摘要:

Abstract. This review deals with the synthesis and properties of 1,2,4-triazine N-oxides and their annelated derivatives. Methods for the incorporation of the N-oxide group in the 1,2,4-triazine ring by direct oxidation and cyclisation involving nitro, nitroso, and isonitroso groups are discussed. Reactions of 1,2,4-triazine N-oxides with electrophiles, nucleophiles, and dienophiles are considered.The effect of the N-oxide group on the chemical shifts in the 1H, 13C, and 14N NMR spectra and the specific features of decomposition of 1,2,4-triazine N-oxides under electron impact are analysed. The bibliography includes 107 references. I. Introduction The present review discusses methods for the synthesis of 1,2,4- triazine N-oxides and reactions of these compounds. 1,2,4-Tri- azine is a heterocycle incorporated in many natural and synthetic compounds that possess biological activity and many practically useful properties. The presence of the N-oxide group in the azine ring makes it sensitive both to nucleophilic and electrophilic attack and expands substantially the synthetic prospects for modifying nitrogen- containing heterocycles.1 This is the reason for the ever increasing interest of investigators in heterocyclic N-oxides.A series of reviews on the chemistry of pyridine N-oxides,2 pyrimidine N-oxides,3 and quinoxaline N-oxides 4 have been published in the 90s. A monograph 5 and several reviews 6± 9 on 1,2,4-triazines include special chapters on the chemistry of triazine N-oxides. However, data on the methods for the synthesis, reactivity, and properties of these compounds have not been systematised to date. The goal of this review is to bridge this gap.II. Methods for the synthesis of 1,2,4-triazine N-oxides Two main approaches are used to synthesise azines containing the N-oxide fragment. First, oxidation of nitrogen atoms of the ring with organic peracids or hydrogen peroxide in acidic media and, second, closing the azine ring with the participation of nitro, nitroso, or isonitroso groups to give an N-oxide group.1 Both of these methods are used for the synthesis of 1,2,4-triazineN-oxides. 1. Synthesis of 1,2,4-triazine 1- and 2-oxides by oxidation of 1,2,4-triazines N-Oxides are formed rather readily in reactions of 1,2,4-triazines with organic peracids or hydrogen peroxide in the presence of carboxylic acids.In this case, only two of the three possible isomers are formed, namely, 1- and 2-oxides. The ratio of these isomers depends on the type of substituents in the starting 1,2,4- triazine. For example, oxidation of 3-amino-1,2,4-triazines 1 gives mainly 2-oxides 2. 3-Alkoxy-1,2,4-triazines 1 react with organic peracids to give solely 1,2,4-triazine 1-oxides 3.11 ± 14 R1 R2 R3 Oxidising agent Yield (%) Ref. 2 3 H H NH2 m-ClC6H4CO3H 80 0 10 H Me NH2 m-ClC6H4CO3H 80 0 10 H H NH(CH2)2Cl m-ClC6H4CO3H 51 0 10 H Me NH(CH2)2Cl m-ClC6H4CO3H 77 0 10 H Ph NH(CH2)2Cl m-ClC6H4CO3H 35 0 10 H H OMe m-ClC6H4CO3H 0 30 11 Me Me NH2 H2O2/AcOH 30 0 12 H Ph NH2 H2O2/AcOH 37 0 13 H Ph NHCOMe H2O2/AcOH 45 0 13 H Ph NHCOEt H2O2/AcOH 41 0 13 Me Me H PhCO3H 0 30 14 Ph Ph H PhCO3H 0 17 14 H Ph H PhCO3H 0 26 14 H H OMe PhCO3H 0 15 14 Ph Ph OMe PhCO3H 0 23 14 H Me OMe PhCO3H 0 26 14 H Ph OMe PhCO3H 0 39 14 Obviously, the possibility of amino ± imino tautomerism 2a>2b in 3-amino-1,2,4-triazine N-oxides stabilises the products of oxidation at position 2 of the triazine system.10 1 3 + 2 N N N R1 R2 R3 N N+ N R1 R2 R3 O7 N N N+ R1 R2 R3 O7 R4CO3H D N Kozhevnikov, V L Rusinov, O N Chupakhin Ural State Technical University, ul.Mira 19, 620002 Ekaterinburg, Russian Federation. Fax (7-343) 274 04 58. Tel. (7-343) 274 04 58 (D N Kozhevnikov), (7-343) 274 44 26. E-mail: azine@htf.rcupi.e-burg.su (O N Chupakhin) Received 15 December 1997 Uspekhi Khimii 67 (8) 707 ± 722 (1998); translated by S S Veselyi UDC 547.853 1,2,4-Triazine N-oxides and their annelated derivatives D N Kozhevnikov, V L Rusinov, O N Chupakhin Contents I.Introduction 633 II. Methods for the synthesis of 1,2,4-triazine N-oxides 633 III. Physicochemical characteristics of 1,2,4-triazine N-oxides 637 IV. Chemical properties of 1,2,4-triazine-N-oxides 639 V. Conclusion 646 Russian Chemical Reviews 67 (8) 633 ± 648 (1998) #1998 Russian Academy of Sciences and Turpion LtdOxidation of 3,5-diaryl-1,2,4-triazines 4 withm-chloroperben- zoic acid gives 1,2,4-triazine 1-oxides 5 in 75%± 98% yields.15 5,6-Diamino-3-methylsulfonyl-1,2,4-triazine 1-oxides 7 were prepared under the same conditions from 5,6-diamino-3-methyl- thio-1,2,4-triazines 6 in 60%± 80% yields.16 Oxidation of 1,2,4-triazines containing the camphor (com- pound 8) or methylcyclopentane fragments (compound 9)17 with m-chloroperbenzoic acid affords solely triazine 1-oxides 10 and 11.The reaction pathway also depends on the temperature. The reaction of 3-phenyl-1,2,4-benzotriazine 12 with peracetic acid affords 3-phenyl-1,2,4-benzotriazine 1-oxide 13 at 50 8C and 2-oxide 14 at 20 8C.18 Only the 1-oxide 16a was obtained in 28% yield in the oxidation of 3-unsubstituted 1,2,4-benzotriazine 15a.Oxidation of 3-methyl-1,2,4-benzotriazine 15b under the same conditions gives a mixture of 3-methyl-1,2,4-benzotriazine 1-oxide 16b and 2-oxide 17b in 25% and 10% yields, respectively. 2. Synthesis of 1,2,4-triazine 1-oxides by cyclisation involving a nitro group Aromatic and heteroaromatic nitro-compounds containing a guanidine fragment at the ortho-position relative to the nitro group readily undergo cyclisation in alkaline or acidic media to give benzo- or hetero-annelated 1,2,4-triazine 1-oxides.For exam- ple, 3-amino-1,2,4-benzotriazine 1-oxide 18 was obtained in 1913 by treatment of 2-nitrophenylguanidine 19 with an alkali.19 Subsequently, this approach was used to synthesise a number of 3-amino-1,2,4-benzotriazine 1-oxides of the type 18.20 ± 27 It is noteworthy that compound 19 can be obtained either by the reaction of guanidine with 2-nitrochlorobenzene 20 or by treat- ment of compound 20 with sodium cyanamide and dimethylamine (in the latter case, compounds 19 and 20 with R1=R2=Me are formed).In a similar way, 3-amino-1,2,4-triazino[6,5-c]quinoline 4-oxides 22 were synthesised in 62%± 95% yields by the reaction of 4-chloro-3-nitroquinoline 21 with guanidine followed by cycli- sation of substituted guanidines formed in an alkaline medium.28 The reaction of 4-methoxy-3-nitropyridines 23a,b with guani- dine under similar conditions affords 3-aminopyrido[3,4-e]-1,2,4- triazine 1-oxides 24a,b.29 2a 2b N N+ N R1 R2 NH2 O7 N N N R1 R2 NH OH R1=H, 2-Me, 3-Me, 4-Me, 2-Cl, 3-Cl, 4-Cl, 3-CF3; R2=H, 4-Br, 2-F, 3-F, 4-F, 4-Cl, 4-CF3.N N N R1 4 N N N+ O7 R1 R2 5 20 8C m-ClC6H4CO3H R2 R=H, CH2Ph. 6 7 20 8C m-ClC6H4CO3H N N N H2N SMe RHN N N N+ O7 H2N SO2Me RHN 8 10 (78%) 20 8C m-ClC6H4CO3H N N N C6H4NO2-m N N N+ O7 C6H4NO2-m 9 11 (73%) 20 8C m-ClC6H4CO3H N N N C6H4NO2-m N N N+ O7 C6H4NO2-m 14 (48%) 12 13 (86%) N N N+ Ph O7 N N+ N Ph O7 N N N Ph MeCO3H 50 8C 20 8C R = H (a), Me (b). 15a,b 16a,b 17b + N N N R N N N+ R O7 N N+ N R O7 18 X N N N+ NR1R2 O7 X=H, Me, Cl, Br, NO2, OMe, CN. 19 20 N NH NR1R2 H NO2 X + NO2 Cl X NH R1R2N H2N OH7 or H+ 20 NaHNCN 19 NO2 NHCN X Me2NH R1=H, Me; R2=H, Me, Et, Bun, n-C10H21, Bn, (CH2)2NEt2. 21 N NO2 Cl + NH R1R2N H2N OH7 N NO2 HN NR1R2 NH N N+ N NR1R2 N O7 22 X = H (a), Cl (b).+ NH H2N H2N N NO2 OMe X 23a,b N N N+ N X O7 NH2 24a (83%), 24b (71%) 634 D N Kozhevnikov, V L Rusinov, O N ChupakhinCyclisation of N-(2-nitrophenyl)-N0-benzoylthiourea and its derivatives (compounds 25) in an alkaline medium affords the corresponding 1,2,4-benzotriazine-3(2H)-thione 1-oxides 26.30 The reaction of o-nitroaniline and its 4-substituted derivatives (compounds 27) with cyanamide gives 3-amino-1,2,4-benzo- triazine 1-oxides 28.22 3.Preparation of 1,2,4-triazine 4-oxides by cyclisation involving a nitroso or isonitroso group Unlike 1- and 2-oxides, 1,2,4-triazine 4-oxides 29 are not formed upon direct oxidation of the corresponding 1,2,4-triazines. Therefore, the only possibility to prepare 1,2,4-triazines with the N-oxide group at position 4 is to synthesise the triazine cycle from compounds with nitroso or isonitroso groups. The synthesis can be carried out in several ways.The reaction of hydroxyamidrazone 30 with dimethylglyoxal 31 in methanol affords 5,6-dimethyl-3-phenyl-1,2,4-triazine 4-oxide 32.31 The condensation of amidrazone 33 with phenylglyoxal monooxime 34 occurs through the formation of hydrazone 35.The elimination of an ammonia molecule from compound 35 gives 3-methyl-6-phenyl-1,2,4-triazine 4-oxide 36 in a good yield.31 If aminoguanidine or S-methylisothiosemicarbazide 37 are used instead of amidrazone, 3-amino-1,2,4-triazine 4-oxides are formed. 3-Amino-5-methyl-6-phenyl-1,2,4-triazine 4-oxide 38 was synthesised in this way.32, 33 5,6-Diphenyl-1,2,4-triazine 4-oxide 39 was obtained by the reaction of diphenylglyoxal mono-2-ethoxymethylenehydrazone 40 with hydroxylamine.31 Obviously, formation of the intermedi- ate 41 followed by its cyclisation to 1,2,4-triazine 4-oxide 39 occurs in this case.A more promising method for the synthesis of 1,2,4-triazine 4-oxides is the cyclisation of a-hydrazonooximes 42 with ortho- carboxylates or iminoesters.Rather a wide range of 1,2,4-triazine 4-oxides 29 was synthesized using this method.31, 34 ± 38 R1 R2 R3 Yield of 29 (%) Ref. Reagent R3C(OEt)3 Me H Me 40 34 Me Me Me 80 34 Ph Ph Me 70 34 Me H Ph 53 34 Ph Me Me 70 34 Ph Me Et 60 34 Ph Me Ph 70 34 2-NO2C6H4 H H 89 36 4-NO2C6H4 H H 84 34 4-NO2C6H4 H H 89 36 4-MeOC6H4 H H 80 34 Ph H H 86 31 Ph H Ph 57 31 Ph Me H 27 31 Me Me H 51 31 Me H H 23 31 But H H 59 38 But H Me 65 38 But H Ph 43 38 Reagent R3C(OEt)=NH 4-MeOC6H4 H 4-NO2C6H4 16 34 Ph Me 4-NO2C6H4 25 34 4-NO2C6H4 H 4-MeOC6H4 16 34 Ph H 4-MeOC6H4 45 34 Ph H 4-NO2C6H4 54 34 Ph H Me 51 31 Similarly, reactions of 5-isonitroso-1,3,3-trimethyl-2-oxabicy- clo[2.3.3]octan-6-one hydrazone 43 and 4-isonitroso-2,2,5,5-tet- ramethyltetrahydrofuran-3-one 44 with the corresponding orthobenzoates afford 3-aryl-5,8-dihydro-6,6,8-trimethyl-5,8- ethanopyrano[4,3-e]-1,2,4-triazine 4-oxides 45 and 3-aryl-5,7- dihydro-5,5,7,7-tetramethylfurano[3,4-e]-1,2,4-triazine 4-oxides 46.39 R=H (77%), 5-Cl (72%), 7-Cl (80%), 6-SH (40%), 7-Me (72%), 7-OMe (75%). NaOH 26 N NH S N+ O7 R N NHBz S H NO2 R 25 X=H, Me, OMe, Br, Cl, OPh, CN, NO2. 27 28 (95% ± 98%) X NO2 NH2 N N N+ X O7 NH2 NCNH2 R1 N N+ R2 N O7 R3 29 30 + N N(OH)H Ph NH2 31 O Me Me O MeOH N+ Ph Me Me O7 32 (41%) N N Ph N N+ N O7 Me 36 (72%) + 34 33 AcOH Ph O NOH N H2N Me H2N 35 7NH3 Me NH2 N N N Ph OH + Ph O NOH N H2N NH2 MeS AcOH Ph N N+ N O7 NH2 Me 38 (35%) 37 Me 40 NH2OH 41 O7 39 (41%) N+ N N Ph Ph N N Ph Ph O H OEt N N N Ph Ph OH H OEt 42 R1 N NOH R2 NH2 R3C(OEt)3 or R3C(OEt)=NH R1 N N+ R2 N O7 R3 29 1,2,4-Triazine N-oxides and their annelated derivatives 635Annelated 1,2,4-triazine 4-oxides, viz., 3-R-fervenulin 4-oxides 47, were synthesised from 6-hydrazino-1,3-dimethyl-5- nitrosouracil 48.40 ± 42 Orthoesters, formic acid, or DMF in the presence of POCl3 or dimethyl sulfate can be used as cyclisation agents.Compound Cyclisation agent (X) Yield of 47 (%) Ref. 47a HC(OEt)3 71 40 ± 42 47b MeC(OEt)3 76 40 ± 42 47c EtC(OEt)3 85 40 47a HCOOH 54 40 47a DMF± POCl3 72 40 47a DMF±Me2SO4 43 40 A new, rather simple method for the synthesis of 1,2,4-triazine 4-oxides 49 was suggested recently. It involves the condensation of isonitrosoacetophenone hydrazone 50 with aldehydes followed by oxidation of the condensation product with lead tetraacetate.This is a simple way to obtain 1,2,4-triazine 4-oxides with almost any aliphatic, aromatic, and heteroaromatic substituents at position 3 of the triazine cycle.43 To prepare fervenulin 4-oxides 47 or toxoflavine 4-oxides 51, it is convenient to use the reaction of 1,3-dimethyl-2,4-dioxopyr- imidin-6-yl hydrazone 52 or N-(3-methyl-2,4-dioxopyrimidin- 6-yl) N-methylhydrazone 53 with potassium nitrate in acetic acid.44 ± 48 Sometimes, diethylazo diformate is used instead of potassium nitrate.49 In this case, cyclisation occurs simultaneously with the formation of the NO group.Compounds 52 and 53 were synthesised from the corresponding hydrazines 54 and 55 and aldehydes. R Yield of 47 (%) Ref. Ph 68 44 54 49 4-ClC6H4 50 44 43 49 3,4-Cl2C6H3 65 44 61 49 4-MeOC6H4 63 49 4-Me2NC6H4 58 49 4-NO2C6H4 45 44 R Yield of 51 (%) Ref.H 56 48 Me 63 49 Ph 51 48 4-ClC6H4 46 48 3,4-Cl2C6H3 67 48 4-MeC6H4 54 48 4-Me2NC6H4 50 49 PhCH=CH 46 48 61 48 3-Anilinofervenulin 4-oxides 47 (R=ArNH) were obtained by the reaction of 6-hydrazino-1,3-dimethyluracil 54 with triethyl orthoformate followed by substitution of the ethoxy group in the resulting hydrazide 56 with an aniline residue and further cyclisa- tion of compound 57 under nitrosation conditions.46 2-Nitrosophenols 58 react with aminoguanidine nitrate in the presence of nitric acid.This method gave 3-amino-1,2,4-benzo- triazine 4-oxides 59.50 X=Me, OMe, NO2, CF3, Cl, Br, F. 43 O Me Me Me N+ N N O7 C6H4X-4 45 O Me NNH2 NOH Me Me 4-XC6H4C(OMe)3 44 O Me Me Me Me N+ N N C6H4X-4 O7 46 O Me Me Me Me NNH2 NOH 4-XC6H4C(OMe)3 X is cyclisation agent; R =H (a), Me (b), Et (c). 48 47a ± c X N N Me N N O O O Me NH2 H N N Me N N+ O O Me N R O7 1. RCHO 2. Pb(OAc)4 50 49 R R=Me, Et, Pri, C7H15, Ph, 4-NO2C6H4, 4-BrC6H4, O . N+ N N Ph O7 NOH NH2 N Ph RCHO AcOH KNO3 N N N N Me Me O O H R 52 N N N NH2 Me Me O O H 54 N N N N Me Me O O R N+ O7 47 N N N N Me O O R N+ O7 Me 51 N N N NH2 H Me O O Me 55 N N N N Me O O R Me H 53 RCHO KNO3 AcOH/H2SO4 N R=ArNH=PhNH (51%), 4-ClC6H4NH (63%), 4-BrC6H4NH (49%), 4-MeOC6H4NH (47%), 4-MeC6H4NH (56%). 54 HC(OEt)3 56 N N N N Me Me O O H OEt ArNH2 57 N N N N Me Me O O H NHAr 47 N N Me N N+ O O Me N R O7 AcOH KNO3 636 D N Kozhevnikov, V L Rusinov, O N ChupakhinReaction of 3-hydrazino-3-methylbutan-2-one oxime 60 with aldehydes and ketones affords 3-R1-3-R2-1,3,4,6-tetrahydro- 5,6,6-trimethyl-1,2,4-triazine 4-oxides 61.51 Condensation of 1-morpholino-6-oximinocyclohexene 62 with hydrazine hydrate and ketones gives 2,3,5,6,7,8-hexahydro- 1,2,4-benzotriazine 4-oxides 63.In the absence of a carbonyl compound, this reaction leads to spiro compound 64.52 4. Other methods for the synthesis of 1,2,4-triazine 4-oxides There is a method for the synthesis of 1,2,4-triazine 4-oxides that is fundamentally different from those discussed above.53 The reac- tion of nitrones 65 with an excess of hydrazine afforded 4-hydroxy-2,3,4,5-tetrahydro-1,2,4-triazines 66.Subsequent oxi- dation with Pb(IV) oxide resulted in the corresponding triazine 4-oxides 29.R1 R2 R3 Yield of 29 (%) Ph Me Et 57 Ph Me Ph 70 Me Me Ph 52 Ph H Ph 51 3-Methyl-1,2,4-benzotriazine 4-oxide 67 was obtained by the reaction of benzofurazan oxide 68 with diethylamine.54, 55 III. Physicochemical characteristics of 1,2,4-triazine N-oxides The incorporation of an N-oxide fragment in the 1,2,4-triazine molecule changes substantially the 1H, 13C, and 15N NMR spectra.In 1H NMR spectra of 1,2,4-triazine 1-oxides, the signals of the protons at positions 3 and 6 are observed at 9.00 and 8.04 ppm, i.e., they are shifted upfield by 0.6 ± 0.7 and 1.1 ± 1.2 ppm, respectively, in comparison with those in the 1,2,4-triazines, but the signal of the H(5) proton (8.57 ppm) remains almost unchanged.10, 14, 56 A comparison of the 1H NMR spectra of 1,2,4-triazine 4-oxides with those of the corresponding 1,2,4-triazines shows that the signals of the H(3) and H(6) protons have an almost similar upfield shift (Dd=70.8 ppm), and their chemical shifts are 8.82 and 8.42 ppm, respectively. The signal of the H(5) proton is also shifted upfield by 0.3 ppm (d=8.00 ppm) (Table 1).10 R1=Cl, Br, Me; R2=H, Me.+ HNO3 58 OH NO R1 R2 NH2 H2N NH .HNO3 HN N+ N N NH2 O7 59 (73% ± 92%) R1 R2 R1=H, Me; R2=H, Me, Pri. 60 + N Me Pr N NH O7 R2 R1 Me Me 61 R1R2CO 20 8C N Me NOH NH2 Pr Me Me R1, R2=Me, CH2Ph; R17R2=(CH2)5, (CH2)6. 62 N O NOH 64 (71%) 63 (35% ± 60%) + N NH N R2 R1 O7 + N NH N NOH O7 N2H4 20 8C R1R2CO N2H4 65 O R1 N+ O7 R3 H R2 66 N N N H H R3 R2 H R1 OH PbO2 AcOH 29 N N+ N R1 R3 R2 O7 N+ O N O7 68 N+ N N O7 Me 67 (20%) Et2NH Table 1 Chemical shifts of cyclic protons in the 1H NMR spectra of 1,2,4-triazines and their N-oxides in CDCl3.Compound d/ ppm Dd/ ppm Ref. H(3) H(5) H(6) H(3) H(5) H(6) 1,2,4-Triazine 9.63 8.53 9.24 10 1,2,4-Triazine 1-oxide 9.00 8.57 8.04 70.63 0.04 71.20 10, 14 1,2,4-Triazine 2-oxide 8.82 8.00 8.42 70.81 70.53 70.82 10 3-Methoxy-1,2,4-triazine 8.56 9.16 56 3-Methoxy-1,2,4-triazine 1-oxide 8.37 7.83 70.19 71.33 14 3-Methoxy-1,2,4-triazine 2-oxide 7.70 8.12 70.86 71.04 10 3-Amino-1,2,4-triazine a 8.53 8.88 10 3-Amino-1,2,4-triazine 2-oxide a 8.19 8.23 70.34 70.65 10 3-(N,N-Dimethylamino)-1,2,4-triazine 8.14 8.15 10 3-(N,N-Dimethylamino)-1,2,4-triazine 1-oxide 7.76 7.86 70.38 70.65 10 3-Morpholino-1,2,4-triazine 8.14 8.54 57 3-Morpholino-1,2,4-triazine 2-oxide 7.81 8.54 70.33 70.52 10 6-Methyl-1,2,4-triazine 9.55 8.55 31 6-Methyl-1,2,4-triazine 4-oxide 9.28 8.22 70.27 70.33 31 6-Phenyl-1,2,4-triazine 9.52 8.91 31 6-Phenyl-1,2,4-triazine 4-oxide 9.31 8.60 70.21 70.31 31 a In [2H6]DMSO. 1,2,4-Triazine N-oxides and their annelated derivatives 637The incorporation of an N-oxide group at position 4 of the triazine system shifts the signals of the H(3) and H(5) protons upfield by 0.1 ± 0.3 ppm (the 9.28 ± 9.47 and 8.55 ± 8.90 ppm regions).It should be noted that, unlike the case of 1,2,4-triazines, these signals in 1,2,4-triazine 4-oxides appear as doublets (J=1.8 Hz) (see Table 1).31 The 13C NMRspectra are also changed upon the introduction of the N-oxide fragment. In 1,2,4-triazine 4-oxides, the signals of the carbon atoms in the ortho- and para-positions with respect to the N7O fragment are shifted upfield by 18 ± 20 ppm for 1-oxides, 9 ± 18 ppm for 2-oxides, and 10 ± 15 ppm for 4-oxides in comparison with those of the corresponding 1,2,4-tria- zines,39, 58 ± 62 but the signal of the carbon atom in the meta- position is almost not shifted (Table 2).10, 39 Thus, comparison of the 13C NMR spectra of 1,2,4-triazines and their oxides allows one to determine easily the position of the N-oxide group. 15N NMR spectroscopic data also allow the determination of the position of the N-oxide group. On going from 1,2,4-triazines to their 1-oxides, the maximum upfield shift is observed for the nitrogen atom in position 1 [Dd=7(83 ± 87) ppm]. The signals of the N(2) and N(4) atoms are shifted upfield to a much smaller extent [Dd=7(39 ± 46) ppm and Dd=7(22 ± 24) ppm, respec- tively]. For 1,2,4-triazine 2-oxides, the situation is somewhat different.The signals of the N(1) and N(2) atoms are shifted upfield by almost the same value [Dd=7(70 ± 75) ppm], but the signal of the nitrogen atom in position 4 is almost not shifted [Dd=7(13 ± 23) ppm] (Table 3).63 ± 65 The IR spectra of 1,2,4-triazine N-oxides,53 as well as those of N-oxides of other azines,1 contain a characteristic band of stretching vibration of the N7O group in the region near 1250 cm71.The absoption maximum in the UV spectrum of 3,4-diphenyl- 1,2,4-triazine 4-oxide is around 286 nm (log e=4.57).53 70.8 7(0.5 ± 1.1) 7(0.3 ± 0.9) N N+ N O7 7(0.1 ± 0.3) 7(0.1 ± 0.3) N+ N N O7 R N N N+ O7 7(1.1 ± 1.4) 7(0.0 ± 0.3) 7(0.6 ± 0.9) N+ N N O7 7(15 ± 16) 7(7 ± 11) N N N+ O7 7(18 ± 27) +(0 ± 4) +(1 ± 3) +(4 ± 5) N N+ N O7 7(3 ± 8) 7(16 ± 18) 7(9 ± 11) Table 2 Chemical shifts of carbon atoms in the 13C NMR spectra of 1,2,4-triazine N-oxides in [2H6]DMSO. Compound d/ ppm Dd/ ppm Ref.C(3) C(5) C(6) C(3) C(5) C(6) 1,2,4-Triazine 1-oxide a 158.5 152.7 129.7 70.4 3.1 721.1 60 1,2,4-Triazine 2-oxide a 143.5 132.5 146.0 714.6 717.1 74.8 60 3-Methoxy-1,2,4-triazine 1-oxide a 166.5 154.0 124.5 2.5 4.0 718.5 10 3-Methoxy-1,2,4-triazine 2-oxide a 152.5 130.0 135.5 711.5 720.0 77.5 10 3-Amino-1,2,4-triazine 1-oxide 165.0 155.9 120.7 1.7 6.1 719.9 60 3-Amino-1,2,4-triazine 2-oxide 151.6 132.4 134.9 711.7 717.4 75.7 60 3-(N,N-Dimethylamino)-1,2,4-triazine 1-oxide a 161.0 152.0 120.0 1.0 4.0 718.0 10 3-(N,N-Dimethylamino)-1,2,4-triazine 2-oxide a 151.0 132.0 133.0 79.0 716.0 75.0 10 3-Amino-5,6-dimethyl-1,2,4-triazine 1-oxide 166.0 164.3 119.4 3.9 5.4 727.7 60 3-Amino-5,6-dimethyl-1,2,4-triazine 2-oxide 148.9 140.2 144.2 713.2 718.7 72.9 60 3-Amino-5,6-dimethyl-1,2,4-triazine 4-oxide 154.4 143.0 148.7 77.7 715.9 1.6 60 5-Methyl-1,2,4-triazine 1-oxide a 158.7 166.1 129.1 1.7 5.6 721.8 60 6-Phenyl-1,2,4-triazine 1-oxide 149.9 132.0 157.5 7 7 7 60 3-Methyl-6-phenyl-1,2,4-triazine 4-oxide 159.4 131.4 156.4 7 7 7 60 3,6-Diphenyl-1,2,4-triazine 4-oxide 156.2 132.8 155.6 7 7 7 60 3-Ethyl-6-phenyl-1,2,4-triazine 4-oxide 161.9 131.4 156.3 7 7 7 60 5-Ethyl-5-(indol-3-yl)-6-phenyl-1,2,4-triazine 4-oxide 161.0 135.5 156.7 7 7 7 62 5-(1-Methylindol-3-yl)-6-phenyl-1,2,4-triazine 4-oxide 149.0 139.4 157.3 7 7 7 62 3-Ethyl-5-(1-methylindol-3-yl)-6-phenyl-1,2,4-triazine 4-oxide 160.8 136.0 135.8 7 7 7 62 5-(1-Methylindol-3-yl)-3,6-diphenyl-1,2,4-triazine 4-oxide 156.1 136.1 156.0 7 7 7 62 5-(2-Methylindol-3-yl)-6-phenyl-1,2,4-triazine 4-oxide 149.9 142.8 160.9 7 7 7 62 3-Methyl-5-(2-methylindol-3-yl)-6-phenyl-1,2,4-triazine 4-oxide 157.9 140.2 158.9 7 7 7 62 a In CDCl3.Table 3 Signals of cyclic nitrogen atoms in the 15N NMR spectra of 1,2,4-triazines and their N-oxides 63 in [2H6]DMSO relative to MeNO2. Compound d / ppm Dd/ ppm N(1) N(2) N(4) N(1) N(2) N(4) 1,2,4-Triazine 40.0 2.0 762.0 1,2,4-Triazine 743.0 7 7 783 7 7 1-oxide 3-Methoxy- 36.0 758.0 7124.4 1,2,4-triazine 3-Methoxy-1,2,4- 750.0 797.1 7148.0 786.0 738.9 723.6 triazine 1-oxide 3-Amino-1,2,4- 35.7 761.0 7130.0 triazine 3-Amino-1,2,4- 751.1 7107.0 7152.0 786.8 746.0 722.0 triazine 1-oxide 3-Amino-1,2,4- 739.0 7137.0 7153.0 774.7 776.0 723.0 triazine 2-oxide 638 D N Kozhevnikov, V L Rusinov, O N ChupakhinA molecular ion peak (often with the maximum intensity) and intense [M716]+ and [M717]+ peaks typical of this class of compounds are observed in the mass spectra of 1,2,4-triazine 1- and 2-oxides.The fragmentation of 1,2,4-triazine 1- and 2-oxides is similar, which prevents an unambiguous determination of the position of the N-oxide group.62, 66, 67 However, a somewhat different picture is observed in the case of 1,2,4-triazine 4-oxides. The characteristic feature of their mass spectra is the existence of an intense molecular ion peak and a very weak [M716]+ peak.31 The X-ray diffraction data for 3,6-diphenyl-5-(indol-3-yl)- 1,2,4-triazine 4-oxide 62 showed that the 1,2,4-triazine 4-oxide fragment and the substituents are non-coplanar, the slopes of the corresponding planes being within 30 ± 50 8.IV. Chemical properties of 1,2,4-triazine-N-oxides 1.Tautomerism The amino ± imino tautomerism is typical of 3-amino-1,2,4-tria- zine 4-oxides 2a. This is the reason for the formation of 2-oxides in the oxidation of 3-amino-1,2,4-triazines 1.10 3-Azido-1,2,4-benzotriazine 1-oxides 69 exist only in the form of azides, both in the crystal state and in solution. This is also true for 3-azido-1,2,4-triazine 1-oxides 70, which have not been found in the tetrazole form in any aggregation state.68 ± 70 Ring ± chain tautomerism is observed for the series of 1,2,3,6- tetrahydro-1,2,4-triazine 4-oxides 61.51 These compounds exist solely as hydrazones 61b both in solution and in the crystal form.In aprotic non-polar solvents (e.g., CCl4), the fraction of the cyclic form 61a is as high as 45%, depending on the nature of the substituents R1 and R2.R1 R2 Proportion of the forms in CCl4 (%) 61a 61b Me Me 25 75 H H 45 55 Me H 40 60 Pri H 10 90 p-ClC6H4 H 0 100 Ring ± chain transformations are also observed for 3,4-dihy- dro-4-hydroxy-1,2,4-triazines 71. For example, compounds 71 in DMSO-d6 exist both in a cyclic form 71a and in an open form 71b. It was found that aliphatic substituents at position 3 of 3,4-dihy- dro-1,2,4-triazine 71 shift the equilibrium towards the cyclic form 71a, while aromatic and heteroaromatic substituents, towards the open form 71b (Table 4). An increase in temperature increases the fraction of hydrazone 71b.Analysis of high-resolution mass spectra of these compounds made it possible to find out that the cyclic form 71a prevails (70% ± 90%) in the gas phase.71 2-Phenyl-1,2,4-benzotriazin-3(2H)-one 1-oxide 72, which exists in the cyclic form 72a when in the crystal, undergoes ring opening in solution to give 2-isocyanatoazoxybenzene 72b.72 2.Deoxygenation Elimination of oxygen (deoxygenation) occurs in 1,2,4-triazine N-oxides, as well as in other azine N-oxides, upon treatment with reducing agents. The reaction of 1,2,4-triazine N-oxides 29 with triethylphos- phine or PCl3 resulted in the corresponding 1,2,4-triazines 1 (in 65%± 95% yield), which were impossible to synthesise by other methods.31, 35 If POCl3 is used in this reaction, deoxygenation is accompanied by chlorination of 1,2,4-triazine. For example, 5-chloro-6-phenyl-1,2,4-triazine 73 was obtained in 37% yield from 6-phenyl-1,2,4-triazine 4-oxide.73 69 70 N N N+ O7 N3 N N N+ O7 N3 61a 61b + N N NH Me Me Me Pr O7 R2 R1 N N N OH R2 R1 Me Me Me Pr 71a 71b N N N R3 R2 OH R1 N N N OH R3 R2 R1 72a 72b N N N+ O7 Ph O N+ N O7 NCO Ph 73 1 PEt3 or PCl3 POCl3 R1=Ph, R2=R3=H 29 N+ N N R1 R2 R3 O7 N N N R1 R2 R3 N N N Ph Cl R3=H, Me, Ph.R1=H, Me, Ph, 4-MeOC6H4; R2=H, Me, Ph, N H ; Table 4. Ratio of the cyclic (71a) to the open (71b) forms of 3,4-dihydro-4- hydroxy-6-phenyl-1,2,4-triazine 71 in [2H6]DMSO and in gas phase.71 R1 R2 R3 Isomer ratio (%) solution gas phase 71a 71b 71a 71b Ph H Me 100 0 72 22 Ph H Et 100 0 Ph H Pri 100 0 90 10 Ph H C7H15 90 10 80 20 Ph H Ph 23 77 82 18 Ph H 2-NO2C6H4 5 95 Ph H 4-NO2C6H4 8 92 Ph H 4-HOC6H4 7 93 75 25 Ph H 3,4-(HO)2C6H3 35 65 85 15 Ph H 4-BrC6H4 15 85 11 89 Ph H 4-NMe2C6H4 0 100 Ph H CO2H 100 0 Ph H 7 93 Ph Me Me 90 10 Ph Me Ph 50 50 Ph Me CH2CO2Et 0 100 Ph 7(CH2)47 96 4 Ph 7(CH2)57 82 18 Me H 4-NO2C6H4 0 100 Me H 4-HOC6H4 0 100 Me H 4-NMe2C6H4 0 100 O 1,2,4-Triazine N-oxides and their annelated derivatives 639Sodium dithionite can be used for the reduction of 1,2,4- triazine 4-oxides.This method has been used in the synthesis of fervenulins 74 from fervenulin 4-oxides 4741 and 3-bromo-1,2,4- benzotriazines 76 from 3-bromo-1,2,4-benzotriazine 4-oxides 75.69 Boiling of fervenulin 4-oxide 47 inDMFresults in its thermal deoxygenation to form fervenulin 74.40 The reaction of 3-morpholino-1,2,4-benzotriazine 4-oxide 77 with zinc in hydrochloric acid afforded 3-morpholino-1,2,4-ben- zotriazine 78.74 UV irradiation of 3-aminopyrido[4,3-e]-1.2.4-triazine 1-oxides 24a,b or 1,2,4-triazine 4-oxides 29 is also accompanied by the loss of the N-oxide group 75, 76 and gives the corresponding 3-aminopyrido[4,3-e]-1,2,4-triazines 79a,b or 1,2,4-triazines 1.The reaction of 2,3-dihydro-6-phenyl-1,2,4-triazine 4-oxide 80 with acetic anhydride leads to deoxygenation and aromatisation of the former to give 6-phenyl-1,2,4-triazine 81.77 3.Reaction with electrophilic agents a. Alkylation The reaction of 3-amino-1,2,4-triazine 1-oxide 82 with methyl iodide in the presence of sodium bicarbonate results in methyl- ation of the amino group to give 3-methylamino-1,2,4-triazine 1-oxide 83. In neutral media, the N(3) atom of the cycle in 1,2,4- triazine 1-oxide 82 undergoes methylation resulting in 3-imino-2- methyl-1,2,4-triazine 1-oxide 84.It is interesting that 1-oxide 83 undergoes rearrangement to 1-oxide 84 in methanol in the presence of methyl iodide. 3-Methoxy-1,2,4-triazine 1-oxide 85 undergoes the same rear- rangement under the same conditions and transforms into 2-methoxy-1,2,4-triazin-3-one 86.78 An abnormal nucleoside, 4-(b-D-ribofuranosyl)-1,2,4-triazin- 3(4H)-one 1-oxide 87, was obtained in 38% yield by the reaction of 2,3,5-tri-O-benzoyl-b-D-ribofuranosyl bromide with 3-methoxy-1,2,4-triazine 1-oxide 88 followed by the removal of the benzoyl protective groups with sodium methoxide.11 The reaction of the sodium salt of pyrido[2,3-e]-1.2.4-triazine- 3(4H)-one 1-oxide 89 (X=N) or 1,2,4-benzotriazine-3(4H)-one 1-oxides 89 (X=CH) with acetobromoglucose allows one to obtain the tetraacetyl derivatives of b-D-glucopyranosides 90, the deacetylation of which affords nucleosides 91.79 The reaction of compounds 89 (X=CH; R=H, Me) with 2-chloromethoxyethyl acetate results in N-alkylation products 92a,b.Their subsequent hydrolysis affords 4-(2-hydroxyethoxy- methyl)-1,2,4-benzotriazin-3(4H)-one 1-oxides 93a,b.79 (a): Na2S2O4 (55% ± 90%); (b): DMF, 150 8C (60%). 47 74 a or b N N N+ N N O7 O O Me Me R N N N N N O O Me Me R Na2S2O4 76 (70% ± 75%) N N N Br R1 R2 N+ N N O7 Br 75 R1 R2 Zn/HCl N+ N N O7 N O 77 N N N N O 78 X = H (a), Cl (b). hn N N N N X NH2 79a,b N N N+ N O7 X NH2 24a,b 29 1 hn Ac2O + N NH N Ph H H O7 80 N N N Ph 81 83 84 N N N+ O7 NH2 82 MeI MeOH MeI NaHCO3 N N N+ O7 NHMe N N N+ O7 NH Me MeI MeOH 85 86 MeI MeOH N N+ N O7 OMe N N N OMe O N N N+ OMe O7 88 2.MeONa, MeOH 1. O OBz Br BzO BzO O OH OH N HO N N+ O O7 87 OAc O AcO OAc Br AcO N N+ X O O7 R 90 OAc O AcO OAc AcO N 89 2. Et2NH, MeOH OAc O AcO OAc Br AcO 1. 91 OH O HO OH HO N N+ X O O7 R N X N N N+ O7 O R Na 89 (R=H, X=N) R=Me; X=CH. 640 D N Kozhevnikov, V L Rusinov, O N Chupakhin3-Amino-1,2,4-benzotriazine 1-oxide 94 undergoes the Chi- chibabin reaction with bromoacetaldehyde to give imidazo[2,1-c]- 1.2.4-benzotriazine 1-oxide 95.80 Reactions of 3-hydrazino-1,2,4-triazine 1-oxide 96 or 3-hydra- zinopyrido[2,3-c]-1.2.4-triazine 1-oxide 97 with diethoxymethyl acetate or triethyl orthoformate followed by cyclisation afford the corresponding pyrazolo[3,4-c]-1.2.4-triazine 6-oxides 98 and 99.81 ± 83 b.Electrophilic substitution of hydrogen Halogenation of 3-R-1,2,4-triazine 1- and 2-oxides has been described.67, 84 The reaction of 3-methoxy and 3-amino(alkyla- mino)-1,2,4-triazine 1-oxides 100 with chlorine or bromine in CCl4 in the presence of triethylamine results in the corresponding 6-chloro- or 6-bromo-1,2,4-triazine 1-oxides 101.Halogenation of 3-methoxy- and 3-methyl(dimethyl)amino- 1,2,4-triazine 2-oxides 102 occurs in a similar way to give 6-halo- derivatives 103. c. Other reactions 1-(Dimethylamino)-1-ethoxyethylene acts as an electrophilic agent in the reactions with 1,2,4-triazine 4-oxides 104 and 105 containing a methyl group at position 5 and/or 6. The addition of an olefin to the methyl group followed by elimination of ethanol results in the corresponding (2-dimethylamino)-1-propenyl-1,2,4- triazine 4-oxides 106 and 107.85 The reactivity of the hydrogen atoms of the methyl group in 1,2,4-triazine 4-oxide 36 allows one to make this compound react with nitrobenzaldehydes.This reaction gave 3-[2-(R-nitrophenyl)- vinyl]-6-phenyl-1,2,4-triazine 4-oxides 108.76 The reaction of 3-hydrazino-1,2,4-triazine 1-oxides 109 with nitrous acid affords 3-azido-1,2,4-triazine 1-oxides 110.68, 84 4.Reactions with nucleophilic agents a. Nucleophilic substitution of readily leaving groups Substitution of nucleofugal groups is a widespread method for the modification of 1,2,4-triazine N-oxides. The reaction of 3-methoxy-5-phenyl-1,2,4-triazine 1-oxide 111 with ammonia afforded 3-amino-5-phenyl-1,2,4-triazine 1-oxide 112.The reac- tion of 3-methoxy-1,2,4-triazine 1-oxide 87 with hydrazine results in 3-hydrazino-1,2,4-triazine 1-oxide 113.14 R = H (a), Me (b). N N N+ O7 O R AcO(CH2)2O 89 OAc OCH2Cl N N N+ O7 O R HO(CH2)2O HCl MeOH 92a (21%) 92b (19%) 93a (94%) 93b (75%) 94 95 (50%) BrCH2CHO N N N+ O7 NH2 N N N+ O7 N 98 (90%) N N N+ O7 N N AcOCH(OEt)2 96 N N N+ NHNH2 O7 97 99 (70%) N N N N+ O7 N N N N N N+ NHNH2 O7 HC(OEt)3 X=Cl, Br; R=OMe, NH2, NHMe, NMe2. 100 101 N N N+ O7 R N N N+ O7 R X X2, NEt3 CCl4 X=Cl, Br; R=OMe, NHMe, NMe2. 102 103 N N+ N R O7 X2, NEt3 CCl4 N N+ N R X O7 104 N+ N N O7 Me Ph + OEt NMe2 N+ N N O7 Ph OEt Me2N Me 106 N+ N N O7 Ph NMe2 Me + 105 N+ N N O7 Me Me OEt NMe2 N+ N N O7 Me Me Me2N EtO 107 Me2N Me Me O7 N N N+ R=2-NO2 (27%), 3-NO2 (47%), 4-NO2 (48%).N+ N N O7 Ph Me 36 + CHO R 108 N+ N N O7 Ph R R=H (80%), Me(82%), Ph (85%). R 110 [HNO2] N N N+ O7 NHNH2 109 N N N+ O7 N3 R 111 112 (51%) N N N+ O7 OMe Ph N N N+ O7 NH2 Ph NH3 1,2,4-Triazine N-oxides and their annelated derivatives 6417-Methyl-1,2,4-benzotriazin-3(4H)-one 1-oxide 114 can be obtained in a good yield by replacement of the diazo group by OH in 3-diazo-7-methyl-1,2,4-benzotriazine 1-oxide 115, which is formed upon the reaction of the corresponding amino derivative 116 with nitrous acid.79 Similarly, diazotisation of 3-amino-1,2,4-triazine 2-oxides 117 or 1-oxides 118 results in the replacement of the diazo group by a halogen on treatment with hydrochloric or hydrobromic acids and affords the corresponding 2-oxides 119 10 or 1-oxides 120.69 In turn, the halogen atom can be replaced by a different functional group. 3-Methoxy-1,2,4-triazine 2-oxide 85 (R=H) was obtained by the reaction of 3-bromo-1,2,4-triazine 2-oxide 119 with sodium methoxide. When secondary amines are used as nucleophiles, 3-amino-derivatives of 1,2,4-triazine 2-oxides 121a ± e are formed. 3-Hydrazino-1,2,4-triazine 2-oxide Compound R1 NR22 Yield (%) Ref. 85 H 10 10 121a H 95 10 121b Me 90 10 121c H 93 10 121d H 95 10 121e H NMe2 93 10 122 H 69 10 123 H 27 10 124 H 86 68 122 was synthesised by the replacement of bromine in 2-oxide 119 by hydrazine. The subsequent oxidation of compound 122 with Mn(IV) oxide afforded 1,2,4-triazine 2-oxide 123,10 but the reaction of compound 119 with sodium azide gave 3-azido-1,2,4- triazine 2-oxide 124.68 Reactions of 3-chloro- or 3-methylthio-1,2,4-benzotriazine 1-oxides 125a,b with amines result in 3-amino-derivatives of 1,2,4-benzotriazine 1-oxides 126.24, 74, 86, 87 Replacement of the halogen in 3-chloro-1,2,4-benzotriazine 1-oxide 125a upon the reaction with methyl 2-(4-hydroxyphenoxy)propionate proceeds in a similar way.For example, compound 127 was synthesised by this method.88, 89 Replacement of chlorine in the 3-chloro-derivative 125a on treatment with sodium cyanide in methanol affords 3-methoxy- 1,2,4-benzotriazine 1-oxide 128.90 b.Nucleophilic substitution of hydrogen The mechanism of the nucleophilic substitution of hydrogen (SNH) in 1,2,4-triazine N-oxides has been studied in most detail using 1,2,4-triazine 4-oxides 29 as an example.This mechanism is common to all 1,2,4-triazine 4-oxides. The reactions of nucleo- philic substitution of hydrogen in 4-oxides 29 occur according to the `addition ± elimination' scheme; the process can stop at the step of addition to form adducts 129. Due to the low probability of the elimination of such a particle as a hydride ion,91 aromatisation of these adducts can follow several paths.Oxidative aromatisation leads to products of the SNH-reac- tion of the type 130 [Scheme 1, pathway (a)]. Auto-aromatisation of the sH-adducts in two directions is also possible. For example, 87 113 (94%) NH2NH2 N N N+ O7 OMe N N N+ O7 NHNH2 116 115 N N N+ O7 NH2 Me N N N+ O7 Ná2 Me H2O [HNO2] 114 (88%) N N N+ O7 Me O H N N+ N R O7 NH2 N N+ N R O7 X HX, [HNO2] NH3,MeOH 117 119 X=Cl: R=H (34%), Me (32%), Ph (26%); X=Br, R=H (47%).R1, R2=H, Me. NaNO2 HBr 118 N N N+ O7 NH2 R1 R2 120 (30% ± 35%) N N N+ O7 Br R1 R2 R1=H, Me; X=Br. 85 N N+ N R1 O7 OMe N N+ N R1 O7 N3 124 MnO2 N N+ N R1 O7 NH NH2 122 123 N N+ N R1 O7 MeONa HNR22 NH2NH2 NaN3 N N+ N R1 O7 NR22 121a ± e N N+ N R1 O7 X 119 N N N O N X =Cl (a), SMe (b). 125a,b 126 HNR1R2 N N N+ X O7 N N N+ NR1R2 O7 125a + K2CO3 HO O CO2Me Me 127 N N N+ O O7 O CO2Me Me 125a N N N+ Cl O7 NaCN MeOH 128 (49%) N N N+ OMe O7 642 D N Kozhevnikov, V L Rusinov, O N Chupakhin1,2-elimination of HX is possible in nucleophiles carrying a vicarious nucleofugal group X. In this case, a hydrogen atom is eliminated from the substrate and the X group is eliminated from the reactive fragment of the sH-adduct 131 [Scheme 1, path- way (b)].Makosza 92 named such reactions vicarious nucleophilic substitution. Another variant of auto-aromatisation is the elimination of the HOE molecule from the sH-adduct 129 which is formed from the cationic derivatives of 1,2,4-triazine N-oxides [Scheme 1, pathway (c)]. In this case, SNH-substitution is accompanied by the loss of an oxygen atom.It should be noted that both the hydrogen atom and the vicarious OE group are eliminated from the substrate fragment of the intermediate. Conceptually, medi- ated (vicarious) nucleophilic substitution of hydrogen atom is observed in this case. Sometimes, the sH-adducts exist in a non- cyclic form. The ring opens readily after the addition of a nucleophile to the 1,2,4-triazine 4-oxide.This process is reversible and the equilibrium is shifted towards the open form 132 [Scheme 1, pathway (d)]. In this way, the sH-adduct is eliminated from the reaction; however, it exists in quasi-steady-state concen- trations and can be easy oxidised to the corresponding 1,2,4- triazine 4-oxide. Oxidative aromatisation [see Scheme 1, path (a)] is achieved by the amination of 6-phenyl-1,2,4-triazine 4-oxide 133 with liquid ammonia in the presence of potassium permanganate as the oxidising agent.The reaction affords 5-amino-6-phenyl-1,2,4- triazine 4-oxide 134.93 The reaction of 6-aryl-1,2,4-triazine 4-oxides 135 with phenol, 2,6-dimethylphenol, resorcinol and phenetol in the presence of trifluoroacetic acid results in stable sH-adducts, 6-aryl-2,4-dihy- dro-4-hydroxy-5-Nu-1,2,4-triazines 136 (Nu=2-hydroxy-, 2-ethoxy-, 4-ethoxy- or 2,4-dihydroxyphenyl).The reaction of resorcinol (R2=R4=OH, R3=R5=H) with a twofold excess of triazine N-oxide 135 (R1=H, Ar=Ph) affords 4,6-bis(4- hydroxy-6-phenyl-1,2,4-triazin-5-yl)resorcinol 137.94 The formation of sH-adducts in SNH-reactions of azine N-oxides was confirmed directly for the first time by the isolation and identification of compounds 136.Before that, it was only postulated in the discussions of the mechanism of such reactions. Dihydro-1,2,4-triazines 136 are rather stable compounds. Boiling in butanol, DMF, or trifluoroacetic acid does not result in their thermal dehydration [see Scheme 1, pathway (c)]. At the same time, their oxidative aromatisation [pathway (b)] occurs readily and in high yields. For example, compounds 136 react with potassium permanganate in acetone to form 6-aryl-5-(4-hydrox- yphenyl)-1,2,4-triazine 4-oxides 138.94 3-R1-6-phenyl-1,2,4-triazine 4-oxides 49 react with indole or its 1- or 2-methyl derivatives in a similar way.When the reaction is carried out in the presence of trifluoroacetic acid, stable 4-hydroxy-5-(indol-3-yl)-6-phenyl-4,5-dihydro-1,2,4-triazines are formed.62 They were isolated both as trifluoroacetates 139 and as free bases 140.Oxidative aromatisation of the sH-adducts obtained with potassium permanganate in acetone affords 3-R1- 5-(indol-3-yl)-6-phenyl-1,2,4-triazine 4-oxides 141.62 NH3 KMnO4 133 N+ N O7 Ph N 134 N+ N N O7 Ph H2N Ar=Ph, p-ClC6H4; R1=H, Me; R2, R3, R4, R5=H, OH, OEt. 136 (70% ± 90%) 138 (60% ± 70%) + N N N R2 R3 R4 R5 Ar R1 O7 KMnO4 Me2CO N N N R2 R3 R4 R5 Ar H OH R1 135 + N+ N R1 O7 Ar N R2 R3 R4 R5 CF3CO2H 135+136 137 (95%) CF3CO2H N N N N N N OH OH HO HO H H Ph Ph 139 (70% ± 95%) 49 N+ N N Ph O7 R1 IndH CF3CO2H [B] 140 (70% ± 90%) N N N Ph R1 H Ind OH N N N Ph R1 Ind H . CF3CO2H OH E=H, COR4.EX N N N H Nu OH R1 N N N Nu R1 N N N Nu H OE 129 R1 [O] a c 7HOE N+ N N O7 Nu 130 R1 NuH 7HX E=H 131 29 N+ N N O7 R1 R2R3CHX N N N OH H X R2 R3 R1 7HX b N+ N N O7 R2 R3 R1 X7 N+ N N OE R1 N+ N N O7 Nu 132 N N N OH H Nu R1 [O] d R1 Scheme 1 1,2,4-Triazine N-oxides and their annelated derivatives 643The reaction of 3-methoxy-1,2,4-triazine 1-oxide 87 with chloromethyl phenyl sulfone gives an intermediate adduct, whose further aromatisation [see Scheme 1, path (b)] leads to 3-methoxy-5-(phenylsulfonyl)-1,2,4-triazine 1-oxide 142 in 70% yield.95 Another variant of auto-aromatisation occurs in the reaction of 3-amino-1,2,4-triazine 2-oxides 143 with alcohols in the pres- ence of HCl or acetyl chloride.Elimination of water or acetic acid from the adduct 144 results in 3-amino-6-alkoxy-1,2,4-triazines 145a ± e.84 It should be noted that 1,2,4-triazine 1-oxides do not react with alcohols under these conditions.84 6-Chloro(bromo)-3-amino-1,2,4-triazines 146a ± f were obtained on passing gaseous hydrogen chloride or hydrogen bromide through a solution of 3-amino-1,2,4-triazine 2-oxide 143.67 Compound R1 R2O X Yield (%) Ref. 145a NH2 OMe 71 84 145b NH2 OEt 64 84 145c NHMe OMe 50 84 145d NMe2 OMe 51 84 145e NH2 OPri 65 84 146a NHMe Cl 85 68 146b NMe2 Cl 64 67 146c Cl 80 67 146d Cl 50 67 146e NHMe Br 25 67 146f NMe2 Br 41 67 Acyl salts of 1,2,4-triazine 4-oxides 147 synthesised by the reaction of benzoyl chloride with the corresponding 1,2,4-triazine 4-oxides 148 react with water according to pathway (c) (Scheme 1).It is evident that after addition of the nucleophile at position 5 of the triazine ring, auto-aromatisation of the adduct occurs with elimination of benzoic acid and formation of 1,2,4- triazin-5-ones 149.76 The reaction of 1,2,4-triazine 4-oxides 49 with acetone cyano- hydrin in the presence of triethylamine affords 5-cyano-1,2,4- triazines 150.96 If potassium cyanide in alcohols (ethanol, propanol, isopro- panol) is used as a cyanating agent, 5-alkoxy-1,2,4-triazines 151 are formed in 80%± 90% yields. Their formation can be explained by replacement of the cyano group by an alkoxide. In fact, 5-cyano-1,2,4-triazines 152 slowly react with ethanol at room temperature to give 3-R1-6-phenyl-5-ethoxy-1,2,4-triazines 151.96 The reaction of 1,2,4-triazine 4-oxide 153 with indole or 2-methylindole in boiling butanol in the presence of trifluoro- acetic acid is accompanied by auto-aromatisation of the products of addition of the nucleophile to the 1,2,4-triazine 4- oxide and results in 5-(indol-3-yl)- and 5-(2-methylindol-3-yl)-3,6-diphenyl- 1,2,4-triazines 154.97 KMnO4 139 140 N+ N N Ph O7 R1 Ind 141 (55%785%) R1 =H, Me, Et, Ph; Ind= ; R2, R3=H, Me.N R3 R2 ClCH2SO2Ph 7HCl N N N+ OMe O7 87 N N N+ OMe O7 H Cl PhO2S N N N+ OMe O7 PhO2S 142 EX 144 X7 N N+ N R1 OE 143 N N+ N R1 O7 R2OH 7HCl, 7EOH 7HCl, 7H2O HX 146a ± f N N N R1 X 145a ± e N N N R1 R2O R2=Me, Et, Pri. O; E=H, Ac; X=Cl, Br; R1=NH2, NHMe, NMe2, N , N O N N R1, R2=H, Me, Et. 147 148 N+ N N R2 R1 O7 BzCl N+ N N R2 R1 OBz Cl7 H2O N N N R2 R1 H O 149 7BzOH N N N R2 R1 OBz H HO R=H, Me, Ph.NEt3 Me Me CN + HO N N N R Ph O7 NC H N+ N N R Ph O7 49 150 (80% ± 90%) 7OH7 N N N R Ph NC 7 N N N R Ph OH NC R1=H, Me, Ph; R2=Et, Pri. N N N R1 Ph R2O 151 49 N+ N N R1 Ph O7 152 N N N R1 Ph NC R2OH KCN EtOH R=H (30%), R=Me (55%). + HN R N+ N N Ph Ph O7 153 BuOH, 117 8C CF3CO2H N N N HN Ph Ph 154 R 644 D N Kozhevnikov, V L Rusinov, O N ChupakhinThe reaction of 6-aryl-1,2,4-triazine 4-oxides 155 with dialkyl- amines or cycloalkylamines occurs by pathway (d) (Scheme 1).98 The adducts 155a, which are in equilibrium with the open-chain form, N,N-disubstituted 3-aryl-1,4,5-triaza-1,3,5-hexatrien-1-ols 155b, are formed in the first step.In this case, the equilibrium is shifted towards the compounds 155b. In spite of the low concen- tration of the form 155a, oxidation of the compounds 155 with potassium permanganate in solution affords 3-amino-6-aryl- 1,2,4-triazine 4-oxides 156. It is noteworthy that it is possible to withdraw the cyclic tautomer from the reaction zone, which allows one to obtain the products of hydrogen substitution at position 3 of the triazine system when the position 5 is free.Such a substitution has been carried out for the first time. Note that all the experimental data obtained until now have indicated that position 5 is the most reactive in 1,2,4-triazines and their oxides.5±8 c. Reaction of 1,2,4-triazine N-oxides with nucleophiles accompanied by destruction of the ring In addition to the formation of nucleophilic substitution products, the reaction of 1,2,4-triazine N-oxides with nucleophiles results in the opening, narrowing, or fragmentation of the 1,2,4-triazine ring.For example, the reaction of 3-methyl-1,2,4-benzotriazine 1-oxide 16b with phenylmagnesium bromide affords 2-phenyl- azoacetanilide 157.99 The reaction of fervenulin 1-oxides 158 with secondary amines results in narrowing of the triazine ring and formation of 2-amino- 5,7-dimethylimidazo[4,5-e]pyrimidine-4,6(5H,7H)-diones 159.The reaction of the same N-oxide with ammonia affords 1,3- dimethyl-5-imino-6-isonitrosouracil 160.100 1,2,4-Triazine 4-oxides undergo hydrolysis both in acidic and basic media. For example, in the presence of 2MKOH, opening of the triazine ring in 1,2,4-triazine 4-oxides 29 occurs with the formation of N0-(2-hydroxyiminoethylidene)hydrazides of car- boxylic acids 161.Hydrolysis of the 4-oxides 29 in acid media results in narrowing of the 1,2,4-triazine ring to 1,2,3-triazole, in particular, in the formation of the compound 162.76 The reaction of fervenulin 4-oxide 47a with hydrogen chloride in ethanolic solution leads to the opening of the triazine ring and the formation of 1,3-dimethyl-5-nitroso-6-hydrazouracil 48.In fact, this reaction is reverse to that for the synthesis of the fervenulin 4-oxide.40, 101 Reactions of the fervenulin 4-oxide 47a with CH-active compounds are also accompanied by the destruction of the triazine ring. In this case, 1,3-dimethyl-5-nitroso-6-(N0-ethen-1-ylhydr- azino)uracils 163 are formed.102 Fervenulin 4-oxide 47a reacts with amines or indoles in a similar way.The nucleophilic attack is accompanied by opening of the 1,2,4-triazine ring and formation of 6-aminomethylenehydrazino-1,3-dimethyl-5-nitrosouracil 164 103 or 1,3-dimethyl-5-nitroso-6-[N0-(indol-3-yl)methylidene- hydrazino]uracil 165.104, 105 The reaction of 3,6-diphenyl-1,2,4-triazine 4-oxide 153 with benzoylacetone under basic catalysis conditions (DMSO, NEt3) affords 1,2,4-triazine 166 in 9% yield and bis(1,2,4-triazin-5- ylmethane) 167.97 According to literature data,97 the 1,3-di- methyluracil derivative 168 with two reactive centres reacts with the N-oxide 153 at the uracil fragment only to form compound 169.NR2=NMe2, NEt2, N , N , N NH, N O; Ar=Ph, p-ClC6H4. N+ N N Ar O7 156 (40% ± 60%) KMnO4 155 N+ N N Ar O7 HNR2 155a N N N Ar OH H NR2 N Ar OH 155b N N NR2 NR2 16b PhMgBr N N N+ O7 Me 157 (20%) N N NPh COMe H 159 HNR1R2 NH3 N N N+ N N O7 Me Me O O 158 N N N N Me Me O O H NR1R2 N N Me Me O O NOH NH 160 161 N N N Ph H 162 N+ N N R1 R2 R3 O7 29 H2O B H+ H2O N N N R1 R2 OH H O R3 HCl EtOH 48 NO NHNH2 N N Me Me O O N+ N N N N Me Me O O O7 47a X, Y=CO2Et, COMe; X=NO2, Y = CO2Et. N+ N N N N Me Me O O O7 47a NO N N N Me Me O O NH H Y X 163 NO N N N Me Me O O N H NH 165 NO N N N Me Me O O N H NR1R2 164 HNR1R2 HCl HN XCH2Y + N+ N N O7 Ph 153 Ph O Ph Me O 1,2,4-Triazine N-oxides and their annelated derivatives 6455. Reactions with dienophiles The direction of the reaction of 1,2,4-triazine N-oxides with dienophiles differs substantially from that for 1,2,4-triazines. 1,2,4-Triazine 4-oxides 147 act as 1,3-dienes only in the reaction with N,N-diethyl-N-(1-propynyl)amine giving 2-R2-5-methyl-4- (dimethylamino)pyrimidines 170.The reaction of these 1,2,4- triazine 4-oxides with 1-(dimethylamino)-1-ethoxyethylene occurs as 1,3-dipolar cycloaddition to produce the corresponding 5-methyl-1,2,4-triazines 171.85 The reaction of the fervenulin 4-oxide 47a, which is not substituted at position 3, with dimethyl acetylenedicarboxylate in various solvents affords compounds 172 ± 174.If methyl propionate is used as the reagent, 6-formyl- 7-(methoxycarbonyl)-1,3-dimethylpyrrolo[3,2-d ]pyrimi- dine-2,4(1H,3H)-dione 175 is formed. A similar reaction of 3-substituted fervenulin 4-oxides 47 (R=Me, Et, Ph) with alkyl acetylenecarboxylates gives com- pounds 176.The reaction of fervenulin 4-oxides 47 with ethyl phenyl- propionate also follows the pathway described above to give, depending on the presence of a substituent at position 3, 6-ben- zoyl- or 6-R-5-benzoyl-7-(ethoxycarbonyl)-1,3-dimethylpyr- rolo[3,2-d]pyrimidine-2,4(1H,3H)-diones 177 and 178, respectively.106, 107 V. 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H Neunhoeffer, in Comprehensive Heterocyclic Chemistry Vol. 3 (New York: Pergamon Press, 1984) p. 385 166 (9%) + 167 (10%) N N N N N N Ph Ph Ph Ph PhOC Ph Ph H N N N 153+ N N O Me O Me N N N N Ph Ph H HN COEt Me 169 N N O Me O Me N N H Me COEt 168 N+ N N O7 R2 R1 147 N N N+ O7 Et2N R1 Me R2 + NEt2 Me N N R2 Me NEt2 170 (35% ± 42%) 171 (47% ± 80%) N N R2 R1 Me N 147+ 7Me2NCO2Et N N R2 R1 O Me2N OEt N NMe2 OEt 172 174 N CO2Me H N COCO2Me CO2Me H 173 N CO2Me CO2Me H C6H5Me (abs.) A EtOH (abs.) A C6H5Me A 47a N+ N N N N Me O Me O O7 47a N+ N N N N Me O Me O O7 C6H5Me (abs.) B 175 N CHO CO2Me H 176 N CO2Me H R A, C6H5Me or B, C6H5Me (abs.) MeO2CC CCO2Me;B�MeO2CC CH.A� 47 N+ N N N N Me O Me O O7 R 47 EtO2CC CPh R=H R=H N N O Me O Me N H CO2Et Bz 177 N N O Me O Me N CO2Et R Bz 178 646 D N Kozhevnikov, V L Rusinov, O N Chupakhin7. H Neunhoeffer, in Comprehensive Heterocyclic Chemistry II Vol. 6 (New York: Pergamon Press, 1996) p. 507 8. 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ISSN:0036-021X    

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Abstract. Data on the interaction of natural carbohydrates (mono-, oligo-, and poly-saccharides, amino sugars, and natural organic acids of carbohydrate origin) with metal cations are surveyed and described systematically. The structural diversity of carbohydrate metal complexes, caused by some specific featu- res of carbohydrates as ligands, is demonstrated. The influence of complex formation on the chemical properties of carbohydrates is discussed.It is shown that the formation of metal complexes plays an important role in the configurational and conformational analysis of carbohydrates. The practical significance of the coordination interaction in the series of carbohydrate ligands is demonstrated. The bibliography includes 571 references. I. Introduction Metal complexes of natural carbohydrates have been attracting interest for many years because these compounds participate in vitally important processes; they are used for configurational and conformational analysis, determination, and separation of sugars.According to our estimates, at least 1000 studies discussing various aspects of complex formation between metal ions and natural carbohydrates (mono-, oligo-, and polysaccharides, amino sugars, their polymers, carbohydrate carboxylic acids, natural organic acids of the carbohydrate origin, and cyclic and acyclic polyols) have been published.2 However, even the most comprehensive monographs dealing with the chemistry of coordi- nation compounds 1 or carbohydrates 2 do not consider carbohy- drates to be ligands.Several reviews published to date 3± 16 cover only some aspects of this topic.The purpose of this review is to survey as fully as possible the published data on the known complexes of natural carbohydrates with metal cations; therefore it includes both recent studies and the most important of early studies. The formation of complexes by nucleosides and nucleotides is beyond the scope of the review, because the carbohydrate fragments of these molecules normally do not participate in the coordination of metals.Moreover, this aspect has been the subject of numerous reviews and monographs (see, for example, Refs 17, 18). The few known examples in which the carbohydrate fragments of nucleotides and nucleosides are involved in the formation of complexes with metals are presented in Section IV.Data on the formation of metal complexes in the series of natural carbohydrates are mainly discussed in relation to reliably established structures. The information is classified according to the type of carbohydrates. Within each type, metal cations are arranged in accordance with their electronic configuration (s-, p-, d-, and f-metals) and their position in the Mendeleev Periodic Table.II. Complexes of mono-, oligo-, and poly- saccharides and their derivatives 1. Ionic complexes with s-metal cations The first review 6 on the complexation of carbohydrates with s-metal compounds was published in 1966, and now it is only of historical interest. X-Ray diffraction data for metal complexes of this type can be found in a number of reviews (see, for example, Refs 19 ± 23) including a review devoted to saccharose.24 The data on the structures of solid ionic metal complexes obtained up to the middle of 1978 are surveyed most fully in the review by Poonia and Bajai.11 A systematic study of the structures of complexes of monosaccharides with s-metal cations in aqueous solutions carried out by Angyal 7, 8, 12 has demonstrated that complexes of 1 : 1 composition predominate.In the case of cyclic forms of ligands, the most stable complexes are those with the axial ± equatorial ± axial orientation of three consecutively located hydroxyl groups in the ligand (complex 1a, the first Angyal rule) or those with the energetically unfavourable triaxial orientation of these groups (complex 1b, the second Angyal rule).Acyclic derivatives obey the first Angyal rule (complex 2), while furanoses obey the second rule (complex 3 with a quasiaxial orientation of the hydroxyl groups). These rules were derived using 1H NMR spectroscopy, i.e. they were first formulated for relatively con- Yu E Alekseev, A D Garnovskii Research Institute of Physical and Organic Chemistry, Rostov State University, prosp.Stachki 194/2, 344104 Rostov-on-Don, Russian Federation. Fax (7-863) 228 56 67. Tel (7-863) 228 56 00 (Yu E Alekseev). Tel. (7-863) 228 56 00. E-mail: garn@ipoc.rnd.runnet.ru (A D Garnovskii) Yu A Zhdanov Rostov State University, prosp. Stachki 194/2, 344104 Rostov-on-Don, Russian Federation. Fax (7-863) 228 56 67. Tel. (7-863) 265 04 77 Received 9 June 1997 Uspekhi Khimii 67 (8) 723 ± 744 (1998); translated by Z P Bobkova UDC 541.49+542.97 : 547.454 Complexes of natural carbohydrates with metal cations Yu E Alekseev, A D Garnovskii, Yu A Zhdanov Contents I.Introduction 649 II. Complexes of mono-, oligo-, and poly-saccharides and their derivatives 649 III. Complexes of cyclodextrins 656 IV. Complexes of nitrogen-containing natural carbohydrates 657 V.Complexes of natural acids of the carbohydrate origin 659 VI. The significance and applications of metal coordination to carbohydrates 660 VII. Conclusion 663 Russian Chemical Reviews 67 (8) 649 ± 669 (1998) #1998 Russian Academy of Sciences and Turpion Ltdcentrated solutions. Their validity for dilute solutions was confir- med later by calorimetry.25 Complex formation can shift the position of a tautomeric or conformational equilibrium for a ligand in an aqueous solu- tion.7, 8, 12 The stability constants of the complexes are relatively low (0.1 ± 6.0).7, 8, 12, 16, 26 ± 30 The ability of s-metals to form complexes with disaccharides is less pronounced than that for monosaccharides.31, 32 Evidently, this is due to the higher confor- mation rigidity of the former.The stability constants of s-metal complexes of monosaccharide carboxylic acids are only an order of magnitude larger.33 ± 35 Thus, this complexation is very weak although fairly stereospecific. In solvents that are less polar than water (methanol, acetone, dioxane), these complexes are more stable because there are no water molecules to compete with the ligands for coordination to metal cations.36 The formation of these ionic metal complexes is usually regarded 7, 11 as consecutive substitution of water molecules in the hydration shell of a metal ion by hydroxyl groups of the ligand, the optimum number of these groups (three) being determined by the Angyal rules.During the formation of solid complexes, this process is continued with participation of other ligand molecules, but does not go to completion.The data for a number of solid complexes of sugars with s-metal salts obtained by X-ray diffrac- tion analysis 10, 15, 37 ± 45 and by IR spectroscopy 46 ± 53 permit the following general conclusions. 1. Carbohydrates act most often as bidentate ligands coordi- nated through vicinal diol fragments, which can be different in identical ligands.In some cases, the formation of a complex ends with incorporation of a monodentate ligand.38, 54 Complexes of acyclic aldonic acids can contain only monodentate ligands.55, 56 2. Since there are only three known examples 57 ± 59 of triden- tate coordination of cyclic ligands conforming to the first Angyal rule, one can conclude that this rule is not necessary for solid ionic metal complexes of sugars.At the same time, sugars containing no vicinal hydroxyl groups characterised by an axial ± equatorial ± axial arrangement (a-D-glucopyranose 4a) do not form complexes of this type.11 3. As a rule, these complexes are crystal hydrates in which all water molecules are coordinated to metal ions. 4. The complexes normally contain two or three ligands, although in some cases they contain only one ligand.60, 61 In the case of acyclic carbohydrate derivatives, the number of ligands increases to four 62, 63 or even to six.55, 56 The number of ligands in less studied disaccharide complexes is two 44, 64 ± 67 or one.68 5.After complexation, the coordination number of the metal remains approximately the same as that in the first coordination sphere of the initial hydration shell of the metal cation; most frequently it is equal to eight (square antiprism), six (octahedron), seven (pentagonal bipyramid), or nine (three-cap trigonal prism).13 The coordination polyhedra formed by calcium(II) ions are especially diverse.39 6.In the majority of complexes of carbohydrate carboxylic acids, a metal ion is coordinated to an oxygen atom of the carboxyl group and to the hydroxyl group in the a-position (a-type coordination 69).Only in complexes with these ligands, can the ring oxygen atom be involved in coordination.70 7. Conformational changes in the ligand following the com- plex formation are typical of neutral carbohydrates and normally reduce to the change in the conformation of the coordinated primary hydroxyl group 44 or in the dihedral angle between the coordinated vicinal hydroxyl groups.11 In anionic ligands, coor- dination mostly involves the carboxyl group; this substantially decreases electrostatic interactions between the hydroxyl groups responsible for the conformational changes.11, 64 8.The cation and the anion of the metal salt are coordinated separately and, thus, they are relatively far removed from each other.There is only one known example 45 of formation of a complex in which a salt occurs as a contact ion pair. 9. The majority of the complexes studied are calcium com- pounds, while the smallest number is represented by magnesium compounds. The particular affinity for calcium is apparently a fundamental property of carbohydrates.11, 39 As regards polysaccharides, complexes of neutral polysaccha- rides with s-metal cations have been relatively little studied to date.Judging by X-ray diffraction data, the K+ and Br7 ions in the complex of potassium bromide with amylose (a polymer of a-1,4-linked a-D-glucopyranose 4a) are coordinated alternately in the cavity of the helix-like polymer chain.71 It has been noted72 that cellulose (a polymer of b-1,4-linked b-D-glucopyranose 4b) only weakly binds Ca2+ ions.It was established unambiguously 73 that reaction of cellulose with alkali metal hydroxides gives inclusion compounds containing metal ions between the planes of the cellulose crystal lattice rather than the corresponding alkoxides.74 The formation of alkoxides was denied even for monosaccharides 75 and disaccharides;75, 76 in these cases, the formation of adducts of the type RO+H(M)OH7 stabilised by hydrogen bonds between the neighbouring hydroxyl groups was postulated.A more detailed study 77 has been devoted to the formation of complexes of s-metal cations with a number of anionic polysacc- harides, first of all, with pectate 5 (a-1,4-linked poly-a-D-galacto- pyranosuronate), alginate 6 (a polymer consisting of a-1,4-linked disaccharides formed by the a-L-gulopyranosuronic and b-D- mannopyranosuronic acid residues), and with carrageenans (poly- saccharides containing 3-substituted residues of b-D-galactose and 4-substituted residues of a-D-galactose or 3,6-anhydro-a-D- galactose sulfated at different OH groups).Studies on this type of compounds have been stimulated by the fact that they form stable gels in the presence of s-metal salts.77 Study of the complex formation with metals in these poly- electrolytes is complicated by the presence of two types of binding: territorial (non-specific) binding involving hydrated counter-ions, and site (specific) binding involving non-hydrated counter-ions.78 The latter type of binding corresponds apparently to the forma- tion of a complex with a metal cation on the polyanion surface.At a definite concentration of counter-ions, a stereoregular anionic polysaccharide, for example, carrageenan, acquires a helical conformation.77, 79 In the case of gel formation, s-metal cations are coordinated between the chains; this yields domains consisting of double or even triple helices.79 Some researchers suggest that only single helices participate in intermolecular complex forma- tion.80 However, it is generally believed that cross-linking of two adjacent chains according to the `egg box' pattern (Fig. 1a) is the primary process. 3 OH O OH OH Mz+ X=O, CHOH; z=1, 2. 1a 1b 2 OH X OH HO Mz+ X OH HO HO Mz+ OH OH HO Mz+ 6 7 7 O2C OH O2C OH O O O HO OH O n 4a: R1=H, R2=OH; 4b: R1=OH, R2=H O R1 R2 HO HO HO OH 5 n O HO CO72 HO O 650 Yu E Alekseev, A D Garnovskii, Yu A ZhdanovThis model was proposed to interpret the gel formation by poly-L-guluronate in the presence of Ca2+ ions.81, 82 Later it was confirmed for systems comprising Ca2+ and polygalacturonate 5 83, 84 or Na+ and alginate 6.85 Intramolecular complexation occurs upon the formation of a hydrophilic cavity between mono- meric units of neighbouring chains (Fig. 1b).86, 87 The formation of these cavities can account for the more efficient binding of Ca2+ cations by poly-L-guluronate 5 87, 88 and also for the preferred binding of K+ and Rb+ cations by carrageenans.89, 90 2. Complexes with p-metal cations Borate complexes of carbohydrates are the most studied com- pounds in this series.They constituted the subject of early classical studies of BoÈ eseken 3 carried out by measuring the electrical conductivity of solutions. Later, the results of this study were supplemented by the data of 1H (Ref. 91), 13C (Ref. 92), and 11B (Refs 93 ± 95)NMRspectroscopy. This resulted in the detection of neutral complexes 7 (which predominate in acidic media), 92, 94 anionic monomeric complexes with five- (8)94 and six-membered (9)94, 95 rings, and anionic dimeric complexes 10 94 of boric acid with polyhydroxyl compounds.All these products are complexes formed by vicinal hydroxyl groups; nevertheless, complexes of the type 1b are the most stable in conformity with the second Angyal rule.91, 92, 95, 96 High stabi- lity constants (10 3 ± 106 litre mol71) 97 ± 99 imply a covalent character of these complexes; however, they have not been iso- lated in the crystalline state.Calorimetric, 100 titrimetric,101 and polarimetric 102 studies have not provided evidence for the exis- tence of the complexes of type 10. However, they were detected in 11B NMR studies.94, 95 Borate complexes of acyclic polyols of type 11a can be additionally stabilised owing to the formation of intramolecular hydrogen bonds.This accounts 103 for the higher stability of these complexes compared to the complexes formed by cyclic forms of sugars. In aqueous solutions in the presence of borate ions, aldonic and aldaric acids2 tend to form complexes with Ca2+ ions of the composition CaBL2 (L is the ligand).This synergism, which is relatively uncommon in the coordination chemistry of carbo- hydrates, has been explained 104 by assuming that the preliminary binding of borate ions makes carboxyl groups approach each other, which facilitates the formation of complexes 11b. The complexation of sugars with other Group IIIA cations has not received much study.Neutral non-hydrolysable comple- xes of GaIII with monosaccharide carboxylic acids such as D-glu- caric acid (LH6 , 12) of variable composition have been synthesised.105 Complexes of InIII with D-glucaric acid 12 of the type [InLH72]+, [InLH73]0, and [InLH74]7 were detected (the negative numerals in the subscripts denote the number of substi- tuted hydrogen atoms).106 The results of a study of complexation of the acid 12 with AlIII and GaIII ions carried out by electropho- resis have been interpreted 107 in terms of an equilibrium between monomer 13a and dimer 13b, only carboxyl groups of the ligands being involved in the coordination.The complex formation of sugars with Group IVA cations is also little studied. It has been noted 108, 109 that germanic acid forms complexes of the composition [Ge(LH72)2OH]7 and [Ge(LH73)2]27 with acyclic polyols and with a,b-D-gluco- pyranose 4a,b and also 1 : 1 complexes with pentoses.98 Note that in the latter case, the first Angyal rule holds. One publication 110 describes the formation of 1 : 1 complexes of aldoses and ketoses with hexahydrostannate at high pH values.The complexation of sugars with PbII has been studied somewhat more comprehensively.It has been shown 111 that pentoses and their glycosides form complexes of the composition PbL and PbL2 . However, other researchers 112 claim that only the former type of complexes exists. D-Xylaric acid reacts with PbII in an acidic medium to give the complex PbLH72 as a result of deprotonation of the carboxyl groups.113 In alkaline media, this complex is hydrolysed giving a hydroxo complex.113 D-Gluconic acid 14a in an acidic medium binds PbII only as a monodentate ligand by the carboxyl group; this gives the complexes [PbLH71]+ and [Pb(LH71)2]. 114 In an alkaline medium, [Pb(OH)3]7 reacts with D-gluconic acid 14a to afford complexes 15 ± 17.115 In solid lead D-gluconate, the metal coordinates two monodentate gluconate residues through the carboxyl groups and two bidentate gluconate residues through the carboxyl group and the hydroxyl group at C(2) (a-type coordination 69). 116 Thus, the Pb2+ cation is surrounded by six oxygen atoms. Evidently, aldaric acids bind PbII more strongly than aldonic acids.117 7 8 9 10 O B O OH O B7 O OH OH O B7 O OH OH O B7 O O O 12 CO2H OH HO OH OH CO2H 11a 11b 7 O OH O B OH OH O O O O B O O OH HO O O Ca2+ H H M=Al, Ga. 13a 13b 47 L L M O O M L L 27 M OH2 OH2 L L 14a: R=H (LH6); 14b: R=COCH2NMe2 (LH5) 14a,b CO2R OH HO OH OH OR 17 7 7 OH O O HO O O Pb Pb O O O OH HO OH OH O 15 16 7 7 OH O O HO O O Pb Pb OH OH O 7 O OH HO OH CO2H O Pb OH Ca2+ Ca2+ Ca2+ a b 7 H H CO72 O CO72 O O O O O O Ca2+ O O O O O O CO72 O O2C H H Figure 1.Formation of the intermolecular complex of a polysaccharide with calcium ions. Complexes of natural carbohydrates with metal cations 651It has been noted 118, 119 that PbII complexes with oligomeric fragments of the pectate 5 are covalent compounds. In all probability, they contain two carboxyl groups per one Pb2+ cation; apparently, this accounts for the high selectivity of formation of PbII complexes with pectin.120 The formation of PbII complexes with pectin can also occur with incorporation between polymer chains.121 The complexation of sugars with Group VA elements is little studied.The formation of complexes of monosaccharides and polyols with AsIII and AsV of the composition [AsV(LH72)3]7, [AsIII(LH72)(OH)2]7, and [HAsIII(LH72)(OH)2] has been repor- ted.109, 122 Recently the BiIII complex with L-tartaric acid 18 has been studied by X-ray diffraction analysis.123 The composi- tion of this complex was found to be Bi[O2C(CHOH)2- CO2][O2C(CHOH)2CO2H]. 3H2O. In this complex, two dicarboxylate ligands are coordinated by the carboxyl and a- hydroxyl groups (a-type coordination 69) and one monocarboxy- late ligand is coordinated by the two oxygen atoms of the carboxylate ion.The coordination number of BiIII is equal to nine due to the additional coordination of three water molecules. Complexes of monosaccharides with telluric acid (TeVI) pro- vide an example of complexes obtained for Group VIA elements. For these compounds, structure 19 was proposed.124, 125 It was found 126 that in addition to the 1 : 1 complex, saccharose forms the complex L(TeO4)4 .Complex formation with Group VIIA elements has been studied only for iodine. Apparently, this is due to the fact that periodate oxidation is an important process in the chemistry of carbohydrates.2 It was suggested 2 that this process starts with the formation of an unstable complex of the IO¡4 anion with a vicinal diol group; the structure of this complex is similar to that of the tellurate complex 19, because the sizes of the corresponding ions are close. However, monosaccharides conforming to the first Angyal rule should form 127 stable complexes with periodate, for example, a complex of type 20.Later, both the fact of formation of the intermediate com- plexes and the observance of the first Angyal rule have been confirmed byNMRspectroscopy 127 and paper electrophoresis.128 3.Complexes with d- and f-metal cations This field of coordination chemistry of carbohydrates has been studied in the greatest detail, although quite irregularly. The vast majority of the data refer to complexes of carbohydrates with Cu, Fe, Co, Ni, Mo, and W. Among complexes with Group IB metal cations, those with Cu2+ have received most study.The dissolution of freshly prepared copper hydroxide in ammonia-containing or alkaline aqueous solutions of polyhydroxyl compounds, including carbo- hydrates, which has long been used in analytical chemistry, was interpreted 129 as the formation of five-membered diolate com- plexes 21. The stability constants of these complexes for L = NH3 are of the order of 102± 104 litre mol71.In thiscase,complexes of the 1 : 1 composition are always for- med.129 ± 131 The assumption 132± 134 that cuprammonium comple- xes of vicinal diols are formed as structure 22 (which apparently involves hydrogen bonds) is hardly consistent with both the stability of these complexes and the maintenance of fixed dihedral angles between the coordinated oxygen atoms.6 The structure 22 also does not agree with the observed induction of optical activity in the central atom (the appearance of optical activity in its electronic transitions);135 in fact, in the complex 22, this would be less likely than in the complexes 21, because in the former case, the chiral centres (inducers) are further removed from the central atom.Mannitol was found to form the complex [Cu(LH72)] when the ligand is present in a large excess 136 or Cu2L when the reactants are present in equimolar amounts.136 The latter complex is apparently anionic. This was confirmed 137 by isolation of a series of analogous anionic copper complexes of carbohydrates. An isomer of mannitol, sorbitol, forms the complex [Cu3(LH76)] in strongly alkaline media 138 and a polymeric complex in less alkaline media.An NMR study with the use of a shift reagent has confirmed 139 that CuII is mostly coordinated to vicinal diol groups of the ligand, although the first Angyal rule can also be observed.140 In neutral and acidic media, polyols do not coordi- nate CuII ions.141 This would require 130 deprotonation of at least one hydroxyl group.Structure 23 similar to 21 was ascribed 142 to complexes containing ethylenediamine in place of ammonia. The complexation of CuII with carbohydrate carboxylic acids has also been studied fairly comprehensively, although, as in the previous cases, these complexes have not been isolated in the solid state. D-Galacturonic acid forms 143 the complexes [CuL2]2+, [CuL2H71]+, [Cu(LH71)2], and [CuL2H74]27, whereas D-glucu- ronic acid forms only the second type of complex.143 In this case, coordination involves the ring oxygen atom,144 as has also been observed for s-metal cations (Section II.1).D-Gluconic acid 14a or its dimethylglycine ester (14b, pangamic acid, vitamin B15) form mixed-ligand copper complexes in the presence of glycine;145 the structure of these complexes is unknown. Glucaric acids form complexes with CuII according to the a-type of coordination (Section II.1).The tartaric acids 18 give hydroxo complexes 24 146, 147 containing a water, ammonia, or amine molecule as a ligand. In the case of D-glucaric acid 12, formation of the complexes [Cu(LH73)]7 (at pH 3.65) and [Cu(LH72)2]27 (at pH 5 ± 9, coordination only through the carboxyl groups) and formation of the polymer [Cu(LH73)n]n7 (coordination through the carboxyl group of one ligand and the a-type coordination in another ligand) have been reported.148 18 CO2H OH HO HO2C 19 7 Te OH O O O HO HO 20 7 7 O O I O O O HO OH OH O L=NH3, H2O, OH7. 21 22 OH OH HO HO Cu(NH3)n O CuLn O 23 N N O Cu O H2 H2 L=H2O, NH3 , RNH2 . 24 Cu OH L O O O O O HO H 7 652 Yu E Alekseev, A D Garnovskii, Yu A ZhdanovBinuclear copper complexes of sugars are less frequently encountered. For example, D-gluconic acid 14a can form 7, 149 complexes of type 25a or 25b.In addition, one of the bridging hydroxyl groups in the complex 25b can be deprotonated. At a favourable arrangement of four vicinal hydroxyl groups (which occurs, for example, in mucoinositol), sugars in cyclic and acyclic forms can react with CuII at pH 5 yielding binuclear complexes of type 26 in which the hydroxyl groups of the tetradentate ligand occupy bridging positions.150 Considerable attention has been devoted to the study of complexation of CuII with polysaccharides.Thus dissolution of cellulose in a cuprammonium solution is an important techno- logical process, which has been studied most vigorously.151 The formation of chelates of the type 21 with coordination through the hydroxyl groups at the C(2) and C(3) atoms of b-D-glucopyranose 4b is considered to be the most likely.Polymers having a similar structure, dextrans, are also capable of binding CuII cations in alkaline media.152, 153 This process might be accompanied by untwisting of the helical chains of the ligand.152 The formation of complexes of the type 23 is apparently responsible for the adsorption of the complex [Cu(en)2]2+ (where en is ethylenedia- mine) on cellulose fibres.154 Study of complexation of CuII with anionic polysaccharides has shown 155 that D-galacturonate itself binds CuII more strongly than its polymer, polygalacturonate 5.The affinity for CuII decreases in the following sequence: pectate (polygalacturonate) 5>alginate 6>polymannuronate. A similar situation was observed for CaII ions.156 The complex formation is a cooperative process.156, 157 The ligand unit in the copper complexes of pectic acids has 158 an octahedral configuration, the CuII cation being coordinated to four oxygen atoms in the symmetry plane.The formation of CuII complexes with anionic polysaccharides changes substantially the conformation of the polymer chains of the ligands. As in the case of CaII, the complex formation is a cooperative process.156, 157 As this takes place, a sulfated poly- saccharide, i-carraginane, passes into a helical conformation.159 The formation of complexes of carbohydrates with AgI has been studied only for the silver nitrate ±D-glucurono-d-lactone 160 and silver nitrate ±D-glucurono-g-lactone 161 systems.It was concluded that in both cases, this affords two types of complexes: `lactone' complex 27 and `carboxyl' complex 28. Among complexes with cations of Group IIB d-metals, com- pounds of ZnII and CdII have been studied most thoroughly.b-D- Fructopyranose 29 and L-arabinopyranose 30 react with these cations, as with HgII cations, to give solid complexes of the composition [MLX2 . 4H2O], where X = Cl, Br. In the complex of fructose, the coordination involves two ligand molecules; one of them binds the central ion through the O(2) and O(3) atoms and the other one binds this ion through O(4) and O(5).162 In the case of L-arabinopyranose 30, the two ligands are also coordinated through different sites: the O(3) and O(4) atoms of one molecule and the O(1) and O(5) atoms of the other molecule.163 In the ZnII and CdII complexes with both ligands (29 and 30), the metal ion coordinates additionally two water molecules, and thus its coordination number is equal to six.For the HgII cation, there is no coordination with water (the coordination number is four).The counter-ion of the initial salt is bound to the metal cation by electrostatic forces. Sugars and their O-glycosides react with cadoxen (a solution of cadmium hydroxide in ethylenediamine) to give complexes incorporating two deprotonated equatorial hydroxyl groups of the pyranose ring. Presumably, they have the structure 31.164 This structure is additionally stabilised by hydrogen bonds.However, as in the copper complexes 22, in this case, too, it is difficult to explain the observed induction of optical activity in the electronic transitions of CdII.165 D-Gluconic acid 14a and CdII form complexes with a Cd :L ratio of 1 : 2 (pH 5.8), 2 : 3, and 2 : 1 (pH 13 ± 14).166 D-Glucuronic acid forms two types of solid complexes with ZnII, CdII, and HgII: complexes produced via coordination through the carboxyl group and the ring oxygen atom of the first ligand molecule and the carboxyl group and the O(4) atom of the second molecule and those (32) in which coordination involves only the carboxyl groups.167 In the O-methylglycoside of D-glucuronic acid, ZnII is bound to the carboxyl group and to the ring oxygen atom.16 It has been noted 148 that D-glucaric acid 12 forms a complex with CdII, but its structure has not been described.Complex formation of O-methylglucosides in aqueous solutions of zinc chloride has been reported.168 Presumably, the metal ion is coordinated to the O(2) and O(3) atoms. The complex formation accounts 168 for swelling of cellulose in these solutions.151 Cellulose is known151 to dissolve in cadoxen.Apparently, this yields polymeric complexes like 31. The reaction of rhodanine with cellulose in the presence of a cadmium salt gives rise to complex 33 with different ligands.169 Substituted rhodanines afford similar complexes.170 It was found that cadmium(II) 171 and zinc(II) 172 ions are bound to pectate 5 through the carboxyl groups, although the a-type coordination also cannot be ruled out.Asimilar situation is observed in the case of oligosaccharide fragments of pectic acids.172 O O Cu O Cu O O O O OH2 OH2 H 25a 25b O O Cu O Cu O O O O H O H 27 26 OH Cu Cu OH HO OH OH OH Gluc O O Ag Ag O O Gluc 28 27 O O Ag NO3 Ag O O 29 30 HO OH OH O OH HO OH OH OH O HO 31 7 2+ 7 O O H H N N Cd NH2 NH2 N N H H H2 H2 C is a cellulose fragment.C Cd N S O S 33 32 O Zn O O O Complexes of natural carbohydrates with metal cations 653Complexes of carbohydrates with Group IIIB d-metals are represented by YIII complexes of tartaric acid, the composition of which varies from 1 : 1 to 1 : 5 depending on the pH,173 and by YIII complexes of D-gluconic acid 14a, the composition of which is 1 : 1 and the charge varies depending on the pH.174, 175 Complexes of LaIII with tartaric, D-glucaric 12, and D-galactaric acids have been obtained, their composition (1 : 1 or 1 : 2) being also dependent on the pH value.176 Nodata on the structures of these complexes have been reported.Several complexes formed by Group IVB elements are known. These are TiIV complexes177 with tartaric (18) and D-gluconic (14a) acids and with mannitol (their composition is 1 : 1 or 1 : 2 depending on the pH), the ZrIV complex with trihydroxyglutaric acid [Zr(OH)3(LH72)]7,178 and ZrIV and HfIV complexes with tartaric, trihydroxyglutaric, and D-galactaric acids, which have similar structures.179 The known complexes of Group VB d-metals are mostly formed by vanadium. For example, metavanadate in aqueous solutions reacts with aldoses to give complexes incorporating the [VO3L]7 and [(VO3)2L]27 anions.180 In the latter case, complex formation is observed only for D-glucitol (sorbitol) and maltose (which is a disaccharide).L-Tartaric acid 18, its D-enantiomer, and the corresponding racemate form binuclear complexes with the vanadyl ion VO2+; the composition of the complexes is [(VO)2L2H7n](n74)7 (n = 5, 6, or 8 depending on the pH).181 Mesotartaric acid forms a trinuclear complex, [(VO)3L3H78]27.For polynuclear complexes of acyclic polyols and aldonic acids in aqueous solutions, several types of structures containing tetraden- tate ligands have been proposed (structures 34 ± 36).181, 182 Cyclic sugars and vanadate ions form mononuclear cyclic esters of 1 : 1 composition.183 In the most stable complexes characterised by the cis ± cis arrangement of three vicinal hydroxyl groups (for example, in the complex of b-D-manno- pyranose), the ligand is coordinated in a tridentate manner, while in the other cases, in a bidentate manner.Polygalacturonates 5 are coordinated to VIVO ions through the carboxyl groups.184 At pH 3 ± 7, NbV ions and D-gluconic acid form the complexes [Nb(OH)n(LH72)](47n)7, while at pH 7 ± 9, the complexes [Nb(OH)m(LH72)](37m)7 are produced.185 The complexation of sugars with cations of Group VIB d-metals has been studied fairly intensively. Primary attention has been devoted to complexes of molybdenum and tungsten.Chromium(III) cations do not form stable complexes with sugars in aqueous solutions,186 whereas in dry methanol, aldoses form complexes with CrCl3 .Py (Py is pyridine); the composition of these complexes is 1 : 3 (aldose : CrCl3 . Py).186 Conversely, D-glu- caric acid 12 (and, perhaps, all the aldaric acids) and CrIII in aqueous solutions form an equilibrium system, similar to the 13a.13b system.107 It has also been reported 187 that a stable complex of CrV of an unknown structure is formed during oxidation of D-galacturonic acid with CrVI cations.The complex formation of sugars and MoVI and WVI oxo cations has been studied most comprehensively. Since the structu- res of carbohydrate complexes formed by these metals are simi- lar,188 ± 190 they will be discussed together. In most cases, binuclear complexes ML2 with bidentate (complex 37) and tridentate (complex 38) types of ligand coordination are produced in aqueous solutions.The structure of 37 was unambiguously established only for the molybdenum complex of D-glucuronic acid O-methylgly- coside. According to X-ray diffraction analysis,15 this complex is characterised by the a-type coordination. For carbohydrates existing in acyclic forms (alditols, aldonic acids), this type of coordination is accomplished in one tetradentate ligand in which the neighbouring hydroxyl groups occupy cis-positions.191 ± 194 The complexes like 38 are formed in conformity with the first Angyal rule 193, 194 even if the initial chair-like conformation of the pyranose ligand is distorted.195, 196 Since, due to their conformational mobility, acyclic forms of sugars are more prone to form complexes, it has been assumed and, to some extent, confirmed 197 that the hydrate of the aldehydo form 39 participates in the complex formation. It has been reported 198 that D-lyxose, D-mannose, and L-rhamnose are coor- dinated as tetradentate ligands only in the cyclic pyranose form, although D-lyxose in the furanose form can be also coordinated in this way (see structures 40 and 41).However, other researchers 199 claim that these ligands are coordinated in a tridentate fashion. Upon the interaction ofWVI ions with an acyclic polyol (sorbitol), in addition to the tetradentate coordination (1 : 1 complexes as two regioisomers), a complex of the type 37 in which the ligand is coordinated bidentately has been detected.200 The carbohydrate complexes ofWVI are three orders of magnitude more stable than complexes of MoVI.This is due 198 to the fact that WVI forms polyoxo anions more readily than MoVI. Attempts to determine the structure of the carbohydrate complexes of MoVI and WVI by X-ray diffraction analysis are not always successful. Thus, according to X-ray diffraction data,201 the crystalline compound isolated upon the interaction of D-xylofuranose with ammonium molybdate proved unexpec- tedly to be a complex of D-lyxose 40.The transformation of D-xylose into D-lyxose, which is the C(2) epimer of the initial ligand, was explained by the Lobry de Bruyn ± Alberda van Ekenstein rearrangement occurring during the synthesis of the complex (Section VI.2).It was shown that the new ligand is coordinated in the furanose form 41. Later, using X-ray diffrac- tion analysis, a similar structure has been found for the molybde- num complex of an acyclic tetraol (erythritol).202 Based on 13C and 95MoNMRspectra, it was shown that in solutions, molybde- num complexes of other acyclic polyols (mannitol, etc.) have similar structures.203 After these publications, there are grounds for believing that the other MoVI and WVI oxo complexes discussed above also have binuclear structures of the type 40.Among complexes of carbohydrates with Group VIIB d-metals, complexes of manganese in various (including low) oxidation states have been studied in most detail, because the low oxidation states of manganese, which are generally unstable, 7 7 36 O O V V O O OH OH O OH OH OH O 7 7 7 7 O O V V O O O O OH O O V V O O HO HO HO OH OH O O O O H H 7 O O V V O O OH OH O O O O O 34 35 M=Mo, W. 37 38 7 7 O L O M O M O L O OH HO OH HO O O 7 7 O L O M O O O M O L O O O OH HO n=1±4. 39 40 41 1 3 2 4 5 OH O OH HO HO C H OH HO (CHOH)n CH2OH 1 2 5 4 3 O O O O Mo O O Mo O O 654 Yu E Alekseev, A D Garnovskii, Yu A Zhdanovcan be stabilised by acyclic polyhydroxyl ligands in aqueous solutions.204 The greater the number of hydroxyl groups in the ligand, the more pronounced this stabilisation, because, according to the principle of hard and soft acids and bases,205 theMncations are more firmly bound to hydroxyl groups than to carboxyl groups.204 Judging by the results of electron ± nuclear relaxation measurements, carbohydrates in the pyranose form coordinate only weakly MnII ions by the O(3), O(4), and O(6) atoms 206 (see the structures 4a,b).It should be noted that acyclic polyols also weakly coordinate MnII, but they form stable complexes with MnIII and MnIVions.204 However, it was stated 207 that the com- plexes of sorbitol with MnII ions are also stable.The composition of complexes of acyclic polyols with MnIII was found 204, 207 to be 1 : 2 or 1 : 3. In aqueous solutions, D-gluconic acid 14a forms complexes [MnII(LH72)2]27, [MnIII(LH72)2OH]27, and [MnIV(LH72)3OH]37 (from data on electrochemical oxidation with variation of the electrode potential).208 The former complex is able to dimerise with successive deprotonation yielding a series of binuclear compounds.The complex of D-gluconic acid of the composition [MnIV(LH72)3OH]37 is the first example of a stable carbohydrate derivative of MnIV. In the solid MnII gluconate, which is the only carbohydrate complex of manganese studied by X-ray diffraction analysis,209 the central ion was found to have an octahedral environment formed by two ligands and containing the carboxyl and hydroxyl oxygen atoms. These ligands exist in two conformations: a zigzag-like (similar to that of alkanes) and a bent conformation.The same conformation of the carbohydrate ligand was found in an aqueous solution of MnII gluconate.210 Tartaric acid 18 forms a neutral MnII tartrate,211 which is deprotonated upon an increase in the pH, and in alkaline solution, it is oxidised by atmospheric oxygen to give hydroxytartrate complexes of MnIII. 212 Manganese(II) does not form complexes with D-glucaric acid 12.148 It has also been noted that MnII is bound by dextrans 153 and by polygalacturonate 5.184 Rhenium(VII) as perrhenate forms complexes with alditols (acyclic polyols), aldonic acids of the type 14a, and their lactones. The complexation involves two hydroxyl groups having the R- and S-configuration, respectively.213 It is believed that pertechnetates form no complexes with these ligands. 213 However these data are disproved in another publication.214 Among Group VIII elements, metals of the iron subgroup are represented most widely in the coordination chemistry of carbohy- drates. Thus sugars and other polyhydroxyl compounds form stable complexes with FeIII ions.215 D-Glucopyranose 4a,b 216 and D-fructopyranose 29 216 ± 218 are the best complexones. Structural studies on the FeIII complex of D-fructopyranose 29 confirm the polymeric polynuclear structure 42.216 In an aqueous solution, the polymer 42 occurs in equilibrium with monomeric and dimeric complexes.The complexation of FeIII with tartaric acid 18 in an alkaline medium leads to the complex [Fe(LH73)3]67 with coordination through both carboxyl groups and a hydroxyl group.219 Appa- rently, a complex of the type 24 is formed.A ternary complex of the composition 1 : 1 : 1 was isolated from the FeIII ± sodium tartrate ± saccharose system.220 This accounts for the dissolution of cellulose in iron ± tartrate solutions.151 The following heteronuclear iron ± vanadium tartrate complexes were prepa- red:221 [FeVO(LH72)2]+, [FeVO(LH73)(LH74)]27, and [FeVO(LH74)2OH]47. D-Gluconic acid 14a forms 7, 222 chelates with FeIII with bi- and tridentate coordination through only hydroxyl groups.Later,223 similar structures have been proposed for FeIII complexes with trihydroxyglutaric acid. However, in this case, coordination can involve either one 223 or two 148 carboxyl groups.The complexes of this type are fairly stable (Ks = 104 ±105 litre mol71).224, 225 Preparation of polymeric FeIII complexes of the type 42 with sorbitol or D-glucuronic acid has been reported.226 Cobalt(II) and nickel(II) cations form 1 : 1 coordination com- pounds with mannitol.136 Ammonia complexes of CoIII react with D-ribose and L-sorbose to give chelates [Co(NH3)4L2]3+ chiroptical properties of which point to a structure like 43.227 In addition to these chelates, CoII ions form a binuclear complex [Co2(N- H3)3(OH)2(H2O)2L]3+ with D-arabinose.228 In the series of carbohydrate carboxylic acids, complex formation of CoII and NiII with D-gluconic acid 14a has been studied most extensively.It has been noted 4 that this is not accompanied by substantial changes in the ligand conformation and that NiII chelates are more stable than CoII chelates.229 It was found that in an acidic medium, unstable complexes [M(LH71)]+ are formed.230 ± 232 Polynuclear complexes [Co2(OH)3(LH71)] .H2O and [Co3(OH)2(LH72)2] . 2H2O were detected in the pH range of 7.5 ± 9.5.231 The latter is a polymer of structure 44.The complexes [Ni2(OH)3(LH71)] and [Ni2(OH)4(LH71)]7, which might have a similar structure, have been obtained.230 Tetraamminecobalt(II) reacts with D-gluconic (14a) and D-glucuronic acids to give the complexes [Co(NH3)nL]2+ (n = 4, 5) in which the ligands behave as monodentate ones.233 Study of solid nickel gluconates [Ni(LH71)2] . 2H2O and [Ni2(OH)2(LH72)] . 2H2O by spectro- scopic and magnetic methods has shown that the chelate units in both complexes have a distorted octahedral configuration.234 The second complex has a polymeric structure with hydroxyl bridges, apparently, similar to the structure 44. The diastereomeric L- and D-complexes [Co(LH71)(en)2]+ have been obtained by the reaction of racemic [Co(CO)3(en)2]2+ with aldonates and separated.13 Aldaric acids form 148 chelates of the type [M(LH73)]7, the structure of which is apparently 24, and a binary complex {[Ni(bipy)3]2(LH72)} (bipy is bipyridine).235 Data on the complexation of CoII and NiII with polysaccha- rides are scarce.Thus it is known that these cations are bound by dextrans 153 and polygalacturonate 5 184 and that cellulose dissolves in solutions of the complexes [Co(en)3(OH)2], [Ni(N- H3)6(OH)2], and [Ni(en)3(OH)2] yielding complexes of an unknown structure 151 (supposedly of the type 31).Complexation of carbohydrates with cations of platinum group metals has been studied mostly in connection with their therapeutic effect (Section VI.1). When cisplatin 45 was made to react with D-mannitol, two complexes with identical structures (46) but with different colours and different chiroptical properties were isolated.236 The reasons for this result are unknown. 43 42 O Fe O O Fe O O O O O O O OH2 OH2 Co O O NH3 NH3 H3N H3N 1 2 3 3 2 1 O O Co O O Co O O O O HO O OH OH OH H H H H H H O Co O O OH OH 44 H2 H2 Pt H3N H3N O O OH OH O O Pt NH3 NH3 46 45 Pt H3N H3N Cl Cl Complexes of natural carbohydrates with metal cations 655The reactions of acyclic polyols with the 1,3-bis(diphenyl- phosphino)propane platinum complex result in the formation of stable diolate chelate-type complexes 47, which are additionally stabilised by intramolecular hydrogen bonds.237 The complexes have been structurally characterised.The reaction is regioselective and occurs most efficiently with vicinal diol groups.Peculiar anionic complexes, so called osmarines, are formed upon the reaction of osmium salt 48 with aldoses.238, 239 These complexes are polymers the backbone of which con- sists of linked (possibly, via oxygen) Os atoms with `grafted' monosaccharide residues. The molecular masses of these com- pounds are between 103 and 106 dalton. Some of the aldose fragments are oxidised to aldonic acids during complex forma- tion; therefore, the complexes can be described by the general formula KmOsOnYxZy(H2O)z , where Y is aldose, Z is aldonate (the therapeutic properties of these polymers are described in Section VI.5).D-Gluconic acid 14a forms two extremely stable complexes of the composition 1 : 1 with PtII cations; these products result from slow hydrolysis of the initial polymers of the composition 6 : 1.7 The RuIII cation also forms a stable complex compound with D-gluconic acid in an alkaline medium.240 Similar stable comple- xes of D-gluconic acid have been obtained for OsIII, OsIV, and OsVI ions.241 Mixed-ligand chelates [PtL(1,3-diamine)] have been obtained with D-gluconate and D-glucuronate in the presence of 1,3-diamines.242 Among the complexes formed from f-metals with sugars, those of lanthanides have been studied most thoroughly.The use of water-soluble lanthanide salts as shift reagents in NMR spectroscopy has demonstrated that the first Angyal rule holds for both cyclic 243 and acyclic 244 carbohydrate forms, while the second Angyal rule is obeyed for furanoses,245 i.e.there is a similarity between the behaviours of lanthanides and s-metals. The complexation of lanthanide cations with carbohydrate carboxylic acids has been studied fairly comprehensively. The chiroptical properties of the complexes of lanthanides with tartaric acid 18 are discussed in a review.246 The a-type bidentate coordination and tridentate coordination through both hydro- xyl groups and the carboxyl group have been assumed for the complexes resulting from the reaction of glyceric acid with CoIII.247 D-Galacturonic acid coordinates EuIII ions through the oxygen atom of the carboxyl group, the hydroxyl group at the C(4) atom, and the ring oxygen atom(1 : 1 complex),248 while the O-methylglycoside of this acid binds EuIII only by the carboxyl group and the ring oxygen atom {the [Eu(LH71)3] complex}.249 D-Gluconic acid 14a forms the most stable chelates with CeIII ions.4 Structures with the a-type coordination and with tridentate coordination involving the carboxyl group have been proposed for 1 : 1 complexes of lanthanides.250, 251 The stability constants of these complexes at low 252 and high 253, 254 pH values have been determined.An increase in the gluconate concentration leads to the formation of complexes [M(LH71)n](37n)+, where n=2±4.255 As regards actinides, only data on the complex formation of UVI (as the uranyl cation, UO2á 2 ) have been reported.This cation coordinates aldopyranoses and cyclic polyols at pH>10 without observance of the first Angyal rule. Apparently, this is due to its large size.199 D-Glucuronic acid forms complexes 49 and 50 with these ions.259 Similar complexes are produced in the case of tartaric acid 18 and trihydroxyglutaric acid.257 III.Complexes of cyclodextrins Cyclodextrins (CD) are cyclic oligosaccharides consisting of six (a-CD), seven (b-CD), or eight (g-CD) residues of a-D-gluco- pyranose 4a. They are capable of incorporating various organic molecules into inner hydrophobic cavities.258 ± 262 Less is known of the ability of cyclodextrins to form comple- xes with metal ions.Thus b-CD complexes alkali metal salts, although this mostly occurs due to binding of the anion.263 Complexes of a-CD with iodine of the type (a-CD)2 . LiI3 . I2 . 8H2O (a model of the blue iodine complex with amylose) and with cadmium ions have been described.264 In the b-CD complex with KOH, the K+ ion is bound by six coordinate bonds with the hydroxyl groups of the glucopyranose residues thus forming a distorted trigonal prism.265 The lutetium ion can also be bound to b-CD.266 Metal complexes of coronands (crown ethers) 267, 268 or their acyclic analogues, podands,268 can be incorporated into the cavities of cyclodextrins.Some complex compounds of cyclodextrins with d-metal cations are also known. a-Cyclodextrin forms binuclear com- plexes 51 with CuII; complexes of b-CD are formed similarly but contain deprotonated oxygen bridges.269 ± 271 Other d-metals are also prone to form polynuclear complexes with b-CD. For example, the complexes [M2(OH)2(b-CD). 2H2O] (M = MnIII, CrIII), Na2[M2(OH)2(b-CD) . 2H2O] (M = CoII, NiII, CuII), and [M4(OH)4(b-CD) . 2H2O] (M = FeIII) have been described.272, 273 However, the primary attention is paid to the inclusion of d-metal complexes into cyclodextrin cavities (second-sphere coor- dination).274, 275 Thus a-, b-, and g-CD form host ± guest comple- xes (inclusion compounds) 52a, 52b, and 52c, respectively, with ferrocene.276 ± 278 The `guest' molecules in these complexes can rotate freely only at elevated temperatures.279 The axial incorporation of ferrocene in the complex 52b was confirmed in a study of complexation of cyclodextrins with a model ferrocene derivative that can be arranged in the cavity only equatorially, as in the complex 52c.280 Since the cavity of a-CD is small, it can incorporate only Ald is the aldose residue. 48 K+ Os OAld OAld O O AldO 7 47 HO Ph Ph Ph Ph OH OH HO O O Pt P P 50 7 7 O U O O O O O 7 7 O OH OH OH HO HO O U O O O OH OH OH OH O 49 O O Cu O Cu O O O O H H 51 52a Fe 52b 52c Fe Fe 656 Yu E Alekseev, A D Garnovskii, Yu A Zhdanovmonosubstituted ferrocenes, whereas the other cyclodextrins form complexes with disubstituted ferrocenes as well.277, 278 In this type of cyclodextrin complex, a chiral `host' molecule induces optical activity in a `guest' molecule.This facilitates investigation of these compounds.281, 282 The complex [(Z5-C5H5)FeC6H6]PF6 . . 2a-CD 283, 284 of the type 52a and its analogues containing naphthalene, indan, tetralin, or thiophene instead of benzene 284 have been prepared. Complexes of Z6-arenetricarbonylchromium with b- and g-CD of the composition 1 : 1 are known.285 Incorporation of organometallic p-complexes such as [(Z3-allyl)Pd],286 [(cod)RhCl2] (cod is cyclooctadiene),287 [(cod)PtX2] (X=Cl, Br, I),287 [(cod)Rh(NH3)2],288 ± 290 and ordi- nary platinum complexes such as 45 290 ± 293 into cyclodextrins has been studied.Bulky metal complexes such as macrocyclic NiII complex 53 294 or the FeIII complex with protoporphyrin IX (hemin) 295 can also occupy the hydrophobic cavities of cyclodextrins.Rotaxane complexes of type 54 have been synthesised.296 ± 299 Since the CD molecule is chiral, the synthesis involves asymmetric induction and yields predominantly stereoisomers with the (D,D)-configuration of the chelate units.298, 299 IV. Complexes of nitrogen-containing natural carbohydrates In the metal complexes of ribonucleosides 55a, metal ions are normally coordinated to endocyclic nitrogen atoms in a base of the pyridine type (B).300 ± 303 In the case of ribonucleotides 55b, additional coordination to the phosphate group is possible; this gives cyclic complexes of the type 56,18 in conformity with the principle of hard and soft acids and bases.205 However, within the scope of this review we are interested in the exceptions to this rule, namely, complexes resulting from coordination of carbohydrate fragments. Thus in disodium uri- dine 30-phosphate, the Na+ cation is coordinated not only to the phosphate but also to the oxygen atoms at C(20 ) and C(50 ).304 Likewise, the ribose residue is one of the sites of coordination of the Li+ ion to the nucleosides 55a.305 In the sodium inosine phosphate, the Na+ cation is coordinated to the hydroxyl groups at the C(20 ) and C(30 ) atoms of the ribose residue.306 The interaction of borate ions with pyrimidine nucleosides involves coordination at the vicinal diol group at C(20 ) and C(30 ) and results in a complex of the type 8.307 Vanadate ions are coordina- ted in a similar way.183, 308 The same hydroxyl groups and CuII ions give binuclear complexes Cu2L2 of the type 51.309, 310 It has been suggested that CuII acetate forms three-dimensional binuc- lear complexes like 57;311 however, other results 312, 313 attest to the formation of ordinary coordination units of the type 21.The uranyl complex of adenosine has the binuclear bridged structure 58.314, 315 Desoxyribonucleosides and -nucleotides do not contain a vicinal diol group; therefore, their carbohydrate fragments do not participate in coordination.Among natural aminosaccharides, D-glucosamine (2-amino- 2-desoxy-D-glucopyranose, 59a) has received most attention. Metal complexes of D-glucosamine have been studied by electro- nic spectroscopy, potentiometric titration, calorimetry, and EPR spectroscopy. No X-ray diffraction data for these complexes are available.The complex formation of D-glucosamine 59a with CuII has received the most study.141, 316 ± 324 This interaction involves coordination not only to the amino group but also to the hydroxyl groups at the C(1) and C(3) atoms adjacent to the amino group.316, 321 In the complexes CuL and CuL2 ,317, 320 the hydroxyl groups of the ligands can be either free 321 or deprotonated.323 Other researchers 141 deny participation of free hydroxyl groups in the coordination and assume that deprotonation is typical first of all of the hydroxyl group at C(1), because it is the most acidic.325 In the case of the CuII complex ofN-acetylglucosamine 59b, theN- acetyl group is not coordinated to the CuII ion but stabilises the complex [Cu(LH71)2(OH)2]27. 141 The complexation of D-glucosamine 59a with NiII,141, 319 ± 322 CoII,316, 319 ± 324, 326, 327 and FeIII 317 ± 320 ions has been studied fairly comprehensively. For complexes of the composition ML, the following stability series was obtained: CuII>PbII>ZnII> NiII:CoII, CdII,MnII CaII,MgII, 321 and for complexesML2 , FeIII>CuII>CoII. 319 The formation of complexes of D-glucosamine 59a of the composition ML2 with the above cations is a multi-stage pro- cess,319, 323 which includes coordination of the cation to the amino group of the first ligand, to the amino group of the second ligand, coordination to the neighbouring hydroxyl groups followed by their stepwise deprotonation, and finally coordination to a hydroxide ion in a strongly alkaline medium.323, 326 However, other investigators 141, 321 deny the possibility of coordination to a hydroxide ion.Solid hygroscopic complexes of D-glucosamine of the composition ML2 with CaII, BaII, and SrII have been obtai- ned.324 The cationic complexes [FeL(OH)2]+ and [FeL(OH)]2+ are formed from FeIII and D-glucosamine 59a in a physiological salt solution.326 The crystalline complexes [NiL2]X (X = 2Cl, SO2¡ 4 ) have been obtained.327 Synthesis of cis-dichlorobis(D-gluco- samine)platinum(II) has been reported.328 The interaction of D-glucosamine 59a with tris(ethylenedi- amine)cobalt has led to contradictory results.First, it was reported 329 that this gives an outer-sphere complex with a structure of the type 31.Subsequently, it was shown 330 that this affords four isomers with a D :L ratio of 7 : 3, which differ in the 2+ 53 H H H H N N N N Ni (CH2)6OH n=8, 10, 12, 14. 2+ 2+ 54 H2 Co NH2 NH2 H2N H2N N Cl H2 N Cl NH2 NH2 H2N H2N Co (CH2)n X=H(a), PO3H2 (b); B is a heterocyclic base. 55a,b 56 2+ O OH OH O P O O M N O 5 O XO OH B OH 4 3 2 1 57 HO Cu Cu HO O O Me 58 7 7 O Ade Ade O O U O U O O O O O O O O O P O O O O P O 59a: X = H; 59b: X = Ac 59a,b 1 2 O HO HO OH HNX OH 3 Complexes of natural carbohydrates with metal cations 657anomeric configuration of the ligand and configuration of the chelate unit (complexes like 43 with an amino group instead of a hydroxyl group).Finally, recently 331 it was shown that the composition of the product mixture is even more complicated; eight(!) isomers were isolated from the mixture and characterised by X-ray diffraction analysis.In all of these compounds, the ligand had been converted preliminarily into a substituted N-glu- coside, and after that, the reaction gave complexes of the type 43 [with an amino group instead of the hydroxyl group at the C(1) atom of the sugar]. The ligand in this complex was either trans- formed into the aldehydo form of the type 39 or into the furanose (keto) form as a result of the Amadori rearrangement,2 or remained in the native pyranose form.In order to model the chemical behaviour of natural polysacc- harides containing residues of D-glucosamine 59a, which might be able to form multi-ligand complexes, a ternary complex consisting of CuII, D-glucosamine, and prometon [2-methoxy-4,6-bis(iso- propylamino)-s-triazine, PR] of the composition [CuPR(LH72)] was synthesised.332 The complex formation of other natural 2-amino sugars has been much less studied.It has only been reported that CuII forms complexes with D-mannosamine,333 D-galactosamine, and D-talosamine.334 The latter complex is the most stable among copper complexes of natural 2-amino sugars.This was explai- ned 334 by the formation of a very strong hydrogen bond between the hydroxyl group at C(4) and the amino group at C(2), owing to their diaxial orientation. An important constituent of natural glycolipids and glyco- proteins is N-acetylneuraminic acid. The b-anomer of this acid 60a forms 335 ± 337 a fairly stable complex with CaII of the composition 1 : 1 (Ks=121 litre mol71).335 The calcium complex with N-glycolylneuraminic acid 60b is even more stable (Ks = 193 litre mol71).336 The complex formation of CaII with the ligand 60a has been reported 335 to involve the ring oxygen atom and the hydroxyl groups at the C(7), C(8), and C(9) atoms; however, according to another publication,337 coordination occurs through the ring oxygen atom and the hydroxyl groups at C(2) and C(8).The natural a-anomer of the N-acetylneuraminic acid 60c weakly binds CaII;337 binding of metal cations by the ligand 60c becomes markedly stronger when CaII is replaced by GdIII or MnII,338 which coordinate 60c in the region of the glycerol `tail' and the carboxyl group. Natural gangliosides (oligosaccharides contai- ning the acid 60c and long hydrocarbon chains attached to them 2) coordinate metal cations by the glycerol fragment of the natural a-anomer 60c.In this case, CaII ions are bound much more strongly than MgII.339 However, since the O-methylglycoside of the a-anomer 60c scarcely binds CaII, the coordination involves neighbouring monosaccharide fragments, in addition to the N-acetylneuraminic fragment.340 A similar enhancement of com- plexation is also observed 341 in the binding of GdIII by glycopho- rin A � a transmembrane glycoprotein with a high content of a-N-acetylneuraminic acid 60c.In aqueous solutions, N-acetyl- neuraminic acids 60a,c do not coordinate Na+andK+cations.342 Glycosaminoglycans are polymers containing 2-amino sugars and occurring in connective tissues (mucopolysaccharides 2); therefore, study of their complexation presents considerable interest from biochemical and medical viewpoints.A typical representative of mucopolysaccharides is an anticoagulant hepa- rin.343 ± 345 The repeating disaccharide unit of this compound 61 consists (from left to right) of an L-iduronic acid residue sulfated at the hydroxyl group at C(2) and aD-glucosamine residue sufated at the amino group and at the hydroxyl group at C(60).On dissolution in water, sodium heparinate dissociates only by 34%.345 This corresponds to the normal behaviour of polyelect- rolytes in which s-metal cations are bound non-specifically (territorial binding, Section II.1). In other words, they merely `condense' on the negative charges in the polymeric chain,346, 347 according to the Manning theory.78 However, in another study,348 specific binding of Na+ by two carboxyl groups of the neighbou- ring L-iduronic acid residues was suggested, based on the results obtained by 23Na NMR spectroscopy.However, later the same results were explained 349 in terms of the concept of condensation of counter-ions.On the other hand, in the case of CaII, ionic coordination with participation of the sulfo group of the L- iduronate and the sulfo group at the C(60) atom of the D-glucosa- mine residue 351 has been suggested.350 In the presence of excess CaII, neighbouring chains of the polymer are linked according to the `egg box' pattern (Section II.1).345 The complexation hypot- hesis is supported by the series of the efficiency of binding of s- metals with heparin 343, 352 (Na+<K+<Mg2+<Sr2+<Ba2+<Ca2+), since, according to the condensation theory,78 the most efficient binding would be observed for the Mg2+ cation characterised by the maximum charge density.The data of circular dichroism spectroscopy,353 which confirm this series, indicate simultaneously that there is no specificity in the binding of CaII.This contradiction might be explained by the fact that heparin is capable of both non-specific (condensation) and specific (complexation) binding of s-metal cations. This was discovered 354 for electrostatic binding of heparin with ZnII. It has been noted 355 that this ability is peculiar only to heparin; however, according to another publication, heparin just possesses the highest affinity for ZnII compared to other glycosaminoglycans.356 The interaction of heparin with CuII cations occurs as chela- tion involving the amidosulfate group.357, 358 At higher pH, the complex formation is enhanced.This was explained 357 ± 359 by straightening (despiralisaton) of heparin molecules resulting in liberation of new coordination sites.It was suggested 357 that CuII is coordinated inside the cavity of a helix, as in the case of CuII complexes with cyclodextrins (see Section III, the compound 51). Among glycosaminoglycans, heparin possesses the highest affi- nity for [Co(NH3)6]3+ cations, apparently due the high negative charge density in its macromolecule.360 Studies on the complexation of other glycosaminoglycans have also been concerned with hyaluronic acid (its dimeric unit 62 consists of the residues of D-glucuronic acid and N-acetylglu- cosamine 59b) and chondroitinsulfates.361 The latter compounds are built of dimeric units comprising a D-glucuronic acid residue and a residue of N-acetyl-D-galactosamine sulfated at the 4- position (chondroitin-4-sulfate, 63a) or at the 6-position (chon- droitin-6-sulfate, 63b).R1=CO2H, R2=OH: R3=Me (a), CH2OH (b); R1=OH, R2=CO2H, R3=Me (c). 60a ± c 61 60 n O OH HO2C O O HO OSO3H OSO3H HO3SNH O O 20 2 2 6 5 8 4 O H OH R3CONH HO R1 R2 H HO HO 3 9 7 X=SO73 , Y =H(a); X =H, Y=SO73 (b). n 62 O O O HO OH O O HO AcNH OH HO2C 63 n O O HO OH HO2C O AcNH O O OY XO 658 Yu E Alekseev, A D Garnovskii, Yu A ZhdanovThe presence of doubly charged s-metal cations ensures 362, 363 a helical conformation of hyaluronic acid 62.In accordance with polarographic data, CuII forms complexes of the type CuL, CuL2 , and CuLn (L is deprotonated hyaluronic acid).364 In the former case (an inner-chain complex), CuII is chelated by the carboxyl group and by the bridging oxygen atom,365 while at high pH values, the deprotonated N-acetyl group also participates in the coordination.366 Chondroitin-6-sulfate 63b binds Na+ and Ca2+ ions non-spe- cifically.367 In terms of the strength of their binding to chondroi- tin-4-sulfate, s-metal cations can be arranged in the same sequence 361 as in the case of heparin (see above).In the case of chondroitin-6-sulfate, there is no difference between the strengths of binding of doubly charged s-metal cations.361 For a mixture of chondroitinsulfates 62a,b, it has been shown 368 that the efficiency of binding increases in the sequence CuII<YbIII<LaIII.In addition, chondroitin-4-sulfate 63a binds YbIII cations by the carboxyl group and the sulfo group of one chain and by two carboxyl groups of a parallel chain.369 V.Complexes of natural acids of the carbohydrate origin In this Section, we describe a number of complexones such as ascorbic (64), shikimic (65), kojic (66), and phytic (phytin, myo- inositol hexaphosphate, 67) acids. These particular subjects were chosen due to their biosynthetic origin from carbohydrates.2, 370, 371 Numerous studies and a comprehensive review 9 covering publications up to 1977 have been devoted to metal complexes with ascorbic acid (vitamin C) 64.Being a dibasic acid [owing to the protic activity of the hydroxyl groups at C(2) and C(3)], ascorbic acid 64 can be converted into two anions, (LH71)7 and (LH72)27. It forms complexes [MxLy]z, [Mx (LH71)y]z, [Mx(LH72)y]z, and [Mx(LH72)yOH]z virtually with all metal cations including oxo cations.9 Salts of ascorbic acid 64 [Mx(LH71)]z are formed upon coordination of a metal cation by the deprotonated hydroxyl group at C(3) (the strongest acidic site).The subsequent coordination involves the hydroxyl group at C(2) (either free or deprotonated) and the lactone carbonyl group at C(1). The vicinal hydroxyl groups in the `tail' at the C(5) and C(6) atoms do not participate in the coordination in solu- tions,372, 373 although in the condensed phase, this coordination is possible.374 ± 377 Thus in solid TlI ascorbate, the metal ion is additionally bound not only to the hydroxyl groups at C(5) and C(6) but also to the lactone carbonyl group.In solid ascorbates of divalent metals, a cation is coordinated to three anions, and only MgII binds two anions.379 In aqueous solutions, cations of univalent s-metals are bound by an ionic bond, except for Li+, which is bound by a covalent bond.380 In the case of InIII and GaIII, polynuclear complexes predo- minate in acidic media,381 while lanthanides form381 complexes [M(LH71)2]+.The following stability series has been elucidated 382 for the complexes of divalent metals: Be>Pb>Mn> Fe>Co>Ni.These metals form complexes of the composition 1 : 1, and only BeII forms stable 1 : 2 complexes.382 Complex formation of VIV 9, 380, 383 and VV,384 which is accompanied by oxidation of the ligand yielding dehydroascorbic acid, has been studied in detail. Upon the reaction with VIV, dehydroascorbic acid undergoes the lactone ring opening being thus converted into diketogulonic acid.Chelate 68 is formed apparently from the enol form of this acid and the vanadyl ion.372, 373, 385 ± 388 Complex formation of ascorbic acid with d- and f-metal cations has been studied.9 This ligand forms solid three-dimen- sional polymeric complexes with ZnII, CoII, and HgII.389 In solutions, monodentate [through the O(3) atom] or bidentate [through the O(2) and O(3) atoms] coordination is possible.389 The complexes of the acid 64 with CoII in solutions have been studied in most detail.9 A study of spin ± lattice relaxation in the 13C NMR spectra has confirmed 390 the predominant chelation of CoII, FeII, and MnII by the O(2) and O(3) atoms, while the lactone and ring oxygen atoms and the hydroxyl groups at C(5) and C(6) are weaker coordination sites. The reaction of the acid 64 with [Co(NH3)4]2+ gives two complexes: a monodentate complex [with coordination through O(3)] and a bidentate one (with coordination to the lactone and ring oxygen atoms).391 A stable ternary complex 69 formed by ascorbic acid and bis(2,20-bipyridyl)copper(II) has been descri- bed.392 Binuclear complexes of CuII 70 are readily reduced by ascorbic acid 64 if the sizes of the reactants are fitted in the intermediate complex 70.393 An unusual organometallic complex of platinum with ascor- bic acid (71) containing a C± Pt s-bond has been synthesised within the framework of studies dealing with the development of new anticancer preparations.394 Complexes of the acid 64 with dicyclopentadienyltitanium [Z-C5H5)2TiL2] and with dialkyltin [R2SnL .H2O] (R = Me, Et) have also been obtained.395 In the latter complex, the ligand L can be coordinated both in mono- dentate [by O(3)] and bidentate [by O(2) and O(3)] fashions.Shikimic acid 65 forms 396 a (1,2-diaminocyclohexane)plati- num complex similar to the compound 71 prepared from ascorbic acid [the metal is coordinated to the carboxyl oxygen atom and to the alkene carbon atom C(2)]. Kojic acid 66a containing an oxo-enol fragment forms nume- rous complexes with various cations 371, 397 including s-metal ions.13, 371 The compounds of kojic acid with metal ions can be built 371 either as complex salts with coordination to the oxygen atom at C(6) or as chelates with an additional coordination to the oxo group.Synthetic 5-phenacylkojic acid 66b also acts as a complexone.11, 398 ± 400 In its complexes, a metal ion is linked to 66a (R=H), 66b (R=CH2COPh) 64 65 4 1 O O HO OH OH HO 6 5 3 2 HO OH CO2H HO 1 2 5 O O OH RO 6 4 3 67 OPO3H2 OPO3H2 OPO3H2 H2O3PO H2O3PO H2O3PO HO OH OH O V O O CO2H 68 70 N N NbipN= . 69 2 3 NbipN NbipN O O Cu Cu NbipN NbipN 2 3 L L HO OH Cu Cu O O H2N Pt NH2 O HO O CH2OH O O 71 Complexes of natural carbohydrates with metal cations 659the carbonyl fragment of the phenacyl group, to the carbonyl group at C(4), and to the oxygen atom at C(6).The formation of metal complexes with phytin has been intensely studied due to the dietary significance of this compound (Section VI.1). The thermodynamics of phytin complexation with CaII,401 ZnII,402 CuII,403 MnII,404 CoII, NiII,405 FeIII, and CrIII 406 have been studied by calorimetry.Complex formation of incom- pletely substituted ester, myo-inositol 1,2,6-triphosphate, with alkali 407 and transition 408 metal cations has been investigated. For none of the complexes obtained, has the structure been determined. VI. The significance and applications of metal coordination to carbohydrates 1.The influence of complex formation on the chemical properties of carbohydrates The catalytic role of metal cations in a key transformation of carbohydrates, namely, in the Lobry de Bruyn ± Alberda van Ekenstein rearrangement 2, 409 [epimerisation of aldoses at the C(2) atom and their conversion into ketoses], has been explained by assuming the intermediate formation of complex 72.409 In a discussion of the dehydration of carbohydrates, the special case of alkaline dehydration of D-mannose was interpreted using the suggestion 410 of formation of a enediol complex of type 73.The formation of similar enediol metal complexes has been assu- med 411 to rationalise the mechanism of oxidation of mono- saccharides by hydrogen peroxide. These complexes have been identified by electronic and NMR spectroscopy.412 The enediol complex 74 has been isolated and characterised.413 Thus, the hypothesis of the formation of enediol forms of carbohydrates stable as metal complexes, put forward 2, 370 to account for the above transformations, can be considered to be experimentally proven.However, in view of the most recent results, participation of these species in epimerisation seems doubtful (see below).Angyal et al.6, 414 ± 417 have shown thatO-glycosylation according to Fischer (treatment of sugars with a methanolic solution of HCl) 2 carried out in the presence of calcium or strontium salts results in increased yields of O-methylfuranosides. This discovery made this type of compound readily accessible.Acyclic forms, aldose dimethyl acetals, can also be formed under these conditions.418 The promotory effects of Ca2+ and Ba2+ ions on the alkaline oxidation of aldoses by 2-anthraquinonesulfate to aldonic acids of the type 14a has been explained 419 by the fact that the stability of the intermediate aldos-2-uloses 75 increases when these metal ions are coordinated to the hydroxyl group at the C(3) atom and to the oxo group.The angle between the two coordinate bonds must be 0 ± 308; otherwise, the influence of these cations is not manifested. Complexation with boric and phenylboronic acid has been used 420 to perform selective acetonation of monosaccharides; a similar approach used in the series of nucleosides and nucleotides is employed for their selective methylation at the base.421 The use of a complexing polymer, polystyrylboronate, made it possible to prepare partially acetylated derivatives of O-methylglycosides, valuable from the synthetic viewpoint.422 The addition of a borate during the aldol condensation of 2-acetamido-2-deoxy-D-glucose 59b with oxaloacetate giving N-acetylneuraminic acid (a mixture of anomers 60a,b) increases the yield of the product.Apparently, complexation suppresses side reactions.423 The presence of a borate shifts the aldose>ketose equilibrium (the Lobry de Bruyn ± Alberda van Ekenstein rearrangement 2, 409) towards the latter.424, 425 Cations of d-metals also catalyse this rearrange- ment.426 It was shown 427, 428 that the main event in the catalytic action of sodium aluminate on the isomerisation of D-glucose to D-fructose is stabilisation of the intermediate enediol via coordi- nation giving a structure like 73.The presence of an anion exchanger in the paramolybdate form also facilitates this trans- formation by suppressing side reactions.429 Complex formation has been successfully used to protect particular functional groups during selective N-acylation of aminoglycoside and aminocyclitol antibiotics in the presence of heavy metal salts.430 ± 432 The direction of acetylation can be changed simply by changing the metal cation used.430 The numerous reactions of oxidation of aldoses in the presence of metal salts often yield initially intermediate metal complexes the stability of which varies over wide limits.Complex formation can occur in a transition state, or it can give highly unstable complexes.433, 434 The intermediates can decompose either in a single-electron process giving free radicals, which act as the reactive species,435 ± 438 or by a two-electron transfer mechanism giving reaction products.439 ± 441 In a number of studies,442 ± 458 a preparative method has been developed, based on the ability of molybdate ions MoO2¡ 4 to catalyse epimerisation of aldoses and ketoses and their derivatives in relation to the carbon atom nearest to the carbonyl group.The most prominent example of this epimerisation,202 the transforma- tion of D-xylofuranose into D-lyxose, was discussed in Section II.3. When molybdate is replaced by tungstate, the complexation is not accompanied by epimerisation,459 because the carbohydrate complexes of tungstate are much more stable than the molybdate complexes 198 (see Section II.3).However, in the presence of a borate, D-arabinose incorporated in the tungstate complex readily epimerises to D-ribose, since the borate complex of the latter is more stable.460 Previously, the mechanism of epimerisation has been inter- preted by assuming 13, 442 the intermediate formation of planar complex 76, deprotonated at the C(2) atom, in which the metal is coordinated to the O(1) and O(3) atoms of the cyclic form of the substrate.The subsequent diastereofacial protonation of the complex 76 was assumed to give both the complex of the substrate and that of the product. However, later, usingNMRspectroscopy of aldoses enriched in the 13C and 2H isotopes at the C(1) atom, it was shown 461 that in reality, this epimerisation includes a rear- rangement of the substrate carbon skeleton. The C(1) and C(2) atoms exchange their positions in the hypothetical binuclear transition complex 77 containing the initial aldose in the acyclic aldehydo form.A similar complexation has been proposed 462 to explain epimerisation of D-glucose to D-mannose catalysed by Mo7O2¡ 24 ions.L= O O OH OH. HO HO 7 72 73 74 HC O O Mn+ C C O O OH H Caá2 7 2+ Mg Cl Cl L L 77 76 2 4 O O O Mo O O Mo O O O O 3 1 2 7 Mo OH O O HO OH OH 1 3 R=H, CH2OH. 75 2 1 O R O OH HO HO 660 Yu E Alekseev, A D Garnovskii, Yu A ZhdanovIt has been suggested 13, 463, 464 that in the presence of NiII and N,N,N0,N0-tetramethylethylenediamine, aldoses are wholly epi- merised at the C(2) atom with a similar rearrangement of the carbon skeleton via transition complex 78 with the aldehydo form of the substrate.An analogous reaction occurs when CaII is used instead of NiII.465 Finally, it has been found 466 that a rearrange- ment of the carbon skeleton of carbohydrates accompanied by epimerisation occurs even in such a simple system as methanol ± calcium hydroxide.It is obvious that in view of these findings, the generally accepted mechanisms of the Lobry de Bruyn ± Alberda van Ekenstein rearrangement 409 should be revised. In the metha- nol ±NiII ±N,N0-diethylethylenediamine system, D-fructose 29 undergoes a more extensive rearrangement of the carbon skeleton resulting in a branched aldose, 2-C-hydroxymethyl-D-ribose.467 It is noteworthy that the side formation of ketoses in these processes is not accompanied by a rearrangement of the carbon skeleton of the initial aldoses.466 Apparently, ketoses are formed via the generally accepted mechanism of the Lobry de Bruyn ± Alberda van Ekenstein rearrangement.2, 409 The discovery of the change of the carbohydrate carbon skeleton upon the formation of metal complexes is undoubtedly an outstanding achievement in the coordination chemistry of carbohydrates. 2. Reactions involving metal complexes of carbohydrates Cyclodextrins react with RhCl3 to give colloidal dispersions of rhodium, which efficiently catalyse hydrogenation of alkenes carried out at 30 8C under atmospheric pressure of hydrogen.468 Complexes of CuII with b-CD and its polyphosphate initiate vinylic polymerisation.469 Sugars are often used as donors of hydrogen in the catalytic hydrogenation of carbonyl compounds with hydrogen transfer.470 The mechanism proposed for this process 470 assumes participation of metal complexes of carbohy- drates formed intermediately.One example of the use of cyclo- dextrin as phase transfer catalyst, owing to its ability to coordinate s-metal cations, was reported.471 The chirality of carbohydrates is employed in enantioselective catalysis.Well known 472 ± 475 catalysts for hydrogenation are L-tartaric acid 18 or its D-enantiomer adsorbed on the metal surface; in this case, chelation leading to the formation of a chiral environment on the metal surface is assumed.The optical yields in these reactions reach 55% ± 63%.476 ± 478 This is a significant achievement, because these catalysts can be used repeatedly. Similar reactions catalysed by palladium supported on cellu- lose 479 resulted in optical yields of only 0.10% ± 0.15%. Appa- rently, in the latter case, no metal binding on the surface of a chiral support is involved.The optical yields in the reduction of the complexes of ferrocenyl ketones with b-CD of the type 52b vary from 5%480 to 32%± 80%.481, 482 3. Modelling of enzymes by metal complexes of carbohydrates This field of application of carbohydrate metal complexes is still limited to cyclodextrins. Thus alkaline hydrolysis of p-nitrophenyl acetate is suppressed almost entirely by the addition of the binuclear complex of CuII with a-CD 51.483 When the correspon- ding complex with b-CD is used, the retardation of the reaction is less pronounced. This is due to the formation of a stable inclusion compound from the former complex and the substrate; this permits regarding this complex as an adequate model of a metal enzyme.483 A structurally related binuclear complex of MnII with b-CD has been proposed 484 as a model of a photosynthesis enzyme, which catalyses water oxidation to oxygen.It has been shown 485, 486 that complex formation of d-metals with cyclo- dextrins is a general way of stabilising hydroxo complexes of d-metals for the modelling of terminal enzyme systems for photosynthesis. One aspect of enzyme activity, namely, the decrease in the number of degrees of freedom of the substrate upon its comple- xation with the enzyme, has been modelled by alkaline hydrolysis of esters of ferrocenecarboxylic acids.487 ± 490 The molecular design was accomplished in such a way that the catalytic centre (a hydroxyl group of cyclodextrin) was located in the optimum vicinity of the reaction centre of the substrate when the latter had entered the cyclodextrin cavity.487 ± 490 4.Analytical methods based on the formation of metal complexes with carbohydrates An important application of complex formation with metals is the solution of analytical and structural problems in the series of carbohydrates. A large set of qualitative and quantitative electro(iono)- phoretic and chromatographic methods for the separation of sugar mixtures based on the complexation with metals have been developed.Early 491, 492 and more recent 493 reviews survey the data on paper electrophoresis of sugar mixtures in aqueous solutions in the presence of various salts such as borates, germa- nates, stannates, arsenites, molybdates, and tungstates. It is significant that these modifications of the method supplement one another.Other efficient procedures are paper electrophoresis in the presence of CuII periodate, tellurate,494 acetate, and basic acetate 150, 495 and capillary electrophoretic separation of enantio- meric monosaccharides in the borate ± dextrin (cyclodextrin) system, i.e. under conditions of double complexation.496 Electro- dialysis through a polymeric membrane with grafted boric acid residues has been proposed as a method for separation of multicomponent product mixtures obtained upon the formose reaction.497 A broad range of methods consisting in paper and column chromatography of carbohydrates based on complex formation with metals have been surveyed in a review.493 The main column chromatography technique is ion exchange chromatography using Li+, K+, Ca2+, and Ba2+ forms of cation exchangers and cellulose or silica gel impregnated with a borate.Column chro- matography of aqueous solutions of sugars on alumina is also accompanied by complex formation.498 Closely related approac- hes are chromatography on anion exchangers in the aluminate form 499 and chromatography on paper (cellulose) containing carboxylate groups grafted as La3+, Ca2+, and Ba2+ salts.500 Yet another efficient method is thin layer chromatography of sugars and their derivatives using the Ca2+ and La3+ forms of cation exchangers.501 Racemic mixtures of ferrocene derivatives are readily separated on polyamide when an aqueous solution of b-CD is used as the eluent.502 Complex formation with metals has long been used for the determination of sugars.The most widely used procedures are the quantitative Bertrand method 503 based on oxidation of copper complexes of aldoses to give CuI oxide and the related qualitative Fehling 2 and quantitative Somogyi 504 methods. There are grounds for believing that oxidation occurs in enediol CuII complexes.505 Determination of sugars based on their oxidation by the CuII periodate complex 506 or CeIV sulfate 507 has also been described. The formation of complexes of carbohydrates with metals proved to be useful for electrochemical, mainly polarographic, determination of metals.In the presence of acyclic or cyclic polyols, the half-wave potential of the metal cation being analysed substantially shifts, which enables its determination in the pre- sence of other metal cations.508 ± 510 The volumetric determination of PtII in an alkaline solution of D-mannitol in the presence of Solv is solvent. 1 2 Ni Me2N NMe2 Solv OH 7 O OH HO 3 78 4 Complexes of natural carbohydrates with metal cations 661cations of other platinum metals is another example of this approach.511 It is difficult to overestimate the role of complex formation in the configurational and conformational analysis of carbo- hydrates.512, 513 Thus, determination of the stability constants of the borate complexes of pyranoses permitted Angyal to propose a method for the calculation of the conformation energies of these ligands,512, 513 while the change of the specific rotation of aldoses following their complexation with borate made it possible to determine their anomeric configuration.2, 3 Several methods of the conformational analysis of carbo- hydrates are based on the correlation between the complexing and rotational (chiroptical) properties of ligands [optical rotatory dispersion (ORD) and circular dichroism (CD) spectro- scopy 514± 518]. Thus CD spectroscopy of molybdate complexes has revealed 469 a correlation between the orientation of the hydroxyl groups at the C(2) and C(3) atoms in the pyranose form (see the structures 4a,b) and the signs of the Cotton effects in the CD spectrum of a colourless solution of the molybdate complex.Chiroptical methods are applied most often to solutions of coloured metal complexes containing Cotton-genic (manifested in the visible ORD and CD spectra) groups.This line of research was initiated by the classical studies of Reeves 4 dealing with the rotational properties of copper complexes of O-methyl- glycopyranosides. As a result of these studies, a clear correlation between the sign of rotation of model compounds with a fixed arrangement of the hydroxyl groups and the sign of the dihedral angle between them was elucidated.Later, these results were confirmed by chiroptical methods 135, 519 ± 522 (ORD and CD spectroscopy). Similar correlations have been found for NiII complexes of carbohydrates.227, 228, 523, 524 Other Cotton-genic derivatives such as MoII acetate 525 and other d-metal acetates,526 which form chiral complexes with vicinal diol groups of sugars, proved to be more convenient compounds from the viewpoint of methodology. Complex formation of sugars with lanthanide cations used as shift reagents has also found a wide utility in the conformational analysis of carbohydrates by NMR spectroscopy.243 ± 245, 527 ± 537 Boric acid 538 and CuII cations 139, 539 have also been used as shift reagents.The complex formation of sugars with metals has been employed 540 ± 542 for improvement of the mass spectrometry methods for their identification.The complexation of anthrylbo- ronic acid with sugars is accompanied by quenching of its fluorescence; therefore, it has been used 543 for the development of fluorescence chemical sensors for sugars. 5. The significance for biology and medicine Previously the views on the biological functions of carbohydrates reduced to their food (glucose, fructose, starch) and structural (cellulose, chitin) properties.However, during the last decades, carbohydrates have been found to play a crucial role in a number of vitally important processes such as mutual recognition of molecules and cells (cell adhesion, agglutination, reception),544 tissue calcification as the initial stage of the formation of verte- brate bones and shells of molluscs and bird eggs.545 These discoveries substantially raised the biological status of carbohy- drates.Since all the processes listed above are Ca2+-dependent, this has also stimulated studies dealing with the complex forma- tion of carbohydrates with s-metal cations (Section II.1). The studies performed have demonstrated that carbohydrates are weak complexones for these cations and that complex formation with s-metals cannot play an important role in the above biologi- cal processes.For example, N-acetylneuraminic acid 60c, which is an indispensable component of biologically significant oligo- and polysaccharides, forms MgII and CaII complexes in aqueous solutions the stability constants of which are 1.5 and 1.9 litre mol71, respectively.342 Since in a living organism, carbohydrates are almost necessarily linked to proteins (glycoproteins and proteoglycans 2), a number of studies 546 ± 548 have been devoted to the complex formation of a model cation (Gd3+) with synthetic glycopeptides.It was found that coordination occurs both in the carbohydrate and peptide fragments, the latter being preferred.In general, there are no grounds to believe that complexation of carbohydrates themselves plays a significant role in biological processes. The examples given below confirm this point. When sugars are specifically bound by protein compounds, lectins,549 ± 552 in the presence of metal cations, the protein ± sugar interaction is accomplished only by hydrogen bonds.552 Appa- rently, metal cations ensure the appropriate conformation of the protein needed for sugar reception.549 At a certain stage of cell recognition, interaction of carbohydrate-containing proteins is due to the Ca2+ cation, but it is unknown to what particular fragment this ion is coordinated.By analogy with lectins, it can be assumed that in this case, too, the metal ion is coordinated to the protein fragment.553, 554 The complex formation of Ca2+ with sulfated polysaccharides is considered to play a certain role in its deposition in tissues.545 Metal complex formation with natural carboxylic acids of carbohydrate origin (see Section V) is important for medicine.Thus ascorbic acid decreases the level of mutations in workers in contact with heavy metals.555 Phytic acid is present in substantial amounts in vegetable oils, and its ability to form an insoluble complex with Ca2+ decreases the removal of calcium with urine.556 Binding with heavy metal cations can even inactivate metal-dependent enzymes, for example, a-amylase 557 and carbo- xypeptidase A.558 The platinum complexes 46 236 and [PtL(1,3-diamine)] 242 (L is D-gluconate or D-glucuronate) exhibited a considerable antitu- mour activity.This activity was also found for the platinum complex 71.394 Polymeric osmium carbohydrate complexes, osmarines,238, 239 (Section II.3) are used as antiarthritis prepara- tions owing to their capability of binding superoxide ions, which are responsible for this disease.239 Copper(II) complexes with cyclodextrin of the type 51 can be used 559 for treating the mildew blight of grapes, because these compounds are not toxic in wine.Water-soluble iron complexes of glucose and fructose 42 are used to treat anemia.560 Phytin 67 prevents foodstuffs from going bad under the action of atmospheric oxygen, because it binds Fe3+ and Cu2+ cations, which can act as efficient catalysts for undesi- rable oxidation processes.561 The complex formation of metals with polysaccharides has also found use in medicine.Pectins (polymers of the type 5 with partly esterified carboxyl groups) isolated from fruits or vegeta- bles efficiently bind toxic metal cations and thus they can be used for detoxification of an organism.562 It has been proposed 563 to use iron complexes of chondroitinsulfates 63a,b for curing iron deficiency anemia. Metal complexes of dextran and inulin can be used as paramagnetic contrasting reagents 564 in medical NMR spectroscopy.Treatment of cellulose with heavy metal salts and subsequent interaction with antibiotics imparts antibacterial pro- perties to textiles.565 In nature, complex formation of metals with polysaccharides can be undesirable.Thus the formation of gels on the surface of plant roots may have negative consequences for plants, since their main components, acidic polysaccharides, bind metal cations, which come directly from soil particles and are needed for nutrition.566 s-Metal cations 567 and d-metal cations 568 are used to strengt- hen agaroid jellies. d-Metal hydroxides treated with sugars are employed for enzyme immobilisation.569 The natural polymer of N-acetyl-D-glucosamine � chitin � has been proposed 570 as a reagent for extraction of heavy metals from waste water; the ferrite ± alginate system is employed for the preparation of ferro- magnetic particles used as a contrasting reagent 571 in NMR spectroscopy for medical purposes. 662 Yu E Alekseev, A D Garnovskii, Yu A ZhdanovVII.Conclusion The modern coordination chemistry of carbohydrates resembles an enormous picture painted with rough strokes in which only some sections are drawn thoroughly. This is due to the extreme complexity of the investigation subjects, caused by the specific character of carbohydrates as complexones. Carbohydrates can exist in both cyclic and acyclic forms; they can act as polydentate ligands and form regioisomeric complexes.In addition, chirality of carbohydrates results in the formation of unequal amounts of diastereoisomers in relation to the chelate unit. This diversity of compounds can be found in a single reaction mixture. Therefore, the overwhelming majority of conclusions concerning the structu- res of carbohydrate metal complexes have been drawn relying on more or less likely suggestions, except for those few cases where researchers were able to obtain a crystalline compound and study its structure by X-ray diffraction analysis.However, with the advent ofNMRtechniques using metal cations as shift reagents, it became possible to determine fairly reliably the structures of a number of metal complexes of carbohydrates in solution.It would hardly be an overstatement to say that nowadays the coordination chemistry of carbohydrates experiences a new stage of its deve- lopment. References 1. G Wilkinson (Ed.) Comprehensive Coordination Chemistry. The Synthesis, Reactions, Properties Vol. 2 (Oxford: Pergamon Press, 1987) 2. N K Kochetkov, A F Bochkov, B A Dmitriev, A I Usov, O S Chizhov, V N Shibaev Khimiya Uglevodov (The Chemistry of Carbohydrates) (Moscow: Khimiya, 1967) 3. J Bo È eseken Adv.Carbohydr. 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ISSN:0036-021X    

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Abstract. Published data on radiolysis of liquid (mainly aqueous, water ± alcohol and alcoholic) and solid [mainly in poly(vinyl alcohol)] solutions of tetrazolium salts are generalised. The mechanism of radiolytic transformations of these compounds is discussed. Their application in dosimetry of ionising radiation is considered in detail. The bibliography includes 60 references. I. Introduction Reduction of colourless or weakly coloured tetrazolium salts yields formazans, which are intensely coloured.This property of formazans has found application in various fields of science and engineering. They have been used in botany as colouring com- pounds sensitive to ultraviolet radiation,1 as substances suitable for estimating the productivity of seeds of agricultural plants 2, 3 and the viability of stem and leaf tissues,4,5 for distinguishing between normal and malignant tissues,6 and for studying the histochemistry of oxidative enzymes.7,8 The use of formazans as analytical reagents for detection of O¡2 radical ions has also been reported.9±11 In addition, it is known (see, for example, Ref. 12) that liquid and solid solutions of formazans can be employed in the dosimetry of ionising radiation.The properties, methods for the synthesis, and the mechanism of chemical reduction of tetrazolium salts have been considered in numerous publications (see, for example, Refs 13 ± 17). The present review is mainly devoted to radiolytic transformations of these salts in various solvents (alcohols, water, aqueous alcohols, etc.). Solutions of 2,3,5-triphenyltetrazolium chloride (TPTC) have been studied most often; solutions of 2-(p-nitrophenyl)-3,5- diphenyltetrazolium chloride (NPTC), 5-(p-nitrophenyl)-2,3- diphenyltetrazolium bromide (NPTB), 3-(1-naphthyl)-2,5-diphe- nyltetrazolium bromide (DPTB), 3,30-bianisylene-4,40-bis(2,5- diphenyl-2H-tetrazolium) chloride (Tetrazolium Blue, TB), 2,20- di(p-nitrophenyl)-5,50-diphenyl-3,30-(dimethoxy-4,40-diphenyl- ene)-2H-tetrazolium chloride (Nitrotetrazolium Blue, NTB) and some other derivatives have been studied more rarely.Consider- able attention is paid to the use of these systems in the dosimetry of ionising radiation. II. Alcoholic solutions Detailed data on the radiation yields of reduction of tetrazolium salts in alcoholic solutions and on the mechanism and kinetics of this process can be found in the literature. 1. Radiation yields of reduction When colourless deaerated alcoholic solutions of tetrazolium (T+) salts are exposed to radiation, the corresponding intensely coloured (pink, orange-red, or red) formazans are produced. For example, in the case of TPTC, this yields 1,3,5-triphenylformazan PhNH±N=CPh±N=NPh. The radiation yields of formazans (F) in these solutions are listed in Table 1. 2. The mechanism of radiolytic reduction Radiolytic reduction of tetrazolium salts is a two-electron process, i.e. the reduction of each tetrazolium salt molecule requires two reducing species. The yield of the formazan in this process is more than half the yield of solvated electrons (e¡s ) (for example, in isopropanol, the yield of e¡s is 1.3 26).Based on this result, it was concluded that the salts are reduced by not only e¡s but also by radicals of type R . CHOH resulting from radiolysis of alcohols. When the doses are large enough, formazans undergo subsequent radiolytic transformations; the solutions become colourless, and hydrazidines are formed. The yields of decomposition of forma- zans have been determined for the radiolysis of solutions of 1,3,5- triphenylformazan,18, 27 3-(p-nitrophenyl)-1,5-diphenylforma- zan,20 and 2,5-diphenyl-3-(1-naphthyl)formazan 20 in isopropanol (Table 2).The conclusion about two-electron reduction of tetrazolium salts is confirmed by the data 19, 28, 29 on pulse radiolysis of solutions of these compounds in ethanol and isopropanol.It was found that the interaction of the tetrazolium salt cation (T+) with e¡s or with an alcohol radical gives a short-lived species, namely tetrazolium radical (T . ). In the case of TPTC, this radical has the following structure: Ph N C N N N Ph Ph A K Pikaev Institute of Physical Chemistry, Russian Academy of Sciences, Leninskii prosp. 31, 117915 Moscow, Russian Federation.Fax (7-095) 335 17 78. Tel. (7-095) 333 95 67 Z K Kriminskaya Russian Research Centre `Research Institute of Organic Intermediates and Dyes', Bol'shaya Sadovaya ul. 1, 103787 Moscow, Russian Federation. Fax (7-095) 254 12 00 Received 28 October 1997 Uspekhi Khimii 67 (8) 745 ± 754 (1998); translated by Z P Bobkova UDC 541.15 Radiolysis of solutions of tetrazolium salts A K Pikaev, Z K Kriminskaya Contents I.Introduction 671 II. Alcoholic solutions 671 III. Aqueous and water ± alcohol solutions 674 IV. Solid matrices 676 V. The use of tetrazolium salts in dosimetry 677 VI. Conclusion 679 Russian Chemical Reviews 67 (8) 671 ± 680 (1998) #1998 Russian Academy of Sciences and Turpion LtdA similar species is formed as an intermediate during the chemical reduction of these compounds (see, for example, Refs 3 and 17).The structure of the tetrazolium radical has been confirmed by the results of EPR studies of irradiated frozen solutions of TPTC and 2,3,5-triphenyltetrazolium tetrafluoroborate.30, 31 It was found that irradiation of these solutions at 77 K affords solvated electrons and alcohol radicals. During the subsequent fast warm- ing up to room temperature, these species react with the tetrazo- lium salt yielding tetrazolium radicals.The EPR spectra of the radicals recorded after cooling the samples to 77 K are identical for these two salts and consist of eight lines with a splitting of *1.4 mT. A similar EPR spectrum has been recorded at 77 K for the T . radical resulting from reduction of TPTC with sodium ethoxide in isopropanol.The spectrum recorded at 300 K is somewhat differ- ent. Due to the anisotropy of the hyperfine coupling tensor, the spectrum of T . in the liquid phase is characterised by smaller splitting (*0.7 mT).31 The data obtained in studies on pulse radiolysis of solutions of tetrazolium salts 19, 28, 29 indicate that tetrazolium radicals arise in two processes, one of which is fast and the other is slow.For example, in the case of a triphenyltetrazolium salt (the TPT+ cation) in isopropanol, this might occur as follows: TPT++e¡s TPT . , (1) TPT++(CH3)2 . COH TPT . +(CH3)2CO+H+. (2) Table 3 contains the rate constants for reactions of this type for tetrazolium salts measured by the method of pulse radiolysis. Calculations using the Debye equation have shown that in the case of NPTC and NPTB, the rate of reaction (1) is controlled by diffusion, whereas for TPTC, the rate is lower than the diffusion limit.The formazans are formed upon disproportionation of T . radicals T . +T . +ROH F+T++R7. (3) Thus, the yield of the formazan (for example, in an isopropa- nol solution) should be equal to G(F)= 1 2 {GÖe¡s Ü+G[(CH3)2 . COH]} .(4) Since G[(CH3)2 . COH] in isopropanol is *5.5 molecule (100 eV)71,26 the theoretical G(F) value amounts to *3.4 mole- cule (100 eV)71. Experimental yields are close to this value only for NPTB and DPTB (see Table 1). For TPTC and NPTC, the yields are substantially smaller. This is due to the fact that the tetrazolium radicals derived from these salts participate not only in reaction (3) but also in another reaction, which does not lead to formazan (for example, they can dimerise to give ditetrazolium salt TT).18, 19 T .+T . TT. (5) According to our estimates,18 the k3/k4 ratio for a solution of TPTC in isopropanol is*1.9. Tetrazolium salts dimerise relatively easily at the 4,40-diphenyl bridge.36 Nitrotetrazolium Blue is an example of this type of dimer.Ditetrazolium compounds have also been described in a review.17 Solutions of tetrazolium radicals in alcohols are characterised by intense optical absorption in the visible and ultraviolet spectral regions (Table 4). These radicals are relatively long-lived species, their lifetimes being of the order of milliseconds. The reduction of formazan to hydrazidine (HH) is also a two- electron process.26 It has been found by pulse radiolysis 27 that formazan reacts first with a solvated electron and an alcohol radical.The rate constants for these reactions in isopropanol are presented in Table 3. It was postulated 27 that the above reactions k1 k2 k3 k5 Table 1. Yields of formazans [G(F), molecule (100 eV)71] in various matrices upon g-radiolysis in the absence of air.Matrix Tetrazo- 103 c/ G(F) Ref. lium salt mol litre71 Liquid isopropyl TPTC 0.1 1.3 18 alcohol TPTC 0.5 1.5 18 TPTC 1.0 1.5 18 TPTC 5.0 1.7 18 TPTC 7.0 2.2 18 NPTC 0.1 1.5 19 NPTC 0.5 2.5 19 NPTC 1.0 2.5 19 NPTC 5.0 2.5 19 NPTB 0.1 2.2 19 NPTB 0.5 3.3 19 DPTB 0.1 ± 5 3.1 20 Water, pH 6.9 TPTC 1.0 0.45 21 7.5 a TPTC 20 0.4 22 10.3 TPTC 1.0 1.2 21, 23 6.9 NPTC 1.0 0.6 21 10.3 NPTC 1.0 1.4 21 6.9 NPTB 0.5 1.2 21 10.3 NPTB 0.5 1.2 21 5.3 DPTB 1.0 0.6 20 10.0 DPTB 1.0 0.7 20 11.5 DPTB 1.0 0.8 20 Water ± isopropanol TPTC 1.0 3.5 21 (2.2 mol litre71), pH 10.3 Water ± isopropanol TPTC 0.8 3.1 23 (20%), pH 11 Water ± isopropanol TPTC 0.8 3.1 24 (1 : 1 by volume), pH 11 Water ±HCOONa TPTC 1.0 3.0 21 (0.2 mol litre71), pH 10.3 Water ±EDTA TPTC 1.0 3.1 21 (0.2 mol litre71), pH 10.3 Poly(vinyl alcohol) TPTC 7.4 0.86 25 film TPTC 11 2.6 25 TPTC 18 3.1 25 NPTC 3.2 2.8 25 NPTC 9.8 4.0 25 NPTC 13 4.8 25 NPTC 16 5.2 25 a For radiolysis induced by X-rays (the highest energy 60 keV).The solution was buffered by triethanolamine and HCl. Table 2. Yields of decomposition of formazans upon g-radiolysis of deaerated isopropanol solutions.Formazan 104 c / G/ Ref. mol litre71 molecule (100 eV)71 1,3,5-Triphenyl- 1.4 3.5 18, 27 formazan 3-(p-Nitrophenyl)- 5.8 3.1 20 1,5-diphenylformazan 2,5-Diphenyl-3- 0.27 1.3 20 (1-naphthyl)formazan 0.77 2.4 20 672 A K Pikaev, Z K Kriminskayayield formazan radical anions F7., which are responsible for an intense optical absorption band with a maximum at 700 nm (the molar extinction coefficient is 3.86103m2 mol71).The lifetime of these species is relatively long (more than 1 ¡¾ 2 ms). By analogy with the behaviour of other radical cations in alcoholic solutions (see, for example, Ref. 37), it was suggested that F7. are protonated in the following way (the reaction is written for isopropanol) F7. +(CH3)2CHOH FH . +(CH3)2CHO7 (6) and disproportionation of the resulting FH .gives HH FH . +FH . F+HH. (7) It should be noted that similar reactions occur during two- electron reduction of quinones to hydroquinones.38 Obviously, the yield of formazan reduction in isopropanol should be determined by the equation G(7F)= 1 2 {GOes ¢§U+G[(CH3)2 . COH]}. (8) The calculated value of G(7F) is *3.4 molecule (100 eV)71, which coincides with experimental results for 1,3,5-triphenylfor- mazan 27 and 3-(p-nitrophenyl)-1,5-diphenylformazan 20 (see Table 2).However, in the case of 3-(1-naphthyl)-2,5-diphenylfor- mazan,20 the experimental yield is much lower than the theoretical yield. This is apparently due to the fact that the rate constant for k6 k7 Table 3.Rate constants [k/ litre mol71 s71] for reactions of tetrazolium salts and formazans measured by pulse radiolysis.Matrix Tetrazol- Reaction k Ref. Matrix Tetrazol- Reaction k Ref. ium salts ium salt Ethanol TPTC TPT++e¢§s 4.16109 29 water, pH TPTC TPT++CH3 . CHOH 2.56108 29 7 TPTC TPT . +O2 3.76107 23 Isopropyl TPTC TPT++e¢§s 2.16109 28 7 NPTB NPT . +O2 4.56107 23 alcohol TPTC TPT++(CH3)2 . COH 3.16108 28 6.9 TPTC TPT . +TPT . 2.06109 32 NPTC NPT++e¢§s 1.561010 19 (see c) NPTC NPT++(CH3)2 . COH 1.96109 19 water TPTC TPT . +TPT . 1.06109 35 NPTB NPT++e¢§s 1.461010 19 (see c) NPTB NPT++(CH3)2 . COH 1.76109 19 water, pH 6.9 NPTC NPT . +NPT . 1.86109 32 Fa F+e¢§s 3.361010 27 (see c) F F+(CH3)2 . COH 1.76108 27 2 TPTC TPTH+. +TPTH+. 5.36107 32 Water, pH (see d) (see c) 6.9 TPTC TPT++e¢§aq 1.161010 32 2 NPTC NPTH+.+NPTH+. 2.86107 32 11.3 TPTC TPT++e¢§aq 6.76109 32 (see d) (see c) 6.9 NPTC NPT++e¢§aq 1.161010 32 5.7 NTB NTB+. +NTB+. 3.86108 33 11.3 NPTC NPT++e¢§aq 9.26109 32 10 NTB NTB+. ...OH7+ 3.76109 33 2 TPTC TPT++H . *1.461010 32 +NTB+. ...OH7 2 NPTC NPT++H . 5.76109 32 water NTB NTB+. + 4.96109 33 6.9 TPTC TPT++ . OH 7.16109 32 +NTB+. ...OH7 6.9 NPTC NPT++ . OH 1.061010 32 6.9 TPTC TPTOH+.? 1.26104 32 7.07 ¡¾ 11.1 NTB NTB2++O¢§2 5.96104 33 ? products (see f) (see b) 33 (see e) 10 TPTC TPT++COO7. 1.16109 21, 34 6.9 NPTC NPTOH+. ? 2.36103 32 10 NPTC NPT++COO7. 5.06109 21 ? products (see f) 10 NPTC NPT++COO7. 1.96109 21 (see e) 10 NTB NTB2++COO7. 6.46109 33 aF �¢ 1,3,5-triphenylformazan. b The constant was determined by the stopped flow method. c The 2k value is given.dTPTH+. and NPTH+. are the H-adducts of the corresponding tetrazolium cations. eTPTOH+. and NPTOH+. are the OH-adducts of the corresponding tetrazolium cations. f Expressed in s71. Table 4. Optical characteristics of the intermediate products of radiolysis of solutions of tetrazolium salts. Matrix Tetrazolium salt Product lmax/ nm 1072 e/ m2 mol71 Ref. Ethanol TPTC TPT .<375, 400 (shoulder) 7 29 Isopropyl alcohol TPTC TPT . 365, 400 (shoulder) 10.7, 4.0 19, 28 NPTC NPT . 405, 620 9.9, 2.5 19 NPTB NPT . 370, 390 (shoulder) 6.3, 2.5 19 Water, pH 6.9, 11 TPTC TPT . 370 7.1 32 Water TPTC TPT . 360 7 35 Water, pH 6.9, 11 NPTC NPT . 415 7.6 32 5.7 ¡¾ 11 NTB NTB+. 405 15 33 2, 6.9 TPTC TPTH+. 380 4.6 32 2, 6.9 NPTC NPTH+. 390 7 32 6.9 TPTC TPTOH+. 365 4.0 32 Water TPTC TPTOH+. 345 7 35 Water, pH 6.9 NPTC NPTOH+. 380 7 32 Radiolysis of solutions of tetrazolium salts 673the reaction of this formazan with the alcohol radical is relatively low. It has been found 18 that the yield of formazan in the radiolysis of alcoholic solutions of tetrazolium salts decreases when the radiation doses are high. This effect is least pronounced for solutions of DPTB in isopropanol.20 Evidently, the yield decreases due to reactions of F with e¡s and (CH3)2C .OH. 2-Isobutylan- thraquinone added to an isopropanol solution of TPTC largely `protects' the formazan from decomposition.18 The dependences of the concentration of the formazan formed in isopropanol solutions of TPTC on the radiation dose in the presence and in the absence of 2-isobutylanthraquinone are shown in Fig. 1. 3. Radiolysis of aerated solutions The yield of formazans in aerated alcoholic solutions is appreci- ably lower than in deaerated solutions; in some cases, formazans are not formed at all. For example, they are not formed upon irradiation of air-saturated 161073 M solutions of DPTB with a dose of 200 ± 300 Gy.20 According to another study,39 the G(F) values for aerated 561073 and 4.561072 M ethanolic solutions of TPTC are 0.048 and 0.135 molecule (100 eV)71, respectively (at a dose of *10 kGy).It was found 22 that in the case of X-ray radiolysis of an aerated solution of TPTC in ethylene glycol (maximum energy 60 keV), G(F) increases with an increase in the concentration and reaches 1.03 molecule (100 eV)71 in a 0.1 M solution at a dose of 9.2 kGy.This type of behaviour can be explained as follows. Since the concentration of TPTC is high, a large portion of tetrazolium radicals, generated, for example, according to reaction (1), are converted again into TPT+. TPT . +O2 TPT++O¡2 . (9) A similar effect is also observed in the case of aqueous solutions of tetrazolium salts (see below).Yet another possible reason (although it is less significant) is that the alcohol radical might react with oxygen to give the peroxy radical RCH(OH)O2 . , and the latter reacts with TPTC slowly or not at all. In an ethylene glycol solution, G(F) is close to 0.5 G(e¡s ). Apparently, due to the high viscosity of this alcohol, reaction (9) in this system is relatively slow, and the TPT .radicals generated mostly disproportionate. The alcoholic radicals do not reduce TPTC, but instead, they react with oxygen to give the peroxy radicals. III. Aqueous and water ± alcohol solutions Radiolysis of aqueous and water ± alcohol solutions of tetrazo- lium salts has been studied in several publications.20plusmn; 24, 32, 35 It was found that as in the case of alcoholic solutions, reduction to formazans is the prevailing process. 1. Characteristic features of radiolytic reduction in deaerated aqueous solutions Irradiation of a deaerated aqueous solution of any of the tetrazolium salts studied results in the formation of a precipitate. The solution obtained by filtering this precipitate off and dissolv- ing it in an alcohol, or by adding a sufficient amount of an appropriate organic solvent to the irradiated solution, or by extracting the product with a solvent exhibits an optical absorp- tion spectrum typical of formazan. Upon irradiation of solutions in aqueous alcohols, when the alcohol concentration is high enough (for example, in a 1 : 1 water ± isopropanol mixture 24), the precipitate does not appear, but solution acquires an intense red colour caused by the formation of formazan.It should be noted that in aqueous solutions, the concentration of formazan arising upon radiolysis depends on the g-radiation dose only at high doses, because the product precipitates. In aqueous alcohols, this dependence is sharper. The measured G(F) values for radiolysis of deaerated solu- tions of some tetrazolium salts are listed in Table 1. It can be seen that without additives G(F) increases from 0.4 to 1.4 molecule (100 eV)71 with an increase in the pH of the solution from 5.3 to 11.5.However, in the case of NPTB, this dependence is not observed. Upon the addition of some organic compounds (for- mates, EDTA, isopropanol) or in water ± isopropanol mixtures, the formazan yield increases to 3.5 molecule (100 eV)71.The radiolysis of water is described by the following greneral scheme:26 H2O e¡aq , H, OH, H2O2, H2, H+, OH7 . (10) Obviously, the first four products can participate in the radiolytic transformations of tetrazolium cations. Hydrated elec- trons e¡aq reduce the T+ cations to tetrazolium radicals T . ; the latter disproportionate to give formazan. Hydrogen atoms do not participate in the reduction,32 but they add to benzene rings giving rise to H-adducts.The OH radical reacts with T+ to give an OH- adduct. Hydrogen peroxide can oxidise T . . T . +H2O2 T++OH+OH7 . (11) Subsequent transformations of the H- and OH-adducts give no formazans. Therefore, we can write G(F)= 1 2 âGÖe¡aqÜ ¡ GÖH2O2Üä . (12) Calculation using this equation affords G(F) = 1.1 molecule (100 eV)71.The experimental G(F) values obtained for alkaline media (except for those for DPTB) are close to this predicted value. In the case of NPTB, the yields measured both in alkaline and neutral media coincide with those calculated from Eqn (12). The experimental G(F) values found for acidic, neutral, and weakly alkaline solutions of TPTC andNPTC are smaller than the theoretical values.As an example, Fig. 2 shows the dependence of G(F) on the pH for a deaerated 161073Msolution of TPTC.34 At pH<4, the formazan yield is close to zero, which is due to the fast reaction e¡aq +H+ H. (13) The H atoms react with T+ giving H-adducts. Apparently, the T . radicals derived from TPTC and NPTC not only disproportionate giving rise to formazan but also participate in some other processes, which do not lead to this k9 k11 105 cF/ mol litre71 8 6 4 2 0 0.2 0.4 0.6 Dose/kGy 2 1 Figure 1.Concentration of the formazan formed versus the dose in a deaerated 361073 M solution of TPTC in the absence (1 ) and in the presence (2) of 561073 mol litre71 of 2-isobutylanthraquinone. 674 A K Pikaev, Z K Kriminskayacompound (for example, they can dimerise).32, 34 The tetrazolium radicals generated from NPTB do not tend to dimerise (appa- rently, due to steric hindrance). In alkaline media dimerisation does not occur either, probably due to the fact that the product formed upon the reaction of T .with OH7 only disproportion- ates.32 It was found by pulse radiolysis 32 that in TPTC solutions at pH>9, whenG(F) increases (see Fig. 2), a new short-lived species appears in place of the T . radicals consumed. 2. Radiolysis in the presence of organic compounds Radiolysis of deaerated alkaline aqueous solutions containing organic compounds (formate, EDTA, alcohols) or solutions in water ± alcohol mixtures results in G(F) values reaching 3.5 molecule (100 eV)71 (see Table 1). Evidently,21 when the concen- tration of an organic compound is relatively high, it reacts with hydrogen atoms and OH .radicals (and O7. ) to give reducing radicals able to reduce an additional amount of T+ to T . . The corresponding reactions for HCOO7 taken as an example can be written as follows: H+HCOO7 C . OO7. +H2 , (14) OH(O7)+HCOO7 COO7. +H2O(OH7), (15) T++COO7. T . +CO2 . (16) The occurrence of reaction (16) is confirmed by high k16 values determined by pulse radiolysis (see Table 3).However, these reactions are not controlled by diffusion; therefore, the k16 values correlate with the potentials of the first reduction wave for the corresponding tetrazolium salts measured by polarography.21 Hydrogen peroxide reacts with T . [reaction (11)], and theOH . radical formed in this process participates in reaction (16).This yields radical anions COO7. , which then reduce T+. Thus, the yield of formazan can be calculated as follows: G(F)= 1 2 âGÖeaq¡ Ü+G(H)+G(OH)]. (17) The calculation by this expression using the yields of the water radiolysis products reported in our monograph 26 affords G(F) = 3.2 molecule (100 eV)71. The corresponding experimental results are close to this value (see Table 1). 3. Mechanism of radiolytic reduction. Intermediate products The properties of tetrazolium radicals T . and the H- and OH- adducts formed by tetrazolium salts in aqueous solutions have been studied by pulse radiolysis.21, 23, 32, 35 The optical character- istics of T . (see Table 4) were measured in deaerated neutral or alkaline aqueous solutions of TPTC and NPTC containing tert- butyl alcohol.32 In these solutions, OH .radicals react with the alcohol OH . +(CH3)3COH H2O+C . H2(CH3)2COH. (18) The tert-butanol radical formed is inert towards tetrazolium salts. tert-Butyl alcohol can also react with hydrogen; however, the rate constant for this reaction is relatively low (1.26105 litre mol71 s71).40 Under the conditions employed in the study cited,32 small amounts of the H-adduct could be formed.The reaction of T+ with e¡aq in these solutions gives mainly T . radicals. The optical characteristics of the T . radicals were obtained after applying a correction for the absorption of the H-adduct. The optical characteristics of the H-adducts TH+. (see Table 4) were determined using deaerated acidic (pH 2) solutions of TPTC and NPTC containing tert-butyl alcohol.32 In these solutions, hydrated electrons react with H+ [reaction (13)] being thus converted into hydrogen atoms, and the OH .radicals react with the alcohol [reaction (18)] to give . CH2(CH3)2COH radicals, which are inert with respect to tetrazolium salts. The subsequent transformations afford only the H-adducts in which hydrogen is attached to the benzene ring of the molecule.This conclusion is based on the following observation.32 Tetrazolium salt molecules contain two types of sites, which could be reactive towards H atoms, namely, the tetrazole heterocycle and the benzene rings. If hydrogen were attached to the tetrazolium ring, the tetrazolium salt would be simultaneously reduced; however, this is not observed experimentally.Formazans are not formed in relatively acidic media (see Fig. 2). The spectra of the OH-adducts of tetrazolium salts were recorded for deaerated neutral aqueous solutions of TPTC and NPTC saturated with nitrogen hemioxide.32, 35 In these solutions, e¡aq reacts with N2O and water giving rise to OH . radicals. e¡aq+N2O+H2O OH . +N2+OH7.(19) When this solution is exposed to radiation, OH-adducts and, to a much lesser extent, H-adducts are formed. The optical character- istics of the OH-adducts listed in Table 4 were determined after applying a correction for the absorption of the H-adducts. The rate constants for the reactions of OH . radicals with tetrazolium salts are close in the order of magnitude to the rate constants for the reactions of OH .with benzene derivatives;40 this confirms the assumption that the OH . groups are attached to a benzene ring in the tetrazolium salt molecule. The structure of the OH-adduct formed by TPTC has been determined by quantum-chemical calculations.41 It was found that the OH . radical in the TPTC molecule is bound most likely to the benzene ring that is attached to the carbon atom of the tetrazolium ring.This structure is described by the formula No formazan is formed in solutions saturated with nitrogen hemioxide;32 this means that the H- and OH-adducts are not formazan precursors. Stable products formed in these solutions are soluble in water and absorb light in the ultraviolet region of the spectrum (the maxima of the absorption bands are at 300 and *320 nm for solutions of TPTC and NPTC, respectively).32 The tetrazolium radicals and the H-adducts are consumed in second-order reactions (see Table 3).It has been noted above that both in aqueous and in alcoholic solutions, the T . radicals derived from TPTC and NPTC disappear not only through disproportio- nation but also through dimerisation. The ratios of the rate constants for disproportionation and dimerisation in neutral aqueous solutions of TPTC or NPTC are equal to 0.5 and 1, respectively (i.e.they are much smaller than the corresponding ratio for isopropanol solutions of TPTC; as noted above, the latter is *1.9).21 The ratio of these rate constants depends on the pH; it is greater in alkaline solutions than in k14 k15 k16 k19 N N Ph N Ph N C HO + Cl7 G(F) /molecule (100 eV)71 1.5 1.0 0.5 0 4 6 8 10 pH Figure 2.Dependence of G(F) in a deaerated 161073 M aqueous solution of TPTC on the pH. Radiolysis of solutions of tetrazolium salts 675neutral ones. This dependence might be due to a change in the structure of the tetrazolium radicals in alkaline media, which decreases the probability of dimerisation because of steric hin- drance.When the pH values are sufficiently high, dimerisation does not occur at all. The OH-adducts disappear in first-order reactions 32 (see Table 3). This might be an intramolecular rearrangement of the OH-adducts or their decomposition with abstraction of a water molecule. Similar processes have been observed for the OH- adducts formed by phenol, aniline and toluene.26 4.Radiolysis of aerated solutions The G(F) values for solutions of TPTC and NPTB saturated with air are substantially smaller than those for deaerated solutions (Table 5). A low yield of formazan [*0.16 molecule (100 eV)71] has also been found 42 for X-ray radiolysis of an aerated 2% aqueous gel of agar-agar containing 0.09 mol litre71 of TPTC (the maximum energy of radiation was 60 keV).However, in the case of aqueous solutions of NPTC, this difference inG(F) is not manifested (see Table 5). This is due to the fact that the tetrazolium radical TPT . generated from TPTC, as in alcoholic solutions, is able to react with oxygen to give the initial TPT+ ion [see reaction (9)], whereas NPTC, on the contrary, can be reduced by the O¡2 .radical ions 24 NPT++O¡2 . NPT . +O2 . (20) Therefore, in aqueous and alcoholic solutions of NPTC, when the concentration of the tetrazolium salt is relatively high, atmospheric oxygen hardly influences the yield of formazan. In the case of solutions in aqueous alcohols, for theR . CHOHradicals to be involved in the interaction with NPTC, the concentration of this salt needs to be high enough.Otherwise some of the alcohol radicals would react with oxygen to give peroxy radicals RCH(OH)O2 . , which are apparently unable to reduce NPTC.24 The conclusions about the reasons for the low yields of formazan in aerated solutions of TPTC and NPTB have been confirmed by the results of a study carried out by the pulse radiolysis method.23 It was found that the tetrazolium radicals T .formed in these solutions in the presence of tert-butyl alcohol disappear much faster than in deaerated solutions. The constants k9 were determined by measuring the kinetics of consumption of T . in the presence of oxygen (see Table 3). The direction of electron transfer in reactions the rates of which are not controlled by diffusion may be determined, for instance, by the electron affinity of the reactants.Evidently, the electron affinity of the oxygen molecule should be higher than that of the TPTC and NPTB molecules but lower than that of the NPTC molecule.23 This is confirmed by the results of determi- nation of the half-wave potentials for the polarographic reduction of tetrazolium salts.21 The potentials for the single-electron reduction of tetrazolium salts and two-electron reduction of oxygen are 70.40, 70.30, 70.17, and 70.30 V for TPTC, NPTB, NPTC, and O2, respectively.21, 23 The G(F) values attained at high concentrations of NPTC are larger than the theoretical value (see Table 5) calculated from Eqn (17) using the known yields of the products of water radiolysis.It cannot be ruled out that in this system, due to the relatively high concentrations of conjugated acceptors (the alcohol, on the one hand, and TPTC and oxygen, on the other hand), the reactions in spurs are largely suppressed, and this results in increased yields of the primary radiolysis products, responsible for the formation of formazan. 5. Radiolytic reduction of Nitrotetrazolium Blue Interesting results have been obtained in a pulse radiolysis study of the mechanism of reduction of Nitrotetrazolium Blue in aqueous solutions.10, 33 The reduction of the two-charged cation, NTB2+, contained in this molecule to give the corresponding diformazan is a four-electron process, which gives consecutively the monotetra- zolium radical NTB+., monoformazan MF+, monoformazan radical MF . and finally diformazan DF.Conditions were selected 33 under which exposure of a for- mate-containing aqueous solution of NTB2+ to an electron pulse affords NTB+. . The rate constant for the reduction of NTB2+ with the COO7. radical anion was measured (see Table 3). Study of the kinetics of consumption of NTB+. showed that the rate constant for this process depends crucially on the pH.The following reaction was postulated for a neutral medium: 2NTB+. +H2O NTB2++MF+...OH7. (21) The reaction in an alkaline medium yields the hydroxy-derivative NTB+. ...OH7, which disappears more rapidly than NTB+. . The corresponding reaction can be written as follows: 2(NTB+. ...OH7)+ H2O (22) NTB2++MF+...OH7+2OH7. The k21 and k22 values found for these reactions are listed in Table 3.The higher rate of reaction (22) is apparently due to the fact that the positive charge of NTB+. is shielded by the hydroxyl ion. Dimerisation of NTB+. does not occur, probably for steric reasons. The kinetics of the reaction NTB2++O¡2 . NTB+. +O2 (23) were studied by the stopped flow method.33 The constant k23 found in this study is presented in Table 3. It was noted that the back reaction does not occur under the conditions employed.It was concluded that Nitrotetrazolium Blue can be used for qualtitative but not quantitative determina- tion of the O¡2 . radical anions. It should also be emphasised that H2O does not react with NTB2+. IV. Solid matrices Polymeric films with tetrazolium salts (mainly TPTC) introduced into them have been mostly studied as applied to the dosimetry of ionising radiation (see above).Radiolytic transformations of k20 k21 k22 k23 Table 5. Formazan yields [G(F)/ molecule (100 eV)71] upon g-radiolysis of deaerated and aerated aqueous and water ± isopropyl alcohol (1 : 1 by volume) solutions of tetrazolium salts at various pH.23, 24 Tetra- Concen- Presence Gas satu- pH G(F) zolium tration/ of rating salts mol litre71 alcohol the solution TPTC 861074 yes argon 11.0 3.1 861074 " air 11.0 0.14 161073 no argon 6.9 0.45 161073 " air 10.3 1.2 161071 (see a) " " 7.0 ± 7.5 0.22 NPTC 161073 " argon 6.9 0.6 161073 " air 6.9 0.45 161073 " argon 11.3 1.3 161073 " air 11.3 1.5 461073 yes " 10.5 4.9 161072 " " 10.5 5.3 NPTB 561074 no " 6.9 0.3 561074 " argon 6.9 1.2 a Radiolysis under the action of X-rays (the maximum energy 60 keV).The solution contained the triethanolamine ± HCl buffer.22 676 A K Pikaev, Z K KriminskayaTPTC and NPTC in poly(vinyl alcohol) films have been studied in detail.25 The paramagnetic species formed in poly(vinyl alcohol) films irradiated under various conditions have been investigated.25, 43, 49 The yield of these species is *4 molecule (100 eV)71.The EPR spectrum of an irradiated film recorded at 77 K points to the presence of three paramagnetic species: a captured electron and the *CH2CH[OC . (CH3)O7H+]CH2* and *CH2C . (OH)CH2* radicals. At room temperature, only the former radical is detected. All the paramagnetic species mentioned above possess reduc- ing properties. At relatively high temperatures, the species become mobile, and their interaction with TPTC and NPTC resulting in the formation of formazans becomes possible. This conclusion is confirmed experimentally.Table 1 presents the G(F) values obtained at room temperature for films containing various amounts of these salts.25 It is noteworthy that the formazan concentration obeys a linear dependence on the radiation dose up to a dose of 25 kGy.Evidently, the formation of formazan in films is also a two- electron process, T+ ions being reduced in reactions with mobile electrons and with the radicals mentioned above. For example, the following reaction is possible 25 Thus, G(F) should be 0.5G(radical),{ i.e. it should be equal to *2 molecule (100 eV)71. However, only in a film containing 7.161073 mol litre71 of TPTC, G(F) < 0.5G(radical); in all other cases, G(F) is greater than 0.5G(radical) (see Table 1), and for large concentrations of NPTC it is more than twice as great.It can be concluded that G(F) is determined both by the distance between tetrazolium salt molecules and by the electron-acceptor properties of these molecules.25 A similar situation has been observed for poly(vinyl alcohol) films containing methylviologenMV2+.47, 48 When these films are exposed to radiation, the colourless MV2+ dication is reduced via a single-electron process to give MV+., which has an intense blue colour. According to several measurements,44, 45 the G(MV+. ) values vary from 8.1 to 9.8 molecule (100 eV)71. This is much larger than the G(radical) value. It was postulated 25 that the high G(F) values observed are due to the reactions of T+ with radical pairsR .1 ...R .2 , which are formed in some polymers including poly(vinyl alcohol) films (see, for example, Ref. 50) T++R . 1...R . 2 R . 1+Rá2 +T . . (25) In the absence of tetrazolium salts, the radical pair undergoes recombination. The EPR spectrum of a poly(vinyl alcohol) film contains an unresolved signal with a g-factor of 4 corresponding to this radical pair;25 the intensity of this signal is four orders of magnitude lower than that of the signal characterised by a g-factor of 2.Another possible reason is the transfer of the excitation energy along the chain of polymer bonds to a tetrazolium salt molecule. Thus, in a solid matrix of a polymeric alcohol, tetrazolium salts are also reduced to formazans by electrons and `alcohol' radicals. V.The use of tetrazolium salts in dosimetry The property of colourless or yellowish liquid or solid solutions of tetrazolium salts to turn pink, orange, or orange-red upon radio- lytic reduction to formazans has been recommended for use in the dosimetry of ionising radiations. 1. Alcoholic, aqueous and water ± alcohol solutions Back in the late 1940s,12 it was found that aqueous solutions and gelatine emulsions of TPTC change to a red colour on exposure to UV light (l < 365 nm), a-particles, or X-rays.It was also found that the colour intensity did not depend on the pH in the range 5.5 ± 6.6 In a number of publications (see, for example, Refs 22, 42, 51 ± 53), it has been suggested to use TPTC in radiology and radiobiology in order to obtain three-dimensional images of dose distribution upon X-ray treatment.For example, a 2% aqueous gel of agar-agar containing TPTC (0.05%) has been used 52 to model the three-dimensional dose distribution in fish and meat foodstuffs treated with X-rays (maximum energy 60 keV, dose *15 kGy). It has been reported 42 that gels of this type are suitable for measurement of three-dimensional dose distribution for X-ray and electron radiations.It was also shown that the concentration of the formazan produced depends linearly on the radiation dose up to a dose of 12 MGy. The influence of various parameters (the nature of the buffer solution, TPTC concentration, the presence of oxygen in the solution, and the dose rate) on the yield of formazan has been studied in detail.22 The precipitate of formazan formed upon irradiation with X-rays with a maximum energy of 60 keV was dissolved in an organic solvent (for example, in tetrahydrofuran) added to the solution. It was found that in aerated solutions, G(F) does not depend on the pH of the solution over the range 5 ± 8.At higher pH values the yield increases, while at lower pH it decreases, and becomes equal to zero at pH 1.5.If the concen- tration of TPTC increases, the yield first increases and then remains constant in the concentration range from 361073 to 161071 mol litre71. The G(F) values in deaerated solutions are approximately twice as large as those in aerated solutions. In systems saturated with oxygen, the G(F) values are 2.7 times lower than in aerated solutions.The addition of hydrogen peroxide decreases G(F). It was proposed to use aerated 261072 ±161071 Maqueous solutions of TPTC containing a triethanolamine ± HCl buffer for the measurement of absorbed X-ray radiation doses ranging from 0.18 kGy to 0.18 MGy. Note that the dosimetric solution should be stored in the dark.The possibility of using aerated ethanolic solutions of TPTC for determination of the absorbed doses of g-radiation has been studied.37 Solutions in ethanol containing 5% of methanol and 5% of isopropanol were used. It was found that a 4.561072 M solution of TPTC can be used to measure radiation doses in the range 1 ± 16 kGy. For lower concentrations of TPTC, the upper limit of the measurable doses decreases (at higher doses, the dependence of the formazan concentration on the dose becomes nonlinear, because the formazan starts to decompose).Figure 3 presents the dependence of the optical absorption of aerated solutions of TPTC on the dose. It can be seen that the yield of formazan diminishes with a decrease in the TPTC concentra- tion; the yield obtained in a 561073 M solution is *2.3 times T++*CH2C .CH2* OH (24) T . +*CH2CCH2*+H+. O {G(radical) implies the yields of both radicals and electrons. Optical density 2.0 1.5 1.0 0.5 0 5 10 15 20 Dose (in water)/ kGy 4 3 2 1 Figure 3. Optical density (l=480 nm) of aerated 561073 (1 ), 161072 (2 ), 1.861072 (3 ), and 4.561072M (4 ) ethanolic solutions of TPTC versus the radiation dose (optical path length 0.1 cm).Radiolysis of solutions of tetrazolium salts 677lower than that in a 4.561072 M solution. The yields also depend on the temperature. The temperature coefficient in the range 0 ± 30 8C is approximately +0.8% per 1 8C, but in the temperature range between 30 and 60 8C, it is substantially larger. Non- irradiated and radiated solutions are stable during storage in the dark in sealed tubes for at least 5 days.However, exposure to daylight and especially to bright sunlight leads to slow formation of formazan upon photolysis. If the solution is saturated with oxygen, the upper limit of determination of the dose increases to 36 kGy. Deaerated solutions are more `sensitive' but the upper limit decreases to *3 kGy. The optical characteristics of 1,3,5- triphenylformazan and other formazans are listed in Table 6.The formation of formazan in solutions of TPTC is inhibited by oxygen. Figure 4 shows the concentrations of the formazan formed in aerated 161073 M aqueous solutions of TPTC versus the g-radiation dose for two different pH values.24 It can be seen that at low doses almost no formazan is formed.When the doses are larger than 0.8 kGy and oxygen in the solution is consumed almost entirely, the yield of formazan increases substantially. A similar type of behaviour has been observed in the case of aerated solutions of Tetrazolium Blue in aqueous alcohols. These properties have been used to develop a threshold chemical dosimeter.54 The threshold dose is detected by a sharp increase in the optical absorption of the solution in the maximum of the formazan band.This dose changes upon variation of the concen- tration of ethanol (the solubility of air in ethanol is approximately an order of magnitude higher than that in water) or tetrazolium salt in the solution. The threshold doses measured by means of aerated solutions of TPTC or TB in aqueous ethanol amount to 1.6 ± 3.4 kGy.It follows from the foregoing that, due to the `inhibiting' effect of oxygen, aerated aqueous and alcoholic solutions of TPTC can be used only for determination of relatively large radiation doses. It has been found 24 that this effect is not manifested in aqueous solutions of NPTC (see Table 5). An aerated (0.4 ± 1)61072 M solution of NPTC in a water ± isopropyl alcohol mixture (1 : 1 by volume) containing 0.2 mol litre71 of formate (pH 9.5 ± 11) can be used to determine absorbed g-radiation doses in the range between 5 and 50 Gy (Fig. 5).Formate is needed to eliminate the short `induction period'. The sensitivity of the spectrophotometric method for formazan analysis based on the use of a system with a 561073M solution of NPTC amounts to 661073 Gy71 cm71.When the NPTC concentration is equal to 161072 mol litre71, the sensitivity of the method increases to 161072 Gy71 cm71, and the threshold of the dose determination decreases to 1 Gy. The optical absorption of irradiated solutions changes by not more than 3% over a period of 24 h. The solutions are sensitive to Table 6. Optical characteristics of formazans.Formazan Matrix lmax/ 107 3 emax / Ref. nm m2 mol71 1,3,5-Triphenyl- ethanol a 480 1.5 39 formazan isopropanol 485 1.6 18 acetone 480 7 42 water ± isopropa- 485 1.6 21, 24 nol mixture (1 : 1 by volume) 2% aqueous 515, 7 42 agar-agar gel 565 poly(vinyl 500 0.92 25 alcohol) the same 493, 540 7 35 (shoulder) b " 490 7 55 polyvinyl- 550 c 7 56 pyrrolidone 1-(p-Nitrophe- water ± isopropa- 475 ± 480 1.9 21, 24 nyl)-3,5-diphe- nol mixture nylformazan (1 : 1 by volume) polyvinyl- 500 0.80 25 pyrrolidone 1,5-Diphenyl-3- water ± isopropa- 480 1.2 21 (p-nitrophe- nol mixture nyl)formazan (1 : 1 by volume) Monoformazan water, pH 5.7 ± 6.7 530 1.28 33 from NTB water, pH 9.5 ± 11.0 530 2.54 33 Monoformazan aqueous 560 7 54 from TB ethanol poly(vinyl 540 7 54 alcohol) a Ethanol contained 5% of methanol and 5% of isopropyl alcohol.b The shoulder at 540 nm belongs apparently to ditetrazolium salt. c The band at 550 nm might belong to ditetrazolium salt. 104 c / mol litre71 2.0 1.5 1.0 0.5 0 0.5 1.0 Dose/kGy 1 2 Figure 4. Dependence of the formazan concentration in an aerated 161073 M aqueous solution of TPTC at pH 10.3 (1 ) and 8.5 (2 ) on the absorbed dose. 0.5 0.4 0.3 0.2 0.1 0 10 20 30 40 Dose/ Gy �1 �2 �3 �4 Optical density Figure 5. Dependence of the optical density (l = 475 nm) of aerated water ± alcohol (1 : 1 by volume) solutions of NPTC on the g-radiation dose; (1) a 461073 M water ± isopropanol solution, pH 10.5; (2) the same solution containing 0.2 mol litre71 of formate; (3) a 161073 M water ± isopropanol solution containing 0.2 mol litre71 of formate, pH 10.5; (4) a 461073 M water ± ethanol solution containing 0.2 mol litre71 of for- mate, pH 9.5 (optical path length 1 cm). 678 A K Pikaev, Z K Kriminskayalight; therefore, they should be stored in the dark. The results are liable to a positive temperature effect, but if the measurements are carried out at 205 8C, this effect can be neglected.Similar results have been obtained with aerated weakly alkaline (pH 8.5 ± 9) solutions of NTB (concentration 1.56 1074 ± 4.561073 mol litre71) in aqueous alcohols (1 : 1 by vol- ume).54 Aqueous solutions of ethanol and isopropanol were used. This method permits determination of doses from 5 to 150 kGy. 2. Polymer films Dosimetric systems based on tetrazolium salts in polymeric films have been described in the literature.The Kodak Pathe company (France) have developed a dosimetric gelatine film containing TPTC, suitable for measuring doses of about tens of kilogray.57 Practical details of the application of these films in the dosimetry of ionising radiation can be found in the literature.55, 58, 59 Other TPTC-containing polymeric films, for example, poly(- vinyl acetate),37 polyvinylpyrrolidone,56 and poly(vinyl alcohol) films 25, 35, 54, 60 have also been proposed for dosimetry.Poly(vinyl alcohol) films have been studied most comprehen- sively. These films can be used to measure absorbed doses in the range from 0.5 to several tens of kilogray.25 Another publica- tion 35 presents a somewhat different range of measurable doses, from 1 to 100 kGy.For NPTC-containing films, the lower limit of determination of absorbed doses is 0.1 kGy.25 In the case of films with TPTC, the readings do not depend on the dose rate, at least in the range from 0.96 to 3.26107 Gy s71.35, 64 The optical absorp- tion of irradiated films containing TPTC or NPTC changes by not more than 14% over a period of 27 days.54 However, the readings are somewhat dependent on the temperature.The temperature coefficient for the readings for TPTC-containing poly(vinyl alco- hol) films is about +0.46% per 1 8C. This can be neglected if the measurements are performed at 205 8C. The main drawback of films containing monotetrazolium salts is that they are sensitive to light. Therefore, they should be stored in the dark.This drawback can be largely eliminated if TB is used as the radiochromic additive.54 During storage under ordinary conditions, the optical absorption of these films remains almost invariable over a period of 14 days. Transparent and matt films containing TB have been used for a long period as dose indicators for radiation sterilisation of medical wares.60 The use of matt films is due to the need to distinguish more clearly the colours of nonirradiated and irradi- ated films.It has been proposed 35 that TPTC-containing poly(vinyl acetate) films can serve for determination of doses between 5 and 50 kGy. In addition, they can be used to obtain radiographic images. It has been suggested 56 that polyvinylpyrrolidone films with TPTC may find application for determination of doses of up to 40 kGy, while NTB can be used as a radiochromic additive to polymeric matrices. VI.Conclusion The above discussion leads to the following conclusions. 1. The use of radiation-chemical methods (first of all, pulse radiolysis) made it possible to study the kinetics of reduction of tetrazolium salts to formazans in aqueous and alcoholic solutions and in solid matrices and to elucidate the nature of the intermedi- ate species. 2. The investigation of radiolytic transformations of tetrazo- lium salts provided more precise data about some aspects of the action of ionising radiation on liquid alcohols and poly(vinyl alcohol) films. In particular, the nature of the free radicals formed in irradiated poly(vinyl alcohol) was determined, and the hypoth- esis of participation of radical pairs in radiation-induced chemical reactions with admixtures present in the polymer was confirmed. 3. Studies of the radiolytic transformations of tetrazolium salts led to new applications of these compounds in chemistry and biochemistry. 4. The development of dosimetric systems based on tetrazo- lium salts suitable for the measurement of different ranges of absorbed doses and their three-dimensional distribution in irradi- ated objects is fairly significant from the practical viewpoint.The main drawback of these systems (their low resistance to light), which holds up their wide use, can be largely eliminated by using poly(vinyl alcohol) films containing Tetrazolium Blue as a radiochromic additive. References 1.H von Pechmann, P Runge Berichte 27 2920 (1894) 2. G Lakon Ber. Deut. Botan. Ges. 60 299 (1943) 3. H J Cottrell Nature (London) 159 748 (1947) 4. A M Mattson, C O Jensen, R A Dutcher 106 194 (1947) 5. T D Waugh Trans. Faraday Soc. 33 314 (1948) 6. F H Straus, N D Cheronis, E Straus Science 108 113 (1948) 7. E Farber, E Bueding J. Histochem. Cytochem. 4 357 (1956) 8. F P Altman Prog.Histochem. Cytochem. 9 51 (1976) 9. D Amano, Y Kagosaki, T Usui, S Yamamoto, O Hayaishi Biochem. Biophys. Res. Commun. 66 272 (1975) 10. B H J Bielski, H W Richter J. Am. Chem. Soc. 99 3019 (1977) 11. C Auclair, M Torres, J Hakim FEBS Lett. 89 26 (1978) 12. Z S Gierlach, A T Krebs Am. J. Roentgenol. Radium Therapy 62 559 (1949) 13. A W Nineham Chem. Rev. 55 355 (1955) 14.O W Maender, G A Russell J. Org. Chem. 31 442 (1966) 15. F A Neugebauer, G A Russell J. Org. Chem. 33 2744 (1968) 16. I S Trubnikov Zh. Org. Khim. 12 1373 (1976) a 17. G G Glenner, in H J Coon's Biological Stains Ch. 9 (Ed. R D Lillie) (St.Louis: Sigma Chemical, 1990) 18. Z K Kriminskaya, K M Dyumaev, G V Fomin, A K Pikaev Khim. Vys. Energ. 17 304 (1983) b 19. Z K Kriminskaya, N P Makshanova, K M Dyumaev, A K Pikaev Khim.Vys. Energ. 21 501 (1987) b 20. Z K Kriminskaya Khim. Vys. Energ. 30 391 (1996) b 21. Z K Kriminskaya, A A Konarev, K M Dyumaev, B V Tolkachev, A K Pikaev Izv. Akad. Nauk SSSR, Ser. Khim. 1746 (1988) c 22. E Winter Z. Phys. Chem. 40 109 (1964) 23. Z K Kriminskaya, A A Konarev, K M Dyumaev, A K Pikaev Khim. Vys. Energ. 23 467 (1989) b 24.A K Pikaev, Z K Kriminskaya Mendeleev Commun. 200 (1995) 25. Z K Kriminskaya, S F Ginzburg, A A Molin Khim. Vys. Energ. 25 335 (1991) b 26. A K Pikaev Sovremennaya Radiatsionnaya Khimiya. Radioliz Gazov i Zhidkostei (Modern Radiation Chemistry. Radiolysis of Gases and Liquids) (Moscow: Nauka, 1986) 27. Z K Kriminskaya, K M Dyumaev, A K Pikaev Izv. Akad. Nauk SSSR, Ser. Khim. 48 (1985) c 28.Z K Kriminskaya, K M Dyumaev, L S Vyshchipanova, Yu V Ivanov, A K Pikaev Khim. Vys. Energ. 18 40 (1984) b 29. Z K Kriminskaya, K M Dyumaev, A K Pikaev Khim. Vys. Energ. 22 276 (1988) b 30. Z K Kriminskaya, A G Kotov, Yu V Ivanov, N P Kon'kova, B V Tolkachev Khim. Vys. Energ. 21 316 (1987) b 31. Z K Kriminskaya, A G Kotov, N P Kon'kova, Yu V Ivanov Khim. Vys. Energ. 25 144 (1991) b 32.Z K Kriminskaya, K M Dyumaev, L S Vyshchipanova, Yu V Ivanov, A K Pikaev Khim. Vys. Energ. 22 13 (1988) b 33. B H J Bielski, G G Shiue, S Bajuk J. Phys. Chem. 84 830 (1980) 34. A K Pikaev, Z K Kriminskaya, in The 10th International Meeting on Radiation Processing (Conference Program and Abstracts), Anaheim, 1997 p. 197 35. A Kovacs, L Wojnarovits,W L McLaughlin, S E E Eid, A Miller Radiat. Phys. Chem. 47 483 (1996) 36. H Zollinger Colour Chemistry. Syntheses, Properties and Applications of Organic Dyes and Pigments (Weinheim: Verlagsgesellschaft, 1972) 37. L M Dorfman, N E Shank, S Arai Advan. Chem. Ser. (82) 58 (1968) 38. A V El'tsov, O P Studzinskii, V M Grebenkina Usp. Khim. 46 185 (1977) [Russ. Chem. Rev. 46 93 (1977)] Radiolysis of solutions of tetrazolium salts 67939. A Kovacs, L Wojnarovits, N B El-Assy, H Y Afeefy, M Al-Sheikhly,M L Walker,W L McLaughlin Radiat. Phys. Chem. 46 1217 (1995) 40. A K Pikaev, S A Kabakchi Reaktsionnaya Sposobnost' Pervichnykh Produktov Radioliza Vody. Spravochnik (Reactivity of Primary Prod- ucts of Water Radiolysis. Handbook) (Moscow: Energoizdat, 1982) 41. Z K Kriminskaya, K A Kon'kov Khim. Vys. Energ. 26 111 (1992) b 42. Th Gruenewald, W Schmidt-Lorenz Atomkernenergie 9 142 (1964) 43. H Hase, H Yamaoka Radiat. Eff. 19 195 (1973) 44. V S Chervonenko Khim. Vys. Energ. 10 458 (1976) b 45. L T Patterson, R D Small, J C Scaniano Radiat. Res. 72 218 (1977) 46. I P Shelukhov, G S Zhdanov, V K Milinchuk Khim. Vys. Energ. 15 324 (1981) b 47. T Ogawa, H Nishikawa, S-I Nishimoto, T Kagiya Radiat. Phys. Chem. 29 353 (1987) 48. S-I Nishimoto,M Ye, Y Lu, T Kawamura, T Kagiya Radiat. Phys. Chem. 32 727 (1988) 49. Z K Kriminskaya Khim. Vys. Energ. 27 37 (1993) b 50. M Iwasaki, T Ishikawa, T Ohmori J. Chem. Phys. 50 1984 (1969) 51. J G Kereiakes, A T Krebs, in Medical Physics Vol. 3 (Ed. O Glasser) (Chicago: The Year Book Publishers, 1960) p. 509 52. W Schmidt-Lorenz, A Berger Int. J. Appl. Radiat. Isot. 11 161 (1961) 53. A T Krebs, in The Encyclopedia of X-Rays and Gamma Rays (Ed. G L Clark) (New York: Reinhold Publishing, 1963) p. 274 54. A K Pikaev, Z K Kriminskaya Radiat. Phys. Chem. 52 555(1998) 55. W L McLaughlin, in Sterilisation by Ionising Radiation Vol. 1 (Eds E R L Gaughran, A J Goudie) (Montreal: Multiscience Pub- lications, 1974) p. 219 56. W L McLaughlin, in High Dose Dosimetry for Radiation Processing (Vienna: IAEA, 1991) p. 3 57. Fr. P. 2 050 221; Chem. Abstr. 76 67 183 (1972) 58. F Bredoux Societe Kodak Pathe Report, Paris 1972 59. E T Snow Report SLA-73-0991, Sandia Laboratories, New Mexico, USA, 1974 60. RF P. 1 739 766; Byull. Izobret. (1) 196 (1994) a Russ. J. Org. Chem. (Engl. Transl.) b High Energy Chem. (Engl. Transl.) c Russ. Chem. Bull. (Engl. Transl.) 680 A K Pikaev, Z K Kriminskaya

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 principal sources of the pollution of the environ- ment by polychlorobiphenyls are indicated and their ecological danger is estimated; the output in the manufacture and applica- tions of polychlorobiphenyls are quoted. The known methods for the neutralisation of polychlorobiphenyls are examined. The methods considered are analysed and their practical significance for industry is estimated.The bibliography includes 277 references. I. Introduction Polychlorobiphenyls (PCB) possess a series of unique physical and chemical properties: exceptional thermophysical and electrical insulating characteristics, thermal stability, inertness to acids and bases, fire resistance, satisfactory solubility in fats, oils, and organic solvents, high compatibillty with resins, plasticity, resist- ance to corrosion, and an excellent capacity for adhesion.1± 9 All these features are responsible for their wide-scale employment as dielectrics in transformers and capacitors,1, 3, 7, 10 ± 18 as hydr- aulic liquids,10, 13, 16 ± 20 as heat exchangers and refriger- ants,1, 3, 6, 9, 10, 12 ± 14, 16 ± 18, 20 as lubricating oils,3, 6, 16, 17, 20 as components of varnishes, paints, and adhesive composi- tions,6, 10, 14, 15 ± 17, 20 ± 24 as plasticisers and fillers in plastics and elastomers,1, 3, 6, 16, 17, 20, 24 as antipyrenes,1, 9, 15, 20, 25 and as sol- vents.1, 6, 16, 22 The industrial synthesis of PCB is based on the substitutional chlorination of biphenyl in the presence of electrophilic substitu- tion catalysts:7, 26 Polychlorodibenzofurans: (PCDF) are formed as side prod- ucts:7 There are 209 individual PCB differing in the number and positions of chlorine atoms in the molecule.Depending on the content of chlorine atoms, PCB have different numbers of isomers (Table 1). Technical PCB mixtures produced by industry consist of 50 ± 70 individual compounds. Most of them contain between 3 and 8 chlorine atoms, although there are small amounts of both more and less chlorinated PCB.These mixtures are known under different names: Arochlor (USA), Phenochlor (France), Chlo- phen (Federal Republic of Germany), Kanechlor (Japan), Fen- chlor (Italy), and Sovol (Russia). The proportions of PCB in the Arochlors are presented in Table 2. The world manufacture of PCB has increased successively from 1929 to 1970 when these compounds were recognised as + (x +y)Cl2 (1) Clx Cly + (x+y)HCl.H2O 7HCl O Clm Cln71 (2) Clm Cln L N Zanaveskin The `Sintez' Research Institute, Ugreshskaya ul. 2, a/Box 56, 109432 Moscow, Russian Federation. Fax (7-095) 279 46 84. Tel. (7-095) 279 83 29 V A Aver'yanov Tula State University, prosp. Lenina 92, 300600 Tula, Russian Federation. Fax (7-087) 233 13 05.Tel. (7-087) 225 18 40 Received 19 August 1997 Uspekhi Khimii 67 (8) 788 ± 800 (1998); translated by A K Grzybowski UDC 614.7 : 547.622'113(048) Polychlorobiphenyls: problems of the pollution of the environment and technological neutralisation methods L N Zanaveskin, V A Aver'yanov Contents I. Introduction 713 II. Reagent-based neutralisation methods 715 III. Electrochemical methods 716 IV.Pyrolytic methods 716 V. Radiation and photochemical dechlorination methods 717 VI. Biotechnological methods 718 VII. Oxidative methods 719 VIII. Hydrogenolysis of polychlorobiphenyls 721 Table 1. The number of possible PCB isomers for different contents of chlorine atoms in the molecules.27 Name of PCB Molecular No. of isomers formula of PCB Monochlorobiphenyl C12H9Cl 3 Dichlorobiphenyl C12H8Cl2 12 Trichlorobiphenyl C12H7Cl3 24 Tetrachlorobiphenyl C12H6Cl4 42 Pentachlorobiphenyl C12H5Cl5 46 Hexachlorobiphenyl C12H4Cl6 42 Heptachlorobiphenyl C12H3Cl7 24 Octachlorobiphenyl C12H2Cl8 12 Nonachlorobiphenyl C12HCl9 3 Decachlorobiphenyl C12Cl10 1 Russian Chemical Reviews 67 (8) 713 ± 724 (1998) #1998 Russian Academy of Sciences and Turpion Ltdpollutants of the environment.16 Towards the end of the 1980s, the total amount of PCB produced was estimated as 1 million tonnes.16, 17 Analysis of the pattern of the consumption of PCB in various countries showed that about 40% of this amount, i.e. 400 000 tonnes enter the environment, while the remaining 600 000 tonnes, at the time when the estimate was made, was still being used or was stored in settling tanks.17 According to later estimates, even after the prohibition of the manufacture of these products in the USA, Japan, and a number of European countries, the content of PCB in the environment hardly changed.The nature and dynamics of the distribution of PCB in the environment is in many respects determined by their physical properties such as persistence, chemical inertness, fairly high vapour pressure, and capacity for diffusion.1±9, 26±33 The persis- tence of PCB makes it possible to include them among typical xenobiotics which are not very susceptible to the action of a wide variety of microorganisms and animal enzyme systems.34 Persis- tence combined with lipophilicity promotes the bioaccumulation of PCB in the fatty tissues of man and animals in amounts dangerous for vital activity.9, 10, 16, 17, 35 ± 37 Chemical inertness is responsible for the resistance of PCB to the action of environ- mental abiotic factors, the relatively high vapour pressure facili- tates their spreading in the atmosphere, while their capacity for diffusion favours their migration in the soil and in subterranean and surface waters.Despite the gradual reduction of the applications of PCB in the economy, they continue to pollute the environment 4, 10 and nowadays these toxic products, which have spread virtually throughout the entire terrestrial globe, are present in the organism of each of us.10, 16 As PCB are incorporated in the biological chains, the weakly chlorinated components are progressively lost by virtue of their selective biotransformation.8, 9, 28, 37, 38 The most dangerous highly chlorinated PCB therefore accumulate in the human and animal organisms.According to data of the World Health Organisation,28 the principal ways in which PCB enter the environment are as follows: vaporisation from plasticisers; evolution on combustion of indus- trial and domestic waste and also when transformers, capacitors, and other industrial equipment in which PCB are used are switched on; leakage together with other industrial waste; the removal of PCB to rubbish dumps and aeration fields; other unmonitored pathways.The environment is polluted mainly via the first three path- ways. The typical PCB concentrations in various objects in the environment 27 are as follows: in the air of agricultural regions 0.05 ng m73, in the air of cities 1 ± 5 ng m73; on the surface of soil 2 ± 50 mg kg71; in plants 10 mg kg71; in water 2 ng litre71; in fatty tissues 1 ng kg71; in human breast milk 10 mg kg71; in the organisms of marine animals 5 ± 50 ng kg71; in the fat of the otter 5 ± 200 ng kg71.The potential danger of PCB is associated with their use in open systems, with possible spillage, with leakage and vapor- isation from capacitors, transformers, and other elements of equipment in the course of their cleaning, emptying, and filling, with the breakdown of hermetic seals in equipment, and with the occurrence of fires in plant where PCB are employed as dielectric liquids or heat exchangers.7, 8, 16, 17, 36 ± 42 An example of mass poisoning of people by PCB as a consequence of the breakdown of hermetic seals in heat-exchange apparatus in the course of the refining of rice oil is known.This incident, which has entered history as the `Yusho incident', occurred in Japan in 1968. The symptoms of poisoning were an increase in the size and hyper- secretion by mammary glands, nausea, vomiting, enlargement and porphyria of the liver, pathological changes in the peripheral nervous system and in the composition of blood, and disturbance of the functioning of adrenal glands.Thermal overloading or fires in plant (transformers, capaci- tors) in which PCB-containing materials were employed as dielectrics or refrigerants constitutes a major hazard to the environment, because uncontrolled combustion of PCB results in the formation of the highly toxic polychlorodibenzodioxins (PCDD) and polychlorodibenzofurans (PCDF).7 ± 9, 39, 40, 42 ± 45 According to certain ideas,7, 46, 47 such transformations may occur in accordance with processes (3).The combination of persistence, chemical stability, and lip- ophilicity of PCB creates the possibility of their bioaccumulation in lipid-rich liver, kidney, adrenal gland, lung, and brain tissues of man and animals.1, 4, 8, 15, 28 The concentration of PCB in human blood and milk has been noted.1, 7, 16, 28 Until recently, the toxicity of PCB remained controversial.Some investigators denied the existence of a connection between various diseases and the presence of PCB in human and animal organisms, others attributed a number of serious toxicological effects, causing chronic illnesses, to the action of PCB.1, 5, 7, 9, 15, 16, 24, 35, 48, 49 More rigorous studies carried out recently made it possible to discover a whole spectrum of the toxic effects of PCB on man and laboratory animals, including lethal effects, harmful influence on reproduction and development, liver porphyria, weight loss, dermatological effects, suppression of the immune system, dis- turbance of the functioning of the kidneys, atrophy of the thymus, carcinogenesis, disorganisation of the homeostasis of the steroid hormones, and a mutagenic effect.37, 45, 50 The massive effect of PCB on ecosystems as a whole and on man in particular is intensified by constantly operating factors such as the increase in the content of PCB in water and aqueous ecosystems as a result of the entry of surfactants into the latter,2 the biotransformation of PCB in the environment into still more Table 2.Approximate composition of various Arochlors (%). PCB [Cl] (mass %) Brand of Arochlor 1242 1248 1254 1260 C12H9Cl 18.8 3 7 7 7 C12H8Cl2 31.8 13 2 7 7 C12H7Cl3 41.3 28 18 7 7 C12H6Cl4 48.6 30 40 11 7 C12H5Cl5 54.4 22 36 49 12 C12H4Cl6 59.0 4 4 34 38 C12H3Cl7 62.8 7 7 6 41 C12H2Cl8 66.0 7 7 7 8 C12HCl9 68.8 7 7 7 1 7HCl H2O OH 7H2O Cln Clm PCB Cl Cln Clm Cl PCDF O Cln Clm (3) H2O 7H O Cl Cln Clm OH Cl O Cln Clm 7HCl PCDD O O Cln Clm [O] 714 L N Zanaveskin, V A Aver'yanovtoxic products,51 and the accumulation of PCB in human and animal organisms as a consequence of their accumulation in the food chains.37 The increase in the level of PCB in living organisms and the destruction of animals induced by this, sometimes on a mass scale, noted in a number of regions of the planet (particularly in the aquatic systems of the Pacific Ocean), indicates the potential danger of the bioaccumulation of PCB to populations of living organisms and whole ecosystems.7, 18, 37 It has to be borne in mind that, by virtue of their chemical and thermal stability and excep- tional operating properties, the PCB-containing materials pro- duced earlier by industry will continue in use for a long time yet (more than 20 years) in active closed systems.52 Thus the danger of the accumulation of PCB in living organisms and the threat of the destruction of populations and whole ecosystems, as well as the potential possibility of leakages or a series of discharges from settling tanks and active plant have raised the problem of the pollution of the environment by these compounds to the class of global environmental problems.Bearing in mind the very serious level of environmental danger, Canada, the USA, Japan, the countries of the EEC, and other states have developed measures regulating the manufacture, use, processing, and destruction of PCB.8, 18, 35, 53 ± 63 These meas- ures include the following: complete prohibition of the manufac- ture of PCB, gradual replacement of PCB by alternative materials with less toxic properties, the monitoring of materials containing PCB in the course of their employment, storage, transport, and distribution, the development of effective ecologically safe tech- nologies for the processing and neutralisation of PCB-containing materials, the monitoring of the neutralisation and processing of waste, and the development of new rules for the operation of plant in which PCB is employed taking into account more stringent requirements for the ecological safety of industries.The possibility of the gradual removal of PCB-containing materials from the sphere of man's economic activity and of a universal ban on their manufacture depends on the solution of the problem of the replacement of PCB by new materials with similar operating characteristics but with a significantly lower toxicity. The question of the search for substitutes of PCB-based dielectric materials is most acute.New compositions and individual compounds have been obtained and tested in recent years. They have been recommended as substitutes for PCB in transformers and capacitors. For example, these are mineral and silicone oils,9, 17, 64 ± 66 high-mo- lecular paraffins,9, 65 alkylated biphenyls and terphenyls,9, 17 esters of phosphoric, phthalic, and other carboxylic acids,9, 17 and esters of polyhydric alcohols.65 While less toxic, these substances approach PCB as regards their dielectric properties but are inferior to them in chemical inertness and resistance to combus- tion.Less toxic polychlorotoluenes 67 and chloromethylbenzenes 68 have been proposed for the replacement of PCB in hydraulic systems.68 The report of the promising application of absolutely nontoxic and chemically stable perfluorinated organic com- pounds as components of lubricating oils merits attention.41 However, overall the search for new materials to be used as substitutes for PCB for various purposes has been fragmentary. In the system of measures designed to lower the degree of pollution of the environment, the conservation of PCB removed from the sphere of economic activity in settling tanks or storage sites occupies a definite place.5, 35, 69 ± 77 In practice, various storage methods are employed, but the safest is the method involving enclosure in glass.71 However, there is no information about the ecological risk when this operation is performed.Thus enclosure in glass may entail the formation of toxic PCDD and PCDF and their subsequent diffusion together with PCB into the environment.The hardening method is widely used in the storage of PCB, but it cannot guarantee their complete isolation from the environment.70, 76, 77 The main disadvantages of the method involving the storage of hardened PCB are as follows: as a consequence of the appreciable volatility and diffusibility as well as the leaching of PCB, one cannot rule out the possibility of their entry into soil, underground and surface waters, and the atmos- phere; the need to search for storage sites remote from populated areas, definite requirements for geological structures at the storage sites, and the continually rising cost of this opera- tion;69, 72, 74 One should also take into account the negative attitude of the population to the possibility of storage of any waste on adjacent territories.The storage of undecomposed PCB in settling tanks is a less reliable method of their conservation. The inevitability of the diffusion of PCB from the settling tanks is aggravated by the probability of accidents at the storage sites. The most promising procedure for lowering the amount of PCB in the environment involves their conversion into environ- mentally safe products.One may identify the following methods for the processing of PCB: chemical and electrochemical dechlori- nation, thermal, photochemical, and radiation-chemical and bio- technological methods, oxidation, and hydrogenolysis. These methods may include operations involving the concentration of PCB before treatment.Such operations include extraction, adsorption, dialysis, vaporisation, distillation, and filtra- tion.5, 18, 25, 63, 50, 77 ± 88 Operations of this kind acquire particular importance when the removal of residual PCB from transformers and capacitors is required. By virtue of the application of extraction by liquids at the critical temperature and pressure, the effectiveness of the extraction of PCB from plant to be cleaned has increased in recent years.80, 85, 87 II.Reagent-based neutralisation methods Diverse reagents, reaction conditions, catalytic systems, and apparatus are used in the chemical methods for the neutralisation of PCB. The reagents are usually alkali metals (Na, K, Li),9, 52, 80, 89 ± 97 with the aid of which a version of the Wurtz reaction takes place:98 2ArCl+2Na Ar7Ar+2NaCl.(4) In this method, use is made of the dechlorinating effect of the alkali metal (in particular, sodium). The organic dechlorination products are high-molecular polynuclear compounds. According to the ideas developed by Oku et al.,99 the mecha- nism of reaction (4) includes the following stages: ArCl+Na Ar +NaCl, (5) 2Ar Ar7Ar.(6) In the presence of compounds containing relatively mobile hydrogen (hexane, cyclohexane, other hydrocarbons), the aryl radicals are involved in a chain of new reactions: Ar +RH R + ArH, (7) R +Ar Ar7R, (8) R +R R7R. (9) The main result is the substitution of the chlorine atoms in PCB by hydrogen via reaction (7). Thus hydrocarbons with fairly reactive C7H bonds regulate the average molecular mass of the dechlorination products, but are themselves decomposed in this process.The regulating function of hydrocarbons is important because it permits the retention of the possibility of further dechlorination of PCB at advanced stages of the reaction with respect to chlorine, whereupon contact between the sodium atoms and the chlorine atoms still present in the polynuclear chlorination products becomes sterically hindered.In order to decompose PCB, the alkali metal is usually dispersed in the bulk of the material being treated or a hydro- carbon solvent is used as the reaction medium. A version of the process in a flow system using the alkali metal (Na or K) deposited on an inert material as the reagent has also been described.89 This method is characterised by a high degree of decomposition of Polychlorobiphenyls: problems of the pollution of the environment and technological neutralisation methods 715PCB, but its application is held back by a series of limitations and deficiencies D the high cost of the neutralisation process, increased danger of the process, and conversion of the treated compounds into high-molecular products which lower the quality of the materials being purified.Furthermore, alkali metals may interact with valuable components of the materials being purified, exerting a negative effect on their operating characteristics.100 There are data concerning the use of alkaline earth and other metals, such as Mg, Ca, Fe, Sb, Zn, and Pb 101, 102 in a molten salt and in the vapour phase 101, 103 for the dechlorination of PCB.As regards safety and dechlorination efficiency alkali metal naph- thalides and anthracides have a definite advantage over alkali metals.18, 77, 104 ¡À 107 The higher efficiency of the dechlorination by the naphthalides and anthracides is due to the possibility of increasing the degree of dispersion of the reagent down to the molecular level.On the other hand, the metals in the compounds specified are chemically bound and this makes them more inert to oxygen and water, which increases the safety of the process in its turn. Compounds between alkali metals and carbon are a variety of reagents of this type.108 The main disadvantages of the dechlorinating agents listed is the difficulty of isolating them from the reaction mass and the fact that high-molecular products, exerting a negative influence on the quality of the neutralised material, are formed with participation of the given reagents.Strong bases D alkali and alkaline earth metals and oxides and hydroxides,77, 80, 101, 102, 109 ¡À 115 alkoxides, glycolates, and polyglycolates 18, 77, 80, 85, 95, 116 ¡À 123 D constitute a large group of reagents.Alkali metal carbonates or hydrogen carbonates make up yet another group.124, 125 Their dechlorinating activity is based on the nucleophilic substitution of the chlorine in PCB. Thus, when aqueous solutions of alkalies are used, the main reaction proceeds in accordance with the equation ArCl+NaOH ArOH+NaCl. (10) Aqueous solutions of alkalies are insufficiently effective and are quite expensive.Furthermore, the presence of chlorine in the 2- and 20-positions in the PCB being neutralised creates structural preconditions for the formation of PCDF: Alkali metal glycolates, polyglycolates, carbonates, and hydrogen carbonates are more effective dechlorinating agents, since the polarisability of their anions is greater:110, 126 In contrast to alkali metals, as well as compounds of alkali metals with naphthalene, anthracene, and carbon, these reagents do not require the use of special safety measures, the processes involving them can be readily controlled, and the products obtained after dechlorination can be readily separated from the purified material.In most cases, the methods for the employment of such reagents are universal in relation to the object being treated: they can be applied in the detoxification of soils, sludges, sewage, and simply PCB-containing materials. The disadvantages of these methods are as follows: the need to neutralise the excess alkaline agent with formation of salt waste, the possibility of the impairment of the operating quality of the materials being neutralised as a consequence of the formation of hydrolysis and alcoholysis products, the rapid wear of the equipment working in corrosive media at high temperatures.In view of the existence of the last problem, the process involving the detoxification of PCB-containing materials by alkaline agents, initiated with ultrasound under milder conditions, merits attention.115 The influence of alkaline reagents on the quality of the processed materials imposes certain limitations on their content of PCB: it should not exceed 1 mass %.100 The oxidation ¡À reduction processes with participation of a wide variety of oxidants and reductants constitute a separate group of methods for the chemical detoxification of PCB-contai- ning materials.The oxidants include hydrogen peroxide, sodium iodate,125, 127 permanganates, persulfates and perborates,49 and peracetic acid,128 while the reductants comprise the hydrides of alkyl derivatives of alkaline metals,95 alkali and alkaline earth metal hydroborates,49, 129 and alcohols.130, 131 When alcohols are used as the reducing agents, the attainment of the necessary rate of the process requires either more severe conditions (170 ¡À 200 atm, 150 ¡À 350 8C) or the radical reduction reaction must be carried out in the presence of alkali metal hydroxides and chemical initiators.The methods indicated require the application of expensive reagents and can hardly be recommended for industrial applica- tion. Methods for the processing of PCB involving their interaction with elemental sulfur in the vapour phase at high temperatures are of undoubted practical interest.59, 130, 132 An environmentally safe polymeric product is obtained and can be used as an additive to asphalt, a binder for concrete, a vulcanising agent for raw rubber, and as a material for the preparation of resistors.The products SCl2 and CS2 formed together with the polymer can be readily separated from the latter together with the unreacted elemental sulfur, which is returned to the process.This method is suitable exclusively for the treatment of concentrated PCB, but the possibilities for its wide-scale application are restricted by the available elemental sulfur resources. III. Electrochemical methods The majority of the known methods for the electrochemical oxidation and reduction of PCB are used within the framework of laboratory research.77, 133 ¡À 141 Certain results are promising as regards energy expenditure 134 and apparent yields,142 but overall the prospects for the application of these methods in industry are at the present time small owing to the insufficiently high degree of conversion of PCB137, 141 and the high requirements which must be met by the purity of the initial PCB.However, the interest in the electrochemical methods has persisted for several reasons. Firstly, it is possible to organise the process under the conditions of cathodic reduction: C12ClnH107n+nH2O+2ne7 (14) C12H10+nCl7+nOH7, which imparts to it resource-saving qualities. Secondly, electro- chemical devices are suitable for the creation of mobile systems for the processing of waste at the site of their formation and accumulation.Thirdly, such devices have an advantage in the conversion of dielectric liquids, lubricating oils, and other spent PCB-containing materials into a valuable hydrocarbon fuel. IV. Pyrolytic methods Among the pyrolytic methods for the decomposition of PCB, the process in which a hollow tube heated from the outside by electrodes or other electrically heated elements merits atten- tion.16, 122, 142 ¡À 144 Porous graphite may be used for the prepara- tion of the tube.In order to avoid the breakdown of the material of the reactor, a stream of nitrogen or other inert gas is passed from the outside into the porous surface. 7NaCl +NaOH +NaOH Clm OH Cl Cln Cl Cl Cln Clm (11) 7NaCl ONa Cl Cln Clm O Cln Clm (13) (12) ArCl+(CH2CH2O)nHO7 ArCl+CO2¡¦ 3 7Cl7 ArOCO¡¦2 ArOCO2H ArO(CH2CH2O)nH+Cl7, 7OH7 H2O ArOH. 7CO2 7 716 L N Zanaveskin, V A Aver'yanovThe PCB decomposition products are a solid carbon residue and gases, mainly HCl and Cl2, as well as a certain amount of organochlorine compounds. The gases are trapped in series- connected absorbers irrigated with water and an alkaline solution and also in an adsorber with activated charcoal. In order to ensure the effective destruction of the PCB and a decrease in process temperature, it is recommended that a small amount of oxygen be added to the initial mixture.122 In order to attain the quantitative decomposition of PCB, in certain cases the pyrolytic processes are carried out on solid catalysts, activated charcoal, metallic Zn, Ni, Cu, Fe, Al, Pb, Pt, Rh, and Cr or the oxides, carbonates, and silicates of these metals.145 ± 147 One of the difficulties in the application of pyrolytic methods is the difficulty of achieving an effective supply of heat to ensure the specified temperature.This problem can be solved successfully if the process is carried out in salt melts.87, 148 Nevertheless pyrolysis in melts has hardly come to be widely used, since equipment wears rapidly in a salt medium and the high temper- atures needed to apply these methods render industries of this kind dangerous.The plasma pyrolysis occurring at temperatures from 5000 to 25 000 8C involves the complete decomposition of PCB; H2, CO, CO2, HCl, CH4, H2O, and elemental carbon being formed as the products.87, 149 ± 151 The presence of oxygen-containing com- pounds in the products is associated with the use of alcohols as solvents for the preparation of the initial mixtures.151 Anovel method for the pyrolysis of PCB has been put forward in France.152 The process is carried out at 1500 8C in the presence of water vapour.The main reaction products are chlorine and Cl±C2 hydrocarbons. The chlorine is absorbed by a solution of alkali while the hydrocarbons are used as a fuel. In the communications quoted above, devoted to pyrolytic decomposition methods, the degree of decomposition of PCB is quoted as the sole criterion of the effectiveness of the processes and this parameter is in all cases close to 100%.The lack of any kind of data on the composition of the products with different degrees of conversion hinders even a preliminary interpretation of the process mechanisms. Certain conclusions about the initial period of the pyrolytic decomposition of PCB can be made on the basis of the results of a detailed study of the pyrolysis of chlorobenzenes in the region of relatively low temperatures.153, 154 The principal pyrolysis products under these conditions are chlorobiphenyl and dichlorobiphenyl and the reactions respon- sible for their formation are reversible.Adopting the principle of microreversibility as a guide,155 the proposed mechanism of the pyrolysis of chlorobenzenes can be extended also to the pyrolysis of polychlorobiphenyls.An important advantage of the pyrolytic methods compared with the widely used combustion is the absence of the highly toxic PCDF and PCDD from the products. However, the large energy consumption in these processes increases their cost and impairs their ecological parameters. Furthermore, the pyrolytic process is relatively unselective and is therefore unsuitable for the dechlori- nation of materials with a low PCB content.To a certain extent, these disadvantages are overcome by employing catalytic pyrol- ysis, but the formation of pyrolytic carbon leads to rapid deacti- vation of the catalyst. V. Radiation and photochemical dechlorination methods The radiation and photochemical dechlorination methods are being rigorously investigated.2, 77, 156 ± 181 Their successful appli- cation does not require additional chemical reagents.77, 156 ± 165 The processes can be described by the following stoichiometric equation in relation to the dechlorination of 2,20,4,40,6,60-hexa- chlorobiphenyl:182 Thermokinetic analysis 155, 183 made it possible to put forward the following mechanism of the photochemical dechlorination: Evidently in the dechlorination initiated by g-quanta the reactions involving the homolysis of the C7Cl bond are accom- panied by competing reactions in which the C7H and C7C bonds are homolysed.An advantage of the radiation and photochemical methods compared with the reagent-based dechlorination methods is simpler composition of the products and the absence of salt waste. However, the very low quantum or radiation-chemical yields of these processes lead to large energy expenditures and hence an impairment of the economic parameters of the industrial processes.In this connection, the search for photocatalytic systems and methods whereby the reagent concentration fields can be altered in the initiation stage in order to achieve the selective absorption of energy quanta and their effective utilisa- tion for the generation of the necessary intermediates are of definite interest.156, 157, 159, 160, 163 ± 167, 173, 184 On the other hand, the possibility of economising on the energy by increasing the quantum and radiation-chemical yield is limited because the rate constants for reaction (17) are low at the low temperatures characteristic of these processes 153 and conditions for the occur- rence of chain processes are not therefore realised.Radiation and photochemical dechlorination may find a practical application for the neutralisation of industrial and domestic sewage, provided that more effective and selective methods are developed for the application of energy to PCB- containing materials. In this sense, the report on the detoxification of waste waters in the presence of titanium dioxide on treatment with ultrasound under normal conditions merits attention.185 The nature of the products of the photochemical and radia- tion-chemical dechlorination changes in the presence of com- pounds containing comparatively mobile hydrogen (cyclohexane, other hydrocarbons, alcohols, water, sodium tetrahydroborate, etc.) 169, 172, 173, 175, 176, 179 ± 184, 186 Some of the reactions occurring are indicated schematically below in relation to 2,20,4,40,6,60- hexachlorobiphenyl.182 Cl Cl Cl Cl Cl 2Cl hn (15) Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl+Cl2.ArCl hn Ar+Cl , (16) Ar+ArCl [Ar...Ar...Cl]# Ar+Cl , Ar (17) Ar+Ar Ar Ar. (18) (19) Cl Cl Cl Cl Cl Cl Cl Cl Cl H Cl Cl Cl Cl O Cl Cl Cl Cl Cl Cl Cl CH3O CH3OH H2O hexane Polychlorobiphenyls: problems of the pollution of the environment and technological neutralisation methods 717As can be seen, in the presence of hydrocarbons chlorine is replaced by hydrogen, which in fact gives rise to the neutralisation effect.On the other hand, when water and alcohols are used, there is a risk of the formation of the highly toxic PCDF. Evidently this risk exists also under the conditions of the photochemical and radiation-chemical dechlorination of PCB in an oxidising medium.46, 166 From the standpoint of the protection of nature, it is therefore useful to employ only hydrocarbons as the reagents.Nevertheless, despite the high reactivity of hydrocarbons in radical reactions, the quantum and radiation-chemical yields remain low and this prevents the introduction of such processes into industry.When caustic alkali is added to the PCB± alcohol reaction system, the radiation or photochemical dechlorination of PCB by the alcohol proceeds via a radical-chain mecha- nism:170, 177 ± 181, 186, 187 (CH3)2CHOH+C12HnCl107n+OH7 (20) (CH3)2C=O+H2O+C12Hn+1Cl97n+Cl7 Here the quantum yield increases by two ± three orders of magni- tude.179 This effect can be accounted for by the operation of the following mechanism (in relation to the radiation-chemical dech- lorination of PCB by the 2-propanol ±NaOH system): (CH3)2CHOH R , e¡solv, other products, (21) R +(CH3)2CHOH (CH3)2C OH+RH, (22) ArCl+e¡solv Ar +Cl7, (23) Ar +(CH3)2CHOH ArH+(CH3)2C OH, (24) (CH3)2C OH+OH7 (CH3)2CO7+H2O, (25) ArCl+(CH3)2CO7 (CH3)2C=O+Ar +Cl7.(26) It is seen from the scheme presented that the function of alkali is associated with the production of the anion (CH3)2CO7, which effectively dechlorinates the PCB molecule and regenerates the initial Ar . radical by means of electron transfer via reaction (26).A significant economy in energy is achieved in this dechlorination method,188, 189 but the additional consumption of expensive reagents limits its application.One should bear in mind that the use of visible and ultraviolet light to initiate the reactions is relatively ineffective owing to the lack of transparency of the majority of the reaction media to waves in this range, while the technique of radiation-chemical initiation is too expensive and the effect obtained does not compensate for the expenditure.When chemical reagents are used as initiators, the caustic alkali ± alcohol system may be recommended for the detoxification of sewage and materials with a low PCB content. In conclusion of the consideration of dechlorination processes initiated by photochemical reactions, we may mention the method for the decomposition of PCB in the plasma of a radiofrequency glow discharge developed in Japan.190 The nature of the products formed under these conditions is determined by the nature of the dechlorinating agent.In an oxygen plasma, PCB decomposes to CO2, CO, C1O2, Cl2 , and HCl, while in the presence of water vapour CO2 and HCl are formed. The use of a hydrogen plasma leads to the formation of C2±C7 hydrocarbons (alkanes, alkenes) and HCl.The application of these processes ensures the quantita- tive binding of PCB without risk of the formation of PCDD and PCDF. Dechlorination in a plasma is most attractive because the hydrocarbons obtained may be used as a fuel. The prospects for this method are associated exclusively with the processing of concentrated PCB. There are so far no data on its industrial tests, which is apparently due to the low productivity of the process and the large energy expenditures.VI. Biotechnological methods During the last two decades, investigators have shown a steady interest in the problem of the search for effective PCB biodecom- position methods. This can be accounted for, firstly, by the high resistance of PCB and, secondly, by the fact that biological purification is the concluding stage in many detoxification proc- esses, including the purification of sewage.The object neutralised usually consists of complex mixtures of toxicants and the decom- position of the PCB present in them limits the entire process as a whole. A series of investigations have been devoted to the problem of the biodegradation of PCB.3, 9, 37, 38, 51, 77, 85, 191 ± 202 It has been shown that both pure cultures of micro organisms and their mixtures can be used for the detoxification of PCB-containing materials.The microflora from the bottom deposits in rivers, lakes, and soils and the active sludge from the purification equip- ment in the cellulose-paper industry and undertakings of the food industry are used as mixtures of microorganism cul- tures.77, 192 ± 198, 200 ± 202 None of the natural strains isolated is capable of fully decomposing PCB, the highly chlorinated PCB being the most resistant to biodegradation.100, 200 The difficulty of the study of the biodegradation mechanism is associated with the complexity of the processes investigated, which constitute a chain of consecutive-parallel reactions, each of which is catalysed by its own enzyme.Nevertheless, many groups of investigators who have studied the aerobic decomposi- tion of PCB by microorganisms maintain a single view on the sequence of reactions leading to the decomposition of these compounds.203 ± 214 This sequence includes the following stages: the interaction of an oxygen molecule with one of the aromatic rings of PCB with formation of the corresponding dihydrodiol; the transformation of the dihydrodiol into a dihydric phenol; the cleavage of the aromatic ring and the formation of the chlorinated 2-hydroxy-6-oxo-6-phenylpenta-2,4-dienecarboxylic acid; the formation of chlorobenzoic acid: The above scheme has been confirmed by mass-spectrometric studies of the intermediate and final biodecomposition products, as well as by chemical tests on the latter.203 At the same time, on the basis of this scheme one cannot answer the fundamental question concerning the possibility of the intensification of bio- decomposition processes. An increase in the effectiveness of the decomposition of PCB may be promoted by the application of substrates such as sodium acetate 200 or inorganic nitrogen and phosphorus compounds 215 as nutrients for the microorganisms, as well as by the use of mixtures of different cultures 200, 201 and by the combination of PCB biodegradation processes with other biotechnological proc- esses, for example composting.216 The biodegradation methods are very convenient for the dechlorination of PCB dispersed in the environment, for example in soils and water sources, and also for the detoxification of Cl Cl Cl Cl H H OH OH Cl Cl OH OH (27) C Cl Cl OH COOH O Cl COOH 718 L N Zanaveskin, V A Aver'yanovsubterranean waters, sewage, sludge, and domestic waste with a low PCB content.3, 9, 51, 77, 85, 192, 194, 195, 200, 216 The rate of biotechnological purification of sewage can be increased by employing emulsifying agents, which increase the solubility of PCB and PCB-containing oils in water.77 The creation of highly productive biotechnological PCB degradation methods is possible if more active strains of microorganisms are cultured.For the productivity achieved at the present time, the biotechnological method for the decomposition of PCB is most reasonably employed at the end of the dechlorination process in combination with other methods, for example chemical and photochemical.77, 123, 130, 202 This is favoured also by the high degree of decomposition of PCB molecules containing fewer chlorine atoms in the concluding stage.Another problem arising when biodegradation methods are employed consists in the preservation of the vitality of the PCB- decomposing microorganisms in the soil, where they should compete effectively with soil microorganisms.Finally, certain difficulties arise owing to the interaction of PCB molecules with compounds in the bottom deposits and the soil. Such interaction prevents the microbiological decomposition of PCB. VII. Oxidative methods Among the methods for the neutralisation of PCB-containing materials, the oxidative procedures predominate.They can be divided into combustion proper and special oxidation methods. The latter include catalytic oxidation, plasma methods, ozonisa- tion, and oxidation under hypercritical conditions. Combustion predominates not only among the oxidative methods but in general among the methods for the detoxification of PCB and PCB-containing materials.This is due to the univer- sality of this procedure as regards the types of materials processed, the ease of controlling the process, and its suitability for various technological versions and conditions of the neutralisation proc- ess, which facilitates the creation of mobile apparatus and ensures the possibility of employing the heat of the combustion process, complete decomposition of the PCB in the cycle, etc.The processes involving the combustion of PCB and polychlorobiphenyl-containing mixtures have been the object of numerous investiga- tions 5, 6, 9, 16, 18, 42, 48, 50, 55, 56, 74, 77, 85, 87, 143, 217 ¡¾ 232 in the course of the last three decades, the aim of which consisted in the search for conditions ensuring the most complete oxidation.The require- ments which must be met by the PCB combustion processes are fairly rigorous. Thus, according to the standards established by the Environmental Protection Agency in the USA the degree of destruction of PCB in these processes should not be less than 99.9999%.233 This is achieved by selecting the optimum ratios of PCB , the oxidants, and the additional fuel as well as the temper- ature and residence time of the mixture in the combustion chamber.234 We shall examine the principles governing this choice.The ratios of the components of the initial mixture are determined primarily by stoichiometric considerations.234 Thus exhaustive oxidation of the C12HxCl107x molecule to CO2, H2O, and HCl should be described by the equation C12HxCl10¢§x a 12 a O2x ¢§ 10U 4 O2 a (28) a 12CO2 a O10 ¢§ xUHCl a O2x ¢§ 10U 2 H2O.This equation has a physical significance only for x>5. When x=5, water is not formed. For x<5, the combustion process proceeds in the direction of the formation of molecular chlor- ine 235 in accordance with the equation C12HxCl10¢§x a 12O2 a 12CO2 a xHCl a O10 ¢§ 2xU 2 Cl2. (29) The formation of molecular chlorine is undesirable for two reasons.Firstly, it has a highly corrosive effect on the material of the apparatus used in the combustion processes. Secondly, its quantitative extraction from effluent gases is a difficult problem and requires the use of expensive alkaline agents. Direct combus- tion of the majority of the commercial PCB mixtures should lead irreversibly to the formation of appreciable amounts of molecular chlorine.The virtually complete suppression of the formation of molecular chlorine in the combustion of highly chlorinated PCB can be achieved by introducing into the initial mixture of PCB and the oxidant an additional hydrocarbon fuel, which is an external source of the hydrogen atoms lacking in the PCB molecules.235, 236 If methane is used as such a fuel, the PCB combustion process can be described by the equation C12HxCl10¢§x a bCH4 a 12 a 2b a 2x ¢§ 10 4 O2 a (30) a O12 a bUCO2 a O10 ¢§ xUHCl a 2b a 2x ¢§ 10 2 H2O The introduction of a fuel, the amount of which is expressed by the stoichiometric coefficient b, should not only make good the deficiency of the hydrogen in PCB but should also ensure the required temperature of the flame and its stability.In its turn, the combustion temperature is determined from the condition for the complete suppression of the formation ofPCDD and PCDF. The Environmental Protection Agency in the USA recommends that this requirement be satisfied by ensuring a temperature in excess of 1200 8C and a residence time in the combustion chamber longer than 2 s.46, 233, 237 A definite excess of the fuel relative to PCB and an excess of the oxidant relative to the fuel are necessary for this purpose.235, 236 There is no need to go far beyond the limit of 1200 8C, because this leads to an excess consumption of fuel and rapid wear of the equipment.A certain excess of the oxidant (oxygen, air) is needed for the exhaustive degradation of PCB and the suppression of soot formation.235, 236 However, this excess should not be enormous, because, in accord- ance with the Deacon equilibrium Cl2+H2O 2HCl+1 2O2 (31) the undesirable formation of chlorine is possible at a high oxygen concentration.There have been few studies devoted to the quantitative aspects and mechanisms of the combustion processes of halohy- drocarbons and they are concerned mainly with halome- thanes.235, 236, 238 ¡¾ 240 We suggest that the ideas developed in these investigations cannot be extended to haloarenes, because the chemical properties of the latter differ too much from those of halomethanes.On the other hand, two phenomena observed in the study of the combustion of halohydrocarbons may have a bearing also on the combustion of PCB.The first concerns the inhibiting effect of halohydrocarbons. By extending the ideas developed in a series of investiga- tions,236, 241 ¡¾ 244 it is possible to put forward the following mechanism of the inhibition of the combustion of the PCB¡¾ fuel mixture, H +HCl H2+Cl , (32) OH +HCl H2O+Cl , (33) Cl +Cl Cl2, (34) Cl +Ar ArCl. (35) Reactions (32) and (33) reflect the role of HCl (the product of the combustion of any chlorohydrocarbon) as a trapping agent for theH .andOH . free radical species responsible for the combustion process. Reactions (34) and (35) describe the involvement of chlorine atoms in chain termination and hence also in the inhibition of the combustion process. The second observed phenomenon is the acceleration of the combustion of chlorohydrocarbons by water vapour: Polychlorobiphenyls: problems of the pollution of the environment and technological neutralisation methods 719Cl +H2O HCl+OH , (36) OH +CO CO2+H , (37) H +O2 +OH, (38) fuel+(H , , OH ) combustion products.(39) Water vapour initiates the formation of the H . , O .. , and OH . radicals which are responsible for the oxidation process. The mechanism examined explains the suppression of the formation of chlorine in the chlorohydrocarbon combustion process.245, 246 Firstly, by virtue of the occurrence of reaction (36), the concen- tration of chlorine radicals falls and hence their recombination [reaction (34)] with formation of C12 diminishes. Secondly, water vapour behaves as a donor of hydrogen atoms [reactions (36) and (37)] and hence it makes good the deficiency of hydrogen in PCB.The technological formulation of the process depends in many respects on the state of aggregation of the material being neutral- ised. The simplest apparatus consists of a hollow combustion chamber fitted with a special burner with attachments for the supply of the PCB-containing material, the fuel (when this is necessary), and air (oxygen).217 ,231 It is used to neutralise PCB- containing liquid waste and sewage.The joint combustion of concentrated sewage and liquid PCB-containing waste makes it possible to avoid the formation of PCDD and PCDF.231 A two- chamber apparatus, consisting of a rotary furnace and a final combustion chamber,6, 18, 42, 77, 179, 183 in which a temperature higher by 200 8C than in the first chamber is maintained to ensure the completion of the process and the suppression of the PCDD and PCDF formation reactions, is used in certain cases.The two- chamber apparatus proved to be the most effective device for the combustion of liquid waste and its universal application has been recommended by the Environmental Protection Agency in the USA.183 The most widely used procedure for the destruction of PCB- containing solid and liquid waste is combustion in cyclone and cement furnaces and incinerators.By virtue of the high temper- ature and a fairly long contact time, the complete decomposition of PCB and the intermediate PCDD and PCDF is achieved in rotating cement furnaces,54, 77, 174, 176 while the limestone present in the initial charge binds quantitatively the acid gases formed on combustion (Cl2, HCl, etc.).The addition of PCB-containing materials to the initial charge improves the quality of the cement obtained.77 The materials combusted served as an additional source of heat and this makes it possible to economise on the main fuel.174 An interesting method involving the combination of the combustion of PCB-containing materials with a blast furnace process has been proposed.174 As in the cement furnaces, here the problem of the recovery of the heat is solved successfully and the acid gases formed are bound by the limestone used as the flux.The highest efficiency of the combustion of solid PCB- containing waste is achieved in special furnaces consisting of three series-connected reaction units: a rotating furnace, a final combustion furnace, and a chamber for the combustion of gaseous products.18, 183 Such devices are suitable for the combus- tion of materials. In the version described, they are used for the combustion of domestic rubbish, whilst liquid PCB-containing waste can be supplied directly into the final combustion chamber.Gas, petroleum products, or coal can be used as the fuel for the combustion of any PCB-containing waste.18 In most cases, the effluent acid gases are absorbed in two series-connected scrubbers irrigated with water and an aqueous solution of alkali.184, 242 Limestone is sometimes added to the initial mixture to bind the acid gases.77, 171 A fluidised bed regime may be established to intensify the process in the combustion chamber,77 but the melting point of the inert material used in this case imposes certain limitations on the combustion conditions.For example, the melting point of sand is 1100 8C. The combustion furnaces can be combined into a single aggregate with any heat consuming unit. Thus examples of the combustion of PCB-containing oils in boiler aggregates,216 for heating aluminium furnaces,223 and for the generation of the additional heat in the lime preparation process 77 are known.The combustion methods are very convenient to use in devising mobile systems designed for the processing of local sources of pollution by PCB on trailers and in ocean-going vessels.77, 219 The main deficiency of the combustion method is the risk of the formation of the highly toxic PCDD and PCDF during the oxidative degradation of PCB.18, 218, 235, 247 In a number of instan- ces, the absence of PCDD and PCDF among the combustion products was noted 54, 217, 221 and these data have been confirmed by kinetic and thermodynamic calculations, according to which these compounds should not be formed at temperatures above 1200 8C and for contact times longer than 2 s.237 Nevertheless, in the highly productive plant which actually exists it is difficult to ensure the ideal functioning of the combustion reactors, i.e.a uniform temperature throughout the volume of the chamber and an identical residence time in the reaction zone for all the particles in the reaction stream. For this reason, there is always a proba- bility of the formation of the highly toxic PCDD and PCDF.A greater uniformity of the temperature field in the combustion chamber can apparently be ensured by employing a fluidised bed technique or by carrying out the process in the melt of an inert material, for example glass.77 The complete suppression of the formation of PCDD and PCDF is achieved when PCB are combusted in an oxygen and water vapour atmosphere.220 One of the deficiencies of the combustion processes is a low selectivity, so that their use for the destruction of PCB is fully justified only for a fairly high content of the latter in the materials being neutralised.87 The Environmental Protection Agency in the USA determined the lower limit of the PCB content in spent materials at the level of 500 mg of PCB per kilogram of the material.224 Among other deficiencies of the combustion processes, one may note the high cost, the additional consumption of fuel, the rapid wear of equipment in corrosive media (Cl2 and HCl) and at high temperatures, and also the irreversible loss of the hydrocarbon component.68, 230 The last deficiency is of a fundamental character, because the aim of the overall strategy in the development of the world technology is the creation of resource-saving industries.Only a few scattered studies have been devoted to the field of the catalytic oxidation of PCB.12, 232, 237, 248 ± 252 The application of catalysts makes it possible to lower appreciably the process temperature and hence to reduce the capital and energy expendi- ture.It is remarkable thatPCDDandPCDF are not formed under catalytic conditions, and the emission of nitrogen oxides is appreciably reduced. RuO2, Cr2 O3/Al2O3, CuO/Al2O3, Co3 O4, the mixed catalysts CuCr2O4, Pt ± Pd, and metal chlorides on an inert porous support, which are capable of being converted into the corresponding oxides on heating in air, are used as catalysts.Despite promising results, systematic studies on the characteristic features of the catalytic PCB oxidation processes are lacking and this hinders an assessment of the prospects for their application. The methods for the oxidative decomposition of PCB in plasma or electric arc discharges are of undoubted inter- est.11, 151, 252, 253 The complete conversion of PCB into gaseous products (CO, CO2, H2O, HCl, Cl2 ClO2) without risk of the formation of PCDD and PCDF is ensured under these conditions.However, such processes are characterised by low selectivity and high energy expenditures, so that their application is justified only if it is necessary to detoxify concentrated PCB-containing materials. The neutralisation of PCB by the ozonisation method has been tested in relation to aqueous solutions of these toxi- cants.77, 254, 255 At the usual temperatures, the degree of decom- position of PCB reaches 97.0% ± 99.4%.The acceleration of this process is promoted by UV irradiation and by the addition of potassium hydroxide to the solution. This method is of interest for the detoxification of sewage, since simultaneous ozonisation ensures its disinfection.O O 720 L N Zanaveskin, V A Aver'yanovPCB can also be oxidised by employing a mixture of oxygen (air) with water as the reagent under conditions ensuring the attainment of hypercritical parameters of the latter.77 In this state, the hydrogen bonds are significantly weakened and the dielectric constant diminishes to 3 ± 10. As a result, water becomes a good solvent for the organic mass and the oxygen supplied to such a system rapidly oxidises the substrate.The exothermicity of the process makes it possible to maintain the temperature at a level of *550 8C. When this method is used, the formation of PCDD and PCDF is ruled out and the complete decomposition of PCB is ensured. However, additional studies are needed in order to analyse the material and energy balances and to elucidate the economic desirability of the development of the method.VIII. Hydrogenolysis of polychlorobiphenyls The interest in detoxification of organochlorine waste by the dechlorination method has increased in recent years.255 This has been induced by a series of evident advantages of this process compared with other procedures for the conversion of organo- chlorine compounds, including PCB.Firstly, hydrogenolysis proceeds fairly `smoothly' under comparatively mild conditions up to the complete conversion of the initial organic reagent. Secondly, the reaction is selective in relation to the object processed, which makes it possible to achieve successfully the dechlorination of organochlorine compounds within any range of their concentrations.If other undesirable organoelement com- pounds are present in the reaction mixture, then they can be readily converted into the corresponding hydrocarbons by hydro- genolysis. Thus there is a possibility of the regeneration of the spent lubricating oils and other PCB-containing materials. Thirdly, in the hydrogenolysis the formation of PCDD and PCDF is ruled out.Fourthly, this method has an evident resource-saving character. Processes involving the hydrogenolysis of organohalogen compounds have been the objects of numerous investigations. Nevertheless, the number of studies in which the chemical behaviour of PCB in these reactions has been considered is limited.49, 80, 129, 256 ± 271 The aim of the majority of studies was to solve applied problems in the detoxification of PCB-containing materials.The hydrogenolysis of PCB can be achieved by the thermal, catalytic, and the usual chemical methods. In the last case, expensive alkali and alkaline earth metal hydrides and hydro- borates 49, 100, 186, 267 as well as silanes and polymethylsilox- anes 129, 268 are used as the dechlorinating agents.These methods are more in the nature of preparative procedures and cannot be considered as a basis for industrial application. There have been several studies devoted to quantitative aspects of the thermal hydrogenolysis of chloroarenes, including chlorobiphenyls.259, 272 ± 274 The results of the investigation of the pyrolytic decomposition of arenes and chloroarenes should be regarded as a component of these studies.152, 275 The gas-phase thermal hydrogenolysis of PCB by hydrogen at 700 ± 925 8C leads to the formation of benzene and hydrogen chloride as the final products with insignificant soot formation.259 Analysis of the results obtained in the studies quoted above and of the thermal kinetic data presented in some of them makes it possible to postulate the following mechanism of the thermal hydrogenolysis (in relation to 4-chlorobiphenyl): Detailed investigation of the behaviour of PCB at different hydrogen concentrations 153, 259, 275 has shown that reactions (43) ± (45) are reversible.The processes which are the reverse of the above reactions may be regarded as stages in the thermolysis of chlorobenzenes. The pyrolysis of chlorobenzenes should then be supplemented by stages involving initiation and the formation of HCl: C6H5Cl H5+Cl , (48) C6H5Cl+Cl H4Cl+HCl, (49) C6H5Cl+Cl H5+Cl2.(50) Under the pyrolysis conditions, the concentration of molec- ular hydrogen is extremely low and equilibrium (41) is signifi- cantly displaced to the left, which leads to high [Cl . ]/[H . ] ratios. This induces in its turn the displacement of equilibrium (43) ± (45) also to the left, i.e.in the direction of the products of the thermolysis of chlorobiphenyls. The main difficulty in the occurrence of thermal hydro- genolysis is the supply of heat for the creation of the required temperature regime. However, at the current level of the technol- ogy of high-temperature processes, this difficulty has been over- come.There have been promising communications concerning the possibility of replacing hydrogen in the thermal hydrogenolysis of PCB by the cheaper methane and other alkanes.257, 263, 275 A tubular furnace, in the intertubular space of which it is possible to combust the methane employed, is entirely suitable for the organisation of such a process. Numerous versions of the catalytic hydrogenolysis of organo- chlorine compounds have been described in the literature.256, 271 The processes are carried out both in the liquid and gas phases, usually on metals such as Pt, Pd, Rh, Ru, Ir, Os, Ni, Co, Fe, Re, Mn, Mo, W, Cr, V, Cu, Ag, and Au.The properties of the catalysts can be varied widely by fusing them with other metals, by adding promoting agents, and by selecting supports.A detailed analysis of the characteristic features of the catalytic hydrogenolysis of various aromatic chloro-compounds, including PCB, has been carried out in mutually complementing reviews 256, 271 and we shall therefore confine ourselves here to a brief description of the existing ideas. The kinetics of the catalytic hydrogenolysis of a series of chloroalkanes, chloroalkenes, and chloroarenes indicate that the majority of the process proceed via the Langmuir ± Hinshelwood mechanism with dissociative adsorption of hydrogen on the catalyst surface.The extensive experimental data accumulated provide guidelines in the search for more effective catalysts and for the extension of the ideas developed to new objects. Many experimental data have been obtained in recent years on the catalytic hydrogenolysis of polychlorobiphenyls.258, 260 ± 262, 264, 265, 270, 276 The reactions take place in the gas and liquid phases and in the latter case alkalis may be added to the reaction mass in H+HCl Cl+H2 (41) (40) p-PhC6H4Cl +Cl (42) 7Ph Ph Cl Cl H Ph p-PhC6H4Cl+H 7PhCl p-PhC6H4Cl+H H Ph Cl Cl+H2 C6H5Cl+H C6H6+H +H2 (44) (43) (45) (46) (47) Ph+ H Ph p-PhC6H4Cl+H Cl H C6H4Cl 7C6H6 C6H6 + H Ph C6 C6 C6 Polychlorobiphenyls: problems of the pollution of the environment and technological neutralisation methods 721order to bind the hydrogen chloride formed.Supported Group VIB and Group VIII metals, Raney nickel, and the nickel ± - molybdenum alloy catalyst have been used successfully as cata- lysts.The hydrogenolysis of PCB on nickel, deposited on kieselguhr, in the gas and liquid phases has been studied in detail.276 The possibility of the quantitative dechlorination of certain PCB to biphenyl under mild conditions indicates major prospects for catalytic hydrogenolysis. The heat of reaction is sufficient to maintain the necessary, comparatively low, temperature in the reaction zone.In connection with the problem of increasing the useful life of the catalyst and of the restoration of its activity in the regeneration cycle, attention has been drawn to a study 277 of the hydrogenolysis of PCB with the aid of a combined reagent comprising alkali and a hydrogen-transferring agent. The authors regard this process as an alternative to the usual catalytic hydro- genolysis.Hydrocarbons incorporating highly mobile hydrogen atoms (alkanes containing tertiary C7H bonds or alkylarenes with benzyl C7H bonds) are used as the hydrogen donor. The role of the hydrogen-transferring agent is performed by anthra- cene, phenanthrene, alkylnaphthalenes, and also graphite, soot, or transition metals (in the first place iron). The overall process can be described by the equation C12HxCl107x+(107x)NaOH+2(107x)H* (51) C12H10+(107x)NaCl+(107x)H2O, where H* are active hydrogen atoms evolved by the hydrogenat- ing form of the transferring agent, for example the dihydroan- thracene formed on interaction with the hydrogen donor, i.e.or the adsorbent (carbon, transition metals). In the latter case, the version proposed by the authors differs little from the usual heterogeneous-catalytic hydrogenolysis, because transition met- als (the classical catalysts for these processes) promote the dissociative adsorption of H2 and the formation of atomic hydro- gen as the active surface intermediate.The idea of hydrogen transfer with the aid of polycyclic aromatic compounds is attrac- tive, but the prospects for the technological application of this process are obscure, because problems arise associated with the application of expensive alkali and the difficulties in the separa- tion of the reaction mass and the utilisation of the products of the conversion of the hydrogen donors.* * * The examination of the problem of the pollution of the environment by PCB and of the known methods for their neutralisation has shown that, in the practical solution of this ecological problem, it is possible to apply both individual methods for the processing of PCB and their various combinations.The use of two and more methods is most rational, for example, in the utilisation of articles containing high PCB concentrations. 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ISSN:0036-021X    

出版商:RSC    

年代:1998

数据来源: RSC