摘要:

QUARTERLY REVIEWS THE SYNTHESIS OF DI- AND TRI-TERPENES By N. A. J. ROGERS and J. A. BARLTROP (THE UNIVERSITY OXFORD) THE total synthesis of terpenoid compounds as in other fields provides the final confirmation of structural investigations. In some cases it enables an unambiguous choice to be made between two or more structures each in itself consistent with the degradative evidence. Apart from this utilitarian purpose however there is an aspect of greater appeal. The higher terpenes are complex molecules and as such provide a considerable intellectual challenge to the aspiring synthetic chemist. Also the measure of a successful synthesis is not simply in that its object is achieved but in the elegance of the route chosen. More perhaps than any other branch of the subject synthesis remains a field where aesthetic as well as scientific satisfaction may be enjoyed.In the opinion of the present authors this aspect of the subject provides a powerful stimulus the reaction to which is well illustrated in the field under review. (THE UNIVERSITY BIRMINGHAM) Acyclic Diterpenes Phyto1.-This diterpene (7) contains two asymmetric carbon atoms and earlier synthetic operations1 led to mixtures of the various epimeric modifications. However the work of Burrell Jackman and Weedon2 not Simonsen and Barton “The Terpenes,” Cambridge Univ. Press 1952 Vol. 111; Lukes and Zubacova Chem. Listy 1957 51 330; Weichet Hodrova and Kvita ibid. p. 568 ; Sacrycheva Vorobeva Kuznetzova and Preobrazhenskii Zhur. obshchei Khim. 1958 28 147; Nazarov Gusev and Gunar ibid. p. 1444. * Burrell Jackman and Weedon Proc.Chem. SOC. 1959,263. 117 1 118 QUARTERLY REVIEWS only gave the naturally occurring optically active compound but also permitted an assignment of absolute configuration at these asymmetric centres. By a nitrile synthesis D-( +)-dihydrocitronellol (1) was converted into the acid (2) which by anodic cross-coupling with the L-( +)- D-( -)- and DL-forms of the glutaric half ester (3) gave rise to three epimeric forms of the ester (4; R=Me). A further anodic synthesis with lavulic acid gave three forms of the ketone (5). A comparison of the rotations of these ketones with the ketone obtained by degrading phytol showed both the asymmetric centres in phytol to have the D-configuration. The synthesis was completed by treating this ketone with methoxyacetylene and rearrang- ing the methoxyethynylcarbinol with acid to give a separable mixture of cis- and trans-methyl phytenoates (6) the trans-isomer of which with lithium aluminium hydride afforded natural phytol (7).Sclareol and Labdanolic Acid.-The problem of synthesising3 these compounds is primarily one of controlling the configuration at the five asymmetric centres. The keto-acid (8) was obtained by ozonolysis of a tricyclic ketone (41; R = H) to be described below. Treatment of it with methyl-lithium followed by dehydration led through the hydroxy-ketone (9) to the unsaturated ketone (10; R = Ac). This on oxidation with hypoiodite gave the corresponding unsaturated acid (10; R = C02H) which was cyclised under acidic conditions to (&-)-ambreinolide (1 1). This furnished a relay. (+)-Ambreinolide was hydrolysed to the lithium salt of the related hydroxy-acid which with methyl-lithium gave the ketone (12).This ketone was converted into a mixture of epimeric acetoxyethynyl- carbinols (13; R1 = Ac R2 = CiCH) which on being separated and reduced with lithium aluminium hydride gave rise to sclareol(l3 ; R1 = H; R2 = CHCH,) and 13-episclareol. Through the dehydration* of sclareol to manool (16) this work also constitutes a formal total synthesis of the latter compound. The ketol (12) was also transformed into methyl labdanolate (15) and Bigley Rogers and Barltrop J. 1960 4613. Buchi and Biemann Croat. Chern. Acfa 1957,29 163. ROGERS AND BARLTROP THE SYNTHESIS OF DI- AND TRI-TERPENES 119 its 13-epimer by reaction with ethoxyacetylene acid-catalysed rearrange- ment of the ethoxyethynylcarbinol (13; R2 = CiC-OEt R1 = H) to the unsaturated ester (14) and hydrogenation.Tricyclic Diterpenoids The biosynthesis of tricyclic diterpenoids appears5 to take place through the cyclisation of acyclic polyisoprenoid precursors and in the attempt to parallel such processes in vitro numerous farnesol derivatives have been shown6 to give rise to bi- and tri-cyclic systems under acidic conditions. For example the ketone (17) has been converted’ into an abietatriene (20). Similarly the unsaturated alcohols (18; R1 = OMe R2 = H) and (19) gave rises,g to A/B-C~S- and -trans-methoxypodocarpatriene (33 ; X = H). The related compound (18; R1 = H R2 = Pri) was cyclised to cis- and trans-abietatriene. Such syntheses appear to offer little control over the configurations of the ring junctions and have not been extended so far to include the introduction of the tertiary 1-carboxyl group characteristic of the diterpenoid acids.Cyclisation of phenethylcyclohexanols and ring extension of naphtha- s Barltrop and Rogers in “Progress in Organic Chemistry,” Butterworths Scientific Publns. London 1961 Vol. V pp. 96-131 and refs. cited therein. Ruzicka in “Perspectives in Organic Chemistry,” Interscience Publ. Inc. London 1956 p. 265; EschenFoser in “Ciba Foundation Symposium on the Biosynthesis of Terpenes and Sterols Churchill Ltd. London 1959 p. 217; Stork and Burgstahler J. Amer. Clzem. SOC. 1955,77 5068; Barton and de Mayo Quart. Rev. 1957 11 190 and refs. cited therein. Caliezi and Schinz Helv. Chim. Acta 1952 35 1649. Fetizon and Delobelle Compt.rend 1958 246 2776. Ansell and Gadsby J. 1959 2994. 120 QUARTERLY REVIEWS lene derivatives have been much more productive from the standpoint of the total synthesis of naturally occurring tricyclic diterpenoids. Podocarpic Acid.-Podocarpic acid (22; R1 = OH R2 = H) though not strictly a diterpenoid has been a key compound in these studies. King King and ToplisslO prepared the ethynylcarbinol from p-methoxy- phenylacetylene and ethyl 1,3-dirnethyl-2-oxocyclohexanecarboxylate and reduced it to the cyclohexanol(21; R = C02Et) which was cyclised with polyphosphoric acid. This gave a mixture of three stereoisomeric esters one of which was identified as (&)-0-methylpodocarpic ester (22; R1 = OMe Ra = Et) identical with a substance which had been earlier syn- thesised by an essentially similar route.f1v12 In a further synthesis13 of podocarpic acid the addition of hydrogen cyanide to the unsaturated ketone (23) followed by hydrolysis and esteri- fication gave the keto-ester (24).Reaction with methylmagnesium iodide then gave a hydroxy-ester and thence on cyclisation a mixture of tricyclic epimers from which was isolated deoxypodocarpic acid (22; R1 = R2 = H) shown to be identical with the acid obtained by Haworth and Barker,l* and cis-deoxypodocarpic acid (45). The synthesis was completed by a Friedel-Crafts acetylation giving the ketone (22; R1 = Ac R2 = Me) which oxidised by peracetic acid gave the acetate (22; R1 = OAc R2 = Me) of podocarpic ester. A different approach to the synthesis of (+)-podocarpic acid is illus- trated by the work of Wenkert and his co-~orkers.~~ The unsaturated lo King King and Topliss Chem.and Ind. 1956 119. l1 Haworth and Moore J. 1946 633. l2 Bhattacharyya J. Indian Chern. Soc. 1945,22 165. l3 Ghatak Tetrahedron Letters 1959 No. 1 19; Ghatak Datta and Ray J. Amer. l4 Haworth and Barker J. 1939 1299. Wenkert and Jackson J. Arner. Chern. Soc. 1958,80,217; 1959,81,5601; Wenkcrt Chem. SOC. 1960,82,1728. and Tahara ibid. 1960,82,3229. ROGERS AND BARLTROP THE SYNTHESIS OF DI- AND TRI-TERPENES 121 ketone (26) prepared by a Robinson ring-extension reaction from the corresponding 2-tetralone was carboxylated with triphenylmethylsodium & - & ___c o& o w H / (2 6) C0,Me (27) C0,Me (28) (+)-Fbdocarpic acid ~ (z:R'=oH,R*=H) 0 and carbon dioxide and then esterified to give a mixture of the ester (27) and the isomeric 3-carboxylic ester.Catalytic hydrogenation of the ester (27) gave the saturated /I-keto-ester (28) which by methylation afforded a mixture of the keto-ester (29) and (mainly) its 1-epimer. Clemmensen reduc- tion of the former followed by resolution then gave (+)-deoxypodocarpic acid (22; R1 = H R2 = H). The introduction of the 6-hydroxyl group by acetylation and per-acid oxidation followed the lines of the Ghatak synthesis13 just discussed. Ferrugino1.-The first synthesis16 of ferruginol (25) proceeded similarly. The ring closure of the alcohol (21 ; R = Me) obtained in two stages from p-methoxyphenylacetylene and 2,2,6-trimethylcyclohexanone gave a mixture of the cis- and trans-isomers of 6-methoxypodocarpatriene (33; X = H,) from which (-J-)-ferruginol was obtained by the reactions shown.Reagents 1 MeMgl then - H,O. 2 Ha-catalyst then HBr. A later but stereospecific synthesis1' of (-j-)-6-methoxypodocarpatriene (33; R = H,) and hence of (&)-ferruginol used the naphthalene approach. The /I-tetralone (30) by a Robinson annellation followed by methylation of the resulting a/?-unsaturated ketone (31) gave the ketone (32). In this compound the ,%oriented methyl groups ensured that the subsequent catalytic hydrogenation took place on the back face of the molecule. l6 King King and Topliss Chem. and Ind. 1954 108; J. 1957 573. l7 Raman and Rao Experientia 1956,12,472; Tetrahedron 1958 4 294. 122 QUARTERLY REVIEWS Removal of the carbonyl group then afforded trans-6-methoxypodo- carpatriene (33; X = H,). The transformation of this compound into ferruginol followed standard procedure.Dehydroabietic Acid.-The higher degree of stereospecificity obtained in synthesis from /?-tetralones and exemplified in the foregoing synthesis is shown again in the stereospecific synthesis of (5)-dehydroabietic acid (37) devised by Stork and Schulenberg.18 This synthesis which was a milestone in diterpene chemistry proceeded according to the sequence (34+37). 2x7 oq%..; H02C &- (37) Et0,C.H :& 2C (36) After methylation of the /?-tetralone (34; R = H) by the enamine methodlg to the ketone (34; R = Me) a ring-extension using ethyl vinyl ketone gave the tricyclic compound (35) in which the 12P-methyl group forced the subsequent alkylation with bromoacetic ester to occur from the less hindered rear face of the molecule.Catalytic hydrogenation of the ester (36) so obtained also occurred from the rear and removal of the carbonyl group and a Barbier-Wieland degradation of the side chain finally gave (&)-dehydroabietic acid (37). Nimbio1.-The synthesis20 of nimbiol methyl ether (39; X = 0 R = Me) followed a parallel course. The compound (38) obtained by annellating the corresponding /3-tetralone was methylated and reduced. Oxidation by chromic acid of the product (39; X = H, R = Me) then gave nimbiol l8 Stork and Schulenberg J. Arner. Chern. Soc. 1956 78 250. l9 Stork Terrell and Szmuszkovicz J. Amer. Chem. Soc. 1954 76 2029. 2o Ramachandran and Dutta J. 1960,4766. ROGERS AND BARLTROP THE SYNTHESIS OF DI- AND TRI-TERPENES 123 methyl ether. This compound which has been obtained21 from podocarpic acid has also been synthesised22 from trans-6-methoxypodocarpatriene (33; X = H,) by oxidation to the ketone (39; X = 0 R = H) followed by insertion of the 7-methyl group through the 7-chloromethyl derivative.Totaro1.-This resinol(43) which does not follow the classical isoprene rule was synthesised by Barltrop and Rogers23 from the tricyclic ether (40) itself prepared by the cyclisatjon of 1-rn-methoxyphenethyl-2,2,6- trimethylcyclohexanol. The ether submitted to a Birch reduction gave a mixture of the unsaturated ketones (41; R = H) and (42; R = H) each of which when alkylated with sodium t-pentyl oxide and isopropyl iodide gave a mixture of the isopropylated ketones (41 and 42; R = Pri). De- hydrogenation of the mixture then gave (&)-totarol. Compounds Related to the Tricyclic Diterpenoids The four possible racemates represented by structures (44-47) are now all known.trans- (44) and cis-Deoxypodocarpic acid (49 which have been synthesised as racemates by methods described earlier in this Review have also been obtained in optically active forms. Deoxygenation of podocarpic acid24 gave trans-( +)-deoxypodocarpic acid ; removal of the isopropyl group from dehydroabietic (37) and its r ~ i t r i l e ~ ~ ~ ~ with 21 Bible Tetrahedron Letters 1960 No. 9 20; Wenkert and Stenhagen Abs. 137th Amer. Chem. SOC. Meeting 1960 36. 22 Fetizon and Delobelle Tetrahedron Letters 1960 No. 9 16. 23 Barltrop and Rogers J . 1958 2566. 24 Wenkert and Jackson J. Amer. Chem. SOC. 1958 80 217. 25 Ohta and Ohmori Pharm Bull. (Japan) 1957 5 96. 26 Wenkert and Chamberlin J .Amer. Chem. SOC. 1959 81 688. 27 Wenkert and Jackson J. Amer. Chem. SOC. 1958 80 211. 124 QUARTERLY REVIEWS aluminium chloride gave as main product the enantiomorph of acid (45) and the corresponding nitrile. The latter transformation has been explained by invoking two retro-Friedel-Crafts reactions ; the first causes the expected replacement of isopropyl by hydrogen and the second a fission of the 12,13-bond and subsequent re-formation of ring B. Deisopropyldehydroabietic acid (46) prepared28 by oxidative removal of the isopropyl group from dehydroabietic acid has been synthesised by two methods ; first,13 from 1-methyl-2-tetralone by a sequence analogous to the previously described synthesis18 of dehydroabietic acid and secondly,29 by a route through the ketone (48).Favorskii rearrangement of this & ~ & NaOMc> (46) Me-OC Br (48) COeMe bromo-ketone gave a mixture of esters from which was isolated a small amount of methyl deisopropyldehydroabietate. The fourth isomer was prepared30 from Stork and Burgstahler’s ketone31 (49) a compound which appears to exist mainly in the cis-form. A condensation with cyanoacetic ester gave the unsaturated ester (50) to which hydrocyanic acid added stereospecifically from the unhindered back face of the molecule to give the adduct (51) from which the acid (52) was X*$C g9 cop (53) HO,C obtained. Bromination of the silver salt of this acid gave a bromomethyl compound (53 ; X = Br R = Me) (and some nuclear brominated material) which when reduced gave the required (-J-)-cis-deisopropyldehydroabietic ester (53; R = Me X = H).Ohta Pharm. Bull. (Japan) 1956,4 273; Ohta and Ohmori ibid. 1957,5 91. Barltrop and Day Tetrahedron 1961 14 310. Saha Ganguly and Dutta J. Amer. Chem. Soc. 1959 81 3670. s1 Stork and Burgstahler J. Amer. Chem. SOC. 1951,73 3544. ROGERS AND BARLTROP THE S ~ I S OF DI- AND TRI-TERPENES 125 Methods have recently been developed32 for introducing the methyl and vinyl groups at position 7 characteristic of the pimaradiene diterpenoids. Methylation of the ethylidene ketone (54) with methyl iodide and potas- sium t-butoxide gave a mixture of epiineric ketones (55; R1 = Me R2 = CH:CH and vice versa) from which were obtained by reduction and dehydration the corresponding epimers pimaradiene and sandaracopi- maradiene (56) neither being identical with rimuene. Similarly methylation of the a l d e h ~ d e ~ ~ ~ ~ (57) gave the epimeric methyl derivatives (56; R1 = CHO R2 = Me and vice versa) which were trans- formed into the corresponding pimaradienes by a Wittig reaction with methylenetriphenylphosphorane.Acyclic Triterpenes the steroids and triterpenes5 has stimulated much interest in its synthesis. Squalene.-The great importance of squalene (58) in the biosynthesis of Early experiment^^^ in which two molecules of farnesyl bromide (49) of doubtful homogeneity were coupled in a Wurtz reaction gave a hydro- carbon resembling squalene but further developments had to await the discovery that natural squalene gave a crystalline clathrate compound with thiourea an X-ray investigation of which that squalene had the all-trans-geometry (58). The coupling of farnesyl bromide was repeated by Isler and his co- w o r k e r ~ ~ ~ a synthetic halide being used and the coupling effected with lithium.From its method of synthesis the farnesyl bromide was largely the all-trans-isomer (59) and in this case it was possible to isolate the all- trans-squalene in low yield as the thiourea adduct. 32 Ireland and Schiess Tetrahedron Letters 1960 No. 25 37. 33 Barltrop Giles Hanson and Rogers J. 1962 in the press. 34 Karrer and Helfenstein Helv. Chim. Acta 1931 14 78. 35 Nicolaides and Laves J. Amer. Chem. SOC. 1954 76 2596. 313 Isler Ruegg Chopard-dit-Jean Wagner and Bernhard Helv. Chim. Acta 1956 39 897. 126 QUARTERLY REVIEWS A different approach has been used by three groups of This employed the Wittig reaction between geranylacetone (60) and the ylide (61) derived from 1,4-dibromobutane.This reaction is known to give a mixture of geometrical isomers and in fact only a low yield of all-trans- squalene was obtained. Purification through the thiourea adduct yielded a product identical with natural squalene. Further refinements in this field awaited a general stereoselective synthesis of olefins. The elegant re- searches of Cornforth and his co-worker~~~ have supplied this need and resulted in a total stereoselective synthesis of ~qualene.~~ This synthesis is based on the ideas that an a-chloro-ketone will be most reactive in the conformation (62) even though this rotational isomer may be present in only low concentration and that attack on such a ketone by a Grignard reagent will occur preferentially from the less hindered side to give pre- dominantly the product (43) (S and L are the smaller and the larger group).The stages shown lead through (64) and (65) to the olefin (66) 80-85 "/ overall selectivity being normal. The three final reactions in this Reagents 1 OH-. 2 Nal-AcOH. 3 POCIS-C,H,N SnCI,. sequence are 100% stereoselective. By use of this principle squalene has been synthesised as illustrated; 18-20 of the product formed a clath- Chem. and Znd. 1956 80; (c) Mondon Annalen 1957 603 1 1 5. 37 (a) Dicker and Whiting Chem. and Znd. 1956 351 ; J. 1958 1994; (6) Trippett 38 Cornforth Cornforth and Mathew J. 1959 112. 39 Cornforth Cornforth and Mathew J . 1959,2539, ROGERS AND BARLTROP THE SYNTHESIS OF DI- AND TRI-TERPENES 127 rate. Since pure all-trans-squalene gives only a 70% yield of clathrate it follows that an overall stereoselectivity of > 25 x or > 70 "/o per double bond was achieved.CI Y Me ,CH ,CH ,C ,CH2C1 ,C' 'CH \C/ CH Me Me hc $-' 4 Stages Squa lene Me.CO-CH-CH,CH,CH .COMe Tricyclic Triterpenes Ambreh-Ambrein (67) is a triterpene derived from ambergris. No synthesis of this compound has been achieved but the dehydration product ambratriene (68) has been synthesised40 from the ambrein degra- dation products ambreinolide (1 1) and dihydro-y-ionone (69) by the route shown. The last stage involved formation of the Grignard reagent reaction with the ketone (69) and dehydration. Both ambreinolide41 and dihydro-y-iononeg2 have been independently synthesised. 40 Durst Jeger and Ruzicka Helv. Chim. Acta 1949,32,46. 41 (a) Dietrich and Lederer Compt.rend. 1952 234 637; (b) Wolff ibid. 1954 238 42 Ruzicka Buchi and Jeger Helv. Chim. Acta 1948 31 293. 1041 ; (c) Barltrop Bigley and Rogers Chem. and Ind. 1958 558; J. 1960,4613. 128 QUARTERLY REVIEWS Lanosterol Group.-The four triterpenes of this group have been partially synthesised from chole~terol.~~ In view of the earlier syntheses44 of cholesterol this constitutes a formal total synthesis. Further discussion of this topic is here omitted since for reasons of space full justice could not be done to the many complexities of what is essentially an exercise in steroid chemistry. Onocerin and the Pentacyclic Triterpenes The problem of total synthesis of the pentacyclic triterpenes e.g. /3-amyrin (70) by stepwise ring-extension would be one of great com- plexity a feature of particular difficulty being the vicinal quaternary centres at positions 8 and 14.Halsall and Thomas45 suggested that this difficulty could be overcome by constructing a tetracyclic (AB-DE) system which would be expected to cyclise under acidic conditions to form ring C . This suggestion was supported by the finding46 that a-onocerin (71 ; R = OH) under acidic conditions gave the pentacyclic y-onocerin (72; R = H). Several successful approaches to the onocerin skeleton have been published in recent years. a- and /3-Onoceradiene (71; R = H and 74) and their cyclisation product pentacyclosqualene (76) already known as degradation products of the onocerins,46 were synthesised4' by the elegant route illustrated the crucial step being a Kolbe electrolytic coupling reaction to the " doubled " compounds (73) (74) and (75).The glycol (73) has been obtained by another group of workers4* using the following ingenious reaction sequence from (77) through (82). 4s Woodward Patchett Barton Ives and Kelly J. Amer. Chem. SOC. 1954,76,2852; Chem. and Ind. 1954,605; J. 1957 1131. 44 Woodward Sondheimer and Taub J. Amer. Chem. SOC. 1951 73 3548; Wood- ward Sondheimer Taub Heusler and McClamore J. Amer. Chem. SOC. 1952 74 4223; Cardwell Cornforth Duff Holtermann and Robinson J. 1953 361. 46 Halsall and Thomas J. 1956 243 1. 46 Barton and Overton J. 1955 2639. 47 Corey and Sauers J. Amer. Chem. SOC. 1957 79 3925. 443 Romann Frey Stadler and Eschenmoser Helv. Chim. Acta 1957 40 1900. ROGERS AND BARLTROP THE SYNTHESIS OF DI- AND TRI-TERPENES 129 Reagents 1 Resolve then NH,.2 Electrolysis. 3 POCI&,H,N. 4 Two stages. (81) . . Tos = p-C,H,Me.SO,. Reagents 1 LiAIHI. 2 p-C,H,Me-SO8CI then CrO,. 3 NaOMe. 4 MgMel. 130 QUARTERLY REVIEWS The dimerisation (79) of the ketone (78) appears49 to be governed by the principle of “maximum accumulation of n-bonds,” as is the normal Diels-Alder reaction leading only to the endo-products. Of the four possible dimers only two (80) appear to have been formed one of which led to racemic bisnoronoceranediol (81) and the other to the meso- compound. Resolution and oxidation to bisnoronoceranedione (82) followed by a Grignard reaction gave the glycol (83). oc-Onocerin itself has been synthe~ised~~ by an anodic coupling similar to that used by Corey and Sauers. The main reaction sequence is as shown. CO,H c- -c- AcO \ o(-Onocerin Acetate Reagents 1 Mel-KOBu t then H,-Pd-C.2 Barbier-Wieland degradation. 3 Resolve then electrolyse. 4 E t O C iC-MgBr then H,SO,MeOH. 5 OH- then decarboxylate. 0 The degradation of the ether (83) to the acid (84) followed the sequence (40)+(41; R = H)+(8) described earlier. An ingenious feature of this synthesis is the conversion of a carbonyl group into an exocyclic methylene via an ocp-unsaturated acid. This constitutes a total synthesis of the three onocerins and since y-onocerin (72; R = H) has been converted5I into hopen-1-one-1 (85) also the first total synthesis of a naturally occurring pentacyclic triterpene. Finally amyra-1 1 ,13( 18)-diene (87) which possesses the carbon skeleton of 15-amyrin (70) has been synthesised albeit in only 2% yield by the route fo~mulated.~~ Its separation was facilitated by its character- istic ultraviolet spectrum.The intermediate (86) has also been obtained by 49 Stadler Nechvatal Frey and Eschenmoser Helv. Chim. Acta 1957 40 1373. 61 Dunstan Fazackerley Halsall and Jones Croat. Chem. Acta 1957 29 173; Fazackerley Halsall and Jones Proc. Chem. SOC. 1957 353; Shaffner Caglioti Arigoni and Jeger Helv. Chim. Acta 1958,41 152. 62 Corey Hess and Proskow J. Amer. Chem. Soc. 1959 81 5258. Stork Davies and Meisels J. Amer. Chem. Soc. 1959 81 5516. ROGERS AND BARLTROP THE SYNTHESIS OF DI- AND TRI-TERPENES 13 1 Reagents 1 OH-. then CH,N, then POCIS-C,H,N. 2 LiAIH, then p-C,H,Me.SO,CI then LiBr then Mg. 3 MeLi then H+-. a different route.53 The halide (88) was obtained from sclareol(l3 ; R1 = H R2 = CHCH,) and used to alkylate the @-unsaturated ketone (89; R = Me).Alkylation of the keto-ester (89; R = C0,Et) has led53 to the potentially valuable intermediate (90). Addendum Since the preparation of this manuscript significant developments have occurred in this field some of which are reported below. Abietic Acid (91) and Palustric Acid (92).-These resin acids have been prepared54 by reducing dehydroabietic acid (37) and then isomerising the double bonds into conjugation. 8 __c HOzC (37) Reagents 1 Li-EtNH,-t-C,H,,-OH. 2 Hf. 3 OH- a t 210". 53 Barltrop Rogers Leggate and Rushton unpublished work. 54 Burgstahler and Worden J. Amer. Chem. SOC. 1961,83,2587. 132 QUARTERLY REVIEWS Totarol (43).-The methyl ether of this substance and 3-oxototaryl methyl ether (95; X = 0) were by hydrogenation of the inter- mediate (94) itself obtained by standard methods from the /3-tetralone (93).& @& - H x& \ (93) (94) H (95) Pimaradienes.-An ingenious reaction sequence by which the aldehyde (96) was transformed into the tricyclic aldehyde (98) via the ketone (96) was devised by Church and Ireland.66 Methylation etc. as described above then led to isomers (99; R = Me R' = CH:CH and vice versa) epimeric at C-13 (C-9 by steroid numbering) of pimaradiene and sandara- copimaradiene respectively. These compounds were found not to be identical with rimuene or isopimaradiene implying the incorrectness of the formulations of these latter compounds. PhyHoc1adene.-A total synthesis of this tetracyclic diterpene (103) has been p~blished.~' The keto-ester (loo) a degradation product of phyllocladene which had already been synthesi~ed,~~ was converted by a Reformatsky reaction followed by reduction and ring-closure into the ketone (101) and thence in several stages into the aldehyde (102). This is another degradation product of phyllocladene convertible into the diterpene by a Wolff-Kishner reduction the reduction being accompanied by migration of the double bond. 56 Taylor J. 1961 3319. 56 Church and Ireland Tetrahedron Letters 1961 493. 57 Turner and Ganshirt Tetrahedron Letters 1961,23 1. 68 Turner and Shaw Tetrahedron Letters 1960 No. 18 24; Church Ireland and Marshall ibid. 1960 No. 17 1.

ISSN:0009-2681    

DOI:10.1039/QR9621600117

出版商:RSC    

年代:1962

数据来源: RSC

摘要:

THE CHEMISTRY OF THE PSYCHOTOMIMETIC SUBSTANCES By D. F. DOWNING (CHEMICAL DEFENCE EXPERIMENTAL ESTABLISHMENT PORTON DOWN SALISBURY WILTS.) 1. Introduction A PSYCHOTOMIMETIC* drug may be defined as one which will consistently produce changes in thought perception and mood occurring alone or in concert without causing major disturbances of the autonomic nervous system or other serious disability. The term was first used by Gerard2 and the definition is modified from that of O s m ~ n d . ~ Dew~bery,~ in remarks on the value of these substances considers them important for three reasons (i) because they can give the investigator an approximate subjective experience of what mental disorder is like; (ii) because model psychoses can be studied in the same way as mental disorders ; and (iii) because a study of their chemical nature can be expected to throw some light on the nature of the hypothetical substances believed to cause mental disorders.It is however frequently emphasised (for example by Rothlin5) that psychotomimetics as the word implies are substances which in the animal body cause symptoms similar to those of schizophrenia and are not necessarily similar to and do not even act in a similar manner to those substances which may be responsible for causing mental disorder. Nevertheless the stimulation of schizophrenic-like states by intoxication with psychotomimetic drugs has been one of the causes of the renewed interest in the idea that schizophrenia can be due to a chemical abnormality in the brain. It is the purpose of this Review to collect the more important information on the organic chemistry of this group of compounds whose members differ widely in structure.The present state of knowledge regarding the chemical aspects of their mode of action is also surveyed. 2. Phenethylamines Mescaline (3,4,5-TriinethoxyphenethyZarnine) (2).-The chewing of “mescal buttons” (“peyotl,” “peyote”) the dried tops of the dumpling * Other terms have been used in the same sense schizogen psychotica psychotogen phantastica hallucinogen psychedelic. Confusion exists as to whether some of these terms include the tranquillising substances (ataractics). “Psychotropic” is a general term which usually is meant to include analgesics euphorics sedatives tranquillisers hypnotics inebriants stimulants and psychoto1nirnetics.l Hofmann Svensk kern. Tidskr .,, 1960 72 12.Gerard “Neuropharmacology Transactions of the 2nd Conference Jos. Macy Jr. Foundation New York 1956. Osmond Ann. New Yovk Acad. Sci. 1957 66,418. Dewsbery Endeavour 1960,19 20. Rothlin in “Neuro-psychopharmacology,” ed. Bradley Deniker and Radouco- Thomas Elsevier Amsterdam 1959 p. 1. 133 134 QUARTERLY REVIEWS cactus Lophophora williarnsii (Anhalonium lewinii) to produce a ritual ecstatic state has long been the practice of the Indians living near to the Mexico-U.S.A. border. More recently what was a pagan rite has tended to be incorporated into the Christian liturgy of the Indian tribes (Peyo- tism).6 This practice was first documented by Lewin’ in 1888. The con- stituents of L. williarnsii and similar cacti were initially investigated chemically by Heffter who reported his results in a series of papers.* He suggested that the chief constituent of L.williarnsii was mescaline which he suggested was 3,4,5-trimethoxy-N-methylbenzylamine. This formula was corrected by Spaths who proved by synthesis from 3,4,5-trimethoxy- benzoyl chloride (l) that mescaline was in fact 3,4,5-trimethoxyphen- ethylamine (2). OMe (1) OMe (*) Reagents 1 H,-Pd. 2 MeNO,. 3 Zn-AcOH then Na-Hg. Probably because of this early interest and its simple formula mescaline has become the most widely known psychotomimetic both scientificallylo and popularly.ll The interest in mescaline is illustrated by the number of syntheses (at least nine) of the compound reported since Spath’s original MeO/ CO2H 1 Me0 \ (3) 0 - OMe OMe OMe (2) OMe Reagents 1 LiAIH.,. 2 HCI. 3 KCN. 4 LiAIH,.La Barre McAllester Slotkin Steward and Tax Science 1951,114 582. Lewin Arch. exp. Path. Pharmak. 1888,24,401; 1894,34 377. Spath Monatsh. 1919 40 129. * Heffter Ber. 1894 27 2976; 1896 29 223; 1898 31 1194; 1901 34 3008; 1905 38 3634. lo For reviews see (a) Beringer “Der Meskalinrausch,” Springer Berlin 1927; (b) Stockings J. MentaZ Sci. 1940 86 29; (c) Mayer-Gross Brit. Med. J. 1951 11 317; ( d ) Stafford J. Arner. Med. Assac. 1921 77 1278; (e) Reutter Schweiz. Apotk- Ztg. 1924 62 441; ( f ) Orlowski Apath.-Ztg. 1952 4 124; ( g ) Ronhier “Le Peyolt,” Doin et Cie Paris 1927. l1 Huxley “The Doors of Perception,” Chatto and Windus London 1945; “Heaven and Hell,” Chatto and Windus London 1956. DOWNlNG PSYCHOTOMIMETIC SUBSTANCES 135 method. Some of these12 are variations of Spath's method but recently13 advantage has been taken of lithium aluminium hydride reduction as in the following synthesis from 3,4,5-trimethoxybenzoic acid (3).This method has also been used14 in the preparation of [14C]mescaline from KWN. A further development was the utilisation of the diazo-ketone (4) which provided two routes to rne~ca1ine.l~ Hahn and Wassmuthls have investigated further synthetic routes. OMe OMe OMe OMe OMe M e 0 0 CH2C02H,-/ Me0 \ OMe OMe Reagents 1 CH2N,. 2 AgN0,-NH,. 3 LiAIH,. 4 Ag,O-MeOH. 5 KOH. 6 SOCI, then CH,N,. 7 AgN0,-NH,. 8 Br,-NaOH. Lophophora williamsii has been shown1' to produce N-methyl- and N-acetyl-mescaline and mescaline has been isolated from other Lophophora species and from Trichocereus terschekiilS and 7'. pachoni,lg and it is also reported from the cacti Gymnocalycium gibbosum2Q and Opuntia cylin- drica.21 Trichocereine from T.terschekii,lE has been shown to be NN- dimethylmescaline and has been synthesi~ed.~~,~~ It has been found to have no sensory effect.22 Many other mescaline analogues have been prepared l2 Slotta and Heller Ber. 1930 63 3029; Slotta and Szyzka f. pvakt. Chem. 1933 137 339; Bennington and Morin J. Amer. Chem. Suc. 1951 73 1353; Erne and Ramirez Helv. Chim. Acta 1950 33 912; Dornow and Petsch Arch. Pharm. 1951 284 160; Kinder and Petschke ibid. 1932,270,410. l3 Tsao J. Amer. Chem. Suc. 1951 73 5495; Dornow and Petsch Arch. Pharm. 1952,285 323. l4 Block and Block Chem. Ber. 1952,85 1009 l5 Barnholzer Campbell and Schmid Helv. Chim. Acta 1952 35 1577; Hadbcek Michalsky and Macholan Chem. Listy 1955 49 271.l6 Hahn and Wassmuth Ber. 1934 67 696. l7 Spath and Bruek Ber. 1937,70,2446; 1938 71 1275. l8 Reti and Castrillon f. Amer. Chem. Soc. 1951 73 1767. l9 Poisson Ann. Pharm. frang. 1960 18 764. 2o Ducloux Rev. Fac. Cienc. quim. Univ. nac. La Plata 1930 6 7 5 ; Chem. Abs. 21 Turner and Heyman f. Org. Chem. 1960 25 2250. 22 Luduenva Compt. rend. Suc. Biol. 1936 121 368. 1930,24,4077. 136 QUARTERLY REVIEWS (see ref. 23a for references up to 1954) and Bennington and his co-workers have been particularly active in this field.23 Mescaline has usually been taken in an oral dose of about 350 mg. and consequently is very much less active per mg. than most of the other well-known psychotomimetics. Vivid accounts of the effect are recorded by Mayer-Grossloc and Mor~elli.~~ The outstanding result of mescaline ingestion is visual hallucination but depersonalisation and time distortion frequently occur.Many other symptoms have been recorded but these vary with the individual. Depression and euphoria may alternate. The effects usually last for 10-12 hours although reactions up to eleven days in duration have been The available analogues of mescaline which have been tested have in general less psychotomimetic activity than mescaline itself. Smythies26 has started an investigation of mescaline analogues and has mentioned that 3,4-dimethoxyphenethylamine has half the activity of mescaline whereas 4-hydroxy-3,5-dimethoxyphenethylamine has none and 4-benzyloxy- 3,5-dimethoxyphenethylamine has greater activity than mescaline. 3,4,5-Trimethoxy-or-methylphenethylamine has been found to produce hallucinations with doses smaller than those required for me~caline.~' B e n n i n g t ~ n ~ ~ ~ has shown that a series of methyl-substituted phenethyl- amines cause rage reactions in cats.Adrenaline and Adrenochromes.-Some of the symptoms (fear anxiety tenseness) of adrenaline (5; R = Me) and noradrenaline (5; R = H) poisoning following intravenous administration resemble those of a psychotomimetic. In larger doses ephedrine (6; R = OH R' = Me) and amphetamine (benzedrine) (6; R = R' = H) have similar effects.28 Large doses of methedrine (6; R = H R' = Me) have been reported as producing symptoms similar to those of lysergic acid diethylamide when given to mentally abnormal These observations when combined with those recording the occurrence of adrenaline and noradrenaline in the brain caused Hoffer Osmond and Srnythies3O to search for a link between 2s Bennington Morin and Clark J.Org. Chem. (a) 1954 19 11 ; (b) 1955 20 102 1292,1454; 1956 21 1470,1545; 1958,23 19; (c) 1958,23,2034. 24 Morselli J. Psychologie normal et path. 1936 33 368. 2s Stevenson and Richards Psychopharmacologia 1960,1,241. 26 Smythies Lancet 1960 I 1287. 27 Shulgin Bunnel and Sargent Nature 1961,189,101 1 ; Peretz Smythies and Gibson 28 Goodman and Gilman "The Pharmacological Basis of Therapeutics," Macmillan 28 Liddel and Weil-Malherbe J. Neurology Neurosurgery and Psychiatry 1953,16 7. J. Mental Sci. 1955 101,317,423. 2nd edn. 1955 p. 553. Hoffer Osmond and Smythies J. Mental Sci. 1954 100 29. DOWNING PSYCHOTOMIMETIC SUBSTANCES 137 adrenaline and mescaline on the one hand and the hallucinogenic indoles on the other.These workers first reported the psychotomimetic activity of adrenochrome [(7) or (8); (8) may be considered to be a more satis- factory repre~entation~l]. Adrenolutin (9) and adrenochrome which are isomeric are normal constituents of the blood and it is believed that schizophrenic subjects are less able to control the destruction of injected adrenochrome than are normal It has previously been indicated that phenethylamines and hydroxyindoles may well be biochemically equivalent since transformation of the former into indoles is certainly possible.33 H O ~ - ~ O H - HO~J-J HO\ ,, HO \ Me (9) Me The status of adrenochromes as psychotomimetics is however still a matter of debate and the work could not be repeated by o t h e ~ s .~ ~ ~ Recent opinion suggests26 that adrenochromes are not psychotomimetic at least in the usual sense. The instability of these compounds may however account for the varying results obtained. The chemistry of adrenochrome and related compounds (aminochromes) has been reviewed recently.35 The red oxidation product of adrenaline has been known for some time but it was not characterised as adreno- chrome (7) until 1937 when it was prepared by enzymic (catechol oxidase) oxidation of ad~enaline.~~ The oxidation of adrenaline to adrenochrome has also been carried out with silver oxide in methanol.37 Purification of the product involved the removal of silver ions by ion exchange38 and a product which was reported to be stable at room temperature was ob- tained. The silver oxide method has been used39 to prepare racemic 31 Harley-Mason Experientiu 1948,4 307.3* (a) Hofftf and Osmond J. Mental Sci. 1959 105 653; (b) Hoffer in “Psycho- tropic Drugs ed. Garattini and Ghetti Elsevier Amsterdam 1957 p. 10; (c) Hoffer in “Hormones Brain Function and Behaviour” ed. Hoagland Academic Press New York 1957 p. 181. 83 Osmond and Smythies J. Mental Sci. 1952,98,309. 34 (a) Feldstein Arner. J. Psychiatry 1959 116 454; SzBra Axelrod and Perlin ibid. 1958,115,162; (b) van Cauvenberge and Lecompte Lancet 1953,264,98; (c) Smythies ibid. 1958,II 308. 36 (a) Heacock Chem. Rev. 1959,59,181; (b) Tatai Seitui no Kagaku 1956,7 296; Chem. Abs. 1959 53 20567; (c) Sobotka Borsel and Chanley Fortschr. Chem. org. Naturstoffe 1957,14,217. 86 Green and Richter Biochem. J. 1937,31 596.37 Veer Rec. Trav. chim. 1942,61,638; Harley-Mason J. 1950,1276. 38 Heacock Nerenberg and Payza Canad. J. Cham. 1958 36 853; Feldstein 39 Schayer J. Amcr. Chem. Soc. 1952,74,2441. Science 1958 128 28. 138 QUARTERLY REVIEWS [3-14C]adrenochrome. Other oxidations have been carried out with potassium iodate40 and with oxygen on a palladium-charcoal catalyst.40u A large bibliography of the methods used for the preparation of adreno- chromes is given in the review by H e a c o ~ k . ~ ~ ~ Adrenolutin (9) is another of the oxidation products of adrenaline and was characterised by Lund41 in 1949 and synthesisedg2 in 1953. The monosemicarbazone of adrenochrome is also psychotomimetic and is known as adren~xyl.~~ Noradrenolutin has been synthesised by Heacock and 3. Lysergic acid diethylamide (LSD-25) The most potent psychotomimetic substance known lysergic acid diethylamide (NN-diethyl-lysergamide) R = NEt,).COR so far is (+)- (LSD-25) (10; A lysergic acid (10; R = OH) residue occurs in the ergot alkaloids45 from which it may be obtained by hydrolysis of the link between the acid and the peptide chains. The simplest ergot alkaloid is ergonovine (10; R = NHCHMeCH,.OH) and the others have more complex polypep- tide fragments46 at C-8. Isolysergic acid differs4’ from lysergic acid only in the configuration at position 8. (&)-Lysergic acid was synthesised by Woodward and his co-workers at the Eli Lilley C O . ~ ~ by a route starting from N-benzoyl-3-2’-carboxyethyl- indoline (1 1). This synthesis differed from previous attempts to prepare the compound in one important characteristic-the maintenance of the di- hydroindole nucleus in the intermediates until the final dehydrogenation step.Since the (&)-acid (10; R = OH) had previously been this synthesis constituted a total synthesis of the natural product. 40 (a) Bergel and Morrison J. 1943,48; (6) Richter and Blaschko J. 1937,601. 41 Lund Acta Pharmacologica et Toxicologica 1949,5,75 121. 42 Balsiger Fischer Hirt and Giovannini Helv. Chim. Acta 1953 36 708. 43 Hukki and Seppalainen Acta Chem. Scand. 1958 12 1231. 44 Heacock and Scott Experientia 1961 17 347. 46 (a) Stoll “Progress in the Chemistry of Natural Products,” Vol. IX Springer Verlag Vienna 1952 p. 114; (6) Glenn Quart. Rev. 1954 8 192. 46 Stoll Petrzilka and Becker Helv. Chim. Acta 1950 33 57; Stoll and Hofmann ibid.p. 1705; Stoll Hofmann and Petrzilka ibid. 1951 34 1544. *’ Stoll Hofmann and Troxler Helv. Chim. Acta 1949,32 506. 48 Kornfeld Fornefeld Kline Mann Jones and Woodward J. Amer. Chem. SOC. 1954,76,5256. 4s Stoll and Hofmann Helv. Chim. Acta 1943 26,944. DOWNING PSYCHOTOMIMETIC SUBSTANCES 139 0 2 Bz I Total synthesis of lysergic acid. Reagents 1 SOCI then AICI,. 2 Br, then 2-rnethyl-2-rnethylaminomethyl-l,3-dioxolan. 3 Acid. 4 NaOMe. 5 Ac,O then NaBH,. 6 SOCI, then NaCN. 7 MeOH then HCI. 8 Deactivated Raney Ni. This and previous methods directed towards the synthesis of lysergic acid together with the theories of its biogenesis are discussed by Saxt~n.~O Earlier reviews on the ergot alkaloids by S t ~ l l * ~ ~ Glenn,45b and Saxton51 include the extensive work of Jacobs’s and Stoll’s groups.Another recent review is by K~rnfield.~~ The stereochemistry of lysergic acid has also been inve~tigated.~~ Because of its relation to the structure of nicotinic acid diethylamide (“coramin”) which has analeptic properties Stoll and his co-workers prepared in 1938 the diethylamide of lysergic acid (10; R = NEt,) from the naturally occurring At this time the substance was found to have 50 Saxton in “The Alkaloids,” Vol. VII ed. Manske Academic Press New York 51 Saxton Quart. Rev. 1956 10 108. 52 Kornfield Record Chem. Progr. 1958 19 23. 53 Schreier Helv. Chim. Acta 1958 41 1984; Leeman and Fabbri ibid. 1959 42 54 Stoll and Hofmann 2. physik. Chem. (Leipzig) 1938 251 155. 1960 p. 4. 2698. 140 QUARTERLY REVIEWS the typical contraction effects of an ergot alkaloid on the uterus and vagina (of the rabbit) but it was not until 1943 that H ~ f m a n n ~ ~ noticed that a profound psychotomimetic effect occurs on ingestion of the com- pound and a dramatic account of this observation has been given by him.56 The results of the first systematic psychiatric investigation of the effects produced by lysergic acid diethylamide were published5’ in 1947; it was clear that it is an extremely active compound.As little as 0.5-1 pg./kg. of (+)-lysergic acid diethylamide has been said to produce behavioural changes in man [the (-)-isomer is more than 100 times less active]. Very marked changes occur at higher dose levels. The effects vary greatly with the individual but optical hallucinations a sense of depersonalisation and schizoid states are particularly characteristic though there is some insight into personal c ~ n d i t i o n .~ ~ The compound also possesses a wide range of other systemic effects in animals including mydriasis piloerection hyper- thermia and antiserotonin activity and these have been re14ewed.l~~~ Stoll and H ~ f m a n n ~ ~ have synthesised over forty other amides of lysergic acid. The same group have introduced substituents into the ring system,60 investigated the saturation of the 9,IO-double bond,61 and altered the spatial arrangement of the atoms within the Published information indicates1 that these compounds all have less behavioural activity than LSD-25 itself except the 1-acetyl derivative which has about the same activity. It has been shown1 that in many instances the production of hyperthermia in the animal body parallels the behavioural activity of these compounds related to LSD-25.Three methods of synthesis for lysergic acid amides have been used. The original method of Stoll and Hofmann proceeds via the methyl ester (10; R = OMe) hydrazide (10; R = NH-NH,) and azide (10; R = N3) the last giving the required amide on treatment with a suitable amine. Ths method has the disadvantage that the reaction conditions for the prepara- tion of the hydrazide are such that a racemised and isomerised product (&)-isolysergic acid hydrazide is obtained. Since (+)-lysergic acid is available from the ergot alkaloids62 this is inconvenient. Recent methods have used trifluoroacetic and sulphur trioxide in dimethyl for- mamide64 to effect direct condensation between the optically active acid and an amine without racemisation or isomerisation.65 See Rothlin in “Psychotropic Drugs,” ed. Garrattini and Ghetti Elsevier 66 Hofmann quoted in “Research Today,” Eli Lilley and Company Indianapolis 67 Stoll Schweiz. Archiv fur Neurologie Psychiatrie 1947 60 279. 68 Rothlin Ann. New York Acad. Sci. 1957 66 668. 60 Stoll and Hofmann Helv. Chim. Acta 1955,38 421. 6 o Troxler and Hofmann Helv. Chim. Acta 1957 40 1706 1721 2160. Stoll and Schlientz Helv. Chim. Acta 1955 38 585. 62 Jacobs and Craig J. Biol. Chem. 1934 104 547. 63 Pioch U.S.P. 2,736,728 1956. 64 Garbrecht J. Org. Chem. 1959 24 368. Amsterdam 1957 p. 36. U.S.A. 1957 13 3. DOWNING PSYCHOTOMIMETIC SUBSTANCES 141 4. Tryptamine derivatives Bu fo ten ine (5 - Hy dr oxy -“-dime t hy I t ryp turn ine) ( 1 3). -This comp o und was first isolated from many toad species,65 together with the related bufotenidine (1 6).The structure (13) of bufotenine was proposed by Wieland and his co-workers66 and confirmed by synthesis shortly afterwards by Hoshino and Shirn~daira.~~ The dried secretion (Ch’an Su) of the Chinese toad65a has long been known to be biologically active and bufotenine is a constituent of this material. However in 1954 bufotenine was shown68 to occur in the seeds of the leguminous shrubs Piptadenia peregrina and P. macrocarpa which when ground up to give a snuff (“cohoba” or “nopo”) is used in rituals in the West Indies and South America to produce hallucinations in man.69 Later experiments70 demonstrated that pure bufotenine has a psychoto- mimetic effect in man (2-16 mg./kg. i.v.) although this observation has since been q~estioned.~~ Bufotenine was later shown to be identical with the “mappine” of the fungus Amanita m a ~ p a ~ ~ and to occur widely in animals and higher plants.73 The small amount of bufotenine occurring in A .muscaria is insufficient to account for the psychotomimetic effect of this fungus even if allowance is made for the activity of m~scarine.l~~* The knowledge of the biological activity of bufotenine and its widespread incidence increased the interest in the compound and further syntheses were developed. Harley-Mason and Jackson’s method75 is of interest because cyclisation takes place to yield the tryptamine directly. 2,5-Dimethoxybenzyl cyanide (12) on reaction with NN-dimethylaminoethyl chloride in the presence of sodamide gives 1-(2,5-dimethoxyphenyl)-3-dimethylaminopropyl cyanide converted by hydrogenation and demethylation into a product which on oxidation with potassium ferricyanide cyclises to give bufotenine.Stoll et aZ.76 used the more usual route via 5-benzyloxygramine. However the third of these recent methods that of Speeter and Anthony,” is one which provides an alternative to the gramine route as a general method for the preparation of tryptamines. Oxalyl chloride reacts readily with indoles 65 (a) Jensen and Chen J . Biol. Chem. 1936 116 87; (b) Deulofeu and Mendive 66 Wieland Konz and Mittasch Annalen 1934 513 1. g7 Hoshino and Shimodaira Annalen 1935 520 19; Bull. Chem. SOC. Japan 1936 68 Stromberg J. Amer. Chem. Soc. 1954 76 1707. 69 Stafford J. Washington Acad. Sci. 1916 6 547. 70 Fabing and Hawkins Science 1956 123 886.71 Turner and Merlis A.M.A. Arch. Neurology and Psychiarry 1959 81 121. 73 Wieland Motzel and Merz Annalen 1953 581 10. 73 Stowe Fortschr. Chem. org. Naturstofe 1959 17 248. 74 Eugster Rev. Mycologie. 1959 24 369. 75 Harley-Mason and Jackson Chem. and Ind. 1952 954. 78 Stoll Troxler Peyer and Hofmann Helv. Chim. Acta 1955 38 1452. 77 Speeter and Anthony J. Amer. Chem. SOC. 1954 76 6208. Annalen 1938,534,288; (c) Deulofeu and Duprat J. Biol. Chem. 194.4,153,459. 11 221. 142 QUARTERLY REVIEWS Y ,CH2CH2.NMe HOa-JCHiCH2*NMe2 ~ 3 H 0 0 0 y C H 2 - N H 2 H u3) Reagents 1 NaNH,-CICH,.CH,.NMe,. 2 H,-Raney Ni then HBr. 3 K,Fe(CN),. to give indol-3-ylglyoxylyl chlorides and in the preparation of bufotenine 5-benzyloxyindole (14) was treated with oxalyl chloride followed by dimethylamine yielding the glyoxylamide (1 5).Reduction of this amide with lithium aluminium hydride followed by catalytic debenzylation gave bufo tenine. Reagents 1 (COCI), then NHMe,. 2 LiAIH, then Pd-C-H,. NN-Diakyltryptamines ( 1 7).-Like bufotenine NN-dimethyltrypt- amine (17; R = Me) occurs together with its N-oxide in the shrubs Pipta- deniaperegrina and P . rnacr~carpa,~~ and it is also present in the hallucino- genic drink prepared by some South American Indians from Prestonia arnazonic~m~~ and in Mimosa hostilissQ and Lespedeza bicolor var. japonica.81 The hallucinogenic effect of the pure compound is similar to that of bufotenine (E.D. 1 mg./kg. i.m.).82 An N-methylating enzyme has Fish Johnson and Horning J. Amer. Chem. SOC. 1955 77 5892. Pachter Zacharias and Ribeiro J.Org. Chem. 1959 24 1285. 7 9 Hochstein and Paradies J. Amer. Chem. SOC. 1957 79 5735. *l Goto Noguchi and Watanabe Yakugaku Zasshi 1958 78 464; Chem. Abs. 1958,52 14083. 82 ( a ) Sztira Experientia 1956,12,441; (b) Halasz Brunecker and Szhra Psychiatrie et Neurologie 1958 138 285; (c) Szara in “Psychotropic Drugs,” ed. Garrattini and Ghetti Elsevier Amsterdam 1957 p. 460. DOWNING PSYCHOTOMIMETIC SUBSTANCES 143 been found (in rabbit lung) which can convert 5-hydroxytryptamine into bufo tenine and t ryptamine into NN-dimethyltry~tarnine.~~ NN-Dimethyltryptamine was prepared by Manskes4 by the separation of the products of the reaction between tryptamine and methyl iodide in chloroform. This method was later improveds5 but a more satisfactory methods6 is by the reaction between dimethylamine and methyl indol-3- ylacetate and reduction of the amide obtained (1 8) with lithium aluminium h ydride.NN-Diethyltryptamine (17; R = Et) has about the same psychoto- mimetic activity as the NN-dimethyl though different in quality.82b It has not been found in Nature but has been prepared8* by a route via the glyoxylamide similar to that used by Speeter and Anthony in the preparation of bufotenine. An alternative methodsg is from chloro- methyl indol-3-yl ketone which on reaction with diethylamine followed by reduction with lithium aluminium hydride gives NN-diethyltryptamine. The corresponding NN-dipropyl (17; R = Pr”) NN-dibutyl (17; R = Bun) and NN-dihexyl (17; R = hexyl) compounds have also been prepared and shown to decrease in hallucinogenic activity with increase in the size of the dialkyl group.g0 Szarag’ has shown that a metabolite of NN-diethyltryptamine NN-diethyl-6-hydroxytryptamine (1 9) is in fact more active in causing behavioural changes in animals than the parent substance.He has further demonstrated that the intensity of the reaction produced in man by NN-diethyltryptamine parallels the amount of the 6-hydroxy metabolite excreted in the urine. 91b Psilocybin (3-2‘- Dimethylarninoethylindol-4-yl phosphate) (20)-This substance and the corresponding phenol psilocin (2 l) are responsible for the psychotomimetic activity of some Mexican mushrooms. The Mexican Indian name “teonanhcatl” is employed collectively for the 83 Axelrod Science 1961 134 343. 84 Manske Canad. J. Res. 1931 5 592. 85 Hoshino and Kotake Annalen 1935 516 76.86 Fish Johnson and Homing J. Amer. Chem. SOC. 1956,78,3668. Boszormknyi Der and Nagy J. Mental Sci. 1959 105 171. Nbgrhdi Monatsh. 1957 88 768. 89 U.S.P. 2,814,62511957; Chem. A h . 1958 52 11948. Szara Biochem. Pharmacol. 1961 8 32. 91 (a) Szara and Putney Fed. Proc. 1961 20 172; (b) SzAra ibid. p . 885. 144 QUARTERLY REMEWS species mostly Psilocybe employed by the Indians in their religious ceremonies. Psilocin is isomeric with bufotenine having the hydroxy- group in the 4- instead of the 5-positiou. Both psilocybin and psilocin were first isolatedg2 in 1958. Previous workg3 on small amounts of fungi was thought to exclude the presence of an alkaloid. Pure psilocybin and psilocin have been shown to produce psychoto- mimetic symptoms (oral dose 4-8 mg./man) similar to those of mescaline and lysergic acid dieth~lamide,~~ and they have been isolateds5 from many Psilocybe spp.and from Stropharia cubensis (which occurs in Mexico and in Thailand). Of the fungi tested P. mexicana Heim was found to contain the most psilocybin when grown in the l a b ~ r a t o r y . ~ ~ Hofmannl has vividly described from his own experience the effect of eating the mush- rooms. Some Psilocybe spp. (P. yungensis P. hooshageni and P. caervules- cens) used by the Indians are hallucinogenic but do not contain psilocy- bin or psilocin.lPg7 The structures of psilocybin and psilocin were elucidated by Hofmann and his co-workers.94~s7 It was shown that methylation of psilocybin with diazomethane gave a dimethyl derivative (22) which produced tri- methylamine on pyrolysis.Hydrolysis of psilocybin resulted in equi- molecular amounts of 4-hydroxy-NN-dimethyltryptamine (psilocin) and phosphoric acid. Psilocybin could be regenerated from psilocin by reaction with dibenzyl phosphorochloridate followed by hydrogenation of the resultant dibenzyl derivative. Psilocin was synthesisedg4 from 4-benzyl- oxyindole by reaction with oxalyl chloride followed by dimethylamine and reduction of the resultant glyoxylamide with lithium aluminium hydride. Subsequent catalytic hydrogenation removed the benzyl group to give the required 4-hydroxy-NN-dimethyltryptamine. The cultivation chemistry pharmacology and clinical aspects of the ‘‘teonanicatl’y group of fungi is the subject of a mon~graph.~~ Psilocybin has attracted pharmacological study.99 It produces similar vegetative symptoms to LSD-25 (including the hyperthermia effect) in the intact animal.The phosphorylation of psilocin to psilocybin has been reported.loO A large number of compounds related to the hydroxytryptamines have been synthesised by the Hofmann group.1o1 It is not yet known whether 92 Hofmann Heim Brack and Kobel Experientia 1958,14 107. 93 Santesson Arch. Botan. 1939 28 A 1. g4 Hofmann Heim Brack Kobel Frey Ott Petrzilka and Troxler Helv. Chim. g5 Heim Compt. rend. 1956,242,965 1389; 1957,244,695. g6 Heim and Cailleux Compt. rend. 1957,244,3109. 97 Hofmann Frey Ott Petrzilka and Troxler Experientia 1958 14 397. g8 Heim and Wasson “Les Champignons hallucinogkne du Mexique,” Ed. du Muskurn National d’Histoire Naturelle Paris 1958. 99 Gnirss Schweiz. Arch. Neurologie Psychiatrie 1959 34 346; Rimmle ibid.p. 348 ; Delay Pichot Lemperikre and Nicolas-Charles Compt. rend. 1958 247 1235; Weidmann Taeschler and Konzett Experientia 1958 14,378. l o o Horita and Weber Proc. Soc. Exp. Biol. Med. 1961 106 37. Io1 Troxler Seeman and Hofmann Helv. Chim. Acta 1959 42 2073. Acta 1959,42 1557. DOWNING PSYCHOTOMIMETIC SUBSTANCES 145 0% ,P(OCH2Ph)2 Reagents 1 Pd-H,. 2 H,O; 150”. 3 CH,N,. 4 (PhCH,*O),POCI. any of these show psychotomimetic activity but some pharmacology of many of them has been reported.lo2 a-Methyltryptamine (23).-( &)-a-Me thyltryptamine is recordedlo3 as producing an effect like that of LSD-25 in man and to be about three times Q-CH,.NH2 H G23) as active as NN-diethyltryptamine.lo4 The biochemical effects of a- methyltryptamine on 5-hydroxytryptamine metabolism have been studied.O5 5. Harmine and its derivatives The literature on the chemistry of the biologically active constituents of Banisteria caapi (“Ayahausca”) and Prestonia amazonicum (Haemadictyon amazonicum) (“YagC”) has been confused because of the use of the same trivial local South American Indian names for extracts of different plants. In particular the names “Ayahausca,” “Yagk,” and “Huanto” have been used indiscriminately for the extracts of either plant and for mixtures of extracts of both. All these preparations have been used amongst South American Indians for the production of ritual hallucinations. A biblio- graphy of the literature concerning them up to 1939 exists.106 The names telepathine,lo7 yageine,lo8 and banisterine1OS for the alkaloids extracted from these sources have been used until quite recently (for lo2 Weidmann and Cerletti Helv.Physiol. Pharmacol. Acta 1959 17 C 46; 1960 lo3 Murphee Jenney and Pfeiffer The Pharmacologist 1960,2 64. lo4 Szara Experientia 1961 17 76. lo5 Van Meter Ayala Costa and Himwich Fed. Proc. 1960 19 265; Grieg Walk and Gibbons J. Pharmacol. 1959 127 110; Yuwiler Geller and Eiduson Arch. Biochem. Biophys. 1959,80 162. lo6 Henry “The Plant Alkaloids,” 4th edn. Blakiston Philadelphia 1949 p.488. lo’ Perrot and Raymond-Hamet Compt. rend. 1927 184 1266; Villalba Bofetin Lab. Sumber-Martinez Bogota 1927 p 9. lo8 Villalba J. SOC. Chem. Ind. 1925,44,205. log Lewin Arch. exp. Path. Pharm. 1928 129 133; Compt. rend. 1928 186 469. 18 174. 146 QUARTERLY REVIEWS example ref. 110). It was subsequently that all these sub- stances were the same and that the only alkaloid present in B.caapi was harmine (27). Hochstein and para die^,^^ however have shown that three alkaloids are present in B. caapi and have identified them as harmine (27) harmaline (28) and 1,2,3,4-tetrahydroharrnine (26). Harmaline has previously been reported as present in B. caapi by Oryekhov.l12 Lepta- florine from Leptactina densiflora has recently been shown113 to be racemic 1,2,3,4-tetrahydroharmine (26). Hochstein and para die^'^ found that P. amazonicum yielded only NN-dimethyltryptamine (see p . 142). Other Banisteria spp. have been shown to contain harmine.l14 Harmine has been known for more than a hundred years115 as a con- stituent of Peganum harmala where it occurs together with harmaline116 and the 0-demethylated derivative of the latter harma10l.l~~ Other alkaloids are also present.ll* The formulae for harmine (27) and harmaline (28) were originally suggested by Perkin and Robinsonllg and the sub- stances were the subjects of extensive research by these workers and by 0.Fischer. The structure of harmaline was confirmed by synthesis120 and two convenient syntheses of harmine appeared simultaneously. Akabori and Saito121 used 6-methoxyindole which was converted into 6-methoxy- tryptamine (25) by reaction with methylmagnesium iodide followed by chloroacet oni t rile to give 6-methoxyind 01-3-ylacet onitrile (24) reduction Reagents 1 MeMgl then CI.CH,.CN. 2 Na-EtOH. 3 H,SO,-AcOH (26) 4 Pd-maleic acid. Costa Rev. brasil. Farm. 1956 37 481 ; Chem. Abs. 1958 52 1550. ll1 Elger Helv.Chim. Acta 1928 11 162; Wolfes and Rumpf Arch. Pharm. 1928 266,188; Chen and Chen Quart. J. Pharm. 1939,12,30. 112 Oryekhov Byull-Nauch Issledovatel Khim.-Farm. Znst. 1930 3 ; Chem. Abs. 1932,26 5699. 113 Paris Percheron Mainil and Goutarel Bull. SOC. chim. France 1957,780. 114 Iberico Boletin del muse0 de historia natural "Javier Prado" (Lima) 1941 5 313; Chem. Abs. 1942 36 1389; O'Connel and Lynn J. Amer. Pharmaceut. Assoc. (Sci. Edn.) 1953,42,753. 115 Fritsche Annalen 1847 64 360. 116 Goebel Annalen 1841 38 363. 117 Fischer Ber. 1885 18 400. 11* Karetskaya Zhur. obshchei Khim. 1957 27 3361 ; Ovejiro Farmacognosia 119 Perkin and Robinson J. 1919 115 933 967. 120 Perkin Robinson and Manske J. 1927 1 . Akabori and Saito Ber. 1930 63 2245. (Madrid) 1947,6 103. DOWNING PSYCHOTOMIMETIC SUBSTANCES 147 of which produced the amine (25).Heating with acetic acid and sulphuric acid resulted in 1,2,3,4-tetrahydroharmine (26) which was dehydrogenated by maleic acid and palladium black to harmine (27). Spath and Lederer122 also used 6-methoxytryptamine (25) which they prepared however by a modification of the Fischer indole synthesis. Acetylation of the amine (25) and cyclisation with phosphoi ic anhydride in xylene gave harmaline (28). Catalytic dehydrogenation gave harmine (27). Reagents 1 Ac,O. 2 P,O,. 3 Pd. A further of interest is that from 6-methoxytryptophan (29) which condenses with acetaldehyde at pH 6.7 to give 1,2,3,4-tetra- hydroharmine-3-carboxylic acid; on decarboxylation and oxidation this produces harmaline (28) which may then be dehydrogenated to harmine (27).This synthesis is of biogenetic interest in relation to the conversion tryptamines into harm an^.^^^ (27) H Reagents 1 pH 6-7. 2 -C02 then CrO,. 3 Pd. The psychotomimetic activity of harmine has been investigated of by Lewinlog and by Pennes and Hoch12* and the pure substance is apparently less active than the crude extract of B. caapi. This has led to the ~uggestion'~ that harmaline and 1,2,3,4-tetrahydroharmine may also have this type of activity but since the tetrahydroharmine may be considered structurally related to N-ethyl-6-methoxytryptamine such psychotomimetic activity would not be surprising. Spath and Lederer Ber. 1930,63 120 2102. l Z 3 (a) Harvey and Robson J. 1938 97; (6) Hopkins and Cole J. Physiol. 1903 29 124 Pennes and Hoch Amer. J. Psychiatry 1957 113 887.451; Kermack Perkin and Robinson J. 1921 119 1617. 148 QUARTERLY REVIEWS It has been that the structure of mitragynine the major alkaloid of the intoxicant Mitragyna speciosa of Borneo is (30) which is related to 1,2,3,4-tetrahydroharrnine and incidentally to a 4-methoxy- indole (in which it is similar to psilocin). It is not known if mitragynine is a true psychotomimetic but yohimbine (3 1) which also contains a 1,2,3,4- tetrahydroharmine residue is said126 to give pronounced psychic effects OH in doses of 0.5 mg./kg. i.v. Reserpine (32) also has this residue but is on the other hand a potent tranquilliser. OMe 6. Iboga alkaloids The root bark of the African shrub Tabernanthe iboga has proved a rich source of a group of at least twelve alkaloids the principal member of which is ibogaine first reported12' in 1901.Extracts of the root are used by some inhabitants of West Africa and of the Congo to increase resistance to fatigue and tiredness.128 It is also reported129 to cause excitement drunkenness mental confusion and possibly hallucinations in higher doses. These reported effects attracted Schneider and Sigg to investigate the central stimulant properties of the pure alkaloid ibogaine,13* and typical fear and escape responses suggestive of hallucinations were obtained with cats (2-10 mg./kg. i.v.). No experiments with ibogaine on man have been reported. Previous pharmacological studies were carried out by Raymond-Hamet and R0th1in.l~' 12& Hendrickson Chem. and Ind. 1961,713 ; Schlittler Experientia 1960,16,244. 12* Holmberg and Gershon Psychopharmacologia 1961,2 93.12' Dybowski and Landrin Compt. rend. 1901 133 748; Heller and Heckel ibid. p. 850. 12* Aubry-Lecompte Arch. mtd. navale 1864 2 264 ; Baillon Bull. mens. Soc. Linntnne (Paris) 1869,1,782 (quoted by Schneider and Sigg see ref 130); Raymond- Hamet and Perrott Bulletin de l'acadimie de mtdecine 1941,124,243. 129 Le Roy quoted by Schneider and Sigg (ref. 130). 130 Schneider and Sigg Ann. New York Acad. Sci. 1957,66 765. 131 Raymond-Hamet and Rothlin Arch. internat. pharmacodynamie 1939 63 27. DOWNlNG PSYCHOTOMIMETIC SUBSTANCES (34) Me $0 (35' CO,H 149 Work on the structure of the iboga alkaloids has been concentrated on ibogaine. The formula (33) suggested by Taylor and his co-worker~'~~ for this compound has been confirmed by X-ray ana1y~is.l~~ Ibogaine has long been thought an indole on the basis of colour tests134 and in 1953 3-ethyl-5-hydroxy- 1,2-dimethylindoIe (34) was isolated after potash fusion of the compound.135 The N-oxalo-derivative (3 5) had previously been obtained by permanganate 0~idation.l~~ Taylor and his c o - w ~ r k e r s ~ ~ ~ repeated the potash fusion and noticed that 3-ethyl-5-methylpyridine was a further product of the reaction.The same workers carried out a selenium dehydrogenation of ibogaine and obtained compounds (36) and (37) from which they deduced the structure (33) for ibogaine. The structures of several of the other alkaloids occurring in T. iboga and containing the ibogaine skeleton were deduced readily. Another alkaloid from T. iboga voacangine was first isolated from Voacanga africana thus stressing the relation between the alkaloids of the Taber- nanthe and Voacanga spp.,13' which was first observed when voacangine was hydrolysed and decarboxylated to give ibogaine.138 Voacangine is 18-methoxycarbonylibogaine (38).The same compound has also been isolated from Stemmadenia spp.139 and similar alkaloids from the African medicinal plant Conopharyngia durissima. I4O Thus recent work has discovered many alkaloids related to ibogaine which however is the only member of the group to have been investigated for psychotomimetic activity. Like LSD-25 bufotenine psilocybin 1,2,3,4-tetrahydroharmimine and similar compounds discussed earlier in this Review ibogaine contains the tryptamine nucleus. ibid. 1957,79 3298. Saxton Ann. Reports 1959 56 278. 1943,25 205.132 (a) Bartlett Dickel and Taylor J . Amer. Chem. SOC. 1958 80 126; (b) Taylor 133 Jeffery Arai and Coppola Abst. Amer. Cryst. Assoc. Cornell 1959 quoted by 134 Raymond-Hamet Bull. Sci. pharmacol. 1926 33 518; Bull. SOC. chim. France 135 Schlittler Burckhardt and GellCrt Helv. Chim. Acta 1953,36 1337. 130 Janot Goutarel and Sneedon Helv. Chirn. Acta 1951 34 1205. 13' Dickel Holden Maxfield Paszek and Taylor J . Arner. Chem. Soc. 1958,80 123. 138 Janot and Goutarel Compt. rend. 1955 241 286. lS9 Walls Collera and Sandoval Tetrahedron 1958 2 173. 140 Renner Prim and Stoll Helv. Chim. Acta 1959 42 1572. 2 150 QUARTERLY REVIEWS 7. Piperidyl glycollates The production of an intoxicated state frequently accompanied by hallucinations and delirium following poisoning by atropine [( &)- hyoscyamine] (39; R = R’ = H) and the epoxide scopolamine [(-)- hyoscine)] (39; R-R’ = 0:) has long been known.Acute schizophrenia has been sometimes diagnosed mistakenly in these cases.28 Russian workers have reported the use of an atropine-induced psychosis as a model for schizophrenia,141 and large doses are said to induce marked psychic disturbance. 142 RsCH-fH-FH2 $H,*OH I SJMe qH.OCO.CHPh (39) R’CH-CH -CH The atropine molecule has been used as a model for the preparation of a large number of potential drugs. In general interest has centred on the mydriatic and spasmolytic properties of these compounds rather than on their effect on behaviour. In 1958 however the psychotomimetic effect of 1-methyl-3-piperidyl benzilate (40; R = Ph R‘ = Me) and substances of related structure was described.143 A relationship of these piperidine derivatives to part of the atropine molecule is apparent.They cause auditory and visual hallucinations mood changes disorientation and hypochondriacal and paranoid delusions in man. has demonstrated that the most effective of a large number of compounds of this series are 1-ethyl-3-piperidyl cyclo- pentylphenylglycollate (“Ditran”) (40; R = cyclopentyl R’ = Et) and the corresponding 1-methyl compound (40; R = cyclopentyl R’ = Me). The corresponding cyclohexyl(40; R = cyclohexyl R‘ = Me) and cyclo- butyl(40; R = cyclobutyl R‘ = Me) and cyclopropyl(40; R = cyclopropyl R‘ = Me) compounds have been named144 as having about the same psychotomimetic activity as the ester (40; R = cyclopentyl R’ = Me). The 4-piperidyl isomers which are closer to atropine in structure are practically inactive as psychotomimetics.Recently 1-methyl-3-piperidyl esters of substituted benzilic and a series of analogous com- p o ~ n d s l ~ ~ have been prepared for evaluation as psychotomimetics. The piperidyl glycollates have been ~ynthesisedl~’ either by reaction of 1-alkyl-3-hydroxypiperidine with the acid chloride or the methyl ester 141 Goldenberg Novosibersk Govt. Med. Inst. Publ. 1957 29 7. 142 Abood Ostfeld and Biel Arch. Internat. Pharmacodynamie 1959,120,186. 143 Abood Ostfeld and Biel Proc. SOC. Exp. Biol. Med. 1958 97 483; Ostfeld Abood and Marcus A.M.A. Arch. Neurology and Psychiatry 1958 79 317; Abood and Meduna J. Nervous and Mental Disease 1958,127 546. 14* Cannon and Kadin J. Org. Chem. 1962,27 240. 145 Cannon J.Org. Chem. 1960,25 959. 146 Biel Abood Hoya Leiser Nuhfer and Kluchesky J. Org. Chem. 1961 26 14‘ Biel Sprengeler Leiser Homer Drukker and Friedmann J. Arner. Chem. SOC. More recent 4096. 1955,77,2250. DOWNING PSYCHOTOMIMETIC SUBSTANCES 151 of an appropriate acid or by reaction between a 1-alkyl-3-chloropiperidine and an acid. It has been noted148 that the reaction between 3-chloro-1- ethylpiperidine (4 1) and cyclopentylphenylglycollic acid (42) results in a mixture of the expected product (40; R = cyclopentyl R‘ = Et) (30%) and the ring-contracted isomer 1 -ethyl-2-pyrrolidinylmethyl cyclopentyl- phenylglycollate (43) (70 %). Distillation of the latter causes ring expansion to the former. This type of ring contraction which takes place under acid conditions has previously been noticed only under basic conditions.149 1 -Ethyl-3-piperidyl cyclopentylphenylglycollate (40 ; R = cyclopentyl R’ = Et) is stated148b to induce a temporary psychosis most nearly imita- tive of schizophrenia.oo.coAQ QC‘ + HO-C- ?)a (4 0 (42) pHio.cof!-p Et / Et 1 (43) The structurally related compound 2-diethylaminoethyl cyclopentyl-2- thienylglycollate (44) has a harmine-like psychotomimetic action,15* and similar effects are reported for compounds (45) (“Pentaphen”),lsl (46) (47; R = cyclohexyl) (“Artane,” “Pipanol”) (47; R = cyclopentyl) (“Cycrimine,” “Pagitane”) and some other synthetic atr~pine-rnimetics.~~~~ (45) 9 ,o.co.c Ph CO; CH2-CH2*NEt2 H3F FH2 s “U \ H2C ,CH ,_1 (44) N Et ()-CH2CPh2-OH 0 Q /OH 0‘ c~co2.CHicH2NEt Me Y (4 6) CH 2.CH2.CRPh.OH (47) (48) (a) Biel Abood Hoya and Leiser Abs.138th Amer. Chem. Soc. Meeting New York 1960 p. 19-0; (b) Biel Chem. Eng. News 1960,38 No. 38 p. 50. Reitsema J. Amer. Chem. Soc. 1949 71 2041. 150 ( a ) Pennes and Hoch Amer. J. Psychiatry 1957,113,887; (6) Himwich van Meter and Owens in “Neuro-psychopharmacology,” ed. Bradley Deniker and Radouco- Thomas Elsevier Amsterdam 1959 p. 329. 15’ (a) Kagan Farmakologiya i Toxikologiya 1956 19,49; (b) Pfeiffer Internat. Rev. Neurohiology 1959 1 195; Pfeiffer Murphee Jenney Robotson and Bryan Fed. Proc. 1958 17 403. 152 QUARTERLY REVIEWS A closely related compound is 2-diethylaminoethyl benzilate (“Ben- actzine”) (48). This substance and compounds related to it are known as ataractics. Russian workers have recently been particularly interested in them152 and 2-diethylaminoethyl benzilate has been reported as causing hallucinations in (accidentally) high dose (1.4 g.per man)lS3 and sub- sequently at a lower dose (40-70 mg./rnan)la. 8. Cannabinoh Hemp (Cannabis sativa L.) produces on its female flowering tops a greenish resin containing an active principle or principles having a pro- found effect on the central nervous system and including the exhibition of psychotomimetic symptoms. The leaves and seeds also contain the same active constituents but in smaller concentration. The names used for this resinous product vary with its origin in the world. Marihuana (The Americas) hashish (Middle East) bhang (India) charas ganja (Far East) dagga (South Africa) and kif (North Africa) are the better-known names for the different local products. The usual effect of smoking or ingestion of cannabis has been described155 as a feeling of well-being alternating with depression distortion of time and space and double consciousness.Personal experiences have been recorded in detail156 and the “use of hemp drugs for euphoric purposes” The euphoric activity in hashish was found to be due to an alkali- insoluble” nitrogen-free principle in the middle of the nineteenth century but it was not until the beginning of the present century that a pure com- pound was isolated from this active f r a ~ t i 0 n . l ~ ~ Until the research of Cahnls0 this substance (cannabinol) was accepted as the active principle of hashish. Cahn however established the structure of cannabinol in all but the orientation of the substituent groups and also cast doubt on the euphoric activity of the substance.The structure of cannabinol was proved at the same time by both Adams’slG1 and Todd’sle2 groups to be 1 -hydroxy-6,6,9-trimethyl-3- pentyldibenzopyran ( 5 1 ). Adams’s synthesis was from dihydro-olivetol * Recently it has been claimed that although the constituents of the alkali-soluble fraction of cannabis resin are inactive they become active on storage or more rapidly if heated.15* 182 Anichkov Ann. Rev. Pharmacology 1961 1 21. 153 Vojtechovsky Vitek RySanek and Bultasovh Experientia 1958 14 422. 154 Bultasovh Grof HoraEkova Kuhn RySAnek Vitek and Vojtechovsky Zdeggyo- gaszati Szernle 1960,13,225; Chem. Abs. 1961,55,9662. 156 Cf. Todd Endeavour 1943 2 69. 156 Adams Harvey Lectures 1942 37 168. 15’ Chopra Chopra Handa and Kapur “Indigenous Drugs of India,” Dhur and 158 GrliC and Andree Experientia 1961 17 325.150 Wood Sprivey and Easterfield J. 1896 69 539; 1899 75 20. 161 Adams Baker and Wearn J . Amer. Chem. Soc. 1940,62,2204. lO2 Ghosh Todd and Wilkinson J. 1940 1121 1393. Sons Calcutta 2nd edn. 1958 p. 87. Cahn J. 1930,986; 1931 630; 1932 1342; 1933 1400. DOWNING PSYCHOTOMIMETIC SUBSTANCES 153 (5-pentylcyclohexane- I ,3-dione) (49) which was prepared by catalytic reduction of olivetol. Condensation of this diketone with 2-bromo-4- methylbenzoic acid in the presence of sodium ethoxide and cupric acetate and dehydrogenation of the product with sulphur gave the pyrone (50) which was converted into cannabinol (5 1) with methylmagnesium iodide. Reagents 1 Cu(OAc),NaOEt. 2 S. 3 MeMgl. Me OH Todd’s synthesis was of especial interest since the intermediate tetra- hydrocannabinol (53) had considerable marihuana activity unlike cannabinol (51) and the cannabidiol (52) [isolated by both Adams (from r n a r i h ~ a n a ) ~ ~ ~ and Todd (from Indian hemp resin)164].Condensation of olivetol with ethyl 4-methyl-2-oxocyclohexanecarboxylate followed by the reaction of methylmagnesium iodide with the resultant dibenzopyrone gave the tetrahydrocannabinol allocated the formula (53) which was dehydrogenated by palladium or selenium to cannabinol (51). A similar method was reported by Adams’s group.le5 The primary purification of hemp extracts and resin gives “red-oil” of hemp. Acetylation of the “red oil” facilitated the isolation of tetra- hydrocannabinol acetate from this source.1ss This was the first isolation of an active compound from Cannabis.Deacetylation of tetrahydrocanna- binol acetate from “red oil” gave (-)-tetrahydrocannabinol. Most work has been done with extracts of Cannabis sativn indica. Recently German workers have extracted the indigenous variety Cannabis sativa non-indica and have used chromatographic and counter-current distribution methods to isolate from it crystalline cannabidiol and probably 163 Adams Hunt and Clark J. Amer. Chem. Suc. 1940,62 196 735; Adams Cain and WOW ibid. p. 732. 184 Jacob and Todd Nature 1940 145 350. 16s Adams and Baker J. Amer. Chem. Suc. 1940,62,2401. 16* Wollner Matchett Levine and Loewe J. Arner. Chem. Soc. 1942 64 26. 154 QUARTERLY REVIEWS 1' @C5H,l - 2 W C 5 H l l Me2C-0 (51) Me&- (53) Reagents 1 MeMgl. 2 Pd or Se.tetrahydrocannabinol. They have used these techniques to acquire two crystalline isomers from synthetic tetrahydrocannabinol resin.167 A cannabidiolcarboxylic acid has also been isolated from C. sativa non- indica. Cannabinol cannabidiol and tetrahydrocannabinol have also been obtained from this source by distillation. 16* Synthetic tetrahydrocannabinol as normally prepared is optically inactive and has less (1/10) marihuana activity than the natural optically active tetrahydrocannabinol. In addition to exhibiting cis-frans-stereoi- somerism tetrahydrocannabinols may exist as double-bond isomers depending on whether the double bond in the left-hand ring of (53) occupies the conjugated position as shown in the formula or any of the other possible positions in that ring. Adams et ~ 1 .l ~ ~ showed that heating cannabidiol with an acid catalyst converted it into a mixture of highly biologically active tetrahydrocanna- binol stereoisomers and double-bond isomers. It is probable that the psychotomimetic activity of Cannabis preparations is due to such a mixture.155 The structure of these tetrahydrocannabinols have not been fully elucidated. Adams et aZ.170 attempted the unambiguous synthesis of the tetrahydrocannabinol which has an 8,9-double bond. Although Adams's group failed recent have successfully adapted this method in the preparation of tetrahydrocannabinol model compounds. It was found that isoprene reacts readily with coumarins substituted with an electro- negative group in the 3-position (CO,Et CN) to give the adduct (54; R = C0,Et or CN). Hydrolysis then gives the stable dicarboxylic acid (55) which on lactonisation produces a separable mixture of cis- and trans-lactones.Treatment of each lactone with methylmagnesium iodide and subsequent cyclisation with toluene-p-sulphonic acid in xylene 16' Korte and Sieper Annalen 1960 630 71. 16* Schultz and Haffner Arch. Pharm. 1958 291 391; Z. Naturforsch. 1959 14b 98 169 Adams Pease Cain and Clark J . Amer. Chem. Soc. 1940 62 2402. 170 Adams and Carlin J. Amer. Chem. SOC. 1943 65 360; Adams McPhee Carlin. 171 Taylor and Strojny J. Amer. Chem. SOC. 1960 82 5198. and Wicks ibid. p. 356; Adams and Bockstahler ibid. 1952,74 5346. DOWNING PSYCHOTOMIMETIC SUBSTANCES I55 resulted in the cis- and trans-6a,7,1O,lOa-tetrahydro-6,6,9-triniethyldi- benzopyrans (56) which lack the 1-hydroxy- and the 3-pentyl groups of the corresponding tetrahydrocannabinols.cis - trans- U A large number of homologues of tetrahydrocannabinol have been prepared especially compounds (57 ; R = alky1).172 These compounds usually have been tested by one or both of the two tests used in thepharma- cological work on marihuana. These are the “dog ataxia” test173 and the Gayer “corneal anzsthesia” test.174 L ~ e w e l ~ ~ has claimed a close parallel between the “dog ataxia” test and psychotomimetic activity but the connection between either test and psychotomimetic activity is doubted by other ~ 0 r k e r s . l ~ ~ eR Me2 (57) In the series (57; R = n-alkyl) the hexyl compound is apparently the most active member according to the animal t e ~ t ~ ~ ~ ~ ~ J ~ though its activity 172 ( a ) Russell Todd Wilkinson MacDonald and Woolfe J.1941 826 and refs. therein; (b) Adams Harfenist and Loewe J. Amer. Chem. Soc. 1949,71 1624 and refs. therein. 173 Liutaud Compt. rend. 1844 18 149; Walton Martin and Keller J. Pharmacol. 1938 62 239. 174 Gayer Arch. exp. Path. Pharm. 1928 129 312; Marx and Eckhardt ibid. 1933 170 395. 175 Loewe Arch. exp. Path. Pharm. 1950 211 175. 176 Avison Morison and Parkes J. 1949 952. 177 Adams Loewe Jelinek and Wolff J. Amer. Chem. SOC. 1941 63 1971; Adams Chen and Loewe ibid. 1945 67 1534. 156 QUARTERLY REVIEWS is surpassed by (57; R = 1-methylheptyl) and by the 1‘,2‘-dimethylhepty1 compound which is about seventy times as potent as natural tetrahydro- cannabinol in the “dog ataxia” The compound (57; R = hexyl) is known as “Parahexyl” or “Synhexyl” and is one of the few members of this series tested for psychotomimetic activity in man,179 where the effective oral dose was found to be 5-15 mg.per man. Loewela0 puts the psychotomimetic threshold at the considerably higher level of 200 mg. per man. 9. Miscellaneous compounds 1 -( 1 -Phenylcyclohexyl)piperidine Hydrochloride (“Sernyl,” “PCP,” “Phenylcyclidine”) (%).-The compound was first reported as an anaes- thetic drug but with the possibility of the production of delirium at higher doses.lS1 Later work has shown that it has an effect different from most other psychotomimetics.ls2 The secondary characteristics (hallucinations delusions etc.) of schizophrenia are absent whereas the primary character- istics (loss of ability to sustain directed thought fluctuations in experiencing time and space etc.) are marked.Trials in psychoneurotic subjects have been recorded.lE3 No information regarding the method of its synthesis has been published. HO Opium Alkaloids.-Many of the morphine alkaloids obtained from the opium poppy (Papaver somniferum) and their synthetic analogues are known to produce euphoria in doses less than those required for analgesia. There is however little evidence apart from mood changes of a psychoto- mimetic action as a side effect. Recent reviews and monographs of the chemistry of this group are available.la4 The morphine antagonist N-allylmorphine (“Nalorphine”) (59) does however cause effects comparable to those of marihuana including uninhibited behaviour and visual h a l l u c i n a t i ~ n s . ~ ~ ~ ~ J ~ ~ 178 Adams MacKenzie and Loewe J.Amer. Chem. SOC. 1948,70 664. 179 Stockings Brit. Med. J . 1947 I 918. 180 Loewe J. Pharmacol. 1946 88 154. 181 Chen Fed Proc. 1958 17 338; Catenacci ibid. p. 357. 182 Luby Cohen Rosenbaum Gottlieb and Kelly A.M.A. Arch. Neurology and Psychiatry 1959 81 363. 183 Bodi Share Levy and Moyer Antibiotic Medicine and Clinical Therapy 1959 6 79. 184 Bentley “Chemistry of the Morphine Alkaloids,” Oxford Univ. Press 1954; Manske and Holmes (eds.) “The Alkaloids,” Academic Press New York Vol. 11,1952; Ginsburg Bull. Narcotics 1957,9 18; 1958,10 1. lS5 Isbell Fed. Proc. 1956 15 442; Goodman and Gilman “The Pharmacological Basis of Therapeutics,” Macrmllan 2nd Edn. 1955 p. 255. DOWNING PSYCHOTOMIMETIC SUBSTANCES 157 “OZoZiuqui”.-The plant known to the Aztecs as “Ololiuqui” (“Bador” “Coatlxoxouhqui” “Piuli” etc.) has long been referred to as containing an active principle with psychotomimetic propertieslse and is still used in Southern Mexico for the production of hallucinations.The plant has been identified with both Rivea corymbosa and Datura meteloides but Schultes (quotedby Kinross-Wrightla7) has demonstrated that it is the former of these. The reported behavioural disturbances caused by oral administration of the macerated seeds of R. corymbosa were confirmed by Osmond.ls8 The more extensive tests of Kinross-Wrightls7 did not confirm the observa- tion and no effect was obtained from the leaves roots or seeds and this author suggests that the crushed seeds of R. corymbosa are adulterated with Datura spp. known to produce behavioural changes.The constituents of “ololiuqui” have been little investigated chemically. The glucoside of an unknown alkaloid was reported18g but more recently Hofmann and Tscherterlgo have shown that lysergic acid derivatives may be isolated from “ololiuqui” and that lysergamide isolysergamide and chanoclavine are present.lgl “Kava-Kava”.-On some South Sea Islands the root of Piper methysticum is called “kava-kava” and is used to prepare a ritual drink thought to contain a psychotomimetically active principle. This principle has not yet been identified although methysticin kavain and other related a-pyrones have been obtained all of which proved to be inactive.Ig2 Organophosphorus Compourtds.-Some of the toxic organophosphorus anticholinesterase compounds have been shown to cause mental as well as functional disturbance.Di-isopropyl phosphorofluoridate (DFP) has produced behavioural changes.lS3 Tetraethyl pyrophosphate (TEPP) and parathion are less and more active respectively in this fashion than DFP.lS4 These observations are chiefly of interest with regard to a possible role for acetylcholine in psychotomimetic action. 10. Theories of the mode of action of psychotomimetics The biochemical theories of schizophrenia have been reviewed re- ~ e n t l y ~ ~ + ~ ~ ~ p ~ ~ ~ and the following brief survey will be confined to the current 186 Guerra and Olivera “Las Plantas Fantasticas de Mexico,” Diaro Espanol Mexico 18’ Kinross-Wright in “Neuro-psychopharmacology,’7 ed. Bradley Deniker and lE8 Osmond J. Mental Sci. 1955 101 526. lEQ Santesson Arch. Pharm. 1937 275 532. 190 Hofmann and Tscherter Experientia 1960 16 414.lQ1 Hofmann quoted in Indian Med. J. 1961 84. lg2 Borsche and Peitzsch Ber. 1927 60 113; 1930 63 2414; Klohs Keller Williams Tolkes and Cronheim J. Medicin. Pharmaceut. Chem. 1959 1 95. lg3 Grob Lilienthal Harvey Jones Langworthy and Talbot Bull. Johns Hopkins Hosp. 1947 81 257; Rowntree Nevin and Wilson J. Neurology Neurosurgery and Psychiatry 1950 13 47. lQ4 Grob and Harvey Bull. Johns Hopkins Hosp. 1949 84 532; Grob Garlick and Harvey ibid. 1950 87 106. lQ6 Kety Science 1959 129 1528 1590. D.F. 1954. Radouco-Thomas Elsevier Amsterdam 1959 p. 453. 158 QUARTERLY REVIEWS theories of the mode of action of psychotomimetics. This as has been mentioned previously may or may not bear some relation to the bio- chemistry of endogenous psychosis.The chief proposals for the mode of action of psychotomimetics concern their role as substances which interfere with the normal action in the body of three compounds 5-hydroxytryptamine (serotonin) (60) adrenaline (61) and acetylcholine (62). + -X Me ,N*CH iCHiO*COMe (62) 5-Hydroxytryptamine.-5-Hydroxytryptamine has been the subject of The creatinine sulphate of this vasoconstrictive substance was symposialg6 and of many review arti~1es.l~~ from serum in 1947 and characterised two years later.lg9 5-Hydroxy- tryptamine was synthesised shortly afterwards.200 Since that date there has been much interest in the substance as is shown by the large numbers of syntheses available.2 O1 Its importance was increased when it was found that in addition to its vasoconstrictor activity it had a constrictive effect on all smooth muscle and was important in the maintenance of the movements of the intestine (peristalsis).202 Furthermore it was present in high concentration (3 mpmoleslg.) in the brain.203 It was found to be especially prevalent in the basal ganglia which are thought to be the area of the brain concerned with emotion.204 g./l.) was shown to antagonise the effect of 5-hydroxytryptamine in contracting smooth muscle.205 Other psychotomimetic substances were shown to have a similar antagonistic effect (anti-serotonin activity) and it was suggested lg6 “Symposium on 5-Hydroxytryptamine,” ed.Lewis Pergamon London 1958 ; Ann. New York Acad. Sci. 1957,66,592. lg7 Page Physiol. Rev. 1958 38 277 and refs. (up to 1957) therein; Cerletti Helv. Med. Acta 1958,25 330; Maupin La Biologie 1960,49 75.19* Rapport Green and Page Fed. Proc. 1947 6 184. lg9 Rapport J. Biol. Chem. 1949 180 961. 2oo Hamlin and Fischer J. Amer. Chem. SOC. 1951 73 5007. 201 Harley-Mason and Jackson J. 1954 1165; Speeter and Anthony J. Amer. Chem. SOC. 1954,76,6208; Young J. 1958,3493; Ash and Wragg ibid. p. 3887; Noland and Hovden J. Org. Chem. 1959,24,895; Abramovitch and Shapiro Chem. andInd. 1955 1255; Bucount Valls and Joly U.S.P. 2,920,080/1960; Chem. Abs. 1960 54 13018. 202 Erspamer and Asero Nature 1952 169 800; Vane Brit. J. Pharmacol. 1957 12 344. 203 Amin Crawford and Gaddum J. Physiol. 1954 126 596. 204 Bogdanski Weissbach and Udenfriend J. Neurochem. 1957 1 272; Costa and Aprison J. Nervous and Mental Disease, 1958,126,289. 205 Gaddum J. Physiol. 1953 121 15.(+)-Lysergic acid diethylamide in very low concentration ( DOWNING PSYCHOTOMIMETIC SUBSTANCES 159 that psychotomimetic action was due to the disturbance of 5-hydroxy- tryptamine balance in the brain.203t206 The tranquilliser reserpine was shown to have the effect of reducing the brain 5-hydroxytryptamine concentra- ti~n.~O’ 5-Hydroxytryptophan decarboxylase the enzyme responsible for the synthesis of 5-hydroxytryptamine from 5-hydroxytryptophan and mono- amine oxidase which converts 5-hydroxytryptamine into 5-hydroxy- indole-3-ylacetic acid are both present in highest concentration in those areas of the brain which have the highest concentration of 5-hydroxy- tryptamine.208 5-Hydroxytryptamine itself does not produce central effects unless administered intravenously at very high dosage or intra- ventricularly since it passes only with difficulty from the blood to the brain.209 However 5-hydroxytryptophan causes marked elevation of the cerebral 5-hydroxytryptamine content and produces typical central effects (rage fear catatonia).It has therefore been suggested that the effects of 5-hydroxytryptophan are due to an increased amount in the brain of 5-hydroxytryptamine produced by a decarboxylation process.21o These considerations resulted in the suggestion that 5-hydroxytrypt- amine is an important chemical mediator in the nervous system interference with which could result in mental changes.211 The action of 5-hydroxy- tryptamine is visualised as an excitant one on the cerebral neurones in the brief period between its formation from 5-hydroxytryptophan and its decomposition by monoamine 0 x i d a s e .~ ~ ~ 9 ~ ~ ~ Iproniazid (1-isonicotinoyl-2-isopropylhydrazine) (63 ; R = Pri) is known to give in some cases psychotic reactions on administration. It is a monoamine oxidase inhibitor and there will be therefore an increased amount of 5-hydroxytryptamine in the brain,210 with characteristic central However isoniazid (isonicotinoylhydrazine) (63 ; R = H) which does not inhibit monoamine oxidase also produces similar There is other evidence against the theory that psychotomimetic activity is due to the disturbance of 5-hydroxytryptamine balance. 2-Bromolysergic acid diethylamide has 50 % more antiserotonin activity than lysergic acid diethylamide itself and it can be demonstrated in the brain after systemic 206 Woolley and Shaw Science 1954 119 587; Proc.Nat. Acad. Sci. U.S.A. 1954 207 Shore Pletscher Tomich Carlsson Kuntzmann and Brodie Ann. New York 208 Himwich Science 1958 127 70. McIlwain “Biochemistry and the Central Nervous System,” 2nd edn. Churchill 210 Udenfriend Weissbach and Bogdanski Ann. New York Acad. Sci. 1957 66 211 Brodie and Shaw Ann. New York Acad. Sci. 1957,66,631. 212 Arioka and Tanimaki J. Neurochem. 1957 1 311; Blaschko Phavmacol. Rev. 213 Paasonen MacLean and Giarman J. Neurochem. 1957,1,326; Davison Biochem. 214 Jackson Brit. Med. J. 1957 11 743; Pleasure A.M.A. Arch. Neurology and 40 228. Acad. Sci. 1957,66,607. 1959 p. 224. 402. 1952 4 415. J. 1957 67 316. Psychiatry 1954,3 13. 160 QUARTERLY REVIEWS administration however it produces none of the psychotomimetic effects of the parent compound.a15 $O.NH-NHR Nevertheless the theory has remained attractive because of the similarity in chemical structure between 5-hydroxytryptamine and many of the known psychotomimetics.Lysergic acid derivatives tetrahydroharmine psilo- cybin bufotenine NN-dimethyltryptamine and ibogaine all contain the tryptamine residue. Mescaline and adrenochrome have structures not far removed from the indole portion of tryptamine. Disturbance of cerebral 5-hydroxytryptamine balance could in fact be caused by monoamine oxidase inhibition by antimetabolic action by compounds of a similar structure or by release of it from its storage sites by reserpine for example. Some synthetic serotonin antimetabolites having indole structures have in fact been shown216 to cause behavioural changes in man and in animals though the effects usually are small compared with those of the psychoto- mimetic substances which have been discussed.Adrenaline.-The realisation of the resemblance in structure between 5-hydroxytryptamine and the indole psychotomimetics has been an important factor in the development of theories of psychotomimetic action involving 5-hydroxytryptamine. It was the structural similarity of mescaline and adrenaline which indicated the possible significance of the latter in psychotomimetic a c t i ~ n . ~ ~ ~ ~ ~ It was further realised that both adrenaline and mescaline could be the precursors of indoles (in vitro or in vivo) and that many psychotomimetics are in dole^.^^^ This suggested that an antimetabolite possibly having a structure related to indole may be psychotomimetic in action and resulted in the work with adrenochrome discussed above (p.136). The doubt surrounding the reported psychotomimetic activity of adrenochrome and its derivatives has meant that work relative to the possible importance of adrenaline in this connexion has tended to concentrate on experiments designed to disclose differences in the adrenaline metabolism of schizophrenics and normal subjects. Possible competition between psychotomimetics and adrenaline requires further study. Tn addition to the adrenochrome hypothesis it has been proposed217 that 0-methylation of adrenaline or a similar compound may be connected with the production of mental disorder since by this means a compound close in structure to mescaline may be produced. 0-Methylation is the main method of adrenaline metabolism when the substance is injected (though 215 Cerletti and Rothlin Nature 1955,176,785.%16 Shaw and Woolley J. Pharmacol. 1954 111 43; J. Amer. Chem. SOC. 1957 79 217 Harley-Mason quoted by Osmond and Smythies (ref. 33). 3561. DOWNING PSYCHOTOMIMETIC SUBSTANCES 161 it may not be for endogenous adrenaline).218 Since very little mescaline reaches the brain the suggestion has been made26 that it produces its effect by an antimetabolic action on for example adrenaline in the body. Both 3,4-di hydroxy- 5-me t hoxy- and 3 - hydroxy-4,5 -dime t hox y - p hene t h y lamine have been isolated from human urine after the consumption of mescaline,21g but only in amounts which account for less than half of the mescaline taken. Finally under this heading the reported psychotomimetic effects of amphetamine,220 which is said to produce symptoms often indistinguish- able from schizophrenia may be mentioned.Acetylcholine.-Acetylcholine occurs together with adrenaline nor- adrenaline and 5-hydroxytryptamine in the brain. Its highest concentra- tion is in the caudate amygdaloid hippocampus and hypothalmus and it is the third substance for which evidence is available supporting the theory that its balance in the brain is necessary for mental ~ t a b i l i t y . l ~ l ~ ~ ~ l The psychotomimetic effect of some anticholinesterases (for example DFP) has been mentioned above (p. 157) and this fact combined with the occurrence of acetylcholine esterase and choline acetylase together with acetylcholine in the brain requires that a possible role of acetylcholine be examined.The original suggestions implicating acetylcholine have been expanded recently by Biel and his ~ o - w o r k e r s ~ ~ ~ ~ ~ ~ ~ as a result of their work with the piperidyl glycollates. They consider the proposal that in the “lower brain” the sympathetic centre (excitatory) controlled by noradren- aline and the parasympathetic centre (depressant) controlled by acetyl- choline or a similar substance are in a balance. Disturbance of this balance allows either the excitatory or the depressant centre to dominate. Such a balance would be similar to that existing between the sympathetic and the parasympathetic nervous system in the rest of the body. Blockage of noradrenaline action allows the depressant centre to dominate the brain. Tranquillisers may act in this way.Likewise mono- amine oxidase inhibitors (which prevent the metabolic destruction of noradrenaline) permit the excitatory centre to dominate accounting for their action as psychic energisers. The experiments of Biel and his c o - w ~ r k e r s ~ ~ ~ ~ ~ ~ ~ with the piperidyl glycollates (see p. 150) have shown that in this series potent anticholinergic action is necessary for good stimulation of the central nervous system. This observation is in agreement with their proposal that acetylcholine (or a similar substance) has an action in the parasympathetic centre of the 218 Axelrod Science 1957 126,400. 219 Ratcliffe and Smith Chem. and Ind. 1959 925; Harley-Mason Laird and Smythies Confin. Neurologica 1958 18 152. 220 Connell Biochem. J. 1957 65 7 P; “Amphetamine Psychosis,” Maudsley Monograph Ny; 5 Chapman and Hall London 1958; Stromgren in “Neuro-psycho- pharmacology ed.Bradley Deniker and Radouco-Thomas Elsevier Amsterdam 1959 p. 183; Tolentino in “Psychotropic Drugs,” ed. Garattini and Ghetti Elsevier Amsterdam 1957 p. 585. 221 (a) Hoffer J. Clinical and Experimental Psychopathology 1957 18 27; (b) Pfeiffer and Jenney Ann. New York Acad. Sci. 1957,66,753. 162 QUARTERLY REVIEWS brain similar to that of noradrenaline in the sympathetic centre since an anticholinergic action will allow the excitatory centre to be dominant. Abood222 has discussed the possible mode of action of the piperidyl glycollates and also points out that they are potent anticholinergic agents and are thus related to acetylcholine. With this group retention of co- planarity within the molecule seems necessary for both high anticholin- ergic activity and psychotomimetic potency.It has been that tritium-labelled 1 -ethyl-3-piperidyl benzilate is localised predominantly in a cytoplasmic granular fraction consisting largely of mitochondria. Abood222 believes that the piperidyl glycollates are actually bound to mitochondria and that they act in the biological system at this level of the cell. The binding of piperidyl glycollates to mitochondria can be interfered with by chlorpromazine reserpine acetylsalicylic acid meprobamate and 9-amino-l,2,3,4-tetrahydroacridine (64). G e r ~ h o n ~ ~ ~ has shown that the last compound (64) is a specific antagonist of the psychotomimetic action of the piperidyl glycollates in man. This acridine derivative prevents the metabolic destruction of acetylcholine and therefore may act by restor- ing the balance of acetylcholine which has been disturbed by the action of an anticholinergic piperidyl glycollate.Although some connexion between anticholinergic potency and psychotomimetic activity has been demon- strated for the piperidyl glycollates there is not as yet a precise explanation of the mechanism of their action. All that is evident is that acetylcholine may have an important role in the interpretation of the mechanism of some psychotomimetic substances. It may be concluded that work on the mode (or modes) of action of the psychotomimetic substances is at present only at an early stage. It is not possible to judge the relative importance in this sense of the three substances reviewed here and other substances may be found later to have more importance.In addition the more neglected hypothesis that the psychotropic substances in general may exert a direct action at receptor sites has been indicated as deserving greater attention.222 The author thanks Drs. A. L. Green and W. D. Ollis for helpful comments on 222 Abood J. Medicin. Pharmaceut. Chem. 1961 4 469. 223 Abood and Rinaldi Psychopharmacologia 1959 1 117. 224 Gershon Nature 1960 186 1072. the manuscript.

ISSN:0009-2681    

DOI:10.1039/QR9621600133

出版商:RSC    

年代:1962

数据来源: RSC

摘要:

THE EFFECTS OF SOLVATION ON THE PROPERTIES OF ANIONS IN DIPOLAR APROTIC SOLVENTS By A. J. PARKER (CHEMICAL INSTITUTE UNIVERSITY OF BERGEN NORWAY and WILLIAM RAMSAY AND RALPH FORSTER LABORATORIES UNIVERSITY COLLEGE LONDON*) CHEMISTS need an understanding of the behaviour of ions in solution and it should be emphasised that the chemistry of anions in dipolar aprotic solvents differs greatly from their chemistry in water because anions are much less solvated in dipolar aprotic than in protic solvents1 such as water. In this Review hydrogen-donors e.g. water methanol and formamide are classed as protic solvents; solvents with dielectric constants > 15 which although they may contain hydrogen atoms cannot donate suitably labile hydrogen atoms to form strong hydrogen bonds with an appropriate species are classed as dipolar aprotic.Common dipolar aprotic solvents are dimethylformamide of dipole moment2 p = 3-82 dimethylacetamide p = 3 ~ 7 9 ~ dimethyl sulphoxide p = 4 ~ 3 ~ tetrahydrothiophen dioxide (sulpholane) p = 4.69,* acetone p = 2 ~ 7 2 ~ acetonitrile p = 3 ~ 3 7 ~ and nitrobenzene p = 3.99 D.5 The classification of solvents as hydrogen-donors explains our opening observation. There are four kinds of strong solvent-solute interaction ion-dipole dipole-dipole r-complex-forming and hydrogen bonding. In protic solvents anions are solvated by ion-dipole interactions on which is superimposed a strong hydrogen bonding which is greatest for small anions. Thus solvation by protic solvents decreases strongly in the series of anions1 OH- F- 9 C1- > Br- > N3- > I- > SCN- > Picrate.In dipolar aprotic solvents anions are solvated by ion-dipole interactions on which is superimposed an interaction due to the mutual polarisability of the anion and the solvent molecule which is greatest for large anions. There is no significant contribution to solvation by hydrogen bonding in dipolar aprotic solvents. Solvation of anions by dipolar aprotic solvents thus de- creases slightly in the reverse order to that given above for protic so1vents.l That there are two distinct types of anion solvation has not been fully appreciated and in this Review it is proposed to illustrate how the concept of differences of anion solvation in ’the two classes of solvent gives a consistent explanation of some solvent effects on rates of reaction on polarographic data on conductance on acid and base strength on basicity of anions on solubility and on spectra.Anion solvation explains * Present address :. Chemistry Dept. University of Western Australia Nedlands Western Australia. Miller and Parker J. Amer. Chem. SOC. 1961 83 117. “A Review of Catalytic and Synthetic Applications for DMF and DMAC,” E.I. du Pont de Nemours and Co. Wilmington 98 Delaware 1959. Schafer and Schaffernicht Angew. Chem. 1960,72 618. Burwell and Langford J . Amer. Chem. SOC. 1959 81 3799. Weissberger “Organic Solvents,” Interscience Publ. Inc. New York 1955. 163 164 QUARTERLY REVIEWS why many reactions with synthetical applications can be performed with advantage in dipolar aprotic solvents. Properties of Solvents.-The dipolar aprotic solvents have large dielec- tric constants5 (e.g.propylene carbonate 65,s sulpholane 44,* dimethyl- formamide 37.62) and large dipole moments (see above). They are high- boiling liquids with a large liquid range2y3s5 and a variety of viscosities and refractive in dice^,^ and are poor conductors of ele~tricity.~-5 Sulpholane dimethylformamide and dimethyl sulphoxide are highly associated liquidP4 and the Trouton constants of dimethylformamide2 (33.4) and dimethyl sulphoxide3 (29.5) are abnormally high. Dimethyl sulphoxide possesses an ordered structure which breaks down sharply between 40" and 60° as shown by the temperature-dependence of its refractive index specific heat density and viscosity.s In this respect it resembles water which has a distinct structural change at 37". Sulpholane and dimethylformamide may also have structures which are temperature- dependent.Schafer and S~haffernicht~ suggest that the structure of dimethyl sulphoxide involves hydrogen bonds between polar oxygen and the hydrogen of the methyl groups. Although the molecules do not dimeri~e,~,~ it is not unlikely that the structure may involve chains of sulphur and oxygen atoms of variable size such as (I); Me \ / Me r e ,Me 1 Me ,Me s-0- s-0-s-0 I n I (1) these could break down on heating or rearrange when a hydrogen-donor is added. Cryoscopic studies7 suggest that dilute solutions in benzene contain chains of sulphoxide molecules. Bonding between first- and second- row elements of the same group analogous to that proposed here is found in phosphonitriles which polymerise readily. Dimethyl sulphoxide has a high entropy of fusion (10.4 cal.deg.-l mole-l),' which supports the idea of a chain structure. Also the small heat of fusion of sulpholane coupled with the large heat of vaporisation suggests that there is little difference between the highly ordered liquid and the solid form of ~ulpholane.~ Sulpholane has a large molal freezing-point-depression constant (66 "/ mole),* as has dimethyl sulphoxide (4*36"/m0le),~ and because so many substances are soluble including inorganic complexes these are useful solvents for semi-quantitative determination of molecular weight provided that the solvent does not react with solute. 1. Effect of solvation on solubility Solvation ranges from one extreme in which donor and acceptor properties result in definite stable compounds through the intermediate ti Fuoss and Hirsch J.Amer. Chem. Soc. 1955,77 6115. Kentamaa Lindberg and Nissema Suornen Kern. 1961 34 B 98. PARKER SOLVATION OF ANIONS 165 dipole associations and unstable co-ordination compounds to the weak van der Waals interactions.8 Solvation is influenced by entropy changes in the solvent and the solute. The classical principle of “similia sirnilibus S O Z V U M ~ U ~ ~ ~ (“like dissolves like”) has frequently “explained” unusual solubility effects and may be a result of entropy changes favouring solva- tion and solubility. (i) Solubility of dipolar solutes. Hydrogen bonding greatly influences the solubility of dipolar solutes in dipolar solvents and in suitable systems outweighs the effect of dipole-dipole interactions. For example nitro- benzene has a larger dipole moment than aniline or phenol but is much less soluble in the strongly dipolar water presumably because it does not form hydrogen bonds with water as do the latter.8 Those dipolar molecules that can form strong hydrogen bonds with water by accepting its hydrogen atoms are completely miscible with water but compounds such as nitromethane which cannot form strong hydrogen bonds are only slightly soluble in water.Doubly bound oxygen is usually a good hydrogen- accept or. When water is mixed with strong hydrogen-acceptors such as dimethyl sulphoxide and dimethylformamide much heat is evolved and under certain conditions the mixture becomes viscous for a short time.@ This may result from breakdown of the sulphoxide rings and formation of a hydrogen-bonded structure such as (11). Polar compounds even insoluble ones such as some nitro-aromatic disulphides and di~elenides,~ dissolve readily in dimethylformamide,2 dimethylacetamide,2 dimethyl s~lphoxide,~ and sulpholane.Thus alcohols aldehydes ketones ethers esters aromatic and heterocyclic compounds organic mercury derivatives polymers (polyacrylonitrile nitrocellulose cellulose acetate and wood extracts) are usually soluble in these solvents. Inorganic complexes which are insoluble in most other solvents frequently dissolve in dimethyl s~lphoxide,~ and/or sulpholane. In some cases the complex is converted into a solvato-complex. Gaseous polq molecules dissolve readily in dipolar aprotic solvents such as dimethylformamide,2 dimethyl s~lphoxide,~ dimethylacetamide,5 and acetone.lo Acetylene sulphur dioxide nitrogen dioxide ammonia and hydrogen chloride can be separated from less polar and less soluble gases (ethane methane nitrogen hydrogen and oxygen) by solvent extraction Remick “Electronic Interpretations of Organic Chemistry,” Chap.10 John Wiley and Sons London 1947. Parker unpublished observations. lo Seidell “Solubilities of Inorganic Compounds,” Van Nostrand New York 1940. 166 QUARTERLY REVIEWS with dimethylformamide,2 dimethylacetamide,2 or dimethyl s~lphoxide.~ Sulphur trioxide forms a complex with dimethylformamide which is an extremely useful and convenient source of the trioxide for a variety of purposes.2 Paraffins saturated cyclic compounds and long-chain alcohols are only very slightly soluble in dimethylformamide,2 dimethylacetamide,2 dimethyl s~lphoxide,~ or sulpholane.It appears that polarisability of the solute is an important factor in the solubility of non-ionic species in dipolar aprotic solvents. (ii) Solubility of electrolytes and anion solvation. A salt dissolves in a solvent if either the ion-pair solvation or the total of anion solvation cation solvation and “dissociating or ionizing power” of the solvent which is usually reflected in its dielectric constant exceeds the crystal energy of the salt. Ionic species are often soluble and are dissociated in dipolar aprotic solvents but usually less so than in water. Most salts are disso- ciated even in acetonitrile,ll which causes little solvation of anions or cations. In water anions have much greater solvation energies than cations of comparable size,12 because of the hydrogen-bonding contribution to solva- tion of anions but in dipolar aprotic solvents anions are poorly solvated and are often less solvated than cations.13 Effects due to differences of anion solvation are found in the solubilities of many sodium and potassium salts in different so1vents.l Thus potassium chloride is much less soluble in dimethylformamide than in methanol which is of comparable dielectric constant but potassium iodide is more soluble in dimethylformamide than in methanol; this suggests that the iodide ion is at least as solvated in this dipolar aprotic solvent as in methanol but that chloride ion is much more solvated in methanol than in the dipolar aprotic so1vent.l The con- clusion is supported by the fact that iodides and thiocyanates are the salts most soluble in acetonitrile,ll and iodides are much more soluble than chlorides in dimethyl s~lphoxide.~ Hydroxides are very slightly soluble in acetonitrile,14 dimethylf~rrnamide,~ dimethyl sulph~xide,~ ~ u l p h o l a n e ~ ~ ~ ~ and dimethylacetamide suggesting that the hydroxide ion is poorly solvated and thus very active in these solvents.(iii) Cation solvation. Cations are strongly solvated in highly polar solvents having a negative charge localised on a bare oxygen atom as in dimethyl sulphoxide dimethylformamide sulphur dioxide dimethyl- acetamide 2-pyridones 2-pyrrolidones7 pyridine N-oxide phosphorus oxides and substituted tertiary amides.16 Sodium and potassium ions in dimethylformamide and dimethyl sulphoxide are solvated to give a solvo- dynamic unit equivalent in size to the tetra-n-propylammonium ion l1 Kolthoff and Coetzee J.Amer. Chem. Suc. 1957 79 870. l2 Buckingham Discuss. Faraday Suc. 1957 24 15 I . l3 Prue and Sherrington Trans. Faruduy Suc. 1961 57 1796. l4 Kolthoff and Coetzee J. Amer. Chem. Suc. 1957 79 1852. l5 Bunvell and Langford J. Amer. Chem. SOC. 1960 82 1503. l6 Zaugg J. Amer. Chem. SOC. 1960,82,2903. PARKER SOLVATION OF ANIONS 167 indicating that strong Kf and Na+ solvent interactions take place.l7,l8 Potassium iodide is less soluble than sodium iodide in methanol or water but in dimethylformamide or dimethyl sulphoxide the reverse is true,s and this may be due to differences of cation solvation. Cations are poorly solvated in for example nitro alkane^,^^ alkyl cyanides,ll and t-butyl alcohol presumably because the negative portion of the solvent dipole is dispersed is on an unfavourable electron-donor atom or is surrounded by bulky groups.If cation solvation by electron-donor solvents decreases in the series Me,SO Me,NAc > Me,NCHO SO, H 2 0 > COMe, sulpholane > MeOH 9 MeCN; MeNO > PhCN PhN02,-6t11,19,20 then some observations dependent on cation solvation are explained as demonstrated in this Review. Specific donor-acceptor interactions between cation and solvent interfere in generalisations about cation solvation. Thus many silver salts are more soluble in acetonitrile than in water,14s21 and cuprous iodide dissolves in acetonitrile but not in ~ a t e r . ~ ~ ~ ~ Acetonitrile readily forms complexes with silver and cuprous ions.14 Silver-ion activity varies greatly with change of ~ o l v e n t ~ ~ ~ ~ ~ suggesting that cation-solvation differences could be used to advantage in electrophilic reactions of cations just as differences of anion solvation are utilised in nucleophilic substituti0ns.l Lithium salts form solvates with many dipolar aprotic solvents e.g.acetone and dimethyl s~lphoxide,~ and their solutions are extremely V~SCOUS.~ Lithium salts dissolve largely as ion pairs in acetone.24 Dimethyl sulphoxide forms stable solvates with many transition-metal ions e.g. of CuCl, FeCl, CrCl, CoCl, NiBr, and A1C1,.3,25 In all cases oxygen is the donor atom except for the dimethyl sulphoxide-palladium com- plexes in which sulphur is the Dimethylformamide acts as a Lewis base and forms complexes with sulphur trioxide and iodine cyanide.26 Dimethylacetamide is a much better base towards iodine than is acetone,,' and basicity of the solvent molecule towards cobalt in the dichlorobisethylenediaminecobalt(rI1) cation de- creases in the series of solvents H,O > Me,SO > MeOH > Me,NAc > Me,NCH0.28 Lewis acids are generally more soluble in dimethyl-for- mamide and -acetamide than is indicated by their dielectric constants and l7 Sears Wilhoit and Dawson J.Phys. Chem. 1955,59 373. Sears Lester and Dawson J. Phys. Chem. 1956,60 1433. l9 Hammett and Looy J. Amer. Chem. SOC. 1959 81 3872. 2o Sears Wilhoit and Dawson J. Phys. Chem. 1955 59 373. 21 Hammond Hawthorne Waters and Graybill J. Amer. Chem. SOC. 1960 82,704. 22 Koch J . 1928 269. 23 Koch Phil. Mag. 1931 11 579. 24 Parker J. 1961 1328. 25 Cotton and Francis J. Amer. Chem. SOC. 1960 82 2986; Drago and Meek J. Phys.Chem. 1961,65 1446. 27 Carson Rose and Wenz J. Amer. Chem. Soc. 1961 83 3572; Schmullbach and Drago J. Amer. Chem. SOC. 1960,82,4478. 28 Watts and Tobe personal communication. Haszeldine J. 1954 4145. 168 QUARTERLY REVIEWS some Lewis acid reactions e.g. of thionyl or sulphuryl chloride halogens or carbonyl chloride are much more effective when performed in these solvent^.^^^ 2. Polarography Cations are reduced at more positive potentials and anions are de- polarised at more negative potentials at the dropping-mercury electrode as they become less so1vated.l1 It is difficult to compare half-wave reduction potentials of cations secured in different Where different reference electrodes are involved the E values cannot be expected to be the same or even to be directly related in any absolute sen~e.~~p~O Relative values for a series of cations however have significance.ll s 2 9 p 3 1 Kolthoff and Coetzee on the basis of relative E+ values conclude that cations are generally much less solvated in acetonitrile than in water,ll but that cuprous and silver ions which strongly interact with acetonitrile are much more solvated than in water.14 Solvation of cations in acetonitrile does not depend on charge density to the same extent or in the same way as in water.The proton is very much less solvated in acetonitrile than in water and would be expected to have.a much greater activity in aceto- nit~-ile.~~ The E4 values for simple cations show that dimethylfonnamide solvates cations much more readily than acetonitrile d o e ~ ~ ~ p ~ ~ and it is claimed that water is more efficient in this respect than dimethylf~rmamide.~~ The polarographic method appears to be a useful means of studying cation solvation especially since ultraviolet spectra solvent basicity and molar refractions of solvents do not reflect the ability to solvate cations.16 The anodic dissolution potentials (EA Table 1) referred to an external calomel electrode14 show that anions are much less solvated in acetonitrile (a dipolar aprotic solvent) than in water.The difference is greatest for small slightly polarisable anions. Hydroxide ion has a very much greater activity (i.e. is less solvated) in acetonitrile than in water since the difference between the EA’s for hydroxide ion in these solvents is twice as great as for any other anion studied. Only fluoride ion might be expected to show a comparable effect.Kolthoff and Coetzee14 found by polaro- graphy that in acetonitrile trihalide ions were more stable than the cor- responding halide ions. This agrees with our postulate1 that large polaris- able anions as in transition states are more solvated than smaller anions by dipolar aprotic solvents. Trihalide ions could be regarded as inter- mediates resembling the transition state for displacement by Hal- of Hal- at a univalent halogen atom. ea Schaap Messner and Schmidt J. Amer. Chem. SOC. 1957,79 870. so Popov and Geske J. Amer. Chem. Soc. 1957,79 2074. s1 Brown and Al-Urfali J. Amer. Chem. Sac. 1958 80,2113. se Kolthoff and Coetzee J. Amer. Chem. SOC. 1957,79,6110. 3s Wawzonek and Runner J . Electrochem. SOC. 1952,99,457. PARKER SOLVATION OF ANIONS 169 TABLE 1.Anodic dissolution potentials (EA in v> of mercury vs. an external calomel electrode at 25 ‘.I4 Anion E A H2O OH- 0.0 c1- + 0.2 Br- +0.1 I- -0.1 SCN- +0.1 4 MeCN - 0.90 - 0.25 -0.35 - 0.45 -0.10 A 4 (H20- MeCN) 0.90 0.45 0.45 0-35 0.20 3. Conductance Recent measurements of conductance in dimethylformamide13~20~s4~35 dimethyla~etamide,~~ dimethyl sulph~xide,~p~~ and sulpholane4 illustrate some anion and cation solvation effects. Prue and Sherringtonl have com- pared the Stokes-law radii of anions and cations in solvents with their crystallographic radii and conclude that cations carry a large solvation sheath in dimethylformamide dimethylacetamide and dimethyl sulph- oxide whereas anions are naked in these dipolar aprotic solvents. Sears Wilhoit and Dawson20 had earlier arranged limiting cationic con- ductances in dimethylformamide in the increasing order Bu,N+ < Pr,N+ < Na+ < K+ < Me,PhN+ < HCO.NMe,H+ < Et,NH+ < Et4N+ < EtNH$ < Me,N+.The lithium cation is less conducting than tetrabutyl- ammonium cation in dimethylf~rmamide.~~ Inasmuch as the cationic conductance of a species is related inversely to the effective cation size this series suggests that lithium sodium and potassium cations are well solvated by dimethylformamide. The partially substituted ammonium cations are apparently solvated by hydrogen bonding to the oxygen of the arnjde. Limiting cationic conductances in a ~ e t o n e ~ ’ ~ ~ ~ fall into the same series arrangement as in dimethyl-formamide and -acetamide pyridine and dimethyl s u l p h ~ x i d e ~ ~ ~ ~ ~ Limiting cation conductances in a number of solvents are compared in Table 2.It is apparent that the alkali-metal cations are well solvated by dimethylformamide dimethyl sulphoxide water and methanol because the solvodynamic units are less conducting than some large alkyl- ammonium cations. Sodium ions have larger solvation sheaths than potas- sium ions. Anion solvation is well illustrated by its effect on limiting equivalent anionic conductances as also shown in Table 2. Anions are as conducting as cations of similar crystallographic radii in methanol and water but anions are much more conducting than cations in the dipolar aprotic solvents dimethylformamide dimethyl sulphoxide and acetone. 34 Ames and Sears J. Phys. Chem. 1955,59 16. 85 Sears Wolford and Dawson J.Electrochem. Soc. 1956,103 633. 36 Lester Gover and Sears J. Phys. Chem. 1956 60 1076. 37 Reynolds and Kraus J. Amer. Chem. SOC. 1948,70 1709. McDowell and Kraus J. Amer. Chem. Soc. 1951,73 3293. 170 QUARTERLY REVIEWS Schafer and SchaffernichP observed that although chloride ion and potas- sium ion were of comparable size in water and methanol the chloride ion is much smaller than the potassium ion in dimethyl sulphoxide. The relative conductances of chloride bromide iodide and picrate ions in methanol follow quite a different pattern from that in dimethylformam- ide and dimethyl sulphoxide. This is because the negative solvodynamic units are hydrogen-bonded and large in methanol whereas in dimethyl- formamide and dimethyl sulphoxide the anions are bare and of a size comparable with their crystallographic radii.Thus chloride ion is more conducting than iodide ion in the two named solvents but less conducting in methanol and water. Dissociation.-Most sodium and potassium salts except the chlorides and nitrates are completely dissociated in < 10-3~-solution in dimethyl- f ~ r m a m i d e ~ ~ ~ ~ dimethyl ~ulphoxide,~,'~ ~ulpholane,~ and acetonitrile.ll Dissociation constants in protic and dipolar aprotic solvents reflect anion- solvation effects. Thus chlorides tend to be weak electrolytes in the differentiating solvent^,^^ dimethylf~rrnamide,~~~~~ dimethyl s~lphoxide,~ and acetone,*p3' but iodides and picrates in these solvents are much stronger. TABLE 2. Limiting ionic conductivities in solvents at 25". Ion X,(Me,NCHO) )c,(Me,SO) Li+ 25.013 - Na+ 29 *913 13-818 K+ 30.813 1 4 *418 13 Me4N+ 38-920 - Pr,N+ 2 9 ~ 1 ~ - Bu,N+ 26-213 1 1 .218 Me,PhN+ 32~2~' 14-118 Cl- 55*113 3 6 ~ 3 ~ Br- 53*613 24*218 I- 52-313 23*818 SCN- 5 9 ~ 8 ~ 29*218 Picrate 38*135 1 7-318 MW)' 38.7 50.1 73.5 44.9 23.4 19.5 76.3 78.4 76.8 30.4 L - A,( MeOH) 39.8' 45*2a 52.4' 66*7b 43*9b 36*gb 52.4' 56.5' 6 2 ~ 7 ~ 64.7b 4 9 ~ 2 ~ - a Robinson and Stokes "Electrolyte Solutions," Butterworths Scientific Publns.London 1959. Evers and Knox J. Amer. Chem. Soc. 1951,73,1739. However in methanol-a levelling solvent-dissociation constants of chlorides bromides iodides and picrates are almost equal., Potassium chloride in methanol is a stronger electrolyte than potassium picrate in methanol,,' but in dimethyl sulphoxide potassium picrate is stronger than potassium chloride,18 suggesting that the chloride ion is much more solvated in methanol than in dimethyl sulphoxide by comparison with picrate ion in methanol and the sulphoxide.Cations with a labile proton available for hydrogen bonding (e.g. Janz and Danyluck Chem. Rev. 1960,60,209. 40 Sears Wilhoit and Dawson J. Chem. Phys. 1955,23 1274. PARKER SOLVATION OF ANIONS 171 R,NH+) form strongly hydrogen-bonded structures with a suitable anion in differentiating (i.e. dipolar aprotic) ~ o l v e n t s ~ ~ ~ ~ ~ ~ where there is no other source of protons for this purpose. The result is that partly sub- stituted ammonium salts such as NHR3X but not R,NX,42 are weakly dissociated in acetone,41 nitromethane,lg nitroben~ene,~~ a~etonitrile,~’ and dirnethylf~rmamide.~~ These salts are strong electrolytes in solvents which compete with R,NH+ to provide hydrogen bonds for X- such as water methanol and ethanol.*l Since salts RNH3X are such weak electrolytes in dipolar aprotic solvents the use of indicators such as the substituted anilines for acid-base studies in dipolar aprotic solvents is more complicated than it appears at first to be.Taylor and K r a u ~ ~ ~ have shown that even the picrate ion has a tendency to form hydrogen bonds with labile hydrogen from the accompanying cation leading to incomplete dissociation of ammonium picrates in nitrobenzene (Table 3). In dimethylformamide which solvates cation more efficiently than nitrobenzene does triethylammonium picrate is completely dissociated but partially substituted ammonium bromides in dimethyl- formamide are weak electrolytes.20 TABLE 3.Dissociation constants of picrates in nitrobenzene at 25°.43 Cation Me4N+ MeO.NMe,+ HOCH2CH2.NMe3+ NHMe3+ HO.NMe,+ 1 0 4 ~ 400 250 70 1.5 0.17 4. Spectra and solvent effects Dimethyl sulphoxide is more transparent than water in the visible portion of the spectrum and is transparent throughout the region 4 0 0 - 1800 m ~ . ~ Dimethylformamide and dimethyl sulphoxide are transparent in the near-ultraviolet region. A pronounced red shift (100 mp) of the absorption maxima for the charge-transfer-transition (111) (where M is a Group VI atom) occurs in the change from a protic to a dipolar aprotic solvent.44 The shift is greatest when M is selenium. It has also been observed that a number of charge- transfer processes involving anions X- and aromatic systems have very much smaller transition energies (i-e.absorb nearer the red region) in dipolar aprotic solvents than in protic solvents. These observations conform with our postulate that dipolar aprotic solvents solvate large polarisable anions 41 Wynne-Jones J. 1931 795. 42 P. Walden “Salts Acids and Bases,” McGraw-Hill New York 1929. 43 Taylor and Kraus J. Amer. Chem. SOC. 1947 69 1731. 44 Parker Acta Chem. Scand. 1962 in the press. 172 QUARTERLY REVIEWS better than they solvate small anions having localised charge whereas in protic solvents the reverse is true'. Solvation of excited states involves of course only mutual polarisability of the loosely held electrons of the solvent and the excited state since other processes e.g. solvent re-orienta- tion require periods much longer than the transition time but apparently such polarisability interactions are strong in dipolar aprotic solvents.The position of the charge-transfer absorption band of I-alkylpyridinium iodide complexes is remarkably sensitive to the nature of the solvent in which it is K o ~ o w e r ~ ~ has adopted the transition energies of this process as an empirical measure of solvent polarity called 2 values. As with so many theories of solvent 2 values give good correla- tions for a number of observations in a series of protic solvents but as with ion association data,45 kinetic measurement^,^^ and transition energies of iodide two behaviour patterns emerge one for protic solvents the other for dipolar aprotic solvents. This may be due to differences of solvation of iodide ion in the two classes of solvent.2 values are much higher in solvents than in dipolar aprotic solvents of comparable dielectric constant indicating that the iodide ion is stabilised by hydrogen bonding in the protic solvents. Spectral shifts illustrate the existence and magnitude of ion-solvent interactions such as hydrogen b ~ n d i n g . ~ ~ - ~ ~ Both the O-H stretching and the bending frequencies of water are shifted strongly by negative ions including iodide but are unaffected by positive ions.5o The shifts increase in magnitude with increasing ability to form hydrogen bonds with water in the series I- < C1- < F-. The idea that the proton-acceptor in hydrogen- bond formation must be an element of small atomic radius and strong electronegativity although true for the strong hydrogen bonding to anions cannot be extended to the much weaker hydrogen bonding with covalently bound electronegative The O-H stretching frequency of methanol in carbon tetrachloride is shifted most in the infrared region for RI and least for RF in a series of alkyl halides5* This has important applications to our understanding of solvent effects on the initial and the transition states of S N 1 and S N 2 reactions.Since in the final state C1- is more solvated by hydrogen bonding than I- but in the initial state the halogen in RI is more solvated than in RCI the question arises at what stage in the S N ~ ionisation in protic solvents do hydrogen bonding forces change from O5 Kosower J. Amer. Chem. SOC. 1958 80 3253. 46 Hughes and Ingold J. 1935 244. 48 Kosower J. Amer. Chem. SOC. 1958 80 3261.O0 Bale Davies Morgans and Monk Discuss. Faraday SOC. 1957 24 94. Waldron J. Chem. Phys. 1957,26,809; Cave11 and Speed J . 1961,226. 61 Badger J. Chem. Phys. 1937 5 839. 52 Lord J. Chem. Phys. 1953 21 166. 53 Kuhn J. Amer. Chem. SOC. 1952,74 2492. Kosower J. Amer. Chem. SOC. 1958 80 3267; Smith Fainberg and Winstein J. Amer. Chem. SOC. 1961,83,618. Schleyer and West. J . Amer. Chem. SOC. 1959 81 3164. PARKER SOLVATION OF ANIONS 173 favouring ionisation of RI more than that of RCl to the reverse? Most important does this change occur before or after the transition state is reached? A similar question arises for sN2 reactions. 6+ 6- 6+ 6- RCI + R.. . .CI + R+ + CI- RI P R . . . .I + R+ + I- Cation-water interactions in acetonitrile as observed by infrared measurements are large when the cation is small but are small when the cation is large e.g.tetra-alkylammoni~rn.5~ Nuclear magnetic resonance measurements show that the 23Na+ ion forms complexes with amides such as N-methylf~rmarnide.~~ Iodine complexes at the oxygen atom of dimethyl- acetamide as shown by the carbonyl band shift in the infrared ~pectrum.~~ Here iodine is a Lewis acid and oxygen acts as the donor atom. 5. Acids and bases Dissociation of HX.-The conductance of hydrogen halides in anhy- drous polar organic solvents has been reviewed recently.39 Two groups of solvents may be distinguished levelling solvents in which the members of a series of electrolytes are approximately of the same strength e.g. hydrogen halides in methanol; and differentiating solvents in which the members possess markedly different strengths e.g.hydrogen halides in dimethyl- formamide dimethyl sulphoxide pyridine acetonitrile acetone nitro- benzene and nitr~methane.~~ It appears that differentiating solvents have this property because being dipolar aprotic they do not efficiently solvate small anions but are slightly more efficient for large than for small anions. The levelling (protic) solvents solvate small anions strongly (i.e. those which form the strongest bonds with hydrogen) because of hydrogen- bonding solvent-anion interactions. It is apparent therefore that solva- tion of A- in protic solvents most assists dissociation of acids with the strongest H-A bonds and thus levels (i.e. distorts) the “absolute” acid strength,l’ which is the tendency of HA to dissociate into ions in the absence of other molecules.Solvation of A- in dipolar aprotic solvents slightly assists dissociation of acids with the weakest H-A bonds (largest most polarisable A-) and reinforces the “absolute” acid strength of HA. To illustrate this the pK values of hydrogen bromide and chloride in aceto- nitrileS8 are 5.5 1 and 8.94 respectively; conductivities of 10-3~-hydrogen halides in acetonitrilesg increase in the ratio 1:20:60 from hydrogen chloride to hydrogen iodide; hydrogen bromide (K = 1.7 x at 25”) is much stronger than hydrogen chloride ( K = 2.8 x at 25”) 55 Scherba and Sukhotin Zhur. fiz. Klzim. 1959,33 2401. 56 Takeda and Stejskal J. Arner. Chem. SOC. 1960 82 27. 57 Schmullback and Drago J. Arner. Chem. Soc. 1960 82,4478. 58 Kolthoff Bruckenstein and Chantooni J. Amer. Chem. SOC.1961 83 3927. 59 Janz and Danyluck J. Arner. Chem. SOC. 1959 81 3854. 174 QUARTERLY REVIEWS in dimethylf~rmarnide,~~,~~ but the differences in acid strength of these three halogen acids in the levelling solvent methanol are less than If A- is small and capable of accepting hydrogen bonds HA will be a very weak acid in dipolar aprotic solvents even although HA may be strong in protic solvents of comparable dielectric constant. Hydrogen chloride is a strong acid in methanol,61 but a weak one in dimethylform- amide,35,60 a ~ e t o n i t r i l e ~ ~ ~ ~ ~ nitrobenzene,62 and nitr~methane~~ despite the very similar dielectric constants of all these solvents. These observations cannot be entirely explained by differences in proton solvation since dimethylformamide appears to solvate protons better than methanol does.Perchloric acid is strong in acetonitrile and hydrogen bromide is much weaker.58 Many acids (HA) in dipolar aprotic solvents form hydrogen bonds from A- through a proton to a solvent molecule to form e.g. Me,S=O . . . HA MeCN . . . HA Me2C=0 . . . HA or to another anion to form HA2-. Molecular complexes of HA and organic solvents are known,39 and dihalide ions (HA,-) are a common and stable species39 in nitrometh- ane,19,64 nitrobenzene,19 a ~ e t o n i t r i l e ~ ~ ~ ~ and other dipolar aprotic sol- v e n t ~ . ~ ~ s66 at 25") than hydrogen bromide (K = 1-7 x lo- at 25") in dimethylf~rmamide,~~ and as strong as hydrogen chloride in a~etonitrile,~~ but in water the halogen acids are much stronger than picric acid. This is in agreement with the order of anion solvation Picrate > Br- > C1- in dipolar aprotic solvents and C1- > Br- > Picrate in protic so1vents.l Hammett and L00y19 have studied acid-base reactions in nitromethane and suggest that the dissimilarity of these reactions from corresponding reactions in water should be attributed to the lack of hydrogen-donor properties of nitromethane and that conversely the familiar properties of acid-base systems in water-like solvents are due much more to the quality of these solvents as hydrogen-donors and much less to their relatively high dielectric constants than has usually been appreciated.Kolthoff Bruckenstein and Chantooni in a paper on acid-base equi- libria in a~etonitrile,~~ point out that an interpretation of differences in acid strength in different solvents must consider the formation and dis- sociation of ion pairs and the degree of solvation of anions in addition to the basic character of the solvent and its dielectric constant.Reactivity of Anions towards Hydrogen.-Turning from acid and base strength in terms of dissociation of HA to acidity and basicity in terms 8o Thomas and Rochow J. Amer. Chem. SOC. 1957,79 1843. 61 Ogston Trans. Faraday SOC. 1936,32 1679. 8a Beckmann and Lockemann 2. phys. Chem. 1907 60 390. 63 Hartley Murray-Rust and Wright J. 1931 199. 84 Pocker J. 1960 1292. 65 Jam and Danyluck J . Amer. Chem. Soc. 1959 81 3850. 88 Kaufler and Kunz Ber. 1909 42 385. 100 x.39 Picric acid is stronger (K = 6.3 x PARKER SOLVATION OF ANIONS 175 of the reactivity of H+ and A- we find that anions in dipolar aprotic solvents are much more reactive towards hydrogen than in protic solvents.Cram Rickborn Kingsbury and Haberfield67 have shown that the sodium methoxide-catalysed H-D exchange at carbon cc to CN C0.NR2 or C0,R is lo9 times faster in dimethyl sulphoxide than in methanol. They attribute the rate increase to the fact that methoxide ion is strongly sol- vated by hydrogen bonding in methanol but is poorly solvated in di- methyl sulphoxide. Sodium methoxide in sulpholane was less reactive than in the sulphoxide but much more reactive than in methanol. It is interesting that potassium t-butoxide in dimethyl sulphoxide displaces carbanions from hydrogen 10l2 times faster than does potassium methoxide in methan01.~' Cram and his co-worker~~~ point out that a large number of organic reactions involve the breaking of carbon-hydrogen bonds as the rate-determining step and it is probable that the rates of many such reactions could be dramatically increased by substitution of dimethyl sulphoxide for the usual hydroxylic solvents.Base-catalysed eliminations (e.g. carbene aryne olefin and acetylene formation) certain condensa- tions prototropic rearrangements and nucleophilic substitutions might be subject to enhancement of rate and possibly yield. Other dipolar aprotic solvents could be used in place of dimethyl sulphoxide if stable to alkali. Fluoride ion is a strong base when not stabilised by hydrogen bonding and in dimethylformamide dimethyl sulphoxide and sulpholane extracts a proton even from primary halides to give olefins.68 Tetraethyl- ammonium fluoride decomposes to ethylene and hydrogen fluoride when warmed in aprotic Chloride bromide and azide ions ac- celerate decomposition of t-butyl bromide to isobutene and by forming HA,- prevent the back-addition of the proton to olefin in a c e t ~ n e ~ ~ ~ a~etonitrile,~ and nitr~methane~,~~ because they are strong bases in these solvents.Reactivity of a Proton towards Bases.-This depends on the electron- donor properties of the solvent i.e. its ability to solvate protons.71 Proton solvation ranging from salt formation in pyridine to weak hydrogen bonding between anions and solvent molecules in a c e t ~ n i t r i l e ~ ~ ~ ~ reduces hydrogen-ion activity and this solvation varies in amount con- siderably from one solvent to another.72 Sulphuric acid in sulpholane is much more acidic than the correspond- ing aqueous s01ution.l~ Powell and Whiting72a suggest that Ho values in the range -4 to -8 would be found for the system sulpholane-hydrogen tetrafluoroborate.They observed that trans- Al-octalin was converted into G7 Cram Rickborn Kingsbury and Habefield J. Amer. Chem. SOC. 1961 83 3687; Cram Kingsbury and Rickborn J. Amer. Chem. SOC. 1961,83 3688. G8 Parker and Banthorpe unpublished work. 6 9 Miller Fried and Goldwhite J. Amer. Chem. SOC. 1960 82 3091. 'O Fuchs and Nisbett J. Amer. Chem. SOC. 1959 81 2371. 71 Mulliken J. Amer. Chem. SOC. 1952 74 811. 72 Braude and Stern J. 1948 1976. 72u Powell and Whiting Proc. Chem. SOC. 1960 412. 176 QUARTERLY REVIEWS A 9-octalin by hydrogen tetrafluoroborate in 1 :2 benzene-sulpholane 8 x lo4 times as fast as in 1 :2 benzene-acetic acid.The proton is extremely active in nitr~methanel~ and the solvated proton in acetonitrile is a “super acid.”32 The indicators o-nitroaniline and o-nitrodiphenylamine are 5 x lo4 times stronger in acetonitrile than in water,68 i.e. the proton is added much more efficiently in acetonitrile. Acidity functions of O.O2~-hydrogen chloride towards p-nitroaniline in various solvents are given in Table 4. More positive values denote greater acidity. Although uncertainties in the absolute values are introduced by incomplete dissocia- tion of hydrogen chloride (which tends to make H more negative),73 this does not change the conclusion that the proton is well solvated in di- methyl sulphoxide poorly solvated i.e. most active in nitromethane with intermediate behaviour in acetone. TABLE 4.Acidity functions and acid strengths of 0-02M-HCl at 25”. Solvent Me2NCHOa H,073 EtOH73 Me2C073 MeNO,’g H - 2.4 - 1.7 - 1.36 - 1.05 +2.14 Acid strength Weak Strong Weak Veryweak Veryweak a Dessy Reynolds and Kim J. Amer. Chem. SOC. 1959,81 2683. 6. Rates and mechanisms of reactions Most anions in dipolar aprotic solvents are much less solvated than in protic solvents but polarisable charged transition states in dipolar aprotic solvents are more solvated than in protic so1vents.l The result is that the bimolecular reactions of anions which pass through a large polarisable transition state containing that anion are much faster in dipolar aprotic solvents than in protic Reactions of small anions are most accelerated and reactions of large polarisable anions are least accelerated in the change from protic to dipolar aprotic so1vent.l~~~ The effect of hydrogen-bonding forces on rate is illustrated in Table 5.The effect is general for ,S”2 and SNAr anion-dipole reactions24 and for S N 2 and SNAr anion-cation reaction^'^ i.e. for a variety of transition states. Bimolecular substitutions not involving anions are much less susceptible to changes in solvent structure provided that the dielectric constant does not change a p p r e ~ i a b l y . ~ ~ ~ ~ ~ Pyridine and butyl bromide react together at substantially the same rate in dipolar aprotic solvents and in water-methanol mixtures of the same dielectric constant at the same ionic strength.77 Although pyridine is not solvated by hydrogen-bonding in dipolar aprotic solvents but is so solvated in protic solvents this rate- 73 Braude J.1948 1971. 74 Cave11 and Speed J. 1961 226. 75 Beringer and Mausner J. Amer. Chem. Soc. 1958 80,4535. 76 Palit J. Org. Chem. 1947 12 752. 77 Parker J. 1961,4398. PARKER SOLVATION OF ANIONS 177 enhancement is nullified by the fact that the departure of bromide ion in the transition state is assisted less in the dipolar aprotic solvents. The trimethylamine-trimethylsulphonium cation reaction is twenty times faster TABLE 5. Relative rates24 in solvents for the reactions at 25”. A CH31 + CI- -+ CH3Cl + I- B p-NO,C,H*F + N3- + p-NO,.C&.N + F- Solvent MeOH NH,CHO Me-NHCHO Me,NCHO Me2NAc Relative rates of reaction A 1 12.5 45.3 1.2 x lo6 7.4 x los Relative rates of reaction B 1 5.6 15.7 2.4 x loll 8.8 x lo4 in nitromethane than in methan01.~~ This may be because in methanol hydrogen bonding reduces the reactivity of trimethylamine but does not assist the departure of dimethyl sulphide from the transition state because neutral sulphur accepts only weak hydrogen bonds.The reaction is there- fore slower in the protic solvent. The accepted order for carbon nucleophilicity is CN- > I- > SCN- > N3- > Br- > Cl- > F- but this is only true for “protic solvated” This series is a function of solvation rather than of size polarisability or ability to form bonds at large separations of r e a c t a n t ~ . ~ ~ ~ ~ ’ Dipolar aprotic solvents exert a “levelling effect” on this series of nucleo- philes in that small slightly polarisable anions are most activated by the change from protic to dipolar aprotic Protic solvents differentiate the nucleophilicity and level the basicity of anions towards carbon and hydrogen.s0 It appears that the complex [Y * - - R - * C1]- in the transition state is more solvated because of hydrogen bonding than is [Y - - R - - .I]- in protic solvents.The reverse is true in dipolar aprotic solvents.24 Anionic reactions are much faster in dipolar aprotic solvents but posi- tions of equilibria which are thermodynamically controlled are similar in protic and in dipolar aprotic solvents unless the displacing and the dis- placed groups have very different polarisabilities and sizes or are of different charge type^.^^^^^ Thus halide ion-alkyl halide exchanges have comparable equilibrium constants in protic and in dipolar aprotic but the equilibrium RX + R2S f R3SX lies much further to the left in dipolar aprotic solvents than in protic solvents of the same dielectric c~nstant.~ Protic molecules added in concentrations slightly greater than an anionic reactant do not sharply lower rates of reaction in acetone,811a2 dimethyl- 78 Hughes ad Whittingham J.1960 806. 7 9 Winstein Savedoff Smith Stevens and Gall Tetrahedron Letters 1960 No. 9 Parker Proc. Chem. SOC. 1961 371. 81 Cave11 and Speed J. 1960 1453. 82 Le Rowr and Sugden J. 1939 1279. 24. 178 QUARTERLY REVIEWS formamide,l dimethyl s u l p h o ~ i d e ~ ~ ~ ~ or a~etonitrile.~~ The solvent molecules as well as the reactant anions are hydrogen-acceptors and being much more numerous than the anions effectively compete for the added protic molecules. Protic additives exert a rate-diminishing influence which increases with their increasing hydrogen-donor ability.74,s3,s4 TABLE 6.Compounds synthesised with advantage in dipolar aprotic solvents. Solvents are denoted DMF = Me,NCHO; DMAC = Me,NAc; DMSO = Me,SO; Sn 5 sulpholane. Reaction RX + CN-+ RCN + X- Primary and secondary Hal Me-SO DMF DMAC DMSO RCN X Solvent alkyl cyanides and Sn dini triles Aromatic nitriles Br DMF 1 -methylpyrroli- Cyanodithioformate Addition DMF “Nylon” Addition DMF DMAC done to cs to RNCO (EtOCH,.CH,),O Reaction RX + NO2- - Primary and secondary Primary and secondary Nitroquinones /3-Nitro-ketones Cycloalkyl nitrites a-Nitro-esters RN02 ni troparaffins dinitroparaffins + RNO2 - X Hal Br c1 Hal Br I Br t x- Solvent DMF DMSO DMF DMF DMF DMF DMSO DMF Reaction RX + R’,N--+ NRR’ + X- NRR’ X Solvent Phthalic acid derivatives Hal DMF DMAC Reference 111-115 24 6-1 6-2 89 90 6-3 110 Reference 116 117 6- 4 6-5 6-6 11 6 6-7 6-8 6-9 123 6-10,6-11 Reference 2 119 120 References in addition to those cited also in the text 6-1 Lawton and McRichtie J.Org. Chem. 1959 24 26. 6-2 Cahana Schmidt and Shah J. Org. Chem. 1959 24 557. 6-3 Bahr and Schleitzer Chem. Ber. 1955 88 1771. 6-4 Kornblum Blackwood and Mooberry J. Amer. Chem. SOC. 1956,78 1501. 6-5 Kornblum and Blackwood U.S.P. 2,791,694/1956. 6-6 White and Considine J . Amer. Chem. Soc. 1958 80 626. 6-7 Stille and Vessel J. Org. Chem. 1960 25 478. 6-8 Belshaw Howard and Irving U.S.P. 2,587,093/1952. 6-9 Fusco and Rossi Chem. and Ind. 1957 1650. 6-10 Kornblum and Blackwood Org. Synth. 1957 37 44. 6-11 Kornblum and Weaver J . Amer. Chem. Soc. 1958 80 4333.83 Leary and Kahn J. Amer. Chem. SOC. 1959 81,4173. 84 Pocker J. 1959 1179. PARKER SOLVATION OF ANIONS TABLE 6.-continued Reaction RX + R’,N-+NRR’ + X- (Gabriel synthesis) NRR‘2 X Solvent 1 O-Propylpheno thiazine Br DMF 5-Arylalkylidene-3-iso- Br I DMF butyIthiazolidine-2,4-diones N- Alkylpurines Hal DMF N- A1 k y lure t hanes Br DMF N-Alkylnaphthalimides Hal DMF Reaction R’X + R & + CR,R’ + X- Alkynes Br Xylene-DMF DMAC 14-Hydroxy- 1 8,19- I DMF a-Alkylacetoacetates Hal DMSO (EtO-CH,. CRaR’ X Solvent 2PO(NMe&S bisnorprogesterone CH2),0 NN-disubs t. amides N-oxides P-oxides ( f )-Baikiain c1 DMSO-C& Acylbenzenes Br (EtO*CH,*CH&,O Et malonate derivatives Br DMF Reaction RX + R’O-+ ROR + X- Alditol ethers Hal DMF Aldose benzoates Tosylate DMF Alkyl glycosides Hal DMF a-Alkoxy-y-lactones Hal DMF Alkylcelluloses I DMF Benzyl esters CI DMF Di-( 2-hydroxethyl) Addition to DMF HO*CH,.CH,.OH ROR’ X Solvent terephthalate ethylene oxide 179 Reference 6-12 6-13 6-14 6-15 6-16 6-14 6-17 6-18 6-19 6-20 Reference 93 94 91,92 95 97 6-18 Reference 6-21 6-22 6-23 122 6-24 6-25 6-26 6-27 6-12 Donahoe Seiwald Neumann and Kimura J.Org. Chem. 1957 22 68. 6-13 Billman and Cash J. Amer. Chem. SOC. 1954,76 1944. 6-14 Lo and Shropshire J. Org. Chem. 1957,22 999. 6-15 Gabriel Ber. 1908 41 1127. 6-16 Zaugg Swett and Stone J. Org. Chem. 1958 23 1389. 6-17 Lo Shropshire and Croxall J. Amer. Chem. SOC. 1953 75 4845. 6-18 Schudy and Collins J. Org. Chem. 1959 24 556. 6-19 Dannley and Sukin J. Org. Chem. 1957 22 268. 6-20 Devereux and Donahoe J. Org. Chem. 1960 25 457.6-21 Wolfrom Juliano Toy and Chaney J. Amer. Chem. Soc. 1959,81 1446. 6-22 Segaller J. 1914 105 113. 6-23 Reist Goodman and Baker J. Amer. Chem. SOC. 1958 80 5775. 6-24 Stacy Cleary and Cortatouski J. Org. Chem. 1957,22 765. 6-25 Barth and Timell J. Amer. Chem. SOC. 1958 80 6320. 6-26 Fekekte U.S.P. 2,830,078/1958. 6-27 Kolb U.S.P. 2,901,505/1959. 180 QUARTERLY REV1 E W S TABLE 6. -con tin ued Reaction RX + R‘O-+ ROR’ + X- ROR‘ X Triscarbamates Addition of cellulose to alkyl iso- cyanates Reaction RX + R’S-t RSR + X- RSR’ X Alkylthiopurines c1 4,7-Dimercapto-1 -methyl- C1 imidazo [4,5-d!] pyridazine Isothiouronium Hal 2-halogenoacetamidates and 2-halogenoacetates Tetrahydrothienyl c1 Vinyl sulphides Addition of R‘S- to acetylenes Reaction RX + Hal-+ RHal + X- RHal X Alkyl and aryl halides Hal Aromatic fluoro-nitro- C1 2-Fluoropyridines c1 Aromatic iodo-nitro- C1 Aromatic bromo-nitro- I Steroids halides Tosylate Fluoro-olefins CI Polymers Addition of Cl- to acrylonitrile and $-halides compounds compounds compounds SF4 c1 CF,*SCI c1 Solvent DMF Solvent DMF DMF DMF COMe DMF DMF Solvent Cf.ref. 5 DMF DMSO MeCN DMF DMSO DMF DMSO DMF COMe DMF MeCN Sn PhCN NH,CHO COMe Sn MeCN DMF Reference 6-28 Reference 121 6-29 6-30 6-31 6-32 6-3 3 Reference 1 24 87 6-34 6 4 3 9 6-3 5 88 6-36 69 107 106 6-37 1 09 6-28 Pikl U.S.P. 2,668,168/1954. 6-29 Carbon J. Amer. Chem. SOC. 1958 80 6083. 6-30 Speziale and H a m J. Amer. Chem. SOC. 1956 78 5580. 6-31 Speziale J. Org. Chem. 1958 23 1231. 6-32 Org. Synth. 1956 36 89. 6-33 Truce and Heine J. Amer. Chem. SOC. 1959 81 592.6-34 Finger and Starr J. Amer. Chem. Soc. 1959 81 2674. 6-35 Blickenstaff and Chang J. Arner. Chem. SOC. 1958 80 2726. 6-36 Tullock Fawcett Smith and Coffman J. Amer. Chem. SOC. 1960 82 539. 6-37 Sheppard and Harris J. Amer. Chem. SOC. 1960,82,5106. PARKER SOLVATION OF ANIONS 181 TABLE 6.-continued Miscellaneous reactions Compound prepared X Solvent Reference Alkyl and aryl nitrates Halogen MeCN 6-38 21 Alkyl isocyanates c1 DMF DMAC 6-39 Phosphonitrilic c1 DMF DMAC SO, 6-40 isothiocyanates COMe, RCN Addition to fluoro- - DMF 6-41 5-Substd tetrazoles Addition of DMF DMSO 6-42 olefins N3- to nitriles 6-38 Ferris McLean Marks and Emmons J. Amer. Chem. SOC. 1953 75,4079. 6-39 Himel and Richards U.S.P. 2,866,801/1958. 6-40 Tesi Otto Sherif and Audrieth J. Amer. Chem. SOC.1960 82 528. 6-41 England Melby Dietrich and Sindsey J. Amer. Chem. SOC. 1960 82 5116. 6-42 Finnegan Henry and Sofquist J. Amer. Chem. SOC. 1958 80 3908. 6-43 Bunnett and Connor J. Org. Chem. 1958 23 305; Org. Synth. 1960 40 34. 7. Reactions of anions and application to synthesis Reactions for which dipolar aprotic solvents have been reported to give higher yields and require shorter reaction times than conventional solvents are illustrated in Table 6. In each case one of the reactants is an anion and the reactions are probably bimolecular in mechanism. The solvent effect must be largely due to the greater reactivity of anions poorly solvated relative to the transition states of their reactions in dipolar aprotic solvents; but there are also other advantages in the use of such solvents.Most organic compounds except hydrocarbons and related non- polar species are soluble in dipolar aprotic solvents as are many electro- lytes. Those dipolar aprotic solvents which solvate cations efficiently are completely miscible with water which is an advantage when water- insoluble products are to be isolated. Dimethyl-formamide and -acetamide can be recovered from aqueous solution by distillation since they do not form azeotropes.2 Higher reaction temperatures (1 50-200") are possible since the highly associated solvents have an extensive liquid range. Solvolysis of reactants by dipolar aprotic solvents is slower than by water or alcohols.24 SN1 ionisation in dipolar aprotic solvents is not com- mon because both ionised groups are weakly solvated the anion because it cannot form a hydrogen bond with the solvent the cation (carbonium ion) because it has a well-shielded charge.An SNl-like process is proposed for chloride exchange of platinum(r1) complexes in dimethyl sulphoxide nitromethane acetonitrile dimethylformamide acetone and ethanols5 and triphenylmethyl chloride is appreciably ionised in sulphur dioxide,s6 which solvates cations efficiently and according to PockeP anions also. 85 Pearson Gray and Basolo J. Amer. Chem. Soc. 1960 82 787. 86 Pocker Proc. Chem. SOC. 1959 386. 3 182 QUARTERLY REVIEWS Why sulphur dioxide solvates efficiently is not made clear and is unexpected since it cannot form hydrogen bonds with anions. The ionising power of protic and dipolar aprotic solvents has been discussed by Smith et al.47 The best sources ofanions for reaction in dipolar aprotic solvents seem to be lithium or tetra-alkylammonium salts since these are most soluble.The latter salts (R4NX) have the advantage that they often can be prepared in situ. Well-stirred finely powdered suspensions of dry sodium or potas- sium salts are satisfactory sources of nucleophiles in the synthesis of aryl fluorides in dirnethylformamide and dimethyl sulphoxidea7 and of sulphur tetrafluoride in acetonitrile.88 When a cation forms a complex with the solvent large amounts of the accompanying anion can be obtained in solution as with silver salts in acetonitrile and cuprous salts in dimethyl- formamidesg or 1 -methylpyrrolidone. Small amounts of water do not greatly affect the aprotic properties of dipolar aprotic solvents but traces of acid or nucleophilic impurities (e.g.dimethyl sulphide in dimethyl sulphoxide dimethylamine in dimethyl- formamide) should be removed by di~tillation.~~ Dipolar aprotic solvents are readily purified by passage through molecular sieves.13y47967,77 Some reactions of Table 6 deserve more detailed discussion. (a) Alkylation of Carbanions R,C- + R’X -+ CR,R’ + X-.-A striking increase of rate and yield in the alkylation of e n o l a t e ~ ~ ~ ~ ~ ~ a~etylides,~ and other car bani on^^^,^^ takes place when some dipolar aprotic solvents are added to an inert solvent such as benzene xylene dioxan or tetra- hydrofuran. Zaugg and his c o - w ~ r k e r s ~ ~ ~ ~ suggest that the additives break up ionic aggregates which form in solvents of low dielectric con- stant releasing very slightly solvated reactive anions.Only solvents that solvate cations well (i.e. molecules with regions of high n-electron density preferably on oxygen) are suitable additives,16 and protic solvents pro- tonate carbanions so are not satisfactory. Dimethyl sulphoxide tertiary amines and the covalent phosphorus sulphur and nitrogen oxides were the best additives of those studied.g1 Some rate measurements have been reported. 96 Dipolar aprotic solvents need not be merely additives for alkylations. Thus enol anions are alkylated smoothly in mono- and di-ethylene 87 Finger and Kruse J. Amer. Chem. SOC. 1956 78,6034. 88 Tullock Smith Muetterties Hasek Fawcett Engelhardt and Coffman J. Amer. Friedman and Schechter J. Org. Chem. 1961,26 2522. Newman and Boden J. Org. Chem. 1961 26 2525. 91 Zaugg Horron and Borgwardt J.Amer. Chem. SOC. 1960 82 2895. O2 Marshall and Cannon J. Org. Chem. 1956 21 245. O3 Rutledge J. Org. Chem. 1959 24 840. O4 Nelson and Garland J. Amer. Chem. SOC. 1957 79 6313. O5 Burgstahler and Aiman J. Org. Chem. 1960,25 489. 96 Zaugg J. Amer. Chem. SOC. 1961 83 837. 97 Zook and Russ J. Amer. Chem. SOC. 1960,82 1258. -CHRCO,Et + R’X -+ CHRR’.CO,Et + X- Chem. SOC. 1959,81 3165. PARKER SOLVATION OF ANIONS 183 and much more rapidly in dimethylforrnamide and diemthyl sulphoxide than in benzene,gs presumably because-in the solvents of high dielectric constant ion pairs are not formed and carbanions although stable are poorly solvated (i.e. active). The following reaction is 75 % complete after 3 minutes in diethylene glycol dimethyl ether whereas in ether this requires 234 hours:97 EtCHNa-COPh + EtBr -f CHEt,COPh + NaBr (b) Dehydrohulogenation B + R*CH2.CH2X + R*CH:CH + BH+ + X- .-As already discussed halide ions in dipolar aprotic solvents are both strong bases and powerful nucleophiles and many dipolar aprotic solvents (e.g.dimethylformamide and dimethyl sulphoxide) solvate cations efficiently and readily act as hydrogen acceptors. A basic halide ion assists elimination by an E2 mechanism and formation of hydrogen-bonded species such as HHa1,- (DMF),H+ and (DMF)HHal (where DMF = dimethylformamide) in for example dimethylformamide deactivates the proton for back addition to the product olefin. It is not surprising there- fore that halide ions in dimethylformamide dimethyl sulphoxide and acetone are such good dehydrohalogenating agents. Halide exchanges are rapid in dipolar aprotic The resulting Walden inversion may give a more favourable orientationg8 of X and H as is required in some cyclic structures for elimination of HX.It is clear that the basicity and the nucleophilicity of halide ions in dipolar aprotic solvents together account for their ability to act as dehydrohalogenating agents. Some applications of this property are the synthesis of cortisone acetateg9 and corticosterone acetateloo which were prepared by dehydrochlorination with lithium chloride in dimethylformamide. A solution of lithium chloride in this solvent and formamide (a protic solvent) did not cause dehydro- halogenati~n.~~ 3a-Acetoxy-20-bromobisnorcholan-22-al has been de- hydrobrominated with dimethylformamide and lithium chloride,lo1 and 3~-acetoxy-2Q-bromo-5a-chlorobisnorcholan-22-a1 is selectively dehydro- brominated by dimethylformamide alone although with added lithium chloride both hydrogen chloride and hydrogen bromide are eliminated.lo2 Other metal halides are effective and dimethylacetamide is an equally effective s01vent.l~~ The dehydrohalogenation of 2-chloro-2-methyl- cyclohexanone by lithium chloride in dimethylformamide has been described in Organic Syntheses.lo4 Elimination of telomer iodides was clean and gave high yields in dimethylformarnide or dimethyl sulph- oxide with LiCl KF NaBr ICl KSH NaCN NaNO, or NaSPh as C2F,CHz.CFzI + C,F,CH=CF + HI g8 Winstein Darwish and Holness J.Amer. Chem. SOC. 1956 78 2915. ss Hoylsz J. Amer. Chem. Soc. 1953,75 4432. loo Chamberlin Tristram Utne and Chemerda J. Org. Chem.1960 25 295. lol Pederson Johnson Hoylsz and Ott J. Amer. Chem. SOC. 1957,79 1115. lo Chamberlin Tristram Utne and Chemerda J. Amer. Chem. SOC. 1957,79,456. lo3 Chemerda Chamberlin and Tristram U.S.P. 2,833,790/1958. Io4 Org. Synth. 1957 37 10. 184 QUARTERLY REVIEWS added base or nu~leophile.~~~ The halide salts were the most effective additives because they do not react with the product i.e. do not displace fluoride ion from doubly bonded carbon. Hauptschein and Oesterlingl05 discarded the E2 mechanism because they believed that halides were not strong bases in the solvents used. The above reaction could however proceed by an E2 mechanism by S N ~ displacement of iodide followed by a cis-elimination or by a merged S N ~ elimination like that suggested by Winstein and his co-workersg8 for the reaction of 4-t-butylcyclohexyl toluene-p-sulphonate with lithium bromide in acetone.(c) Synthesis of Fluoro-compounds RX + F- + RF + X-.-Fluoride ion in dipolar aprotic solvents is a powerful nucleophile and a strong base. Eliminations compete with substitution by fluoride except in the synthesis of non-eliminating compounds such as MeF,g SF4,88 ArF,87 CF :CClCF,,6g and CF3.SC1106 from the appropriate chloride bromide iodide or nitro-compound. Exchanges are sensitive to moisture and do not take place in hydroxylic Fluoride ion in formamide is a strong n u c l e ~ p h i l e ~ ~ ~ ~ ~ ~ and metal fluorides are soluble. Although formamide is a protic solvent hydrogen bonding is less effective than in hydroxylic solvent^,^^^^ so that fluoride ion is less solvated i.e.more reactive in formamide than in water. (d) Anionic Polymerisation.-Vinyl compounds polymerise in the presence of strong bases (B-) and chain growth occurs in the absence of proton-donor solvents. The reactions involve anions rather than radicals and can be described by the sequence initiation Propagation Termination B- + CH,=CHX -+ BCH,-CHX- B-CH,CHX- + CH,CHX -+ BCH,*CHXCH,CHX- B.[CH,CHX]nCH,-CHX- + H+ -+ B-[CH,.CHX]nCH,.CH,X It is not surprising that dipolar aprotic solvents are the best media for such reactions.los They are not proton donors reactants and products are soluble the propagation step is rapid because the carbanion is very reactive (being poorly solvated and not in an ion pair with the cation) and the common initiators [chloride and cyanide ion (B-)] are very strong bases and nucleophiles in such solvents.It is well knownlo8 that acrylonitrile with cyanide ion as initiator readily gives Orlon in dimethylformamide sulpholane or oc-methoxy-NN- dimethylacetamide and that Dyne1 is formed from vinyl chloride and acrylonitrile in acetone with chloride or cyanide as initiator. The explana- tions given above are not so well known. Bamford Jenkins and Johnstonlog found that acrylonitrile polymerised in dimethylformamide when initiated by lithium chloride nitrate or 105 Hauptschein and Oesterling J. Amer. Chem. Soc. 1960 82 2868. lo6 Tullock U.S.P. 2,884,453/1959. lo7 Fried and Miller J. Amer. Chem. SOC. 1959 81 2078. lo* Hammond and Cram “Organic Chemistry,” McGraw-Hill New York 1959. lo9 Bamford Jenkins and Johnston Proc. Roy. SOC. 1957 A 241 364.PARKER SOLVATION OF ANIONS 185 perchlorate the efficiency decreasing in that order. Perchloric acid sup- pressed the polymerisation. The initiators and the anions involved in pro- pagation are strong nucleophiles in dimethylformamide unless protons are present and this explains their observations. Nylon-like polymers are best formed at low temperatures. Shashoua Sweeny and TietzllO proposed the reaction scheme Initiation RNCO + B- -f -NRCO.B Propagation BCO-NR- + RNCO -+ B.CO*NRCO.NR- L/ .1 NR B*CO*[NR*CO]n*NR- 07’ ‘yo RN ,NR co Termination B*CO.[NR.CO]n.NR- + H+ -f B.CO.[NR.CO]n.NHR At low temperatures (-50”) the required polymer is formed at higher temperatures only the cyclic trimer. Dimethylformamide and its mixtures with dimethylacetamide and diethylene glycol dimethyl ether with sodium cyanide or naphthalide as initiator gave high yields of the polymer.l1° In these solvents low temperatures could be used presumably because of the high nucleophilicity of the initiators and of the interme- diate BCO-NR-.As might be expected formamide a protic solvent inhibited polymerisation and acids terminated it. (e) Nitrile Synthesis RX + CN- -+ RCN + X-.-Cyanide ion reacts > 5 x lo5 faster with methyl iodide in dimethylformamide than in Primary and secondary alkyl halide+ or methanesulphonates,l12 and presumably toluene-p-sulphonates react rapidly and cleanly with alkali- metal cyanides in dimethyl s ~ l p h o x i d e ~ ~ ~ ~ ~ ~ ~ dimethyl-formamide113 and -acetamide,l15 sulpholane,lll and dimethylsulpholanelll to give nitriles in 60-90% yield. No isocyanide is formed.lll Even neopentyl and neophyl halides react without rearrangement but t-butyl chloride gives only isobutene,lll emphasising the extreme reluctance of t-butyl compounds to take part in ,S”2 reactions.Sodium cyanide is preferred to potassium cyanide because it is more soluble and dimethyl sulphoxide dissolves more sodium cyanide than other dipolar aprotic solvents.ll1 However suspensions of alkali-metal cyanides in less ionising dipolar aprotic solvents (e.g. dimethylformamide) give good yields.l12 Aromatic nitriles can be prepared in high yield from the bromo-analogue by using cuprous cyanide in dimethylformamidesg or in 1 -methylpyrrolidoneg0 as the source of soluble cyanide ion. 110 Shashoua Sweeny and Tietz J. Amer. Chem. SOC. 1960 82 867. ll1 Friedman and Schechter J.Org. Chem. 1960 25 857. 112 Newman and Otsuka J . Org. Chem. 1958 23 797. 113 Cava Little and Napier J. Amer. Chem. SOC. 1958 80 2260. 114 Smiley and Arnold J . Org. Chem. 1960 25 257. 115 Copelin U.S.P. 2,715,137/1955. 186 QUARTERLY REVIEWS Synthesis of Nitro-compounds RX + NO2- + RNO + X-.-Kornblum and his co-workersll6 found that nitrite ion and 1-iodo-octane in dimethyl- formamide gave 57% yield of 1-nitro-octane after 2.5 hours at room temperature but in ethanol the yield was only 3974 with 5% of iodo- octane still unchanged after 108 hours.11G To their surprise117 phloro- glucinol (a strongly hydrogen-bonding additive) decreased the rate con- siderably and in some cases completely suppressed the reaction. Rates in dimethyl sulphoxide and in nitromethane were similar to those in dimethyl- formamide and are measurable at -2Oo.llG The products are nitro- compounds rather than nitrates.llS Since nitrite ion in dipolar aprotic solvents is a strong base labile hydrogen atoms may be extracted from the reactants as in the following reaction :118 Ph.CH2.NO2 + NO2- -+ -CHPh.N02 + HNO += Ph'C02H t-Butyl compounds give isobutene.llG Lithium nitrite is the most soluble alkali-metal nitrite but sodium nitrite is soluble in dimethyl sulphoxide and is more soluble than potas- sium nitrite in dimethylformamide.Yields in the former are slightly lower than in the latter s01vent.l~~ Some highly explosive nitro- and dinitro-alkanes as well as nitro- ethylene could no doubt be synthesised by nitrite-halide exchange. There seems no reason why the SNAr reactions should not take place readily in dimethyl sulphoxide or dimethylformamide (f) Halogen Exchanges RX + X'- + RX' + X- or ArX + X'- $ ArX' + X- (where X = F C1 Br I SCN or N,).-,S"2 reactions of methyl iodide with fluoride ion are on the average lo7 times faster with chloride ion lo6 times faster with bromide and azide ions 5 x lo4 times faster with iodide ion lo4 times faster and with thiocyanate ion lo2 times faster in dipolar aprotic solvents than in water or For this reason and because of favourable solubility factors halogen exchanges are usually highly successful in dipolar aprotic solvents provided the reaction is favoured thermodynamically.80 Iodide ion is the most solvated halide in dipolar aprotic solvents and is displaced from carbon by all other halides.80 Alkyl iodides are the most reactive alkyl halides in S N 2 reactions and are most susceptible to the change from protic to dipolar aprotic solvent,24 and are thus the best source of alkyl groups for alkylation.116 Kornblum Larson Blackwood Mooberry Oliveto and Graham J. Amer. Chem. SOC. 1956 78 1497. 117 Kornblum and Powers J. Org. Chem. 1957 22 455. 11* Kornblum Blackwood and Powers J. Amer. Chem. SOC. 1957 79 2507. PARKER SOLVATlON OF ANIONS 187 (g) Phthalimide Synthesis.-The Gabriel phthalimide synthesis of phthalic acid derivatives in dimethylformamide has been extensively studied2 since the pioneer work of Sheehan and B01hofer.l~~ The yield of 1 ,4-diphthalimidobutane7 which was used in the preparation of putrescine prepared from 1,4-dichlorobutane was 88 in dimethylformamide (containing potassium carbonate to form potassium phthalimide) 47 % in benzyl alcohol 51 % in ethylene glycol and 22 in xylene.Lower temper- atures could be used with dimethylformamide and the product was readily isolated by pouring the mixture into water.120 (h) Miscellaneous Syntheses.-In dimethylformamide containing potas- sium carbonate 6-mercaptopurine reacts much faster than in aqueous systems with suitable akyl halides; the solvent affords the reactive thio- anion.121 The alkylation occurs at sulphur only in high yield. Under some conditions N-alkylation of the imidazole ring of purines takes place readily in dipolar aprotic solvents.121 Alkyl halides react rapidly and cleanly with the sodium derivative of saccharin in dimethylformamide to give alkyl derivatives of saccharin.122 In protic solvents or solvents of low dielectric constant yields are poor.A variety of alkyl aryl dialkyl and diary1 ethers and sulphides can be synthesised rapidly in high yield in dimethylformamide or dimethyl sulphoxide reaction^,^ RO- + R’I -+ ROR’ and RS- + R’I -+ RSR’. Cellulose esters of excellent quality are produced in dimethylformamide. One reason of several postulated is that this solvent reduces the hydrogen bonding between cellulose chains permitting more rapid diffusion of the reagents to the reaction This conforms with other observations that dimethylformamide is a good hydrogen-acceptor. Dipolar aprotic solvents such as dimethyl-formamide and -acetamide and dimethyl sulphoxide which are good hydrogen-acceptors may have applications in the study of other complex hydrogen-bonded systems.Table 6 contains a by no meansexhaustive survey of anion-dipolereac- tions in dipolar aprotic solvents but it does indicate how solvation energy can be used to assist a variety of reactions. Explanations have rarely been given in the literature for the solvent effects noted and it is hoped that the principles of this Review can be applied to many related bimolecular substitution reactions. The support of a Royal Norwegian Council for Scientific and Industrial Research Fellowship and of an I.C.I. Fellowship are gratefully acknowledged. The author thanks Professors Olav FOSS E. D. Hughes and Sir Christopher Ingold and Dr. C. A. Bunton for reading the manuscript. llS Sheehan and Bolhofer J. Amer. Chem. Soc. 1950 72 2786. lao Vassel U.S.P. 2,757,198/1956. 121 Johnston Holum and Montgomery J. Amer. Chem. SOC. 1958 80 6265. 123 Rice and Pettit J. Arner. Chem. Soc. 1954 76 302. la3 Blume and Swezey TAPPI 1954,37 481.

ISSN:0009-2681    

DOI:10.1039/QR9621600163

出版商:RSC    

年代:1962

数据来源: RSC

摘要:

CYANIDE COMPLEXES OF THE TRANSITION METALS By W. P. GRIFFITH (DEPARTMENT OF CHEMISTRY UNIVERSITY OF CHICAGO CHICAGO 37 ILL. U.S.A.) THE first known co-ordination complex was Prussian Blue prepared in 1704 by the German artist Diesbach who heated animal refuse and sodium carbonate together in an iron p0t.l Subsequent work led to the isolation of potassium ferrocyanide K4 [Fe(CN),] .2 Since then cyanide complexes of most transition metals have been prepared as well as simple cyanides of non-transition metals. The CN- group is capable of stabilising a wide range of stereochemical configurations and metal oxidation states in unsub- stituted cyanide complexes co-ordination numbers from eight to two and oxidation states from (+5) to (0) are known. Bonding Properties of the Cyanide Ion.-The CN- group may be de- scribed in molecular-orbital symbolism as KK(a2s)2(a*2s)2(a2p)2(n2p)4 and may be represented diagrammatically as in Fig.1. Overlap of the (~“2s) n FIG. 1 U orbitals with the nd, (n + l)s and (n + l)p metal orbitals constitutes the normal ligand-metal a-bond and there are vacant (n*2p) orbitals available for receipt of d,-electrons from the metal atom. Alternatively it may be considered that CN- has its a-lone-pairs in sp-hybrids one on the carbon and one on the nitrogen projecting outwards along the C-N axis; one of these pairs would then overlap with the appropriate metal orbitals to give a o-bond. Since nitrogen is more electronegative than carbon it is likely that the (2sC2) pairs will be used for bonding though there is no evidence that all metal cyanide complexes have metal-carbon rather than metal-nitrogen bonds.In most cases X-ray structure deter- minations do not give the required information because the electron densi- ties around carbon and nitrogen are too ~imilar,~ but recent spectroscopic and neutron-diffraction measurements indicate that a metal-carbon bond Anon. “Miscellanea Berolinensia ad Incrementum scientiarum,” Berlin 1710 p. Stahl “Experimentia Observationes Animadversiones CCC numero chymicae et Wells “Structural Inorganic Chemistry,” Oxford Univ. Press 1950. 277. physicae,” Berlin 1731 p. 281. 188 GRIFFITH CYANIDE COMPLEXES OF THE TRANSITION METALS 189 is present in all the compounds s t ~ d i e d ~ and the fact that methylation of complex cyanides gives methyl isocyanides supports this conclusion. The limited amount of structural data available indicates that the M-C-N bond is linear in cyanide c~mplexes.~ However the possibility of bent or side-on bonding cannot be excluded (cf.Fig. 2). In the case of metal RN C M I C M--a N FIG. 2 carbonyl complexes the linear M-C-0 bond is energetically preferable to the side-on form,6 and the same is probably true for the cyanide group since CO and CN- are iso-electronic. Bent M-N-0 bonds are known in a few compounds such as (Me,NCS,),Co(NO) (ref. 7) and may conceivably occur with cyanides CN- and NO+ also being iso-electronic. The bonding characteristics of a ligand are determined largely by its a-donor and 7r-accepting properties and although both are intimately connected and interdependent it is easier for these qualitative purposes to consider the two effects separately.The cyanide ion as a o-bonding 1igand.-Since NO+ CO and CN- are isoelectronic it is interesting to compare their donor strengths. Of the three CN- has the best a-bonding properties which follows from the fact that it is a stronger base than the other two. It is doubtful whether NO+ has any basic character at all but the existence of BH,,CO suggests that CO has some a-donor power. It is significant that the cyanide salts of alkali and alkaline-earth metals are well known whereas the “nitroxyls” M(NO) and “carbonyls” M(CO) have very low chemical stabilities uncertain compositions and unknown structures. Furthermore whereas cyanide complexes are commonly formed by transition metals with oxidation states of (+3) and (+2) analogous compounds are unusual with carbonyl or nitrosyl groups unless suitably efficient a-bonding ligands also participate although Hieber and Kruck5 recently demonstrated the existence of cationic carbonyl complexes such as [Fe”(CO) J2+.The cyanide ion as a rr-bonding 1igand.-One of the consequences of efficient ligand-metal a-bonding is that the donor atom becomes more electropositive and therefore more receptive to “back-donation” from the metal d,-electrons provided of course that suitable orbitals are available on the ligand and such 7r-bonding also relieves the central metal atom of Jones J. Clzem. Phy~. ( a ) 1957,26 1578; (b) 27 468; (c) Curry and Runciman Hieber and Kriick Angew Chem. 1961,73 580. Orgel “Introduction to Transition-metal Chemistry,” Methuen London 1960 Alderman and Owston Nature 1956 178 1071.Acta Cryst. 1959 12 674. p. 138. 190 QUARTERLY REVIEWS some of the negative charge which accumulates on it as a result of a- bonding. Back-donation of metal d,-electrons to the vacant (n*2p)-carbon orbitals on CN- (d,-p,-bonding) undoubtedly occurs in many or all transition-metal cyanide complexes especially those which involve the metal in a low oxidation state. However one would expect CN- to be a poorer acceptor than CO since it carries a negative charge which will produce a lower relative electronegativity. It is interesting that the iso- cyanide group RNC which is iso-electronic with CO and CN- resembles the former rather than the latter in its tendency to stabilise complexes with the metal in a low oxidation state; since there is no formal negative charge on the group the acceptance of metal d,-electrons is facilitated.Evidence for n-Bonding in Cyanide Complexes.-(a) Chemical evidence. Stabilisation of low oxidation states is typical of good n-accepting ligands (CO RNC Ph,P) and there is some evidence in the case of carbonyls at least that their complexes have some metal-ligand multiple-bond character.8 Efficient a-bonding ligands do not normally stabilise low oxidation states unless they can readily accept metal d,-electrons. Thus such groups as OH- and Cl- form no complexes of metals in low oxidation states whereas CN- does so though the compounds that cyanide does form are chemically less stable than the analogous carbonyls presumably because CO is a better n-accepting ligand. (b) Structural evidence.-Values of metal-ligand bond distances do not provide impressive evidence for n-bonding owing to lack of information on the length that the bond would have if it were exclusively a in character.For cyanides the difficulties are increased by the fact that many of the bond distances reported in the literature are of dubious accuracy (e.g. the data of Table 1 show the Co-C bond lengths in K3[Co(CN),J and Cd3[Co(CN)J2 to be 1-89 and 2.05 A respectively but it seems highly unlikely that a change of cation should cause such a change of metal- ligand distance). Values of k,- and k c- (force constants for metal-carbon and carbon- nitrogen bonds) have sometimes been used to assess M-C and C-N bond orders. However unless accurate values are available for the degree and strength of ligand-metal a-bonding this method is not valid and not all force constant values are reliable since in some calculations certain im- portant interactions have been neglected or overlo~ked.~ Nevertheless it is apparent from Table 1 that d10 complexes have lower kM-c and higher kCeN values than those with fewer d-electrons presumably because there is little n-bonding in d10 systems.8 The C-N force constant in simple cyanides is usually higher than in cyanide complexes which may indicate a certain degree of metal-ligand multiple bonding.Carbon-metal a-bonding will tend to increase kCmN by drawing negative charge from the carbon 8 Nyholm Proc. Chem. SOC. 1961,280; Westward and Owen J. 1959,1055; Chantry and Plane J. Chem. Phys. 1961,35 1027. L. H. Jones personal communication. GRIFFITH CYANIDE COMPLEXES OF THE TRANSITION METALS 19 I atom whereas a return of electron density to the carbon by d,-p,-bonding will decrease kC-N and the observed C-N stretching frequency will arise from a combination of these two effects.In complexes of high oxidation state where 0- is more important than n-bonding a high C-N stretching frequency is to be expected and the reverse for low oxidation states; other effects such as the number of d,-electrons on the metal may also influence the frequency. Spectroscopic studies have indicated that unlike the carbonyls metal cyanides of the form [M(CN),]"- have negligible CN-CN bond interaction since the symmetric and the antisymmetric Structural data on cyanide complexes. 2.1 2a 2- 1 3a 1 *92a 1 .994c 1-95' 1.93" 1.97' 1-86' 1-1 5' 1 ~ 1 5 ~ 1.133' 1.30' 1*16e 1.20' 1.18' 1 -22' 1.159 1.1Sh 1.18' 1-15' 1.15' 1-83b 17-Wb Linear Spiral 1 -30b 16.31 Tetrahed.3*42d 1643d Planar ~ 3 . 4 2 ~ ~ 1 6 . 8 3 ~ Planar 3.12d 16.82d Planar Planar Planar Clathrate 2.3 1 j 16.5j Octahed. Octahed. Oc t ahed . 3.34j 14.9j Octahed. 2-79i 1 5 ~ 3 ~ Octahed. 2-43j 15. li Octahed. 1 ~ 9 3 ~ 1 6 ~ 4 2 ~ Octahed. 1.73j 17.0j Dodecahed. 17.5 +0.5" *kM-c and kICC-N are the force constants of the M-C and C-N bonds in dyne/cm. ( a ) Rosenzweig and Cromer Acta Cryst. 1959 17 709 and refs. therein. (b) McCullough Jones and Crosby Spectroschim. Acta 1960 16 424 and refs. (c) "Interatomic Distances," Chem. Soc. Special Publ. No. J 1 and refs. therein. ( d ) Pistorius 2. phys. Chem. (Leipzig) 1960,23 200. ( e ) Monfort Bull. SOC. Sci. Likge 1942,11,567. (.f) Rayner and Powell J. 1952,319.( g ) Curry and Runciman Acta Cryst. 1959 12 674. (h) Ferrari Tani and Magnano Gazzetta 1959 89 2512. ( j ) Nakagawa and Shimanouchi Spectrochim. Acta 1962 18 101. (k) Caglioto Sartori and Furlani Atti Accad. Naz. Lincei Rend. Classe sci. fis. mat. ( I ) Hoard and Nordsieck J. Amer. Chem. SOC. 1939,61,2853. (rn) Leroi and Klemperer J. Chem. Phys. 1961 35 774. therein. nat. 1958,2S 260. 192 QUARTERLY REVIEWS C-N stretching frequencies are fairly close together and there are no significant changes in n-bonding during vibration although this does not necessarily imply that there is less n-bonding in cyanides than in car- b o n y l ~ . ~ * ~ ~ Crystal$eld strength of the cyanide ion.-The position of CN- in the spectrochemical series is (in order of increasing D,) :11 I- < Br- < Cl- < F- < Oxalate < H 2 0 < NH3 < en < NO2- < CN- - CO -NO+ < P(OCH,),CMe and some approximate values of lOD (in crn.-l) are:12 [CO”’(CN)6]3- 33,500 [MnlI1(CN) 6]3- 30,000 [FeI1(CN),l4- 32,500 [CrlI1(CN) 26,700 These values of D are comparable with those for CO in carbonyls but this does not necessarily imply that CN- is as good a n-acceptor as CO.It has recently been shown that alkyl groups which cannot easily form n-bonds also give rise to large D values as apparently do all ligands with carbon as the donor atom.13 The value of D depends not only on the degree of metal-ligand and ligand-metal n-bonding but also on the effect of ligand lone-pairs and electrostatic repulsions.14 The CN- group also shows one of the largest observed trans-effects in the substitution reactions of square-planar platinum(I1) complexes (although the hydride ion may be even more powerful in this respect).13 The Stabilisation of High Oxidation States.-The cyanide group is not noted for its ability to stabilise high oxidation states since ligands which are capable of this (e.g.F- 02- 022-) are usually small and highly electro- negative. The only well-established unsubstituted cyanide complexes with high oxidation states are the eight co-ordinated dl- and d2-compounds of Re(vI) Re(v) Mo(v) Mo(Iv) W(v) and W(rv) and the stability of the compounds is likely to be due to the special stereochemical arrangement of the ligands around the metal atom. Apart from these cases there are two others to be considered namely [MnIV(CN),]*- and [VIV(CN)J2- neither of which has been satisfactorily characterised.14 It seems probable that the vanadium complex contains some hydroxyl groups and it is exceedingly unlikely that manganese(1v) would be eight co-ordinated.There are also a number of substituted cyanides which involve the metal atom in an unusually high oxidation state but in all cases the other ligands present are good a-bonding groups. Known oxide cyanides are [OSV~O,(CN),]~- lo Jones “Advances in Co-ordination Chemistry,” Macmillan New York 1961 p. 310; Gaufrb Compt. rend. 1960,251,2001 ; Nakagawa and Shimanouchi Spectrochim. Acta 1962 18 101. l1 Verkade and Piper ref. 12 p. 634; Tsuchida Bull Chem. SOC. Japan 1938 13 388 436 471; Schaffer and Jorgensen J. Inorg. Nuclear Chem. 1958 8 143; Orge1,J. Chem. Phys. 1955,23 1004. l2 J. S. Griffith “Theory of Transition Metal Ions,” Cambridge Univ.Press 1961 p. 310. l3 Chatt and Hayter J. 1961 2605. l4 Dunn “Modern Co-ordmation Chemistry,” ed. Lewis and Wilkins Interscience Publ. Inc. New York 1960 p. 267. GRIFFITH CYANIDE COMPLEXES OF THE TRANSITION M E T ~ S 193 and [ReVO2(CN),l3- which may exist in solution as the eight co- ordinated species [ReV(OH),(CN),I3- and there are peroxide cyanides of cobalt(II1) and chromium(1v) (see below). A number of vanadyl cyanides have been reported,l4#l5 and have been formulated as [VIvO(CN)4]2- [VlVO(CN),]3- and [V1vO(CN)6]4-; as written these involve vanadium(1v) in some curious stereochemical arrangements but they have not been prop- erly characterised and may well be hydroxide complexes of vanadium(1v) or vanadium(II1). Platinum(1v) halide cyanides [Pt1VX2(CN),l2- are known but the only evidence for the existence of [ Pt1v(CN),l2- is polaro- graphic based on observations of the reduction of platinum(1v) in cyanide media.l6 The Stabilisation of Low Oxidation States.-Unsubstituted cyanide complexes which involve the metal atom in an abnormally low oxidation state are listed in Table 2. It has already been mentioned that the reluctance of CN- to form strong n-bonds is reflected in the comparatively instability of its complexes with metals in low oxidation states. It is noteworthy that cyanide nitrosyls and carbonyls of nickel(r) and nickel(0) are more stable than the corresponding unsubstituted cyanides presumably because they carry lower external charges and because CO and NO+ are better 7-accep- tors than CN- and drain off negative charge from the nickel atom more efficiently.Because of their extreme instability the structures of none of these complexes have been studied by diffraction methods. The degree of metal- ligand multiple bonding would presumably be higher for complexes of low oxidation state and there is some qualitative evidence for this in the case of [NiO(CN),]*- which has an infrared C-N stretching frequency at 1985 cm.-I as compared with 2127 cm.-l for [NiI1(CN),I2- implying a lower C-N bond order and consequently a higher degree of bond multiplicity in the nickel(0) c0mp1ex.l~ As is the case with the carbonyls cyanide complexes of metals in a low oxidation state are diamagnetic and most of them obey the inert-gas rule. Stereochemistry of Cyanide Complexes.-(a) lo- 9- and 8-Co-ordina- tion.Ten-co-ordinate complexes of unknown structure of the form [MoIv(OH) (CN),R2I4- (where R = H20 NH3 or N2H4) have been reported,18 but little evidence in support of this very unusual co-ordination number has been presented; recently it has been suggested that [ PtvIII(CO),F,] is also of this form.19 Nine-co-ordinated rhenium(vr1) has l5 Yakimach Compt. rend. 1930,190,681 ; 191,789; Rivenq Bull. SOC. chim. France 1947 971; Barbieri and Parisi Ber. 1927 60 2415; Brintzinger and Jahn 2. anorg. Chem. 1938,235,244. l6 Rius and Molera Anales real SOC. espafi. Fiz. Quim. 1949,45 B 1151. l7 El-Sayed and Sheline J. Amer. Chem. SOC. 1958 80 2047; Nyholm Chem. Rev. 1953,53 303. l* Jakob and Jakob Rocznicki Chem. 1952,26 492. l@ Sharp Proc. Chem. SOC. 1960 317. 194 QUARTERLY REVIEWS been suggested20 for [ReV"(OH)(CN),]2- but since there are no d,-elec- trons available in rhenium(vI1) this seems unlikely.TABLE 2. Cyanide complexes of unusually low oxidation states d10 d9 d8 d7 Complex [ Pt0(CN) p- ; [Pd0(CN),l4- ; [Nio(CN) 34- mir( CN)4]3- [Nii2(cN)6 14- Co-ordn. Structure Iso-electronic number carbonyl of metal 4 Tetrahedral "i0(co)4 1 4 Tetrahedral* 4 Planar with metal- metal bond 5 Square pyrimidal [Coo2(C0),] with metal-metal bond 4 Square planar* [Feo(CO),] 6 Octahedral with [Mno2(CO),,] metal-metal bond 6 Octahedral [cro(co)6 1 6 Octahedral [vo(c0),1 * Structure uncertain. t Existence of complex as formulated uncertain. Apart from the doubtful case of [Mn1V(CN),]4- mentioned above all the known eight-co-ordinated complexes involve metal atoms with one or two d-electrons and are usually confined to transition elements of the second and the third row though recently some eight-co-ordinated titanium complexes have been reported.Two arrangements are favoured for this co-ordination number the antiprism and the dodecahedron and in both cases the crystal-field forces would lead to the stabilisation of one d-orbital over the other four (the dzz in the case of the square antiprism and the dZy in the case of dodecahedron).21 The tendency of dl- and d2- complexes to adopt eight-co-ordination is therefore understandable. Only one cyanide complex with this co-ordination number has been studied by X-ray diffraction and from this it appears that K,[Mo(CN),] has a dodecahedral c~nfiguration,~~ although it would be expected that the antiprismatic structure might be more stable.* OrgeP has explained the favouring of the dodecahedron for [Mo(CN),*- on the grounds that the d,,-orbital has the correct symmetry for metal-carbon rr-bonding whereas the &orbital would provide poor back-bonding facilities.On this basis four of the ligands would be in a better position to form n-bonds by * The view that the antiprismatic arrangement is inherently moxe stable than the dodecahedral has been proposed by Gillespieal and challenged by Hoard et ~ 1 2 . ~ ~ 2o Colton Dalziel Peacock and Wilkinson J. 1960 1374. 21 Orgel J. Znorg. Nuclear Chem. 1960 14 136; Gillespie ref. 10 p. 34; Canad. J. Chem. 1961,39,2336. aa Hoard Glen and Silverton J. Amer. Chem. SOC. 1961 83 4293. 23 Hoard and Nordsieck J. Amer. Chem. SOC.1939,61,2853. GRIFFITH CYANIDE COMPLEXES OF THE TRANSITION METALS 195 receiving &.,-electrons from the metal than the other four so it would be expected that four of the cyanide groups would be less strongly held to the metal atom and could be replaced by four non-n-bonding ligands (R) to give [M(CN),R,]”-. This is in the formation of such complexes as [MoIV(CN),(OH),]~- although complexes with five cyanide groups also e x i ~ t ~ ~ ~ ~ such as [Mo1V(CN),(OH),l4. However a recent Raman spectro- scopic study of the [Mo1v(CN),J4- ion indicates that the structure in solution is that of an Archimedean antipri~m,~~ in which case the possibili- ties of metal-ligand n-bonding would seem to be greatly reduced if the dz2 were to be the only metal d,,-orbital available. The very unstable compound Ti(CN)3,5KCN may be either K [Tixn(CN),] or K3 [Ti111(CN)6],2KCN;26 and although the dodecahedra1 configuration is known for some titanium the absorption spectra in this case favour a hexaco-ordinated configuration,26 though it is not clear how the two molecules of potassium cyanide are attached to the complex.(b) 7- 6- and 5-Co-ordination. No heptaco-ordinated cyanide com- plexes have been definitely established. The black compound K4 [Mo(CN),] H20 contains molybdenum(rIr)28 and has an unpaired electron per molybdenum atom,29 so that it may be [MoIII(CN),]~- or [MolI1(CN) (H20)]*-. On the basis of the “nine-orbital rule” heptaco-ordination may be expected for technetium(1v) or molybdenum(II1) (both have three d-electron~),~~ and a technetium(1v) cyanide has been shown to exist in the presence of an excess of cyanide ion perhaps as [TcrV(CN),l2- or as [Tc1v(CN),l3- ;31 and recently [TcIv(CN),(OH),I3- has been The vanadyl complex [vIvO(cN)6] 4- has already been mentioned.The formation of a heptaco-ordinated intermediate during reaction of CN- with [Mn111(CN)6]3- has been proposed with a water molecule occupying the seventh co-ordination Hexaco-ordination is the commonest stereochemical arrangement in cyanides and will not be considered separately here. There is little evidence for the existence of pentaco-ordinated cyanides in the solid state; most of the complexes alleged to have this structure exist only in solution where they probably take up a solvent molecule as the sixth ligand. K [Mo’V(CN),] has been briefly reported but incompletely character- i ~ e d ~ ~ and the same is true of [VIVO(CN)4]2-.15a The species [Co1*(CN),l3- and [NiI1(CN),I3- have been reported to exist in solution; the former is 24 Bertoluzza Carassiti and Marinangeli Ann.Chim. (Italy) 1960,50,806. 25 Stammreich and Sala 2. Elektruchem. 1960 64 741. 26 Schlaffer and Gotz 2. anorg. Chem. 1951 309 105. 27 Clark Lewis Nyholm Pauling and Robertson Nature 1961 192 222. 28 Young J. Amer. Chem. SOC. 1932 54 1402. 29 Lewis Nyholm and Smith J. 1961,4590. 30 Nigam Nyholm and Stiddard J. 1960 1806. 31 Colton Dalziel Grfith and Wikinson J. 1960 71. 32 Herr and Schwochau Angew. Chem. 1961,73,492. 33 Adamson Welker and Wright J. Amer. Chem. SOC. 1951 73 4789; Basolo and 34 Steele Austral. J. Chew. 1957 10 404. Pearson “Mechanisms of Inorganic Reactions,” Wiley New York 1958 p.114. 196 QUARTERLY REVIEWS probably [COII(CN),(H,O)]~-,~~ and the latter may be [NiII(CN) (H,0)]3-,36 though [Nir1(CN),I4- has also been ~uggested.~’ Recently,36 the formation constants of [Ni(CN),(H,0)I3- and [Ni(CN)6]4- have been measured for solutions of [Ni(CN),I2- in excess of cyanide ion and evidence has also been obtained for the existence of [Ni(CN),C1I4-. A cupric cyanide complex [CuI1(CN),(HCN)l3- has been reported to exist in solution :38 a more reasonable formulation would be [CUII(CN),]~- or [Cu1I(CN),(H,0)l3-. It is possible that pentaco-ordinated intermediates are formed during the exchange of CN- and the tetracyano-complexes of nickel palladium and platinum.39 (c) 4- 3- and 2-Co-ordination. Both planar and tetrahedral cyano- complexes are known confined to metal ions having eight nine or ten d-electrons.The complexes [Cu1(CN),I2- and [Agr(CN),l2- are probably tetrahedral with a water molecule occupying the fourth co-ordination position. The only established trico-ordinate cyanide is [Cul(CN),]- which has a curious polymeric spiral structure with a C-Cu-C angle of 134” and linear C-Cu-N bridging such that each copper atom is linked to three other Silver(i) and gold(i) which have filled d10 shells form the linear two co-ordinated complexes [Ag(CN),]- and [Au(CN),]-. The tendency of these ions to form such complexes is favoured according to Orge1,6,41 by the fact that the d-s separation is small such that the two electrons which in a d10 ion normally occupy the dz2 orbital occupy in these cases a d-s hybrid orbital which leads to the formation of strong bonds along the z-axis.A somewhat different interpretation has been given by Nyholm.* Stabilities of Cyanide Complexes.-Very few facts are available on the stabilities of cyanide complexes and they are certainly insufficient to justify general conclusions. Bjerrum4 has calculated some free energies of complex formation (relative to the values for the corresponding aquo- complexes) computed from mean complexity constants and thus demon- strated that most cyanide complexes have a metal-ligand affinity greater than those of aquo- ammino- or halogeno-complexes. Chemically the most stable cyanide complexes are those of Mn(IiI) Fe(m) Fe(II) CO(III) Ni(Ir) CU(I) Mo(Iv) Ru(II) Rh(IrI) Pd(rI) Ag(r) W(IV) Re(vr) Re(v) 35 Adamson J. Amer. Chem. SOC. 1951 73 5110; Griffith and Wilkinson J.1959 2757. 36 McCullough Penneman and Jones J. Inorg. Nuclear Chem. 1960 13 286; Penneman and Jones Abstracts of Papers read at the 141st ACS Meeting American Chemical Society Washington 1962; Penneman personal communication. 37 Kisova and Cuprova Chem. Listy 1958,52 1422; Blackie and Gold J. 1959,4033. 38 Glasner and Asher J. 1959 3296. 39 Grinberg and Nikol’skaya Zhur. priklad. Khim. 1951 24 893. 41 $-gel J. 1958 4186; Orgel and Dunitz “Advances in Inorganic Nuclear Chem- 42 Bjerrum Chem. Rev. 1950 46 381. Cromer J. Phys. Chem. 1957,61 1388; Lindquist Acta Cryst. 1957 10 29. istry ed. Emelkus and Sharpe Academic Press New York 1960 Vol. 11 p. 1. GRIFFITH CYANIDE COMPLEXES OF THE TRANSITION METALS 197 OS(II) Ir(m) Pt(Ir) AU(III) and Au(I) ; Ta(rIr) Ti(Irr) V(II) V(III) Cr(Ir) (Cr(rrI) Mn(II) and Co(rr) have markedly lower chemical stabilities.(There are no known cyanide complexes of zirconium hafnium or niobium.) The former group resembles Chatt’s “group b” of transition metals namely those which are most likely to co-ordinate with carbon their “class b” character depending on the availability of lower d-orbitals for 77-bonding with the ligand. Standard oxidation potentials have been determined for a few cyanide systems (see Table 3). It will be seen that in general the most stable complexes are those in which there is the highest degree of spin-pairing the diamagnetic d6-state being the most favoured. Replacement Reactions.-Since cyanide complexes are anionic the difficulty of outer-sphere association between reacting species in the study of replacements is avoidable and it becomes possible to distinguish SN2 and SNI mechanism^.^^ Little work has been done on cyanide systems how- ever and there is room for much more investigation in this field especially TABLE 3.Standard electrode potentials for cyanide systems. Couple E” (v) Couple E” (v) [MO(CN),]4-/[MO(CN),]3- -0.73 [RU(CN)6I4-/[RU(CN)6I3- -0*89* [W(CN) i4-/ [W(CN)8 i3- -0.57 [OS(CN),]4-/[OS(CN),]3- -0.99” [Mn(CN)6]5-/ [Mn(cN),l4- + 0.70 [Cr(CN),I4-/ [Cr(CN)6I3- - 1.28 [Mn(CN),I4-/ [Mn(CN),I3- + 0.22 [Ni2(CN),I4-/ [Ni(CN),I2- +0*8 [Fe(CN),I4-/ [Fe(cN),l3- -0.36 Co(I1) to Co(II1) (in excess of co-) - 0.8 * Estimated from polarographic data. Other values from Latimer’s “Oxidation Potentials,” Prentice-Hall New York 1952. with the pentacyano-iron(I1) and -iron(III) systems.It has been shown that the replacement of water in [Co(CN),(H20)I2- by various ligands such as N3- SCN- and Br- follows a SNl mechanism with [COI~I(CN)~]~- as intermediate.43 A curious reaction between ferrocyanide and nitrite ion has been reported44 in which nitroprusside is formed [Fe(CN),I4- + NO,- + H,O -+ [Fe(CN),N0I2- + CN- + 2OH- The rate is increased by the addition of mercuric ion. Studies have also been made on the rate of exchange of CN- with cyanides [M(CN),]“- where M is vanadium chromium manganese iron and cobalt and orders of lability have been Photochemical Reactions.-It is to be expected that irradiation of solu- tions of complex ions with light of frequency corresponding to the region of 43 Grassi Haim and Wilmarth ref. 10 p. 276.44 Schwarzkopf Abh. Deutsch. naturmed. Vereins Bohmen Lotos 1911 3 1. 45 MacDiarmid and Hall J. Amer. Chem. Soc. 1954,76 4222; Basolo and Pearson “Mechanisms of Inorganic Reactions,” Wiley New York 1958 p. 113. 198 QUARTERLY REVIEWS charge-transfer spectra may cause oxidation-reduction reactions and that irradiation with light of the same frequency as the d-d-transitions of com- plex ions may induce replacements. It has been observed that photolysis of the hexacyanides of manganese(m) iron(Irr) chromium(rrr) and cobalt(rr1) results in the formation of cyanogen and reduced forms of the com- plexes and that this occurs most easily in the sequence Mn > Fe > Cr > C O . ~ ~ Irradiation of ferrocyanide solutions and of solutions of [Mo(CN),I4- leads to aquated p r o d u ~ t s .~ ~ ~ ~ The action of light on [FeI1(CN),N0l2- (nitroprusside) is to result in the formation of the paramagnetic species [ Fe11(CN),N0l3-. Specific Cyanide Systems.-(a) Titanium vanadium and chromium groups. In general there are either no cyanide complexes of transition elements of the left-hand side of the Periodic Table or they are chemically unstable. No cyanide complex has been reported for zirconium hafnium or niobium. An unstable titanium(1Ir) complex exists,26 and there is a report of a tantalum(Ir1) cyanide which was not isolated from ~ 0 1 u t i o n . ~ ~ ~ Vanadium(rv) cyanides have been discussed above. The complexes of mnadium(rrI) vanadium(II) chromium(rr1) and chromium(rr) are not markedly stable the lower oxidation states being very sensitive to aerial oxidation while the tervalent compounds are prone to hydrolysis in aqueous solution (they are also light-sensitive).The reason for the instability of the cyanides of this group is presumably that there are insufficient d,-electrons for back- donation to the ligand and hence for stabilisation of the complex except in the case of the eight-co-ordinate molybdenum and tungsten com- pounds. The complex [Cr0(CN),ls- isoelectronic with [Cr*(CO),] and (MnI (CN),I5- has recently been (b) Manganese group. Manganese forms hexaco-ordinated univalent bivalent and tervalent cyanides. The comparative stability of [Mn1(CN),l5- is accounted for by the fact that it has the maximum stabilisation from metal-ligand back-donation having an inert-gas configuration. A man- ganese(0) cyanide has also been but the existence of such a compound with six cyanide ligands seems unlikely in view of the fact that it would be paramagnetic and require the promotion of a metal electron to an anti-bonding orbital.Technetium is represented by the complex ~CIV(OH),(CN),]~- alone.32 Rhenium cyanide complexes are unique in that they adopt either hexa- or octa-co-ordination in a wide range of oxidation states. Both 46 Schwartz and Weiss Ber. 1925 58 746; Schwartz and Tede Ber. 1927 60 69. 47 Baudisch Ber. 1929 62 By 2706; Ilimori 2. anorg. Chem. 1927,. 167 157; Kenney Flynn and Gallin J. Inorg. Nuclear Chem. 1961 20 75; MacDiarmid and Hall J. Amer. Chem. SOC. 1953 75 5204; Adamson and Sporee ibid. 1958,80 3865; Asperger Trans. Faraday SOC. 1952,48,617. 48 Baudisch Science 1948 108 443 ; Jakob Sanotus-Kosinska and Stasicka Roczniki Chem.1962 36 165. 49 ( a ) Ruff and Thomas Ber. 1922 55 1466; (b) Heintz J. Inorg. Nuclear Chem. 1961 21 262; (c) Christensen Kleinberg and Davidson J. Amer. Chem. SOC. 1953 75 2495. GRlFFlTH CYANIDE COMPLEXES OF THE TRANSITION METALS 199 [Rev' (CN),12- and [ReV(CN),I3- have been described as well as the possible [ReV11(CN),(OH)]2- (which may be nine-co-ordinated) ;20 and octahedral [ReVO2(CN),I3- [RetVO2(CN),I4- [Re(CN)6]3-,t1t [Re"(CN)6I4- and [Re1(CN)6]5- have recently been reported.50 It will be seen that rhenium adopts eight-co-ordination when it has one or two d-electrons and hexaco-ordination when it has more than two. Conductometric and E.M.F. measurements have indicated the existence of mono- and bi-nuclear complexes with the oxidation state of the rhenium varying from (c) Iron group.Iron forms the familiar ferri- and ferro-cyanides [Fe"'(CN)6]3- and [Fe"(cN),l4- and there is a report that electrolytic reduction of these in aqueous solution gives a Fe(1) complex.52 The stability of the ds- is higher than that of the d5-configuration in the cases of ruthenium and osmium [RU~~~(CN),]~- exists as a very unstable species in solution,53 and there is polarographic evidence5 only for the existence of (d) Cobalt group. The cobalticyanides rhodicyanides and iridicyanides [M(CN),I3- are all very stable having six d-electrons and inert-gas con- figurations. The bivalent cyanides would require promotion of an electron to an anti-bonding orbital if they are to have octahedral (spin- pared) co-ordination. The cobaltocyanide ion formerly formulated as [COII(CN),]~- is now known to be [CoI1(CN),l3- and is diamagnetic in the solid state which supports its formulation as [CO$(CN),,]~-.~~ Measurements of the infrared-active C-N stretching vibrations indicate that the complex may have a structure analagous to that of manganese carbonyl with which it is formally iso-electronic :55 (+5) to [os1'1(cN)6]3-.FIG. 3. The D4h structure for [Co,(CN),,,] 6-. A staggered D,,-configuration is probably more likely than a D,, one since repulsions would be minimised in the former. There is a report56 of 50 Sen Science and Culture 1960 26 139 Clauss and Lissner Z. anorg. Chem. 1948,297,300; Walter Kleinberg and Griswold Znorg. Chem. 1962 1 10. 51 Meier and Treadwell Helv. Chim. Acta 1955,38 1679; Meier Dim. Eidg. Techn. Hochschule Zurich 1955 No.2461; Klemm and Frischmuth 2. anorg Chem. 1937 230,209. 55. Treadwell and Huber Helv. Chim. Acta 1943 26 10. 53 Krauss and Schrader 2. anorg. Chem. 1928 173 65; De Ford and Davidson J. Amer. Chem. Soc. 1951,73,1469. 54 Meites J. Amer. Chem. SOC. 1957 79 4631. 65 Griffith and Wilkinson J. Inorg. Nuclear Chem. 1958 7 295. 56 Nartius AmZen 1961,117 357. 200 QUARTERLY REVIEWS the existence of [Ir11(CN)6]4- but by analogy with the cobalt case and the rarity of iridium(1r) complexes it is unlikely to exist or would at least not have the formulation above. Polarographic evidence for the existence of a rhodiurn(I1) cyanide complex57 has recently been re-interpreted, as indicat- ing the existence of rhodium(1) in the compound. In aqueous solution [CoI1(CN),l3- absorbs hydrogen to give a cobalt(1) species which may be [COI(CN),H]~-,~~ and takes up acetylene to give a curious binuclear species formulateds0 as [CO,II~(CN),,(C,H,>]~-.It also absorbs carbon monoxide nitric oxide and oxygen. Aqueous solutions of [CoI1(CN),l3- compounds slowly reduce water to hydrogen in concentrated solution while in more dilute solutions they disproportionate to cobalt(1) species possibly [Co1(CN),H)I3- and a cobalt(rr1) complex.59 There have also been re- portss1 of cobalt(I1) tetracyanides either [CoI1(CN),I2- or [CoII(CN) (H2O)3Cl2-. A cobalt@ complex formulated as [COI(CN),]~- has been isolated,62 and other cobalt@) cyanides have been reported.63 Reduction of aqueous solutions of cobalt(m) and cobalt(1i) cyanides has been shown to give a hydride species probably [Co1(CN),Hl3- (see below) and similar hydrides of univalent species are apparently formed by rhodium and iridium cyanide^.^ The chemistry of the cobalt cyanides especially those with cobalt in the lower oxidation states is still obscure and needs considerable further investigation.The cobalt(0) complex [Co ,(CN),]*- and its rhodium ano1gue5* have been reported. Infrared studies of the C-N stretching frequency region indicate that the structure is probably that of Fig. 4 with a metal-metal bond. There is no evidence of CN bridging groups and so though the complex is formally iso-electronic with cobalt carbonyl [co~(co)8] it does not have the same FIG. 4. Suggested structure for [Co,(CN),] 8-. 57 Willis J. Amer. Chem. Sue. 1944 66 1067. 58 Griffith and Wilkinson J. 1959 2757.59 Iguchi J. Chem. SOC. Japan 1952 63 634 1752; Winfield Austral. J. Sci. Res. 1951 A? 4 385; Kelso? King and Winfield J. Amer. Chem. Sue. 1961 83 3366. 6o Grfith and Wilkinson J. 1959 1629. 61 Muller and Schluttig 2. anurg. Chem. 1924 134 327; CrCmoux and Mondain- Monval Bull. Sue. chim. France 1949,700. 62 Watt Hall Choppin and Gentile J. Amer. Chem. Suc. 1954 76 373; Watt and Thompson J. Inurg. Nuclear Chem. 1959,9 31 1. 63 Grube 2. Elektrochem. 1926 32 561; Maki and Tsuchida Bull. Chem. Suc. Japan 1960,34,891. (e) Nickel group. Nickel palladium and platinum(I1) complexes of the form [MI1(CN),l2- all planar and diamagnetic are among the most stable of cyanide complexes. In the presence of an excess of cyanide ion [Ni1I(CN),l2- increases its co-ordination number to five or six by forma- tion of the aquo-complex [Ni1r(CN),(H,0),_.]("-2)- (see above); however no such complex is formed by platinum or palladium(I1) cyanide.64 No nickel(II1) or nickel(1v) cyanide is known but platinum forms halide cyanides of the form [PtIV(CN),X2I2-.The so-called platinum(Ii1) cyanide [Pt(CN),]- is now believed65 to have the structure [Pt1v(CN)4,Pt11(CN)4] '-. There is no convincing evidence for the existence of a palladium(1) or platinum(1) cyanide ; and it appears that the strongly reducing solutions obtained by reduction of the bivalent-metal cyanides obtained by Manchot et aL6 probably contain a hydride cyanide complex (see below). Uni- valent nickel cyanides are however known; [NiI(CN)4] 3- has been reported and may have either a tetrahedral or a planar structure67 (the planar form is the more probable being favoured by dg-complexess) ; and Bellucci's salt originally formulated as K,[NiI(CN),] was recently shown68 to be dimeric and diamagnetic.Studies of the infrared C-N stretching frequen- cies indicate that there may be a "half-bridged" structure presumably involving some sort of three-centre molecular orbitals (111)69 or a metal- bonded structure (IV) (D2d or D2J similar to that proposed for the cobalt(@ cyanide complex.55 A third possibility (V) is that of a bridged sfructure,68 but this seems unlikely in view of the spectroscopic evidence. FIG. 5. Suggested structures for [Ni,(CN),] ,-. In all cases there would be planar co-ordination around the nickel atoms. The complex reacts with nitric oxide to give a compound [NiO(CN),NO] and with carbon monoxide to give the dimeric complex [Ni12(cN)6(CO)2] 4- and absorbs acetylene though the composition of this product is un- known.,O 64 Reddy Thesis London 1961.65 Terry J. 1928 202. *6 Manchot and Schmid Ber. 1931 64 2672; Manchot and Lehman Ber. 1930 67 Nast and Krakkay Z. Naturforsch. 1954,9b 798. 68 Bellucci Gazzetta 1919,49 TI 70; Nast and Krakkay 2. Naturforsch. 1957 12b 63 2775. 122; Pfab and Nast,Z. Krist. 1959,111,4. El-Sayed and Sheline J. Amer. Chem. Soc. 1956,78,702. 202 QUARTERLY REVIEWS Zerovalent complexes of nickel palladium and platinum of the form [MO(CN),]*- are known and they presumably have a tetrahedral structure. However it has recently been questioned whether any platinum(0) complex at all exists since certain “zerovalent” phosphine complexes of platinum are in fact dihydrides of platinum(~r),~~ though this is apparently not the case for all phosphine complexes of pl&in~m(O).~~ It has been observed that reduced solutions of platinum and palladium(1r) cyanides contain hydride atoms bonded to the metal atom so these solutions may contain the ion [PtII(CN)4H2]4-.58 Whether or not these species are identical with the previously reported ions [Pt0(CN),l4- and [Pd0(CN),l4- is not clear but there seems no doubt that [Ni0(CN),l4- does not contain hydride atoms.(f) Copper group. The most stable cyanides in this group are the univalent [M1(CN),]s-l series where M is copper silver or gold and x is 2-4. Gold(rr1) cyanides [AuIII(CN),]- are also known but there is no evidence for the existence of copper(r1r) or silver(r1r) analogues.Although no silver(I1) or gold(r1) cyanide complexes have been reported there seems to be no doubt that copper(r1) cyanides exist. The reaction in aqueous solution between cupric ion and cyanide ion gives cyanogen and cuprocyanide [E” for the Cu2+ + 3CN- = [Cu(CN),]- + 4(CN) is + 1.3 v). Addition of cupric to cyanide ion gives a transient purple colour attributed38 to a material [CuI1(CN),,HCNI2- and addition of cupric ion to a methanolic cyanide solution at -70” gives an intense purple colour without precipitation of cuprocyanide this colour persists until the temperature is raised.73 On the basis of viscosity and cryoscopic determinations Molis and Izaguirre7* claim to have detected the presence of { CuI~[Cu~I(CN),] j2- ions in cyanide-cupric ion mixtures and [Cun(CN)J2- has been suggested as an intermediate in certain reactions.75 There is an early report of the preparation of a compound [CUII(CN)C~],~~ and of mixed copperlrr) cyanide arnmine~.~’ It seems likely that copper(r1) cyanide complexes might be stabilised by the participation in the co- ordination sphere of good a-bonding ligands such as F- C1- or OH-.* Substituted Cyanide Complexes.-Many substituted cyanides are known most of them of the form [M(CN),X]”- where M is iron(m) iron@) * Recently evidence has been obtained for the existence of a copper nitrosyl cyanide complex [Cu(NO)(CN),] (possibly associated with solvent molecules) derived from the cupri-cyanide ion (R.T. Frazer and M. Mercer personal communication). 70 Chapoorian Lewis and Nyholm Nature 1961 190 528. 72 Latimer “Oxidation Potentials,” 2nd edn.Prentice -Hall New York 1952 p. 186. 78 D. F. Evans personal communication. 74 Molis and Izaguirre Anales real Soc. espan’. Fiz. Quirn. 1921 19 33. 76 Tanaka Kamada and Murayama Bull. Chem. SOC. Japan 1958,31 895. 76 Rabaut Bull. Soc. chim. France 1898,19,786. 77 Treadwell and Girsewald 2. anorg. Chem. 1904,39 87. Chatt and Rowe Nature 1961 191 1191. GRIFFITH CYANIDE COMPLEXES OF THE TRANSITION METALS 203 cobalt(m) or cobalt@) and where X may be one of a wide range of neutral or charged ligands. The known carbonyl cyanides and nitrosyl cyanides are summarised in Table 4. Carbonyl cyanides involving the central metal atom in a (+3) or (+2) state are uncommon an ion [FeII(CN),COl3- is known but not the iso-electronic [CO~~I(CN),CO]~- or [Mn1(CN),COl4- { the cobalt carbonyl cyanide [COIII(CN),CO]~- recorded in the literat~re'~ has been shown to consist of a mixture of [Co-I(CO),]- and [Co1II(CN),J3- A rhenium complex [ReII(CN),C0l3- has been reportedso and would be of particular interest if this formulation were correct since it would be the only known paramagnetic carbonyl cyanide.A number of carbonyl cyanides of metals. in a low oxidation state are known including [Nir,(CN),(C0),I4- which though it is iso-electronic with cobalt carbonyl [ c o o ~ ( c o ) ~ ] has apparently no bridging carbonyl groupE1 (this view has been disputedE2). The structure (VI) in Fig. 6 (C2h) is favoured for this complex and is analogous to that of [CO,(CN),]~- (Fig. 4). Structure (VII) is also a possibility. The complex [COI(CN),CO]~- is apparently planar5E and may be an analogue of the postulated but unknown planar [Feo(C0),].83 FIG 6.Suggested structures for [Ni,(CN),(CO),] 4-. Octahedrally co-ordinated nitrosyl cyanides are particularly stable and most of them have inert-gas configurations although the formal oxidation state may be very low since normally the nitric oxide donates three electrons to the metal atom.E4 That in most cases nitric oxide does co-ordinate as the nitrosonium (NO+) ion has been shown by magnetochemical spectroscopic and-in one caseE5-paramagnetic resonance measurements. However in the ion [COIIICN),NO]~- the ligand may be bonded as an NO- group or attached Manchot and Gall Ber. 1926 59 1056. Hieber and Bartenstein 2. anorg. Chem. 1954,276 12. 8o Bandopadhyay Science and Culture 1959 25 278. *l Griffith Cotton and Wilkinson J.Inorg. Nuclear Chem. 1959,10,23. 82 Nast and Kasperl Chem. Ber. 1959 92 2135. 83 Orgel Chem. SOC. Special Publ. 1959 No. 13 p. 93. Irving Lewis and Wilkinson J. Inorg. Nuclear Chem. 1958,7 32. 85 Bernal and Harrison J. Chem. Phys. 1961,34 102; Naiman ibid. 1961,35 1503. 204 QUARTERLY REVIEWS TABLE 4. Nitrosyl and carbonyl cyanide complexes. Complex Structure d10 [Ni0(CN),NOl2-; [Nio(CN)r(CO)2]2- d9 [CO~,(CN),(CO),]~-; [CO~,(CN),(CO)]~-; d8 [Cor(CN),(CO)I2-; [CoI(CN),(CO),]- d [ V-I( CN),NO I,-; [Cr o(CN)5NO]4- [Mnr(CN),NOI3-; [Fer1(CN),NOI2-; [Fe”( CN),CO 13- [CoTrr(CN),NOI3-; [Ferr(CN),NOI4-; [Ferr(CN),NO 13- d5 [Mnr1(CN),NOI2-; [Rer1(CN),NOl2-; [Cr1(CN),NOI3-; [Rer1(CN),COI3- d4 [Re1rr(CN),NO]3-; [MO~~(CN),(NO)(OH),]~- ICr”(CN),NO 12- [CO-’( CN)( C0)2( NO)]- ; [Co-’(CN)( CO) 12- “ir2(CN)6(CO)2 14- Tetrahedral Tetrahedral Square-based pyramidal* Planar Octahedral Octahedral Octahedral? Octahedral 1 Octahedral Dodecahedra1 Octahedral * Structure uncertain.t NO bonded as NO- or through oxygen. 2 NO bonded as a neutral ligand. through the oxygen atom,86 and the same may be true of the incompletely characterised material [Fe(CN),N0]4-.87 In the case of the curious paramagnetic complex [FeI1(CN),N0l3- magnetic measurements and chemical reactions indicate that the single unpaired electron may be localised on the nitrogen rather than on the iron atom,88 B a u d i s ~ h ~ ~ reports that photolysis of nitroprusside [FeI*(CN),NOl2- gives this complex; if this is so the series of complexes [FeI1(CN),N0l2- [Fe“(CN),N0I3- and [Fe11(CN),N0l4- may be considered to differ in external charge simply because the nitric oxide co-ordinates respectively as NO+ NO- (radical) and NO- (or ON).It is interesting that in the similar series [Cr0(CN),N0l4- [Cr1(CN),N0I3- and [CrI1(CN),N0l2- magnetic and spectrochemical measurements indicate that the nitric oxide co-ordinates as NO+ in all three cases while the oxidation state of the chromium atom changes.9o There are two eight-co-ordinated nitrosyl cyanide complexes known namely [Mo~~(CN),NO(OH),]~- and [ReII1(CN),N0l3- which have d4-configurations and are d i a m a g n e t i ~ . ~ ~ ~ ~ It seems likely that there should exist a series of nitrosyl cyanides analagous to the carbonyl nitrosyl complexes [Co(CO),NO] [Fe(CO) (NO),] [Mn(CO)(NO),] but only one compound of this type is known 86 Nast and Rohmer Z.anorg. Chem. 1956,285,271 ; Griffith Lewis and Wilkinson J. Inorg. Nuclear Chem. 1958 7 38; Nast and Thorne 2. anorg. Chem. 1961 309 283; Griffith Lewis and Wilkinson J. 1961,775. Ungarelli Atti Zstit. Veneto 1924 83 11 81; Giral Anales real SOC. espan“. Fiz. Quim. 1923,21,236. 88 Sidgwick “Chemical Elements and their Compounds,” Oxford Univ. Press 1950 p. 1360; Krauss and Rittenberg J. Amer. Chem. SOC. 1955,77 5296; Morgan Talanta 1959,3,113; Griffith Lewis and Wilkinson J. 1958 3993. 89 Griffith Lewis and Wilkinson J. 1959 872. Griffith unpublished work. GRIFFITH CYANIDE COMPLEXES OF THE TRANSITION METALS 205 namely [CO-I(CO),(CN)NO]-,~~ though reaction of CN- in methanol with [Fe(CO),(NO),] gives a very unstable product which may have the structure [ Fe -I1( CO) (CN) (NO) 3 - .O Peroxide cyanides.-An interesting complex of cobalt(m) analogous to the cobalt peroxide ammines has been prepared by direct oxidation of the cyanide [CoII(CN),I3-. 91 The product is diamagnetic and probably identical with the reported substance “ [COIII(CN),OH]~-” 92 and it has the composition [(NC),CO~~~-O~-CO~~~(CN),]~-. This may be further oxidised to the paramagnetic material [(NC),CO-O,-CO(CN),]~- which has a single unpaired spin as has [(H3N)5Co-0,-Co(NH3),]5+ and presumably as with the latter complex the electron is not predominantly localised on the oxygen atom.93 Slightly acidic solutions of the ion [FeI1(CN),NH3l3- absorb oxygen to give a dark product which may be a peroxide cyanide complex 94 B a ~ d i s c h ~ ~ reports that irradiation of ferrocyanides in the presence of oxygen also gives peroxides of un- specified nature but recent work by Kenney et al.47 indicates that there is oxidation to iron(I11) cyanides rather than oxygenation.In view of the similarity between the co-ordination chemistry of cobalt and chromium it might be expected that oxidation of chromium(I1) cyanid.es would give binuclear oxide or peroxide species especially since oxidation of [Crr1(H2O),l2+ and [CrII(NH3),I2+ gives dihydroxide or oxide complexes.95 However the cyanide [Cr*1(CN)6]4- with air or with hydrogen peroxide simply gives an ion [Cr1II(CN),l3- and this difference in behaviour between cyanide and ammine complexes of chromium(I1) has been attributed to the fact that electrons can travel more easily through CN- groups than H20 or NH3 or that there is spin-pairing in the cyanide.g1 This does not however explain the formation of peroxide complexes or oxidation of cobalt(@ ammines and cyanides.The complexes [Cr04(CN)3]3- and [Cr04(CN)2NH3]2- have been reported and appear to contain the two peroxide groups co-ordinated to a chromium(1v) atom.90p95 Systems Involving Bridging Cyanide Groups.-From the well-known tendency of carbon monoxide to participate as a bridging :CO group and not merely as -C-0 it might be expected that the iso-electronic CN- group should behave similarly but there is no convincing evidence of this. However linear -C-N- bridges are quite common especially in the simple cyanides such as AgCN AuCN Zn(CN), and Cd(CN), which are polymeric with infinite chains and also in KFe2(CN)696 and in 91 Haim and Wilmarth J .Amer. Chem. Soc. 1961 83 509. 92 Smith Kleinberg and Griswold J. Arner. Chem. SOC. 1953 75,449. 93 Ebsworth and Weil J. Phys. Chem. 1959,63 1890. 9 p Manchot Merry and Worringer Ber. 1912 45 2869. 95 Wiede Ber. 1899 32 378; Reisenfeld Ber. 1908 41 3536. O6 Zhdanov DokIady Akad. Nauk S.S.S.R. 1941 31 352. 206 QUARTERLY REVIEWS [R2Aux1’(CN) ]4.97 It has recently been observed that the infrared C-N stretching frequency is about 50 cm.-l higher for bridging CN groups than for terminal CN-.98 The complex [NC,COIICC-N-F~~I(CN),]~- has been prepared by the reaction of the two ions [Fe1I1(CN),I3- with [COI*(CN)~]~-;~~ this presumably has the same geometry as the activated complex proposed for the electron-transfer reaction in this process.99 The curious compound Ag,[Co(CN),] reported by Ray and Duttloo as feebly paramagnetic and pentaco-ordinate has been showng9 to be polymeric with linear -C-N- bridging groups.Cyanide Hydrides.-Ligands such as cyclopentadienyl carbon monox- ide and phosphines which are assumed to have good v-bonding properties form hydrides with a number of transition metals in low oxidation states. In these compounds it appears that the proton is directly bonded to the metal atom and a convenient way of detecting these shielded protons is by the observation of their nuclear magnetic resonance chemical shifts.lo1 It is to be expected that CN- which is a moderately good n-bonding ligand should be capable of participating in hydride complexes and recent studies on solutions of the complex ions [PtI1(CN),l2- [Pd1I(CN),l2- [COIII(CN)~]~- [RhIII(CN)6]3- and [IrIII(CN),l3- after reduction with aqueous borohydride or with potassium in liquid ammonia do show such s h i f t ~ .~ ~ l ~ l In none of these cases has a product been isolated or the composition determined. It is curious that since a hydride complex of rhenium in a low oxidation state is known involving no ligand other than OH- H20 and (presumably) H- none of which can form n-bonds no cyanide hydride of rhenium has been detected :32 it may be that the external charge required would be too great for stability of the complex. Recently Schiltlo2 has found that acidification of iron@) bipyridyl and o-phenan- throline dicyanide complexes causes marked shifts in the spectra of the compounds and suggests that a metal-hydrogen bond may be present. However there are no proton resonances in the nuclear magnetic resonance spectrum of the compo~nds,~O~ and recent work by Orgel and Harnerl0* suggests that it is the CN groups that have been protonated.Cyanide Systems of Biological Interest.-Various porphyrin-type iron complexes contain cyanide groups as part of the co-ordination sphere. It is interesting that whereas such compounds as the haemoglobins catalase and peroxidase may be “poisoned” by cyanide (presumably by the block- ing of reactive positions around the metal atom and formation of mono- and di-cyanide complexes) one form of vitamin BIZ contains a cyanide 97 Kharasch and Isbell J. Amer. Chern. SOC. 1931 53 2701. 98 Dows Haim and Wilmarth J. Inorg. Nuclear Chem. 1961 21 83. gg Taube Chem. Rev. 1952,50,69. loo Ray and Dutt 2. anorg.Chem. 1937,234 65; Current Sci. 1937 5 476. lol Green Angew. Chem. 1960,72 719. loa Schilt J. Amer. Chem. SOC. 1960 82 5779. lo3 G. Wilkmson personal communication. lo4 Orgel and Hamer Nature. 1961 190,439. GRIFFITH CYANIDE COMPLEXES OF THE TRANSITION METALS 207 group in the sixth co-ordination position of cobalt(IIr) though it is very liable to replacement by other groups. Dicyanide complexes of certain transition-metal phthalocyanines are also known.lo5 Poisoning by cyanide has been attributed to inhibition of a number of enzymes including the cytochrome oxidase system for oxygen stabilisation in cells ;loS in general complex cyanides do not appear to have markedly poisonous properties unless one or more cyanide groups are easily removable from the co- ordination sphere. The author is indebted to Professors J. Lewis H. Taube and G. Wilkinson and to Dr. L. Pratt for helpful criticism of the manuscript. Support from the Louis Block Fund and the Conference Board of Associated Research Councils is also gratefully acknowledged. lo5 A. B. P. Lever personal communication. lo6 Dreisbach “Handbook of Poisons Diagnoses and Treatment,” 2nd edn. Lange Medical Publ. Los Altos p. 179.

ISSN:0009-2681    

DOI:10.1039/QR9621600188

出版商:RSC    

年代:1962

数据来源: RSC

摘要:

OXIDATION OF TERVALENT ORGANIC COMPOUNDS OF PHOSPHORUS By J. I. G. CADOGAN (UNIVERSITY OF LONDON KING'S COLLEGE) ALTHOUGH the organic chemistry of phosphorus has been studied for over a century widespread exploitation of the synthetical possibilities so revealed has occurred only recently. Tervalent organic compounds of phosphorus have proved to be particularly useful in this respect as a result of the high reactivity of the unshared pair of electrons and of the strength of the bonds which phosphorus forms with carbon oxygen sulphur nitrogen and the halogens and it is doubtful whether another class of compounds exists which shows greater diversity in its chemical reactions. This Review is intended as an illustration of this and is directed towards reactions of organic compounds of the type PXYZ in which tervalent phosphorus is converted into quinquevalent phosphorus.Reactions of the so-called dialkyl phosphites or phosphonates (RO),P(O)H have not been included. Reactions with Oxygen and Oxygen-containing Compounds.-(i) With oxygen. Of the reactions to be considered in this Review those of tervalent organophosphorus compounds with air or oxygen are probably among the least satisfactorily documented. In general such compounds react more or less readily with oxygen to give the corresponding _P=O compounds but in many cases as a result of the vigour of the reaction products have not been identified. It has been reported,l for example that dialkyl alkylphosphonites (RO) ,PR are converted into the phosphonates by exposure to oxygen but a thin film of the phosphonite on filter paper rapidly inflames in air.Direct oxidation of tri- l-cyanoisopropyP and tri-p-chloropheny14 phosphites to the corresponding phosphates is moder- ately successful but fails with the simpler triethyl ph~sphite.~ The monothio- phosphites (RO),PSR on the other hand react vigorously in air to give unidentified products.e Triphenylphosphine in benzene in contact with air and light forms triphenylphosphine oxide to the extent of 20 % in five days A recent study7 has led to the conclusion that in an oxygen-deficient atmosphere the phosphine under photo-excitation yields an unidentified Razumov Mukhacheva and Sim-Do-Khen Bull. Acad. Sci. U.S.S. R. (English Arbusov and Rizpolozhenskii Doklady Akad. Nauk S.S.S. R. 1952 83 581 ; Kuznetsov and Valetdinov Trudy Kazan. Khim. Tekhnol.Inst. im S.M.Kirova Kamai and Koshkina Trudy Kazan. Khim. Tekhnol. Inst. irn S. M. Kirova 1953,17 Cox and Westheimer J. Amer. Chem. SOC. 1958 80 5441. Arbusov and Nikonorov Doklady Akad. Nauk S.S.S.R. 1948,62,75; Chem. Abs. ' Bartlett Cox and Davis J. Amer. Chem. Soc. 1961 83 103. Trans.) 1952 797; see also Chern. A h . 1956,50 7050. Chem. Abs. 1953,47,3226. 1956,21 167; Chem. Abs. 1957 51 11,985. 11 ; Chem. Abs. 1956,50 634. 1949,43 1004. 208 CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 209 long-lived but reactive product possibly a peroxide which is destroyed at the boiling point of benzene and reacts with an excess of oxygen to give the phosphine oxide but survives under limited oxygen supply. A similar peroxide has also been postulated as an intermediate in the explosive oxidation of triethylphosphine.8 No definite evidence in favour of such intermediates is available however.Preparation of phosphates phosphonates and phosphine oxides by direct oxidation of the corresponding tervalent compounds has rarely been found to be of practical value and alternative methods are used. (ii) With ozone. Triarylphosphines triaryl phosphites,1° and tri- alkyl phosphiteslO in the presence of ozone afford excellent yields of the corresponding f P = 0 compounds. The mechanisms of the reaction with phosphites has been studied with the aid of nuclear magnetic resonance spectroscopy by ThompsonlO who unexpectedly observed that one two or in certain cases with triaryl phosphites all three of the oxygen atoms in ozone could be utilised depending on experimental factors. Although the mechanistic details have not been established it appears that the primary product of the reaction of ozone with aryl or alkyl phosphites is a compound of type (1) which in the latter case has little stability even at low temperatures and rapidly decomposes into the phosphate and oxygen giving an overall 1 :1 ozone to phosphite stoicheiometry.In the presence of an excess of trialkyl phosphite the intermediate (1) is assumed to react through attack by another molecule of phosphite rather than by decomposition to give the trialkyl phosphate and a new zwitterion (2). This is also the preferred reaction with triaryl phosphites as a result of the high stability of in this case the intermediate (1). When the proportion of phosphite to ozone is 2:l another mole of phosphate must be produced together with Q mole of oxygen.This can be accomplished by dimerisation to the cyclic peroxide (3) followed by decomposition as shown in Scheme 1. Although many of the mechanistic details have not been satisfactorily established it is clear that the alternative zwitterion mechanism given Engler Ber. 1897 30 1670; Engler and Weissberger Ber. 1898 31 3055; see Homer Schaefer and Ludwig Chern. Ber. 1958 91 75. also Thompson and Kelland J. 1933 1231. l o Thompson J. Amer. Chem. SOC. 1961 83 845. 210 QUARTERLY REVIEWS below will not accommodate all of Thompson's findings (Scheme 2). (RO),P + 0 4 (RO),6*O*O.O- -f (RO)*PO + 0 (RO),&O.O.O- + ( RO),P -+ (RO),&O.O-+ (RO),PO (RO),~O.O- -+ (RO),PO + go SCHEME 2 (iii) With peroxides hydroperoxides peresters and ozonides.The deoxygenation of dibenzoyl peroxide by triphenylphosphine to give benzoic anhydride and triphenylphosphine oxide was first observed by Challenger and Wilson,ll and confirmed and extended by Horner and Jurgeleit12 to include the reduction of perbenzoic acid to benzoic acid. Other diaroyl peroxides which have been successfully reduced by triphenylphosphine include phthaloyl and biphenoyl peroxides (4) which are converted into phthalic anhydride13 and diphenic anhydride,14 respectively. The mechanism of the reaction between triphenylphosphine and diben- zoyl peroxide has been studied by Denney and his co-workers using carbonyl-180 labelled peroxide.15 They established that the heavy isotope appeared in the resulting anhydride and not in the phosphine oxide so that any mechanism involving transfer of carbonyl-oxygen to tervalent phosphorus can be eliminated.Examination of the isotopic distribution in the anhydride revealed that oxygen atom (a) contained an amount of l 8 0 equivalent to that in the corresponding oxygen atom in the original peroxide while atoms (18) and (y) each contained equal amounts of l80 equivalent to half of the remaining l80. Such a distribution is compatible a B Y PhCO*O*COPh only with attack of the phosphine on peroxidic oxygen to give an ion pair which subsequently decomposes by nucleophilic displacement to give the observed products (* =L I unit of lea) l1 Challenger and Wilson J. 1927 213. l2 Homer and Jurgeleit Annalen 1955 591 138. l3 Homer and Brueggemann Annalen 1960,635 27. l4 Ramirez Desai and Mitra J. Amer. Chem. SOC. 1961,83,492.l5 Greenbaum Denney and Hoffmann J . Amer. Chem. SOC. 1956,78,2563. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 21 1 A free-radical path to the reaction products is discounted since no attack on the solvent occurs and it has been shown that foreign anions can participate in the reaction. In accordance with these conclusions it has been noted12@ that unsymmetrically substituted peroxides react with tributylphosphine to give the corresponding unsymmetrical anhydride. Denney and GreenbaumlG have further shown by the use of oxygen-18 tracers that the phosphine displaces the more electropositive oxygen of the aroyl peroxide ArCO-0-OCOAr’ as shown in the Table. (1)(2) Ar Ar’ % Attack at 0(1) p-NO2.CGH4 Ph 95 p-NO2.CGH4 p-MeO.CGH 100 p-Ph CcH Ph 50 The 4-nitro-group has a marked effect on the position of attack which is due to the lowering of electron density at oxygen(l) and the effect is enhanced if a p’-methoxy-group is present.It is noteworthy that in these cases the ion-pair which is formed almost exclusively is the least stable thermodynamically which suggests therefore that the process is kinetically controlled. That the reaction is random in the third case is in accord with negligible electronic effect in the ground state exerted by the p-phenyl group on the carboxyl group (Hammett’s o = 0.009). The reaction of dialkyl peroxides with triphenylphosphine has also been formulated by Horner and Jurgeleit12 as a nucleophilic displacement on peroxidic oxygen giving rise to an ether thus Ph,P + ButO-OBut + [Ph,&But ButO-1 -+ Ph,PO + ButOBut Walling and Rabinowitz,17 however isolated bi-a-cumyl and triethyl phosphate from the products of the reaction of triethyl phosphite and di-a- cumyl peroxide conducted either thermally or photochemically at 25 O.Since the isolation of bi-a-cumyl under these conditions is indicati\ie of a homolytic process Walling and Rabinowitz assumed that the reaction proceeded by way of an intermediate phosphoranyl radical thus RO*OR 3 2RO* ROO + (EtO),P +- (EtO),iOR + R* + (EtO),PO R* + R* -+ R-R (R* = PheMe,) A similar process was also invoked in the case of the reduction of di-t- butyl peroxide (1 mole) by triethyl phosphite (4 moles) to give triethyl phosphate and products arising from the dimerisation and disproportiona- tion of free t-butyl radicals. That products of decomposition of cumyl or l6 Denney and Greenbaum J.Amer. Chem. Soc. 1957,79,979. l7 Walling and Rabinowitz J. Amer. Chem. Soc. 1959,81 1243. 212 QUARTERLY REVIEWS t-butyl radicals were not detected in these reactions is an indication that the reaction of triethyl phosphite with alkoxy-radicals is very rapid and indeed Walling and Rabinowitz17 calculate that for the overall reaction ButO* + (EtO),P -+ But- + (EtO),PO AH = -30 kcal. mole-l. At lower ratios of phosphite to peroxide however acetone the product of decomposition of t-butoxy-radicals was isolated. Since di-t-butyl ether was not detected in this reaction Walling Basedow and Savas18 re- investigated the reaction of triphenylphosphine with di-t-butyl peroxide and found products consistent with the radical process previously postu- lated.17 Walling’s free-radical mechanism must be held to be correct since it is based on the sensitive gas-liquid chromatographic method of analysis whereas Horner and Jurgeleit12 reached their conclusion on the basis of a distillation temperature.It is noteworthy that triethyl phosphite reacts with alkyl peroxides in the presence of air to give more than an equivalent of phosphate a process attributed17 to autoxidation involving recycling of alkyl radicals R* + 0 + ROO* ROO* + (EtO),P -+ (EtO),FO*OR -+ (EtO),PO + RO. RO. + (EtO),P -+ (EtO),PO + R* etc. Unlike reactions involving alkyl peroxides those between trialkyl- and triaryl-phosphines and t-butyl perbenzoatel resemble heterolytic reactions with diaroyl peroxides. The products of the former reaction the corres- ponding phosphine oxide and t-butyl benzoate are believed to occur by way of a transition state in which little separation of charge has taken place rather than by way of ion pairs such as (6).This conclusion follows from the observation that changes in solvating power of the solvent did not appreciably affect the rates of reaction of a series of p-substituted peresters. Experiments involving perester carbonyl-labelled with oxygen- 18 exclude displacement on the /&oxygen atom to give the ion pair (7) since the ester from its subsequent decomposition would contain equal amounts of oxygen-18 in both oxygen atoms. Formation of the ion pair (6) is also precluded because anion exchange with alcoholic solvents did not occur. The decomposition of the intermediate (5) into products is assumed to be l8 Walling Basedow and Savas J.Amer. Chem. SOC. 1960 82 2181. Is Denney Goodyear and Goldstein J. Amer. Chem. SOC. 1961 83 1727. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 213 ionic involving ion pairs although the oxygen-18 results show that in benzene and ether completely free PhC02- is not formed. The reduction of hydroperoxides to alcohols by tertiary phosphines was first reported by Horner and Jurgeleit :12 R,P -+ R'OOH -+ R,PO + R'OH Walling and Rabinowitzl' extended the reaction to trialkyl phosphites and formulated the extremely easy reaction as an ionic process f+ (EtO)3P:? Bu'O-OH - (EtO$-OBu' OH-(EtO),PO + Bu'OH (9) Denney and his co-workers20 in a more detailed investigation showed that the reduction of trans-9-decalyl hydroperoxide proceeded with retention of configuration and that reductions by triphenylphosphine carried out in ethanol-[lsO]water mixtures gave lSO free phosphine oxide and alcohol.Provided that similar mechanisms operate for both phosphites and phosphines intermediates such as (9) and (10) are therefore unlikely to be involved since it would be necessary for them to decompose faster than hydroxyl ion will equilibrate with [lsO]water. Further in the case of phosphites decomposition of (9) might be expected to give two alcohols. Denny Goodyear and Goldstein20 hold that the most reasonable mechan- ism involves either attack by the phosphine on the hydroxyl oxygen of the hydroperoxide to give an intermediate (1 1) which yields products by a simple proton transfer or a simultaneous proton transfer via the transition state (12). H . . . . [R360R' H d ] [R36-OH R'O-] [R3P ...O...O-R'] (1 0) (11) (1 2) The valuable reaction between ozonides and tertiary phosphines which gives carbonyl compounds21 also probably proceeds by nucleophilic attack on oxygen (iv) With oxides of nitrogen. Staudinger and Hauser22a reported that nitrous oxide is reduced by triethylphosphine to nitrogen while the oxidation of tertiary phosphines by dinitrogen tetroxide has also been said to be of preparative va1ue.12s22b This reagent is also valuable in the z o Denney Goodyear and Goldstein J . Amer. Chem. SOC. 1960 82 1393. 21 Staudinger and Criegee Annalen 1953,583 1. ** (a) Staudinger and Hauser Heh. Chim. Acta I921,4,861; (6) Addison and Sheldon J. 1956 2705. 4 214 QUARTERLY REVIEWS preparation of trialkyl phosphates5 and tetra-alkyl pyrophosphate~~~ from the corresponding phosphites.The mechanism of its reaction with triethyl phosphite5 has not been established but the major part of the reaction can be represented as 3(EtO),P + N204 -f 3(EtO),PO + N20 4(EtO),P + N,O -+ 4(EtO),PO + N Although it had been previously stated5 that nitric oxide does not react with triethyl phosphite this reaction has now been to be a convenient method of oxidising phosphites to phosphates. As a result of the insensitivity of the reaction rate to the polarity and dielectric constant of the solvent the reaction has been formulated as a radical process although there is some doubt over the nature of the intermediate in the reaction slow NO- NO. -k (EtO),P -+ (EtO),b.N:O -4 (EtO),PO 4- N,O fast or (EtO),bON Triethyl phosphite is also oxidised to a mixture of phosphate and tetraethyl pyrophosphate by nitrosyl chloride and nitryl chloride.25 The mechanisms of these reactions are still obscure although it is possible that formation of pyrophosphate is a side reaction (RO),P + CI -+ RCI + (RO),P(O)CI (Ro)'p (RO),P(O).O*P(O)(OR) + RCi (v) With amine N-oxides.Phosphorus trihalides are now established26 as excellent oxygen-acceptors for the reduction of pyridine N-oxides to pyridines. In general substitution of halogen atoms in phosphorus tri- halides by organic groups tends to impair the activity of the tervalent phosphorus atom as a reducing agent. Ramirez and Aguiar*' noted without experimental details that the ease of reduction of pyridine N-oxide de- creased in the series PCl > PhPCl > Ph2PC1)) (PhO)3P > (EtO)3P >>) Ph3P > Bu,P > Et2PPh i.e.reduction was retarded by the presence of electron-releasing groups attached to phosphorus. Contrary to the sugges- tion by Katritzky28 these results indicate that the role of the tervalent phosphorus compound in the reduction is that of an electrophilic rather than a nucleophilic agent. In accord with this 4-nitropyridine 1-oxide is reduced less readily by phosphorus trichloride than is pyridine 1-0xide.~~ 23 Samuel and Silver Chem. and Ind. 1961 556. 24 Kuhn Doali and Wellman J. Amer. Chem. SOC. 1960 82 4792. 25 Arbusov and Ukhvatova Zzvest. Akad. Nauk S.S.S. R. Otdel. khim. Nauk 26 See for example Ochai J. Org. Chem. 1953 18,534. 27 Ramirez and Aguiar Amer. Chem. SOC. Abs. 134th Meeting 1958 p. 28 Katritzky Quart. Rev. 1956 10 395.29 Emerson Ph.D. Thesis University of London 1960. 1395. Aguiar Dim. A h . 1960,21,457. 1958 42N; CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 215 The low positions of triphenyl phosphite and phosphine in this reactivity sequence do not however appear to preclude their effective use as deoxy- genating agent~,~O,~l although at the high temperatures (ca. 200") required in the latter case it is perhaps not surprising that an anomalous reaction occurred in the case of 4-nitropyridine 1 -oxide-nitrous fumes were evolved and the fate of the remainder of the molecule could not be determined.31 A further demonstration of the complexities that sometimes arise in reactions of tervalent phosphorus compounds with N-oxides has been provided by Emerson and Rees who that pyridine N-oxide was rapidly reduced to pyridine by triethyl phosphite at room temperature in unpurified (i.e.peroxidised) diethylene glycol diethyl ether in the pres- ence of oxygen. These observations have been rationalised as follows RO-OR -+ 2RO. (1) (EtO),P + RO* -+ (EtO),bOR 2 (EtO),P(OR)-O.O. (19 (111) Stage (11) has been postulated in reactions between alkoxy-radicals and trialkyl phosphites,17 and oxygen is regenerated in agreement with the finding that little is needed to maintain reaction. Little is known about the peroxides involved although they are unlikely to be hydroperoxides which react rapidly with p h o s p h i t e ~ ~ ~ ~ ~ and the formation of triethyl phosphate is only presumed to occur. Whatever the mechanistic details it seems that this reaction is a further example of the high reactivity of trialkyl phosphites towards free radicals.(vi) With epoxides. Both triethyl phosphitea3 and triphenylphosphines* smoothly reduce epoxides to the corresponding olefin. Boskin and D e n n e ~ ~ ~ noted that tributylphosphine reacted with trans-2,3-epoxy- butane to give both cis- (72%) and trans-but-2-ene (28 %) whereas the cis-epoxide gave cis- and trans-but-Zene in the ratio of 19:81. These observations are only partly in accord with mechanisms proposed e a ~ l i e r ~ ~ ~ ~ which involve displacement by phosphorus on carbon rather than oxygen to give an intermediate (13) followed by rotation and bond 30 Hamana J. Pharm. SOC. Japan 1955,75 139; Chem. Abs. 1956,50 1818. 31 Howard and Olszewski J. Amer. Chem. SOC. 1959 81 1483. 33 Scott J. Org. Chem. 1957 22 1118. 34 Wittig and Haag Chem.Ber. 1955 88 1654. 36 Boskin and Denney Chem. andznd. 1959 330. Emerson and Rees Proc. Chem. Soc. 1960,418. 4* 216 QUARTERLY REVIEWS formation to give (14). Cleavage of (14) to give olefin and phosphine oxide then accounts for the bulk of the reaction but not for the minor product; n- Me Me the latter requires attack of phosphorus directly on oxygen although no other experimental evidence for this is available. The reaction of epoxides with trialkyl phosphites containing one or more secondary or tertiary alkyl groups is reported to give phosphonates rather than olefins and pho~phates.~~ Clearly in this case the intermediate reacts by nucleo- philic attack on an alkyl-carbon rather than by nucleophilic attack on phosphorus thus A (PriO&P(0)CH$ZH2-0Pr /o\ ' + (PriO),P:3 H,C- CH - (Pr'O),PCH,CH,-O- (PriO),PO t CH,= CH A similar deoxygenation of oxazirans to irnines has been reported37 but has not been investigated in detail.0 / \ >C-N- + RSP + >C=N- + RSPO (vii) With p-benzoquinones. Schonberg and I ~ r n a i l ~ ~ first observed a colour on mixing triphenylphosphine and chloranil in chloroform and suggested structure (15) for the product whereas the adduct from tri- ethylphosphine and benzoquinone was formulated as (1 6).sg This was later re-formulated as the phosphonium enolate (17).40 Homer and his co-worker~*~~ accepted the latter and advanced similar structures for the adducts of triphenylphosphine with o-benzoquinone and its tetrachloro- derivative. A re-examination of the reaction of triphenylphosphine and p-benzo- quinone by Ramirez and D e r s h o ~ i t z ~ ~ revealed that the adduct was in " Scott U.S.P.2,793,275; Chem. A h . 1951 16,515. 87 Homer and Jurgens Chem. Ber. 1957 90,2184. 40 Schonberg and Michaelis Chem. Ber. 1936,68 1080. 41 (a) Homer and Spietschka Annalen 1955 591 1 ; (b) Homer and Klupfel ibid. la Rarmrez and Dershowitz J. Amer. Chem. Soc. 1956 78 5614. Schonberg and Ismail J. 1940 1374. Davies and Walters J. 1935 1786. p. 69; (c) Hoffmann Homer and Hassel Chem. Ber. 1958,91 58. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 217 fact that produced by 1,4-addition to the conjugated system and con- firmation by synthesis of this structure was later provided by Horner and his co-w~rkers.~~C Reactions of triphenylpho~phine,~~ triphenyl pho~phite,~~ and triethyl phosphiteg3 with chloranil and of triethyl phosphite with p-benzoquinone 2,5-dichlorobenzoquinone and 2,5-dimet hylbenzo- quinone take a different course44 and are believed to involve initially the donation of one electron by the phosphorus compound to the quinone with the formation of a positive ion-radical exhibiting a strong electron- spin resonance signal.These reactions are exemplified by Scheme 3. OH OH (R=H CI) (X=EtO PhO and when R=CI Ph) SCHEME 3 In all cases involving triethyl or trimethyl phosphite the zwitterion de- composes to give the corresponding monoal kylquinol phosphate. Hydro- lysis of the zwitterion (18) occurs if the reactions are carried out in the presence of aqueous ethanol excellent yields of the corresponding dihydroxybenzene and phosphate or phosphine oxide being obtained. The apparent difference in behaviour of benzoquinone and chloranil towards triphenylphosphine has been attributedg2 to the steric hindrance and higher oxidation-reduction potential of chloranil.Phosphites containing secondary alkyl groups however react by C-P rather than 0-P bond f o r m a t i ~ n ~ ~ thus recalling their behaviour with epoxides described above :36 43 Ramirez and Dershowitz J . Amer. Chem. SOC. 1959 81 587. 44 Ramirez Chen and Dershowitz J. Amer. Chem. SOC. 1959,81,4338. 46 Reetz Powers and Graham Amer. Chem. SOC. Abs. 134th Meeting 1958 p. 86P. 218 QUARTERLY REVIEWS It is clear that slight changes in the structures of both the tervalent phosphorus compound and the quinone can bring about changes of mechanism completely satisfactory accounts of which have yet to be given.(viii) With o-benzoquinone and a-diketones. P-0 rather than P-C bond formation was also originally favoured by K ~ k h t i n ~ ~ and by Birum and Deverg7 to account for the products of the reaction of a-diketones with trialkyl and triaryl phosphites (reaction VI). & k ..... (VI) The formulation (19) is also assumed for the adduct formed between o-quinones and phosphites and it is noteworthy that dealkylation to give the monoalkyl ether of the quinol phosphate apparently does not occur in this c a ~ e . ~ l * ~ ~ These adducts are attacked by oxygen to give the cor- responding phosphate and the original d i k e t ~ n e ~ ~ ~ ~ ~ and by ozone to give peroxides such as biphenoyl peroxide (4).14 The reactions of this peroxide have not been investigated and it seems likely that its decomposi- tion in an inert solvent might lead to interesting products including possibly biphenylene.The general agreement that reactions involving 1 ,Zdiketones proceeded by P-0 bond formation [reaction (VI)] has recently been questioned by Kukhtin and O r e k h o ~ a ~ ~ who have re-investigated the earlier resultsg6 and now conclude that P-C bonds are formed by reaction (V). Clearly further investigation of these reactions is necessary. Lactones undergo ring scission with trialkyl phosphites :60 (ix) With lactones and anhydrides. (RO),P(O)CHR!CH,.CH,.CO R dB Kukhtin Doklady Akad. Nairk S.S.S.R. 1958,121,426; Chem. Abs. 1959 1105. 47 Birum and Dever Amer. Chem. SOC. Abs. 134th Meeting 1958 p. 101P. 48 Ramirez and Desai J . Amer. Chem. SOC. 1960,82 2652. 4g Kukhtin and Orekhova Zhur.obshchei Khim. 1960 30 1208; Chem. Abs. 1961 6o McConnell and Coover J . Amer. Chem. Soc. 1956 78 4453; Kreutzkamp 358. Naturwiss. 1956,43 81. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 219 while acetic anhydride similarly gives a mixture of an acylphosphonate and alkyl acetate :51 (RO),P + Ac,O -+ (RO),$.Ac AcO- -+ (RO),P(O)-Ac + AcOR With phthalic anhydride and trialkyl phosphites however a startling difference in behaviour has been reported,52a the main product being 3,3'-biphthalidylidene (20) (70 %). It was suggested that reaction involves attack of the phosphorus atom of the ester on a carbonyl oxygen of the anhydride to give a resonance-stabilised carbene (21) which reacts by dimerisation to give product (20) although attempts to confirm the existence of the carbene by carrying out the reaction in the presence of olefins as carbene traps were unsuccessful.Pertinent to these conclusions however is the recent observation that triphenylphosphine itself reacts with carbenes to give methylenephos- phoranes (see thus CH,CI + BuLi -+ :CHCI Ec Ph,P:CHCI + LiCl + BuH If the key to the differences in behaviour of simple anhydrides and phthalic anhydride lies in the possibility of formation of resonance- stabilised carbenes then the reaction has interesting possibilities as a source of such intermediates. Such reactions are of interest only as preparative methods for the formation of phosphates phosphine oxides etc. Among the reagents which have been used with varying success are manganese dioxide and mercuric lead tetra-a~etate,~~ hydrogen peroxide,55 and aqueous chloramine-~.~~ 61 Kamai and Kukhtin Akad.Nauk S.S.S.R. Trudy I-Oi Konferents 91 ; Chem. Abs. 64 (a) Ramirez Yamanaka and Basedow J. Amer. Chem. Soc. 1961 83 173; (b) 63 Ayres and Rydon J. 1957 1109. 54 Dimroth and Lerch Angew. Chem. 1960,72 751. 55 Stetter and Steinacker Chem. Ber. 1952 85 451 ; but see ref. 5. 56 Cadogan and Moulden J. 1961 3079. (x) With simple oxidising agents. 1958,52,241. Seyferth Grim and Read ibid. 1960,82 1510. 4.' 220 QUARTERLY REVIEWS Reactions with Halogens and Halogen-containing Compounds.-(i) While trialkyl phosphites react with chlorine and bromine to give the corresponding phosph~rohalidates,~~ tertiary ph~sphines~~ and triaryl pho~phites~~ give the corresponding 1 1 adducts. Triphenylphosphine dihalides react with carboxylic acids to give acyl halides with aldehydes and ketones to give the corresponding gem-dihalides and with amides to give while reaction with compounds containing an active methylene group result in the formation of the corresponding methylene- phosphoranes (see below) :58c %,PO+ RCN + 2HCl R-COCL + Ph3PO+ HCl L)2 - PCiN4-* Ph3P=C(N02)Ph - Ph,W + PhCNO Triphenyl phosphite dihalides and the related triphenyl phosphite alkyl- halides [(PhO)3$R Hal] have been shown to be useful in the preparation of alkyl halides thus? (PhO),PHal + ROH -+ (PhO),P(O)Hal + RHal + PhOH (ii) With alkyl halides the Arbusov-Michaelis and Wittig reactions.The reaction of trialkyl phosphites and related compounds with simple alkyl halides was discovered by Michaelis and Kaehne60 and explored later by Arbusov.61 It is one of the most widely used methods of forming C-P bonds.Its simplest form is the reaction of an alkyl halide with a tri- alkyl phosphite to give a dialkyl alkylphosphonate (RO),P + R'X -f [(Ro),P+R~ x-1 3 (RO),P(O)R' + RX The mechanism receives support from (a) the iso1ation6O of the intermediate (22) on reaction of triphenyl phosphite and methyl iodide (b) phys- icochemical evidence,62 and (c) the observations that triphenyl phosphite methiodide on treatment with optically active octan-2-01 gave inverted 2-iod0-octane,~~ and that the analogous reaction of active 57 McCombie Saunders and Stacey J. 1945 380; cf. ref. 64. 58 (a) Michaelis Annalen 1901 315 43; (6) Horner Oediger and Hoffmann ibid. 1959,626 26; (c) Horner and Oediger Chem. Ber. 1958 91 437. 69 Rydon Chem.Soc. SpeciaIPubl. No. 8,1957 p. 61. 6 o Michaelis and Kaehne Ber. 1898,31 1048. Arbusov J. Russ. Phys. Chem. SOC. 1906 38 687. 62 Arbusov and Fuzhenkova Doklady Akad. Nauk S.S.S.R. 1957 113 1269; 114 63 Landauer and Rydon J. 1953,2224. (22) 89. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 22 1 trioctyl phosphite with bromine to give bromo-octane also proceeded with inversion.64 The reaction of alkyl halides with tertiary phosphines results in the formation of stable phosphonium halides such as (23) which on treat- ment with a strong base give methylenephosphoranes. Further reaction Ph,Pf-CHR X 2 Ph,P=CHR +-+ Ph$-CHR + LiX (23) of the latter with carbonyl compounds provides a valuable route to olefins and is known as the Wittig which has been reviewed.66 P h P =CHR &R2 - Ph,PO + R,C=CHR It is noteworthy that the reaction between trialkyl phosphites and hexachlorocyclopentadiene proceeds by nucleophilic displacement on allylic halogen followed by dealkylation by the cyclopentadienide ion :67 a-Halogeno-aldehydes do not react with trialkyl phosphites in the expected fashion to give phosphonates.6s~69 The reaction appears to involve nucleophilic attack of the phosphite on the carbonyl group elimination of chloride ion and subsequent dealkylation e.g.Bromomalonic ester and triethyl phosphite similarly react to give the ester (24) which has been shown to be a very reactive phosphorylating agent for carboxylic sulphonic and phosphoric acids,'O and also for adenylic acid :'l ? 0 Ft (E t O) P-O-C=<H * CO E t (24) A>- H+ - (EtO),P(O)OAc + CHdC02Et) 64 Gerrard and Jeacocke J.1954 3647. 65 Wittig and Schollkopf Chem. Ber. 1954 87 1318. 66 Levisalles BUZZ. SOC. chim. France 1958 1021 ; Schollkopf Angew. Chem. 1959 67 Mark Tetrahedron Letters 1961 9 295. 68 Allen and Johnson J. Amer. Chem. SOC. 1955,77 2871. 6 g Perkow Krokow and Knoevenagel Chem. Ber. 1955,88,662; Perkow Chern. Ber. 'O Cramer and Gartner Chem. Ber. 1958 91 704. 'l Cramer Angew. Chem. 1960,72 236. 71,260. 1954,87 755. 222 QUARTERLY REVIEWS In a related reaction between trialkyl phosphites or phosphines and NN- disubstituted trichloroa~etamides,~~ it is probable that attack on the carbonyl oxygen occurs first followed by formation of the corresponding phosphate and a trichlorovinylamine thus Extensions of the reaction of a-halogeno-aldehydes with phosphites the Perkow reaction as well as those of the Arbusov reaction have been re~iewed.7~~73 Methylene and ethylene dibromide react normally with trialkyl phosphites in the Arbusov reaction one or both halogens being replaced according to the ratio of reactant^,^^ but more recently side reactions have been discovered with the aid of gas- liquid chr~matography.~~ Carbon tetrachloride reacts with phosphites at temperatures lower than those required for Arbusov reactions of alkyl halides to give high yields of diethyl trichloromethylphosphonate.76 The reaction was first formulated as a radical-chain process by Kamai and Kharra~ova,~~ and this was confirmed by Griffin.78 Further confirmation of the homolytic nature of the reaction has recently been provided by Burn and C a d ~ g a n ~ ~ who noted that in a reaction between triethyl phosphite and carbon tetrachloride in the presence of oct-1-ene initiated by ultra- violet light or peroxides characteristic free-radical addition of the halide to olefin also occurred.On this basis alternative reaction schemes can be (iii) With polyhalogenomethanes. CCI + (RO),P -+ (RO) k C l (RO),kCI + CCI -+ [(RO),P.CCI,]+CI- +-CCI [(RO),PCCl,]+CI- 4 (RO),P(O)*CCl + RCI *CCI + (RO),P -+ (RO),kCI -+ (RO),P(O)-CCI + R* R- + CCI -+ RCI + CCI SCHEME 4 formulated. Under Scheme 4B diethyl ,8p-dimethylphenethyl and benzyl diethyl phosphite would be expected to produce free ,8,8-dimethylphenethyl (PhCMe,CH,) and benzyl radicals. The former would be expected to 7t Speziale and Freeman J. Amer. Chern. SOC. 1960 82 903. la Crofts Quart. Rev. 1958 12 341 ; Lichtenhaler Chern.Rev. 1961 61 607. 74 Ford-Moore and Williams J . 1947 1465. 76 Garner Chapin and Scanlon J. Org. Chern. 1959,24 532. Kamai and Egorava Zhur. obshchei Khim. 1946 16 1521. 77 Kamai and Kharrasova Zhur. obshchei Khim. 1957 27 953. Griffin Chem. and Ind. 1958,415. Burn and Cadogan unpublished observation. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 223 rearrange in part to the more stable act-dimethylphenethyl radical (PhCH,CMe,.) and both radicals would be detectable by the products of their dimerisation and disproportionation,80 whereas the latter would be expected to dimerise to give bibenzyl. Cadogan and Fosters1 showed that such products were not obtained from radical-induced reactions of carbon tetrachloride with benzyl and pp-dimethylphenethyl phosphites hence strong evidence was produced in favour of Scheme 4A.These workers pointed out however that with a suitable choice of substituents it is possible that the trichloromethylphosphoranyl radical might decompose as in Scheme 4B since conditions are known under which the related thiophosphoranyl radical [(RO),P.SR’] can react according to both schemes as discussed below. Bromotrichloromethane and carbon tetra- bromide react extremely vigorously with trialkyl phosphitess2 also by a radical process.83 Chloroform does not react with triethyl phosphite even under drastic condition^,^^ unless benzoyl peroxide is present when the product according to an unsubstantiated report without experimental CHCI + (EtO),P -+ (EtO),P(O)CHCI + EtCl This reaction is assumed to be homolytic but in view of the heterolytic nature of the reaction between dibenzoyl peroxide and triphenyl- phosphine this conclusion requires further experimental substantiation.Bromoform and triphenylphosphine similarly react by a radical-chain process to give dibromoethyltriphenylphosphonium bromide :s5 Ph,P + CHBr + Ph,kHBr zBra -;t [Ph,&CHBr &] + CHBr By analogy with these reactions trifluoroiodomethane which readily undergoes free-radical reactions would be expected to react by a radical- chain process with tervalent phosphorus. Its reaction with trimethyl phosphine is described as a nucleophilic process howevers6 (Scheme 5). Me,P + CF,I - Me3P.I CF,- - Me36.CF I- is diethyl dichloromethylphosphonate -i- Mc,P + - MsPeCF3 + Me1 - Me,PI rt or Ma,Pi? Me-PMe2-CF - Me,; + Me2 PCF SCHEME 5 Reactions with Sulphur and Sulphur-containing Compounds.-(i) Tervalent phosphorus has a high affinity for free and bound sulphur 8o Uny and Kharasch J.Amer. Chem. SOC. 1944 66 1438; Winstein and Seubold ibid. 1947,69,2916; Smith and Anderson ibid. 1960,82,656. 81 Kamai Doklady Akad. Nauk S.S.S.R. 1951,79 795; Chem. Abs. 1952,46 6081. 84 Crofts and Kosolapoff J. Amer. Chem. SOC. 1953 75 5738. 86 Ramirez and McKelvie J. Amer. Chem. SOC. 1957 79 5829. E6 Haszeldine and West J. 1956 3631. Cadogan and Foster J. 1961 3071. Griffin Amer. Chem. Soc. Abs. of 135th Meeting 1959 p. 690. 224 QUARTERLY REVIEWS presumably because its size and high polarisability enable it to utilise the empty orbital of sulphur more effectively than is the case for oxygen or nitrogen. Indeed sulphur adds readily to phosphines and phosphites in air to give the corresponding sulphide rather than the oxide,,' PX3 + S -+ SPX3.The uncatalysed reaction between freshly prepared triphenyl- phosphine and common monoclinic sulphur (S,) under nitrogen has a second-order rate constant which is increased by ionising solvents and by the presence of electron-releasing groups in the phosphine,, and has many characteristics in common with quaternary ammonium salt formation in the Menschutkin reaction. Bartlett and Megueriana8 have therefore con- cluded that the reaction proceeds by successive nucleophilic displacement reactions of sulphur on sulphur (Scheme 6). Ph,P + Phs~.S.S.S.S.S.S.S.S- -+ Ph,PS + Ph,kS.S.S-S.S.S.S- Ph,P + Ph86.S.S.S.S-S.S.< -+ Ph,PS + PhS6-S.S.S.S.S-S- etc. Ph,P + Ph$SS- -+ 2Ph,PS.SCHEME 6 In contrast to the above clear picture a number of puzzling catalytic phenomena occur if a solution in benzene of triphenylphosphine which has been kept in light in a limited supply of oxygen is used.89 Under these conditions a product is formed which causes strong autocatalysis in subsequent reaction with sulphur and is destroyed at the boiling point of benzene in the presence of an excess of oxygen. The formation of this product is attended by the development of paramagnetic resonance absorption consistent with the presence of the triphenylphosphonium cation radical Ph,P-+ which has also been postulated as an intermediate in reactions of triphenylphosphine with quinones (see above). The reaction with sulphur is also complicated by the presence of cocatalysts in the sulphur.It is noteworthy in this respect that both hexasulphur and light- produced polysulphur react very much more rapidly than does octa- sulphur with triphenylphosphine and Bartlett Cox and Davis8 have shown that hexa- and octa-sulphur differ by a factor of 25,000 in their reactivity toward triphenylphosphine at 7-35 '. Rates of reaction of sulphur with other tervalent phosphorus compounds have not been reported. 87 See for example Hoffmann and Moore J. Amer. Chem. SOC. 1958 80 1150; Bartlett and Meguerian J . Amer. Chem. Soc. 1956,78 3710. 8s Bartlett Cox and Davis J. Amer. Chem. SOC. 1961 83 103. Strecker and Spitaler Ber. 1926,59,1772. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 225 (ii) With thiuls. An unusual light-catalysed reaction in which thiols are reduced to the corresponding hydrocarbons by trialkyl phosphites was first observed by Hoffmann and his co-workers in 1956:90 That the reaction was homolytic was later established by Walling and Rabinowitz who concluded that direct reaction of thiyl radicals with tervalent phosphorus occurred to give an intermediate quadricovalent phosphoranyl radical of a type similar to that formed in similar reactions with alkoxyP7 and trichloromethyl r a d i c a l ~ ~ ~ ~ ~ in which phosphorus has undergone an expansion of its outer shell to accommodate nine electrons R’S- + (RO),P + (RO),+.SR~ -+ (RO),PS + R’- Since the reaction occurs very rapidly with strongly electron-accepting thiyl and alkoxyl radicals but not with alkyl radicals,17 it is plausible as Walling and Rabinowitz point out that the reaction derives consider- able driving force from the contribution of polar structures to the transi- tion state (EtO),P + RSH -f (EtO),PS + RH R’.+ R’SH 4 R’H + R’S- RS. P(OEt) c+ RS -$(OEt) Subsequent breakdown of the phosphoranyl radicals in turn must derive its driving force from the very strongg1 P=O or P=S bonds in the product. Walling Basedow and SavaP investigated the possibility that R-OP fission might occur in favourable cases. The product obtained from benzyl diethyl phosphite which could in theory give the resonance- stabilised benzyl radical and butane-1-thiol did in fact contain toluene (3 %) as well as benzyl diethyl phosphorothionate indicating that the reactions shown in Scheme 7 had probably occurred although the detec- tion of the equivalent amount of S-butyl diethyl phosphorothioate was not (EtO),P(S)*O*CH,Ph + Bug (EtO),P(O)-SBu + PhCH,* -c (EtO),P.OCH,Ph + BUS* 4 (EtO),~(SBu).OCH,Ph PhCH,.+ BUSH -+ PhCH + BUS* SCHEME 7 reported. The small amount of PO-R fission even in this favourable case is in keeping with the higher strength of the bonds involved. Decomposition of the phosphoranyl radical formed from triethyl phosphite and thio- phenol [(EtO)&Ph] is strongly retarded probably as a result of the small resonance energy of the resultant phenyl radical and the possibility of additional strengthening of the Ph-S bond due to overlap between the 90 Hoffmann Ess Simmons and Hanzel J. Amer. Chem. SOC. 1956,78 6414. s1 Chernick Pedley and Skinner J. 1957 1851. 226 QUARTERLY REVIEWS n-electron system and the unshared electrons of the sulphur. In this case largely ionic alkylation takes place and only 15% of the products are formed by the free-radical route.PhSH + (EtO),P -+ PhSEt + (EtO),POH (Ionic 85%) PhH + (Et0)PS (Radical 15%) The free-radical reduction of thiols to hydrocarbons can also be effected by trialkylphosphines.l* The features of the radical-chain reactions of thiols and carbon tetra- chloride with trialkyl phosphites have recently been combined by Cadogan and his co-workersa1 sQ2 to provide a new route to phosphorothiolates. Thus triethyl phosphite on reaction with an equimolar mixture of carbon tetrachloride and butane- 1 -thiol gives diethyl trichloromethylphosphonate (22 %) triethyl phosphorothionate (1 8 %) and S-butyl diethyl phosphor- othioate (60%). The major product is believed to arise as shown in Scheme 8 whereas the thionate arises by competing decomposition of the (EtO),P + Buns* 4 (EtO),b.SBun (EtO)$SBun + CCI -+ [(EtO),P-SBun]+CI- + *CCI .. . . . ("'I) [(EtO),P.SBun]+CI- -+ (EtO),P(O).SBun + EtCl . . . . . . . (VIII) SCHEME 8 S-butyl phosphoranyl radical (reaction IX) and the trichloromethyl- phosphonate by the previously described reaction of the trichloromethyl radical with triethyl phosphite (Scheme 9). Substitution of bromotrichloro- methane which is a better chain-transfer agent for carbon tetra~hloride,~~ (EtO),;.SBun -+ (EtO),PS + Bun* . . . . . . . . . . . . . . (IX) (EtO),P + CCI + (EtO),F-CCI z( (EtO),P(O)CCI + *CCI + EtCl . . (X) SCHEME 9 should favour the chain-transfer step (VII) at the expense of the decompo- sition (IX). In accord with this the use of this reagent in the presence of an excess of butane-1-thiol which reacts with the trichloromethyl radicals produced in (VII) thus depressing the formation of trichloromethyl- phosphonate by reaction (X) results in an almost quantitative conversion of triethyl phosphite into S-butyl diethyl phosphorothioate.These experiments are significant since they indicate that the thiophosphoranyl radical can react by abstraction of a halogen atom from polyhalogeno- methanes as well as by decomposition (reaction IX). 92 Bunyan and Cadogan unpublished observations. O3 See for example Cadogan and Hey Quart. Rev. 1954 8 308. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 227 (iii) With disulphides. The desulphurisation of disulphides to sulphides by reaction with tertiary phosphine~,~~ is generally acceptedgs to be an ionic process Ph,P + R-S.S-R -+ Ph,PfSR RS- -f Ph,PS + RSR and the reaction has recently been extended by Moore and his co-workersg6 to include the reduction of tetrasulphides to disulphides These workers also report that the reaction of triphenylphosphine with di- 1,3-dimethylbut-2-enyI) disulphide proceeds by way of an allylic rearrange- ment thus providing an example of the rather rare SJ' reaction.2Ph,P + RS,R -+ 2Ph,PS + RS-SR CH CH Me2C4 ' V M e -> Me,CRd'yHMe, - k2f CH:CHMe ? 7-S f:PPh 4-9.. . ..s?. ...pph Me&:CH-CHMe ~ C C H ~ H M ~ Me2C:CH-CHMe t Ph,PS Reduction of disulphides also occurs if trialkyl phosphites are used at high t e m p e r a t ~ r e s ~ ~ ~ ~ ~ and in this case even diethyl disulphide which is resistant to reduction by triphenylphosphine B4 is reduced (EtO),P + EtS,Et -+ (EtO),hSEt E t f + (EtO),P(O)SEt + EtSEt The reaction is analogous to the Arbusov reaction and it is noteworthy that 0- rather than S-dealkylation occurs as is the case in related systems.99 An alternative reaction similar to that between phosphite and thiols in which triethyl phosphorothionate (106 %) and the di-isobutyl mono- sulphide (92%) are formed has been shown to occur at lower temperatures in the presence of free-radical initiators :17 BuSSBU -+ 2 BUS* BUS* + (EtO),P + (EtO),P.SBu -+ (EtO),PS + Bu* .Bu* + BuS-SBU -+ BuSBU + BUS* Small amounts of by-products included isobutane and isobutene formed by disproportionation of isobutyl radicals The additional butanethiyl radicals so formed also react with phosphite thus accounting for the greater-than-theoretical yield of phosphorothionate BuSBu -t BUS* + Bu* 94 Schonberg and Barakat J.1949,892 Challenger and Wilson J . 1950,26. 95 Parker and Kharasch Chem. Rev. 1959,59,621. 96 Evans Higgins Moore Porter Saville Smith Trego and Watson Chem. and 97 Jacobsen Harvey and Jensen J. Arner. Chern. SOC. 1955,77,6064. 98 Poshkus and Henveh J . Amer. Chern. SOC. 1957,79,4245. 99 Burn and Cadogan .I. 1961,5532. Znd. 1960,897. 228 QUARTERLY REVIEWS which is observed. The possibility that the high-temperature reaction between phosphites and disulphides involves the free-radical formation of thionate followed by isomerisation of thionate to the observed thiolate [(EtO),PS -+ (EtO)2P(0)SEt]100 can be disc~unted.‘~ The homolytic reaction of disulphides with phosphites has been adapted to provide a new route to thioesters by performing the reaction under a high pressure of carbon monoxide1* when the following series of reactions occurs RS- + (RO),P -+ (RO),~SR -+ (RO),PS + R- R ~ O + RSSR -f RCO-SR + RS- etc.R* + CO -+ R-do The related reaction with thiols which would give aldehydes occurs only to the extent of 1-2% however as a result of the high rate of the re- action Re + RSH -+ RH + RS. compared with Re + RS-S-R + RSR + RS.. Cyclic disulphides have been reportedlO1 to react with trialkyl phosphites to give thiolates such as diethyl S-2-ethylthioethyl phosphorothioate the insecticide “Systox”. The concomitant formation of the thiono-isomer in these cases is extremely puzzling however in view of the foregoing dis- cussion and of the known higher stability of the thiolate isomer in this case.lo2 S-CH2 (EtO),P + LLH2 -+ (EtO),~S*CH,*CH,.S- + (EtO),P(O)S*CH,CH,.SEt The reaction has also been extended to include compounds of the type (EtO),P(O)S,Bu and [(EtO),P(0)S],.103 In these cases the anion produced in the initial displacement is bidentate and can react to give two products (Scheme 10).The thiopyrophosphate formed in the latter reaction has the (Et0)aP + (EtO),P(O)S,Bu -+ (EtO),P+*SBu (EtO)gP.OS- -+ (E~O),P(O).SBU + (EtO),P(O)-SEt + (EtO),PS (EtO),P + [(EtO)2P(O)S] + (EtO)a$*S*P(O)(OEt) (EtO),P(O)S-* (EtO),P(S)O-P(O)(OEt) + (EtO),P(O)SEt + (EtO),PS SCHEME 10 thiono (P-S) rather than the thiolo (P-S-P) arrangement.104 100 See for example Burn Cadogan and Foster Chem. and Znd. 1961,591. 101 McConnell U.S.P. 2,865,950; Chem.Abs. 1959 12,181. lo2 Fukoto and Metcalf,J. Amer. Chem. Sac. 1954,76,5103. 103 Michalski and Wiecmrkowski Bull. Acad. polon. Sci. CZ. ZZI 1957,5917; Chem. 104 Jones Katritzky and Michalski Proc. Chem. Soc. 1959 321. A h . 1958,6157. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 229 (iv) With thiolsulphonates and thiosulphinates. Alkyl but not aryl esters of aliphatic and aromatic thiosulphonic acids react readily with trialkyl phosphites to give 00s-trialkyl phosphorothioates and the corresponding alkyl sulphinates :lo5 + - (EtO),P + R*SO,*SR’ + (EtO),P.SR’ RSO + (EtO),P(O)SR’ + R*SO,Et The isomeric alkyl ethyl sulphone probably arising from the btdentate nature of the sulphinic anion which is capable of forming 0- or S-deriva- tives,lo6 sometimes appears as a by-product. The corresponding reaction with aryl esters of aromatic thiosulphonic acids e.g.PhS.S02Ph is more complicated and involves three processes (a) the formation of diethyl S-phenylphosphorothioate and ethyl benzenesulphinate as described above (b) the reduction of thiosulphonate to give diphenyl disulphide and tri- ethyl phosphate and (c) the slower reaction of diphenyl disulphide with phosphite to give the S-phenylphosphorothioate and ethyl phenyl sul- hide,^* as discussed in a previous section. Similar reductions of aryl thiosulphonates and of diphenyl disulphone to diary1 disulphides by tertiary phosphines have also been reported.lo7 In a related investigation Carson and WonglW note that alkyl or aryl thiosulphinates react with triphenylphosphine to give high yields of disulphide and phosphine oxide but they are undecided whether hetero- lytic or homolytic reaction paths are being followed.In view of the fore- going discussion of reactions of thiyl radicals with tervalent phosphorus however it is unlikely that Carson and Wong’s homolytic formulation (below) is correct because phosphine sulphide is not formed in their reaction RSO-SR + RSO + RS. RSO + Ph,P + RS- + Ph,PO RS. + RS. + RS*SR They alternatively invoke polarisation of the bivalent sulphur atom by the sulphoxide group followed by nucleophilic attack by the phosphine while direct reaction of electrophilic phosphorus on the sulphoxide oxygen atom in a manner analogous to the reaction of N-oxides discussed above is not considered. (v) With episulphides. That trisubstituted phosphites and phosphines could be converted into the corresponding sulphides by reaction with episulphides has been known since 1949,1°9 and Davis and Schuetz and lo5 Michalski and Wieczorkowski Bull.Acad. polon. Sci. C1. HI 1956 4 279 redescribed in J. 196q 1665. lo6 Gilman “Organic Chemistry” Wiley New York 1947 Vol. I 916. 107 (a) Horner and Hoffmann Angew. Chem. 1956,68,473; (b) Horner and Nickel Annalen 1955 597 20. 108 Carson and Wong J. Org. Chem. 1961,26 1467. los Culvenor Davies and Heath J. 1949 282. Davis J. Org. Chem. 1958 23 1767. 230 QUARTERLY REVIEWS Jacobslll later showed that the episulphide was thereby converted into the parent olefin. Since the reaction therefore formally corresponds to that between epoxides and tervalent phosphorus c o m p o ~ n d s ~ ~ ~ ~ Schuetz and Jacobslll concluded that the reactions proceeded by similar mechanisms.That this is incorrect has been shown by Neureiter and Bordwel1112 and by Denney and Boskin.l13 The former workers demonstrated that the reactions of triethyl phosphite with cis-2,3-epithiobutane and the trans-isomer proceeded with 97 % stereoselective removal of sulphur from the three-membered ring with the formation of cis- and trans-but-2-eneY respectively. This result rules out a mechanism involving nucleophilic attack by phosphorus on carbon to give inteimediates such as (25) and (26) a path favoured for the comparable reaction of epoxides since this would lead to the opposite stereochemical result. In view of this Neureiter and Bordwell preferred to formulate the reaction as a nucleophilic attack on sulphur but were not prepared to exclude a short-lived dipolar ion (EtO)3$.SCHMerCHMe.Denney and Boskin,l13 on the other hand confirmed the stereospecificity of the reaction and considered a dipolar intermediate of this type to be unlikely because it would be required to decompose to the products faster than rotation about the central C-C bond can occur and such rotation would have led to a mixture of olefins + R,P-S) C- MMe Further a 16-fold alteration in the dielectric constant of the solvent resulted in very little change in the rate of the reaction which was bimole- cular and of first order in each component. The results are therefore most consistent with the existence of a transition state which has little or no charge separation formed by a smooth displacement reaction at the sulphur atom It was considered possible however that desulphurisation of a less sterically hindered episulphide might proceed by nucleophilic attack on ll1 Schuetz and Jacobs J.Org. Chem. 1958,23 1799. lla Neureiter and Bordwell J . Amer. Chem. SOC. 1959 81 578. 118 Denney and Boskin J . Amer. Chem. SOC. 1960,82,4736; cf. ref. 35. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 23 1 carbon but the rate constants for the reaction with 1,Zepithiobutane in solvents of different dielectric constant closely corresponded to those found for cis- and trans-2,3-epithiobutane so no change of mechanism is indicated. Attack by tervalent phosphorus on sulphur in episulphides and on carbon in epoxides may be rationalised114 by the following (a) sulphur is more electropositive and polarisable than oxygen (b) the C-S dipole is small and (c) bivalent sulphur in disulphides and sulphonyl halides is known to be susceptible to attack by nucleophilic reagents in dispkacement-type reactions.96 A similar situation has been observed between chlorine and bromine in reactions with phenyl-lithium ; whereas 1,2-dichlorocyclohexane reacts with elimination of hydrogen chloride (nucleophilic attack on hydrogen) the 1,2-dibromide reacts by elimination of bromine (nucleophilic attack on bromine).l15 The mechanism of the desulphurisation of episulphides given above does not account for the formation of dimethyl s-pen tylthioethylphosphonate from the correspond- ing phosphite and ethylene sulphide which apparently proceeds by nucleophilic attack on carbon :36 -+ (MeO),kH,CKS -+ I OCHMePr (MeO),P(O)CH,CH,-S.CHMePr \ CH 'iH (MeO),P.OCHMePr + S Why attack should take place at carbon rather than sulphur in this case is not clear.(vi) With sulphenyl chlorides sulphonyl chlorides and organic thiocyan- ates. Trialkyl phosphites and related compounds react very rapidly with both aliphatic and aromatic sulphenyl halides at -70" to give the corres- ponding thiolates,l16 probably by way of an Arbusov intermediate (EtO),P + RSCl -+ (EtO),&SR CI- -+ (EtO),P(O).SR + EtCl By analogy with reactions of triphenyl phosphite with disulphides already described the corresponding reaction with an alkanesulphenyl chloride might have been expected to yield the thionate thus (PhO),P + EtSCl -f (PhO)$SR CI- + (PhO),PS -+ EtCl In practice the course of this reaction is obscure since triphenyl phosphate (100 %) is reported to be formed.l17 With arenesulphenyl c h l o r i d e ~ ~ ~ ~ J ~ 114 Cf.Bordwell Anderson and Pitt J. Amer. Chem. SOC. 1954 76 1082. ll6 Wittig and Henborth Ber. 1944 17 306. ll8 (a) Gilbert and Clough U.S.P. 2,690,450; G e m . Abs. 1955 11,682; (b) Morrison J. Amer. Chem. SOC. 1955,77 181; (c) idem J . Org. Chem. 1956,21 705; ( d ) Asinger Thiel and Schafer Annalen 1960 637 146. 11' Petrov Sokolskii and Poles Zhur. obshchei Khim. 1956 26 3387; Chem. A h . 1957,9473. 118 Poshkus and Herweh J. Amer. Chem. Soc. 1957,79,4245. 232 QUARTERLY REVIEWS the following reaction the mechanism of which is also not yet established occurs The reaction appears to occur in two stages probably through the inter- mediate [(PhO)&Ph Cl] since passage of moist air through the reaction mixture produces triphenyl phosphate.A similar reaction has been re- ported with tripheny1pho~phine.l~~ In the presence of free-radical initiators the reaction of tervalent phosphorus with sulphenyl halides might be expected to give the corres- ponding thionate and halide although this has not yet been realised experimentally (PhO),P + 2PhSCI + PhS-SPh + (PhO),PCI (RO),P + R’S* 3 (RO),bSR’ 3 (RO),PS + R’* R’+ R’SCI -f R’CI + R’S- Similarly the corresponding nitrile and phosphorothiolate are obtained in good yields from reactions of trialkyl phosphites with aryl and alkyl thiocyanates.lZ0 The former also react in a predictable fashion with tertiary phosphines (RO),P + R‘SCN -+ (RO),&SR CN-t (RO),P(O)-SR’ + RCN + - EtaP + EtSCN -t Eta6SEt CN - Et,q EtsPS + EtdP CN Although the products of the reactions of sulphonyl chlorides with phos- phites are known their modes of formation have not yet been established.Trialkyl esters116a~122 react according to the following equation The formation of phosphorothiolate suggests that reduction of the sulphonyl chloride to sulphenyl chloride first occurs followed by reaction with more phosphite although reduction of the as yet unknown sulphon- ate (EtO),P(O)-SO,R which could be a transient intermediate cannot be entirely ruled out. Poshkus and Herweh’s isolation118 of diphenyl disul- phide as well as the phosphate after reaction of triphenyl phosphite and benzenesulphonyl chloride points to the intermediate formation of benzenesulphenyl chloride but the genesis of other products is still un- certain. Uncertainty is also associated with the corresponding reaction with triphenylphosphine 3(EtO),P + R-S02.CI -+ (EtO),P(O).SR + 2(EtO),PO + EtCl 6(PhO),P + 2Ph-S02CI -+ S(PhO),PO + PhCl + PhS,Ph 3 (PhO),PCI 3Ph,P + Ph.SO,CI -f An adduct 2 PhS,Ph + Ph,PO + PhSH 2Ph,P + Ph.SO,CI -f An adduct 2 Ph.SO,H + Ph,PO + PhS,Ph ll0 Morrison Amer.Chem. SOC. Abs. 134th Meeting 1958 p. 87P. 120 Michalski and Wieczorkowski Bull. Acad. polon. Sci. CI. 111 1956 4 4729; Roczniki Chem. 1959,33,105; Sheppard J . Org. Chem. 1961,26 1460. 121 Hofmann Annalen 1861 Suppl. 53. lZ2 Hoffmann Moore and Kagan J . Amer. Chem. SOC. 1956 78,6413. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 233 (vii) With chlorides and oxychlorides of sulphur. Sulphur monochlor- ide and dichloride react with phosphites according to Scheme 11. Poshkus S,CI + 3(RO),P -+ 2(RO),PS + RCI + (RO),P(O)CI (R = alky1116b) or Z(RO),PS + (RO),PCI (R = aty124) SCI + 2(RO),P -+ (RO),PS + RCI + (RO),P(O)CI (R = a l k ~ l l ~ ~ ) or (RO),PS + (RO),PCI (R = a r ~ l l ~ ) SCHEME 11 and his co-worker~~~~ favour radical reaction paths (Scheme 12) for the reactions with triphenyl phosphite mainly because the reactions occur readily in petrol at low temperatures.It is fair to state however that no (ArO),P + SCI -f (ArO),bCI + CIS. CIS* + (ArO),P -+ (ArO),bSCI (Aro)a! (ArO),PS + (Ar0);PCI (ArO),kI + SCI + (ArO),PCI + CIS- (ArO),fkI + S&I + (ArO),PCI + CIS,* (Aro)a! (ArO),bS,CI (ArO),k,CI -f (ArO),PS + X I *SCI + S,CI + SCI + CIS,. SCHEME 12 experimental evidence in favour of these otherwise plausible mechanisms has so far been advanced. Similar radical intermediates are invoked to account for the reactions of triphenyl phosphite with thionyl and sulphuryl chlorides :124 Elucidation of the mechanisms of these and related reactions of phos- p h i t e ~ l ~ ~ which give sulphur dioxide alkyl chloride and the dialkyl phosphorochloridate has not yet been achieved.Reactions with Compounds having Reactive Nitrogen-containing Groups.- (i) With azides. Both tertiary phosphines126 and triesters12' react with azides by displacement of nitrogen to give imines R3P + R'N3 -+ [R,P*N:N*NR'] -+ R,P:NR' + N, and in some cases isolation of the intermediate has been achieved.128 The phosphinimines are particularly (PhO),P + SO,CI (or SOCI,) -f (PhO),P + SOCI (or SCI,) 12 Poshkus and Herweh Chem. and Ind. 1961 1316. lar Poshkus Herweh and Haas J .Amer. Chem. SOC. 1958,80 5022. 125 Poshkus and Herweh h e r . Chem. Soc. Abs. 136th Meeting 1959. p. 30N; Staudinger and Hauser Helv. Chim. Acta 1921 4 861. Kabachnik and Gilyarov Izvest. Akad. Nauk S.S.S. R. Otdel. khim. Nauk J. Amer. Chem. SOC. 1957,79 6127. 1956,790; Chem. A h . 1957,1823. lP8 Homer and Gross Annalen 1955 591 117. 234 QUARTERLY REVIEWS useful synthetical intermediates since they readily react with a variety of unsaturated compounds (Scheme 13). The Wittig reaction of carbonyl R,C=C=NR‘ + R,PO RhCO + R,PO CQ Y C O ,ssf R’Na + R p S +% R’NSO+ R,PO RNC\ RN=C=NR’ + R Po R,PO + R*C=NR’ R,P=NR’ - RN=C=NR‘ + R,PS A c s SCHEME 13 compounds with ~nethylenephosphoranes~~ can be considered to be an extension of these reactions which all probably proceed by way of four- membered transition states R P=NR R P=CHR >=CR &CR 4 __t R,PO+ R,C=NR; L __c R,PO + R2C=CHR Phosphinimines derived from acyl azides afford the corresponding nitrile on thermal decomposition,126 while those derived from a-azido- carboxylic acids can be converted into a-amino-acids :lz8 Ph.CO*N 3 Ph.CON:PR + PhCN + R,PO R*CH(N,)*CO,H 3 R.CH(CO,H)*N:PR HBr R.CH(NH,)*CO,H + RSPO (ii) With diazo-compounds.Diazomethane reacts with tertiary phos- p h i n e ~ l ~ ~ and triesters130 to give the so-called phosphazines which on thermal decomposition provide an alternative route to methylenephos- phoranes,131 and on hydrolysis give hydrazones :129 R,PO + R,’C:N-NH R,P + R,’CN -+ R,P:N*N:CR,’ R,P:CR,’ + N The products of the reactions of diazonium salts with triphenylphosphine vary with the proportions of r e a ~ t a n t ~ .~ ~ ~ ~ ~ ~ ~ J ~ ~ ~ A 1:l ratio results in reduction of the diazonium compound to the aromatic hydrocarbon (50 %) ArN,CI + PhaP +- [Ph,hN:NAr]CI- 2 ArH + Ph,PO + HCI las Staudinger and Meyer Helv. Chim. Ada 1919 2 619. lao Kabachnik and Gilyarov Doklady Akad. Nauk S.S.S.R. 1956,106,473. 131 Staudinger and Meyer Helv. Chim. Acfa 1919 2 635; Horner and Lignau 13* Homer and Stohr Chem. Bet. 1953,86 1073. Annalen 1955,591 135. Homer and Hoffmann Chem. Ber. 1958 91,45. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 235 whereas a 1 mole excess of phosphine leads ultimately to the formation of the aryl hydrazine [Ph,$-N:NAr]CI-+ Ph3P + H,O -+ [Ph,&NH.NHAr]CI- + Ph3P0 - HI0 [Ph36NH*NHAr]CI -+ Ph3P0 + Ar.NH.NH HCI Reaction of acetate-buffered diazonium salt with triphenylphosphine on the other hand gives rise to aryltriphenylphosphonium salts which are also formed from the corresponding reaction with N-nitrosoacylaryl- amines.Horner and H ~ f f m a n n l ~ ~ are of the opinion that free aryl radicals are present in this reaction since the same products are obtained from the reaction of triphenylphosphine with bromobenzene in the presence of cobaltous chloride and phenylmagnesium bromide Ar.N,CI + Ph3P Acetate buffer Ph3PAr+ CI- + N -+ (iii) With nitrosobenzene. Recent work by Bunyan and Cadogang2 has shown that triethyl phosphite and triphenylphosphine react rapidly with nitrosobenzene to give azoxybenzene and the corresponding oxide (RO),P + 2PhNO 3 (RO),PO + PhN(O).NPh) Although the mechanism of this reaction has not been established it is possible that an electron-deficient nitrogen intermediate an azene is involved PhNO + (RO),P -f PhN + (RO),PO PhN + PhNO -f PhN0:NPh This interpretation also accounts for the ready formation of carbazole in the reaction of 2-nitrosobiphenyl with triethyl phosphite.(iv) With ON-dibenzoylhydroxylamine. Triphenylphosphine reacts with ON-dibenzoylhydroxylamine by way of attack by tervalent phos- phorus on nitrogen with displacement of benzoate ion followed by or concurrent with proton removal to give benzoic acid and triphenylphos- phine benzoylimine :135 1 134 135 PhC0,H + Ph,P=N*COPh Horner and Hoffmann Chem. Ber. 1958 91 50. Wasserman and Koch Chem. and Ind. 1956 1014. 236 QUARTERLY REVIEWS The reaction is similar to that involving the related dibenzoyl peroxide discussed earlier.The reaction is also similar to the cleavage of N-halogen bonds by phosphines and phosphates observed in other systems e.g. in reactions of anhydrous chloramhe-T :56336 Ph,P [or (RO),P] + Ar.SO,.NNaCl -+ Ph,P:N.SO,Ar + NaCl Reactions with Unsaturated Compounds.-Tertiary phosphines form stable zwitterionic phosphonium salts with compounds containing activated double e.g. ArCH:C(CN) + R,P -+ R,&.CHAr.C(CN) Maleic anhydridea reacts similarly while the reactions of maleic and cinnamic acid with triethyl phosphite appear to involve similar resonance- stabilised intermediate~l~~ which are able to rearrange by dealkylation thus (EtO),P + HO,C*CH:CH.CO,H + (Et0)akH(COzH).CH-C02H -t (EtO),P(O).CH-(CO,H)*CH2.CO,Et Such reactions are a function of the nucleophilicity of tervalent phosphorus and occur most readily when the double bond is activated by electron- withdrawing substituents.In cases where stabilisation of the initial 1 1 adduct is not pronounced reaction with successive molecules of olefin can occur to give long-chain telomers :Isg I + R CH,:CHR f (R=CN,COMe,CHO ,CO,R) R;P:? CH,=CH R - R ,P-CH,.CHR - R;;”(CH,CHR)~=CH,.CHR Similar reactions with triethyl phosphite have been reported,140 as in Scheme 14. (EtO),P + n CH,:CMeCOIH +- (EtO),pf.[CH,CHMeCO,H CH,.cMe.CO -f (EtO),P(O).[CH,CH MeCO,H],-,-CH,CH Me-C0,Et SCHEME 14 Dipheny1ketenl3’ reacts with triethylphosphine analogously to give a 1 1 adduct while the following conversion of NN’-diphenylcarbodi- imide into phenyl isocyanide and aniline by reaction with tertiary phosphine 136 Mann and Chaplin J.1937 527. 13’ Staudinger and Meyer Helv. Chim. Acta 1919 2 612. lS8 Kamai and Kukhtin Trudy Kazan. Khim. Tekhnol. Inst. im S.M. Kirova 1957 130 Homer Jurgeleit and Klupfel Annalen 1955 591 108. 140 Kukhtin Kamai and Sinchenko Doklady Akad. Nauk S.S.S.R. 1958 118 505. 23,133; Chem. Abs. 1958,52,9948. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 237 followed by hydrolysis,41b probably involves a similar intermediate thus HtO PhN:C:NPh + R,P += [R,k(NPh):NPh] -+ R,PO + PhNC + PhNH Nucleophilic attack on oxygen occurs in the reaction of tertiary phosphines with cis- or trans-dibenzoylethylene however,41b thus recalling similar reactions which occur with some 1,4-quinones described above. Ph Ph Several products have been isolated from the reaction of triphenyl- phosphine with dimethyl acetylenedicarboxylate under various condi- t i o n ~ .~ ~ ~ The unstable 2:l adduct formed at -50" under nitrogen is formulated as (27) and readily isomerises to give the more stable isomer (28) which is assumed to arise by way of an unusual 1,5-migration of the phenyl group. F02Me $02M@ + %=F.C02Me ~ PhC=F C02Me Ph,P- = CCO Me Ph3P\y=CC02 Me (27) C02Me f0,Me (28) When the reaction is in carbon dioxide on the other hand it is believed that the first-formed zwitterion obtained by reaction of equimolar quanti- ties of reactants is stabilised by combination with carbon dioxide to give the product (29) which on reaction with methyl iodide base or dimethyl acetylenedicarboxylate gives a further product formulated as (30) and on hydrolysis gives dimethyl fumarate and triphenylphosphine oxide - Ph,P PPh MeO2CMCO2Me It has been suggestedi42 that the ready reaction of triethyl phosphite and diethyl azodicarboxylate proceeds as indicated but confirmation of the formulation must await adequate identification of the product.(EtO),P + EtO,C.N:NCO,Et -+ (EtO),$-N(CO,Et)-NCO,Et -+ (EtO),P(O)*N(CO,Et)*N Et-C02Et 141 Johnson and Tebby J. 1961 2126. Morrison J. Org. Chern. 1958 23 1072. 238 QUARTERLY REVIEWS Wittig and B e n ~ l ~ ~ ” have shown that in company with other nucleophilic reagents,144 triphenylphosphine reacts with benzyne in this case to give phenylbiphenylenephosphine. Benzyne has also been reported to convert triethyl phosphite into diethyl pheny1pho~phonate.l~~~ Reactions with Carboxylic Acids.-Trialkyl phosphites react with carboxylic acids to give the corresponding alkyl esters.145 Tetra-alkyl- pyrophosphites on the other hand behave as anhydrides of diethyl hydrogen phosphite in their reactions with carboxylic acids and as such are useful in peptide (Scheme 15).The so-called “amide (EtO),P.O.P(OEt) + R.CO.NH-CHR’.CO,H -+ R-CO*NH*CHR’*CO,*P(OEt) + (EtO),P*OH ReC0.N H‘CH R’*CO,.P(OEt) + H2N’CH R”*CO,R”’ -+ ReC0.N H*CH R’*CO*N H-CH R”.CO,R” + (EtO),P(O)H SCHEME 15 modification” of this process has been utilised in du Vigneaud’s synthesis of o x y t o ~ i n l ~ ~ (Scheme 16). Peptides as well as simple amides are also (EtO),P.O.P(OEt) + H,N*CHR*CO,R’ -+ (EtO),P*NH-CHR*CO,R’ + (EtO),P-OH (EtO),P*NH.CHR*CO,R’ + R”CO*NH*CHR”*CO,H + R”.CO*NH*CH R”*CO.N H.CH R*CO,R’ + (EtO),P.OH SCHEME 16 formed by reaction of phosphazo-compounds with carboxylic acids1‘* (Scheme 17) and the related triamide P(NMePh) appears to offer some PCI + 2Et02C*CH2*N H2 -+ EtO,C*CH,N :P*N H*CH,-CO,Et -+ EtO,C.CH,.N P*N HCH,.C02Et + 2 H0,C*CH2*N HC02CH,Ph 2 Et02C~CH,~NH*CO~CH,~NH.C0,.CH,Ph SCHEME 17 143 (a) Wittig and Benz Chem.Ber. 1959 92 1999; (6) Griffin and Castellucci J. 144 Huisgen and Sauer Angew. Chem. 1960,72 91. 145 Kamai Kukhtin and Strogova Trudy Kazan. Khim. Tekhnol. Inst. im S.M. 146 Anderson Blodinger Young and Welcher J. Amer. Chern. SOC. 1952 74 5304; 147 du Vigneaud Ressler Swan Roberts and Katsoyannis J. Amer. Chem. SOC. 148 Goldschmidt and Lautenschlager Annalen 1953 580 68; Wunsch Fries and Org. Chem. 1961 26 629. Kirova 1956,21 155. Anderson Blodinger and Welcher ibid. p. 5309.1954,76,3115. Zwick Chem. Ber. 1958,91,542. CADOGAN ORGANIC PHOSPHORUS COMPOUNDS 239 advantages in the preparation of N-methylanilide~.~~~ Phosphazo-compounds also react with diacylhydrazines to give 1,2,4- triazoles ; thus N-benzoyl-N'-isonicotinoylhydrazine has been converted into 3,4-diphenyl-5-4'-pyridyl-l,2,4-triazole in 95 "/o yield :150 Ph In this reaction as in many others involving phosphazo-compounds the nature of the phosphorus-containing products has not been deter- mined. 14' Abramovitch Hey and Long,J. 1957 1787; Habib and Rees J. 1960 3371. 150 Klingsberg J. Org. Chent. 1958,23 1086.

ISSN:0009-2681    

DOI:10.1039/QR9621600208

出版商:RSC    

年代:1962

数据来源: RSC