摘要:

Mendeleev Communications Electronic Version, Issue 1, 2002 1 Reactions of the pentaphospholide anion with half-sandwich complexes of iron: a new route to pentaphosphaferrocenes Vasily A. Miluykov,*a Oleg G. Sinyashin,a Otto Schererb and Evamarie Hey-Hawkinsc a A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Centre of the Russian Academy of Sciences, 420088 Kazan, Russian Federation.Fax: +7 8432 76 7424; e-mail: miluykov@iopc.knc.ru, oleg@iopc.knc.ru b Universität Kaiserslautern, Fachbereich Chemie, D-67663 Kaiserslautern, Germany. Fax: +49 631 205 2432; e-mail: oscherer@rhrk.uni-kl.de c Universität Leipzig, Institut für Anorganische Chemie, D-04103 Leipzig, Germany. Fax: +49 0341 973 9319; e-mail: hey@rz.uni-leipzig.de DOI: 10.1070/MC2002v012n01ABEH001517 Pentaphosphaferrocenes were prepared in good yields by the reaction of the pentaphospholide anion P5 – with half-sandwich complexes of iron containing carbonyl groups or tertiary phosphine ligands.The pentaphospholide anion P5 –, which is an isolobal analogue of the cyclopentadienyl anion,1 is of interest as a convenient reagent in organometallic and coordination chemistry.2,3 However, only a few organometallic compounds with P5 fragments were synthesised from NaP5 1.4,5 In particular, pentamethylpentaphosphaferrocene 2 was prepared in 12% yield by the reaction of 1 with iron(II) chloride and lithium pentamethylcyclopentadienide. 4 Recently, we reported a new method for preparing 1 by the reaction of sodium metal with white phosphorus under the conditions of phase-transfer catalysis.6 This simple method makes it possible to study the chemical behaviour of 1 towards various organometallic compounds.It was also of interest to develop a general high-yield route to pentaphosphaferrocenes and to determine the factors affecting the product yields. We based our approach on the well-known reaction of half-sandwich iron complexes with sodium cyclopentadienide.7 The reaction of 1 with pentamethylcyclopentadienyl(dicarbonyl) iron bromide† 3 in diglyme at 110 °C for 2 h gave pentamethylpentaphosphaferrocene 2 in ~70% yield.The structure of 2 was determined by 1H and 31P NMR spectroscopy and by a comparison with the published data.8,9 The reaction of 1 with 1,3-di-tert-butylcyclopentadienyl- (dicarbonyl)iron bromide 4† under similar conditions gave compound 5 in a yield of at most 5%.The structure of 5 was determined by 1H and 31P NMR spectroscopy and mass spectrometry. This compound also was prepared by the interaction of Cr(CO)5PCl3 with Cp''Fe(CO)2K in a yield of about 10%.10 The 31P NMR spectrum exhibits a singlet at 167 ppm, and the 1H NMR spectrum exhibits a singlet at 1.06 ppm due to methyl groups and a broad singlet at 3.71 ppm due to the protons of the cyclopentadienyl ring.Relative to tetra-tert-butylferrocene, the 1H NMR signals are shifted by an average of 0.26 ppm.11,12 The mass spectrum showed a peak of the molecular ion (m/z 388). The main product of this reaction was 1,1',3,3'-tetra-tertbutylferrocene 6, which was identified by 1H NMR spectroscopy and by a comparison of the physical properties with published data.9 Clearly, at a reaction temperature of 110 °C, pentaphosphaferrocene 5 decomposes to give compound 6.We postulated that a decrease in the reaction temperature increases the yield of 5. It is known that the replacement of CO ligands in organometallic compounds with better leaving groups, such as tertiary phosphines, facilitates the process of ligand exchange.Therefore, we treated 1 with 1,3-di-tert-butylcyclopentadienyl[ bis(trimethylphosphine)]iron bromide 7.‡ This reaction was conducted at 70 °C to form compound 5 in high yield (about 80%). Thus, we developed a new route to pentaphosphaferrocenes based on the reaction of the pentaphospholide anion with halfsandwich iron compounds containing carbonyl or tertiary phosphine ligands. V.Miluykov thanks the Deutsche Akademische Austauschdienst (A/00/06361) and the Sächsisches Ministerium für Wissenschaft und Kunst (SMWK, Az. 4-7531.50-04-0361-00) for financial support. † A solution of pentamethylcyclopentadienyl(dicarbonyl)iron bromide (260 mg, 0.8 mmol) in diglyme (20 ml) was added to a solution of NaP5 in diglyme (40 ml, 0.02 mol dm–3) at room temperature.The reaction mixture was stirred for 2 h at 110 °C. After cooling, the solvent was evaporated and the residue was purified by chromatography with light petroleum to give 2 (190 mg, 70%) as green crystals. 1H NMR, d: 1.08. 31P NMR, d: 153. A solution of 1,3-di-tert-butylcyclopentadienyl(dicarbonyl)iron bromide (295 mg, 0.8 mmol) in diglyme (20 ml) was added to a solution of NaP5 in diglyme (40 ml, 0.02 mol dm–3) at room temperature.The reaction mixture was stirred for 2 h at 110 °C. After cooling, the solvent was evaporated and the residue was purified by chromatography with light petroleum to give 5 (15 mg, 5%) as green crystals and 1,1',3,3'-tetra-tertbutylferrocene 6 (215 mg, 65%) as a yellowish orange powder (mp 193 °C; lit.,9 196 °C).P P P P P Me Me Me Me Me Fe CO OC Br + NaP5 110 °C – 2CO, – NaBr Me Me Me Me Me Fe 1 3 2 (~70%) ‡ A solution of 1,3-di-tert-butylcyclopentadienyl[bis(trimethylphosphine)]- iron bromide 7 (295 mg, 0.8 mmol) in diglyme (20 ml) was added to a solution of NaP5 in diglyme (40 ml, 0.02 mol dm–3) at room temperature. The reaction mixture was stirred for 2 h at 70 °C.After cooling, the solvent was evaporated and the residue was purified by chromatography with light petroleum to afford 5 (250 mg, 80%) as green crystals. P P P P P Fe CO OC Br + NaP5 110 °C – 2CO, – NaBr Fe 1 4 5 (~5%) P P P P P Fe PMe3 Br PMe3 + NaP5 70–80 °C – 2PMe3, – NaBr Fe 1 7 5Mendeleev Communications Electronic Version, Issue 1, 2002 2 References 1 R.Hoffmann, Angew. Chem., 1982, 94, 752 (Angew. Chem., Int. Ed. Engl., 1982, 21, 711). 2 O. Scherer, Angew. Chem., 1990, 102, 1137 (Angew. Chem., Int. Ed. Engl., 1990, 29, 1104). 3 M. Scheer and E. Herrmann, Z. Chem., 1990, 30, 41. 4 M. Baudler, S. Akpapoglou, D. Ouzounis, F. Wasgestian, B. Meinigke, H. Budzikiewicz and H. Münster, Angew. Chem., 1988, 100, 288 (Angew. Chem., Int.Ed. Engl., 1988, 27, 280). 5 M. Baudler and T. Etzbach, Angew. Chem., 1991, 103, 590 (Angew. Chem., Int. Ed. Engl., 1991, 30, 580). 6 V. Miluykov and O. Sinyashin, Russ. Patent, no. 2000106504/12 (006673). 7 A. N. Nesmeyanov and Yu. A. Chapovskii, Izv. Akad. Nauk SSSR, Ser. Khim., 1967, 223 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1967, 16, 224). 8 O. Scherer and T. Brück, Angew. Chem., 1987, 99, 59 (Angew. Chem., Int. Ed. Engl., 1987, 26, 59). 9 O. Scherer, T. Brück and G. Wolmershaüser, Chem. Ber., 1988, 121, 935. 10 M. Scheer, G. Friedrich and K. Schuster, Angew. Chem., 1993, 105, 641 (Angew. Chem., Int. Ed. Engl., 1993, 32, 593). 11 T. Leigh, J. Chem. Soc., 1964, 3294. 12 A. N. Nesmeyanov, N. S. Kotshetkova, S. V. Vitt, V. B. Bondarev and E. I. Kovshov, Dokl. Akad. Nauk SSSR, 1964, 156, 99 [Dokl. Chem. (Engl. Transl.), 1964, 156, 464]. Received: 17th September 2001; Com. 01/1843

ISSN:0959-9436     

出版商:RSC    

年代:2002

数据来源: RSC

摘要:

Mendeleev Communications Electronic Version, Issue 1, 2002 1 A phosphinic analogue of methionine is a substrate of L-methionine-ã-lyase and induces the synthesis of the enzyme in Citrobacter intermedius cells Kirill V. Alferov,a Nikolai G. Faleev,b Elena N. Khurs,a Yurii N. Zhukova and Radii M. Khomutov*a a V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russian Federation.Fax: +7 095 135 1405; e-mail: khomutov@genome.eimb.relarn.ru b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 135 5085; e-mail: ngfal@ineos.ac.ru 10.1070/MC2002v012n01ABEH001550 1-Amino-3-(methylthio)propylphosphinic acid likewise methionine, is a substrate in á,ã-elimination and ã-substitution reactions catalysed by pyridoxal-5'-phosphate-dependent L-methionine-ã-lyase and is capable to induce the synthesis of this enzyme in Citrobacter intermedius cells as does L-methionine.Among organophosphorus analogues of amino acids, biologically active compounds were found whose activity is determined by competition with natural amino acids and their ability to participate in amino acid metabolism. 1-Amino-3-(methylthio)propylphosphinic acid 1, which is an analogue of methionine, is an interesting compound of this kind. It displays high antimicrobial activity1 and suppresses the growth of malignant tumors.2 The origin of the biological activity of 1 remains unclear, although it is known that compound 1 can affect protein biosynthesis at the stage of methionyl-t-RNA formation3 and, probably, biomethylation processes as a result of its conversion into an analogue of S-adenosylmethionine.2 On the other hand, the influence of 1 on pyridoxal-5'-phosphate (PLP)-dependent enzymes was not studied.These enzymes play an important role in the metabolism of sulfur-containing amino acids; consequently, the effects on them should be taken into consideration in the studies of the biological activity of 1.In this work, we examined the interaction of 1 with PLPdependent L-methionine-ã-lyase [L-methionine-methanethiol lyase (deaminating) E.C. 4.4.1.11] from C. intermedius. This enzyme is a typical representative of á,ã-eliminating lyases, which catalyses decomposition of L-methionine to methanethiol, á-ketobutyrate and the ammonium ion.Methionine-ã-lyase is contained in many microorganisms, and the pathogenicity of some of them is associated with the activity of this enzyme.4 Methionine-ã- lyase displays broad specificity with respect to substrate structures and types of chemical reactions;5 however, its interaction with organophosphorus substrate analogues and related compounds was not studied.We found that compound 1 is a substrate in á,ã-elimination and ã-substitution reactions catalysed by methionine-ã-lyase, and it induces formation of this enzyme in C. intermedius cells. Methionine-ã-lyase from C. intermedius catalyses the stereospecific formation of S-alkylhomocysteins from L-methionine and thiols.6 We found that compound 1 is a substrate in the reaction of ã-substitution, and its interaction with benzylthiol in the presence of methionine-ã-lyase affords optically active 1-amino- 3-(benzylthio)propylphosphinic acid 2 (a phosphinic analogue of S-benzylhomocysteine) in 12% yield (Scheme 1).† The optical activity of compound 2 indicates that ã-substitution is enantioselective as it is in the case of the natural substrate.‡ This opens new possibilities for the synthesis of optically active phosphinic analogues of sulfur-containing amino acids that otherwise may be prepared only by very complicated methods.We found that amino acid 1 is a substrate in á,ã-elimination reaction catalysed by methionine-ã-lyase,§ and it is decomposed to 1-oxopropylphosphinic acid 3 (a phosphinic analogue of á-ketobutyrate) (Scheme 1), which was identified as 2,4-dinitrophenylhydrazone 4.¶ The values of Km for compound 1 (1.25 mM) and L-methionine (1.13 mM) are almost equal but taking into account that only one enantiomer of racemic 1 is transformed in the reaction the real Km value is two times lower (0.625 mM).Judging from these values, the affinity of 1 to the enzyme is comparable to the affinity of the natural substrate.Thus, the obvious difference between structural parameters of H(HO)(O)P- and HOOC- groups has no effect at the stage of Michaelis complex formation. At the same time, the value of kcat for 1 was lower than that for L-methionine by a factor of 35. MeS P O X OH NH2 1 X = H 5 X = OH PhCH2S P O H OH NH2 H + MeSH P O H O O + NH4 + MeSH 2 3 Met-ã-lyase, PhCH2SH Met-ã-lyase Scheme 1 † The cells of Citrobacter intermedius AKU-10 containing methionine- ã-lyase were grown according to published procedure.6 Racemic 1-amino-3-methylthiopropylphosphinic and phosphonic acids (1 and 3) were synthesised according to the published procedure.7 Benzylthiole (0.5 ml) and frozen cells of Citrobacter intermedius (0.5 g) were added to a solution of 1 (169 mg, 1 mmol) in 20 ml of a 0.1 M potassium phosphate buffer solution containing 0.1 mM PLP.The reaction mixture was stirred on a shaker for five days at 25 °C. The protein was denatured by adding 30% trichloroacetic acid (1 ml) and removed by centrifugation. The solvent was evaporated in vacuo, the residue was dissolved in water (1 ml) and applied to a 40 ml column with Dowex 50x8 (H+ form).The column was washed with water (100 ml), and product 2 was eluted with a 5% ammonia solution. The fractions containing 2 were evaporated in vacuo to dryness. The residue was dried in vacuo over P2O5 to give phosphinic analogue 2 (30 mg, 12%), mp 221 °C, [a]D 20 –16.3° (0.5% in 1 M HCl). Rf 0.61 (PriOH–25% NH4OH–H2O, 7:1:2); Rf 0.46 (BunOH–AcOH–H2O, 12:3:5). 1H NMR (0.25 M NaOD in D2O) d: 1.63–2.05 (m, 2H, CH2CH), 2.53–2.79 (m, 3H, SCH2CH2 and CH), 3.80 (s, 2H, CH2Ph), 6.72 (dd, 1H, PH, J 486 Hz, J 1.8 Hz), 7.40 (s, 5H, Ph). Found (%): C, 48.68; H, 6.31; N 5.41.Calc. for C10H16NO2PS (%): C, 48.97; H, 6.57; N, 5.71. ‡ The stereochemistry of this reaction most likely is the same as for the natural substrate because no reasons for its changing are evident. Note that the absolute stereospecificity of another PLP-dependent lyase, tyrosine plenol-lyase, was not changed on going from the natural substrate to its phosphinic analogue.8 § The cell extract containing methionine-ã-lyase was prepared from C.Intermedius cells according to published procedure.6 Protamine sulfate as a 5% solution was added to the extract in an amount equal to 5% of the total protein amount.The precipitate formed was separated by centrifugation, the solution was kept at 60 °C for 5 min, and the denatured protein was separated by centrifugation. The activity of the preparation was assayed by measuring the rate of á-ketobutyrate formation from L-methionine according to Friedemann.9 One unit of enzymic activity was determined as the enzyme amount catalysing the transformation of 1 µmol of L-methionine per minute at 30 °C and a concentration of L-methionine equal to 40 mM.Mendeleev Communications Electronic Version, Issue 1, 2002 2 Thus, the enzyme is specific to the structure of the acid fragment at the intermediate stages of substrate transformation. Note that 1-amino-3-methylthiopropylphosphonic acid 5 (a phosphonic analogue of methionine), which is different from compound 1 only by an additional HO group at the phosphorus atom, is not a substrate of the enzyme, although the structural parameters of the phosphorus-containing fragment remained almost unchanged. These data suggest that the biological activity of acid 1 can be associated with PLP-dependent transformation into 1-oxopropylphosphinic acid, which is an organophosphorus analogue of á-ketoacids known as effective inhibitors of thiaminepyrophosphatedependent transformations.We also examined the properties of compound 1 in vivo, i.e., with respect to C. intermedius culture cells. We found that 1 had almost no effect on cell growth; however, it can penetrate into the cells like L-methionine and induce the biosynthesis of methionine-ã-lyase when the cells were grown in a synthetic medium containing acid 1 instead of L-methionine.†† However, these properties were not found in acid 5; this is most probably due to the well-known problem of aminophosphonate transport through the cell wall.It is noteworthy that regulatory activity of this kind was not observed previously at the cell level in organophosphorus analogues of amino acids.With respect to the biological activity of acid 1, a principally new possibility exists to affect the metabolism of amino acids by influencing the biosynthesis of enzymes of this metabolic pathway. Thus, compound 1 can be considered as a competitive inhibitor of the PLP-dependent enzyme, which is capable to undergo slow substrate transformations to form new organophosphorus compounds.It acts as an inductor of the biosynthesis of the enzyme similarly to the natural amino acid. This work was supported by the Russian Foundation for Basic Research (grant nos. 00-15-97844, 00-04-48242 and 01-04- 48636). References 1 J. G. Dingwall, in Proc. III Int. Conf. Chem. Biotech. Biol. Active Comps., Sofia, Bulgaria, 1985, vol. 1, p. 87. 2 R. M. Khomutov, Yu. N. Zhukov, A. R. Khomutov, E. N. Khurs, D. L. Kramer, J. T. Miller and K. V. Porter, Bioorg. Khim., 2000, 26, 735 (Russ. J. Bioorg. Chem., 2000, 26, 647). 3 A. I. Biryukov, T. I. Osipova and R. M. Khomutov, FEBS Lett., 1978, 91, 246. 4 M. Yoshimura, Y. Nakano, Y. Yamashita, T. Oho, T. Saito and T. Koga, Infect. Immun., 2000, 68, 6912. 5 H. Tanaka, N. Esaki and K. Soda, Biochemistry, 1977, 16, 100. 6 N. G. Faleev, M. V. Troitskaya, V. S. Ivoilov, V. V. Karpova and V. M. Belikov, Prikl. Biokhim. Mikrobiol., 1994, 30, 458 (in Russian). 7 T. I. Osipova, A. R. Khomutov, Yu. N. Zhukov and R. M. Khomutov, Izv. Akad. Nauk, Ser. Khim., 1999, 1360 (Russ. Chem. Bull., 1999, 48, 1348). 8 N.G. Faleev, Yu. N. Zhukov, E.N.Khurs, O.I.Gogoleva, M.V.Barbolina, N. P. Bazhulina, V. M. Belikov, T. V. Demidkina and R. M. Khomutov, Eur. J. Biochem., 2000, 267, 6897. 9 F. Friedemann and G. Haugen, Z. Biol. Chem., 1943, 177, 415. ¶ Amino acid 1 (169 mg, 1 mmol) was dissolved in 15 ml of 0.1 M potassium phosphate buffer (pH 8.0), which contained 2 µmol of pyridoxalphosphate and 0.22 U ml–1 of methionine-ã-lyase. The reaction mixture was allowed to stand in the dark at 30 °C for 72 h.A 30% aqueous CCl3COOH solution (25 ml) was added to the reaction mixture, and the precipitate formed was separated by centrifugation. The resulting solution was treated with an excess of 2,4-dinitrophenylhydrazine in 2 M HCl for 2 h at 25 °C, and a mixture of hydrazone 4 and 2,4-dinitrophenylhydrazine was extracted with EtOAc.Compound 4 was isolated from an EtOAc solution by extraction with 0.1 M potassium phosphate buffer (pH 8.0). Extracts containing 4 were combined, acidified with an aqueous 10 M HCl solution (5 ml) and acid 4 was extracted with EtOAc. The solvent was evaporated, the residue was washed with Et2O and dried in vacuo over P2O5/KOH to give 15 mg (5.5%) of hydrazone 4 (a mixture of syn- and anti-isomers). Rf 0.69 (BuiOH–H2O–EtOH, 5:4:2). 1H NMR (CD3OD– D2O, 3:2) d: 1.07–1.20 (m, 3H, syn- and anti-MeCH2), 2.98 and 3.24 (2q, 2H, syn- and anti-MeCH2, J 7.5 Hz), 6.99 (d, 1H, PH, J 751 Hz), 7.83 and 7.91 [2d, H(6), syn- and anti-C6H3N2O4, J 9 Hz], 8.15 and 8.23 [2d, H(5), syn- and anti-C6H3N2O4, J 9 Hz], 8.85 and 8.88 [2s, H(3), syn- and anti- C6H3N2O4]. UV, lmax/nm (1.6 M NaOH): 546 (6340). ††The specific activity of methionine-ã-lyase in C. intermedius cells grown in a synthetic medium containing acid 1 as an inductor was found to be 0.5 mU mg–1 of protein. Received: 9th January 2002; Com. 02/1876

ISSN:0959-9436     

出版商:RSC    

年代:2002

数据来源: RSC

摘要:

Mendeleev Communications Electronic Version, Issue 1, 2002 1 Directed synthesis of compounds capable to spontaneous resolution Remir G. Kostyanovsky,*a Irina A. Bronzovaa and Konstantin A. Lyssenkob a N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax:+7 095 938 2156; e-mail: kost@center.chph.ras.ru b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation.Fax: +7 095 135 5085; e-mail: kostya@xrlab.ineos.ac.ru 10.1070/MC2002v012n01ABEH001516 A qualitative conception for constructing conglomerates has been proposed; bis-lactam 1 has been synthesised by two methods, and it exhibited a priori predicted properties like formation in the optically active form under conditions of a routine crystallization.Crystallization of a racemate as a mixture of homochiral crystals (conglomerate) makes it possible to carry out a simple spontaneous resolution into enantiomers.1 However, in most cases, the racemates yield heterochiral crystals,1(a) the known list of conglomerates is rather short, and for the most part they have been found by a lucky chance.Naturally, it was a matter of interest to elucidate possibilities for constructing conglomerates on the basis of prediction of the crystal structure. However, such a predictivity was entirely denied (‘…nothing can be said a priori on the spontaneous resolution of racemic solutions by crystallization, …there are at present no really predictive concepts on this fascinating subject, which may be related to the chirality of the chemistry of life’.2(a) ‘In crystal engineering… design and control packing arrangements… are not routinely possible from knowledge of the molecular structure alone’.2(b)).Nevertheless, we have launched attempts to construct conglomerates of chiral bicyclic bis-lactams (BBL) starting from our qualitative predictive concepts as a basis.The racemates of BBL of types A3,4 and B5 seemed to be doomed for cocrystallization of the enantiomers [Scheme 1(a),(b)]. In crystals, they are combined in a strictly alternating sequence by H-bonds of the lactam groups into tapes of either linear (A)3,4 or diagonal (B)5 zigzag. These tapes are assembled into walls where the BBL skeletons are tightly packed into columns.The same pattern is observed for co-crystals of both quasi-racemate, (1R,4R)-(–)-A (R = Et) with (1S,4S)-(+)-A (R = Pr),4(b) and diastereomers B [R = (S)-Et(Me)CHCH2O].5(c) The latter cannot be separated by chromatography, and enantiomers A' have been obtained only after the chiral chromatographical resolution of a 2,5-bis-pmethoxybenzyl derivative3,6 (where the lactam-type H-bonding is absent).Comparison between the racemate4(a) and enantiomer4(b) of A (R = Et) points out a significant difference in the homochiral assembling of molecules in the crystal [Scheme 1(a),(c)] and a greater stability of the less soluble racemic crystal (higher density, and the melting point is higher by 37 °C). As a first approximation to arranging a homochiral assembling of BBL and its analogues there was the following assumption.At the step of prenucleation, the self-association of the molecules occurs solely by means of H-bonding each molecule with two other ones [Scheme 1(a)–(c)]. Then, in case of BBL A a homochiral association through the stable lactam–lactam H-bonding is forbidden, since termination of the H-bond polymerization chain is inevitable due to the formation of a cyclic hexamer.3,6(a) At the same time, in case of BBL B and its analogues a homochiral association to form helical tapes is possible; however, some transformation to flatten these tape is necessary in order to provide a tight packing.Motive of the structure (–)-A (R = Et) displays a possibility for such a transformation of helix though with the weakened H-bonding O–C=O…H–N [Scheme 1(c)].A perfect version of the desirable flattening may be seen in the structure of enantiomer (–)-A' [Scheme 1(d)].3(b) Each of its molecules is connected with four other ones by the same strong H-bonds similar to those in the structure of a racemate [Scheme 1(a)] and, also, it is an element of two reciprocally perpendicular flattened helices, which form corrugated layers.A tight packing of the latter occurs in such a way that a skeleton of each molecule goes into a well-shaped column. It is interesting that the racemate N N H R R O O H N N H R R O O H (a) N N RO2C CO2R H O O H (b) N N RO2C CO2R H O O H Heterochiral tapes of the types of linear (a) and diagonal (b) zigzags (±)-A' (H instead of CO2R)3 (±)-A (R = Me, Et, Pri)4 (±)-B, R = Et [ref. 5(a)], n-C12H25 [ref. 5(b)], RO = (S)-Et(Me)CHO [ref. 5(c)] (c) Homochiral six-membered ring for BBL of the type of [2.2.2] Homochiral helix for BBL of the type of [3.3.1] N N N N H CO2R CO2R O O H (–)-A, R = Et [ref. 4(b)] (–)-A', R = H dihydrates [ref. 4(c)] (±) and Homochiral tapes of the type of double zigzag (helices) O RO O H O H OR O (d) N N H H H O O H N N H H H H O O N N H H H O O H N N H H H H O O N N H H H O O H N N H H H O O H (–)-A' [ref. 3(a)], confer with 1 (Figure 1) Homochiral corrugated layer Scheme 1 120°Mendeleev Communications Electronic Version, Issue 1, 2002 2 and enantiomer structures do not differ in the parameters of H-bonds and density.3(a) Moreover, the melting point of the homochiral crystal (300.305 ¡ÆC)3(a) is higher than that of the racemate (275.277 ¡ÆC).3(c) This suggests that for ensuring the homochiral self-assembling of BBL like B and its analogues the substituents CO2R, which hinder the self-assembling by Scheme 1(d), should be removed.Therefore, the synthesis of earlier unknown BBL 1,5(a) C6 has been worked out, and their analogues like chiral glycolurils D7 (Scheme 2) have been studied.Indeed, it was found that 1 is crystallised in the form of a conglomerate (space group P212121, Z = 4), and as it was expected a priori its structure is very similar to that of (.)-A' [Scheme 1(d), Figure 1].5(a) In this work, the synthesis of 15(a) has been optimised by two methods providing total yields of 30 and 21% (Scheme 3). Yields of compounds at the separate steps have been increased; at the next to last step (in the second method) the product, 3,7-bisp- methoxybenzyl derivative of BBL 1, has been obtained in a crystal form suitable for X-ray diffraction analysis (this product has been isolated earlier as an oil5(a)).For the first time, the spontaneous resolution of 1 has been accomplished by crystallization from H2O. The separate well-formed crystals of 1 have a noticeably higher melting point than that of the racemate, and possess an optical activity¢Ó (Figure 2).A random crystal of 1 taken from the racemic mixture was used as a seed for crystallization resolution of the racemate by an internal entrainment procedure.6(b),(c) By analogy with (1R,4R)-(.)-A' [see ref. 3(a)] the absolute configuration of (1R,5R)-(.)-1 can be accepted.On the basis of the above conception, we succeeded in finding one more conglomerate in the series of chiral glycolurils D (R = Me)7(b) (Scheme 2). Spontaneous resolution of D (R = Me, Et)7(a),(b) has been carried out, and enantiomers D (R = Et) have been used in the synthesis of the chiral drug Albicar.7(b),(c) However, in these cases, though the molecular packing is similar to those shown in Scheme 1(d) but it is complicated by H-bonding between the layers to form three-dimensional nets.7(b),8 Note that in case of the unsubstituted glycoluril two different patterns of packing are observed for its two forms of crystals, one being H-bonded corrugated layers according to Scheme 1(d), and another being three-dimensional nets9 like D.In conclusion, it may be said that the main feature for originating the proposed conception is a comparative analysis of both enantiomer and racemate crystal structures of key compounds in the series under study. Such an approach seems to be universal. This work was supported by the Russian Academy of Sciences, the Russian Foundation for Basic Research (grant nos. 00-03-32738 and 00-15-97359) and INTAS (grant no. 99-00157).HN NH O O C6 N N N N H H D, R = Me,7(b) Et7(a),(c),8 R R O O Scheme 2 Figure 1 Homochiral corrugated layer in the crystal structure of BBL 15(a) [cf. Scheme 1(d)]. O(1') H(2N') N(2') N(1') H(1N') O(2') O(1) N(1) N(2) H(1N) H(2N) O(2) O(1'') O(2'') N(1'') N(2'') H(1N'') H(2N'') ¢Ó Characteristics and spectroscopic data. Compounds presented in Scheme 3, have been characterised by 1H and 13C NMR spectra identical to those described earlier.5(a) (.)-1, upon crystallization from H2O with self-evaporation at 20 ¡ÆC the crystals up to 14 mg in weight have been obtained; mp 364 ¡ÆC (decomp.), [a]17 D = .3.0¡Æ; [a]17 578 = .3.2¡Æ; [a]17 546 = .4.2¡Æ; [a]17 436 = .8.2¡Æ; [a]17 406 = .9.5¡Æ (c 1.3, H2O); CD spectrum (c 3.25¡¿10.5 M in H2O), .e (lmax/nm): 0.75 (212).For grinded mixtures the melting point is 355.358 ¡ÆC (decomp.) in case of the crystals of opposite signs of optical rotation and to 350 ¡ÆC (decomp.) in case of a non optically active mixture [cf. ref. 5(a)]. Then, the mother liquor and precipitate were combined, and crystallization from H2O with self-evaporation at 20 ¡ÆC was repeated.Solution of (.)-1 used for the measurement of the optical rotation angle was evaporated entirely, the crystals were isolated, grinded and taken as a seed. Using an internal entrainment procedure,6(b),(c) the precipitate of (.)-1 has been obtained in 26% yield, [a]17 D = .2.8¡Æ (c 1.5, H2O). Scheme 3 Reagents and conditions: i, Ce(NH4)2(NO3)6 in MeCN.H2O, 2 days at 20 ¡ÆC, then NaHCO3 and extraction of the product with MeCO2Et; ii, KOH in EtOH.H2O, 2 days at 20 ¡ÆC and 1.1.5 h at 4 ¡ÆC, then with CF3CO2H in H2O, 2 h at 20 ¡ÆC and 5 days at 4 ¡ÆC, then separation of the product precipitate; iii, heating 2 h at 125.150 ¡ÆC (2.3 mmHg) and sublimation, 10 h at 230.250 ¡ÆC (2.3 mmHg); iv, KOH in EtOH, 2 days at 20 ¡ÆC, 1.1.5 h at 4 ¡ÆC, then with CF3CO2H in wet EtOH 1 day at 20 ¡ÆC and 3 h at 4 ¡ÆC, then separation of the product precipitate; v, heating 2 h at 145.150 ¡ÆC (2.3mmHg) and sublimation of the residue, 10 h at 170.180 ¡ÆC (2.3 mmHg), in contrast to the earlier reported5(a) the product has been isolated in a crystal form, mp 31.33 ¡ÆC; vi, Ce(NH4)2(NO3)6 in MeCN.H2O, 2 days at 20 ¡ÆC, then NaHCO3, extraction of anisaldehyde with diethyl ether, heating 2 h at 145. 150 ¡ÆC (2.3 mmHg), and sublimation of the residue, 10 h at 170.180 ¡ÆC (2.3 mmHg). RN NR O O CO2Et EtO2C HN NH O O CO2Et EtO2C HN NH O O CO2H HO2C HN NH O O H H RN NR O O CO2H HO2C RN NR O O H H i 52.3% ii 86% iii 78.7% vi 40.5% v 61.4% iv 80.9% R = p-MeOC6H4CH2 1 0 .0.2 .0.4 .0.6 200 220 240 .e l/nm 230 210 Figure 2 CD Spectrum of BBL (.)-1.Mendeleev Communications Electronic Version, Issue 1, 2002 3 References 1 (a) J.Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates, and Resolutions, Krieger Publishing Company, Malabar, Florida, 1994; (b) A. Collet, in Comprehensive Supramolecular Chemistry, ed. D. N. Reinhoudt, Pergamon, Oxford, 1996, vol. 10, ch. 5, pp. 113–149; (c) A. Collet, Enantiomer, 1999, 4, 157. 2 (a) A.Gavezzotti, Acc. Chem. Res., 1994, 27, 309; (b) G. R. Desiraju, Nature, 2001, 412, 397. 3 (a) M.-J. Brienne, J. Gabard, M. Lecklercq, J.-M. Lehn, M. Cesario, C. Pascard, M. Heve and G. Dutruc-Rosset, Tetrahedron Lett., 1994, 35, 8157; (b) J.-M. Lehn, Supramolecular Chemistry, VCH, Weinheim, 1995; (c) P. A. Sturm, and D. V. Henry, J. Med. Chem., 1974, 17, 481. 4 (a) R. G. Kostyanovsky, Yu.I. El’natanov, O. N. Krutius, I. I. Chervin, and K. A. Lyssenko, Mendeleev Commun., 1998, 228; (b) R. G. Kostyanovsky, K. A. Lyssenko and D. A. Lenev, Mendeleev Commun., 1999, 154; (c) R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, K. A. Lyssenko, I. I. Chervin and D. A. Lenev, Mendeleev Commun., 1999, 109. 5 (a) R. G. Kostyanovsky, K. A. Lyssenko, D. A. Lenev, Yu.I. El’natanov, O. N. Krutius, I. A. Bronzova, Yu. A. Strelenko and V. R. Kostyanovsky, Mendeleev Commun., 1999, 106; (b) R. G. Kostyanovsky, K. A. Lyssenko, I. A. Bronzova, O. N. Krutius, Yu. A. Strelenko and A. A. Korlyukov, Mendeleev Commun., 2000, 106; (c) R. G. Kostyanovsky, O. N. Krutius, I. A. Bronzova, D. A. Lenev, K. A. Lyssenko and B. B. Averkiev, Mendeleev Commun., 2001, 6. 6 (a) R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, K. A. Lyssenko and Yu. A. Strelenko, Mendeleev Commun., 1999, 70; (b) R. G. Kostyanovsky, V. R. Kostyanovsky, G. K. Kadorkina and V. Yu. Torbeev, Mendeleev Commun., 2000, 83; (c) R. G. Kostyanovsky, V. Yu. Torbeev and K. A. Lyssenko, Tetrahedron Asymmetry, 2001, 12, 2721. 7 (a) R. G. Kostyanovsky, K. A. Lyssenko, G. K. Kadorkina, O. V. Lebedev, A. N. Kravchenko, I. I. Chervin and V. R. Kostyanovsky, Mendeleev Commun., 1998, 231; (b) R. G. Kostyanovsky, K. A. Lyssenko, A. N. Kravchenko, O. V. Lebedev, G. K. Kadorkina and V. R. Kostyanovsky, Mendeleev Commun., 2001, 134; (c) R. G. Kostyanovsky, G. K. Kadorkina, K. A. Lyssenko, V. Yu. Torbeev, A. N. Kravchenko, O. V. Lebedev, G. V. Grintselev-Knyazev and V. R. Kostyanovsky, Mendeleev Commun., 2002, 6. 8 E. B. Shamuratov, A. S. Batsanov, Yu. T. Struchkov, A. Yu. Tsivadze, M. G. Tsitsadze, L. I. Khmel’nitskii, Yu. A. Simonov, A. A Dvorkin, O. V. Lebedev and T. B.Markova, Khim. Geterotsikl. Soedin., 1991, 937 [Chem. Heterocycl. Compd. (Engl. Transl.), 1991, 27, 745]. 9 N. Li, S. Maluendes, R. H. Blessing, M. Dupuis, G. R. Moss and G. T. DeTitta, J. Am. Chem. Soc., 1994, 116, 6494. Received: 13th September 2001; Com. 01/1842

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年代:2002

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Mendeleev Communications Electronic Version, Issue 1, 2002 1 Chiral drugs via the spontaneous resolution Remir G. Kostyanovsky,*a Gul’nara K. Kadorkina,a Konstantin A. Lyssenko,b Vladimir Yu. Torbeev,a Angelina N. Kravchenko,c Oleg V. Lebedev,c Gennadii V. Grintselev-Knyazevb and Vasily R. Kostyanovskya a N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russian Federation.Fax: +7 095 938 2156, e-mail: kost@center.chph.ras.ru b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 135 5085, e-mail: kostya@xrlab.ineos.ac.ru c N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 135 5328 10.1070/MC2002v012n01ABEH001521 The psychotropically active drug Albicar 1 has been prepared for the first time in both enantiomerically pure forms starting from the (+)-2 and (–)-2 precursors obtained by spontaneous resolution; the crystal structures of (–)-1 and (±)-1 have been solved by X-ray diffraction study. A perfect medicine (‘the Erlich magic bullet’) should match a biological target.The latter is inherently a chiral species; therefore, the racemate and both enantiomers of the medicinal compound may differ strongly in activity, toxicity and side effects (for example, both enantiomers of the chiral drug Thalidomid exhibit sedative action but only one of them is teratogenic).1 That is why in the last decade the world pharmacy intensively turned to the production of enantiomerically pure medicines.2 The simplest ways for obtaining enantiomers are spontaneous crystallization resolution and absolute asymmetric synthesis (i.e., crystallization under conditions of the fast enantiomerization in a solution or melt that gives rise to the complete transformation of a racemate into one enantiomer).2(b)–(e),3(b) The ability of a racemate for crystallization in the form of a conglomerate (i.e., a mixture of homochiral crystals of the enantiomers) is a critical requirement in both methods.3(a)–(d) Recently, data on the spontaneous crystallization resolution of the pseudo-racemates3(e) (in their crystals, the relative positions of the enantiomers are statistically disordered3(a)) were reported.In this work, we describe the synthesis of both enantiomers of the psychotropically active medicine Albicar,4 2,6-diethyl- 4,8-dimethylglycoluril 1.Albicar has passed pre-clinical tests and was recommended for clinical tests as a tranquilizer and a remedy for treating vegetative neuroses. According to the qualitative concepts for constructing conglomerates developed previously,5 there were the chiral glycolurils that seemed to be the most promising objects.Indeed, whereas the Albicar itself is crystallised as a racemate (space group P21/a, Z = 4)4(c) its possible precursors, 2,6-dialkylglycolurils, both do form conglomerates [R = Me (space group P212121, Z = 4),5(b) R = Et, 2 (space group P41212, Z = 4)6] and undergo spontaneous resolution by crystallization from water under normal conditions.5(a),(b) It should be noted that in some instances crystallization in the form of a conglomerate occurs only under high pressures or elevated temperatures;3(a)–(c) sometimes, the conglomerates do not undergo spontaneous resolution due to epitaxy.5(b) By a comparative analysis of the crystal properties of Albicar precursors, the advantage of 2 was shown;5(b) therefore, its spontaneous resolution into enantiomers was completed using an internal entrainment procedure (the novel method including applying a single crystal as the seed from primary racemic conglomerate;7 early resolution by mechanical sorting of crystals was described5( a)). Among the known methods for the N-alkylation of glycolurils,4(b),8–11 we have selected the simplest one7 and found conditions to provide quantitative yields of the product.The obtained enantiomers of 1 have been purified by crystallization from diethyl ether until the constancy of melting points and optical rotation angles, and characterised by 1H NMR (Figure 1) and CD spectra (Figure 2).† The absolute configuration of the enantiomers of 1 is apparent from those established earlier5(a) for precursors 2 (Scheme 1).The purity of (–)-1 exceeds 95% as it is evident from the absence of the signals due to MeN, CH2O, and HC relating to another enantiomer and observed for the racemate in 1H NMR spectrum in the presence of the chiral shift reagent Eu(tfc)3 (Figure 1). It should be noted that the melting points of the enantiomers are higher than that of the racemate by 25 °C.† This uncommon case3,12 may indicate to a metastable state of the racemate.3 However, crystallization of (±)-1 from toluene at an elevated temperature (80–100 °C) 4.6 4.4 3.4 3.2 3.0 2.8 2.6 d/ppm d/ppm 4.5 4.0 3.5 3.0 2.5 Figure 1 Partial 1H NMR spectra of (±)-1 (400MHz) in C6D6; below: normal spectrum; above: in the presence of the chiral shift reagent Eu(tfc)3. 1 1 1 1 (W + 2 (W + 2 66 ± 1 1 1 1 (W 0H 2 (W 0H 2 66 ± LL 1 1 1 1 (W + 2 (W + 2 55 1 1 1 1 (W 0H 2 (W 0H 2 55 LL . L L Scheme 1 Reagents and conditions: i, resolution by an internal entrainment procedure; ii, (MeO)2SO2 and KOH in H2O, 3 h at 70–75 °C, neutralization with HCl at 20 °C, extraction with CH2Cl2 at 20 °C, chromatography on silica (eluent CH2Cl2), and crystallization from Et2O.Mendeleev Communications Electronic Version, Issue 1, 2002 2 led to lower melting racemic crystals.In order to compare the peculiarities of the crystal structures of enantiomerically pure and racemic 1, the X-ray investigation of both crystals (grown from Et2O at 20 ¡ÆC) was carried out.¢Ô The geometries of 1 in homo- and heterochiral crystals are similar (Figure 3).The conformations of the five-membered rings are slightly different. Thus, in (.)-1 both five-membered rings are characterised by the envelope conformation with the deviations of the N(2) and N(4) by 0.11 and 0.13 A, respectively, while in (¡¾)-1 the maximum deviations of atoms from the mean square planes are less than 0.05 A. The angles between planes in both structures are similar and, in average, equal to 121¡Æ.The comparison of the crystal packings has revealed that in accordance with the greater value of the mp of (.)-1 its density (1.217 g cm.3) at room temperature is slightly higher than the corresponding value in (¡¾)-1 (1.188 g cm.3). However, the C.H¡�¡�¡�O contacts (cf. ref. 13), which are observed in both crystals, are shorted in (¡¾)-1.In (.)-1, the C.H¡�¡�¡�O contacts of the hydrogen atoms attached to the C(2) and C(4) atoms assemble molecules into a three-dimensional framework and with the C¡�¡�¡�O distances from 3.309(6) to 3.435(6) A (Figure 4). While in (¡¾)-1 the molecules are assembled into layers with hydrophobic coatings (Et groups) parallel to the bc crystallographic plane by the C.H¡�¡�¡�O contacts with the C¡�¡�¡�O distances varying in a range of 3.214(4).3.345(4) A (Figure 5).Taking into account that the C.H¡�¡�¡�O contacts play a great role in the formation of crystals, the above shortening of the C.H¡�¡�¡�O contacts can be responsible ¢Ó The NMR spectra were measured on a Bruker WM-400 spectrometer (400.13 MHz for 1H), optical rotation was measured on a Polamat A polarimeter, and CD spectra were recorded on a JASCO-J500A instrument with a DP-500N data processor.(¡¾)-1, obtained from (¡¾)-2 by Scheme 1, mp 112.114 ¡ÆC (Et2O) (lit.,4(b) mp 108.110 ¡ÆC). 1H NMR (C6D6) d: 0.85 (t, 6H, 2MeCH2, 3J 7.4 Hz), 2.5 (s, 6H, 2MeN), 3.05 (m, 4H, 2CH2N, ABX3 spectrum, .n 152 Hz, 2J .14.8 Hz, 3J 7.4 Hz), 3.99 (s, 2H, 2HC).When adding the chiral shift reagent in the molar ratio 1/Eu(tfc)3 = 20 a low-field shift of all the signals and splers are observed (.n/Hz), 1H NMR [C6D6 + Eu(tfc)3] d: 0.99, 2.69 (4.4), 3.07, 3.42 (2.8), 4.3 (1.2), upon adding an amount of Eu(tfc)3 the signal of MeN moves to 2.8 ppm (.n 23.1 Hz), and the signal of HC, to 4.58 ppm (.n 12.7 Hz).(1S,5S)-(.)-2 and (1R,5R)-(+)-2, upon complete crystallization of (¡¾)-2 from H2O, a racemic mixture of the well-formed crystals was obtained; two crystals of the opposite optical rotation signs were selected, rubbed to powder and used as seeds for resolution of (¡¾)-2 by an internal entrainment procedure.7 Repeated crystallization of the enantiomerically enriched products resulted in preparing enantiomerically pure samples [cf.ref. 5(a)]. Starting from 5 g of (¡¾)-1, 2.3 g of (.)-2 (91.4%) and 2.1 g of (+)-2 (84%) were obtained. (1S,5S)-(.)-1, obtained from (1S,5S)-(.)-25(a) (Scheme 1), yield 96%, mp 137.5.139 ¡ÆC (Et2O). 1H NMR spectrum (C6D6) is similar to that for (¡¾)-1; when adding Eu(tfc)3 gradually until the low-field shift of the signals at 2.74 (MeN) and 4.5 ppm (HC) the splitting was not observed; [a]20 578 .17.3¡Æ, [a]20 546 .20.9¡Æ, [a]20 436 .40.8¡Æ, [a]20 406 .47.1¡Æ (c 0.38, MeOH); CD spectrum (c 3.76¡¿10.3 M MeOH), .e (l/nm): 5.8 (207.5), 0.0 (202), .10.0 (196).(1R,5R)-(+)-1, obtained from (1R,5R)-(+)-25(a) (Scheme 1), yield 96.5%, mp 137.5.138 ¡ÆC (Et2O). 1H NMR spectrum (C6D6) is similar to those for (¡¾)-1; [a]20 578 +18.3¡Æ, [a]20 546 +21.0¡Æ, [a]20 436 +39.3¡Æ, [a]20 406 +44.5¡Æ (c 0.38, H2O); CD spectrum (c 9.3¡¿10.3 M MeOH), .e (l/nm): .5.8 (207.5), 0.0 (202), +10.0 (196). 1 2 10 8 6 4 2 0 .2 .4 .6 .8 .10 .e l/nm 200 220 Figure 2 CD spectra (MeOH) of (1) (1S,5S)-(.)-1 and (2) (1R,5R)-(+)-1. C(7) N(2) C(3) O(2) N(3) C(8) C(9) C(4) N(4) C(10) C(1) O(1) N(1) C(5) C(6) C(2) Figure 3 The general view of (.)-1.¢Ô Crystallographic data for (.)-1 and (¡¾)-1: at 295 K, the crystals of C10H18N4O2 (.)-1 are orthorhombic, space group P212121, a = 9.460(3) A, b = 11.225(4) A, c = 11.626(4) A, V = 1234.6(7) A3, Z = 4, M = 226.28, dcalc = 1.217 g cm.3, m(MoK¥á) = 0.87 cm.1, F(000) = 488; (¡¾)-1 monoclinic, space group P21/c, a = 10.042(2) A, b = 11.022(2) A, c = 11.950(2) A, b = 106.963(4)¡Æ, V = 1265.1(4) A3, Z = 4, M = 226.28, dcalc = 1.188 g cm.3, m(MoK¥á) = 0.85 cm.1, F(000) = 488.Intensities of 6917 and 12096 reflections were measured with a Smart 1000 CCD diffractometer at 295 K [l(MoK¥á) = 0.71073 A, w-scans with a 0.3¡Æ step in w and 30 and 15 s per frame exposure, 2q < 50¡Æ, 2q < 60¡Æ for (.)-1 and (¡¾)-1, respectively], and 2123 and 3627 independent reflections were used in a further refinement.The structures were solved by a direct method and refined by the full-matrix least-squares technique against F2 in the anisotropic.isotropic approximation. Due to high libration of the ethyl group C(5).C(6) in (.)-1, it was refined with the constrained bond lengths (C.C of 1.55 A and N.C of 1.44 A). Hydrogen atoms were located from the Fourier synthesis and refined using a riding model in (.)-1 and an isotropic approximation in (¡¾)-1.The refinement converged to wR2 = 0.1218 and GOF = 1.006 for all independent reflections [R1 = 0.0625 was calculated against F for 799 observed reflections with I > 2s(I)] for (.)-1 and to wR2 = 0.1101 and GOF = 0.957 for all independent reflections [R1= 0.0465 was calculated against F for 1399 observed reflections with I > 2s(I)] for (¡¾)-1.All calculations were performed using SHELXTL PLUS 5.1 on IBM PC AT. Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). For details, see ¡®Notice to Authors¡�, Mendeleev Commun., Issue 1, 2002.Any request to the CCDC for data should quote the full literature citation and the reference number 1135/103. a0 b c Figure 4 The intermolecular C.H¡�¡�¡�O contacts in (.)-1. The parameters of the C.H¡�¡�¡�O contacts are: C(2).H(2)¡�¡�¡�O(1') (.x, .1/2 + y, 1/2 . z) {H(2)¡�¡�¡�O(1') 2.43 A, �¢C(2)H(2)O(1') 155¡Æ, C(2)¡�¡�¡�O(1') 3.435(6) A}; C(4).H(4)¡�¡�¡�O(2') (1/2 . x, .y, 1/2 + z) {H(4)¡�¡�¡�O(2') 2.41 A, �¢C(4)H(4)O(2') 141¡Æ, C(4)¡�¡�¡�O(2') 3.309(6) A}.C.H distances in (.)-1 are normalised to the ideal values 1.07 A.Mendeleev Communications Electronic Version, Issue 1, 2002 3 in part for the metastable formation of a racemic crystal upon the crystallization of a racemic solution. This work was supported by the Russian Academy of Sciences, Russian Foundation for Basic Research (grant nos. 00-03-32738 and 00-03-81187Bel), and INTAS (grant no. 99-00157). References 1 (a) G. Blaschke, H. P. Kraft, K. 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Kadorkina, O. V. Lebedev, A. N. Kravchenko and V. R. Kostyanovsky, Mendeleev Commun., 1998, 231; (b) R. G. Kostyanovsky, K. A. Lyssenko, A. N. Kravchenko, O. V. Lebedev, G.K. Kadorkina and V. R. Kostyanovsky, Mendeleev Commun., 2001, 134; (c) R. G. Kostyanovsky, I. A. Bronzova and K. A. Lyssenko, Mendeleev Commun., 2002, 4. 6 E. B. Shamuratov, A. S. Batsanov, Yu. I. Struchkov, A. Yu. Tsivadze, M. G. Tsintadze, L. I. Khmel’nitskii, Yu. A. Simonov, A. A. Dvorkin, O. V. Lebedev and T. B. Markova, Khim. Geterotsikl. Soedin., 1991, 937 [Chem. Heterocycl. Compd.(Engl. Transl.), 1991, 27, 745]. 7 (a) R. G. Kostyanovsky, V. R. Kostyanovsky, G. K. Kadorkina and V. Yu. Torbeev, Mendeleev Commun., 2000, 83; (b) R. G. Kostyanovsky, V. R. Kostyanovsky, G. K. Kadorkina and K. A. Lyssenko, Mendeleev Commun., 2001, 1; (c) R. G. Kostyanovsky, V. Yu. Torbeev and K. A. Lyssenko, Tetrahedron Asymmetry, 2001, 12, 2721. 8 J.378. 9 (a) M. M. Conn and J. Rebek, Jr., Chem. Rev., 1997, 97, 1647; (b) R. Meissner, X. Garcias, S. Mecozzi and J. Rebek, Jr., J. Am. Chem. Soc., 1997, 119, 77; (c) C. Valdes, V. P. Spitz, S. W. Kubik and J. Rebek, Jr., Angew. Chem., Int. Ed. Engl., 1995, 34, 1885; (d) R.Wyler, J. de Mendoza and J. Rebek, Jr., Angew. Chem., Int. Ed. Engl., 1993, 32, 1699. 10 R. J. Jansen, A. E. Rowan, R. de Gelder, H. W. Scheeren and R. J. M. Nolte, Chem. Commun., 1998, 121. 11 P. R. Dave, F. Forohar, M. Kaselj, R. Gilardi and N. Trivedi, Tetrahedron Lett., 1999, 40, 447. 12 C. P. Brock, W. B. Schweizer and J. D. Dunitz, J. Am. Chem. Soc., 1991, 113, 9811. 13 (a) G. R. Desiraju, Acc. Chem. Res., 1991, 24, 290; (b) Y. Gu, T. Kae and S. Scheiner, J. Am. Chem. Soc., 1999, 121, 9411. 0a b c Figure 5 The intermolecular C–H···O contacts in (±)-1. The parameters of the C–H···O contacts are C(2)–H(2)···O(1') (x, 1/2 – y, –1/2 + z) {H(2)···O(1') 2.34 Å, �C(2)H(2)O(1') 155°, C(2)···O(1') 3.3452(4) Å}; C(4)–H(4)···O(2') (2 – x, –1/2 + y, 1/2 – z) {H(4)···O(2') 2.17 Å, �C(4)H(4)O(2') 165°, C(4)···O(2') 3.213(4) Å}. C–H distances in (±)-1 are normalised to the ideal values 1.07 Å. Received: 21st September 2001; Com. 01/

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Mendeleev Communications Electronic Version, Issue 1, 2002 1 Thermal-lens spectrometry for studying molecular layers covalently bonded to a flat glass surface Mikhail Yu. Kononets, Svetlana N. Bendrysheva, Mikhail A. Proskurnin,* Elena V. Proskurnina, Evgenii M. Min’kovskii, Aleksei R. Tarasov and Georgii V. Lisichkin Department of Chemistry, M. V. Lomonosov Moscow State University, 119992 Moscow, Russian Federation.Fax: +7 095 939 4675; e-mail: michael@analyt.chem.msu.ru 10.1070/MC2002v012n01ABEH001522 The molecular layers of the Reactivrot B5A dye covalently bonded to flat quartz glass surfaces was studied by thermal lensing in combination with electron-probe microanalysis. Studies of the structure of chemically bonded molecular layers are of importance in the chemistry of surface compounds.1 A small contribution from the layer mass to the total sample mass does not allow methods traditionally used for solving the problems of three-dimensional chemistry to be applied.Therefore, the composition and structure of bonded molecular layers on porous substrates with high specific surface areas are usually studied. In the case of developed surfaces, the mass fraction of a bonded layer can reach 10%, which is sufficient for elemental microanalysis, IR, UV, and EPR spectroscopy etc.2 However, in the case of a chemical modification of the surface of flat substrates, the study of the bonded layer becomes a complicated problem.We applied thermal lens spectrometry (TLS) to study chemically modified flat surfaces of quartz glasses.Thermal lensing is a thermooptical method commonly used in analytical practice.3 This method is based on detecting heat effects due to the non-radiative relaxation of molecules that absorbed electromagnetic radiation.3,4 In thermal lensing, an equilibrium redistribution of temperature in the irradiated sample results in a Gaussian profile of refractive index determined by the spatially Gaussian form of the excitation laser beam.This profile can be treated as an optical element similar to a lens with the focal distance being a function of the absorbance of the test sample.3 Thermal lensing has such features as (i) high instrumental sensitivity, which makes it possible to detect absorbances in liquid samples down to 10–7–10–8, to determine concentrations down to 10–12 mol dm–3, to analyse volumes down to 10–15 dm3 and to detect hundreds of molecules in such volumes; (ii) the possibility to use all the variety of methods and approaches of conventional spectrophotometry; and (iii) non-destructivity, which makes it possible to apply TLS to a wide range of test substances.3–5 Usually, thermal lensing is applied to determine substances like dyes or metal chelates absorbing the radiation of an excitation laser in liquids.3–5 However, the sensitivity of the method is sufficient to measure the concentration of a dye on a nonporous glass surface.Shimosaka et al.6 studied the Acridine Orange dye adsorbed on glass using total-internal-reflection thermal lensing. The aim of this study was to examine the uniformity and surface concentration of a bonded layer. A dual-laser parallel-beam (collinear) thermal lens spectrometer was used.7 The thermal lens was excited with an INNOVA 90-6 argon-ion laser (Coherent, USA) with le = 514.5 nm (TEM00 mode); the maximum power at the sample was 180 mW. The probe was a SP-106-1 helium–neon laser (Spectra Physics, USA) with lp = 632.8 nm (TEM00 mode).The signal (the intensity at the centre of the probe beam) was measured with an FD-7K photodiode.Next, the signal was amplified, and it entered an ADC–DAC board of an IBM PC/AT computer. The measurement was synchronised using the special software.7 The optical parameters of the spectrometer are summarised in Table 1.8 The beam waist location and waist spot sizes of laser beams were measured using an 818-SL digital power meter (Newport Corp., Fountain Valley, CA, USA) according to Snook and Lowe.5 Electron-microscopic images were taken on a CamScan 44 scanning electron microscope with a thermal-emission tungsten cathode.Due to the very low conductivity of the samples, measurements were made at low acceleration voltages at the equilibrium point (2 kV or lower).At this potential, the total secondary current is equal to the primary electron current. For each sample, the equilibrium points were selected to eliminate charging effects on the images. At this potential, photographs were made every 2 min during 20 min (the images did not change). Focussing was performed at low magnifications (×25) to prevent charging. Secondary-electron images were obtained with a magnification of 200 to 1500.The thermal lens signal qj for a single j-th measurement of a sample was calculated as the average of i = 50–100 signals of on-off thermal-lens excitation cycles resulting in a series of the relative change in intensity in the central part of the probe beam for a steady-state thermal lens [qj1, qj2, … qji]. The values of qji were calculated from the equation:3,4 where Ioff is the time-averaged probe beam intensity without a thermal lens (excitation beam is off) and Ion is the timeaveraged probe beam intensity for a steady-state thermal lens (excitation beam is on) for a single cycle.Recalculation of the signal q to absorbance A was made using the equation:3,5 where J = 2.303E0PeA, Pe is the power of the excitation laser at the sample, m is the mode-mismatching factor and V is the distance from the probe waist to the sample normalised to the corresponding confocal length.5 The parameter E0 = (dn/dT)(lpk)–1 is the reduced enhancement factor for thermal-lens measurements, dn/dT is the temperature gradient of the refractive index, lp is the wavelength of the probe laser, and k is the thermal conductivity. In thermal-lens measurements, the following parameters were measured: an averaged signal of the sample for j subsequent cycles qj and the measurement precision (deviation of the signal from cycle to cycle).For each test sample with the concentration of the test component c, the average signal qn(c) was calculated for n replicate measurements. The repeatability of measurements was characterised by the relative standard deviation.Table 1 Parameters of the dual-beam thermal lens spectrometer. Excitation laser Wavelength le (nm) 514.5 Focussing lens focal length (nm) 300 Confocal distance (mm) 19.5 Laser power at cell (mW) 180 Spot size at the waist (µm) 60±1 Probe laser Wavelength lp (nm) 632.8 Focussing lens focal length (nm) 185 Confocal distance (mm) 3.1 Laser power at cell (mW) 4 Spot size at the waist (µm) 25±1 Other parameters Cell length (mm) 2 Sample-to-detector distance (cm) 200 m in equation (2) 2.0±0.1 V in equation (2) 3.1±0.1 qji= , Ioff – Ion Ion (1) qj= 1– arctan – 1 J2 2mV 1 + 2mV + V2 2 (2)Mendeleev Communications Electronic Version, Issue 1, 2002 2 The value of J is proportional to absorbance A = al, where a (cm–1) is the absorptivity of the layer of the test compound and l (cm) is the sample depth. The absorptivity can be estimated as a = escs, where es (cm mol–1) is the surface absorption coefficient and cs (mol cm–2) is the surface concentration of the absorbing layer.Taking into account the sufficient precision of measurements of beam radii at the sample (see Table 1), this makes it possible to calculate the surface concentration of the dye from the thermal-lens signal.In our experiments (le = 514.5 nm), es = 9×106 cm mol–1, E0 = 6.3W–1, and Pe = 0.180 W. The selection of the dye was dictated by its absorption-band parameters, by the absence of radiation losses under light absorption, and by the possibility of its chemical immobilization on the surface.We selected the Reactivrot B5A dye (Scheme 1). Modification of glasses with a sublayer of (3-aminopropyl)- trimethoxysilane was made from a toluene solution in the presence of trace moisture according to Lisichkin et al.9 The dye was bonded to a (3-aminopropyl)trimethoxysilane sublayer under the conditions providing an incomplete surface coverage to reveal the possibility of detection of ‘holes’ in the bonded layer. A dye solution in dry methanol was used, and the reaction was carried out in a sealed ampoule at 70 °C for 16 h.Next, the ampoule was opened, and the sample was washed with dry methanol. The conditions of bonding the dye to aminated quartz glasses were selected from preliminary experiments with a porous silica substrate, Silochrom S-120.The dye was bonded by amino groups of (3-aminopropyl)trimethoxysilane as a modifier, which react with a SiO2 surface (see Scheme 2).9 Thermal-lens studies of modified samples with the bonded dye showed that certain areas of a single glass plate are characterised by two significantly different signals. One of them is the response of the modified surfaces without the dye (a ‘background’ line in Table 2), which is mainly determined by background photothermal defocusing and light scattering.Another signal corresponds to the bonded dye and shows a curve with a plateau, and the signal of the plateau also corresponds to the thermal-lens signal of the modified surface before dye bonding (Figure 1). Subsequent measurements at the same sample position give the same signal.The data obtained evidenced that the selected modification conditions result in ‘holes’ or sites without the dye. This is confirmed by the measurements of the same samples using scanning electron microscopy (see Figure 2). Thus, thermal lensing can be used for estimating the uniformity of the bonded layer in the scale corresponding the linear dimensions of the thermal lens (about 60 µm in our case).In electron-probe experiments, the stability of so called ‘chemically labile’ substances, i.e., substances with low thermo- and electroconductivity, which may decompose under vacuum and electron-probe effects, is a very complicated problem that requires special studies. Previously, we developed several approaches to the analysis of chemically labile samples, including non-conducting organic samples.10,11 Especially important is the time dependence of the thermallens signal for areas with a bonded dye. As the temperature gradient of the refraction index for the used glass is positive, the signal J increases with the concentration of the test substance on the surface (photothermal focussing).Thus, the term in parentheses in equation (2) and the signal q increase with a decrease in the absorption of the bonded layer.Therefore, a reproducible increase in the signal for glass surfaces with a bonded dye is likely due to the decomposition of the dye under laser irradiation. This was confirmed by comparing electron-probe images of the plates before and after thermal lens measurements: the images show new ‘holes’ in dye covers with a round symmetry and a rough size of 60 µm.Under the same conditions, Reactivrot B5A in an aqueous solution is resistant to laser radiation. Probably, the rigid fixation of the dye on a solid substrate results in a decrease in its photostability. However, the residence time of the dye at the surface was much longer than the characteristic time of the thermal lens effect (~100 ms).Thus, it provided reliable thermal-lens determination of the dye by photodestruction kinetic curves (Figure 1). The photodestruction curves showed that the process is complex. We suppose that TLS would provide data on the thermal stability of bonded molecular layers. The surface concentrations of bonded dyes were found experimentally (Table 2).It is noteworthy that these data are not averaged through the whole surface and relevant only to the surface areas with the dye. Previously, it was shown12 that the bonding of trifunctional silanes on porous substrates may result in the formation of polylayers. It is also known1,2 that the maximum bonding of monofunctional silanes to silica is limited by the area of the anchor group of a modifier, and it is 2.5 group nm–2. Taking into account steric hindrances, the limiting density of a Reactivrot B5A monolayer is about 1.1 group nm–2 (calculated using the PM3 method, WinMOPAC, Chem3D, CambridgeSoft).These calculations are in good agreement with the experimental data for Sample 1 (very close to the limiting density of a mono- 1 1 1 &O &O 1+ 2+ 1 621D 1 1D26 Scheme 1 Reactivrot B5A.Table 2 The bonding density of the dye to samples. Sample 1: (3-aminopropyl) trimethoxysilane was applied directly without a solvent. Sample 2: (3-aminopropyl)trimethoxysilane was applied from dry toluene. Sample 3: (3-aminopropyl)trimethoxysilane was applied from wet toluene. The bonding density of (3-aminopropyl)trimethoxysilane to Silochrom S-120 is about 1.6 group nm–2.Blank sample is a glass treated with (3-aminopropyl)- trimethoxysilane only (n = 15). Sample Average signal qn(c) Bonding density of the dye Number of layers mol cm–2 group nm–2 Background 0.025±0.002— — — Sample 1 0.022±0.002 (1.6±1.0)×10–10 1.0±0.6 0.87 Sample 2 0.018±0.003 (3.2±1.4)×10–10 1.9±0.8 1.74 Sample 3 –0.01±0.01 (1.6±0.5)×109 9±3 8.7 Silochrom S-120 — 8.3×10–11 0.5 0.45 SiOH + (EtO)3Si(CH2)3NH2 SiO Si(OEt)2(CH2)3NH2 – EtOH SiOH + (EtO)3Si(CH2)3NH2 SiO O Si(OEt)(CH2)3NH2 – EtOH + H2O [Si(OEt)(CH2)3NH2]n Scheme 2 The bonding of (3-aminopropyl)trimethoxysilane to a glass surface under dry conditions and in the presence of water traces. Figure 1 Thermal-lens measurements.Photodestruction of the Reactivrot B5A dye bonded to a glass surface.The curve corresponds to the photodestruction of the bonded dye, dashed line is the average signal of the surface modified with (3-aminopropyl)trimethoxysilane, solid line is the average signal of the initial unmodified glass surface. le = 514.5 nm, Pe = 180mW. 0.035 0.030 0.025 0.020 0.015 0.010 0.005 0.000 0 50 100 150 200 250 300 t/s qMendeleev Communications Electronic Version, Issue 1, 2002 3 layer of the dye).If the bonding density exceeds this value, this unambiguously shows the formation of a polylayer, which is the case of Sample 3 in Table 2. However, if the experimental bonding density is lower than the theoretical value, it hardly gives an unambiguous answer. Nevertheless, the homogeneity of a monolayer can be estimated indirectly, e.g., from the repeatability of TLS measurements at different sites of a sample.The data (Table 2) suggest that the bonding density for the dye on a glass surface unambiguously correlates with the amount of water at the stage of surface modification with a (3-aminopropyl) trimethoxysilane sublayer. High amounts of water result in a developed structure of the modifier sublayer (see Scheme 2), which is in good agreement with the data of Fadeev and Lisichkin.2 This leads to high concentrations of the dye bonded to the surface (Sample 3).The oligomerization of this trifunctional modifier was completely suppressed only in a pure modifier without a solvent (Sample 1). Thus, thermal lensing combined with scanning electron microscopy is a promising approach to study chemically modified surfaces of non-conducting substrates.This study was supported by the Russian Foundation for Basic Research (grant no. 01-03-33149a). References 1 G. V. Lisichkin and A. Yu. Fadeev, Zh. Ross. Khim. O-va im. D.I. Mendeleeva, 1996, 40, 65 (in Russian). 2 A. Yu. Fadeev and G. V. Lisichkin, in Adsorption on New and Modified Inorganic Sorbents.Series ‘Studies in Surface Science and Catalysis’, Elsevier, Amsterdam, 1996, vol. 99, p. 191. 3 S. E. Bialkowski, Photothermal Spectroscopy Methods for Chemical Analysis, Wiley, New York, 1996, and references therein. 4 J.Georges, Talanta, 1999, 48, 501. 5 R. D. Snook and R. D. Lowe, Analyst, 1995, 120, 2051. 6 T. Shimosaka, T. Sugii, T. Hobo, J. B. Alexander Ross and K. Uchiyama, Anal. Chem., 2000, 72, 3532. 7 M. A. Proskurnin, A. G. Abroskin and D. Yu. Radushkevich, Zh. Anal. Khim., 1999, 54, 101 [J. Anal. Chem. (Engl. Transl.), 1999, 54, 91]. 8 M. A. Proskurnin and V. V. Kuznetsova, Anal. Chim. Acta, 2000, 418, 101. 9 Modifitsirovannye kremnezemy v sorbtsii, katalize i khromatografii (Modified Silicas in Adsorption, Catalysis and Chromatography), ed. G. V. Lisichkin, Khimiya, Moscow, 1986 (in Russian). 10 F. A. Guimelfarb, M. N. Filippov and E. V. Kletskina, Fresenius’ Z. Anal. Chem., 1997, 357, 796. 11 E. V. Kletskina, M. N. Filippov, A. G. Borzenko and F. A. Guimelfarb, Microscopy and Analysis, 1997, 49, 5. 12 A. Yu. Fadeev and T. J. McCarthy, Langmuir, 2000, 16, 7268. Figure 2 Secondary-electron image of a glass surface with the bonded Reactivrot B5A dye (acceleration voltage of 2 kV, magnification of 1500. Darker regions correspond to the bonded dye). Received: 25th September 2001; Com. 01/1848

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Mendeleev Communications Electronic Version, Issue 1, 2002 1 Prospects for the determination of thermodynamic and kinetic parameters of electrode reaction intermediates by laser photoemission Alexander G. Krivenko,* Vladimir A. Kurmaz and Alexander S. Kotkin Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation. Fax: +7 096 524 9676; e-mail: krivenko@icp.ac.ru 10.1070/MC2002v012n01ABEH001533 The method of voltammetric time-resolved waves (TRW) based on a comparative analysis of experimental and simulated curves of photoemissionally generated intermediates was used to determine the thermodynamic and kinetic properties of the R/R– redox pairs for the benzyl PhCH2 · and benzhydryl Ph2CH· radicals.Interest in the redox properties of intermediates including free radicals R in liquid media is stimulated by their ability to determine the direction and efficiency of electrode processes, e.g., in organic electrochemistry.1 The thermodynamic characteristics of redox pairs R/R– and R/R+ can be determined from standard potentials E0, e.g., pK and BDE values.2–4 The standard potentials of intermediates obtained by various methods are available.2–11 However, the main drawbacks of many experimental methods consist in their insufficient versatility and the influence of side processes leading to the inconsistency of measured values with thermodynamic characteristics.Therefore, the experimental values should be corrected depending on the life times of intermediates and the rates of their electrode reactions.It is possible to determine the values of E0 for R/R– redox pairs by traditional electrochemical methods such as voltammetry only in rare cases when the rate of the first electron transfer to an organic halide is much higher than that of the second.12 The relative stability of intermediates is a necessary condition for the majority of methods for E0 measurements3,8,10 and a more powerful method of indirect reduction9(a),(b) requires the knowledge of the full reorganization energy of intermediate self-exchange. Laser photoemission (LPE) can be used to overcome such difficulties; in particular, the method of voltammetric time-resolved waves (TRW) of photoemission-generated intermediates was proposed. 13 The values of E0 were determined by this method for a number of organic and inorganic intermediates in aqueous and aprotic solvents.4–7,11 An analysis5(c),7 demonstrated a similarity between E0 and the half-wave potentials E1/2, measured under conditions of the TRW method, i.e., intermediate generation in a thin near-electrode layer is followed by an equilibrium establishment at the electrode between adsorbed intermediates (radicals) Rads and products X of their reduction/oxidation.However, for the development of a complete kinetic model for an electrode process, it is also necessary, along with E0, to know the rate constants of redox reactions W0 and the dependence of rate constants WR of electrode reactions of intermediates on the potential WR = f(E) within a sufficiently broad range and their activation energies Ea, as well as the times of bulk decay of an intermediate tR and a product of its reduction/oxidation tX in a given solvent.All these values can also be determined by TRW. The long-lived benzyl PhCH2 · and benzhydryl Ph2CH· key organic radicals14 were chosen for the study. The redox potentials of their R/R– pairs were reliably determined by various methods,2 and tR and tX parameters may substantially differ.14 The set of R transformations, generated by photoemission current IP, can be represented by the following scheme: where kR, kX, Wd and W'd are the rate constants of adsorption and desorption, respectively; WR and WX are the rate constants of electrode reactions, and GR and GX are the surface concentrations of adsorbed intermediates (radicals) Rads and products X, respectively.A decrease in the surface concentration of stable reagents is compensated by their diffusion from the bulk of a solution during the diffusion-controlled discharge. However, R and X discharge occurs at their zero bulk concentrations and competes with desorption accompanied by the decay of intermediates.The kinetic equations for surface and bulk concentrations of reagents nR and products nX take the form Bulk concentrations obey the diffusional equations where DR and DX are the diffusion coefficients of reagents and products, respectively; Ip f(t) is the impulse of intermediate generation in the near-electrode layer with a characteristic length of x0.4 The boundary conditions determine the continuity of reagent and product streams on the interface (Scheme 1):† The solution of nonstationary diffusional equations (2)–(4) were analysed7 based on ref. 15. A number of parameters of Scheme 1 are estimable. The values of GR and GX are controlled in the photoemission measurements, and they are equal to 1010– 1011 particle per cm2. Such an estimation as kR, kX ~ D/l » » 102 cm s–1 is valid for the rate constants of adsorption if the 7.0 6.0 5.0 4.0 3.0 1.0 1.2 1.4 1.6 lg WR –E/VNHE (a) (b) 0.35 0.30 0.25 0.20 1.25 1.35 1.45 1.55 Ea/eV –E/VSCE Figure 1 (a) Electroreduction rate constants as functions of potential at various temperatures for PhCH2 · .DMSO; supporting electrolyte, 0.4 M LiClO4; stationary mercury electrode. (1) 98, (2) 51 and (3) 22 °C.(b) Apparent activation energy Ea for the electroreduction of the benzyl radical at various potentials determined from the data in Figure 1(a). 1 2 3 † The absence of such boundary conditions led5(c) to a decrease of requirements to the time interval of measured TRWs, which are necessary for the unambiguous interpretation of experimental data, and caused a partial loss of information at their treatment.tR IP R GR GX X kR Wd WR WX W'd kX , (1) tX dGR dt = kRnR(0) – (WR + Wd)GR + WXGX; dGX dt = kXnX(0) + WRGR – (WX + W'd )GX. (2) ¶nR dt = DR – + e–x/x0 f(t); ¶nX dt = DX – , (3) ¶2nR dx2 nR tR Ip x0 ¶2nX dx2 nX tX ¶nR dx DR = kRnR(0) – WdGR, (4) x = 0 ¶nX dx DX = kXnX(0) – WdGX. x = 0Mendeleev Communications Electronic Version, Issue 1, 2002 2 diffusion coefficient D of intermediates is ~ 5¡¿10.6 cm2 s.1 and the diffusional jump l is (2.3)¡¿10.8 cm.For kR and Wd, using the detailed equilibrium principle,4 we can derive We can obtain from (5) that Wd is 102.104 s.1 at standard values of the parameters (G0 = 1014 cm.2, N0 = 6.4¡¿1020 cm.3) and the typical standard adsorption free energy of organic radicals ..G0 a(R) ¡í .(0.3.0.4) eV.4 W'd >> Wd since ..G0 a(R) for radicals is sufficiently lower than the standard adsorption free energy of carbanions ..G0 a(R.).The value of ..G0 a was determined7 for the redox pair CF3 ¡� /CF3 . (..G0 a = 0.3¡¾0.06 eV), and the difference in the standard free energies of adsorption of organic acids and their anions is equal to 0.1.0.15 eV, which may serve as its lower estimation [..G0 a = .(.G0 a(R) ..G0 a(R.))] (see, e.g., ref. 16 and references therein). The parameter tX is relatively controllable, and it can range from 100.10.7 s in aprotic solvents7,8 to 10.8.10.10 s in aqueous solutions.4 The previously developed procedure13 was improved to obtain TRWs. TRWs were recorded by the measurements and numerical Fourier transformation of signals from a photoelectrochemical cell illuminated with modulated light with a period of tm = 1.0. 10.3 s. Converting from the repetition frequency to frequency W was achieved using the relation W = 5.31tm . 1. A program package was elaborated to expand an effective W range, and that allows the recording of TRWs within the range W ~ (4.5)¡¿104 s.1. This enables us to determine E1/2 on the highest harmonics of modulation frequency, up to 10th.The values of WR = f(E,T) were determined for irreversible electroreduction (E < E0) from the kinetics of the electrode charge during electrodeeactions of Rads. The experimental procedure was described elsewhere.4,17 The transition from WR(E) to E1/2(W) dependences is based on the coincidence of E1/2 and the potential, where WR = W for a given W at the irreversible electroreduction of Rads with an accuracy of 0.01 V.The precision of E1/2 determination is no worse than ¡¾0.005 V.5(b) The radicals R were generated by the dissociative electron transfer17 where e. s is a solvated electron, RX is PhCH2Cl or Ph2CHCl, ka is the rate constant of its capture by an acceptor, and kd is the dissociation rate constant of an anion radical.The values of ka for PhCH2Cl and Ph2CHCl are (1.6.4.5)¡¿109 and 9.5¡¿108 dm3 mol.1 s.1, respectively,18 i.e., they exceed the rate constant of e.s capture by a solvent by more than an order of magnitude. This provides an increase in the signal by a factor of 3.4 in comparison with the background signal on the addition of 0.08.0.2 M of acceptors.The experiments were carried out in DMSO because it is much more stable than DMF and, especially, acetonitrile19 with respect to the action of strong bases such as carbanions. The life times of benzyl and benzhydryl carbanions are considered to change oppositely to pKa values of respective CH acids, consisted of 35 and 32.2 in DMSO;19 51.2 and 43.1 in acetonitrile, 3(b) while tX is usually ¡Ì 10.3 s19(b) in this solvent.The WR(E,T) functions are presented in Figure 1(a) for the irreversible reduction of the benzyl radical at E < E1/2.¢Ô They follow the equation of slow discharge with the transfer coefficient a ~ 0.45 at t = 22 ¡ÆC, as well as other organic radicals (a ~ 0.5¡¾0.05).4 Similar functions were also obtained for the benzhydryl radical. Apparent activation energies Ea for various E values were found from these data to estimate the reorganization energy Es of outer-sphere electron transfer by quadratic Marcus equation1 (Es = 4Ea at E = E0).The values of Es are 0.32.0.35 eV in DMSO, which is close to the published data6 for a number of alkyl radicals (Es is 0.34.0.38 eV). The TRWs of benzyl and benzhydryl radicals obtained on a mercury electrode in DMSO.LiClO4 solutions are similar to those described previously4,5(a),(b),6,7.No serious differences were found in the wave forms and their location on the E-axis at transition to DMF and acetonitrile, the use of LiCl as a supporting electrolyte or the replacement of a Hg electrode with Au. The experimental and simulated E1/2(W) functions for the radicals are represented in Figure 2(a),(b).They are plotted in the lg W.E1/2 coordinates. Figure 2 demonstrates a satisfactory coincidence of experimental data and numerical simulation in each case, even in spite of complex character of the dependence and significant range of W change. Hence it follows that the necessary interval of W change has to override all transition region from reversible to irreversible reduction, i.e., not to be less than 5.7 orders (W is 1.107 s.1) to obtain reliable results.It is possible to measure WR(E) and Ea in this case, to determine tR, tX and ..G0 a(R) and to estimate the standard potentials of redox pairs R/R. on the basis of these data with the precision better than ¡¾0.04 V (Table 1). Table 1 Thermodynamic and kinetic properties of benzyl and benzhydryl radicals in DMSO, DMF and acetonitrile.R¡� Es (E = E0)/eV W0/s.1 ..G0 a(R) ¡¾ 0.02a/eV aThis study, DMSO + 0.4 M LiClO4. bRef. 5(a), the illumination period tm = 2¡¿10.6 s; supporting electrolyte 0.1 M Et4NClO4. cRef. 9, ¡¾0.05 V, supporting electrolyte 0.1 M TBABF4 (acetonitrile). dRef. 3(b), ¡¾0.05 V, supporting electrolyte 0.1 M Bu4NClO4, the illumination period tm = 2¡¿10.2 s.eRef. 5(b), supporting electrolyte 0.1 M Et4NClO4 (DMF) and 0.1 M Bu4NPF6 (acetonitrile), the illumination period tm = 10.3 . 3¡¿10.6 s. fRef. 8(d), ¡¾0.05 V, supporting electrolyte acetonitrile + 0.1 M Bu4NClO4, the illumination period tm = 2¡¿10.2 s. gRef. 9(c), quantum-chemical simulation. hRef. 8(d), ¡¾0.05 V, supporting electrolyte acetonitrile + 0.1 M Bu4NClO4, the illumination period tm = 10.2 s.iRef. 8(e), supporting electrolyte 0.1 M Bu4NClO4 (acetonitrile). a,b,c,eHg electrode. e,f,hAu electrode. iGlassy carbon or Hg-electrode. tR¡¿104/s tX¡¿104/s .E0 (.E1/2)/VSCE DMSO DMF Acetonitrile PhCH2 ¡� 0.34¡¾0.01a (2.6)¡¿103 a 0.45 0.05.0.15a 5.15a 1.35¡¾0.03a (1.37)b (1.35)b 0.433,c 0.733g 4¡¿106 e (11.15)¡¾0.3f 0.2e (1.36)b 1.40c (1.45)d 0.925e 0.1.0.001i ~0.0001i 1.215e ~1.42e Ph2CH¡� 0.33¡¾0.015a (1.3)¡¿104 a 0.39 50.150a 500.1500a 0.97¡¾0.02a (1.12)b (1.16)b 0.703e 2.8¡¿107 e (16.20)¡¾0.2f 0.033e (1.07)b 1.07c (1.14)d 0.1.0.001i 1.107e (1.115), f (1.130)h kR Wd = exp.. (5) G0 N0 .G0 a(R) kBT RX + e.s RX.¡� R¡� + X., ka kd (6) ¢Ô Note that the maximum of the measured WR values was ca. 5¡¿106 s.1 and, consequently, kd ©ø 107 s.1 for both ion radicals, and similar values may be considered as typical for such systems.20 For instance, kd value for the anion radical ClC6H4Me.¡� was estimated to be20(b) 7.6¡¿109 s.1. 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.9 1.0 1.1 1.2 1.3 1.4 1.6 1.8 1.2 1.4 lg W .E1/2/VSCE .E1/2/VSCE 7.0 6.0 5.0 4.0 3.0 2.0 1.0 lg W 1 2 (a) (b) Figure 2 The comparison of the experimental E1/2.W relation with the numerical simulation.DMSO; supporting electrolyte, 0.4 M LiClO4; stationary mercury electrode; 22 ¡ÆC. (1) The data of kinetic measurements; (2) TRWs. The areas of E0 dispersion are depicted by vertical dotted lines: the deviation of E0 to anodic direction from the most positive E1/2(W) values is systematic in nature and may consist of 0.025.0.075 V for systems with such parameters.7 (a) The radical Ph2CH¡�.The parameters of calculation: Wd = 104 s.1; W'd = 107 s.1; tR = 10.4 s and tX = 1 s. (b) The radical PhCH2 ¡� . The parameters of numerical simulation: Wd = 104 s.1; W'd = 108 s.1; tR = 10.5 s and tX = 10.3 s.Mendeleev Communications Electronic Version, Issue 1, 2002 3 The results of measurements and the simulated parameters of Scheme 1 were tabulated together with published data.It follows from Table 1 that the available thermodynamic and kinetic characteristics of the radicals are consistent with those determined in this work. Hence, the proposed method of the timeresolved voltammetric waves can be promising not only for their determination but it provides necessary thermodynamic and kinetic information on a studied intermediate over a broad range of temperatures and observation times.This work was supported by the Russian Foundation for Basic Research (grant no. 00-03-32135). References 1 L. Eberson, Electron Transfer Reactions in Organic Chemistry, Springer-Verlag, New York, London, Paris, Tokyo, 1997. 2 (a) K. Daasbjerg, S. U. Pedersen and H.Lund, in General Aspects of the Chemistry of Radicals, ed. Z. B. Alfassi, John Wiley, Chichester, New York, Weinheim, Brisbane, Singapore, Toronto, 1999, p. 385; (b) D. M. Stanbury, in General Aspects of the Chemistry of Radicals, ed. Z. B. Alfassi, John Wiley, Chichester, New York, Weinheim, Brisbane, Singapore, Toronto, 1999, p. 349. 3 (a) D. D. M. Wayner and V. D. Parker, Acc. Chem.Res., 1993, 26, 287; (b) D. D. M. Wayner, D. J. McPhee and D. Griller, J. Am. Chem. Soc., 1988, 110, 132; (c) D. K. Smith, W. E. Strohben and D. G. Evans, J. Electroanal. Chem., 1990, 288, 111. 4 V. A. Benderskii and A. G. Krivenko, Usp. Khim., 1990, 59, 3 (Russ. Chem. Rev., 1990, 59, 1). 5 (a) Ph. Hapiot, V. V. Konovalov and J.-M. Savéant, J. Am. Chem. Soc., 1995, 117, 1428; (b) J.Gonzalez, Ph. Hapiot, V. V. Konovalov and J.-M. Savéant, J. Am. Chem. Soc., 1998, 120, 10171; (c) J. Gonzalez, Ph. Hapiot, V. V. Konovalov and J.-M. Savéant, J. Electroanal. Chem., 1999, 463, 157. 6 A. G. Krivenko a XIV Soveshchanie po Elektrokhimii Organicheskikh Soedinenii (XIV Russian Symposium on Organic Electrochemistry), Novocherkassk, 1998, p. 14 (in Russian). 7 A.G. Krivenko, A. S. Kotkin, V. A. Kurmaz, V. E. Titov, V. A. Lopushanskaya and V. G. Koshechko, Teor. Eksp. Khim., 2000, 36, 354 [Theor. Exp. Chem. (Engl. Transl.), 2000, 36, 325]. 8 (a) E. W. Oliver and D. G. Evans, J. Electroanal. Chem., 1997, 432, 145; (b) T. Lund and S. U. Pedersen, J. Electroanal. Chem., 1993, 362, 109; (c) B. Jaun, J. Schwarz and R. Breslow, J.Am. Chem. Soc., 1980, 102, 5741; (d) T. Nagaoka, D. Griller and D. D. M. Wayner, J. Phys. Chem., 1991, 95, 6264; (e) A. Gennaro, A. A. Isse and F. Maran, J. Electroanal. Chem., 2001, 507, 124. 9 (a) R. Fuhlendorf, D. Occialini, S. U. Pedersen and H. Lund, Acta Chem. Scand., 1989, 43, 803; (b) H. Lund, K. Daasbjerg, D. Occialini and S. U. Pedersen, Elektrokhimiya, 1995, 31, 939 (Russ.J. Electrochem., 1995, 31, 865); (c) K. V. Mikkelsen, S. U. Pedersen, H. Lund and P. Swanström, J. Phys. Chem., 1991, 95, 8892. 10 A. Henglein, in Electroanalyt. Chem., ed. A. J. Bard, Marcel Dekker, New York, 1976, vol. 9, p. 163. 11 V. A. Benderskii, A. G. Krivenko and A. S. Kotkin, Elektrokhimiya, 1993, 29, 348 (Russ. J. Electrochem., 1993, 29, 449). 12 C. P. Andrieux, I.Gallardo and J.-M. Savéant, J. Am. Chem. Soc., 1989, 111, 1620. 13 (a) V. A. Benderskii and A. G. Krivenko, Elektrokhimiya, 1985, 21, 1507 [Sov. Electrochem. (Engl. Transl.), 1985, 21, 1422]; (b) V. A. Benderskii, A. G. Krivenko and E. A. Ponomarev, Elektrokhimiya, 1989, 25, 186 [Sov. Electrochem. (Engl. Transl.), 1989, 25, 161]. 14 A. L. Buchachenko and A. M. Vasserman, Stabil’nye radikaly (Stable Radicals), Khimiya, Moscow, 1973 (in Russian). 15 A. V. Benderskii, V. A. Benderskii and A. G. Krivenko, J. Electroanal. Chem., 1995, 380, 7. 16 C. Fontanesi, R. Andreoli and L. Benedetti, Electrochim. Acta, 1998, 44, 977. 17 (a) A. G. Krivenko, A. S. Kotkin and V. A. Kurmaz, Mendeleev Commun., 1998, 56; (b) A. G. Krivenko, A. S. Kotkin and V. A. Kurmaz, Mendeleev Commun., 2000, 46; (c) V. A. Kurmaz, A. G. Krivenko, A. P. Tomilov, V. V. Turigin, A. V. Khudenko, N. N. Shalashova and A. S. Kotkin, Elektrokhimiya, 2000, 36, 344 (Russ. J. Electrochem., 2000, 36, 308); (d) A. G. Krivenko, A. P. Tomilov, Yu. D. Smirnov, A. S. Kotkin and V. A. Kurmaz, Zh. Obshch. Khim., 1998, 68, 292 (Russ. J. Gen. Chem., 1998, 68, 266). 18 G. V. Buxton, C. L. Greenstock, W. Ph. Helman and A. R. Ross, J. Phys. Chem. Ref. Data, 1988, 17, 513. 19 (a) O. A. Reutov, A. L. Kurz and K. P. Butin, Organicheskaya khimiya (Organic Chemistry), Izd-vo MGU, Moscow, 1999, vol. 1, ch. 3 (in Russian); (b) K. P. Butin, M. T. Ismail and O. A. Reutov, J. Organomet. Chem., 1979, 175, 157; (c) F. Maran, D. Seladon, M. G. Severin and E. Vianello, J. Am. Chem. Soc., 1991, 113, 9320; (c) F. G. Bordwell and Xian-Man Zhang, Acc. Chem. Res., 1993, 26, 510. 20 (a) Ch. Amatore, C. Combellas, J. Pinson, M. A. Oturan, S. Robveille, J.-M. Savéant and A. Thiébault, J. Am. Chem. Soc., 1985, 107, 4846; (b) V. G. Mairanovsky, J. Electroanal. Chem., 1981, 125, 231. Received: 20th November 2001; Com. 01/1859

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Mendeleev Communications Electronic Version, Issue 1, 2002 1 Synthesis and reactivity of extremely thermally stable trialkylpalladium(IV) complexes supported with 1,4,7-triazacyclononane Anton A. Sobanov,a Andrei N. Vedernikov,*a Gerald Dykerb and Boris N. Solomonova a Department of Chemistry, Kazan State University, 420008 Kazan, Russian Federation. Fax: +7 8432 38 0994; e-mail: ave@ksu.ru b Institute of Chemistry, Duisburg University, 47048 Duisburg, Germany 10.1070/MC2002v012n01ABEH001530 The dimethylpalladium(II) PdMe2(tacn) complex supported with 1,4,7-triazacyclononane (tacn), obtained in situ via a reaction between PdMe2(tmeda) and tacn reacts with methyl or ethyl iodide (RI) to form the most stable trialkyl palladium(IV) complexes [PdMe2R(tacn)]I.The chemistry of organopalladium(IV) compounds has been rapidly developed in the last two decades.1 Being related to palladium( II)-mediated coupling reactions,2 this chemistry is therefore of synthetic interest.In most cases, organopalladium(IV) species appear as unstable intermediates, and they cannot be fully characterised or isolated even when polydentate ligands are used to increase their stability.3 This fact raises additional interest in these compounds, which can be good models for studying structure–reactivity relationships for organic transition metal complexes.Recent computational results in the oxidative addition–reductive elimination chemistry involving d8–d6 platinum metal complexes4 allow one to design species to support d6 metal complexes such as palladium(IV) coordination compounds or to find them among already known ligands.In particular, using model compounds, we found that 1,4,7-triazacyclononane can be more suitable for this role as compared with hydridotrispyrazolylborate or 1,4,7-trithiacyclononane.4(a) In this communication, we describe the synthesis and reactivity of new stable trialkylpalladium(IV) complexes supported with 1,4,7-triazacyclononane (tacn), [PdMe2(R)(tacn)]+I– (R = Me or Et).To the best of our knowledge, these are the most thermally stable complexes of this class. New trialkylpalladium(IV) complexes were obtained as fine pale yellow powders in 50–60% yield by reacting one equivalent of iodomethane or iodoethane with an equimolar mixture of dimethyl(N,N,N',N'-tetramethylethanediamine)palladium(II), PdMe2(tmeda), and 1,4,7-triazacyclononane dissolved in deaerated dry acetone at –40 °C: Since PdMe2(tacn)† involved in the synthesis was obtained in situ in a fast reversible ligand exchange reaction, at room temperature (60% conversion under equilibrium conditions, acetone, 20 °C), iodoalkane behaved as a trapping reagent towards organopalladium(II) species.Thus, higher product yields can not be obtained. The new complexes are insoluble in water and poorly soluble in acetone or methanol, but they are readily soluble in DMSO. Other components of the equilibrated reaction mixture, PdMe2(tmeda), N,N,N',N'-tetramethylethanediamine and tacn, react with these iodoalkanes but with formation of compounds of higher solubility. Thus, the reaction product of iodomethane with PdMe2(tmeda), the iodomethyl(N,N,N',N'- tetramethylethanediamine)palladium(II) complex PdMeI(tmeda)5 was isolated from the filtered reaction mixture after the addition of pentane at –10 °C and characterised by X-ray diffraction analysis.6 Therefore, tmeda-supported palladium(IV) trialkyl complexes, which are presumably intermediates in a reaction between PdMe2(tmeda) and the iodoalkanes, are short-lived. The pure compound [PdMe3(tacn)]+I– was characterised by elemental analysis, 1H and 13C NMR spectroscopy and electrospray mass spectrometry.‡ As compared with other trimethylpalladium( IV) compounds, this complex is extremely thermally stable, and it decomposes in the solid state at 152–154 °C.Ethane rather than methane is the sole hydrocarbon formed in the course of slow decomposition of [PdMe3(tacn)]+I– at 140 °C in a [2H6]DMSO solution.The ethyldimethylpalladium(IV) derivative [PdEtMe2(tacn)]+I–,§ which is more stable than its trimethyl analogue, melts at 170 °C with decomposition. Its heating at 140 °C in a [2H6]DMSO solution for 4 h leads to the formation of propane as a major product, ethane and small amounts of ethene and methane (38:11:9:2 molar ratio according to NMR data).Whereas propane and ethane result from the reductive elimination of methyl and ethyl or two methyl ligands from the [PdEtMe2(tacn)]+ species, respectively, the accumulation of ethene may be due to hydride â-elimination from an iodoethylpalladium(II) complex, which is expected according to the reaction This behaviour is similar to that of diorganopalladium(IV) intermediates, which exhibit much lower thermal stability.For example, the reaction of PdMe2(tmeda) with ethyl iodide leads to the evolution of propane and ethane in a 3:2 ratio,7 and the synthesised compounds can be used to model the chemistry of organopalladium(IV) intermediates. Methane traces can be due to hydride â-elimination from [PdEtMe2(tacn)]+ and the subsequent decomposition of the unstable [PdMe2H(tacn)]+ species.All the known trialkylpalladium(IV) complexes supported with tridentate N-donor ligands can be decomposed at temperatures † 1H NMR spectral data for C8H21N3Pd at 300 MHz, d: ([2H6]acetone) –0.43 (s, 6H, Pd–Me), 2.83 (m, 6H, N–CHa), 3.19 (m, 6H, N–CHb); (C6D6) 0.54 (s, 6H, Pd–Me), 2.23 (m, 6H, N–CHa), 2.83 (m, 6H, N–CHb); (CD3CN) –0.43 (s, 6H, Pd–Me), 2.88 (m, 6H, N–CHa), 3.20 (m, 6H, N–CHb); ([2H6]DMSO) –0.43 (s, 6H, Pd–Me), 2.77 (m, 6H, N–CHa), 3.09 (m, 6H, N–CHb).N N N H H Pd Me Me H N N N H H Pd Me Me H R PdMe2(tmeda) + tacn room temperature I RI –40 °C ‡ For C9H24N3IPd: 1H NMR (300 MHz, [2H6]DMSO) d: 0.82 (s, 9H, Pd–Me), 2.78 (m, 6H, N–CHa), 2.90 (m, 6H, N–CHb), 5.22 (s, 3H, N–H). 13C{1H} NMR (500 MHz, [2H6]DMSO) d: 9.66 (Me), 47.3 (CH2). ES-MS, m/z: 280 [M]+. Found (%): C, 27.21; H, 5.91; N, 10.26. Calc. for C9H24N3IPd (%): C, 26.52; H, 5.93; N, 10.31. § For C10H26N3IPd: 1H NMR (300MHz, [2H6]DMSO) d: 0.81 (s, 6H, Pd–Me), 1.00 (t, 3H, C–Me, 3JH–H 7.6 Hz), 1.75 (q, 2H, Pd–CH2, 3JH–H 7.6 Hz), 2.78 (m, 6H, N–CHa), 2.92 (m, 6H, N–CHb), 5.02 (s, 3H, N–H). 13C{1H} NMR (300 MHz, [2H6]DMSO) d: 12.95 (Pd–Me), 17.57 (Pd– CH2–Me), 26.36 (Pd–CH2–Me), 47.50 (N–CH2), 47.87 (N–CH2), 48.04 (N–CH2). Found (%): C, 28.72; H, 6.30; Pd, 25.20. Calc. for C10H26N3IPd (%): C, 28.48; H, 6.22; Pd, 25.24. [PdMe3(tacn)]+I– ® C2H6 + PdMeI(tacn) ® decomposition products [PdEtMe2(tacn)]+I– ® Me–Me + PdEtI(tacn) ® CH2=CH2 [PdEtMe2(tacn)]+I– ® CH2=CH2 + [PdMe2H(tacn)]+I– ® CH4Mendeleev Communications Electronic Version, Issue 1, 2002 2 only slightly higher than room temperature.3,5(b) Other more thermally stable triorganopalladium(IV) compounds are a thioanalogue of the complex [PdMe3(tacn)]I, derived from 1,4,7-trithiocyclononane (ttcn), [PdMe3(ttcn)]I8 and two neutral complexes supported with an anionic ligand, PdMe3[CpCo{PR2(O)}3] (R = OMe, OEt), which are decomposed at 117 °C (R = OMe) or 120 °C (R = OEt).9 Thus, the stability of cationic trialkylpalladium(IV) compounds can be increased with the help of facially chelating tridentate ligands, and quantum-chemical calculations can be used to trace trends in the effectiveness of the ligands.4 This work was supported by the Russian Foundation for Basic Research (grant no. 01-03-32692). A.A.S. thanks the Deutsche Academische Austauschdienst for a scholarship (A/99/41055). References 1 (a) A. J. Canty, Acc. Chem. Res., 1992, 25, 83; (b) A. J. Canty, Platinum Metals Rev., 1993, 37, 2; (c) A. J. Canty and G. van Koten, Acc. Chem. Res., 1995, 28, 406; (d) A. Bayler, A. J. Canty, P. G. Edwards, B. W. Skelton and A. H. White, J. Chem.Soc., Dalton Trans., 2000, 3325; (e) A. Bayler, A. J. Canty, B. W. Skelton and A. H. White, J. Organomet. Chem., 2000, 595, 296. 2 (a) M. Catellani, G. P. Chiusoli and C. Castagnoli, J. Organomet. Chem., 1991, 407, C30; (b) M. Catellani and G. P. Chiusoli, J. Organomet. Chem., 1988, 346, C27. 3 (a) P. K. Byers, A. J. Canty, B. W. Skelton and A. H. White, J. Chem. Soc., Chem.Commun., 1986, 1722; (b) P. K. Byers, A. J. Canty, R. T. Honeyman and A. A. Watson, J. Organomet. Chem., 1989, 363, C22; (c) P. K. Byers, A. J. Canty, B. W. Skelton and A. H. White, J. Chem. Soc., Chem. Commun., 1987, 1093; (d) P. K. Byers, A. J. Canty, B. W. Skelton and A. H. White, Organometallics, 1990, 9, 826; (e) A. J. Canty, H. Jin, A. S. Roberts, B.W. Skelton, P. R. Traill and A.H.White, Organometallics, 1995, 14, 199. 4 (a) A. N. Vedernikov, G. A. Shamov and B. N. Solomonov, Zh. Obshch. Khim., 1999, 69, 1144 (Russ. J. Gen. Chem., 1999, 69, 1102); (b) A. N. Vedernikov, G. A. Shamov and B. N. Solomonov, Ross. Khim. Zh., 1999, 43, 22 (in Russian). 5 (a) W. de Graaf, J. Boersma, D. Grove, A. L. Spek and G. van Koten, Recl. Trav. Chim. Pays-Bas, 1988, 107, 299; (b) W. de Graaf, J. Boersma, W. J. J. Smeets, A. L. Spek and G. van Koten, Organometallics, 1989, 8, 2907. 6 A. A. Sobanov, A. N. Vedernikov, G. Dyker and G. Henkel, Acta Crystallogr., Sect. C, in press. 7 W. de Graaf, J. Boersma and G. van Koten, Organometallics, 1990, 9, 1479. 8 M. A. Bennett, A. J. Canty, J. K. Felixberger, L. M. Rendina, C. Sunderland and A. C. Willis, Inorg. Chem., 1993, 32, 1951. 9 W.Kläui, M. Glaum, T. Wagner and M. A. Bennett, J. Organomet. Chem., 1994, 472, 355. Received: 12th November 2001; Com. 01/1856

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Mendeleev Communications Electronic Version, Issue 1, 2002 1 Novel synthesis of chromene and benzofuran derivatives via the Nenitzescu reaction Valeria M. Lyubchanskaya,a Lyudmila M. Alekseeva,a Svetlana A. Savina,a Alexander S. Shashkovb and Vladimir G. Granik*a a Russian Research Centre ‘Research Institute of Organic Intermediates and Dyes’, 101999 Moscow, Russian Federation. Fax: +7 095 254 9724; e-mail: makar-cl@Ropnet.ru b N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 135 5328 10.1070/MC2002v012n01ABEH001525 The condensation of 3-oxocaprolactam piperidine enamine with 2,6-dibromoquinone and quinone gave 6,8-dibromo-7-hydroxy- and 7-hydroxy-10a-piperidine-2,3,4,5,5a-hexahydro-1H-benzofuro[2,3-c]azepine-1-one adducts, the acid treatment of which afforded novel 9-hydroxy-1,2,3,4-tetrahydro-5H-chromene[3,4-b]pyridine-5-one derivatives.The Nenitzescu reaction of enamines and quinones is the most important method for the synthesis of 5-hydroxyindole and 5-hydroxybenzofuran.1,2 Obviously, the condensation rate is determined by a high electron density at the â-position of enamines and quinone electronegativity at the 2-position.Therefore, few examples of enamines having electron-withdrawing substituents at the á-position, which lower a partial negative charge at the â-position, were described for this reaction. These are á-diketone enamines of the carbocyclic series.3–5 The first step is the condensation with quinones to form hydroquinone adducts.1,2 However, further acid treatment at the second step leads not only to 5-hydroxyindole and 5-hydroxybenzofuran derivatives but also heterocycles such as benzoxazepines, benzoxazines or isoquinolines. 3–5 We used 3-piperidine-1H-2,5,6,7-tetrahydroazepine-2-one 1 with an electron-withdrawing lactam group at the á-position as an enamine component. Enamine 1 was used in cyclization with quinone 2 and 2,6-dibromoquinone 3 in order to obtain novel benzofuro[2,3-c]azepine derivatives. The condensation of enamine 1 with quinones 2 and 3 is readily achieved in acetone at room temperature.Apparently, under these conditions, hydroquinone adducts 4 are formed at the first step, immediately giving cyclic adducts 7-hydroxy-10a-piperidino-2,3,4,5,5a-hexahydro-1Hbenzofuro[ 2,3-c]azepine-1-one 5 (73% yield, mp 258–260 °C, M+· 302†) and 6,8-dibromo-7-hydroxy-10a-piperidino-2,3,4,5,5ahexahydro- 1H-benzofuro[2,3-c]azepine-1-one 6 (83% yield, mp 173–175 °C, M+· 460‡), respectively.The formation of such cyclic adducts was studied previously4,5,7,8, and their stability was considered in detail.9 On this basis, we assumed that the stability of adducts 5 and 6 is associated with the S-syn-positions of a piperidine fragment and a hydrogen atom in relation to each other, which may significantly hamper piperidine removal.9 This was supported by spectroscopic data: a correlation peak with d 2.91/3.52 ppm in the NOESY spectrum of 6 indicates that a proton at the 5aposition and the methylene protons of a piperidine ring 2''-CH2 and 6''-CH2 are spatially close, indicating the S-syn-conformation.The adducts of this stereochemistry are known to form aromatic benzofurans upon acid treatment,4 though some unexpected transformations were observed.7,8 Adduct 5 was treated with acetic acid resulting in the formation of a benzofuran derivative as a product, namely, 7-hydroxybenzofuro[2,3-c]azepine-1-one 7 in 6% yield, mp 244–257 °C (isopropanol), M+· 217.§ However, the major product was 9-hydroxy-1,2,3,4-tetrahydro- 5H-chromeno[3,4-b]pyridine-5-one 8 in 58% yield, mp 213– 216 °C (isopropanol), M+· 217.¶ The structures of 7 and 8 were determined by HMBC spectrum analysis.The greatest difference between the spectra of 7 and 8, † For 5: 1H NMR ([2H6]DMSO) d: 1.42, 1.66, 1.93 (m, 10H, 3''-CH2, 4''-CH2, 5''-CH2, 4'-CH, 4-CH, 5'-CH, 5-CH), 2.47–2.65 (m, 4H, 2''-CH2, 6''-CH2), 2.96 (m, 1H, 3'-CH), 3.28 (d, 1H, 5a-CH, J 11 Hz), 3.96 (m, 1H, 3-CH), 6.51 (m, 3H, 6-CH, 8-CH, 9-CH), 7.52 (t, 1H, 2-NH, J 7 Hz), 8.66 (br.s, 1H, 7-OH). Found (%): C, 67.60; H, 7.36; N, 9.26. Calc. for C17H22N2O3 (%): C, 67.52; H, 7.34; N, 9.26. ‡ For 6: 1H NMR ([2H5]pyridine) d: 1.32 (m, 2H, 4''-CH2), 1.45 (m, 4H, 3''-CH2, 5''-CH2), 1.69–1.82 (m, 3H, 4'-CH, 4-CH, 5-CH), 2.56 (m, 1H, 5'-CH), 2.82–2.91 (m, 4H, 2''-CH2, 6''-CH2), 3.23 (m, 1H, 3'-CH), 3.52 (d, 1H, 5a-CH, J 11 Hz), 4.16 (m, 1H, 3-CH), 7.10 (s, 1H, 9-CH), 8.21 (t, 1H, 2-NH, J 7 Hz). 13C NMR ([2H5]pyridine) d: 24.5 (4''-C), 25.8 (5-C), 26.2 (3'',5''-C), 27.5 (4-C), 47.3 (3-C), 48.9 (2'',6''-C), 50.6 (5a-C), 109.1 (10a-C), 109.7 (6-C), 111.8 (9-C), 112.5 (8-C), 129.7 (5b-C), 145.8 (7-C), 152.5 (9a-C), 169.6 (1-C).Found (%): C, 44.32; H, 4.69; N, 5.72. Calc. for C17H20Br2N2O3 (%): C, 44.37; H, 4.38; N, 6.09. § For 7: 1H NMR ([2H6]DMSO) d: 2.00 (m, 2H, 4-CH2), 2.90 (t, 2H, 5-CH2, J 6.2 Hz), 3.23 (m, 2H, 3-CH2), 6.95 (m, 2H, 6-CH, 8-CH), 7.40 (d, 1H, 9-CH, J 8.7 Hz), 8.00 (br. s., 1H, 2-NH), 9.40 (s, 1H, 7-OH). 13C NMR ([2H6]DMSO) d: 23.8 (5-C), 26.3 (4-C), 40.8 (3-C), 104.7 (6-C), 111.9 (9-C), 116.4 (8-C), 123.1 (5a-C), 129.1 (5b-C), 143.8 (10b-C), 147.6 (9a-C), 153.4 (7-C), 161.5 (1-C). Found (%): C, 66.30; H, 5.06; N, 6.72. Calc. for C12H11NO3 (%): C, 66.35; H, 5.11; N, 6.45. ¶ For 8: 1H NMR ([2H6]DMSO) d: 1.88 (m, 2H, 2-CH2), 2.59 (t, 2H, 1-CH2, J 6.2 Hz), 3.23 (m, 1H, 3-CH2), 5.77 (br.s, 1H, 4-NH), 6.67 (q, 1H, 8-CH, J1 8.7 Hz, J2 2.5 Hz), 6.74 (d, 1H, 10-CH, J 2.5 Hz), 7.08 (d, 1H, 7-CH, J 8.7 Hz), 9.32 (br. s, 1H, 9-OH). 13C NMR ([2H6]DMSO) d: 20.1 (2-C), 21.0(1-C), 39.8 (3-C), 105.9 (10-C), 112.9 (8-C), 114.3 (10b-C), 116.3 (7-C), 122.3 (10a-C), 129.2 (4a-C), 140.4 (6a-C), 154.0 (9-C), 157.5 (5-C). Found (%): C, 66.08; H, 5.20; N, 6.03. Calc. for C12H11NO3 (%): C, 66.35; H, 5.11; N, 6.45.Scheme 1 Reagents and conditions: i, 1 was added to a solution of 2 (or 3) in acetone, stirred (20 °C, 6 h), filtered (5 or 6); ii, 5 (or 6) is refluxed in acetic acid for 2 h, then diluted with water, and a mixture of compounds 7, 8 (or 9, 10) is filtered. The mixture was separated by column chromatography. N H O N 1 O R' R O 2 R = R' = H 3 R = R' = Br OH OH R' R NH N O i O NH R HO R' H N O 1 2 3 4 5 6 7 8 9 10a 5a ii 5 R = R' = H 6 R = R' = Br 4 O NH R HO R' O 1 2 3 4 5 6 7 8 9 7 R = R' = H 9 R = R' = Br R HO R' 1 2 3 4 5 6 7 8 9 8 R = R' = H 10 R = H, R' = Br O NH 10 OMendeleev Communications Electronic Version, Issue 1, 2002 2 displaying structural particularity, was observed for the quaternary carbon atoms.The most characteristic quaternary carbon atom correlation peaks of adduct 7, d/ppm: 3-CH2/1-C = 3.23/161.5, 4-CH2/5a-C = 2.00/123.1, 5-CH2/5a-C = 2.90/123.1, 6-CH/5a-C = = 6.95/123.1, 9-CH/5b-C = 7.40/129.1, 5-CH2/5b-C = 2.90/129.1, 6-CH/5b-C = 6.95/129.1, 4-NH/10b-C = 8.00/143.8, 5-CH2/10b-C = = 2.90/143.8, 9-CH/9a-C = 7.40/147.6, 8-CH/9a-C = 6.95/147.6, 6-CH/9a-C = 6.95/147.6; adduct 8, d/ppm: 4-NH/5-C = 5.77/157.5, 1-CH2/4a-C = 2.59/129.2, 7-CH/10a-C = 7.08/122.3, 1-CH2/10a-C = = 2.59/122.3, 4-NH/10b-C = 5.77/114.3, 1-CH2/10b-C=2.59/114.3, 10-CH/10b-C = 6.74/114.3, 7-CH/6a-C = 7.08/140.4, 8-CH/6a-C = = 6.67/140.4, 10-CH/6a-C = 6.74/140.4.Under the same conditions, adduct 6 also forms 6,8-dibromo-7-oxybenzofuro[2,3-c]- azepine-1-one 9 in 14% yield [mp 228–231 °C (EtOH), M+· 375††] and 8-bromo-9-hydroxy-1,2,3,4-tetrahydro-5H-chromeno- [3,4-b]pyridine-5-one 10 in 22% yield [mp 191–193 °C (EtOH), M+· 296‡‡].Note that compound 10 contains only one bromine atom at the 8-position; therefore, the rearrangement in this case proceeds by halogen removal. It is believed that the formation of chromene 8 is associated with an equilibrium in solution between adduct 5 with noncyclic hydroquinone adduct 4 (R = R' = H), which is ‘usual’ for this reaction. The opening of a lactam ring in 4 (R = R' = H) leads to chromene 8 according to Scheme 2.Unexpected debromination with the formation of compound 10 is probably associated with the presence of hydroquinone adduct 4 (R = R' = Br) in the reaction mixture. Compound 4 (R = R' = Br) can undergo oxidation to quinone adduct 11.An activated bromine atom at the 6-position is reduced by adduct 4 (with the transformation of 4 to a ‘new portion’ of quinone adduct 11) (Scheme 3). The mechanism of formation of chromene observed in the Nenitzescu reaction, as well as intriguing debromination in the transformation of dibromoadduct 6, invite further investigation.The structures of all compounds were determined by 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The work was supported by the Russian Foundation for Basic Research (grant no. 99-03-32973). References 1 G. R. Allen, in Organic Reactions, ed. W. G. Dauben, Wiley-Interscience, New York, 1973, vol. 20, p. 337. 2 V. G. Granik, V. M. Lyubchanskaya and T.I. Muckhanova, Khim.-Pharm. Zh., 1993, 6, 37 (in Russian). 3 U. Kucklander and R. Kuna, Arch. Pharm. (Weinheim), 1993, 326, 415. 4 U. Kucklander, R. Kuna and B. Schneider, J. Prakt. Chem., Chem-Zeit, 1993, 335, 345. 5 U. Kucklander and B. Schneider, Chem. Ber., 1986, 119, 3487. 6 R. G. Glushkov, V. A. Volskova, V. G. Smirnova and O. Yu. Magidson, USSR Inventor’s Certificate no. 239963, Bull. Izobr., 1969, 12, 18 (in Russian). 7 R. Cassis, R. Tapia and J. A. Valderrama, J. Heterocycl. Chem., 1984, 21, 869. 8 L. Barries, V. M. Ruiz and R. Tapia, Chem. Lett., 1980, 2, 187. 9 T. I. Muckhanova, E. K. Panisheva, M. Lyubchanskaya, L. M. Alekseeva, Yu. N. Sheinker and V. G. Granik, Tetrahedron, 1997, 53, 177. †† For 9: 1H NMR ([2H6]DMSO) d: 2.09 (m, 2H, 4-CH2), 3.28 (m, 4-H, 5-CH2, 3-CH2), 7.96 (s, 1H, 9-CH), 8.19 (br. s, 1H, 2-NH), 9.60 (br. s, 1H, 7-OH). Found (%): C, 38.74; H, 2.40; Br, 43.00; N, 3.63. Calc. for C12H9Br2NO3 (%): C, 38.43; H, 2.42; Br, 42.62; N, 3.73. ‡‡ For 10: 1H NMR ([2H6]DMSO) d: 1.89 (m, 2H, 2-Me), 2.58 (t, 2H, 1-CH2, J 6.2 Hz), 3.23 (m, 1H, 3-CH2), 5.96 (br. s, 1H, 4-NH), 6.90 (s, 1H, 10-H), 7.44 (s, 1H, 7-H), 10.07 (br. s, 1H, 9-OH). Found (%): C, 48.24; H, 3.30; Br, 27.40; N, 4.26. Calc. for C12H10BrNO3 (%): C, 48.67; H, 3.40; Br, 26.99; N, 4.73. 2+ 2+ 1+ 1 2 2+ 2+ 1 &22+ 1+ 2+ 2+ 2 1+ &22+ 6FKHPH Br NH N O 4 Br 10 Scheme 3 Br OH Br O NH O N (11) Br O NH O N HO O O 4 Received: 16th October 2001; Com. 01/1851

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Mendeleev Communications Electronic Version, Issue 1, 2002 1 Synthesis of 3-aryl-5,7-dinitrothiochromane 1,1-dioxides based on 2,4,6-trinitrotoluene Mikhail D. Dutov, Ol’ga V. Serushkina and Svyatoslav A. Shevelev* N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 135 5328; e-mail: shevelev@mail.ioc.ac.ru 10.1070/MC2002v012n01ABEH001551 3-Aryl-5,7-dinitrothiochromane 1,1-dioxides are formed by the condensation of methyl (2-methyl-3,5-dinitrobenzenesulfonyl)acetate and ethyl (2-methyl-3,5-dinitrobenzenesulfonyl)propionate, which are the products of 2,4,6-trinitrotoluene transformations, with aromatic aldehydes under conditions of the Knoevenagel reaction.This study was performed in the context of the chemical utilization of 2,4,6-trinitrotoluene (TNT)1 to prepare multipurpose intermediates for the synthesis of polyfunctional heterocyclic compounds.We examined the reactions of sulfone 1, which was synthesised previously2 from TNT, with aromatic aldehydes under conditions of the Knoevenagel reaction. The equimolar amounts of the sulfone and ArCHO in benzene in the presence of secondary aliphatic amine acetates were heated with the continuous removal of water formed in the reaction (Scheme 1).Under these conditions, 3-aryl-5,7-dinitrothiochromane 1,1- dioxide 6 was the reaction product. It can be formed either by the initial formation of stilbene 4 in the condensation of ArCHO 3 with the methyl group of sulfone 1 followed by the addition of an active methylene unit at the double bond of stilbene 4 (pathway a) or by the condensation of aldehydes 3 with the active methylene unit of sulfone 1 to form arylidene 5 followed by the intramolecular addition of an active methyl group at the double bond of arylidene 5 (pathway b).It is likely that the reaction can simultaneously proceed via pathways a and b. At least, the feasibility of pathway a was demonstrated by the formation of 3-aryl-2-methyl-5,7-dinitrothiochromane 1,1-dioxides 7 with the use of sulfone 22 in this reaction (Scheme 2).Thus, we developed a general procedure† for preparing previously unknown 3-aryl-5,7-dinitrothiochromane 1,1-dioxides 6 and 7. Compounds 6 and 7 were identified by 1H NMR spectroscopy and elemental analysis.‡ The stereochemistry of these compounds will be published elsewhere.This study was supported by the Russian Foundation for Basic Research (grant no. 01-03-32261) and the International Science and Technology Centre (project no. 419). Me O2N NO2 SO2CH2CO2Me + ArCHO 1 3 HC O2N NO2 SO2CH2CO2Me 4 CHAr CH3 O2N NO2 SO2CCO2Me 5 HC Ar R2NH·AcOH, C6H6, reflux a b – H2O S NO2 O2N O O Ar CO2Me 6 a Ar = Ph b Ar = 4-MeOC6H4 c Ar = 4-Me2NC6H4 d Ar = 4-ClC6H4 e Ar = 4-FC6H4 f Ar = 4-NO2C6H4 g Ar = 3-pyridyl Scheme 1 † General procedure.Piperidine (0.1 ml) and glacial acetic acid (0.11 ml) were added to a mixture of 0.01 mol of sulfone 1 or 2 and 0.011 mol of ArCHO in 30 ml of benzene. The mixture was refluxed for 2–5 h (with TLC monitoring) with the use of a Dean–Stark trap to remove water and then cooled.The precipitated product was filtered off, washed with a dilute aqueous NaCl solution, dried in air, and recrystallised from an acetone–methanol mixture. ‡ The 1H NMR spectra (in [2H6]acetone) were measured on a Bruker AC-200 instrument. 6a: 53% yield, mp 217–219 °C. 1H NMR, d: 9.02 (d, 1H, 4J 2.0 Hz), 8.90 (d, 1H, 4J 2.0 Hz), 7.31–7.48 (m, 5H), 5.17 (d, 1H, 3J 11.0 Hz), 4.07–4.20 (m, 1H), 3.56–3.75 (m, 5H). Found (%): C, 50.44; H, 3.29; S, 8.11; N, 7.02.Calc. for C17H14N2O8S (%): C, 50.25; H, 3.47; S, 7.89; N, 6.89. 6b: 82% yield, mp 197–199 °C. 1H NMR, d: 9.03 (d, 1H, 4J 2.2 Hz), 8.89 (d, 1H, 4J 2.2 Hz), 7.38 (d, 2H, 3J 8.6 Hz), 6.95 (d, 2H, 3J 8.6 Hz), 5.16 (d, 1H, 3J 11.1 Hz), 4.00–4.15 (m, 1H), 3.75–3.85 (m, 8H). Found (%): C, 49.83; H, 4.00; S, 7.47; N, 6.15.Calc. for C18H16N2O9S (%): C, 49.54; H, 3.70; S, 7.35; N, 6.42. 6c: 35% yield, mp 185–187 °C. 1HNMR, d: 9.03 (d, 1H, 4J 2.0 Hz), 8.89 (d, 1H, 4J 2.0 Hz), 7.28 (d, 2H, 3J 8.5 Hz), 6.72 (d, 2H, 3J 8.5 Hz), 5.02 (d, 1H, 3J 11.0 Hz), 3.90–4.05 (m, 1H), 3.60–3.72 (m, 5H), 2.94 (s, 6H). Found (%): C, 51.03; H, 4.37; S, 7.23; N, 9.07. Calc. for C19H19N3O8S (%): C, 50.78; H, 4.26; S, 7.13; N, 9.35. 6d: 24% yield, mp 234–236 °C. 1H NMR, d: 9.05 (d, 1H, 4J 2.1 Hz), 8.91 (d, 1H, 4J 2.1 Hz), 7.52 (d, 2H, 3J 8.9 Hz), 7.44 (d, 2H, 3J 8.9 Hz), 5.29 (d, 1H, 3J 11.3 Hz), 4.10–4.25 (m, 1H), 3.62–3.78 (m, 5H). Found (%): C, 46.14; H, 3.11; S, 7.05; Cl, 8.42; N, 6.03. Calc. for C17H13ClN2O8S (%): C, 46.32; H, 2.97; S, 7.27; Cl, 8.04; N, 6.35.Me O2N NO2 SO2CH(Me)CO 2Et + ArCHO 2 3 R2NH·AcOH, C6H6, reflux S NO2 O2N O O Ar CO2Et 7 Me b Ar = 4-MeOC6H4 e Ar = 4-FC6H4 g Ar = 3-pyridyl Scheme 2Mendeleev Communications Electronic Version, Issue 1, 2002 2 References 1 V. A. Tartakovsky, S. A. Shevelev, M. D. Dutov, A. Kh. Shakhnes, A. L. Rusanov, L. G. Komarova and A. M. Andrievsky, in Conversion Concepts for Commercial Applications and Disposal Technologies of Energetic Systems, ed.H. Krause, Kluwer Academic Publishers, Dordrecht, 1997, p. 137. 2 O. V. Serushkina, M. D. Dutov and S. A. Shevelev, Izv. Akad. Nauk, Ser. Khim., 2001, 252 (Russ. Chem. Bull., Int. Ed., 2001, 50, 261). 6e: 68% yield, mp 220–222 °C. 1H NMR, d: 9.04 (d, 1H, 4J 2.0 Hz), 8.90 (d, 1H, 4J 2.0 Hz), 7.45–7.58 (m, 2H), 7.19–7.21 (m, 2H), 5.18 (d, 1H, 3J 10.3 Hz), 4.10–4.25 (m, 1H), 3.61–3.75 (m, 5H).Found (%): C, 48.36; H, 3.01; S, 7.84; N, 6.73. Calc. for C17H13FN2O8S (%): C, 48.12; H, 3.09; S, 7.56; N, 6.60. 6f: 52% yield, mp 264–266 °C. 1HNMR, d: 9.05 (d, 1H, 4J 2.2 Hz), 8.92 (d, 1H, 4J 2.2 Hz), 8.29 (d, 2H, 3J 8.8 Hz), 7.80 (d, 2H, 3J 8.8 Hz), 5.44 (d, 1H, 3J 11.0 Hz), 4.26–4.45 (m, 1H), 3.70–3.81 (m, 2H), 3.64 (s, 3H).Found (%): C, 45.42; H, 3.10; S, 7.15; N, 9.03. Calc. for C17H13N3O10S (%): C, 45.24; H, 2.90; S, 7.10; N, 9.31. 6g: 55% yield, mp 183–185 °C. 1H NMR, d: 9.04 (d, 1H, 4J 2.1 Hz), 8.91 (d, 1H, 4J 2.1 Hz), 8.67 (m, 1H), 8.55 (m, 1H), 7.93 (m, 1H), 7.41 (m, 1H), 5.36 (d, 1H, 3J 11.0 Hz), 4.12–4.30 (m, 1H), 3.70–3.80 (m, 2H), 3.63 (s, 3H). Found (%): C, 47.48; H, 3.14; S, 8.13; N, 10.04.Calc. for C16H13N3O8S (%): C, 47.18; H, 3.22; S, 7.87; N, 10.32. 7b: 53% yield, mp 145.5–147.5 °C. 1HNMR, d: 9.05 (d, 1H, 4J 2.3 Hz), 8.90 (d, 1H, 4J 2.3 Hz), 7.32 (d, 2H, 3J 8.8 Hz), 6.95 (d, 2H, 3J 8.8 Hz), 4.41–4.49 (m, 1H), 4.08–4.22 (m, 2H), 3.74–3.83 (m, 5H), 1.58 (s, 3H), 1.16 (t, 3H, 3J 7.1 Hz). Found (%): C, 52.01; H, 4.32; S, 7.24; N, 5.88. Calc.for C20H20N2O9S (%): C, 51.72; H, 4.34; S, 6.90; N, 6.03. 7e: 40% yield, mp 149–151 °C. 1H NMR, d: 9.06 (d, 1H, 4J 2.3 Hz), 8.90 (d, 1H, 4J 2.3 Hz), 7.40–7.53 (m, 2H), 7.12–7.22 (m, 2H), 4.47–4.57 (m, 1H), 4.10–4.22 (m, 2H), 3.77–3.87 (m, 2H), 1.60 (s, 3H), 1.15 (t, 3H, 3J 7.2 Hz). Found (%): C, 50.22; H, 3.94; S, 6.93; N, 5.98. Calc. for C19H17FN2O8S (%): C, 50.44; H, 3.79; S, 7.09; N, 6.19. 7g: 74% yield, mp 177.5–179.5 °C. 1HNMR, d: 9.08 (d, 1H, 4J 2.3 Hz), 8.55–8.62 (m, 2H), 7.94–7.89 (m, 1H), 7.45–7.39 (m, 1H), 4.62–4.57 (m, 1H), 4.19–4.12 (m, 2H), 3.93–3.87 (m, 2H), 1.70 (s, 3H), 1.15 (t, 3H, 3J 7.2 Hz). Found (%): C, 49.91; H, 4.06; S, 7.52; N, 9.47. Calc. for C18H17N3O8S (%): C, 49.65; H, 3.94; S, 7.36; N, 9.65. Received: 9th January 2002; Com. 02/1877

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Mendeleev Communications Electronic Version, Issue 1, 2002 1 A novel transformation of 2-acetylthiophene and its halogen derivatives under Vilsmeier reaction conditions Valerii Z. Shirinian,* Leonid I. Belen¡�kii and Mikhail M. Krayushkin N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 137 6939; e-mail: shir@ioc.ac.ru 10.1070/MC2002v012n01ABEH001529 Under conditions of the Vilsmeier reaction either ¥â-chloro-¥â-(2-thienyl)acrylic aldehydes or N,N-dimethyl-2-thiophenecarboxamides can be synthesised from 2-acetylthiophenes depending on the reaction temperature and time.The Vilsmeier reaction is a general procedure for introducing an aldehyde group into activated aromatic rings.1.3 This method has been widely used for the synthesis of various aldehyde derivatives of benzene, thiophene, furan, pyrrole etc., via a complex derived from DMF and POCl3, SOCl2 or COCl2.The Vilsmeier complex is also used as a halogenating and dehydrating agent.4.6 In particular, the dehydration of N-monosubstituted formamides by DMF.POCl3 is a simple procedure for the synthesis of isonitriles.4 Specific transformations under the action of Vilsmeier¡�s reagent are known, e.g., the synthesis of previously unknown amidomercaptals from the 2-thienyl sulfides or alkanethiols. 5,6 Interesting synthetic possibilities are offered by the joint action of Vilsmeier¡�s reagent and hydride reductants.7 In addition to the electrophilic formylation of aromatic compounds, Vilsmeier¡�s reagent has been also widely used in reactions with carbonyl compounds.8 Arnold and Zemlicka9,10 found that the reaction of Vilsmeier¡�s reagent with ketones containing methyl or methylene groups adjacent to the carbonyl group affords substituted ¥â-chloroacrylaldehydes. The reaction can be used for the preparation of ¥â-chloroacrylaldehydes from ketones including aryl alkyl ketones.8 The reaction proceeds on the addition of a ketone to Vilsmeier¡�s reagent at 5.10 ¡ÆC followed by heating the reaction mixture at 60 to 100 ¡ÆC up to the complete transformation into ¥â-chloroacrylaldehyde.However, we found that 2-acetylthiophenes 1a.c heated with Vilsmeier¡�s reagent above 120 ¡ÆC afforded N,N-dimethylthiophene- 2-carboxamides 3a.c rather than expected ¥â-chloroacrylaldehydes 2a.c (Scheme 1).¢Ó The structures of amides 3a.c were found from spectroscopic data and the results of elemental analyses,¢Ô in the case of 3a the characteristics were compared with published data.The structure of amide 3b was found by spectrometric techniques, elemental analysis and through its independent synthesis from known 4-bromothiophene-2-carboxylic acid.15 As to the replacement of bromine by a chlorine atom on the interaction of 2-acetyl- 4,5-dibromothiophene 1c with Vilsmeier¡�s reagent, the preparation of 5-chlorothiophene-2-carbaldehyde by the reaction of 2-bromothiophene with N-methylformanilide and POCl3 at 100 ¡ÆC should be mentioned.16 Note that there is a weak parent peak (m/z 313) of N,N-dimethyl-4,5-dibromothiophene-2-carboxamide in the mass spectrum of unpurified amide 3c.The mechanism of this novel transformation remains unclear. The reaction likely involves many steps (Scheme 2) and includes the formation of intermediate 6, which is analogous to key compounds yielding ¥â-chloroacrylaldehydes.8 The formation of ¥â-chloroacrylaldehydes from acetylthiophenes and Vilsmeier¡�s reagent at 60.100 ¡ÆC was described.8,17,18 In particular, 3-chloro- 3-(2-thienyl)propenal was obtained in 11% yield by treatment of 2-acetylthiophene with Vilsmeier¡�s reagent at 60 ¡ÆC.17 The formation of both 3-chloro-3-(2-thienyl)propenal and N,N-dimethylthiophene- 2-carboxamide in the ratio ~1:1 on the heating of 2-acetylthiophene with Vilsmeier¡�s reagent for 1 h instead of 3 h¡× may indirectly indicate that ¥â-chloroacrylaldehydes are inter- ¢Ó Preparation of N,N-dimethylthiophene-2-carboxamides 3a.c (general procedure).Phosphorus oxychloride (2.5 ml, 4.1 g, 0.027 mol) was added dropwise to DMF (8.5 ml, 8.2 g, 0.11 mol) cooled to 0.10 ¡ÆC. The mixture was kept for 15 min at this temperature, then for 15 min at 45.50 ¡ÆC and cooled again to 0.10 ¡ÆC; a starting 2-acetylthiophene (0.024 mol) was added.(2-Acetylthiophene was purchased from Aldrich, 2-acetyl- 4-bromothiophene 1b and 2-acetyl-4,5-dibromothiophene 1c were prepared according to the published procedure.11) The reaction mixture was gradually heated to 120.130 ¡ÆC and kept at this temperature for 2.5.3 h. After cooling, CH2Cl2 (50 ml) was added, and the organic layer was washed successively with concentrated AcONa and NaHCO3 solutions and finally with water.The residue after evaporation of the extract was recrystallised from a suitable solvent. ¢Ô N,N-Dimethylthiophene-2-carboxamide 3a: yield 41%, mp 44.45 ¡ÆC (from light petroleum, lit.,12 mp 44.45 ¡ÆC). 1H NMR [200 MHz, (CD3)2CO] d: 3.18 (br. s, 6H, Me2N), 7.09 (dd, 1H, 4-H), 7.43 (dd, 1H, 3-H), 7.62 (dd, 1H, 5-H); J45 4.8 Hz, J34 3.7 Hz, J35 1.1 Hz (cf.ref. 13). MS (EI, 70 eV), m/z (%): 155 (46) [M]+, 111 (100) [M . NMe2]+. N,N-Dimethyl-4-bromothiophene-2-carboxamide 3b: yield 39%, mp 98. 100 ¡ÆC (from heptane). 1H NMR (200 MHz, CDCl3) d: 3.21 (br. s, 6H, Me2N), 7.25 (s, 1H, 5-H), 7.38 (s, 1H, 3-H). 13C NMR (50 MHz, CDCl3) d: 30.85 (Me), 109.12 (C.Br), 126.36 [C(3)], 131.12 [C(5)], 139.21 [C(2)], 162.80 (C=O).MS (EI, 70 eV), m/z (%): 235 (59) [M]+, 191 (99) [M . NMe2]+. Found (%): C, 36.41; H, 3.83; Br, 33.78; S, 13.55; N, 6.24. Calc. for C7H8BrNOS (%): C, 35.91; H, 3.44; Br, 34.13; S, 13.7; N, 5.98. N,N-Dimethyl-4-bromo-5-chlorothiophene-2-carboxamide 3c: yield 47%, mp 75.76 ¡ÆC (from heptane). 1H NMR (200 MHz, CDCl3) d: 3.19 (br. s, 6H, Me2N), 7.13 (s, 1H, 3-H). 13C NMR (50 MHz, CDCl3) d: 34.74 (Me), 35.37 (Me), 98.92 (C.Cl), 107.48 (C.Br), 128.34 [C(3)], 133.96 [C(2)], 159.35 (C=O). MS (EI, 70 eV), m/z (%): 271 (11) [M]+, 269 (38) [M]+, 267 (24) [M]+, 227 (24) [M . NMe2]+, 225 (78) [M . NMe2]+, 223 (64) [M . NMe2]+. Found (%): C, 31.32; H, 2.52; Br, 30.32; Cl, 13.46; S, 12.17; N, 4.39. Calc. for C7H7BrClNOS (%): C, 31.22; H, 2.60; Br, 29.74; Cl, 13.19; S, 11.89; N, 5.24.Found (by the Schoniger14 method) (%): S, 10.81. Calc. for C7H7BrClNOS (%): S, 11.89. ¡× On the interaction of 2-acetylthiophene 1a with Vilsmeier¡�s reagent at 100.120 ¡ÆC for 1 h, the residue (2.06 g of a yellow oil) obtained after evaporation of the solvent was chromatographed on silica gel (light petroleum.EtOAc, 2.5:1, as an eluent) to give two substances. After recrystallization from light petroleum the following compounds were obtained: 3-chloro-3-(2-thienyl)propenal 2a, 0.75 g (yield 21%), mp 54. 55 ¡ÆC (lit.,17 55.57 ¡ÆC). 1H NMR (200 MHz, CDCl3) d: 6.55 (d, 1H, C=CH, J 3.6 Hz), 7.08 (dd, 1H, 4-H, J45 4.8 Hz, J34 3.7 Hz), 7.51 (dd, 1H, 5-H, J35 1.2 Hz), 7.61 (m, 1H, 3-H), 10.08 (d, 1H, CH=O, J 6.05 Hz). Amide 3a, 0.92 g (yield 25%), identical to the above substance mp and 1H NMR spectrum. 1.3: a R1 = R2 = H b R1 = H, R2 = Br 1c, 2c R1 = R2 = Br 3c R1 = Cl, R2 = Br Scheme 1 S R2 R1 O S R2 R1 Cl O S R2 R1 N O 1a.c 2a.c 3a.c 60.100 ¡ÆC > 120 ¡ÆC DMF/POCl3Mendeleev Communications Electronic Version, Issue 1, 2002 2 mediates in the formation of the carboxamides. However, compound 3 cannot be obtained from aldehyde 2 under these conditions: the heating of 3-chloro-3-(2-thienyl)propenal under Vilsmeier reaction conditions leads to decomposition and tar formation.On the assumption that aldehydes 2 are formed from intermediates 6 on the treatment of the reaction mixture, the transformation of compounds 6 into amides 3 can be considered as a process including the formation of enamines 7 by the interaction DMF) with 6 like the synthesis of N,N-dimethylcarboxamides from DMF and acyl chlorides at 140–150 °C.19 Since intermediate 7 is a vinylog of amidines, a further transformation into N,N-dimethylamide 3 may be similar to the formation of amides from amidines on hydrolysis.It is also similar to the acidic cleavage of â-dicarbonyl compounds.The transformation 7 ® 3 is likely to proceed via amidinium salt 8. In conclusion, we found a new transformation under Vilsmeier reaction conditions, which is promising for the one-step preparation of N,N-dimethylthiophenecarboxamides from 2-acetylthiophenes. The heating of acetylthiophenes with Vilsmeier’s reagent can lead to both â-chloro-â-(2-thienyl)acrylaldehydes and N,N-dimethylthiophene- 2-carboxamides depending on the heating temperature and reaction time.Vilsmeier’s reagent can also be used as a transhalogenating agent. This work was supported by the Russian Foundation for Basic Research (grant no. 01-03-33150). References 1 L. Fieser and M. Fieser, Reagents for Organic Synthesis, Wiley, New York, 1967, p. 284. 2 H. Eilingsfeld, M. Seefelder and H.Weidingen, Angew. Chem., 1960, 72, 836. 3 J.C.Thurman, Chem. Ind., 1964, 752. 4 H. M. Walborsky and G. E. Niznik, J. Org. Chem., 1972, 37, 187. 5 B. P. Fedorov and F. M. Stoyanovich, Izv. Akad. Nauk SSSR, Otdel. Khim. Nauk, 1960, 1828 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1960, 9, 1700). 6 F. M. Stoyanovich, B. P. Fedorov and G. M. Andrianova, Dokl. Akad. Nauk SSSR, 1962, 145, 584 [Dokl.Chem. (Engl. Transl.), 1962, 640]. 7 D.Burn, Chem. Ind. (London), 1973, 870. 8 Ch. M. Marson, Tetrahedron, 1992, 48, 3659. 9 Z. Arnold and J. Zemli ka, Collect. Czech. Chem. Commun., 1959, 24, 2385. 10 Z. Arnold and J. Zemli ka, Proc. Chem. Soc., 1958, 227. 11 Ya. L. Gol’dfarb and Yu. B. Vol’kenshtein, Dokl. Akad. Nauk SSSR, 1959, 128, 536 [Dokl. Chem. (Engl.Transl.), 1959, 767]. 12 M. Davis, R. Lakhan and A. Ternai, J. Org. Chem., 1976, 41, 3591. 13 F. Fringuelli, S. Gronowitz, A.-B. Hornteldt, I. Jonson and A. Taticchi, Acta Chem. Scand., Ser. B, 1976, 30, 605. 14 Metody kolichestvennogo organicheskogo elementnogo mikroanaliza (Quantitative Methods for Organic Elemental Analysis), eds. N. E. Gel’man and E. A. Terent’eva, Nauka, Moscow, 1987, pp. 149–154 (in Russian). 15 Ya. L. Gol’dfarb, Yu. B. Vol’kenshtein and B. V. Lopatin, Zh. Obshch. Khim., 1964, 34, 969 [J. Gen. Chem. USSR (Engl. Transl.), 1964, 34, 961]. 16 W. J. King and F. F. Nord, J. Org. Chem., 1948, 13, 635. 17 K. Bodendorf and R. Mayer, Chem. Ber., 1965, 98, 3554. 18 Z. Vegh and D. Vegh, 17th International Congress of Heterocyclic Chemistry, Book of Abstracts, Vienna, 1999, p. 571. 19 G. M. Copinger, J. Am. Chem. Soc., 1954, 76, 1372. S R2 R1 O S R2 R1 Cl O S R2 R1 N O 1a–c 2a–c 3a–c HCl S R2 R1 OH – 2HCl DMF–POCl3 S R2 R1 O N 4 S R2 R1 O N 5 2Cl– DMF–POCl3 < 120 °C S R2 R1 Cl N Cl– N 6 NaOAc aq > 120 °C S R2 R1 N N Cl– S R2 R1 N N Cl– 7 S R2 R1 N N Cl– 8 Scheme 2 DMF c c Received: 1st November 2001; Com. 01/1855

ISSN:0959-9436     

出版商:RSC    

年代:2002

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