摘要:

The Sulphoximides By P.D. Kennewell and J. B. Taylor ROUSSEL LABORATORIES LIMITED, KINGFISHER DRIVE, COVINGHAM, SWINDON, WILTSHIRE 1 Introduction It was demonstrated by Mellanbyl that when dogs are fed a diet rich in flour pre-treated with the commercial flour improver 'Agene' (which is essentially nitrogen trichloride), they develop a condition known as canine hysteria. The manifestations of this disorder are bouts of hysterical barking and aimless running leading to epileptiform fits in severe cases. Moran established that the toxic factor is produced by the interaction of nitrogen trichloride with the protein fraction of wheaten flour, namely gluten, and that the proteins zein and casein also become toxic when treated with the gas.2 Not all proteins are rendered toxic by interaction with nitrogen trichloride and it was concluded by Bentley that the proteins which become toxic are relatively rich in methionine.3 Subsequent work by Bentley led to the isolation of the toxic factor as a pure substance and to its characterization as methionine sulphoximide (l), the first member of a new family of sulphur compound^.^ Since their initial discovery by Bentley, considerable work has been carried out on this versatile class of compounds, and it is the aim of this article to review concisely the major aspects of progress to date in this field.The nomenclature of sulphur-nitrogen compounds is highly confusing and for the purpose of this review the IUPAC convention will be followed, according to which the members of the family (2) are termed sulphoximides and the related families (3) and (4) are termed sulphimides and sulphur di-hides respectively. E.Mellanby, Brit. Med.J., 1946,2,885. T. Moran, Lancet, 1947,2,289.* H. R. Bentley, R. G. Booth, E. N. Greer, J. G. Heathcote,J. B. Hutchinson, andT. Moran, Nature, 1948,161,126.* H. R. Bentley, E. E. McDermott, T. MoraD, J. Pace, and J. K. Whitehead, Proc. Roy. SOC., 1950,B137,402;J. K.Whitehead and H. R. Bentley,J. Chem. SOC.,1952,1572. The Sulphoximides 2 Synthesis The initial synthesis of methionine sulphoximide (1) was accomplished by treatment of methionine sulphoxide with hydrazoic acid. The general applicability of the reaction was demonstrated by Reiner and his co-workers who prepared aryl and alkyl sulphoximides from the corresponding sulphoxides and showed that reaction proceeded best under conditions essentially similar to those used for the Schmidt rea~tion.~ This method remains one of the most convenient general methods for preparing sulphoximides, providing that the sulphoxide used is stable to the strong acid conditions employed and not susceptible to heterolysis.In a modification of the method, Stoss and Satzinger used poly- phosphoric acid as both acid catalyst and solvent to prepare a large number of sulphoximides in good yields.6 Although the reaction of hydrazoic acid with sulphoxides is formally related to the Schmidt reaction, it seems unlikely that the same mechanism applies. The mechanism proposed by Bentley’ and extended by Johnson,* who established the necessity for two equivalents of acid in the reaction, involves nucleophilic attack by sulphoxide on a protonated hydrazoic acid intermediate (Scheme 1).\s=o 0 H~ /..4 pi. RzSO II HN, H2N-Nz -H2N-SR2 Scheme 1 A general route to N-substituted sulphoximides is provided by trapping, with sulphoxides, the ‘nitrenes’ generated by photolytic, thermolytic, and a-elimina- tion reactions from appropriate precursors. Such a reaction was first described by Kwart and Kahng and extended by others,1° and depends on the trapping, by a suitable sulphoxide, of the transient nitrene generated from the copper- catalysed decomposition of an aryl sulphonyl azide. The catalysis by copper was suggested to be due to the formation of a 4-centre azidecopper complex (5) which could conceivably give rise to an intermediate copper-nitrene ultimately captured by the sulph~xide.~ In an extension of the work of Kwart and Kahn, Carr and his co-workers prepared N-arylsulphonylsulphoximides (6) by heating a sulphoxide with chloramine-T in the presence of copper powder.ll Evidence for the formation of an intermediate copper-sulphonyl nitrene was provided by an insertion reaction with dioxan to give the sulphonamide (7).When copper was absent or when zinc dust was used as an alternative catalyst, little or no reaction took F. Misani, T. W. Fair, and L. Reiner, J. Amer. Chem. Soc., 1951,73,459. G. Satzinger and P. Stoss, Arzneim.-Forsch., 1970,20, 1214.H. R. Bentley, E. E. McDermott, and J. K. Whitehead, Proc. Roy. SOC.,1951, B138,265. C. R. Johnson and E. R. Janiga, J. Amer. Chem. SOC., 1973,95,7692. M. Kwart and A. A. Kahn, J. Amer. Chem. SOC.,1967,89,1950. lo C. R. Johnson, R. A. Kirchhoff, R. J. Reischer, and G. F. Katekar, J. Amer. Chem. SOC., 1973,95,4287. D. Carr, T. P. Siden, and R. W. Turner, Tetrahedron Letters, 1969,477. Kennewell and Taylor cu \N' I ONa1 S0,Ar place. For high-yield preparative purposes the reaction appears to be limited to dimethyl sulphoxide. It has recently been shown that soluble copper salts are more convenient catalysts, providing the simplest preparation of SS-dimethyl-N-p-to1ylsulphonylsulphoximide.lo Homer and Christmann prepared a series of N-arylsulphonylsulphoximides by photolysis or thermolysis of arylsulphonyl azides in the presence of sul-phoxides.12 The yields were low and the reaction worked best when the sulphox- ide was used as solvent.The same authors found that photolysis of benzoyl azidc in DMSO resulted in the trapping of the generated nitrene by the solvent to give the N-benzoylsulphoximide. In an extension of this work Robson and Speakman generated nitrenes thermally, but not photolytically, from alkane- sulphonamidates (8) in DMSO solution, enabling them to prepare the hitherto unknown alkyl sulphonylsulphoximides. l3 Conversely the related alkanamidates (9) did not decompose to give sulphoximides under photolytic or thermolytic conditions.The reaction of carbamoyl azides (10) with aryl sulphoxides pro- vided the corresponding N-carbamoylsulphoximides in low yields.14 Thermolysis of the dioxazolines (11) in DMSO gave the N-aroylsulphoximides in good yields.15 The base-catalysed elimination reactions of the N-arylsulphonoxy- sulphonamides (12) with DMSO gave the related N-arylsulphonylsulphoximides, albeit in poor yields.16 Pentafluorophenyl azidel7 and 4-azidotetrafl~oropyridine~~decompose la L. Homer and A. Christmann, Chem. Ber., 1963,96,388. lS G. Robson and P. R.H. Speakman, J. Chem. SOC.(B),1968,463. l4 V. J. Bauer: W. J. Fanshawe, and S. R. Safir, J. Org. Chem., 1966,31,3440. 16 J. Sauer and K. K. Mayer, Tetrahedron Letters, 1968, 319. l6 M. Okahara and D.Swern, Tetrahedron Letters, 1969,3301. l7 R.E. Banks and A. Prakash, J. C. S.Perkin I, 1974,1365.'' R.E. Banks and G. R.Sparkes,J. C. S.Perkin I, 1972,2964. me Sulphoximides thermally in DMSO at high temperatures to give moderate yields of the N-aryl- sulphoximides. 2-(p-Tolylsulphonyloxyimino)pyrrolidinedecomposes in DMSO to give, after basification, the sulphoximide (13) in high yield.19 0 Rees and his co-workers have prepared a series of N-aminosulphoximides such as (14) from the corresponding N-aminolactams by lead tetra-acetate oxidation in the presence of a wide variety of sulphoxides.20 The reaction has been used to synthesize the optically active sulphoximides (15) in high yield from optically active sulphoxides.21 The formation of analogous N-amino-SS-dimethylsulphoximideshas been used to assign the structure to cyclic products obtained from 1,2-dicarboxylic anhydrides with hydrazine.24 Ohashi and his colleagues synthesized N-sulphonylsulphoximides (16) by oxidation of primary sulphonamides with lead tetra-acetate in DMS0,23 but the reaction could not be extended to the synthesis of N-sulphamoylsulphoxiides (17).24 Perhaps the most versatile method of preparing sulphoximides has been introduced by Tamura and his co-workers who demonstrated that a wide variety of sulphoxides undergo ready amination under mild conditions with O-mesitylene- sulphonylhydroxylamine (MSm.25 The main restriction is the limited stability Is A. Le. Beme, C. Renault and P. Giraudeau, Bull.SOC.chim.France, 1971,3245. ao D. J. Anderson, D. C. Horwell, E. Stanton, T. L. Gilchrist, and C. W. Rees, J. C. S. Perkin I, 1972,13 17. a1 S. Colonna and C. J. M. Stirling, Chem. Comm.,1971,1591 ;J. C. S. Perkin I, 1974,2120. aa B. Stanovnik and M. Tisler, Org. Prep. andProc., 1973,5,87. M. Okahara, K. Matsunaga, and S. Komori, Synthesis, 1971,96. M. Okahara, K. Matsunaga, and S. Komori, Synfhesis,1972,203. 2.5 Y.Tamura, K. Lumoto, J. Minamikawa, and M. Ikeda, Tetrahedron Letters, 1972,4173. Kennewell and Taylor of MSH even in solution at room temperature which prevents the use of more forcing conditions. Stoss and Satzinger have used MSH to prepare some previously unobtainable tricyclic sulphoximides (1 8) in good yieldsq26 Recently it has been established that sulplioxides react with O-acetyl-p-nitro- benzohydroxamic acid to give the N-(p-nitrobenzoyl)suIphoximides, base hydrolysis of which liberates the free s~lphoximides.~7 The direct oxidation of sulphimides (19), readily accessible by a variety of 0 0II R'R2NS02N=SMe2 0 IIX=CH,,C,O,S,NR (18) synthetic methods, in principle offers an attractive route to the sulphoximides.To date, no oxidant offers any improvement over potassium permanganate or the peracids, both of which frequently give poor yields.28~29~30 A route to ap-unsaturated sulphoximides is provided by the reaction of olefins and acetylenes with N-tosylalkyliminosulphonylchlorides (2O).31 P. Stoss and G. Satzinger, Tetrahedron Letters, 1974, 1973.''Goedecke A.-G., Ger. P. 2 220 256 (Chem. Abs. 1974,80,26 991). a* H. R. Bentleyand J. K. Whitehead, J. Chem. Soc., 1950,2081. G. Kresze and B. Wustrow, Chem. Ber., 1962,95,2652. 30 D. R. Rawer, D. M. von Schriltz, J. Day, and D. J. Cram,J. Amer. Chem. SOC.,1968,90, 2721. s1 Ya. N. Derkach, N. A. Pasmutseva, L. N. Markovskii, and E. S. Levchenko, Zhur. org.Khim., 1973,9,1411. The Sulphoximides 0 II I R-s=N'Jos CI CH?=CHPh) 0 0 il I NEt3 > R-S=NTosR=S=NTOS CHzCHPh I II 1 CH=CHPh (20) HCzCPh 0 0 II II R-S =NTos R-S=NHII CH-CPh CH=CHPh I CI 3 Physical Properties Since the first reports by Bentley and Reiner describing the sulphoximides very few spectral data have been published. Some Lr., n.m.r., and m.s.studies have been published by Oae and his group,32 who reported that all the sulphoximides studied exhibited strong i.r. absorption bands at 3200-3250 cm-1 (N-H stretch) and 1200-1230 cm-l (N-S=O stretch) not correlatable with changes in structure. In addition further characteristic bands were observed around 1100 and lo00 cm-l. The chemical shifts in the n.m.r. spectra were similar to those for the corresponding sulphones, the increased acidity of the a-methylene protons in the sulphoximides being reflected in a small downfield shift. The sulphoximide group thus appears to be slightly more electron-withdrawing than the sulphone and considerably more so than the sulphoxide. The chemical shift of the imino proton appears at nearly the same position (7-8 7) regardless of substitution on sulphur, and the proton is readily exchanged with D2O.The marked solvent effects observed in the n.m.r. study, namely pronounced down- field shifts in protic as compared with aprotic solvents, indicate strong solvation of the sulphoximide groups. Corroborative data was obtained in a U.V. study by Bara~h.~~ The ready solubility of sulphoximides in protic solvents, such as water and alcohols, compared with that of the corresponding sulphones is considered to result from the relatively large pKa values for the sulphoximides. (Typical pKa values are in the range 1.5-2.9.34) The mass spectra of some arylalkylsulphoximides have been rationalized in terms of an initial aryl to nitrogen migration giving the sulphinyl anilide cation 3a (a) N.Furukewa, K. Taujihara, Y. Kawakatsu, and S. Oae, Chem. and Znd., 1969, 266; (6) S. Oae, K. Harada, K. Tsufihara and N. Furukawa, Internat. J. Sulphur Chem. (A), 1972,2,49 33 M. Barash, Chem. and Ind., 1964, 1261. s4 S. Oae, K. Tsufihara,and N. Furukawa, Chem. and Ind., 1968,1568. Kennewell and Taylor (21) which subsequently fragments.a2 For N-substituted sulphoximides, in the absence of competitive rearrangements, the mass fragments are largely derived from the ion (22). Phenyl to nitrogen migration does take place, but the rearrange- ment no longer predominate^.^^ 0 II H Ar-S-R'.[ B ]+'Ar-N--S-R2 II N=C=O Hydrogen-exchange reactions of sulphoximides and sulphimides with D2O in alkaline media indicate that the a-protons in sulphoximides are markedly less a~idic.3~ The nature of the bonding to SIV has been the subject of debate for some considerable time.a7 Mixan and Lambert carried out an ESCA study on a series of derivatives of benzyl methyl suphide to provide information on the nature of the sulphur-nitrogen bond.38 From the measurement of the S(2p) binding energies for the compounds they concluded that, although the actual nature of the bonds must lie between the covalent and semipolar extremes (23 and 24), the N-tosylsulphimide (23, R = Tos) is more polar than the sulphoxide (24) and that the N-tosylsulphoximide (25) is more polar than the corresponding sulphone. Their work suggested that there is little difference in polarity between the S=NH and S=O bond.The N(1s) binding energies indicated that although the S=N bond is more polar in (25, R = Tos) than in the parent sulphoximide (25, R = H), the electron-withdrawing nature of the N-tosyl group leaves a smaller negative charge on nitrogen. 4 Synthetic Applications The sulphoximide group is an extremely versatile one for organic synthesis by virtue of the amphoteric nitrogen, the acidic a-methylene protons, and the chiral sulphur atom. The reactions of sulphoximides can be conveniently divided into their use as a versatile source of new ring systems and, alternatively, as alkylidene transfer reagents. The first new ring system incorporating the sulphoximide group was reported by Stoss and Satzinger who obtained the benzoisothiazoles (26) via the Schmidt C.P. Whittle, C. G. MacDonald, and G. F. Katekar, Org. Mass Spectrometry, 1974,9,422. M. Kobayashi, A. Mori, and H. Minato, Bull. Chem. SOC.Japan, 1974,47,891. 37 A. W. Johnson in 'Organic Compounds of Sulphur, Selenium, and Tellurium', ed. D. H. Reid (Specialist Periodical Reports), The Chemical Society, London, 1973, Vol. 2, p. 322. 30 C. E. Mixan and J. B. Lambert, J. Org. Chem., 1973,38,1350. me Sulphoximides -Me Me B~--S=NRI B~--s~RI+ (23) reaction of the esters (27).39 The products exhibit remarkable chemical stability. In a subsequent extension of this work the same authors synthesized the analo- gous 6-and 7-ring systems (28 and 29).40 The generation of a sulphoximide group during ring closure was also used by Cram and Williams to synthesize the ring systems (28), (30), and (31).4l Other ring systems (32), (33), (34), (35),42 and (36)43 have been synthesized utilizing the nucleophilic character of the sulphoximide nitrogen and the acidity of the a-methylene protons.The thiazine (34) was synthesized in an optically pure form starting from (-)-(R)-p-tolyl-methyl-sulphoximide. In a recent publication Stoss and Satzinger have described the synthesis of a series of tricyclic sulphoximides (1 8).26 Aikylidene Transfer Reagents.-Although Johnson has recently reviewed the work of his group on the synthesis and reactions of the ylides derived from ~ulphoxirnides,~~it is felt that the importance of this work in synthetic chemistry is such that a short review of the work is relevant.The general principle involves the reaction of an ylide (37), in which the carbanion is stabilized by resonance with an electron-deficient sulphur atom, with a carbonyl group or an electrophilic double bond. The first-formed betaine (38) collapses to give a three-membered ring with the expulsion of a sulphur species (Scheme 2). P. Stoss and G. Satzinger, Angew. Chem. Internat. Edn., 1971, 10,76. 40 P. Stoss and G. Satzinger, Chem. Ber., 1972,105,2575. T. R. Williams and D. J. Cram, J. Org. Chem., 1973,38,20. A. C. Barnes, P. D. Kennewell, and J. B. Taylor,J.C.S. Chem. Comm., 1973,776. 4s C. R. Johnson, G. F. Katekar, R. F. Huxol, and E. R. Janiga, J.Amer. Chem. SOC.,1971, 93,3771. 44 C. R. Johnson, Accounts Chem. Res., 1973,6,341. Kennewell and Taylor It can be seen that the sulphur group in (37) needs to provide the ylide with the correct degree of stability. If the ylide is too stable then formation of the betaine is too slow and if it is too reactive then a-elimination to give a carbene becomes the dominant reaction. The function also needs to be a good leaving group to facilitate breakdown of the betaine. Corey and Chaykovsky first showed =s I + I Scheme 2 The Sulphoximides that ylides (39) and (40) generated by strong bases from trimethyloxosulphonium chloride and trimethylsulphonium iodide would act as methylene transfer reagents with aldehydes and ketones to give oxirans.45 0 II +-Me,S3-CH, Me,SCH, Although (39) anti (40) are readily prepared and furnish high yield reactions, the extension from methylide to alkylide is not easy owing to the difficulty of S-alkylation of sulphoxides and the extreme instability of the corresponding ylides.46~47 Consequently Johnson introduced the three sulphoximide-derived reagents (41),48 (42),49 and (43)50which are prepared by the strong base deproto- nation of dialkylaminoalkylaryloxosulphonium fluoroborates, dialkylamino- dimet hyloxosulphonium fluoro borate, and a1 kyl aryl N-t osylsulphoximides. Such reagents are not only readily prepared, but are also very stable, the ylide (41) (R1= R2 = H) remaining unchanged in DMSO solution at room tempera- ture for two months.NMcz NMc, N Tos Whilst ylide (42) was introduced specifically as a methylene transfer reagent, (41) and (43) are more versatile and the groups studied include methyl, ethyl, isopropyl, cyclohexyl, and cyclopentyl. The precursors (41) are readily prepared by exhaustive alkylation of the appropriate alkyl aryl sulphoximide with tri- alkyloxonium fluoroborates, whilst alkyl aryl N-tosylsulphoximides are available by the synthetic routes discussed earlier. The reagents react with aldehydes and ketones to give oxirans, with imines to give aziridines, and with electrophilic olefins to give acyl cyclopropanes (Scheme 3). In the latter reaction, it is found 45 E. J. Coreyand M. Chaykovsky,J. Amer. Chem. SOC.,1962,84,867; ibid., 1965,87,1353. E.J. Corey, M. Jautelat and W. Oppolzer, Tetrahedron Letters, 1967,2325; E. J. Corey and M. Jautelat, J. Amer. Chem. SOC.,1967, 89, 3912. 47 For the preparation and uses of the much more stable diphenyl sulphonium cyclopropylide see B. M. Trost and M. J. Bogdanowicz, J. Amer. Chem. SOC.,1971,93,3773. 48 C. R. Johnson, E. R. Janiga and M. Haake, J. Amer. Chem. SOC.,1968, 90, 3890; C. R. Johnson, M. Haake, and C. W. Schroeck, ibid., 1970,92,6594; C. R. Johnson and E. R. Janiga, ibid., 1973,95, 7692. 48 C. R. Johnson and P. E. Rogers, J. Org. Chem., 1973,38,1793. C. R. Johnson and G. F. Katekar, J. Amer. Chem. SOC.,1970,92,5753. 198 Kennewell and Taylor that irrespective of the geometry of the starting olefin, the stereochemistry of the cyclopropane is trans.0 .,I1Ar-S-CR1R2 4-ArSONMe.)0K+ I 0)iC.NMez R2 0 RI R, 0II ll --"A rCH=C H COA r $-Ar-S-CR,R, P-x -I-ArSNTosII NTos h, Na '. Scheme 3 The cyclopropyl ylide (41) (RlR2 = -CH2CH2-) is especially interesting because it reacts with electrophilic olefins to give spiropentanes (e.g. Scheme 4), but does not add to carbonyl groups except that of cyclohexanone, when the presumed intermediate oxaspirapentene (44)rearranges to the cyclobutanone (45). These results should be contrasted with those of Trost who succeeded in transferring cyclopropyl groups from diphenyl sulphonium cyclopropylide to carbonyl groups to give 0xaspiropentanes.~7 (44) (45) Scheme 4 Whilst the different ylides discussed have many reactions in common, there are some intriguing differences between them; in particular the ylide (40) appears to be a species apart.Thus with 4-t-butyl-cyclohexanone the ylide (40) gives the The Sulphoximides E oxiran and the others the Z isomer; and with +unsaturated ketones the ylide (40) gives vinyl oxirans whereas the rest give acyl cyclopropanes.51 A further advantage of (41) and (43), over (39) and (40) is that the sulphur atoms are chiral and the resultant ylides can be obtained in optically active forms. The reactions of these optically active ylides with achiral olefins, aldehydes and ketones lead to the induction of optical activity in the resultant oxirans and cyclopropanes. This point will be discussed in greater detail in the section on stereochemistry.Reactions of Sulphoximide Carbanions.-In addition to the transfer reactions described above, a number of other reactions involving sulphoximides have been described. As has been shown previously, the alkyl protons of an alkylsulphoxi- mide are sufficiently acidic to be removed by strong bases. Condensation with aldehydes such as benzaldehyde gives the isolable hydroxy alkyl sulphoximides (46) which undergo three new reaction^.^^^^^^^^ Dehydration followed by alkylation gives the salt (47), a powerful Michael receptor, which with dibasic nucleophiles produces a range of novel products (Scheme 5). 0 OH ArII I i. -HzOAr-S-CH,-CHAr ii,Me30+ BF4-) uHBFI-II rsqo NMe H AF “Me, (46) (47) -* Ar-C-C-S-NMe2 IllH H Ar H H Ar Scheme 5 61 C.R. Johnson and C. W. Schroeck, J. Amer. Chem. SOC.,1971,93, 5303; C. R. Johnson, C. W. Schroeck and J. R. Shanklin, ibid., 1973,95,7424. 6p C. R. Johnson and J. P. Lockard, Tetrahedron Letters, 1971,4589, 6a C. W. Schroeck and C. R. Johnson, J. Amer. Chem. SOC.,1971,93,5305. 64 C. R. Johnson, J. R. Shanklin, and R. A. Kirchhoff, J. Amer. Chem. SOC.,1973,95,6462. Kennewell and Taylor The sulphoximide (46) can also be reduced by aluminium amalgam in aqueous THF, this reaction removing the sulphur and generating an alcohol (Scheme 6). The condensation product (46) contains two asymmetric centres ;the diasterec- 0II IIAr-S-CH,-CHAr OHI 0 II ArSNHMe OH I+ CH,-CHAr NMe Scheme 6 mers can be separated, and subsequently reduced to yield the optically pure alcohols.Under these conditions no hydrogenolysis or racemization of the benzylic position occurs.When acetic acid is added to the reaction mixture in the reduction step dehydration results, giving rise to olefins (Scheme 7). 0 R OHII I I Ar-S-CH-CHAr ___) ArCH =CHR IINMe Scheme 7 When R # H the olefinic products are mixtures of cis-and trans-isomers. Further transformations result when the ylide is contained in a ring structure (48).55 -H NMe, In these cases, the betaine (49) is readily formed on reaction with an olefm or a carbonyl group, but its breakdown now involves ring opening and the sulphini- mide is part of the final structure (50)."C. R.Johnson and L.J. Pepoy, J. Org. Chem., 1972,37,671. TheSulphoximides 5 Stereochemistry In one of their original publications, Bentley’s group suggested that, by analogy with sulphones, the sulphur atom in a sulphoximide should be tetrahedral and that when the groups on sulphur are different the molecule should be chira1.56 The tetrahedral orientation of the atoms around the sulphur atom has been verified by X-ray crystallography~7~58 and electron-diffraction studies,59 whilst chirality was first demonstrated by the separation of the diastereomers of (51) prepared by condensing racemic S-p-nitrophenyl-S-methyl-sulphoximidewith optically active 4-(3-menthyl)benzenesulphonyl chloride.6O Subsequently S-methyl-S-(3-carboxypheny1)-N-benzenesulphonylsulphoximide(52) was resolved (51) (52) via salt formation with (-)-a-phenylethylamine,29 and S-phenyl-S-methyl- sulphoximide via salt formation with (+)-10-camphorsulphonic acid.61 The preparation of optically active sulphoximides from both sulphoxides and sul- philimines using the various synthetic methods discussed previously has been the subject of a number of papers.It has recently been shown that the reaction of MSH with optically active sulphoxides is the best general method for preparing, in high yield, sulphoximides with high optical purity.62 The resolved sulphoximides have, to date, found two principal applications in asymmetric induction, particularly during alkylidene transfer reactions, and in the investigations of the stereochemistry of reactions on the sulphur atom.The alkylidene transfer reactions from racemic dialkylamino phenyloxosul- phonium alkylides to alkenes, aldehydes, and ketones have been discussed pre- viously. Alkylation of sulphoximides with trialkyloxonium fluoroborates H. R. Bentley, E, E. McDermott, and J. K. Whitehead, Proc. Roy. SOC.,1951, B138,265. 51 B.W.Christensen, A. Kjaer, S. Neidle, and D. Rogers, J.C.S. Chem. Comm.,1969, 169. G. D. Andreetti, G. Bocelli, and P. Sgarabotto, Cryst. Struct. Comm., 1973,2, 171. kB M.Oberhammer and W. Zeil, Z. Naturforsch., 1970,25a, 845. 6o M.Barash, Nature, 1960,187, 591. 81 R.Fusco and F. Tenconi, Chimicu e Industria, 1965,47,61. C. R. Johnson, R. A. Kirchhoff, and H. G. Corkins, J.Org. Chem., 1974,39,2458. Kennewell and Taylor proceeds with retention of configuration and the resultant ylides, generated by sodium hydride in THF or DMSO, react with electrophilic olefins, aldehydes, and ketones to yield optically active cyclopropanes and 0xirans.~3 In all cases where comparative data are available the optical purities of the products are the highest reported during asymmetric synthesis. Thus the ylide from dimethyl- amino-methyl-p-tolyloxosulphoniumfluoroborate reacts with trans-methyl cinnammate to give (+)-(1S, 2S)-trans-methyl-2-phenyl-cyclopropanecarboxy-late in 30.4%optical purity. Even greater asymmetric induction results when a substituted methylide is transferred to a symmetrical ketone or a terminal methylene group since here the carbon of the ylide becomes the chiral centre. An example is the reaction of (+)-(R)-dimethylamino-ethyl-p-tolyloxosul-phonium fluoroborate with methyl acrylate which gives, after hydrolysis, (+)-(1S, 2S)-trans-2-methyl-cyclopropane-carboxylicacid with an optical purity of 43%.A different type of asymmetric induction is involved in the chlorine transfer reaction between (+)-(S)-N-chloro-methyl-phenyl-sulphoxi-mide and 2,2-diphenylaziridine to give (+)-N-chlor0-2,2-diphenylaziridine.~~ The extent of asymmetric induction in this case is not known. The mechanisms and stereochemistry of reactions on tetrahedral sulphur are of considerable interest.65 The ease and variety of methods for preparing sulphoximides from sulphoxides and sulphilimines, and the versatility of their reactions have resulted in sulphoximides being widely used in such studies.The work of Cram66 on stereochemical reaction cycles involving, inter aka, sulphoxi- mides, has been recently reviewed67 and attention will here be concentrated on those reactions involving sulphoximides. The sequence of reactions which con- stitutes the first example of a monoligostatic stereochemical reaction cycle, i.e. one in which only one ligand is common to all the chiromers in the cycle is outlined (Scheme 8).68 This represents the culmination of a number of smaller cycles. The absolute configuration of (+)-(R)-p-tolyl-methyl-sulphoxide(53) has been established by X-ray crystall~graphy,~~ that of (-)-(R)-S-methyl-S-p-tolyl-N-tosylsulphoximide(54) by X-ray crystallography of its N-(3-endo-bromo- 2-0x0-9-bornane-sulphonyl)derivative, and that of the sulphilimine (55) by the phase-diagram method.66 Once the configurations of (55) and (54) were known it could be shown that the conversion of (53) to (55) occurs with inversion of con- figuration and those from (53) to (54) and (55) to (54) with retention.De- imidation of the sulphoximide (56) to sulphoxide (53) also proceeds with retention as has also been found in the deimidation of L-methionine-S-(or R)-sulphoximide C. R. Johnson and C. W. Schroeck, J. Amer. Chem. SOC.,1973,95,7418. 64 R. Annunziata, R. Fornasier, and F. Montanari, J.C.S. Chem. Comm., 1972, 1133. O5 K. K. Andersen, Internat.J. Sulphur Chem. (B), 1971,6,69. 66 D. J. Cram, J. Day, D. R. Rayner, D. M. von Schriltz, D. J. Duchamp, and D. C. Garwood, J. Amer. Chem SOC.,1970,92,7369. G. C. Barrett, ref. 37 p. 45. T. R. Williams, A. Nudelman, R. E. Booms, and D. J. Cram, J. Amer. Chem. SOC.,1972, 94,4684. 6@(a) M. Axelrod, P. Bickart, J. Jacobus, M. M. Green, and K. Mislow, J. Amer. Chem. Sac., 1968,90,4835; (b) M. Hope, U. de la Camp, G. D. Homer, A. W. Messing, and L. H. Sommer, Angew. Chem. Internat. Edn.. 1969, 8, 612. The Sulphoximides m-CPBA retention MeMgBr inversionr2 J. TosNMe TosN-\ \\:ms=o MeCc/S=O 8 8 f01 fol (-1 -(W(54) TosCltretention MeN HN \\ HCHO-HC02 H \\MebS=O Meb,S =08 I retention 6I ToI TI01 to L-methionine-S(or R)-sulphoximide with nitrous acid.70 Detosylation of (54) to (56) and methylation of (56) to (57) do not involve the chiral centre and are assumed to proceed with retention of configuration.For further verification (-)-(R)-(56) was tosylated to (-)-(R)-(54). By analogy with other nucleo- philic substitutions on sulphinamides if it was assumed that the conversion of (58) to (53) involves inversion, the cycle then requires that the curious demethylation of (57) to (58) occurs with retention of configuration. It was therefore concluded that the substitution reactions leading to the sulphoximides studied can be re- garded as electrophilic attack on the sulphur lone-pair electrons proceeding with retention of configuration. The desubstitution reactions which leave a lone pair of electrons on the sulphur atom also proceed with retention of configuration. The conclusions reached from studies of acyclic compounds have recently been confirmed for the cyclic compound shown in Scheme 9.71 The generalization 'O R.A. Stephaniand A. Meister, Tetrahedron Letters, 1974,2307. 71 F. G. Yamagishi, D. R. Rayner, E. T.Zwicker, and D. J. Cram, J. Amer. Chern. Soc., 1973, 95,1916. 204 Kennewell and Taylor that electrophilic attack on sulphur proceeds with retention of configuration is found to hold. t "yJ) L xm //"b p...0 *NH 0 NTOS (-)-W (-)-(R) Reagents: i, TosN=S=O; ii, HaSol; iii, KMnO,; iv, TosC1; v, HNOI. Scheme 9 6 The Aromaticity of Azathiabenzene-S-oxides The preparation, reactions, and electronic structures of the SIV and SVI hetero-cycles, thiabenzenes and thiabenzene-S-oxides, have been the subject of a number of st~dies.~~$7~*~~ Of particular interest is the nature of p,,-d,, bond between the sulphur atom and its adjacent atom, and the possibility of con-jugation through this bond in potentially 'aromatic' cyclic conjugated systems.75 The reactions, stabilities, and proton and 13C n.m.r.spectra of such com- pounds have shown that genuine thiabenzenes (59) and thiabenzene-S-oxides (34) are not aromatic and that ylidic forms (59b, c) are significant contributors to their resonance structure. The synthesis of conjugated cyclic sulphoximides has been described and those proton n.m.r. shifts which provide information pertaining to the aromaticity of these azathiabenzene-S-oxides are listed (Table 1).41s42976 From the results available 3-H lies between 1.5 and 1.87, 4-H between 3.3 and 3.47 and 6-H between 3.9 and 4.757.For the interpretation of such chemical shifts in terms of aromaticity the choice of model compounds is always a matter of contention, G. H. Sinkler, Jun., J. Stackhouse, B. E. Maryanoff, and K. Mislow, J. Amer. Chem. SOC., 1974,96,5648, 5650, and 5651. A. G. Hortmann, R. L. Harris, and J. A. Miles, J. Amer. Chem. Soc., 1974,96, 6119. 74 A. G. Hortmann and R. L. Harris, J. Arner. Chem. SOC.,1971,93,2471. "D.H. Reid, ref. 37 p. 341 ;W. G. Salmond, Quart. Rev., 1968,22,253. "Y. Tamura, T. Miyamoto, H. Taniguchi, K.Sumoto, and M. Ikeda, Tetrahedron Letters, 1973,1729. Table (CDC13 solution; shiJts in r values) Compound 3-iH 4-H 6-H Reference 41 42 COzEt 41 76 COR 206 Kennewell and Taylor but 3-carbethoxy-4-hydroxypyridine(60)and vinyl methyl sulphoxide (61) were chosen as models for 4-carbethoxy-3-hydroxy-l-phenyl-1,Zthiazabenzene (62). It can be seen that whereas 3-H of (62) lies close to 2-H of (60), 6-H lies upfield of l-H in (61); a logical explanation is that the 6-H shift reflects the lack of aromaticity of the system whilst the low-field shift of 3-H results from the in- ductive effect of the nitrogen atom. Furthermore, in the benzo-[e]-1,2,4-thiadi- azine (63) the shift of 3-H is clearly closer to the open-chain model (64)than the aromatic quinazoline (65). These conclusions are supported by the 13C n.m.r.shifts for (62). The low solubility of the pyridine model (60) prevented its 13C n.m.r. spectrum from being recorded and shifts had to be compared with those in ethyl salicylate (66) and 1,3,5-trimethylthiabenzene-l-oxide(67). However, C-4 (97.48) in (62) is considerably shielded relative to C-2 in (66) (78.66), and C-6 (113.88) can be directly compared with C-6 in (67) (109.1). These high shieldings were interpreted as showing the considerable carbanionic nature of C-4 and C-6, suggesting significant contribution from the ylide structures (62a, b). All these studies, coupled with the more complete analysis of thiabenzene-S- oxides strongly indicate that the compounds are not aromatic and that ylidic structures are a better representation of their true nature.7 Applications of Suiphoximides Patents have appeared claiming a wide variety of uses for sulphoximides. Thus methionine sulph~ximide,~~ its saltsY78 and amides have been suggested as cotton defoliants and herbicides, whilst simple long-chain alkylsulphoximides (68) have been patented as detergent^,^^ lubricating oil additives,gO corrosion in- hibitors for ferrous metals in contact with acids,sl and as one element of a three- element catalytic system for polymerization of olehs.82 Patented alkyl N-sub- st i tu ted sulp hoximides include the anti- bac ter ial and ant i-fungal S-me t hyl-S- dec yl-N-chl orosulp hoximide, 83 the phosphorus-subs t i t u ted sulphoximides (69) claimed as pesticides,84 and a fabric softener (70).85 Amongst applications mentioned for arylalkylsulphoximides, (71) has herbi- cidal and pest icidal act ivi ty8 whilst the SS-diphen yl-N-(a1 kylaminoalky1)sulph- oximides (72) are anti-spasm0dics.8~ Other pharmacologically active sulphoximides include the indole derivative (73)88 (claimed as a muscle-stimulant), the benzo- ?' Monsanto, U.S.P.3 179 510; American Cyanamide, U.S.P. 3 323 895. 78 American Cyanamide, U.S.P. 3 295 949.'@ The Proctor and Gamble Company, U.S.P. 3 255 116. The Chevron Research Company, U.S.P. 3 376 338. The Proctor and Gamble Company, U.S.P. 3 535 240. 82 Eastman Kodak Company, U.S.P. 3 026 31 1.''The Proctor and Gamble Company, U.S.P.3 557 206. *I''The Proctor and Gamble Company, U.S.P. Roussel-Uclaf, Ger. P. 2 247 191. 3 637 496. Shell International Research, Ger. P. 2 129 678. Warner Lambert, B.P. 1 168 700; see also ref. 6. '* Merck. Sharpe and Dohme Corporation, Ger. P. 2 062 017. The Sulphoximides thiodiazines (74) (antihypertensives),*O the benzothiazines (7990 (anti-secretory agents), and the benzisothiazolones (26) which are claimed to reduce blood sugar levels.39 The benzothiadiazepine-S-oxides(76) have been claimed to have CNS-depressant activity albeit at a much lower level than the corresponding benzo- 1,4-diazepines.91 Ph 2.5-2.3 HO C0,Et CO,Et C0,Et CO,Et (62a) (62b) Beiersdorf A.G., Be1g.P. 814 400. Warner Lambert, U.S.P.3 803 131, @l E. Cohen and J. Mahnke, Chem. Ber., 1972,105,757. Kennewell and Taylor 0 0 0 0II II II II -I--R-S-R (R0)2PSCHZCON=SR2 R,S=NPR, C1IINH (68) (49) (70)

ISSN:0306-0012    

DOI:10.1039/CS9750400189

出版商:RSC    

年代:1975

数据来源: RSC

摘要:

The Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena By M. R. J. Dack RESEARCH SCHOOL OF CHEMISTRY, AUSTRALIAN NATIONAL UNIVERSITY, CANBERRA, AUSTRALIA, 2600 1 Introduction Intermolecular forces give a liquid its cohesion. The attractive forces mainly comprise hydrogen bonding, dipole-dipole, multipolar, and dispersion inter- actions. Repulsive forces, acting over very small intermolecular distances, play a minor role in the cohesion process under normal circumstances. Cohesion creates a pressure within a liquid of between lo3and 104 atmospheres. Dissolved solutes experience some of this pressure, and the amount of pressure on the solutes increases whenever they interact with solvent through hydrogen bonding, charge-transfer, coulombic, or van der Waals interactions.Thus a solute in solution is subject to a ‘structural pressure’ from the solvent and a ‘chemical pressure’ from interactions with the solvent. The solution exists under a higher internal pressure than the pure solvent. This concept of internal pressure provides an excellent basis for examining solution phenomena. The first review of the subject by Richards1 appeared in 1925, but the full potential of internal pressure as a structural probe did not become apparent until Hildebrand‘s2J work a decade later. A liquid undergoing a small, isothermal volume expansion does work against the cohesive forces which causes a change in the internal energy, U.The function (aU/i3V)~is known as the internal pressure, Pi.Hildebrand showed that for non-polar liquids, (aU/aV)!P = nA UVap/V, where A Uvap represents the energy of vaporization of the liquid and V its molar volume. The quantity, n, approaches unity for non-polar liquids, and so Pi can be equated to dUvap/ V, the cohesive energy density. For polar liquids, however, n ranges from 0.32-1 .62.4 Internal pressure and cohesive energy density (c.e.d.), evidently, do not reflect the same physical property of these liquids. Many workers have failed to discriminate between Pi and c.e.d. One of the aims of this Review is to analyse the physical significance of Pi and c.e.d. and to demonstrate the usefulness of both properties in the light of their differences. We also intend to show the ability of the pressure concept5 to explain many T.W. Richards, Chem. Rev., 1925,2, 315. J. H. Hildebrand and R. L. Scott, ‘Solubility of Non-Electrolytes’, 3rd Edn., Reinhold, New York, 1950. J. H. Hildebrand and R. L. Scott, ‘Regular Solutions’, Prentice-Hall, Englewood Cliffs, New Jersey, U.S.A., 1962. ‘G. Allen, G. Gee, and G. J. Wilson, Polymer, 1960, 1, 456. G. Tammann, 2.phys. Chem., 1893,11, 676. 211 The Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena observations in solution. The approach successfully predicted isothermal compressibilities and coefficients of thermal expansion for dilute aqueous solutions in 1929,6 and it related internal pressure to the electrostatic field of dissolved ions as early as 1894.7Interest in Pi and c.e.d.has increased in recent years. Thus, we feel that the time is appropriate to examine such topics as solvent structure, salt effects, conductivity, chemical reactivity, spectroscopy, molal voIumes, and solubility with these properties in mind. The work cited below is illustrative rather than exhaustive, and the features discussed tend to be salient rather than detailed. In this way we hope that the reader will acquire more rapidly a feeling for this old, but newly rediscovered concept of solvent pressure. 2 Physical Significance of Internal Pressure and Cohesive Energy Density A. Measurementof Pi and C.E.D.-Cohesive energy densities are readily obtained from experimentally determined heats of vaporization, AHvap, via the relationship where M and p are the molecular weight and density, respectively, of a liquid at a temperature, T K.Heats of vaporization, mostly obtained from vapour pressure data, are unavailable for some liquids. Small8 has assembled existing heat of vaporization data for a large number of non-associated liquids and has assigned values for the molar attraction constant, (AUvBpV)+,to constituent groups in the liquids. Addition of the individual molar attraction constants enables an estimate to be made of the c.e.d. of new liquids or compounds. This method would not be able to predict the c.e.d. of liquids in which hydrogen bonding contributed to the cohesion. Table 1 contains the cohesive energy densities (cal cm-3) of a selection of common organic solvents at 25 "Cobtained directly from AHvap.Internal pressure is obtained by using the so-called 'thermodynamic equation of state'? For most liquids, the thermal pressure coefficient, (aP/aT)v,multiplied by the absolute temperature is many thousands of atmospheres, so that the atmospheric pressure, P, becomes negligible by comparison. Measurement of Pi is thereby reduced to measurement of the thermal pressure coefficient. Apparatuses of various designs have been used in these mea~urements,~-~~ but they all operate on H. M. Evjen and F. Zwicky, Phys. Rev., 1929,33,860. P. Drude and W. Nernst, 2.phys. Chem., 1894,15,79. P. A. Small, J. Appl. Chem., 1953, 3, 71. 0 W. Westwater, H. W. Frantz, and J. H. Hildebrand, Phys. Rev., 1928, 31, 135.lo H. E. Eduljee, D. M. Newitt, and K. E. Weale, J. Chem. Sac., 1951, 3086. l1 C. F. Lau, G. N. Malcolm, and D. V. Fenby, Austral. J. Chem., 1969, 22, 855. la E. B. Bagley, T. P. Nelson, and J. M. Scigliano, J. Paint Technol., 1971,43,35. l3 A. F. M. Barton, J. Chem. Educ., 1971, 48, 156 l4 D. D. Macdonald and J. B. Hyne, Canud. J. Chem., 1971,49,611. Dack Table 1 Internal pressures (Pi) and cohesive energy densities (c.e.d.) for selected organic solvents at 25 "C Solvent c.e.d. c.e.d. Pi Pi (calc. (experi- (experi- (measured from Ta/R mental) mental) directly) Water (cal cm-9 550.2" (am) 22 703 (cal cm-3) 41.Oa (cal cm-3) 36b Formamide 376.46 15530 13Ic 1306 Ethylene glycol Methanol 213.2b 208.8b 8675 8615 1 28d 70.9e 120b 68.11 Propylene carbonate ca.182.3g ca.7522 1 2gC Dimethyl sulphoxide 168.6a 6955 123.7a4 1206 Ethanol 161.3b 6655 69.5f Nitromet hane 158.8' 6550 I-pro pano 144.01 5941 68.8f Dimethylformamide 1 39.26 5743 1 14c Acetonitrile 1 39.2b 5743 96" 93b 2-Propanol l-Butaol 132.35 1143 5457 4724 67.0f 71.71 Pyridine Nitrobenzene t-ButylalcohoI 112.4" 110.35 108.2" 4636 4549 4463 8If Acetophenone Carbon disulphide Methyl iodide Dioxan 108.25 100.0' 98.01 94.7k 4463 4126 4044 3906 89.0" 9o.v 89.5f 119.3f Acetone 94.3k 3890 79.9 809 Tetrahydro furan 86.9" 3584 Chloroform 85.4" 3523 88.Y Benzene 83.7k 3454 88.4m 90.5f Ethyl acetate 81.7k 3372 84.5f Toluene 79.4k 3276 84.8f Carbon tetrachloride 73.61 3037 80.6hJ" 82.4b Cyclohexane 66.9k 2761 77.81 Diethyl ether 59.9k 2472 63.01 Hexane 52.4k 2163 57.If a Ref 14. * Ref. 40. C M.R. J. Dack, preliminary and unpublished results, 1974. Ref. 35. e Ref. 39. (Ref. 12 gives a value of 68.5 cal crn-91 Ref. 4 at 20 "C;values of Pi at 25 "C will be approximately 1-2 cal cm-* lower. Calculated from data extrapolated to 25 "C in 'Propy-lene Carbonate Technical Bulletin', Jefferson Chemical Co. Inc.,Houston, 1962. h Ref. 11.6 Ref. 2. f Ref. 52. k Ref. 48. Z Ref. 3. * Ref. 9. n Ref. 9 (Ref. 12 ghes a value of 78.8 cal cm-9. the same principle. A piezometer is filled to a known volume with the solvent or solution, and the temperature raised to cause expansion of the liquid.Pressure is then applied to restore the liquid to its original volume. The procedure is repeated many times. The Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena The thermal pressure coefficient can be equated to a/P,where a is the coefficient of thermal expansion and fi is the isothermal compressibility, Allen, Gee, and Wilson4 calculated Pi for a large number of pure liquids from Ta/fi,and although the values obtained are extremely useful, errors in the individual properties are compounded in the ratio. Direct measurement of (aP/aT)vis essential for accurate determinations of Pi, especially when differences in Pi between the solvent and very dilute solutions are being examined.Internal pressures (cal cm-3) for a number of solvents appear in Table 1. Multiplication of c.e.d. or Pi by 41.29 converts the values to atmosphere units for an easier evaluation of the pressures involved. B. Description of Pi and C.E.D.-The energy of vaporization is the energy required to break all the forces associated with one mole of liquid during removal of that mole from the liquid to the vapour state. Assuming negligible interaction in the vapour, values of c.e.d. therefore measure the total molecular cohesion per ml of the liquid. To understand the physical significance of internal pressure, one must con- sider a liquid undergoing a small, isothermal volume expansion. Total dis- ruption of all the interactions associated with one mole of liquid will not occur.We might intuitively expect those interactions varying most rapidly near the equilibrium separation in the liquid to make the most significant contribution to Pi. The statistical mechanical equation of statel5 leads to an expression for Pi which supports this view: pi= --2.rr p2KT r3$ (r)2(r)dr (3)3 The expression is derived from consideration of two-body interactions, where $(r) is the potential energy between a pair of molecules separated by a distance, r, and g(r)is the radial distribution function-the probability of finding a molecule at a distance, r, from the reference molecule. Summation of these functions for the system as a whole assumes an additivity of the pair potentials. The probability of finding a particle at a given point is given by the number density, p. An analysis of how the various components of equation (3) vary with intermolecular separation confirms the huge dependence of Pi upon rapidly varying interactions (i.e.repulsion, dispersion, and polar interactions). The statistical mechanical internal energy equationls converts into the fol- lowing expression for c.e.d. : Nc.e.d. = 27rp r3~(r)g(r)dr (4) where V is the molar volume. It is apparent from this treatment that Pi is not strictly a component of c.e.d. However, a number of experimental observations l6 For a discussion of statistical mechanical treatments, see R.0.Watts, Rev. Pure Appl.Chern. (Australia), 1971,21, 167. The author is indebted to Dr. Watts for the derivation of equations (3) and (4).Dack indicate that it may still be possible to regard Pi as measuring some part of c.e.d. Values of Pi approach those of c.e.d. in the case of non-polar liquids (see Table 1) where repulsion and dispersion interactions mainly occur. That is, the small volume expansion associated with Pi totally disrupts these interactions. The two properties are also approximately equal for weakly polar liquids (p < 2D), so that Pi successfully accounts for weak dipole-dipole interactions. Hamade has calculated the following values for liquid argon from the statis- tical mechanical data of Barker, Fisher, and Watts:17 Pi = 43.1 cal cm-3 and c.e.d. = 41.8 cal crn-I. These results agree excellently with experiment, and they illustrate the success of statistical treatments in explaining solution phenomena.The presence of hydrogen bonding in liquids causes the very large c.e.d. values in Table 1. Pi does not change in this way, and it appears that although hydrogen bonding varies rapidly with intermolecular separation, a localized and ‘chemical’ nature prevents its detection by a minute volume expansion. Thus, it may be concluded that Pi measures the polar and non-polar (non-chemical) interactions within a liquid. The quantity (c.e.d. -Pi) measures the intermolecular bonding energy due to hydrogen bonding. Bagley, Nelson, and Sciglianol2 have also arrived at this conclusion. Further support for this hypothesis will be generated in Section 3.C. Relationship between Pi, C.E.D.,and other Solvent Properties.-Coomberl8 found that a linear relationship exists between the internal pressure of non-polar liquids and their dielectric constants at high temperatures. This observation was subsequently justified theoretically.lg Deviations from the relationship which occurat lower temperatures are ascribed to an increased contribution of repulsive forces to As the liquid contracts on cooling, intermolecular separations decrease and repulsion between molecules becomes intensified. The sensitivity of Pi to its repulsive component can be judged from values at high compression for diethyl ether.21 The internal pressure decreases very slightly on increasing the external pressure from 200 to 5000 atm.Further compression causes such a dramatic decrease in Pi that it becomes highly negative. Clearly a point is reached in the intermolecular separation where repulsive forces completely dominate the attractive forces. Molar volumes reflect changes in the intermolecular separation as an external pressure is applied. Barton13 has discussed the relationship between Pi and molar volumes in some depth, and has shown that maxima occur in internal pressure-volume plots which can be detected at moderate pressures and temperatures. Calculations of the attractive versus repulsive contributions to Pi with respect to volume predict such be- havi~ur.~*~J~Attractive and repulsive forces both increase as the molar S.D. Hamann, personal communication, 1974.D. I. Coomber, Trans. Faraday SOC.,1939, 35, 304. l7 J. A. Barker, R. A. Fisher, and R. 0. Watts, Mol. Phys., 1971, 21, 657. lo G. H. Meeten, Nature, 1969, 223, 827. ao J. R. Partington, ‘An Advanced Treatise on Physical Chemistry’, Vol. 5, Longmans,London, 1950, p. 444. a* W. J. Moore, ‘Physical Chemistry’, 4th Edn.,Longmans,London,1965, p. 713. 215 The Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena volume (intermolecular separation) is decreased. Initially, the attractive com- ponent of Pi predominates, and Pi increases with decreasing volume. At smaller volumes, the repulsive component predominates, causing Pi to decrease. The observations above concerning diethyl ether were made at this region of the curve.It should be emphasized that intermolecular repulsion does not contribute greatly to Pi at normal temperatures and at atmospheric pressure. This fact enabled Cammarata and Yau22 to express the internal pressure for fifty solvents of low polarity in the following manner: faPi = 2.65 x lW*v3 where I and V are the molecular ionization potential (ev) and molar volume, respectively, and a is the molecular polarizability. The expression was derived from the simple London treatment23 of dispersion energies between like mole- cules. Equation 6 is claimed by Sri~astava~~ to relate the internal pressures of sixty liquids to their boiling point temperature, T K, and molar volume, V. 4.5Pi = (24.5T-1400) -V Hildebrand has pointed out that approximate heats of vaporization can be obtained from boiling point temperatures,2 and so it is not too surprising that the internal pressures calculated by equation (6) approach c.e.d. values for hydrogen-bonded solvents like water, and for dipolar aprotic solvents like dimethyl sulphoxide.The sixty liquids used to establish equation (6) are all relatively non-polar; their internal pressures can therefore be equated to cohesive energy densities. In his account of various methods for determining ‘internal, molecular, or intrinsic pressure,’ Lewis25 recalled Young’s26 earlier suggestion that the attractive forces responsible for cohesion are also responsible for the surface tension of liquids. Hildebrand2 later predicted a relationship between c.e.d.and y/V1’3, where y is the surface tension and V the molar volume. The relationship is linear for non-polar liquids. It breaks down in polar solvents, but in a given class of polar solvent (e.g. alcohol, dipolar aprotic solvent), values of y appear to run parallel to c.e.d. Gordon27 used cohesion, as represented by y/Ylh, to estimate the cohesive nature of molten inorganic salts in relation to polar liquids of known cohesion. He also made use of the complex relation between viscosity and cohesion28s2cforthe same purpose. Viscous flow can be regarded as a rate process 22 A. Cammarata and S. J. Yau, J. Pharm. Sci.,1972, 61, 723. F. London, Trans. Faraday SOC.,1937,33, 8. 2* S. C. Srivastava, Indian J. Phys., 1959, 33, 503.as W. C. M. Lewis, Trans. Faraday SOC.,1911,7,94. ae T. Young, Phil. Trans., 1805, 1, 65. J. E.Gordon, J. Amer. Chem. SOC.,1965,87,4347. IBC. V. Suryanarayana, Indian J. Chem., 1972, 10, 713.* R. V. Gopala Rao and V. Venkata Seshaiah, Z. phys. Chem. (Frankfurt), 1972,78,26. Dack in which molecules migrate into neighbouring holes in the liquid.30 Thus, the energy of activation of this process becomes related to the energy required to create a hole-the molar energy of vaporization. 3 An Examination of Solvent Structure in Terms of Pi and C.E.D. A. General.-The term structure can mean different things to different people. Does it refer to the strength of intermolecular bonding within a liquid, or does it refer to the geometry of the molecules of the liquid? An answer to the question clearly depends on the problem in hand.For example, a dissolved solute may be small enough to rest within the tetrahedral skeleton of water molecules without substantially affecting the intermolecular bonding, but in a hydrocarbon, the same solute may have to break many bonds to create a hole for itself. Solvent structure is affected in both cases. In addition, does it matter whether we mean chemical (hydrogen bonding) or non-chemical (polar and non-polar) interactions when discussing the strength of structure? Water is always regarded as a highly structured solvent, and so it is from a geometrical and hydrogen-bonding view- point. However, contributions from non-chemical forces to water cohesion are much lower than for any other solvent.It should be pointed out that 'structure' can be rigorously defined in terms of $(r) and g(r) (Section 2B), both of which are measurable quantities. Nevertheless, much chemistry is still at the 'physical picture' stage, and so the remainder of the discussion adopts a non-rigorous approach. Intermolecular bonding energies are not usually expressed in cal cm-3 units. Energies due to non-chemical interactions (E" = Pi)and those due to chemical interactions (Ec = c.e.d. -Pi)are therefore presented in units of kcal mol-1 in Table 2 for a selection of solvents. The fact that E" increases with solvent molecular polarizability-a property related to dispersion interactions31- supports the premise that Pi depends heavily on such interactions.EC increases with increasing dipole moment of the dipolar aprotic solvents (p > 2D). Large dipolar interactions appear to restrict the movement of molecules in a manner similar to hydrogen bonding; such action goes undetected by Pi. Bagley et aZ.12 believe that (c.e.d. -Pi) measures only hydrogen-bonding energies. This assumption does not seem reasonable since it would give the dipolar aprotic solvents an appreciable amount of hydrogen-bonded structure. Molecular orbital studies32 indicate intermolecular hydrogen bonding in formaldehyde dimers of less than 0.6 kcal mol-l. Similar bonding in dipolar aprotic solvents possessing no acidic hydrogen must be insignificant. It is encouraging to find that values of EC for the alcohols agree with hydrogen bonding energies obtained by other means.33 The EC value of 9.8 kcal mol-l for formamidecannot be entirely due to hydrogen bonding because of contributions H.Eyring, J.Chem. Phys., 1936, 4,283. " Ref. 21, p. 715.''K. Morokuma, J. Chem. Phys., 1971,55, 1236. 33 I. A. Wiehe and E. B. Bagley, Amer. Inst. Chem. Engineers J., 1967, 13, 836. 217 The Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena from dipole-dipole interactions caused by the large dipole moment of the solvent (p = 3.37 D). A similar dipole moment for dipolar aprotic solvents yields EC z 2 kcal mol-l. The resulting hydrogen bonding energy for formamide of ca. 7.8 kcal mol-l agrees very well with values calculated by Dreyfus and Pull- man34 for the linear dimer (8 kcal mol-l).The solvents listed in Table 2 illustrate three classes of solvent: protic, dipolar Table 2 Splitting of the intermolecular bonding energies of selected solvents into non-chemical (E")and chemical (EC) contributions at 25 "C (kcal mol-1) Solvent ax 1024 E" p (Debye) EC (dipole- (ml at (dispersion, dipole, 20 "C)" repulsion, hydrogen dipole- bonding) dipole) Water 1.48 0.67 1.84 9.2 Methanol 3.24 3.0 1.66 5.6 Formamide 4.22 5.2 3.37 9.8 Acetoni tr ile 4.45 5.1 3.84 2.3 Ethanol 5.12 4.1 1.68 5.7 Ethylene glycol 5.73 6.7 2.31 5.2 Acetone 6.41 6.0 2.88 1.o Methyl acetate 6.96 7.0 1.61 0 Dimethylformamide 7.91 8.7 3.82 2.1 Dimethyl sulphoxide 7.97 8.6 4.49 3.3 Propylene carbonate 8.51 11.0 4.94 ca.4.5 Dioxan 8.75 10.1 0.45 0 Ethyl acetate 8.82 8.3 1.88 0 Benzene 9.91 8.O 0 0 Carbon tetrachloride 10.47 8.O 0 0 a Obtained from a = [W -l)/(n* + 2)] (M/d)(3/47rN)for sodium I)-line.85 aprotic (p > 2)F5 and solvents of low polarity (p -c 2). Hydrocarbons and solvents of low dipole moment have E" values of between 7 and 8 kcal mol-1. Cohesion comes entirely from dispersion forces. The appearance of EC values in the dipolar aprotic solvents shows the significant contribution of dipole- dipole interactions to cohesion.36 Compared with the non-polar solvents, there- fore, greater non-chemical interactions cause the dipolar aprotic solvents to be more rigid and less open.On the other hand, the protic solvents possess small E" values and chemical bonding energies which always exceed E". Intermolecular hydrogen bonding gives these solvents a distinct geometrical structure in the form of chains or three-dimensional arrays. This structure prevents the effective operation of the non-chemical forces. The extreme solvent is water, where 34 M. Dreyfus and A. Pullman, Theor. Chim. Acra, 1970,19,20. s6 A. J. Parker, Chem. Rev., 1969,69, 1. 36 G.F. Longster and E. E. Walker, Trans. Faraday SOC.,1953,49,228. 218 Dack non-chemical forces comprise only 7% of the total cohesion at 25 "C. The relative lack of non-chemical forces gives the structure of the protic solvents an openness and/or a flexibility unmatched by other solvents.In terms of non-chemical structuring, the dipolar aprotic solvents are the most structured of all solvents, while water is the least structured. The distinction between the non-chemical and chemical interactions in liquids should aid an understandingof phenomena in solution. Prausnitz?' Hansen,38 and Bagley,lz for example, have used this approach to find the best solvent for a given polymer. Working on the principle that 'like dissolves like', they sought the best match between solvent and polymer according to their component intermolecular bonding energies. Several empirical methods were developed which enable hydrogen bonding energies to be separated from the energies of non-chemical interactions. An application of the c.e.d./Pi approach to the structure of water and binary solvent mixtures is now discussed.B. Water Structure.-The internal pressures of most liquids decrease with increasing temperat~re.~J~ Additional thermal motion of liquid molecules enhances the probability that two molecules will approach each other close enough for the repulsive component of Pi to increase its magnitude. Water does not share this behaviour; values of Pi rise with increasing temperature until reaching a maximum in the region of 150 "C.At the same time, c.e.d. for water decreases regularly with increasing temperat~re,~~ as do the values of EC obtained from (c.e.d. -Pi). Falling EC values result from the destruction of water's three-dimensional skeleton as the temperature is raised.Hydrogen bonds bend or break, so that the open geometry of the molecules becomes distorted, and, depending on the water model chosen, monomeric species either fill sites in the distorted skeleton41 or join the dense monomeric fluid surrounding the Frank and Wen flickering clusters.42 The net result of these two processes is to bring an increasing number of water molecules to an intermolecular distance where attractive non-chemical forces operate. Thus, Pi and E" rise with increasing temperature until the effect of the rate of breakdown of the water skeleton on Pi is insufficient to counteract the build-up of repulsive forces at 150 "C. It appears that water retains its uniqueness due to an open structure well past a temperature of 35-45 "C where properties like compressibility and heat capacity show discontinuities.43 Ethylene glycol must also possess a certain amount of open structure since its Pi rises 37 R.F. Blanks and J. M. Prausnitz, Znd. and Eng. Chem. (Fundamentals), 1964 3, 1. 88 C. M. Hansen, 'The Three Dimensional Solubility Parameter and Solvent Diffusion Coefficient', Danish Technical Press, Copenhagen, 1 967. R. E. Gibson and 0.H. Loeffler, J. Amer. Chem. Soc., 1941, 63, 898. 40 Values of Pi and c.e.d. at various temperatures obtained from data in 'Organic Solvents', ed. J. A. Riddick and W. B. Bunger, 3rd Edn., Wiley-Interscience, New York, 1970. I1 0.Ya. Samoilov, Zhur.$z. Khim., 1946, 20, 12.4a H. S. Frank and Wen Yang Wen, Discuss. Faraday SOC.,1937,24, 133.''D. Eisenberg and W. Kauzmann, 'The Structure and Properties of Water', University Press, Oxford, 1969. 2 219 The Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena slightly with temperat~re.3~ Other protic solvents behave normally, reflecting the non-open nature of their structure. Gibson and L~effler~~ found that plots of Pi for water vs. molar volume at various temperatures show a change of slope at about 40 "C. Lee and Hyne44 discovered that plots of Pi vs. temperature show anomalies at about 35 "C for aqueous potassium chloride solutions. Both experiments involve water in a compressed state, caused by either external compression or internal electro- striction by an electrolyte.Pi is related to isothermal compressibility through the expression, Pi = Ta/p. It must be supposed that Pi for compressed systems is more sensitive to the anomalous behaviour of 18 at 35-45 "Cthan to changes in the coefficient of thermal expansion. C. Binary Liquid Mixtures.-Early studies by Westwater et al.9 showed that Pi for 50 mol% binary mixtures of several liquids of low polarity is approximately given by the mean of the individual values. More recently, Hyne and his co- w~rkers~~s~bfound that certain compositions of alcohol-water and DMSO-water mixtures produced a Pi value higher than that of either component. A maximum appears in the Pi-composition curve for aqueous DMSO at 0.34.4mole fraction of DMSO, and at very small concentrations of alcohol in water. In both types of mixture, c.e.d.decreases regularly from its high water value to the much lower value of the co-solvent. Calculated values of EC also decrease with added co-solvent. These maxima occur at mixture compositions possessing other anomalous pr0perties.4~~~7The addition of alcohols to water is accompanied by large negative excess entropies, a fact which points to a considerable structural enhan~ement.~~A maximization of structure when DMSO is co-solvent has been attributed to the formation of complexes such as DMSO, 2H2O.47 However, much doubt exists about the exact nature of the structure-making effect of the co-solvents. Pi/c.e.d. results suggest that structure-making takes place via non-chemical rather than chemical interactions. An increased degree of hydrogen bonding interaction would reveal itself in c.e.d.or EC. This does not happen in the systems being analysed. Small amounts of added alcohol or DMSO form hydro-gen bonds with water molecules, a process in which the energy lost in the dis- ruption of water structure is not totally replenished in the formation of bonds with the co-solvent. Once again, depending on the water model selected, molecules of water and/or co-solvent enter the disrupted skeleton or join the existing layers of water monomers around the clusters. In either case, compressibility decrease@ (even though alcohols are more compressible than water), and non-chemical attractive interactions increase.Pi rises to a value greater than that of the co-solvent before further addition of co-solvent totally destroys the three- 44 I. Lee and J. B. Hyne, Canad.J. Chem., 1973,51,1885. 45 D. D. Macdonald, J. B. Hyne, and F. L. Swinton, J. Amer. Chem. SOC.,1970, 92, 6355; D. D. Macdonald and J. B. Hyne, Canad. J. Chem., 1971,49,2336. I6 F. Franks and D. J. G. Ives, Quart. Rev., 1966,20, 1. 47 J. J. Lindberg and J. Kenttamaa, Suomen Kem., 1960, B33,104. Dack dimensional arrangement of water molecules. With no intimate sites in which to place themselves, or no clusters to separate the monomeric layers, the water molecules find themselves increasingly interacting with, and surrounded by, more and more co-solvent.Pi falls to the value of the alcohol or DMSO. This analysis of water and liquid mixtures depends entirely on the validity of assumptions made in Section 2B. The possibility always exists that Pi contains contributions from hydrogen bonding which dictate the above phenomena. Clearly much more effort is required in this area before firmconclusions can be drawn and categorical statements can be made. 4 Relationship between Pi, C.E.D., and Selected Solution Phenomena A. Solubility.-Two liquids do not completely mix if one liquid has a much greater cohesion than the other. Conversely, molecules in liquids of similar cohesion are just as likely to interact and mix with each other as with their own kind. In this way we can rationalize the low miscibility of paraffins (low c.e.d.) in water (high c.e.d.), and the complete miscibility of acetonitrile and DMF.Any interaction between unlike molecules enhances the changes of miscibility. Thus, although water (c.e.d. = 550 cal cm-3) and acetone (c.e.d. = 94.3 cal cm-3) differ considerably in cohesion, hydrogen bonding between the two liquids overcomes the natural reluctance of water to link with the co-solvent. Hilde- brand2 has referred to the square root of c.e.d. as the sohbility parameter, 8, because of its frequent use in solubility problems. This approach explains why water becomes increasingly miscible with the normal paraffis as the chain length is increased. Cohesion rises with increasing chain length, resulting in 8pararrin moving closer to swater.On the other hand, the complete miscibility of the lower alcohols with water falls off as the alkyl group is enlarged.Hydrogen bonded interactions lessen on transfer to the higher alcohols, and cohesion falls; 8alcohol becomes less like Swater. The same conditions of relative cohesion apply to the solubility of solids in solvents. We have already referred to attempts at matching the contributing interactions to cohesion for polymers and solvents. C.e.d.'s for polymers of high molecular weight cannot be obtained directly from vaporization experiments. Values are therefore obtained experimentally via swelling measurements,48 or empirically by Small's estimation.8 Allen et aZ.49investigated the possibility of using Pi for polymers in place of c.e.d.They found that for all the polymers investigated Pi was some 30-50% higher than c.e.d., and they concluded that c.e.d. may underestimate the cohesion of a polymer. It would appear that 82 is better represented by Pi when being used for predicting polymer solubility. Whenever a solute dissolves, a hole has to be created in the solvent to accom- modate that solute. The energy required to make the hole depends on the cohesion of the solvent and on the volume of the hole. The effect is most notice- able in the solubility of large molecules. Tetraphenylarsonium tetraphenylboride , '' G. M. Bristow and W.F.Watson, Trans. Faraahy SOC.,1958,54, 1731. 40 G.Allen, G.Gee, D.Mangaraj, D.Sims, and G. Wilson, Polymer, 1960, 1,467.The Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena for example, is a large organic salt in which the ions are often considered to be buried beneath the phenyl groups. In terms of its solubility product, the boride is 1013 times more soluble in DMSO than in water.50 Although some of the in- creased solubility must be due to enhanced interaction of DMSO with the cationic part of the salt, the difficulty of creating a large enough hole in water for the salt must be the major factor in its relative insolubility. Den0 and Berk- heirner51 noticed the effect during their solubility measurements of a series of R4NC104 salts in water, ethanol, and benzene. When R was small, the salt dissolved to advantage in water because of strong ion-water interactions.As R increased from CH3 to CHsHrs, the energy needed to make a hole rises much more rapidly in water than in ethanol or benzene, and becomes the solubility determining factor. Thus, a change from water to benzene enhanced the solubility of (GH13)4NC104 two-thousand fold. B. Electrolytesin Solution.-Dissolved electrolytes increase the internal pressure within a solvent.5~~~ The increase is achieved through electrostriction-a volume-reducing process which involves polarization and attraction of solvent molecules around the ionic species; e.g., a 3M aqueous solution of sodium bromide exhibits a Pi value of ca. 75 cal CM-~, 53 whereas the value for water at 25 "C is only 41 cal cm-3. Thus the change in internal pressure gives a measure of the electrostrictive effect of a certain concentration of dissolved electrolyte.As Gordon27 points out, uncertainties about the intrinsic volumes of ions in solu- tion make an estimation of their electrostriction abilities very difficult. Use of internal pressure for such estimations surmounts these difficulties, as illustrated in the following two examples of electrolyte behaviour in solution. (i) Saltingout, Salting in, and Salt Efects on ChemicalReactivity. Dissolved sodium chloride separates l-butanol and water into two layers, and the ability of inorganic salts to separate other organic compounds from water is well known. McDevit and Long 54 explained this effect in terms of a changing internal pressure of the medium.Dissolved salts increase the internal pressure/electrostriction of the aqueous solutions to such an extent that the non-electrolyte is squeezed out (salting out). When the dissolved salt reduces the internal pressurelelectro- striction of the solution, more of the non-electrolyte is able to dissolve (salting in). The salting out/in process can be described by equation (7), wherey is the activity coefficient of non-electrolyte in solution, ksis the Setschenow constant, and cs is the concentration of dissolved salt in mol 1-l. McDevit and Long's treatment leads to equation (8). The volume 7'1 refers to the molar R. Alexander and A. J. Parker, J. Amer. Chem. SOC.,1967, 89,5549. I1N. C. Den0 and H. E. Berkheimer, J. Org. Chem., 1963, 28, 2143.6a H. F. Herbrandson and F. R. Neufeld, J. Org. Chem., 1966, 31, 1140; A. P. Stefani, J. Amer. Chem. Soc., 1968, 90, 1694. Calculated from data in E. B. Freyer, J. Amer. Chem. SOC.,1931, 53, 1313. 64 W. F. McDevit and F. A. Long, J. Amer. Chem. Soc., 1952,74, 1773. Dack volume of the non-electrolyte, VS and psare the intrinsic and apparent molar volumes of the salt, respectively, and #?o is the compressibility of the solution. The Setschenow constant is positive for salting out and negative for salting in. Equation (8) shows that the effect is greatest for non-electrolytes of largest molar volume, and for salts that cause the most electrostriction, Vs-ps.The effect of inorganic salts on ksvalues for benzene, naphthalene, and biphenyl in water appear in Table 3.54v55All the electrolytes, except perchloric acid, cause electro- Table 3 Setschenow constants at 25 "Cfor the salting outlin of benzene, naphtha- lene, and biphenyl from aqueous solutions of ele~trolytes.~~955(Molar volumes appear in parentheses) Electrolyte Benzene Naphthalene Biphenyl (89.4 cm3 mol-1) (125 cm3 mol-1) (149 cm3 mol-1) NaCl 0.195 0.260 0.276 KCI 0.166 0.204 0.255 LiCl 0.141 0.180 0.218 NaBr 0.155 0.169 0.209 NaC104 0.106 0.096 0.113 HCl 0.048 0.046 0.070 HClO4 -0.041 -0.08 1 -0.116 striction of water and a salting out of the organic species.It appears that the volume of the system is increased by perchloric acid to give a 'negative electro- striction'; salting in occurs.Other workers56 have obtained satisfactory agree- ment between experimental results and those predicted fromequation(8). However, until salting out/in effects in solvents other than water have been examined, the universality of the theory cannot be judged. Clarke and Taft5' examined the effect of added salts on the rates of chemical reactions in terms of internal pressures. A study of the solvolysis of t-butyl chloride in water convinced these authors that although internal pressure effects (induced by the salt) influence the activity coefficient of both the reactants and the activated complex, a cancellation of effects occurs during the reaction. Kinetic salt effects were adequately explained by Ingold's ion-atmosphere treatment.5* (ii) Conductivity.Electrochemists have long asked : why does the equivalent conductance of a strong electrolyte decrease with increasing concentration ? In an effort to solve the problem, theories of condu~tivity~~ have considered the dependence on concentration of degrees of dissociation, ionic mobility, ion M. A. Paul, J. Amer. Chem. SOC.,1953, 75, 251 3. N. C. Den0 and C. H. Spink, J. Phys. Chem., 1963, 67, 1347; E. Grunwald and A. F. Butler, J. Amer. Chem. SOC.,1960, 82, 5647. '' G. A. Clarke and R. W. Taft, J. Amer. Chem. SOC.,1962, 84,2295. L. C. Bateman, M. G.Church, E. D. Hughes, C. K. Ingold, and N. A. Taher, J. Chem.SOC., 1940,979.''R. M. FUOSS,in 'Chemical Physics of Ionic Solutions', ed. B. E.Conway and R. G. Barradas, Wiley, New York,1966, p. 463. The Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena pairing, dielectric constant, and viscosity. In 1959 Suryanarayana and Venka- tesan60 put forward a theory of conductance which overcame the apparent inability of theories then prevailing to explain the behaviour of concentrated solutions of electrolytes. They recognized that solvent internal pressure was closely related to all of the above parameters, and they proposed that a moving ion is subject to the structural pressure of the surrounding solvent. An increase in concentration of the electrolyte simply increases the work necessary to move an ion through a medium of enhanced internal pressure with a given electric field.Ionic mobility and the equivalent conductance of the electrolyte fall. As the authors mentioned, the effect is not just one of changing the viscosity of the solution, since classical experiments have already shown that the conductivity of an electrolyte in a jelly does not change appreciably when the jelly sets. Although we have stated that the internal pressure of a solution rises with added electrolyte, only regions around the ions really experience the increased pressure. In 1966 Fu0ss5~ speculated that any improvement of existing theories of con- ductivity must include ‘the discrete structure of the solvent’ in the neighbourhood of the ions. Electrostricted solvent enlarges the effective size of the moving ions. In a concentrated solution, therefore, the probability of an ion and its attendant solvent environment being hindered in its movement by other moving species becomes greater than in more dilute solutions. Thus, the internal pressure concept leads to two explanations for the behaviour of strong electrolytes in solution.One explanation envisages ionic mobility to be related to the internal pressure of the medium, while the other relates ionic mobility to an electrostriction process which determines the internal pressure in the vicinity of the ions. C. Apparent MOMVolumes of Dissolved Species.-Internal pressure, electro- striction, and apparent molal volumes are interconnected phenomena. Three factors determine the apparent molal volume of a dissolved solute: (i), the intrinsic size of the solute, (ii), the ability of the solute to cause electrostriction of the solvent, and (iii), the ability of solvent to prevent electrostriction.Electro- striction depends on the chemical and/or electrostatic affinity of solvent molecules for the solute. Although electrostriction increases as the internal pressure of a system increases, internal pressure monitors rather than creates the electro- strictive effect. Total collapse of solvent molecules around a charged solute, and the ability of a neutral solute to make a hole for itself, are affected by solvent compressibility and cohesion. Both properties are related to internal pressure, but the contribution of electrostriction to apparent molal volumes is usually so large that it demotes the internal pressure effect of a solvent to a minor role.That role might be expected to increase when the solute species do not interact with the solvent. Miller061 has comprehensively reviewed the whole subject of apparent molal @OC.V. Suryanarayana and V. K. Venkatesan, Acta Chim. Acad. Sci. Hung., 1959, 19, 441. F. J. Millero, Chem. Rev., 1971,71, 147. Dack volumes; thus we make no attempt to do so here. We merely re-emphasise the amstion between electrostriction and the internal pressure of solutions, and suggest that the effect of solvent internal pressure on apparent molal volumes might become evident in the absence of electrostriction. For a determined test of the relevance of internal pressure, measurements should be made in dipolar aprotic solvents and protic solvents of high dipole moment (Pi = 80-130 cal a-3) as well as the solvents of low dipole moment that have hitherto been used (Pi= 70-80 cal ~m-~).D. ChemicalReactivity.-In 1929 Richardson and SoperG2 noticed that reactions in which the products had greater cohesion than the reactants proceed faster in solvents of highest cohesion. The converse also applied. Reactions which undergo little change in cohesion of the species respond poorly to solvent change. Glasstones3 later predicted the same results from theoretical considerations. This promising approach to solvent effects on chemical reactivity fell into disuse when Hughes and IngoldM formulated their theory based on the energetics of species.The Hughes-Ingold theory compares the relative solvation of reactants and transition state complex by different solvents, and examines the effect of differing degrees of solvation on the free energy of activation of a reaction. However, the theory cannot deal in detail with electro-neutral reactions. With no movement of charge occurring on passing from the ground state to the transition state of these reactions, a change of solvent should have no effect on their rates. Small rate changes are observed, and they warrant inclusion in any theory of solvent effects. Dack65 recently showed how a consideration of vohmes of activation, instead of free energies of activation, gives rise to a more general account of solvent effects on reaction rates.In its simplest terms, the account proposes that solvent internal pressure acts on the volume of activation (0V*) of a reaction like an externally applied pressure. If a change of solvent polarity alters d V* in some way, the structural pressure of the new solvent acts on the changed A V*. When this happens, the polarity effect should outweigh any pressure effect on the reaction rate. Such an approach thereby covers non-polar reactions, since changes in rate caused by solvent transfer will only depend on changes in the solvent in- ternal pressure. The following predictions were made9 (i) Solvent internal pressure acts on the rates of non-polar reactions, and on polar reactions in non-polar solvents, in the same direction as external pressures.(ii) Solvents which lower the value of the volume of activation of a reaction by electrostriction accelerate the rate of that reaction. (iii) Those solvents able to raise the value for the volume of activation of a reaction cause the rates to fall. 62 M. Richardson and F. G. Soper, J. Chem. SOC.,1929, 1873. 63 S. Glasstone, J. Chern. SOC.,1936, 723. 64 E. D. Hughes and C. K. Ingold, J. Chem. SOC.,1935, 244; C. K. Ingold, ‘Structure and Mechanism in Organic Chemistry’, 2nd Edn., Cornell University Press, Ithaca, 1953. M. R. J. Dack, J. Chem. Educ., 1974, 51,231. 225 The Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena The scheme in Table 4 depicts passage of eight reaction types from ground state to transition state in terms of the volume of each state.Types 1 and 2 are non-polar unimolecular and bimolecular reactions respectively. Bond breaking occurs in the unimolecular reaction to give a positived Vf, while reactants come together in the bimolecular reaction to give a negative dV*. An increased solvent polarity has little effect on d Vf ;an increased solvent internal pressure decreases and increases the rates, respectively. Electrostriction of solvent around species in the polar reactions (types 3-8) yields the signs of dV* shown in Table 4.Solvents of increased polarity cause a greater increase of electrostriction (volume-reducing process) around charged species and around species with the greater concentration of charge.It is therefore possible to predict the effect of solvent transfer on the magnitude of dVf. Rate increases occur if the new solvent lowers the value of the volume of activa- tion. The reader is referred to the original paper65 for a more detailed discussion and for illustrative data. Some doubt has been cast on the relevance of solvent internal pressure to chemical reactivity.66 Predictions made by the pressurejvolume approach are based on the transition state theory, and on theories of regular solutions involving the solubility parameter, 6. However, a non-polar solute of a given volume will not experience the full internal pressure of its solvenP7 (Section 4F).Nevertheless, other workers believe that solvent internal pressure plays a large role in polar as well as non-polar reactions.52 When solvation of reactants and transition state complex occurs to a similar extent, polarity effects are thought to cancel out, thus promoting the structural pressure of the solvent to a new importance. Fleischmann and Kelm68 have separated the ‘intrinsic’ and ‘electrostrictive’ components of d V* for a cycloaddition reaction in a number of solvents. More work of this precise nature is needed before the quantitative usefulness of the pressure/volume approach to solvent effects can be evaluated. E.Conformational Equilibria.-The pressure/volume approach to chemical reactivity considered the equilibrium between reactants and transition state complex in terms of volumes. For non-polar reactions, pressure exerted by a solvent (Pi or c.e.d.) acted on the equilibria in the same manner as an external pressure.Ouellette and WilliamP proposed the same principle for determining the relative population of non-polar conformers when the non-interacting solvent is changed. An increase in solvent pressure favours the conformer with the smaller molar volume. These workers supported their proposal by finding a linear correlation between conformational equilibrium constants for the trans + gauche equilibrium of 4,4-dimethyl-2-silapentaneand 2,3-dimethyl-2-silabutane and Pi for four non-polar solvents. WJ R. G. Pearson, J. Chem. Phys., 1952,20, 1478; A. K. Colter and L. M. Clemens, J. Phys.Chem., 1964, 68, 651; R. C. Neuman, J. Org. Chem., 1972, 37,495.67 P. J. Trotter, J. Amer. Chem. SOC.,1966, 88, 5721; J. Chem. Phys., 1968, 48, 2736. e8 F. K. Fleischmann and H. Kelm, Tetrahedron Letters, 1973, 39,3773. es R.J. Ouellette and S. H. Williams, J. Amer. Chem. SOC.,1971, 93,466. 226 Dack Table 4 Scheme for the pressurelvolume approach to solvent e$ects on chemical reactivity.64 (The eflects of increased solvent polaritylinternal pressure are dis-cussed in text) 0 02 Rl ..... R2 None Increase 5 More negative Increase More positive Decrease 7 More positive Decrease 8 -d"_' .Decrease0 0More positive Eckert70 recognized the good correlation obtained by Ouellette and Williams, but lamented that no external pressure results were available for comparison. Earlier work by Le Noble7 has shown that equilibrium constants for the reaction 'O C.A.Eckert, Ann. Rev. Phys. Chem., 1972, 23,239. 227 me Importance of Solvent Internal Pressure and Cohesion to Solution Phenomena of (11to y-methylalkyl azide in both solution and in the gas phase could be fitted to the same pressure curve if Pi for the solvent (methylene chloride) was included in the total pressure. The dependence on Pi of the dissociation of Nz04 in the gas and in solution has been known for many years.71 Thus, solvent pressure certainly affects chemical equilibria, but once again, it must be emphasized that its effect on conformer equilibria and other solution phenomena will be small in relation to the effect of any solute-solvent interactions.F. Spectroscopic 0bservations.-Statistical mechanical calculations show that solvents exert a mechanical pressure (PM)of 103-104 atm on dissolved molecules. PM is the actual pressure that a molecule of a given size experiences and not just the internal pressure of the solvent. Trotter67 has calculated PM for a solute molecule with a 11.O A molecular diameter in a number of non-polar solvents at 25 "C: benzene, PM = 1550 atm (Pi= 3631 atm); ccl4, PM = 3320 atm (Pi = 3342 atm); CSZ,PM = 1470 atm (Pi= 3672 atm). Such pressures are extremely pertinent to an analysis of the spectral data of weak molecular complexes on transfer of the complexes from the vapour to the condensed state. Bonding in weak molecular complexes (charge-transfer, and to a lesser extent, hydrogen bonding) can be compressed by a pressure.Ample evidence exists72 to show that applied pressures of a few thousand atmospheres cause large red shifts and intensity enhancements (external compression of bonding) in the charge-transfer bands of molecular complexes. The complexes experience similar pressures when transferred from the vapour to the liquid (internal compression of bonding), and the question is asked: should the same spectral shifts be expected? Trotter67 believes that the internal compression effect of a non-polar solvent causes red shifts in weak charge-transfer complexes of between 10OO--4000cm-1, and an intensity enhancement, when transferring the complexes from the vapour. Hydrogen bonds are much stronger than charge-transfer complexes and less compressible. Red spectral shifts of -20 --40 cm-l for O-H .. . 0 bonds might be expected from internal compression, plus a small downfield n.m.r. shift. As judged from existing experimental data, these predictions appear to be reasonable. Other solvent effects may contribute to the spectral shifts, but the ability of solvent pressure to change the bond lengths of molecular complexes must be a major factor. G. Biological Observations.-Large biochemical molecules also experience internal compression from the surrounding medium, water. The mechanical pressure on a molecule like insulin (molecular diameter z 50 A) is thought67 to be in the region of 500 atm at 25 "C.Any biological process which is sensitive to externally applied pressures (e.g.the unfolding of ribonuclease) may therefore be 'l W.J. Le Noble, Progr. Phys. Org. Chem., 1967,5,230. 73 J. R.Gott and W.G. Maisch, J. Chem.Phys., 1963,39,2229;A.H.Ewald, Trans. Faraday SOC.,1968,64,733. Dack affected by this type of solvent pressure, and the ability to alter the solvent pressure presents a possible mechanism for influencing that process. Work by Ginzburg and Cohen73 indicates that ‘internal hydrostatic pressures’ created in gels are responsible for squeezing out non-electrolytes from the gels. Proteins and carbohydrates are among those macromolecules able to form gels. Ginzburg and Cohen exemplified the biological implications of their observa- tions as follows: ‘it can be predicted that large molecules such as hemoglobin should be totally excluded from gels with an internal pressure of 10 atm,’ while ‘even molecules of low molecular volume (e.g.sucrose) should be excluded from gels having high internal pressures.’ However, the relevance of solvent pressure to biological systems has not yet been established. It would be unwise to speculate further until connecting evidence is obtained. 5 Concluding Remarks The aim of the Review has been to promote a wider awareness of the concept of solvent pressure. Internal pressure, mechanical pressure, or cohesion plays its largest role in non-interacting systems, and although its effect will be very small in many solution phenomena, it must always be present. It is possible that we have overstated the importance of solvent pressure. Many of the solution phenomena discussed can certainly be explained by other means. Maybe the legitimate place for solvent pressure is alongside steric effects in organic chemistry-to be invoked when all else fails. Only time and an appropriate amount of experi- mental effort can resolve the full importance of the concept. It is a pleasure to acknowledge the helpfulness of several discussions held with Dr. R. 0.Watts during the preparation of this Review. The advice arid encourage-ment of Dr s.D. Hamann, Professor A. J. Parker, and Professor J. B. Hyne have been greatly appreciated. B. 2. Ginzburg and D.Cohen, Trans. Faraday Soc., 1964,60,185.

ISSN:0306-0012    

DOI:10.1039/CS9750400211

出版商:RSC    

年代:1975

数据来源: RSC

摘要:

Acylation by Ketens and Isocyanates. A Mechanistic Comparison By D. P. N. Satchell DEPARTMENT OF CHEMISTRY, UNIVERSITY OF LONDON, KING’S COLLEGE, STRAND, LONDON, WC2R 2LS R. S. Satchell DEPARTMENT OF CHEMISTRY, QUEEN ELIZABETH COLLEGE, CAMPDEN HILL ROAD, LONDON, W8 7AH 1 Introduction Ketens (R2C=C=O) and isocyanates (RN=C=O) possess similar chemical structures and both types of compound have considerable industrial importance ; usually, however, they feature only briefly, or not at all, in textbooks of organic chemistry. And although on occasion they crop up close together accidentally in chapters on molecular rearrangements, being produced respectively during the Wolff and Curtius rearrangements, their general preparation and, in particular, their reactions, are seldom compared.This general absence of what is really an obvious comparison is also noticeable in the research literature, and until very recently there had been virtually no cross-fertilization between researches with these two classes of compound. All this is now rapidly changing and the aim of this Review is to demonstrate how valuable such comparisons can be in the field of reaction mechanisms. Ketensl and isocyanates 2~3both undergo a variety of addition reactions to either single or double bonds in other compounds. Particularly characteristic are the additions to compounds HX and to molecules containing the ‘C= /?’9 \C=N-and ‘C=O groups, [equations (1)-(4)]; these are the reactions /which have been most studied kinetically with a view to discovering their mechanisms.We shall concentrate particularly on reactions such as (1) and (2) and their catalysed counterparts. What is occurring here is, in effect, an acylation by the keten or isocyanate, the opening of the C=C, or N=C, double bond being the equivalent of leaving group departure in a more conventional acylation [e.g.equation (S)].* The most studied substrates HX have been alcohols, water, thiols, phenols, carboxylic acids, and amines. We deal with these in turn R. N. Lacey, in ‘The Chemistry of Alkenes’, ed. S. Patai, Interscience, New York, 1964. a A. Farkas and G. A. Mills, Adv. Catalysis, 1962, 13, 393. a S. Ozaki, Chem. Rev., 1972, 72, 457. D. P. N. Satchell, Quart. Rev., 1963, 17, 160.231 Acylation by Ketens and Isocyanates. A Mechanistic Comparison R,C=C=O + HX -R,CHC //O ‘X RN-C-0 -k HX + RNHC //O ‘X R,C=C==O -1 I RN=C=O + )c=c< -+ RN-CeO \ (4)0c-c, below, but first consider the general effects of changes in the groups R in the keten or isocyanate. RC=O -f-Hx --+ RC-0 HY \ \ Y X Virtually all the known reactions like (1) and (2) are heterolytic processes and, as we shall see, these mostly involve a kinetically dominant nucleophilic attack by X on the carbonyl carbon atom. In such circumstances it is natural to expect, as found experimentally, that electron withdrawal by R will facilitate reaction, the assumption being that this withdrawal will magnify the positive charge on the carbonyl carbon atom.However, the various theoretical calculation^^^^ on these unusual compounds with two perpendicularv-electron systems, although in very poor quantitative agreement, and even in places contradictory, do suggest, both for ketens and isocyanates, that changes in R have virtually no effect on the charge on the terminal oxygen atom, and that the charge on the carbonyl carbon atom is affected less than the charge on the isocyanate nitrogen atom (or the keten /%carbon atom). And, contrary to simple expectation, this latter charge can become more negative as electron withdrawal by R increase^.^ It is possible therefore that changes in R affect the overall velocity of reaction in the expected way mainly owing to their influence on the ease of proton transfer to the nitrogen and /%carbon atoms, processes which we shall find cannot, in fact, be kinetically P.J. Lillford and D. P. N. Satchell, J. Chem. Soc. (B), 1970, 1016; A. C. Hopkinson,J. C.S. Perkin 11, 1973, 795. B. M. Rode, W. Kosmus, and E. Nachbaur, Chem. Phys. Letters, 1972, 17, 186; K. N. Houk, R. W. Strozier, and J. A. Hall, Tetrahedron Letters, 1974,897; V. B. Zabrodin, Rum. J. Phys. Chem., 1971,45, 376; S. P. Bondarenko, R. P. Tiger, E. V. Borisov, A. A. Baga-turyants, and S. G. Entelis, Zhur. org. Khim, 1974, 10, 271. Satchell and Satchell ignored under the usual experimental conditions. Bulky R groups generallyl.2 hinder reactions (1) and (2) as they do also reactions (3) and (4). In any syn- chronous attack on the N=C or C=C bonds of the isocyanate or keten the substrate must approach from either above or below the molecular plane.This both minimizes steric effects and maximizes orbital overlap. With some, although by no means all, substrates HX the reactions of most ketens and isocyanates with the pure liquid substrate is too fast for measurement by conventional techniques. It happens that in almost all kinetic studies to date inert solvent has been used. The same is true of reactions like (3) and (4). The use of a solvent has the advantage that the reaction orders in both substrate and keten (or isocyanate) can be determined. Isocyanates appear stable in a variety of solvents, but ketens deteriorate rapidly in a surprising number of supposedly inert media owing to their ready polymerization and to their reactions with dis- solved oxygen.It is found that ethers and aromatic hydrocarbons are the best solvents for kinetic work with ketens and it is fortunate for purposes of compari-son that the bulk of the studies with isocyanates have also used such solvents. Only ketoketens (RK=C==O) have been successfully examined kinetically ; aldoketens (RHC=C=O) are particularly susceptible to polymerization.1 Iso- thiocyanates (RN=C=S) appear to behave mechanistically very much as do isocyanates. 2 Reaction with Alcohols Reactions (6) and (7), whose equilibrium positions lie far to the right, lead to an ester and a urethane, respectively. In synthetic work a catalyst is normally added R1zC==C=O + R20H -+ RLzCHC//O (6) \OR2 R'N=C=O + R~OH R~NHC4 //O (7) 'OR' since otherwise the reactions can be quite slow.Process (7) is of particular industrial importance because the reactions of di-isocyanates with glycols lead to the valuable polyurethane^.^ Probably owing to this commercial interest the literature concerning reaction (7) is voluminous and includes the majority of the kinetic studies with isocyanates.2s8 Much of this work is, however, of only marginal interest mechanistically, having been conducted under unsatisfactory conditions and/or having received incorrect interpretation. Moreover, kinetic ' J. H. Saunders and K. C. Frisch, 'Polyurethanes, Chemistry and Technology', Interscience, New York, 1962. S. G.Entelis and 0.V. Nesterov, Rum. Chem. Rev.,1966,35, 917; A. Petrus, Internat. Chem. Eng.,1971,11, 314. Acylation by Ketens and Isocyanates. A Mechanistic Comparison studies with di-isocyanates have only recently begun to use correct algebraic analyses.9 Compared with isocyanates there have been few kinetic studies of any sort with ketens, but of these the largest group again concerns alcoholysis. The results, put alongside the picture emerging for isocyanates, provide an interesting parallel. A. Isocyanates.--(i) The spontaneous reaction. Kinetic studies with isocyanates got offto an unfortunate start,l0J1 and the influence of this has been long-lasting both procedurally and interpretively. Thus even today most studies still use Baker’s conditions (employing roughly equal concentrations of isocyanate and alcohol and determining the apparent second-order rate constant), and Baker’s mechanism for the spontaneous alcoholysisll is still sometimes alluded to as if it were a real possibility, whereas it has been evident for some years that it is not.2J2 The difficulty in determining the second-order constant arises from the facts, now known, that the reaction proceeds largely (or even entirely) via certain alcohol polymers, and that the concentrations of these relative both to monomers and to each other must normally change as alcohol is consumed during the reaction.The observed second-order constant is therefore rarely properly constant even within a single kinetic run, and almost invariably depends upon the initial stoicheiometric alcohol concentration-as discovered by Baker and many The situation is further complicated by the circum- stance that apparently good second-order behaviour can sometimes be found, over a limited concentration range, owing either to the insensitivity of second- order plots or to the alcohol being present largely in one polymeric form.These various complications have led to much confused rationalization from which the field has been slow to emerge. By far the best way to examine these, and indeed most, systems is to use pseudo-first order conditions; in the present context this means keeping the alcohol in a ten (or more) fold excess over the isocyanate. Unfortunately this approach has been adopted only recently and by only a few workers.Ephraim, Woodward, and Mesrobian,13 followed by Oberth and Bruenner,14 were among the earliest to suggest that both the kinetic complexities, and the fact that alcoholysis is almost invariably fastest in non-co-ordinating solvents,2 can be explained by the participation of polymeric alcohol. But their treatments were rather elaborate and based on conjectures about the polymer concentrations, and their ideas were largely disregarded. It is now evident, however, that the L. I. Sarynina, V. V. Evreinov, E. K. Khodzhasva, and S. G. Entelis, Kinetika i Kataliz, 1972, 13, 314; G. Borkent and J. J. Van Aartsen, Rec. Trav. chim., 1972, 91, 1079. loJ. W. Baker and J. B. Holdsworth, J. Chem. SOC.,1947, 713. l1 J.W. Baker and J. Gaunt, J. Chem. SOC.,1949, 9. la W. G. P. Robertson and J. E. Stutchbury, J. Chem. SOC.,1964, 4000. l3 S. Ephraim, A. E. Woodward, and R. B. Mesrobian, J. Amer. Chem. SOC.,1958, 80, 1326. l4 A. E. Oberth and R. S. Bruenner, J. Phys. Chem., 1968, 72, 845. Satchell and Satchell contribution of polymeric alcohol is of paramount importance.15-17 One analysis,15 using diethyl ether as solvent, shows that towards p-chlorophenyl isocyanate the reactivity sequence is tetramer M trimer 9dimer + monomer. In this solvent the monomer (which contributes negligibly) and dimer are hydrogen-bonded to solvent molecules, (l), whereas the higher polymers are cyclic, [e.g. (2)]. In non-co-ordinating solvents all the alcohol species will be R 1 solvent-free; in such systems the importance of polymer is again evident, but it seems that the monomers can also contribute significantly.16 The reason15 that the most reactive species are the polymers (and in co-ordinating solvents the solvent-free, cyclic polymers) is that the transition states in these isocyanate additions are probably cyclic.If it were just a matter of nucleophilic attack on carbon, species (1) should be as effective as species (2), if not more effective. The cumulative evidence for the involvement of cyclic transition states in the majority of the reactions we shall be considering is formidable. For RNCO systems, independent experimental work l8 suggests that the proton can be expected to be transferred directly to the nitrogen atom, as in species (3), rather than to the oxygen atom.This is in keeping, as noted above, with the effects observed on changing R in RNCO and also avoids the necessity of postulating a subsequent rapid prototropic rearrangement. 3R'OH (R20H), fast Scheme 1 l5 S. A. Lammiman and R. S. Satchell, J. C. S. Perkin 11, 1972, 2300. l6 R. P. Tiger, L. S. Bekhli, S. P. Bondarenko, and S. G. Entelis, Zhur. org. Khim.,1973, 9, 1563.''0.I. Kolodyazhnyi and L. 1. Samarai, Ukrain. khim.Zhur., 1973, 39, 1260.'* G. A. Olah, J. Nishimura, and P. Kreienbuehl, J. Amer. Chem. SOC.,1973, 95, 7672. Acylation by Ketens and Isocyanates. A Mechanistic Comparison The dependence of overall alcohol reactivity on the group R in ROH is complex and indicates competing steric, electronic, and possibly other fac- tor~.~JjJ~This complexity, the moderate hydrogen isotope effectgel7 (k~/k~ 1.7), the large negative value* of A,!?* (ca.-40 cal degree-1 mol-l) and the small value8 of AH* (ca. 8 kcal mol-l) are all compatible with a transition state such as (3). The small value of AH+ probably arises from the opposing effects of temperature on pairs of reactions such as those in Scheme 1. The fact that phenols, and alcohols carrying electron-withdrawing substituents, react relatively slowlys suggests that the nucleophilic attack on carbon is the dominant factor in fixing the energy of the transition states. It is no surprise that thiols, which are poor nucleophiles and form polymers with reluctance, react negligibly slowly with isocyanates in the absence of catalysts.19 (ii) The carboxylic acid catalysed reaction.20 Relatively low concentrations of carboxylic acids catalyse the alcoholysis of isocyanates but their catalytic efficiency is inversely related to their acid strength.In ethereal solvents, in concentration regions where the acids are largely monomeric, the catalysed route displays a simple kinetic form, being fmt order in each reactant, i.e., d[product ]/dt = k[isocyanate] [alcohol]stoich [acid]. It has been shown, using ethanol, p-chlorophenylisocyanate,and a series of acids, that reaction proceeds via a 1:l-alcohol-catalyst adduct whose concentration, although proportional to the product [alc~hol]~t~i~h x [acid], depends little on acid strength.This,and other evidence, suggests that the adduct is cyclic. Scheme (2), in which the acid acts as a bifunctional catalyst, and assumes the role of the extra alcohol molecules -+ R'NHCO~R~3-R3COZH slow I -Scheme 2 l@J. Hetfleys, P. Svoboda, M. Jakcubkova, and V. Chvalovsky, Colt. Czech. Chem. Comm., 1973, 38, 717. eo S. A. Lammiman and R. S. Satchell, J. C. S. Perkin II, 1974, 877. 236 Satchell and Satchel1 in the spontaneous reaction, is compatible with all the facts. The magnitude of krr is inversely dependent on acid strength and this suggests that the acid's role in increasing the nucleophilicity of the alcohol is more important than its role in proton transfer. (iii) Zhe tertiary amine catalysed reaction.A good deal of attention has been paid to this type of catalysis2,8 which (probably) most often obeys the simple kinetic form dbroduct ]ldt = k[isocyanate] [alcoh~l]~t~~~h[amine]. Baker and co-workedo found that normally the strongest bases were the best catalysts, but that sterically hindered bases were comparatively inactive. This has been largely confirmed by later work.* Two mechanisms (Schemes 3 and 4) are compatible with these and other facts and it is difficult as yet to choose definitely between them. Baker, using methanol and working under unfavourable kinetic conditions, supported a scheme like Scheme 3 in view of the observed steric effects.lO R'NCO + R3,N .A RIN---C=O fast I [ ~(6) 3-R20H4 H-0-:R2] 3 R'NHC0,R2 d-Ra3N slow R" -C =O 6-6 +NR3, Scheme 3 However, with thiols, phenols, and other acidic alcoholPJ1polar complexes like (7) are certainly formed.with tertiary bases in the usual solvents, and steric effects seem less important. Hence for these alcohols Scheme 4 is probably 3 --t(7) -t R'NCO R'NHCOtR2 + R33N sfow (8) Scheme 4 *l A. Farkas and P. F. Strohm, Ind. and Eng. Chem. (Fundamentals), 1965, 4, 32; A. Farkas and K. G. Flynn, J. Amer. Chem. SOC.,1960, 82, 642; J. Burkus, J. Org. Chem., 1962, 27, 474; E. Dyer, J. F. Glenn, and E. G. Lendrat, ibid. 1961, 26, 2919; A. K. Zhitinkina and M.V. Shoshtaeva, Sin. Fiz. khim. Polim., 1968, 117. Acylation by Ketens and Isocyanates. A Mechanistic Comparison followed.The parallel work with ketens also argues strongly in favour of this scheme for all alcohols (see below) but it may be that in the isocyanate reaction there is a transition from the mechanism of Scheme 3 to that of Scheme 4 as the interaction between catalyst and alcohol becomes stronger. Certainly complexes like (6) seem possible, if only because the dimerization of isocyanates can be catalysed by tertiary bases.22 However, for isocyanates, unlike ketens, there has been no comparison of the effects of tertiary bases on the dimerization and on the alcoholysis. More work is needed here. Because the spontaneous reactions of phenols and thiols are so slow, the effect of tertiary base catalysis is especially marked for these substrates. (iv) Catalysis by metal derivatives.8 By far the most effective catalysts, and therefore the most interesting to industry, are various metal derivatives, notably metal acetylacetonates ;alkyl-, alkoxy-, and halogeno-tin and lead compounds (such as dibutyltin dilaurate); and a variety of other, broadly similar species.2s8 With weakly acidic alcohols these catalysts have activities a million, or more, times greater than tertiary amines, although with phenols they are less effective than are the amines.The metal-based catalysts are normally liquids or contain groups which render them soluble in organic solvents. At present there exists little understanding either of their sometimes great efficiency or of its dependence on structure. In essence they appear to be Lewis acid catalysts co-ordinating to either (or both) the alcohol and the isocyanate.Studies exist which favour all these po~sibilities.~~ A co-ordinated alcohol molecule would be rendered a much more powerful hydrogen acid and would perhaps readily protonate a free, or better, an adjacently bound isocyanate species, so leading to an ion-pair which could subsequently provide the products; Scheme 5 illustrates such a process. R2 R20H -/-MXn \04MXn1H R2~~ R'NCO + R2-O-tMX, %='O+MXn H'.t'H/ N=C=O / (9) --t R1NHC+=O[R20MX,]-'3 R1NHCOOR2 MXn Scheme 5 ** K. G. Flynn and D. R. Nenortus,J. Org. Chem., 1963,28, 3527. '3 A. E. Oberth and R. S. Bruenner, Ind. and Eng. Chem. (Funamentals), 1969, 8, 383; V. B. Zabrodin, 0.V. Nesterov, and S. G. Entelis, Kinetika i Kataliz, 1969, 10, 663; T. E. Lipatova, L. A. Bakalo, and L. V. Rachcva, Sin. Fir. khim. Polim., 1973, 80. Satchell and Satchell Such a scheme could perhaps account qualitatively for all the facts. It involves an intramolecular electrophilic addition; this could be fast. B. Ketens.-(i) The spontaneous and carboxylic acid catalysed reactions. Kinetic studies of these systems reveal in all essentials the pattern described above for isocyanates. For the spontaneous reaction24 there is as yet no hard evidence for the participation of alcohol monomers, although they may be involved with sterically hindered alcohols which polymerize with The predominant route for various alcohols and dimethylketen in diethyl ether s0lution2~ is shown in Scheme 6 (cf.Scheme 1). 3R20H 4 (R*OH)~ fast -(R~oH)~ RL2CHC0,R2f 2R'OH slow Scheme 6 For the carboxylic acid catalysis in ethereal solvents it is found,24 as for isocyanates, that the catalytic efficiency falls as the acid strength rises and that the rate equation is d [products]/dt = k[keten] [alCOhOl]stoich [acid]. A mechanism similar to Scheme 2 is highly probable. As with isocyanates, thiols react very slowly with ketens in the absence of catalysts. There is good evidence that the spontaneous addition of alkyl thiols is predominantly a radical reaction.26 However, in the presence of carboxylic acids26a powerful catalysis results whose mechanism is again probably analogous to Scheme 2. (ii) The tertiary amine catalysed reaction.In an important series of studies, principally using toluene as solvent, Pracejus and co-workers27 have shown that low concentrations of tertiary amines catalyse not only the reaction of ketens with alcohols, but also the dimerization of the keten. And although sterically hindered bases are less effective in both reactions, the dimerization is particularly depen- dent upon an unencumbered nitrogen atom. Since the catalysed dimerization presumably proceeds via an outline scheme such as Scheme 7, it seems unlikely *' P. J. Lillford and D. P. N. Satchell, J. Chem. SOC.(B), 1968, 889. "W. T. Brady, W. L. Vaughn, and E. F. Hoff, J. Org. Chem., 1969,34, 843. ''P. J. Lillford and D. P. N. Satchell, J. Chem. SOC.(B), 1970, 1303.''A. Tille and H. Pracejus, Chem. Ber., 1967,100, 196; R. Samtleben, J. prakt. Chem., 1972, 314, 157. Acylation by Ketens and Isocyanates. A Mechanistic Comparison NfI‘R2 Ra 2’ Scheme 7 that the alcoholysis can employ a mechanism in which the catalyst plays a similar (nucleophilic) role. Two other facts in strong support of a mechanism like Scheme 4, rather than one like Scheme 3, for the alcoholysis of ketens are (i), that alcohol-tertiary base equilibria are known in toluene, and (ii), that with the strongest bases, the rate equation d[products]/dt = k[keten] [alCOhOl]stoich pasel observed at the higher temperatures reduces at low temperatures to d [product ]/dt = k’[keten] [base].27 This can be accounted for by pre-equilibrium of Scheme 4 shifting well to the right under the latter conditions.A mechanism like Scheme 3 cannot account for this kinetic effect. Other factors also point to the correctness of a scheme analogous to Scheme 4, and moderate steric effects would be expected in forming a transition state like (8), unless the groups R1 and R3are quite small. The rather complete work with ketens therefore sup ports the suggestion of Farkas and Strohm21 concerning isocyanates. (iii) Catalysis by acid amides.as As we have seen, in the spontaneous and the carboxylic acid-catalysed reactions, alcoholysis is facilitated by species which effect a cyclic proton transfer to the /hubon atom. It is no surprise to find therefore that acid amides, which can act as bifunctional catalysts [e.g.(12)], accelerate the alcoholysis. The rate equation is d [product ]Idt = [keten] [amide] [alc~hol]~t~i~h;the mechanism is doubtless Scheme 8. A similar route probably underlies the autocatalysis by urethane2 sometimes observed in the isocyanate reaction. (iv) Catalysisby metal derivatives. One of the few groups to notice the similarity between keten and isocyanate reactions, Pracejus and co-workersFQ have tested the effects of metal derivatives on keten alcoholysis. Surprisingly they drew a blank :only one compound (copper acetylacetonate) provided powerful catalysis. The significance of this result is not yet understood. 88 H. Pracejus and R. Samtleben, Tetruhetlron Letters, 1970, 2189. H. Pracejus and R.Samtleben, 2.Chern., 1972,12, 153. Satchell and Satchell R3 R3c"o'..H'c=o fast 11I fast+ R*OH .A ,N,H...O\/N-H R4 R2 R' (11) R'zC=C=O R'$-=C=O 4 R'CHCOiR2 f RSCONHR4 '0-RZ 1Y-H R4-N. ';'c.-..o--' slow I R3 3 Reaction with Water The acylations (8) and (9) lead to substituted acetic and carbamic acids, res- pectively. Under appropriate conditions further reaction is possible in both R2C=C=0 -k HpO R2CHC02H3 (8) RN=C=O + HpO -+ RNHC02H (9) cases.1~2Anexcess of keten gives the anhydride (lo), but with an excess of water little anhydride results, carboxylic acids mostly being less reactive than water towards ketens. Similar considerations probably also apply for isocyanates but with the added complication that carbamic acids and their anhydrides lose carbon dioxide readily.An excess of isocyanate will eventually result in forma-tion of the urea [equations (11) and (12)]. This release of carbon dioxide is the basis of the production of polyurethane foams.' -cop RNCORNHC0,H -RNH, ___) (RNH),CO (1 1) RNCO -coz RNHCOzH -(RNHCO),O -(RNH),CO (12) Acylation by Ketens and Isocyanates. A Mechanistic Comparison A. Ketem24--The spontaneous reaction of ketens with water is auto-catalytic. This is expected in view of the catalysis of alcoholysis by carboxylic acids (p. 239). For dimethylketen in diethyl ether at water concentrations 5 0.3M, the spontaneous and acid-catalysed routes have the rate equations d [product]/dt = k[keten] [waterI2 and d [product]/dt = k[keten] [water] [acid], respectively.When [HzO] < 0.3M little polymeric water exists in ether at ordinary tempera- tures, but significant amounts of polymer form at higher concentrations. In this region the reaction order in water rises above 2 in the spontaneous hydrolysis. With [HzO] ;L 0.3M, the mechanism of Scheme 9 is probable for the spon- taneous reaction. The involvement of polymeric water is supported by the increase in order in this species at high concentrations. Other polymers will then doubtless coexist with the dimer and more than one route will be viable. Polymeric water is clearly much more reactive than the monomer for whose participation there is no evidence. The parallel with alcoholysis is striking (p.239). In the product-catalysed reaction the acid presumably takes over the role of the second water molecule in (13) in a mechanism analogous to Scheme 2. In non-co-ordinating solvents different reactions orders may prevail owing to the greater extent of hydrogen-bonding. No studies exist of catalysis by tertiary bases. B. 1socyanates.-The hydrolysis of isocyanates has not yet been studied under satisfactory conditions. However, it is evidently catalysed by tertiary bases,2 and, as for ketens, the spontaneous reaction shows every sign of involving polymeric water. Thus the order in water is greater than unity,50 and the reaction is faster in benzene than in dioxan.2 The latter type of finding is common to all the spon- taneous reactions with which we are dealing.It arises not because the mono- meric substrate is deactivated in the co-ordinating solvent by hydrogen-bonding to the solvent, as has often been suggested-quite the reverse, such solvents so R.P. Tiger, L. S. Bekhli, and S. G. Entelis, Kinetiku i Kutuliz, 1971, 12, 318. Satchell and Satchell act as feeble base catalysts-but because polymeric substrate is more abundant in non-co-ordinating solvents and this is the dominant factor in fixing reactivity. 4 Reaction with Carboxylic Acids For both ketens and isocyanates the initial product here is an anhydride, usually an unsymmetrical anhydride. In the presence of an excess of acid the initial product tends to react further, as shown in (13) and (14). The particular product R',C=C=O + R'CO,H -R~~CHCOO-COR' (13) .1 R?CO,H (R"CO),O + K1.,CHC02H 1 (R?CO)~O+ R'NHCO~H R'NH, + co2 mixture depends upon the contact time and the other conditions.31 Reaction (13) is used industrially to manufacture acetic anhydride and in the laboratory for preparation of unsymmetrical carboxylic anhydrides.All but the strongest carboxylic acids react relatively slowly at ordinary temperatures so that in most cases where other keten and isocyanate additions are catalysed by carboxylic acids little of the catalyst is consumed. A. Ketens.32-Kinetic studies of the first step of equation (13), using a series of substituted acetic acids with diphenylketen in dichlorobenzene and with di- methylketen in diethyl ether solution, show that for acids weaker than mono- chloroacetic acid the rate of spontaneous addition is inversely related to acid strength.On the other hand the strongest acids, dichloro- and especially trifluoro-acetic acid, add relatively rapidly. The rate equation is normally d [product ]/dt = k[keten] [acidIstoich. At the concentrations used the acids are largely monomeric in ether and dimeric in dichlorobenzene. For the weaker acids, whose nucleophilicity is evidently more important than their acidity, the O1 W. D'Olieslager and I. De Aguirre, Bull. Sod. chim. France, 1967, 179; M. L. P. De Troparevsky, A. E. A. Mitta, and A. Troparevsky, Anales Asoc. quim.argentina, 1973, 61, 227. ** J. M. Briody, P. J. Lillford, and D. P. N. Satchell, J.Chern. SOC.(B), 1968, 885. Acylation by Ketens and Isocyanates. A Mechanistic Comparison transition states (14) and (15) are probable. With a bifunctional substrate the polymer is clearly of no great advantage, but happens to be the predominant form in dichlorobenzene. In the vapour phase33 the reaction of keten with acetic acid also involves just the monomer and the appropriate transition state is (14; R1 = H, R2 = Me) which, sensibly enough, and as pointed out by Blake and Davies, is the same as that proposed for the thermal decomposition of acetic anhydride. Indeed it is important to realize that the mechanisms of all the various additions we are considering have implications for the transition states of the corresponding eliminations (which in most cases have not yet been studied).The predominantly electrophilic mechanism involved for addition of the strongest acids is discussed below. B. Isocyanates.-Little clear-cut kinetic work exists here. What is known= is strikingly similar to the findings with ketens. Again there is an evident change in mechanism from predominantly nucleophilic to predominantly electrophilic addition at an acid strength about that of monochloroacetic. The nucleophilic route can be catalysed by tertiary amines, the electrophilic route by boron fluoride. 5 Reaction with Amines With ketens primary and secondary amines lead to amides and with isocyanates to ureas [equations (15) and (16) respectively]. Normally the equilibrium posi- tions of processes (15) and (16) lie far to the right1s2 but for isothiocyanates a R12C=C--r' + R2NHz + RlzCHCONHR2 (15)RlN=C==O + R2NHzf RlNHCONHR2 (16) more evenly balanced position can be obtained;% in this case primary amines lead to ureas which can cleave in two directions [equation (17)l.RlNCS + R2NH2 f R1NHCSN€€R2+ R2NCS + RlNHs (17) 33 P. G. Blake and H. H. Davies, J. Chern. SOC.(B), 1971, 1727. 34 S. Ozaki and S. Shimada, Nippon Kagaku Zasshi, 1959,80,430. 36 W. Vanasshe and G. Hoornaert, Bull. SOC.chim. beiges, 1971,80, 505. 244 Satchell and Satchell A. Isocyanates.-(i) The spontaneous reaction. It is now widely36 agreed that the general kinetic form of the spontaneous reaction is d[product]/dt = (kl[amine] + ka[amine]2 + ks[amine] [urea product]) [isocyanate]. Clearly the monomer can react, but the relative importance of each of the terms for any given system depends upon the amine, the solvent and the relative concentrations of amine and isocyanate.With an excess of amine the auto-catalytic term is of little importance. As the dielectric constant of the medium is raised the overall velocity rises but, for any fixed value of [amine]stoich, the ratio kl[amine]/ k2[amineI2 falls as the hydrogen-bonding capacity of the solvent, and therefore the ratio [monomer]/[dimer], decreases. Bulky substituents in either the iso- cyanate or the amine slow the reaction down, but otherwise an increase in amine basicity leads to a faster rate. The same kinetic pattern is found for the forward steps of the isothiocyanate equilibria.35 (ii) Catalysis by tertiary nitrogen bases.Catalysis has been observed2 but it is relatively feeble on a PKa basis: for a tertiary base of the same PKa as the amine undergoing acylation the kinetic term representing self-catalysis (i.e. k2 [aminelz) is normally much more important than that for catalysis by the tertiary base in spite of the fact that steric effects seem small in the latter catalysis.37 In general therefore the presence of a tertiary base appears to add a small extra term to the rate equation, but the exact kinetic form of this catalysis is still uncertain?J7,38 (iii) Catalysis by bifunctional catalysts such as amides, ureas, and carboxylic acids. Such catalysts are relatively very effective compared with tertiary amines.37 As for the addition of O-nucleophiles to isocyanates, the efficiency of carboxylic acids varies inversely with their acid strength.This fact, and the great efficiency of bifunctional catalysts generally, points strongly to the occurrence of cyclic transition states in their reactions [e.g. (18)]. The same type of cycle cannot be written for tertiary bases which may assist here via transition states like (16) in which the base plays two contradictory roles; the net effect is slight catalysis because in all the cycles it is nucleophilic attack on the carbonyl carbon atom which is the dominant feature. Overleaf are illustrated the likely transition states (16&(19) for the various catalytic paths to aminolysis.These routes almost certainly involve a rapid, prior association of amhe with catalyst, followed by a rate-determining attack on the isocyanate, e.g. Scheme 10. If the pre-equi- librium lies well to the left this scheme leads to the correct kinetic form; the scheme is also compatible with the moderate primary hydrogen isotope effects35137 and with the usual values of AS* (ca. -40 cal deg-1 mol-l) and of AH* (ca. 6 kcal mol-1) for the various catalysed routes.58~39 The low value of AH* is again expected (see p. 236) from the opposing effects of temperature on the processes of Scheme 10. All these conclusions are strongly supported by related work~Q940 on the I. De Aguirre and J. C. Jungers, Bull. SOC.chim. France, 1965, 1316; N.K. Vorob’ev and 0.K. Shebanova, Izvest. V.U.Z.Khim. i. khim. Teknol., 1974,17,688. J. M. Briodqt and D. Narinesingh, Tetrahedron Letters, 1971, 4143.** N. K. Vorob’ev, E. A. Chizhova, G. E. Titova, and 0.K. Shebanova, Izaest. V.U.Z.Khini. I khim. Teknol., 1972,15,700. m A. P. Grekov and V. V. Shevchenko, Reakts. spos. org. Soedinenii, 1968, 5,47. 4D A. P. Grekov and G. V. Ostrosko, Zhur. org. Khim., 1974,14530. Acylation by Ketens and Isocyanates. A Mechanistic Comparison R' R''N-q-0 R:, T\T"q=o "-Cm 0 .. *.....&....N H N-H H'" ON-H / \ ' '\ N A'RZ (Or solvent) R3,N... H R2 R3/ I 'c=o..'H/Y-*H R2 R2 INHR3 (16) (1 7) (18) 2R2NH, 4 (R2NH2), fast acylation of hydrazides in benzene solution [reaction (18)].Here the spon- taneous reaction probably has no important kinetic terms in [R2NR3NH2I2 when R3 = H. This is sensible since the hydrazide itself can then act as a bifunc- tional reagent, as in (20). R'NCO + R2NR3NH, -* R1NHCONHNR2R3 (1 8) N=C=O .. H N-H 'N' \ IH B. Keten~.~l~~~-Theinformation available for ketens again bears a striking similarity to that outlined for isocyanates. Thus the rate equation for the spon- taneous reaction has the form d[product]/dt = (kl[amine] + kz[amineI2} 41 P. J. Lillford and D. P. N. Satchell,J. Chem. SOC.(B), 1967, 360. 42 J. M. Briody and D. P. N. Satchel], Tetrahedron, 1966,22,2649; P. J. Lillford and D. P. N. Satchel], J. Chem. SOC.(B), 1968, 54. Sdtchell and Satchel1 [keten] in both ether and benzene solutions.In both solvents, in the absence of steric hindrance, both kl and k2 are directly related to the strength of the base. Auto-catalysis by the amide product has not been observed, probably because the experimental conditions involved use of an excess of amine. Minor catalysis by tertiary amines and major catalysis by carboxylic acids are again found and their kinetic forms have been more clearly established than for the isocyanate reactions. With carboxylic acids the inverse dependence on acid strength appears yet again, and in diethyl ether where the acids exist as monomers, the observed rate equation is d[product]/dt = k[amine] [keten] [acidIstoich. Scheme 11, H (22) Scheme 11 analogous to Scheme 2, is strongly suggested. An amine-catalysed addition of the acid, followed by acylation of amine by the anhydride formed, plays a negligible part in these reactions.In catalysis by tertiary amines the rate equation for the spontaneous reaction is augmented to d[product]/dt = {(kl + k’l[tertiary amine]) [amine] + (k2+ k’2 [tertiary amine]) [aminelz) [keten]. Hence the tertiary amine can evidently assist both the monomer and dimer routes. The transition state for the path controlled by k’2 is presumably (23), and could be formed from keten and the species R2NHz..HNH ..NR33. I R2 R12CmC-=o H ~\I-H....NR~~ \ ’\R2 H0 ‘i’‘*-HRZ Acylation by Ketens and Isocyanates. A Mechanistic Comparison 6 Reaction with Strong Hydrogen Acids As mentioned above, carboxylic acids which are stronger than monochloroacetic acid undergo electrophilic addition to both ketens and isocyanates.Other classes of powerful hydrogen acids have been little studied with isocyanates, but with ketens the hydrogen halides also display electrophilic addition43 to give finally acyl halides, as in equation (19). These hydrogen halide additions, like RaC=C=O + HHal R,CHCOHal (19)---t that of trifluoroacetic acid, are very fast compared to the other types of addition so far considered; the catalysis of reactions of ketens@ (and probably of iso-cyanates) by hydrogen halides and other mineral acids arises from their pre- liminary conversion into the acyl halide, acyl hydrogen sulphate, etc. The wide- spread belief, often voiced in textbooks,45 that ketens are more reactive species than the corresponding acyl halides is mistaken.It arose because ketens are often used in the presence of sulphuric acid as catalyst, when the observed re- activity is probably that of the acyl hydrogen sulphate, which is indeed greater than that of the acyl halide.46 In the absence of catalysts ketens have reactivities lying between those of the corresponding acyl halides and anhydrides.a The kinetics of addition of hydrogen halides and of trifluoroacetic acid to ketens in ethereal solvents exhibit43 a rate equation of the form d[product]/dt = a[hydrogen halide12 Peten]/(l + bbydrogen halide]). One explanation is mechanism (20), since application of the steady-state approximation leads to : kl HHal -t-R2C=C=0 ?R,C= C/OH R,CHCOHal 3-HHal (20) k-1 ‘tIal d[product]/dt = klka@IHal]* [keten]/(k-l + kz [HHal]).In this mechanism the prototropic second step thus becomes rate-determining at small values of [HHal]. Observed isotope effects and relative reactivities are also compatible with this mechanism which constitutes the only substantial evidence for an initial O-protonation of ketens throughout the field. Everywhere else the facts point to the direct, usually synchronous, transfer to the p-carbon at0m.~p43 The general findings for isocyanates are, of course, similar and it will be interesting to learn whether the addition of strong acids to isocyanates does in fact continue the parallelism. 43 P. J. Lillford and D.P. N. Satchell, J. Chern. SOC.(B), 1968, 897. 44 D. P. N. Satchell, Chem. and Ind., 1974, 683. 46 N. L. Allinger,M. P. Cava, D. C. De Jough, C. R. Johnson, N. A. Lebel, and C. L. Stevens, ‘Organic Chemistry’, Worth Publications Inc., New York, 1971. 40 E. A. Jeffrey and D. P. N. Satchell,J. Chern. Soc., 1962, 1887. Satchell and Satchell 7 Addition to Compounds Containing Double-bonds This is another type of reaction in which the behaviour of ketens and isocyanates is evidently very similar. Briefly it can be said that two heterolytic mechanisms have been identified: a zwitterionic, step-wise scheme and a simple four-centre addition. The step-wise scheme is found in the tertiary base-catalysed dimeriza- tion of both ketens, (Scheme 7), and isocyanates,*7 (Scheme 12), and the straight- 0 Ph -PhNCO PhN-C-N-C=OII I-PhNCO +B PhN-C-0 I I Bf B' 0 0 Scheme 12 forward four-centre route (which is believed to involve a weakly polar and slightly distorted transition state) in the uncatalysed dimerization of ketensts (Scheme 13), 2MeeC=C=0 Scheme 13 and in many additions of ketens and isocyanates to olefir~s.~~ On the other hand, addition of isocyanates to C-N bonds is normally step-~ise,~O while both routes occur simultaneously in particularly favourable circumstance^.^^ The balance 47 R.E. Buckles and L. A. McGrew, J. Amer. Chem. SOC.,1966,88, 3582. 48 R. Huisgen and P. Otto, J. Amer. Chem. SOC.,1968, 90, 5342. 'O J. E. Baldwin and J. A. Kapecki, J.Amer. Chem. SOC.,1970,92,4868; F. Effenberger, G. Prossel, and P. Fischer, Chem. Ber., 1971, 104, 2002. 'O H. Ulrich, Accounts Chem. Res., 1969,2, 186. I1 R. Huisgen and P. Otto, J. Amer. Chem. SOC.,1969,91,5922. Acylation by Ketens and Isocyanates. A Mechanistic Comparison between these heterolytic routes depends upon solvent polarity and other factors as yet unelucidated. The myth that electrocyclic reactions proceed via mechanisms which are neither heterolytic nor homolytic has fortunately not yet affected discussion in this part of the electrocyclic field. 8 Conclusions The remarkable similarity between the results obtained with isocyanates and with ketens hardly needs further emphasis. What is particularly impressive is the virtual identity of the respective rate equations and the close parallelism in substrate reactivity towards both classes of compound i.e., amines 5 alcohols 2: water $= thiols < carboxylic acids < trihaloacetic acids and hydrogen halides.For both classes there exist also both a nucleophilic and an electrophilic route to addition, with the changeover point in mechanism occurring in each case at species HX of pKa close to that of chloroacetic acid. Cyclic transition states are, of course, to be expected for reactions like (3) and (4), but the widespread occurrence of cyclic transition states during the addition of species HX in non-hydroxylic solvents, is also now hardly to be doubted. As explained in the Introduction such addition is equivalent to the acylation of HX and the frequently proposed synchronous transfer of a proton to the nitrogen or /%carbon atoms is equivalentM to acid-catalysed assistance of leaving-group departure in more conventional acylations, e.g.(5). In conventional acylations in hydroxylic media this catalysis is effected by solvent molecules (or by deliberately added acid) and is always available. It is most significant therefore that in non- hydroxylic media, where solvent hydrogen-bonding is not available, the mecha- nisms of conventional acylations are invariably observed to change towards routes involving cyclic transition states, closely resembling those considered in this Review, in which extra substrate or catalyst molecules effect the cyclic transfer of protons from substrate to leaving gro~p.~~g~~ These cycles not only provide catalysis of leaving group departure, they supply too a simultaneous base-catalysis of proton removal from the substrate and also help to minimize charge separation. Acylation by ketens and isocyanates therefore fits nicely into the current overall picture of acylation in non-hydroxylic solvents.

ISSN:0306-0012    

DOI:10.1039/CS9750400231

出版商:RSC    

年代:1975

数据来源: RSC

摘要:

The Contribution of Ion-pairing to ‘Memory Effects’* By C. J. Collins CHEMISTRY DIVISION, OAK RIDGE NATIONAL LABORATORY, OAK RIDGE, TENNESSEE 37830, AND DEPARTMENT OF CHEMISTRY, UNIVERSITY OF TENNESSEE, KNOXVILLE, TENNESSEE 37916, U. S.A. In 1961, Silver1 reported that the 2-methylbutyl cation formed from different reactants through deaminationz gave different yields of products, and commented upon this ‘transference of unusual behaviour’ from reactant to intermediate. Berson and co-worker~,~*~ beginning in 1962, published a series of papers dealing with the same phenomenon for both solvolytic and deamination (amine-nitrous acid) reactions. The phenomenon was relabelled a ‘Memory Effect’, and its origin was ascribed to ‘twisted ions’ (2) and (4). Thus reactants (1) and (9,when treated with nitrous acid, were visualized as going to the ions (2) and (4),respectively, which differed from each other only in the direction of the ‘twist’.The ‘twisted’ ions (2) and (4) presumably react with the entering group faster than they go to the normal ion (3), explaining potentially, at least, why the compounds produced in the product mixtures I and I1 should occur in CH,NH2 H.,NCH2 Products I Products I1 *Dedicated to Prof. Dr. Eugen Miiller on the occasion of his 70th birthday.M. Silver, J. Amer. Chem. SOC.,1961, 83, 3482. a For an excellent review see H. Soll, in Houben-Weyl, ‘Methoden der organischen Chemie’, ed. E. Muller, George Thieme, Stuttgart, XI/2, 1958, pp. 133-181.* J. A.Berson and P. Reynolds-Warnhoff, J. Amer. Chew. Soc., 1962, 84, 682; 1964, 86, 595; J. A. Berson and D. Willner, ibid., 1962, 84, 575; 1964, 86, 609.‘ J. A. Berson, Angew. Chem., 1968, 80, 765. 251 The Contribution of Ion-pairing to ‘Memory Efects’ different proportions. Berson4 states ‘The “twisted” cations therefore are true metastable intermediates occupying minima in the potential energy surface of the reaction’. The possibility that ion-pairing might be responsible for the ‘memory effect’ was considered by Berson, but was dismissed-particularly for the amine- nitrous acid rea~tion,~ since ‘The return process in deamination would involve molecular nitrogen. ..’. We believe, contrary to Berson’s explanation, that ion pairs play an important role in ‘memory effects’, and especially so in the amine-nitrous acid reaction. Huisgen5 and Whites demonstrated beyond doubt that ion pairs are present during thermal decompositions of N-nitrosoacylamines, and we showed’s8 in 1960-61 that the thermal decompositions and nitrous acid deaminations are mechanistically related when the two reactions are carried out in acetic acid- sodium acetate solution.In these experiment^,^^^ optically active, labelled isomers both of (6) and of (7) were subjected, respectively, to deamination with NO I NH, Ph . NCOMe I* ‘ *IH6C-C H6C-C.1 $\H Ph Ph Ph Ph nitrous acid or to thermal decomposition (acetic acid-sodium acetate solution). The distributions of 14C(*) in the re-resolved products, as well as the fractions of racemization, indicated7s8 the similarity in mechanism of the two reactions.9 The involvement of ion pairs in the thermal decomposition of (7) was established by the experiment with optically active, acetate-labelled reactant (7a), in which 1,2,2-triphenylethyl [14C]acetate (10) of retained configuration was formed predominantly by cation-anion collapse of ion pair (9) whereas the product (11) of inverted configuration was formed principally through reaction of the cation of (9) with unlabelled acetate from the solvent. That ion pairs (9) should also be involved during the deamination of (6) is understandable, for the nitrosating agent in the solvent employed is undoubtedly acetyl nitrite, leading to the formation of diazonium acetate by the following, or similar, reactions (1)-(5) : R.Huisgen and Ch. Ruchardt, Annalen, 1956,601,21; R. Huisgen and H. Reirnlinger, ibid., 1956, 599, 161, 183. E. H. White, J. Amer. Chem. SOC.,1955,77,6011,6014; E. H. White and C. A. Aufdermarsh, ibid., 1958, 80, 2597. See particularly the discussion by E. H. White and D. J. Woodcock, in ‘The Chemistry of the Amino Group,’ ed. S. Patai, Interscience, New York, 1968, Chap-ter 8. 1 C. J. Collins and J. B. Christie, J. Amer. Chem. SOC.,1960, 82, 1255; C. J. Collins, J. B. Christie, and V. F. Raaen, ibid., 1961, 83, 4267.* C. J. Collins, W. A. Bonner, and C. T. Lester, J. Amer. Chem. SOC.,1959, 81,466. C. J. Collins and B. M. Benjamin, J. Arner. Chcm. SOC.,1963, 85,2519.Collins -I-RNH2 + MeC02NO -+ [RNHzNO MeC02-] (3) + +-[RNHzNO MeCOz- J [RNH=NOH MeC02-1 (4) + + [RNH=NOH MeC02-] ---+ (RN2 MeC02-] + H2O (5) f CH, I Co&%o0 It* k0 Ph, OCCH, Ph, MeC I -k0 0 (10) (9) retention It is, therefore, not the nitrogen, as assumed by Ber~on,~ which would be responsible for controlling the stereospecificity of product formation, but rather the counter-ion formed on decomposition of the diazonium acetate, reaction (6): The counter-ions [reaction (6)] must be ‘oriented’ as originally suggested by Huisgen5 and by White.lo The question we must now answer is whether these lo E. H. White, H. P. Tiwari, and M.J. Todd, J. Amer. Chem. Soc., 1968,90,4734. The Contribution of Ion-pairing to ‘Memory Eflects’ oriented ion pairs can also be responsible for the retention of optical configuration.In the case of reactants (6)’99 and (7)899 the steric properties of 1,2,2-triphenyl-ethyl cation appeared dominant, and it was not possible to recognize any con- tribution by the ion pair to configurational retention, although such a possibility could not be denied. There are several indications, however, that oriented ion pairs are capable of influencing the steric outcome of a reaction. Ott,ll for example, noted that treatment of optically active a-phenylethylamine (12) in acetic acid solution with sodium nitrite yielded the carbinol (15) of like sign of rotation (retentiorP), Me Me 1 I O*d c f -%CMe.y /H Ph1’11 (13) ion pair collapse Me Me 0 I I It f--,C-0-CMe H Ph PI1 whereas when very dilute (0.6% by weight) aqueous acetic acid was used as the solvent, a-phenylethanol of opposite sign of rotation (inversion12) was obtained.Partial racemization accompanied both reactions. Ion pairs (13) must be res- ponsible for the retention of configuration observed by Ott.ll The data of Lee and Lam13 for the acetolysis of 1-(d S-cyclopentenyl)[2-14C]-ethyl nosylate (1 6) (nosylate = p-nitrobenzenesulphonate) are also strongly presumptive evidence that the counter-ion can be influential in product control. Thus (16), on acetolysis, is presumed14 to yield a non-classical ion (17) which can react with acetate anion to produce [5-14C]norbornyl acetate (19) or undergo 6,2-hydride shift to yield the non-classical ion (18).The cation (18) should react l1 E. Ott, Annulen, 1931, 488, 186. la Beilstein’s ‘Handbuch der organischen Chemie’, Band VI, Drittes Erggnzungswerke (System Nummer 473, pp. 1671-1672. l3 C. C. Lee and L. K. M. Lam, J. Amer. Chem. SOC.,1966,88,2834. l4 R. G. Lawton, J. Amer. Chem. SOC.,1961, 83, 2399; J. D. Roberts, C. C. Lee, and W. H. Sanders, jun., ibid., 1954, 76, 4501. Collins with solvent to yield equal amounts of [3-14C]norbornyl (20) and [7-14C]norbornyl (21) acetates. Surprisingly, the results13 [38 % (20), 25 % (21)] cannot be rational- ized with the non-classical ion (18), which should be (except for 14C labelling) * a symmetrical intermediate.The observationsl3 of Lee and Lam are explainaMe15 as follows:the non-classical ion14 (23) formed directly from norbornyl brosylate (22) (brosylate = p-bromobenzenesulphonate)is associated with a counter-ion (-OBs) which is oriented symmetrically across the charge-bearing C-1 and C-2 positions.16 We believe that the counter-ion is responsible for the symmetrical properties usually associated with the norbornyl cation. In the solvolysis of (16), the counter-ion cannot be oriented as in (23), but must approximate the situation shown in (24). Although the ion pair (24) may undergo several Wagner-Meerwein t -0Bs l6 C. J. Collins and M. H. Lietzke, J. Amer. Chem. SOC.,1967, 89, 6570. lo C. J. Collins and C. E. Harding, Annulen, 1971,745, 124.The Contribution of Ion-pairing to ‘MemoryEfects’ or 6,2-hydride shifts, there will never be in any of the subsequent species a substantial contribution of structure (23). One explanation, therefore, for the data of Lee and Lam13 is that owing to the almost random orientation of the counter-ion, the cations themselves are classical in character. The cation (25) can then react with solvent to yield 2-ex0-[3-1~C]norbornyl acetate (20; 38 %) faster than it reaches equilibrium with the cation (26), which itself collapses with (19) 37% solvent to produce 2-exo-[7-14C]norbornyl acetate (21 ; 25 %). An alternative possibility is that the cation of an oriented ion pair such as (27) will not possess an equal charge distribution between C-1 and C-2 and will react with acetate anion at those two positions with different rates to yield more (20) than (21).Collins Finally, the results of my co-worker, Dr. C. E. Harding,l6 should be mentioned. The [41*C]norbornyl cation (28), formed through either the ‘sigma’ or ‘pi’ routes14 underwent 3,2-hydride shift to yield the Wagner-Meerwein cation pair (29) P(30). This cation pair did not act like a non-classical norbornyl cation since the two products, (31) and (32), were not formed in equal amounts. Again the possibility must be considered that oriented ion pairs are responsible for these results. m-Route 3,2 hydride shift 0-Route 6 + (28) * (32) Because of the facts given in the foregoing discussion, we devised a series of experiments to allow us to test further the role of ion pairs in ‘memory effects’, under conditions which preclude the intervention either of normal conformational effects or of abnormal effects of the type which might lead to ‘twisted ions’.In the first experiment, the reactions with nitrous acid (in acetic acid-sodium acetate) of the two endo-amines (33) and (34) were investigated.17-20 It was established through isotopic labelling18 for both reactions that the ion (35) was C. J. Collins, V. F. Raaen, and M, D. Eckart, J. Amer. Chem. Soc., 1970,92,1787. C. J. Collins, B. M. Benjamin, V. F, Raaen, I. T. Glover, and M. D. &kart, Annulen, 1970, 739, 7. C. J. Collins, Accounts Chem. Res., 1971,4, 315. ‘O C. J. Collins,I. T.Glover, M.D. Eckart,V. F. Raaen, B. M. Benjamin, and B. S. Benjaminov,J. Amer. Chem. SOC.,1972, 94, 899. The Contribution of Ion-pairing to ‘Memory Eflects’ the precursor of the two products, d3-cyclohexenyl phenyl ketone (36) and syn-7-phenyl-7-hydroxy-2-exo-norbornylacetate (37). Yet from (33), after a single Wagner-Meerwein rearrangement, the cation (35) yields two products in nearly equal amounts, whereas from (34), after Wagner-Meerwein and 6,2-hydride shifts, only one product, (37), was formed. We ascribe these results to ion-pairing, in which the amine (33) yields the ion pair (38) whereas the amine (34) yields the ion pair (39). In these two structures the cations are written as if they were identical, but the anions are in different relative positions. The exo- anion in (39) is situated for easy exo-collapse to product (37), whereas the acetate NaNO, i-ti ‘ NaN02+ H’ Wagner-Meerwcin Wagner-Meerwein .I-6,2 hydride shirt QHNH, (75)(33) (33) ! (36) (37) 18.5 22.1 [Percent yield from (33)] 0 29.2 [Percent yicld from (34)] anion in (38)is unavailable for exo-product formation; here reaction of the cation with acetate anion from the solvent (instead of with the counter-ion) is necessary, and must compete with ring-opening.Thus, from (38), both products (36) and (37) result. This is a true ‘memory effe~t’,~ yet twisted ions are not possible here. We conclude that the oriented ion pairs (38) and (39) are responsible for the results. /Me 0 (39) 0\./ C IMe Collins Ratio (42:43) = 18: 1 OAc (44) (45) Ratio (44 :45) = I8 :I The exo:endo stereospecificities in the deaminations, in acetic acid-sodium acetate solution, of the em-amines (40) and (41) were determi~~ed~l-~~ to be 18:1 for both reactants.In the deamination, under identical conditions, of the endo- amine (46), however, the yield of endu-product (45) was greater than that of Ratio (44:45) = f:f.2 em-product (44) [ratio of yields (44): (45) = 1:1.21. These results are clear evidence, we think, that the ion pairs from (40) and (41) must resemble structures (47) and (48), respectively, in which the em-counter-ions dictate collapse from the em-direction. In the case of the endo-amine (46), the ion pair must resemble structure (49), and the endo-counter-ion here dictates a preponderance of collapse with the cation from the endo-direction.A final example of the importance of ion-pairing in controlling product formation will be given. In the Scheme are portrayed portions of the deamination C. J. Collins and B. M. Benjamin, J. Amer. Gem. Soc., 1970,92,3182.*' B. M.Benjamin and C. J. Collins,J. Amer. Chem. Soc., 1970,92,3183. a3 C.J. Collins and B. M. Benjamin, J. Org. Chem., 1972, 37,4358. The Contribution of Ion-pairing to ‘Memory Eflects’ Me Me (47) f I Me reactions of the two amines (41) and (46), which differ only in the ex0 vwsus endo placement of amino-groups. The stereospecificities for exo- versus endo-attack of acetate ions on the respective cations formed from the reactants after Wagner- Meerwein rearrangement are also shown. The cation in each of the two ion pairs (47) and (50) is the same: the only difference we have assumed is that the counter- acetate anions are oriented in the same relative positions as were the amino-groups in the two reactants. As is clear from the experimental results shown in the Scheme, there is only a trace (0.04 %) of endo-product (43) from the exo-amine (41) (exo: endo product ratio = 640).From the endo-amine (46), 1.8% of the endo-acetate (43) was isolated, and the ratio of exo- to endo-products formed [(42):(43)] is 8. The differences in em: endo stereospecificities for attack on the two identical cations of the ion pairs (47) and (50) we ascribe to the orientations of the counter-acetate ions as follows: ion pair (47) is well situated for collapse from the exo-direction to yield the exo-product (42).The endo-acetate (43) must be formed by endo-attack from solvent, a process which cannot successfully compete with collapse of an intimate ion pair. The exo-orientation of acetate anion in (47) imparts a serious bias in favour of exo-attack which, when combined with the strong steric factor24 inhibiting endo-attack, results in overwhelming production of the exo-product (42). In structure (50), however, ion-pair collapse is severely restricted, and the H. C. Brown and K. T. Liu, J. Amer. Chem. SOC.,1970, 92, 200; ibid., 1971, 93, 7335; H. C. Brown and J. H. Kawakami, ibid., 1970,92,201,1990; H.C. Brown, J. H. Kawakami, and S. Igekami, ibid., 1971, 93, 7335. Collins sx X z20 do 234 4e4e f 4 I + h00 s i 1I z h I h \o3 3 a =if; The Contribution of Ion-pairing to ‘Memory Efects’ cation must react with acetate from the solvent, rather than with the counter-ion. The solvent, however, is free to attack the cation from either direction, subject only to the steric24 hindrance to approach from the endo-direction. There is no serious external bias in favour of em-product, so the cation reacts with its 8 :1 steric preference. In conclusion, the evidence for ion-pairing during the amine-nitrous acid reaction of aliphatic amines has been partially reviewed, and the experimental evidence, primarily from our own research at Oak Ridge National Laboratory, that these ion pairs are responsible for stereochemical control or ‘memory effects’ has been presented.We believe that the weight of evidence is against ‘twisted’ ions and strongly in favour of counter-ion control as the cause of these ‘memory effects’ during aliphatic deaminations.

ISSN:0306-0012    

DOI:10.1039/CS9750400251

出版商:RSC    

年代:1975

数据来源: RSC

摘要:

The Chemistry of Aphids and Scale Insects By K. S. Brown, jun. LABORAT~RIODE ECOLOGIA QU~MICA, DEPARTAMENTO DE ZOOLOGIA, INSTITUTO DE BIOLOGIA, UNIVERSIDADE ESTADUAL DE CAMPINAS, C.P. 1170, CAMPINAS, SZO PAUL0 13.100, BRAZIL 1 Introduction Aphids or plant lice (Homoptera: Aphidoidea) and scale insects or mealybugs (Homoptera: Coccoidea) represent two of the most successful groups of herbi- vores in the temperate and tropical regions of the Earth.l Unique biological adaptations, such as phloem feeding, surface protection by a hard or waxy covering, rapid growth, the telescoping of generations by asexual reproduc- tion, and a variety of life forms, have permitted these insects to adapt to a wide range of plants, multiply explosively under favourable conditions, and survike topical applications of modern chemical insecticides. Thus, they represent an appreciable component in many terrestrial agroecosystems. Some members of these groups may be classified as useful to man, yielding such important commercial products as dyes (cochineal, widely used before 1900), varnishes (shellac), and waxes.The scale insects Trabutina mannipara Ehrenburg and Naiacoccus serpentinus Green played a key role in world history; the nutritious manna they secrete when feeding on tamarisk trees (Tamarix gallica, var. ‘mannifera’ Ehr.) in the Sinai Peninsula helped the children of Israel to survive the march through the desert when they left Egypt,2 and still repre- sents an important food and export product of the area. On the other hand, the reproductive potential, genetic adaptability, and feed- ing methods of aphids and scales cause them to be classified among the most destructive of agricultural pests.Pandemic prejudicial species include the cabbage aphid, Brevicoryne brassicae (L.);the greenbug, Schizaphis graminurn (Rondani); the pea aphid, Acyrthosiphon pisi (Harris); the green peach aphid, Myzus persicae (Sulzer); the melon aphid, Aphis gossypii Glover; the woolly apple aphid, Eriosoma lanigerum (Hausmann); the grape phylloxera, Viteus vitifolii (Fitch);the black scale, Suissetia oleae (Bernard); citrus mealybugs (Planococcus and Pseudococcus species);the California red scale, Aonidiella aurantii (Maskell); the San JosC scale, Quadraspidiotus perniciosus (Comstock);and the oyster-shell (a) A.F. G. Dixon, ‘Biology of Aphids’, The Institute of Biology’s Studies in Biology, No. 44, Edward Arnold, London, 1973; (6) ‘Aphid Technology’, ed. H. F. van Emden, Academic Press, London, 1972; (c) C. L. Metcalf, W. P. Flint, and R. L. Metcalf, ‘Destruc- tive and Useful Insects’, McGraw-Hill, New York, 1962; (d) J. S. Kennedy and 1. H. M. Fosbrooke, ‘The Plant in the Life of an Aphid’, in ‘Insect/Plant Relationships’, ed. H. F. van Emden, Blackwell, Oxford, 1973, pp. 129-140. Exodus 16: 4-5, 11-36; ‘Ergebn. Sinai-Expedition der Hebrgischen Universitat, Jeru- salem’, various authors, Leipzig, 1929. 2Family Margarodidae (DClass INSECTA rGenus Icerya Order HOMOFTERA -Family Ortheziidae (no chemical investigation) 5Suborder STERNORRHY NCHA 4I .Family Diaspididae Suborder Genus Aonidiella < Superfamily Psylloidca Superfamily Aleyrodoidea Superfamily Coccoidea (Psyllids or (Whiteflies) (Scale insects -Family Coccidae jumping plantlice) Genera Coccus. Genera Aleyodes,Family Psyllidae Family Aleyrodidae mealybugs) Ceroplastes, Ericerus. Genus Psylla Trialeurodes Garcardia 3Super family Aphidoidea t(no chemical investigation) Family Aclerdidae $ dl -Family Lacciferidae1 Family Phylloxeridae Family Adelgidae Family Aphididae Genus Luccifer nGenera Viteus, Genera Pineus, Genera Acyrtliosiplion, Aphis, Aulacorthum. x Pliylloxera. Adeiges Bracliycaudus. Breivicoryne, Cavariella, Pliy lloxerina Cliaitophorus, Cinara, Cryptomyzus. -Family Asterolecaniidae fiactynotus, Drepanosiphum, Dysaphis, Eriosoma. (no chemical investigation) Horniapliis, Hyadaphis, Hyalopterus, Liosomaphis, Longicaudux.Macrosiphoniella, Macrosiphum, -Superfamily Cicadoidea Megoura. Metopolophiurn, Microlophium, Mysaphis, Family Pseudococcidae (Cicadas. Leafhoppers, Myzus, Nasono ria, Paraprocipliilus, Peripliyllus, Gene ra Psiw1ococcu.v Treehoppers. and Phodobium, Phorodon, Pteroconima, Rhopalosiphum Traburiiia Froghoppers Rhopalosiponinus, Scliizaphis, Sclrizoneura. Schizolachnus. Sipha. Sitobion, Symydobius, Terraneura, Family Eriococcidae or Spittlebugs) Tliela.res, Tuberolachnus. Genus Diococcus -Superfamily Fulgoroidea (Planthoppers and Family Dactylopiidac Lan tern-flies) Genus Dactyli~piii.~E Filmily Kermesidae Genus Kcwiii~s Scheme 1 Brown scale, Lepidosuphes ulmi (L.).These and many other widespread pests probably cause as much agricultural loss per year as any other major group of insects, largely through weakening plants, aborting fruit ripening, and transmitting plant diseases. The chemistry of these small insects is no less unusual than their biology. A large number of apparently polyketide-derived compounds dominates the picture of secondary metabolism of aphids and scales; some unique terpenoids have also been isolated. Essentially none of these compounds has any relation- ship with constituents of the host-plants. It seems possible that many substances are synthesized for the aphids and scales by species-specific endosymbiotes, using catabolic products of ingested carbohydrates and free amino-acids.These are the principal nutrients which the insects take in from phloem sap.* Many species can also be reared for multiple generations on artificial diets.3 The symbiotic micro-organisms have been suggested as providers of necessary vitamins and steroids to the aphids, and may synthesize many additional compounds which accumulate in the insect’s hemolymph. The importance of the endosymbiotes to the animals is shown by the rapid weakening and death observed in anti- biotic-treated aphids,lt4 and the elaborate mechanisms used to ensure passage of the micro-organisms from generation to generation.5 2 Systematics The presently accepted taxonomic arrangement of the superfamilies Aphidoidea and Coccoidea and their close relatives is presented in Scheme 1.The close relationship of Homoptera to the true bugs (Hemiptera) has persuaded many authors to link these two groups, and indeed intermediate taxa are known. Other minor differences between recent authors involve family status and genus names. The arrangement given here is slightly modified from that according to Borrer and deLong,O using information received from Dr. V. F. Eastop of the British Museum (Natural History). Chemical structures have been established for secondary products isolated from species in the indicated genera. 3 Ecology As a significant element in the ecosystem almost wherever they occur, aphids and scales are among the more important controlling elements on higher plants throughout the world (primary herbivores).On the other hand, they constitute significant food elements for vertebrate and invertebrate predators (prey of primary carnivores). The complicated life cycles of many aphids frequently involve obligatory alter- * Some groups, especially scale insects in the family Diaspididae, are reported to feed on parenchyma or other non-phloem material. a J. L. Auclair and J. J. Cartier, Ann. SOC.Entomol. Quebec, 1964, 9, 68; R. H. Dadd and T. E. Mittler, Experientia, 1966, 22, 832; D. L. Krieger, Ann. Entomol. SOC.Amer., 1971, 64, 1176; D. H. Akey and S. D. Beck, J. Insect Physiol., 1972, 18, 1901, and references therein; see also J.B. Adams and H. F. van Emden, in ref. 16, pp. 61-71. T. E. Mittler, J. Insect Physiol., 1971, 17, 1333. R. Hinde, J. Insect Physiol., 1971, 17, 1791. D. J. Borrer and D. M. delong, ‘An Introductionto the Study of Insects’, Holt, Rinehart, and Winston, New York, 1971, 3rd edn. The Chemistry of Aphids and Scale Insects nation of host plants and production of a variety of adult forms. A typical example (the hops aphid) is illustrated in Scheme 2.7 Species are often purely THE HOPS APHID(PHORODON HUMCJL-I)’ tmtic to 1Hatch first oduction of wingless sexual females on plum Fertilization; overwintering eggs laid on plum trees Scheme 2 parthogenetic in the tropics, with males as yet unknown, but multiple host plants are still frequent.Although scale insects often have more simple sexual cycles, their breadth of host-plant acceptance may be far greater than that of aphids. The abundance and dispersal of aphids and scales are strongly dependent upon weather (especially moisture) and availability of food-plants. Adverse conditions, crowding, host-plant senescence, or seasonal changes often lead to the production of alate (winged) individuals which disperse with the wind, covering from one to hundreds of miles before alighting and searching for satisfactory food-plants.1 The factors which cause the aphids first to leave the host-plant in flight and then, after a given time (two hours to a full day), settle and search for a new host-plant have been extensively investigated.lS8 Both L.0. Howard, ‘The Insect Book‘, Doubleday, New York, 1901, pp. 265-268. H. F. van Emden, ‘Aphids as Phytochemists’, in ‘Phytochemical Ecologf, ed. J. B. Har-borne, Academic Press, New York, 1972, pp. 25-43. Brown nutrient value and secondary constituents of the plant determine acceptability to the aphid, which tests plants by multiple probes with its stylet and takes off again on a short flight if not satisfied. Young scale insect larvae are often dispersed by the wind or by birds; adult females are wingless. Adult males are usually alate, but without functional mouthparts, so the food-plant choice must be made by other chemoreceptors or different life forms.* The excessive weakening of the plants attacked, through loss of nutrients, often results in stunted growth, reduced fecundity, minimal fruit maturation, permanent damage, and death.The weakened plant is further rendered more susceptible to attack by fungi and viruses. The latter are often carried from diseased to healthy plants on the homopteran stylets,l~S entering through the punctures made for phloem feeding. The most important natural controls on the fantastic reproductive potential of aphids and scales (a single fundatrix could give rise to over 10’6 individuals in one summer) are by fungal infection and parasitic microhymenoptera (Chalcidoi- dea and Ichneumoidea : Braconidae, Aphidiinae). Even so, where favourable plant conditions occur locally, these insects can rapidly destroy crops, trees, and fruits.Ideal conditions for adult multiplication and plant saturation may be created in agricultural monocultures which have suffered an indiscriminate application of insecticides; these tend to kill the parasitic wasps and other predators, but have little effect (except for the systemic poisons) on the phloem- feeding homopterans. Aphids and scales are heavily preyed upon by a variety of invertebrates, chiefly ladybugs (Coleoptera :Coccinellidae), true bugs (Reduviidae and Miridae), syrphid fly larvae, Neuropteran larvae (Chrysopidae), and midge maggots (Diptera:Cecidomyiidae and Chamaemyiidae). They are also often ingested by larger herbivores (including lepidopterous larvae and larger vertebrates) grazing on the plant, and probably represent a staple food for some insectivorous birds and reptiles.At least two species examined (Aphis nerii Fonscolombe, Aphididae and Aspidiotus nerii BouchC, Diaspididae) apparently ingest poisonous carden- olides from their host-plants (Nerium oleander, Apocynaceae, and various Asclepiadaceae). The first may advertise to vertebrate predators distasteful properties by a bright orange (aposematic or warning) coloration. Among its invertebrate predators, some continue to store the cardenolides, while others apparently metabolize them.10 While some animals feed on aphids and scales, others are attracted to the sweet honeydew they excrete from the anus. Certain species of ants form a mutualistic relationship with the homopterans, protecting them from predators, carrying them to new host-plants, and stimulating them with their antennae * Information on scale insects was received from Dr.D. J. Williams of the Commonwealth Institute of Entomology.M. A. Watson and R. T. Plumb, Ann. Rev. Entomol., 1972,17,425, and references therein. lo M. Rothschild, J. von Euw, and T. Reichstein,J. fnsect Physiol., 1970, 16, 1141 ;M. Roths-child, ‘Secondary Plant Substances and Warning Coloration in Insects’, in ‘Insect/PlantRelationships’, ed. H. F. van Emden, Blackwell, Oxford, 1973, pp. 59-43; M. Rothschild, J. von Euw, and T. Reichstein,J. Entomol. (A),1973,48,89. me Chemistry of Aphidr and Scale Insects in order to obtain honeydew.lOG For this reason, some aphids have been called ‘ant cows’.Bees often facilitate their honey production by collecting honeydew from aphids, sometimes with disastrous results when the melezitose in the secretion crystallizes in the combs.ll The internal ecology of aphids and scales is also complicated. Each species houses one or more types of degenerate symbiotic micro-organism, which have been variously regarded as similar to Rickettsiae, gram-negative Eubacteria, Myco- bacteria, or Mycoplasma,12 within specialized structures (mycetomes) and cells (mycetocytes).13 These symbiotes have been suggested to produce compounds useful to the insects but not sufficiently available from their diet or their own bio- synthetic abilities, such as sterols,3J4 amino-acids15 (with possible fixation of Nz), vitamins,l5J6 and organosulphur compounds17 (with kation of inorganic sulphate).It is still in debate whether they also produce the many secondary poly- ketide-related compounds isolated from aphids and scales, normally regarded as products of biosynthetic pathways of micro-organisms rather than animals. Although it is rarely mentioned in print, the attractive if fantastic hypothesis that mitochondria are merely further evolutionary degenerates of endosymbiotes is supported by both the close intracellular relationship of the homopteran symbiotes, and their suspected prodigious biosynthetic prowess. Removal of the nucleic acid to the outside of such degenerate organisms, accompanied by control of their enzyme systems by the cells in which they are housed, might give a useful biochemical system not unlike that in which mitochondria participate (for a discussion of and a conservative view against this suggestion, see ref. 13, pp.69-74). 4 Secondary Compounds of Scale Insects The commercial production of dyes, varnishes, and waxes from scale insects has facilitated the chemical investigation of secondary metabolic products of these organisms. Nevertheless, the structural complexity of these compounds is such that only recently have some definitive results come to light. A. Lac Resin.-The Indian scale insect Laccifer Zacca Kerr (also known as Tachardia Zacca) produces a hard secretion which accumulates along infested branches, eventually swallowing up the insects themselves and remaining as a thick cylinder.Removed by melting, the secretion is known as stick-lac;l* when loaM. J. Way, Ann. Rev. Entomol., 1963, 8, 307. l1 C. S. Hudson and S. F. Sherwood, J. Amer. Chem. SOC.,1918,40, 1456. la C. Vago and M. Laporte, Ann. SOC.entomol. France, N.S., 1965,1,181; R. Hinde, J. Insect Physiol., 1971, 17,2035; D. McLean and E. Houk, ibid., 1973, 19, 625; E. J. Houk, ibid., 1974, 20,471. la P. Buchner, ‘Endosymbiosis of Animals with Plant Microorganisms’, Interscience, New York, 1965, pp. 23-34, 58-66,232-345, 619-829. P. Ehrhardt, Experientia, 1968, 24, 82. l6 R. Fink, 2.Morphol. Okol. Tiere, 1952, 41, 78. la P. Ehrhardt, Z. vergl. Physiol., 1968, 60,416. l7 P. Ehrhardt, Biol. Zbl., 1969, 88, 335. la M. S.Wadia, R. G. Khurana, V. V. Mhaskar, and Sukh Dev, Tetrahedron, 1969,25,3841. Brown ground and washed with water, eliminating most of the1 pigments, it is called seed-lac. A number of varieties exist, depending upon the host-plant, but they are physically and chemically very similar, showing principally quantitative variation in the several components. Further industrial purification of seed-lac gives the more homogeneous shellac of commerce, a useful hard varnish for which no perfect synthetic substitute is yet known. Laboratory fractionation of Palas seed-lac (from L. Zacca on Butea monosperma Lamk.,Legumino~ael~)gave by water extraction 2% residual pigments (with some carbohydrates also). Subsequent extraction with 78 % aqueous ethanol left behind waxes (5%) and insect and plant debris.The ethanol extract could be fractionated with ether to give insoluble hard resin (57%) with the desirable properties of commercial shellac, and more soluble soft resin (19 %) and neutral components (5 %). The hard and soft resins, prepared similarly from a variety of lac samples, are complex oligomers of hydroxy-acids, joined by ether20 and ester linkages. Although both resin types contain essentially the same acids, the proportions and intermolecular bonds are different. Careful purification of hard resin by fractional precipitation from benzene-dioxan mixtures gave a series of 12 fractions,21 quite different in content and in proportions of the constituent hydroxy-acids. Further purification of one fraction by progressive solution in ethyl acetate-dioxan and precipitation from dioxan with benzene gave an apparently pure oligomer denominated 'pure lac resin' (12%of the original hard resin).This was chosen for detailed structural studies.22 The principal hydroxy-acids of lac resin are probably threo-aleuritic acid [= 9,10,16-trihydroxypalmiticacid (l)], 18*23jalaric acid and laccijalaric acid (3).25 An important minor constituent of some fractions is butolic acid (4).26 Other minor acids detected include myristic, palmitic, palmitoleic, and other C14-cl8 straight-chain acids, Cl6 w-hydroxy-acids, c14 and Cla 9,lO-dihy- droxy-acids, and 6-oxotetradecanoic acid.23~27 The sesquiterpenic aldehyde-acids (2) and (3) have been suggested to give rise to complex mixtures [(5)-(12)] when the resin is hydrolysed by alkali.This unusual reaction would be basically a Cannizzaro-type disproportionation, lBR. G. Khurana, A. N. Singh, A. B. Upadhye, V. V. Mhaskar, and Sukh Dev, Tetrahedron, 1970,26,4167. I0 R. Madhav, T. R. Seshadri, and G. B. V. Subramanian, Indian J. Chem., 1967, 5, 182;T. R. Seshadri, N. Sriram, and G. B. V. Subramanian, ibid., 1971, 9, 524. A. B. Upadhye, M. S. Wadia, V. V. Mhaskar, and Sukh Dev, Tetrahedron, 1970,26,4177. IP A. B. Upadhye, M. S. Wadia, V. V. Mhaskar, and Sukh Dev, Tetrahedron, 1970,26,4387. H. Singh, R. Madhav, T. R. Seshadri, and G. B. V. Subramanian, Tetrahedron, 1967, 23, 4795. I4 M. S. Wadia, R G. Khurana, V. V. Mhaskar, and Sukh Dev, Tetrahedron Letters, 1964, 513.I6 A. N. Singh, A. B. Upadhye, M. S. Wadia, V. V. Mhaskar, and Sukh Dev, Tetrahedron, 2§, 3855. "J. W. Christie, F. D. Gunstone, and H. G. Prentice, J. Chem. SOC.,1963, 5768; R. G. Khurana, M. S. Wadia, V. V. Mhaskar, and Sukh Dev, Tetrahedron Letters, 1964, 1537. I' J. W. Christie, F. D. Gunstone, H. G. Prentice, and S. C. Sen Gupta, J. Chem. Soc., 1964, 1537. The Chemistry of Aphids and Scale Insects OH I CH,?(CHJpCH(CH,);COOH (4) butolic acid (5) R = CH,OH: (7) R = CH,OH: epishellolic acid shellolic acid (6)R = CH,: (8)R =, CH,: epilaccishellolic acid laccishellolic acid H tH3 (2) R = CH,OH: HOH~C~ jalaric acid (3)R = CH,: L' laccijalaric acid SIX CH, 6H3 (9) R = CH,OH: (11) R = CHIOH: epilaksholic acid laksholic acid (10) R = CH,: (12) R = CH,: epilaccilaksholic acid laccilaksholic acid possible in these aldehydes which are too sterically hindered to undergo norma1 aldol condensation.l8*24 There is still some doubt, however, as to whether the unique building-blocks of the resin are only (I), (2), and (3), with (5)--(12) arising only as artefacts; a recent publication has indicated the presence of further components, including epishellolic acid (3,in untreated lac resin.28* An extensive series of chemical modifications and hydrolyses Ied to a defini-tion of the oligomer linkage points in the fraction called 'pure lac resin',22but the exact structure of this individual compound is still uncertain.The molecular weight is 2432, comprising two molecules of aleuritic acid linked through the carboxyl (with all three hydroxyls free), and one probably linked through the * In ref. 28, the names jalaric (2) and laccijalaric (3) acids are changed to epijalaric and epilaccijalaric, respectively, to correspond to tht-,configurational nomenclature of epishel-lolic acid (5).Although this change may be rationally defensible, we prefer not to follow it as it will promote confusion with the older, weli-establishednames for (2) and (3). as T. R. Seshadri, N. Sriram, and G. B. V. Subramanian, Indian J. Chem., 1971, 9, 528. Brown 9-and 16-hydroxyls; one molecule of laccijalaric acid linked through the 5-hydroxyl; and five molecules ofjalaric acid: three linked through the 5-hydroxyl and possibly the carboxyl, one linked through the carboxyl only, and one linked through the 5-hydroxyl and the CHzOH, and possibly the carboxyl; in all, eight intermolecular bonds are present.B. Pigments.-All known pigments of scales are polyketide anthraquinones, sometimes condensed further with amino-acid or carbohydrate moieties (see Schemes 3 and 4).29930* While the lac pigments, in spite of their large production and potential commercial value20 have had limited use, the colours isolated from the Mexican scale Dactylopius coccus Costa (feeding principally on Opuntia cacti) and the Mediterranean scale Kermes ilicis Linnaeus (feeding principally on Quercus coccifera, an oak), were among the most important commercial dyes before the advent of synthetics.Their names (carmine and Venetian red) conjure up to the mind certain rich shades of natural coloration which, because of their high saturation, low brilliance, and permanent character, have not yet been fully duplicated by aniline dyes. The structural formulations of carminic and kermesic acid and the lac pigments have had a rather chequered history, due to the difficult chemical nature of these compounds which are poorly crystalline, form solid mixtures, and decompose at very high temperatures. The first is an unusual C-glycoside with only one position free on the aromatic nucleus. The structure presently accepted (13) is well founded upon degradative and spectroscopic evidence.31,32 Likewise, the recently revised structure for erythrolaccin (14),33 the principal pigment from seed-lac, is surely correct (by unambiguous synthesis).Laccaic acids A (15) and B (16)34*35are appreciably more complicated ;like carminic and kermesic (1 7)36t * The ‘ommochrome’ pigment of lac larvae, lacciferic acid (H. Singh, T. R. Seshadri, and G. B. V. Subramanian, Tetrahedron Letters, 1966, 1101), is now regarded as a mixture of laccaic acids A, B, and C, with the latter existing partly as a protein complex: B. V. Ramachandran, A. V. Rama Rao, and I. N. Shaikh, Indian J. Chem., 1970,8,783.t Kermesic acid has also been found in stick-lac from Thailand, along with laccaic acids A, B, and C, and emodin (27).30 MIR. H. Thomson, ‘Naturally Occurring Quinones’, Academic Press, New York, 1971, 2nd ed., pp.418-422,443,453, and 455-472. K. Venkataraman and A. V. Rama Rao, in ‘Some Recent Developments in the Chemistry of Natural Products’, ed. S. Rangaswami and N. V. Subba Rao, Prentice-Hall of India, New Delhi, 1972, pp. 341-352. 31 J. C. Overeem and G. J. M. van der Kerk, Rec. Trav. chim., 1964, 83, 1023. sa S. B. Bhatia and K. Venkataraman, Indian J. Chem., 1965,3,92. s3 P. Yates, A. C. Mackay, L. M. Pande, and M. Amin, Chem. and Ind., 1964, 1991; N. S. Bhide, A. V. Rama Rao and K. Venkataraman, Tetrahedron Letters, 1965, 33; N. S. Bhide and A. V. Rama Rao, IndianJ. Chem., 1969,7,996. sp R. Burwood, G. Read, K. Schofield, and D. E. Wright, J. Chem. SOC.,1965, 6067; 1967, 842; R. Burwood, G.Read, and K. Schofield, Tetrahedron Letters, 1966,3059;N. S. Bhide, E. D. Pandhare, A. V. Rama Rao, 1. N. Shaikh, and K. Venkataraman, Tetrahedron Letters, 1967,2437; N. S. Bhide, E. D. Pandhare, A. V. Rama Rao, I. N. Shaikh, and R. Srinivasan, Indian J. Chem., 1969, 7, 987. E. D. Pandhare, A. V. Rama Rao, R. Srinivasan, and K. Venkataraman, Tetrahedron, 1966, Supplement 8, 229; E. D. Pandhare, A. V. Rama Rao, and I. N. Shaikh, Indian J. Chem., 1969,7,977. ”D. D. Gadgil, A. V. Rama Rao, and K. Venkataraman, Tetrahedron Letters, 1968, 2223. The Chemistry of Aphids and Scale Insects (14) e&hrolrccin (15) R=CHINHCOCHta;lacuic(16)acid A HOOC 0 OH no R=CH,OH laccaic acid B 0 0 laccaic acid E R= CH.NH1 (1) (19) untholaacaic acid 0 OCH, (20) methylared laccaic acid 1 Scheme 3 272 Brown acids, they undergo the purpurin-xanthopurpurin transformation [-+ (1 8), (1 9)]3593e upon reduction.Furthermore, when methylated under forcing condi- tions, they undergo partial ring-closure to furanoid compounds and in some cases even suffer carbonation from the KzCO3 catalyst [-+ (2O)].35 Additional com- pounds in this series include laccaic acids C (2l),37 D [= xanthokermesic acid (18)],38*38and E (22),30 desoxyerythrolaccin (23),38.39 isoerythrolaccin (24),39 and ceroalbolinic acid (25)40 from the Mexican Ceroplastes albolineatus Cockerell and the Japanese C.rubens Maskell. The correctness of the present formulations for the structures of these pigments is greatly supported by the unified simplicity of their biogenetic scheme, starting from a hypothetical octaketide (Scheme 3).36 All except laccaic acids A, B, C, and E and the erythrolaccins give cochenillic acid (26)31932 upon oxidation.A number of simpler, carboxyl-free anthraquinones related to the widespread emodin (27), the derived purpurin (28), and 7-acetylemodin (29) occur free and/or as glycosides in Australian Eriococcus species.41~42 All of these compounds [(27)-(33)] are apparently derived from a cyclization mode of the presumed octa- or nona-ketide precursors different from that which produces the lac pigments (Scheme 4).42 C. Waxes.-The wax secreted copiously by certain coccids is collected by many peoples around the world and used in medicine, for making candles, and in diverse other household activities.The prototype wax scale [Ericerus pela (Chavannes)] is thus used in China; the related Gascurdia cerijiera (F.) similarly serves the people of India, and Ceroplastes scale insects have been used for millenia for the production of wax by many peoples in Central and South America. Although a large but varying fraction of scale wax is composed of standard long-chain ester~,4~ -46* analysis of hydrolyoates has turned up some surprising constituents. Most waxes also seem to include a small amount of straight-chain hydrocarbons, containing from 15 to 33 or more carbon atoms (both even and odd numbers), with the higher molecular weights usually pred0minating.~5 Many also contain a surprisingly large percentage of free fatty acids in the The ‘longchain ketone C,,H,,O’ mentioned in ref.41 may well be an ester, C&HQ~O~ or CbQH18808. 37 A. V. Rama Rao, I. N. Shaikh, and K. Venkataraman, Indian J. Chem., 1969, 7, 188. 38 A. R. Mehandale, A. V. Rama Rao, I. N. Shaikh, and K. Venkataraman, Tetrahedron Letters, 1968, 223 1. 3e A. R. Mehandale, A. V. Rama Rao, and K. Venkataraman, Indian J. Chem., 1972,10,1041. 40 T. Rios, Tetrahedron, 1966,22,1507;D. D. Gadgil, A. V. Rama Rao, and K. Venkataraman, Tetrahedron Letters, 1968, 2229; K. Doi, Sci. Rep. Hirosaki Univ., 1972, 18, 37 (Chem.Ah., 1972, 77, 72 697v). 41 A. W. K. Chan and W. D. Crow, Austral. J. Chem., 1966, 19, 1701. 4a H. J. Banks and D.W. Cameron, Chem. Comm., 1970, 1577. 43 Y.Tamaki, Botyu-Kagaku, 1969, 34, 86. 44 E. Faurot-Bouchet and G. Michel, J. Amer. Oil Chemists’ SOC.,1964, 41, 418. 4b Y. Tamaki, Nogp Gijutsu Kenkyusho Hokoku (Bulletin 0f the National Institute of Agricultural Sciences), C, 1970, 1. ‘@A.C. Chibnall, S. H. Piper, A. Pollard, E. F. Williams, and P. N. Sahai, Biochem. J., 1934,28,2189, The Chemistry of Aphids and Scale Insects OH 0 OH OH 0 OH 3 -mCH3"OWCH (0) HO HO 0 0 (30) (27) 2-h ydroxyemodin emodin/ J.(O) -3H20 -coo OH 0 OH OH 0 OH HOf$& HOf$pCHzOH \ CH8 0 OH 0 (31) (28)\(0)w-hydroxyemodin \ 4-hydroxyemodin \ OH 0 OH OH 0 OH HO HO CHSOH. 0 OH 0 (29) (33) 7-acety1,modin 5-hydroxy-7-hydroxymethy lpurpurin OH 0 OH COCHJ \WCHaHO OH 0 (32) 5-h ydroxy-7-methyl-6-acety lpurpurin Scheme 4 Brown 26-34 carbon range;& in the case of Gascardia madagascarensis Targioni- Tonetti, these are mostly hydroxylated on a carbon near the middle of the chain.& The wax of the lac insect (Laccifer Zacca), by way of contrast, contains mostly free alcohols.46 The wax of the cochineal insect, Dactylopius coccus, is principally 1 5-keto-n-tetratriacontanyl-13-keto-n-dotriacontanoate.47*The ester waxes generally possess over 50, often up to 70 carbon atoms, with the ester function near the middle of the chain.43~45 Unsaturated and/or shorter-chain waxes are occasionally f0und;~3#~8 the corresponding acids and alcohols are commoner in the body lipids of the insects than in the waxes.43~~9 A major esterified acid of the citrus pest Pseudococcus comstocki (Kuwana) is the dibasic tetradecane-l,14-dioic acid.50 In Ceroplastes rubens Maskell, a fair portion of the esterified alcohols and acids in the wax may consist of modified diterpenes, which have been named rubabi- etic acid (34), rubenic acid (35), and rubenol (36).51It is possible that these stuc- tures may need revision in light of modern methods of physical analysis.The waxes of first and second instar Ceroplastes contain mostly eicosanoic a~id,4~p~~suggesting that not only the thickness of the coating, but also the chain length of its constituents grows along with the insects. Saponification of the wax of the Mexican CeropZastes aZboZineatus gave not only n-alkanols and n-alkanoic acids, but also an exceptional series of sesterter- penes (c25), including the parent geranylfarnesol (37).52 Also found were four tricyclic compounds [(38)-(41)], two acids and two alcohols, having the same fundamental skeleton (but a different stereochemistry) as the fungal ophiobolins [e.g.(42)].s3 The structure of the major alcohol, ceroplastol-I (38), was established by X-ray crystallographic analysis of its p-bromobenzoate.54 The structures of ceroplastol-I1 (39),55 ceroplasteric acid (40),= and albolic acid (41)56 followed from spectral measurements and chemical interrelations [the double bond isomerized from the exocyclic to the endocyclic location upon treatment of the compounds (38) and (40) with toluene-p-sulphonic acid in pyridine].Albolineol (42a), also found in the hydrolysate, is apparently a bicyclic precursor to, or fragmentation product of, (38).56a A further sesterterpene acid (gascardic acid), not possessing the ophiobolane skeleton but having many elements in common with the CeropZastes sesterter- * Similar scale waxes, with both elements always hydroxylated on the twentieth carbon in from the end of the chain, have been studied recently by J. Meinwald and co-workers (Ninth IUPAC Symposium on the Chemistry of Natural Products, Ottawa, June 1974). 47 A. C. Chibnall, A. L. Latner, E. F. Williams, and C. A. Ayre, Biochem. J., 1934,28,313. 48 M. Kono and T. Maruyama, J. Agric. Chem.SOC.Japan, 1939,15, 177, quoted in ref. 45. 4B Y. Tamaki and S. Kawai, Botyu-Kagaku, 1967,32,63. Y. Tamaki, Lipids, 1968, 3, 186. 51 M.Kono and T. Maruyama, J. Agric. Chem. SOC.Japan, 1938,14, 318, quoted in ref. 45. 6* T. Rios and S. Perez C., Chem. Comm., 1969, 214. 68 T. Rios and F. Coiunga, Chem. and Ind., 1965, 1184. Y. Iitaka, I. Watanabe, I. T. Harrison, and S. Harrison, J. Amer. Chem. SOC.,1968, 90, 1092. 66 T. Rios and L. Quijano, Tetrahedron Letters, 1969, 1317. *' T.Rios and F. G6mez G., Tetrahedron Letters, 1969, 2929. 6caT.Rios. L. Ouiiano. and J. Calder6n. J.C.S. Chem. Comm., 1974, 728. 275 The Chemistry of Aphids and Scale Insects HOMO --H (42)ophiobolin C 1 HO,C (42b) gascardic acid H (37) geranylfarnesol I 11+ (42a) albolineol R' R' (34) R' = COOH, R2,R3 = CHa rubabietic acid (35) R' = COOH, R3,R3 = CH3, CH20H rubenic acid (36) R' = CH,OH, R2,RS= CH3, CH,OH rubenol (38) R (39) R (40)R (41) R = CH,OH,da(W: ceroplastol-I = CH20H,dS(4):ceroplastol-I1 = COOH,L~~(~):ceroplasten'cacid = COOK,L~~(~)):albolic acid penes, has been isolated from Gascardia madagascarensis56b and subjected to a variety of interesting chemical reactions, leading to the determination of its nsbG.Brochtre and J.Polonsky, Bull. SOC.chim. France, 1960,963. Brown structure (42b).5sb15sc Its biogenetic pathway from a presumed geranylfarnesyl pyrophosphate precursor includes migration of the methyl group from C-11 to c-10.56~ D.Honeydew.-Most scales (and many aphids) excrete copious quantities of clear, sweet liquid known as honeydew.57 In addition to minor metabolic products, this fluid contains many compounds, either unchanged or in slightly modified form, which are present in the excess sap of the plant which is ingested by the scale or aphid. It is often used by animals, from ants (which tend aphids and scales as if they were domestic cattleloa) and bees to hummingbirds and man. Aphid and scale honeydew has the trisaccharide melezitose, synthesized within the insect, as a frequent major componenf.11~43-45Jj* Other important compounds detected (varying in composition and concentration with the homop- teran and host-plant species) include ribitol, glucosucrose (also synthesized in the insect), d-mannitol, raffiose, stachyose, maltose, sucrose (usually a principal component), trehalose, gluco~e,~~~~~ and a variety of both ~01ll1110n59 and unusualso amino-acids (such as p-alanine, y-aminobutyric acid, methionine sulphoxide, homoserine, and dopa).The nutritional value of honeydew, though somewhat variable, is sufficient to make of it an excellent potential source of carbohydrate food. E. Manna.-The true ‘celestial manna’ which brought the people of Israel through the march across the Sinai Peninsula in good health during the Exodus, was extensively studied by a Hebrew University expedition in 1927.aIt is appar- ently produced by the scale insects Trabutina mannipara and Naiacoccus ser-pentinus, feeding on the desert tamarisk trees.Precisely as documented in the Biblical account, it drops to the ground during the night like a light snow; spoils rapidly in the morning sun, unless baked; and is very nutritious. Chemical analysis indicated sucrose and invert sugar as principal components.61 North Iraquian manna, claimed to be very similar, is nonetheless chemically distinct from the celestial manna of Sinai. It has been claimed to be an exudate of trees (oaks and/or Fraxinlcs ornus L., the common European ash) which have been pierced by homopterans, not a secretion of the homopterans themselves. ‘6CR. Scartazzini, Diss. Nr. 3899, E. T. H., Zurich, 1966; and D. Arigoni, J. Polonsky,R. Scartazzini, G. Settim, and G. Wolff, unpublished work, reported by J.R. Hanson, in ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1974, Vol. 4, p. 174. 57 R. H. Hackman and V. M. Trikojus, Biochem J., 1952,51,653; H. E. Gray and G. Fraenkel, Physiol. Zool., 1954, 27, 56; W. H. Ewart and R. L. Metcalf, Ann. Entomol. SOC.Amer., 1956, 49, 441; J. S. D. Bacon and B. Dickinson, Biochem J., 1957, 66, 289; T. E. Mittler, J. Exp. Biol., 1958, 35,74; J. L. Auclair, Ann. Rev. Entomol., 1963, 8,439. m Y. Tamaki, Seibutsu Kagaku, 1968, 17; S. Kawai and Y. Tamaki, Jap. J. Appl. Entomol. Zool., 1969, 13, 150. 6g R. A. Gray, Science, 1952,115,129; Y. Tamaki, Jap. J. Appl. Entomol. Zool., 1964,s’ 227, and references therein; H. S. Salama and A. M.Rizk, J. Insect Physiol., 1969, 15, 1873; M. Saleh and H. S. Salama, ibid., 1971, 17, 1661. eo J. B. Maltais and J. L. Auclair, Canad. J. Zool., 1952, 30, 191; Y. Tamaki, Jap. J. Appl. Entomol. Zool., 1964, 8, 159, and references therein. 61 A. Fodor and R. Cohn, in ref. 2, p. 89. The Chemistry of Aphids and Scale Insects In addition to nearly 15 % of fat, protein, fiber, and ash,62*63 it also may include, like insect honeydew, appreciable amounts of melezitose (10-12 %),63 or trehalose (w 7%).64 Only 10%of the carbohydrates are red~cing;~~.63 most of the remainder is sucrose, and raffinose was also detected.G2 Neither natural Arabian manna contains mannitol or mannose, but these have been detected in other manna-like materials (solid honeydews), apparently also produced from scale insect/tree interactions.F. Pheromones.-Presumed sex pheromones have been detected in females of three species of scale: Matsucoccus resinosue Bean and Godwin (red pine scaIe),66 Aonidiella citrina Coquillet (yellow scale),66 and A. aurantii (Maskell) (California red scale).G7 Partial isolation of the sex attractant from the latter has been reported.@3 Very little chemical work was done on the natural pheromone, but it was observed to co-chromatograph on Carbowax 20M with methyl and ethyl myristates, compounds isolated in the same workG8 (this is one of the few reports of the occurrence of an ethyl ester in nature; as the pheromone was collected by passage of air over the feeding scales, however, the myristyl esters could originate from either the animals or the citrus fruits). The chromatographic behaviour and chemical reactions of the pheromone suggested that it might be an acetate of an unsaturated branched-chain alcoh01.~~~~9 5 Secondary Compounds of Aphids A.Trig1ycerides.-Early workers verified three unusual facts concerning aphid lipids: (i) they were almost exclusively composed of triglycerides; (ii) they amoun- ted to as much as one-third of the weight of the insects, without forming an external secretion like the waxy covering of many scale insects; and (iii) in many cases, they contained almost exclusively myristic acid, with other acids being of short chain length (C6, CE).~O Further investigation, with isolation of individual compounds, led to the identification of t r imyr is t in and 2-trans,tvuns-sorboyl-1,3-dim yris t in from temperate-zone ~pecies,~l*~~ and 2-trans,trans-sorboyl-l,3-dipalmitinfrom the more tropical Aphis nerii Fonscolombe.73 The unusual sorbic acid-containing Oa Z.I. Sabry and N. A. Atallah, Nature, 1961, 190, 915. H. Colin and H. Belval, Bull. Assuc. Chim., 1937, 54, 12. J. Leibowitz, Biochem. J., 1944, 38, 205. O6 C. C. Doane, J. Econ. Entomol., 1966, 59, 1539. 68 D. S. Moreno, G. E. Carman, R. E. Rice, J. G. Shaw, and N. S. Bain, Ann. Entomol. SOC. Amer., 1972, 65,443; D. S. Moreno, ibid., p. 1283. 13' H. Tashiro and D. L. Chambers, Ann. Entomol. SOC.Amer., 1967, 60, 1166; H. Tashiro, D. L. Chambers, D. Moreno, and J.Beavers, ibid., 1969,62,935. a J. D. Warthen, jun., M. Rudrum, D. S. Moreno, and M. Jacobson, J. Insect Physiol., 1970,16,2207. W. Roelofs, personal communication. 70 F. E. Strong, Hilgardia, 1963, 34, 43. 71 J. H. Bowie and D. W. Cameron, J. Chem. Soc., 1965, 5651. Y. Shimizu, Nuturwiss., 1971,58, 366. 73 K. S. Brown, jun., D. W. Cameron, and U. Weiss, Tetrahedron Letters, 1969, 471. Brown glycerides are apparently restricted to aphids; it has been recently demonstrated that they are biosynthesized within the aphids from acetate.74 The glycerides have been reported to possess antifungal activity,72 but the erratic test results suggest that this may be due to sorbic acid (formed by hydrolysis and known to possess antibiotic properties).A significant use of these triglycerides by the aphids is in defence. When dis- turbed or attacked, aphids produce from their cornicles (rodlike projections on their abdomens) a supercooled liquid which rapidly becomes a sticky solid upon contact with any ~urface;~5 this is almost totally composed of a low-melting triglyceride mixture, sometimes similar to but rarely identical with that in the total body lipids76 The esterified acids are almost wholly palmitic, myristic, sorbic, and n-hexanoic (= caproic); the latter is, like sorbic acid, esterified to the central oxygen of the glycerol.77 Lesser acids found in aphid triglycerides include stearic, oleic, and la~ric.'~ The triglyceride mixtures seem to be species-specific with wide variation between species, but no good systematic correlation can be constructed in accord with accepted taxonomic divisions, using the proportions of the various acids in the trigly~erides.7~ The proportions are not normally changed by the diet, genetic selection, colour, form, or food-plant of an aphid species, again indicating that the compounds are synthesized de novo by the aphids (or their symbiotes).However, they may vary in widely separate populations, or be affected by ambient temperature; the sorbic acid glyceride isolated from a temperate population mode Island, USA) of the normally tropical Aphis nerii* had an appreciably lower melting point (53-54 "C)than that from Arizona or Brazilian populations (2-sorbo-l,3-dipalmitin,m.p. 62-63 "C), and appeared to be 2-sorbo-l,3-dimyristin.78 Presuming that the melting point of this compound is important in the properties of the supercooled and potentially antifungal defensive secre- tion, it might be expected that colder-climate populations would synthesize triglycerides with shorter-chain a~ids.~~,~~ An investigation of 30 aphid species for acid proportions in the triglycerides of the cornicle secretion compared with those in the total body lipids indicated wide variation and appreciable discrepancies.76 Although there is a strong trend toward higher concentrations of myristoyl (lower-melting) and sorboyl (more anti-fungal) triglycerides in the cornicle secretion with relation to total lipids, several exceptions are evident.Successive drops from the cornicles of a contin- uously stimulated aphid show compositions progressively closer to those of body lipids.76 * The temperate populations have been separated from A. nerii by some specialists; the foodplant preferences are identical, however. 74 R. T. Aplin and P. Fairweather, manuscript in preparation. 75 A. F. G. Dixon, Entomol. Mon. Mag., 1958, 94, 8; J. S. Edwards, Nature, 1966, 211, 73; F. E. Strong, Ann. Entomol. SOC.Amer., 1967, 60, 668. R. K. Callow, A. R. Greenway, and D. C. Griffiths, J. Insect Physiol., 1973, 19, 737; A. R. Greenway and D. C. Griffiths, ibid., p. 1649. "K. S. Brown, jun. and A. M. Duffield, unpublished results. '* Y. Shimizu, personal communication (to U. Weiss). me Chemfstry of Aphids and Scale Insects As was found in the case of scale wax, triglycerides from immature aphids have a larger percentage of unsaturated and shorter-chain fatty acids (especially myri~toleic)~6than those in mature individuals; this may be a compensation for a volume/surface effect or for less effective chitin insulation, causing a lower body temperature in the juveniles.B. Pigments.-Although investigations by L'Helia~'~ suggested the presence of a number of pterins in the eyes of aphids, which were regarded as intermediate photoreceptors facilitating the synthesis of hormones which regulated the com- plex sexual and morphological changes during the aphids' yearly cycles, this conclusion has been cast in doubt by recent work showing a complete absence of detect able^ pteridines in Aphidoidea or Coccoidea.80 The 'pterins' detected by L'Helias were reidentified as aphid glycosides (see below) with deceptively similar RKvalues and fluorescence; the photoreceptors were suggested to be carotenes or still unidentified polar pigments.80 Pteridines (leucopterin, erythropterin, xanthopterin and isoxanthopterin) were detected and identified, however, in Psyllids and Aleyrodids as well as various Auchenorrhyncha,8°* perhaps indicat- ing that these two families either do not belong to the Sternorrhyncha or are much more primitive than the aphids and scale insects.Carotenes have been detected in small amounts in almost all species of aphid inve~tigated.~3*8~98~tIn one of the many species which demonstrate colour dimorphism, Macrosiphum Ziriudendri (Monell), the difference between the green and the pink forms was shown to be entirely due to the presence of differing and characteristic carotenoids.82 The green phenotype was found to possess the blue- green aphinin (see below) and yellow carotenes with a y-ionone ring [(43), (44)], while the pink morph produced red carotenoids bearing an open chain at one or both ends [(45a), (45b), (46a), and (46b)l.Both forms contained p,p-carotene, probably widely distributed in aphids.73.*0 The compounds (44),(45a), and (46a) had been previously isolated from micro-organisms, while (43) was new;sz carotenes with the yionene ring [(43), (44)] are so far known only from this aphid and a discomycete. A number of carotenoids have also been isolated from Aphisfabae: p-carotene, diepoxy-/%carotene, lutein, flavaxanthin, and y-car0tene.8~ The first four were also present in the foodplant (Vicia Zutea), while y-carotene was apparently formed within the aphid.83 * The green colour of the apple psyllid (Psylla rnali) has been shown to be an 'insectoverdin' (combining yellow and blue components) of unknown structure, close to that found in true bugs (Hemiptera).80 t Carotenoid-like materials were detected but not isolated in two scale insects in the family Diaspididae, but were absent from other families investigated in the Coccoidea.80 '9 C.L'Helias, Compt. rend., 1961, 253, 1353; Bull. Biol. France Belg., 1962, 36, 187. Bo H.J. Banks and D. W. Cameron, Insect Biochem., 1973, 3, 139. J. H. Bowie, D. W. Cameron, J. A. Findlay, and J. A. K. Quartey, Nature, 1966,210, 395. K. H. Weisgraber, R. J. J. C. Lousberg and U. Weiss, Experientia, 1971,27, 1017; A. G. Andrewes, H. Kjssen, S. Liaaen-Jensen, K. H. Weisgraber, R. J. J. C. Lousberg, and U. Weise, Acta Chim. Scand., 1971, 25, 3878. 83 L. R. G. Valadon and R. S. Mummery, Comp. Biochem. Physiol., 1973,46B, 427. Brown Green Aphids (44) &y-carotene Pink Aphids (45a) torulene (dehydro-p,#-carotene) (46a) 3,4-dehydro-#,#-carotene (46b) lycopene (#,$-carotene) (45b) S,$-carotene(=“y-carotene”) The aphins or aphid glycosides are characteristic, biogenetically unified but structurally diversified pigments found in all aphids so far investigated.They have been excellently reviewed several times in recent years.81~8~-86 Only the newer developments and more interesting reactions and structures will be highlighted in this review. The known natural compounds, with principal biosynthetic Lord Todd, Chem. in Britain, 1966,2,428. O6 Ref. 29, pp. 597-623. *ID. W. Cameron and Lord Todd, in ‘Oxidative Coupling of Phenols’, ed. W. I. Taylorand A. R. Battersby, Marcel Dekker, New York, 1967, pp. 203-241. The Chemistry of Aphids and Scale Insects MONOMERS Brown 283 The Chemistry of Aphids and Scale Insects Table List of aphid species investigated*; source numbers for Scheme 5 I Aphis nerii Fonscolombe 2 Dactynotus cirsii (L.) 3 Dactynotus jaceae (L.) 4 Aphis fabae Scopoli 5 Aphis rumicis L.6 Aphis sambuci L. 7 Aphis farinosa Gmelin 8 Aphis corniella H.R.L. 9 Brevicoryne brassicae (L.) I0 Hyalopterus prunii (Geoffr.) 41 Aphis acanthi Schrank 42 Aphis armata Hausmann 43 Aphis newtoni Theobald 44 Aphis epilobiaria Theobald 45 Symydobius oblongus (V. Heyd.) 46 Aphis grossulariae Kltb, 47 Aphis lamiorum Borner 48 Aphis thalictri Koch 49 Macrosiphoniella sanborni (Gillette) 50 Thelaxes dryophila (Schrank) 1I MacrosiphonielIa artemisiae (Fonsc..) 51 Tetraneura uImi (L.) 12 Megoura viciae Buckton 13 Periphyllus testudinaceus (Fernie) 14 Hormaphis betulina (Horvath) 15 Hormaphis spinosus (Shimer) 16 Macrosiphum rosae (L.) 17 Aphis epilobii Kltb.18 Aphis craccivora Koch 19 Aphis cytisorum Hartig 20 Aphis sarothamni Franssen 21 Aphis taraxacicola (Borner) 22 Dysaphis crataegi (Kltb.) 23 Dysaphis devecta (Walker) 24 Dysaphis plantaginea (Pass.) 25 Dysaphis pyri (Fonsc.) 26 Cinara pilicornis (Hartig) 27 Aphis philadelphi Borner 28 Aphis viburni Scopoli 29 Aphis evonymi Fabr. 30 Aphis hederae Kltb. 31 Aphis ilicis Kltb. 32 Brachycaudus klugkisti (Borner) 33 Brachycaudus rociadae (Cockerell) 34 Eriosoma lanigeru’m (Hausmann) 35 Schizoneura ulmi (L.) 36 Myzus cerasi (F.) 37 Rhopalosiphum nymphaeae (L.) 38 Schizolachnus pineti (F.) 39 Tuberolachnus salignus (Gmelin) 40 Pterocomma populium (Kltb.) 52 Macrosiphoniella absinthii (L.) 53 Dactynotus rudbeckiae (Fitch) 54 Dactynotus taraxaci (Kltb.) 55 Dactynotus tanaceti (L.) 56 Dactynotus ambrosiae Thomas 57 Dactynotus nigrotuberculatus Th.Olive 58 Dactynotus cichorii (Koch) 59 Dactynotus sonchi (L.) 60 Pineus strobi (Hartig) 61 Pineus pini (Gmelin) 62 Macrosiphum liriodendri (Monell) 63 Aphis cognatella M. G. Jones 64 Aphis urticata F. 65 Chaitophorus populicola Thomas 66 Cryptomyzus ribis (L.) 67 Drepanosiphum platanoides (Schrank) 68 Hyadaphis foeniculi Pass. 69 Hyalopterus arundinus (F.) 70 Liosomaphis berberidis (Kltb.) 71 Macrosiphum gei (Koch) 72 Macrosiphu-m albgrons Essig. 73 Microlophium carnosum Buckton 74 Myzaphis rosarum (Kltb.) 75 Nasonovia ribis-nigri Mosley 76 Periphyllus acericola (L.) 77 Paraprociphilus tessellata (Fitch) 78 Dysaphis viburnicolum Gillette 79 Rhopalosiponinus calthae (Koch)? * Mostly from the older literature; updated in thesis and manuscripts of H.J. Banks. t H. J. Banks, personal communication. Brown precursors and chemical transformation products, are represented in Scheme 5.* The natural pigments range in colour from very light yellow through oranges and reds to deep blue-green; all aglycons are apparently derived from cyclization of hepta- or octa-ketide precursors. They may be preliminarily divided into two classes, monomers (c13 or cl5) and dimers (c30). The monomeric pigments, of re- cent discovery, fall into three subclasses : (i) heptaketide-derived compounds [6-hydroxymusizin (47), possibly an artefact, and its glycosidic derivatives (48) and (49)], known only from Aphis r~erii;~3987~88(ii) octaketide-derived compounds [glucoside B (50) ;73J@-90 fluoraphin (51) and acetylfluoraphin (52),73+81987988990 very widely distributed and easily detected through their intense yellow-white fluorescence; neriaphin (53),73s90 the principal pigment of Aphis nerii, and its acetyl derivative (54);88and quinone A (55) gluc~side~~~~~*];and (iii) the biacetyl methides (56) and (57),88*92of problematical biogenetic origin.The dimeric pigments include the widely distributed and epimeric protoaphins-fb (58) and -sl (59);8g9gothe blue-green aphinin (60)81~82985@ of near-general occurrence (as both fb-and sl-isomers) but still uncertain structure; the recently discovered deoxyprotoaphin (61) rhodoaphin (62);93 and the dactynaphins (63)-(66).90194 The last are among the most complex natural products known; (65) and (66) con-tain a theoretically aromatizable but sterically fixed cyclohexadienone ring, and a quinone acetal.The two series (63)--(64) and (65)-(66) are interconvertible by simple equilibration in aqueous or methanolic sol~tion.~0~9* The protoaphins undergo a characteristic series of transformations95 when the ghcosyl group is removed by the aphid’s own enzymes or other fi-glucosidases,96 terminating in two isomeric perylenequinones, erythroaphins-fb (67) and -sl (68).97 The fb-reaction series is straightforward, as the first intermediate, * Much additional information on more than 40 aphid pigments and allied colourless materials is presented in ‘Glycosides from the Aphidoidea,’ the Ph.D.thesis of H. J. Banks, Cambridge, 1969, and in manuscripts in preparation by Dr. Banks (Canberra) and Prof. D. W. Cameron (Melbourne). A full account of their newer and very significant work will be left for description in their forthcoming publications. The Banks thesis also presents a lucid discussion summarizing much experimental evidence for the synthesis of aphin pigments by endosymbiotes. K. S. Brown, jun. and U. Weiss, Anais Acad. Bras. Cigncias, 1971,42, Supplement, 205. K. S. Brown, jun. and U. Weiss, Tetrahedron Letters, 1971, 3501. D. W. Cameron, R. I. T. Cromartie, D. G. I. Kingston, and Lord Todd, J. Chem. SOC., 1964, 51. H.J. Banks and D. W. Cameron, Austral. J. Chem., 1972, 25,2199. D. W. Cameron, personal communication; D. W. Cameron, D. G. 1. Kingston, N. Shep-pard, and Lord Todd, J. Chem. SOC.,1964, 98. K. S. Brown, jun. and P. M. Baker, Tetrahedron Letters, 1971, 3505; A. T. Henriques, J. A. Rabi, P. M. Baker, and K. S. Brown, jun., in preparation. S. F.MacDonald, J. Chem. SOC.,1954,2378; J. H. Bowie and D. W. Cameron, J. Chem. SOC.(C), 1967,704. U. Weiss and H. W. Altland, Nature, 1965,207, 1295; J. H. Bowie and D. W. Cameron, J. Chem. SOC.(C), 1967, 708, 712, 720. OaA. Calderbank, D. W. Cameron, R.I. T. Cromartie, Y. K. Hamied, E. Haslam, D. G. I. Kingston, Lord Todd, and J. C. Watkins, J. Chem. SOC.,1964, 80; H. J. Banks, D. W. Cameron, and J.C. A. Craik, J. Chem. SOC.(0,1969, 627. O8 D. W. Cameron and J. C. A. Craik, J. Chem. SOC.(C), 1968, 3068. O7 D. W. Cameron, R. I. T. Cromartie, Y.K. Hamied, P.M.Scott, and Lord Todd, J. Chem. SOC.,1964,62; D. W. Cameron, R. I. T.Cromartie, Y.K.Hamied, P. M. Scott, N. Shep-pard, and Lord Todd, ibid., p. 90. The Chemistry of Aphids and Scale Znsects xanthoaphin-fb (69), is symmetrical, giving a single chrysoaphin-fb (70) by elimination of water from either side of the molecule. Removal of an additional mole of water gives erythroaphin-fb (67). The initially formed and analogous xanthoaphin-sl-2 (71) is highly strained and unstable, rapidly being converted into xanthoaphin-sl-1 (72) and chrysoaphin-sl-1 (73) at room temperature, or chrysoaphin-sl-3 (74) at -35 "C.The stable but unsymmetrical xanthoaphin-sl-1 (72) can undergo dehydration in two different manners, giving chrysoaphin-sl- 1 (73) and 4-2 (75). All three chrysoaphins-sl give the single erythroaphin-sl(68) upon loss of a further molecule of water.95 Enzymic hydrolysis of deoxyprotoaphin (61) led directly to a deoxychryso-aphin, as (70) but with an enolic hydroxy-group in place of the enol ether arrowed. The dimeric protoaphins could be cleaved by mild reduction in vitro to give glucoside B (50) and quinone A (55) (from protoaphin-fb) or A' (76) (from protoaphin-s2).89 Conversely, simple incubation of a mixture of the glucoside with either quinone at pH 6.6 produced a small amount of the respective proto- aphin and a major product (77) from symmetrical condensation.The latter could be converted by hydrolysis into a compound (78) having a chromophore very similar to that of aphinin (60), and easily oxidized to xylaphin (79).98 The last compound was also produced directly and in high yield by heat-induced self-coupling of quinone A at pH 6.2.g9 Solution of either quinone A or A' in concentrated sulphuric acid produced the same brown entity (Amax 851 nm) with a strong e.s.r. signal. Dilution of the mixture resulted in the precipitation of an anhydro-compound (8O).lO0 Similar ion-radical formation was observed for erythroaphins and derivatives, and attri- buted to protonation at the quinone carbony1.100 C. Other Secondary Compounds.-Among the various other compounds reported from aphids, a few are worthy of special mention.The bright orange aphid, Aphis nerii, is apparently aposematic (warningly coloured), and is almost always found on plants containing poisonous cardenolides. Analysis of populations feeding on oleanders (Nerium oleander L.) and tropical milkweeds (Asclepias curassavica L.) revealed the presence of cardenolides in the tissues of the aphid: strospeside, odoroside-H, and adynerin* (but no oleandrin) in oleander-feeding, and calotropin and proceroside (but no calactin) in milkweed-feeding aphids.10 The three oleander glycosides were also present in large quantities in the honey- dew of oleander-fed A. nerii, although the phloem sap contained none of these.101 The plants on which the aphids were collected were not completely analysed, and it is not established whether the differences in composition between the aphids and the reported cardenolide mixtures for leaves of these plants are due to *These same three compounds were found in a scale insect, Aspidiotus nerii BouchC, feed- D.W. Cameron and H. W.-S. Chan, J. Chem. SOC.(C), 1966, 1825. G. M. Blackburn, D. W. Cameron, and H. W.-S. Chan, J. Chem. SUC.(0,1966, 1836. ing on N.oleander (ref. 10).*@ looD. W. Cameron, H. W.-S. Chan, and M. R Thoseby, J. Chem. Soc. (C),1969, 631. lol R. T. Aplin and M. P. Bailey, manuscript in preparation. Brown seasonal or populational variations in the plants, selective occurrence of cardeno- lides in the phloem ingested by the aphids, or selective metabolism by the aphids.10 As no large quantities of cardenolides are stored by the aphids73 (as is done by many other Asclepias- and Nerium-feeding aposematic insects),lO the exact role of the cardenolides in protection of A.nerii is still somewhat uncertain. Some invertebrate predators of A. nerii (Chrysopa sp. larva, Coccinella undecem- punctata L.) contained cardenolides sequestered from their prey, while others (Coccinella septempunctata L. and a Syrphidae larva) did not.1° The aphid Megoura viciae was shown to be very toxic to some coccinellid larvae, but a systematic investigation of its chemical constituents failed to reveal any basis for this character; the chloroform extract contained a number of waxes and hydrocarbons, in addition to triglycerides.102 Other aphids which feed on poisonous plants have been observed to cause illness and/or death in, or be avoided by, many species of coccinellid.1°3 D.Pheromones.-The presence of sex pheromones, released by complex 'scent plaques' located on the hind tibiae, has been reported for oviparous females of Schizaphis borealis Tambs-Lyche,lW Brevicoryne brassicae,lO5 and Megoura viciae;Ios although some biological and isolational work has been undertaken on these pheromones, no chemical structures are yet known. Because of the complex life cycles and dispersal ability of aphids, it is not sure how useful such compounds would be in their control. The supercooled cornicle secretion of many aphids contains, in addition to triglyceride, an alarm pheromone identified as trans-p-farnesene (81).lo7 Of obvious utility to the aphids, this pheromone could also be of assistance in their control by man, causing feeding aphids to remove their stylets and walk over contact insecticides applied to the ~lants.10~ (8 1) rrans-/%farnesene 6 Summary and Perspective All of the secondary substances reported for aphids and scales, with the excep- tion of cardenolides, common carbohydrates and amino-acids, and possibly some wax constituents, are apparently produced within the insects.In the cases lo' A. F. G. Dixon, M. Martin-Smith, and G. Subramanian, J, Chern. SOC., 1965, 1562. lo8I. Hodek, 'Biology of Coccinellidae', Junk, The Hague, 1973, chapter 6.lo' J. Pettersson, Entomol. Scad., 1970, 1, 63; 1971,2, 81. 'OS J. Pettersson, Swedish J. Agric. Res., 1973, 3, 95. lo8D. Marsh, Nature New Biology, 1972,238, 31. lo' C. J. Kislow and L. J. Edwards, Nature, 1972,235,108; W. S. Bowers, L. R. Nault, R. E. Webb, and S. R. Dutky, Science, 1972, 177, 1121; L. J. Edwards, J. B. Siddall, L. L. Dunham, P. Uden, and C. J. Kislow, Nature, 1973, 241, 126; W. H. J. M. Wientjans,A. J. Lakwijk, and T. van der Marel, Experientia, 1973, 29, 658. The Chemistry of Aphids and Scale Insects where this has been investigated, the production of these species-specific com- pounds is also independent of the host-plants chosen by the homopterans. This would not be so unusual, were it not for the large number of typical fungal metabolites known from these insects.Anthraquinone pigments, ophio- bolin-type sesterterpenes, y-and $-carotenoids, and polyketide naphthotriols are typical products of biosynthetic pathways of micro-organisms, known only very occasionally in higher plants and practically restricted to aphids and scales among the animals. Even the cedrene-type sesquiterpenes and the sorbic acid- containing triglycerides stretch the known limits of normal animal metabolic pathways. The interpretation which immediately suggests itself is the biosynthesis of these metabolites by the homopteran endo~ymbiotes.12~73~~0~~~At least with relation to the polyketide pigments, this suggestion is strongly supported by the colours observed in the mycetomes, which are often so tinged with red, yellow, or green as to be easily visible through the insect’s body wall; some of these compounds have been shown to be synthesized from acetate within the insects.74 To investigate this hypothesis further, it will be necessary to expand to other components the sort of careful experiments conducted by Ehrhardt,14J7 who demonstrated steroid synthesis from radioactive acetate in normal aphids (Neomyzus circumflexus Buckton, feeding on artificial medium) and lack of any incorporation in chlortetracycline-treated(aposymbiotic) colonies ;and synthesis of methionine and cysteine from radioactive sulphate, absent in aureomycin- treated aphids.It is predictable that many aphids and scales will also be found to depend upon their symbiotes for synthesis and accumulation of many of the secondary compounds which characterize these insects.The aphids and scales may thus represent a new, barely opened chapter in the growing book of chemical ecology, in which the chemical interactions between species, at the level of secondary metabolism, take place and might be studied in the internal micro- cosm of the individual organism. This paper was first outlined while the author was at the Centro de Pesquisas de Frodutos Naturais of the Universidade Federal do Rio de Janeiro. Drs. Ulrich Weiss, D. W. Cameron, H. J. Banks, Y.Tamaki, T. R. Seshadri, K. Venkataraman, Sukh Dev, M. Jacobson, A. D. Lees,R. T. Aplin, M. Roths-child, V. F. Eastop, and W. B. Mors aided substantially in the preparation and revision of the manuscript at various stages.

ISSN:0306-0012    

DOI:10.1039/CS9750400263

出版商:RSC    

年代:1975

数据来源: RSC

摘要:

Cancer and Chemicals By Lloyd N. Ferguson CALIFORNIA STATE UNIVERSITY, LOS ANGELES, CALIFORNIA 90032, U.S.A. 1 Introduction Cancer is a formidable disease that is killing increasing numbers of people every year in virtually all the countries of the wor1d.l Surgery and/or radiation therapy have a great curative potential for localized tumours. Unfortunately, by the time such tumours are detected they have usually spread to other organs and the only treatment for disseminated cancer is chemotherapy, although immuno- therapy holds encouraging promise for the future. The circumstances will be improved as we recognize and eliminate many of the environmental carcinogens. Some epidemiologists estimate that up to 90 per cent of all cancers are produced by environmental factors (see ref.36). It is now generally agreed that drugs are the key factor responsible for normal life expectancy in 10 types of previously fatal cancer. This paper reviews the chemical aspects of some of the developments in cancer chemotherapy with the hope that it will attract additional chemists into the war on cancer. A brief look first at chemical carcinogenesis is appropriate. 2 Chemical Carcinogenesis The successive steps by which a normal cell becomes malignant have not been delineated. Nevertheless, it is well known that a wide variety of chemicals can induce cancer. For the present discussion, chemical carcinogens can be divided into five groups : polycyclic aromatics, biological alkylating agents, aromatic amines and azo-compounds, N-nitroso-amines and -amides, and metallic substances.Examples of each group are shown in Figures 1-5. It was recognized early that certain occupations, such as chimney sweeping, carried a high cancer risk. Recently, however, the incidence of cancer has been found to be high in a number of other types of employment, e.g. among nickel ore miners and workers in plants manufacturing or using vinyl chloride, bis- chloromethyl ether, asbestos, and aromatic amines. In fact, there is a higher percentage of cancer among chemists than in the general population. More and more compounds are being identified as having carcinogenic activity in animals and are therefore suspect in humans. These include relatively common com- pounds such as dioxan, methyl iodide, and most chlorinated hydrocarbons; this is the basis for the questions raised in the United States by the Environ- mental Protection Agency about the cancer risk of city water supplies which National Cancer Institute 1973 Fact Book, U.S.Department of Health, Education, and Welfare, Washington, D.C.;‘75 Cancer Facts and Figures’, American Cancer Society, New York, 1975.Cancer and Chemicals I MeH Dibenz [c,g]carbazole 7.12-Dimet hylbenz [alanthracene Figure 1 Some polycyclic aromatic carcinogens N (CH,CH,C1)z Me\/ N I H C hlornaphazin Propyleneimine ,B-PropioIactone Figure 2 Some carcinogenic alkylating agents Benzidine 4-Aminost ilbene NH2 4-Dimethylaminoazobenzene ,&Naphthylamine Figure 3 Somecarcinogenic amines and azo-compounds are purified by chlorination.Most chemical carcinogens are really carcinogen precursors and are activated in vivo by oxidizing enzymes, the so-called micro- soma1 mixed-function oxygenases. The work of the Pullmans on the electronic structure of carcinogenic hydro- carbons was a pioneering application of molecular orbital theory to a major biological problem.2 They proposed that carcinogenic activity depends on the presence of a K region with high olefinic character and an L region of low reactivity {as in benz[a]anthracene (1) below}. Morerecent MO calculations have * A. Pullman and B. Pullman, Adv. Cancer Res., 1971, 3,129. Ferguson 0,N-NH Me \ \ C=NH I MeYNOMe-N \ NO N-Meth yl-N-nitrosonitroguanidine N -Nitrosodi me thy lamine ,NH2 0-c QI N I Me/\ NONO N-Methyl-N-nitrosourea N-Nit rosopiperidine Figure 4 Some carcinogenic N-nitroso-compounds H2C=CHCl CONHNHl4 Vinyl chloride Ni(CO) Aflatoxin B1 Isoniazid Nickel carbonyl Figure 5 Miscellaneous carcinogens supported this view.3 It is interesting, for instance, that benz[a]pyrene (2) is carcinogenic whereas benz[e]pyrene (3) is not.*L. B. Kier, ‘Molecular Orbital Theory in Drug Research’, Academic Press, New York 1971, p. 129; W. C. Herndon, Trans. New York Acud. Sci., 1974,36,200. 291 Cancer and Chemicals It has been proposed that the carcinogenic process involves enzymatic epoxi- dation of the K bond and subsequent reaction with an essential protein or nucleic acid.4 Since most of the fluoro-derivatives of the rat liver carcinogen 4-dimethylaminoazobenzene are as active or more reactive than the parent compound, it has been proposed by analogy that if a fluoro-derivative of any of these carcinogenic aromatic amines or hydrocarbons is inactive, then the carbon which is fluorinated must occupy a critical position in the carcinogenesis process.5 On this basis, it has been deduced that the C-5 position of benz[u]-anthracenesis the initial point of attack; i.e.all of the monofluoro-7-methylbenz-[alanthracenes are carcinogenic except the 5-fluoro-isomer. Even the 6-fluoro-analogue is carcinogenic.6 Structural studies of carcinogenic hydrocarbons attached to proteins show that, indeed, the union is at the K region of the hydrocarbons.7~8 In some cases, the least stable K-region oxides are the most carcin~genic.~ The structure of the critical ‘active’ molecule is not known.Some work indicates that it is not the K-region epoxide itself which reacts with DNA in vivo.10 Some results favour a carbocationll whereas other work supports the notion of a cation-radical intermediate in the biological activation.12 The in vitro peroxide-catalysed binding of carcinogenic hydrocarbons to DNA has been demonstratedl3 and others14 have induced the chemical linkage of these hydrocarbons to DNA by U.V. or X-ray radiation. The K-region oxides usually are more carcinogenic than the corresponding hydrocarbons, but there are exceptions.l5 Although there is not a good correlation between the binding of these hydrocarbons to DNA and their carcinogenic activity,l5J6 there are quantitative correlations of carcinogenicity with their hydrophobicity, K-region reactivity, and charge-transfer complex forming ability.17 It has been suggested that the hydrocarbon enters the cell as a hydrocarbon, forms a loose molecular complex with the cellular component with which it is going to react, and is then activated through oxygenation by a hydroxylase enzyme.8 It is noteworthy E.Boyland, Biochem. SOC. Symp., 1950, 5, 40; ‘Chemical Carcinogenesis’, Part A, ed., P.O.P. Ts’O and J. A. DiPaolo, Dekker Inc., New York, 1974. J. A. Miller, E. C.Miller, and G. C.Finger, Cancer Res., 1957, 17, 387.M. S. Newman and R. F. Cunica, J. Medicin. Chem., 1972, 15, 323. ‘I T. J. Siaga, J. D. Scribner, and J. M. Rice, Cancer Res., 1973, 33, 1032. M. Calvin, Radiation Res., 1972, 50(1), 105. S. H. Goh and R. G. Harvey, J. Amer. Chem. SOC.,1973, 95,242. loP. Brookes and W. M. Baird, Proc. Amer. Assoc. Cancer Res., 1973, 14, 30; E. Cavalieri and M. Calvin, Photochem. and Photobiol., 1971, 14, 641. E. Cavalieri and R. Auerbach, Proc. Amer. Assoc. Cancer Res., 1973, 14, 123. la W. Caspary, B. Cohen, S. Lesko, and P. 0.P. Ts’O, Biochemistry, 1973,12, 2649. ’ IaL. E. Morreal, T. L. Dao, K, Eskins, C. L.King, and J. Dienstag, Biochim. Biophys. Acta, 1968, 169, 224. l4 S. A. Rapoport and P. 0.P. Ts’O, Proc. Nut. Acad. Sci.U.S.A., 1966,55,381; M. Calvin, Radiation Res., 1972, 50(1), 105. D. M. Jerina and J. W. Daly, Science, 1974, 185, 573. laT. Kuroki, E. Huberman, H. Marquardt,J. K. Selkirk, C. Heidelberger, P. L. Grover, and P. Sims, Chem.-Biol. Interactions, 1972, 4, 389. l7 R. Franke, Chem.-Biol. Interactions, 1973, 6, 1. Ferguson that there is a statistical correlation between the concentration of the arylhydro- carbon hydroxylases in individuals and the chances of getting lung cancer.18 To induce cancer the aromatic amines need to undergo N-hydroxylation.19 One extensive study,20 for example, has shown that N-(2-fluorenyl)acetamide (FAA) (4) is enzymatically oxidized21 in the male rat liver by NADPH and oxygen to N-hydroxy-FAA. This is converted by 3’-phosphoadenoxyl-Y- phosphosulphate into FAA-N-sulphate, a highly reactive electrophile which attacks nucleophilic tissue constituents. It is significant that N-hydroxy-FAA is inactive in species lacking sulphotransferase, and that FAA-N-sulphate reacts with methionine or guanine residues to produce some of the same derivatives as obtained from the liver protein or DNA and RNA of rats given injections of N-hydroxy-FAA.20 In connection with this work, a convenient method for assessing the electrophilic reactivity of these N-arylacethydroxamic acids has been developed.22 Similarly 3-hydroxyxanthine (5) and 3-hydroxyguanine (6), following reaction with sulphotransferase, yield derivatives which induce tumours via cationic or free-radical ~pecies.~3 0 0 The N-nitroso-amines and -amides and halogen compounds are thought to be enzymatically converted into cationic or free-radical species?4 R\ enzymes N-NO 1R/ N-NO 4-R’ or R’ enzymesR-C1 CVYWCC.) [ R’ or R’ i-C1’ 1 C’ T.H. Maugh, Science, 1974,183,940. la J. L. Radomski, G. M.Conzelman, jun., A. A. Rey, and E. Brill, J. Nut. Cancer. Inst., 1973, 50, 989; P. D. Lotlikar, L. Luha, and K. Zaleski, Biochem. Biophvs. Res. Comm., 1974,59, 1349. 2o J. A. Miller and E. C. Miller, in ‘Molecular Biology of Cancer’, ed. H. Bush, Academic Press, New York, 1974; J. D. Scribner and N. K. Naimy, Cancer Res., 1973, 33, 1159; E. J. Barry and H. R. Gutmann, J. Biol. Chem., 1973, 248, 2730. 21 Experiments indicate that amine oxidase is not involved in the N-hydroxylation: P.D. Lotikar, K. Wertman, and L. Luha, Biochem. J., 1973, 136, 1137. 28 H. Bartsch, M. Dworkin, J. A. Miller, and E. C. Miller, J. Medicin. Chem., 1974,17,386. 23 C. B. Brown, M. N. Teller, I. Smullyan, N. J. M. Birdsall, T.X. Lee, J.C. Parham, and G. Stohrer, Cancer Res., 1973,33, 11 13. 44 Y. Ioki, Minority Biomedical Research Seminar, California State University, Los Angeles,Nov. 14, 1974. Cancer and Chemicals Skin cancers can be induced by U.V. radiation but little is known about the oncogenic sequence. U.v.-radiated proteins are carcinogenic upon subcutaneous injection whereas normal proteins are not.25 Tyrosine and tryptophan are suspected of being the major absorbing units.26 Either direct radiation of DNA 1 or DNA-photoproduct interactions could produce changes in nucleic acids to induce malignancy.Biological constituents, particularly lipids, might serve as photosensitizers to trigger tumour growth, not only of skin cancer but other I types as well. For instance, the carcinogen cholesterol-5a,6a-epoxide(CAE) is formed in both human and hairless mouse skin upon exposure to U.V. light.27 The study of the mechanisms of radiation carcinogenesis offers special oppor- tunities for photochemists to contribute to the war on cancer. Although a definitive picture cannot be given for the role of polysaccharides in the carcinogenic process, there is some evidence that mucopolysaccharides are involved in cell-cell association and therefore affect metastasis of cancer 1 cells.Experimental results have been reviewed recently.28 An experimental confluence between carcinogenesis and oxidative phos- phorylation has been observed and is the basis for an hypothesis for carcino- genesis. This view proposes that a metabolite of a carcinogen interferes with the flux of energy in the mitochondria to release mitochondria1 genetic material which may behave like an oncogenic ~irus.~’J Certain metal salts and metallo-organics are rapid-acting carcinogens in , animals, notably cadmium and nickel compounds.30 The carcinogenic activity of metal ions has only recently received serious attention31 and could play an important role in the regulation of our environmental health conditions. For example, metal catalysts are sometimes added to commercial commodities.In one case, however, the use of chromium was discontinued when it was learned that it is carcinogenic in laboratory animak30 3 Cancer Chem0therapy3~ Cancer chemotherapy made its initial defined thrust in 1941 when Huggins and Hodges reported that the sex hormone oestrogen is useful in the treatment of , prostatic cancer in men. Later, wartime research on chemical warfare agents led to the discovery of the destruction of white blood cells by nitrogen mustards and hence the potential antileukaemic action of these compounds. In 1948, Farber and associates noticed that folic acid treatment of anaemic children with acute leukaemia led to a worsened leukaemic condition. This suggested the use of antifolic acid compounds for treatment of leukaemia.The first one tried was 26 A. K. Brewer, Amer. Scientist, 1968,56, 254. I6 D. C. Neckers, J. Chem. Educ., 1973, SO, 164. J. T. Chan and H. S. Black,Science, 1974, 186, 1216. V. N. Nigam and A. Cantero, Adv. Cancer Res., 1972, 16, 1. *8 H. 1. Hadler, Medikon, in press; H. I. Hadler and B. G. Daniel, Cancer Res., 1972, 32, 1037. A, Furst, Chemical Seminar, California State University, Los Angeles, Oct. 15, 1974. 31 D. R. Williams, Chem. Rev., 1972,72,203; A. Furst and R. T. Haro, Progr. Exp. Tumor Res., 1969, 12, 102. ‘CancerMedicine’, ed. J. F. Holland and E. Frei, jun.,Lea and Febiger, Philadelphia, 1973. 294 Ferguson aminopterin (26a) which was too toxic, but several changes led to MTX (26b).MTX was strikingly effective, not only in acute childhood leukaemia but also against the rare uterine cancer, choriocarcinoma. Prior to this time, five of every six women diagnosed to have this or a related type of cancer died within a year. By 1961, 44 percent of such patients treated with MTX were completely cured from all evidence of cancer and by 1971 MTX and other drugs had raised this recovery rate to 95 percent, some patients being without symptoms for more than five years. In 1947, children with acute leukaemia had only two to four months life expectancy but by 1973 over half of such patients could expect at least a five-year survival. There are now about 45 anticancer drugs in medical practice on the official list of the National Cancer Institute with about 40 more in, or close to, clinical trials.33 These antitumour agents can be placed in four classes which are dis-cussed below : (i) alkylating agents, (ii) antimetabolites, (iii) antibiotics, and (iv) miscellaneous. A number of differences have been observed between cancer and normal cells; e.g.compared with normal cells, cancer cells have: lower pH,34 greater free-radical character,35 tumour-produced hormone peptides,36 tumour-associated antigens,36 lower calcium ion and higher potassium ion ~oncentrations,3~ different potassium isotope ratios,37 elevated amounts of methylated nucle~sides,~~ higher concentration of plasma mu cop rote in^^^ and mucopolysaccharides,28 greater need of exogenous ~inc,~O higher biowater contentF1 and some types (leukaemia cells) need exogenous casparagine.42 However, these differences are of more use in detecting cancer cells than in being therapeutically exploitable.Most drugs in current use inhibit cell division by interfering in one way or another with the synthesis or use of nucleic acids, or in a few cases during mitoses.43 a3 ‘Report of the Division of Cancer Treatment’, National Cancer Institute, Bethesda, Md., 1974, Vols. 1 and 2. 34 Z. B. Papanastassiou, R. J. Bruni, E. White, and P. L. Levins, J. Medicin. Chem., 1966, 9, 725; P. Weiss and I?. I. H. Scott, Proc. Nut. Acad. Sci. U.S.A., 1963, 50, 330. 35 R. A. Passwater, Amer. Laboratory, 1973, 5(6), 10; H. M. Swartz, Adv.Cancer Res., 1972, 15, 227. 36cf.T. H. Maugh, jun., Science, 1974, 184, 147. 37 A. K. Brewer, Amer. Laborutory, 1973, 5(1 l), 12. 38 C. C. Cheng, J. Pharm. Sci., 1972, 61, 645. 38 D. W. Dixon, Cancer, 1973, 31, 596. P. Li, ‘Anticancer Agents Recently Developed in the People’s Republic of China’, D.H.E.W. Publn. No. (NIH) 74-441, Washington, D.C., 1974. 41 B. D. Allan and R. L. Norman, Cancer Chemotherapy Reports Part I, 1974,58,296. 4* C. Tan, Hosp. Pract., 1972, 7(7), 99. O3 R.W. Brockman, Cancer Chemotherapy Reports Part 2, 1974, 4(1), 115; V. H.Bono, jun., ibid., p. 13 1. Cancer and Chemicals A. Alkylating Agents.-Alkylating drugs include nitrogen mustard (7), cyclo-phosphamide (Cytoxan or CTX) (8), busulphan (9), L-Pam (melphalan or Sarcolysin) (1 0), cyclohexylchloroethylnitrosoureas(CCNU) (1l), streptozotocin (12), prospidin (13), and dipin (14) [(13) and (14) are drugs synthesized in the C1-CH,CH,CI OSO..Me +/NH (7) 0 II NH--C-N-Cfl,Cfl,Cl CH,-CH-CO,HINtT3 NO N H -CO -N, ,NO Me CH,CI CH&l I I U.S.S.R.].Many contain a nitrogen mustard, aziridine, or methanesulphonate group.44 The alkylating agents react with the nucleophilic hydroxy-, amino-, mercapto-, or imidazole groups of proteins and nucleic acids. However, there is little correlation between their in vitro alkylation activities toward 4-b-nitro- benzyl)pyridine, which is often used to assess the alkylating activity of a sub- stance,45 and their cytotoxicity. In one study, the combined alkylating plus carbamoylating activity correlated with the therapeutic index of a series of drugs.46 Sulphur mustards are rarely active and simple substitution of phosphorus for nitrogen is ineffective. The length of the chain is important, probably owing to a neighbouring group effect (shown in Scheme l), and, indeed, several drugs 44 T.J. Bardos, Z. F. Chielewicz, and P. Hebborn, Ann. New York Acad. Sci.,1969, 163, 1006. 46 J. Epstein, R. W. Rosenthal, and R. J. Ess, Analyr. Chem., 1955, 27, 1435. 4t1 G. P. Wheeler, B. J. Bowdon, and J. A. Grimsley, Proc. Amer. Assoc. Cancer Res., 1973 14,26. 296 Ferguson contain the aziridine ring. Vinylsulphones are ineffective as antitumour agents.47 Simple alkylating agents react indiscriminately with cellular nucleophiles and consequently have limited therapeutic indexes.Some of the cytotoxic natural products appear to exert their cytotoxic activity via alkylations, particularly thiol groups.48 It is thought that their special stereochemical and molecular structures make them more specific in their alkylation reactions and that they should lead to more effective drugs. The nitroso-ureas and guanidines have a broad spectrum of antitumour activity;49e.g., CCNU (1 1) cyclohexylcarbamoylates lysine residues of proteins and alkylates nucleic acids: this dual reactivity might explain its broad cyto- toxicity against tumours which are resistant to conventional alkylating agents.50 The N-nitroso-amides are being studied for possible brain tumour treatment51 because of their ability to cross the blood-brain barrier.Certain benzo- and naphtho-quinone derivatives may undergo bioreduction to cytotoxic alkylating agents (Scheme 2).s2 None of these compounds has yet reached the clinical stage. &HyBr reduction ___) DNA-eHZBr-2HBr [ b::]-&I13A CH,Br CH,Br OH 0 OH Scheme 2 Quite a number of y-lactone sesquiterpenes have shown antitumour activity but significant cytotoxicity is dependent upon the presence of an a-methylene gr0up.~3 Cysteine adds readily to these sesquiterpenes and the rates of addition are enhanced when there is a hydroxy or acyl group adjacent to the methylene group. On the other hand, the highly active antileukaemic (toward L-1210 in mice) plant extracts triptolide (15) and tripdiolide (16) appear to alkylate thiols *' R.1. Polkina and A. L. Remizov, Cancer Chemotherapy Abs., 1973, 14(10), 637. 48 S. M. Kupchan, Symposium on Antibiotics and Neoplasia, 13th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., Sept. 1973 ;Fed. Proc., in press. 49 F. M. Schabel, jun., Cancer Chemotherapy Reports, 1973, 4(3), 3; S. K. Carter, ibid., p. 35. so C. J. Cheng, S. Fujimura, D. Grunberger, and I. B. Weinstein, Cancer Res., 1972, 32, 22. I1L. E. Broder and D. P. Rall, Progr. Exp. Tumor Res.. 1972, 17, 373. sa A. J. Lin, C. W. Shansky, and A. C. Sartorelli, J. Medicin. Chem., 1974, 17,558. 63 G. A. Howie, P. E. Mad, and J. M. Cassady, J, Medicin.Chem., in press; S. M. Kupchan,M. A. Sakin, md A. M. Thomas, J. Medicin. Chem., 1971, 14, 1147; K.-H. Lee, E.4. Huang, C. Piantadosi, J. S. Pagano, and T. A. Geissman, Cancer Res., 1971, 31, 1649; K.-H. Lee, S.-H. Kim, H.Furukawa, and C. Piantadosi, J. Medicin. Chcm., 1975,18, 59. 297 Cancer and Chemicals by epoxide ring opening and the process is assisted by the 14-hydroxy-group.54 Thus, the ketone (17) and a-oriented 14-hydroxy-isomer (18) are cytotoxic against KB cells in culture but inactive in vivo against L-1210. The strong intra- OH 0 (15) R= H (17) (16) R= OH \ molecular H-bond in (15) and (16) is revealed by n.m.r. spectroscopy. Similarly, maytansine (19) is an anticancer drug (in clinical trials) which exhibits powerful antileukaemic action whereas its methyl ether (20) shows no antileukaemic activity (although it is cytotoxic in (19) R' = Me ;R2 = H (20) R' = Me ;R' = Et S.M. Kupchan and R. M. Schubert, Science, 1974, 185,791.S. M. Kupchau, Y. Komoda, A. R. Branfman, R. G. Dailey, jun., and V. A. Zimmerly, J. Amer. Chem. SOC.,1974, 96, 3706. Ferguson Several attempts have been made to identify the portion of the camptothecin drug molecule (21) responsible for its oncolytic property.56 Not only is the a-hydroxy-lactone portion necessary for antitumour activity but also the A and B rings appear to be crucial to activity, since fragments (I) and (11) have no useful a~tivity.~' Considerable effort has been expended toward an identification of the cyto- toxic active metabolite of cyclophosphamide (CTX) (8).58 Recent work has shown that an early step in its activation involves C-4 hydroxylation of the oxazaphosphorine ring.5e Indeed, the 4-peroxycyclophosphaide has been isolated.60 It is stable and cytotoxic in vitru as well as in vivo in L-1210.A later metabolite is NN-bis(chloroethy1)phosphoradiamidic acid (22), which is itself a potent cytotoxic agent in vivu with antitumour effects resembling those of its precursor, CTX.61 Although isophosphamide (23) is more cytotoxic than CTX in preclinical studies, it offers no useful increased antitumour effect in clinical trials.e2 One rationale of designing a more effective drug is to attach the nitrogen c!-NHCH&H2Cl0 I N-CH,CH,CI brM.Shamma and V.St. Georgiev, J. Pharm. Sci., 1974, 63, 163; A. G. Schultz, Chem. Rev., 1973, 73, 385. b7 S. Danishefsky, J. Quick, and S. B. Horwitz, Tetrahedron Letters, 1973, 2525; S. Danishef-sky and J. Etheredge, J. Org. Chem., 1974, 39, 3430. N. E. Sladek, Cancer Res., 1973, 33, 651. s9 A. Takamizawa, S. Matsumoto, T. Iwata, K. Katagiri, Y. Tochino, and K. Yamaguchi, J. Amer. Chem. SOC.,1973, 95, 985. R. F. Struck, J. Amer. Chem. SOC.,1974,96, 313. M. Colvin, C. A. Padgett, and C. Fenselau, Cancer Res., 1973, 33,915. O*D. L. Ahmann, H. F. Bisel, and R. G. Hahn, Cancer Chemotherapy Reports, Part I, 1974, 58(6), 861; D. N. Bremmer, J. St.C. McCormick, and J. W. W. Thomson, ibid., p. 889. Cancer and Chemicals mustard moiety on to a biological carrier such as a polypeptide, carbohydrate, nucleoside, or even a tumour-specific antib0dy,~3 which would deliver the drug to the tumour site.For instance, the cholesterol ester phenesterin (24) is at least as effective as CTX and more potent than chlorambucil.~4 However, a recent survey of steroid mustards has revealed that very few are effective anti- tumour agents.65 The Japanese were the first to make use of an amino-acid carrier, such as the phenylalanine mustard, L-Pam (10). The original notion in synthesizing LPam was that it might exhibit selective cytotoxic action against melanoma cells, which utilize phenylalanine in melanin synthesis. Although this expectation did not materialize (it is inferior to CTX),LPam is the drug of choice against multiple myeloma (diffuse cancer in bone marrow).The ,Chinese have found the N-formyl derivative (N-F) of LPam to be less toxic and to have a higher therapeutic index.40 Among the many ring-substituted analogues of N-F synthesized and tested, the o-methoxy-derivative is the most effective. The Russians have developed promising drugs of this type with a tetrapeptide or pentapeptide chain attached. Usually, but not always, the L-amino-acid units are more active than the D-isomers. A considerable number of analogues of Streptozotocin (12) have been prepared, mostly with structural modifications of the sugar moiety. Generally, differences in their antitumour activity are not large, which suggests that the sugar fragment is functioning as a non-specific hydrophilic carrier for the N-methyl-N-nitroso- urea group.66 Replacement of the methyl group in Streptozotocin by CH2CH2CI gives a more active agent against leukaemic L1210 in mice.The compound is undergoing pharmacological evaluation preliminary to clinical trials.66a Some metals are involved in chemical carcinogenesis whereas others are connected with therapy. In fact, one of the most potent, broad-spectrum anti- tumour agents yet developed is a metal complex, cis-dichlorodiammineplatinum (44).67 It is noteworthy that both the cis-and the trans-isomers bind to DNA O3 J. H. Linford, G. Froese, I. Berczi, and L. G. Iraels, J. Nat. Cancer. Znst., 1974,52, 1665. E. B. Feldman, H. Paul, and R.Cheron, Cancer Chemotherapy Reports Part I, 1972,56, 1. O5 J. B. Jones, D. J. Adam, and J. D. Leman, J. Medicin. Chem., 1971, 14, 827. 66 A. N. Fujiwara, E. M. Acton, and D. W. Henry, J. Medicin. Chem., 1974, 17, 392. eeaT.P. Johnston, G. S. McCaleb, and J. A. Montgomery, J. Medicin. Chern., 1975, 18, 104. B. Rosenberg, Naturwiss., 1973, 60, 399. Ferguson but only the &isomer forms interstrand cross links and is cytotoxic.68 Spectral measurements indicate that the cis-isomer binds at either N-1 and 6-NH2 or N-7 and 6-NHz of adenosine and cytidine.69 A wide variety of platinum(l1) complexes have been investigated, and although cis-Pt(NH3)~Ch is well along in clinical trials, there are several analogues found to be more potent and less toxic in in vivo and in vitro tests.One of these is the cyclohexylamine complex70 and another is a group of pyrimidine complexes.71 In contrast to the strongly cytotoxic platinum complexes, palladium analogues have little activity.72 The mainland Chinese have developed antimony complexes of EDTA which have some therapeutic use.4o The activity of these compounds appears to depend on their ability to inhibit the incorporation of zinc into tumour cells. Gallium (citrate) is another metal which preferentially localizes in certain human tumours and, indeed, gallium nitrate has reached the stage of clinical trials.73 Residual protein bound to DNA contains sulphydryl groups which could be the site of electrophilic attack or free-radical attack of carcinogens.In any event, such protein has excess negative charge. Anti-neoplastic agents have been prepared by placing the sulphydryl-inhibiting group three carbon atoms from a cationic centre, supposedly complementing the structure of the DNA-bound protein.74 Arsenic and mercury compounds act as sulphydryl inhibitors and sometimes preferentially attack cancer cells.75 Many studies have been made on the cytotoxic activity of copper chelates.'B There is a significant correlation between the antitumour activity of a group of heterocyclic aldehyde thiosemicarbazones in animal systems and their metal chelating proper tie^.^^ These compounds are thought to exert their antitumour activity by inhibition of DNA synthesis at the level of the enzyme, ribonucleoside diphosphate reductase, presumably by chelation of the iron moiety of the enzyme molecule.There is a relationship between serum copper level and disease activity in patients with Hodgkin's disease.78 J. J. Roberts and J. M. Pascoe, Nature, 1972,235,283; M. Slavik and S. K. Carter, Cancer Chemotherapy Reports Part 3, 1973, 4(2), 265. 6o S. Mansy, B. Rosenberg, and A. J. Thomson, J. Amer. Chem. SOC.,1973,95, 1633; R. M. Izatt, J. J. Christensen, and J. H. Rytting, Chem. Rev., 1971,71, 439; U. Weser, Strucfure and Bonding, 1968, 5, 42. ?OT. A. Connors, M. Jones, W. C. J. Ross, P. D. Braddock, A. R. Khokhar, and M. L. Tobe, Chew-Biol. Interactions, 1972, 5, 41 5. 71 J. P. Davidson, P. J. Paula, R. G. Fischer, jun., S.Mansy, H. J. Peresie, B. Rosenberg, and L. VanCamp, Cancer Chemotherapy Reports, in press. 72 M. J. Cleare and J. D. Hoeschele, Bioinorg. Chem., 1973, 2, 187. 73 M. M. Hart, R. H. Adamson, and V. T. Oliverio, Proc. Amer. Assoc. Cancer Res., 1971, 12, 81 ;J. Nut. Cancer Ins?., 1971, 47, 1121. 74 F. E. Knock, Abstracts of the 150th meeting, American Chemical Society, 1965, 6-P. 76 F. E. Knock, 'Anticancer Agents', Thomas, Springfield, Illinois, 1967. "E. A. Coates, G. Holbein, J. McDonald, R. Reed, and H. G. Petering, Abstracts, Division of Medicinal Chemistry, American Chemical Society National Meeting, Los Angeles,April, 1974. 77 1. H. Krakoff, E. Etcubanas, C. Tan, K. Mayer, V. Tethune, and J. H. Burchenal, Cancer Chemotherapy Reports, Part I, 1974, 58(2), 207; F. A.French, E. J. Blanz, jun., S. C. Shaddix, and R. W. Brockman, J. Medicin. Chem., 1974, 17, 172; K. C. Agrawal, A. J. Lin, B. A. Booth, J. R. Wheaton, and A. C. Sartorelli, J. Medicin. Chem., 1974, 17, 631. "C. F. Tessmer, M. Hrgovcic, and J. Wilbur, Cancer, 1973, 31, 303, 1337. Cancer and Chemicals The process of chelation is also intimately involved in the role of metals in metallochemotherapy.7Q For example, some drugs have increased activity when administered as metal cornplexes3l and a number of metal chelates inhibit tumour growth.80 Pre-administration of the chelating agent EDTA or the di- imide ICRF-159 (25) prevents increase coronary perfusion pressure induced by H-NpN-CH,-CH-N I -N-H 0 Me 0 the drugs Daunomycin (37) or Adriamycin (38), two effective drugs with high cardiac toxicity.It is speculated that the chelating agents reduce the concen- trations of certain metabolites of the drugs by removing cations needed for formation of the metabolites and thereby reduce the toxicities.81 Thus, chelates may be cytotoxic by reacting directly with cellular components or they may be involved by serving as metal transport systems to get metal ions into the cell. B. Antimetabo1ites.-Antimetabolites are substances mistakenly incorporated by a cell and, when inside, these ‘look alike’ antagonists interfere with the normal activities of the cell. Various substances are needed by the cell to form nucleic acids for proliferation. Tetrahydrofolic acid plays a key role in the synthesis of purines and thymidylate and thus is a vital cofactor for nucleic acid synthesis and cellular replication.Because interference with foliate metabolism can influence cell growth, compounds which affect foliate metabolism inhibit the growth of bacteria, protozoa, and neoplastic cells and suppress the immune responses. In this connection, many purines and nucleosides have antitumour properties. Some of the antimetabolite cancer drugs in use [(26)-(31)] and the correspond- ing nucleic acid precursors are shown in Figure 6. MTX (26a) has been used for more than 20 years against a wide variety of malignancies.S2 Although many structure-activity studies have been made on the pteroyl-glutamic acid MTX is still the single drug of choice for 70 A.Furst, ‘Chemistry of Chelation in Cancer’, Thomas, Springfield, Illinois, 1963. F. P. Dwyer, E. Mayhew, E. M. F. Roe, and A. Shulman,Brit. J. Cancer, 1965,19, 195. *lE. H. Herman, R. M. Mhatre, I. P. Lee, and V. S. Waravdekar, Proc. SOC.Exp. Biol. Med., 1972, 140(1), 234. 81 R. B. Livingston and S. K. Carter, ‘Single Agents in Cancer Chemotherapy’, Plenum Press, New York, 1970. 83 J. A. R. Mead, H. B. Wood, jun., and A. Goldin, Cancer Chemotherapy Reports, Part 2, 1968, 1, 273; J. R. Bertino, Ann. New York Acud. Sci., 1971, 196, 7-519; E. C. Roberts and Y. F. Shealy, J. Medicin. Chem., 1974, 17, 219. Ferguson Drug Metabolite (26) a; X=CH,NH, G= NH, (Aminopterin) (26)c; X=CH,NH, G=OH (Folic acid) b; X=CH,NMe, G=NH, [Methotrexatc (MTX)] SH (27) 6-Mercaptopurine (6-MP) OH OH I H Uracil (5-FU) (29) Ftorafur (a drug synthesized in the U.S.S.RJ 0 HO,* n ,N-C-NH, H Urea (31) HydroxyureaHO (30) Cytosine arabinoside Cytidine Figure 6 Some antimetabolite cancer drugs and their metabolite analogues.*Sites of structural differences meningeal leukaemia.84 Some generalizations on the effects of structural changes on antitumour activity for the folic acid congeners are: (i) significant activity is found only when there is a free 4-NHz group, with the exception of 5,6,7,8-tetrahydrohomofolicacid (32) and its 5-Me deriva- tive; 84 L. E. Broder and S. K. Carter, ‘Meningeal Leukemia’, Plenum Press, New York, 1972; J.H. Burchenal and M. R. Dollinger, in ‘Chemotherapy of Cancer’, ed. W. H. Cole, Lea and Febiger, Philadelphia, 1970, p. 75. Cancer and Chemicals (ii) introduction of halogen into the benzene ring of MTX increases activity; (iii) fragments of the folic acid molecule shown in Figure 7 have little or no antitumour activity ; H Of 61 tested, only a small number active. Of 140 tested, none active. Figure 7 (iv) modifications of the glutamic acid moiety does not increase antileukaemic activity; (v) lipid-soluble dialkyl esters of MTX offer additional promise for the treatment of meningeal Ieukaemia in man because of their ability to cross the blood-brain barrier;B5 (vi) the 1-and 3-deaza-analogues of MTX and their dihydro-derivatives,86 as 85 D.G.Johns, D. Farquhar, M. K. Wolpert, B. A. Chabner, and T. L. Loo, Drug Metabolism and Disposition, 1973, 1, 580. R. D. Elliott, C. TempIe, jun.,and J. A. Montgomery, J. Medicin. Chem., 1974, 17, 553. Ferguson well as homofolic acid [(26d); X = CH2CH2NHYG = OH] and isofolic acid [(26e); X = NHCH2, G = OH]s7 retain some activity. 6-Mercaptopurine(27) is the most extensively used of the purine antagonists.88 5-FU (28) is the most effective single agent for the treatment of cancer of the c~lon,~~or rectum, but is inferior to CTX (8) against lung cancer.82 Hydroxy- urea (31) is a highly selective inhibitor of DNA synthesis by interfering with the enzyme that reduces ribonucleotides to deoxyribonucleotides. Hydroxyurea may also act as a radiosensitizer in brain tumours and preliminary trials in its use with radiotherapy have given some very encouraging res~lts.~O Many amino-acid antagonists (i.e.compounds which act to inhibit the incorporation of amino- acids in purine biosynthesis) such as ethionine (33), selenium cystine (34), or azaserine (39, are extremely toxic and are not useful in clinical cancer chemo- therapy. The amino-acid derivative, S-trityl-L-cysteine (36) is active against leukaemiaL-1210, and apparently the zwitterion form isimportant for activity.91 NH,iEt -S -CH,CH,CH -C02H Se-CHaCH -COZHI INHa Se-CH2CH-COzH I NH, (33) (34) (35) (36) Since fluorine imparts antitumour activity to some pyrimidines, there is the notion that the same result might occur with amino-acids.Accordingly, some mainland Chinese prepared a series of fluorine-containing amino-acids, some of which exhibit in vivo antitumour a~tivity.~O A wide variety of nucleoside analogues are being synthesized and tested for M. G. Nair and C. M. Baugh, J. Medicin. Chem., 1974, 17, 223.** On structure-activity, see: A. Goldin, H. B. Wood, jun., and R. R. Engle, Cancer Chemo- therapy Reports, Part 2, 1968, 1, 1. M. Slavik and S. K. Carter, Cancer Chemotherapy Reports Part 3, 1973, 4(2), 265. so L. E. Broder and D. P. Rall, Progr. Exp. Tumor Res., 1972, 17, 363. s1 K. Y. Zee-Cheng and C. C. Cheng, J. Medicin. Chem., 1972, 15, 13. Cancer and Chemicals their cytotoxicity. Among the structural modifications are use of different purines and heterocyclic bases, their combination with different sugars, forma- tion of C-nucleosides,92 and 0ligomers.9~ Various groups have been substituted into purine molecules, and deazapurines (carbon in place of a nitrogen atom) and azapurines (nitrogen for carbon) have been used.94 Sugar fragments, such as &ribose, p-arabinose, or a-xylose, have been modified with sulphur or selenium in place of oxygen atoms and alternatively converted into the respective alkyl ethers or phosphate ester^.^^^^^ C. Antibiotics.-There are several very effective antibiotic cancer drugs.These compounds may act at various points in the sequence of DNA to RNA to protein but most bind to the DNA molecule and inhibit the production of DNA-dependent RNA.A few inhibit RNA-dependent DNA polymerase (reverse transcriptase).gO In some cases, the DNA-drug complex has greater antitumour activity than the drug alone.97 Currently there is intense international interest in a drug synthesized in Italy, Adriamycin (38).98 It has the widest spectrum of clinical activity of any known compo~md.~9Adriamycin is much more effective than Daunomycin (37). The \ I (37) R=H (38) R=OH 92 E. M. Acton, K. J. Ryan, D. W. Henry, and L. Goodman, Chem. Comm., 1971,986. s3 S. A. Hiller, US-U.S.S.R. Joint Meeting on Treatment of Lung Cancer, Institute Experimental and Clinical Oncology, Moscow, March, 1974. Qp J. A. Montgomery, A. K. Shortnacy, and H. J. Thomas, J. Medicin. Chem., in press.W. W. Lee, A. P. Martinez, L. Goodman, and D. W. Henry, J. Org. Chem., 1972, 37, 2923; J. Medicin. Chem., 1973, 16, 570; N. Ototani and R. L. Whistler, ibid., 1974, 17, 535; G. H. Milne and L. B. Townsend, ibid., 1974, 17, 263. Q6 Cf. R. D. Johnson, A. Haber, and K. L. Rinehart, jun., J. Amer. Chem. Soc., 1974,96. 3316. Q7 D. W. Henry, Cancer Chemotherapy Reports Part 2, 1974, 4(4), 1974. O8 F. Arcamone, G. Cassinelli, G. Franceschi, R. Mondelli, P. Grezzi, and S. Penco, Gazzetta, 1970,100,949. OD S. Perry, Cancer Chemotherapy Reports Part I, 1974, 58(1), 117. Ferguson fact that this change in activity can be brought about by merely replacing a hydrogen atom by a hydroxy-group in this large molecule lends hope that other molecular changes can further improve the therapeutic index.However, simple chemical derivatives, such as esterification of the hydroxy-groups or Schiff base carbonyl derivatives of the ketone, are not markedly more effective.100 The quinone structure occurs in several natural product anticancer drugs. The structure-antitumour activity relationships of over 1500 quinones have been summarized recent1y.lo1 The aziridinyl quinones are of special interest because of their CNS anti-neoplastic activity. There is great hope in the Soviet Union for Variomycin A (39), a drug syn-thesized in the U.S.S.R. Both drugs, Adriamycin and Variomycin A, form complexes with DNA in yitro and are believed to do so in vivo. Extensive structure-activity studies of the mitomycin structure (40) have been made, particularly with changes at X, Y, and Z.lo2 Mitornycin C (40a), a drug synthesized in Japan, is shown.These changes filter the toxicity, cytotoxicity, and reduction potential of the quinone, among other properties. Degradative studies have shown that although the aziridine ring is an important contributor to the antitumour activity, it is not an absolute requirement.lo3 Also, the looL. Lenaz, A. Necco, T. Dasdia, and A. DiMarco, Cancer Chemotherapy Reports Part 1, 1974, 58(6), 769. lol J. S. Driscoll, G. F. Hazard, jun., and H. 8.Wood, Cancer chemotherapy Reports Part 2, 1974, 4(2), 1. loaR. Kojima, J. Driscoll, N. Mantl, and A. Goldin, Cancer Chemotherapy Reports Part 2, 1972, 3(1), 121. lo' T.R.Witty and W.A. Remers, J. Medicin Chem., 1973, 16, 1280. Cancer and Chemicals observation that the bioreductive benzoquinone derivatives103a mentioned among the alkylating agents are potent inhibitors of DNA and RNA synthesis 0 II (40) a; X=NH2, Y=OMe, Z= H after bioreduction adds further evidence to the claim that the carbamyl group and the aziridine ring of mitomycin C are replaceable without substantial loss of cytotoxic activity. D. Miscellaneous Agents.-Several miscellaneous antitumour agents are shown in Figure 8. (43) Ellipticinc *2N\P t NHs c1’‘c, (41) R = Me (42) R= CHO (44)cis-Diclilorodiamminepl~i~inum Figure 8 Hormonal compounds are among the oldest of anticancer drugs. Male and female hormones are effective against breast cancer, and female hormones are effective against prostate cancer.A large number of plant extracts exhibit antitumour activity and two drugs 103uA. J. Lin, L. A. Cosby, and A. C. Sartorelli, Cancer Chemorheapy Reports Parr2,1974, 4(4), 23. Ferguson from such sources are the antimitotic agents (agents which destroy mitotic spindle, thereby halting cell division) Vinblastine (41) and Vincristine (42), isolated from the periwinkle Vinca rosea. An as yet unidentified alkaloid extrac- ted from narcissus bulbs exhibits better antileukaemic activity in mice than several DNA-binding agents (CTX, BCNU, Daunomycin), antimetabolites (MTX, 6-MP, 5-FU), other alkaloids (Vincristine), reverse transcriptase in- hibitors (rifamycin), and interferon inducers (poly I:C).104 That is quite a claim.pharmaceutical, toxicological, and clinical tests will show what future there is for the alkaloid. A 1 :2 copolymer of divinyl ether and maleic anhydride (45)-called DIVEMA by some-is active against several solid tumours and has been approved for clinical trials.lo5 The fractions of m.w. in the 2500-15 000 range are less toxic and maintain the activity shown by the heavier cuts of m.w. 45 OOO. The polymer induces interferon and stimulates the immune response. One of the few antineoplastic agents which exploits a difference between normal and cancer cells is L-asparaginase (LA). Whereas normal cells can synthesize their own asparagine and are not affected by the presence of L-A, certain leukaemia cells are dependent on exogenous L-asparagine. The enzyme eliminates exogenous L-asparagine in vivo and inhibits the growth of the depen- dent cancer cells.Although the use of L-A in combination chemotherapy has shown superior results, its high toxicity has limited its use so far.42 A laboratory in theU.S.S.R. has found that hindered phenols, the free radicals of which are stable because steric hindrance prevents their dimerization,1°6 make good anticancer agents and they are undergoing clinical trials.lo7 Similarly, in the preclinical stage, the spin-labelled antitumour agent PAT (46) is more effective than the analogue, Thio-TEPA.lo7 The observation that carcinogen- induced cancers can be prevented by free-radical scavengers is of wide current interest.los The free-radical character of cancer tissue not only provides a potential looN.Suzuki, S. Tani, S. Furusawa, and E. Furusawa, Proc. SOC.Exp. Biol. Med., 1974, 145, 771. Io5 G. B. Butler, J. Pure Appl. Chem., in press. lo*L. N. Ferguson, 'Organic Molecular Structure', Willard Grant, Boston, 1975, p. 528. lo' N. M. Emanuel, Acad. Sci. U.S.S.R.,Moscow, Preprint, 1974; See also, G. Sosnovsky,Y.4.Yeh, and G. Karas, 2. Nuturforsch, 1973,28c, 781. lo' K. K. Geogrieff, Science, 1972, 173, 537. Cancer and Chemicals avenue for treatment but also offers a possible means of early detection of cancer cells.1°8a There are several isolated bits of circumstantial evidence for the free-radical nature of chemical carcinogenesis.For instance, induction of stomach cancer by aromatic hydrocarbons, logFAA,110 or N-nitroso-compoundslll is markedly less in animals fed antioxidant^.^^ The urine of heavy smokers with a high incidence of bladder cancer is deficient in vitamin C (a possible protective agent) but high in free radicals and the carcinogen cannabaric acid-presumably a metabolite of tryptophan.35 The increased electron spin resonance (e.s.r.) signals112 observed for the plasma of cancer patients has been attributed to the presence of a copper protein ceruloplasmin.113 Soviet scientists have found an inverse relationship between the level of lipid free radicals and antioxidation activity (A.O.A.) in tumour cells. Agents which reduce the A.O.A. inhibit the growth of tumours.It has been observed that as solid animal tumours or human leukaemia grow, the e.s.r. signal reaches a peak and then declines. Even in remissions, the free- radical level remains higher than in healthy controls, implying the persistence of latent leukaeniic foci. For instance, uranium miners and heavy smokers have high e.s.r. signals for their sputum although regular histological tests fail to reveal the presence of cancer cells. Drugs kill only a fixed percentage of tumour cells. If treatment ceases too soon, the tumour regrows from the remaining cells. Hence it is important to be able to detect cancer cells at a low concentration to know when treatment is needed as well as when it can be stopped. What is needed is a simple biochemical or physical organic method for the early detection of cancer.Cancerous tissue is diagnosed by histological examina- tion. It is accompanied, however, by certain biological changes, such as those listed on page 295. Accordingly, cancer detection methods are being explored less Gordon Research Conference on Magnetic Resonance in Biology and Medicine, Tilton, New Hampshire, August 1974. loS R. J. Shamberger, J. Nat. Cancer Znst., 1970, 44(4), 931 ;ibid, 1972, 48(5), 1491 ;S. L. Haber and R. W. Wissler, Proc. SOL.Exp. Biol. Med., 1962, 111, 774; L. W. Wattenberg, J. Nat. Cancer Inst., 1972, 48(5). 1425. ll0 J. R. Harr, J. H. Exon, P. D. Whanger, and P. H. Weswig, Clin. Toxicol., 1972,5(2), 187. S. S. Mirvish, L. Wallcave, M.Eagen, and P. Shubik, Science, 1972, 177, 65. lIa Staff report, Medical World News, Jan. 12, 1973, p. 20. 113 C. Mailer, H. M. Swartz, M. Konieczny, S. Ambegaonkar, and V. L. Moore, Cancer Res., 1974, 34, 637. 3 10 Ferguson which involve, among others, the measurement of these biological constituents* and of potassium isotope ratios36 and n.m.r. spectroscopy.l14 For instance, the concentration of potassium ions in cancer cells is twice that in normal cells. Water molecules are less rigidly bound and this is reflected in the shapes of the n.m.r. signals. Another experimental technique which offers promise for the detection of solid tumours such as breast, lung, skin, and others, is thermovision. presumably, the greater metabolic rate in tumour cells causes an elevation in tissue temperatures, which can be detected and located by an i.r.scanning instnunent.ll5 4 Search for New Drugs Many antitumour compounds to reach medical practice in the United States came through the mass screening programme of the National Cancer Institute. Thus, the N.C.I.33 screens 15 000-50 000 substances annually, including compounds submitted by the scientific community, some especially synthesized, fermentation products, extracts of plants (ca. 4000 per year) from all over the world,116 and extracts of marine anirnal~ll~J~~ and insects.ll* Many cytotoxic substances have been isolated but surprisingly to date no clinically useful antitumour drug has been developed from the sea except cytosine arabinoside.119 It might be mentioned that clams and seaweed were frequently used for cancer therapy in Chinese traditional medicine.40 As is to be expected, the specifically synthesized compounds are the most expensive but yield the largest percentage of agents to reach the clinical trial stage.What is sorely needed is a good guide or rationale for planning the structure of an effective cytotoxic agent. This stage will come when we have an under- standing of the mechanisms of action of antitumour drugs, which in turn is fostered by having a working hypothesis for the mode of action of a given type of drug. Organic chemists can play a leading role here, From their ex- perience in probing reaction mechanisms in vitro, they can postulate likely intermediate metabolites and design experiments to follow the reaction sequences of drugs.Related to this, Hoffmann-LaRoche sells a kit to measure traces of carcinoembryonic antigen (C.E.A.) in blood plasma. Abnormally high levels of C.E.A. have been linked to cancer of the colon, lung, rectum, and other organs. However, the tests are often false and need to be used in conjunction with other diagnostic methods. 114 I. D.Weisman, L. H. Bennett, L. R. Maxwell, jun., M. W. Woods, and D. Burk, Science, 1972,178,1288; R. Damadian, Science, 1971,171,1151; A. K. Brewer, Amer. Laboratory, 1973,5(1l), 12; C. F. Hazlewood, D. C. Chang, and D. Medina,Proc. Nat. Acud. Sci., 1972, 69, 1478. ll6 'Thermovision in Medicine', ed. G. D. Shushkov and M.M. Miroshnikov, Leningrad, 1972; see N.I.H. Library Translation, N.I.H.-74-418C. ll6 S. M. Kupchan, Y. Komoda, A. R. Branfman, R. G. Dailey, jun., and V. A. Zimmerley, J. Amer. Chem. SOC.,1974, 96, 3706; S. M. Kupchan, T. Fujita, M. Maruyama, and R. W. Britton, J. Org. Chem., 1973, 38, 1260; M. C. Wani, H. L. Taylor, and M. E. Wall, J.C.S. Chem. Comm., 1973, 390. 11' R.J. Quinn, M. Kashiwagi, R. E. Moore, and T. R. Norton, J. Pharm. Sci.,1974,63,257. G. R. Pettit, R. H. Ode, and T. E. Harvey, tert., Lloydia, in press. 'la C. P. Li,A. Goldin, and J. L. Hartwell, Cancer Chemotherapy Reports Part 2, 1974, 4(3), 97. Cancer and Chemicals Some of the approaches used presently as guidelines in searching for potential antitumour agents are described below.A. Quantitative Structure-Activity Relationships (Q.S.A.R.)-Several techniques have been developed for the strategic design of molecules with maximum bio- activity. There are two general approaches used: ranking substructure contribu- tions to biological activity by statistical methods, and correlating physiochemical properties of a family of molecules with their bioactivity. In the first group are the pattern recognition method120 and molecular orbital121 andquantum chemical treatments,122 while in the latter category are the widely used Hansch method123 and Free-Wilson rn0de1.12~ Extensive use has been made of linear free energy equations in recent years to correlate the bioactivity of chemicals. The general procedure is to take a biologically active compound and study the effects of structural changes on its activity, directed toward finding the substitution pattern of the derivative expec- ted to be the most potent.In the Hansch approach, an equation is used of the type 1log -= k1m + k20 + k3Es + k4 CS where Cs= the concentration of member s which gives a standard response, e.g. LD50,150, etc.; 7r= hydrophobic subst i tuent cons tan ts (determined from distribution coefficients of model compounds between n-octanol and water), which reflect lipophilic character of substituents ; Hammett substituent constants, which reflect electronic effects of substituents; Taft steric constants, which reflect spatial requirements of groups. kl, kz, k3, and k4 are constants, determined by multiple regression analysis.The substituent constants are available in tables for many common groups. The rationale is that the bioactivity of a drug is determined by a summation of its hydrophobic-lipophilic character, its charge distribution, and its molecular shape. By choosing the proper substituent changes, guided by the use of the equation above, attempts are made to predict the structure of the most effective laoB. R. Kowalski and C. F. Bender, J. Amer. Chem. SOC.,1974, 96, 916; R. D. Cramer, tert., G. Redl, and C. E. Berkoff, J. Medicin. Chem., 1974, 17, 533. lS1 L. B. Kier, ‘Molecular Orbital Theory in Drug Research’, Academic Press, New York, 1971; A. J. Wohl, ‘DrugDesign’, Vol. 1, ed. E. J. Ariens, Academic Press, New York.1971, p. 391. lZ2T. K. Lin, J. Medicin. Chem., 1974, 17, 151 ;J.-L. Montero, J. L. Imbach, R. E. Christof-fersen, D. Spangler, G. G. Hall, and G. M. Maggiora, J. Amer. Chem. SOC.,1973, 95, 8526. 123 Two recent reviews are: (a)A. Verloop, in ‘Drug Design’, Vol3, ed. E. J. Ariens, Academic Press, New York, 1972, Chap. 2; (b) Biological Correlations-The Hansch Approach’, ed. R. F. Gould (Advances in Chemistry Series), No. 114, American Chemical Society, Washington, D.C., 1972. la4W. P. Purcell, G. E. Bass, and J. M. Clayton, ‘Strategy of Drug Design’, Wiley-Interscience, New York, 1973, Chaps. 5 and 6; P. N. Craig, ref. 123b, p. 115. Ferguson member in a class of drugs. Such studies are being made on several antileukaemic molecular types, such as, for illustration,l25 nitrosoureas (47), triazines (48), aziridines (49), and pyrimidines (50).X-CH,CH,-N-CO-NHR CONH,I NO Rf X = F or C1 / HI 'R3 (47) (48) CONHR The Hansch treatment can give a partial answer to the questions of how many compounds in a given class should be tested and what is the probability that the most active member of a given class has been found. When applied to the nitrosoureas, for example, and neglecting steric and electronic effects, it predicts that for optimal therapeutic properties, the nitrosourea should have a log P value (P = partition coefficient between l-octanol and water) in the range -1.5 to -0.5.12s Higher log P values are associated with decreased antitumour activity or greater toxicity.Following this prediction, the cyclohexyl group in CCNU (11) was replaced by a carbohydrate moiety and the product was actually more active and less toxic than CCNU.lZ7 Perhaps this greater therapeutic value is due to the enhanced hydrophilic character of the compound or because the sugar serves as an effective carrier to the tumour cells. Antitumour activity is also correlated with a low carbamoylating activity.12* If tumour cells do have a large free-radical character, as implied earlier, then the use of radical substituent constants ER~~~might give more significant and useful regression equations. l*' C. Hansch, N. Smith, R. Engle, and H. Wood, jun., M. D. Anderson Symposium on Fundamental Cancer Research, Houston, Texas, February, 1974; E.J. Lein and G. L. Tong, Cancer Chemotherapy Reports Part I, 1973, 57(3), 251. lZ6 J. A. Montgomery, J. G. Mayo, and C. Hansch, J. Medicin. Chem., 1974, 17, 477; A. N. Fujiwara, E. M. Acton, and D. W. Henry, ibid., 1974, p. 392. la' J.-L. Montero, J. L. Imbach, and M. M. Mousseron, Compt. rend., in press. la* G. P. Wheeler, B. J. Bowdon, J. A. Grimsley, and H. H. Lloyd, Cancer Res., 1974,34,194.'*'T. Yamamoto and T. Otsu, Chem. and Ind., 1967, 787. Cancer and Chemicals Although these Q.S.A.R. methods have a great potential, they provide little help in finding new molecular types with antitumour activity. The quantum chemical techniques provide a useful tool for learning more about drug-receptor site interactions, particularly conformations and charge distributions necessary for maximum interaction and molecular sites of reactivity.130 Some of the molecular types exhibiting a range of antitumour activity have been reviewed recently.131 B.Target-specific Approach.-This method uses as a guide the structures of compounds known to localize in a certain part of the body or have a specific biological activity. Examples are metal chelates or organoboron compounds which concentrate in specific organs. For instance, CNS drugs with no known antitumour activity are molecularly altered to give them cytotoxic activity without destroying their ability to reach the brain or CNS. In one case, a group of phenothiazines among many psychotropic (tranquillizers, energizers) drugs were found to be active in the L-1210 tumour.C. Active Molecular Fragment. It is the usual practice to seek a similar molecular fragment in a group of compounds exhibiting some property in common. An example among anticancer agents is the 0-N-0 triangulation observed in some non-alkylating antileukaemic drugs.132 The presence of this molecular pattern does not mean that a compound must have antileukaemic activity but it is noteworthy that the 0-N-0 group can be found in several different classes of antitumour drugs including Adriamycin, MTX, and those shown below. It is hypothesized that such a structural fragment might assist the in vivo binding of the drug to one of the critical biological receptor sites involved in leukaemia genesis.O--OH o\ -0-0 3.4 A Me0 01IOH W 0 O-N-0 Triangle NH, Daunomycin lSoR. E. Christoffersen, D. Spangler, G. G. Hall, and G. M. Maggiora, J. Amer. Chem. Soc., 1973,95, 8526. 131 C. C. Cheng and K. Y. Zee-Cheng, Ann. Reports Medicin. Chem., 1973, 8, 128. lSpC. G. Zubrod, Life Sciences, 1974, 14(5), 809; K.-Y. Zee-Cheng and C. C. Cheng, J. Pharm. Sci., 1970, 59, 1630. HO ,hie R C0,Me Vinblastine R= Me Cytosine arabinoside Vincristiiie R = CHO D. DNA-intercalators.-Some drugs are known to form complexes with DNA and it is thought that antitwnour activity is related to their intercalation between base pairs of the DNA chain.133 Most of these agents are planar, polycyclic quinones or nitrogen heterocyclics with several methoxy- or hydroxy- groups attached.The binding characteristics of such compounds with DNA and other biological constituents are being studied by physical methods. E.Multi-component System.-The rationale in this approach is to use an agent which is inert or non-toxic but which can be converted by enzymes or radiation into a cytotoxic substance at the tumour site. For example, masked alkylating agents have been used which are cleaved enzymatically or chemically to biological alkylating agents.134 This same scheme is the foundation of the neutron capture technique.135 Ideally, a drug containing an atom with a high rate of neutron capture would localize selectively in tumour cells. The irradiated drug would then emit destructive alpha particles to kill the nearby cells.Boron- 10 and uranium-235 have large neutron capture cross-sections. Few non-toxic uranium compounds have been prepared but a number of boron-containing drugs have been found to concentrate preferentially in brain tumour cells. Although this technique offers promise of producing antitumour drugs, especially for brain cancers, no such compound has progressed beyond the clinical stage. Alternately, the B-10 could be incorporated into a tumour-specific antibody protein which would subsequently concentrate the boron in the tumour cell laS W. J. Pigram, W. Fuller, and L. D. Hamilton, Nature New Biol., 1972,235, 17. lS4 K. C. TSOU, M. D. Anderson Symposium on Fundamental Cancer Research, Houston, Texas, February 1974; Z.B. Papanastassiou, R. J. Bruni, and E. White, V, J. Medicin. Chem., 1967,10,701. lS6 W. M. Baird, A. Dipple, P. L. Grover, P. Sims, and P. Brookes, Cancer Res., 1973, 33, 2386; A. H. Soloway, Progr. Boron Chemistry, ed. A. L. McCloskey and H. Steinberg,Pergamon Press, New York, 1964; A. H. Soloway, H. Hatanaka, and M. A. Davis, J. Medicin. Chem., 1967, 10, 714. Cancer and Chemicals antigen. Neutron radiation could then be applied to kill specifically the tumour ceiis.13* Chemoimmunotherapy is yet another conceivable multicomponent system for cancer therapy. The basic concept consists of the preparation of tagged haptens which may be infused to label neoplastic cells. Then a cytotoxic antibody may be generated against these hap tens.I37 F.Natural Sources.-Not to be overlooked is the search for anticancer agents in agricultural and marine plants and animals. In this approach, the chase is guided by testing for antitumour activity, generally in vitro against KB cells. Promising fractions are then followed by in vivu tests against several animal ~LEIIOU~~~Such activity-directed isolation of new tumour inhibitors of plant origin has yielded several compounds which are in or nearing clinical trials, such as bruceantin (51), maytansine (19), ellipticine (49, taxol (52), and VM-26 (53). 5 Cancer Treatments Related to Chemotherapy There are other modes of cancer treatment which are somewhat related to chemotherapy, such as radioisotope therapy and immunotherapy. In the former modality, a radioisotope is administered which is known to localize in an organ.139 For example, iodine-131 is used for thyroid cancer, yttrium-90 coated microspheres for metastases in lung and liver cancer, or phosphorus-32 for lymphomas and leukaemias.Actually, a useful role that organic chemists can play here is to synthesize radiolabelled agents, not for radiation therapy but for diagnosing or locating tum~urs.~~~ Thus, compounds known to accumulate selectively in certain tumours could be radio-tagged as a means of detecting the tumour. An example is stilbestrol di-iodide which localizes rapidly in pros- tate cancers. Other examples are 19-radio-iodinated cholesterol for the diagnosis of adreno-cortical carcinoma,l41 and radio-iodinated tyramines for adrenal medullary t umours ,142 Immunotherapy is a promising mode of cancer treatment and warrants some comment here. In the 189Os, William Coley first injected 250 cancer patients with bacterial toxins who all improved and survived many years of life.However, his results were generally unaccepted for several decades. Evidence of the role of the body’s immunity system infighting cancer comes in- la6M. F. Hawthorne, R. J. Wiersema, and M. Takasugi, J. Medicin. Chem., 1972, 15, 449; R. L. Sneath, jun., A. H. Soloway, A. S. Dey, W. D. Smolnycki, and S. M. O’Keefe, J. Medicin. Chem., in press. I*’ A. H. Soloway, I. Agranat, A. R. Chase, R. E. Hernandez, E. S. Kimball, T. Cascieri, jun., and C. H. Cox, J. Medicin.Chem., in press. 138 S. M. Kupchan, Fed. Proc., 1974,88(11), 2288. la) M. Brucer, in ‘Progress in Clinical Cancer’, Vol. 1, ed. I. M. Ariel, Grune and Stratton, New York, 1965, p. 74. 140 R. E. Counsell and R. D. Ice, ‘The Design of Organ Imaging Radiopharmaceuticals’, University of Michigan, Ann Arbor, 1973; R. E. Counsell, T. Yu, V. V. Ranade, and A. Buswink, J. Medicin. Chem., 1973, 16, 1038, and previous articles. lA1 L. M. Lieberman, W. H. Beierwaltes, and J. W. Conn, New Engl. J. Med., 1971, 285, 1387. 14* R. E. Counsell, T,D. Smith, V. V. Ranade, 0.P. D. Noronha, P. Desai, T. Yu, and A. Buswink, J. Medicin. Chem., 1973, 16, 684, 1038. Ferguson OH directly from several observations: (i) cancer strikes hardest in the young and the old, the two periods when the immune system is least organized; (ii) there is a high correlation between cancer and immuno-deficiency diseases, in which patients with a given type of tumour suffer from certain types of infections, Cancer and Chemicals e.g.those with Hodgkin’s disease, a cancer of thelymphoidsystem, are particularly susceptible to tuberculosis and viral infections, and those with multiple myelo- mas, cancer of the bone marrow, are vulnerable to streptococcus and pneumo- coccus bacterial infections, and (iii) cancer occurs 100-fold more frequently in transplant patients-patients whose immune systems are suppressed by drugs to prevent rejection of the new organ-than in the general population. Our bodies make some loll cells (ca. 1 Ib.of tissue) daily and it is statistically expected that some will be imperfect (estimates range from 104 to 106).Ap- parently, cells of neoplastic potential are continually being destroyed by our immune surveillance system, and the development of a tumour implies a break- down in this process. The immunological approaches used vary widely. Some doctors use Coley’s bacterial-toxin formula; others inject vaccine made from killed mumps virus and diphtheria bacteria; many physicians prefer a live bacteria tuberculosis vaccine called BaciZZus Calmette-Guerin (B.C.G.).143B.C.G., for instance, is used to stimulate the immune systems of patients suffering from malignant melanoma, a cancer that first appears on the skin and spreads rapidly to other parts of the body.Some of these patients have been free of the disease for two years or more. Administration of B.C.G. has also achieved remissions in patients with breast cancer and cancer of the thymus. Candidates for B.C.G. immunotherapy are often chosen by a test of their immune sensitivity toward dinitrochlorobenzene-a reagent used to assess a patient’s immune system.144 Although some encouraging dramatic results have been achieved by immunotherapy, there are still many problems facing this modality of treating cancer patients.145 One is the fact that most antitumour drugs suppress the immune system and another is the apparent presence of complexes in some cancer patients that prevent the immune system from attack- ing cancer cells.Because of the severe side effects usually occurring from B.C.G. treatment (fevers, liver disorders, inflammations and abscesses at the injection points), there is a wide international search for chemical stimulators of the immune system. Two promising compounds in extensive clinical trials are levamisole (54) and tilorone (55).146 fJ-gJEt 2 NCH ZCHZO ’OCH,CH,NEt 0 (54) (55) 143 P. H. O’Brien, J. South Carolina Med. ASSOC.,1972, 68(12), 466. 144 D. Morton, Report to the American Association for the Advancement of Science, San Francisco, Feb., 1974. 145 R. T. Prehn, Proceedings of the 10th Canadian Cancer Research Conference, 1973, ed. P. G. Scholefield, University of Toronto Press, Toronto, 1974, p. 136. 148 H. J.Sanders, Chem. and Eng. News, Dec. 23, 1974, p. 14. Ferguson Whereas the major thrust of cancer chemotherapy is the destruction of malignant cells after they have been formed, immunotherapy is aimed at the preneoplasia phase-the period between exposure to carcinogen or initiation and the transformation to malignancy. This induction or preneoplasia period may last 20 or more years. Another effort to halt oncogenesis at the preneo- plasia point is being made by the administration of vitamin A or its analogues. Some of the evidence of the role of vitamin A or its congeners was presented at a conference at the National Institutes of Health, Washington, November, 1974, sponsored by the N.C.I. and Hoffmann-LaR0~he.l~~ It was shown, for example, that various carcinogens bind much more tightly to DNA in cultural hamster tracheas from vitamin A-deficient hamsters than to DNA in tracheas from healthy animals.Also, colon tumours produced by aflatoxin B1 are more preva- lent in rats deficient in vitamin A than in normal controls. Others showed that vitamin A exerts a protective action when fed to animals simultaneously with known carcinogens. It is noteworthy that there is a higher incidence of lung cancer among persons with vitamin A deficiency.18 As with other types of medication, tumours change their sensitivities toward a given drug. Hence there is a biochemical problem to learn the mechanisms of anticancer drug resistance. In the case of alkylating agents, for instance, it is possible that deactivation results from reaction of the drugs with non-protein sulphydryl groups.14* Any number of modes of deactivation are conceivable, e.g.149 decreased concentration of critical targets or masking of the active functional groups, changed cellular transport, increased competition by normal or protective metabolites for an enzyme, the drug, or for an essential metal ion, failure of the necessary activation of the drug, to name a few.6 Conclusion The major criterion used to measure the success of the chemotherapy programme is the number of patients to achieve normal life expectancy who would otherwise have died from cancer. There are now ten human cancers which are highly responsive to chemotherapy and 50 per cent of these patients should achieve normal life expectancy.150 Although longer remissions of many cancers are achieved through chemotherapy, these successes do not include the big cancer killers such as breast, colon, or lung cancer so that the incidence of cancers is still on the rise.Drugs now in use are not highly effective against oId tumours which have low rates of DNA synthesis, such as colon and lung cancer: e.g., the median survival rate of all lung cancer patients from diagnosis to death remains less than six months.151 To make the big breakthrough here, we will need a better understanding of the mechanisms of action of antitumour agents. The identi- 14' Cf. T. H. Maugh, jun., Science, 1974,186, 1198. 148 G. P. Wheeler, Cancer Res., 1963, 23, 1334.119 Symposium, Cancer Res., 1965, 25, 1581. 160 C. G. Zubrod, Cancer, 1972,30, 1474. lS1 0. S. Sclawry, Cancer Chemotherapy Reports Part 3, 1973, 4(2), 5. 319 Cancer and Chemicals fication of additional biochemical targets for antitumour agents would help too. Known targets of some cIinicalIy established drugs are? Drug Target Methotrexate Dihydrofolate reductase 5-Fluorouracil Thymidylate synthet ase Hydroxyurea Ribonucleotide reductase Arabinosylcytosine DNA Polymerase Actinomycin D and Adriamycin Intercalation with DNA Nitrogen mustard and CCNU Reaction with DNA 6-Thioguanine Incorporation into DNA Vincristine Mitotic blockade Hence, biochemical mechanistic studies of carcinogenesis and cytotoxic actions are sorely needed.It is generally believed that the rational design of cancer drugs will ultimately be based on an exploitable biochemical difference between normal host cells and the invading cancer cells. Moreover, in all previous successes over biological systems with chemicals, e.g., antimalarials, pesticides, etc., the development of cellular resistance has always necessitated a change in the bioactive chemicals used. Consequently, eventually resistance to the present successful cancer drugs can be expected and our search for new drugs must continue unabated. Two recent strategies for more effective use of our present arsenal of drugs are described below : (i) to administer several drugs either together or in succession;l53 only a few drugs effect cures when used singly, such as CTX for Burkett’s tumour, MTX in choriocarcinoma, or Actinomycin D in WiIm’s tumour.Drugs for combination are usually chosen on a basis of having different modes or sites of action, different times of action in the cell cycle,154 or different host resistances or carcinostatic a~ti0n.l~~ One variation here is the ‘rescue’ technique of administer- ing an excessive quantity of a drug, a potentially lethal amount, and shortly thereafter of giving the patient an antidote to counteract the action of the anti- tumour drug.ls6 (ii) A second modification in the practice of chemotherapy is an early combination of chemotherapy with surgery and/or radiation therapy.157 An excellent example of this is the recent finding that the administration of 152 J.A. R. Mead, M. D. Anderson Symposium on Fundamental Cancer Research, Houston, Texas, February, 1974. 15s J. R. Bertino, M. B. Mosher, and R. C. DeConti, Cancer, 1973, 31, 1141; H. H. Hansen, Cancer Chemotherapy Reports Part 3, 1973, 4(2), 25; A. Goldin, ibid, p. 189. 154 V. H. Bono, jun., Cancer Chemotherapy Reports, Part 2, 1974, 4(1), 131 ;A. M. Zimmer-man, G. M. Padilla, and I. L. Cameron, ‘Drugs and the Cell Cycle’, Academic Press, New York, 1973. lSs W. M. Kirsch, D. Schulz, J. J. Van Buskirk, and H. E. Young, J. Med. (Basel), 1974, 5, 69. 150 M. Levitt, M. B. Mosher, R. C. DeConti, L. R. Farber, R. T. Skeel, J. C. Marsh, M. S. Mitchell, R. J. Papac, E. D. Thomas, and J. R. Bertino, Cancer Res., 1973,33, 1729; Staff report, Chem.and Eng. News, April 8, 1974, p. 21. lS7 S. K. Carter, Cancer Chemotherapy Reports Part 2, 1974, 4(1), 3; F. 0. Stephens, Men. J. Austral., 1972, 1(12), 591. 320 Ferguson L-PAM (10) immediately following a simple mastectomy for breast cancer is more effective than a radical mastectomy. In the past, drugs have usually been given when cancers had reached the inoperable stage, when chemotherapy has a lower probability for success. There are four widely used modes of cancer treatment: surgery, radiation therapy, chemotherapy, and immunotherapy. There are other less developed' approaches being explored, such as electrosurgery, chemosurgery (use of zinc chloride paste in situ) cryosurgery (use of liquid nitrogen),l58 and thermo- therapy.159 In the latter modality, either local or total-body hyperthermia (excess heat) is used to destroy cancer cells and potentiate the immune response. It appears that tumour growth increases at temperatures above 37.5 "C until about 42 "C where there is a sudden inhibition of metabolism.This review was devoted to the more chemical aspects of cancer but there are other major phases which inter-relate with the chemotherapy programme: e.g., studies are being made to find better screening methodsl60 and develop screens using transplanted human cancer cells.161 Clinical and preclinical testing of drugs is a big operation, involving extensive biostatistics ;I62 the pharmacological and toxicological actions of drugs must be learned prior to making clinical trials, and the logistics of drug acquisitions must be well organized. Also, important supportive studies are being made in an attempt to understand DNA replication, control of gene expression in animal and human tissue, and the interaction of known effective antitumour agents with these processes.163 The epidemiology of cancer is an international co-operative programme,164 and the recognition and removal of environmental carcinogens will undoubtedly be a major factor in the success over cancer.Rather than the prevention of cancer, it may turn out that the best that can be hoped for in cancer treatment is its con- troL1G5 Probably the greatest long-range chances of conquering cancer lie in the success of immunotherapy and the elimination or avoidance of environmental carcinogens.We see then, that there are many ways in which chemists can help in the war on cancer. This includes analytical, inorganic, organic, pharmaceutical, and physical chemists, and, of course, biochemists. The author is grateful to the National Cancer Institute for making assessable much of the information given herein, particularly that from outside the U.S. lm W. A. Clabaugh, Amer. Fam. Physician, 1973, 7(5), 78. 159 J. A. Dickson, Cancer Chemotherapy Reports Part 2, 1974,58,294; D. S. Muckle, Cancer Therapy Abstracts, 1974, 3(15), NO.74-1045, 214. 160 F. E. Knock, R. M. Galt, Y. T. Oester, and R. Sylvester, Oncology, in press; F. E. Knock, R. M. Galt, Y.T. Oester, and R. Sylvester, S. African J. Med.Sci., 1973, 38, 43. L. M. Cobb and B. C. V. Mitchley, Cancer Chemotherapy Reports Part I, 1974, 58(5), 645. la*M. Zelen, Cancer Chemotherapy Reports Part 3, 1973, 4(2), 31. F. M. Thompson, A. N. Tischler, J. Adams, and M. Calvin, Proc. Nut. Acad. Sci. U.S.A., 1974, 71, 107. la4 International Agency for Research on Cancer, Science, 1972, 178,844. 'Chemotherapyof Cancer Dissemination and Metastasis', ed. S. Garattini and G. Franchi, Raven Press, New York,1973. Cancer and Chemicals However, the N.C.I. is not responsible for any errors or misconceptions stated. Support was also provided by the Minority Biomedical Research Support Program of the National Institutes of Health.

ISSN:0306-0012    

DOI:10.1039/CS9750400289

出版商:RSC    

年代:1975

数据来源: RSC