Topological Electron Density Analysis and Electrostatic Properties of

Article pubs.acs.org/crystal

Topological Electron Density Analysis and Electrostatic Properties of Aspirin: An Experimental and Theoretical Study David Stephen Arputharaj,† Venkatesha R. Hathwar,‡ Tayur N. Guru Row,‡ and Poomani Kumaradhas*,† †

Department of Physics, Periyar University, Salem 636 011, India Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India

‡

S Supporting Information *

ABSTRACT: The topological and the electrostatic properties of the aspirin drug molecule were determined from highresolution X-ray diffraction data at 90 K, and the corresponding results are compared with the theoretical calculations. The electron density at the bond critical point of all chemical bonds including the intermolecular interactions of aspirin has been quantitatively described using Bader’s quantum theory of “Atoms in Molecules”. The electrostatic potential of the molecule emphasizes the preferable binding sites of the drug and the interaction features of the molecule, which are crucial for drug−receptor recognition. The topological analysis of hydrogen bonds reveals the strength of intermolecular interactions.

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INTRODUCTION Aspirin, acetyl salicylic acid (Scheme 1), is unique among conventional nonsteroidal anti-inflammatory drugs, because it

density distribution of the molecule. The structure of aspirin was previously determined by X-ray diffraction;13 further it has been redetermined by Kim et al.14 and Wilson15 by neutron diffraction at 100 K. We have redetermined the structure and the electron density distribution of the aspirin molecule from high-resolution X-ray diffraction at 90 K, as well as quantum chemical calculations to understand its bond topology and electrostatic properties. Here, we report the charge density analysis of the aspirin molecule in gas phase as well as in crystal phase, which provides the fine details about the molecule at electronic level. One of the most exciting applications of charge density analysis is the evaluation of one-electron properties in molecular crystals. The widely used method for this analysis is the Hansen−Coppens formalism,16 in which individual atomic densities are described in terms of a spherical core and valence densities together with an expansion of atom-centered spherical harmonic functions.

Scheme 1. Aspirin

has both anti-inflammatory and cardioprotective properties.1 It is the most commonly used analgesic, antipyretic, and antiplatelet drug.1 Generally, it is being used for both primary and secondary prevention of myocardial infarction (MI), stroke, and cardiovascular death.2−5 Moreover, aspirin is the inhibitor of many receptor complexes;6 concerning its anti-inflammatory therapy, it acts by irreversibly inhibiting the cyclooxygenase-1 (COX-1) enzyme through acetylating the serine residue.7 Despites its various bioactive properties, many adverse effects also been suggested due to its anticoagulant properties8 and the risk of Reye's syndrome9,10 for the children under 12 years of age. Its structural modification and understanding its electrostatic properties may allow researchers to redesign this drug to reduce these fatal side effects.8,9 Recently, several studies11,12 have been conducted on this drug. Such publicity fueled our interest to predict the strength of electrostatic interaction with the receptor, which in turn derived from the detailed electron © 2012 American Chemical Society

ρatom (r ) = ρc (r ) + Pvκ 3ρv (κr ) +

l max

l

l=0

m=0

∑ κ′3Rl(κ′r) ∑ Plm±Ylm±(θ , ϕ) (1)

where ρc and ρv are the spherical core and valence densities, respectively, and the summation in the third term accounts for the valence deformation. Pv is the valence population parameter, which gives the estimate of the net atomic charge. Rl = rnl exp(−ζr) is a radial Slater-type function and the coefficients κ Received: February 25, 2012 Revised: July 9, 2012 Published: July 17, 2012 4357

dx.doi.org/10.1021/cg300269n | Cryst. Growth Des. 2012, 12, 4357−4366

Crystal Growth & Design

Article

and κ′ describe the contraction−expansion for the spherical and multipolar valence densities, respectively. Plm are the multipole populations and Ylm± are the real spherical harmonics of order l. The topology of the charge density can be explored from the Bader’s quantum theory of atoms in molecules.17 The maxima of the electron density are the bond critical points (bcp) where the first derivatives of the electron density become zero. The second derivative of the density at the same point is the Laplacian of electron density and gives the areas of local charge concentration/depletion.18 If ∇2ρ(r) < 0, the density is locally concentrated, whereas if ∇2ρ(r) > 0, the electron density is locally depleted.

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Table 1. Experimental Details chemical formula Mr cell setting, space group temp (K) a, b, c (Å) β (deg) V (Å3) Z Dx (g/cm3) radiation type μ (mm−1) cryst form, color cryst size (mm3) diffractometer data collection method total reflns redundancy obsd reflns criteria for obsd reflns Rint θmax (deg) range of h, k, l

C9H8O4 180.15 monoclinic, P21/c 90(2) 11.2680(8), 6.5498(4), 11.2646(7) 95.933(4) 826.9(1) 4 1.447 Mo Kα (λ = 0.71073 Å) 0.115 block, colorless 0.25 × 0.22 × 0.14 Bruker SMART APEX CCD area detector ω-scans 81045 9.6 5569 I > 2σ(I) 0.033 52.3 −24 < h < 0 −13 < k < 0 −24 < l < 24 Spherical Atom Model Refinement R(F), wR(F2) 0.049, 0.137 GOF 1.046 no. reflns used in refinement 8199 Multipole Model Refinement R(F), wR(F2) 0.033, 0.053 GOF 1.896 Nref/Nv 22.73 no. reflns 5569 no. params 245 (Δ/σ)max 0.8 Å−1. During the refinement, all hydrogen atom positions were adjusted to neutron bond distances.24 Further, Pv, κ, Plm, and scale factor were refined; during the refinement, chemical constraints [C(3) = C(4) = C(5) = C(6); C(9) = C(7); H(3) = H(4) = H(5) = H(6); H(7) = H(8) = H(9)] were imposed, and the κ values for H-atoms were fixed to 1.2. All non-hydrogen atoms were refined up to hexadecapole level, whereas the hydrogen atoms were refined up to dipole level. This model refinement was carried out until the parameters were converged. The above procedure has been repeated again, in which the κ′ values for the non-hydrogen atoms were fixed with the reported values.25 Subsequently, the positional parameters x,y,z, Uij, and then the scale parameters were refined. In further cycles of refinement, Pv + κ, scale factor, and then Plm + κ′ were refined. After converging these parameters, the chemical constraints were released progressively except for the aromatic carbon atoms C(3), C(4), C(5), and C(6) and their respective hydrogen atoms. Finally, the following model refinements were carried out iteratively several times until the convergence: (a) Pv + κ, (b) Plm + κ′, (c) scale factor, and (d) xyz + Uij. During the entire model refinements, the electroneutrality constrain was imposed on the molecule. The crystal data and the multipole refinement details are given in Table 1. The total electron density, ρbcp(r), the Laplacian, ∇2ρbcp(r), the ellipticity, ε, at the bond critical points, and the eigen values (λ1, λ2, λ3) were calculated by using XDPROP routine of XD program suite.23 Theoretical Calculations. A density functional calculation (DFT) was performed to determine the charge density distribution of the aspirin molecule using GAUSSIAN03 software.26 A single point energy calculation was carried out for the molecule lifted from the crystal at B3LYP27 level of theory with the standard basis set, 6-311G**.

Figure 1. ORTEP representation of molecular structure of aspirin with atom numbering scheme. Thermal ellipsoid atoms are drawn at 50% probability level. The H-atoms are shown as spheres of arbitrary radii. 4358



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Table 2. Geometric Parameters Bond Lengths (Å) C(1)−C(2) C(2)−C(3) C(3)−C(4) C(4)−C(5) C(5)−C(6) C(1)−C(6) C(1)−C(9)

1.4057(5) 1.3907(6) 1.3944(6) 1.3943(6) 1.3905(6) 1.4029(5) 1.4885(5)

C(7)−C(8) C(9)−O(1) C(9)−O(2) C(7)−O(3) C(7)−O(4) C(2)−O(3)

1.4925(6) 1.2334(5) 1.3153(5) 1.3660(5) 1.2066(5) 1.3927(4)

Bond Angles (deg) C(1)−C(2)−C(3) C(2)−C(3)−C(4) C(3)−C(4)−C(5) C(4)−C(5)−C(6) C(1)−C(6)−C(5) C(2)−C(1)−C(6) C(9)−O(2)−H(2) C(2)−O(3)−C(7) C(2)−C(1)−C(9) C(6)−C(1)−C(9) O(3)−C(2)−C(1) O(3)−C(2)−C(3) C(2)−C(3)−H(3) C(4)−C(3)−H(3) C(3)−C(4)−H(4) C(5)−C(4)−H(4)

121.0(3) 119.7(3) 120.3(2) 119.6(1) 121.2(2) 118.1(3) 107.1(3) 116.2(3) 125.1(3) 116.7(3) 122.1(3) 116.8(3) 116.7(4) 123.5(3) 119.1(2) 120.6(1)

C(4)−C(5)−H(5) C(1)−C(6)−H(6) C(5)−C(6)−H(6) O(3)−C(7)−O(4) O(3)−C(7)−C(8) O(4)−C(7)−C(8) C(7)−C(8)−H(7) C(7)−C(8)−H(8) C(7)−C(8)−H(9) H(7)−C(8)−H(8) H(7)−C(8)−H(9) H(8)−C(8)−H(9) O(1)−C(9)−O(2) O(1)−C(9)−C(1) O(2)−C(9)−C(1) C(6)−C(5)−H(5)

121.4(1) 120.4(2) 118.4(1) 122.4(4) 111.4(3) 126.3(4) 108.3(4) 108.2(4) 110.4(4) 111.2(5) 112.3(4) 106.4(4) 122.9(4) 120.8(4) 116.4(3) 119.0(3)

Torsion Angles (deg) C(1)−C(2)−C(3)−C(4) C(2)−C(3)−C(4)−C(5) C(3)−C(4)−C(5)−C(6) C(4)−C(5)−C(6)−C(1) C(2)−C(1)−C(6)−C(5) C(6)−C(1)−C(2)−C(3) C(2)−C(1)−C(6)−H(6) C(2)−C(1)−C(9)−O(1) C(2)−C(1)−C(9)−O(2) C(9)−C(1)−C(2)−O(3) C(9)−C(1)−C(2)−C(3) C(6)−C(1)−C(9)−O(1) C(6)−C(1)−C(9)−O(2) C(9)−C(1)−C(6)−C(5) C(9)−C(1)−C(6)−H(6) O(3)−C(2)−C(3)−C(4) O(3)−C(2)−C(3)−H(3) C(1)−C(2)−C(3)−H(3) C(2)−C(3)−C(4)−H(4) H(3)−C(3)−C(4)−C(5)

0.9(1) −0.4(1) −0.4(1) 0.7(1) −0.2(1) −0.6(1) 178.3(1) 178.6(1) −1.7(1) 1.9(1) 179(1) −1.8(1) 177.8(1) −179.8(1) −1.4(1) 178.1(1) −4.9(1) 177.9(1) −177.1(1) −177.1(1)

H(3)−C(3)−C(4)−H(4) H(2)−O(2)−C(9)−O(1) H(2)−O(2)−C(9)−C(1) C(2)−O(3)−C(7)−O(4) C(7)−O(3)−C(2)−C(1) C(7)−O(3)−C(2)−C(3) C(2)−O(3)−C(7)−C(8) C(6)−C(1)−C(2)−O(3) C(3)−C(4)−C(5)−H(5) H(4)−C(4)−C(5)−C(6) H(4)−C(4)−C(5)−H(5) C(4)−C(5)−C(6)−H(6) H(5)−C(5)−C(6)−C(1) H(5)−C(5)−C(6)−H(6) O(3)−C(7)−C(8)−H(7) O(3)−C(7)−C(8)−H(8) O(3)−C(7)−C(8)−H(9) O(4)−C(7)−C(8)−H(7) O(4)−C(7)−C(8)−H(8) O(4)−C(7)−C(8)−H(9)

Subsequently, the bond topological28 and electrostatic properties of the molecule were determined from the wave functions using Bader’s theory of Atoms in Molecules,17 which is incorporated in the AIMPAC software.29 These theoretical charge density parameters were compared with the experimentally derived values.

6.1(1) 6.7(1) −172.9(1) −3.7(1) −82(1) 100.8(1) 176.6(1) −177.6(1) −178.9(1) 176.3(1) −2.2(1) −177.8(1) 179.2(1) 0.7(1) −58.3(1) −179(1) 64.9(1) 121.9(1) 1.3(1) −114.8(1)

geometrical difference between these structures, except the C(9)−O(2) bond; the low-temperature C(9)−O(2) distance [1.315(5) Å] is found to be much longer than the reported room-temperature distance [1.287(1) Å],13 and it is slightly longer [1.308(1) Å] than the reported low-temperature neutron structure.15 This bond lengthening may be attributed to the involvement of a strong intermolecular interaction of the carboxyl group. The bond angles are almost equal to the reported room-temperature and low-temperature structures.13−15 The torsion angle of C(9)−C(1)−C(2)−O(3) bonds is 1.9(1)°; this small twist angle indicates that the O-acetyl and the carboxyl groups attached at C(1) and C(2) atoms, respectively, exhibit cis conformation in the molecule. However, the torsion angles of all remaining bonds of the structure agree well with

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RESULTS AND DISCUSSION Molecular and Crystal Structure. Figure 1 depicts the structure of the aspirin molecule with thermal ellipsoidal atoms determined from the low-temperature measurement (90 K). The geometric parameters of this molecule have been compared with the reported room temperature structure,13 as well as the low-temperature structure (100 K) determined from the neutron diffraction15 (Table 2). We did not find any significant 4359



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Figure 2. (a) Hydrogen bonding network in the monoclinic aspirin lattice, (b) molecular stacking, and (c) face−face lock representation.

the reported low-temperature neutron structure.15 The dihedral angle between the carboxyl group and the aromatic ring (1.7°) confirms that the carboxyl group is located at the equatorial position of the molecule. On the other hand, the O-acetyl group is present at the axial position, and the corresponding angle is 82.3°. The molecular packing is predominantly stabilized by intermolecular O−H···O and C−H···O types of hydrogen bonding interactions. Figure 2a−c shows the molecular stacking, face− face lock representation (with the angle of 71.9°) of molecular packing, and intermolecular hydrogen bonding interaction of the molecule in the crystal. A strong O(2)−H(2)···O(1)i hydrogen bonding interaction forms a dimer in the crystal. The H-bond parameters are H(2)···O(1)i = 1.732(5) Å, O(2)···O(1)i = 2.640(1) Å, and the angle is 172.2(8)°. Besides this strong hydrogen bonding interaction, several weak C−H···O type hydrogen bonding interactions are also found in the crystal. The hydrogen bonding parameters of both types are presented in Table 3 [(i) −x, −y + 1, −z + 1].

the aromatic ring illustrate the covalent bonding between the carbon−carbon and carbon−hydrogen atoms. The electron density, ρbcp(r), in the C−C bonds of aromatic ring ranges from 1.95(4) to 2.26(3) e Å−3 [Table 4], in which the C(2)−C(3) bonding region has high charge accumulation. The trend remains same in theory also; the corresponding experimental and the theoretical ρbcp(r) values are 2.26(3) and 2.13 e Å−3 respectively. These values agree well with those reported for salicylic acid.30 The low charge accumulation in C(1)−C(2) [1.95(4) e Å−3] and C(1)−C(6) [1.97(4) e Å−3] bonds are found to be less compared with other C−C bonds in the ring. The same scenario is also found in theory; the corresponding electron density ρbcp(r) values are 2.06 and 2.05 e Å−3 respectively. The average electron density of C(3)− C(4), C(4)−C(5), and C(5)−C(6) bonds are 2.13/2.09 e Å−3, which well agree with the reported values for aromatic C−C bonds.31,32 The nonring C−C bonds carry markedly different densities; among these, the electron density of C(1)−C(9) bond is 1.92(4) e Å−3, which is little higher than the density of the C(7)−C(8) [1.72(3) e Å−3] bond of the O-acetyl group. However, this value is in good agreement with the reported value of similar bonds in the paracetamol molecule.33 As expected, the electron-rich CO bonds exhibit a large amount of electron density at the bcp. The experimental and theoretical ρbcp(r) values of CO bonds of carboxyl and acetyl groups are 2.78(5)/2.69 e Å−3 and 2.81(6)/2.83 e Å−3 respectively. These values are in good agreement with those reported for salicylic acid.30 The charge accumulation in the C−O bonds of carboxyl and O-acetyl groups are unequal; the charges in the C−O bonds of the carboxyl group are more highly concentrated than those in the O-acetyl group [Table 4]. This difference may be due to the presence of different environment and the participation of these groups in the hydrogen bonding interaction in the crystal. The lone pair electrons of O-atoms are very prominent in both static and dynamic deformation density maps. On comparison the theoretical and experimental deformation density maps (Figure 3), a large difference is found around the O(1) atom; this difference may be attributed to the limited flexibility of the radial functions used in the multipole model as well as the basis set and the electron correlation effect in theory.34−37 The C−H bonds of the aromatic ring have almost equal electron density values [1.76(1)/1.91 e Å−3]; the predicted density values are slightly higher than the experimental ones. In the methyl group, the electron density values

Table 3. Hydrogen Bonding Interactions and Short Contacts D−H···Aa

H···A (Å)

D···A (Å)

∠D−H···A (deg)

O(2)−H(2)···O(1)i O(2)−H(2)···O(2)i C(3)−H(3)···O(4)ii C(8)−H(8)···O(4)iii C(6)−H(6)···O(1)iv C(4)−H(4)···O(4)v C(5)−H(5)···O(1)iv C(6)−H(6)···O(2)vi C(8)−H(9)···O(4)vii

1.732(15) 2.951(16) 2.658(12) 2.648(13) 2.690(13) 2.577(13) 2.571(13) 2.951(13) 2.702(17)

2.640(1) 3.661(1) 3.564(1) 3.564(1) 2.758(1) 3.338(1) 3.268(1) 3.457(1) 3.349(1)

172(1) 136(1) 155.1(9) 167(1) 122.0(9) 134.2(9) 126.0(9) 112.8(9) 123(1)

(i) −x, −y + 1, −z + 1. (ii) −x + 1, −y + 2, −z + 1. (iii) −x + 1, −y + 1, −z + 1. (iv) −x, y + 1/2, −z + 1/2 + 1. (v) x, +y + 1, z. (vi) x, −y + 1/2 + 1, z + 1/2. (vii) x, −y + 1/2 + 1, z − 1/2. a

Electron Density. The topological analysis of all chemical bonds of the aspirin molecule including intermolecular interactions has been carried out from the electron density analysis of the molecule via high-resolution X-ray diffraction as well as high-level quantum chemical calculations. Figure 3 shows the static and dynamic deformation density maps of the aspirin molecule in different planes. The deformation density maps of 4360



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Figure 3. The experimental (a) static and (b) dynamic and (c) theoretical deformation density maps of aspirin molecule drawn at C(3), C(6), C(9) and O(3), O(4), C(8) planes. Contours are drawn at 0.05 e Å−3 intervals. Solid lines represent positive contours, dashed lines are negative contours, and the dotted lines are zero contours. 4361



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Table 4. Topological Parameters of Electron Density of Aspirin Molecule Derived from Experiment (First Line) and DFT Calculation (Second Line)a bonds

R (Å)

ρbcp(r) (e Å−3)

∇2ρbcp(r) (e Å−5)

λ1 (e Å−5)

λ2 (e Å−5)

λ3 (e Å−5)

ε

d1 (Å)

d2 (Å)

D (Å)

Δd%

C(1)−C(2)

1.4057(5)

C(2)−C(3)

1.3907(6)

C(3)−C(4)

1.3944(6)

C(4)−C(5)

1.3943(6)

C(5)−C(6)

1.3905(6)

C(6)−C(1)

1.4029(5)

C(1)−C(9)

1.4885(5)

C(7)−C(8)

1.4925(6)

C(9)−O(1)

1.2334(5)

C(9)−O(2)

1.3153(5)

C(2)−O(3)

1.3927(4)

C(7)−O(3)

1.3660(5)

C(7)−O(4)

1.2066(5)

C(3)−H(3)

1.083

C(4)−H(4)

1.083

C(5)−H(5)

1.083

C(6)−H(6)

1.083

C(8)−H(7)

1.059

C(8)−H(8)

1.059

C(8)−H(9)

1.059

O(2)−H(2)

1.015

1.95(4) 2.06 2.26(3) 2.13 2.13(1) 2.08 2.03(1) 2.09 2.23(1) 2.11 1.97(4) 2.05 1.92(4) 1.80 1.72(3) 1.78 2.78(5) 2.69 2.22(6) 2.16 1.77(4) 1.80 2.19(5) 1.93 2.81(6) 2.83 1.76(3) 1.91 1.76(1) 1.91 1.76(1) 1.91 1.76(1) 1.93 1.84(8) 1.98 1.87(6) 2 1.73(7) 1.97 2.13(8) 2.14

−14.0(2) −20.0 −23.7(1) −21.6 −21.3(1) −20.7 −19.3(1) −20.9 −23.1(1) −21.2 −18.0(1) −20.1 −14.2(2) −16.2 −14.9(1) −16.2 −33.8(3) −9.9 −31.6(3) −8.6 −17.6(2) −9.6 −21.7(2) −11.2 −24.5(4) −4.8 −17.1(1) −23.4 −17.1(1) −23.7 −17.1(1) −23.5 −17.1(1) −24.1 −15.9(2) −25 −17.2(2) −25.4 −14.9(2) −24.8 −34.5(5) −47.9

−14.5 −15.6 −17.7 −16.3 −16 −15.5 −15.4 −15.6 −16.9 −15.8 −14.8 −15.2 −15.4 −13.2 −12.3 −12.7 −30.4 −24.3 −21.3 −17.6 −14.3 −12.6 −21.5 −14.3 −31.2 −26.7 −17.2 −18.2 −17.2 −18.3 −17.2 −18.2 −17.1 −18.8 −15 −18.8 −16.5 −19.2 −14.7 −18.6 −33.5 −34.6

−11.1 −12.5 −14.1 −13 −12.5 −12.9 −11.4 −13.1 −13.5 −13.2 −11.9 −12.7 −11.8 −11.8 −11.5 −12.0 −20.2 −22.4 −19.8 −17.3 −13.0 −11.9 −14.7 −13.9 −22.7 −24.3 −15.6 −17.9 −15.6 −18.0 −15.6 −17.9 −15.6 −18.5 −12.7 −18.7 −14.2 −18.9 −12.7 −18.5 −30.9 −34.0

11.5 8.1 8.1 7.8 7.2 7.8 7.5 7.8 7.3 7.8 8.7 7.9 12.9 8.8 9 8.5 16.8 36.8 9.5 26.2 9.7 14.9 14.4 16.9 29.5 46.3 15.7 12.6 15.8 12.6 15.8 12.5 15.7 13.2 11.8 12.5 13.6 12.7 12.4 12.3 29.9 20.6

0.31 0.25 0.26 0.25 0.28 0.2 0.36 0.19 0.25 0.2 0.24 0.2 0.31 0.13 0.07 0.06 0.5 0.09 0.08 0.02 0.1 0.06 0.46 0.03 0.37 0.1 0.1 0.02 0.1 0.01 0.1 0.02 0.1 0.01 0.18 0.01 0.16 0.01 0.15 0.01 0.08 0.02

0.726 0.686 0.729 0.723 0.667 0.7 0.697 0.704 0.699 0.691 0.677 0.691 0.768 0.722 0.801 0.788 0.453 0.425 0.478 0.447 0.537 0.478 0.561 0.476 0.423 0.414 0.744 0.696 0.745 0.694 0.744 0.693 0.744 0.703 0.63 0.673 0.677 0.674 0.649 0.671 0.799 0.798

0.692 0.721 0.663 0.668 0.727 0.694 0.698 0.69 0.692 0.699 0.73 0.712 0.722 0.768 0.698 0.705 0.783 0.808 0.838 0.869 0.86 0.916 0.807 0.891 0.784 0.793 0.34 0.372 0.339 0.374 0.339 0.375 0.34 0.365 0.429 0.371 0.384 0.37 0.414 0.373 0.216 0.196

1.419 1.407 1.391 1.391 1.395 1.394 1.395 1.394 1.39 1.39 1.407 1.403 1.489 1.489 1.499 1.493 1.235 1.233 1.316 1.316 1.397 1.394 1.367 1.367 1.207 1.207 1.084 1.068 1.084 1.068 1.084 1.068 1.084 1.068 1.059 1.044 1.061 1.044 1.064 1.044 1.016 0.994

1.2 1.3 2.4 2 2.2 0.2 0 0.5 0.2 0.3 1.9 0.7 1.5 1.5 3.5 2.8 13.4 15.5 13.7 16 11.6 15.7 9 15.2 15 15.7 18.7 15.1 18.7 15 18.7 14.9 18.6 15.9 9.5 14.5 13.8 14.6 11 14.3 28.7 30.3

R, interatomic distance; ρbcp(r) and ∇2ρbcp(r), electron density and the Laplacian of electron density at bond critical point; λ1, λ2, λ3, eigenvalues; ε, bond ellipticity; d1, d2, the distance between bcp and each bonded atom; D, the total bond path length; Δd%, displacement of the bcp from the bond midpoint. a

[1.80(6)/1.98 e Å−3] of C−H bonds are comparable with those of the aromatic C−H bonds. Relatively, the electron density at the bcp of the polar bond O−H is highly concentrated, and the value is 2.13(8) e Å−3; the experimental density is almost equal to the theory (2.14 e Å−3). Further, a bond path analysis has been carried out for all bonds of the molecule, which reveals the position of bcp in the bonding region. The bond charge polarization of each bond of the molecule has been calculated. The bcp’s of C−O bonds are located away from the O-atoms at about 12.5%/15.6% from the bond midpoints toward the carbon atoms. This indicates that the O-atoms are larger in size and more polar in nature than the other non-hydrogen atoms. The polarization effect in C−H and

O−H bonds is predominantly higher compared with the nonhydrogen bonds (C−O). This difference is due to the heavy and light atom interaction; theory also predicts the similar kind of polarization. Laplacian of Electron Density. The Laplacian of electron density, ∇2ρbcp(r), at the bond critical points of the molecule bears the chemical significance of the bond topological theory of molecular structure.17 Figure 4 shows the Laplacian of electron density of the aspirin molecule drawn from experimental and theoretical results. The Laplacian of the electron density is negative for all bonds in the molecule and exhibits (3,−1) type of bond-critical points. As we noticed in the previous section, the charge accumulation is not same for all (C−C)ar bonds of 4362



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Figure 4. Laplacian of electron density maps of aspirin molecule shown in two fragments: (a) experimental and (b) DFT. The contour intervals are ±2 × 10n, ±4 × 10n, and ±8 × 10n, (n = −2, −1, 0, 1, 2). Solid lines indicate positive contours, and dashed lines are negative contours.

inspection of the eigen values, λ1, λ2, and λ3. Recent reports outline that this might be due to the different behavior of Gaussian and Slater-type radial functions at the vicinity of the bcp.34−37 However, it seems clear from the recent comparative study between theory and experiment for C−O bonds38 that this is due to the rapid variation of Laplacian along the internuclear vector including the location of the bcp. The ∇2ρbcp(r) value of O(2)−H(2) bond being −34.5(5) e Å−5 indicates that charges of this bond are highly concentrated, which well agrees with the reported value.39 Gradient Vector Field. Figure 5 depicts the gradient of vector field of electron density, ∇ρ(r), of the aspirin molecule, plotted from the experimental data using WINXPRO program.40 The gradient trajectories originate at atomic centers and terminate at bond critical points, ring critical points (rcp), and cage critical points (ccp) (rcp and ccp were not discussed here). The zero-flux surfaces of atoms in the molecule define the boundary of an atomic basin. The highly electronegative oxygen atoms display large volume compared with the carbon atoms in the molecule. The atomic basins of carbon atoms have a prismatic form, whereas the O atoms are drop shaped. Figure 5 shows the (3,−1) type of bcp between covalently linked atoms. Invariably, the gradient lines are dominant in the core of the atomic basin of all atoms, and it decreases as the distance to

the aromatic ring; a similar trend can also be seen in the Laplacian of electron density distribution. The Laplacian values for (C−C)ar bonds ranges from −14.0(2) to −23.7(1) e Å−5, of which the Laplacian values of C(1)−C(2) [−14.0(2) e Å−5] and C(1)−C(6) [−18.0(1) e Å−5] bonds are smaller than those for the other C−C bonds. Further, similar negative Laplacian values are also found in C(1)−C(9) [−14.2(2)/−16.2 e Å−5] and C(7)−C(8) [−14.9(1)/−16.2 e Å−5] bonds of carboxyl and O-acetyl groups, in which the charges are not very compact and are considerably depleted. The same trend is found in the reported salicylic acid30 and the paracetamol33 molecules. The high negative Laplacian values of C−O bonds [C(9)−O(2), −31.6(3) e Å−5] and CO bonds [C(9)O(1), −33.8(3) e Å−5] of the carboxyl fragments confirm that the charges are highly concentrated. These values are in good agreement with the values reported in salicylic acid structure.30 In O-acetyl group, the ∇2ρbcp(r) value for the C(7)O(4) bond is −24.5(4) e Å−5; notably, this value is much less compared with the C(9)O(1) bond [−33.8 e Å−5] of the carboxyl group; however, this value is similar to that reported for the paracetamol molecule.33 Overall, there are significant discrepancies between the experimental and theoretical ∇2ρbcp(r) values for C−O and CO bonds [Table 4]. The origin of this discrepancy can be well understood on careful 4363



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Figure 5. Gradient trajectory plots of the experimental electron density distribution showing (a) aromatic ring with carboxylic group and (b) O-acetyl group of the aspirin molecule. The closed black thick solid lines around an atom are the boundaries of the atomic basin and the red open circles represents the (3,−1) critical points.

atoms of carboxyl and acetyl groups in the molecule (Figure 6). Apart from these, we have noticed an electronegative region just above and below the aromatic ring; this is attributed to the π-cloud of electrons. A similar kind of negative ESP region has been found in the reported bioactive molecules estrone,43 estradiol-17β,44 genistein,45 diethylstilbestrol, and dienestrol.46 The high positive and negative ESP areas in the molecule can be considered as the possible locations for intermolecular interaction. Matching of these ESP regions of the ligand to the complementary surface in the receptor is responsible for molecular recognition.47 Intermolecular Interactions. The molecular packing in the crystal is governed by the O−H···O and several weak C−H···O types of interactions (Table 3). As mentioned earlier, the O(2)−H(2)···O(1)i [i = −x, −y + 1, −z + 1] is the strongest hydrogen bonding interaction and is responsible for the formation of molecular dimers in the crystal. To understand the strength of this hydrogen bonding interaction, a bond topological analysis has been carried out (Table 5). The bond critical point search on H(2)···O(1)i bond produced a (3,−1) type of critical point at the distance of 0.522 Å from the H(2) atom towards the symmetrically sitting acceptor O(1)i atom in the neighboring molecule of the crystal. The H-bond topological parameters are as follows: ρbcp(r) at bcp is 0.23(5) e Å−3, and the corresponding Laplacian is 6.45(4) e Å−5. The positive value of the Laplacian confirms that this interaction is a closed shell type of interaction. Figure 7 shows the relief plot of Laplacian of electron density in the region of the dimer, which is formed by a O(2)−H(2)···O(1)i hydrogen bonding interaction between two neighboring molecules in the crystal. The relief map (Figure 7) illustrates the alignment of lone pairs of O

the nucleus increases. This is because of asphericity of the valence electron density.41 The volumes of O atoms of carboxylic and acetyl groups are unequal, ranging from 14.71 to 18.59 Å3, and these experimental values agree well with the values (13.7−18.92 Å3) determined from the theoretical electron density. In the carboxylic group, the O atoms are involved in hydrogen bonding interaction, in which the volume of O(1) atom [16.62 Å3] has been found to be smaller than that from theoretical prediction [18.92 Å3]. No such trend was found in hydroxyl O(2) atom and the acetyl O-atoms. The atomic volumes of aromatic carbon atoms are larger than C(7) and C(9) atoms; theoretical QTAIM also predicts the similar volumes. The volumes of aromatic and methyl H-atoms were found to be similar to each other and in agreement with the theoretical data. The volume of the hydrogen bonded hydroxyl H-atom [1.42 Å3] is much smaller than that in the isolated molecule [3.57 Å3]. To validate our AIM calculations, we have calculated the net molecular charge and the total molecular and unit cell volume. The accuracy of the AIM calculation has been verified by comparing the total AIM volume [822.3 Å3] with the volume of the unit cell [826.9(1) Å3] calculated from the unit cell parameters. These two volumes almost agree with each other. Electrostatic Potential. The electrostatic potential (ESP) of a molecule gives an idea that the molecule is expected to align and bind to other molecules or to the active site of biological receptors.42 ESP is also being considered as a tool to predict the reactive sites of the molecule. The regions of negative potential are expected to be the sites of nucleophilic attack, while the regions of positive potential are the electrophilic sites. A large negative region (red) is found in the vicinity of O(1) and O(4) 4364



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Figure 6. Isosurface representation of experimental ESP of aspirin molecule. Blue, positive potential (+0.3 e Å−1); red, negative potential (−0.15 e Å−1).

Table 5. The Topological Parameters of Hydrogen Bonds Characterizing the Intermolecular Interactions of Aspirin Molecule

a

interactionsa

ρbcp(r) (e Å−3)

∇2ρbcp(r) (e Å−5)

λ1 (e Å−5)

λ2 (e Å−5)

λ3 (e Å−5)

d1 (Å)

d2 (Å)

D (Å)

H(2)···O(1)i H(3)···O(4)ii H(4)···O(4)iii H(5)···O(1)iv H(6)···O(1)iv H(9)···O(4)v

0.23(5) 0.040(4) 0.044(2) 0.048(1) 0.034(1) 0.036(3)

6.45(4) 0.654(2) 0.705(1) 0.764(1) 0.570(1) 0.582(2)

−1.40 −0.14 −0.15 −0.19 −0.12 −0.14

−1.10 −0.13 −0.13 −0.15 −0.09 −0.07

8.90 0.93 0.98 1.10 0.78 0.80

0.522 1.066 1.115 1.105 1.189 1.423

1.117 1.516 1.439 1.466 1.495 1.536

1.640 2.582 2.554 2.571 2.684 2.959

(i) −x, −y + 1, −z + 1. (ii) −x + 1, −y + 2, −z + 1. (iii) x, y + 1, z. (iv) −x, y + 1/2, −z + 1/2 + 1. (v) x, −y + 1/2 + 1, z − 1/2.

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CONCLUSION The topological and the electrostatic properties of the aspirin drug molecule have been determined from high-resolution X-ray diffraction data, and the results were compared with those obtained from DFT calculations. The geometry of the aspirin molecule was also compared with the reported structures determined at room and low temperatures. No significant differences except for the C(9)−O(2) bond length were found. The charge density distribution of C−C bonds of the aromatic ring are not equal; the C(1)−C(2) bond differs from the other bonds in the ring because both bonded atoms [C(1) and C(2)] are attached to the carboxyl and O-acetyl groups. The charges are highly concentrated in the C−O and CO bonding regions of carboxyl [C(9)−O(2), −31.6(3); C(9)O(1), −33.8(3) e Å−5] and acetyl groups [C(7)O(4), −24.5(4) e Å−5] in the molecule. The bond topological analysis shows that the O(2)−H(2)···O(1)i hydrogen bonding interaction is much stronger than the other hydrogen bonds in the crystal. A highly negative ESP region is found at the vicinity of O(1) and O(4) atoms of carboxyl and acetyl fragments. The negative ESP above the aromatic ring

Figure 7. Relief map of the negative Laplacian of electron density (range −250 to +250 e Å−5) for the O(2)−H(2)···O(1)i hydrogen bonded dimer of aspirin.

atoms in the hydrogen bonding interactions. The orientation of the lone pair lobe of O(1) atom towards the H(2) atom indicates the direction of interaction; this feature can be clearly visualized from the relief map. 4365



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shows the π electron contribution; this can be visualized just above and below the aromatic ring. This study provides the fine details of structural, charge density distribution, and the electrostatic properties of the aspirin molecule, which are very useful for designing new aspirin-based drug molecules with fewer side effects.

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ASSOCIATED CONTENT

S Supporting Information *

X-ray crystallographic information file (CIF) is available for the aspirin compound. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +91-(0)427-2345520. Fax: +91-(0)427-2345565. E-mail address: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.D. is grateful to CSIR-INDIA, for providing the Senior Research Fellowship (SRF) to carry out this research.

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REFERENCES

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Topological Electron Density Analysis and Electrostatic Properties of

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