Influence of Noncovalent Interactions on Uracil Tautomer Selection: Coordination of Both N1 and N3 Uracilate to the Same Metal in the Solid State Inmaculada Escorihuela, Larry R. Falvello,* Milagros Toma´s, and Esteban P. Urriolabeitia
CRYSTAL GROWTH & DESIGN 2004 VOL. 4, NO. 4 655-657
Department of Inorganic Chemistry and Arago´ n Materials Science Institute, University of Zaragoza-C.S.I.C., Plaza San Francisco s/n. E-50009 Zaragoza, Spain Received March 9, 2004;
Revised Manuscript Received April 29, 2004
ABSTRACT: The reaction of uracil and [Zn(H2O)6](NO3)2 in aqueous ammonia solution produces, after treatment with iProOH, the complex [Zn(uracilate-κN1)(uracilate-κN3)(NH ) ]. This compound in the solid state presents a complete set of 3 2 hydrogen bonds and electrostatic interactions including those mediating the self-recognition of the uracilate groups. The unique characteristics of this complexssmall size and the presence of both N1 and N3 uracil tautomers among otherss eliminate possible factors in uracil tautomer selection, demonstrating the overriding importance of noncovalent interactions in tautomer selection during crystallization. This result can probably be extended to other, uracil-related ligands. Extensive hydrogen bond and/or electrostatic interaction nets in crystalline coordination compounds can influence even the molecular nature of the coordination compound itself, originating interesting and novel molecules, for instance, the dinuclear compound [(CN)3Pt(µ-CN)Cu(NH3)4] with a very bent cyanide bridge1 or the complex [Ni(cyanurate-κN)2(NH3)4] that changes its shape in the solid state through a second-order phase transition.2 In both these cases, the presence of NH3 ligandssNH3 is a threehydrogen donor groupsfavors the formation of a network of energetically significant intermolecular interactions. In a very different field, as one of the four RNA bases, uracil (H2U) is a vital component in the complex processes of molecular genetics. The correct functioning of these processes depends on covalent bonds and directed electrostatic interactions, which enable the mating of complementary topologies. The steric and electrostatic topologies that H2U presents to its surroundings are, in turn, directly dependent on the tautomer that it presents and on the consequent manner in which it is bound to its supporting backbone. H2U can be deprotonated at N1 or N3, Figure 1, to give one of the two principal tautomers of deprotonated uracil (HU). It was established as early as 19613 that H2U is deprotonated in alkaline aqueous solutions to give an approximately 1:1 mixture of the two tautomers, thus leaving open the question of the factors that influence the bonding of HU through N1 or N3. N1 bonding is important in biological compounds; HU is N1 bonded to the ribosyl sugar group in RNA. HU is also N1 bonded to the deoxyribosyl group of DNA when erroneously incorporated; it is excised by HU-DNA glycosylase,4 in a highly specific process now established to be dependent on a set of coordinated, directed electrostatic contacts that would not be possible if the N3 tautomer of HU were present. Numerous experimental and theoretical studies have been directed at understanding H2U chemistry,5,6 at least with regard to the formation of the N1 and N3 tautomers. The N1 monoanion is favored in nonpolar media, including the gas phase.6a Intermolecular interactions, of the sort present in biological systems, stabilize the HU tautomers, and one study has implicated the approach of possible hydrogen-bond donors in the selective stabilization of the N1 monoanion.6c * To whom correspondence should be addressed. E-mail: falvello@ unizar.es.
Figure 1. Atom numbering in uracil.
As is the case for the other nucleobases, the coordination chemistry of HU has been examined, in part because d-block elements participate in biochemical processes involving the nucleic acids and in part because coordination compounds can serve as simple vehicles for examining the steric and electronic factors that influence the behavior of the nucleobases. It was suggested early on that in the coordination chemistry of uracil and thymine (5-methyluracil) such factors as the metal, reaction time, pH, packing factors, and solvent may exert more influence on tautomer selection than does the “negligible difference in the nucleophilicities at the deprotonated ring N atoms”.7 Although the topologies of important intermolecular interactions can usefully be studied in molecular solids, for which the process of crystallization can select the more stable aggregates8 and in which molecular shapes can in fact have certain degrees of freedom,2 there is a paucity of structural data on HU complexes. Except for platinum,9 complexes of few d-block elements with HU have been characterized structurally. With the biologically important metal zinc, only two complexes have been analyzed by X-ray diffraction, both containing only one HU per Zn atom.10 In general, structural data on complexes of HU derivatives, rather than on complexes of HU, have been obtained with the aim of studying deprotonation and binding modes.6c Only two complexes with two HU groups bonded to the same metal have been structurally characterized, namely, [Ni(HU-κN1)2(H2O)2(NH3)2],11 and [Cd(HUκN3)2)(H2O)3].7a Thus, in coordination complexes HU has been observed as either the N1 or N3 tautomer, but despite their near parity in aqueous solution, the two forms have not as yet been observed to coexist in the same compound. We report here the synthesis and structure of [Zn(HUκN1)(HU-κN3)(NH3)2] (1), which presents both tautomeric forms of deprotonated uracil bonded to the same metal. This result eliminates from consideration, at least in this
10.1021/cg0499111 CCC: $27.50 © 2004 American Chemical Society Published on Web 06/04/2004
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Figure 3. Packing of compound 1 showing the noncovalent interactions involving the HU-κN1 and HU-κN3 groups. The NH3 groups of compound 1 have been eliminated for clarity. Figure 2. Perspective drawing of compound 1. Non-hydrogen atoms are represented by their 70% probability ellipsoids.
case, some of the parameters that have previously been imputed in the selection of uracil tautomers. Complex 1 can be prepared from an aqueous ammonia solution to which H2U and [Zn(H2O)6](NO3)2 have been added.12 Its structure has been analyzed by single-crystal X-ray diffraction.13 Complex 1 is insoluble in common organic solvents and soluble in H2O with decomposition by hydrolysis. Figure 2 shows a drawing of complex 1. The Zn atom is in a tetrahedral environment formed by the two HU groups and two NH3 ligands. One of the HU groups is coordinated to the Zn atom through its deprotonated N1 site, (N(11) in Figure 2), and the other HU is coordinated through its deprotonated N3 (N(23) in Figure 2). The four Zn-N distances are essentially equal (1.993(4)-2.016(4) Å). The angles around the Zn atom lie between 107.0 (2) and 113.5(2)°, the most obtuse angle being H3N-Zn-NH3. The bond distances within the two HU ligands are nearly equal to within experimental error. The angles observed, especially those for N1, accord with the results of an extensive study by Mutikainen on the structural consequences of tautomeric differences.14 Thus, with all intramolecular shape parameters in good accord with what is expected and with what has been observed in the past for the HU tautomers, we see that nothing intrinsic to the HU ligands or to the compound as a whole offers an explanation for the unprecedented observation of different tautomers and binding modes in the same complex. So the interactions in intermolecular space should provide an explanation of this phenomenon. Compound 1 possesses eight hydrogen atoms bonded to electronegative atoms, namely, the six H(NH3) atoms and the two H(NH) atoms of the HU groups. There are, in addition, four electronegative sites able to act as hydrogen bond acceptors, namely, the four carbonyl oxygen atoms of the two HU ligands. All of these atoms participate in their full complement of directed electrostatic interactions; each H bound to N points at one of the carbonyl oxygen atoms, and each of the latter in turn has contacts with two H atoms. Of these eight contacts, two are intramolecular and the rest are intermolecular. Those distances range between 2.880(5) and 3.051(5) Å, and any of them could be termed hydrogen bonds. The HU-κN1 forms a self-complementary interaction with the HU-κN1 of a neighboring molecule, through a hydrogen bond between its N3 position and the O4 carbonyl of its neighbor, N(13)‚‚‚O(14′) ) 2.880(5) Å; N(13)-H(13) ‚‚‚O(14′) ) 168(4)°, Figure 3. This same topology, the well-known R22(8) ring structure, is observed in the crystal structure of Tp*Zn(HU-κN1)10 and also in the crystal structure of H2U itself.15 As for the HU-κN3 ligand, it forms an unbounded, selfcomplementary chain structure mediated by a hydrogen bond between its N1 imine function and the C4 carbonyl of a neighbor, N(21)‚‚‚O(24′′) ) 2.930(5) Å; N(21)-
H(21)‚‚‚O(24′′) ) 167(5)°, Figure 3. This interaction, with the same chain topology, is observed in the crystal structures of [Cd(HU-κN3)2)(H2O)3],5 and of H2U itself, albeit with different specific shapes. In complex 1 the chain is essentially linear, while in H2U neighboring hydrogen bonds form an angle of 48.2°, and in [Cd(HU-κN3)2)(H2O)3] successive HU moieties are not even coplanar. In the preparation of compound 1 both HU groups have experienced the same conditions of pH, temperature, and reaction time, and they are bonded to the same metal. Moreover, in this tetrahedral d10 complex there will be no intrinsic factors such as the trans effect to influence the preference of any given ligand for one binding mode or another. Neither would steric crowding influence the selection in this case. The 1H NMR spectum of complex 1 in D2O shows a single set of signals for the olefinic protons, indicating that the solid structure of 1 is not preserved in solution. Moreover, the 1H NMR spectrum of the reaction solution before precipitation with 1PrOH shows the same pattern with virtually the same chemical shifts, implying identical compositions of the solutions. In both cases, the position of these signals changes with varying ND3 concentrations, suggesting the presence of fast-operating equilibria involving free and coordinated uracilate and/or uracil moieties.16 We conclude that it is the extensive set of directed hydrogen bonds/electrostatic interactions in the crystal that determines the product isolated in this case, with the unprecedented combination of two coordination modes for deprotonated uracil. This result demonstrates that selection can be based on such interactions alone, because the deprotonated forms of uracil do not differ in stability appreciably enough to offer an intrinsic selection criterion. Further studies aimed at exploiting topological factors to isolate high-yield products containing specific uracil tautomers are currently underway. Acknowledgment. This work was supported by the Directorate General for Higher Education (Spain) under Grant BQU2002-00554. Supporting Information Available: X-ray crystallographic file (CIF). This material is available free of charge via the Internet at http:/pubs.acs.org.
References (1) Escorihuela, I.; Falvello, L. R.; Toma´s, M. Inorg. Chem. 2001, 40, 636-640. (2) Falvello, L. R.; Hitchman, M. A.; Palacio, F.; Pascual, I.; Schultz, A. J.; Stratemeier, H.; Toma´s, M.; Urriolabeitia, E. P.; Young, D. M. J. Am. Chem. Soc. 1999, 121, 28082819. (3) Nakanishi, K.; Suzuki, N.; Yamazaki, F. Bull. Chem. Soc. Jpn. 1961, 34, 53-57. (4) Savva, R.; McAuley-Hecht, K.; Brown, T.; Pearl, L. Nature 1995, 373, 487-493. (5) (a) Wierzchowski, K. L.; Litonska, E.; Shugar, D. J. Am. Chem. Soc. 1965, 87, 4621-4629. (b) Bensaude, O.; Aubard, J.; Dreyfus, M.; Dodin, G.; Dubois, J. E. J. Am. Chem. Soc.
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(8) (9) (10)
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1978, 100, 2823-2827. (c) Lippert, B. Inorg. Chem. 1981, 20, 4326-4343. (a) Kurinovich, M. A.; Lee, J. K. J. Am. Chem. Soc. 2000, 122, 6258-6262. (b) Drohat, A. C.; Stivers, J. T. J. Am. Chem. Soc. 2000, 122, 1840-1841. (c) Kimura, E.; Kitamura, H.; Koike, T.; Shiro, M. J. Am. Chem. Soc. 1997, 119, 10909-10919. (d) Bencivenni, L.; Ramondo, F.; Pieretti, A.; Sanna, N. J. Chem. Soc., Perkin Trans. 2000, 1685-1693. (e) Rodgers, M. T.; Armentrout; P. B. J. Am. Chem. Soc. 2000, 122, 8548-8558. (a) Mutikainen, I.; Lumme, P. Acta Crystallogr., Sect. B 1980, 36, 2237-2240, and references therein. (b) Pfab, R.; Jandik, P.; Lippert, B. Inorg. Chem. Acta 1982, 66, 193204. Falvello, L. R.; Pascual, I.; Toma´s, M.; Urriolabeitia, E. P. J. Am. Chem. Soc. 1997, 119, 11894-11902. Rauter, H.; Hillgeris, E. C.; Erxleben, A.; Lippert, B. J. Am. Chem. Soc. 1994, 116, 616-624 and references therein. (a) Ruf, M.; Weis, K.; Vahrenkamp, H. Inorg. Chem. 1997, 36, 2130-2137. (b) Bazzicalupi, C.; Bencini, A.; Berni, E.; Bianchi, A.; Ciattini, S.; Giorgi, C.; Paoletti, P.; Valtancoli, B. Eur. J. Inorg. Chem. 2001, 629-632. Lumme, P.; Mutikainen, I. Acta Crystallogr., Sect. B 1980, 36, 2251-2254. Synthesis of compound 1. A suspension of 0.4 g of uracil in 7 mL of H2O was heated until uracil was dissolved; then 1 mL of concentrated NH4OH was added and the solution was cooled to room temperature. To that solution, 0.53 g of [Zn(H2O)6](NO3)2] was added and then 30 mL of 2-propanol. A quantity of 0.1825 g of unpurified complex 1 was obtained from that solution at 5 °C. That solid was removed by filtration, whereupon crystals of pure complex 1 (0.10 g, 20%
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(14) (15) (16)
yield) were obtained from the remaining solution at 5 °C. IR spectra: ν(NH), 3330(s) and 3264(s) cm-1; ν(CO), 1627(s)(wide) and 1547(s) cm-1; others: 1379(s), 1367(s), 1294(s), 1201(s). Anal.: 29.87 (30.01) %C; 26.13 (25.63) %N; 3.73 (3.91) %H. X-ray structure analysis of 1: (150 K), colorless, C8H12N6O4Zn, MW ) 321.61. CAD-4 diffractometer. Monoclinic, space group P2/c, Z ) 4, cell (150 K): a ) 9.3896(7), b ) 6.9093(10), c ) 19.3766(16) Å, β ) 90.951(8)°, V ) 1256.9(2) Å3, µ(MoKa) ) 1.975 mm-1, Θmax ) 25°. 2358 reflections, 2214 unique. 1681 reflections with I > 2σ(I); R1 ) 0.0684, wR2 (all data) ) 0.1014, GOF ) 1.020. Maximum/minimum residual electron density ) 0.43 and -0.43 e Å-3. The positions and isotropic displacement parameters of the H atoms were refined freely. All other atoms were refined anisotropically. SHELX-97 was used for structure solution and refinement. Mutikainen, I. Ann. Acad. Sci. Fenn. Ser. A2 Chem. 1988, 217, 1-39. Stewart, R. F. Acta Crystallogr. 1967, 23, 1102-1105. 1H NMR spectra were recorded at room temperature on a Bruker ARX-300 spectrometer in D2O or D2O/NH3 solutions. The signals were referenced using the solvent signal as internal standard. NMR experiments: (a) 1 (freshly prepared solution in D2O) δ (ppm) ) 7.36 (d, 1H, dCH, 3JHH ) 7.2 Hz), 5.58 (d, 1H, dCH); (b) reaction solution of 1 (before 1PrOH addition) δ(ppm) ) 7.36 (d, 1H, dCH, 3J HH ) 6.6 Hz), 5.59 (d, 1H, dCH).
CG0499111
