摘要:

Abstract. The review systematises and summarises the oxidative methods for the synthesis of compounds with vicinal carbonyl functions. The oxidative reagents used for this purpose, their scope and limitations are discussed. The bibliography includes 307 references. I. Introduction Alicyclic and cyclic 1,2-dicarbonyl and vicinal polycarbonyl compounds have been known for over 150 years. The properties of many of them have been well studied, and some have found practical use as biologically active compounds, intermediates in the synthesis of various heterocyclic compounds, analytical reagents, photopolymerisation initiators etc.Bis-1,2-diketones find use as monomers for the preparation of thermostable poly- phenylquinoxalines. Some representatives of this class (e.g., `oxocarbons' and `pseudooxocarbons') are rather exotic compounds but present considerable interest for theoretical organic chemistry.1 ±3 To date, vicinal polycarbonyl compounds with five carbonyls have been obtained.Activity in this field of research does not cease. Methods for the synthesis of 1,2-, bis-1,2- and polycarbonyl compounds1, 4 and cyclic oxocarbons and pseudooxocarbons2 have been reviewed.The present review systematises and summarises the literature data on the oxidative methods for the synthesis of di- and polycarbonyl compounds with preservation of the carbon skel- eton of the starting substrates. The existing methods for the synthesis of these compounds are divided into the following main groups: (1) introduction of a carbonyl group at the a-posi- tion with respect to the existing one in aldehydes, ketones, carboxylic acids and their a-substituted (hydroxy-, halogeno-, etc.) derivatives; (2) oxidative transformations of epoxides and vicinal compounds containing the CHX-CHY moiety; (3) oxida- tion of the alkyl groups and compounds with multiple bonds.The reagents used for oxidation are described for each of the above substrate types. Generally, we refer to studies not included in the reviews mentioned above.1, 2, 4 However, in some instances we mention them in order to give a full picture of the existing reagents and the most reliable methods.One should bear in mind that vicinal di- and polycarbonyl compounds tend to undergo hydration, and their mono- or dihydrates, i.e., gem-diols, are commonly obtained as the final products.It is also typical of vicinal di- and polycarbonyl com- pounds to exist as various types of enols; the ratio of the carbonyl and enol forms has not been always determined with certainty. II. Oxidation of carbonyl compounds and their derivatives Syntheses of vicinal di- and polycarbonyl compounds are most commonly based on substrates already containing at least one carbonyl group. 1.Oxidation of the a-methyl and a-methylene groups of aldehydes, ketones and carboxylic acids The reagents known for the preparative oxidation of the a-methyl and a-methylene groups of aldehydes and ketones are listed in Table 1. Nitrogen oxides and aromatic nitrosamines were the first reagents used for the oxidation of ketones (more seldom, alde- hydes).They had been used rather widely in the synthesis of 1,2- dicarbonyl compounds before such reagents as selenium dioxide and DMSO appeared.1, 2, 4, 5 Since the turn of the century, treatment of 1,3-diarylpropan-2- ones with `nitrous gas', which is generated from nitric acid and arsenic oxide at 730 8C, has been known to give `isonitroso- dimers'. The latter decomposed on heating to give nitrogen and aromatic vicinal triketone hydrates.6 This reaction was used in the synthesis of diethyl oxomalonate from diethyl malonate andN2O3 (yield 75%).7 It was pointed out that the oxidation of diethyl malonate is more convenient if NO2 is used.1 Later, diaryl triketones were obtained in high yields using an equimolar mixture of NO and NO2.8 In 1901, the oxidising effect of p-nitrosodimethylaniline on the methylene group of certain b-diketones and/or b-oxo esters, which resulted in contiguous tricarbonyl derivatives, was discovered.Examples of such reactions have been presented in reviews.1, 5 Despite the high toxicity of the reagent, the method is sometimes used even now. For example, the following scheme for the preparation of dioxo esters (1a ± c) from esters has been imple- mented.9 V D Filimonov, MS Yusubov Tomsk Polytechnical University, 634004 Tomsk, prosp.Lenina 30, Russian Federation. Fax (7-382) 241 52 35. Tel. (7-382) 241 56 37. E-mail: filim@org.chtd.tpu.edu.ru Ki-Van Chi Ulsan University, 680-749 Ulsan, Republic of Korea. Tel. (10-82522) 44 77 53. E-mail: kwchi@uou.ulsan. ac.kr Received 2 April 1998 Uspekhi Khimii 67 (9) 803 ± 826 (1998); translated by S S Veselyi UDC 547.443+66.094.3 Oxidative methods in the synthesis of vicinal di- and polycarbonyl compounds V D Filimonov, MS Yusubov, Ki-Van Chi Contents I.Introduction 725 II. Oxidation of carbonyl compounds and their derivatives 725 III. Oxidation of 1,2-diols, epoxides and other vicinally substituted compounds 735 IV.Oxidation of alkanes, alkenes, alkynes and their derivatives 738 V. Conclusion 743 Russian Chemical Reviews 67 (9) 725 ± 747 (1998) #1998 Russian Academy of Sciences and Turpion LtdIt was noted that compounds 1a ± c could not be obtained by the photooxidation of the phosphorylides of intermediate b-dike- tones.9 Certain ketones react with pentyl nitrite to give a-nitroso derivatives (oximes); this reaction with an excess of the reagent under mild conditions gives a-diketones.10 This procedure made it possible to synthesise 1-phenylpropane-1,2-dione from propio- phenone and camphorquinone from camphor. Alkyl nitrites react with ketones as sources of the nitrosonium ion (NO+).Ketones are also successfully oxidised with other reagents that generate NO+ in situ, for example, inorganic nitrites in the presence of acids, nitrosyl halides and nitrososulfates.Some of aryl methyl ketones were oxidised with these reagents under mild conditions into arylglyoxals or their acetals.11 Acetals are formed in 50%± 70% yields in the reaction of acetophenones with MeONO in a mixture of MeOH with HCl at 0 ± 5 8C in 4 h. Heating of aryl methyl ketones with NaNO2 in HCl at 60 8C gives the corresponding arylglyoxals directly in yields higher than 60%.11 The oxidative properties of organic nitrosonium salts are similar to those of nitrosodimethylaniline and alkyl nitrites.Their use as oxidants of alcohols, amines and ketones is covered in a review,12 and we shall not dwell on this topic. Such a popular oxidant as potassium permanganate generally cleaves ketones to carboxylic acids or (in basic media) transforms them to oxocarboxylic acids.5 However, KMnO4 immobilised on alumina can selectively oxidise the a-methylene groups of ketones.Oxidation of cyclohexanone in dichloromethane at room temper- ature for 120 h results in cyclohexane-1,2-dione in 58% yield.13 The same reagent oxidises ethyl phenylacetate in 161 h to give ethyl phenylglyoxylate in an almost quantitative yield.However, phenylacetic acid undergoes decarboxylation under these condi- tions to give benzaldehyde.13 Ferrocenyl diketones (2a ± c) were first obtained 14 in 50%± 65% yields upon the oxidation of the corresponding ferrocenyl ketones with MnO2 in boiling dichloromethane. Yet another example of a fundamental change in the proper- ties of an oxidant after its immobilisation on a support was demonstrated for V2O5 adsorbed on montmorillonite or SiO2, which is an efficient catalyst for the oxidation of the methylene group of methyl phenylacetates with tert-butylhydroperoxide to give alkyl arylglyoxylates (3a ± j).15 Choudary et al.15 claimed that they were the first to oxidise the a-methylene group in arylacetic esters to the carbonyl group.However, as early as in 1957 phenylacetic acid was transformed to the acid 3a in 86% yield upon treatment with air in the presence of cobalt benzoate at 110 ± 115 8C.16 Diethyl malonate is oxidised with N2O3 as discussed above. Butan-2-one is oxidised on V2O5 under aerobic and anaerobic conditions at 250 ± 350 8C to butane-2,3-dione.17, 18 Experiments involving 18O2 showed that the resulting diketone did not contain this isotope.Acetic acid and acetaldehyde are the main side products, which are formed mainly due to the decomposition of butanedione. To a smaller extent, these products result from the oxidation of the original ketone in the enol form. Copper acetate has been long used for the synthesis of 1,2- dicarbonyl compounds from a-hydroxy ketones (see Section III).An equimolar mixture of I2 and Cu(OAc)2 oxidises the a-methyl- ene group in cyclohexanone and its derivatives on boiling in aqueous acetic acid for 15 h to give the corresponding cyclo- hexane-1,2-diones (4a ± h) in up to 70% yields.19 R1=R2=R3=H, R4=(a), Me (b), Et (c), cyclo-C6H11 (d), Ph (e); R1=R2=H, R3=R4=Me (f); R1=R4=H, R2=R3=Me (g); R1=R2=R3=Me, R4=H(h).The same procedure made it possible to obtain cholestane-2,3- dione (5) from cholestan-3-one in 40% yield.19 According to IR, 1H and 13C NMRspectral data, compounds 4a ± h and 5 exist in the enol form.19 2. b R=1-allyl-3-indolyl (a), 4-Me2NC6H4 (b), 1-methyl-2-pyrrolyl (c); (a) 4-Me2NC6H4NO, KOH, EtOH; (b) HCl, CH2Cl2.O R OBut O O R OBut O O 1a ± c O OEt R OLi OBut THF 1. a + Fc is ferrocenyl; R=Ph (a), 4-C6H4Ph (b), Fc (c). FcCOCH2R MnO2 CH2Cl2 FcCOCOR 2a ± c RC6H4COCOOMe 3a ± j R=H(a), 2-MeO(b), 4-MeO(c), 4-Me(d), 4-NH2(e), 4-NO2(f), 2-Cl(g), 4-Cl(h), 2-PhCH2(i), 4-PhCH2(j). RC6H4CH2COOMe ButOOH, V2O5, N2 PhH, 70 8C O R4 R3 R2 R1 I2, Cu(OAc)2 AcOH, H2O OH R4 R3 R2 R1 O 4a ± h O C8H17 I2, Cu(OAc)2 AcOH, H2O HO C8H17 O 5 Table 1.Reagents used for the oxidation of carbonyl compounds and their derivatives into vicinal di- and polycarbonyl compounds. Substrate Reagent Product RCOMe AlkONO, NaNO2±H+, HalNO, HSO4NO, NH4CrO3Cl, nitrosonium salts, RCOCHO SeO2, H2SeO3, PhSeSePh ± (NH)4S2O8 ± MeOH, HBr ±DMSO RCOCH2R and cyclic ketones KMnO4±Al2O3, NH4CrO3Cl, O2±V2O5 or V2O5, nitrosonium salts, SeO2, RCOCOR H2SeO3, HBr ± DMSO, NBS±DMSO b-Diketones NO±NO2, 4-Me2NC6H4NO, 1O2 ± hn±Bu4NF, PhIO, SeO2, H2SeO3, HBr ±DMSO, Vic.triketones NBS±DMSO b-Oxo esters NO±NO2, 4-Me2NC6H4NO, KMnO4±Al2O3, ButOOH±V2O5 ± SiO2, CrO3, R1COCOCOOR2 O2 ± Co(OBz)2, PhSeSePh ± (NH)4S2O8 ±MeOH R(Me3SiO)C=CR(OSiMe3) Br2 ±CHCl3 RCOCOR Note. NBS is N-bromosuccinimide. 726 V D Filimonov,MS Yusubov, Ki-Van ChiOxidation of cyclic a-chloro b-diketones with hydrogen per- oxide in the presence of MeReO3 resulted in their decomposition to dicarboxylic acids via intermediate contiguous tricarbonyl compounds, which were detected in some instances by NMR spectroscopy.20 The methylene group in barbituric acid can be oxidised with CrO3 to give alloxan (6).The same result was obtained in the oxidation of benzylidenebarbituric acid (yield 75%± 84%).21, 22 The other known reagent based on CrO3, namely, pyridinium chlorochromate introduced in practical organic synthesis in 1977 by Corey, oxidises successfully various benzyl ketones (but not aliphatic ketones) in boiling CH2Cl2.23 Compound R1 R2 Yield (%) 7a H Ph 80 7b H Me 85 7c H Et 80 7d 4-MeO Me 60 7e 2-Me Me 65 A similar reagent, ammonium chlorochromate (NH4CrO3Cl), transforms acetophenone to phenylglyoxal rather easily (DMF, 75 8C, 6 h) in 80% yield.24 The same authors 25 used this reagent to oxidise butan-2-one to a mixture of ethylglyoxal and butane- 2,3-dione and to oxidise 3-methylbutan-2-one to isopropyl- glyoxal.A new method for the photooxidation of the methylene group of acyclic and cyclic b-diketones by singlet oxygen was suggested in 1985.26, 27 The reaction occurs successfully only in the presence of tetrabutylammonium fluoride.Presumably, the fluoride anion enhances the nucleophilic properties of the enol forms, thus activating the electrophilic attack by singlet oxygen. This method gave high yields (60% ± 97%) of tricarbonyl compounds (8 ± 11, 12a ± c).R1=R2=Ph (12a); R1=Ph, R2=Me (12b); R1=R2=Me (12aÊ ). It should be noted that the similar photooxidation of five- and six-membered cyclic a-diketones results in ring opening to give aldehydo or oxo carboxylic acids, probably via intermediate endo- peroxides.26 ± 29 It is well known that the oxidation of acyclic ketones with oxygen in the presence of bases serves as a method for the synthesis of carboxylic acids.Oxidation of 3-methyl- and 3-ethyl- pentane-2,4-diones gives a mixture of acetic acid and the corre- sponding 3-hydroxy 2-ketones and 2,3-diketones.30 This process is not a preparative method for the synthesis of diketones. However, it was found that cyclohexanone and cyclopentanone dissolved in dimethoxyethane undergo oxidation with atmospheric oxygen in the presence of ButOK at 720 8C to give the diketone 4a and cyclopentane-1,2-dione, respectively.31 The yields of cyclopenta- nedione and especially diketone 4a are low due to ring opening resulting in dicarboxylic acids.The similar reactions with cyclo- heptanone and cyclooctanone also give the corresponding dike- tones, but only as intermediates, which undergo subsequent aldol condensation.The stability of the diketone 4a and cyclopentane- 1,2-dione under these conditions is explained 31 by the predom- inance of the enol forms. 1,2-Diketones and a-oxo esters (13a ± g) are obtained in moderate to high yields (21% ± 83%) by the ozonolysis of Na- salts of b-diketones and b-oxo esters followed by treatment of the intermediate ozonides with hydrogen peroxide or dimethyl sul- fide.32 R1=OEt: R2=Bu (a), PhCH2 (b), 4-EtOCH2C6H4CH2 (c), (EtO)2- P(O)CH2CH2 (d); R1=Me: R2=But (e), PhCH2 (f), 4-EtOCH2C6H4CH2 (g).Compounds of hypervalent iodine are used very widely in organic synthesis, particularly as oxidising reagents for the a-hydroxylation of carbonyl compounds (see e.g., the reviews 33 ± 36).Much less is known about direct oxidation of ketones with these reagents to a-dicarbonyl compounds. The use of 1,1,1-triacetoxy-1-l5-benzo-1,2-iodoxol-3-one (`periodinane' or the Dess ± Martin reagent) in moist CH2Cl2 in the presence of pyridine for the oxidation of tert-butyl 2-hydroxy-2-phenylpropi- onate to the corresponding dioxo ester 14 was reported.37 Diacetoxy-l3-iodanylbenzene oxidises 1,3-indanedione in alcohols in the presence of H2SO4 to the corresponding 2,2- dialkoxyindanediones.38 HO Cl O H2O2,MeReO3 O O O 7CO2 HOOC(CH2)3COOH O O OH Cl 7H+,7Cl7 HN N O O O H HN N O O O H PhCHO CHPh CrO3 HN N O O O OH OH H 6 CrO3 R2 O R1 CrO3, Py, HCl CH2Cl2 R2 O O R1 7a ± e OH Me Me OH O 8 (72%) O O OH OH O O HO OH 9 (75%) 10 (60%) OH OH OH 11 (70%) O R1 R2 O O 12a ± c O Me R1 O R2 EtONa/EtOH O Me R1 O R2 Na+ 7 O3 O O O NaO Me R2 R1 O O R2 R1 O 13a7g OH Ph OBut O CH2Cl2, H2O, Py O Ph OBut O O 14 (80%) I O OAc AcO OAc O Oxidative methods in the synthesis of vicinal di- and polycarbonyl compounds 727The kinetics and mechanism of the oxidation of cyclopenta- none and cyclohexanone to the corresponding 1,2-diketones with bromoamine-T (4-MeC6H4SO2NNaBr) in acidic media was studied.39 Enolisation of the starting ketones was found to be the limiting step of the oxidation.Selenium dioxide is a much more versatile reagent for the synthesis of vicinal polycarbonyl compounds. Its extensive use in practical organic synthesis started in the early 30's, and this reagent is still important today. Both SeO2 and selenious acid (H2SeO3), which is prepared by concentrating aqueous solutions of selenium dioxide, are used in syntheses of dicarbonyl com- pounds.Both reagents selectively oxidise the a-methyl groups of aliphatic and aromatic ketones and acetaldehyde as well as the a- methylene groups of cyclic ketones. Oxidation can be carried out by heating the reagent and substrates in the absence of solvents.However, the reaction is more commonly performed in such solvents as water, ethanol, acetic acid and dioxane; sometimes, xylene, acetic anhydride and pyridine are used. A wide range of aryl methyl ketones with various donor and acceptor substituents in the ring are oxidised with SeO2 to the corresponding arylglyox- als in yields usually exceeding 70%.4, 5, 40 However, ortho-acetyla- cetophenone, unlike the para-isomer,4 gives 2-hydroxy-1,4- naphthoquinone rather than bisglyoxal.41 It is reported in patent literature that the oxidation of acetophenone with SeO2 in C1 ±9 aliphatic alcohols at 100 8C gives the corresponding phenyl- glyoxal acetals.42 Acetaldehyde is oxidised withH2SeO3 to glyoxal (isolated as a bisulfite derivative in 72%± 74% yield 43).It can be noted that glyoxal is also formed from acetone by refluxing the latter with SeO2 in xylene in the presence of water.40 Selenious acid in aqueous dioxane readily oxidises cyclohexanone at room temperature to give cyclohexane-1,2-dione (yield 60%).44 The use of SeO2 in this reaction gives nearly the same yield but requires more drastic conditions (refluxing for 6 ± 8 h).45 Selenium dioxide has also been used to oxidise many b-dike- tones (acetylacetone, benzoylmesitoylmethane, dimesitoylme- thane, 5-hydroxy-4-phenylcyclopent-4-ene-1,3-dione, etc.) to the corresponding 1,2,3-triones.1 Bisglyoxals (15a,b) used in the syn- thesis of cyclic vicinal tetraketones were also obtained with this reagent.46 The possible mechanisms of oxidation with selenium dioxide have been discussed in reviews.4, 40 Despite the high efficiency and selectivity combined with mild conditions of the reaction, SeO2 has a serious drawback noted in many works, namely, the difficulty of purification of the final products from selenium that is formed.Black selenium that is evolved can be filtered off, but a small amount of colloidal selenium (`red selenium') remains in solution and cannot be removed even by distillation. This necessitates an additional work-up of the products, viz., shaking with mercury or inactive Raney nickel or treatment with potassium cyanide, SO2, potas- sium hydrogensulfite in acidic media or thiourea.5, 40 Yet another selenium-based oxidant, diphenyl diselenide, has been suggested recently.47 It proved to be very efficient (in catalytic or stoichiometric quantities) for the preparation of a-oxo acetals 16 from the corresponding methyl ketones in the presence of ammonium peroxodisulfate (NH4)2S2O8.The reaction is carried out in boiling methanol and is applicable to a broad range of aromatic and heterocyclic methyl ketones (except for acetylpyridine) as well as to unsaturated, cycloaliphatic and, in certain cases, aliphatic methyl ketones.It is assumed that the process occurs through electrophilic attack of PhSe+ on the enol form of the ketone.47 The same group of authors 48 expanded this oxidation method to b-diketones and b-oxo esters. In this case, only a catalytic amount of PhSeSePh was used, and the yields of oxo acetals 17 were considerably lower (10% ± 75%), especially for the diketones containing the acetyl fragment, which also undergoes partial oxidation.This reaction affords side products 18 and 19.48 Since the discovery of a very simple method for the oxidation of activated alkyl halides, including phenacetyl bromides, with DMSOin the presence of bases (the Kornblum reaction),49 a large number of studies have appeared in which DMSO is used as a convenient oxidant (for the relevant reviews, see Refs 5, 50 ± 52).No wonder thatDMSOplays an important role in the synthesis of a-dicarbonyl compounds as well. For example, DMSO in the presence of dry HBr oxidises the methylene groups in cyclic b-diketones to produce 1,2,3-triones 9 and 20 in 80% and 30% yields, respectively.53, 54 It was found later that the oxidation of another cyclic diketone, dimedone (21), with DMSO in the presence of hydrogen bromide brings about not only oxidation of the methylene group but also ring bromination to give dibromotriketone 22.In addition, a product of ring contraction, viz., tribromocyclopenta- nedione 23, is formed.55 The DMSO± aqueous HBr system turned out to be very efficient in the transformation of acetylarenes to arylglyoxals 24a ± e.56 This is probably the most convenient reagent presently avail- able for this transformation.The reaction is carried out at 55 8C for 1 ± 24 h to give the corresponding arylglyoxals in high yields (42% ± 94%). Side processes have been noted in two cases only. n = 6 (a), 8 (b). (CH2)n COMe COMe SeO2 (CH2)n COCHO COCHO .H2O 15a,b RCOMe PhSeSePh, (NH4)2S2O8 MeOH RCOCH(OMe)2 16 (56% ± 95%) R1=Alk, Ph; R2=Alk, Ph, OAlk, OCH2Ph.O R1 R2 O O R1 R2 O MeO OMe 17 (MeO)2CHCOC(OMe)2COR O MeO O OMe OMe OMe R 18 19 O O O 20 O O DMSO, HBr, H2O OH Br Br Br O 21 23 (17%) + HO OH O Br Br 22 (46%) R=4-Ph (a), 4-MeO (b), 4-NO2 (c), 4-Br (d), 2-Ph (e). COMe R DMSO, HBr, H2O COCHO R 24a ± e 728 V D Filimonov,MS Yusubov, Ki-Van ChiFor example, the oxidation of 2-acetylbiphenyl results in oxidative cyclisation to give phenanthrenequinone in 47% yield.In the case of 4-acetyldiphenylamine, oxidation is accompanied by bromina- tion of the unsubstituted phenyl ring to afford 4-(4-bromoanili- no)phenylglyoxal (90%). Under the same conditions, 1,2- diphenylethanone affords quantitatively diphenylethanedione 7a in 24 h, while 1,3-diphenylpropane-1,3-dione gives diphenyltrike- tone hydrate 12a.56 The following point related to the mechanism of this reaction is worthy of note.It is generally accepted that the Kornblum reaction occurs through the following pathway (without details of the decomposition step of the dimethylsulfoxonium intermediate 25):50 ± 52 However, comparison of the results of oxidation of aryl methyl ketones in the DMSO± HBr ±H2O system and oxidation of a-bromoacetophenone in dry DMSO made it possible to suggest a different mechanism for oxidation with aqueous DMSO.56 It was assumed that in this case the role of DMSO is reduced to the oxidative generation of a small amount of bromine followed by bromination and debromination of ketones with subsequent hydrolysis to arylglyoxal hydrates.Whatever the actual mechanism of this reaction, the DMSO± HBr ±H2O sys- tem is the most convenient for the preparative oxidation of acyclic ketones to a-dicarbonyl compounds and of acyclic b-diketones to triketones, provided that the substrates subject to oxidation are insensitive to bromine. A method has been patented for the synthesis of benzil 7a using a concentrated HBr ±DMSO sys- tem.57 Other examples of smooth oxidation of methylene groups in bisdeoxybenzoins 26, 27 to bis-a-diketones (28, 29) are also known.58, 59 The latter reaction, which serves as one of the steps in the synthesis of an aromatic tris-a-diketone 59 (see Section IV), dem- onstrates the high regioselectivity of the DMSO± HBr oxidising system with respect to the methyl groups in the acetylenic diketone 27, since the triple bond remains unaffected.It is difficult or impossible to reach such a selectivity with other oxidants, e.g., SeO2. The methylene groups in 1,2-diphenylethanone and 1,3-di- phenylpropane-1,3-dione are smoothly oxidised with a mixture of DMSO with concentrated H2SO4 in the presence of a catalytic amount of iodine.60 However, the use of the same oxidative system for 1-phenylpropan-2-one and cyclohexanone gives very low yields of the diketones 7b and 4a.In this case, acetophenone gives a mixture of Z- and E-isomers of the enol form of 2-methylthio-1,4-diphenylbutane-1,4-dione, which are formed as products of phenylglyoxal transformation.60 On prolonged action, N-bromosuccinimide in dry DMSO oxidises 1,2-diarylethanones at room temperature to give the corresponding diarylethanediones and oxidises indan-1-one, indan-2-one and indane-1,2-dione to indane-1,2,3-trione (9).The reaction with 1,3-diphenylpropane-1,3-dione under the same conditions affords diphenyl triketone 12a.61, 62 It is assumed62 that N-bromosuccinimide acts as a brominating agent to give the intermediate 3-bromoindan-1-one, which is then oxidised with DMSO according to the Kornblum reaction.The methyl groups of aryl methyl ketones are oxidised on treatment withDMSOand benzoyl chloride at room temperature. However, instead of arylglyoxals, the reaction gives acetals of their fully hydrated forms with formaldehyde, i.e. 1-aryl-2,4,6,8- tetraoxabicyclo[3.3.0]octanes.63 The vast variety of methods and reagents for the synthesis of a-hydroxycarbonyl compounds by hydroxylation of stable enol forms, e.g., of vinyl ethers/esters and thioethers/thioesters, enol silyl ethers and ketene silylacetals (for reviews, see Refs 5, 35, 64, 65) contrasts with the surprisingly small number of reagents known for their direct transformation to a-dicarbonyl derivatives.In fact, even the formation of a-dicarbonyl structures 30 and 31 in the oxidation of bissilyl ethers 32 and 33 with m-chloroperbenzoic acid (the Rubbotom method)46, 66, 67 actually occurs due to hydroxylation. It is known that 1,2-bis(trimethylsilyloxy)alkenes, which are stable under non-hydrolytic conditions, can be oxidised with bromine in chloroform or CCl4 to the corresponding cyclic diketones.This reaction occurs most successfully if it results in cyclobutanedione or non-enolizing diketones.68 ± 71 In other cases, Me3SiBr that is formed reacts with the enol forms of the resulting diketones, giving new silyl ethers of enols and, subsequently, various halogen-containing compounds.70 A similar approach afforded 3,3,7,7-tetramethylcyclohep- tane-1,2-dione 72, 73 and adamantylcyclobutanedione.74 Likewise, the reaction of bromine with the bissilyl ether of bicy- clo[4.2.0]octa-2,6-diene gives benzocyclobutanedione (34) through bromination and dehydrobromination.73 2.Oxidation of a-hydroxycarbonyl compounds Transformations of a-hydroxycarbonyl compounds to a-dicar- bonyl compounds are well studied. Undoubtedly, the largest number of reagents for this kind of transformations have been CHBr+Me2SO 7Br7 CH O S+Me2 B7 25 O +SMe2+BH PhCH2CO COCH2Ph 26 DMSO, HBr, H2O DMSO, HBr, H2O PhCH2CO COCH2Ph 27 PhCOCO COCOPh 29 PhCOCO COCOPh 28 n=6, 8.(CH2)n OSiMe3 OSiMe3 m-ClC6H4CO3H CH2Cl2 (CH2)n O O OH OH 32 30 m-ClC6H4CO3H CH2Cl2 OSiMe3 OSiMe3 OH OH O O 33 31 OSiMe3 OSiMe3 Br2 770 to7100 8C OSiMe3 Br O 7Me3SiBr O O (70%) OSiMe3 OSiMe3 Br Br 7Me3SiBr OSiMe3 OSiMe3 O O 34 O O Br Br Br Br2, Py 770 8C Oxidative methods in the synthesis of vicinal di- and polycarbonyl compounds 729approved using the oxidation of benzoin as a very convenient model.Even 150 years ago, Laurent 75 and Zinin 76 showed that benzoin can be oxidised to benzil 7a on treatment with chlorine or nitric acid.However, these reactions, unlike those developed later, did not become preparative methods. Treatment of a solution of benzoin in pyridine with air in the presence of copper(II) sulfate at 100 8C for 2 h oxidises it to diketone 7a in 86% yield.77 Compound 7a is obtained in quanti- tative yield by refluxing a solution of benzoin in acetic acid in the presence of a catalytic amount of copper acetate and ammonium nitrate.78 Similar results are obtained if a catalytic amount of cobalt,78, 79 iron or nickel salts 78 or complexes of Fe(II) with certain cysteine-containing peptides 80 are used.Complexes of Fe(II) with a,a 0-xylenedithiolates catalyse the oxidation of ben- zoin to benzil 7a in DMF at room temperature both by the atmospheric oxygen and p-benzoquinone; the latter oxidant was found to be more efficient in this reaction.81 It was suggested 82 to prepare 4,4 0-bis(carboxyphenyl)ethanedione ethers by oxidation of the appropriate benzoins with air in ethanol in the absence of catalysts at 60 8C for 13 h. 2-Hydroxy-1-phenyl-2-(2-quinolyl)e- thanone (a-quinaldoin) is readily oxidised on passing air through its boiling solution in dioxane to give phenyl(2-quinolyl)ethane- dione.5 The most commonly used oxidants are listed in Table 2 together with the relevant reaction conditions.These data make it possible to compare the reactivities of different reagents with respect to the oxidation of a-hydroxy ketones. Quinolinium fluorochromate, Bi(MnO4)2, AgBrO3, AlCl3, and o-iodylbenzoic acid can be regarded as the most efficient reagents. In several studies,87 ± 92 benzoin and other alcohols were oxidised with the same reagents under similar conditions.It turned out that such alcohols as benzyl alcohol, diphenylmetha- nol, and 1-phenylethanol were comparable with each other and with benzoin with respect to the time required for their oxidation and the yields of the monoketones in the preparative experiments, i.e. the activity of these substrates is quite similar.However, oxidation of 4- and 4 0-chloro-, bromo-, and methoxy-substituted benzoins with sodium or silver bromates in the presence of AlCl3 90 or barium permanganate 88 is accompanied by an insignificant decrease in the yields of the corresponding diarylethanediones and an approximately twofold increase in the reaction time.The oxidation of 2-furoin with barium permanganate occurs much more slowly (4 h, yield 80%). These results of preparative experi- ments provide no more than a qualitative picture of the effect of the nature of a-hydroxy ketones and oxidants on the oxidation to 1,2-diketones. In order to reveal distinct regularities, one has to determine the rates of oxidation of different substrates under similar conditions. However, to our knowledge, there are no comparable kinetic experiments of this kind, although both the kinetics and the oxidation mechanism of a-hydroxy ketones have been studied rather thoroughly.For example, it follows from kinetic studies on the oxidation of benzoin with quinolinium dichromate to compound 7a that the oxidation is 6 times slower than the substrate enolisation. Oxidation occurs through the initial coordination of the chromium atom with the carbonyl group of the substrate.97 Many other reagents are known that oxidise benzoin to the diketone 7a.For example, anhydrous Fe(NO3)3, which is nor- mally unstable, is rather stable if impregnated in acidic montmor- illonite. It affords benzil 7a in a higher yield (85% ± 95%) than ytterbium nitrate.98 On the other hand, K2FeO4 immobilised on the same support gives the diketone 7a in only 36%yield, since this reagent cleaves the C7C bond of benzoin, producing benzalde- hyde.99 It was reported,100 without specifying the conditions and yields of the reaction products, that catalytic amounts of tris(2,4- dibromophenyl)aminium hexachloroantimonate oxidise benzoins to the corresponding diarylethanediones. Benzoin can be oxidised with titanium isopropoxide,101 benzyltriethylammonium tribro- mide,102 triphenylstibine dibromide (Ph3SbBr2),103 Ph3PBr2,104 and PhMe3N+Br73 .NBS105 to benzil 7a in almost quantitative yield.Cobalt(III) acetate in acetic acid oxidises deoxybenzoins to benzoins and further to diphenylethanedione derivatives.106 Copper sulfate and acetate have long been widely used for the oxidation of various benzoin structures.For instance, stoichio- metric amounts of CuSO4 . 5H2O oxidise 1,2-difuryl-2-hydroxy- ethanone (2-furoin) and 2-phenyl-1-(2-pyrrolyl)-2-hydroxy- ethanone in aqueous pyridine at 100 8C in 2 h to give difuryl- ethanedione (furil) 107 and phenyl(2-pyrrolyl)ethanedione 108 in 63% and 95% yields, respectively.Probably, copper acetate has an even higher oxidising activity. It oxidises 3-hydroxy-1,4- diphenylbutan-2-one to 1,4-diphenylbutane-2,3-dione in almost quantitative yield on refluxing for 7 min in 70% AcOH109 and 2-hydroxycyclodecanone (sebacoin), also in aqueous AcOH,110 to cyclodecane-1,2-dione (sebacil) in 1 min. Copper acetate in AcOH was successfully used in the synthesis of cyclic diketones 35 and 36a,b.46, 65 35 (90%) Cu(OAc)2, AcOH, H2O 120 ± 140 8C, 8 h O O OH O (CH2)n OH O (CH2)n O O 36a,b (80%) Cu(OAc)2, AcOH, H2O 100 8C n=6 (a), 8 (b).Table 2. Reagents and reaction conditions for the oxidation of 2-hydroxy- 1,2-diphenylethanone (benzoin) to diphenylethanedione (benzil). Reagent Solvent Tempera- Time Yield Ref.ture /8C /h (%) O2, CuSO4 C5H5N 100 2.0 86 77 Cu(OAc)2, AcOH reflux 1.5 90 ± 100 78 NH4NO3 PhSe(O)Se(O)Ph THF " 3.0 92 83 Quinolinium CH2Cl2 20 2.0 98 84 fluorochromate Trichloromelamine CH2Cl2 20 125.0 98 85 DMSO, HBr, H2O 7 55 24.0 95 56 Bi2O3 AcOH, 104 1.0 95 86 EtO(CH2)2OH Zn(BiO3)2 Xylene reflux 0.7 97 88 Ba(MnO4)2 MeCN " 0.25 96 88 BaFeO4 .H2O MeCN " 6.0 95 89 AgBrO3, AlCl3 MeCN " 0.5 97 90 NaBrO3, AlCl3 MeCN " 0.75 97 90 Chromium MeCN " 3.0 90 91 bipyridylperoxide Bu4N+IO¡4 CHCl3 " 2.5 85 92 FeCl3 .6H2O AcOH, H2O " 0.8 90 ± 95 93 o-Iodylbenzoic THF, DMSO 20 6.0 >90 94 acid THF, DMSO reflux 0.2 92 94 NaBrO3, NaOH H2O 100 5 ± 6 84 ± 95 a 95 N-Chlorosuccin- MeC6H5 0 2.0 93 96 imide, Me2Se, base a Benzylic acid is formed as a product of benzylic rearrangement of diphenylethanedione. 730 V D Filimonov,MS Yusubov, Ki-Van ChiSodium salts of enolic forms of hydroxy ketones that are formed in the acyloin condensation of esters (enedioxides 37) are oxidised with thionyl chloride in situ at low temperature to symmetric a-diketones 39 via intermediate sulfites 38.111 Reagents based on DMSO were successfully used for the oxidation of a-hydroxycarbonyl compounds.An aqueous solu- tion of HBr inDMSO readily oxidises benzoin to benzil 7a in high yield.56 It is interesting that the same reagent also oxidises o-methylbenzoin to compound 7a.112 The reactivity of deoxyben- zoin and its a-substituted derivatives in the oxidation to benzil 7a was studied.113 The series of reactivities, benzoin>2-bromo-1,2- diphenylethanone > 1,2-diphenylethanone, is a good confirma- tion of the suggested scheme of the oxidation of ketones with HBr in DMSO.56 A combination of DMSO with P2O5 was used in the synthesis of azetidine-2,3-diones 40, which were then oxidised to a-amino acid N-carboxyanhydrides according to Baeyer ± Villiger.114 Such reagents as N-chlorosuccinimide with Me2S and Et3N, pyridinium chromate, pyridinium chlorochromate, the Jones reagent (CrO3, H2SO4, H2O), trifluoroacetic anhydride in DMSO, tetra-n-propylammonium perruthenate, RuO4, and NaIO4 proved to be unsuitable for this purpose.The Corey reagent (Me2SBr2, Et3N) was also inefficient,114 although it has been used successfully in the synthesis of various azetidine-2,3- diones from a-hydroxy-b-lactams.115 Treatment of hydroxy-b- lactams with sodium hypochlorite also leads to their oxidation according to Baeyer±Villiger.116 The Swern reagent (DMSO± ClCOCOCl) oxidises dihydrox- y[12]paracyclophanedione 31 to the tetraketone 41 under mild conditions (740 8C, 45 min).67 Oxidation of cyclotridecanedione 42 to the tetraketone 43 has been performed successfully by the same authors 68 with such a well-known reagent for the oxidation of alcohols as N-bromosuc- cinimide in CCl4.However, bistetraketones 44 were obtained using nitric acid.46 As a rule, aromatic derivatives of a-hydroxy ketones are readily oxidised with DMSO±Ac2O, but the yields of a-diketones from aliphatic derivatives are low.117 a-Oxocarboxylic acids are important biologically active com- pounds and are of considerable interest for organic synthesis.It is not surprising that the development of methods for their synthesis draws much attention. Many reagents for the oxidation of alkyl a-hydroxycarboxylates to the corresponding oxo derivatives are known. These include Pb(OAc)4, Ph3SbBr2, tertiaty amine oxides, sodium peroxodisulfate, 2-fluoro-1-methylpyridinium tosylate, DMSO with hexamethylenetetramine, PhSOCl, a complex of dimethyl selenide with N-chlorosuccinimide, sodium hypochlor- ite, diacetoxy-l3-iodanylbenzene, Co(II) compounds, bis(tetra- butylammonium) dichromate, KMnO4 ±CuSO4, ammonium vanadate, manganese pyrophosphate, immobilised chromic acid, chromyl chloride, vanadium(V) derivatives, periodinane (see e.g.Ref 118 and the references cited therein).A review published recently 119 deals with the use of tetrapropylammonium per- ruthenate (Pr4NáRuO¡4 ) as a mild catalytic reagent, particularly for the synthesis of a-keto acids. It was suggested to obtain esters of b,g-unsaturated a-oxocarboxylic acids by the oxidation of the corresponding a-hydroxy derivatives according to the Swern procedure (DMSO, ClCOCOCl, CH2Cl2,750 8C).120 In view of the abundance of studies in this field, the detailed discussion of oxidative methods for the synthesis of a-oxocarbox- ylic acids is beyond the scope of our review.Therefore, we shall discuss here only relatively new and, in our opinion, versatile reagents applicable for the synthesis of other a-dicarbonyl com- pounds as well. For example, the importance of tetramethyl-1-piperidinylox- yls (TEMPO) has increased in recent years.In particular, it was shown that various linear and cyclic primary and secondary alcohols are oxidised in high yields to high-purity aldehydes or ketones under mild conditions on treat- ment with 4-acetylamino-TEMPO (R=AcNH) in dichlorome- thane in the presence of p-TsOH.121 The reagent is readily generated in the reaction mixture.Phenylglyoxylic acid is formed under these conditions in 91% yield from phenylglycolic acid.121 Oxaziridines, particularly various 2-sulfonyloxaziridines, are powerful oxidants due to the high electrophilicity of the ring oxygen atom. They are used most widely for the a-hydroxylation of carbonyl compounds.64, 122 It was found that perfluoro-cis-2,3- dialkyloxaziridines also oxidise secondary alcohols to ketones at room temperature.In particular, they oxidise ethyl lactate (45) to ethyl pyruvate (46).123 7SO O S O O R R 38 R=Me, Et, But, cyclo-C3H5, adamantyl, Ph. O R R O 39 (62% ± 85%) O OEt R Na Et2O, 20 8C SOCl2 778 8C NaO R ONa R 37 R1=Me, Bu, Pri, But; R2=Ph, Ar, CH2Ph. NR2 H H HO O R1 NHBoc DMSO, P2O5 NR2 H O O R1 NHBoc 40 O O O O 31 DMSO, ClCOCOCl CH2Cl2 41 OH OH O O (CH2)3 (CH2)3 Me Me Me Me O NBS CCl4 O O O O (CH2)3 (CH2)3 Me Me Me Me O 43 42 HNO3 CH2Cl2 OH (CH2)n O O O O O O (CH2)n OH O (CH2)n O O O O O O (CH2)n O 44 n =4, 6.+ N Me Me Me Me R O7 N O R0 F R CFCl3 O Me OEt O + 46(81%) OH Me OEt O + 45 RN C(F)R0 Oxidative methods in the synthesis of vicinal di- and polycarbonyl compounds 731Finally, let us note a recently observed example of the oxidation of alkyl hydroxycarboxylates to a-oxo esters 46 and 47 on treatment with tert-butyl hydroperoxide in the presence of copper(I) and (II) salts and even metallic copper under phase- transfer catalysis conditions.124 Dibismuth trioxide oxidises 12-hydroxy-11-ketosteroids to 11,12-diketosteroids in up to 70% yields.125 This reagent can also be used for the synthesis of vicinal vinyl diketones from the corresponding vinyl a-hydroxy ketones.126 Iodine combined with AcOH and MeOH oxidises D-(7)-ascorbic acid to D-(7)-dehy- droascorbic acid in low yield.127 Aliphatic a-hydroxy ketones are transformed to the corresponding a-diketones on treatment with N-bromosuccinimide in dry CCl4 or aqueous dioxane.128 Basic copper(II) carbonate [CuCO3 .Cu(OH)2] acts in a similar way.129 Acyloins of dioxepane structure were successfully oxidised to the corresponding a-diketones upon boiling with SeO2 in a mixture of toluene and acetic acid.130 The action of a solution of ferric chloride in HCl on 2-hydroxycyclohexanone results in a high yield of cyclohexanedione 4a.131 3. Oxidation of a-halocarbonyl compounds Oxidation of a-halocarbonyl compounds is one of the most convenient and popular methods for the synthesis of diketones.132 A very simple and convenient method is the oxidation of halo ketones according to Kornblum with DMSO in the presence of bases.49 ± 52, 133 In this case, a-bromocarbonyl compounds are oxidised more readily than alkyl or even benzyl bromides.The oxidation of a-bromo ketones with DMSO is commonly carried out at room temperature. This is explained by easier elimination of the proton from the intermediate dimethylsulfoxonium salt 48 due to the adjacent carbonyl group (see also Section II.1).134, 135 The method is particularly convenient for the oxidation of acyclic a-bromocarbonyl compounds. For example, phenyl- glyoxal (yield 71%) and diketone 7a (yield 95%) were obtained by the oxidation of 2-bromo-1-phenylethanone and diphenylbro- moethanone in dry DMSO at 25 and 45 8C, respectively.49 The addition of sodium carbonate accelerates the process.However, the oxidation of e.g. ethyl bromoacetate with DMSO was also carried out without a base, using 2-phenoxymethyloxirane to bind the HBr evolved (the yield of ethyl glyoxylate was 70%).136 However, it was noted 137 that tert-butyl bromoacetate could not be oxidised with DMSO.It was also shown that the addition of potassium iodide to a mixture of DMSO and Na2CO3 accelerates the oxidation of bromo ketones.138 In the first studies by Kornblum and co-workers and in many subsequent studies, dry DMSO was used. Thorough dehydration of such a hygroscopic compound as DMSO is a difficult proce- dure. It was shown56 that it is easier to oxidise aryl methyl ketones, a-hydroxy- and a-bromoacetophenone with aqueous HBr in DMSO.In this case, the oxidation mechanism differs consider- ably from that of the classical Kornblum reaction. The role of DMSO in an aqueous medium is reduced to the generation of Br2 from HBr, while the dimethylsulfoxonium ion 48, which is the key intermediate in the Kornblum reaction, is not formed in aqueous HBr (see Section II.1). 3-Bromocamphor is oxidised to camphoroquinone upon passing air through a solution of the substrate and NaI in DMSO.139 However, despite the apparent similarity with the Kornblum reaction, its mechanism is different: DMSO serves as a solvent, while the process goes via free-radical intermediates.139 Complications are observed in the oxidation of cyclic a-bromo ketones with DMSO.In this case, oxidation often competes with elimination of the DMSO molecule from the intermediate 48. Instead of diketones, or along with them, this process produces a,b-unsaturated ketones and a-hydroxy ketones. This reaction pathway is particularly typical of steroid derivatives.140 Heating of 2-bromocyclohexanone and 2-bromocyclopentanone in DMSOat 100 8C gives 3-bromocyclohexane-1,2-dione and 3-bro- mocyclopentane-1,2-dione rather than the corresponding dike- tones.141, 142 Under these conditions, the bromo ketone 49 gives the diketone 50, which exists in the enol form, only in the presence of epichlorohydrin to bind the HBr that evolves.The reaction in the absence of epichlorohydrin results in the compound 51 as the main product.142, 143 It was suggested 142, 143 that this effect is due to the oxidation of the hydrogen bromide, which is formed in the primary oxidation act, with dimethyl sulfoxide to bromine, which bromi- nates the intermediate diketone. Nitrates formed in the reaction of a-bromo ketones and a-bromo acids with AgNO3 undergo smooth transformations on treatment with a catalytic amount of sodium acetate in DMSO at room temperature to give high yields of a-dicarbonyl compounds or a-oxo acids.144 ± 146 The KroÈ hnke method (treatment of a-bromo ketones with pyridine and 4-nitrosodimethylaniline followed by hydrolysis) is of very limited use in the synthesis of 1,2-dicarbonyl com- pounds.132 The oxidation of a-bromo acids and their esters with pyridine N-oxide is an efficient method for the synthesis of a-oxo acids and their esters.147 Compound 52 R1 R2 Yield (%) a H H 37 b H But 97 c H CH2 Ph 89 d Ph H 70 e Ph Me 95 The addition of silver nitrate facilitates the formation of alkoxypyridinium salts.Their subsequent decomposition is car- ried out by heating in methanol or acetonitrile in the presence of Et3N or in aqueous NaOH at room temperature.147 A stronger nucleophile, 4-dimethylaminopyridine N-oxide, was also used in an oxidative transformation of this kind.However, in this case the intermediate salt was decomposed with the use of 1,8-diazabi- cyclo[5.4.0]undec-7-ene.148 ButOOH, CuX2, Bun4 NBr CH2Cl2, H2O, 25 8C, 24 h 46, 47 (60% ± 96%) R=Me (46), Ph (47).OH R OEt O O R OEt O + R1COCHBrR2+O SMe2 7Br7 7H+ R1COCR2 H O SMe2 48 R1COCOR2+SMe2 DMSO 70 8C, 1 h ClCH2 O O Br Me CO2Et 51 (70%) O HO Me CO2Et 50 (58%) DMSO 70 8C, 10 h O Br Me CO2Et 49 + Br R1 OR2 O C5H5NO CH2Cl2 O R1 OR2 O N 7C5H5N B : O R1 OR2 O 52a ± e 732 V D Filimonov,MS Yusubov, Ki-Van ChiSimilar oxidative properties are manifested by N,N-diethylhy- droxylamine, which oxidises, readily and in high yields, various aromatic bromomethyl ketones to arylglyoxals in boiling meth- anol in the absence of bases.149 The method is attractive due to its simplicity and serves as a rare example in which a-oxo aldehydes are formed more easily than aromatic a-diketones.The method is not applicable to 2-bromo-1,2-diphenylethanone, 2-chlorocyclo- hexanone and 2-bromo-1-phenylpropanone.a-Bromocarbonyl compounds (as well as other activated alkyl halides) react with N-phenyltrifluoromethanesulfonamides under mild conditions. The resulting products 53 are readily decom- posed with bases to anils 54, which are, in turn, hydrolysed to a- dicarbonyl compounds 55.150 R1=C8H17, R2=Me (79%); R1=OEt: R2=Pr (67%), C6H13 (62%).Monoketals of aliphatic diketones 56 were obtained in 43%± 87% yields in two stages according to the following scheme:151 The method has the advantage that it provides the possibility of direct regiospecific synthesis of dimethyl ketals with involve- ment of only one carbonyl group of a-diketones that are difficult to obtain directly from the corresponding dicarbonyl compounds.The method is a good supplement to the synthesis of a-oxo acetals by the oxidation of methyl ketones with diphenyl diselenide as discussed in Section II.1.47 It is interesting that the formation of an acetal from an aromatic bromo chloro ketone, namely, 2-bromo-2-chloro-1- phenylpropan-2-one, is accompanied by a rearrangement 151 that gives 1,1-dimethoxy-1-phenylpropan-2-one.Cyclic and acyclic geminal dibromo diketones are trans- formed under conditions of photochemical oxidation at room temperature to hydrates of the corresponding vicinal triketones 57 in good yields.152 Structure 57 Yield (%) 80 90 90 Structure 57 Yield (%) 87 83 85 4. Oxidation of other classes of compounds with the CX±C=O function and oxidative rearrangements In certain cases, carbonyl compounds containing nitrogen, sulfur or phosphorus in the a-position are rather accessible and can serve as good precursors in the synthesis of 1,2-dicarbonyl compounds.A general method for the insertion of an a-oxo group in ketones, esters, amides and lactams has been elaborated. This method is based on photooxidation of a-oxo enamines obtained from the corresponding carbonyl compounds according to the general scheme: Dicarbonyl compounds obtained by this method are pre- sented in Table 3.The photooxidation is carried out at 778 8C with subsequent heating of the reaction mixture to 25 8C. The method shows high selectivity. Using the same approach, the allylic vicinal tricarbonyl compound hydrate 57a, which is a versatile di- and trielectrophilic synthon, was synthesised.154 The same method was used to obtain polyfunctional a-dike- tones 58 and 59 from carboxylic acids.155 It was shown that treatment of a-hydroxyimino ketones with N2O4 in THF or acetonitrile at 720 8C gives diketones 7a,e and triketone 12a in over 60% yields.156 Cyclohexane-1,2,3-trione hydrate was synthesised in an analogous way.156 The reaction is assumed to occur via the intermediates 60, since isotope-labelling experiments have shown157 that the oxidation of oximes to ketones with NO+ occurs via oxaziridine intermediates.O R1 R2 NPh H3O+ O R1 R2 O 54 55a ± c O R1 R2 Br +PhNHSO2CF3 K2CO3 O R1 R2 N(SO2CF3)Ph B : 53 R1=R2=Me; R1=Et, R2=Me; R1=Me, R2=Et. Cl R1 R2 O NBS, Bz2O CCl4, D, 1.5 ± 2 h Cl R1 R2 O Br Ag2CO3 MeOH, D, 24 ± 72 h R1 R2 O OMe MeO 56 O Ph Me Br Cl Ag2CO3 MeOH, D, 72 h O Me Ph OMe MeO O R R O 57 Br Br hn; O2 O R R O OH HO O O OH OH N O OH OH O Me O O Ph OH HO N O OH OH O H O O O OMe O O Ph OH HO ButOCH(NMe2)2 O X Y O X Y O ±Me2NCHO [O] O X Y NMe2 O Cl OBut O O Cl OBut O NMe2 [O] or O3 O Cl OBut O OH HO O OBut O OH HO 57a R1=H, COOH, CH2COOBut (58); R2=H, COOBut (59).R1 O Me O Ph 58 N R2 H Me O O 59 O R1 R2 NOH +NO+NO¡3 O R1 R2 N OH N O + Oxidative methods in the synthesis of vicinal di- and polycarbonyl compounds 733Autooxidation of a-hydroxy imines 61 to diketones is rather a general method. Compounds 61 are obtained by the SmI2-induced coupling of alkyl halides with xylyl isocyanide and aldehydes.158 The yields of diketones 62a ± f are higher than 90%.Organosamarium intermediates 63 obtained similarly are so nucleophilic that they readily react with esters and carbonates, thus providing a general way to vicinal triketones 64a ± c.159 Aroylation of a-chloro imines in the presence of 1,3-dimethyl- imidazolinium iodide is rather a general method for the synthesis of aromatic 1,2-diketones. The oxo imines that are formed readily undergo hydrolysis to give the diketones ArCOCOPh (Ar = Ph, 3-ClC6H4, 4-ClC6H4, 4-MeOC6H4, 4-NO2C6H4) in excellent yields.160 The method was found to be applicable to the synthesis of heterocyclic diketones ArCOCOR (R=thienyl).160 Examples of the oxidation of a-diazo ketones and diazo diketones are known.161, 162 For instance, treatment of a-diazo ketones with triphenylphosphine gave phosphoranes, which were converted to a-oxo aldehydes with nitric acid.Phenylglyoxal was obtained by this method in 70% yield with respect to the starting benzoyl chloride.161 At present, there are reliable methods for direct oxidation of diazo ketones. For example, tert-butyl hypo- chlorite was used in one stage of the synthesis of pentaketones 65a,b.162 Vicinal triketones 66 (in the form of mohohydrates) were obtained in nearly quantitative yields by prolonged oxidation (10 ± 30 h) of diazo diketones with dimethyldioxiranes (DMO, `oxone') in acetone at room temperature.163 Oxidation of diazo ketones, that are obtained from substi- tuted a-amino acids and dipeptides, with DMSO provides a general route for the synthesis of homochiral amino oxo aldehydes 67, which exist as hydrates.164 It was shown that phenylglycine undergoes oxidation with atmospheric oxygen in ethanol in the presence of an equimolar amount of VO(OEt)Cl2 to give ethyl phenylglyoxylate.165 The preparative value of this method is diminished by the side reaction of decarboxylation leading to the formation of a considerable amount of ethyl benzoate.It is well known that the oxidation of bishydrazones of 1,2- diketones with mercury(II) oxide is one of general methods to synthesise disubstituted alkynes. In the case of diphenylethane- dione (benzil) monohydrazone, oxidation with Ag2O results in benzil 7a.166 The use of some other oxidants mostly gives a-diazo ketones or ketazines, whereas diketones are only formed as by- products (see, e.g., Ref. 167 and the references cited therein). It was shown that cyclic ketones can be transformed to the corresponding a-diketones 68 by oxidation of their methylthio derivatives under mild conditions (acetone, 25 ± 35 8C).168 The overall yield of diketones over two stages is 42%± 76%. Methyl- glyoxal was obtained in a similar way.169 R1=Ph: R2=Ph (7a), CH2Ph (7e), COPh (12a).+ O R1 R2 N N O O 7 O R1 R2 O +N2O 60 7a,e; 12a R1NC+R2Br+SmI2 THF, HMPO 715 8C N SmI2 R2 R1 R3CHO R1N 61 R2 R3 OH O2, AcOEt 80 8C, 11 h R2=Pri , R3=CH2CH2Ph (c); R2=Et, R3=Ph (d); R2=(CH2)4OBu, R3=2-furyl (e); R2=cyclo-C6H11, R3=2-pyridyl (f). R1= ;R2 =CH2CH2Ph: R3=Et (a), Pri (b); Me Me R1N R2 R3 O H3O+ R2 R3 O O 62a ± f 2 R1NC+EtBr+SmI2 R1N Et NR1 SmI2 7 1.R2COOR3 2. H3O+ O Et O R2 O 63 64a ± c R1= :R2 =Me (a), Et (b), OMe (c). Me Me + R=But (a), Ph (b). O R N2 O N2 R O 1. ButOCl, HCOOH 2. P2O5, CHCl3 O R O O O R O 65a,b O R1 R2 O N2 + O O O R1 R2 O O 66 R1=R2=Me, Ph, OEt; R1=Me, R2=Ph, OEt; R1=Ph, R2=OEt; R1, R2=(CH2)3, CH2CMe2CH2, o-phenylene. NHX R OH O NHX R O N2 NHX R O O 67 O O X=(CH2)n, n=5 ± 12. 1. NaNH2, DME, THF 2. MeSSMe CuCl2, CuO O SMe 68 X O O X O X Table 3.Dicarbonyl compounds obtained by photooxidation of a-oxo enamines.153 Compound Yield (%) Compound Yield (%) PhCOCOMe 68 PhCOCOPh 89 PrCOCOEt 74 82 81 Cholestanedione (5) 87 PhCOCOOEt 91 4-MeOC6H4COCOOEt 92 EtCOCOOEt 81 Me(CH2)3COCOOEt 75 74 78 58 O O OH Me O Me Me N Me O O N Me O O N Bu O O 734 V D Filimonov,MS Yusubov, Ki-Van Chi(Biphenyl)phenylethanedione was isolated in 90% yield after heating of ketone sulfur-containing derivatives 4-PhC6H4COCH(X)Ph (X=SMe, S+Me2Br7) with aqueous HBr in DMSO at 55 8C.56 It is known that derivatives of dithiane 69, which are readily formed from aldehydes and 1,3-dithianyllithium, give a-hydroxy ketones in the presence of mercury(II) salts.170 In another study,171 1,3-dithiane was used as an acylic synthon, but the intermediate product 69 was then oxidised with an excess of N-bromosuccini- mide to give a series of a-diketones 70, including fluorine- containing ones, in 54%± 87% yields.The oxidation of a-hydroxyalkyl-1,3-dithianes with NaNO2 in trifluoroacetic acid to ketones was used 172 for the synthesis of certain alkaloid analogues containing an a-diketone fragment.Iodine is yet another reagent for desulfurisation of a-oxo thioacetals. For instance, azetidine-2,3-diones were synthesised by refluxing diethyl dithioacetals of 2-oxo b-lactams with iodine in aqueous acetonitrile for 35 ± 45 min.114 Very mild oxidative desulfonylation of a-sulfonyl ketones is carried out with oxaziridine 71.173 The method is unique due to its selectivity, as it makes it possible to obtain a wide range of complex cyclic and acyclic a-diketones containing such reactive functional groups as the azide, allenyl, acetal, furyl and other groups.Unfortunately, the more readily accessible (+)- and (7)-(camphorsulfonyl)oxazir- idines turned out to be unsuitable for this reaction.173 Various phosphorus and iodine ylides readily formed from b-diketones can serve as convenient precursors of vicinal tricar- bonyl compounds.164, 174, 175 For example, oxidation of phospho- rus ylides with singlet oxygen or ozone was used in the synthesis of allylic tricarbonyl compounds 57 and dioxo diester ButOCOCO- COCH2CH2CO2Et.164, 175 Potassium permanganate oxidises b- oxo(triphenylphosphoranylidenes) in a two-phase system to give substituted benzils or 1-arylpropane-1,2-diones in high yields.176 Ozonolysis of a,a 0-dioxoalkyl phenyliodonium 72 at low temper- ature made it possible to synthesise more than 20 cyclic and acyclic triketones 73 containing various fragments (alkyl, aryl, acetal, carbamido and other groups).174 The important advantage of this method over the majority of others is that compounds 73 are formed and isolated on a preparative scale in the ketone rather than hydrate form.174 A rearrangement of diarylacetaldehydes that can be used for the synthesis of substituted benzils occurs at room temperature in the presence of tris(2,4-dibromophenyl)aminium hexachloroan- timonate as the oxidant.99 However, diphenylacetaldehyde and D,L-2-phenylpropional- dehyde do not enter into this reaction.99 Oxidation of chalcones with thallium(III) nitrate 177 or PhIO178 also results in benzils.For example, treatment of chal- cones 75 with Tl(NO3)3 in aqueous solutions of glym in the presence of acids is a convenient way to synthesise benzils. The reaction scheme involves hydroxythallation of the double car- bon7carbon bond, oxidative migration of an Ar group in the intermediate 76, retro-Claisen condensation to give benzoins 77 and subsequent oxidation to diketones.III. Oxidation of 1,2-diols, epoxides and other vicinally substituted compounds The oxidation of glycols to a-dicarbonyl compounds can serve as a versatile method for the synthesis of the latter. However, these methods have been developed rather little, except for the indus- trial synthesis of glyoxal by gas-phase oxidation of ethylene glycol on copper or silver contacts.Various reactions leading to o-qui- nones are also known; these will not be considered in the present review. Much more commonly, syntheses of carbonyl compounds or carboxylic acids utilise the oxidative cleavage of the carbon ± - carbon bond in vicinal diols. The classic reagents of this type include lead tetraacetate, periodic acid and its salts (of which sodium periodate is particularly popular) (see, e.g., the reviews 179, 180).In addition, cleavage of glycols occurs on treat- ment with KMnO4, MnO2, NaBO3, NaBiO3 and organobismuth salts (Ph3BiCO3), Ce(IV) and Co(II) salts, hypochlorites, pyridi- nium chlorochromate, I2 with AgOAc or iodine triacetate (ICl3, AgOAc), N-iodosuccinimide in THF, VO(acac)2, H2O2 in the presence of metal salts, tert-butyl peroxide with Al(OBut)3, upon anodic oxidation, etc.180 ± 182 Considerable interest of researchers is attracted to the selective monooxidation of 1,2-diols aimed at the synthesis of chiral a-hydroxy ketones.Probably, the most general reagents used for the oxidation of glycols to dicarbonyl compounds include DMSO, the H2O2 ± per- oxytungstate system, o-iodylbenzoic acid and TEMPO-based reagents.Dry DMSO in the presence of (CF3CO)2O and triethylamine oxidises acyclic and cyclic 1,2-diols to 1,2-diones at 760 8C.183 Benzil 7a and 1,2-dicarbonyl compounds 78 ± 81 (some of these, in the enol form) were obtained by this method in 54%± 98% yields with conservation of the carbon skeleton of the original diols.S S R1 1. BuLi, THF,778 8C 2. R2CHO S S R1 R2 HO NBS Me2CO, H2O,75 8C O R1 R2 O 69 70 R1=Ph, R2=2-FC6H4, 3-FC6H4, 4-FC6H4; R1=2-FC6H4, R2=3-FC6H4, 4-FC6H4. O R1 R2 SO2Ar + N O H Ar0 ArO2S ButOOK THF, 778 8C O R1 R2 O 71 O R1 R2 O O 73 O R1 R2 O PhI(OAc)2 O R1 R2 O I+Ph O3, CH2Cl2 740 8C 72 Y X R O (2,4-Br2C6H3)3N+SbCl¡6 CH2Cl2 Y X O R O 74 X=H: Y=Me, R=4-MeC6H4; Y=OMe, R=4-MeOC6H4; X=H, Y=Cl, R=4-ClC6H4; X=Cl, Y=Me, R=4-ClC6H4.Ar1CH CHCAr2 O Tl(NO3)3 glym, H2O 75 OCHCHCAr2 O Ar1 Ar1CH2CAr2 O 77 Ar1C CAr2 O O Ar1CHCHCAr2 Tl OH O 76 OH O 78 CH3(CH2)8 O O 79 CH3(CH2)4 Oxidative methods in the synthesis of vicinal di- and polycarbonyl compounds 735Treatment of diols containing the bicyclo[4.1.0]heptane skel- eton with DMSO in trifluoroacetic acid results in tropolones 82 and 83.It is assumed that the reaction occurs through ring expansion of the originally formed bicyclic diketones. The oxidation of 5a-cholestane-2a,3b-diol affords a mixture of 2-hydroxy-5a-cholest-1-en-3-one and 3-hydroxy-5a-cholest-3- en-2-one in 84% overall yield.183 The use of the Swern reagent in this reaction gives poorer results.183 DMSO oxidises cyclohexane-1,2-diol and a number of acyclic vicinal diols to the corresponding 1,2-diketones at room temper- ature in the presence of dicyclohexylcarbodiimide in 60% ±75% yields.184 Diketone 7a and its 4,40-dibromo derivative are obtained smoothly and in high yields by oxidation of the corresponding 1,2-diarylethane-1,2-diols with DMSO in aqueous HBr at 110 ± 115 8C.59,112 It was found that o-iodylbenzoic acid 84 is a very mild oxidant for alcohols in DMSO at room temperature. It can also oxidise glycols without cleavage of the C7C bond giving the correspond- ing 1,2-diketones at room temperature in almost quantitative yields.185 A method for the oxidation of primary and secondary alcohols and 1,2-diols with the reagent 84 has been patented.186 Hydrogen peroxide usually cleaves glycols.However, it has recently been shown that acyclic vicinal diols are oxidised byH2O2 in a two-phase system in the presence of a catalytic amount of the [p-C5H5N(CH2)15Me]3{PO4[W(O)(O2)2]4} complex to give dike- tones in 70%± 93% yields.187 The reaction occurs in a stepwise manner via intermediate a-hydroxy ketones.The results of the oxidation of cyclic diols are noticeably poorer: cyclooctane-1,2- dione was obtained in yields as low as 48%± 58%, while cyclohexane-1,2-diol gives adipic acid rather than the diketone 4a.187 It is well known that such efficient oxidants as TEMPO transform vicinal diols to a-hydroxycarbonyl compounds (see, e.g., Refs 188 and 189) and oxidise 1,2-diphenylethane-1,2-diol 85 to benzil 7a.190 It was shown that the readily accessible 4-acet- amido-TEMPO in combination with toluene-p-sulfonic acid in chloroform or CH2Cl2 can serve as a general reagent for the mild oxidation of linear and cyclic vicinal diols to a-diones.191 At present, the majority of other reagents for the oxidation of glycols are used less commonly.For example, it was shown that cis-cyclododecane-1,2-diol is oxidised to cyclododecane-1,2-dione on treatment with tris(triphenylphosphine)ruthenium dichloride [(Ph3P)3RuCl2] in 53% yield.192 Later, an almost identical result was obtained using tert-butyl hydroperoxide in benzene in the presence of a phase-transfer catalyst, namely, PhCH2N+Me3 7OMoBr4.193 Cyclohexane-1,2-diol undergoes oxidation to cyclohexane-1,2-dione 4a in 51% yield at room temperature on treatment with a ruthenium complex (LPh4)(RuO2Cl3), where L=P or As.194 It was shown that KMnO4 in the presence of nonionic tris[2- (2-methoxyethoxy)ethyl]amine, unlike other phase-transfer cata- lysts, oxidises phenylethane-1,2-diol and the diol 85 to phenyl- glyoxal and diketone 7a in high yields.195 Hydrogen peroxide applied onto the TS-1 zeolite converts one or both of the hydroxy groups in 1,2-diols to carbonyls, while cleavage of the C7C bond occurs only if an excess of the reagent is used.196 Solvents affect strongly the reaction selectivity.For example, butane-2,3-diol is converted into 3-hydroxybutan-2-one in methanol and to butane- 2,3-dione in acetone. Unlike other periodates, tetrabutylammonium periodate in the presence of AlCl3 in boiling chloroform oxidises the diol 85 to give mostly the diketone 7a (yield 70%), and glycol cleavage occurs to a small extent (20% of benzaldehyde).87 PhSe(O)Se(O)Ph is another reagent that enables the selective oxidation of the diol 85 to benzil 7a (refluxing in THF for 3 h, yield 77%).83 Quantitative yield of the compound 7a in the oxidation of the diol 85 under very mild conditions is also provided by the system N-chlorosuccinimide ±Me2Se.96 The cata- lytic system RuO¡4 ± BrO¡3 cleaves the diol 85 to benzoic acid, whereas trans-RuO3(OH)2¡ 2 ±S2O¡8 affords benzil 7a in 65% yield.197 The mechanism of oxidation of meso- and d,l-diol 85 with peroxomolybdenum complexes, viz., neutral MoO5 .HMPA and anionic (MoO5 .PICO)7Bu4N+ (PICO is picoline N-oxide) was studied.198 In all cases, the oxidation of the diol 85 results in benzil 7a and benzaldehyde. The latter is formed due to glycol cleavage of the diol 85. The ratio of the reaction products is strongly affected by the nature of the substrates and oxidants. For example, the action of MoO5 .HMPA on both meso- and d,l-diol 85 results almost exclusively in benzaldehyde.However, the (MoO5 . PICO)7- Bu4N+ oxidant mostly converts the meso-form of the diol 85 to the diketone 7a, while the d,l-diol 85 is converted to benzaldehyde. Benzil 7a is formed from a complex of the substrate with the oxidant in which the glycol is coordinated as a monodentate ligand, while benzaldehyde is formed from a complex in which the substrate plays the role of a chelating ligand.If the reaction is carried out in air, autooxidation takes place. There is evidence that the reaction occurs in the coordination sphere of the metal according to a homolytic mechanism.198 A biochemical method was suggested for the transformation of ethylene glycol to glyoxal by treatment with oxidoreductase or microorganisms containing oxidoreductase, at 30 8C in aqueous solutions.199 Ethylene glycol can also be oxidised to glyoxylic acid.Acces- sible oxidants based on nitric acid, namely, HNO3±H2SO4 ± HO O Cl Cl 81 O O Br Br 80 Br Br OH OH DMSO, (CF3CO)2O O Br OH 82 Br Br OH OMe OH DMSO, (CF3CO)2O O Br OMe OH 83 HO HO H Me Me C8H17 O HO H Me DMSO (CF3CO)2O + HO O H Me R1, R2=Me, Ph, (CH2)4. R1 OH HO R2 + I O O HO O 84 DMSO R1 O O R2 MoO5 .HMPA or (MoO5 .PICO)7Bu4N+ Ph OH HO Ph 85 Ph O O Ph 7a +PhCHO 736 V D Filimonov,MS Yusubov, Ki-Van ChiV2O5 200 and HNO3 with Co, Al and Cu acetylacetonates,201 have recently been suggested for this purpose. Such an efficient reagent as dimethyldioxirane can oxidise 1,2- diols without cleavage of the C7C bond of the glycol. However, the reaction stops at the step of the formation of hydroxy ketones, while diketones are found in the reaction mixture only as traces, since the carbonyl group that is formed deactivates the methine group as regards further oxidation.202 Glycol cleavage can be used for the synthesis of a-dicarbonyl compounds.Cleavage of methyl and ethyl D-tartrates in dry ether to the corresponding alkyl glyoxylates in 80%± 85% yields on treatment with periodic acid 203 can serve as an example.Oxidation of epoxides usually results in a-hydroxy ketones. This was found for the first time in the treatment of epoxides with DMSO in the presence of a catalytic amount of BF3 etherate.204 The same result was obtained on passing air through solutions of epoxides in DMSO. It was assumed205 that the oxidation follows a radical mechanism.It was shown subsequently that the reaction follows an ionic mechanism with epoxide ring opening on treat- ment with DMSO in the presence of various protic acids (CF3COOH, H2SO4, MeSO3H, HBF4, HNO3) resulting in the formation of an a-hydroxysulfoxonium salt. In turn, the latter decomposes to a-hydroxy ketones according to Kornblum.206, 207 Hydroxy ketones are also formed on treatment of epoxides with DMSO in the presence of molecular sieves 208 or clay with micro- wave heating.209 Epoxysilanes are also oxidised in DMSO in the presence of triflates and tertiary amines to give a-hydroxy- acylsilanes.210 Unlike the reagents indicated above, the aqueous HBr ±DMSO system smoothly converts diphenyloxirane to ben- zil 7a in 71% yield; however, bis(a-diketone) 28 is formed from the corresponding bis(epoxide) in 31% yield only.211 1,2-Diones are formed upon oxidation of a-nitro epox- ides.212 ± 214 This process occurs in the presence of tetrakis(triphe- nylphosphine)palladium and triethylamine in boiling benzene and gives satisfactory yields of a-diketones.212, 214 The oxidation of nitro epoxides with the BF3 .Et2O (or Me3SiCl) ±DMSO system in CH2Cl2 at 0 8C followed by the addition of triethylamine gives the corresponding diketones in somewhat higher yields (54% ± 87%).213, 214 The same method afforded the triketone ketal 86.213, 214 The reaction of a-nitro epoxides with BF3 . Et2Oin acetonitrile in the presence of NaI gave good yields of a-iodo ketones.213, 214 Transformations of vicinal dihalides (or halohydrins) to a-dicarbonyl compounds are not typical in organic synthesis, although dibromination of alkanes or bromination of alkenes followed by transformation to a-diketones can serve as an alter- native to hydrocarbon oxidation.These transformations can be performed efficiently with a number of reagents that have appeared in the last few years.Refluxing of 2-aryl-1,2-dibromo-1-phenylethanes in acetic acid in the presence of tellurium dioxide gives benzil 7a and its derivatives (yields 19% ± 82%) as well as the diacetates of the corresponding 1,2-diols and stilbenes.215 The diacetates and stilbenes predominate among the products in the case of sub- strates with electron-withdrawing substituents. DMSO is a more convenient and accessible reagent for this kind of transformation.216 For example, it was found that heating of meso- and d,l-2-aryl-1,2-dibromo-1-phenylethanes in the aque- ous HBr ±DMSO system at 110 8C for 4 ± 8 h readily gives benzil 7a and its derivatives in 70%± 80% yields.This transformation occurs also without HBr but requires a longer time.112 Later, this reaction was carried out with many acyclic and cyclic vicinal dibromides under microwave irradiation and gave a-diketones in 51%± 75% yields.217 2-Bromo-1,2-diphenylethanol and even its methyl ether and formate undergo oxidation to diphenylethanedione in aqueous HBr ±DMSO even more readily than 1,2-dibromo-1,2-diphenyl- ethane.112 If the oxidation is carried out without HBr, it follows the same direction but occurs more slowly.112 The cheapest way to oxidise 1,2-dibromo-1,2-diphenylethane to benzil (yield 80%) is heating the substrate in acetic acid in the presence of sulfuric acid.218 It was found later that the addition of such compounds as iodine, potassium iodide or sodium sulfite to the reaction mixture accelerates considerably the oxidation of vicinal dibromides.219 The possibility of the synthesis of 1,2,5,6-tetraketopyracene (87), a structural element of buckminsterfullerene, according to the following scheme was studied:220, 221 Oxidation of the starting 1,2-dioxopyracene (88) with sodium dichromate resulted in the cleavage of the diketone carbon ± carbon bond.However, the target tetraketone 87 could be obtained by the oxidation of the dibromide prepared by bromi- nation of the diketone 88 with N-bromosuccinimide according to the reported procedure.222 The oxidation of the dibromide was carried out by treatment with the AgNO3 ±MeCN system and then with NaOAc . 3H2O±DMSO.220 The yield of the tetraketone 87 reached 80% but was irreproducible. Later, the same research BF3 . Et2O (or Me3SiCl) DMSO O NO2 R2 R1 O R1 R2 O R1, R2=Ph, Pr, Me, (CH2)4Me, (CH2)3, (CH2)4.O O O O 86 Ph Br Br Ar TeO2 AcOH Ph O O Ar + Ph OAc AcO Ar + Ph Ar 4-NO2C6H4, 4-NCC6H4, . Ar=Ph, 4-MeOC6H4, 4-MeC6H4, 2,3,4-MeC6H2, 4-ClC6H4, O CH2 O R=H, Me, MeO, Cl, NO2. Ph O O Ph Br Br C6H4R-4 C6H4R-4 HBr ±DMSO R=H, Me, CHO. Ph OR Br Ph Ph Br Br Ph Ph O O Ph HBr ±DMSO AcOH±H2SO4 7a O O 88 NBS O O Br Br [O] O O O O 87 Oxidative methods in the synthesis of vicinal di- and polycarbonyl compounds 737group found that the dioxopyracene 88 could be directly oxidised to the tetraketone 87 by treatment with benzeneseleninic anhy- dride221 (see Section IV).Methods are known for the transformation of five-membered heterocycles to a-diones. Certain 5-hydroxyoxazolines of the type 89 decompose in formic acid at room temperature to give the corresponding a-diketones in good yields.A method based on this reaction was elaborated for the synthesis of a-diketones from a-amino acids, as shown below.223 A number of acetylenic a-diketones used in the synthesis of tetrasubstituted furans were obtained according to the same scheme.224 Diaryl-substituted glycolurils 90 ± 92 are oxidised to benzil 7a and diketone 28 (yield 80%± 90%) on heating with nitric acid in aqueous acetic acid in the presence of H2SO4.225 The oxidation of 4,5-diphenylimidazole to the benzil 7a occurs at milder conditions than that for glycolurils.It does not require the presence of sulfuric acid and water and affords the products in 80%± 85% yield. The reaction involves the intermediate forma- tion of 2-nitro-4,5-diphenylimidazole.225 IV. Oxidation of alkanes, alkenes, alkynes and their derivatives Of the classes of compounds listed above, alkynes can be con- verted to a-dicarbonyl compounds most easily (followed by alkenes and finally alkanes).Table 4 lists the reagents used for the preparative oxidation. For many reasons, direct oxidation of alkanes to a-dicarbonyl compounds is a difficult technical problem, and only a few examples of this kind of oxidation are known.For example, in view of the great practical importance of acenaphthenequinone, processes for its synthesis by direct oxida- tion of acenaphthene were studied. Such oxidants as H2O2, HNO3, permanganates and oxygen under pressure or in the presence of various catalysts were used.226 None of these methods gave good yields of acenaphthenequinone. The oxidation of acenaphthene with Na2Cr2O7 in AcOH with addition of cerium acetate at 40 8C does not provide high yield of acenaphthene- quinone either (38% ± 60%).On the other hand, as noted above, sodium dichromate does not oxidise dioxopyracene 88 to the tetraketone 87. However, this was performed with the use of benzeneseleninic anhydride (PhSeO)2O, which oxidises com- pound 88 to the tetraketone 87 in 82% yield on heating in chlorobenzene at 125 8C.221 1,2-Diphenylethane and its derivatives undergo oxidation with oxygen in the liquid phase in the presence of Co ±Mn ±MBr catalysts to give the corresponding diphenyl- ethanediones.228 ± 230 If oxygen is passed through a solution of compound 93 in glacial acetic acid containing the tetrahydrates of manganese and cobalt acetates and NaBr, not only the a-keto- methylene groups but also the ethane fragment are oxidised at 110 8C, leading to the formation of the hexaketone 94 in 70% yield.228 O R1 R2 O R1=Pri : R2=Ph, C CPh; R1=Bus, R2=Bun; R1=Ph, R2=Bun; R1=CH2CH2SMe, R2=Me; R1=(CH2)3NHCOCF3: R2=Bun, Ph.NH2 R1 COOH (CF3CO)2O N O CF3 O R1 CH2 CHCOOBut, Et3N N O O R1 F3C COOBut R2MgX or R2Li N O R1 F3C COOBut OH R2 89 HCOOH HN NH HN NH Ph Ph O O HNO3, H2SO4, H2O AcOH, 120 8C, 4 h PhCOCOPh 7a 90 HN NH HN NH Ph O O O O Ph NH HN NH HN 91 HNO3, H2SO4, H2O AcOH, 120 8C, 8 h 28 HN NH HN NH Ph O O O Ph O HNO3, H2SO4, H2O AcOH, 120 8C, 6 h 28 92 N NH Ph Ph HNO3, AcOH D N N H Ph Ph NO2 7a O2, cat.O Ph O Ph 93 O Ph O Ph 94 O O O O Table 4.Reagents used for the preparative oxidation of alkanes, alkenes, alkynes and their derivatives to a-dicarbonyl compounds R1COCOR2. Substrate Reagent R1CH2CH2R2 Na2Cr2O7 ±AcOH± Ce(OAc)3, (PhSeO)2O, O2 ± (Co(OAc)2, Mn(OAc)2, NaBr); Gif-system: Fe(NO3)3 .9H2O±ButOOH±MeCOCH=CH2 R1CH=CHR2 SeO2, KMnO4, CrO3 ± AcOH, O2 ± (Co(OAc)2, Mn(OAc)2, NaBr), OsO4, HBr ±DMSO, I2 ± DMSO, NaBr ± HCl ± DMSO, Bu4NBr ± HCl ±DMSO, Br2 ± H2SO4, I2±H2SO4, HBr ±H2SO4, NaBr ±H2SO4 R17C:C7R2 O3, KMnO4, NH4MnO4, Zn(MnO4)2, RuO4, OsO4, Tl(NO3)3, SeO2, O2, PhSeSePh ±(NH4)2S2O8 ±MeOH, MoO(O2)2 ± Hg(OAc)2, H2O2±H3PMo12O40, H2O2 ± H3PW12O40, H2O2 ±MeReO3, CF3COOOH, HNO3 ± NaNO2 ± PdCl2, Cr(V)±N,N0-ethylenebissalicylydene iminate, H3PO5, dialkyldioxiranes, PhIO ± RuCl2(PPh3)3, PhI(OCOCF3)2, H5IO6, I2O5, HgO± I2, NBS± DMSO, I2 ±DMSO, anodic oxidation 738 V D Filimonov,MS Yusubov, Ki-Van ChiA study of the oxidation of 1,2-diphenylethane with oxygen in the presence of Co ±Mn ±MBr catalysts showed that this process follows the radical mechanism.In the first step, it gives 1,2- diphenylethane-1,2-diol, which is then oxidised to 1,2-diphenyl- ethanone.The latter is transformed to benzil 7a. The overall selectivity reaches 80%.229, 230 The selectivity of oxidation is affected only by the reaction temperature and the concentration of Mn(OAc)2 . 4H2O.230 Oxidation of pentane and hexane with the Ph3Bi ± ButOOH system at room temperature initially gives a-diketones, which are then oxidised to carboxylic acid anhydrides.231 In this case, it is the oxygen formed from the hydroperoxide in the coordination sphere of the metal that serves as the actual oxidant.231 Dicarbonyl compounds are also obtained upon oxidative formation or cleavage of the C7C bonds.Oxidation of cyclo- hexane, cyclooctane and cyclododecane in Gif-systems under the action of Fe(NO3)3 . 9H2O±ButOOH in the presence of methyl vinyl ketone results in the corresponding 1-cycloalkylbutane-2,3- diones as the main products.232 The reaction occurs through the Michael-type addition of the cycloalkane to methyl vinyl ketone followed by the insertion of the tert-butylperoxy group at the a- position to the carbonyl group of the adduct, which then slowly eliminates ButOH to give a-diketones.232 Oxidative cleavage of the C7C bonds can also result in dioxo carboxylic acids.For instance, the oxidation of the enol forms of cyclic 1,3-diketones with copper(II) salts and oxygen results in acids 95.233 Over ten years ago, Haines 234 noted that there are probably few reliable methods for the transformation of alkenes to 1,2- dicarbonyl compounds. This statement is no longer wholly true since the late 80's when new oxidising DMSO-based reagents appeared.Selenium dioxide was among the first reagents that oxidise alkenes to a-dicarbonyl compounds. It oxidises alkenes contain- ing no allylic hydrogen atoms rather successfully on heating them in acetic acid, trichlorobenzene or without a solvent. For example, ethylene and stilbene are oxidised to glyoxal and benzil 7a in up to 70% yields;35, 234 styrene is converted to phenylglyoxal along with hydroxylation products,235 while propene, a representative of allylic alkenes, gives methylglyoxal in only 19% yield.234 The direction of the oxidation of alkenes with potassium permanganate strongly depends on the reaction conditions.In alkaline media, internal alkenes mostly form 1,2-diols, while in nearly neutral or weakly alkaline media (pH 9 ± 9.5) a-hydroxy ketones are formed.234 Symmetric cyclic and acyclic alkenes are oxidised with potassium permanganate in cold acetic anhydride (not above 10 8C) to give the corresponding a-diketones in moderate yields.236, 237 The selectivity of the process is not high as noticeable amounts of 2-acetoxy ketones and dicarboxylic acids are formed.It was noted that the reaction may be hazardous.237 In addition, attempts to synthesise diketones from cyclohexene and norbornene failed.234 The oxidation of E-alkenes gives somewhat higher yields of diketones than the oxidation of the Z-iso- mers.234, 236 Styrene can be converted to phenylglyoxylic acid by oxidation with potassium permanganate under alkaline condi- tions.238 Oxidation of nonterminal alkenes with permanganate under conditions of phase-transfer catalysis gives a-diols, a-diketones and a-hydroxy ketones along with carboxylic acids.The ratio of the oxidation products can be controlled by varying the con- ditions.234 For example, cyclododecane-1,2-dione and decane-5,6- dione were obtained in 69% and 53% yields from the correspond- ing alkenes in the KMnO4±CH2Cl2±H2O system containing acetic acid and Adogen 464.239 Such a heterogeneous reagent as KMnO4 ± CuSO4 . 5H2O± Cu(OAc)2 .H2O in CH2 Cl2 oxidises cyclooctene and cyclodo- decene to the corresponding diketones in moderate yields.240 In the absence of copper acetate, the reaction stops in the step of formation of a-hydroxy ketones.240 Oxidation of nonterminal fluoroalkenes with permanganate under strictly controlled conditions (the ratio alkene :KMnO4= 1 : 0.3 ± 0.7, acetone : water=24 : 1; 730 to 720 8C) affords diketones 96 in 30%± 80% yields.241, 242 It is assumed that this reaction occurs via an intermediate product of hydroxylation of the C=C bond, which undergoes dehydrofluorination to give the target products.Although sat- isfactory yields are obtained, cleavage of theC7Cbond cannot be avoided completely, even at 50% conversion of the starting olefin.242 Perfluoroalkenes can also be converted to dicarbonyl com- pounds by catalytic or stoichiometric oxidation with osmium tetroxide. In this case, tetrafluoroethylene is converted to glyox- ylic acid in good yield, while perfluorocyclohexene gives perfluor- ocyclohexane-1,2-dione.243, 244 Chromium(VI) compounds are mostly known as oxidants that cleave the C=C bonds. However, a few cases have been reported in which dicarbonyl compounds were obtained upon oxidation of the double bonds with chromium trioxide.For example, CrO3 in acetic acid was used for the oxidation of a series of 1,2-dihydroi- soquinolines to the corresponding 3,4-dioxo derivatives 97.245 Both stilbene isomers are converted on treatment with a catalytic amount of CrO3 and an excess of aqueous tert-butyl hydroperoxide to give mixtures of oxidation products, trans- stilbene oxide being the major component.In this case, approx- imately equal amounts of benzil 7a, benzophenone and benzoin benzoate are formed.246 Norbornene was found to be inert under these conditions.246 A study of the liquid-phase oxidation of (E)-stilbene with oxygen in acetic acid at 105 8C in the presence of a Co ±Mn± - bromide catalyst showed that rapid and total conversion of the substrate results in a complex mixture of products [PhCOOH, Ph2CO, Ph2CHCHO, PhCOCOPh, PhCH2COPh, PhCH(OAc)- COPh, PhCH(OAc)CH(OAc)Ph, etc.] with up to 46% content of benzil 7a.247 These products are formed from the primary oxida- tion product, i.e. 1,2-diphenyloxirane.247 Peracetic acid oxidises trans-1-acetoxy-2-iodo-1,2-diphenyl- ethylene to diketone 7a in low yield.248 DMSO-based oxidants are much more versatile and conven- ient reagents for the synthesis of a-dicarbonyl compounds from alkenes. This was first discovered in 1989 for stilbene, which was oxidised readily and in high yield to benzil 7a in the HBr ±H2O2 ±DMSO system.249 It was found subsequently that hydrogen peroxide accelerates the reaction but does not act as an oxidant.A solution of aqueous HBr in DMSO successfully oxidises stilbenes with both donor and acceptor substituents to (CH2)n R O HO Cu(ClO4)2 .6H2O, O2 MeCN, 20 8C, 10 ± 15 h O R (CH2)n O COOH 95 n=0,R=Me; n=1: R=Me, CH CH2, CH2CH CH2, Ph.R=CF3, Ph. KMnO4 O R CF3 O 96 F R CF3 F N R1 R2 CrO3 AcOH N R1 R2 O O 97 R1=2,4,6-(NO2)3C6H2CH2, R2=PhCO; R1=2,4-(NO2)2C6H3CH2: R2=PhSO2, 4-NO2C6H4CO. Oxidative methods in the synthesis of vicinal di- and polycarbonyl compounds 739give the corresponding diarylethanediones in 56%± 86% yields. It turned out that the first act of the process involves the electrophilic addition of bromine, which is formed in situ from HBr and DMSO, to the double bond, but it is the intermediate 1,2-diaryl- 1,2-dibromoethanes that undergo oxidation.In this case, DMSO plays a dual role, specifically, it generates a microscopic amount of bromine from HBr (it is this reaction that is accelerated by hydrogen peroxide) and oxidises dibromides by a mechanism resembling that of the Kornblum reaction.112, 157 Since the first act of the reaction is the electrophilic addition of bromine to the double bond, it becomes clear why the oxidation of 4-nitrostilbene requires much longer time than that of stilbene, while 4,40- dinitrostilbene does not undergo oxidation at all.112 Compounds other than hydrogen bromide can be successfully utilised as the bromine sources.For instance, good results were achieved in the NaBr ±H2SO4 ±DMSO, NaBr ± HCl ±DMSO, and Bu4NBr ± HCl ±DMSO systems.114 In some cases, passage of air through a solution of HBr in DMSO increases the oxidation efficiency.250 Triple bonds are practically inert with respect to HBr in DMSO. This fact was successfully used to perform selective oxidation of double bonds in the enynes 98 and 99 in the synthesis of acetylenic a-diketones 100 and 101.251 Iodine in DMSO can also oxidise alkenes to dicarbonyl compounds, but it is much less reactive than HBr ± DMSO.251 ± 254 This reagent oxidises only stilbene and its deriva- tives containing electron-donating or weak electron-withdrawing substituents (Me, OMe, Cl) at position 4.252, 253 The decrease in the reaction rate caused by electron-withdrawing substituents made it possible for the first time to perform selective oxidation of only one bond in 1,4-(E,E)-distyrylbenzene (102) to give compound 103.251 Styrene, being an alkene with a terminal double bond, is oxidised both with bromine and HBr in DMSO to give phenyl- glyoxal.This results in a much larger amount of side products than in the oxidation of stilbenes.255 In the oxidation of 3-styryl- and 3,6-distyrylcarbazoles with the HBr ±DMSO system, oxidation of the double bonds is accompanied by side processes such as bromination of the carbazole moiety and methylenation of the free NH groups to give dioxo- and tetraoxocarbazole derivatives 104 and 105.256 These side processes that are beneficial in this case occur due to the reaction of the carbazole moiety with bromine and form- aldehyde generated upon the reaction of HBr with DMSO at 120 8C.256 The most efficient method for the oxidation of stilbenes to diketones (yields 50%± 81%) is probably refluxing the substrates in acetic acid in the presence of H2SO4 containing admixtures of bromine, iodine, HBr, NaBr or sodium sulfite.218, 219 As men- tioned above, the reaction involves intermediate electrophilic halogenation of double bonds if halogens, hydrogen halides or their salts are used.218, 219 In addition, examples of the specific oxidation of double bonds with the formation of specific types of dicarbonyl com- pounds are worth noting. Oxidation of compounds 106 with RuO4 (formed from RuCl3 . 3H2O and NaIO4) in a mixture of CCl4 and aqueousMeCNaffords macrocyclic bis-a-diketones 107 in yields up to 40%.257 Aroylketene dithioacetals 108 are oxidised with Pb(OAc)4 in boiling benzene to give acetoxy dithioacetals, which are hydro- lysed under mild conditions to compounds 109.Under similar conditions, their vinylogues 110 undergo oxidative cyclisation according to Nazarov, giving 2-acetoxycyclopentenone deriva- tives 111, which are precursors of di- and tri-ketones.258 Oxidation of alkynes to a-dicarbonyl compounds, unlike that of alkanes and alkenes, is one of reliable methods to obtain compounds of this class.Numerous reagents are known to perform this type of transformation successfully, although there is always a danger of cleavage of the carbon ± carbon bond both in substrates and in products.The oxidation of alkynes has been covered in reviews and books rather thoroughly,4, 5, 40, 234 and in most cases we are going to refer to the newer studies or those not included in these sources. Alkynes are comparatively resistant against oxygen, and only few examples of their oxidation with oxygen to diketones are known. Passage of air through a solution of diphenylacetylene in acetic acid containing a Co ±Mn±MBr catalyst for 3 h at 110 8C gives benzil 7a in up to 90% yield.259 Oxidation of cyclooctyne with air at low temperatures to give the corresponding a-dione was also reported.260 Ozonisation of both terminal and internal alkynes in alcohols at low temperatures serves as a method for the synthesis of oxo aldehydes and a-diketones.The ozonisation of 1-ethoxypent-1- yne in hexane gave ethyl 2-oxopentanoate.234 Oxidation of alkynes that do not contain methylene groups adjacent to the triple bond to a-dicarbonyl compounds is carried out with selenium dioxide.40, 234 The oxidation is facilitated upon addition of catalytic amounts of sulfuric acid. For example, refluxing diphenylacetylene with SeO2 in AcOH containing sulfu- ric acid gives diketone 7a.The reaction with phenylacetylene HBr, DMSO 100 8C, 11 h Ph 100 Ph O O Ph 98 Ph Ph Ph HBr, DMSO 110 8C, 10 h Ph Ph O O 101 99 Ph Ph O O 103 (86%) Ph Ph 102 I2, DMSO 100 8C, 11 h N R1 R2 O Ph O R1=H, Me; R2=H, Br. N O Ph O Br N Br Ph O O 105 104 n=6, 10. O (CH2)n (CH2)n 106 RuO4 (CH2)n (H2C)n O O O O 107 Ar O SMe SMe 108 Pb(OAc)4 PhH Ar O SMe SMe AcO H2O, HO7 Ar O SMe SMe O 109 Ar O SMe SMe Pb(OAc)4 PhH 110 OAc Ar SMe SMe O 111 740 V D Filimonov,MS Yusubov, Ki-Van Chiunder the same conditions gives phenylglyoxylic acid.234 Diphenyl diselenide is another selenium-containing reagent that oxidises the triple bond.It converts alkynes to diketone and oxo aldehyde monoacetals in high yields in boiling methanol in the presence of ammonium peroxodisulfate.261 Potassium, zinc and ammonium permanganates are widely used to oxidise alkynes (for the reviews, see Refs 4, 234, 262).To our knowledge, in these reactions terminal alkynes undergo only oxidative cleavage with the formation of carboxylic acids and loss of one carbon atom, whereas a-diketones can be obtained only from internal alkynes.A particularly efficient general method for the synthesis of a-dicarbonyl compounds from alkynes involves the oxidation of the latter with potassium permanganate in aqueous acetone or dioxane under nearly neutral conditions provided by the addition of sodium hydrogen carbonate and magnesium sulfate.234 Of potassium, magnesium and zinc per- manganates, the latter is the most efficient reagent for the oxidation of alkynes in dichloromethane.263 Potassium perman- ganate in aqueous acetone proved to be a convenient oxidant of 3,6-di(phenylethynyl)carbazoles to the corresponding 3,6- bis(phenylglyoxylyl)carbazoles.264, 265 The mechanism of the oxi- dation of alkynes with KMnO4 and the effect of the substrate structure on the process were studied.266 It was shown that the oxidation rate depends on electronic rather than on steric factors.Certain similarity is observed between the oxidation of alkynes with osmium and ruthenium tetroxides. Terminal alkynes are oxidised with OsO4 to carboxylic acids. On the other hand, alkynes with an internal triple bond can be oxidised to a-diketones using this reagent.234, 267 It was found that OsO4 forms complexes with alkynes in the presence of pyridine or isoquinoline, 2OsO4L4R1C:CR2 (where L is pyridine or isoquinoline); these complexes are hydrolysed in the presence of sodium sulfite to the corresponding diketones, R1COCOR2.However, phenylacety- lene is converted to benzoic acid under these conditions.268 There are methods for the transformation of alkynes to dicar- bonyl derivatives with a catalytic amount of OsO4 in the presence of co-oxidants, such as potassium chlorate, hydrogen peroxide, tert-butyl hydroperoxide and morpholine N-oxide.234 It is believed that OsO4 is the actual oxidant, while a co-oxidant, for example, potassium chlorate, regenerates OsO4 from the osmium dioxide formed in the first step.269 Acetylene is oxidised with the OsO4 ± KClO3 system to give glyoxylic acid,267 and alkoxyalkynes form a-oxo esters in high yields under similar conditions.269 Trimethylsilylalkynes are oxidised to methyl or butyl phenyl(- alkyl)glyoxylates on treatment with a catalytic amount of OsO4 in the presence of ButOOH in methanol or tert-butyl alcohol at 0 8C.270 It is believed that a-oxo esters are formed from the primary oxidation products, i.e.silylated diketones, on decom- position with an alcohol.270 Ruthenium tetroxide, which is generated in situ from RuO2 dihydrate, RuCl3 or tris(triphenylphosphine)ruthenium dichlor- ide and such oxidants as NaIO4, NaOCl or PhIO or by electro- chemical oxidation, serves as an efficient reagent for the transformation of internal alkynes to a-diketones under mild conditions.234, 271 Probably, the main advantage of RuO4 is that its reacts under mild conditions (often at, or below, room temper- ature) and its high selectivity.For example, benzil 7a and a- diketones 112 ± 117 with various functional groups are obtained in 27%± 95% yields from the corresponding internal alkynes and ruthenium dichloride with NaIO4.272 The same method was used in the synthesis of dioxo amides 118 ± 120 from the corresponding acetylenic carboxamides.273 Terminal alkynes are converted to carboxylic acids upon oxidation with a catalytic amount of ruthenium tetroxide gener- ated electrochemically from ruthenium dioxide.271 On the other hand, dialkyl- and phenylalkylalkynes are oxidised with RuO4 to give a-diketones in high yields in a two-phase system CCl4 ± satu- rated aqueous NaCl.271 Iodosylbenzene combined with RuCl2(PPh3)3 in CCl4 readily oxidises internal alkynes to the corresponding a-diketones.274 The same reagent oxidises alkoxy- and aminoalkynes to a-oxo esters and a-oxo carboxamides in 44%± 84% yields.275 Thallium nitrate is one more reagent that readily oxidises triple bonds.However, its use in the synthesis of a-dicarbonyl compounds is rather limited.Symmetric dialkylalkynes are con- verted with Tl(NO3)3 in acidic methanolic medium to give a-hydroxy or a-methoxy ketones, whereas alkylarylalkynes undergo oxidation with 1,2-alkyl shift to give a-branched carbox- ylic acids.5 It is only diphenylacetylene and its substituted deriv- atives that undergo oxidation on refluxing with Tl(NO3)3 in glym containing HClO4 to give benzils in 45%± 97% yields.276 In recent years, molybdenum and tungsten peroxocomplexes have been extensively studied as oxidants of alkynes.277 ± 282 It was R1 C C R2 PhSeSePh, (NH4)2S2O8 MeOH R1 C C R2 O OMe OMe R1=Ph: R2=H, Ph, 3-ButC6H4, 4-FC6H4, 2-BrC6H4; R2=H:R1=PhCH2, Bun, C6H13, HOOCCH2; R1=R2=Prn.R1=Ph, C5H11, C6H13; R2=Me, But.R1 C C SiMe3 OsO4 ButOOH R1 C C SiMe3 O O R2OH R1COCOOR2 O Me O Me Me OR1 112 Me O O R2 113 Me O O OR3 114 O Me(CH2)12 Si(But)Me2 O 116 O O O O 115 O O O OR4 O C5H11 117 R1=Ac, tetrahydropyran-2-yl; R2=COOMe, OCOBut; R3=CH2Ph, tetrahydropyran-2-yl; R4=Si(But)Me2. R=Ph, Bu, BuO(CH2)4. Bu3SiO O O N O H OSiBu3 Me OMe 120 O R O NEt2 O 118 O Ph O O N COOCH2Ph 119 R1=Me, R2=Et; R1=Pri , R2=Me; R1=Ph, R2=Me, Et.R1C COR2 PhIO ±RuCl2(PPh3)3 R1COCOOR2 R1=Me, R2=Et; R1=Pri , R2=Me; R1=n-C6H13, R2=Me; R1=Bu, R2=Pri ; R1=Ph, R2=Et. R1COCONR22 PhIO ±RuCl2(PPh3)3 R1C CNR22 Oxidative methods in the synthesis of vicinal di- and polycarbonyl compounds 741shown that both terminal and internal alkynes undergo oxidation to the corresponding a-oxo aldehydes and a-diketones in rather good yields (55% ± 90%) on treatment with a MoO(O2)2 ± hex- amethylphosphoramide complex in the presence of mercuric acetate in a dichloroethane ± methanol mixture.277 No oxidation occurs in the absence of Hg(OAc)2.It is known that the action of hydrogen peroxide on Na2MO4 salts [wherein M=Mo(VI) orW(VI)] results in oxodiperoxo complexes with the composition MoO(O2)2, which possess strong oxidative proper- ties.It turned out that dilute H2O2 oxidises phenylacetylene and hex-1-yne rather readily in the presence of a catalytic amount of molybdates or tungstates (Na2MO4), phase-transfer catalysts, and mercuric acetate. However, the yields of the resulting oxo alde- hydes are low, while carboxylic acids are the main products.278 Diphenylacetylene was inert under these conditions.Heteropo- lyacids, such as H3PMo12O40 and H3PW12O40, manifest higher catalytic activity in the oxidation of alkynes with hydrogen peroxide;280 ± 282 these catalysts convert acetylene to glyoxal (yields up to 63%).280 However, phenylacetylene and certain dialkyl- and alkylphenylalkynes are oxidised under these condi- tions mostly to give carboxylic acids, unsaturated ketones and a-oxo epoxides.279, 281, 282 Generally, this type of catalytic oxida- tion of the triple bond to a-dicarbonyl compounds is no more selective than the oxidation with hydrogen peroxide or peroxy acids.For instance, it is known that trifluoroperacetic acid oxidises diphenylacetylene to afford a mixture of benzil 7a and benzoic acid.283 Mixtures of products are also formed upon oxidation of alkynes with hydrogen peroxide in the presence of methylrhenium trioxide MeReO3.284 The reaction in the two- phase system CH2Cl2±H2O converts diphenyl-, dipropyl-, and tert-butyl(methyl)alkynes to the corresponding a-diketones (yields 38%± 67%), and terminal alkynes (phenylacetylene and non-1-yne) are oxidised to phenyl- and heptylglyoxalic acids (yields 68% and 47%).284 Nitrogen oxides catalyse the oxidation of acetylene to glyoxal at temperatures from 170 to 250 8C,285 and Pd(II) catalyses its oxidation in 30%± 60% HNO3 to oxalic acid.286 It was shown that acetylene is not oxidised in HNO3 at 25 8C or in the HNO3 ±NaNO2 system, but PdCl2 ±NaNO2 in nitric acid at 15 8C favours the formation of glyoxal in 40%± 50% yield with respect to the acetylene consumed.287 Hg(NO3)2 is less reactive.Methylacetylene was found to be more reactive than acetylene with respect to oxidation, while phenylacetylene gives stable organopalladium compounds that do not undergo further oxida- tion under the reaction conditions.287 Diphenylacetylene is oxidised in high yield to benzil 7a under the action of complexes of Cr(V) with N,N0-ethylenebissalicylide- neiminate (salen-complexes).However, phenylacetylene is mostly converted to benzoic acid under these conditions, while only a small amount of phenylglyoxal is formed.288, 289 Phenylacetylene and certain internal alkynes are efficiently oxidised with monoperoxyphosphoric acid (H3PO5). However, this reaction produces mixtures of the corresponding a-dicarbonyl compounds with benzoic acid and rearrangement products.The reaction involves a-oxo carbenes as intermediates.290 The oxidation of alkynes with dimethyl- and methyl(tri- fluoromethyl)dioxiranes also occurs via a-oxo carbene intermedi- ates. The reaction results in mixtures of oxidation products, including a-diketones and a-oxo acids.291, 292 Bis(trifluoroacetoxy)-l3-iodanylbenzene 121 smoothly oxi- dises internal alkynes to a-diketones and terminal alkynes to a-hydroxy ketones.293 ± 296 Two equivalents of the reagent 121 selectively oxidise one triple bond in bisphenylethynylbenzene to give acetylenic diketone 100, while four equivalents of the reagent oxidise the substrate completely, converting it to the tetraketone 28.293 Compound 121 oxidises only one triple bond in diphenylbu- tadiyne to produce a mixture of diphenyl-1,4-dioxobutyne (40%) and acetylenic diketone 101 (30%).296 Compound 121 oxidises diphenylacetylene and its derivatives with electron-donating or moderate electron-withdrawing groups to the corresponding benzils in yields above 70%.However, (4-nitrophenyl)phenylace- tylene is converted to 4-nitrobenzil in only 28% yield.294 Despite the high selectivity of the reagent 121 as the oxidant, cleavage of the triple bond cannot be avoided completely.For example, the oxidation of bisphenylethynyldurene gives the acid 123 in addition to the tetraketone 122.294 The action of compound 121 on 1,4-dihydroxybutynes results, as expected, in the oxidation of the triple bond along with the intramolecular dehydration to give substituted tetrahydrofuran- diones 124 in one step and in high yields.297 Like compound 121, iodosylbenzene oxidises diphenylacety- lene to benzil 7a.The mechanism of its action is somewhat analogous to the mechanism of oxidation of alkynes with ozone.298 Periodic acid (H5IO6) is yet another iodine-based oxidant, which converts diphenylacetylene to benzil 7a in almost quantita- tive yield on heating in acetic acid.299 Like I2O5, this oxidant has the advantage that treatment of diphenylacetylene in boiling methanol or ethylene glycol affords mono- and diketals of benzil 7a, which are difficult to obtain by other methods.299 It is believed that I+rather than I7+ or I5+ is the actual oxidising particle in this case.This opinion is supported by the conversion of diphenylace- tylene to mono- and dimethyl ketals of benzil 7a on heating in methanol with HgO± I2.299 N-Bromosuccinimide in dry DMSO is an efficient oxidant of triple bonds in phenylacetylene, diphenyl-, dimethyl- and methyl- phenylacetylene.300 The reaction can occur even at room temper- ature. The yield of benzil 7a reaches 98%, but other alkynes mentioned above form a-dicarbonyl derivatives in lower yields.Diphenylbutadiyne is oxidised to diphenyl tetraketone (PhCO ± COCOCOPh) isolated as the dioxime.300 A certain drawback of R1COCOR2 (HMPA)MoO(O2)2, Hg(OAc)2 C2H4Cl2 R1C CR2 R1=Ph, R2=H, Ph; R1=R2=C6H13; R1=Bu, R2=H, Ph. 2 equiv. PhI(OCOCF3)2 121 4 equiv. 121 C C CPh PhC 100 Ph COCOPh PhCOCO COCOPh 28 Me Me Me Me Ph Ph PhI(OCOCF3)2 CHCl3 Me Me Me Me O Ph O O Ph O + Me Me COOH Me Me Ph 122 123 R1=R2=Me, R1, R2=(CH2)4.R1 R2 HO OH R2 R1 PhI(OCOCF3)2 CHCl3 O O O R1 R2 R2 R1 124 742 V D Filimonov,MS Yusubov, Ki-Van Chithis oxidising system is that DMSO has to be dried thoroughly, as the oxidation of diphenylacetylene does not occur even in the presence of 0.5% water.300 Oxidative reagents based on commer- cial, non-dried DMSO, viz., HBr, I2 or PdCl2 in DMSO,253, 254 do not have this drawback.Heating of diarylalkynes in DMSO containing iodine at 115 ± 155 8C provides high yields of ben- zils.253, 254 High reactivity and selectivity of the reagent are confirmed by the fact that it oxidises (4-nitrophenyl)phenyl- acetylene in 90% yield and does not affect the formyl group in (4-formylphenyl)phenylacetylene, which is very reactive and liable to oxidation.Various bisphenylethynylarenes are oxidised to the tetrake- tone 28, as well as tetraketones 125, on heating in DMSO with an equimolar amount of iodine (yields 71%± 90%).253, 254 The same reagent was successfully used in the synthesis of 4,40- bis(arylglyoxylyl)benzophenones from 4,40-bis(arylethynyl)ben- zophenones301 and a series of fluoro-derivatives of bis-a-dike- tones, FC6H5COCOC6H5XC6H5COCOC6H5F (X=CO, COCO, Het).302 By decreasing the quantity of iodine to a catalytic amount, it was possible to oxidise only one triple bond in bis(phenyl- ethynyl)benzene and to obtain the diketone 100.252 It was noted above that the reactivity of iodine in DMSO as an oxidant of the double bonds in stilbenes is low.This enables selective oxidation of only the triple bond in compound 98 giving (E)-styrylbenzil 103.251 The acetylene-containing tetraketone 29 is readily con- verted on treatment with the I2 ±DMSO system to the hexaketone 94 in 90% yield.59 Thus, the use of a combination of two oxidants, HBr ±DMSO and I2 ±DMSO, opens for the first time the possi- bility of the selective oxidation of either triple or double bonds in enynes.The reactivity of iodine in DMSO decreases abruptly in the oxidation of a sterically hindered acetylenic substrate, viz., mesi- tylacetylene, although the direction of the oxidation does not change.253, 254 A new oxidative process has been discovered recently.303 Prolonged heating of sterically hindered bis(phenyle- thynyl)durene with iodine in DMSO gave duroquinone, 2,3,5,6- tetramethyl-4-hydroxybenzil and benzoic acid as the main prod- ucts, instead of the expected tetraketone 122.This reaction is a rare example in which iodine in DMSO causes the cleavage of the carbon ± carbon bonds. A similar process was observed in the oxidation of the enyne 99, which resulted in benzil 7a and benzoic acid instead of the expected diphenylbutenedione.251 The I2 ±DMSO system also proved to be inefficient in the oxidation of a terminal alkyne, viz., phenylacetylene.In this case, a complex mixture of oxidation products with a content of phenylglyoxal no more than 20% is formed even if the conversion of the substrate is incomplete.255 It was shown251, 253, 254, 304 that internal alkynes [diarylalkynes and bis(phenylethynyl)benzenes] are readily oxidised to benzil 7a and tetraketones 28 and 125 on heating in DMSO in the presence of a catalytic amount of PdCl2.This reagent proved to be even more selective with respect to the triple bonds than I2 ±DMSO. It is totally inert to alkenes. This enables its efficient use in the oxidation of acetylenic compounds containing double bonds.251 On the other hand, PdCl2 ±DMSO is more sensitive to steric factors in substrates than I2 ±DMSO.253, 254 A method for the synthesis of a-diketones 126 from a-acetox- yalkynes 127 in high yields was suggested.305 In the first step, substrates 127 are oxidised with complexes of PdCl2 with acetoni- trile or benzonitrile under very mild conditions at room temper- ature.The resulting enol acetates are readily hydrolysed to diketones 126 in the presence of cation-exchange resins. Anodic oxidation of diarylalkynes in acetonitrile on a graphite electrode gives mixtures of products, of which 1,2,3,4-tetraaryl- but-2-ene-1,4-diones 128 are the main components.306 The corre- sponding benzils 129 are formed in only 12%± 35% yields. Anodic oxidation of diarylbutadiynes 130a,b under similar conditions results in the respective 1,2-diketones 101 (5%) and 131 (28%) and butyne-1,4-diones 132a,b (60% and 12%).306 As shown previously, a mixture of the same products, viz., 101 and 132a, results from the oxidation of diphenylbutadiyne with bis(trifluoroacetoxy)-l3-iodanylbenzene 121.296 V.Conclusion Despite the great diversity of oxidative methods for the synthesis of vicinal di- and polycarbonyl compounds (most often, a-dike- tones), extensive studies in this field are being continued.In our opinion, several most topical problems can be distinguished. For example, now there are many reliable and general reagents for the oxidation of such substrates as ketones, their a-hydroxy and a-halogeno derivatives and b-diketones.On the other hand, methods for the oxidation of alkenes, vicinal dihalides and especially alkanes have been developed insufficiently. There are almost no versatile reagents for the oxidation of these classes of compounds, except for the recently suggested DMSO-based oxidants suitable for the oxidation of alkenes and substituted 1,2- dibromoethanes.Only after such reagents as HBr ±DMSO, I2 ±DMSO and PdCl2 ±DMSO had appeared, did selective oxi- dation of either the triple or the double bond in enynes become possible. The results presented in Section IV show convincingly that alkynes rather than alkenes, and even more so alkanes, are the most suitable as substrates in the synthesis of a-dicarbonyl compounds.Thus, the traditional belief that `alkynes are more difficult to oxidise than alkenes' has to be reconsidered.307 Yet another problem is the obvious lack of reliably proven mechanisms for the oxidation reactions presented in this review. Although a great deal of studies have been carried out, the mechanisms of action of even such well-studied oxidants as SeO2 andKMnO4 remain debatable.There are relatively few systematic studies on the quantitative estimation of the effect of the structure of substrates and oxidants on the reactivity. Because of the insufficiency of the theoretical basis, new reagents in this branch PhC CArC CPh I2, DMSO Ar=1,4-C6H4, 4,40-C6H4C6H4, 4,40-C6H4OC6H4, dibenzofuran-3,8-diyl, 4,40-C6H4CH2C6H4, 4,40-C6H4COC6H4, fluorene-2,7-diyl, fluorenone-2,7-diyl.Ar O Ph O O Ph O 125 cation- exchange resin R1, R2, R3=H, Alk, cyclo-Alk, Ar. R1R2CHCOCOR3 126 PdCl2(MeCN)2 R1R2C C(OAc)COR3 H2O R1R2C(OAc)C 127 CR3 R1, R2=H, OMe. R1C6H4C CC6H4R2 R1C6H4CO R2C6H4 C6H4R2 COC6H4R1 + R1C6H4COCOC6H4R2 128 129 R = H (101, 130a, 132a), OMe (130b, 131, 132b). 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M S Yusubov, E A Krasnokutskaya, V D Filimonov, L F Kovaleva Khim. Geterotsikl. Soedin. 1477 (1992) e 257. W Tochtermann, M Haase, R Dibbern Tetrahedron Lett. 29 189 (1988) 258. L Bhat, A Thomas, H Ila, H Junjappa Tetrahedron 47 305 (1991) 259. S R Trusov, A L Madelis Neftekhimiya 33 345 (1993) 260. A Krebs, H Kimling Tetrahedron Lett. 761 (1970) 261. M Tiecco, L Testaferri, M Tingoli, D Chianelli, D Bartoli J. Org. Chem. 56 4529 (1991) 262. A J Fatiadi Synthesis 85 (1987) 263. S Wolf, C F Ingold J. Am. Chem. Soc. 105 7755 (1983) 264. A N Novikov, L F Kovaleva, V P Lopatinskii, L P Borodulina Zh. Org. Khim. 22 2214 (1986) b 265. L F Kovaleva, O I Reutova, T A Sarycheva, O A Sheludyakov, A N Novikov, V D Filimonov Zh. Org. Khim. 24 650 (1988) b 266. D G Lee, E J Lee,W D Chandler J. Org. Chem. 50 4306 (1985) 267. M Schroder Chem. Rev. 80 178 (1980) 268. M Schroder,W P Griffith J. Chem. Soc., Dalton Trans 1599 (1978) 269. Bassignani, A Brandt, V Caciagli, L Re J. Org. Chem. 43 4245 (1978) 270. P C B Page, S Rosenthal Tetrahedron Lett. 27 1947 (1986) 271. S Torii, T Inokuchi, Y Hirata Synthesis 377 (1987) 272. R Zibuck, D Seebach Helv. Chim. Acta 71 237 (1988) 273. G Pattenden, M Tankard, P C Cherry Tetrahedron Lett. 34 2677 (1993) 274. P Mu È ller, J Godoy Helv. Chim. Acta 64 2531 (1981) 275. P Mu È ller, J Godoy Tetrahedron Lett. 23 3661 (1982) 276. A McKillop, O H Oldenziel, B P Swann, E C Taylor, E C Robey J. Am. Chem. Soc. 95 1296 (1973) 277. F P Ballistreri, S Failla, G A,Tomaselli, R Curci Tetrahedron Lett. 27 5139 (1986) 278. F P Ballistreri, S Failla,G A,Tomaselli J. Org. Chem. 53 830 (1988) 279. F P Ballistreri, S Failla, E Spina, G A,Tomaselli J. Org. Chem. 54 947 (1989) 280. F P Ballistreri, S Failla, G A,Tomaselli Tetrahedron 48 9999 (1992) 281. Y Ishii, Y Sakata J. Org. Chem. 55 5545 (1990) 282. S Sakaguchi, S Watase, Y Katayama, Y Sakata, Y Nishiyama, Y Ishii J. Org. Chem. 59 5681 (1994) 283. W D Emmons, A S Pagano J. Am. Chem. Soc. 77 80 (1955) 284. Z Zhu, J H Espenson J. Org. Chem. 60 7728 (1995) 285. J P Guette, G Mattioda B Metivier Actual. Chim. 23 (1982) 286. Yu I Kukushkin, V V Kobzev, L P Morozova Zh. Prikl. Khim. 43 2759 (1970) f 287. A I Kozlov, S M Brailovskii, O N Temkin Kinet. Katal. 35 551 (1994) g 288. B Rihter, J Masnovi J. Chem. Soc., Chem. Commun. 35 (1988) 289. B Rihter, S SriHari, S Hunter, J Masnovi J. Am. Chem. Soc. 115 3918 (1993) 290. Y Ogata, Y Sawaki, T Ohno J. Am. Chem. Soc. 104 216 (1982) 291. R Curci, M Fiorentino, C Fusco, R Mello Tetrahedron Lett. 33 7929 (1992) 292. R W Murray, M Singh J. Org. Chem. 58 5076 (1993) 293. E B Merkushev, L G Karpitskaya, G I Novosel'tseva Dokl. Akad. Nauk SSSR 245 607 (1979) h 294. V P Vasil'eva, I L Khalfina, L G Karpitskaya, E B Merkushev Zh. Org. Khim. 23 2225 (1987) b 295. L G Karpitskaya, V P Vasil'eva, E B Merkushev Zh. Org. Khim. 27 1961 (1991) b 296. E B Merkushev, L G Karpitskaya, G I Novosel'tseva, in V Vsesoyuz. Konf. po Khimii Dikarbonil'nykh Soedinenii (Tez. Dokl.), Riga, 1981 [The Fifth All-Union Conference on the Chem- istry of Dicarbonyl Compounds (Abstracts of Reports), Riga, 1981] p. 143 746 V D Filimonov,MS Yusubov, Ki-Van Chi297. B S Zhaishinbekov,A K Patsiev,K B Erzhanov Zh. Org. Khim. 24 2460 (1988) b 298. S Ranganathan, D Ranganathan, P V Ramachandran Tetrahedron 40 3145 (1984) 299. G Gabeyehu, E McNelis J. Org. Chem. 45 4280 (1980) 300. S Wolf, W R Pilgrim, T F Garrard, P Chamberlain Can. J. Chem. 49 1099 (1971) 301. M L Keshtov, N M Belomoina, T M Kazieva, A L Rusanov, A K Mikitaev Izv. Akad. Nauk, Ser. Khim. 670 (1996) c 302. A L Rusanov, M L Keshtov, N M Belomoina, A K Mikitaeva, G B Sarkisyan, S V Keshtov Izv. Akad. Nauk, Ser. Khim. 810 (1997) c 303. M S Yusubov, G A Zholobova, V P Vasil'eva, V Khabikher, V D Filimonov Zh. Org. Khim. 32 1276 (1996) b 304. Ki-Whan Chi,M S Yusubov, V D Filimonov Synth. Commun. 24 2119 (1994) 305. BRD P. 296 274; Chem. Abstr. 116 193 773 (1993) 306. M Cariou Tetrahedron 47 799 (1991) 307. Comprehensive Organic Chemistry Vol. 1 (Oxford: Pergamon Press, 1973) a�Russ. J. Gen. Chem. (Engl. Transl.) b�Russ. J. Org. Chem. (Engl. Transl.) c�Russ. Chem. Bull. (Engl. Transl.) d�Russ. Organomet. Chem. (Engl. Transl.) e�Chem. Heterocycl. Compd. (Engl. Transl.) f�Russ. J. Appl. Chem. (Engl. Transl.) g�Kinet. Catal. (Engl. Transl.) h�Dokl. Chem. Technol., Dokl. Chem. (Engl. Transl.) Oxidative methods in the synthesis of vicinal di- and polycarbon

ISSN:0036-021X    

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Abstract. Data on reactions of N-silylated amines, carboxamides, amino acids, and their derivatives with trivalent and pentavalent phosphorus acid halides are summarised. The effect of structural factors on the direction of phosphorylation is discussed. The bibliography includes 133 references. I. Introduction The necessity of development of new methods for the synthesis of phosphorus acid amides is associated with the fact that some of these compounds are widely used as bioregulators and key reagents in the synthesis of new medicinal preparations.1 The phosphoramidite method for the formation of internucleotide bonds remains so far the most efficient in the automated synthesis of oligonucleotides.2 However, analysis of literature data on the methods for the preparation of compounds with the P7N bond allows one to reveal certain drawbacks in the popular methods for the synthesis of amides of phosphorus acids.3, 4 The vast majority of the methods is based on low-selective reactions of phosphor- ylating reagents with amines or their salts.The use of a large excess of bases (sometimes toxic) hinders purification of the target amides, which creates additional experimental difficulties.The use of N-silylated nitrogen-containing compounds may appear to be the solution of the problem. At present, serious attention has been drawn to the studies on the reactivity of these compounds.5, 6 The reaction of these silylated compounds with phosphorus acid halides is very attractive for the synthesis of phosphoramidites and phosphoramidates, as it produces volatile halogenosilanes, which can be easily removed from the reaction mixture and repeatedly used in the reaction cycle.Other advan- tages of the use of silylamines instead of amines have been reviewed.5 The ultimate result of this type of reactions definitely depends both on the structural features of the electrophilic phosphorylating agent and on the nature of the silicon ± nitrogen bond that affects the nucleophilicity and configuration of the nitrogen atom.7, 8 Since there is no universal scale of nucleo- and electrophilic- ity,9 this review compares the reactivity of N-silylated nitrogen- containing compounds, which are combined into different groups according to formal structural features, with respect to phospho- rus acid halides.In each case, the reaction features that can be attributed to the contribution of the phosphorus component are discussed additionally. II. Reactions with N-silylamines A characteristic feature of N-silylamines is their rather high reactivity with respect to phosphorus acid halides, particularly those of trivalent phosphorus. This may result from changes in hybridisation of the nitrogen atom and, as a consequence, from changes in its nucleophilicity due to the introduction of the silyl group.5, 7 The steric factor also exerts a significant effect on the reactivity of silylamines.Generally speaking, the N7Si bond in silylamines is so labile that the latter may act as silylating agents, for example, diethyl(trimethylsilyl)amine (1). However, the ability of the Si7N bond to undergo cleavage decreases dramatically with an increase in the volume of the alkyl groups at the silicon atom (e.g., in the case of triisopropyl and tert-butyldimethylsilyl groups).10 A similar effect was also noted in acid hydrolysis of N-tert-butyldimethylsilyl- and N-triisopropylsilyl-b-lactams.11 Methods for the synthesis of N-triisopropylsilylated compounds and their stability have been reviewed.12 tert-Butyldipropylsily- lated primary amines appeared to be inert to acylation.13 There- fore, this review deals exclusively with the replacement of the trimethylsilyl group at the nitrogen atom by a phosphorus- containing fragment. 1. Reactions with trivalent phosphorus acid halides It has been shown14 ± 21 that reactions of silylamines, mainly amine 1, with a series of trivalent phosphorus acid chlorides occur under mild conditions.P X R2 Cl R1 + 2HN R3 R4 P X R2 NR3R4 R1 + NH2Cl7 R4 R3 + 20 8C MeOP(NR2)2+2Me3SiCl (68%782%) MeOPCl2+2Me3SiNR2 1, 2 R2N=Et2N (1), Me2N (2), . N A B Ouryupin, I A Rakhov, T A Mastryukova A N Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, 117813 Moscow, Russian Federation.Fax (7-095) 135 50 85. Tel. (7-095) 135 92 49 (T A Mastryukova) Received 2 December 1997 Uspekhi Khimii 67 (9) 827 ± 838 (1998); translated by S S Veselyi UDC 547.10118:564.268 Reactions of phosphorus acid halides with N-silylated organic compounds { A B Ouryupin, I A Rakhov, T A Mastryukova Contents I. Introduction 749 II. Reactions with N-silylamines 749 III.Reactions with N-silylamides 753 IV. Reactions with N-silylated amino acids and other N-silylated compounds 756 V. Conclusions 757 { The review is devoted to the memory of academician M I Kabachnik (1908 ± 1997). Russian Chemical Reviews 67 (9) 749 ± 759 (1998) #1998 Russian Academy of Sciences and Turpion LtdFor example, arylphosphonous dichlorides,16 alkylphosphor- odichloridites,17, 18 and heterocyclic phosphorochloridites 19 ± 21 react with amine 1 at room temperature or even at lower temperatures to give the corresponding phosphoramidites in high yields.An appropriate ratio of the reagents makes it possible to obtain products of the stepwise replacement of the halogen atoms at the phosphorus atom by amino groups.14 A decrease in reactivity of trivalent phosphorus acid chlorides with respect to N-silylamines upon replacement of the chlorine atoms with amino groups has also been found in the studies of the reaction of dimethyl(trimethylsilyl)amine (2) with methylenebi- s(phosphonous dichloride) (3).22 Sequential substitution of the chlorine atoms at different phosphorus atoms in methylenebis(phosphonous dichloride) takes place at room temperature with an excess of amine 2.The chlorine atom in the diamide 4 is replaced by the dimethylamino group only on heating of the reaction mixture. The chlorine atom in the triamide 5 is even more difficult to replace. Mild reaction conditions and completeness of the reaction of aminosilanes with trivalent phosphorus acid chlorides were dem- onstrated for compounds the preparation of which by other methods had been a problem.For example, dehydrochlorination could be avoided in the synthesis of N,N-diethyl-P-(2-chlorocy- clopentyl)- and -(2-chlorocyclohexyl)phosphonamidites.15 Tris(diphenylamino)phosphine was synthesised in quantita- tive yield from tetraphenylphosphorodiamidochloridite and N-(trimethylsilyl)diphenylamine.In this case, it was possible to escape difficulties associated with the purification of the product from triethylamine hydrochloride.23 The synthesis of 5-tert-butyl-2-chloro-3-isopropyl-1,3,2-oxa- zaphospholene from phosphorus trichloride and 5-tert-butyl-3- isopropyl-2,2-dimethyl-1,3,2-oxazasilolene was described.24 Silylamines were also used in syntheses of heterocyclic deriv- atives of trivalent phosphorus. The reaction of alkylphosphorodi- chloridites with N,N,O-tris(trimethylsilyl)-3-aminopropanol afforded 2-alkoxy-3-trimethylsilyl-1,3,2-oxazaphosphorin- anes.25 Cyclic products are also formed in the reaction of N,N0- bis(methylchlorophosphino)urea with amines 1 and 2.26, 27 It is worth noting that in this case the nucleophilicity of the amide nitrogen atom becomes comparable with that of the nitro- gen atom in silylamines.This opens possibilities for the intra- molecular replacement of the chlorine atom. The participation of the P7N fragment in the delocalisation of the positive charge enables the formation of cyclic products 6 in reactions of di- and trihalides of trivalent phosphorus with N,N,N0-trimethyl-N0-trimethylsilylethylenediamine.28 The pres- ence of an unshared electron pair on substituent Y at the phosphorus atom is a prerequisite for cyclisation.The result of phosphorylation of silylamines depends also on the nature of the halogen at the phosphorus atom. Unlike acid chlorides, which react completely with amines according to 31P NMR spectroscopy, acid bromides react with amines in a reversible manner.29, 30 An equilibrium mixture containing com- parable amounts of the reaction product, i.e.phosphoramidite, and acid bromide is formed at room temperature.29, 30 It was noted previously 31, 32 that the reaction of phosphorus triiodide with silylamides does not go to completion. A similar phenomenon was also observed for phenylphosphonous diiodide.33 Moreover, the reverse reaction is possible theoretically.This has been shown using the reaction of tris(dimethylamino)- phosphine with iodotrimethylsilane as an example.32 PCl3 1, 0 8C 2 1, 20 8C 3 1, 20 8C 72Me3SiCl 7Me3SiCl 73Me3SiCl Et2NPCl2 (72%) (Et2N)2PCl (70%) (Et2N)3P (68%) Me2NSiMe3+Cl2PCH2PCl2 2 3 20 8C 4 Cl2PCH2P Cl NMe2 PCH2P Cl NMe2 Cl Me2N + 3 2+3 65 8C 4+Me2NP(Cl)CH2P(NMe2)2+(Me2N)2PCH2P(NMe2)2. 5 n=1, 2; X=Cl, MeO. 7Me3SiCl +1 (CH2)n P Cl (CH2)n P Cl (51% ± 69%) X Cl X NEt2 N SiMe2+PCl3 O But Pri 20 8C 7Me2SiCl2 N PCl O But Pri (70%) AlkOPCl2+(Me3Si)2N(CH2)3OSiMe3 7Me3SiCl N P O SiMe3 OAlk (32% ± 45%) R=Et (1), Me (2). +R2NSiMe3 1, 2 75 to+20 8C P P NH HN O Me NR2 Me + (94%) O NHP PNH Cl Me Me Cl YPX2+Me2N(CH2)2N Me SiMe3 7Me3SiX + Me2N(CH2)2N(Me)PYX N P N Me Me Y Me X7 6 X=Cl, Br; Y=Cl, Br, MeO, PhO, Et2N.R1R2PBr+Me3SiNR32 R1R2PNR32 +Me3SiBr R1=R2=Me2N, R1+R2=7OCH2CMe2CH2O7; R3=Me, Et. PhPI2+R2NSiMe3 20 8C PhP(I)NR2 (85% ± 90%) 7Me3SiI R=Me, Et. (Me2N)3P+Me3SiI 20 8C (Me2N)2PI+Me3SiNMe2 . 750 A B Ouryupin, I A Rakhov, T A MastryukovaFinally, the reversibility of the reaction of dialkylphosphinous diiodides with the amine 1 in dichloromethane at room temper- ature has been demonstrated recently.34 Studies of this kind of reactions are complicated by side reactions of phosphoramidites that are formed with organoiodine compounds.29, 32, 34 For example, the reaction of the amine 1 with 2-iodo-5,5-dimethyl-1,3,2-dioxaphosphorinane results in the phosphoramidite 7, which immediately reacts with the product of this reaction, viz., iodotrimethylsilane.29 Unlike acyl fluorides,35 trivalent phosphorus acid fluorides do not react with silylamines.All attempts to carry out such trans- formations failed.29, 36, 37 Thus, the reaction of silylamines with P(III) acid chlorides remains the most suitable for the synthesis of phosphoramidites. It should be noted that phosphorylation of silylamines in the presence of a base may occur with the preservation of the N7Si bond.For example, the reaction of 2-chloro-1,3,2-diheterophos- pholanes with N-trimethylsilylaniline under mild conditions afforded the corresponding 2-(N-trimethylsilyl-N-phenylamino)- 1,3,2-diheterophospholanes.38 Similarly, Menshutkin's chlorides can react, though partly, at the N±H bond of N,N0-bis(trimethylsilyl)trimethylenedi- amines.39, 40 With disilazanes, it becomes possible to obtain products of substitution of one or two trialkylsilyl groups, depending on the reaction conditions.Monosubstitution occurs with equimolar amounts of the reagents and at low temperature.41, 42 The resulting N-silylamidophosphorodihalidites are ther- mally unstable and can be transformed to cyclotriphosphazanes on heating of the reaction mixture.42,43 The reaction of alkylphosphonous dichlorides with methyl- bis(trimethylsilyl)amine also affords mono- and diphosphoryla- tion products, depending on the ratio of the reagents,44 and boiling of equimolar amounts of the reagents in acetonitrile leads to cyclotetraphosphazanes.45, 46 The synthesis of N-trimethylsilyldialkylphosphinamidites by boiling dialkylphosphinous chlorides with an excess of hexame- thyldisilazane in the presence of a catalyst was also described.47 Trivalent phosphorus acid fluorides are inert with respect to disilazanes.48 The Si7N bond remains unchanged after heating a mixture of F2PCl with (Me3Si)2NPF2 or Me3Si(But)NPF2.This is explained 49 by pp±dp overlapping of orbitals of the Si, N, and P atoms resulting in a corresponding decrease in the nucleophilicity of nitrogen.A method for the synthesis of a series of compounds of two- coordinated phosphorus 9 from N,N,N0-trisubstituted N-(trime- thylsilyl)phosphorodiamidohalidites 8, which had been synthes- ised from R1R2NPX2 and LiN(R3)SiMe3, was developed.50 ± 56 X=Cl, Br; R1 or R2 are bulky substituents, R3=Pri, But, R43 Si, C6H2But 3, adamant-1-yl. In this case, it was possible to isolate only compounds with bulky substituents at both nitrogen atoms.Otherwise, dimerisa- tion of the imidophosphorous amides 9 to 1,3-diaza-2,4-diphos- phetidines takes place.52 ± 55 The nature of the halogen at the phosphorus atom has no significant influence on the elimination of the halosilane.50 ± 56 The same method was used for the preparation of the less stable P,N- dialkyl(aryl)- 57, 58 and P-aryloxy-N-aryliminophosphines.59 Reactions of phosphorochloridites with hexa- and hepta- methyldisilazanes were studied.60, 61 The attractiveness of these reactions is explained by the fact that they allow the syntheses of functionally substituted amides of trivalent phosphorus acids.Unfortunately, phosphorylation of disilazanes occurs under more drastic conditions than phosphorylation of monosilylamines. Alk2PI+Et2NSiMe3 Alk2PNEt2+Me3SiI. 1 O P O I+ 1 O P O NEt2+Me3SiI 7 O P O SiMe3 NEt2 + I7 X=O, NPh. X P O Cl+PhNHSiMe3 5± 10 8C, Et3N 7Et3N. HCl X P O N Ph SiMe3 (33% ± 39%) NHSiMe3 NHSiMe3 R1 R1 R2 +R3OPCl2 Et3N, 0 8C 7Et3N. HCl N N R1 R1 R2 P SiMe3 SiMe3 OR3 (12% ± 25%) R1, R2=H, Me; R3=Me, Et, Ph.X=Cl, Br. PX3+MeN(SiMe3)2 X2P N Me SiMe3 X=Cl, Br; R=Me, Et. 80 8C P N P N P N X R X R X R (29% ± 74%) X2P N Me SiMe3 2 AlkPCl2+2 MeN(SiMe3)2 N P N P N P N P Me Alk Me Alk Me Alk Me Alk (15% ± 50%) Alk2PCl+(Me3Si)2NH R3N. HCl Alk2PNHSiMe3. R1R2N P NR3 9 (30% ± 85%) X P NR1R2 N(R3)SiMe3 8 >100 8C 7Me3SiX R1R2NPX2+LiN(R3)SiMe3 7LiX R1, R2=Me, Et, Pr.P N P N R3 NR1R2 R3 R1R2N (25% ± 60%) 9 X=O, NPh; X P O Cl +MeN(SiMe3)2 130 8C X P O N Me SiMe3 (20% ± 31%) X P O N P X O Me + (13% ± 30%) 7Me3SiCl Reactions of phosphorus acid halides with N-silylated organic compounds 751Phosphorylation of phosphorus-substituted disilazanes can be accompanied by rearrangement to give compounds containing phosphorus in different coordination states.62 2.Reactions with pentavalent phosphorus acid halides Since pentavalent phosphorus has lower electrophilicity than trivalent phosphorus, a general decrease in the rates of phosphor- ylation of silylamines with the corresponding phosphorus(V) acid halides is observed. The replacement of the chlorine atoms in pentavalent phos- phorus acid chlorides by the amino groups in reactions of acid chlorides with amines 1 and 2 is incomplete even on heating.14 Complete replacement of the chlorine atoms in methylenebi- s(phosphonic dichloride) in its reaction with the amine 2 is possible only on heating.22 The phosphorylating ability of N-methyliminodiphosphonic tetrachloride (10) is even lower.63 Nucleophilic substitution of the chlorine atom at a less electrophilic thiophosphoryl centre occurs more readily when the latter is incorporated into a strained four-membered ring, as in compound 11.64 However, the presence of electron-withdrawing and bulky phenyl groups at the nitrogen atom of the silylamine prevents the cleavage of the Si7N bond in this reaction. Chlorocyclotriphosphazenes also belong to pentavalent phos- phorus acid chlorides, but we considered that there is little sense in repeating in this review the previously published data 65, 66 on their reactions with silylamides. Unlike trivalent phosphorus acid fluorides, P(V) fluoro-deriv- atives react with silylamines in some cases.For example, the reaction of N-trimethylsilylmorpholine with the mixture of iso- butenyl- and 2-chloroisobutylphosphonic difluorides affords products of replacement of one of the fluorine atoms.67 N-Silylated pyrrolidine and piperidine react rather smoothly with phosphorus oxofluoride POF3.However, in their reaction with phosphorus oxochloridedifluoride, substitution of the chlor- ine atom is the first to occur.68 Unlike N-methyliminodiphosphonic tetrachloride (10), N-ethyliminodisphophonic tetrafluoride (12) reacts with the amine 1 with the cleavage of the P7N bond.69 Although reactions of silylamines with phosphorus acid fluorides are rather interesting from the synthetic point of view, they are little studied.Undoubtedly, this can be explained by the high toxicity of the latter compounds. Phosphorylation of silyl- amines with phosphorous acid bromides and iodides has not been described in literature.The reaction of the amine 2 with mixed amidotetrachloride 13 can serve as a characteristic of the relative ability of the halogen atoms in trivalent and pentavalent phosphorus acid halides to be replaced by the amino groups of silylamines.70,71 At 778 8C and with an equimolar ratio of the reagents, the product of the replacement of one chlorine atom at the trivalent phosphorus atom by the dimethylamino group (compound 14) is formed selectively.The structure of compound 14 is confirmed by 1H and 31P NMR spectroscopic data. An increase in the reaction temperature to 30 8C and exposure of the reaction mixture at this temperature for 1 h result in migration of the dimethylamino group from the trivalent phosphorus atom to the pentavalent one to give compound 15.The reaction of the tetrachloride 13 with 2 equivalents of the amine 2 at room temperature affords the product of replacement of both chlorine atoms at the pentavalent phosphorus atom by the dimethylamino groups (compound 16). In the authors' opinion, compound 17 is formed as an intermediate in this reaction. This assumption is supported by the fact that compound 17, synthesised independently, undergoes rearrangement at room temperature to form compound 16.ROPCl2+2 MeN(SiMe3)2 D ROP[N(Me)SiMe3]2 . (10% ± 21%) 7Me3SiCl R2PN(SiMe3)2+R02PCl 7Me3SiCl R2P( NSiMe3)PR02. R=Et (1), Me (2). (R2N)2P(O)Cl (60% ± 70%) POCl3+2R2NSiMe3 72Me3SiCl 1, 2 Cl2P(O)CH2P(O)Cl2+42 85 8C 74Me3SiCl (Me2N)2P(O)CH2P(O)(NMe2)2 (100%) O Cl2P N PCl2+22 O Me 10 72Me3SiCl O P N P O Me Cl Cl NMe2 Me2N (90%) R=Me, Et. 7Me3SiCl P N N O S Cl Me Me +R2NSiMe3 P N N O S NR2 Me Me 11 (64% ± 83%) O R=Me2C=CH, Me2CClCH2. RP(O)F2+Me3Si N O 40 ± 45 8C 7Me3SiF P N O F R F2P(O)Cl+ (H2C)n N SiMe3 7Me3SiCl (H2C)n N P O F F (31% ± 33%) n=1, 2. O F2P N PF2+1 O Et F2P N O Et SiMe3 + F2P NEt2. O 12 Cl2P N PCl2+2 O Me 778 8C 7Me3SiCl Cl2P N P O Me Cl NMe2 30 8C 13 14 P N PCl2 O Me Me2N Cl 15 (95%) 13+22 20 8C (Me2N)2P N PCl2 Me O 16 P N P Me Cl NMe2 O Me2N Cl 17 752 A B Ouryupin, I A Rakhov, T A MastryukovaAs in the case of P(III) derivatives, the reaction of P(V) acid chlorides with disilazanes can be used for the preparation of N-silylated amides.72,73 Successful synthesis of these amides requires that appropriate reaction conditions are selected depending on the structure of the phosphorylating agent used.Reactions at room temperature mainly involve more electrophilic MePOCl2 and 1-chloro-1- oxophosphol-3-ene,72 whereas diphenyl phosphorochloridate reacts at 60 8C,73 and phosphinothioic chlorides react only at 130 ± 150 8C.74 N,N-Bis(trimethylsilyl)-P-phenylphosphono- thioic diamide is obtained under even more drastic conditions (in the presence of aluminium chloride).75 As a rule, reactions of this type afford a monophosphorylation product, except for the reaction of disilazanes with POCl3.76 The reaction of hexamethyldisilazane with POF3 afforded the corresponding N-silylmonoamide in moderate yield.76 Monosubstitution of the chlorine atoms in mixed imidochlor- ides can be used for the preparation of acyclic oligophosphazenes.77 Thus, reactions of both trivalent and pentavalent phosphorus acid chlorides with silylamines are of significant interest for the synthesis of phosphoramidites and phosphoramidates.III. Reactions with N-silylamides Many N-phosphorylated amides and lactams are known to be physiologically active substances with a broad spectrum of action.1, 78 In addition, certain N-phosphorylated amides are used as condensation agents in the synthesis of carboxamides and esters.79 The development of convenient methods for their synthesis is therefore of large practical importance.The introduction of an acyl group into a silylamine molecule changes substantially both the nucleophilic properties of the nitrogen atom and the geometry of the molecule.Studies of the reactivity of silylamides performed by representatives of the Kazan' school of chemists allowed them to elucidate the regular- ities of the reaction of silylamides with trivalent and pentavalent phosphorus acid chlorides.80 ± 87 Reaction conditions have a significant effect on the direction of the reaction of diethyl phosphorochloridites with N-trimethyl- silylacetamide (18).8, 80 For example, cleavage of the Si7N bond with the formation of N-diethoxyphosphinetriylacetamide takes place at room temperature.The Si7N bond remains unchanged in the presence of triethylamine; in this case, the reaction product is N-trimethyl- silyl-N-(diethoxyphosphinetriyl), and only heating of the reaction mixture to 110 ± 130 8C brings about the elimination of the acetonitrile molecule and the formation of a Si7O7P bond. Under similar conditions (room temperature, inert solvent), 2-chlorobenzo-1,3,2-dioxaphospholene reacts with amide 18 to give 2-acetylaminobenzo-1,3,2-dioxaphospholene.81 Similarly, but in the presence of triethylamine, the reaction of 2-chloro-1,3,2-dioxaphospholane with amide 18 afforded 2-(N- acetyl-N-trimethylsilylamino)-1,3,2-dioxaphospholane, which is transformed to 2-trimethylsilyloxy-1,3,2-dioxaphospholane on heating.82 The product of disilylation of acetamide, compound 19, has the structure of an imidate in which one of the trimethylsilyl groups is linked with the nitrogen atom, and the second group, with the oxygen atom.8, 88 Phosphorylation of this compound with phosphorochloridites at room temperature affords N-trimethyl- silyl-N-dialkoxy- or alkoxy(amino)phosphinetriyl)acetylamides. Their structures were confirmed by IR and 1H and 31P NMR spectra.82 ± 86 Their conversion into the corresponding trimethyl- silyl phosphites was explained by the possible presence of isomeric N-(1-trimethylsilyloxyethylidene)phosphoramidites in the reac- tion mixture.The O-silylated isomer appeared to be more stable than the N-silylated one and was isolated after phosphorylation of com- pound 19 with dialkyl phosphorochloridedithioite.85 The reaction under discussion also proceeds in a similar way with other phosphorochloridites. In this case, the ease of the formation of silyl phosphites increases in the following series:83 R1, R2=Alk, Ar, AlkO, ArO; X=O, S, NR4. P Cl +R3N(SiMe3)2 X R1 R2 7Me3SiCl P X R1 R2 SiMe3 R3 N (40% ± 90%) P .n P(O)Cl3+n RN(SiMe3)2 N O n Cl R 72nMe3SiCl P(O)F3+HN(SiMe3)2 7Me3SiF F2P(O)NHSiMe3. 40 ± 50 8C 7Me3SiCl Cl2P N P Cl+HN(SiMe3)2 Cl Cl X n X=O, S. Cl2P N P NHSiMe3. Cl Cl X n (EtO)2PCl+MeCONHSiMe3 7Me3SiCl 20 8C (EtO)2PNHCOMe. 18 (EtO)2PCl+18 20 8C, Et3N 7Et3N.HCl (EtO)2P N COMe SiMe3 110 ± 130 8C 7MeCN (EtO)2POSiMe3. O P O Cl+18 20 8C O P O NHCOMe (60%) O P O Cl+18 20 8C, Et3N 7Et3N. HCl O P O N SiMe3 COMe D 7MeCN P O OSiMe3 (40%) O P Cl+Me R2 R1 C NSiMe3 OSiMe3 P R2 R1 COMe SiMe3 N 19 20 8C 7Me3SiCl P N R2 R1 OSiMe3 Me D 7MeCN P OSiMe3 R2 R1 (40% ± 60%) R1=R2=OAlk, R1=OAlk, R2=NHR3. C (RS)2PCl+19 (RS)2P N SiMe3 COMe 20 8C 7Me3SiCl, fast 20 8C slow N C OSiMe3 Me (RS)2P 1507180 8C 7MeCN (RS)2P OSiMe3 (28%763%) Reactions of phosphorus acid halides with N-silylated organic compounds 753Isomerisation of the phosphorylation intermediate followed by its decomposition is also observed in some cases.86, 89 If the latter reaction is carried out with an excess of F2PBr, bisphosphorylated acetamide is obtained. It is formed as a mixture of N,N- (20) and N,O-isomers (21), the isomer 20 undergoing rearrangement into the isomer 21.89 Thus, the reaction of trivalent phosphorus acid chlorides with N,O-bis(trimethylsilyl)acetamide is a convenient general method for the synthesis of highly reactive trivalent phosphorus acid silyl esters.The reactivity of disilylamides with respect to phosphoro- chloridites decreases upon introduction of electron-withdrawing substituents at the carbonyl carbon atom, for example, when methyl group of acetamide is substituted by a phenyl or methoxy group.Methyl N,N-bis(trimethylsilyl)carbamate does not react with diethyl phosphorochloridite and 2-chlorobenzo-1,3,2-dioxa- phospholene,86, 89 and N,O-bis(trimethylsilyl)trifluoroacetamide does not react with PF2Br.89 Contrary to silylated primary amides, N-silylated secondary amides and lactams can be selectively phosphorylated at the nitrogen atom with phosphorus trichloride and alkylphos- phonous dichlorides.90, 91 Nevertheless, there is an example of the formation of a mixture of N- and O-phosphorylation products in the reaction of N-methyl-N-trimethylsilyltrifluoroacetamide with 2-chloro- benzo-1,3,2-dioxaphospholene.92 It was found recently that the reaction of some trivalent phosphorus acid chlorides with silyllactams 22 may be reversible, and the position of equilibrium is determined by the structure of the phosphorylating agent.93 The reversibility of the process was proved by mixing equi- molar amounts of N-phosphoryllactams and chlorotrimethylsi- lane. In this case, the compositions of the reaction mixtures were the same as those in the reactions of phosphorochloridites with silyllactams.The reversibility of the reaction of N-trimethylsilyl- b-lactams with trivalent phosphorus acid chlorides was postulated on the basis of indirect data. Reactions of silylated amides with pentavalent phosphorus acid chlorides are insufficiently studied. It was shown that, as in the case of phosphorochloridites, the reaction of N,O-bis(trime- thylsilyl)acetamide 19 with phosphorus oxochloride, methylphos- phonic dichloride, diethyl phosphorochloridate, diethyl and dimethyl phosphorothiochloridate is accompanied by the forma- tion of silyl phosphates.87 Previously, it was found that N-silylated lactams react, although under drastic conditions, with alkyl(aryl) methylphos- phonochloridates and N,N-diethyl-P-methylphosphonamido- chloridate to form the products of substitution at the nitrogen atom, as in the reaction with phosphorus trichloride.94 A scheme was proposed recently, according to which penta- valent phosphorus acid chlorides R1R2P(O)Cl react with silyllac- tams 22 both at the nitrogen atom and the oxygen atom of the carbonyl group (Scheme 1).95 Strictly speaking, the possibility of silylotropy should be taken into account when estimating the reactivity ofN-silyllactams; however, under the conditions used,95 the trimethylsilyl group had to be bound to the nitrogen atom.Therefore, the nature of the products obtained was explained by the authors from the viewpoint of dual reactivity of the silyllactam system.The formation of N-phosphoryllactams 23 may result from both the direct attack at the nitrogen atom and the O!N isomerisation of the O-phosphorylated intermediates which are also the sources of side products, namely, silyl phosphates 24 and pyrophosphates 25. The predominance of one or another pathway of decomposition of the intermediates depends on different factors including the nature of the organophosphorus fragment.Successive replacement of the alkyl groups in the chloride by < < < < N P O Cl Me N P O Cl Ph O O P Cl O O P Cl < N O O Cl N P N CH2Ph CH2Ph Cl+19 100 8C 7Me3SiCl,7MeCN N P N CH2Ph CH2Ph OSiMe3 , (41%) F2PBr+19 F2PN C Me OSiMe3 780 8C 7Me3SiBr 20 8C 7MeCN F2POSiMe3 . 2F2PBr+19 780 8C 72Me3SiBr Me C O N(PF2)2 20 20 8C F2PN C OPF2 Me 21 n=1, 2. PCl3+3 RCON(Me)SiMe3 (52% ± 56%) 20 8C 73Me3SiCl RPCl2+MeCON(Et)SiMe3 20 8C 7Me3SiCl MeCON(Et)PRCl (60% ± 65%) PCl3+3 20 8C 73Me3SiCl P (83% ± 87%) 3 RCON Me P 3 N (CH2)n O N (CH2)n O SiMe3 O P O Cl+CF3CON(Me)SiMe3 5 8C 7Me3SiCl O P O NCOCF3+ Me O P O OCCF3 (40%) (60%) NMe n=1±4. P Cl+Me3Si R1 R2 P R1 R2 O (CH2)n N +Me3SiCl 22 N (CH2)n O P Cl R1 X R2 +Me C OSiMe3 NSiMe3 120 ± 130 8C 7MeCN P OSiMe3 R1 X R2 (35% ± 72%) 19 P Cl O +Me3Si 110 ± 130 8C P O (60% ± 80%) R=OEt, OPh, NEt2; n=2, 3.Me R Me R N (CH2)n O N (CH2)n O 754 A B Ouryupin, I A Rakhov, T A Mastryukovaalkoxy groups decreases the yield ofN-phosphorylated derivatives 23. The authors explain this fact by a decrease in the rate of nucleophilic attack by the nitrogen atom on the phosphorus atom in the intermediate and by a larger contribution of other directions of its transformation.It should be noted that attack on the oxygen atom of N-trimethylsilyl-b-lactams by pentavalent phosphorus acid chlor- ides is hindered by severe steric requirements to the assumed transition state. The structure of the products formed in the reaction of N,N0- bis(trimethylsilyl)ureas with trivalent phosphorus acid chlorides is determined by the nature of substituents at the phosphorus atom.96 ± 100 The attack of phenyl- and methylphosphonous dichloride on the nitrogen atom of the Si7N bond in urea is accompanied by subsequent cleavage of one of the P7N bonds, probably due to the high strain of the corresponding diazaphosphetidine ring.96, 97 In the presence of an excess of phenylphosphonous dichloride, the reaction stops at the usual step of replacement of the trimethylsilyl group.99 Replacement of the alkyl groups in the starting alkylphosph- onous dichlorides by electron-withdrawing groups (CCl3 or C2F5) changes the direction of this reaction resulting in the formation of 1,3,2-diazaphosphetidin-4-ones.97, 98 On the contrary, replacement of the alkyl group in alkyl- phosphonous dichlorides by a chlorine atom97 or a dialkylamino group99 favours the formation of bicyclic compounds.Phosphorylation of unsymmetrical N,N0-bis(trimethyl-sily- l)ureas 26 with phenyl (chloromethyl)phosphonochloridate is complicated by the attack by the second silylamide group of urea on the carbon atom of the chloromethyl group to give 1,4,2- diazaphospholane-2,5-diones.101 It is interesting that the nucleophilicity of the nitrogen atom in N,N-bissilylated sulfamides is so much lower than that in N-silyl- carboxamides that the former do not react with phosphonous dichlorides.100 Reactions of halophosphoranes with silylamides are also ambiguous.The reaction of N-methyl-N-(trimethylsilyl)tri- fluoro- and -trichloroacetamides with the chlorophosphorane 27 affords a mixture of N- (28) and O-phosphorylated (29) trihalo- acetamides.It is noteworthy that, like the product of the reaction of the silylamide 19 with dialkyl phosphorochloridodithioites, the N-phosphorylated isomer is less stable and is converted on storage into the O-phosphorylated isomer.102 + N OP(O)R1R2 Ph Me3Si Cl7 2R1PCl2+2Me3Si R1=Me, Ph; R2=Me, Ph, 3-CF3C6H4. N SiMe3 N O Me R2 20 8C 74Me3SiCl P P N N O R1 R1 N N O R2 R2 Me (80% ± 87%) Me N SiMe3 N 2 PhPCl2+Me3Si O Me Me 72Me3SiCl 20 8C N P N P O Me Me Ph Ph Cl Cl (63%) R1=CCl3, C2F5; R2=Me, 3-CF3C6H4. 72Me3SiCl N SiMe3 N R1PCl2+Me3Si O Me R2 N N P O R1 R2 Me R=3-CF3C6H4. N SiMe3 N PCl3+Me3Si O Me R 72Me3SiCl 20 8C H2O N P N N P N O O O Me R R Me 7Me3SiCl N SiMe3 N O Me Ar 26 +Me3Si P O ClCH2 Cl PhO N SiMe3 N P O Me Ar ClCH2 PhO 7Me3SiCl N P N Me O PhO Ar O O + RCON(Me)SiMe3 N O P N O N N RCONMe Ph Ph 28 N O P N O N N Cl Ph Ph 27 R1R2P(O)Cl+Me3Si N (CH2)n 22 P O R2 OSiMe3 R1 24 O (CH2)n Cl N 7 P N (CH2)n O R1 R2 23 7Me3SiCl + Me3Si N (CH2)n O P R1 R2 Cl7 7Me3SiCl Me3SiCl N (CH2)n O P O R1 R2 O R1R2P(O)Cl (CH2)n Cl N 7 P O P R1 R1 R2 R2 25 O O R1R2P(O)Cl+24 25 7Me3SiCl N (CH2)n Cl +22 7Me3SiCl (CH2)n N N (H2C)n O O Scheme 1 Reactions of phosphorus acid halides with N-silylated organic compounds 755It is assumed that the reaction of 2,2,2-trichlorobenzo-1,3,2- dioxaphospholene (30) with disilylamide 19 occurs through the step of O-phosphorylation of silylamide.With the ratio of the reagents 1 : 1, 2-chloro-2-oxobenzo-1,3,2-dioxaphospholene (31) is formed. With an excess of silylamide, the reaction affords the silyl phosphate 32.103 N,N0-Disilylated ureas react with fluorophosphoranes to give cyclic phosphoranes 33.104 Thus, practical application of silylamides requires additional studies on the optimisation of conditions for the synthesis of N-phosphorylated amides.IV. Reactions with N-silylated amino acids and other N-silylated compounds N-Silylated amino acids can be regarded as N-silylamines that contain a functional group in their alkyl part. Reactions of N,O-bis(trimethylsilyl) derivatives of natural a-amino acids with acyl chlorides were used for the protection of the amino group.105 N-Acyl derivatives of a-aminoalkylphosphonic acids were synthesised in a similar way.106 No other examples of this type of reaction have been documented.However, it turned out that N-phosphorylated amino acids can be obtained by the reaction of N,O-bis(trimethylsilylated) amino acids with pentavalent phosphorus acid halides.107 ± 109 N-Phosphorylated acids are formed in high yields.Intermedi- ate silyl esters of N-phosphorylated amino acids were isolated in the case of glycine derivatives.107 This type of selective N-phosphorylation of N,O-bissilylated compounds was also used in the synthesis of N-(dialkoxy- phosphoryl)hydroxylamines.110 Both silyl groups participate in the reaction of bis(trimethylsi- lyl)proline with diethylphosphoramidodichloridite, which results in the formation of a bicyclic product (34).111 Phosphorylation of silylated a-amino ketones occurs at the nitrogen atom.Phosphoro- and prototropic transformations of primary phosphorylation products 35 are observed in this case.112 X=O, S or unshared electron pair. The reaction of 1-(N-isopropyl-N-trimethylsilylamino)-3,3- dimethylbutan-2-one with spirophosphorane 36 was complicated by the formation of an N!P donor-acceptor bond.As a result, the tricyclic compound 37 with the hexacoordinated phosphorus atom was formed.113 The peculiarities of the reactions of phosphorus acid chlorides with such amino acid derivatives as N-silyllactams, which may be also attributed to N-silylamides, have been discussed in Section III. In the studies of the reactivity of compounds containing a silyl group at the imine nitrogen atom,114, 115 it was found that phosphorochloridites react with aldimines 114 and ketimines 115 under mild conditions and the N-(dialkoxyphosphinetriyl)aldi- mines that formed undergo rapid dimerisation.N O P N O N N O Ph Ph R N Me 29 R=CCl3, CF3. O P O O Cl 31 O PCl3+19 O 30 19 O P O O OSiMe3 32 N SiMe3 N R1n PF57n+Me3Si O R2 R3 N N PR1n F37n O R2 R3 33 n=1±3.RO O Cl +Me3SiN OSiMe3 O R H 7Me3SiCl N OSiMe3 O R H O RO RO O Cl P(OSiMe3)2 O NHSiMe3 R + 7Me3SiCl P(OSiMe3)2 O NHCOOR R 7Me3SiCl OSiMe3 N R3 H O +Me3Si Cl O P R1 R2 OSiMe3 N R3 H O O P OH N R3 H O O P (70% ± 98%) R1 R2 R1 R2 H2O (AlkO)2P(O)Cl+Me3SiNHOSiMe3 20 8C 7Me3SiCl 7MeOSiMe3 MeOH (AlkO)2P(O)NHOH (55% ± 60%) (AlkO)2P(O)NHOSiMe3 Et2NPCl2+ N CO2SiMe3 SiMe3 N O P Et2N O 34 O Me NHR0 R2(X)P O Me R2(X)P O Me NR0 P(X)R2 35 NR0 O P O O O Cl 36 + O But N SiMe3 Pri 20 8C 7Me3SiCl O O O P O N O H Pri But 37 (93%) RO=EtO; (RO)2=O(CH2)2O, 1,2-OC6H4O.N P(OR)2 N (RO)2P Ph Ph 0 ±15 8C NSiMe3+(RO)2PCl PhCH (RO)2PN CHPh 20 8C Ph2C NSiMe3 + O P Cl O Me O P N O Me (60%) CPh2. 20 8C 756 A B Ouryupin, I A Rakhov, T A MastryukovaAmong other N-silylated compounds containing a C=N bond, isocyanates and isothiocyanates are worth noting.Phosphorylation of isocyanatosilanes has been studied very little. Only the syntheses of diethylphosphoramidobisisocyanati- dite 116 and phosphorisocyanatidic difluoride 117 have been reported. Recently, the reaction of isocyanatotrimethylsilane with phosphinic chlorides was used in the synthesis of 1,3,4- oxazaphosphol-2-enes.101 Trimethylsilyl isothiocyanate reacts with trivalent and penta- valent phosphorus acid chlorides only on strong heating.118, 119 R=Ph, Me, EtO; X=O, S or unshared electron pair; n=0±2.Because of the large practical importance of phosphoryl isothiocyanates, which are the products of this reaction and which are widely used as intermediates in the synthesis of pesticides and complexones, attempts were made to decrease the reaction temperature by adding catalysts.The use of tin and titanium tetrachlorides for this purpose was unsuccessful.118, 120 On the contrary, when the reaction was carried out in the presence of N-methylmorpholine, it became possible to obtain thermally unstable phosphoryl isothiocyanates at 20 8C in high yields.121 In some cases, the reaction of isothiocyanatotrimethylsilane with pentavalent phosphorus acid chlorides is reversible.122 Using the 31P NMR method, it was found that the compositions of the reaction mixtures prepared from methylphosphonic dichloride and 2 equivalents of isothiocyanatotrimethylsilane and from methylphosphonic diisothiocyanate and 2 equivalents of chloro- trimethylsilane were identical.The yield of phosphonic diisothiocyanate may be increased by distilling off the chlorotrimethylsilane that formed in the reaction. The low yield of dibutylphosphinic isothiocyanate in compar- ison with those of the corresponding phosphoric and phosphonic isothiocyanates is also explained by the reversibility of the reaction under study.The use of isothiocyanatoalkoxydimethylsilane instead of isothiocyanatotrimethylsilane increases the reactivity of the Si7N bond in reactions with trivalent and pentavalent phospho- rus acid chlorides;123 however, the Si7O bond is cleaved even at low temperatures (20 ± 60 8C) to afford a mixture of products. Phosphoric acid fluorides are rather low-reactive with respect to Me3SiNCS even on heating, and the fluorine atom of the phosphorimide moiety is more reactive than that of the thiophos- phoramide moiety.124 The increased reactivity of the Si7N bond in azidotrimethyl- silane and the commercial availability of this compound allow one to consider it as a convenient reagent for the synthesis of thermally labile phosphorus acid azides.For example, phosphorochloridites react with Me3SiN3 to give high yields of the product even at 0 8C.125 ± 130 R1, R2=Cl, Cl3CCMe2O, Et2N, Pri 2N; R1+R2=O(CH2)2O, 1,2-OC6H4O. Pentavalent phosphorus acid chlorides 127 and chlorophos- phoranes 131 behave similarly. V. Conclusions Reactions of phosphorus acid halides, particularly chlorides, with N-silylated organic compounds are undoubtedly of interest for synthetic chemists, since they can serve as the basis for the development of methods for the synthesis of both new types of compounds and reactive intermediates.However, no strict quan- titative analysis of the regularities of this reaction has been carried out so far, which inhibits practical recommendations regarding optimum conditions of this reaction in particular cases in order to reach the required selectivity.In the recently published special issues of the `Chemical Reviews' devoted to current problems of the chemistry of silicon132 and phosphorus,133 the problems concerning the appli- cation of compounds with a nitrogen7silicon bond in the organo- phosphorus synthesis were not properly taken into account. We hope that the present review fills this gap.Based on the literature data and their own experience, the authors have the courage to state that the potential of the reactions under discussion has not been totally exploited. In particular, this refers to phosphorylation of biopolymer fragments under mild conditions, for which methods of silylation have been largely developed. In this case, the result of the reaction may be controlled by varying substituents at the silicon and phosphorus reaction centres.Such studies may be carried out in the near future. This review was written with the financial support of the Russian Foundation for Basic Research (Project No. 96-15-97298). References 1. N G Zabirov, F M Shamsevaliev, R A Cherkasov Usp. Khim. 60 2189 (1991) [Russ.Chem. Rev. 60 1128 (1991)] 2. E Uhlmann, A Peyman Chem. Rev. 90 544 (1990) 3. E Fluck, in Organic Phosphorus Compounds (Eds G M Kosolapoff, L Mayer) (Interscience: Wiley, 1973) p. 6 4. 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ISSN:0036-021X    

出版商:RSC    

年代:1998

数据来源: RSC

ISSN:0036-021X    

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Abstract. The results of the application of radiation-chemical methods for the preparation of polymeric biomaterials are sur- veyed and treated systematically. The characteristic features of these methods and their advantages and disadvantages are indi- cated. The properties of polymeric biomaterials prepared using ionising radiation are examined. Particular attention is devoted to studies carried out during the last 10 ± 15 years.The bibliography includes 492 references. I. Introduction Polymeric biomaterials are usually understood as polymeric materials and articles made from them which are used in medicine or biotechnology. Such materials are frequently prepared by the specific modification of well known polymers. The range, scale of manufacture, and importance of biomaterials have increased appreciably during recent years.A series of reviews and monographs have been devoted to problems of their preparation, properties, and applications (see, for example, Refs 1 ± 6). Radiation-chemical technology has now become one of the effective methods for the preparation of polymeric biomaterials. The studies on the employment of radiation-chemical methods for the synthesis of polymeric biomaterials have been carried out on the following lines: radiation-induced modification of various polymers and articles made from them in order to obtain haemocompatible polymers (polymers which are in prolonged contact with blood during their employment), polymeric sorbents, prostheses for blood vessels, etc.; immobilisation of various bio- logically active substances (BAS) (enzymes, medicinal drugs, etc.) in polymeric matrices using radiation-induced polymerisation; radiation-chemical synthesis of polymeric carriers for medicinal preparations; radiation-induced cross-linking of polymers in order to obtain mechanically strong hydrogels (BAS carriers, dressings, eye lenses, etc.).An advantage of the radiation-chemical methods for the preparation of polymeric biomaterials compared with traditional methods is the purity of the materials (there is no need to add additional ingredients during the synthesis), the possibility of carrying out the processes at reduced temperatures, and the ease of regulation of the rate of the processes by altering the radiation dose rate.Another advantage of the radiation-chemical methods is the fact that the biomaterials can in certain cases be sterilised on the same sources of ionising radiation which were used for their preparation.It is essential to note that in the majority of cases low radiation doses, as a rule not exceeding 30 kGy, are required for the preparation of polymeric biomaterials, which makes it possi- ble to use low-power radiation sources.A disadvantage of radiation-chemical methods is the necessity to use, as a rule, g-radiation sources and electron accelerators which are comparatively expensive and difficult to use. The mechanisms of the radiation-chemical processes, the devices, the dosimetry, and the methods involving the employ- ment of ionising radiation sources have been described in detail in a series of monographs (see, for example, Pikaev and Woods 7, 8).In the present review, these questions are not considered. II. Preparation of haemocompatible polymeric materials The preparation of haemocompatible polymeric materials is an extremely complex problem. When polymers come into contact with blood, biochemical reactions inducing a change in the physiological functions of blood are initiated and the blood clotting system with subsequent thrombus formation on the surface of the polymer is `switched on'.Reviews have been devoted to the mechanisms of thrombogenesis on the surface of polymers.9 ±15 Important factors increasing the haemocompati- bility of polymers are their properties such as minimal capacity for the adhesion and aggregation of thrombocytes, the lack of activation of blood clotting contact factors, participation in the lysis of the thrombus formed, and a selective capacity for the adsorption of blood plasma proteins, especially albumin. Accord- ing to current ideas, the first stage, when the polymer comes into contact with blood, is rapid sorption of proteins from blood plasma.The nature and conformational state of the protein determine the subsequent biochemical reactions.The problems of the sorption of proteins on various polymeric surfaces have been considered in numerous investigations (see, for example, Refs 1, 16, and 17). Unfortunately, at the present time V Yu Kabanov Institute of Physical Chemistry, Russian Academy of Sciences, Leninskii prosp. 31, 117915 Moscow, Russian Federation.Fax (7-095) 335 17 78. Tel. (7-095)335 20 02 Received 4 January 1997 Uspekhi Khimii 67 (9) 861 ± 895 (1998); translated by A K Grzybowski UDC 541.15.64 Preparation of polymeric biomaterials with the aid of radiation- chemical methods V Ya Kabanov Contents I. Introduction 783 II. Preparation of haemocompatible polymeric materials 783 III. Preparation of special sorbents 792 IV.Synthesis of polymeric carriers for medicinal preparations 792 V. Immobilisation of biologically active substances 794 VI. The use of radiation-induced cross-linking for the preparation of polymeric biomaterials 807 VII. Conclusion 809 Russian Chemical Reviews 67 (9) 783 ± 816 (1998) #1998 Russian Academy of Sciences and Turpion Ltdthe level of our knowledge precludes sufficiently effective predic- tion of the nature and properties of the polymer surface which would fully satisfy the requirement of haemocompatibility. It is clear from the foregoing that the surfaces of polymers must be modified in order to obtain haemocompatible materials.The following measures are taken for this purpose. 1. Polymers are created with surfaces possessing a reduced adsorption capacity in relation to protein and are close in their nature to the natural medium of the organism.In the main, these are hydrogel surfaces. It has been assumed 17 that both an approximate equality, pairwise, of the dispersion and polar components of the free surface energy of blood and materials and the closeness of the distribution of the above energy param- eters, also pairwise, are needed for haemocompatible materials. 2. Polymeric materials with a definite domain structure of the surface (polyurethanes) are created. 3. Polymeric hydrocarbon materials (polyethynes) are created. 4. Polymers are created the surfaces of which model, in terms of their nature, blood anticoagulants (this is achieved by introduc- ing sulfo- and carboxy-groups into the surface layers of polymers, by generating a negative charge on the surfaces of polymers). It is usually endeavoured to obtain a heparin-like surface, since the widely used method for the preparation of haemocompatible materials by introducing heparin suffers from a series of disad- vantages due to the partial loss of activity by the heparin on covalent immobilisation and its weak anticomplement activity and biodegradation. 5. Physiologically active substances (blood anticoagulants, enzymes, etc.), interacting with blood components and arresting the thrombogenetic process, are introduced into the surface hydrogel layers. In selecting the method for the modification of the polymer surface, it is essential to bear in mind the principle that the physicomechanical parameters of the initial polymer should not change significantly on modification.One of the methods for the modification of polymers is radiation-induced graft polymerisa- tion. A series of reviews have been devoted to various problems of the radiation-induced graft polymerisation and the methods for carrying it out.7, 18 ± 22 Its advantages as a method for the mod- ification of polymeric materials in order to increase their haemo- compatibility are, firstly, a high universality which makes it possible to modify over a wide temperature range virtually any polymeric materials (stitches, catheters, tubes, tablets, powders, grafts, etc.) and secondly the possibility of creating on the polymer surface of modified layers of different thickness.The thickness of the layer depends on the conditions under which the graft polymerisation is carried out � the dose rate, the choice of the solvent for the monomer, etc.The modified layer is then strongly bound to the support and is not washed off on contact with the medium of the living organism. All these features promote a fairly wide-scale employment of radiation-induced graft polymerisation for the solution of prob- lems associated with the enhancement of the haemocompatibility of various polymeric materials and articles made from them.The principal task of such investigations is the creation of polymers with a functionalised surface, definite hydrophilic-hydrophobic properties, and a negative charge on the surface.23 ± 25 A large number of studies have been carried out on the modification of various polymers using highly hydrophilic monomers such as N-vinylpyrrolidone, 2-hydroxyethyl methacrylate, and acryla- mide and its derivatives.26 ± 72 In a series of investigations, fairly complex copolymers have been used for modification.73 ± 87 Thus, polyurethanes, polyesters, and natural rubber have been mainly used for the manufacture of blood vessel prostheses.88 ± 118 Table 1 presents data on the employment of the radiation- induced graft polymerisation methods for the modification of polymers.The radiation-induced graft polymerisation was carried out in most cases by the direct method from aqueous alcoholic solutions with low irradiation doses. In certain cases, especially in the grafting of acrylamide, the method involving preirradiation was used.41 The investigations carried out led to the preparation of a wide variety of modified polymeric materials with hydrogel surfaces.These materials are fairly strong and soft and exhibit a high swellability in water. The biomacromolecules in such materials are characterised by enhanced diffusion. The polymeric hydrogels obtained by radiation-chemical methods have been tested for haemocompatibility in experiments in vitro and in vivo on mon- keys, sheep, and dogs.The tests for the haemocompatibility of the radiation-grafted polymeric hydrogels revealed the following general features: with increase in the water content from 15% to 85%, the sorption of proteins diminishes, the rate of desorption increases, and thrombogenesis takes place on the hydrogels, but the bond between the thrombus and the hydrogel surface is appreciably weakened compared with the bond between them and the unmodified polymers.The appreciable decrease in the interfacial tension between the hydrogel and the aqueous solution is very important. The hydrogel coating on the polymers should be prepared from very pure monomers. Thus a slight methacrylic acid impurity in 2-hydroxyethyl methacrylate appreciably impairs the quality of the hydrogel coating and its haemocompatible properties.93 Interesting results have been obtained in the study of the copolymers of 2-hydroxyethyl methacrylate (a hydrophilic mono- mer) with ethyl methacrylate (a hydrophobic monomer) radia- tion-grafted onto polyethylene (PE).93 For a low water content (*10%), the above graft copolymers were characterised by unexpectedly low thrombocyte adsorption parameters, which was not due to the water content but to the composition of the copolymer.For a higher water content, the adsorption of throm- bocytes was inversely proportional to the water content. Evi- dently, the composition of the copolymers and the state of water in it are important.The surface of radiation-grafted copolymers is very nonuniform (there are mounds, projections, etc.) and the thickness of the modified layer is as a rule 15 ± 45 mm. Hoffman et al.93 concluded that a definite combination of hydrophilic and hydrophobic sections on the surface is needed to increase the haemocompatibility. The state of water in radiation-grafted copolymers has been investigated.94, 95 The state of water in radiation-grafted PE hydrogels with grafted polyacrylamide has been studied.94 It has been established by differential scanning calorimetry (DSC) that the water in hydrogels does not freeze down to 750 8C and that the amount of unfrozen water per unit surface of the modified polymer which has undergone equilibrium swelling or per mole of the grafted polyacrylamide depends on the methods used to carry out the graft polymerisation. The presence of unfreezing water in radiation-grafted hydrogels with polyacrylamide chains is due to the rearrangement of the water framework in the hydrogel owing to the formation of a strong hydrogen bond between the H2O molecule and the carbonyl group of polyacrylamide, which has been demonstrated by IR Fourier spectroscopy.94 Data on the employment of the ESCA method for the investigation of the influence of hydration on the state of the grafted chains in a thin layer on the surfaces of polymers *50 A thick have been published.95 The following systems have been investigated: low- density polyethylene (LDPE)+grafted poly(2-hydroxyethyl methacrylate), LDPE+grafted polyacrylamide, silicone rubber (Silastik)+poly(2-hydroxyethyl methacrylate), and polyur- ethane (Tufthane)+poly(2-hydroxyethyl methacrylate).The sur- face was analysed by studying the C1s, O1s, and Si2p peaks. The C/ Si, O/Si, C/O, C/N, and O/N peak ratios for the hydrated and dehydrated surfaces of various radiation-grafted copolymers have been published.95 These data make it possible to determine the location of the grafted chains in the surface layer of the polymers in the hydrated and dehydrated states.For example, in the case of the grafting of poly(2-hydroxyethyl methacrylate) on polyur- ethanes, the concentration of the grafted chains on the surface diminishes appreciably after dehydration. On the other hand, 784 V Ya KabanovTable 1.Radiation-induced graft polymerisation of monomers for the preparation of various polymers with the aim of regulating haemocompatibility. Monomer Conditions in radiation-induced Remarks Ref. graft polymerisarion Polymer�polyethylene Acrylic acid post-radiation grafting the adsorption of antitumour preparations on adsorbents 29 with grafted poly(acrylic acid) was studied direct grafting from aqueous phase the hydrophilic properties of the surface were studied in detail 96, 97 ditto the carboxy groups were converted into acid chloride 90 groups by treating the surface with thionyl chloride and the latter were used for the covalent binding of BAS Acrylic acid chloride direct grafting from vapour phase 23, 26 Acrylic acid, acrolein; direct grafting from liquid phase sulfonation of graft copolymer 31 mixture of monomers Acrylamide grafting by the preirradiation method the amide groups of the grafted polyacrylamide 27 from aqueous and acetone solutions were converted into amino groups; heparin was bound to the amino groups; tests in vivo and in vitro ditto polymer tubes were used; tests in vivo 28 direct grafting from solution the surface of the modified polymer was studied 33 various grafting methods, including 107 grafting from the vapour phase, were used Acrylamide, N,N0-methylene- direct grafting from 10% aqueous alcoholic 24 bisacrylamide solution in the presence of Fe2+ Allylamine direct grafting in the presence of phosphoric acid increases the yield of the graft polymer 25 phosphoric acid Diallyldimethylammonium direct grafting 35 chloride, sodium styrene sulfonate 2-Hydroxyethyl methacrylate, direct grafting from water ± methanol surfaces with different hydrophilicities were obtained 30, 37 ethyl methacrylate; mixture at low dose rates mixture of monomers 4-Vinylpyridine+ direct grafting of monomers from alkylation of graft copolymer 32 2-(N,N-diethyl- vapour phase amino)ethyl methacrylate; 4-vinylpyridine+methyl methacrylate; 4-vinyl- pyridine+methacrylic acid N-Vinylpyrrolidone grafting from liquid phase by 36 the preirradiation method Methyl acrylate direct grafting from water ± acetone hydrazinolysis of graft copolymers 59 mixture Styrene direct grafting introduction of sulfonate and sulfonamide groups; 48 tests in vitro 2-Hydroxyethyl meth- direct grafting from liquid phase the structure of the surface was investigated 93 acrylate, 2-hydroxyethyl by electron microscopy methacrylate+ethyl methacrylate 2-Hydroxyethyl meth- dit06 acrylate, N-vinylpyr- rolidone, acrylamide Polymer�polyethylene, silicone rubber 2-Hydroxyethyl meth- direct grafting from liquid phase the state of water was investigated by 94, 95 acrylate, acrylamide the DSC and ESCA methods Preparation of polymeric biomaterials with the aid of radiation-chemical methods 785Table 1 (continued).Monomer Conditions in radiation-induced Remarks Ref. graft polymerisarion Polymer�polypropylene 2-Hydroxyethyl direct grafting from 20% monomer a grafting maximum is observed for a dose of 5 kGy 39 methacrylate solution grafting by the preirradiation method hydrophilisation of polypropylene stitch material 98 Monomer mixtures: direct grafting the polyacrylic acid in the modified polymer 40 N-vinylpyrrolidone+ was partly neutralised with alkali acrylic acid; vinyl acetate+ crotonic acid Acrylamide postradiation grafting after vacuum 41 irradiation of polymer Polymers �polyethylene, polypropylene, polyesters, poly-4-methylpentene, polyvinyltrimethylsilane Acrylic acid, grafting from vapour phase the formation of polyelectrolytic complexes 34 methacrylic acid, on the surfaces of the polymers was investigated 4-vinyl-pyridine Polymers �polyethylene, polypropylene, polyamides, polyurethanes, etc.N-Methyl-N-vinylacetamide direct grafting from liquid phase the properties of the surfaces of the modified polymers 89 were characterised by the critical surface tension; polymer tubes were used for modification Polymers �polyethylene, polypropylene Vinylidene chloride direct grafting from gas phase dehydrochlorination of materials obtained 101 ± 104 Polymer�ethylene-propylene rubber 2-Hydroxyethyl methacrylate, direct grafting from aqueous medium in 70 N,N-dimethylacrylamide, the presence of Cu2+ ion 2-(N,N-dimethylamino)ethyl methacrylate Acrylamide, N-vinyl- direct grafting from aqueous the morphology of the surface and the influence 71 pyrrolidone, 2-hydroxy- monomer solution of O2 on the grafting were investigated ethyl methacrylate Different vinyl monomers direct grafting from liquid phase grafting onto a film, a tube, and a fibre 42 was studied; the surface properties were investigated Polymer�ethene ± propene copolymer N-Vinylpyrrolidone, direct grafting from liquid phase 86 2-hydroxyethyl methacrylate, acrylamide Polymers �polyolefins Macromonomers direct grafting review of studies on the grafting of macromonomers; 91 macromonomers were obtained by the acylation of the amino groups in enzymes or heparin using acrylic acid chloride Polymer�polytetrafluoroethylene Acrylic acid chloride direct grafting from monomer gas phase 23 N,N-Dimethylacrylamide direct grafting from liquid phase the influence of dose rate, solvent, and temperature on 45 the grafting was investigated Acrylamide grafting by the preirradiation method the surface of the polymer was investigated by the ESCA 46 method and by scanning electron microscopy tert-Butyl crotonate+ direct grafting from liquid phase the influence of the graft polymer on the 47 methyl acrylate+ haemocompatibility was investigated sulfonic acid Methyl methacrylate phase direct grafting from liquid phase modification of blood vessel prostheses 49 Styrene ditto the grafted chains were nitrated and the nitro groups 43 were reduced to amino groups 786 V Ya KabanovTable 1 (continued).Monomer Conditions in radiation-induced Remarks Ref. graft polymerisarion Polymers �polytetrafluoroethylene, tetrafluoroethene ± ethene copolymer N,N-Dimethylacrylamide direct grafting at different dose rates 50 Polymer�tetrafluoroethene ± propene copolymer N,N-Dimethyl acrylamide direct grafting from liquid phase the influence of solvents on the grafiting was investigated 76 Polymer�poly(vinyl fluoride) 2-Hydroxyethyl methacrylate, grafting by the preirradiation method from the kinetics of graft polymerisation were investigated 51 vinyl acetate, acrylic acid, the liquid phase of the monomer; N-vinylpyrrolidone, irradiation by electron accelerator 4-vinylpyridine, acrylamide, vinylene carbonate Polymer�poly(vinylidene fluoride ± hexafluoropropene) Styrene grafting by the preirradiation method; functionalisation of grafted chains; modification of 62 irradiation by accelerated heavy ions blood vessel prostheses Polymers �poly(vinylidene fluoride), hexafluoropropene ± vinylidene difluoride copolymer Styrene grafting by the preirradiation method; introduction of sulfo groups; formation of 87 irradiation with accelerated heavy ions a heparin-like surface Organosilicon polymers N-Vinylpyrrolidone direct grafting from monomer solution in grafting on silicone rubber tubes 52, 58 methanol or toluene direct grafting from liquid phase review of studies on radiation-induced grafting 60 of N-vinylpyrrolidone N-Vinylpyrrolidone, direct grafting from aqueous monomer the influence of Cu2+ on the distribution of 57 2-hydroxyethyl methacrylate; solution in the presence of Cu2+ ions the grafted layer and the degree of grafting mixture of monomers was investigated direct grafting from 20% aqueous solution the influence of the irradiation dose on the grafting 53 and the swelling of the modified polymers in water was investigated N-Vinylpyrrolidone direct grafting from aqueous solution 63 mixture of N-vinyl- of monomers pyrrolidone and 2-hydroxyethyl methacrylate 2-Hydroxyethyl methacrylate direct grafting 64 Different hydrophilic grafting from aqueous solution 67 monomers 2-Hydroxyethyl meth- direct grafting from water ± methanol the rate of grafting depends significantly on 54 acrylate, ethyl acrylate; mixture the water : monomer ratio mixture of monomers 2-Hydroxyethyl meth- direct grafting from aqueous phase separate grafting of each monomer and of 56 acrylate, ethyl meth- the mixture of monomers; the surface of acrylate; mixture of polymers was investigated by scanning monomers electron microscopy Acrylamide direct grafting from liquid phase in 55 the presence of Cu2+ ions Polymers �polyurethane, silicon rubber Acrylamide direct grafting from liquid phase sections through films and the swelling of 38 the polymers in water were investigated N-Vinylpyrrolidone ditto grafting onto polymer tubes; tests for 69 haemocompatibility in vivo Preparation of polymeric biomaterials with the aid of radiation-chemical methods 787Table 1 (continued). Monomer Conditions in radiation-induced Remarks Ref.graft polymerisarion Polymer�segmented polyurethane N-Vinylpyrrolidone direct grafting from monomer the influence of the degree of swelling and of 75 solution in water the irradiation dose on the grafting was investigated 2-Hydroxyethyl methacrylate direct grafting in swollen state the influence of the degree of swelling and temperature 74 on the grafting was investigated Polymer�polyesterurethane 2-Hydroxyethyl methacrylate direct grafting from water ± ethanol modified blood vessel prostheses were obtained; 72 mixture the swelling of the modified polymers was investigated Polymer�polyurethanepolyester (Upjohn) N-Vinylpyrrolidone direct grafting from monomer solution the influence of temperature on the grafting and 77 in water, benzene, toluene, and Freon the cross-sectional distribution of the grafted polymer was investigated; the grafting was carried out on tubes Polymer�polyurethane 2,3-Epoxypropyl meth- direct grafting from liquid phase the influence of solvents on the grafting was investigated; 73 acrylate, acrylamide, 2-hydr- the best solvent is acetone oxyethyl methacrylate Monomers with ditto the haemocompatibility was investigated in vivo 105 sulfonate groups Polymer ± polyamide 6 Various monomers direct grafting from liquid phase the grafting was carried out from solvents with 61 a specific solubility parameter; modification of polyamide beads; preparation of new adsorbents 2-Hydroxyethyl methacryl- ditto grafting onto polymer beads; the modified beads 84 ate, glycidyl methacrylate obtained were used as carriers for affinity chromatography Polymer�poly[bis(trifluoroethoxyphosphazene)] N-Vinylpyrrolidone direct grafting from aqueous monomer 67 solution Polymers �polyphosphazenes N-Vinylpyrrolidone direct grafting from aqueoussolution Polymer�natural rubber N,N-Dimethyl acrylamide direct grafting from monomer 99 solution in CCl4 grafting by the preirradiation method the haemocompatibility was investigated 108 as a result of the decomposition of hydroperoxy groups 2-(N,N-Dimethylamino)- direct grafting from monomer grafting onto polymer tubes 92 ethyl methacrylate solution in CCl4 tubes Polymer�natural leather Butyl methacrylate, direct grafting 81 styrene, methyl methacrylate Polymers �poly(vinyl alcohol), polyamide 6 Acrylamide, N-vinyl- direct grafting from aqueous solution adsorbents for affinity chromatography 44 pyrrolidone, 2-hydroxy- in the presence of added formamide and ethyl methacrylate, tetrahydrofuran 2-(N,N-dimethylamino)ethyl methacrylate Polymer�poly(ethylene glycol dimethacrylate) 2-Hydroxyhexyl methacrylate direct grafting the adsorption of g-globulin on the polymers obtained 66 was investigated 788 V Ya Kabanovwhen poly(2-hydroxyethyl methacrylate) is grafted on the LDPE surface, dehydration does not affect the concentration of the grafted chains in the surface layer while the concentration of polyacrylamide grafted on polyurethanes does not change on the surface after dehydration.In the case of organosilicon rubbers, the number of grafted chains on the surface diminishes as dehydration proceeds and the grafted chains are gradually immersed in the film.The second process occurring on dehydration is the formation of clusters by the grafted chains. The clusters are formed from several macro- molecules. The disposition of the clusters on the surface depends on the degree of dehydration.Hydration significantly increases the concentration of the grafted chains on the polymer surfaces. This is particularly notable in the case of radiation-grafted silicone rubbers. Such data are important for the biomedical employment of the hydrogels obtained by radiation-induced graft polymer- isation, since it is essential to take into account the change in the state of the grafted chains in the hydrogels on contact with blood or other biological liquids.The hydrophilic properties of LDPE with grafted poly(acrylic acid) have been investigated.96, 97 It was established that the hydrophilic properties are stabilised after a 15%± 17% graft (complete surface coverage). The polar component of the free surface energy then increases appreciably and the molecules of poly(acrylic acid) are reorganised under the influence of water.The preparation of a hydrophilic stitch material by the radiation-induced grafting of 2-hydroxyethyl methacrylate on a single polypropylene fibre has been described.98 The influence of solvents and irradiation conditions on the graft has been inves- tigated. Hydrophilic polypropylene filaments were obtained as a result.The view has been expressed in certain investigations that the modified layer must be of definite thickness for the successful increase in haemocompatibility. In a study of the radiation- induced graft polymerisation of 2-hydroxyethyl methacrylate and acrylamide on polyolefin films and blood vessel prostheses, it has been established 72 that the adsorption of proteins is reduced if the amount grafted does not exceed 10%.On the other hand, an appreciable decrease in interfacial tension and in the adsorption of thrombocytes is observed only after the attainment of a 20%± 30% graft. The adhesion of thrombocytes diminishes significantly after the film has been coated with albumin. Haemo- compatibility (investigated in vivo on sheep) as a rule increases significantly only for comparatively high amounts grafted (exceeding 30%).33, 72, 75 The study of the haemocompatibility of high density polyethylene (HDPE) modified by the radiation- induced grafting of polyacrylamide (the tests were carried out in vivo) showed 33 that after modification the thromboresistance of the polymer increases several fold.The haemocompatibility of segmented polyurethane after the radiation-induced grafting of N-vinylpyrrolidone has been investigated by Hongfei et al.75 The influence of pH on the radiation-induced grafting of N-vinylpyrrolidone has been studied.The surface of the modified polymer is rough and its swelling in water increases exponentially with the amount grafted. An appreciable increase in thrombore- sistance is achieved in tests in vivo after the attainment of a 20% graft.The haemocompatibility of modified silicone tubes (in vivo tests) has been investigated by Chapiro et al.52 The modification was carried out by the radiation-induced grafting of N-vinyl- pyrrolidone from a solution of the monomer in methanol or toluene. It was established that the haemocompatibility increases significantly after a 33% graft.On the other hand, the adsorption parameters of the proteins have a minimum at a certain thickness of the grafted layer. For example, in a study of the radiation- induced grafting of methoxypoly(ethylene glycol methacrylate) with 2-hydroxyethyl methacrylate by the direct method onto silicone rubber (Silastik), it was observed that the adsorption of fibrinogen has a minimum for an 8% graft.Table 1 (continued). Monomer Conditions in radiation-induced Remarks Ref. graft polymerisarion Polymers �polystyrene, polyester N-Vinylpyrrolidone, direct grafting from liquid phase hydrophilisation of polystyrene articles for 78 2-hydroxyethyl phase immunodiagnostics; modification of polyester blood methacrylate vessel prostheses in order to increase haemocompatibility Polymer�polystyrene N-Isopropylacrylamide direct grafting transition from a hydrophilic to a hydrophobic surface 79 with the increase in temperature; the study of the adhesion of endothelial cells Polymer�polycarbonatepolysiloxane Acrylic acid grafting by the preirradiation method; 82 irradiation by electron accelerator Polymer�triblock copolymer (styrene ± butadiene ± styrene) 2-Hydroxyethyl methacrylate direct grafting from aqueous the modified specimens were investigated by 83 monomer solution electron microscopy and IR spectroscopy; the wetting angles were measured Polymer�poly(vinyl chloride) 2-(N,N-Dimethylamino)- grafting by the preirradiation method grafting on polymer powder; preparation of 85 ethyl methacrylate immunoadsorbents Polymer�poly(ethylene terephthalate) Acrylamide direct grafting modification of blood vessel prostheses 80 Polymer�poly(methyl methacrylate) Acrylic acid direct grafting binding of enzymes to the polymer surface 88 Preparation of polymeric biomaterials with the aid of radiation-chemical methods 789The texture of the surface also influences the haemocompat- ibility.The radiation-induced graft polymerisation of N,N-dime- thylacrylamide on polytetrafluoroethylene and the tetrafluoroethene ± ethene copolymer (Aflon) has been investi- gated.27, 50 The influence of the monomer concentration and the dose rate on the haemocompatibility of the modified polymers obtained was studied.It was established that a decrease in dose rate from 1 to 0.1 kGy h71 increases the haemocompatibility (in vivo tests), which is associated with the increase in the smoothness of the surface.Collin et al.85 studied the adhesion of red blood cells on polycationic carriers, which were prepared by modifying poly(vinyl chloride) grains by means of radiation-induced graft polymerisation of dimethylaminoethyl methacrylate; electron micrographs of the system with adhering cells have been pub- lished.The radiation-induced graft polymerisation of acrylamide on polypropylene (PP) films by the post-effect method in order to render them hydrophilic is also promising.100 Another method for the preparation of haemocompatible polymeric material involves the creation of hydrocarbon polymers (polyethynes). For this purpose, vinylidene chloride was radia- tion-grafted from the gas phase onto polymeric materials with subsequent dehydrochlorination of the modified polymers obtained. These materials are used in endosurgery.101 ± 104 One of the methods of increasing haemocompatibility involves the use of radiation-induced graft polymerisation in order to obtain negatively charged surfaces of polymers contain- ing carboxy, hydroxy and sulfo groups.The communication of Stever et al.105 is devoted to the study of polyurethanes modified by the grafting of propanesulfonate func- tional groups. It was established in experiments in vivo that the haemocompatibility of such polyurethanes increases, the adhe- sion of blood cells to the surface is low, and the adhering cells do not undergo marked changes.The conversion of the adsorbed fibrinogen into fibrin is blocked and inhibited, i.e. the surface modification acts in approximately the same way as heparin � a blood anticoagulant. The radiation-induced grafting of the bisul- fite derivative of acrolein mixed with acrylic acid followed by the sulfonation of the grafted layer with sulfurous acid and neutral- isation of the sulfo and carboxy groups has been investigated.31 Modified materials with a thromboresistant effect were created.Ratner et al.106 described a study of the influence of the nature of the monomer used for radiation-induced graft polymerisation on the antithrombogenic properties of the modified materials. The authors studied the thrombogenic properties (in vivo) of the hydrogels obtained by the radiation-induced grafting of 2-hydrox- yethyl methacrylate, acrylamide, a mixture of 2-hydroxyethyl methacrylate and ethyl methacrylate, and a mixture of 2-hydrox- yethyl methacrylate and N-vinylpyrrolidone on LDPE.The influence of the composition of the copolymer and the water content on the deposition of thrombi is described in detail. It has been noted that the use of radiation-modified polyphosphazenes as haemocompatible materials is promising.70 It has been shown 72 that the number of attached thrombocytes diminishes with decrease in the interfacial free energy (in vivo tests in the canine carotid arteries of polyurethane tubes modified by the grafting of 2-hydroxyethyl methacrylate). The interfacial free energy decreases significantly after the grafting of 30% of 2-hydroxyethyl methacrylate.The coating of the graft polymer with albumin or g- globulin decreases the adhesion of thrombocytes. In a study of the influence of the radiation-induced grafting of acrylamide on LDPE and PP tubes on the antithrombogenic properties, it was efitablished that the best antithrombogenic properties are attained for a 30% graft (the wetting angle is<28 8).27, 28, 41 The influence of the conditions in the graft polymerisation on the antithrombo- genic properties has been demonstrated.When N-vinylpyrroli- done is grafted on polyurethane; the best antithrombogenic properties are also attained for a 30%± 35% graft (experiments on the blood circulatory system of sheep).69 The study of the radiation-induced grafting of acrylamide and acrylic acid on LDPE and HDPE showed that the radiation-induced graft polymerisation of acrylamide takes place most effectively in the case of HDPE.24, 33, 107 The modified PE polymers with grafted polyacrylamide have a low wetting angle and exhibit enhanced antithrombogenic properties in tests in vivo in the carotid arteries of rats.The thrombus formation time increases several fold compared with pure PE.33 The cross-linking of the polyacryla- mide chains in the radiation-induced grafting of acrylamide together with the N,N0-methylenebisacrylamide cross-linking agent leads to a decrease in thromboresistance.28 The radiation-induced graft polymerisation of N,N-dimethyl- acrylamide on natural rubber tubes has been studied in detail.92, 108 It was established that the best solvent for grafting is CCl4 and that satisfactory haemocompatibility is manifested for a 30% graft.The presence on the polymer surface of uniformly distributed negatively charged functional groups is important for increasing haemocompatibility.47 Studies on the use of radiation-induced graft polymerisation for the modification of blood vessel prostheses made from poly- ester materials have been carried out in Poland (Institute of Applied Radiation Chemistry, Lodz).Acrylamide was used for the radiation-induced graft polymerisation. The influence of the dose and the monomer concentration on the process was inves- tigated. Grafting results and an increase in hydrophilicity and a decrease in the gas-permeability of the prostheses.Tests on the prostheses demonstrated their fairly satisfactory biocompatibil- ity. Thus acrylamide and its derivatives are promising monomers for increasing the hydrophilicity and biocompatibility of various polymeric materials. Another monomer which being vigorously employed for increasing biocompatibility is the highly hydrophilic monomer N-vinylpyrrolidone.48, 52, 58, 60, 67, 68, 75, 78 The radiation- induced grafting of N-vinylpyrrolidone is as a rule carried out by the direct method from its solutions in water, toluene, or meth- anol, using low radiation doses.As in the case of acrylamide, after the graft polymerisation of N-vinylpyrrolidone the hydrophilicity increases significantly with increasing amount of the grafted material. The antithrombogenic properties of polyesterurethane tubes modified by the radiation-induced grafting of 2-hydrox- yethyl methacrylate have been investigated.109 Tests in vivo showed that a considerable amount of graft is required for an appreciable enhancement of the antithrombogenic properties.The radiation-induced grafting of 4-vinylpyridine (4-VP)+ 2-(N,N-diethylamino)ethyl methacrylate and 4-vinylpyridine+- methacrylic acid mixtures on polyethylene catheters has been studied.110 The catheters were tested in vivo.The operational lifetime of the catheters depends significantly on the amount of graft. The haemocompatibility of the radiation-grafted PE poly- mers with poly(2-hydroxyethyl methacrylate) and poly(2,3-di- hydroxypropyl methacrylate) has been studied.111 In the investigation of the adhesion of thrombocytes on poly(vinyl chloride) with radiation-grafted polyacrylic acid, it was estab- lished that the adhesion of thrombocytes diminishes significantly with increase in the amount of graft and with decrease in the wetting angle.112 One of the ways of enhancing the antithrombo- genic properties of polymers involves the formation on their surfaces of polyelectrolyte complexes (PEC).113, 114 PEC are formed on the surfaces of polymers as a result of the interaction of the radiation-grafted poly(acrylic acid) with polyamines.The appearance of PEC gives rise to the formation of a microheter- ogeneous structure with alternation of hydrophilic and hydro- phobic sections. Lundell et al.40 investigated the radiation-induced grafting on the surfaces of PP of mixtures of N-vinylpyrrolidone and acrylic acid and also vinyl acetate and crotonic acid.Pronounced antithrombogenic properties were attained after partial neutrali- sation of crotonic acid with alkali. It was concluded that the negative surface charge plays an important role.40 ± 47 It was established 42 that polymers with grafted poly(vinyl acetate) 790 V Ya Kabanov(with subsequent partial hydrolysis of the acetate groups) and N-methyl-N-vinylacetamide exhibit the best haemocompatibility.The main conclusion which may be reached from the data described above concerning the use of hydrophilic monomers in order to enhance the antithrombogenic properties of polymers is that, with increase in the water content, thrombogenesis dimin- ishes, but, in prolonged tests in vivo the minimum thrombogenesis is attained for a definite water content.105 Radiation-induced grafting of N-vinylpyrrolidone as well as acrylamide and its derivatives affords good results.The presence of negatively charged groups on the surface is important.115 The adsorption of enzymes and blood cells diminishes with increase in the amount of graft.116 The presence of certain admixtures in the monomers employed for radiation-induced graft polymerisation influences significantly the haemocompatibility because it can alter the nature of the sorption of proteins.117 An extremely promising aspect of the preparation of antith- rombogenic polymeric materials involves the modification of the surface of polymeric materials by radiation-induced graft poly- merisation followed by the introduction into the modified layers of physiologically active substances (PAS), which act in thelood clotting stage.The radiation-induced grafting of monomers with active functional groups capable of reacting with the PAS is usually carried out for this purpose. The form of the bond between the PAS and the polymer (covalent, ionic, or physical capure) as well as the microenvironment of the PAS in the polymer are important. Radiation-induced graft polymerisation has been used 63, 118 ± 122 to obtain modified polymeric materials containing on the surface organic cations to which heparin is attached as a result of the formation of ionic bonds.As an example, styrene was grafted to different polymers with subsequent chloromethylation and quaternisation.118 4-Vinylpyridine was used for radiation- induced grafting followed by quaternisation.119 Polyolefins, sili- cone rubber, and polytetrafluoroethylene have been used as the polymers.The modified polymers thus obtained exhibited a satisfactory haemocompatibility, possibly as a result of the partial washing away of heparin during use.123 Another monomer which is employed for grafting to achieve ionic binding of heparin is 2-(N,N-diethylamino)ethyl methacrylate.124, 125 In all probability, the covalent binding of PAS is more promising.Radiation-grafted polymers with grafted poly(2-hydroxyethyl methacrylate) chains, which were activated by bromocyanogen with subsequent addi- tion of streptokinase (lysis of fibrinogen on the surfaces), were obtained.123 Another method of binding enzymes is the radiation- induced grafting of methacrylic acid followed by the application of the carbodiimide method in order to bind the BAS.123, 125 The employment of a spacer for the attachment of biomacromolecules to radiation-grafted polymers is very important in this proce- dure.123 The binding of albumin to the radiation-grafted hydrogel, obtained by the radiation-induced grafting of a mixture of N-vinylpyrrolidone and 2-hydroxyethyl methacrylate, greatly increases when a spacer is used.123, 126 The process involving the attachment of PAS to modified polymer surfaces using bromo- cyanogen is illustrated in Scheme 1.126 A significant increase in the sorption of albumin after the modification of polytetrafluoroethylene by the radiation-induced grafting of N-vinylpyrrolidone has been established.127 The copolymers obtained by the radiation-induced grafting of acrylic acid, 2-hydroxyethyl methacrylate, a mixture of maleic anhydride and acrylic acid, as well as a mixture of acrylic acid and acrylamide, which are used for the immobilisation of human albumin, were grafted by MuÈ ller-Schulte and Horster.128 In the covalent binding of albumin, bromocyanogen, hydrazine and glutaraldehyde, as well as 1-hydroxybenzotriazole, which ensures the maximum binding of human albumin, were used as the condensing agents.Glutaraldehyde has also been used for the covalent binding of PAS to radiation-grafted polyacrylamide.123 Scheme 1 Novel methods for the enhancement of haemocompatibility using radiation-induced graft copolymerisation have been described.23 ± 26 One of them consists in the radiation-induced grafting on polymer surfaces of acrylic acid chlorides 23 and subsequent introduction of PAS.26 Modified polymers containing on the surface heparin, various enzymes (for example, fibrinoly- sin), albumin, etc.have been obtained in this way. The simulta- neous presence of heparin and enzymes on the polymer surface gives rise to effective thromboresistant properties of polymeric materials.26 Reactive acid chloride groups may be obtained also by treating with thionyl chloride radiation-grafted copolymers with polyacrylic acid.129 Another procedure consists in the radi- ation-induced grafting of allylamine on the polymer surface.The grafting of this monomer was achieved solely in the presence of orthophosphoric acid (suppression of the degradative chain trans- fer in the polymerisation of allylic monomers). Glutaraldehyde has been used to bind enzymes with an amino group.25 Hydrazide groups may be used for the immobilisation of PAS.The hydrazi- dation of radiation-grafted copolymers of PE with acrylic mono- mers has been investigated.59, 130 Methods have been developed for the modification of polymer surfaces by the radiation-induced grafting of macromonomers in the presence of hydrophilic monomers (acrylamide, N-vinylpyr- rolidone, etc.) and a cross-linking agent.26, 131 ± 133 The macro- monomers may be obtained by introducing an active double bond into the PAS (heparin, enzymes) molecules in acylation by the chlorides of acrylic and methacrylic acids.25, 134 ± 136 It was estab- lished that the acylation process does not affect the structure of the molecules of the PAS and its physiological activity. The macro- monomers are capable of entering into the copolymerisation reaction with various monomers (acrylamide, N-vinylpyrroli- done).134 The homopolymerisation of macromonomers leads to the formation mainly of products with a low degree of polymer- isation.136 The radiation-induced grafting of PAS macromonomers jointly with hydrophilic monomers on various polymeric materi- als afforded biospecific sorbents and modified materials employed in contact with blood.In the latter case, the polymer was modified by grafting the heparin macromonomer and trypsin or fibrinoly- sin as the fibrinolytic enzyme. It was shown that the polymers modified by a mixture of heparin and trypsin exhibit a higher haemocompatibility than the polymers containing only heparin. The increased thromboresistance of such materials, which has been investigated in experiments in vitro and in vivo, can be explained by the fact that heparin binds fibrinogen, which is Polymer g-Radiation 2-Hydroxyethyl methacrylate (monomer, graft) OH OH BrCN NH2 PAS O C=NH O NH2 RN=C=NR0 O C=N O Attachment without spacer H2N(CH2)5COOH (spacer) O C=N(CH2)57C7OH O O O C=N(CH2)57C7NH O Attachment with spacer O Preparation of polymeric biomaterials with the aid of radiation-chemical methods 791lysed by trypsin.137 ± 139 The grafting of a mixture of acrylamide and the cholesterol ester of N-methacryloyl-o-aminocaproic acid on PE has been investigated.140 The graft results in the formation on the PE surface of a hydrophilic layer in which cholesterol groups are immobilised covalently. This led to the formation of modified polymers capable of adsorbing heparin selectively from the blood flow.It has been shown 89, 141 that the employment of N-methyl-N- vinylacetamide for the modification of polymers in order to increase their haemocompatibility is promising.89, 141 Diverse polymers, modified by grafting N-methyl-N-vinyl-acetamide, have been investigated in detail by various physicochemical methods.141 The haemocompatibility of ethylene ± propylene rub- ber, modified by the radiation-induced grafting of acrylamide, N-vinylpyrrolidone, and 2-hydroxyethyl methacrylate, has been studied.142, 143 The experiments were performed in vitro.It was established that there is no linear relation between the amount of the graft and the hydrophilicity, on the one hand, and the degree of haemocompatibility, on the other.The relation is complex. During recent years, there has been a growth of interest in the use of polyphosphazenes as biomaterials. The radiolysis of poly- phosphazenes has been investigated 144 and it has also been established (in experiments in vivo) that the modification of polyphosphazenes by the radiation-induced grafting of N-vinyl- pyrrolidone makes it possible to increase their haemocompatibil- ity.145 The influence of the preliminary 60Co g-irradiation of polyurethane on its coating with albumin has been studied.146 Radiation-induced graft polymerisation has been used to modify various polymers in order to accelerate the growth of endothelial cells on the surface.147, 148 It has been suggested 10 that the lack of success in the creation of polymeric materials designed for prolonged use in contact with blood within a living organism is associated with the inadequate knowledge of the biochemical processes occurring at the implant ± blood interface and also with the attempts to relate to haemocompatibility to any one parameter of the surface (hydro- philicity, free surface, morphology, etc.).Radiation-induced graft polymerisation has been used in a series of investigations 64, 149, 150 to modify the surfaces of poly- meric articles used in contact with blood and its components.Studies have been performed in recent years on the preparation of haemocompatible polymers by radiation-induced graft polymer- isation initiated when polymers are irradiated with accelerated heavy ions.62 Studies have been carried out on the use of radiation-induced graft polymerisation for the creation of various medical polymeric materials: blood vessel prostheses, intravenous catheters, implants, tissue-protecting, antiinflammatory, and opthalmolog- ical materials, etc.The materials have been called `hydrografts'.150 III. Preparation of special sorbents Radiation-induced graft polymerisation is used in the creation of carriers for affinity chromatography,44, 61, 155 immunoadsorb- ents,156 ± 165 and biospecific sorbents 66, 148, 166, 167 and also for the growth of endothelial cells.147, 168 ± 171 Effective sorbents for affinity chromatography, obtained by modifying polyamide-6 beads by means of radiation-induced graft polymerisation, have been described. Mainly 2-hydroxyethyl methacrylate,N-vinylpyrrolidone, and acrylamide have been used as the monomers.44, 61, 151, 153 ± 155 The conditions in the graft polymerisation and primarily the choice of solvents with specific solubility parameters, as well as the choice of swelling agents are very important.61, 154 Compared with the known sorbents (agar- ose), the capacity of the sorbents obtained is appreciably higher in the separation of low-density lipoproteins and antibody immuno- globulin G.The properties of the adsorbents may be varied by varying the conditions in the graft polymerisation. The carriers obtained for affinity chromatography are cheaper compared with the known and expensive carrier �sepharose with protein A.61 The sorbents obtained may be used for the removal of excess cholesterol in patients suffering from cholesterinemia.61 It has been established that, when sorbents based on poly- amide-6 modified by radiation-induced graft polymerisation are used, the amount of lectin extracted from mistletoe increases appreciably.Sorbents with immobilised urease may be used for the rapid determination of the content of urea in kidney diseases.The method is based on the continuous and rapid enzymic hydrolysis of urea and the determination of ammonia.155 The modification of polystyrene plates by the radiation- induced grafting of monomers containing hydrazide groups has been described.156 The modified plates adsorbed effectively immunoglobulin E and low-molecular proteins. In order to increase the hydrophilicity of polystyrene, it is 60Co g-irradiated.By employing the modified polystyrene plates, it is possible to determine the concentration of immunoglobulin E (down to 0.1mg ml71).156 The modification of LDPE, poly(vinyl chloride) and poly- styrene by the radiation-induced graft polymerisation of meth- acrylic acid and acrylamide with subsequent immobilisation of the Brucella antigen resulted in the formation of systems for diagnos- tic tests (ELISA).The sensitivity was improved and the reactivity of the antibodies increased significantly.164 Methods have been developed for the modification of agar- ose,66 sepharose, and sephadex 166 by the radiation-induced graft- ing of N-acryloyloxysuccinimide with subsequent addition of bovine serum albumin (BSA).The separation of D,L-tryptophans was studied.166 Radiation cross-linked poly(vinyl alcohol) has been used in affinity chromatography. The carriers based on this polymer are distinguished by a satisfactory morphology, biocompatibility, and a high capacity.152, 153 Blood detoxicants based on modified polypropylene fibres have been obtained.140 Specific sorbents for the removal of heparin have been created with the aid of radiation-induced grafting.140 Radiation-induced graft polymerisation has been used to modify various polymers in order to form on their surface a coating comprising endothelial cells.This problem has been examined in greatest detail by Kirkpatrick et al.147 The radiation-induced graft polymerisation of 2-hydroxyethyl methacrylate, N-vinylpyrrolidone and 2-(N,N- dimethylamino)ethyl methacrylate on a whole series of polymers (LDPE, polytetrafluoroethylene, polyamide, etc.) has been inves- tigated.It was established that the conditions in the graft polymer- isation (solvent, composition of copolymers, etc.) are very important for the successful growth of cells. Electron micrographs of the surface with layers of endothelial cells have been obtained.It was noted that the presence of OH groups on the surfaces of polymers is important for cell growth. Methods have been devised for the modification of polymeric materials,as a result of the application of which the polymers can undergo a change in their hydrophilic and hydrophobic properties under the influence of small changes in temperature. This makes it possible to regulate the adhesion and viability of the cultures.168 IV.Synthesis of polymeric carriers for medicinal preparations Radiation-induced polymerisation is used in the synthesis of polymeric carriers for medicinal preparations (antibiotics, anti- septics, etc.). The following advantages of the radiation initiation of polymerisation in the synthesis of polymeric carriers for medicinal preparations compared with `material' initiation have been noted.Firstly, fairly pure polymers are obtained (without initiator residues). Secondly, it is possible to regulate compara- tively easily the molecular-mass characteristics of the polymers by 792 V Ya Kabanovvarying the radiation dose rate. Thirdly, in a number of instances the yield of the polymers is much higher than the yield obtained on initiation with `material' initiators. Radiation-induced polymerisation has been used in a series of studies 172 ± 175 for the creation of copolymers based on N-vinyl- pyrrolidone with undecenoic, oleic, and crotonic acids.Modifying agents for PAS, ensuring a fairly intense hydrophobic interaction between the copolymer and the PAS, are obtained in this case.On initiation using `material' initiators, it is impossible to obtain copolymers in a sufficiently high yield. The radiation-induced copolymerisation of N-vinylpyrrolidone with undecenoic and oleic acids in ethanol for doses of 50 ± 150 kGy (dose rates of 0.23 and 0.04 Gy s71) has been investigated.172 It was established that the yield of the copolymer and the rate of copolymerisation depend significantly on the mixture composition, a statistical copolymer without adjacent COOH units being formed.The relative reactivity of the acids is zero, while the reactivities of N- vinylpyrrolidone vary in the ranges 0.61<r<0.94 for undece- noic acid and 0.90<r<1.31 for oleic acid. The copolymer units are enriched in N-vinylpyrrolidone.The radiation-induced copolymerisation of N-vinylpyrroli- done with crotonic acid in ethanol at different dose rates in the range 0.25 ± 3.26 Gy s71 has been investigated.173 In the initial stage, the rate of polymerisation is proportional to the radiation dose rate raised to the power 0.5, but, with increase in the degree of conversion, the above parameter tends to 0.8.With increase in dose rate and degree of conversion, the molecular mass of the copolymer diminishes. The composition of the copolymer is independent of the dose rate and its molecular mass may be regulated by varying the dose rate. Copolymers with a viscosity- based mean molecular mass of 1.26104 77.06104 have been obtained. The dependence of the molecular mass and the molecular mass distribution in the radiation-induced copolymerisation of N-vinylpyrrolidone with crotonic acid (CA) in ethanol or 2-prop- anol on the dose for a constant monomer ratio N-vinylpyrrolido- ne :CA=85 : 15 has been examined.174 It was established that the molecular mass distribution can be regulated by selecting the radiation dose.It was shown that in alcohols the yield of the copolymer is high (93% ± 98%) r a dose of 4.56104 Gy.The radiation-chemical yield of the copolymerisation is (6 ± 7)6103 molecules per 100 eV (dose rate 0.28 Gy s71). The radiation- induced copolymerisation of N-vinylpyrrolidone with allylamine and 2-(N,N-dimethylamino)ethyl methacrylate in aqueous organic solvents and the properties of the copolymers have been studied.In this process, the copolymers are obtained in a high yield and with a narrow molecular mass distribution in the molecular mass range from 103 to 46106.175 Thus copolymers based on N-vinylpyrrolidone can be obtained by the radiation-induced polymerisation method with a fairly high yield and their molecular mass characteristics may be varied in the required direction by selecting the polymerisation conditions.The rate of polymerisation depends significantly on the mixture composition, while the composition of the copolymer is independent of the dose rate. A distinctive feature of these copolymers is that, together with the strongly hydrophilic compo- nent (carboxy groups, N-vinylpyrrolidone units), the polymer chain contains a significant hydrophobic component (the hydro- carbon part of the carboxylic acids).Such copolymers are non- toxic. The radiation-induced copolymerisation of N-vinylpyrroli- done with allyl alcohol in ethanol or 2-propanol at a dose rate of 2 Gy s71 (for doses in the range 30 ± 200 kGy) has been studied by Solovskii et al.176 The radiation-induced and `material' copoly- merisations were compared. The yields in the radiation-induced copolymerisation exceed by a factor greater than 2 the yields in the `material' polymerisation.The yield of the copolymer is 50%± 90% and diminishes with increase in the concentration of allyl alcohol. The maximum yield occurs for a 30% content of the comonomers in the alcohol. Conditions for the preparation of copolymers with a low molecular mass and a narrow molecular mass distribution have been found.The radiation-induced copolymerisation of N-vinylpyrroli- done with vinyl acetate at 5 8C and a dose rate of 14.5 Gy min71 has been studied 177, 178 and the copolymerisation constants have been determined. Panarin et al.,179 investigated the radiation-induced polymer- isation of N-vinylpyrrolidone under various conditions. The molecular-mass characteristics of N-vinylpyrrolidone were deter- mined.An important advance in radiation-induced polymerisa- tion is in this case the possibility of the fine regulation of the molecular-mass characteristics, which is particularly important for this polymer, used as a blood plasma substitute. The carriers based on N-substituted acrylamide and metha- crylamide are extremely interesting.The water content in these hydrogels depends significantly on the external conditions (tem- perature, pressure, etc.), which makes it possible to increase the effectiveness of the action of the medicinal preparations immobi- lised in them.180 The study of methacrylic acid ± triethylene glycol dimethacry- late copolymers as carriers for medicinal substances (insulin) demonstrated their resistance to the action of the acid medium in the stomach and the rapid liberation of the hormone on entering the intestine.181 The radiation-induced copolymerisation of N-vinylpyrroli- done with various aminoacrylates and methacrylates has been investigated.Polymeric carriers for BAS with a high molecular mass have been obtained in a satisfactory yield.182, 183 The radiation-induced polymerisation of hydrophilic mono- mers is used for the creation of porous polymeric carriers for the immobilisation of insulin and interleukin.The pore dimensions and the rate of liberation of medicinal substances are regulated by the polymerisation conditions.184 The radiation-induced copoly- merisation of 2-hydroxyethyl methacrylate and methacrylic acid is used to prepare carriers for contraceptives.185 The radiation-induced polymerisation of acrylamide and N-vinylpyrrolidone in aqueous solutions has been investigated.186 The influence of the dose rate and the concentration of monomers on the rate of polymerisation was studied.The role of the water radiolysis products in the initiation of polymerisation was estab- lished and the dependence of the gel formation dose on the concentration of monomers was determined.The methods for the preparation and properties of antimicro- bial polymers have been described in a monograph.187 Foss and Ebersol 188 used the radiation-induced polymerisa- tion of acrylamide for the preparation of thin (0.25 ± 1 mm) films of polyacrylamide gels with a specified pore distribution.The standard size distribution of pores was ensured by the conditions in the 60Co g-irradiation with computer control. The films were used for the high-resolution separation of proteins by electro- focussing and electrophoretic methods. The employment of radiation-induced polymerisation for the preparation of polymer microspheres occupies a special place. The formation of microspheres from various acrylates as a result of radiation-induced polymerisation has been examined in a number of studies.189 ± 200 The diameter of the microspheres increases with increasing hydrophilicity of the monomer 189 and the nature of the solvent is also important.190 Polymer microspheres containing amino acids have been obtained with the aid of radiation-induced polymerisation.The microspheres have been used for immuno- chemical assay in relation to malaria.191 The preparation of microspheres by the radiation-induced copolymerisation of diethylene glycol dimethacrylate with acryl- amide has been described in review.192 The size of the micro- spheres was 10 ± 10 000 A. The microspheres are used mainly for immunoassay. The synthesis of microspheres based on polyacry- lamide, poly(2-hydroxyethyl methacrylate), poly(methyl metha- crylate), and poly(acrylic acid) by radiation-induced suspension polymerisation in methanol has been described.194 The radiation- Preparation of polymeric biomaterials with the aid of radiation-chemical methods 793induced grafting of 2-hydroxyethyl methacrylate, acrylamide, and their mixtures on microspheres has been studied.194 The preparation of microspheres based on polyacrolein, on the surface of which there are aldehyde groups which react readily with proteins, is of significant interest.195 ± 197 Cross-linked poly- acrolein has been synthesised by the radiation-induced polymer- isation of acrolein in bulk or in a water ± acetone mixture at temperatures ranging from 715 to 25 8C.The yield of this polymer depends on the reaction conditions and may reach 100%. The principal polyacrolein unit is a six-membered oxy- gen-containing ring and the interchain cross-links are formed by ester bonds; furthermore, free aldehyde groups are present in polyacrolein. It has been established by electron microscopy that polyacrolein consists of microspheres with a particle size of 1 ± 30 mm.The size of the particles depends on the conditions in the preparation of the polymer. The formation of microspheres in the radiation-induced copolymerisation of acrolein with hydrox- yethyl methacrylate or poly(ethylene glycol dimethacrylate) in1% PVA solution at 778 8C has been studied.196 The yield of the copolymers depends on the content of the vinyl monomer.The size of the microspheres increases with increase in the concen- tration of the vinyl monomer. The properties of the microspheres obtained, containing aldehyde groups, have been investigated.197 Microspheres of the `core ± shell' type, having aldehyde groups on the surface, have been synthesised with the aid of the radiation- chemical modification of polystyrene particles (0.6 mm in diame- ter) by acrolein.The structure and properties of the polymers obtained were studied by various methods.198 It was established that the content of aldehyde groups is 60% of the theoretically possible. A structure was proposed for graft polyacrolein. It was shown that the radical polymerisation of acrolein involves mainly the vinyl bond. The form of the microspheres does not change as a result of the polymerisation.199 The principal advantages of the preparation of polymer microspheres with the aid of radiation-chemical methods are the high purity of the product (the absence of impurities arising from the initiator) and the possibility of carrying out the polymerisation under a wide range of conditions (temperature, rate of initiation), and this makes it possible to regulate the size of the microspheres comparatively readily.It is sometimes possible to achieve rela- tively easily the radiation-induced cross-linking of the micro- spheres, which is difficult to do by traditional methods. Thus the radiation-induced polymerisation is a promising method for the creation of polymeric materials used as carriers for medicinal preparations.In many instances, it is possible to achieve the synthesis of unique copolymers, the preparation of which with the aid of `material' initiators is very difficult. The vast majority of studies have been devoted to the synthesis of copoly- mers based on N-vinylpyrrolidone. The choice of the solvent, of the radiation dose and of the radiation dose rate is very important for radiation-induced polymerisation, determining the yield of the copolymer and its molecular-mass characteristics. V.Immobilisation of biologically active substances 1. Immobilisation of enzymes During recent years, radiation-induced polymerisation has been used for the immobilisation of various BAS in polymer matrices. Such a process is carried out in order to fix the BAS for reuse in order to achieve economies in their employment (some are very expensive), in order to stabilise the BAS in relation to thermal influences, solvents, and pH, in order to prepare polymeric articles of different shape (films, tablets, needles, cylinders, etc.), for the controlled liberation of BAS under the conditions of a specific application, and for the employment of effects associated with the polymer matrix (strength, rheology, etc.).The immobilisation of BAS in polymer matrices is achieved by the joint polymerisation of monomers mixed with the BAS or by the covalent attachment of these compounds to different polymers with active functional groups. Reviews have been devoted to various aspects of the preparation of polymeric biomaterials by radiation-induced poly- merisation and grafting.201 ± 211 A wide range of substances have been used as the BAS: enzymes,212 ± 265 yeast cells,266 ± 270 haemo- globin,271 ± 275 anticancer preparations,276 ± 279 chloroplasts,280, 281 various medicines, antibodies, microorganisms and microbial cells.281 ± 297 Polymeric biomaterials with immobilised BAS have a wide range of applications.Allowance for the specific features of particular spheres of their application is important. Table 2 presents data on the immobilisation of BAS using radiation- chemical methods. The radiation-induced polymerisation for the immobilisation of BAS has the following advantages.201, 202 1. The possibility of carrying out the process over a wide range of conditions, including polymerisation at low temperatures of supercooled viscous monomers, solid monomers and multiphase systems. 2. A fairly wide selection of monomers for polymerisation. 3. A decrease in the inhibiting effect of oxygen and other impurities. 4. The absence of residual amounts of the catalyst and the unpolymerised monomer in the polymer. The latter is very important, since a partly unpolymerised monomer has a toxic effect, particularly in the immobilisation of cells. 5. The ease of cross-linking to different extents by selecting the dose absorbed. 6. The comparative simplicity of the preparation of porous and complex composite structures. 7. The simplicity of the manufacture of preparations of any arbitrary shape (tablets, cylinders, needles, etc.). 8. A decrease in the deactivation of unstable BAS in the polymer. 9. The high productivity of the immobilisation apparatus when electron accelerators are used as the sources of radiation. 10. The possibility of preparing ultrathin particles and mem- branes. There are three main immobilisation methods: covalent bind- ing of the BAS to the polymer � the chemical method, ionic binding or physical adsorption of the BAS, and physical capture of BAS in the polymer.An advantage of the chemical method is the solid-phase fixation of the BAS and the impossibility of its removal on prolonged use. The disadvantage of the method are as follows: a comparatively low yield of the activity of the BAS (a significant loss of activity in the immobilisation process), an appreciable selectivity in relation to the BAS reaction conditions, and the difficulty of its employment for the immobilisation of microorganisms.The chemical immobilisation method works as a result of the formation of chemically reactive functional groups in the polymer, mainly7COOH,7OH,7NH2 , and others capable of covalent binding of the BAS. The reactive functional groups are introduced into the polymer by radiation-induced graft polymerisation (for more details, see Section II as well as other communications 2, 4, 18, 26, 210, 211).Mainly the immobilisation of BAS as a result of physical capture, ionic binding, or physical adsorption in polymer matrices is considered in this section. The advantages of the physical capture method are as follows: com- parative ease of application, a fairly high reactivity and universal- ity of the BAS (BAS without specific functional groups �various microorganisms, cells, etc.� may be used for immobilisation), and the possibility of employing monomers with a wide range of hydrophilic and hydrophobic properties. The physical capture of the BAS in polymers is achieved by means of the radiation- induced polymerisation of the monomer mixed with the BAS.Radiation-induced polymerisation for the immobilisation of enzymes was first described by Dobo,212 who obtained immobi- lised enzymes in polyacrylamide matrices by the solid-phase polymerisation of acrylamides mixed with the enzyme. Subse- quently Kaetsu and co-workers 201 ± 205 developed a method for the immobilisation of BAS mixed with monomers capable of Cl O C 794 V Ya KabanovTable 2.Immobilisation of BAS in polymer matrices with the aid of radiation-induced polymerisation. Monomers, Immobilisation conditions Remarks Ref. immobilisation components BAS�trypsin Acrylamide radiation-induced polymerisation solid-phase polymerisation using 212 of acrylamide mixed with the enzyme 60Co g-radiation 2-Hydroxyethyl meth- radiation-induced polymerisation of monomers mixed polymerisation resulted in the formation 216 acrylate, tris(hydroxy- with aqueous BAS solution; irradiation was of a porous structure; the influence of pore methyl)propane triacryl- carried out at778 8 C with a dose of 10 kGy size on enzyme activity and the thermal ate, 2-hydroxyethyl acryl- stability of the immobilised trypsin were ate, poly(ethylene glycol investigated diacrylate), methoxypoly- (ethylene glycol methacrylate) 2-Hydroxyethyl meth- radiation-induced graft polymerisation on polyethylene the influence of pH on the stability of 218 acrylate powder, hydrolysis of the copolymer and the enzyme was studied the attachment of the enzyme to the functional groups with the aid of the carbodiimide method 2-Hydroxyethyl radiation-induced graft polymerisation on natural the activity of the immobilised enzyme 221 methacrylate rubber by the preirradiation method was studied p-Nitrostyrene direct radiation-induced graft polymerisation the nitro groups in the graft copolymer 219 of p-nitrostyrene on polypropylene and are converted into isothiocyanate groups poly(vinyl chloride) radiation-induced grafting of p-nitrostyrene the mechanism of the action of additives 220 to different polymers; radiation-induced grafting accelerating the graft polymerisation of polystyrene with subsequent nitration of polystyrene was examined Acrylic acid, acrylonitrile, radiation-induced graft polymerisation using a wide preparation of polymer membranes; 217 2-hydroxyethyl meth- range of monomers; trypsin was attached covalently the study of prospects for the employment acrylate, N-vinyl- with the aid of the carbodiimide method or of these membranes in the milk industry pyrrolirylamide glutaric dialdehyde in order to diminish the allergenic effect of milk (decomposition of proteins with a low molecular mass) BAS�trypsin, glucose oxidase 2-Hydroxyethyl radiation-induced graft polymerisation by three it was established that the immobilised 222 methacrylate different methods enzymes are stable over a wide pH range BAS�a-chymotrypsin, ribose, urease, ribonuclease Methacrylic acid esters, radiation-induced polymerisation of monomers in 224 acrylamide, and its a mixture with aqueous enzyme solutions; irradiation derivatives at720 8C; dose 5 kGy BAS�a-chymotrypsin, trypsin, glucose oxidase, papain Methacrylic acid, radiation-induced graft polymerisation of covalent immobilisation on the grafted chains 259 2-hydroxyethyl 2-hydroxyethyl methacrylate and methacrylic methacrylate acid on polyethylene BAS�a-chymotrypsin, trypsin, fibrinolysin Acrylic acid chloride, radiation-induced graft polymerisation of acrylic acid covalent binding of the BAS 215 allylamine chloride on various monomers with subsequent addition of the BAS via the acylation of the acid chloride group; graft polymerisation of allylamine and attachment of the BAS with the aid of glutaric dialdehyde BAS�urease Acrylamide starch with grafted polyacrylamide the dependence of the enzyme activity 213 on the method of application was studied Poly(dimethoxy- irradiation of enzyme in polymer solution retention of 80% of enzyme activity 223 ethoxy)phosphazene BAS�glucoamylase Poly(ethylene glycol irradiation by electron accelerator; dose 50 kGy specimens of planar polymeric materials 234 diacrylate), 2-hydroxyethyl with immobilised enzymes were obtained acrylate, tris(hydroxy- methyl)propane triacrylate Preparation of polymeric biomaterials with the aid of radiation-chemical methods 795Table 2 (continued).Monomers, Immobilisation conditions Remarks Ref. immobilisation components BAS�glucoamylase Hydroxyalkyl meth- radiation-induced polymerisation at a low the influence of the nature of the monomer 252, 253 acrylate, poly(ethylene temperature on the character of the immobilisation glycol diacrylate) of the enzyme was studied 2-Hydroxyethyl radiation-induced copolymerisation of 2-hydroxyethyl immobilisation of enzymes in different 255 methacrylate, methacrylate with comonomers at a low temperature copolymers; the influence of the composition N-vinylpyrrolidone, of the copolymer on the immobilisation acrylamide was studied 2-Hydroxyethyl radiation-induced polymerisation at reduced the distribution of the enzyme in the polymer 235 methacrylate, diethylene temperature of the monomers mixed with matrix and the rate of its liberation glycol dimethacrylate an aqueous enzyme solution were investigated Poly(vinyl alcohol) (PVA) irradiation of aqueous PVA solutions in the presence the influence of the irradiation dose 236 of the enzyme up to a dose of 40 kGy on the enzyme activity was studied PVA was mixed with the enzyme and irradiated on a linear accelerator with a beam energy 237 an electron accelerator up to doses of 60 ± 360 kGy of 7.5MeV was used; a PVA strip 20 cm wide and containing the enzyme was irradiated BAS�glucoamylase, b-galactosidase, invertase Acrylamide, N,N-di- electron irradiation on accelerators was the influence of the irradiation dose 225 ± 229 methylacrylamide, employed; radiation-induced grafting on the rate of liberation of the enzyme was 2-hydroxyethyl meth- of poly(acrylic acid) with subsequent studied, methods were developed for acrylate, N-vinylpyr- immobilisation of the BAS the preparation of membranes with immobilised rolidinone, acrylic acid enzymes, and procedures were devised for salts, acrylic acid the preparation of spherical particles with immobilised enzymes BAS�glucoamylase, AFP-antibodies Poly(ethylene glycol irradiation on an electron accelerator of thin preparation of polymer membranes containing 233 dimethacrylate), monomer films containing the BAS at the BAS; the influence of the monomer poly(ethylene glycol temperatures from775 to 35 8C and concentration and of the dose on the diacrylate), tris(hydroxy- for electron energies of 150 ± 300 KeV enzyme activity was studied methyl)propane triacrylate BAS�glucoamylase, invertase, b-galactosidase Acrylamide irradiation of enzymes in aqueous acrylamide solution the method of preparation of the specimens 256 was described in detail; the irradiation doses are given BAS�amylase, yeast cells Acrylic acid radiation-induced grafting of poly(acrylic acid) on covalent binding of the BAS 232 low- and high-density polyethylene by the direct method from aqueous solution BAS�protease (Bacillus mesentericus) Acrylic acid, allyl alcohol direct grafting of the monomers on polyethylene preparation of polymers with hydrazide 214 and azide groups; covalent binding BAS�lipase 2-Hydroxyethyl meth- radiation-induced polymerisation in the presence of the influence of the structure of the 238 acrylate, 2-hydroxyethyl the enzyme at a low temperature; dose 10 kGy polymer matrix and the monomer acrylate, poly(ethylene concentration on the enzyme activity glycol diacrylate), was studied tris(hydroxymethyl)propane trimethacrylate BAS�cellulase Hydroxylated acrylates radiation-induced polymerisation at a low temperature membranes with different monomer 240 concentrations and different hydrophilicities were prepared Poly(ethylene glycol radiation-induced polymerisation at the structure and nature of the pores in diacrylate) a low temperature; dose 10 kGy the polymer matrix and its influence on the enzyme activity were studied 796 V Ya KabanovTable 2 (continued).Monomers, Immobilisation conditions Remarks Ref. immobilisation components BAS�cellulase Glycidyl methacrylate, radiation-induced polymerisation of glycidyl polymer microspheres were obtained; 242 polystyrene methacrylate in the presence of polystyrene the influence of the conditions in the at778 8C with subsequent immersion in cooled preparation on the number and diameter methanol; dose 10 kGy of the microspheres were studied Dispersed polyurethane toluylene and 2-hydroxyethyl methacrylate were disperse particles of different size were obtained 243 prepolymer mixed; the mixture was kept for several minutes and treated with an aqueous solution of cellulase; irradiation at778 8C; dose 10 kGy 2-Hydroxyethyl radiation-induced polymerisation at778 8C in discs 1 mm thick were prepared; the influence 244 methacrylate the presence of aqueous enzyme solution of the thickness of the disc and the monomer concentration on the enzyme activity was studied 2-Hydroxyethyl radiation-induced polymerisation of monomers tubular enzyme reactors were created 251 methacrylate, tetra- on the surfaces of tubes ethylene glycol diacrylate 2-Hydroxyethyl radiation-induced polymerisation in the presence of polymer particles 50 ± 1000 mm in diameter 254 methacrylate, neopentyl sodium acetate were obtained; the influence of various glycol dimethacrylate factors on the enzyme activity was studied BAS�cellulase, cellobiase 2-Hydroxyethyl meth- radiation-induced polymerisation of aqueous monomer discs 1 ± 2 mm thick were prepared; 239 acrylate solution in the presence of the enzyme; the influence of added silica gel and irradiation at778 8C poly(ethylene glycol) on the enzyme activity was studied Acrylamide radiation-induced polymerisation of acrylamide the hydrolysis of plant raw material 245 with the aid of immobilised cellulase is described in detail; methods for the determination of the activity of cellulolytic enzymes are described BAS�catalase Acrylamide radiation-induced polymerisation of the monomer the enzyme was immobilised on 246 at778 8C in the presence of N,N0-methylene- polyacrylamide gels modified by acyl azide bisacrylamide BAS�glucose oxidase 2-Hydroxyethyl meth- the enzyme was deposited on a nylon net in the network materials with immobilised 248 acrylate presence of the monomer with subsequent enzymes were obtained radiation-induced polymerisation Acrylic acid, radiation-induced graft polymerisation of immobilisation using the carbodiimide method 263 methacrylic acid the monomers on polyethylene BAS�grradiation of the enzyme mixed with an aqueous dose<5 kGy 296 acrylamide solution BAS�glucose oxidase, glucose peroxidase, urokinase Hydrophilic monomers radiation-induced polymerisation at778 8C; immobilisation of the BAS on the surfaces 249 dose 5 kGy of polyethylene and poly(vinyl chloride) tubes BAS�penicillin acylase Acrylates, N-vinyl- irradiation of comonomers mixed with the BAS in the influence of the nature of the monomer 250 pyrrolidone the presence of a cross-linking agent�tris(hydroxy- and of the degree of its conversion on methyl) propane methacrylate; irradiation time 3.5 h the amount of immobilised acylase and at778 8C; dose rate 0.65 Gy s71 the rate of its liberation were investigated BAS�asparaginase Methacrylic acid radiation-induced grafting of poly(methacrylic acid) covalent immobilisation 257 on porous polypropylene fibres Radiation-induced grafting by the preirradiation ditto 258 method on ethylene ± propylene rubber, a polypropylene film, and a porous polypropylene fibre Preparation of polymeric biomaterials with the aid of radiation-chemical methods 797Table 2 (continued).Monomers, Immobilisation conditions Remarks Ref. immobilisation components BAS�b-galactosidase, pepsin, invertase, phosphatase Acrylic acid radiation-induced graft polymerisation of acrylic acid the modified polyamide powder was used 260 from aqueous solution on polyamide powder for the immobilisation of enzymes BAS�tryptophan, insulin, albumin, lysozyme, peptides 2-Hydroxyethyl meth- radiation-induced polymerisation the influence of the molecular mass of 230 acrylate+poly(ethylene the BAS on the rate of their liberation glycol) was investigated BAS�invertase, phosphatase, albumin, trypsin, galactosidase Acrylic acid radiation-induced grafting of poly(acrylic acid) activation of the graft copolymer by SOCl2 262 on polyethylene and attachment of the BAS via the acid chloride groups or by means of the carbodiimide method BAS�albumin, b-galactosidase, phosphatase Acrylonitrile radiation-induced grafting of polyacrylonitrile hydrolysis of the graft copolymer and the 265 to nylon attachment of the enzymes to the hydrolysed groups; immobilisation of the enzymes in the nylon polymeric materials BAS�horseradish peroxidase Acrylic acid, acrylamide grafting on polyurethanes by the preirradiation immobilisation of the enzyme on the 261 method in air; grafting from aqueous solution graft copolymers in the presence of Fe2+ ions BAS�yeast cells Methoxypoly(ethylene radiation-induced polymerisation of the influence of the composition of 266 glycol methacrylate), monomer mixtures; irradiation at778 8C the mixture of monomers on the glycol methacrylate, activity of the cells was studied hexanediol methacrylate, 2-hydroxyethyl methacrylate 2-Hydroxyethyl acrylate, polymer hydrogels were obtained by the radiation- the adhesion method for immobilisation 267 2-hydroxyethyl meth- induced polymerisation of the monomers in water on the prepared polymeric materials acrylate, N,N-dimethyl- Irradiation with 60Co g-rays at778 8C was used; electron micrographs of the acrylamide, N-vinyl- polymer particles are presented; the pyrrolidone methoxy- fermentation of glucose was investigated poly(ethylene glycol and the yield of ethanol was determined methacrylate) as a function of the nature of the polymer used for immobilisation Methoxypoly(ethylene radiation-induced polymerisation; irradiation adsorption of the cells on porous 268 glycol methacrylate), at778 8C; dose 10 kGy polymeric carriers 2-hydroxyethyl methacrylate Tetraethylene glycol the monomer was deposited on muslin and irradiated the specific surface of the modified muslin 269 dimethacrylate with 60Co g-rays is important for the enzyme activity 2-Hydroxyethyl radiation-induced polymerisation at a low specimens of different forms were prepared 270 methacrylate temperature; dose 10 kGy BAS�haemoglobin 2-Hydroxyethyl radiation-induced polymerisation of the monomer the interaction of haemoglobin with CO 271 methacrylate in the presence of haemoglobin and O2 was investigated Phospholipids with radiation-induced postpolymerisation of the the radiation-stability of haemoglobin within 274, 275 double bonds phospholipids; preparation of vesicles 200 nm in size the vesicles was studied BAS�CO-haemoglobin 2-Hydroxyethyl meth- irradiation of the monomers jointly with haemoglobin the CO-haemoglobin phase was obtained 272 acrylate, tetraethylene at75 8C; dose 5 ± 15 kGy; preparation of immediately after the removal of blood from glycol dimethacrylate semisynthetic blood the animal and oxyhaemoglobin was saturated with CO; CO-haemoglobin does not induce antibody ± antigen reactions; a polymer film containing 0.4% of CO-haemoglobin was prepared 2-Hydroxyethyl radiation-induced polymerisation at a low temperature the absorption of oxygen was studied 273 methacrylate 798 V Ya KabanovTable 2 (continued).Monomers, Immobilisation conditions Remarks Ref. immobilisation components BAS�antitumour preparations (Ara-C) Methyl methacrylate, the immobilisation of anticancer preparations in polymer the influence of various factors on 231 ethyl methacrylate, butyl matrices obtained by radiation-induced polymerisation the rate of liberation of medicinal substances methacrylate, 2-hydroxy- at room temperature was studied from polymer matrices was investigated ethyl methacrylate 2-Hydroxyethyl meth- radiation-induced polymerisation of the hydrophilic the influence of various factors on the 295 acrylate with added monomer with added hydrophobic monomers rate of liberation of Ara-C was investigated; hydrophobic monomers it was established that the addition of hydro- phobic monomers diminishes the rate of liberation of Ara-C BAS�antitumour preparations (Ara-A) Methyl ester of radiation-induced polymerisation immobilisation of Ara-A in 247 N-acryloyl-L-proline a thermosensitive gel BAS�antitumour preparations: mitomycin, 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil 2-Hydroxyethyl immobilisation of anticancer preparations in the effect of ionising radiation on the 264 methacrylate a poly(2-hydroxyethyl methacrylate) matrix anticancer preparation was investigated BAS�antitumour preparations: mitomycin, adriamycin, 1-(2-tetrahydrofuryl)-5-fluorouracil Diethylene glycol radiation-induced polymerisation at778 8C the rate of liberation of medicinal substances 276 dimethacrylate, tris(hydr- from polymer matrices was investigated oxymethyl)propane trimethacrylate BAS�antitumour preparations: mitomycin, bleomycin, 5-fluorouracil Diethylene glycol irradiation at778 8C of the monomer in a mixture the specimens were prepared in the form 277 dimethacrylate with anticancer preparations and added polystyrene, of discs, a powder, etc.; the rate of liberation poly(methyl methacrylate), polyvinylformal, and of medicinal substances from the specimens poly(ethylene glycol); dose 20 kGy was studied BAS�antitumour preparation: methoxyprogesterone acetate Poly(ethylene oxide) radiation-induced crosslinking of poly(ethylene tests in vivo and in vitro 278 oxide) with incorporation of the BAS BAS�antitumour preparation: narciclasine 2-Hydroxyethyl meth- radiation-induced polymerisation; additives regulate tests in vivo; the structure of the matrix 279 acrylate, tris(hydroxy- the rate of liberation of the medicinal substance was investigated methyl)propane trimeth- acrylate, methyl ester of poly(ethyleneglycol) BAS�chloroplasts 2-Hydroxyethyl meth- radiation-induced polymerisation at778 8C; the influence of the nature of the monomer 280 acrylate, poly(ethylene dose 10 kGy on the activity of chloroplasts and the glycol) dimethacrylate, distribution of the chloroplasts in the methoxypoly(ethylene polymer matrix were investigated glycol methacrylate), glycidyl methacrylate, tetraethylene glycol diacrylate, tetraethylene glycol dimethacrylate BAS�chloroplasts from spinach 2-Hydroxyethyl meth- radiation-induced polymerisation at724 8C in the liberation of O2 and the influence 281 acrylate, poly(ethylene the presence of additives preventing the of 60Co g-radiation were investigated; glycol) deactivation of chloroases appreciably on immobilisation BAS�pilocarpine hydrochloride Acrylamide radiation-induced grafting of polyacrylamide on a review article on the modification 282 polyester materials by impregnating the monomer of polyester blood vessel prostheses by with subsequent irradiation the grafting of polyacrylamide; preparation of polyacrylamide disc containing pilocarpine hydrochloride Preparation of polymeric biomaterials with the aid of radiation-chemical methods 799Table 2 (continued).Monomers, Immobilisation conditions Remarks Ref. immobilisation components BAS�salicylic acid Methyl methacrylate, radiation-induced graft polymerisation of a mixture the sorption of salicylic acid on a 283 methacrylic acid of methyl methacrylate with methacrylic acid on modified polymer from aqueous alcoholic porous cellulose spheres solution was investigated BAS�steroids: cholic acid, testosterone, progesterone, corticosterone Styrene radiation-induced grafting of polystyrene on introduction of the thiosemicarbazide 284 polytetrafluoroethylene, polyamides, poly(p- xylylene); group, which is capable of reacting with nitration of the graft polystyrene and reduction of the carbonyl group of steroids the nitro group to an amino group BAS�acetylcholine, serotonin, secretin, actinomycin 2-Hydroxyethyl meth- radiation-induced polymerisation at 28 8C for 2 h; the rate of liberation of the BAS from 286 acrylate, methyl, ethyl, dose rate 5 kGy h71 the polymer matrices was investigated; glycidyl, and lauryl it was established that the rate of liberation (meth)acrylates, acrylic of medicinal substances may be controlled acid, acrylonitrile, vinyl by selecting the polymerisation conditions acetate, styrene BAS�thermolysin 2-Hydroxyethyl meth- radiation-induced polymerisation at room temperature the thermal stability of the immobilised 287 acrylate, tetradecaethylene thermo lysin was investigated glycol dimethacrylate BAS�medicinal drugs with antiandrogenic properties, steroids, and hormones Diethylene glycol the medicinal drugs were mixed with the monomer and the rate of liberation of the medicinal 285 dimethacrylate, poly- irradiated with 60Co g-rays at778 8C for 2 h; substances was investigated; tests in vivo (ethylene glycol dose rate 5 kGy h71 and in vitro dimethacrylate) Microorganisms Acrylic and methacrylic radiation-induced graft polymerisation of acrylic or a review article on the covalent 288 acid chlorides methacrylic acid chlorides and covalent binding immobilisation of cells; biosensors based of photobacteria on the immobilisation of photobacteria were made; the functional activity of cells may be regulated A fumarase producing microorganism Acrylamide irradiation of the BAS mixed with an aqueous solution the immobilised microorganism exhibits 289 of acrylamide in the presence of a cross-linking agent; a high fumarase activity and converts fumaric dose 0.5 kGy acid into L-malic acid; the preparation was produced in the form of grains Enzymes and subcellular organelles Acrylic acid, allyl radiation-induced graft polymerisation of acrylic acid the enzymes were attached to graft 290 alcohol and allyl alcohol on polyethylene polymers by the carbodiimide method; the stability of the enzymes was investigated; the use of the immobilised enzymes in the hydroxylation reaction was investigated Enzymes, antibodies Diallyldimethyl- the monomer was deposited on electrodes and cross-linked products containing enzymes 293 ammonium chloride irradiated; dose 10 kGy strongly bound to the electrode were obtained Various BAS Diethylene glycol radiation-induced polymerisation preparation of polymer microspheres 191 dimethacrylate, acrylamide Various BAS containing an NH2 group Acrolein radiation-induced polymerisation of acrolein preparation of microspheres with aldehyde 195 groups for the immobilisation of the BAS Mixture of the BAS isolated from leeches Acrylic acid radiation-induced grafting of poly(acrylic acid) to the components of the BAS are bound 90 polyethylene and treatment with SOC12 covalently to the modified polymer 800 V Ya Kabanovforming glassy viscous liquids in the supercooled state (usually at 778 8C, dry ice).In the supercooled state, the BAS are little damaged on irradiation and the yield of their activity is high.Doses of 10 kGy (60Co g-radiation) and a dose rate of 5 kGy h71 are usually employed for radiation-induced polymerisation. For such does, the enzyme activity of the BAS hardly changes. Glass-forming alkyl acrylates and methacrylates of the type CH2=CXCOO(CH2)nOH and CH2=CXCOO(CH2CH2O)m ± OCXC=CH2, where X=H or CH3, are usually employed as the monomers. 2-Hydroxyethyl methacrylate is widely used. The presence of water and the enzyme accelerates the radiation- induced polymerisation. The immobilisation process consists of the following stages: mixing of the biocomponent with the mono- mer, preparation of the mould, cooling, and polymerisation.A mixture of the glass-forming monomer with the usual monomers (styrene, methyl methacrylate, vinyl acetate, acrylamide, etc.) is used in some cases. Aqueous solutions of the BAS at specific pH are normally employed for immobilisation. The phase state of the system is altered on freezing the monomer mixed with an aqueous solution of the BAS. Phase analysis showed that an appreciable proportion of the water begins to crystallise at a temperature below 724 8C, forming a suspension of ice in the supercooled monomer.The radiation-induced polymerisation results in the formation of a porous system and the BAS is partly located on the surfaces of the pores. This immobilisation method has been called the adhesion method. The distribution of the BAS between the aqueous phase and the porous polymer (the degree of adhesion of the BAS on the surface) depends on the nature and concen- tration of the monomer.The rate of freezing also influences in many instances the pore dimensions. The monomer concentration is very important. With its increase (above 30%), the porosity of the matrix begins to diminish and the activity of the BAS falls.At a monomer concentration in excess of 50%, part of the BAS is captured by the polymer and does not participate in the reaction. Thus the adhesion method requires the optimum (as a rule *30%) monomer concentration.201 Under these conditions, 20%± 30% of the activity of the BAS is usually retained and changes little on reuse of the BAS. The hydrophilic or hydro- phobic properties of the monomer are very important.With increase in the hydrophilicity of the monomer, the rate of liberation of the BAS during use also increases. In certain cases, this rate may be regulated by mixing hydrophilic and hydrophobic monomers and also by employing mixtures of glass-forming monomers with natural polymers (albumin, collagen, etc.). The addition of various cross-linking agents as well as BAS adsorbents (for example, silica gel) to the monomers has a significant influence on the rate of liberation of the BAS.By selecting glass- forming monomers and the conditions for the radiation-induced polymerisation, it is possible to regulate the rheological properties of polymer matrices with immobilised BAS. Another method of obtaining biocomposites involves the mixing of the BAS with the polymer (usually in the form of a powder) and pressing under a pressure of *100 kg cm71 with subsequent cross-linking under the influence of radiation (with a dose of *10 kGy).204 However, this method is used much more rarely.Its main disadvantage is that it is difficult to achieve a uniform mixing of the BAS with polymers.The immobilisation of glucoamidase, invertase, and b-galac- tosidase in polymer gels obtained by the radiation-induced polymerisation of acrylamide, N,N-dimethylacrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone and by the radiation-induced cross-linking of poly(vinyl alcohol) has been described.225 ± 228 The influence of the irradiation dose on gel formation processes has been investigated.For each monomer, there is a definite dose above which the enzyme ceases to be liberated. If the N-vinylpyrrolidone irradiation dose is above 30 kGy, while that for PVA is above 50 kare not liberated. By selecting the dose, it is possible to regulate the rate of liberation of the enzyme. Satisfactory results have been obtained using acrylamide and N,N-dimethylacrylamide (for a dose of 10 kGy).In the case of 2-hydroxyethyl acrylate, gel formation begins at a dose of 2.5 kGy and the enzyme is liberated within a fairly wide dose range. Yoshida and Kaetsu 235 investigated the immobilisation of glucoamylase in polymer matrices obtained by the low-temperature radiation-induced polymerisation of 2-hydroxyethyl methacrylate (hydrophilic monomer) and dieth- ylene glycol dimethacrylate (hydrophobic monomer) in the pres- ence of the enzyme in an aqueous buffer solution (for a dose of 5 kGy).In the case of the hydrophilic matrix, the glucoamylase was in the gap between a thin polymer layer (polymer membrane), formed on radiation-induced polymerisation, and the porous structure of the polymer, as well as partly in the polymer itself, but in the hydrophobic matrix the glucoamylase was present virtually only on the surface of the porous structure of the polymer.The rates of liberation of glucoamylase from the hydro- philic and hydrophobic polymer matrices were compared. Fluo- rescence photomicrographs were obtained for the distribution of glucoamylase in various polymer matrices.It was established that the diffusion of glucoamylase diminishes appreciably with Table 2 (continued). Monomers, Immobilisation conditions Remarks Ref. immobilisation components Bacillus Stearohermpohelus cells Maleic anhydride, reaction copolymerisation of the monomers immobilisation of the cells on the copolymer 291 styrene vinyl acetate Microbial cells 2-Hydroxyethyl meth- 2-hydroxyethyl methacrylate deposited on a sheet of it was established that an increase in the 297 acrylate paper and irradiated with 60Co g-rays; a medium for hydrophilicity by adding methoxytetra- the dilution of microbes was created ethylene glycol methacrylate leads to an appreciable increase in the activity of the microbes Monoclonal antibodies Methacrylic acid radiation-induced grafting of poly(methacrylic acid) immobilisation of antibodies with 292 on the ethene ± propene copolymer the aid of the carbodiimide method BAS�transferrin, heparin, rabbit antibodies Glycidyl methacrylate radiation-induced grafting of poly(glycidyl the BAS were attached to the copolymer 294 methacrylate) on polyethylene and polystyrene via the epoxide groups; the biological activity was retained Preparation of polymeric biomaterials with the aid of radiation-chemical methods 801increase in the content of the monomer in the mixture.The highest rate of liberation is observed at a monomer concentration of 10%. The immobilisation of glucoamylase in thin polymer mem- branes, formed on irradiation of hydrophilic or hydrophobic polymers by a low-energy electron beam in the presence of an aqueous solution of the enzyme, has been investigated.233 The polymers employed were poly(ethylene glycol dimethacrylate) or poly(ethylene glycol diacrylate).Thin polymer membranes with a high enzyme activity were obtained. The influence of the irradi- ation dose, the energy, and the concentration of the polymer on the enzyme activity of the membranes was studied.In the presence of tris(hydroxymethyl)propane triacrylate (a hydrophobic mono- mer), the activity of the membranes depends to a considerable degree on the irradiation conditions and the monomer concen- tration. The immobilisation of glucoamylase in a poly(vinyl alcohol) gel on electron irradiation 236 has been investigated.235, 236 Doses ranging from 60 to 360 kGy were used.At 120 kGy, the enzyme activity fell appreciably, while at 360 kGy it vanished completely. A strip which moved under the beam from the accelerator was used for irradiation. The immobilisation of invertase and glucoa- mylase in a PVA gel obtained on g-irradiation of the above polymer in the presence of an aqueous enzyme solution was studied in detail. The irradiation dose is very important.The enzyme was liberated only for doses not exceeding 40 kGy. Up to 70 kGy, the dose does not affect the enzyme activity. Adisadvant- age of the immobilisation of enzymes in the poly(vinyl alcohol) gel was noted�an unduly high (75% ± 90%) loss of enzyme activity. The immobilisation of urease on starch with grafted poly- acrylamide has been studied.213 The use of low irradiation doses is important.The activity of urease fell to 60% of the initial value after the enzyme had been used seven times. Kumakura and Kaetsu 238 investigated the immobilisation of lipase by the low-temperature polymerisation of 2-hydroxyethyl methacrylate, tris(hydroxymethyl)propane trimethacrylate, and poly(ethylene glycol diacrylate) in the presence of an aqueous enzyme solution.All the specimens had a porous structure. The enzyme activity was a maximum in 40% solution of the monomer. It was established that the maximum enzyme activity of the lipase is attained for the optimum hydrophobicity of the polymer matrix. When poly(ethylene glycol) is used in the immobilisation the enzyme activity increases with increase in the number of ethylene glycol units in the monomer molecule.The communication of Guanghui et al.246 is devoted to the study of the immobilisation of catalase on acyl azide-modified porous polyacrylamide particles obtained by the radiation- induced polymerisation of acrylamide in the presence of N,N0- methylenebisacrylamide at 778 8C. The activity of catalase increases appreciably on immobilisation via glycine groups.The immobilised catalase has been used to decompose H2O2 in irradiated wines. Kaetsu et al.201 studied the immobilisation of a-amylase in polymer matrices produced from the copolymer of 2-hydrox- yethyl methacrylate and poly(tetraethylene glycol diacrylate). The immobilisation was carried out by the radiation-induced polymerisation of a mixture of monomers containing an aqueous BAS solution and using a dose of 10 kGy at724 8C.At a certain temperature, the phase state of the system changes and the ice phase is formed. The biologically active substance is concentrated on the surface of the porous polymer matrix. In the case of a hydrophobic polymer matrix, an appreciable proportion of the BAS remains in the ice, so that the activity of the BAS increases with increase in the monomer concentration.However, starting from a certain monomer concentration, the activity of the test substance diminishes owing to occlusion within the polymer. Photomicrographs of the polymeric composite with the immobi- lised BAS have been published. In the case of the hydrophilic polymer matrix, the reactions of a-amylase take place as a result of the diffusion of the enzyme in the swollen polymer gel.A method has been developed for the preparation of spherical particles (100 ± 150 mm) in the copolymerisation of hydrophilic and hydrophobic monomers (neopentyl glycol diacrylate or tetra- ethylene glycol diacrylate). In this case, the activity of the enzyme is independent of the monomer concentration in polymerisation at 778 8C and for a dose of 10 kGy.Methods have been developed for the preparation of tubes and filaments containing immobilised BAS. The immobilisation of a-amylase in poly(2-hydroxyethyl methacrylate) matrices has been investigated 296 with the aid of radiation-induced polymerisation (dose 5 kGy). The immobilisa- tion of trypsin using low-temperature radiation-induced polymer- isation has been investigated in detail.216 The enzyme activity was studied in the hydrolysis of casein (substrate). 2-Hydroxyethyl methacrylate, poly(ethylene glycol diacrylate), and methoxypoly(- ethylene glycol methacrylate) were used as the components for the immobilisation of trypsin. The irradiation of the monomers mixed with an aqueous enzyme solution was carried out at 778 8C with a dose of 10 kGy.If the monomers are hydrophilic, the enzyme activity falls with increase in their concentration, whereas in the case where they are hydrophobic the activity passes through a max- imum. When 2-hydroxyethyl methacrylate is used, a porous polymer matrix with a pore size of 1 mm at a monomer concen- tration of 50%± 70% is formeith increase in this concen- tration, the pore size diminishes. When tris(hydroxymethyl)propane triacrylate (a hydrophobic mono- mer) is used for immobilisation, a polymer is formed in the form of a suspension with a particle size of 50 ± 200 mm and the enzyme is immobilised on the polymer surface.In the case of poly(ethylene glycol diacrylate), the degree of hydration and the enzyme activity increase with increase in the number of oxyethylene units 7CH2CH2O7 (n).For n44, large formations 100 ± 200 mm in diameter are produced, whereas for n59 a continuous porous structure is formed. If methoxypoly(ethylene glycol methacrylate) is used, a cross-linked structure appears. Such a matrix is soft and hydrophilic and the enzyme is readily trapped in it. The study of the influence of the nature of the polymer matrix on the thermal stability of the immobilised enzyme showed that the highest thermal stability occurs when 2-hydroxyethyl acrylate and 2- hydroxyethyl methacrylate are used. The thermal stability of the enzyme depends on the hydrophilicity of the polymer matrix; the maximum stability is attained on increase in the degree of hydration, which is associated with the influence of the latter on the rigidity of the matrix.The immobilisation of trypsin in the radiation-induced poly- merisation of crystalline monomers (acrylamide, methylenebisa- crylamide, and acrylic acid salts) has been investigated.212, 229 A deficiency of the polymer matrix was discovered�an unduly high hydrophilicity. The communication of Carenza et al.230 was devoted to the study of the influence of the molecular mass of proteins and peptides on the rate of liberation of these compounds from hydrogels obtained by the radiation-induced polymerisation of 2-hydroxyethyl methacrylate. It was established that the rate of liberation diminishes linearly with increase in logMw.The rate of decrease may be regulated by adding poly(ethylene glycol) with differentMw to 2-hydroxyethyl methacrylate.The immobilisation of glucose oxidase, glucose peroxidase, and urokinase on the inner surfaces of poly(vinyl chloride) tubes and on LDPE films has been described.249 The immobilisation method consists in the prelimi- nary radiation-induced polymerisation of 2-hydroxyethyl meth- acrylate and the subsequent decomposition on the grafted surface of a mixture of the monomer with an aqueous solution of the enzyme.The tube is frozen and irradiated at 778 8C (dose 5 kGy). The structure of the surface depends on the polymerisation conditions and the nature of the monomer. These factors influence the uniformity of the coating. The thinnest and most uniform coatings are obtained when a 1 : 1 mixture of 2-hydroxyethyl methacrylate and tetraethylene glycol diacrylate is used.A high 802 V Ya Kabanovstability of the immobilised enzymes was established, which can be partly accounted for by the employment of cross-linked systems. Glucose oxidase and glucose peroxidase have been used to assay glucose in blood.234, 248 The immobilisation was carried out in such investigations by irradiating the monomers mixed with an aqueous enzyme solution.The mixture was deposited on a nylon net or filter paper in a thin layer and was irradiated in an accelerator (dose 10 kGy). Poly(ethylene glycol diacrylate) and tris(hydroxymethyl)propane triacrylate were used as the compo- nents for the immobilisation. The maximum activity of the enzymes was attained at a concentration of the components of 20%± 30% and the highest enzyme activity was observed when poly(ethylene glycol diacrylate), deposited on a nylon net, was employed.Polymer sheets with immobilised enzymes were obtained as a result. The immobilisation of fumarase in a polyacrylamide gel has been described (dose 5 ± 10 kGy).289 A high activity of fumarase was achieved under the conditions of the enzymic synthesis of malic acid from fumaric acid.The results of the study of the immobilisation of penicillin acylase in polymer matrices of different hydrophilicity (2-hydrox- yethyl acrylate, 2-hydroxyethyl methacrylate, N-vinylpyrroli- done, etc.) by means of low-temperature radiation-induced polymerisation have been described.250 The influence of the monomer : enzyme ratio on the immobilisation was investigated. It was established that the rate of liberation of the enzyme is independent of the nature of the monomer, the degree of polymer- isation, and the porosity, but does depend strongly on the presence in the system of the cross-linking agent tris(hydroxy- methyl)propane trimethacrylate even in small amounts (*0.03% ± 0.04%).The enzyme is retained in the polymer matrix as a result of hydrophobic interactions.The activity of penicillin acylase is preserved for a long time in the presence of the cross- linking agent. A series of publications 239 ± 244, 251, 270 have been devoted to questions concerning the immobilisation of cellulase. The immo- bilisation of cellulase and cellobiase in polymer matrices obtained by the low-temperature polymerisation of 2-hydroxyethyl meth- acrylate in the presence of an aqueous enzyme solution has been studied in detail.239 The enzyme activity was determined from the yield of glucose in the decomposition of cellulose.It was noted that in the presence of additives in the monomer [silica gel and poly(ethylene glycol)] the enzyme activity is retained for a longer time. The effectiveness of the additive depends on the monomer concentration.The maximum activity is attained at a monomer concentration of 60%. Discs 12 mm thick containing the immo- bilised enzyme were obtained. Kumakura and Kaetsu 240 studied the immobilisation of cellulase in polymer membranes prepared from hydroxylated acrylates. The maximum activity of cellulase was attained at a monomer concentration of 20% and for a membrane thickness of 1 mm, which is associated with the formation of the most porous structure of the polymer under these conditions.The dependence of the enzyme activity on the water content in the polymer has a maximum. In the immobilisation of cellulase in the porous polymer matrix formed by the radiation-induced polymerisation of poly(ethylene glycol diacrylate), the pore structure is deter- mined to a large extent by the polymer concentration and temperature.241 The enzyme activity depends on the pore size, the degree of hydration, and the particle size of the composite.The degree of hydration of the polymer increases with increase in the number of oxyethylene groups in the monomer. Continuous changes in the porous structure associated with the change of the polymerisation phase have been noted in the temperature range from 710 to 740 8C.With increase in pore size, the enzyme activity falls. Yoshida et al.242 achieved the immobilisation of cellulase in polymer microspheres. The latter were formed as a result of the radiation-induced polymerisation of glycidyl methacrylate in the presence of polystyrene and the enzyme with subsequent immer- sion of the mixture in cooled methanol.The influence of various conditions on the number and diameter of the microspheres was investigated. Soft and hard microspheres with different diameters were obtained. The enzyme activity of cellulase in the soft micro- spheres was 4.6 times higher than in the hard ones. The communication of Kumakura and Kaetsu 243 was devoted to the study of the immobilisation of Streptomyces phalochromogenes cells (which produce cellulase) using the 2-hydroxyethyl methacrylate+methoxytetraethylene glycol me- thacrylate mixture.The mixture together with the cells was deposited on paper and irradiated. Paper sheets with immobilised cells were obtained. The immobilisation of cellulase in poly(2-hydroxyethyl meth- acrylate) polymer matrices has been described.244 The immobili- sation was carried out by the low-temperature polymerisation of 2-hydroxyethyl methacrylate in the presence of an aqueous enzyme solution.The specimens were prepared in the form of discs. The enzyme activity is a maximum at a monomer concen- tration of 50% and the optimum thickness of the disc is 1 mm.With increase in cellulase concentration, the specific enzyme activity diminishes. Photicrographs of the specimens with the immobilised cellulase were published. The immobilised cellulase preparation may be used repeatedly. In another study, Kumakura and Kaetsu 251 immobilised cellulase on the inner surfaces of polyethylene tubes by the low-temperature radiation-induced polymerisation of a mixture of 2-hydroxyethyl methacrylate and tetraethylene glycols diacrylate. The mixture of the monomers with the enzyme was deposited on the inner surfaces of the tubes, frozen, and irradiated (dose 10 kGy).The thickness of the layer of coating was 300 mm, the optimum monomer concentration was 60%± 70%, and the enzyme concentration was 0.5%. This immobilisation method can be used to create enzyme reactors.The immobilisation of yeast cells in various hydrogels has been studied and the conditions for the maximum yield of ethanol in the enzyme hydrolysis of a cellulose-containing raw material were discovered.270 Immobilised cellulase has been used for the enzymic hydrolysis of a cellulose-containing raw material: paper waste,270, 297, 298 starch,299, 300 biomass (wood chips, sugar beet waste, rice straw),299, 300 and lignin-containing waste.245 After the preliminary irradiation of the cellulose-containing waste (paper, sawdust, etc.) with a dose up to 1 MGy, the yield of glucose in the hydrolysis of the raw material increases appreciably (by a factor of *3),297 ± 301 which is associated with the appreciable decrease in the degree of polymerisation of cellulose and the partial break- down of its structure.The yield of ethanol in the hydrolysis of plant waste after preliminary irradiation has been studied in detail.270 For the successful enzyme hydrolysis of lignin-contain- ing waste, it is desirable to subject it to preliminary irradiation (dose 1 MGy) and grinding. The influence of preliminary irradi- ation up to different doses on the subsequent hydrolysis of cellulose (from rice, straw, etc.) has been described.301 The results of the employment of the radiation technique for the conversion of biomass into sugar and its fermentation in order to obtain ethanol have been surveyed in a review.300 The possibility of the reuse of the immobilised enzymes has been studied.Functional polymers, obtained by radiation-induced graft polymerisation, have been used in a series of studies for the immobilisation of enzymes. A method for the covalent binding of enzymes, based on the grafting of p-nitrostyrene to polymers (mainly polyolefins), the reduction of the nitro groups to amino groups, and the conversion of the latter into isocyanate groups, which readily react with enzymes, has been devised.210, 219, 220 In n=2, 3, 4, 9, 14.n CH2 CH C OCH2CH2 C CH CH2 , O O Preparation of polymeric biomaterials with the aid of radiation-chemical methods 803the case of amino groups, glutaric dialdehyde was used for the covalent binding of enzymes. Another procedure consists in the radiation-induced grafting of styrene with subsequent nitration of the graft copolymer.Trypsin was used as the enzyme. A method for the immobilisation of asparaginase on porous polypropylene fibres, an ethene ± propene copolymer, and a poly- propylene film has been created.257, 258 The first stage is the radiation-induced grafting of acrylic acid, after which asparagi- nase is attached covalently to the carboxy groups by the carbodii- mide method.An enzyme reactor was developed and was tested in vitro and in vivo. The immobilisation of enzymes and subcellular organisms in polyethylene has also been described.290 The activity and stability of the enzymes were investigated. The immobilisation of papain, trypsin, glucose oxidase, and a-chymotrypsin on powdered polyethylene with grafted poly(me- thacrylic acid) and poly(2-hydroxyethyl methacrylate) has been studied.259 The covalent binding of the enzyme was achieved with the aid of the carbodiimide method.It was established that each enzyme requires its own microenvironment. a-Chymotrypsin proved to be the most active. The best results were obtained in the grafting of poly(2-hydroxyethyl methacrylate) with subse- quent partial hydrolysis. The covalent immobilisation of inver- tase, phosphatase, albumin, trypsin, and galactosidase on polyethylene modified by the grafting of poly(acrylic acid) has been described.262 The enzyme was attached by means of the carbodiimide method. The influence of the methods used for grafting and activation of poly(acrylic acid) on the activity of the enzymes was examined.The immobilisation of horseradish peroxidase on segmented polyesterurethane films has been described.261 The immobilisa- tion of glucose oxidase on polyethylene films has been inves- tigated.242 A study has been made of the influence of the degree of grafting, the hydrophilicity, and the electrical properties on the enzyme activity. The radiation-induced grafting of 2-hydroxymethyl metha- crylate has been used to bind trypsin and glucose oxidase to natural rubber.221, 222 Cyanuric chloride and toluene-p-sulfonyl chloride were used for the covalent binding.The immobilisation conditions and the activity of trypsin have been examined in detail. The immobilisa- tion of enzymes on polyamide materials (with the aid of radiation- induced graft polymerisation of acrylic acid or acrylonitrile) has been described.260, 264, 265 The immobilisation of protease with the aid of radiation-induced grafting of acrylic acid has been inves- tigated.214 The reactivity of a-chymotrypsin immobilised on radiation- grafted hydrogels obtained by the grafting of 2-hydroxyethyl methacrylate and methacrylic acid on silicone rubber has been studied.302, 303 a-Chymotrypsin was bound covalently using N-hydroxysuccinimide. The influence of pH and the content of acrylic acid on the enzyme activity was investigated (hydrolysis of N-acetyl-L-tyrosine).The rate of hydrolysis is greatly influenced by the negative charge of the hydrogel. The immobilisation of trypsin on a wide range of polymers modified by the radiation- induced grafting of poly(acrylic acid), polyacrylonitrile, poly(2- hydroxyethyl methacrylate), poly(N-vinylpyrrolidone), polyacry- lamide, etc.has been studied in detail.213, 214 The covalent binding of trypsin was achieved by means of the carbodiimide method or glutaric dialdehyde. The polymer membranes obtained were designed for use in the milk industry. Methods for the covalent immobilisation of enzymes with the aid of aldehyde groups, which readily react with amines, have been devised.198, 199, 304, 305 The methods involve the radiation-induced graft polymerisation of acrolein.The reactivity of the aldehyde groups was studied. Radiation-induced graft polymerisation is used for the mod- ification of agarose (by grafting a complex of N-acryloylsuccini- mide and BSA) in order to obtain a material for the chromatographic separation of biomacromolecules.306 Novel methods for the immobilisation of enzymes on poly- meric materials have been developed by Plate' and Valuev.215 This is a new aspect of the use of radiation-chemical methods for the immobilisation of BAS, because it concerns the radiation-induced graft polymerisation of macromonomers formed by the introduc- tion of a reactive double bond into BAS macromolecules. Thus the nature of the monomer and in the first place its hydrophilic and hydrophobic properties as well as the monomer concentration are important in the immobilisation of BAS with the aid of radiation-induced polymerisation.These factors influ- ence most significantly the activity of the enzyme, the duration of its use, and its thermal stability.Cross-linking agents and BAS adsorbents can be usefully added at a low concentration in a number of instances in order to regulate the rate of liberation of the enzyme. The radiation dose should not exceed 10 kGy in most cases. The modification of various polymers by the radiation- induced grafting of acrylic acids or 2-hydroxyethyl methacrylate with subsequent binding of the enzymes by the carbodiimide method is employed most frequently for the covalent binding of enzymes.The specific activities of the enzymes fall with increase in their content in the modified layer (a 5%± 10% graft is optimal). The method for the covalent binding of the enzyme is very important. Radiation-induced graft polymerisation makes it possible to employ polymers of virtually any nature and form (powders, fibres, films, etc.) for the binding of enzymes.The possibility of creating enzyme reactors has been demonstrated. 2. Immobilisation of medicinal preparations In the employment of radiation-induced polymerisation for the immobilisation of medicinal substances, the greatest advances have been achieved in the immobilisation of antitumour compo- sitions in polymer matrices.The antitumour substances employed have been adriamycin, mitomycin C, and 5-fluorouracil. In many cases, treatment with immobilised antitumour preparations is combined with hormone therapy. The immobilised antitumour substances are used as a rule in the form of polymer tablets or needles which are inserted in the tumour.The application of immobilised antitumour preparations has the following advan- tages compared with their introduction in the form of injections or orally: a low concentration of medicinal preparations in the blood, the medicine spreads from the administered preparation into a small region. This reduces to a minimum the side effects of the medicines. The duration of the use of the immobilised antitumour preparations is several months.These preparations have under- gone extensive tests in many Japanese clinics.204 In the vicinity of the preparation introduced into the tumour, the cancer cells undergo necrosis and the diffusion of the antitumour preparations terminates in the necrosed layer. The rate of liberation of medicinal substances does not change in the course of 40 days.The number of specimens introduced into the tumour, their density, and form (needles, tablets) are very important. The concentration of antitumour substances in the blood is insignificant. A mixture of poly(ethylene glycol dimethacrylate) (20%) and diethylene glycol dimethacrylate (80%) is usually employed for the immobilisation of the antitumour preparation mitomycin C.204 The behaviour of the immobilised antitumour preparations in the organism and the methods for the treatment of cancer have been examined in a number of studies.307 ± 312 Meth- ods whereby immobilised antitumour preparations can be pro- duced have been described in detail in a series of studies.204, 205, 249, 276, 278, 313, 314 The low-temperature polymerisa- tion of diethylene glycol dimethacrylate mixed with various polymers [polystyrene, polyvinylformal, poly(ethylene glycol), poly(methyl methacrylate)] is used for the immobilisation of mitomycin, 5-fluorouracil, and bleomycin. It is emphasised that irradiation must be carried out in an oxygen-free medium and the dose must not exceed 10 kGy.Otherwise the activity of the antitumour preparations is significantly reduced.277 Specimens 804 V Ya Kabanovwith the immobilised antitumour preparations are made in the form of a powder, tablets, cylinders, membranes, etc.277 The immobilisation of multicomponent cytotoxic (antitu- mour) agents in polymer matrices based on poly(diethylene glycol dimethacrylate) and poly[tris(hydroxymethyl)propane trimetha- crylate] has been studied.The cytotoxic agents employed are mitomycin C, adriamycin, and 1-(2-tetrahydrofuryl)-5-fluorour- acil. The rate of liberation of the medicinal preparations is regulated by introducing a pore-forming agent or adsorbent (for example, activated charcoal) into the polymer matrix. The surfa- ces of the polymers obtained with the immobilised cytotoxic agents have been studied by electron microscopy.276 The immobilisation of the antitumour preparations 5-fluo- rouracil and mitomycin C by dispersing the preparations in polymer matrices obtained by the radiation-induced polymer- isation of 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, and methyl methacrylate has been examined.313 A cross-linking agent � ethylene glycol dimethacrylate � is added for the effective control of the rate of liberation of the medicinal prepa- rations. The rate of liberation of medicines from polymer matrices obtained under different conditions has been studied in detail.The rate of liberation increases with increase in the hydrophilicity of the matrix and diminishes significantly with increase in the content of the cross-linking agent. The influence of the porosity of the matrix on the liberation of medicinal substances has been studied and electron micrographs of the porous structure have been published.A study has been made of the therapeutic effect of immobilised preparations placed in the form of tablets in the vicinity of a tumour (sarcoma) in mice. The slow liberation of the medicinal drugs led to a greater therapeutic effect compared with direct injection.The methods and results of clinical tests of the local chemo- therapy of malignant glyoma have been examined. The following immobilised antitumour preparations have been used: adriamy- cin, 5-fluorouracil, and nimustine hydrochloride.314 The preparation of poly(ethylene oxide) gels with immobilised hydroxyprogesterone acetate for the treatment of carcinoma has been described.278 The controlled liberation of adriamycin from polymer needles has been investigated.315 Summarising the foregoing, one may conclude that the application of antitumour preparations immobilised in polymeric materials is promising.When they are used, the cancer cells undergo necrosis within the limits of 0.5 ± 1 cm2 around the specimen and the diffusion of the antitumour preparations ceases in the necrosed layer.The number of specimens in the tumour and the rate of liberation of the preparation, which may be regulated within wide limits are very important. Side effects are not observed when immobilised antitumour preparations are employed. The technology of the use of immobilised antitumour preparations may be improved by varying the hydrophilic-hydrophobic proper- ties of the polymer matrix and also by using biodegradable polymers (polypeptides or polylactides).Methods have been developed for the immobilisation of the antitumour preparation narciclasine.279, 316 Chemical and radia- tion methods for the initiation of polymerisation with the aim of its immobilisation have been compared.Astudy has been made 231 of the immobilisation of the antitumour preparation Ara-C in hydrophobic matrices obtained by the radiation-induced poly- merisation of alkyl acrylates and methacrylates.It was shown that the rate of liberation of Ara-C may be varied widely by altering the composition of the matrices. The prospects for the employment of thin polymer particles, obtained by emulsion polymerisation (0.1 ± 3 mm particles) or suspension polymerisation (10 ± 100 mm particles), for immobilisation have been noted.205 Significant results in therapy have been achieved in the joint study of immobilised antitumour preparations and hormones.The immo- bilisation and use of the immobilised hormones (testosterone) have been described.317 ± 320 The hormones were immobilised in polymer needles.An important feature is that the hormones enter the organism for a long time in small amounts. Definite successes have been achieved in the treatment of the cancer of digestive organs, the bladder, pancreas, the brain, etc. Radiation-induced polymerisation has been used in a series of studies 159, 202, 205, 321 ± 325 for the immobilisation of antibodies in order to investigate the antibody ± antigen reactions.The sensi- tivity of the reactions of the immobilised antibody with the antigen depends on the choice of monomer and its concentration needed to create a porous medium. An important problem is the mini- misation of nonspecific reactions of the polymeric carrier with the antigen. For this purpose, it is necessary to make the polymer matrix more hydrophobic.The immobilised preparations are usually made in the form of microspheres or microcapsules. Microspheres obtained by the polymerisation of acrolein or its copolymers with 2-hydroxyethyl methacrylate or methacrylic acid are also used for the immobilisation of antibodies. Within the framework of the program of the Internati Atomic Energy Agency, studies with immobilised monoclonal antibodies have been carried out at the Pasteur Institute (Paris).205, 292 The immobilisation of the latter is achieved by the low-temperature polymerisation of 2-hydroxyethyl methacrylate.An advantage of radiation-induced polymerisation for the immobilisation of antibodies is the fairly high purity of the product obtained.326, 327 These preparations may be used for immunological assay.The immobilisation of a calcium antagonist in a prepolymer- ised poly(2-hydroxyethyl methacrylate) gel has been described.285 The rate of liberation of the medicinal preparation can be varied widely by means of the radiation-induced cross-linking of the gel and the added methyl methacrylate and N±vinylpyrrolidone. The immobilisation of hydrocortisone in gels obtained by the radiation-induced polymerisation of acrylic acid has been inves- tigated.The rate of liberation is regulated by the irradiation dose and by treating the gels with zinc acetate.317 3. Immobilisation of blood components Haemoglobin has been immobilised in a poly(2-hydroxyethyl methacrylate) polymer matrix using radiation-induced low-tem- perature polymerisation.271 ± 273 Special attention was devoted to the selection of the optimum immobilisation conditions in order to protect the haemoglobin.Haemoglobin is convenient for the study of the state of the immobilised molecule in a polymer matrix, since it has a characteristic optical absorption. The haeomoglobin in the membrane was subjected to reversible oxy- genation, which may take place to almost the same extent as in native haemoglobin.A method for the preparation of semisyn- thetic blood based on immobilised carboxyhaemoglobin has been described.272 Radiation-induced polymerisation has been used for the immobilisation of erythrocytes in the form of cells without haemolysis. The radiation-induced polymerisation of phospholipids has been used for the immobilisation of haemoglobin.274, 275 The phospholipids contained two long polymerisable octadecadienyl groups.Artificial red blood cells were obtained by encapsulating haemoglobin with the aid of the radiation-induced polymerisation of bilayer phospholipids � liposomes. The artificial blood cells proved to be mechanically stable and readily withstood freezing. The oxygen transport is similar to the transport by native haemoglobin.Tests in vivo (on mice) were carried out and indicated the biocompatibility of such cells. Methods have been developed for the preparation of poly- cationic carriers for red blood cells.85 The carriers were formed by the polymerisation and grafting of 2-(N,N-dimethylamino)ethyl methacrylate. The grafting was carried out on poly(vinyl chloride) beads by a method involving preliminary irradiation. 2-(N,N- Dimethylamino)ethyl methacrylate was polymerised in bulk in the presence of tris(hydroxymethyl)propane trimethacrylate and also in suspension and in emulsion. Cationic immunoadsorbents were obtained. Their adsorption capacity was determined. The density of the positive charges on the adsorbent is important.Preparation of polymeric biomaterials with the aid of radiation-chemical methods 8054. Immobilisation of yeast cells and microorganisms In a series of studies,202, 266, 269, 328, 329 radiation-induced polymer- isation has been used for the immobilisation of yeast cells in order to employ the resulting preparations for the synthesis of ethanol from plant waste. The nature of the carrier, especially its porosity, plays an important role.The porous matrix is formed as a result of the copolymerisation of methoxypoly(ethylene glycol methacrylate) and 2-hydroxyethyl acrylate. The yeast cells are adsorbed on this matrix, are coated by methoxypoly(ethylene glycol methacrylate), and are polymerised at 778 8C (dose 10 kGy).268 The activity of Saccharomyces formosensis cells (yeast cells) on polymeric carriers obtained by the radiation-induced polymerisation at 778 8C of mixtures of 45% of methoxypoly(ethylene glycol methacrylate) containing 23 ethylene glycol units, 45% of hexane diol meth- acrylate, and 10% of water (fine pores and a low water content) or 15% of methoxypoly(ethylene glycol methacrylate), 15% of 2-hydroxyethyl methacrylate, and 70% of water (structure with wide pores).In the first case, the immobilised cells had an activity greater by a factor of 6 than in the second case. As a rule, the activity of the immobilised cells increases with increase in the water content.266 The influence of the composition of the mono- mer mixture and the conditions in the immobilisation of yeast cells on the yield of ethanol has been studied in detail.267 Conditions have been found for the multiplication of the yeast cells and for the manifestation of their high activity.A significant role of water in the activity of the cells was observed. A study has been made 269 of the immobilisation of Trichoderma reesei (QM 9414) cells. Muslin was used as the carrier, which was coated with a solution of the monomer mixed with the cells and irradiated.It was shown that the concentration of the monomer used for immobilisation exerts a significant influence on the activity of the cells. The capture of the microorganism producing fumarase in a cross-linked polyacrylamide gel has been investigated. A prepara- tion with a high enzyme activity and an increased thermal stability was obtained.330 The immobilisation of bacteria in hydrophilic gels based on poly(ethylene glycol) and poly(propylene glycol) led to the creation of a bioreactor.331 The rate of liberation of testosterone was regulated by immobilising it in a thermosensitive gel obtained by the radiation-induced polymerisation of the methyl ester of acryloyl-L-proline.332 A method for the covalent immobilisation of luminescent bacteria on the surface of a polyethylene film has been developed with the aid of the radiation-induced graft polymerisation of methacryloyl chloride on the film.288, 333 5.Immobilisation of photosynthetic substances and organelles Chloroplasts and chlorophyll may be immobilised with the aid of low-temperature radiation-induced polymerisation.202, 280, 281 The immobilisation of chloroplasts extracted from spinach was achieved by the radiation-induced polymerisation of 2-hydrox- yethyl methacrylate in the presence of special additives which prevent the deactivation of the chloroplasts.The liberation of O2 and the influence of g-radiation on this process were investigated. The influence diminishes appreciably on irradiation at reduced temperatures (724 and 778 8C).The chloroplasts immobilised at reduced temperatures in a hydrophilic polymer matrix exhib- ited a stable long-term liberation of O2: more than 700 h at 4 8C. The thermal stability of chloroplasts increases appreciably on immobilisation. The photoreductive activity of chloroplasts falls to zero after 5 min at 50 8C, whilst immobilised chloroplasts retain their activity for more than 60 min.281 The influence of the nature of the monomer and its concentration on the activity of immobilised chloroplasts was investigated.280 2-Hydroxyethyl acrylate, poly(- ethylene glycol diacrylate), poly(ethylene glycol dimethacrylate), methoxypoly(ethylene glycol methacrylate), glycidyl methacry- late, glycidyl diacrylate, tetraethylene glycol diacrylate, and tetra- ethylene glycol dimethacrylate were used as the monomers.The optimum monomer concentration was 10%. The best monomer for immobilisation proved to be a mixture of methoxypoly(- ethylene glycol methacrylate) and 2-hydroxyethyl acrylate. The activity of the immobilised chloroplasts (liberation of O2) was high and was retained for 30 days. When hydrophobic monomers were used, the activity of the chloroplasts decreased rapidly as a function of time. 6. Preparation of polymer implants Technical procedures and methods used for the immobilisation of BAS (radiation-induced polymerisation) may be employed for the preparation of implants of various kinds, mainly for the therapy of damaged sections of the skin and also for the creation of prostheses.Methods have been developed for the preparation of collagen implants by irradiating mixtures of monomeror poly- mers with collagen.334 ± 336 The implants are satisfactorily com- patible with blood and do not give rise to inflammation. The implants are used in surgery and can be employed as substrates in biotechnology.334 Prostheses based on polyesterurethane with a radiation-modified inner surface have been investigated.The modification was achieved by the radiation-induced grafting of 2-hydroxymethyl acrylate or acrylamide on the inner surfaces of the tubes. The prostheses were studied in vivo. The histological and mechanical properties were investigated. Their improved throm- boresistance was established.337 A method has been developed for the modification of polymer fillers used in dental technology. The fillers based on glass or quartz fibres were modified by the radiation-induced grafting of acrylic acid from the vapour phase.The physicomechanical properties of resins containing different amounts of the modified filler were studied in detail. The advan- tages of the modified filler employed compared with the filler modified by silanes were noted.338 Polymeric-ceramic materials for dentistry have been created by irradiating mixtures of alumina and acrylic acid.339 Implants for the therapy of the skin on sections of the human body damaged by burns have been created with the aid of radiation-induced graft polymerisation.340, 341 Silicone rubber modified by the grafting of hydrophilic monomers or natural rubber modified by vulcanisation are normally employed for this purpose.341 A method for the hydrophilisation of silicone contact lenses has been created with the aid of radiation technol- ogy.As a result of hydrophilisation, the wetting angle decreases from 150 8 to 20 8 and the hydrophilic effect persists for a long time.342 Radiation-modified polymers have been used for the initiation of the growth of various cells.147, 343, 344 7.Preparation of `smart' polymers and their use for the immobilisation of biologically active substances `Smart' polymers have acquired in recent years an increasing importance for medicine and biotechnology. This is the term given to polymers capable of responding to small changes in the environment (temperature, pH, electric field, etc.).345 `Smart' polymers with immobilised BAS are used for the liberation of medicinal substances under certain conditions, usually at a specified temperature or pH.`Smart' polymers are normally obtained by traditional methods, but radiation-induced polymer- isation has also come to be employed recently for this pur- pose.165, 247, 332, 346 Among the `smart' polymers, the greatest number of publications have been devoted to poly(N-isopropyla- crylamide) (poly-N-IPAA).345, 347 This polymer has a lower con- solute temperature (LCT) of *32 8C in water, i.e.close to the temperature of the human body. Phase separation, caused by the conformational transition of the poly-N-IPAA macromolecule from a loose globule to a compact coil,345, 348, 349 which is accompanied by a sharp decrease in the size of the macromolecule, takes place above 32 8C.350 The radiation-induced polymerisation of N-isopropylacryla- mide has been investigated.351 ± 353 Poly-N-IPAA gels have been obtained by irradiating aqueous solutions of the monomer.The gel formation dose is 71 Gy (dose rate 1 kGy h71). The temper- 806 V Ya Kabanovature dependence of the swelling in water of these gels, obtained for different doses, has been studied.It was established that the degree of collapse of the gels beyond the phase transition point depends significantly on the dose, which was explained by the structure of the polymer network. An important factor is that by selecting the dose it is possible to achieve a fairly fine regulation of the degree of collapse of the gels.The radiation-induced polymerisation of N-isopropylacryla- mide in water and the cross-linking of the resulting gels have been investigated 352 by nuclear magnetic resonance. The influence of solvents on the radiation-induced polymerisation of N-isopropy- lacrylamide and the molecular mass of the resulting polymers have been studied.353 The lower consolute temperature of the resulting polymers is in the range 30.5 ± 31.50 8C and depends little on the polymerisation conditions.353 The radiation-induced copolymerisation of N-isopropylacry- lamide with N-acryloyloxysuccinimide has been investigated.354 The resulting copolymer was used for the immobilisation of bovine serum albumin, horseradish peroxidase, and monoclonal antibodies.It was shown that the dose at which the copolymer was obtained influences significantly the immobilisation process. The lower consolute temperature of the copolymers is in the range 30 ± 35 8C and depends little on the concentration of the como- nomers and the chain length. Asparaginase was immobilised in the gel obtained. The influence of temperature and the pH on the activity of the immobilised BAS was studied.Radiation-induced copolymerisation led to the formation of copolymers of N-isopropylacrylamide and methacrylic acid.355 pH-Sensitive hydrogels were obtained by the radiation-induced copolymerisation of polydimethylsiloxane, containing vinyl groups, with N-isopropylacrylamide and acrylic acid. The lower consolute temperatures of the copolymers depend on the pH.The immobilisation of indomethacin 356 and amylase 357 in gels has been investigated and it has been established that indomethacin and amylase are slowly liberated from the hydrogels at 37 8C and pH 1.4 (the conditions in the stomach), but at pH 7.4 (conditions in the intestine) the liberation of the medicinal substances is appreciably accelerated. The copolymers of N-isopropylacryla- mide with polydimethylsiloxane containing vinyl groups have been used for the immobilisation of progesterone.These copoly- mers were obtained for a dose of 10 kGy (dose rate 5 kGy h71). They have the same LCT as pure poly-N-IPAA. The gels contract rapidly on passing through the LCT. The microdomain structure of the gels was established.358 Thermosensitive gels based on alanine derivatives have been obtained.359 Radiation-induced graft polymerisation of N-isopropylacrylamide on silicone rubber has been studied.360 The hydration of the resulting graft copoly- mers has been investigated as a function of temperature and the copolymer composition.The unusual character of the hydration, influenced by the phase transitions in the grafted chains, was established.79 The preparation of another `smart' polymer � the methyl ester of poly(acryloyl-L-proline), which is synthesised by the radiation-induced polymerisation of the methyl ester of acryloyl- L-proline�has been described.352, 361 This polymer has a LCT of 14 8C.361 The LCT of the polymer may be regulated either by the radiation-induced copolymerisation with 2-hydroxypropyl meth- acrylate 361 or by adding sodium dodecyl sulfate.362 The coil ± - globule transitions and the cross-linking of the methyl ester of poly(acryloyl-L-proline), obtained by radiation-induced polymer- isation, have been investigated.363 Testosterone was introduced into the gel of the methyl ester of poly(acryloyl-L-proline) by means of radiation-induced polymer- isation.It was established that testosterone is uniformly liberated from the gel (30 mg per day) in the course of 54 weeks (tests on rats). The gel shrinks on the surface during dehydration, forming a rigid membrane barrier lacking micropores. Compact clusters are formed above the LCT. A gel of the methyl ester of poly(methacryloyl-D,L-alanine) has been obtained by the radiation-induced polymerisation of the methyl ester of methacryloyl-D,L-alanine.364, 365 The kinetics of the swelling and dehydration of the gel were investigated.It was established that, on dehydration at 40 8C, a bark (skin) is formed on the surface of the gel, closing the pores. The gel was studied by scanning electron microscopy. The gel contracts rapidly on heating.364 The radiation-induced grafting of the methyl ester of acryloyl-L-proline on polymeric materials irradiated by heavy ions has been studied.365, 366 The influence of surfactants on the phase transitions in polymers with o acid side groups has been investigated.367 The antitumour preparation 9-b-D-arabinofuranosyladenine (Ara-A) was immobilised in a thermosensitive gel based on the copolymer of 2-hydroxyethyl methacrylate, styrene, and the methyl ester of acryloyl-L-proline cross-linked by nonaethylene glycol dimethacrylate.The gel was obtained by radiation-induced copolymerisation. The phase transition occurs at 14 8C. The gel shrinks rapidly on passing through the phase transition point. The liberation of Ara-A was investigated at 10 ± 37 8C. The gel operates via a pulsating mechanism resembling a pump.Rapid shrinkage and liberation of Ara-A take place at 37 8C.368 Ther- mosensitive gels, obtained by the radiation-induced cross-linking of poly(methyl vinyl ether) (PMVE) dissolved in water, have been described.369 ± 372 The phase transition is at 38 8C. Porous and fibrous gels were obtained and their swelling was studied under various conditions.Artificial muscles and fingers have been created on the basis on the PMVE gels.369 According to the data of Kobra et al.,370 the LCT for aqueous PMVE solutions is in the range 34 ± 38 8C. By selecting the irradiation conditions, it is possible to obtain PMVE gels with high rates of swelling and dehydration.370 ± 371 Aqueous 50% solutions of PMVE and doses of 60 ± 110 kGy are used.A characteristic feature of the PMVE gels is larger volume changes compared with other thermosensi- tive gels. On heating, the gels contract rapidly and a microporous structure develops.372, 373 The transitions in the PMVE gels have been investigated.374 The immobilisation of exo-1,4-a-D-glucosi- dase in the PMVE gel has been described.375 The formation of glucose from maltose with the aid of this enzyme has been investigated and a marked influence of temperature on the activity of the enzyme has been established, this being associated with a phase transition in the gel.374 A series of data on the application of radiation-induced polymerisation and cross-linking for the creation of `smart' polymers and their employment for the immobilisation of various medicinal preparations have been presented in reviews.346, 376 ± 378 The problems of the employment of radiation-induced polymer- isation for the creation of signal-sensitive systems consisting of a biosensor, an activator, and a reservoir have been consid- ered.346, 378 Special systems with a biosensor for glucose are being developed.They are switched on in accordance with the on ± off principle for the liberation of specific portions of insulin immobilised in gels.377, 378 New thermosensitive hydrogels have been obtained by the radiation-induced copolymerisation of vinyl ethers of glycols with various alkyl vinyl ethers.379 Certain theoretical problems associated with `smart' polymers have been considered in a review.380 VI.The use of radiation-induced cross-linking for the preparation of polymeric biomaterials The interest in the preparation of polymeric biomaterials by radiation-induced cross-linking has grown significantly at the present time.Such cross-linking is most frequently used to prepare hydrogels, mainly based on polyacrylamide poly(vinyl alcohol), poly(ethylene oxide), and poly(N-vinylpyrrolidone).381 ± 383 An advantage of the radiation-induced cross-linking is the compara- tive simplicity of its implementation, the possibility of the wide scale regulation of the network density by selecting irradiation conditions (dose rate, dose), the possibility of using reduced temperatures, the purity of the product obtained (the absence of initiators), and simultaneous sterilisation.The radiation-cross- Preparation of polymeric biomaterials with the aid of radiation-chemical methods 807linked hydrogels are used as BAS (enzymes, medicinal substances, etc.) carriers, implants, prostheses, eye lenses, medical mem- branes, dressings, and biological media for the study and culturing of microorganisms.The methods of preparation and properties of hydrogels based on radiation-cross-linked polyacrylamide have been studied in greatest detail.384 ± 401 The formation of gels of this compound on irradiation of aqueous acrylamide solutions over a wide range of conditions (monomer concentration, dose, and dose rate) has been investigated.282, 384, 388, 398 The dose for gel formation is in the range 0.1 ± 2.5 kGy.It falls rapidly with increase in the monomer concentration and increases with increase in dose rate.On irradiation of aqueous acrylamide solutions up to high doses, decomposition with formation of aldehydes and carboxylic acids takes place.388 The mechanism of the cross-linking of polyacrylamides is associated with the abstraction of a hydrogen atom from a tertiary carbon atom.387 Various procedures for the preparation of gels based on poly- acrylamide have been studied.395 Using radiation-induced poly- merisation, it is possible to obtain readily hydrogels of this polymer with a wide range of properties (hydrophilicity, modulus of elasticity, swellability, etc.).The hydrogels formed as a result of the radiation-induced copolymerisation of acrylamide and maleic acid exhibit a satisfactory biocompatibility with the serum pre- pared from human blood.391 Methods have been developed for the preparation of dressings based on radiation-cross-linked polyacrylamide gels 282, 385 as well as polymer eye lenses.282 A three-stage radiation technology for the manufacture of dressing hydrogels to achieve the healing of extensive areas of burns and its advantages over other technolo- gies have been described.401 Polyacrylamide, obtained by radia- tion-induced polymerisation, has been used as the coating agent in X-ray films in order to economise on silver.386 A series of studies 397, 402 ± 420 have been devoted to the preparation of hydrogels by the radiation-induced cross-linking of poly(vinyl alcohol).The mechanism of the formation of its gel on irradiation in water and the properties of the gels,402, 403 in particular their swelling,397 have been studied in detail.The hydration of poly(vinyl alcohol) gels leads to crystallisation. Biomembranes for the selective transport of macromolecules as well as materials used as cartilage for joints have been obtained from radiation-cross-linked poly(vinyl alcohol).406 Radiation methods for the immobilisation of heparin,407 cellulase, urease,409 glucoamylase, and invertase 405 as well as other BAS in poly(vinyl alcohol) hydrogels have been developed.Data on the use of radiation-cross-linked poly(vinyl alcohol) hydrogels for the fix- ation and controlled liberation of BAS have been presented in a review.411 A disadvantage of such gels is their low mechanical strength. The use of poly(vinyl alcohol) hydrogels as dressings has been described 418 and its advantage over muslin has been noted: homogeneous adhesion to the entire wound and easy removal without damaging the skin.Schemes for the preparation of heat- resistant hydrogels have been described 418, 419 and methods have been proposed for the improvement of their mechanical proper- ties.418 Radiation-cross-linked poly(ethylene oxide) hydrogels have been investigated in fair detail.397, 421 ± 431 A characteristic feature of such gels is an anomalous decrease in swelling and an increase in the modulus of elasticity on drying, caused by the formation of additional units as a result of crystallisation. The possibility of obtaining porous gels in which the pore size can be varied widely as a function of the irradiation dose is very important.The structure of the ultrahigh-molecular poly(ethylene oxide) after g-irradiation has been investigated.430, 431 It has been suggested that radiation-cross-linked hydrogels of this polymer be used as the medium for the culturing of microorganisms.429 The prepara- tion of biocompatible materials based on radiation-cross-linked poly(ethylene oxide),420 the hydrophobic properties of which may be enhanced by the radiation-induced grating of butadiene, styrene, or ethene,420 has been described.420 Hydrogels based on poly(N-vinylpyrrolidone) are highly hydrophilic and are satisfactorily biocompatible.432 ± 442 The methods of preparation of such gels by the irradiation of aqueous N-vinylpyrrolidone solutions have been studied in detail.438, 443 The radiation-induced cross-linking and degradation of poly(N- vinylpyrrolidone) have been studied.435 The radiation technology for the preparation of gels of this polymer, used as a material for the treatment of burns and trophic ulcers, has been described in detail.436, 440 These materials are sold in Poland under the com- mercial names HDRR and AQUA-GelR. A therapeutic system based on the poly(N-vinylpyrrolidone) gel has been developed for use in obstetric practice to accelerate births and to induce abortions. In this case, the gel consists of a thin rod containing prostaglandin.The methods for the preparation of such gels have been described in detail.432, 436 Data on the biological and physical properties of the hydrogels used as dressings have been described and compared with the usual muslin bandages.441 The influence of the irradiation dose on the mechanical properties of poly(N- vinylpyrrolidone) gels filled with agar and poly(ethylene glycol) has been studied (Fig. 1).442 The technology for the preparation of hydrogels for dressings has now been developed in fair detail and they have undergone extensive clinical tests.439 An important factor is the possibility of obtaining gels for dressings containing medicinal preparations (for example, chloramphenicol).440 In the case of large wounds, such a hydrogel is significantly more effective than the usual dressings.Radiation-cross-linked hydrogels based on poly(N- vinylimidazole), the properties of which are close to poly(N- vinylpyrrolidone) gels,444, 445 as well as radiation-cross-linked gels based on microbial poly-g-glutamic acid with a high mois- ture-absorbing capacity 446 and hyaluronic acid gels with a high biocompatibility 447 have been obtained.Practical advice concern- ing the preparation of various hydrogels � optically homoge- neous and with a minimal content of the residual monomer�has been given.448 a 400 300 200 100 Elongation before rupture (%) 1 2 b Dose /kGy 14 12 10 8 6 10 20 30 40 Tensile strength /N cm72 1 2 Figure 1.Dependence of the elongation before rupture (a) and of the tensile strength (b) on the irradiation dose for poly(N-vinylpyrrolidinone) gels 2.50.5 mm thick. (1) Gels filled with agar and poly(ethylene glycol); (2) gels filled with agar. 808 V Ya KabanovInteresting studies have been carried out in order to obtain polymeric materials based on collagen.334 ± 336, 449 ± 454 The forma- tion of gels on irradiation of collagen solutions has been studied in detail.449, 454 These solutions have been used for the creation of radiation-modified medical implants.449 ± 451, 454 Collagen coat- ings on silicone rubber, subsequently radiation-cross-linked and sterilised, are used in medicine.453 Another natural product employed for the preparation of biomaterials is gelatin.454 ± 457 The radiolysis of gelatin has been studied and the conditions for the formation of three-dimensional structures on irradiation of its solutions have been discovered.454 It has been suggested that a radiation-cross-linked composition comprising poly(vinyl alco- hol) and gelatin be used as a dressing.457 Gels based on polyphosphazenes have been investigated.458 A new method has been proposed 459 for the preparation of hydro- gels using natural polymers: gelatin, dextran, and albumin.The method consists in the functionalisation of natural polymers by introducing into them double bonds with subsequent cross-link- ing by g-irradiation.The method makes it possible to introduce a large amount of a BAS into the hydrogels. Radiation-induced cross-linking has been used for the prepa- ration of medical articles made from polysiloxanes: biologically inert porous cord, syringe tubes, capillaries,460 and various implants.461 ± 463 In the radiation-induced cross-linking of poly- dimethylsiloxane under specially pure conditions, its haemocom- patibility increases significantly.462 The radiation-cross-linked polyvinylmethylsiloxane has been used to prepare thin mem- branes for the making of medicinal preparations (for example, levonorgestrel).463 The radiation-induced cross-linking of trans-1,4-polyisoprene has been used to create thermoshrinking materials for the tying of large blood vessels.The materials have undergone extensive tests in vitro and in vivo (on dogs).464, 465 Radiation modification makes it possible to improve the properties of medical prostheses based on polyolefins.466 Polymeric biomaterials with enhanced adhesion to human skin have also been obtained with the aid of radiation- induced cross-linking.466, 467 The manufacture of a synthetic dressing, obtained by the radiation-induced grafting of hydrophilic monomers on polyur- ethane, has been initiated in Israel.The material is water-imper- meable and transparent, is readily attached to the skin, and is permeable to medicinal drugs. The material is manufactured under the name Omiderm.468 A pilot plant has been created for the manufacture of radiation-cross-linked natural rubber latexes.469 The production of the plant is 1000 tonnes of the product per year (Malaysia).These materials are used to manufacture high-quality medical gloves, thin-walled articles, etc.469 ± 471 Radiation-induced cross- linking polymerisation is particularly important in the manufac- ture of polymeric biomaterials for ophthalmology.Procedures for the hydrophilisation of contact lenses by the radiation-induced graft polymerisation of N-vinylpyrrolidone 472 ± 476 or hydroxy- ethyl methacrylate 477, 478 have been described. Methods have been developed for the preparation of an artificial cornea and contact lenses with a high swellability in water from radiation- cross-linked poly(vinyl alcohol) with added sodium chondroitin sulfate.479 Ionising radiation has been used to ensure complete hardening and to minimise the amount of residual monomer in the prepara- tion of contact lenses.480 ± 482 In order to increase significantly the permeability of the contact lenses to oxygen, it is suggested that they be irradiated with accelerated heavy ions having a mass of 2 ± 100.483 Hydrogel materials for soft contact lenses have been created with the aid of radiation-induced polymerisation.484, 485 These materials are produced in China.485 Radiation-cross-linked collagen, isolated from the sclera of animal eyes, has found an application in the manufacture of ophthalmological materials.This material has been used for the creation of temporary allodrainages in antiglaucoma opera- tions.486 Thus the use of ionising radiation for the preparation of polymer hydrogels is promising.Considerable progress has been achieved in the study of the mechanisms of the radiation-induced cross-linking of hydrogels and their practical applications have expanded, particularly in the preparation of polymeric materials used for the rapid healing of various wounds.An advantage of the radiation-induced cross-linking is the possibility of regulating comparatively easily not only the network density but also the nature of the radiation-induced cross-linking itself by varying the dose rate and the polymer concentration. It has been established that, at a low polymer concentration and at a high dose rate, intramolecular cross-linking predominates over intermolecular cross-linking.487, 488 VII.Conclusion The scale and level of studies on the employment of radiation- chemical methods for the preparation of polymeric biomaterials designed for application in medicine and biotechnology has expanded significantly in recent years. Certain advantages of these methods compared with traditional ones have been clearly established. The use of ionising radiation for the preparation of polymeric biomaterials is one of the examples of the application of atomic energy for the benefit of humanity.Considerable advances have been achieved in the employment of low-temperature radiation-induced polymerisation for the immobilisation of various BAS. The immobilisation of antitu- mour preparations has beeudied in greatest detail and exten- sive investigations of their application in clinics have been performed.Low-temperature radiation-induced polymerisation has been applied in the immobilisation of enzymes designed for the enzymic hydrolysis of plant waste (Japan). Extensive studies on the use of the radiation-chemical technology for the processing of plant raw material have been carried out in Russia. Sorbents which have increased significantly the effectiveness of the chromatographic separation of mixtures of certain BAS have been created with the aid of radiation-induced graft polymer- isation.Much work has been done on the application of radiation- induced graft polymerisation for the modification of polymeric materials in order to increase their haemocompatibility.A whole series of novel methods for the immobilisation of BAS using radiation chemistry have been developed in our country.1 Studies on the employment of radiation-chemical methods for the preparation of a wide variety of polymer hydrogels have been developed very successfully. Some of them (in the form of dressings and polymer eye lenses) have been introduced into clinical practice (Poland, Israel, China).Immunodiagnostic sets employing the radiation-induced polymerisation of 2-hydroxy- ethyl methacrylate are being manufactured on an industrial scale [K Vacek (Czech Republic), private communication]. The immu- nodiagnostic sets are used to determine the activity of phagocytes. The radiation-induced graft polymerisation of organotin mono- mers has been used to prepare modified polymers with fungicidal properties.489 New extremely promising aspects of the application of radia- tion-chemical methods for the preparation of `smart' polymers designed to be used in biotechnology and medicine have appeared in recent years.They are designed in particular for the deliberate introduction of medicinal substances at the required site in the human organism and also for the preparation of polymer mem- branes responding to changes in the environment (pH, temper- ature, etc.), which may find an important application in medicine and biotechnology.In all probability, there is a great future for this aspect of the application of radiation-chemical methods. Studies on the use of ionising radiation for the creation of polymeric biomaterials are being coordinated by the International Atomic Energy Agency (IAEA) and are being prosecuted most vigorously in the USA and Japan.490 Preparation of polymeric biomaterials with the aid of radiation-chemical methods 809Significant advances have been achieved by specialists in Poland.491, 492 Hydrogels are being developed most vigorously at the Insti- tute of Applied Radiation Chemistry at the Technical University of Lodz in Poland.Two of the polymer hydrogels developed for the treatment of bed sores, burns, wounds, and transplanted skin tissues and also in the therapy of ulcers have become commercially available in a number of European countries.492 The development of materials for an artificial pancreas (it produces insulin), graft tissues for blood and other vessels, and materials for employment in ophthalmology and dentistry is in the completion stage.492 There is no doubt that one may expect in the immediate future the appearance in the market place of new polymeric biomaterials obtained with the aid of radiation-chemical methods.References 1. 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ISSN:0036-021X    

出版商:RSC    

年代:1998

数据来源: RSC