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Communication

Structural and Theoretical Evidence of the Depleted Proton Affinity of the N3-Atom in Acyclovir

by
Esther Vílchez-Rodríguez
1,
Inmaculada Pérez-Toro
1,
Antonio Bauzá
2 and
Antonio Matilla-Hernández
1,*
1
Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
2
Department of Chemistry, Faculty of Science, University of the Balearic Islands, Crta. de Valldemossa km 7.5, 07122 Palma de Mallorca (Baleares), Spain
*
Author to whom correspondence should be addressed.
Crystals 2016, 6(11), 139; https://doi.org/10.3390/cryst6110139
Submission received: 27 September 2016 / Revised: 20 October 2016 / Accepted: 21 October 2016 / Published: 29 October 2016
(This article belongs to the Special Issue Crystal Structure of Complex Compounds)
Browse Figures
Versions Notes

Abstract

:
The hydronium salt (H3O)2[Cu(N7–acv)2(H2O)2(SO4)2]·2H2O (1, acv = acyclovir) has been synthesized and characterized by single-crystal X-ray diffraction and spectral methods. Solvated Cu(OH)2 is a by-product of the synthesis. In the all-trans centrosymmetric complex anion, (a) the Cu(II) atom exhibits an elongated octahedral coordination; (b) the metal-binding pattern of acyclovir (acv) consists of a Cu–N7(acv) bond plus an (aqua)O–H···O6(acv) interligand interaction; and (c) trans-apical/distal sites are occupied by monodentate O-sulfate donor anions. Neutral acyclovir and aqua-proximal ligands occupy the basal positions, stabilizing the metal binding pattern of acv. Each hydronium(1+) ion builds three H-bonds with O–sulfate, O6(acv), and O–alcohol(acv) from three neighboring complex anions. No O atoms of solvent water molecules are involved as acceptors. Theoretical calculations of molecular electrostatic potential surfaces and atomic charges also support that the O-alcohol of the N9(acv) side chain is a better H-acceptor than the N3 or the O-ether atoms of acv.

Graphical Abstract

1. Introduction

During the past decades, various contributions on metal ion complexes with acyclovir (acv, Figure 1) have been reported. This acyclic guanine nucleoside analog has proved to bind nucleoside phosphorylases [1] as well as several metal ions. Structural knowledge on mixed-ligand metal–acv complexes (see selected reference [2,3,4,5,6,7,8,9,10,11,12]) supports a variety of metal binding patterns (MBPs) and interesting molecular recognition features. So far, the reported MBPs can be summarized as follows: (a) the formation of the M–N7 bond, with [2,3,4,5,6,7,8,9,12] or without [8,10] the cooperation of an intra-molecular interligand A–H···O6(acv) interaction (A=O or N acceptor); (b) the N7,O6-chelation mode [11]; (c) the µ2-N7,O(ol) (see Figure 1) bridging role [3]; and finally, (d) a multi-functional role featured by the µ3-N7,O6,O(e)+O(ol), which comprises the bridging, chelating, and tetradentate modes of acv [12].

2. Results and Discussion

As part of our program expanding the frontiers of acv as a ligand, different reactions between acv and metal chelates were performed, using a large variety of tri- and tetra-dentate chelators. An attempt to obtain the ternary complex Cu(II)–DEA–acv (DEA = diethanolamine) yielded a DEA-free greenish powder with a few well-shaped single crystals corresponding to the formula (H3O)2[Cu(acv)2(H2O)2(SO4)2]·2H2O (1, 100 K, monoclinic system, space group P21/c, final R1 = 0.045. Table A1) along with bluish Cu(OH)2. The all-trans centrosymmetric anions (Figure 2 and Figure A2) have symmetry-related pairs of O–aqua, N7–acv, and O–sulfate donor atoms featuring a rather typical elongated-octahedral Cu(II) coordination, type 4 + 2, with bond lengths of Cu–O(aqua) of 1.963(2) Å, of Cu–N7(acv) of 2.018(2) Å, and of Cu–O(sulfate) of 2.427(2) Å, respectively (Table A2). It seems clear that the, shortest strongly-bound Cu–O(aqua) favor the cooperation of each Cu–N7(acv) bond with an intra-molecular interligand (aqua)O1–H1B···O6(acv) interaction (2.615(3) Å, 157.3°) (Table A3), thus leading to the most common MBP of the acv ligand [2,3,4,5,6,7,8,9,12]. This fact imposes the coordination of O–sulfate atoms towards the apical/distal sites of the copper(II) surrounding. In addition, three (hydronium)O–H···O interactions stabilize the structure involving the O6, O(ol), and O(sulfate) atoms from three neighboring complex anions as acceptors, excluding the participation of O-water molecules within the intermolecular network (Table A4, Figure A3 and Figure A4). The novel compound is closely related to the molecular compound all trans-[Cu(acv)2(H2O)2Cl2] [5] where chloride ligands are also moved to the trans-apical/distal coordination to favor the cooperation between Cu–N7(acv) bonds and (aqua)O–H···O6(acv) interactions.
In the Fourier transform infrared (FT-IR) spectrum of 1 (see also Figure A5 for acv·0.68 H2O and Figure A6, Table A5), the monodentate sulfate ligands (~C3v symmetry) split the ν3 mode in two intense bands at 1122 and 1041 cm−1, while only one ν3 band is observed for the free ion at about 1033–1440 cm−1. Likewise, the sulfate ν4 mode consists of two medium intensity bands at 652 and 611 cm−1, but only one at 613 cm−1 for the free ion [4]. The identification of the hydronium ion by FT-IR spectroscopy is not an easy task. In compound 1, the H3O+ ion seems responsible of the broad absorption (ν1 and/or ν3) at ~2743 cm−1 and the defined band (ν4) at 1190 cm−1 [13]. The electronic spectra of compound 1 (Figure A8) explain its greenish color (see Appendix A4).
This structure, therefore, exhibits two uncommon features: (a) the apical/distal copper(II) coordination of the divalent sulfate anions versus the basal coordination of neutral aqua and acv ligands, and (b) the unexpected formation of hydronium(1+) cations instead of the protonation of the N3–acv atom. The molecular electrostatic potential surface (MEPS) was computed in the complex anion (Figure 3, Cartesian coordinates in Table A6) in order to better understand the basis of these features. As expected, the most negative region is located around the sulfate ligands, which are the best candidates to participate in H-bonding interactions with the H3O+ ion. Indeed, this is observed in the crystal packing of compound 1. A comparison of MEPS values at the N3 and O(ol) atoms of the N9-acyclic chain reveals that the most negative electrostatic potential falls at the O(ol) atom, supporting the observed (H3O+)O–H···O(ol) interaction, whereas no interaction with (H3O+)O–H···N3(acv) is built. To further discuss the ability of the O(ol) atom and the N3(acv) atom, from the acv N9-side chain and the purine-like moiety, respectively, to participate in H-bonding interactions as acceptors, the atomic charges for [Cu(acv)2(H2O)2(SO4)2]2−·2H2O were also computed. Results computed using two different methods for deriving atomic charges (see ESI for details) yield a more negative charge on the O(ol) atom than on the O(ether) and N3 atoms (Figure 4), in agreement with the experimental results. Therefore, the N3-acv atom is not protonated in the structure due to the significant depletion of its basicity. The steric hindrance on the N3(acv) atom imposed by the acv N9-side chain and ortho-2-amino group should also be considered.
We have also evaluated, energetically, the interaction energy of the H3O+ ion with the O(ol) atom (observed experimentally) and the hypothetical complex with N3(acv), as indicated in Figure 4 (see Cartesian coordinates in Table A7). The interaction energies in both cases are very large (−88.8 and −88.1 kcal/mol, respectively) due to the strong electrostatic attraction between the counter ions. Interestingly, the complexation energy is slightly more favorable with the O(ol) atom than with N3(acv), in agreement with the experimental observation. We have also evaluated the complexation energy of the solid state assembly commented above in Figure 2 and the theoretical model is depicted in Figure 4c. The interaction energy of this assembly is very large (−100.3 kcal/mol) due to the contribution of both H-bonding interactions and also the pure electrostatic effects.

3. Materials and Methods

3.1. Synthesis of Compound 1

Equimolar amounts (0.5 mmol) of CuSO4·5H2O and DEA were dissolved in 70 mL of methanol. Acyclovir (acv·0.66H2O, 0.5 mmol) was added in small amounts to yield an apple-greenish solution that was filtered into a crystallizing dish. Slow evaporation yields compound 1 and bluish Cu(OH)2. Compound 1 can easily be collected by filtration and dried on a filter paper. Yield: 65%.

3.2. Crystal Structure Determination

A green plate crystal of (H3O)2[Cu(acv)2(H2O)2(SO4)2]·2H2O was mounted on a glass fiber and used for data collection. Crystal data were collected at 100(2) K, using a Bruker X8 KappaAPEXII diffractometer. Graphite monochromated MoK(α) radiation (λ = 0.71073 Å) was used throughout. The data were processed with APEX2 [14] and corrected for absorption using SADABS (transmissions factors: 1.000—0.907) [15]. The structure was solved by direct methods using the program SHELXS-2013 [16] and refined by full-matrix least-squares techniques against F2 using SHELXL-2013 [16]. Positional and anisotropic atomic displacement parameters were refined for all non-hydrogen atoms. Hydrogen atoms were located in difference maps and included as fixed contributions riding on attached atoms with isotropic thermal parameters 1.2 times those of their carrier atoms. Criteria of a satisfactory complete analysis were the ratios of the RMS shift to standard deviation less than 0.001 and no significant features in final difference maps. Atomic scattering factors were taken from the International Tables for Crystallography [17]. Molecular graphics were plotted from DIAMOND [18].

3.3. Theoretical Calculations

The energies and atomic charges of the compound included in this study were computed using the BP86-D3 functional [19,20] and def2-TZVP [21] basis set using the crystallographic coordinates within the TURBOMOLE 7.0 program [22]. This level of theory, which includes the latest available dispersion correction (D3) [23], is adequate for studying non-covalent interactions, for which dispersion effects are important. The MEP surfaces were generated using Spartan’10 v. 1.1.0 software [24] using the B3LYP [25,26,27] method and the 6-31+G* basis set.

Acknowledgments

Support of the Intramural CSIC project 201530E011, the Research Group FQM-283 and the Project MAT2010-15594 of MICINN-Spain are acknowledged. ERDF Funds and Junta de Andalucía support to acquire the FT-IR spectrophotometer Jasco 6300.

Author Contributions

Esther Vílchez-Rodríguez and Inmaculada Pérez-Toro have performed the synthesis of compound and preparation of samples. Antonio Bauzá has performed the MEPS calculations. Data analysis and write manuscript by Antonio Matilla-Hernández. All authors have participated in the discussion of results.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Crystallographic data for 1 has been deposited with the Cambridge Crystallographic Data Centre, CCDC No. 1433120. Copies of this information may be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-1223-336-033; email: [email protected] or http://www.ccdc.cam.ac.uk).
Crystals 06 00139 g005 550
Figure A1. Structural correlation between guanosine and acyclovir.
Figure A1. Structural correlation between guanosine and acyclovir.
Crystals 06 00139 g005

Appendix A1. Structural Data

Table
Table A1. Crystal data, structure solution, and refinement of compound 1.
Table A1. Crystal data, structure solution, and refinement of compound 1.
Identification code14jnac876
Empirical formulaC16H36CuN10O20S2
Formula weight816.21
Crystal system, space groupMonoclinic, P21/c
Unit cell dimensionsa = 12.1489(4)Å, α = 90°
b = 18.2712(5)Å, β = 102.755(1)°
c = 6.8294(2) Å, γ = 90°
Volume1478.55(8) Å3
Z, Calculated density2, 1.833 Mg/m3
Absorption coefficient0.987 mm−1
F(000)846
Crystal size0.100 × 0.080 × 0.040 mm
Theta range for data collection (°)2.229 to 29.204
Limiting indices−15 ≤ h ≤ 16, −24 ≤ k ≤ 24, −9 ≤ l ≤ 9
Reflections collected/unique19,513/3985 [Rint = 0.0392]
Completeness to θ = 25.24299.8%
Absorption correctionSemi-empirical from equivalents
Max. and min. transmission1.0000 and 0.9069
Refinement methodFull-matrix least-squares on F2
Data/parameters3985/223
Goodness-of-fit on F21.092
Final R indices [I > 2σ(I)]R1 = 0.0449, wR2 = 0.1042
R indices (all data)R1 = 0.0559, wR2 = 0.1099
Largest diff. peak and hole1.260 and −0.907 e.Å−3
Table
Table A2. Coordination bond lengths (Å) and angles (°) for compound 1.
Table A2. Coordination bond lengths (Å) and angles (°) for compound 1.
Bond Lengths (Å) of Compound 1
Cu(1)–O(1) a1.9630(18)
Cu(1)–O(1)1.9630(18)
Cu(1)–N(7) a2.018(2)
Cu(1)–N(7)2.018(2)
Cu(1)–O(15)2.4271(17)
Cu(1)–O(15) a2.4271(17)
Angles (°) for Compound 1
O(1) a–Cu(1)–O(1)180.0
O(1) a–Cu(1)–N(7) a90.48(8)
O(1)–Cu(1)–N(7) a89.52(8)
O(1) a–Cu(1)–N(7)89.52(8)
O(1)–Cu(1)–N(7)90.48(8)
N(7) a–Cu(1)–N(7)180.0
O(1) a–Cu(1)–O(15)88.41(7)
O(1)–Cu(1)–O(15)91.59(7)
N(7) a–Cu(1)–O(15)86.78(7)
N(7)–Cu(1)–O(15)93.22(7)
O(1) a–Cu(1)–O(15) a91.59(7)
O(1)–Cu(1)–O(15) a88.41(7)
N(7) a–Cu(1)–O(15) a93.22(7)
N(7)–Cu(1)–O(15) a86.78(7)
O(15)–Cu(1)–O(15) a180.00(8)
Symmetry transformation used to generate equivalent atoms, a: −x, −y + 1, −z.
Crystals 06 00139 g006 550
Figure A2. Structure of compound 1, corresponding to two symmetry-related asymmetric units (symmetry transformation, a: −x, −y + 1, −z).
Figure A2. Structure of compound 1, corresponding to two symmetry-related asymmetric units (symmetry transformation, a: −x, −y + 1, −z).
Crystals 06 00139 g006
Table
Table A3. Hydrogen bonds for compound 1 (Å, °).
Table A3. Hydrogen bonds for compound 1 (Å, °).
D–H···Ad(D–H)d(H···A)d(D···A)Z(DHA)
O(1)–H(1A)···O(17)0.872.172.727(3)121.3
O(1)–H(1B)···O(6)0.871.792.615(3)157.3
O(14)–H(14)···O(16) c0.841.822.647(3)166.2
N(1)–H(1)···O(18) d0.881.962.832(3)170.2
N(2)–H(2A)···O(17) e0.882.112.905(3)149.4
N(2)–H(2B)···O(15) d0.882.082.859(3)147.3
O(2)–H(2C)···O(6) f0.872.062.825(3)146.2
O(2)–H(2D)···O(18) g0.871.962.808(3)165.5
O(2)–H(2E)···O(14)0.981.822.786(3)170.4
O(3)–H(3A)···O(14) h0.842.613.124(3)121.0
O(3)–H(3A)···O(16) i0.842.593.101(3)120.2
O(3)–H(3A)···O(2) j0.842.483.053(4)125.8
O(3)–H(3B)···O(17)0.981.832.751(3)153.9
Symmetry transformations used to generate equivalent atoms, c: −x + 1, −y + 1, −z + 1; d: −x, y − 1/2, −z + 1/2; e: x, −y + 1/2, z − 1/2; f: x + 1, −y + 1/2, z + 1/2; g: −x + 1, y − 1/2, −z + 3/2; h: −x + 1, −y + 1, −z + 2; i: x, y, z + 1; j: −x + 1,y + 1/2, −z + 3/2.
Crystals 06 00139 g007 550
Figure A3. π,π-interactions between the six-membered rings of guanine moieties building 2D frameworks parallel to the bc plane of the crystal.
Figure A3. π,π-interactions between the six-membered rings of guanine moieties building 2D frameworks parallel to the bc plane of the crystal.
Crystals 06 00139 g007
Table
Table A4. π,π-Staking interaction parameters in the crystal of compound 1 (Å, °).
Table A4. π,π-Staking interaction parameters in the crystal of compound 1 (Å, °).
π···π interactionsCg(I)···Cg(J)α
Cg(1)···Cg(1) e3.42353.00
Cg(1)···Cg(1) k3.42353.00
Cg(1): ring [N(1)/C(2)/N(3)/C(4)/C(5)/C(6)]. Symmetry transformations used to generate equivalent atoms, e: x, −y + 1/2, z − 1/2; k: x, −y + 1/2, z + ½; Cg(I)···Cg(J): distance between ring centroids; α: dihedral angle between planes I and J.
Crystals 06 00139 g008 550
Figure A4. Many H-bonds, some of them involving H3O+ ions, H2O molecules, and acv-O(ol)H groups as H-donors, linking the π,π-stacked 2D-layers in a 3D array in the crystal of compound 1.
Figure A4. Many H-bonds, some of them involving H3O+ ions, H2O molecules, and acv-O(ol)H groups as H-donors, linking the π,π-stacked 2D-layers in a 3D array in the crystal of compound 1.
Crystals 06 00139 g008

Appendix A2. FT-IR Spectrum

Crystals 06 00139 g009 550
Figure A5. FT-IR spectrum of a commercial sample of acv·0.66 H2O (KBr disks).
Figure A5. FT-IR spectrum of a commercial sample of acv·0.66 H2O (KBr disks).
Crystals 06 00139 g009
The absorption band of the stretching mode ν(C=O) in various spectra recorded for commercial samples of acv·0.66H2O splits into two partially-overlapped bands at 1720(3) and 1695(2) cm−1.
In the FT-IR spectra of copper(II) complexes having solvate and/or coordinated acv, this band is located very close to 1695 cm−1. However, this is not the case of compound 1 (see Figure A6), where this ν(C=O) band appears at 1683 cm−1 because the exocyclic O6 atom of acv acts twice as an H-acceptor for an intra-molecular and an inter-molecular H-bonding interaction.
An additional band with good diagnostic value is that of the out-of-plane deformation mode δ(O–H) for the terminal alcohol functional group of the N9-side chain, –O(ol)–H, that appears as a more or less defined band near 1387(3) cm−1 (see band 33 at 1387 cm−1).
However, attention must be paid if the studied copper(II) complexes contain nitrate or carboxylate anions, which produce stretching bands near to 1385 cm−1.
Crystals 06 00139 g010 550
Figure A6. FT-IR spectrum of compound 1.
Figure A6. FT-IR spectrum of compound 1.
Crystals 06 00139 g010
Table
Table A5. Assignation peaks of compound 1.
Table A5. Assignation peaks of compound 1.
Ligand or SolventChromophoreModeWavenumber (cm−1)Band Number in the Read Spectrum
H3O+ ionH3O+ν1(A1) and ν3(E)2743 (broad)9
ν2(A1)119024
H2OH2Oνas34302
νs~3450N/M *
δ165211
acvO(ol)–Hν35021
δ138520
–N(2)H2νas33273
νs31954
δ159812
–N(1)–Hν31395
δ154114
–C=O(6)ν168310 **
C–O(e)–Cνas117826
sulfateSO42−ν3112225
104127
ν198928
ν465236
61139
ν244844
* N/M = not measured. ** This band usually splits in two at 1720(3) and 1695(3) cm−1 in the spectra of acv·0.66H2O samples, and appear at about 1695 cm−1 in the spectra of Cu(II)-acv complexes with monodentate acv ligands. Note that, in compound 1, the O6 atom of acv is involved as an acceptor in two H-bonds.

Appendix A3. ESR Spectrum and Magnetic Properties of Compound 1

X-band ESR (Electronic Spin Resonance) measurements were carried out on a Bruker ELEXSYS 500 spectrometer equipped with a super-high-Q resonator ER-4123-SHQ. For Q-band studies, ESR spectra were recorded on a Bruker EMX system equipped with an ER-510-QT resonator. The room temperature X-band powder spectra are not well resolved due to a rather large line width. However at the Q-band (Figure A7) the signal is clearly characteristic of an axial g tensor with the following main values: g∥ = 2.339, and g⊥ =2.086 (computer simulation: WINEPR-Simfonia, version 1.5, Bruker Analytische Messtechnik GmbH.
The g values are typical of Cu(II) ions in distorted octahedral environments in good agreement with the structural characteristics of the CuN2O4 chromophore. Moreover, the lowest g deviates appreciably from the free electron value (g0 = 2.0023) indicating a dx2-y2 ground state, as corresponds to an axially-elongated octahedral environment for Cu(II) ions. The absence of well-resolved hyperfine lines contrasts with the structurally monomeric nature of the compound. The collapse of the hyperfine structure usually indicates the presence of long-range exchange coupling. The hydrogen bonding and/or the π,π-stacking of the acyclovir rings can provide the necessary exchange pathway.
Crystals 06 00139 g011 550
Figure A7. Q-band ESR powder spectrum of compound 1 registered at room temperature. Dotted line is the best fit; see text for the fitting parameters.
Figure A7. Q-band ESR powder spectrum of compound 1 registered at room temperature. Dotted line is the best fit; see text for the fitting parameters.
Crystals 06 00139 g011
Variable temperature (5–300 K) magnetic susceptibility measurements on polycrystalline samples were carried out with a Quantum Design MPMS-7 SQUID magnetometer under a magnetic field of 0.1 T. The experimental susceptibilities were corrected for the diamagnetism of the constituent atoms by using Pascal’s tables. Magnetic susceptibility data show typical Curie–Weiss behavior. The calculated Curie constant (Cm = 0.44 cm3·K/mol) is in good agreement with the g-values obtained from ESR experiments (g = 2.170; Cm = 0.442). The Weiss temperature intercept is close to zero indicating that magnetic interactions between Cu(II) centers are very weak.

Appendix A4. Electronic Spectrum of Compound 1

Crystals 06 00139 g012 550
Figure A8. Electronic spectrum (diffuse reflectance) of compound 1 (Abs. vs: wavelength, nm.).
Figure A8. Electronic spectrum (diffuse reflectance) of compound 1 (Abs. vs: wavelength, nm.).
Crystals 06 00139 g012
The asymmetric d-d band spectrum exhibits a maximum of absorption at 881 nm (11,350 cm−1) with an intensity barycenter at 950 nm (10,525 cm−1) according to the apple-greenish color of compound 1.
For comparison, the electronic spectrum for a blue solution of the aqua-complex ion, [Cu(H2O)6]2+, shows a νmax near 800 nm (~12,500 cm−1).

A5. Cartesian Coordinates

Table
Table A6. Model in Figure 3
Table A6. Model in Figure 3
Cu0.000000559.13598209−0.00000659
S1.9500005510.318982092.88599341
O−1.551999458.267982090.83299341
H−1.606999458.501982091.67299341
H−1.463999457.399982090.78199341
O−1.592999455.768982090.06499341
O4.642000555.817982092.09099341
O5.764000556.146982094.77399341
H6.389000556.694982094.64399341
O0.7190005510.047982092.13099341
O3.1450005510.128982092.04599341
O2.017000559.385982094.04799341
O1.9070000011.715000003.40000000
N−0.212999453.976982090.19599341
H−0.922999453.458982090.14899341
N1.008000552.021982090.31099341
H1.762000551.574982090.37999341
H0.244000551.587982090.24399341
N2.162000554.026982090.40799341
N1.085000557.449982090.22599341
N2.977000556.295982090.45999341
C1.020000553.355982090.30799341
C1.976000555.359982090.36699341
C0.796000556.080982090.22499341
C−0.421999455.340982090.15099341
C2.385000557.521982090.37599341
H2.863000558.340982090.42199341
C4.393000556.036982090.72299341
H4.680000555.241982090.20799341
H4.929000556.809982090.41299341
C4.540000557.038982092.85799341
H3.704000557.514982092.61799341
−H5.304000557.631982092.64799341
C4.536000556.713982094.32899341
H4.358000557.541982094.84099341
H3.801000556.078982094.51699341
S−1.949999457.95198209−2.88600659
O1.5520005510.00298209−0.83300659
H1.607000559.76998209−1.67300659
H1.4640005510.87098209−0.78200659
O1.5930005512.50198209−0.06500659
O−4.6419994512.45298209−2.09100659
O−5.7639994512.12398209−4.77400659
H−6.3889994511.57698209−4.64400659
O−0.718999458.22298209−2.13100659
O−3.144999458.14198209−2.04600659
O−2.016999458.88498209−4.04800659
O−1.906999456.55698209−3.40000659
N0.2130005514.29398209−0.19600659
H0.9230005514.81198209−0.14900659
N−1.0079994516.24898209−0.31100659
H−1.7619994516.69598209−0.38000659
H−0.2439994516.68298209−0.24400659
N−2.1619994514.24398209−0.40800659
N−1.0849994510.82198209−0.22600659
N−2.9769994511.97498209−0.46000659
C−1.0199994514.91498209−0.30800659
C−1.9759994512.91198209−0.36700659
C−0.7959994512.18998209−0.22500659
C0.4220005512.92998209−0.15100659
C−2.3849994510.74898209−0.37600659
H−2.862999459.92998209−0.42200659
C−4.3929994512.23398209−0.72300659
H−4.6799994513.02898209−0.20800659
H−4.9289994511.46198209−0.41300659
C−4.5399994511.23198209−2.85800659
H−3.7039994510.75598209−2.61800659
H−5.3039994510.63898209−2.64800659
C−4.5359994511.55698209−4.32900659
H−4.3579994510.72898209−4.84100659
H−3.8009994512.19198209−4.51700659
O3.5350000010.006000006.25700000
H2.9500000010.553000006.51100000
H3.167000009.552000005.46800000
O−3.535000008.26500000−6.25700000
H−2.950000007.71800000−6.51100000
H−3.167000008.71900000−5.46800000
Table
Table A7. Models in Figure 4
Table A7. Models in Figure 4
(a)
Cu0.0009.1360.000
S1.95010.3192.886
O−1.5528.2680.833
H−1.6078.5021.673
H−1.4647.4000.782
O−1.5935.7690.065
O4.6425.8182.091
O5.7646.1474.774
H6.3896.6954.644
O0.71910.0482.131
O3.14510.1292.046
O2.0179.3864.048
O1.90711.7153.400
N−0.2133.9770.196
H−0.9233.4590.149
N1.0082.0220.311
H1.7621.5750.380
H0.2441.5880.244
N2.1624.0270.408
N1.0857.4500.226
N2.9776.2960.460
C1.0203.3560.308
C1.9765.3600.367
C0.7966.0810.225
C−0.4225.3410.151
C2.3857.5220.376
H2.8638.3410.422
C4.3936.0370.723
H4.6805.2420.208
H4.9296.8100.413
C4.5407.0392.858
H3.7047.5152.618
H5.3047.6322.648
C4.5366.7144.329
H4.3587.5424.841
H3.8016.0794.517
S−1.9507.952−2.886
O1.55210.003−0.833
H1.6079.770−1.673
H1.46410.871−0.782
O1.59312.502−0.065
O−4.64212.453−2.091
O−5.76412.124−4.774
H−6.38911.577−4.644
O−0.7198.223−2.131
O−3.1458.142−2.046
O−2.0178.885−4.048
O−1.9066.556−3.400
N0.21314.294−0.196
H0.92314.812−0.149
N−1.00816.249−0.311
H−1.76216.696−0.380
H−0.24416.683−0.244
N−2.16214.244−0.408
N−1.08510.822−0.226
N−2.97711.975−0.460
C−1.02014.915−0.308
C−1.97612.912−0.367
C−0.79612.190−0.225
C0.42212.930−0.151
C−2.38510.749−0.376
H−2.8639.930−0.422
C−4.39312.234−0.723
H−4.68013.029−0.208
H−4.92911.462−0.413
C−4.54011.232−2.858
H−3.70410.756−2.618
H−5.30410.639−2.648
C−4.53611.557−4.329
H−4.35810.729−4.841
H−3.80112.192−4.517
H7.9014.0033.867
H7.2453.4094.980
H6.5604.5574.397
O−7.12914.485−4.204
H−7.90114.268−3.867
H−7.24514.862−4.980
H−6.56013.714−4.397
(b)
Cu0.000000009.136000000.00000000
S1.9500000010.319000002.88600000
O−1.552000008.268000000.83300000
H−1.607000008.502000001.67300000
H−1.464000007.400000000.78200000
O−1.593000005.769000000.06500000
O4.642000005.818000002.09100000
O5.764000006.147000004.77400000
H6.389000006.695000004.64400000
O0.7190000010.048000002.13100000
O3.1450000010.129000002.04600000
O2.017000009.386000004.04800000
O1.9069994511.715017913.40000659
N−0.213000003.977000000.19600000
H−0.923000003.459000000.14900000
N1.008000002.022000000.31100000
H1.762000001.575000000.38000000
H0.244000001.588000000.24400000
N2.162000004.027000000.40800000
N1.085000007.450000000.22600000
N2.977000006.296000000.46000000
C1.020000003.356000000.30800000
C1.976000005.360000000.36700000
C0.796000006.081000000.22500000
C−0.422000005.341000000.15100000
C2.385000007.522000000.37600000
H2.863000008.341000000.42200000
C4.393000006.037000000.72300000
H4.680000005.242000000.20800000
H4.929000006.810000000.41300000
C4.540000007.039000002.85800000
H3.704000007.515000002.61800000
H5.304000007.632000002.64800000
C4.536000006.714000004.32900000
H4.358000007.542000004.84100000
H3.801000006.079000004.51700000
S−1.950000007.95200000−2.88600000
O1.5520000010.00300000−0.83300000
H1.607000009.77000000−1.67300000
H1.4640000010.87100000−0.78200000
O1.5930000012.50200000−0.06500000
O−4.6420000012.45300000−2.09100000
O−5.7640000012.12400000−4.77400000
H−6.3890000011.57700000−4.64400000
O−0.719000008.22300000−2.13100000
O−3.145000008.14200000−2.04600000
O−2.017000008.88500000−4.04800000
O−1.907000006.55700000−3.40000000
N0.2130000014.29400000−0.19600000
H0.9230000014.81200000−0.14900000
N−1.0080000016.24900000−0.31100000
H−1.7620000016.69600000−0.38000000
H−0.2440000016.68300000−0.24400000
N−2.1620000014.24400000−0.40800000
N−1.0850000010.82200000−0.22600000
N−2.9770000011.97500000−0.46000000
C−1.0200000014.91500000−0.30800000
C−1.9760000012.91200000−0.36700000
C−0.7960000012.19000000−0.22500000
C0.4220000012.93000000−0.15100000
C−2.3850000010.74900000−0.37600000
H−2.863000009.93000000−0.42200000
C−4.3930000012.23400000−0.72300000
H−4.6800000013.02900000−0.20800000
H−4.9290000011.46200000−0.41300000
C−4.5400000011.23200000−2.85800000
H−3.7040000010.75600000−2.61800000
H−5.3040000010.63900000−2.64800000
C−4.5360000011.55700000−4.32900000
H−4.3580000010.72900000−4.84100000
H−3.8010000012.19200000−4.51700000
O7.129000003.786000004.20400000
H7.901000004.003000003.86700000
H7.245000003.409000004.98000000
H6.560000004.557000004.39700000
O−4.6511413015.47000153−0.72450806
H−4.6449357115.98253054−1.42730071
H−4.7596699315.95560247−0.01024322
H−3.8019335215.01038869−0.57267532
(c)
Cu0.0009.1360.000
S1.95010.3192.886
O−1.5528.2680.833
H−1.6078.5021.673
H−1.4647.4000.782
O−1.5935.7690.065
O4.6425.8182.091
O5.7646.1474.774
H6.3896.6954.644
O0.71910.0482.131
O3.14510.1292.046
O2.0179.3864.048
O1.90711.7153.400
N−0.2133.9770.196
H−0.9233.4590.149
N1.0082.0220.311
H1.7621.5750.380
H0.2441.5880.244
N2.1624.0270.408
N1.0857.4500.226
N2.9776.2960.460
C1.0203.3560.308
C1.9765.3600.367
C0.7966.0810.225
C−0.4225.3410.151
C2.3857.5220.376
H2.8638.3410.422
C4.3936.0370.723
H4.6805.2420.208
H4.9296.8100.413
C4.5407.0392.858
H3.7047.5152.618
H5.3047.6322.648
C4.5366.7144.329
H4.3587.5424.841
H3.8016.0794.517
S−1.9507.952−2.886
O1.55210.003−0.833
H1.6079.770−1.673
H1.46410.871−0.782
O1.59312.502−0.065
O−4.64212.453−2.091
O−5.76412.124−4.774
H−6.38911.577−4.644
O−0.7198.223−2.131
O−3.1458.142−2.046
O−2.0178.885−4.048
O−1.9066.556−3.400
N0.21314.294−0.196
H0.92314.812−0.149
N−1.00816.249−0.311
H−1.76216.696−0.380
H−0.24416.683−0.244
N−2.16214.244−0.408
N−1.08510.822−0.226
N−2.97711.975−0.460
C−1.02014.915−0.308
C−1.97612.912−0.367
C−0.79612.190−0.225
C0.42212.930−0.151
C−2.38510.749−0.376
H−2.8639.930−0.422
C−4.39312.234−0.723
H−4.68013.029−0.208
H−4.92911.462−0.413
C−4.54011.232−2.858
H−3.70410.756−2.618
H−5.30410.639−2.648
C−4.53611.557−4.329
H−4.35810.729−4.841
H−3.80112.192−4.517
O7.1293.7864.204
H7.9014.0033.867
H7.2453.4094.980
H6.5604.5574.397
O−7.12914.485−4.204
H−7.90114.268−3.867
H−7.24514.862−4.980
H−6.56013.714−4.397
C9.8870.0009.991
S7.9371.1837.106
O11.439−0.8679.159
H11.494−0.6348.318
H11.351−1.7369.209
O11.480−3.3669.927
O5.245−3.3177.900
O4.123−2.9885.217
H3.498−2.4415.347
O9.1680.9127.860
O6.7420.9937.946
O7.8700.2505.943
O7.9802.5796.592
N10.100−5.1589.795
H10.810−5.6779.842
N8.880−7.1149.680
H8.125−7.5619.612
H9.644−7.5489.747
N7.725−5.1089.583
N8.802−1.6869.765
N6.910−2.8399.532
C8.867−5.7809.683
C7.911−3.7769.624
C9.091−3.0549.766
C10.309−3.7959.841
C7.503−1.6139.615
H7.024−0.7959.570
C5.494−3.0999.269
H5.207−3.8949.783
H4.958−2.3269.578
C5.348−2.0977.134
H6.183−1.6217.374
H4.583−1.5047.344
C5.352−2.4215.662
H5.529−1.5935.150
H6.087−3.0575.475
S11.837−1.18312.877
O8.3350.86710.824
H8.2800.63411.665
H8.4241.73610.773
O8.2953.36610.056
O14.5293.31712.082
O15.6512.98814.765
H16.2762.44114.635
O10.606−0.91212.122
O13.032−0.99312.037
O11.904−0.25014.040
O11.794−2.57913.391
N9.6745.15810.187
H8.9645.67710.141
N10.8957.11410.302
H11.6497.56110.371
H10.1317.54810.236
N12.0495.10810.400
N10.9721.68610.218
N12.8652.83910.451
C10.9075.78010.300
C11.8633.77610.358
C10.6833.05410.216
C9.4663.79510.142
C12.2721.61310.368
H12.7500.79510.413
C14.2813.09910.714
H14.5673.89410.200
H14.8162.32610.404
C14.4272.09712.849
H13.5921.62112.609
H15.1911.50412.639
C14.4232.42114.320
H14.2451.59314.832
H13.6883.05714.508
O12.646−3.78615.779
H11.873−4.00316.115
H12.530−3.40915.003
H13.214−4.55715.586
O2.759−5.3505.788
H1.986−5.1326.124
H2.643−5.7265.012
H3.327−4.5795.594

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Crystals 06 00139 g001 550
Figure 1. Formula of acyclovir and the numbering used in this work (see also Figure A1).
Figure 1. Formula of acyclovir and the numbering used in this work (see also Figure A1).
Crystals 06 00139 g001
Crystals 06 00139 g002 550
Figure 2. Structure and H-bonding interactions (dashed lines) in 1. The H3O+ ion is H-bonded to O-acceptors of three neighboring complex anions. Symmetry codes: a = –x, –y + 1, –z; f = x + 1, –y + 1/2, z + 1/2; g = –x + 1, y –1/2, –z + 3/2.
Figure 2. Structure and H-bonding interactions (dashed lines) in 1. The H3O+ ion is H-bonded to O-acceptors of three neighboring complex anions. Symmetry codes: a = –x, –y + 1, –z; f = x + 1, –y + 1/2, z + 1/2; g = –x + 1, y –1/2, –z + 3/2.
Crystals 06 00139 g002
Crystals 06 00139 g003 550
Figure 3. Compound 1: (a) molecular electrostatic potential surface (MEPS). The values at selected points of the surface are indicated. Color code: from red to blue, with red being the most negative and blue the most positive values; (b) Mulliken and Merz-Kollman charges obtained at the BP86-D3/def2-TZVP level of theory.
Figure 3. Compound 1: (a) molecular electrostatic potential surface (MEPS). The values at selected points of the surface are indicated. Color code: from red to blue, with red being the most negative and blue the most positive values; (b) Mulliken and Merz-Kollman charges obtained at the BP86-D3/def2-TZVP level of theory.
Crystals 06 00139 g003
Crystals 06 00139 g004 550
Figure 4. Theoretical models used to evaluate the electrostatic assisted H-bonding interactions in the solid state of compound 1. (a): Interaction of H3O+ with O(ol) atom of acv; (b): Interaction of H3O+ with N3 atom of acv; (c): Interaction of H3O+ with O(ol) of acv and O-Sulfate atom.
Figure 4. Theoretical models used to evaluate the electrostatic assisted H-bonding interactions in the solid state of compound 1. (a): Interaction of H3O+ with O(ol) atom of acv; (b): Interaction of H3O+ with N3 atom of acv; (c): Interaction of H3O+ with O(ol) of acv and O-Sulfate atom.
Crystals 06 00139 g004

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MDPI and ACS Style

Vílchez-Rodríguez, E.; Pérez-Toro, I.; Bauzá, A.; Matilla-Hernández, A. Structural and Theoretical Evidence of the Depleted Proton Affinity of the N3-Atom in Acyclovir. Crystals 2016, 6, 139. https://doi.org/10.3390/cryst6110139

AMA Style

Vílchez-Rodríguez E, Pérez-Toro I, Bauzá A, Matilla-Hernández A. Structural and Theoretical Evidence of the Depleted Proton Affinity of the N3-Atom in Acyclovir. Crystals. 2016; 6(11):139. https://doi.org/10.3390/cryst6110139

Chicago/Turabian Style

Vílchez-Rodríguez, Esther, Inmaculada Pérez-Toro, Antonio Bauzá, and Antonio Matilla-Hernández. 2016. "Structural and Theoretical Evidence of the Depleted Proton Affinity of the N3-Atom in Acyclovir" Crystals 6, no. 11: 139. https://doi.org/10.3390/cryst6110139

APA Style

Vílchez-Rodríguez, E., Pérez-Toro, I., Bauzá, A., & Matilla-Hernández, A. (2016). Structural and Theoretical Evidence of the Depleted Proton Affinity of the N3-Atom in Acyclovir. Crystals, 6(11), 139. https://doi.org/10.3390/cryst6110139

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