 238 1287. 235 3123. 200 QUARTERLY REVIEWS differing with respect to the degree of substitution at C(4) and the presence or absence of the ~ I ~ ~ - b o n d . The results suggested that neither dihydrolan- osterol nor desmosterol was on the main pathway of cholesterol synthesis but precise identification of the stage of reduction of the side chain was not made.This result agrees with the earlier obser~ation~~ that lanosterol but not dihydrolanosterol acquires the label from [14C]acetate in preparation from rat liver in vitro. It is also consistent with the absence of dihydro- lanosterol from rat skin,ljo though not with its reported presence in a preputial gland tumour of mice.154 The detailed study of the sterols of rat skinljO further revealed that in this tissue all components beyond lanosterol occur as mixtures of di- and d8-isomers. The question therefore arises of whether one or several enzymes are responsible for this type of isomerisation. Triparanol not only inhibited the 24-reduction but also effected the ratio of d8 to d7-isomers. In the compounds following lanosterol in the biosynthetic sequence triparanol shifted this ratio in favour of the d8-components but lanosterol itself was apparently almost entirely replaced by its d 7-analogue (LXXVI).The significance of these observations is uncertain. Apart from its well established inhibition of the d24- reductase triparanol also inhibits the reduc- tion of the d ‘-bond in d5*7-intermediates.155 If it also inhibits rearrangements between d8 and d 7 these observations suggest that d 7~24-lanostadienol may be an alternative to lanosterol as an initial product of cyclisation of squalene in the skin. This possibility though speculative is also suggested by the work of G a y l ~ r l ~ ~ who has isolated d7~24-lanostadieno1 (LXXVI) from rat skin and has presented data consistent with its possible formation independently of lanosterol. It also recalls the unexplained observationz3 that pure lanosterol was less effective than crude “iso-cholesterol” in trapping radioactivity from [14C]acetate in a liver homogenate.Isocho- lesterol contains lanosterol and agnosterol (d ‘ 9 9~24-lan~~tatrienol) as well as both of their 24,25-dihydro-derivatives. Its effect as a trapping agent was approached though not equalled by a mixture of lanosterol with agnos- terol of about 80% purity. It is possible in the light of these more recent observations that the synergistic effect of agnosterol could be due to its structural resemblance to d 7s24-lanostadienol or even to the presence of this compound as a previously unidentified contaminant of agnosterol. I thank Dr. George Popjak F.R.s. for making available much unpublished material. This Review was written during the tenure of an Established Invest- igatorship of the American Heart Foundation. 15( Kandutsch and Russell J. Biol. Chem. 1959,234 2037. 165 Dempsey 6th International Congress of Biochemistry New York 1964 Abstracts lS6 Gaylor J. Biol. Chem. 1963 238 1643 1649. p. 570.

ISSN:0009-2681    

DOI:10.1039/QR9651900168

出版商:RSC    

年代:1965

数据来源: RSC