摘要:

DALTON J. Chem. Soc., Dalton Trans., 1997, Pages 2369–2372 2369 Potentiometric and spectroscopic study of ternary complexes of copper(II), substituted 1,10-phenanthrolines and oxidised glutathione Paola Piu,a Gavino Sanna,a Andreina Masia,a Maria Antonietta Zoroddu a and Renato Seeber b a Dipartimento di Chimica, Università di Sassari, Via Vienna 2, 07100 Sassari, Italy b Dipartimento di Chimica Fisica e Inorganica, Università di Bologna, Viale del Risorgimento 4, 40136 Bologna, Italy A series of ternary systems consisting of copper(II), oxidised glutathione (a S]S9 bonded hexapeptide) and five differently substituted 1,10-phenanthrolines has been studied in aqueous solvent in the range pH 3–8. The stability constants of the complexes formed, together with the relevant distributions as a function of pH, have been evaluated by elaboration of data from acid–base potentiometric titrations.Electron paramagnetic resonance and electronic spectroscopy have been used to identify the chromophore in the 1 : 1 : 1 complexes, i.e.the ternary species are in all cases the predominant ones at pH close to the physiological values. The data from the spectroscopic measurements, when considered together with the trend in stability constant values, allowed reasonable hypotheses about the effect of the substituents on the phenanthroline ring on the stability and configuration of the complexes. The tripeptide glutathione (L-g-glutamyl-L-cysteinylglycine) is one of the naturally most abundant non-proteic thiols; it participates in redox reactions involving the CuII–CuI couple.1 Usually, the fast oxidation of the sulfhydryl group is catalysed by traces of metal ions such as copper(II).2 Some complexes also show catalytic activity; for example, chelation of copper(II) by 1,10-phenanthroline (phen) strongly enhances the catalytic ability with respect to the oxidation.3,4 As a part of our studies on the co-ordination of copper with ligands of biological interest we reported a study on the ternary system copper(II)-oxidised glutathione–1,10-phenanthroline.5 In the present paper we extend that study to differently substituted 1,10-phenanthrolines, bearing one or more substituents with different electronic effects on the aromatic system and, consequently, on the basicity of the nitrogen atoms, but also with different possible steric hindrances with respect to the co-ordination with copper ion.The main goal was to ascertain how the nature of the substituent( s) on the phenanthroline moiety affects the stability of the resulting ternary complex, as well as to collect information about the spectroscopic and structural modifications induced. The substituents have been suitably chosen, in order to be able to make appropriate comparisons based on electronic and steric arguments.Potentiometric acid–base titrations have been performed and elaborated in order to calculate the composition of the systems at varying pH of the solution and to evaluate the stability constants of the complexes formed.The EPR and UV/ VIS spectra have been recorded in order to acquire structural information on the complexes of interest. The studies have been carried out in aqueous solutions, in the range pH 3–8. Experimental Materials, instrumentation and methods The methods followed and the instrumentation used both in potentiometric and in spectroscopic measurements have been described.5 2,9-Dimethyl-, 4,7-dimethyl-, 5,6-dimethyl-, 5- methyl- and 5-nitro-1,10-phenanthroline were all from Aldrich (99% purity).Oxidised glutathione was a Sigma product (99% purity). Stock solutions of the phenanthrolines were standardised by acid–base titrations,5 those of the metal [Cu(NO3)2? 3H2O, Fluka] by common analytical procedures.6 The experimental procedures followed in the acid–base potentiometric titrations performed to evaluate the stability constants have also been described.5 The metal-tophenanthroline ratio varied from 2 : 1 to 1 : 4 in the binary copper–substituted phenanthroline systems, and was equal to 1 : 1 : 1 in the ternary systems.The concentrations were about 1023 mol l21. The temperature was controlled at 25.0 ± 0.1 8C and the ionic strength of the solutions was 0.1 mol l21 (KNO3). The computer program SUPERQUAD7 was employed to elaborate the results of the potentiometric titrations. X-Band EPR spectra were obtained on a Varian E-9 spectrometer equipped with a standard low-temperature apparatus, under the same conditions as those employed in the potentiometric measurements.The microwave frequency was calibrated against diphenylpicrylhydrazyl (dpph) powder (g = 2.0036). Spin-Hamiltonian parameters were obtained by simulating experimental EPR spectra by means of a revised version of the MONOCLIN program.8 Estimated errors in the reported g and A values are ±0.01 and about ±2 × 1024 cm21, respectively. Electronic absorption spectra of the ternary systems were recorded on a JASCO Uvidec 610 spectrophotometer, under conditions analogous to those of the pH-metric and EPR measurements.Results and Discussion Potentiometry For reader’s convenience, we summarise in two tables the literature data on the formation constants of adducts between oxidised glutathione or substituted phenanthrolines and proton(s) or copper(II) ions, in aqueous solution: the protonation con- N N R4 R3 R2 R1 R2 R1 R1 = R2 = R3 = R4 = H R1 = Me, R2 = R3 = R4 = H R2 = Me, R1 = R3 = R4 = H R3 = R4 = Me, R1 = R2 = H R3 = Me, R1 = R2 = R4 = H R3 = NO2, R1 = R2 = R4 = H 1,10-phenanthroline (phen) 2,9-dimethyl-1,10-phenanthroline (2,9-dmphen) 4,7-dimethyl-1,10-phenanthroline (4,7-dmphen) 5,6-dimethyl-1,10-phenanthroline (5,6-dmphen) 5-methyl-1,10-phenanthroline (5-mphen) 5-nitro-1,10-phenanthroline (nphen)2370 J.Chem. Soc., Dalton Trans., 1997, Pages 2369–2372 stants of the hexapeptide oxidised glutathione, as well as of the different substituted phenanthrolines, are in Table 1, the formation constants of the complex species in the binary systems copper–oxidised glutathione and copper–substituted phenanthroline in Table 2.It is evident that the trend in the values of the protonation constants reflects the presence in the phenanthroline ligand of one or more electron donors or electron-withdrawing substituents. Analogously, trends consistent with the different basicity of the phenanthroline nitrogen atoms are found for the binary 1 : 1, 1 : 2 and 1 : 3 metal : phenanthroline complexes, with the significant exception of the 2,9-dimethylphenanthroline. In this case, steric effects play the major role, not allowing the formation of a stable 1: 3 complex and causing a distortion in the planar configuration of the 1 : 2 and 1 : 1 complexes, with consequent decrease in the relevant stability, much lower than that of the corresponding complexes with unsubstituted phenanthroline.The ternary systems copper–substituted phenanthroline– oxidised glutathione were studied in solutions at 1 :1 : 1 molar ratios, in the range pH 3–8. We did not use higher metal : ligand molar ratios, eventually capable of leading to significant concentrations of dinuclear species in the solution, since the main goal of the study was a comparison of 1 : 1 : 1 substituted and unsubstituted ternary complexes,5 with particular attention to the relevant biological activity.Table 3 reports the log b values for the different ternary complexes identified. They all are 1 : 1 : 1 complexes, with different protonation levels of the peptide moiety. It is evident from Table 3 that the steric hindrance of the methyl substituents in positions 2 and 9 of the phenanthroline ring plays a major role also in conditioning the stability of these ternary complexes, since all the four complexes with differently protonated peptide ligands are much less stable than the corresponding ones with unsubstituted phenanthroline.5 On the other hand, the electronic effects of the substituents on the ring are much less evident in the ternary complexes than in the binary ones.Fig. 1 reports the distribution diagram of the species in the ternary system with the metal in the presence of oxidised glutathione and of 2,9-dmphen as a function of pH. Qualitatively Table 1 Protonation constants of oxidised glutathione and substituted phenanthrolines.Standard deviations in parentheses Species log ba Species log b HL32 9.59 (0.01) Hphen1 4.88 b H2L22 18.65 (0.01) H(2,9-dmphen)1 5.85 c H3L2 22.64 (0.03) H(4,7-dmphen)1 5.95 d H4L 26.07 (0.02) H(5,6-dmphen)1 5.60 d H5L1 28.53 (0.04) Hmphen1 5.28 e H6L21 30.87 (0.08) Hnphen1 3.57 b H4L = oxidised glutathione. a From ref. 5 (0.1 mol l21 KNO3). b From ref. 9 (0.1 mol l21 KCl, 25 8C). c From ref. 12 (0.1 mol l21 KCl, 25 8C).d From ref. 11 (0.1 mol l21 KCl, 25 8C). e From ref. 10 (0.1 mol l21 KCl or KNO3, 25 8C). similar trends are obtained for the other systems and can be easily computed on the basis of the data in Table 3. The different systems exhibit quite a number of similarities, the differences being, in turn, qualitatively in accord with the expectations based on the electronic but, even more, on the steric effects of the substituents present on the phenanthroline ring. The most stable species in the systems are, over a wide pH range, the ternary complexes [Cu(HL)L9]2.In particular, the last complexes are the most stable at pH > 4, up to pH > 8, in all systems except for those bearing 2,9- and 5,6-dmphen. The relative weakness of chelation of the metal centre by the 2,9- dmphen ligand, already evidenced and discussed with respect to the corresponding binary complexes, causes the predominant species at pH > 7 to be the 1 : 1 complex with the oxidised glutathione.More surprisingly, a similar trend is observed for the system with 5,6-dmphen: the ternary complexes are not stable enough to compete with the particularly stable binary copper– oxidised glutathione complex.11 The acidic strength of the ternary complexes can also be computed; the relevant pKa values are reported in Table 4. Useful information can be obtained by considering equilibrium (1) where L9, as seen in the Tables, indicates a generic phenanthroline ligand.[CuL9]21 1 [Cu(HL)]2 [Cu(HL)L9]2 1 Cu21 (1) log Keq1 = log b[Cu(HL)L9]2 2 log b[CuL9]21 2 log b[Cu(HL)]2 (2) Equation (2) follows a criterion suggested by Sigel and coworkers 13,14 to account for the stability of a ternary complex with respect to the corresponding binary ones. In a comparison Table 3 Formation constants of ternary complexes [Cu(HnL)L9](n22)1 L9 n log b phen* 2,9-dmphen 4,7-dmphen 5,6-dmphen mphen nphen 012301230123123123012 17.91 (0.04) 27.04 (0.01) 31.21 (0.02) 34.44 (0.04) 17.24 (0.10) 24.73 (0.03) 28.65 (0.03) 31.92 (0.07) 18.41 (0.08) 27.57 (0.05) 31.62 (0.05) 35.10 (0.06) 26.74 (0.03) 30.68 (0.04) 33.66 (0.10) 26.72 (0.02) 30.76 (0.04) 33.93 (0.07) 17.62 (0.09) 25.93 (0.02) 30.25 (0.02) * From ref. 5 (0.1 mol l21 KNO3, 25 8C). Table 2 Overall formation constants for the species present in the binary systems copper(II)–hexapeptide and –substituted 1,10-phenanthroline. Standard deviations in parentheses log b Species log ba L9 [CuL9]21 [CuL92]21 [CuL93]21 [CuL]22 14.34 (0.01) phenb 9.08 15.8 21.00 [Cu(HL)]2 18.72 (0.01) 2,9-dmphen 6.01 (0.13) 11.8 (0.08) — [Cu(H2L)] 22.43 (0.01) 4,7-dmphenc 8.76 16.0 22 [Cu(H3L)]1 25.51 (0.02) 5,6-dmphenc 8.71 15.7 21.1 [Cu2L] 17.39 (0.02) mphend 8.55 15.02 20.12 nphenb 8.00 13.47 17.61 L9 = Phenanthroline ligand.a From ref. 5 (0.1 mol l21 KNO3, 25 8C). b From ref. 9 (0.1 mol l21 KCl, 25 8C). c From ref. 11 (0.1 mol l21 KCl, 25 8C). d From ref. 10 (0.1 mol l21 KCl or KNO3, 25 8C).J.Chem. Soc., Dalton Trans., 1997, Pages 2369–2372 2371 involving different phenanthrolines and a single HL32 species, the stability of the ternary complex can be related to that of the 1 : 1 metal–phenanthroline adduct. The log Keq1 values found for the different phenanthrolines are 20.76,5 0.0, 10.09, 20.69, 20.55, 20.79 for phen, 2,9-, 4,7-, 5,6-dmphen, mphen and 5- nphen, respectively. This series reveals that equilibrium (1) is significantly shifted towards the formation of the ternary complex; the stability of such a species, with respect to the corresponding 1 : 1 copper–phenanthroline complex, is the highest for 2,9- and for 4,7-dmphen.As suggested in our previous work,5 a different equilibrium (3) could be proposed to account for the tendency of oxidised [CuL92]21 1 [Cu(HL)]2 [Cu(HL)L9]2 1 [CuL9]21 (3) log Keq2 = log b[Cu(HL)L9]2 1 log b[CuL9]21 2 log b[Cu(HL)]2 2 log b[CuL92]21 (4) glutathione to substitute a phenanthroline ligand.The following log Keq2 [see equation (4)] values are obtained: L9 = phen, 1.6;5 2,9-dmphen, 0.22; 4,7-dmphen, 1.61; 5,6-dmphen, 1.03; mphen, 1.53; nphen, 1.74. In view of these data, the inadequacy of such an equilibrium to give suitable indications is evident, since the listed values mainly reflect the strength of the resulting binary Cu]L9 complexes. Interestingly, the value of log Keq2 for nphen is quite high, despite the low stability of the Cu]nphen complex.In the context of a comparison in stability among the members of the series studied, equilibrium (5) can also be proposed. [CuL92]21 1 HL32 [Cu(HL)L9]2 1 L9 (5) By trivial combination of log b computed for the ternary and for the binary complexes, the following log Keq3 values are obtained: L9 = phen, 11.24; 2,9-dmphen, 12.93; 4,7-dmphen, 11.57; 5,6-dmphen, 11.04; mphen, 11.70; nphen, 12.46. It is once more evident that the different affinity of the various phenanthrolines for the metal centre plays the predominant Fig. 1 Distribution diagram of the species in the ternary system Cu:L: 2,9-dimethyl-1,10-phenanthroline. 1, [CuL]22; 2, [Cu(2,9- dmphen)]21; 3, [Cu(2,9-dmphen)2]21; 4, [Cu(H3L)(2,9-dmphen)]1; 5, [Cu(H2L)(2,9-dmphen)]; 6, [Cu(HL)(2,9-dmphen)]2; 7, [CuL(2,9- dmphen)]22 Table 4 pKa Values of the ternary complexes: pKa,1 refers to [Cu(H3L)L9]1, pKa,2 to [Cu(H2L)L9], pKa,3 to [Cu(HL)L9]2 L9 pKa,1 pKa,2 pKa,3 phen* 3.23 (0.05) 4.17 (0.03) 9.13 (0.04) 2,9-dmphen 3.27 (0.08) 3.92 (0.04) 7.49 (0.10) 4,7-dmphen 3.48 (0.08) 4.05 (0.07) 9.16 (0.09) 5,6-dmphen 2.98 (0.10) 3.94 (0.05) — mphen 3.17 (0.08) 4.04 (0.04) — nphen — 4.32 (0.03) 8.31 (0.09) * From ref. 5 (0.1 mol l21 KNO3, 25 8C). role, the highest values found for 2,9-dmphen and for nphen being in agreement with the easiest release of phenanthroline ligands by the relevant 1 : 2 metal–ligand binary complexes. A sound confirmation that the nature of the phenanthroline moiety constitutes the most important factor in conditioning the relative stability within this series of compounds is given by the values found for the constants of equilibrium (6), simply [CuL9]21 1 HL32 [Cu(HL)L9]2 (6) accounting for the tendency of the binary 1 : 1 Cu]L9 complexes to add an oxidised glutathione ligand to form the ternary complex.The following values are found for log Keq4: L9 = phen, 17.96; 2,9-dmphen, 18.72; 4,7-dmphen, 18.81; 5,6-dmphen, 18.03; mphen, 18.17; nphen, 17.93.Quite significantly, there are no remarkable differences within this series. EPR and UV/VIS spectroscopy The EPR spectra of the ternary systems of copper(II) with the different substituted phenanthrolines and oxidised glutathione were recorded at room temperature as well as in frozen solution, under the same conditions as those employed for the potentiometric measurements. In the EPR spectra the presence of various complex species, in addition to the binary copper– phenanthroline complexes, can be evidenced at low pH values.At pH > 4 the signal of a single species progressively increases and it is finally the only one present up to pH 7–8. From the EPR data, as already reported for the ternary system with unsubstituted phenanthroline,5 at increasing pH a decrease in g|| values and a corresponding increase in A|| values are observed; moreover, a corresponding blue shift in the lmax value is evidenced in the electronic spectra, suggesting an involvement in the co-ordination to the metal ion of the donor atoms from the hexapeptide molecule.The distribution diagrams computed from the potentiometric data were employed in order to evaluate the pH values of the solution at which the complex [Cu(HL)L9]2 is largely predominant. These values were quite close to those characterising the physiological pH. The electronic absorption spectra at pH ª 6 exhibit peaks consistent with CuN2O2 or CuN3O chromophores and an essentially square-planar or octahedral arrangement15,16 (lmax = 610 nm for the ternary complex with 5-methylphenanthroline, 615–620 nm with 4,7-dimethyl-, 5,6-dimethyl- and 5-nitrophenanthroline, and 640 nm with 2,9-dimethylphenanthroline). The higher lmax value found for the ternary system with 2,9- dimethylphenanthroline may be accounted for by a higher distortion of the copper square plane.17,18 The room-temperature EPR spectra are essentially isotropic. The good correlation between giso and gm obtained from roomtemperature and frozen-solution spectra, respectively, suggests that no changes in the co-ordination occur on passing from aqueous solution at 298 K to water–glycol (5 : 1) at 110 K.The frozen-solution EPR spectra obtained close to the physiological pH are quite similar for all the ternary systems and can be described by an axial spin Hamiltonian, in accord with an octahedral arrangement having tetragonal distortion. This does not hold for the Cu]L]2,9-dmphen complex, which is of rhombic type, in agreement with a distortion of the copper square plane.As an example, in Fig. 2(a) and 2(b) the frozen-solution EPR spectra of the [Cu(HL)(nphen)]2 and of the [Cu(HL)- (2,9-dmphen)]2 complexes, respectively, are reported. As shown by the data in Table 5, the presence of methyl groups on the phenanthroline ring in positions far from the coordination sites does not change the EPR parameters signifi- cantly.The differences found for the [Cu(HL)(2,9-dmphen)]2 complex can be ascribed to differences in the arrangement of the ligand around the metal centre in this unique compound. In the perpendicular part of the spectra a poorly resolved structure was evidenced; however, seven lines attributable to the2372 J. Chem. Soc., Dalton Trans., 1997, Pages 2369–2372 interaction between the unpaired electron of copper and the nitrogen atoms of the ligands can be identified in the case of the [Cu(HL)(5,6-dmphen)]2 and [Cu(HL)(4,7-dmphen)]2 ternary complexes, giving AN ª 12.6 × 1024 cm21 [Fig. 2(c)].Fig. 2 X-Band EPR spectra of (a) [Cu(HL)(nphen)]2 (110 K, pH 6), (b) [Cu(HL)(2,9-dmphen)]2 (110 K, pH 5.5) and (c) [Cu(HL)(5,6- dmphen)]2 (110 K, pH 6, perpendicular region). G = 1024 T Table 5 The EPR parameters for selected ternary systems obtained at pH 6 Compound T/K gxx gyy gzz 104Azz/ cm21 104AN/ cm21 [Cu(HL)(phen)]2 * 110 2.06 2.06 2.24 182 12.67, 298 2.13 2.13 2.13 76 11.0 [Cu(HL)(2,9-dmphen)]2 110 2.09 2.04 2.27 177 — 298 2.138 2.138 2.138 74.8 [Cu(HL)(5,6-dmphen)]2 110 2.06 2.06 2.24 184 12.6 298 2.13 2.13 2.13 76 [Cu(HL)(mphen)]2 110 2.06 2.06 2.23 182 — 298 2.13 2.13 2.13 76 * From ref. 5 (0.1 mol l21 KNO3). On the basis of the EPR results, any involvement of sulfur atoms from the hexapeptide molecule in the co-ordination to copper ion, as well as any antiferromagnetic coupling between copper atoms in a dimeric structure, can be excluded.Our results suggest that CuN3O is in all cases the chromophore close to the physiological pH, involving N and O donor atoms from only one glutamyl moiety of the hexapeptide ligand, the other two positions in the plane being occupied by the two nitrogen donor atoms from the phenanthroline ligands. In addition, stability data and EPR parameters obtained for the ternary systems are well comparable with those reported for similar copper–phenanthroline–amino acid complexes.19–21 In conclusion, the steric effects seem definitely to play a major role in determining the different chemical arrangements within this series of ternary complexes.Besides, it is noteworthy that the structural variety that can be found in the copper(II)– phenanthroline binary complexes 22 is preserved when passing to these ternary species, with oxidised glutathione as an additional ligand. Acknowledgements Financial support from Ministero dell’Università e della Ricerca Scientifica e Tecnologica, Rome (40 and 60% funds) is gratefully acknowledged.References 1 E. M. Kosower, Glutathione: Metabolism and Function, eds. I. M. Arias and W. B. Jakobi, Raven Press, New York, 1976, p. 1. 2 C. C. Tsen and A. L. Tappel, J. Biol. Chem., 1958, 233, 1230. 3 K. Kobashi, Biochem. Biophys. Acta, 1968, 158, 239. 4 I. G. Fels, Exp. Eye Res., 1971, 12, 227. 5 P. Piu, G. Sanna, M. A. Zoroddu, R. Seeber, R. Basosi and R. Pogni, J. Chem. Soc., Dalton Trans., 1995, 1267. 6 G. Charlot, Chimie Analitique Quantitative, Masson, Paris, 1974. 7 P. Gans, A. Sabatini and A. Vacca, J. Chem. Soc., Dalton Trans., 1985, 1195. 8 A. D. Troy, C. H. H. Chaston and T. R. Pilbrow, Inorg. Chem., 1970, 10, 2219. 9 L. V. Banks and R. I. Bystroff, J. Am. Chem. Soc., 1959, 81, 6153. 10 W. A. E. McBryde, D. A. Brisbin and H. Irving, J. Chem. Soc., 1962, 5251. 11 D. A. Brisbin and W. A. E. McBryde, Can. J. Chem., 1963, 41. 12 H. Irving and D. H. Mellor, J. Chem. Soc., 1962, 5239. 13 H. Sigel, Angew. Chem., Int. Ed. Engl., 1975, 14, 394. 14 H. Sigel, B. E. Fischer and B. Prijs, J. Am. Chem. Soc., 1977, 99, 4489. 15 B. J. Hathaway and D. E. Billing, Coord. Chem. Rev., 1970, 5, 143. 16 B. J. Hathaway and A. A. G. Tomlinson, Coord. Chem. Rev., 1970, 5, 1. 17 A. Battaglia, G. Bonamartini Corradi, L. Marcotrigiano, G. Menabue and C. Pellacani, Inorg. Chem., 1979, 18, 148. 18 M. Elleb, J. Meullemeestre, M. J. Schwing-Weill and F. Vierling, Inorg. Chem., 1982, 21, 1477. 19 G. Antolini, L. Marcotrigiano, G. Menabue, C. Pellacani, M. Saladini and M. Sola, Inorg. Chem., 1985, 24, 3621. 20 B. E. Fischer and H. Sigel, J. Am. Chem. Soc., 1980, 102, 2998. 21 A. Gergely, I. Sovago, I. Nagypal and R. Kiraly, Inorg. Chim. Acta, 1972, 6, 435. 22 M. A. Zoroddu, S. Zanetti, R. Pogni and R. Basosi, J. Inorg. Biochem., 1996, 63, 291. Received 9th December 1996; Paper 6/08272F

ISSN:1477-9226    

DOI:10.1039/a608272f

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

DALTON J. Chem. Soc., Dalton Trans., 1997, Pages 2373–2375 2373 About the aromaticity of Al2N3H5 † László Nyulászi * Department of Inorganic Chemistry, Technical University of Budapest, H-1521 Budapest Gellért tér 4, Hungary Ab initio quantum-chemical calculations showed that the Al2N3H5 ring is not planar, mainly as a result of the repulsion of the neighbouring nitrogen lone pairs. The planar structure, which is a saddle point on the potential energy surface, however, is 1.01 kcal mol21 less stable at the CCSD(T)/6-311 1 G(2D)//MP2/6-311 1 G(2D) 1 ZPE level of theory than the minimum-energy structure.According to energy criteria, the aromaticity of the molecule is small, if any. The geometric criteria on the other hand were shown to be useless in the prediction of aromaticity in this case. In a recent work Wehmschulte and Power 1 reported the synthesis and structural characterization of the first (heavily substituted) Al2N3 type ring 1. Discussing the bond-length distribution and the non-planarity about the two neighbouring nitrogen atoms, they concluded that the delocalization in the ring is negligible.This non-aromatic behaviour, however, could be explained, as noted by the authors,1 by the steric crowding of the substituents, enforcing a non-planar and thus non-conjugated arrangement. The aim of the present work was to investigate the aromaticity of the parent 1, substituted by hydrogens only, using ab initio quantum-chemical calculations.Earlier ab initio works on some possibly aromatic six-membered systems containing boron, aluminium, gallium and nitrogen,2 as well as divalent silicon (silylene) and nitrogen,3 have shown that such systems have varying extents of aromaticity. Six-membered rings built up from atoms with large electronegativity differences (such as Al and N) were shown to be slightly aromatic, according to different isodesmic reactions.2 However, the six-membered ring Al3N3H6 was found to be planar by quantum-chemical calculations, 2 and the crystal structure of its alkylated derivative was planar as well.4 In the case of heavy-atom-containing possibly aromatic rings, non-planarity is a quite common phenomenon.5 On the other hand, there are non-planar rings which have sizeable aromatic character,6 since the overlap of their ‘p’ orbitals allows a certain amount of delocalization. Calculations Quantum-chemical calculations were carried out by using the GAUSSIAN 94 package 7 at the Hartree-Fock (HF) and Møller-Plesset second-order perturbation (MP2) levels of the theory with 6-31G* as well as 6-311 1 G(2D) basis sets.Second-derivative calculations were carried out at the HF/6- 311 1 G(2D) and MP2/6-31G* levels, on the corresponding optimized structures. For the zero point energy (ZPE) corrections the MP2/6-31G* zero-point energies were considered when investigating the relative stabilities of the planar and nonplanar forms, while the HF/6-311 1 G(2D) ZPEs were used in the other cases.Results and Discussion Geometry optimization on Al2N3H5 was first carried out under planarity constraint. The calculation of the second derivatives showed that this structure is a first-order saddle point, charac- * E-Mail: nyulaszi@iris.inc.bme.hu † Non-SI unit employed: cal = 4.184 J. terizable by a i431 cm21 imaginary harmonic frequency at the MP2/6-31G* level (i488 cm21 at the HF/6-311 1 G* level). This frequency corresponds to the out-of-plane movement of the hydrogens situated at the two neighbouring nitrogen atoms.Releasing the constraint, the optimization resulted in a structure with C2 symmetry. The ring atoms themselves remain planar, while the two hydrogens on the neighbouring N atoms have a 638 tilt angle with respect to each other. This structure is a minimum on the MP2/6-31G* and the HF/6-311 1 G(2D) potential energy surfaces. Its energy is lower by 1.08 kcal mol21 at the MP2/6-311 1 G(2D) 1 ZPE2 level than that of the planar form [1.67 kcal mol21 at the HF/6-311 1 G(2D) level].To assess the effect of a higher level of electron correlation, CCSD(T)/6-311 1 G(2D)//MP2/6-311 1 G(2D) 1 ZPE calculations were carried out for the planar and non-planar structures, resulting in an energy difference of 1.01 kcal mol21. Since the level of the theory applied has little effect on the barrier to planarity it is quite safe to assume this value to be 1–1.5 kcal mol21 for the unsubstituted ring.This barrier is significantly smaller than the ca. 14 (or 18, see ref. 1) kcal mol21, which could be derived from the NMR data for the substituted ring.1 It seems likely that the large difference between the calculated and the observed barriers is due to the steric repulsion of the substituents on the ring, although solvent effects might play some role as well. Since the non-planarity is characteristic for the N]N fragment of the ring only (cf.ref. 1), it is reasonable to consider that the repulsion of the two neighbouring nitrogen lone pairs should be responsible for the folding of the ring. Planarity of hydrazine (H2N]NH2) requires a substantial energy [31.50 and 33.37 kcal mol21 at the MP2/6-311 1 G(2D) and HF/6- 311 1 G(2D) levels, respectively]. For H2Al(NHNH2) 16.08 (MP2) and 17.81 kcal mol21 (HF) are needed to make the system planar. On substituting the hydrazine by two AlH2 groups (AlH2]NH]NH]AlH2), 4.11 and 5.43 kcal mol21 are required for planarity at the MP2/6-311 1 G(2D) and HF/6-311 1 G(2D) levels, respectively.Clearly, as the empty p orbital on Al interacts with the nitrogen lone pairs, their mutual repulsive interaction diminishes. Planarity of the four-membered chain (AlH2]NH]NH]AlH2), however, still requires more energy (by about 3–4 kcal mol21) than in the case of the five-membered N N Al N Al 12374 J. Chem. Soc., Dalton Trans., 1997, Pages 2373–2375 Table 1 Selected structural parameters (in Å), total energies in atomic units and Wiberg bond indices for the planar and non-planar forms of Al2N3H5 at different levels of the theory.Bonds are marked a to e as shown N N Al N Al c d b a e Non-planar structure, Etot = 2650.900 770 4 a Planar structure, Etot = 2650.898 325 0 a HF/1b MP2/2c MP2/1b X-Ray d IWib a a 1.781 1.806 1.801 1.809 0.529 b 1.788 1.811 1.805 1.834 0.553 c 1.442 1.454 1.459 1.443 1.040 d 1.788 1.810 1.805 1.825 0.553 e 1.781 1.807 1.801 1.816 0.529 a 1.783 1.809 1.803 — 0.528 b 1.772 1.799 1.793 — 0.575 c 1.440 1.447 1.451 — 1.045 d 1.772 1.799 1.793 — 0.575 e 1.783 1.809 1.803 — 0.528 a For the MP2/6-311 1 G(2D) geometry using the 6-311 1 G(2D) basis.b 6-311 1 G(2D) basis. c 6-31G* basis. d For a substituted derivative.1 ring. It would be tempting to explain this difference by some small aromatic character of the ring, since a planar ring structure should benefit more from aromaticity than a non-planar one.To estimate the effect of aromaticity on the non-planar structure an isodesmic reaction, termed semihomodesmic, introduced for five-membered rings 8 was considered. It was shown that the energy of these reactions, which contain delocalized fragments with four p electrons at the right-hand side of the equation, is close to the result obtainable by (super)homodesmic reactions.8 In the present case two such reactions are (1) and (2). The energy of reaction (1) is 210.44 and 215.31 kcal mol21 at the MP2/6-311 1 G(2D) 1 ZPE and HF/6-311 1 G(2D) 1 ZPE levels, respectively, showing destabilization upon ring formation.In reaction (2) 212.52 (MP2) and 220.06 kcal mol21 (HF) destabilization can be obtained. For the sixmembered ring Al3N3H6,3 however, the homodesmic reaction was nearly thermoneutral. Furthermore, this significant destabilization seems to be in contrast with the near-planar structure and with the near 4 kcal mol21 difference in the energies for planarity of the ring and the Al]N]N]Al fragment.Ring strain may be an important factor in this difference. In the case of the six-membered ring Al3N3H6 it was shown3 that the bond angles are near to 1208. Similarly, near 1208 (or even larger) angles can be found in the optimized structures of the fragments used in reactions (1) and (2). Since in the fivemembered ring the bond angles are between 103 and 1138, considerable ring strain should be expected, which might account for the destabilization in the semihomodesmic reaction. In the case of the six-membered ring 3 this angle strain should be negligible. To estimate the ring strain, H2NAl(H)NH2 has been calculated with a 1078 N]Al]N angle, which is the value obtained in the ring.The structure optimized under the above constraint is 2.31 kcal mol21 less stable than the minimum and similar destabilization can be expected at each ring atom. This estimate is however an upper bound of the strain, since the repulsion of the in-plane hydrogens in the compressed form should have some effect.A further factor to be considered is the enforcement of the NN fragment to be near planar in the ring. Summing all these contributions for the five ring atoms, an estimated strain of 10 kcal mol21 is reasonable for the Al2N3 ring. The structural characteristics of the planar and non-planar N N Al N Al Al N Al N N + NH3 + 2H2NAlH2 2H2NAlHNH2 + H2AlNHNHAlH2 (1) + NH3 + 2H2NAlH2 H2NAlHNH2 + NH2NHAlH2 + H2AlNHAlHNH2 (2) rings are collected in Table 1 at the investigated levels of the theory.The bond lengths of the two structures differ only slightly. This is reasonable, taking the small barrier to planarity into consideration. The four Al]N bond lengths are nearly identical at all the levels investigated here. This bond-length equalization would result in a large Bird aromaticity index,9 indicating significant aromaticity.A comparison of the Al]N bond lengths of the different fragments used in the isodesmic reactions (1) and (2), however, shows that the lengths vary between 1.777 and 1.788 Å (MP2) only (1.763–1.794 Å at the HF level), thus they cannot be used to judge the aromaticity in the ring. Furthermore, the average Al]N bond length in the ring (1.803 Å at the MP2 level) is somewhat longer than any such length in the fragments, indicating some weakening of the Al]N bonds in the ring. This behaviour can be interpreted by the ring strain and NN lone-pair repulsion as discussed above.It should be noted that H2AlNH2 with the nitrogen lone pair fixed in the AlH2 plane has a bond length of 1.794 Å [HF/6-311 1 G(2D)]. This value is just slightly larger than the length in case of the planar minimum (1.773 Å), despite the missing nitrogen lone pair– empty aluminium orbital interaction. Nevertheless, the rotated form is less stable than the planar structure by 9.75 kcal mol21.It is widely accepted that aromatic molecules are planar and thus non-planar systems are not aromatic. This behaviour was an important argument used by Wehmschulte and Power 1 when stating that the Al2N3 ring is not aromatic. For the AlN rings the planarity criterion, however, is not informative. Owing to the dative p bond formed between the nitrogen lone pair and the empty aluminium p orbital, all fragments investigated here are planar about the Al and N atoms (bonded to aluminium). The calculated second derivatives of planar H2NNH2, H2Al- NHNH2 and H2AlNHNHAlH2 show the flattening effect of aluminium clearly, having three, two and one imaginary frequencies, respectively.(In the case of hydrazine two frequencies correspond to pyramidalization of the two nitrogens and one to the rotation about the N]N bond to avoid the repulsion of the nitrogen lone pairs. For H2AlNHNH2 one, while for H2AlNHNHAlH2 both pyramidalization motions became real frequencies.) Thus, all rings with an AlN fragment tend to be planar (cf.Al3N3 rings 3,5). So the non-planarity of the five-membered Al2N3H5 ring is attributable to the NN lone-pair repulsion only, which cannot be compensated by the energy needed to bend at the Al atoms and the small (if any) aromaticity of the ring. To investigate the bonding situation in the ring, Wiberg bonding indices 10 were calculated and are collected in Table 1. Their values are very similar for the different Al]N bonds and indicate that the bond has a significant ionic character.Similarly the Wiberg bond index for H2AlNH2 is 0.587, indicating the similarity of the bonding in the ring and the ‘monomeric’ building block (note again the small decrease of the bonding index in the ring). The index of the N]N bond in the ring is just slightly larger than 1. The distribution of the electron density about the Al]N bond is quite asymmetric as shown by the analysis developed by Bader and co-workers.11 The ellipticity, e,J.Chem. Soc., Dalton Trans., 1997, Pages 2373–2375 2375 which is 0 in case of a ‘perfect’ single bond (as in ethane), is 0.228 in case of the Al]N bonds of the ring. The ellipticity at the N]N bond critical point is 0.051, indicating a very small p interaction between the two nitrogens. The Al]N bond critical point is quite close to the aluminium atom (at 60% of the bond path length) and the laplacian of the density (D) is 10.68.Such behaviour is in accordance with ionic bonding.11 Since e = 0.222 for H2NAlH2, and the density at the critical point is again of similar value (0.093) to that in the ring, it seems that the ring formation has little effect on the electron distribution of the Al]N bond. The aromatic character of the Al2N3 ring is small, if any. Conclusion The present calculations show that the non-planar arrangement of the heavily substituted Al2N3 ring is mainly due to repulsion of the substituents.Nevertheless, Al2N3H5 has C2 and not Cs symmetry, with the two hydrogens on the neighbouring N atoms occupying an out-of-plane position with a 368 H]N]Al]N dihedral angle. The aromaticity of the ring is very small, if any, and cannot overcome the repulsion of the neighbouring nitrogen lone pairs and angle strain of the ring. The use of geometric criteria only in the assessment of aromaticity for AlN rings is misleading, since NAl structures are inherently planar even without aromaticity, and the Al]N bond length varies only slightly in the different chemical environment.Acknowledgements Financial support from Országos Tudományos Kutatási Alap (OTKA) Grant T014955 is gratefully acknowledged. References 1 R. J. Wehmschulte and P. P. Power, Inorg. Chem., 1996, 35, 2717. 2 W. H. Fink and J. C. Richards, J. Am. Chem. Soc, 1991, 113, 3393; N. Matsunaga, T. R. Cundari, M. W. Schmidt and M. S. Gordon, Theor. Chim. Acta, 1992, 83, 57. 3 M. Denk, J.C. Green, N. Metzler and M. Wagner, J. Chem. Soc., Dalton Trans., 1994, 2405; L. Nyulászi, T. Kárpáti and T. Veszprémi, J. Am. Chem. Soc., 1994, 116, 7239; C. Heinemann, T. Müller, Y. Apeloig and H. Schwarz, J. Am. Chem. Soc., 1996, 118, 2023; C. Boehme and G. Frenking, J. Am. Chem. Soc., 1996, 118, 2039; P. Blakeman, B. Gehrhus, J. C. Green, J. Heinicke, M. F. Lappert, M. Kindermann and T. Veszprémi, J. Chem. Soc., Dalton Trans., 1996, 1475; T. Veszprémi, L. Nyulászi and T. Kárpáti, J. Phys. Chem., 1996, 100, 6262. 4 K. M. Waggoner and P. P. Power, J. Am. Chem. Soc., 1991, 113, 3385; K. M. Waggoner, H. Hope and P. P. Power, Angew. Chem., Int. Ed. Engl., 1988, 27, 1699. 5 S. Nagase, Polyhedron, 1991, 10, 1299 and refs. therein; N. Matsunaga and M. S. Gordon, J. Am. Chem. Soc., 1994, 116, 11 407. 6 L. Nyulászi, J. Phys. Chem., 1996, 100, 6194. 7 GAUSSIAN 94, Revision B.2, M. J. Frisch, G. W. Trucks, H. B. Schlegel, P. M. W. Gill, B. G. Johnson, M. A. Robb, J. R. Cheeseman, T. Keith, G. A. Petersson, J. A. Montgomery, K. Raghavachari, M. A. Al-Laham, V. G. Zakrzewski, J. V. Ortiz, J. B. Foresman, J. Cioslowski, B. B. Stefanov, A. Nanayakkara, M. Challacombe, C. Y. Peng, P. Y. Ayala, W. Chen, M. W. Wong, J. L. Andres, E. S. Replogle, R. Gomperts, R. L. Martin, D. J. Fox, J. S. Binkley, D. J. Defrees, J. Baker, J. P. Stewart, M. Head-Gordon, C. Gonzalez and J. A. Pople, Gaussian Inc., Pittsburgh, PA, 1995. 8 L. Nyulászi, P. Várnai and T. Veszprémi, THEOCHEM., 1995, 358, 55. 9 C. W. Bird, Tetrahedron, 1985, 41, 1414. 10 K. B. Wiberg, Tetrahedron, 1968, 24, 1083. 11 R. W. F. Bader, T. S. Slee, D. Cremer and E. Kraka, J. Am. Chem. Soc., 1983, 105, 5061; R. W. F. Bader, Acc. Chem. Res., 1989, 10, 392. Received 3rd December 1996; Paper 6/08189D

ISSN:1477-9226    

DOI:10.1039/a608189d

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

DALTON J. Chem. Soc., Dalton Trans., 1997, Pages 2377–2379 2377 Metal complexes of the angiotensin-converting enzyme inhibitor, lisinopril. Solution studies and the crystal and molecular structure of a dimeric copper(II)–lisinopril complex Elena Bermejo Gonzalez,a Etelka Farkas,*,b Ali A. Soudi,a Terence Tan,a Alexander I. Yanovsky c and Kevin B. Nolan *,a a Department of Chemistry, Royal College of Surgeons in Ireland, St. Stephen’s Green, Dublin 2, Ireland b Department of Inorganic and Analytical Chemistry, Lajos Kossuth University, Debrecen, H-4010, Hungary c X-Ray Structural Centre of the Russian Academy of Sciences, Institute of Organoelement Compounds, 28 Vavilov St., Moscow, 117813, Russia The binding of the angiotensin-converting enzyme inhibitor lisinopril to zinc(II), copper(II) and nickel(II) has been investigated in solution by pH-metric methods and the crystal structure of the dimeric copper(II)–lisinopril complex, [Cu2(HA)2(H2O)2][ClO4]2 (H4A21 = fully protonated lisinopril), has been determined.In the case of the metal ions investigated a major species present in neutral or weakly acidic solution is M(HA)1, the formation constants of which suggest that co-ordination to the metal ions occurs through the amino nitrogen, carboxylate oxygen and the amide oxygen atoms. The crystal structure of the dimeric copper complex shows that each copper is in a distorted square-pyramidal environment in which the basal plane is occupied by carboxylate (Cu]O 1.944 Å) and carbonyl (Cu]O 1.996 Å) oxygens, and an amino group nitrogen (Cu]N 1.989 Å) from one ligand as well as the prolyl carboxylate of another ligand (Cu]O 1.909 Å).An aqua ligand Cu]O (2.355 Å) is axially bonded to each copper. Hypertension is a serious health problem in both developed and developing countries,1 leading to complications such as cardiovascular disease, stroke and renal failure.2 Antihypertensive drug therapy is therefore an area of major importance in medicine and among the groups of drugs in current use are inhibitors of the angiotensin-converting enzyme (ACE).This is a zinc metalloenzyme which is responsible for the hydrolysis of the decapeptide angiotensin I to angiotensin II, a vasoconstrictive octapeptide.3 The ACE inhibitors of which captopril (1), enalapril, perindoprilat (2) and lisinopril (3) are examples,2 compete with the natural substrate by binding to ZnII at the active site of the enzyme and also by hydrogen bonding and hydrophobic interactions.3–5 While captopril contains a thiol group which binds to the zinc ion of ACE, the other drugs contain instead a carboxylate group (or carboxylate ester which is metabolised by esterase enzymes to carboxylates) which according to the proposed models for site recognition of ACE co-ordinates to the zinc in a bidentate manner.5 However the above non-thiolcontaining drugs also contain a secondary amino group which with the carboxylate group could form a much more stable fivemembered ring chelate with the zinc.Despite this and the recognised ability of catalytic zinc sites in enzymes to exhibit flexibility in co-ordination number and geometry,6 none of the proposed models for enzyme–inhibitor interactions implicates the amino group in metal-ion binding. It is surprising that although the above drugs owe their activity to complex formation no structures of complexes of any of them have yet been reported.We report herein the structure of a copper(II)– lisinopril complex in the solid state as well as structures of complexes in solution inferred from pH-metric titration data, and contend that the aminocarboxylate moiety may well act as a binding locus for the metal ion in vivo. Results and Discussion The pKa values of lisinopril, H4A21, at 25 8C, I = 0.2 mol dm23 KCl are 1.4 ± 0.1, 3.00 ± 0.01, 7.10 ± 0.01 and 10.78 ± 0.01. These were assigned as follows: 10.78 to the lysyl 1NH3 by comparison with lysine,7 7.10 to the secondary 1NH group which is more acidic than the lysyl 1NH3 due to the proximity of the electron-withdrawing amide group, 3.00 to the prolyl CO2H8 and 1.4 to the central CO2H which is more acidic than the prolyl CO2H due to the proximity of the 1NH group.Species distribution curves for zinc(II)–, copper(II)– and nickel(II)– lisinopril solutions are shown in Fig. 1 with formation con- (CH2)2CH CO2H NH N CHC CO2H O (CH2)4 NH2 (CH2)2CH C O O M NH CH N C CO2 – O (CH2)4 +NH3 3 4 M(HA)+ N CO2H HSCH2CH(CH3)C O 1 N CH3(CH2)2CHNHCH(CH3)C CO2H O CO2H 22378 J.Chem. Soc., Dalton Trans., 1997, Pages 2377–2379 stants (log b) summarised in Table 1. In the presence of these metal ions a major complex species in neutral or weakly acidic solution is M(HA)1. From the formation constants, log K values for the equilibria M 1 HA M(HA) of 3.57(1) in the case of ZnII, 6.52(1) in the case of CuII and 4.36(1) in the case of NiII have been calculated (Table 1, footnote).Since these values are similar to those for complexes of a-amino acidates,7 the most Fig. 1 Species distribution curves for (a) zinc(II)–, (b) copper(II)– and (c) nickel(II)–lisinopril systems at [lisinopril] = 5.00 × 1023 mol dm23, [metal ion] = 1.65 × 1023 mol dm23, I = 0.2 mol dm23 at 25 8C Table 1 Complex-formation constants (log b) for metal–lisinopril complexes at 25 8C, I = 0.2 mol dm23 KCl Metal Ion ZnII CuII NiII M(HA)1 * 14.34(1) 17.28(1) 15.14(1) M(HA)2 27.38(1) 31.85(2) 29.79(1) MA(HA)2 — 22.97(2) 19.77(2) * From these values [M21 1 H1 1 A22 b M(HA)1] and the value of pKa4 for lisinopril (HA2 Ka4 A22 1 H1), log K values for the equilibrium M21 1 HA2 K M(HA)1 were calculated using the equation log K = log b 2 pKa4: ZnII, 3.57(1); CuII, 6.52(1); NiII, 4.36(1).likely co-ordination site for metal ions involves the secondary amino group and the adjacent carboxylate group. The values may be compared with those of analogous sarcosine, MeNHCH2CO2H, complexes which have similar donor sites and for which log KMA1 values are 4.31 for ZnII, 8.83 for CuII and 5.95 for NiII.9 Since the amino and the carboxylate groups in sarcosine are more basic than the corresponding groups in lisinopril (D pKa = 2.81 and 0.5 respectively), the stability constants of the lisinopril complexes are higher than expected and indicate that the carbonyl oxygen may also be involved in co-ordination, as shown.Dark blue crystals of the copper(II)–lisinopril complex [Cu2(HA)2(H2O)2][ClO4]2 suitable for structure determination were obtained by adding a solution of Cu(ClO4)2?6H2O in methanol to a solution of lisinopril dihydrate–triethylamine in methanol and recrystallising the resulting precipitate from acetone–water (1 : 1). The molecular structure of the complex is shown in Fig. 2 with selected bond lengths and angles in Table 2. The structure confirms that the complex is dimeric with each lisinopril acting as a bridging ligand.The geometry around each copper is a distorted square pyramid for which binuclear complexes of copper(II) exhibit propensity.10 In this complex oxygen atoms of carboxylate (1.944 Å) and carbonyl (1.996 Å) groups as well as the secondary amino nitrogen (1.989 Å) of one lisinopril ligand occupy three positions in the basal plane while the fourth is occupied by the prolyl carboxylate of a second lisinopril ligand (1.909 Å).An oxygen atom of water is located at the apex at a distance of 2.355 Å from the copper. Square-pyramidal geometry surrounding copper(II) has previously been observed in many copper(II)–peptide and other Fig. 2 Molecular structure of [Cu2(HA)2(H2O)2][ClO4]2 showing the atom numbering scheme Table 2 Selected bond lengths (Å) and angles (8) with estimated standard deviations for [Cu2(HA)2(H2O)2][ClO4]2 Cu(1)]O(1) Cu(1)]O(6) Cu(1)]O(4a) O(2)]C(3) O(4)]C(9) N(1)]C(2) N(2)]C(1) O(1)]Cu(1)]O(2) O(2)]Cu(1)]O(6) O(2)]Cu(1)]N(1) O(1)]Cu(1)]O(4a) O(6)]Cu(1)]O(4a) Cu(1)]O(1)]C(1) C(9)]O(4)]Cu(1a) Cu(1)]N(1)]C(4) O(1)]C(1)]C(2) N(1)]C(2)]C(1) O(2)]C(3)]C(4) N(1)]C(4)]C(3) 1.996(7) 2.355(10) 1.909(8) 1.272(13) 1.285(15) 1.490(15) 1.312(12) 157.0(4) 93.6(4) 85.0(3) 96.8(3) 85.8(4) 111.9(7) 119.7(7) 110.3(6) 119.9(9) 103.0(10) 118.6(9) 108.8(8) Cu(1)]O(2) Cu(1)]N(1) O(1)]C(1) O(3)]C(3) O(5)]C(9) N(1)]C(4) O(1)]Cu(1)]O(6) O(1)]Cu(1)]N(1) O(6)]Cu(1)]N(1) O(2)]Cu(1)]O(4a) N(1)]Cu(1)]O(4a) Cu(1)]O(2)]C(3) Cu(1)]N(1)]C(2) C(2)]N(1)]C(4) O(1)]C(1)]N(2) O(2)]C(3)]O(3) O(3)]C(3)]C(4) O(4)]C(9)]O(5) 1.944(8) 1.989(8) 1.260(14) 1.226(13) 1.190(19) 1.527(13) 103.9(4) 80.2(3) 90.4(4) 99.2(3) 174.4(4) 115.3(7) 107.4(6) 118.9(10) 120.0(10) 122.1(10) 119.2(10) 126.4(11)J. Chem.Soc., Dalton Trans., 1997, Pages 2377–2379 2379 complexes. In the dimer [Cu2(L-Leu-L-Tyr)2]?8H2O?Et2O (L-Leu- L-Tyr = L-leucyl-L-tyrosinate) for example the basal plane around each metal contains two oxygen atoms (carbonyl and carboxylate) and two nitrogen atoms (amino and amido) at distances of 1.92–2.02 Å from the metal with oxygen atoms from H2O and bridging carboxylate occupying the axial sites at distances of 2.57 and 2.32 Å respectively from the two copper ions.11 Although the current models for site recognition of ACE by non-thiol containing inhibitors such as perindoprilat and lisinopril do not implicate the secondary amino group in coordination to the zinc ion, the results of our solution studies show that this may be a realistic model and is confirmed by the crystal structure, albeit of a dimeric copper complex, whereas the inhibitor–ACE interaction is monomeric and involves zinc(II).Moreover the flexibility in co-ordination number and geometry shown by catalytic zinc(II) sites in many enzymes lends further weight to this possibility.6 Experimental Solution studies Lisinopril dihydrate was kindly provided by Zeneca Pharmaceuticals. Stock copper(II) and nickel(II) solutions were prepared from CuCl2?2H2O and NiCl2?2H2O and standardised with ethylenedinitrilotetraacetate (edta).12 The stock zinc(II) solution was prepared by dissolving ZnO in an excess of 0.1 mol dm23 HCl and was also standardised with edta.12 In order to obtain pKa values a 5.0 × 1023 mol dm23 solution (25.0 cm3) of lisinopril dihydrate in 0.015 mol dm23 HCl–0.2 mol dm23 KCl was titrated with 0.20 mol dm23 NaOH.To obtain formation constants of the metal complexes, solutions (25.0 cm3) containing 5.0 × 1023 mol dm23 lisinopril and 1.65 × 1023 mol dm23 metal ion in 0.20 mol dm23 KCl–0.015 mol dm23 HCl were titrated with 0.20 mol dm23 NaOH. The pH-metric titrations were carried out on a Mettler DL 25 Automatic Titrator fitted with a Mettler DG III combined electrode. Electrode calibration was carried out as previously described,13 by a strong acid vs. strong base titration at the same ionic strength as above.Concentration stability constants were calculated from pH-metric data using the PSEQUAD computer program.13,14 Crystallography Crystals of [Cu2(HA)2(H2O)2][ClO4]2 suitable for structure determination were obtained as follows. The addition, with stirring, of a solution of Cu(ClO4)2?6H2O (0.426 g, 1.15 mmol) in methanol (2 cm3) to a solution of lisinopril dihydrate (0.51 g, 1.15 mmol) and triethylamine (0.116 g, 1.15 mmol) in methanol (15 cm3) at room temperature gave, on standing overnight, a blue precipitate which was filtered off, dried and recrystallised from acetone–water (1 : 1).This gave dark blue crystals of [Cu2(HA)2(H2O)2][ClO4]2 (0.48 g, 71%) (Found: C, 42.4; H, 5.5; Cu, 11.0; N, 7.0. C42H64Cl2Cu2N6O20 requires C, 43.1; H, 5.5; Cu, 10.9; N, 7.2%); n& max/cm21 3410 (OH), 3190 (NH), 1610 (CO), 1135, 1120, 1105, 1090 (ClO). CAUTION: as this preparation involves reaction of a metal perchlorate with an organic ligand due care must be taken.Crystal data and data-collection parameters. C42H64Cl2- Cu2N6O20, M = 1170.6, orthorhombic, space group C2221, a = 10.412(4), b = 15.630(5), c = 32.074(12) Å, U = 5220(3) Å3, Z = 4, F(000) = 2440, Dc = 1.490 Mg m23, blue plates, dimensions 0.3 × 0.2 × 0.2 mm, m(Mo-Ka) = 9.97 cm21. 2834 Independent reflections were collected on a Siemens P3/PC diffractometer (T = 293 K, graphite-monochromated Mo-Ka radiation, l = 0.710 73 Å, w-scan technique, 2q < 528, two standards measured every 98 reflections).The structure was solved by direct methods and refined by full-matrix least squares (based on F) using 1697 reflections with I > 3s(I ). The H atoms of the water molecule were located in the Fourierdifference synthesis and refined isotropically; all other H atoms were included in the final refinement in the riding model approximation. A weighting scheme w21 = s2(F) 1 0.0005F 2 was employed.Final R and R9 factors were 0.0730 and 0.0786 respectively. The absolute structure was determined using the Hamilton test: the R factor for the inverted structure was 0.0780. All calculations were carried out on an IBM personal computer using the SHELXTL PLUS program package.15 Atomic coordinates, thermal parameters, and bond lengths and angles have been deposited at the Cambridge Crystallographic Data Centre (CCDC). See Instructions for Authors, J. Chem. Soc., Dalton Trans., 1997, Issue 1.Any request to the CCDC for this material should quote the full literature citation and the reference number 186/486. Acknowledgements We thank the Research Committee of the Royal College of Surgeons in Ireland, the Royal Irish Academy, the Hungarian Academy of Sciences and the Xunta de Galicia, Spain for supporting this work. We thank the University of Santiago de Compostela, Spain, for granting sabbatical leave to E. B. G. and the University of Zanjan, Iran for granting sabbatical leave to A.A. S. We thank Zeneca Pharmaceuticals, Macclesfield for supplying lisinopril. References 1 R. Beaglehole, R. Bonita and T. Kjellstrom, in Basic Epidemiology, World Health Organisation, Geneva, 1993, p. 8. 2 S. Oparil, in Cecil Textbook of Medicine, eds. J. C. Bennett and F. Plum, W. B. Saunders, Philadelphia, 20th edn., 1996, pp. 256–271. 3 W. G. J. Hol, Angew. Chem., Int. Ed. Engl., 1986, 25, 767. 4 R. J. Hansin and P. W. Codding, J. Med. Chem., 1990, 33, 1940. 5 C. Pascard, J. Guilhem, M. Vincent, G. Remond, B. Porteven and M. Laubie, J. Med. Chem., 1991, 34, 663. 6 B. L. Vallee and D. S. Auld, Proc. Natl. Acad. Sci. USA, 1990, 87, 225. 7 T. Kiss, in Biocoordination Chemistry, ed. K. Burger, Ellis Horwood, Chichester, 1990, ch. III, Table 3.2. 8 I. Sovago, in Biocoordination Chemistry, ed. K. Burger, Ellis Horwood, Chichester, 1990, ch. IV. 9 P. Daniele and G. Ostacoli, Ann. Chim. (Rome), 1977, 67, 311. 10 B. J. Hathaway, in Comprehensive Coordination Chemistry, eds. G. Wilkinson, R. D. Gillard and J. A. McCleverty, Pergamon, Oxford, 1987, vol. 5, pp. 619–635. 11 D. Van der Helm and W. A. Franks, J. Am. Chem. Soc., 1968, 90, 5627. 12 A. I. Vogel, A Textbook of Quantitative Chemical Analysis, Longmans, Essex, 5th edn., 1989, ch. 10. 13 E. Farkas, E. Kozma, T. Kiss, I. Toth and B. Kurzak, J. Chem. Soc., Dalton Trans., 1995, 447. 14 L. Zekany and I. Nagypal, in Computational Methods for the Determination of Formation Constants, ed. D. J. Leggett, Plenum, New York, 1985. 15 G. M. Sheldrick, SHELXTL PLUS, Siemens Analytical X-Ray Instruments, Madison, WI, 1989. Received 4th March 1997; Paper 7/01500C © Copyright 1997 by the Royal Society of Chemistry

ISSN:1477-9226    

DOI:10.1039/a701500c

出版商:RSC    

年代:1997

数据来源: RSC