11 Polymer-supported Catalysts and Reagents By P. HODGE Department of Chemistry University of iancaster Lancaster LA 1 4YA 1 Introduction Since Merrifield reported his method of ‘solid-phase peptide synthesis’ in 1963,’ there has been considerable interest in carrying out organic reactions on polymer supports. Several books and reviews have been published The supported species may be either a catalyst a reagent or the substrate. A very large number of each type have been reported in the last 20 years and there is clearly insufficient space in this Report to cover all the aspects. The Report must therefore be selective. It will consider the practical advantages of PS” catalysts and reagents their prepar- ation some general features of PS reactions and selected examples of PS catalysts and reagents likely to be of interest to synthetic organic chemists.It will concentrate on recent developments. PS transition metal complex catalysts will not be considered as this topic is sufficiently large and specialized to justify a Report of its own.8 Reactions using PS substrates will not be considered because these have a more limited range of applications in organic synthesis than PS catalysts and reagenk4v9 The subject of this Report involves both organic chemistry and polymer chemistry. Readers not familiar with the latter may find the texts listed in ref. 10 useful. 2 Practical Advantages of PS Catalysts and Reagents The features of PS catalysts and reagents which usually prompt the initial studies are the practical advantages which result from the easy separation of the supported and the non-supported species.The separation is easiest if the polymer is crosslinked R. B. Merrifield J. Am. Chem. SOC.,1963 85 2149. ‘Polymers as Aids in Organic Chemistry’ N. K. Mathur C. K. Narang and R. E. Williams Academic Press New York 1980. ‘Polymer-supported Reactions in Organic Synthesis’ ed. P. Hodge and D. C. Sherrington Wiley Chichester 1980. J. M. J. FrCchet Tetrahedron 1981 37 663. A. Akelah and D. C. Sherrington Chem. Rev. 1981 81 557. A. Akelah and D. C. Sherrington Polymer 1983 24 1369. ’ ‘Polymeric Reagents and Catalysts’ ed. W. T. Ford ACS Symposium Series 308 Washington 1986. * P. E. Garrou Chapter 5 in ref. 7; F. R. Hartley ‘Supported Metal Complexes’ D. Reidel Publishing Co.Dordrecht 1985; F. Ciardelli G. Braca C. Carlini G. Sbrana and G. Valenti J. Mol. Cutal. 1982 14 1; D. C. Bailey and S. H. Langer Chem. Rev. 1981 81 110. J. M. J. FrCchet Chapter 6 in ref. 3. ‘Contemporary Polymer Chemistry’ H. R. Allcock and F. W. Lampe Prentice-Hall Englewood Cliffs New Jersey 1981; ‘Textbook of Polymer Science’ by F. W. Billmeyer 3rd Edition Wiley New York 1984. * Throughout this Report ‘Polymer-supported’ is abbreviated to PS. 283 284 P. Hodge (and therefore insoluble in all media) and in the form of beads at least 50 p in diameter. Separation can then be achieved simply by filtration using common laboratory equipment. Somewhat larger beads are easily separated by decantation and can also be used in columns.The separation of polymeric and non-polymeric species is less easy if the polymer is linear and therefore soluble. Separation must then be achieved by selective precipitation or by membrane filtration. This Report unless noted otherwise will therefore just consider catalysts and reagents prepared from crosslinked polymers. Work with linear polymers has been reviewed." The advantages resulting from an easy separation include the following. (i) Product isolation is simplified. This may make it possible to avoid exposing reaction products to water to avoid chromatographic separations or to allow the rapid isolation of unstable products. (ii) If the use of an excess of a reagent results in a greater reaction yield then an excess can be used without causing separation problems.(iii) The polymer is easily recovered and can possibly be re-used. If the polymer can be re-used successfully it becomes economically feasible to prepare complex and sophisticated catalysts or reagents. (iv) It may be possible to automate the whole reaction procedure. This has obvious attractions to industry. The practical advantages are likely to be most useful in the preparation of valuable materials on a small scale for example in the preparation of certain pharmaceuticals and of labelled compounds. They are also likely to be valuable in asymmetric synthesis since attaching complex chiral species to polymers provides a 'handle' which permits their easy removal from the chiral reaction products and also allows the complex species to be re-used.3 Preparation of Functionalized Polymers A number of PS catalysts and reagents are available commercially and the range is increasing steadily. However on most occasions the polymer required for a particular application will need to be synthesized. In most cases the functionalized polymers used have been derivatives of cross- linked polystyrenes. Polystyrenes are particularly attractive as supports because they are readily available they are hydrophobic (and hence compatible with many organic solvents) and the unfunctionalized phenyl residues do not usually interfere in subsequent reactions. Other hydrophobic polymers are beginning to be investi- gated.I2 When hydrophilic supports are required polymers prepared from monomers such as acrylamide N,N-dimethylacrylamide or 2-hydroxyethyl methacrylate (HEMA) may be used.The two main approaches to the synthesis of functionalized crosslinked polymers are as follows. *'(a) K. Geckeler V. N. R.Pillai and M. Mutter Adv. Polym. Sci. 1981 39 65; (6) D. E. Bergbreiter Chapter 2 in ref. 7. 12 P. Hodge B. J. Hunt and I. H. Shakhshier Polymer 1985. 26,1701; A. A. H. Al-Kadhumi P. Hodge and F. G. Thorpe ibid. 1985 26,1695; F.Anwar C. Bain M. Bakhshaee and D. C. Sherrington J. Chem. SOC.,Chem. Commun. 1984 1363; D. Lindsay and D. C. Sherrington Reactive Polymers 1985 3 327. Polymer-supported Catalysts and Reagents 285 By Copolymerization.-This approach involves copolymerizing the appropriate func- tional monomer any monomer used as a diluent and a crosslinking agent.An example is the preparation of a polymer containing triphenylphosphine residues by the free radical-initiated copolymerization of p-styryldiphenylphosphine,styrene and di~inylbenzene.'~ To obtain products in the form of beads suspension copoly- merizations must be carried out. By careful control of the conditions including the feedstock composition the vessel and the stirrer shapes the stirrer speed and the types and amounts of suspending agents products of quite different size and morphology can be ~btained.'~ With only a small amount of crosslinking agent (1YO or 2% of divinylbenzene for polystyrenes) and no additives (compare below) a microporous polymer is obtained. On drying the polymer matrix collapses to leave a product with only very small pores.With a relatively large amount of crosslinking agent (>20% of divinylbenzene for polystyrenes) and the addition of porogens (for example toluene amyl alcohol or linear polystyrene) macroporous polymers are obtained. These are rigid and do not collapse when they are dried but remain in an expanded porous form. In general considerable experimentation is needed to optimize the polymerization conditions for a particular feedstock. As a result this approach to functionalized polymers is not often used by organic chemists. Finally it should be noted that with this approach the distribution of the functional monomer in the final product will depend on the reactivity of ratios of the various monomers and that some functional groups may subsequently prove to be inaccess- ible to low molecular weight reactants.By Chemical Modification of Preformed Polymers.-Several unsubstituted cross-linked polystyrenes of good physical form are available commercially and many PS catalysts and reagents have been prepared by chemical modification of these prod- ucts. The reactions used for the chemical modification must be essentially free of sidz reactions and reaction sequences must be short for there is no way of removing the products of side reactions which are bound to the polymers. Many groups can be introduced into crosslinked polystyrenes by electrophilic aromatic substitution reactions. Some important examples are given in Scheme 1 together with some important transformations of the products.Polystyrene reacts directly with n-butyl lithium and N,N,N',N' -tetramethylethyl-enediamine to give lithiated polystyrene but the maximum degree of functionaliz- ation obtained is only CQ. 25% and it is a mixture of m- and p-isomers." Essentially quantitative para-lithiation can be achieved by bromination with bromine and thallic acetate followed by treatment of the product with n-butyl lithium." These lithiated polystyrenes (6) react with a wide range of electrophiles to give useful products see Scheme 2. Another much-used sequence is chloromethylation of polystyrene then reaction of the products with nucleophiles. Chloromethyl ether was originally used for the chloromethylation'6 but it contains highly carcinogenic impurities.A more l3 D. C. Sherrington D. J. Craig J. Dalgleish G. Domin and J. Taylor Eur. Polym. J. 1977 13 73. 14 R. Arshady and A. Ledwith Reactive Polymers 1983,1 159; D. C. Shemngton Macromol. Synfh. 1982 8 69; Appendix section of ref. 3. IS M. J. Farrall and J. M. J. Frichet J. Org. Chem. 1976 41 3877. 16 K. W. Pepper H. M. Paisley and M. A. Young J. Chem. SOC. 1953 4097. 286 P. Hodge CHZCI Q co vii Ref. d,f CHO COzH (5) Reagents i C1S03H in CH,Cl,; ii Br, Tl(OAc),; iii CICHz AlCl,; iv 2-chloroben- zoyl chloride AlCI,; v KOBut/H20 (3 1); vi ClCH20CH, SnCI,; vii NaHCO, DMSO; viii Na,Cr,O, HZSO References (a) J. R. Millar D. G. Smith W. E. Marr and T. R. E. Kressman J. Chem. Soc. 1963 218; (b) See ref. 15 in text; (c) R.Kalir M. Fridkin and A. Patchornik Europ. J. Biochem. 1974 42 151; (d) C. R. Harrison P. Hodge J. Kemp and G. M. Perry Makromol. Chem. 1975 176 267; (e) See refs. 16 and 17 in text; (f) H. W. Gibson and F. C. Bailey J. Polym. Sci. Chem. Ed. 1975 13 1951. Scheme 1 satisfactory procedure uses dimethoxymethane thionyl chloride and zinc chloride.” Some of the nucleophiles which have been used are shown in Scheme 3. Often the reactions are best carried out using phase-transfer catalysis. ’* Further less expensive chemical modifications of readily available polymers are required as routes to functional polymers. One recent approach involves phase- 17 J. P. C. Bootsma B. Eling and G. Challa Reactive Polymers 1984 3 17. 18 J. M. J. Frichet M.D. de Smet and M. J. Farrall J. Org. Chem. 1979 44 1774. Reagents i LiPPh,; ii Bu"Li TMEDA; iii Ph,PCI; iv CO,; v MgBrz then BunSnCl3 then LiAIH,; vi (MeS),; vii As(OEt) then H20 References (a) H. M. Relles and R. W. Schluenz J. Am. Chem. Soc. 1974; 96 6469. (6) See ref. 15 in text. (c) S. V. McKinley and J. W. Rakshys J. Chem. SOC.,Chem. Commun. 1972 134. (d) See ref. 100 in text. (e) See ref. 88 in text. (f)See ref. 48 in text Scheme 2 transfer-catalysed Wittig reactions between aldehydes and PS phosphonium salts [(13) in Scheme 3].19 Another involves reacting a commercial crosslinked poly- methacrylic acid (14) (a weak acid cation-exchange resin) with benzyltrimethyl- ammonium hydroxide followed by reaction of the PS salt (15) with appropriate alkyl bromides iodides or tosylates see Scheme 4.20The ester linkage is relatively unreactive as it is in effect a PS pivalate ester.It should be noted that the distribution of functional groups introduced by chemical modification will depend on many factors e.g. the rate of the chemical reaction compared to the rate of diffusion of the reagent into the polymer beads and the effect of functional groups already introduced on the ease of introduction of other functional groups in the vicinity. The groups may be evenly distributed or 19 P. Hodge and J. Waterhouse Polymer 1981 22 1153. 20 P. Hodge and M. Houghton unpublished results. 288 P. Hodge Q CH20R I sf. --CH-CHZ--CH2C1 Rex _--CH-CH2 -___ (1) 0 CH26Ph~ CH~NU c1-(13) Reagents i NR,; ii N&-OR; iii Various nucleophiles Nu-; iv PPh References (a) S.L. Regen and D. P. Lee J. Am. Chem. SOC 1974,96 294. (b) W. M. MacKenzie and D. C. Shemngton J. Chem. SOC.,Chem. Commun. 1978 541. (c) See ref. 18 in text. (d) See ref. 19 in text Scheme 3 Me -FH Me Me I PhCH,NMe I I ...C-CH2.. ...C-CH,... RCH,Br ...C-CH,... . b -+ ICO2H I c02- IC02CH2R PhCH2&’Me (14) (15) Where R = functional group Scheme 4 clustered but in general they will all be accessible in subsequent reactions. Clearly the distribution obtained will differ from that obtained by direct copolymerization. 4 Some General Features of PS Reactions Selection of Reaction Conditions.-The reaction conditions used with PS catalysts and reagents are not necessarily the same as those used with their low molecular weight counterparts.The choice of reaction solvent is particularly important. PS catalysts and reagents are usually prepared in the form of crosslinked beads with diameters of 50-100 p. If the beads were only functionalized on the surface their maximum capacities would be of the order of 0.01 mmol g-’. It is clear that Polymer-supported Catalysts and Reagents 289 for applications in synthetic organic chemistry the beads need to be functionalized throughout their volume. They will then have maximum capacities of several mmol g-’. Because the vast majority of the functional groups are within the beads low molecular weight substrates must diffuse into the beads to react.To obtain adequate diffusion rates with microporous beads (see section on copolymerization above) they must be swollen by the reaction solvent. The extent of swelling with a given solvent will depend on the support polymer the functional groups present and on the concentration and distribution of both. The reaction solvent must not only swell the beads initially but throughout the reaction as the original bound functional groups are transformed into others. The choice of solvent is less important with macroporous polymers (see section above on copolymerization) since functional groups in the porous regions should be accessible in most solvents. However the high percentage of crosslinking in macroporous polymers generally means they have lower capacities than microporous polymers.The choice of solvent is also important because the substrate will not in general be evenly distributed between the polymer phase and the surrounding solution. Ideally the substrate will concentrate in the polymer beads and this may lead to enhanced reaction rates but the substrate may also tend to stay in the surrounding solution so leading to decreased reaction rates. These effects may well change as the reaction proceeds. Apart from its influence on diffusion rates and on the distribution of the substrate between the polymer and the surrounding solution the reaction solvent will also influence the rates of reactions as in low molecular weight systems. The factors are so complex that in general the best solvent for a particular reaction system should be determined by experiment.The rates of many PS reactions are limited by diffusion. Many PS reactions are therefore slower than their low molecular weight counterparts and longer reaction times and/or higher reaction temperatures are often necessary. Microenvironment in the Vicinity of PS Reactive Groups.-In the presence of the reaction solvent the functional groups in most PS catalysts or reagents will be surrounded by the reaction solvent. The reactivity of the group will therefore generally be the same as its low molecular weight counterpart. The microenvironment may differ however if the substrate accumulates in the polymer beads and/or other groups in the polymer interact strongly with the functional group before or during reaction.The latter is most likely to be the case if charged groups are present and/or hydrogen-bonding is possible. Such ‘polymer effects’ have been observed in a few cases.21-22 There is no clear evidence that functional groups bound to polystyrenes have different steric requirements than their low molecular weight counterparts. They are not expected to since in most cases the functional groups are bound at the para-position. Steric effects may be found with functional groups bound closer to the polymer backbone as for example the acyl groups in addition polymers prepared from maleic anhydride. 21 C. R. Harrison P. Hodge B. J. Hunt E. Khoshdel and G. Richardson J. Org. Chem. 1983,48 3721. 22 C. Yaroslavsky A. Patchornik and E.Katchalski Tetrahedron Lett. 1970 3629; G. L. Baker S. J. Fritschel and J. K. Stille. J. Org. Chem. 1981 46.2960. 290 P. Hodge Ease of Intrapolymeric Reactions.-This has been a topic of interest with PS reactions for many years. The subject has been reviewed recently.23 It will be useful here to draw together the main conclusions. There are two main types of situation (i) those where the functional groups react together and then separate and (ii) those where the functional groups react and then remain bound together. Consider the former type first. In general there is no reason why two functional groups (potentially capable of reacting together) bound to a linear polymer chain existing as a random coil should not be able to react together however! low the degree of functionalization.The introduction of crosslink-ing will tend to limit the movements of bound functional groups but with the low degrees of crosslinking present in microporous polymers this does not significantly limit intrapolymeric reactions. At high levels of crosslinking (>20% with poly- styrenes) a small proportion of the functional groups particularly in polymers with a few uniformly distributed groups will not be able to react with others. For these ‘permanent site isolation’ will have been achieved. This can be useful with PS catalysts; the classical example is a PS titanocene hydrogenation catalyst.24 Titanocene itself dimerizes and the catalytic activity is lost but with the PS catalyst prepared from a highly crosslinked polymer and relatively lightly loaded a significant proportion of the titanocene sites were permanently isolated from the others with the result that the catalytic activity was higher and a significant amount remained over long periods.When intrapolymeric reactions do take place because the polymer chains reduce the mobility of the functional groups the reactions are usually slower than with their low molecular wieght counter parts. Consequently it is possible to have what might be termed ‘kinetic site isolation’. This has been exploited in selectively binding difunctional substrates to polymers by just one of the two possible groups.25 With 2-l0% crosslinked polystyrenes in swelling solvents reduced mobility results in 1 to 10 minute life-times of PS ester eno1ates,26a benzyneTb and a glycine active ester.26c The second type of situation is similar to the first but is more complicated and less predictable because each reaction leads in effect to a further crosslink.The distribution of these crosslinks and their effect on the swelling properties of the polymers can limit the extent of further reaction. In most cases the crosslink is probably formed between nearby groups on the same section of polymer chain. 5 Selected Examples of PS Catalysts These are the most attractive type of PS reactant because a relatively small amount of polymer can be used chemically to transform a relatively large amount of substrate into product. In principle it should be possible to re-use the recovered catalyst but 23 W.T. Ford Chapter 11 in ref. 7. 24 W. D. Bonds C. H. Brubaker E. S. Chandrasekaran C. Gibbons R. H. Grubbs and L. C. Kroll J. Am. Chem. SOC.,1975,97 2128. 2s C. C. Leznoff Acc. Chem. Res. 1978 11 327. 26 (a) Y. H. Chang and W. T. Ford J. Org. Chem. 1981 46 3756 and 5364; (b) S. Mazur and P. Jayalekshrny J. Am. Chem. Soc. 1979,101,677; (c) J. Rebek and J. E. Trend J. Am. Chem. SOC.,1979 101 737. Polymer-supported Catalysts and Reagents 29 1 unfortunately this aspect has not usually been pursued to any significant extent. A complex PS catalyst that retained significant activity through ten or more reaction cycles would probably justify its synthesis for laboratory applications. It was originally anticipated that PS catalysts would display useful substrate selectivity based on size because the substrates need to diffuse into the polymer to react.However the need to use good swelling solvents with microporous polymers and the highly porous nature of macroporous polymers generally militate against significant size selectivities. PS Acids.-The simplest PS acids are the various commercially available strong acid cation exchange resins containing residues (2) (see Scheme 1).These have long been utilized to catalyse such reactions as esterification ester hydrolysis and acetal and ketal f~rmation.~ A milder catalyst for these reactions2' and for enamine formation28 is the hydrochloride form (16) of poly(viny1pyridine). The activity of the sulphonic acid resins (2) can be increased considerably either by combination with aluminium tri~hloride~~ or by fluorination to give acid (17).30 Commercial products similar to the latter are Nafion resins (18).Olah and his co-workers have shown that these can be used to catalyse esterificati~n,~'~ dehydration^,^'^ hydrations of alkyne~,~'" and many other reac- Friedel-Craft alkylations31d and acylation~,~'~ tions. c1-rn = 1,2,3 ... (16) n = 5 to 13.5 x = ca. 1000 Various PS Lewis acids have been described.32 Aluminium tribromide in a poly- styrene matrix catalyses the alkylation of aromatic compounds in good yields and is reported to be superior to the original aluminium trichloride analogue.33 Even more effective are polystyrene resins which have been reacted with PCl3/A1Cl3 or PBr,/A1Br3 .33,34 PS Bases.-The simplest are the hydroxide forms of anion exchange resins (11) (see Scheme 3).These have been used to catalyse ester hydrolyses condensations 27 J. Yoshida J. Hashimoto and N. Kawabata Bull. Chem. SOC.Jpn. 1981 54 309. 28 Reilly Tar and Chemical Co. Indianapolis Indiana. Product Bulletih R-8050. 29 V. C. Magnotta and B. C. Gates J. CufuL 1977 46 266. 30 J. Klein. F. Doscher and H. Widdecke. Roc. Svmn Mucromol. Strussbourg 1981 403. 31 (a)G. A. Olah T. Keumi and D. Meidar Synthesis 1978 929; (b) G. A. Olah A. P. Fund and R. Malhotra Synthesis 1981 474; (c) G. A. Olah and D. Meidar Synthesis 1978 671; (d) G. A. Olah D. Meidar R. Malhotra J. A. Olah and S. C. Narang J. CutuL 1980 61 96; (e) G.A. Olah R. Halhotra S. C. Narang and J. A. Olah Synthesis 1978 672. 32 E. C. Blossey L. M. Turner and D. C. Neckers J. Org. Chem. 1975 40 959. 33 J. Schliiter and H. Widdecke paper presented at EUCHEM Conference at Cirencester September 1984. 34 H. Widdecke J. Klein and K. Struss Erdol U. Kohle Compendium 1982/83 199. 292 P. Hodge Michael reactions,35 and numerous other reaction^.^ The polymers shown in formula (19) also serve as catalysts for Michael reaction^.^^ Chiral anion-exchange resins have been prepared by quaternizing the cinchona alkaloids (20)-(23),36*37 N-meth~lephredrine,~~ or amino acid derivatives3* with chloromethylated polystyrenes (l) and various anionic forms of these have been used as catalysts for Michael reactions.CH=CH2 0-x QH I+ CH2NMe2 I ,CHOH CH2CH2OH I X-= C1- F- OH-HC0,-(19) Conjguration at Alkaloid C-8 C-9 X (20) Cinchonidine S R H (21) Cinchonine R S H (22) Quinine S R OMe (23) Quinidine R S OMe Polyvinylpyridine (24) which is commercially available catalyses acylation~.~~ PS 4-dimethylaminopyridine (2q40p41 and several related polymers incorporating spacer groups for example polymer (25),42have been prepared and successfully e~terification,~~"'~~ used as catalysts for acylation~,~~~ transesterification:' enol acetate formation:' O-alkylation;' and O-~ilylation.~' I I Me (24) n = 1 (25) n = 7 35 E. D. Bergmann and R. Corrett 1. Org. Chem. 1958,23 1507. 36 P. Hodge E. Khoshdel and J. Waterhouse J.Chem. SOC.,Perkin Trans. 1 1983 2205. 37 N. Kobayashi and K. Iwai Makromol. Chem. Rapid Cornmun. 1981 2 105. 38 S. Banfi M. Cinquini and S. Colonna Bull. Chem. SOC.Jpn. 1981 54 1841. 39 F. LeGoffic S. Sicsic and C. Vincent Tetrahedron Lett. 1976 17 2845. 4o M. Tomoi Y. Akada H. Kakiuchi Makromol. Chem. Rapid Commun. 1982 3 537. 41 F. M. Menger and D. J. McCann J. Org. Chem. 1985 50 3928. 42 (al M Tornoi. M Goto and H. Kakiuchi Makromol. Chem. Rapid Commun. 1985 6 397; (b) F. Guendouz R. Jacquier and J. Verducci Tetrahedron Lett. 1984 25 4521. 43 S. Shinkai H. Tsuji Y. Ham and 0. Manabe Bull. Chem. SOC.Jpn. 1981 54 631. Polymer-supported Catalysts and Reagents 293 Various PS chiral amine catalysts have been prepared from the cinchona alkaloids (20)-(23)44 and from other chiral ami11es.4~ Catalysts derived via acylation of the 9-hydroxyl group of these alkaloids generally give very poor asymmetric induc- tion,44eJ but polymer (26) catalysed the addition of methanol to phenylketene to give the S-isomer of ester (27)in an enantiomeric excess of 32%.44f Better asymmetric induction is obtained if the P-hydroxy amine unit is retained and this has prompted the utilization of the vinyl group for the preparation of PS Thus Kobayashi copolymerized the alkaloids with acrylonitrile and used the copolymer products (28) as catalysts for Michael additions.44a-b A copolymer prepared from quinidine (23) gave an enantiomeric excess of 42% of the R-isomer in Scheme 5 whilst a similar Copolymer prepared from quinine (22) gave an enantiomeric excess of 30% of the S-enantiomer.44b Optical yields of up to 57% were obtained in additions of thiols to en one^.^^ Ph-EH-CO,Me I Me &"\ 4c\ 0-Cinchonine NH 0 (27) I &O-Cinchonine o-+ /NH 0 CN alkaloid CH2=CH mH2CH2COMe \c=o -C02Me m C 00 2 M e + Me/ 0 Scheme 5 Other catalysts have been prepared by the addition of PS thiols (29) to the vinyl groups of cinchona alkaloids.44' In Michael additions these catalysts (30) gave lower optical yields than the corresponding free alkaloids.However low molecular weight 44 (a) N. Kobayashi Br. Polym. J. 1984,16,205; (b)N. Kobayashi and K. Iwai J. Am. Chem. Soc. 1978 100 7071; (c) P. Hodge E. Khoshdel J. Waterhouse and J. M. J.Frtchet J. Chem. Soc. Perkin Trans. 1 1985 2327; (d)P. Hodge E. Khoshdel and P. Stratford unpublished results; (e) K. Hermann and H. Wynberg Helu. Chim. Acra 1977 60,2208; (f)T. Yamashita H. Yasueda N. Nakatani and N. Nakamura Bull. Chem. Soc. Jpn. 1978 51 1183 and 1247. 45 (a) K. Kondo T. Yamano and K. Takemoto Makromol. Chem. 1985 186 1781; (b) T. Yamashita E. Kagigaki N. Takahashi and N. Nakamura Makromol. Chem. 1983 184 675. 46 N. Kobayashi and K. Iwai Macromolecules 1980 13 31. 294 P. Hodge catalysts prepared by the addition of simple aliphatic thiols to the vinyl groups of the alkaloids gave essentially the same optical yields as the PS catalysts.4c This indicates that the polymer itself did not have an adverse effect on the optical yields and that to make meaningful studies of 'polymer effects' carefully chosen model compounds must be used.Catalysts (31) prepared by the addition of polymethylhy- drosiloxane to the vinyl groups of the alkaloids gave enantiomeric excesses in Michael additions for example Scheme 5 essentially the same as those obtained with the free alkaloids.44d Various PS L-prolines have been used as catalysts for Robinson cy~lizations.~~" Me I -+Si-O j;-I CH2CH2Q (30) Where QCH=CH represents (20)-(23) PS Oxidation Catalysts.-It has been known for a long time that various oxometal ions containing tungsten molybdenum or vanadium when bound to anion exchange resins (1 1) or other polymers serve as PS catalysts for the epoxidation of olefins by hydrogen peroxide or alkyl hydro peroxide^.^^ More recently the PS arsonic acid and PS tellurinic acid (32)49 have been shown to catalyse epoxidations.The latter is particularly interesting as low molecular weight analogues appear to have no catalytic activity and the activity of the PS catalysts depends greatly on the polymer structure and increases with increased crosslinking. The PS seleninic acid (33)" also catalyses epoxidation but the epoxides are usually hydrolysed to truns-diols. Certain PS porphyrin-manganese( 111) complexes catalyse epo~idations.'~ TeOzH Se02H The PS arsonic acid ( and PS seleninic acid (33)" catalyse Baeyer-Villiger reactions. The latter also catalyses the t-butyl hydroperoxide oxidation of activated 47 See for example G. G. Allan and A.N. Neogi J. Catal. 1970 19 256; T. Yokoyama M. Nishizawa T. Kimura and T. M. Suzuki Bull. Chem. SOC.Jpn. 1985,58 3271; K. Zhang G. S. Kumar and D. C. Neckers J. Polym. Sci. Polym. Chem. Ed. 1985 23 1213. 48 S. E. Jacobson F. Mares P. M. Zarnbri J. Am. Chem. SOC.,1979 101 6946. 49 W. F. Brill J. Org. Chem. 1986 51 1149. 50 R. T. Taylor and L. A. Flood J. Org. Chem. 1983 48 5160. 5' A. W. van der Made J. W. H. Srneets R. J. M. Nolte and W. Drenth J. Chem. Soc. Chem. Comrnun. 1983 1204. 52 S. E. Jacobson F. Mares and P. M. Zambri J. Am. Chem. SOC., 1979 101 6938. Polymer-supported Catalysts and Reagents 295 alcohols to aldehydes and ketones.50 Certain PS porphyrin-cobalt(111) complexes53 and phthalocyanine-Co” complexes54 catalyse the aerial oxidation of thiols.Kawabata et al. have reported several novel oxidizing reagents which can be electrically recycled in situ and are therefore catalysts.’’ Thus the bromide form of a particular ion exchange resin (1 1) was used to catalyse electrochemical epoxida- ti on^,^^^ a polyvinylpyridinium hydrobromide was used to catalyse the oxidation of primary and secondary alcohol^,^' and a mixture of polyvinylpyridinium hydro- bromide and hydrosulphate catalysed the electrochemical oxidation of aromatic alkyl side ha ins.''^ PSPhase-transfer Catalysts.-Reactions using PS phase-transfer catalysts have been studied extensively and the s~ope~~,’~ and mechanisms7 of the reactions have been reviewed. The reactions proceed in three-phase mixtures consisting of aqueous salt solution organic solution and insoluble polymer and the method has been called triphase catalysis.For displacement reactions such as the reactions of alkyl halides with -CN or -0COMe in liquid-liquid systems as expected PS quaternary ammonium and PS quaternary phosphonium salts are generally more active catalysts than PS crown ethers and PS (polyethylene glyco1)s. The use of ‘spacer arms’ between the active site and the polymer backbone often increases a~tivity.~’ Hence polymers such as (34) are the best types for displacement reaction^.^' Since in PS phase-transfer catalysis both the organic substrate and the reactive anion need to diffuse into the polymer beads to react the hydrophobic-hydrophilic balance of the catalyst is very important.For polystyrenes carrying quaternary ‘onium sites loadings of 10-20% of the phenyl residues are often ~ptimal.’~ Alkylations of active nitriles and ketones with aqueous NaOH or KOH as base proceed readily with commercial anion- exchange resins (1 1);’ PS(polyethy1ene glycol)s,61 or PS crown ethers6’,62 as catalysts. PS(polyethy1ene glyco1)s (12; R = polyethylene glycol) are also active catalysts for dehydrohalogenations by aqueous base.63 Other catalysts investigated are PS sulph~xides~~ and PS crypt and^.^^ Attempts to achieve asymmetric syntheses using PS chiral phase-transfer catalysts have generally been unsuccessful.66 Surprisingly since two solid-phases are involved examples are known of the catalysis of solid-liquid reactions by insoluble PS phase-transfer catalysts.’ 53 L.D. Rollman J. Am. Chem. Soc. 1975 97 2132. 54 W. M. Brouwer P. A M. Traa T. J. W. de Weerd P. Piet and A. L. German Angew. Makromol. Chem. 1984 128 133. 55 (a) J. Yoshida J. Hashimoto and N. Kawabata J. Org. Chem. 1982 47 3575; (b) J. Yoshida R. Nakai and N. Kawabata J. Org. Chem. 1980,45 5269; (c) J. Yoshida K. Ogura and N. Kawabata J. Org. Chem. 1984 49 3419. 56 S. L. Regan Angew. Chem. Inr. Ed. Engl. 1979 18 421. 57 W. T. Ford and M. Tomoi Ado. Polym. Sci. 1984 55 49. 51 See for example M. Tomoi S. Shiiki and H. Kakiuchi Mocrornol. Chem. 1986,187,357; and M. Tomoi E. Ogawa Y. Hosokama and H. Kakiuchi J. Polym. Sci.,Polym. Chem. Ed. 1982 20 3421. 59 Ref. 57 pp. 67-68.60 T. Balakrishnan and W. T. Ford J. Org. Chem. 1983 48 1029 and Tetrahedron Lett. 1981 22 4377. 61 Y. Kimura P. Kirszensztejn and S. L. Regen J. Org. Chem. 1983 48 385. 62 F. Montanari and P. Tundo J. Org. Chem. 1982,47 1298. 63 Y. Kimura and S. L. Regen J. Org. Chem. 1983,48 195. 64 (a) V. Janout H. Hrudkova and P. Cefelin Collect. Czech. Chem. Commun. 1984 49 2096; (b) S. Kondo K. Ohta and K. Tsuda Makromol. Chem. Rapid Commun. 1983 4 145. 65 F. Montanari and P. Tundo Tetrahedron Lett. 1979 20 5055. 66 J. Kelly and D. C. Sherrington P-lymer 1984 25 1499 and references cited therein. 296 P.Hodge I I n = lor7 (35) R = Me (34) (36) R = H II n = 1,2,3 ... R = H or Me Closely related to PS phase-transfer catalysis is the use of PS solvents and co-s~lvents.~~ Thus polymers (35),67 (36),67 (37),68 and (38)640catalyse displacement reactions under triphase conditions.Polymers (35)69and (37)6*have also been shown to be active under biphase conditions. Other PS Catalysts.-The cyanide forms of polymer (1 1) and other anion-exchange resins catalyse the conversion of aromatic aldehydes into ben~oins.~' Chiral anion- exchange resins result in asymmetric synthesis in some case^.^'" When dimethyl sulphoxide is the solvent 2-and 4-methoxybenzaldehydes give the corresponding benzils PS thiazolium salts of the type (39) in combination with a base such as triethylamine have a wider range of application than PS cyanide. Thus as Q R Ph-As=O I R = Me or -CH2CH,0H Ph (39) (40) 67 S.L. Regen and A. Nigam J. Am. Chem. Soc. 1978 100 7773; S. L. Regen A. Nigam and J. J. Besse Tetrahedron Lett. 1978,19,2757; M. Tomoi,M. Ikeda and H. Kakiuchi Tetrahedron Lett. 1978,19,3757. 68 V. Janout and P. Cefelin Tetrahedron Lett. 1986 27 3525. 69 G. Nee and J. Seyden-Penne Tetrahedron 1982 38 3485. 70 (a) J. Castells and E. Dunach. Chem. Lett.. 1984 11 1859; (b) S. Xie. J. Tu. F. Ji. J. Zhang and W. Huang Zhongshan Duxue Xuebo Zirun Kexuebun 1984 11. [Chem. Abs. 102 13129721. Polymer-supported Catalysts and Reagents 297 R' I RCHO + RCH=CHCOMe --* RCOCHCH,COMe Scheme 6 well as catalysing the formation of benzoins they catalyse the formation of acyloins and the additions of aldehydes to enones (Scheme 6).71 PS-triphenylarsine oxide (40) catalyses the conversion of isocyanates into carb~diimides.~~ Many PS photosensitizers have been in~estigated.~~ The best and most intensively studied example is Rose Bengal covalently bound to crosslinked chloromethylated polystyrene (l).73" When used in non-polar solvents in the presence of oxygen it is an excellent source of singlet oxygen.The topic has been reviewed recently.73b 6 Selected Examples of PS Reagents For the purposes of this report PS reagents are considered to be functional polymers used in one-step processes in at least stoicheiometric amounts to transform low molecular weight substrates into products. Because they need to be used in st'oicheiometric amounts to be useful they generally need to have capacities that is millimoles of reactive functional groups per gram as high as is practicable.They will usually be more expensive than analogous low molecular weight reagents and ideally the spent reagent should be capable of recycling. Unfortunately this aspect has rarely been pursued to any significant extent. PS Reagents where the Reactive Groups are Ionically Bound.-The most readily available PS reagents are the various anionic forms of strong base anion-exchange resins (1 1). The commercial chloride forms can be converted into the desired anionic forms either by direct anion exchange or in the case of anions such as fluoride for which the resins generally have a low affinity by conversion of the chloride form into the hydroxide or bicarbonate form followed by neutralization of this with the appropriate acid.The various anionic forms are in effect PS lipophilic quaternary ammonium salts and if the resin is of the macroporous type the anions often react successfully in solvents such as hexane ether or dichloromethane. These PS reagents are therefore an alternative to phase-transfer catalysis. The reagents may show some substrate selectivity based on the size and/or polarity of the They also have the potential to be regioselective. PS oxidizing agents derived from polymer (1 1) include the HCr04- form which oxidizes primary and secondary alcohols to aldehydes or ketones,75 and the 10 71 S. Shinkai Y. Hara and D. Manabe J. Polym. Sci. Polym. Chem. 1982 20 1097; C. S. Sell and L. A. Dorman J.Chem. SOC. Chem. Commun. 1982 629; K. Karimian F. Mohanazedeh and S. Rezai J. Heterocycl. Chem. 1983 20 1119; T.-L. Ho and S.-H. Liu Synth. Commun. 1983 13 1125; B.-H. Chang and Y. L. Chang J. Chin. Chem. SOC.,1983 30,55. 72 C. P. Smith and G. H. Temme J. Org. Chem. 1983,48 4681. 73 (a) See J. Paczkowski and D. C. Neckers Macromolecules 1985 18 1245; (b) D. C. Neckers Chapter 6 in ref. 7. 74 G. Cainelli M. Contento F. Manescalchi and L. Plessi J. Chem. SOC.,Chem. Comrnun. 1982 725. 75 G. Cardillo M. Orena and S. Sandri Terrahedron Lett. 1976 17 3985; G. Cainelli G. Cardillo M. Orena and S. Sandri J. Am. Chem. Soc. 1976 98 6737. 298 P. Hodge form which can be used to cleave 1,2-diols or oxidize ~ulphides.~~ The BH form reduces aldehydes and ketones to and the Fe(CO) form reduces acid chlorides to aldehydes.78 PS nucleophiles studied include F-,79%80a -Br-,80a I-,80a HCO 292o RC0;,20,80b C032-,80c Ar0-,80d SCN-,80e RS-,80f ArS-,80f RCOS-,80g CN-,80e and -CH(CO,Me)PO(OEt) .81 In most cases these have been reacted with alkyl halides or mesylates or acid chlorides in displacement reactions but the F-form has also been used to remove silyl protecting groupss2 and the phosphonate has been used in Horner-Wittig reactions.81 The Br3- and IC12- forms have been used to brominate or chlorinate olefins and ketones.83 Crosslinked polyvinylpyridine is commercially available and various salts ( 16) similar to those above have been prepared and studied.The chlorochromate form has been used to oxidize primary and secondary alcohols to aldehydes and ketones but a substantial excess of reagent is required.84 The Cr20:- form of a synthetic crosslinked polyvinylpyridine proved to be a better reagent than that prepared from the commercial resins.85 PS pyridinium hydrobromide perbromide brominates olefins and ketones.86 One interesting feature of PS reagents which has yet to be fully exploited is that if two separate reagents prepared from crosslinked polymers are mixed together the reactive groups do not come into contact (apart from the negligible amounts at the surface of the beads).Hence reagents which are mutually antagonistic can be used in combination in the same reaction vessel. Thus the conversion shown in equation 1 can be achieved using PS 104-in combination with PS BH4-,87 and that shown in equation 2 by polymer (2) in combination with PS cyanomethylphosphonate.81 I1 II II -C-C-+ -C C-+ -CH CH-II I1 II II OHOH 0 0.OH OH RCH:) + RCHO + RCH=CHCN 0 76 C. R. Harrison and P. Hodge J. Chem. Soc. Perkin Trans. I 1982 509. 77 A. R. Sande M. H. Jagadale R. B. Mane and M. M. Salunke Tetrahedron Lett. 1984 25 3501. 78 G. Cainelli F. Manescalchi and A. U. Ronchi J. Org. Met. Chem. 1984 276 205. 79 C. L. Borders D. L. MacDonell and J. L. Chambers J. Org. Chem. 1972 35,3549; S. Colonna A. Re G. Gelbard and E. Cesarotti J. Chem. Soc. Perkin Trans. I 1979 2248. 80 (a)G. Cainelli and F. Maneschalchi Synthesis 1976,472; (6)G. Cainelli and F. Maneschalchi Synthesis 1975,723; (c) G.Cardillo M. Orena G. Porzi and S. Sandri Synthesis 1981,793; G. Cardillo M. Orena and S. Sandin J. Org. Chem. 1986 51,713; (d) G. Gelbard and S. Colonna Synthesis 1977 113; T. Iverson and R. Johansson Synthesis 1979,823; (e) C. R. Harrison and P. Hodge Synthesis 1980 299; (f)G. Cainelli M. Contento F. Manescalchi and L. Plessi Gazz. Chim. Ital. 1982 112 461; (g) G. Cainelli M. Contento F. Manescalchi and M. S. Mussatto Synthesis 1981 302; G. Cainelli M. Contento F. Manescalchi L. Plessi and M.Panunzio Gazz. Chim. Ital. 1983 113,528. 81 G. Cainelli M. Contento F. Manescalchi and R. Regnoli J. Chem. Soc. Perkin Trans. I 1980 2516. 82 G. Cardillo M. Orena S. Sandri and C. Tomasini Chem. Ind. 1983 643. 83 (a) A. Bongini G. Cainelli M.Contento and F. Manescalchi Synthesis 1980 143; (b) A. Bongini G. Cainelli M. Contento and F. Manescalchi J. Chem. SOC.,Chem. Commun. 1980 1278. 84 J. M. J. FrCchet J. Warock and M. J. Farrall J. Org. Chem. 1978 43,2618. 85 J. M. J. Frichet P. Darling and M. J. Farrall J. Org. Chem. 1981 46 1728; T. Brunelet G. Gelbard and A. Guyot Polym. Bull. 1981 5 145. 86 J. M. J. FrCchet M. J. Farrall and L. J. Nuyens J. Macromol. Sci. Chem. 1977 A-11,507. 87 M. Bessodes and K. Antonakis Tetrahedron Lett. 1985 26 1305. Polymer-supported Catalysts and Reagents 299 PS Reagents where the Reactive Groups are Covalently Bound.-Polymer-supported reagents where the reactive groups are covalently bound are less readily available than those where the reactive groups are anions but a greater variety of reactions can be carried out.PS Oxidizing Agents. Reagents used to oxidize alcohols include PS thioanisole and chlorine,88a N-chl0ronylon-66,~~~ and a PS carbodiimide in combination with dimethyl sulphoxide.g8' Primary halides and tosylates have been oxidized to aldehydes by a PS amine oxideg9 and benzyl chloride has been oxidized to benz-aldehyde by a PS ~ulphoxide.~' PS aromatic peroxy acids prepared from polymer (5) have been used successfully to oxidize di- and tri-substituted olefin to epoxides but monosubstituted olefins only reacted ~luggishly.~' Sharpless oxidation of geraniol using a PS tartrate gave the 2S,3S-epoxide with up to 66% enantiomeric excess.92 PS aromatic peroxy acids oxidize sulphides including penicillin and cephalosporins to sulphoxides and s~lphones.~~ Several PS selenium-containing oxidants have been prepared.94 Unlike their low molecular weight analogues they are odourless and non-toxic.The selenium-containing polymers are easily recovered. PS Reducing Agents. Many PS reducing agents convert aldehydes and ketones into alcohols. The simplest are the complexes of borane with PS aminesg5 and with PS dimethyl~ulphide.~~ Prochiral ketones have been reduced by the complexes formed from PS chiral amino alcohols and diborane and in favourable cases optical yields of up to 80% have been ~btained.~' Reagents of this general type can reduce aldehydes in the presence of ketones.98 The activity of lithium aluminium hydride has been modified by PS chiral amino alcoh01s,~~~ a PS chiral dihydr~xybiphenyl,~~~ and a PS chiral bornane di01.'~' The latter gave the best results with acetophenone being reduced to 1-phenylethanol in up to 61% enantiomeric excess.The PS tin hydride (8) not only reduces aldehydes and ketones to alcohols but also reduces bromides and iodides to hydrocarbons."' Finally in this section aromatic disul- phides are reduced to thiophenols by treatment with PS phosphine (7) in aqueous tetrahydrofuran containing a catalytic amount of hydrochloric acid."' nn (a) G. A. Crosby and M. Kato J. Am. Chem. SOC. 1977,99 278; (b) H. Schuttenberg G. Klump,.U. Kaczmar S. R. Turner and R. C. Schulz J. Macromol. Sci. Chem. 1973 A7,1085; (c) N. M. Weinshenker and C.-M.Shen Tetrahedron Lett. 1972 13 3285. 89 J. M. FrCchet M. J. Farrall and G. Darling Reactive Polymers 1982 1 27. 90 J. A. Davies and A. Good Makromol. Chem. Rapid Commun. 1983 4 777. 91 C. R. Harrison and P. Hodge J. Chem. SOC.,Perkin Trans. 1 1976 605; J. M. J. FrCchet and K. E. Haque. Macromoleculev. 197C. U. 170. 92 M. J. Farrall M. Alexis and M. Trecarten Nouu. J. Chim. 1983 7 449. 93 C. R. Harrison and P. Hodge J. Chem. SOC. Perkin Trans. 1 1976 2252. 94 R. Michels M. Kato and W. Heitz Makromol. Chem. 1976 177 2311; N. Hu Y. Aso T. Otsubo and F. Ogura Chem. Lett. 1985 603. 95 F. M. Menger H. Sinozaki and L. C. Lee J. Org. Chem. 1980 45 2724; T. Yamashita H. Mitsui H. Watanabe and N. Nakamura Makromol. Chem. 1980 181 2563.96 G. A. Crosby U.S. Pat. 3 928 293 (Chem. Abstr. 1976 84 106499~). 91 S. Itsuno K. Ito A. Hirao and S. Nakahama J. Chem. Soc. Perkin Trans. 1 1984 2887. 9R S. Itsuno T. Wakasugi K. Ito. A. Hirao and S. Nakahama Bd/.Chem. SOC., Jpn. 1985 58 1669. 99 (a) P. Lecavalier E. Bald Y. Jiang J. M. J. Frechet and P. Hodge Reactive Polymers 1985 3 315; (b) H. Suda S. Kanoh N. Umeda M. Ikka and M. Motoi Chem. Lett. 1984 899; (c) J. S. Lui K. Kondo and K. Takemoto Makromol. Chem. 1983 184 1547. 100 N. M. Weinshenker G. A. Crosby and J. Y. Wong 1. Org. Chem. 1975,40 1966. 101 R. A. Amos and S. M. Fawcett J. Org. Chem. 1984 49 2637. 300 P. Hodge (41) n = 1 (42) n = 4 (43) n = 7 Other PS Reagents.PS alkoxides'02 and PS( 1,8-diazabicyclo[ 5,4,0]~ndec-7-ene),'~~ PS DBU (41) have both been used to carry out elimination reactions. Other bases investigated are in effect PS-butyl lithium,'04" PS-phenyl lithium,'04b and PS-trityl lithium.'04c All of these have been used for hydrogen-lithium exchange and some for halide-lithium exchange. Salts formed from the PSDBUs (41) to (43) arid carboxylic acids react with alkyl halides to give This procedure has been extended to the cyclization of a-bromo acids to 1a~tones.l~~ PS Wittig reactions were some of the first PS organic reactions to be studied and many examples have been reported the attraction being the easy separation of the PS phosphine oxide (which can be regenerated) from the olefinic prod~ct~.'~~~'~~ The Wittig reactions are generally carried out by reacting lightly crosslinked PS phosphines (7) with alkyl halides.A wide variety of bases have been used to generate the PS ylides from the phosphonium salts. In the case of salts prepared from allylic or benzylic halides aqueous sodium hydroxide or solid potassium carbonate have been used as the base under phase-transfer conditions.'08 In the relatively few cases studied lightly crosslinked polymer supports give E-and 2-olefins in similar proportions to the corresponding low molecular weight Wittig reactions. Interest- ingly however highly crosslinked supports show a marked tendency to give more of the E-alkene.lo7 When unstabilized ylides are generated using organolithium bases the presence of the lithium halide produced depresses the proportion of 2-olefin obtained.In PS reactions the lithium halide is easily washed away from the PS ylide before the carbonyl compound is added."' Dichloro- and dibromo-methylene phosphorus ylides prepared from PS phos- phine (7) and carbon tetrahalides have been used to prepare 1,l-dichloro- and 102 I. Artaud and P. Viout Polym. Commun. 1986 27 26; I. Artaud and P. Viout J. Chem. Soc. Perkin Trans. 1 1985 1257. 103 M. Tomoi Y. Kato and H. Kakiuchi Mukromol. Chem. 1984 185 2117. 104 (a) M. L. Hallensleben Angew. Mukrornol. Chem. 1973 31 147; (b) D. Braun and E. Seelig Chem. Ber. 1964,97,3098; (c) B. J. Cohen M. A. Kraus and A. Patchornik J. Am. Chem. SOC.,1977,99,4165. 105 M. Tomoi T. Watanabe T.Suzuki and H. Kakiuchi Mukromol. Chem. 1985 186 2473. 106 This topic has been reviewed. P. Hodge Chapter 2 in ref. 2; W. T. Ford Chapter 8 in ref. 7. 107 See for example M. Bernard and W. T. Ford J. Org. Chem. 1983 48 326; M. Bernard W. T. Ford and E. C. Nelson J. Org. Chem. 1983 48 3164. 108 S. D. Clarke C. R. Harrison and P. Hodge Tetrahedron Lett. 1980 21 1375. 109 W. Heitz and R. Michels Liebigs Ann. Chem. 1973 227. Polymer-supported Catalysts and Reagents -dibromo-olefins.' lo Wittig-type reactions using PS triphenylarsine have recently been reported." ' PS sulphur ylides prepared under phase-transfer conditions from sulphonium salts (44) react with aldehydes and ketones to give high yields of epoxides."2 The PS phosphine (7) has found numerous other app1i~ations.l'~ In combination with carbon tetrachloride it has been used to convert alcohols or thiols into alkyl chlorides,21 carboxylic acids into acid chlorides,2' mixtures of acids and amines into amides," primary amides into nitriles,' l4 and secondary amides into imino- chlorides.' l4 In combination with bromine or(better) carbon tetrabromide alcohols are converted into alkyl bromides.' '' In combination with diethyl azodicarboxylate esters can be prepared from acids and alcohols."6 Finally with diethyl peroxide diols can be cyclodehydrated to give epoxides tetrahydrofurans or tetrahy-dropyrans.' l7 s+ OH QN/N-N R' 'R (45) HO SCH2Li HgOCOCFs An alternative to Merrifield's solid-phase peptide synthesis has the growing peptide chain in solution and uses PS acylating agents.l18 Many such reagents have been described the most useful of which are esters of PS o-nitrophenols e.g.(4) and (45),119" and PS hydroxybenztriazole (46)."9b I LO P. Hodge and E. Khoshdel Reactive Polymers 1985 3 143. 111 W. Tao and X. Hu Huaxue Shiji 1984 6,207 Chem. Abs. 1984 101 192101g. 112 M. J. Farrall T. Durst and J. M. J. Frichet Tetrahedron Lett. 1979 20 203. 113 A review P. Hodge B. J. Hunt E. Khoshdel and J. Waterhouse Nouu. J. Chem. 1982 6 617. 114 C. R. Harrison P. Hodge and W. J. Rogers Synthesis 1977 41. 115 P. Hodge and E. Khoshdel J. Chem SOC.,Perkin Trans. I 1984 195. 116 R. A. Amos R. W. Emblidge and N. Havens J. Org. Chem. 1983,48 3598. 117 J.W. Kelly P. L. Robinson and S. A. Evans J. Org. Chem. 1985 50 5007. 118 For leading references see A. Patchornik E. Nov K. A. Jacobson and Y. Shai Chapter 10 in ref. 7; Y. Shai K. A. Jacobson and A. Patchornik J. Am. Chem. SOC.,1985 107 4249. 'I9 (a) M. Fridkin A. Patchornik and E. Katchalski J. Am. Chem. Soc. 1966 88 3164; (b) R. Kalir A. Warshawsky M. Fridkin and A. Patchornik Eur. J. Biochem. 1975 59 55. 302 P. Hodge Finally homologation of alkyl iodides can be achieved by treatment with PS phenylthiomethyl lithium (47) prepared from polymer (9) then with NaI/ Me1 in N,N-dimethylformamide.88" PS carbodiimides88c~'20 and PS ynamines have been used to prepare acid anhydrides and peptide bonds.'21 PS phenylmercury tri- fluoroacetate (48) cleaves dithio-acetals and -ketals smoothly.'22 The potassium salt of PS thiol (29) efficiently regenerates olefins from 1,2-dibromide~.'~~ 7 Conclusions Many PS catalysts and PS reagents have been investigated.Those referred to in this Report are simply examples. Much is now known about the preparation of reactive crosslinked polymers the selection of reaction conditions for their use and the way in which the PS reactions differ from their low molecular weight analogues. However much remains to be done to establish the extent to which the polymers can be recycled. Thus even modest physical losses and chemical side-reactions which would not otherwise be important can after perhaps only 10 reaction cycles significantly reduce the capacity and usefulness of the polymers.In many cases so far the polymer may have simply served as a 'handle' on the reactive species but with a better understanding of reactive macromolecules more sophisticated PS systems may be prepared in which the polymer enhances the reactivity and selectivity of the bound groups. Such polymers are likely to have controlled microenvironments with specific hydrophobic and/or hydrophilic regions and ordered regions resulting from particular conformations of the polymer or the presence of mesogenic groups into which one or more types of reactive groups are carefully located. 120 Y. Wohlman S. Kivity and M. Frankel J. Chem. SOC.,Chem. Comrnun. 1967 629. 12' J. A. Moore and J. J. Kennedy J. Chern. SOC.,Chem. Cornmun. 1978 1079. 122 V.Janout and S. L. Regen J. Org. Chem. 1982 47 2212. 123 V. Janout and P. Cefelin Tetrahedron Left. 1983 24 3913.