DALTON FULL PAPER J. Chem. Soc., Dalton Trans., 1999, 167–173 167 Synthesis and structural characteristics of metal–acyclovir (ACV) complexes: [Ni(or Co)(ACV)2(H2O)4]Cl2?2ACV, [Zn(ACV)- Cl2(H2O)], [Cd(ACV)Cl2]?H2O and [{Hg(ACV)Cl2}x]. Recognition of acyclovir by Ni–ACV Ángel García-Raso,*a Juan J. Fiol,a Ferran Bádenas,a Rosa Cons,a Ángel Terrón a and Miguel Quirós b a Departament de Química, Universitat de les Illes Balears, 07071 Palma de Mallorca, Spain. E-Mail: dquagr0@ps.iub.es b Departamento de Química Inorgánica, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain Received 6th October 1998, Accepted 10th November 1998 The monomeric [M(ACV)2(H2O)4]Cl2?2ACV (M = NiII 1 or CoII 2), [Zn(ACV)Cl2(H2O)] 3 and the polymeric [Cd(ACV)Cl2]?H2O 4 [ACV = acyclovir = 9-(2-hydroxymethoxymethyl)guanine] complex have been prepared and characterised by X-ray diVraction and IR data; 1H and 13C NMR have been used to interpret the structural characteristics of the complexes in solution.Compounds 1 and 2 exist as octahedral complexes with four H2O ligands in the basal plane [Ni–OW 2.053(2) and 2.057(7) Å] and two axial ACV molecules linked to Ni through N(7) [Ni–N(7) 2.160(2) Å]. Two additional ACV molecules are included in the outer sphere of the complex, interacting by means of hydrogen bonds with the co-ordinated ACVs. This reveals the unprecedented recognition of free acyclovir molecules by Ni(or Co)-ACV (1 and 2). The monomeric zinc(II) complex 3 exhibits a distorted-tetrahedral geometry, involving two chlorides, the N(7) of the ACV ligand [Zn–N(7) 2.009(2) Å] and a water molecule.The hydrogen bonding of two guanine bases via NH2 and N(3) (unit 1) with N(3) and NH2 (unit 2) represents a novel type of interaction between nucleobases. In the case of the cadmium(II) complex 4 the structure is built by polymeric (CdCl2)n chains which are held together by ACV ligands. The cadmium cation is octahedrically coordinated by four chlorides, the N(7) from an ACV molecule and the hydroxylic oxygen from another ACV molecule, the latter two atoms being placed in cis disposition. On the other hand, the complex [{Hg(ACV)Cl2}x] 5 can be tentatively assigned as a polymer by comparison with analogous guanosine systems and spectroscopic and conductometric data.Acyclovir (ACV), 9-[(2-hydroxyethoxy)methyl]guanine, an analogue of 29-deoxyguanosine is an eYcient topically active acyclic nucleoside with inhibitory activity towards several herpes viruses, especially HSV-1 and HSV-2.1 Several studies have shown that the antiviral action of acyclovir involves its enzymatic conversion into the triphosphate of acycloguanosine {9-[(2-hydroxyethoxy)methyl]guanine}.2 It is converted into the monophosphate in herpes-infected cells (yet only to a very limited extent in uninfected cells) by viral-induced thymidine kinase.It is further phosphorylated by the host cell guanosine monophosphate kinase to acyclovir diphosphate, which in turn is phosphorylated to the triphosphate by unidentified cellular enzymes.The triphosphate of acycloguanosine is more inhibitory to the viral DNA polymerase than to the a-DNA polymerase of the cell.3 As a result, acyclovir is much more toxic to herpes viruses in an HSV-infected cell than to the cell itself. Metals can play an important role in both the mechanism of action and toxic side eVects of organic drugs and their metabolites.4 Although several acyclovir complexes and derivatives have been described 5–8 very little structural information is available.8–10 Thus in the present work studies of several metal(II) complexes with acyclovir have been carried out.Experimental Reagents were used as received from Roig Farma (acyclovir) and Aldrich (metallic salts). Syntheses [M(ACV)2(H2O)4]Cl2?2ACV (M 5 NiII 1 or CoII 2). To an aqueous solution (20 ml of water at 70 8C) of 12 mmol of MCl2?6H2O (M = Ni or Co), 6 mmol of acyclovir were added.The resulting solution was stirred for 2–3 h. After several days crystals were obtained. Complex 1 exhibits a mass decrease (Found: 28.5. Calc.: 29.0%) between 30 and 335 8C corresponding to the loss of 4 H2O 1 4 CH2OH–CH2OH per formula unit (Found: C, 34.78; H, 4.84; N, 25.19. Calc. for C32H52Cl2N20NiO16: C, 34.83; H, 4.72; N, 25.37%). Selected IR bands (cm21): 1123s, 1182m, 1403m, 1462m, 1490s, 1537m, 1574s, 1637vs, 1670vs and 1682 (sh).UV/VIS (DMSO): l 786 (e 5.4), 720 (sh), 425 (13) and 259 nm (7.2 × 104 dm3 mol21 cm21). The complex undergoes solvation in solution and Ni(DMSO)6 21 seems to be formed. LM/W21 cm2 mol21 (1023 mol dm23 in DMSO, 25 8C) = 63.7. Complex 2 exhibits a first mass decrease (Found: 3.4. Calc.: 3.3%) between 40 and ca. 150 8C corresponding to the loss of two water molecules per formula unit and a second mass decrease (Found: 25.0. Calc.: 25.9%) between 150 and 330 8C corresponding to the loss of 2 H2O 1 4 CH2OH–CH2OH per formula unit (Found: C, 34.76; H, 4.80; N, 25.19.Calc. for C32H52Cl2CoN20O16: C, 34.84; H, 4.72; N, 25.41%). Selected IR bands (cm21): 1122s, 1186m, 1404m, 1460m, 1488s, 1539m, 1574s, 1635vs, 1669vs and 1683 (sh). UV/VIS (DMSO): l 678 (e 90), 610 (sh) and 259 nm (8.2 × 104 dm3 mol21 cm21). The complex undergoes solvation in solution and Co(DMSO)6 21 seems to be formed. LM/W21 cm2 mol21 (1023 mol dm23 in DMSO, 25 8C) = 47.7.[Zn(ACV)Cl2(H2O)] 3, [Cd(ACV)Cl2]?H2O 4 and [{Hg(ACV)- Cl2}x] 5. To an aqueous solution (20 ml of water at 70 8C) of 12 mmol of MCl2 (M = Zn or Hg) or CdCl2?2.5 H2O, 6 mmol of168 J. Chem. Soc., Dalton Trans., 1999, 167–173 acyclovir were added. The resulting solution was stirred for 2–3 h. The complex precipitated during the reaction and was filtered oV, washed with water and air dried. Crystals of 3 and 4 were obtained by slow evaporation of mother-liquors. Complex 3 exhibits a mass decrease (Found: 4.9.Calc.: 4.7%) between 30 and 190 8C corresponding to the loss of the water molecule per formula unit (Found: C, 24.99; H, 3.42; N, 18.29. Calc. for C8H13Cl2N5O4Zn: C, 25.30; H, 3.42; N, 18.44%). Selected IR bands (cm21): 1130s, 1188m, 1403m, 1461w, 1494m, 1548m, 1587vs, 1651vs and 1690vs. UV (DMSO): l 259 nm (e 1.4 × 104 dm3 mol21 cm21). 1H NMR (DMSO-d6): d 10.86 [s, 1 H, H(1)], 8.04 [s, 1 H, H(8)], 6.68 (s, 2 H, NH2), 5.48 [s, 2 H, C(10)H], 4.79 (br t, 1 H, OH, J = 3.6 Hz) and 3.56 [s, 4 H, C(11)H and C(12)H]. 13C NMR (DMSO-d6): d 160.5 [C(6)], 158.0 [C(2)], 155.3 [C(4)], 142.4 [C(8)], 119.7 [C(5)], 76.2 [C(10)], 74.5 [C(12)] and 63.9 [C(11)]. LM/W21 cm2 mol21 (1023 mol dm23 in DMSO, 25 8C) = 6.8. Complex 4 exhibits a mass decrease (Found: 16.7. Calc.: 16.7%) between 40 and 280 8C corresponding to the loss of two chlorine atoms per formula unit (Found: C, 22.45; H, 3.07; N, 16.20. Calc. for C8H13CdCl2N5O4: C, 22.50; H, 3.05; N, 16.41%).Selected IR bands (cm21): 1118m, 1190m, 1398w, 1456 (sh), 1471m, 1539m, 1571 (sh), 1635vs and 1676s. UV (DMSO): l 259 nm (e 1.4 × 104 dm3 mol21 cm21). 1H NMR (DMSO-d6): d 10.75 [s, 1 H, H(1)], 7.93 [s, 1 H, H(8)], 6.62 (s, 2 H, NH2), 5.45 [s, 2 H, C(10)H], 4.78 (br t, 1 H, OH, J = 2.4 Hz) and 3.56 [s, 4 H, C(11)H and C(12)H]. 13C NMR (DMSO-d6): d 160.5 [C(6)], 158.1 [C(2)], 155.2 [C(4)], 142.1 [C(8)], 119.4 [C(5)], 76.4 [C(10)], 74.6 [C(12)] and 64.0 [C(11)].LM/W21 cm2 mol21 (1023 mol dm23 in DMSO, 25 8C) = 17.3. Complex 5 is thermally stable until 230 8C (Found: C, 19.22; H, 2.16; N, 13.83. Calc. for C8H11Cl2HgN5O3: C, 19.33; H, 2.22; N, 14.10%). Selected IR bands (cm21): 1112s, 1183m, 1396 (sh), 1463 (sh), 1485m, 1539m, 1585s, 1624s, 1666 (sh) and 1694vs. UV (DMSO): l 260 nm (e 1.6 × 104 dm3 mol21 cm21). 1H NMR (DMSO-d6): d 10.85 [s, 1 H, H(1)], 8.01 [s, 1 H, H(8)], 6.67 (s, 2 H, NH2), 5.48 [s, 2 H, C(10)H], 4.78 (br s, 1 H, OH) and 3.58 [s, 4 H, C(11)H and C(12)H]. 13C NMR (DMSO-d6): d 160.6 [C(6)], 158.3 [C(2)], 155.1 [C(4)], 142.9 [C(8)], 119.4 [C(5)], 76.7 [C(10)], 74.7 [C(12)] and 64.0 [C(11)]. LM/W21 cm2 mol21 (1023 mol dm23 in DMSO, 25 8C) = 2.6. Physical measurements Elemental analyses were carried out using a Carlo Erba model 1106 microanalyser. The infrared spectra in the solid state (KBr pellets) were recorded on a PE 683 spectrometer with a PE 1600 infrared data station and electronic spectra on a PE 552 spectrophotometer.The 1H and 13C NMR spectra were recorded on a Bruker AMX 300 spectrometer. Proton and carbon chemical shifts in DMSO-d6 were referenced to DMSOd6 [1H, d(DMSO) 2.60; 13C, d(DMSO) 43.5]. The 1H NMR temperature studies were referenced to tetramethylsilane [d(DMSO) 2.50 relative to TMS]. Thermogravimetric data in the range from 30 to 900 8C were obtained in air (heating rate 10 8C min21) on a PE TGA-2 thermobalance. Crystallography Crystal of compounds 1, 3 and 4 were mounted in a Siemens P4 diVractometer equipped with Mo-Ka radiation.The unit cell was determined in each case from 40 random reflections in the range 4 < q < 258. The number of independent reflections measured and the ranges of q, h, k and l are indicated together with other procedural data in Table 1. Three standards reflections were measured every 100, showing slight decomposition of samples 1 and 3 (around 5%). Data were corrected for Lorentz-polarisation eVects and empirically (y scans) for absorption in compounds 3 and 4 (not for 1); the transmission ranges were 0.333–0.503 and 0.462–0.516 respectively.The structures were solved by the heavy atom method and refined by full-matrix least squares on F 2. Extinction was corrected for compound 4 by means of the method implemented in SHELXTL-V5,11 the corresponding parameter reaching the value c = 0.0482(13). Hydrogen atoms were introduced in their ideal positions, except those of water molecules and the hydroxyl group of the ligand that were found in DF maps and refined with fixed (0.86 Å) O–H distances; thermal parameters 1.2 times those of their parent atoms were applied to all H atoms.Final residuals as well as crystal data are in Table 1. The program package SHELXTL-V5 was used for structure solution and refinement and for the drawings. CCDC reference number 186/1242. Powder X-ray diVraction diagrams were collected on a Siemens D5000 diVractometer with secondary graphitemonochromated Cu-Ka radiation (l = 1.54056 Å).Reflections were placed in the range 2 < 2q < 60. Results and discussion Crystal structures Nickel(II) and cobalt(II) complexes (1 and 2). The structure of complex 1 consists of elongated centrosymmetric octahedral molecules with H2O ligands in the basal plane [Ni–OW 2.053(2) and 2.057(7) Å] and two ACV molecules bound to Ni through N(7) [Ni–N(7) 2.160(2) Å] (Table 2). In order to complete the structural unit, two other ACV molecules are included in the outer sphere of the complex, interacting by means of hydrogen bonds with the co-ordinated ACVs [N(1A) ? ? ? O(12B) 2.803(3); N(2A) ? ? ? O(12B) 3.001(3); O(12A) ? ? ? N(1B) 2.776(3); O(12A) ? ? ? N(2B) 2.885(3) Å; O(1W) ? ? ? O(6A) 2.634(2); O(2W) ? ? ? O(6B) 2.696(2) Å] (Fig. 1). The oxygen atom of the carbonyl group of both co-ordinated and secondary ACV are involved in hydrogen bonds to the co-ordinated water molecules [O(1W) ? ? ? O(6A) 2.634(2); O(2W) ? ? ? O(6B) 2.696(2) Å] as observed in several Cu–ACV complexes.8,9 Values of Ni–OW and Ni–N(7) are similar to those in other structurally related complexes such as [Ni(IMP)(H2O)5],12 [Ni(en)(IMP)2(H2O)2],13 [Ni(GMP)(H2O)5],14 [Ni(GMP)2(H2O)4]22,15 [Ni(en)0.7 (dGMP)2- (H2O)0.6(H2O)2]2215 and [Ni(dGMP)(H2O)5].16 The guanine moiety, of all ACV molecules presented in complex 1, is essentially planar.The bond lengths and angles of guanine conform well to those found in the three molecules of the asymmetric unit of crystalline ACV?2 3 – H2O17 and those corresponding to [Cu(ACV)2Cl2(H2O)2],9 [Cu(ACV)2(H2O)x]21 (x = 2 10a or 310b), [Cu(ACVP)2(H2O)2] 8 (ACVP = acyclovir monophosphate) and [Pt(ACVA)Cl2(h2-C2H4)] 7 (ACVA = acyclovir monoacetate).In previously described complexes the C(10) is coplanar to the plane of guanine however in 1 a noticeable distortion {t[N(7)–C(8)–N(9)–C(10)] = 171.048 (8.98 up to plane)} appears.The Ni bonded to N(7) is placed 11.28 below the plane of guanine {t[N(9)–C(8)–N(7)–Ni] = 168.788}. This Fig. 1 Molecular structure of [Ni(ACV)2(H2O)4]Cl2?2ACV 1.J. Chem. Soc., Dalton Trans., 1999, 167–173 169 Table 1 Crystal data and structure refinement for [Ni(ACV)2(H2O)4]Cl2?2ACV 1, [Zn(ACV)Cl2(H2O)] 3 and [Cd(ACV)Cl2]?H2O 4 Empirical formula M Crystal system Space group Crystal dimensions/mm a/Å b/Å c/Å a/8 b/8 g/8 U/Å3 Dc/g cm23 Z m(Mo-Ka)/cm21 T/K q Range/8 hkl Ranges No.reflections collected No. independent reflections (Rint) F(000) Data/restraints/parameters Goodness of fit on F 2 Final R1, wR2 [I > 2s(I)] (all data) Largest diVerence peak, hole/e Å23 1 C32H52Cl2N20NiO16 1102.55 Monoclinic P21/n 0.45 × 0.3 × 0.25 12.6672(8) 15.1340(12) 12.8273(11) 111.077(5) 2294.5(3) 1.596 2 6.31 293(2) 1.94–25.00 21 to 15, 21 to 17, 215 to 14 4999 4035 (0.0241) 1148 4035/6/340 1.027 0.0383, 0.0973 0.0443, 0.1019 1.051, 20.374 3 C8H13Cl2N5O4Zn 379.50 Triclinic P1� 0.5 × 0.4 × 0.2 7.7878(7) 8.6616(6) 10.9133(10) 97.841(7) 106.910(7) 94.220(6) 692.74(10) 1.819 2 21.78 293(2) 1.98–30.0 21 to 10, 212 to 12, 215 to 15 4815 4001 (0.0171) 384 3999/3/190 1.087 0.0327, 0.0873 0.0385, 0.0928 0.455, 20.940 4 C8H13CdCl2N5O4 426.53 Triclinic P1� 0.2 × 0.3 × 0.4 7.2653(5) 7.9452(6) 12.5441(10) 84.702(6) 75.186(6) 78.932(5) 686.30 2.064 2 20.00 293(2) 1.68–30.00 21 to 10, 211 to 11, 217 to 17 4879 4008 (0.0175) 420 4008/3/191 1.141 0.0220, 0.0580 0.0225, 0.0584 0.514, 20.562 value is higher than those of the corresponding Pt 7 (8.28) and Cu9 (5.28) complexes.The acyclic chains of the two diVerent ACVs present in the structural unit of 1 are folded, with C(11)– C(12) bonds in gauche conformation, but a syn conformation between N(7) and O(12) appears † which permits five hydrogen bonds to stabilise the non-co-ordinated ACVs in the complex structure. On the other hand, stacking between co-ordinated and non-co-ordinated ACVs is present (average distance between the two rings = 3.4 Å; this distance is essentially the same as that found between adjacent base pairs in DNA17).These subtle changes in the lateral chains could be responsible for the recognition of non-co-ordinated ACV by Ni–ACV. The powder X-ray diVraction diagrams of the nickel 1 and cobalt 2 complexes clearly demonstrate that the compounds are isostructural, diVraction peaks changing only slightly in position and intensity from one diagram to the other.Zinc(II) complex 3. The co-ordination geometry about the ZnII in complex 3 is approximately tetrahedral with an ACV molecule [Zn–N(7) 2.009(2) Å], two chlorine atoms [Zn–Cl(1) 2.2544(6) and Zn-Cl(2)=2.1976(6) Å] and a water molecule [Zn– OW 1.996(2) Å] [Table 2 and Fig. 2(a)]. The crystal structure is formed by three types of hydrogen bonds between ACVs [N(2)H2(unit 1) ? ? ? N(3)(unit 2) 3.041(2) Å], between acyclovir and the chlorine atom [N(1)(unit 1) ? ? ? Cl(1)(unit 3) 3.255(2) and N(2)H2(unit 1) ? ? ? Cl(1)(unit 3) 3.473(2) Å] and between the hydroxyl group of the lateral chain of ACV and the water molecule [O(12)(unit 2) ? ? ?OW(unit 3) 2.690(2)].The hydrogen bond scheme of two guanine bases via NH2 and N(3) (unit 1) with N(3) and NH2 (unit 2) could represent a novel type of interaction between nucleobases as described by Lippert and co-workers.18 The value of Zn–N(7) is similar to that of polymeric Zn(59-IMP)19 [Zn–N(7)(distorted tetrahedral coordination) 1.99 Å] but lower than those corresponding of [Zn(H2O)4(Me-59-IMP)] and [Zn(H2O)4(Me-59-GMP)] 20 [Zn– N(7)(octahedral co-ordination) 2.158 and 2.143 Å] [Fig. 2(b)]. † A similar C(11)–C(12) gauche conformation but an anti conformation between N(7) and C(12) is present in units A and B of free ACV (see ref. 16). Like in the other complexes, the guanine moiety of ACV in 3 is essentially planar and bond lengths angles are similar.7–10,17 Nevertheless, this complex presents an important noncoplanarity of C(10) {t[N(7)–C(8)–N(9)–C(10)] = 190.908} and Zn{t[N(9)–C(8)–N(7)–Zn] = 164.178} with these two atoms placed on the same side of the plane of guanine [C(10) 10.98 and Zn 15.88].As in 1, the acyclic chain of ACV in 3 is folded Fig. 2 (a) Molecular structure of [Zn(ACV)Cl2(H2O)] 2. (b) Packing of three complex units showing the hydrogen bonds and the novel type of interaction between two guanine nucleobases [NH2 and N(3) (unit 1) with N(3) and NH2 (unit 2)].170 J.Chem. Soc., Dalton Trans., 1999, 167–173 Table 2 Bond lengths (Å) and angles (8) Nickel complex 1 Ni–O(1W) N(1A)–C(2A) N(1A)–C(6A) C(2A)–N(3A) C(2A)–N(2A) N(3A)–C(4A) C(4A)–N(9A) C(4A)–C(5A) C(5A)–N(7A) C(5A)–C(6A) 2.053(2) 1.369(3) 1.389(3) 1.324(3) 1.331(3) 1.349(3) 1.372(3) 1.382(3) 1.400(3) 1.422(3) Ni–O(2W) N(1B)–C(2B) N(1B)–C(6B) C(2B)–N(3B) C(2B)–N(2B) N(3B)–C(4B) C(4B)–N(9B) C(4B)–C(5B) C(5B)–N(7B) C(5B)–C(6B) 2.057(7) 1.371(3) 1.387(3) 1.319(3) 1.333(3) 1.356(3) 1.371(3) 1.384(3) 1.383(3) 1.416(3) Ni–N(7A) C(6A)–O(6A) N(7A)–C(8A) C(8A)–N(9A) N(9A)–C(10A) C(10A)–O(10A) O(10A)–C(11A) C(11A)–C(12A) C(12A)–O(12A) 2.160(2) 1.237(3) 1.313(3) 1.369(3) 1.471(3) 1.387(3) 1.428(3) 1.498(4) 1.418(3) C(6B)–O(6B) N(7B)–C(8B) C(8B)–N(9B) N(9B)–C(10B) C(10B)–O(10B) O(10B)–C(11B) C(11B)–C(12B) C(12B)–O(12B) 1.238(3) 1.304(4) 1.375(4) 1.464(3) 1.390(3) 1.386(4) 1.482(5) 1.398(3) Hydrogen bonds present in the molecular unit N(1A) ? ? ? O(12B) O(1W)–Ni–N(7A) O(1W)–Ni–O(2W) C(2A)–N(1A)–C(6A) N(3A)–C(2A)–N(2A) N(3A)–C(2A)–N(1A) N(2A)–C(2A)–N(1A) C(2A)–N(3A)–C(4A) N(3A)–C(4A)–N(9A) N(3A)–C(4A)–C(5A) N(9A)–C(4A)–C(5A) C(4A)–C(5A)–N(7A) C(4A)–C(5A)–C(6A) N(7A)–C(5A)–C(6A) O(6A)–C(6A)–N(1A) 2.803(3) 87.23(7) 91.51(8) 126.2(2) 120.7(2) 122.7(2) 116.6(2) 112.4(2) 124.7(2) 129.2(2) 106.0(2) 109.9(2) 117.6(2) 132.2(2) 119.1(2) N(1B) ? ? ? O(12A) O(2W)–Ni–N(7A) C(2B)–N(1B)–C(6B) N(3B)–C(2B)–N(2B) N(3B)–C(2B)–N(1B) N(2B)–C(2B)–N(1B) C(2B)–N(3B)–C(4B) N(3B)–C(4B)–N(9B) N(3B)–C(4B)–C(5B) N(9B)–C(4B)–C(5B) C(4B)–C(5B)–N(7B) C(4B)–C(5B)–N(7B) N(7B)–C(5B)–C(6B) O(6B)–C(6B)–N(1B) 2.776(3) 90.76(7) 125.7(2) 120.9(2) 123.6(2) 115.6(2) 112.1(2) 125.9(2) 128.3(2) 105.7(2) 110.7(2) 118.8(2) 130.5(2) 118.8(2) N(2A) ? ? ? O(12B) C(8A)–N(7A)–Ni O(6A)–C(6A)–C(5A) C(5A)–C(6A)–N(1A) C(8A)–N(7A)–C(5A) N(7A)–C(8A)–N(9A) C(8A)–N(9A)–C(4A) C(8A)–N(9A)–C(10A) C(4A)–N(9A)–C(10A) O(10A)–C(10A)–N(9A) C(10A)–O(10A)–C(11A) O(10A)–C(11A)–C(12A) O(12A)–C(12A)–C(11A) 3.001(3) 121.0(2) 129.2(2) 111.7(2) 104.4(2) 113.1(2) 106.6(2) 127.6(2) 125.3(2) 113.0(2) 114.4(2) 108.6(2) 109.4(2) N(2B)–O(12A) C(5A)–N(7A)–Ni O(6B)–C(6B)–C(5B) C(5B)–C(6B)–N(1B) C(8B)–N(7B)–C(5B) N(7B)–C(8B)–N(9B) C(8B)–N(9B)–C(4B) C(8B)–N(9B)–C(10B) C(4B)–N(9B)–C(10B) O(10B)–C(10B)–N(9B) C(10B)–O(10B)–C(11B) O(10B)–C(11B)–C(12B) O(12B)–C(12B)–C(11B) 2.885(3) 133.38(14) 129.7(2) 111.5(2) 104.1(2) 113.8(2) 105.7(2) 128.4(2) 125.9(2) 112.9(2) 115.7(3) 110.9(3) 110.6(3) Zinc complex 3 Zn–O(1W) N(1)–C(2) N(1)–C(6) C(2)–N(2) C(2)–N(3) N(3)–C(4) O(1W)–Zn–Cl(1) N(7)–Zn–Cl(1) Zn–N(7)–C(8) O(1W)–Zn–N(7) C(2)–N(1)–C(6) N(3)–C(2)–N(2) N(2)–C(2)–N(1) N(3)–C(2)–N(1) 1.996(2) 1.379(2) 1.389(2) 1.329(2) 1.331(2) 1.350(2) 108.49(7) 110.92(5) 123.08(12) 104.53(7) 125.42(14) 120.0(2) 116.7(2) 123.3(2) Zn–N(7) C(4)–N(9) C(4)–C(5) C(5)–N(7) C(5)–C(6) O(1W)–Zn–Cl(2) N(7)–Zn–Cl(2) Zn–N(7)–C(5) O(6)–C(6)–C(5) C(5)–C(6)–N(1) C(8)–N(7)–C(5) N(7)–C(8)–N(9) 2.009(2) 1.378(2) 1.382(2) 1.385(2) 1.416(2) 111.58(6) 106.96(5) 129.50(12) 127.6(2) 111.38(14) 105.16(14) 112.4(2) Zn–Cl(1) C(6)–O(6) N(7)–C(8) C(8)–N(9) N(9)–C(10) C(2)–N(3)–C(4) N(3)–C(4)–N(9) N(3)–C(4)–C(5) N(9)–C(4)–C(5) C(4)–C(5)–N(7) C(4)–C(5)–C(6) N(7)–C(5)–C(6) O(6)–C(6)–N(1) 2.2544(6) 1.236(2) 1.316(2) 1.364(2) 1.470(2) 112.37(14) 126.36(14) 128.01(14) 105.62(14) 109.99(14) 119.5(2) 130.4(2) 121.0(2) Zn–Cl(2) C(10)–O(10) O(10)–C(11) C(11)–C(12) C(12)–O(12) C(8)–N(9)–C(4) C(8)–N(9)–C(10) C(4)–N(9)–C(10) O(10)–C(10)–N(9) C(10)–O(10)–C(11) O(10)–C(11)–C(12) O(12)–C(12)–C(11) 2.1976(6) 1.389(2) 1.426(2) 1.501(3) 1.421(3) 106.84(13) 125.09(14) 127.06(14) 113.0(2) 113.2(2) 108.6(2) 112.9(2) Cadmium complex 4 Cd–Cl(1) Cd–Cl(2) N(1)–C(2) N(1)–C(6) C(2)–N(2) C(2)–N(3) N(3)–C(4) O(12*)–Cd–N(7) O(12*)–Cd–Cl(2) O(12*)–Cd–Cl(1)2 O(12*)–Cd–Cl(1) O(12*)–Cd–Cl(2)3 C(2)–N(1)–C(6) N(3)–C(2)–N(2) N(2)–C(2)–N(1) N(3)–C(2)–N(1) C(2)–N(3)–C(4) N(3)–C(4)–N(9) N(3)–C(4)–C(5) 2.6631(5) 2.5654(5) 1.374(2) 1.386(2) 1.351(2) 1.323(2) 1.344(2) 83.11(5) 163.99(4) 89.87(3) 88.45(4) 81.25(4) 125.2(2) 119.5(2) 117.1(2) 123.4(2) 112.4(2) 125.4(2) 128.9(2) Cd–Cl(19) Cd–Cl(20) C(4)–N(9) C(4)–C(5) C(5)–N(7) C(5)–C(6) Cd–Cl(2)–Cd3 Cd–Cl(1)–Cd2 Cd–N(7)–C(8) Cd–N(7)–C(5) N(9)–C(4)–C(5) C(4)–C(5)–N(7) C(4)–C(5)–C(6) N(7)–C(5)–C(6) O(6)–C(6)–N(1) Cd4–O(12)–O(6)4 2.5993(5) 2.6884(5) 1.374(2) 1.385(2) 1.393(2) 1.419(2) 94.66(2) 96.82(2) 115.94(12) 138.97(11) 105.66(14) 110.2(2) 118.0(2) 131.8(2) 119.4(2) 108.76(6) Cd–N(7) C(6)–O(6) N(7)–C(8) C(8)–N(9) N(9)–C(10) N(7)–Cd–Cl(2) N(7)–Cd–Cl(1)2 N(7)–Cd–Cl(1) N(7)–Cd–Cl(2)3 Cl(1)–Cd–Cl(2)3 O(6)–C(6)–C(5) C(5)–C(6)–N(1) C(8)–N(7)–C(5) N(7)–C(8)–N(9) C(8)–N(9)–C(4) C(8)–N(9)–C(10) C(4)–N(9)–C(10) 2.402(2) 1.243(2) 1.313(2) 1.369(2) 1.458(2) 88.52(4) 165.91(4) 84.43(4) 91.29(4) 169.26(2) 128.4(2) 112.15(14) 104.45(14) 113.0(2) 106.64(14) 125.8(2) 127.2(2) Cd–O(12*) C(10)–O(10) O(10)–C(11) C(11)–C(12) C(12)–O(12) Cl(1)–Cd–Cl(1)2 Cl(2)–Cd–Cl(1)2 Cl(2)–Cd–Cl(2)3 Cl(1)2–Cd–Cl(2)3 O(10)–C(10)–N(9) C(10)–O(10)–C(11) O(10)–C(11)–C(12) O(12)–C(12)–C(11) C(12)–O(12)–O(6)4 C(12)–O(12)–Cd4 2.3050(13) 1.405(2) 1.443(2) 1.496(2) 1.433(2) 83.18(2) 101.02(2) 85.34(2) 99.73(2) 111.70(14) 113.58(14) 107.56(14) 109.27(14) 107.24(11) 123.22(10) a Superscripts represent other diVerent monomeric units.J.Chem.Soc., Dalton Trans., 1999, 167–173 171 with C(11)–C(12) bonds in gauche conformation and syn conformation between N(7) and O(12). Cadmium(II) complex 4. The CdII in the polymeric complex 4 presents a distorted octahedral co-ordination with four chlorine atoms, N(7) from an ACV molecule and O(12) from another ACV molecule [Cd–Cl between 2.5654(5) and 2.6884(5), Cd– N(7) 2.402(2), Cd–O(12) 2.3050(13) Å] (Table 2). These two ACVs are placed in cis disposition [Fig. 3(a)]. The value of the distance Cd–N(7) is slightly higher than that of the octahedral monomeric structure of Cd(59-GMP)21 [Cd–N(7) 2.37 Å]. The guanine moiety of ACV in 4 is also essentially planar. As in 3, C(10) and Cd atoms of the complex are placed on the same side of the plane of guanine [C(10) 6.88 and Cd 7.78] and although the acyclic chain of ACV is folded with C(11)–C(12) bonds in gauche conformation a trans conformation between N(7) and O(12) can be observed.To our knowledge, this is the first example where the hydroxyl group of the lateral chain of ACV interacts directly with the metal. The structure is built by polymeric (CdCl2)n chains linked by ACV ligands [Fig. 3(b)]. The chains run along the a axis and cadmium atoms alternate in them with pairs of bridging chlorine ligands. Four-membered Cd2Cl2 centrosymmetric rings are generated in this way, which considerably deviate from a perfect square-planar geometry as far as the angles are concerned.Consecutive Cd2Cl2 rings are almost perpendicular (average dihedral angle = 81.528) and therefore the polymeric chain is twisted.22 The chains are linked to each other by the acyclovir ligands which are co-ordinated via N(7) to a cadmium atom of one chain and via the terminal hydroxyl group O(12) to a cadmium atom of another chain. This latter bond is reinforced by a hydrogen bond formed with the carbonyl oxygen atom O(6) of the ACV molecule co-ordinated via N(7) [O(12) ? ? ? O(6) 2.636(2) Å], yielding a two-dimensional polymer perpendicular to the c axis. An interstitial water molecule completes the asymmetric unit, being strongly attached to the structure via Fig. 3 (a) Molecular structure of [Cd(ACV)Cl2]?H2O 3. (b) Drawing of the polymeric chain (CdCl2)n. hydrogen bonds [N(1) ? ? ?OW 2.801(2), O(6) ? ? ?OW 2.893(2) and O(10) ? ? ?OW 2.841(2) Å]. The Ni–ACV 1, Zn–ACV 3, Cd–ACV 4, Cu–ACV8–10 and Pt–ACV7 complexes present a lateral chain with a global conformation type: gauche [N(9)–C(10)], gauche [C(10)–O(10)], trans [O(10)–C(11)] and gauche [C(11)–C(12)] which is equivalent to those observed in the A and B molecules of free acyclovir 17 (Table 3).The gauche conformation of the glycosidic bond N(9)–C(10) is consistent with the observed distances [from 1.459(2) to 1.471(3) Å] which are longer than those usually found in the opposite trans conformation [1.441(5) Å].7 Infrared spectra The IR spectra of the obtained complexes were compared with that of acyclovir.23,24 The more relevant features are: (a) shift to lower frequencies of the strong band at 1718 cm21 (1682, 1670 for 1; 1683, 1669 for 2; 1690 for 3; 1676 for 4 and 1694, 1666 cm21 for 5) which is assigned to the vibration n[C(6)]] O(6)] in free ACV. This is consistent with the C]] O group involved in hydrogen bonds.In some Cu–ACV complexes 8,9 it has been observed that short hydrogen bonds involving O(6) significantly diminish the carbonyl stretching frequency in the IR spectra. The 1634 cm21 band related to d(NH2) is not appreciably shifted for 1, 2, 4 and 5, although for 3 it is shifted to 1651 cm21, possibly due to the double interaction of the NH2 group present [N(3) ? ? ?H2N, Cl ? ? ?H2N].(b) Splitting of the 1487 cm21 band23 (1490, 1462 for 1; 1488, 1460 for 2; 1494, 1461 for 3; 1471, 1456 for 4 and 1485, 1463 for 5) assigned to d[C(8)– H] 1 n[C(8)–N(7)] and these variations, related to the fivemembered ring, have been observed in the spectra of several structurally known N(7)-metallated complexes.23,25 The far-IR spectra of the complexes show a new band at 312 1 and 313 cm21 2 assigned as essentially n(M–N).26 The low frequency band at 332 cm21, found for compound 3, may be attributed to the Zn–Cl stretching mode of the terminal chlorides.27 NMR spectra Unequivocal assignments of 1H and 13C NMR spectra of compounds 3, 4 and 5 are shown in Table 4.As can be appreciated, the spectra of the compounds of ZnII, CdII and HgII show small diVerences with regards to the ACV ligand, but are similar to those of other equivalent guanosine complexes,28 which can be explained by the practically no modification of the structural features of the guanine ring and the lateral chain (see X-ray section). Thus, at room temperature, in the 1H NMR only slight modifications (Zn 10.12, Cd 10.01 and Hg 10.09 ppm) of H(8) of the guanine ring can be observed.On the other hand, the 13C NMR of these complexes show a slight general upfield shift of C(5) (Zn 20.7, Cd 21.0 and Hg 21.0 ppm) and down- field shift of C(8) (Zn 10.7, Cd 1 0.4 and Hg 11.2 ppm), which can be explained by the formation of the metal(II)–N(7) bond. Although we cannot discard the substitution of the remaining ligands by DMSO molecules, the existence in solution of ACV–metal interaction has been studied between 20 and 60 8C (internal reference: tetramethylsilane). In the Zn–ACV 3 and Hg–ACV 5 complexes the resonance of the aromatic H(8) proton shows an upfield shift when the temperature is increased (ca. 0.04 ppm per 10 8C) compared with free ACV which remains practically unaltered. A possible explanation is the reversible labilisation of the N(7)–M bond which diminishes the non-shielding eVect of the metal over H(8). The H(8) of the Cd–ACV complex 4 shows similar behaviour to that of ACV and we cannot conclude whether in solution the N(7)–M bond remains unaltered.Conclusion The compound ACV presents a general N(7)–M interaction172 J. Chem. Soc., Dalton Trans., 1999, 167–173 Table 3 Dihedral angles (8) corresponding to the lateral chain in ACV and ACV complexes ACV Molecule Dihedral angle C(4)–N(9)–C(10)–O(10) N(9)–C(10)–O(10)–C(11) C(10)–O(10)–C(11)–C(12) O(10)–C(11)–C(12)–O(12) A 276.5 276.9 173.2 60.6 B 274.4 266.3 2176.2 73.5 C 290.5 2173.3 2171.9 2174.4 Ni–ACV 273.8 282.8 2179.5 266.6 (272.7) a (2103.2) (172.5) (260.8) Zn–ACV 74.6 73.2 178.8 59.3 Cd–ACV 282.7 271.2 2170.8 63.2 Cu–ACV 92.5 288.7 2178.2 269.1 Pt–ACV 74.2 77.0 2178.4 265.9 a Non-co-ordinated ACV.Table 4 Proton and 13C NMR (selected peaks, at 294 K) of ACV and complexes 3–5 Dd H(1) H(8) NH2 C(6) C(2) C(4) C(8) C(5) C(10) C(12) C(11) ACV 10.77 7.92 6.62 160.8 157.8 155.4 141.7 120.4 76.0 74.4 63.9 3 10.86(10.09) 8.04(10.12) 6.68 160.5(20.3) 158.0(10.2) 155.3(20.1) 142.4(10.7) 119.7(20.7) 76.2(10.2) 74.5(10.1) 63.9(0.0) 4 10.75(20.02) 7.93(10.01) 6.62 160.5(20.3) 158.1(10.3) 155.2(20.2) 142.1(10.4) 119.4(21.0) 76.4(10.4) 74.6(10.2) 64.0(10.1) 5 10.85(10.08) 8.01(10.09) 6.67 160.6(20.2) 158.3(10.5) 155.1(20.3) 142.9(11.2) 119.4(21.0) 76.7(10.7) 74.7(10.3) 64.0(10.1) [Hg(Guo)Cl2] (10.21) (10.08) (20.4) (10.1) (20.3) (0.0) (20.6) [Hg(Guo)Br2] (10.06) (10.11) (20.4) (10.1) (20.6) (10.3) (0.0) [Hg(Guo)(SCN)2] (10.21) (10.21) (20.5) (10.3) (20.7) (10.8) (20.4) which is accompanied by hydrogen bonds, stabilising a monomeric unit and/or the crystal structure.Although all heteroatoms of the ligand constitute potential sites to form hydrogen bonds in metal chloride complexes of Co, Ni, Cu, Zn, Cd and Hg with ACV, there is a preference of the guanidine moiety of the guanine ring [N(1), N(2) and N(3)] for ACV? ? ?ACV interactions, whereas oxygens [O(6), O(10) and O(12)] are normally involved in ACV? ? ?H2O interactions. On the other hand, Ni (and Co)–ACV constitute examples of recognition of ACV for Ni(or Co)–ACV.The Cd–ACV complex is the first example where an oxygenated group [O(12)H] of the lateral chain of ACV interacts directly with the metal. In the Zn–ACV complex the hydrogen bonding of two guanine bases via NH2 and N(3) (unit 1) with N(3) and NH2 (unit 2) represents a novel type of interaction between nucleobases. Based on X-ray and spectral data we can conclude that Co–, Ni–, Cu–9 and Zn–ACV are monomeric complexes and Cd– ACV is a polymeric structure (Figs. 1–3). The complex Hg– ACV could be tentatively assigned as a [{Hg(ACV)Cl2}x] polymer based on spectral data which show direct N(7)–Hg interaction, conductometric measurements (no electrolyte) and comparison with other similar structures [{Hg(Guo)X2}x] (X = Cl, Br or SCN).28 Acknowledgements We are grateful to Dirección General de Investigación Científica y Técnica, Ref. PB94-0922-C02-02, for financial support. References 1 H.J. SchaeVer, L. Beauchamp, P. de Miranda, G. B. Elion, D. J. Bauer and P. Collins, Nature, 1978, 272, 583. 2 J. A. Fyfe, P. M. Keller, P. A. Furman, R. L. Miller and G. B. Elion, J. Biol. Chem., 1978, 253, 8721; G. B. Elion, J. Antimicrob. Chemother., 1983, 12, Suppl. B, 9. 3 R. B. Silverman, in The Organic Chemistry of Drug Design and Drug Action, Academic Press, New York, 1992, p. 392; C. J. Coulson, in Molecular Mechanisms of Drug Action, 2nd edn., Taylor & Francis, London, 1994, p. 30. 4 P. J. Sadler, Adv. Inorg. Chem., 1991, 36, 1. 5 S. Grabner and N. Bukovec, 4th FGIPS Meeting in Inorganic Chemistry, European Mediterranean Conference in Inorganic Chemistry, Corfu, October 1997, Abstract PA32. 6 Z. Balcarova, J. Kasparkova, G. Natile and V. Brabec, 4th FGIPS Meeting in Inorganic Chemistry, European Mediterranean Conference in Inorganic Chemistry, Corfu, October 1997, Abstract ORA 20. 7 L. Cavallo, R. Cini, J. Kobe, L. G. Marzilli and G. Natile, J.Chem. Soc., Dalton Trans., 1991, 1867. 8 I. Turel, I. Leban and K. Gruber, J. Inorg. Biochem., 1996, 63, 41. 9 B. Blazic, I. Turel, N. Bukovec, P. Bukovek and F. Lazarini, J. Inorg. Biochem., 1993, 51, 737. 10 (a) B. Andersen, T. I. Sjastad, I. Turel, A. Emwas, E. Sletten, C. A. Blindauer and H. Sigel, COST D8 — Chemical Properties of Platinum and Other Metal Ion Complexes with Nucleobases and Antiviral Nucleotide Analogues. Dortmund, September 1998; (b) I. Turel, N. Bukovec, M.Goodgame and D. J. Williams, Polyhedron, 1997, 16, 1701. 11 G. M. Sheldrick, SHELXTL Version 5 for PC, Siemens Analytical X-ray Instruments, Inc., Madison, WI, 1994. 12 K. Aoki, Bull. Chem. Soc. Jpn., 1975, 48, 1260; G. R. Clark and J. D. Orbell, J. Chem. Soc., Chem. Commun., 1974, 139. 13 J. J. Fiol, A. Terrón, A. M. Calafat, V. Moreno, M. Aguiló and X. Solans, J. Inorg. Biochem., 1989, 35, 191. 14 P. de Meester, D. M. L. Goodgame, A. C. Skapski and B. T. Smith. Biochem.Biophys. Acta, 1974, 340, 113. 15 N. S. Begum, M. D. Poojary and H. Manohar, J. Chem. Soc., Dalton Trans., 1988, 1303. 16 R. W. Gellert, J. K. Shiba and R. Bau, Biochem. Biophys. Res. Commun., 1979, 88, 1449. 17 G. I. Birnbaum, M. Cygler and D. Shugar, Can. J. Chem., 1984, 62, 2646. 18 R. K. O. Sigel, E. Freisinger and B. Lippert, Chem. Commun., 1998, 219; R. K. O. Sigel, E. Freisinger, S.M. Thompson and B. Lippert, COST D8 — Chemical Properties of Platinum and Other Metal Ion Complexes with Nucleobases and Antiviral Nucleotide Analogues, Dortmund, September 1998. 19 P. de Meester, D. M. L. Goodgame, T. J. Jones and A. C. Skapski, Biochem. Biophys. Acta, 1974, 353, 392. 20 S. K. Miller, D. G. VanDerveer and L. G. Marzilli, J. Am. Chem. Soc., 1985, 107, 1048. 21 K. Aoki, Acta Crystallogr., Sect. B, 1976, 32, 1454. 22 (a) A. Bonamartini, M. R. Cramarossa and M. Saladini, Inorg. Chim. Acta, 1997, 257, 19; (b) E. A. H. GriYth, N. G. Charles and E. L. Amma, Acta Crystallogr., Sect. B, 1982, 38, 942. 23 H. A. Tajmir-Riahi and T. Theophanides, Can. J. Chem., 1984, 62, 1429.J. Chem. Soc., Dalton Trans., 1999, 167–173 173 24 M. Tsuboi, S. Takahoshi and I. Harada, in Physicochemical Properties of Nucleic Acids, ed. J. Duchesne, Academic Press, New York, 1973, vol. 2, p. 91; H. A. Tajmir-Riahi and T. Theophanides, Inorg. Chim. Acta, 1983, 80, 223; D. U. Young, P. Tollin and H. R. Wilson, Acta Crystallogr., Sect. B, 1974, 30, 2012; T. Theophanides and H. A. Tajmir-Riahi, in Spectroscopy of Biological Molecules, eds. C. Sandorfy and T. Theophanides, D. Reidel, Dordrecht, 1982, p. 137; S. Shirotake and T. Sakaguchi, Chem. Pharm. Bull., 1978, 26, 2941. 25 H. A. Tajmir-Riahi and T. Theophanides, Can. J. Chem., 1985, 63, 2065. 26 K. Nakamoto, Infrared and Raman Spectra of Inorganic and Coordination Compounds, Wiley, New York, 1978. 27 N. B. Behrens and D. M. L. Goodgame, Inorg. Chim. Acta, 1980, 46, 15. 28 M. Quirós, J. M. Salas-Peregrín, M. P. Sánchez-Sánchez and R. Fauré, An. Quim., 1990, 86, 518. Paper 8/07787H