Quantum-Chemical Insight into StructureâReactivity Relationship in 4

Article pubs.acs.org/JPCA

Quantum-Chemical Insight into Structure−Reactivity Relationship in 4,5,6,7-Tetrahalogeno‑1H‑benzimidazoles: A Combined X‑ray, DSC, DFT/QTAIM, Hirshfeld Surface-Based, and Molecular Docking Approach Jolanta Natalia Latosińska* and Magdalena Latosińska Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland

Jan Krzysztof Maurin National Medicines Institute, Chełmska 30/34, 00-750 Warsaw, Poland ́ Poland National Centre for Nuclear Research, Andrzeja Sołtana 7, 05-400 Otwock-Swierk,

Andrzej Orzeszko and Zygmunt Kazimierczuk Institute of Chemistry, Warsaw University of Life Sciences, 159C Nowoursynowska St., 02-787 Warsaw, Poland ABSTRACT: The weak interaction patterns in 4,5,6,7-tetrahalogeno-1H-benzimidazoles, protein kinase CK2 inhibitors, in solid state are studied by the X-ray method and quantum chemistry calculations. The crystal structures of 4,5,6,7-tetrachloro- and 4,5,6,7-tetrabromo1H-benzimidazole are determined by X-ray diffraction and refined to a final R-factor of 3.07 and 3.03%, respectively, at room temperature. The compound 4,5,6,7-tetrabromo-1Hbenzimidazole, which crystallizes in the I41/a space group, is found to be isostructural with previously studied 4,5,6,7-tetraiodo-1H-benzimidazole in contrast to 4,5,6,7-tetrachloro-1Hbenzimidazole, which crystallizes as triclinic P1̅ with 4 molecules in elementary unit. For 4,5,6,7-tetrachloro-1H-benzimidazole, differential scanning calorimetry (DSC) revealed a second order glassy phase transition at Tg = 95°/106° (heating/cooling), an indication of frozen disorder. The lack of 3D isostructurality found in all 4,5,6,7-tetrahalogeno-1Hbenzimidazoles is elucidated on the basis of the intra- and intermolecular interactions (hydrogen bonding, van der Waals contacts, and C−H···π interactions). The topological Bader’s Quantum Theory of Atoms in Molecules (QTAIM) and Spackman’s Hirshfeld surface-based approaches reveal equilibration of electrostatic matching and dispersion van der Waals interactions between molecules consistent with the crystal site-symmetry. The weakening of van der Waals forces accompanied by increasing strength of the hydrogen bond (N−H···N) result in a decrease in the crystal sitesymmetry and a change in molecular packing in the crystalline state. Crystal packing motifs were investigated with the aid of Hirshfeld surface fingerprint plots. The ordering 4,5,6,7-tetraiodo > 4,5,6,7-tetrabromo > 4,5,6,7-tetrachloro > 4,5,6,7-tetrafluoro reflects not only a decrease in crystal symmetry but also increase in chemical reactivity (electronic activation), which could explain some changes in biological activity of compounds from the 4,5,6,7-tetrahalogeno-1H-benzimidazole series. The ability of formation of a given type of bonds by 4,5,6,7-tetrahalogeno-1H-benzimidazole molecules is the same in the crystal and in CK2. Analysis of the interactions in the crystal permits drawing conclusions on the character (the way) of connections between a given 4,5,6,7-tetrahalogeno-1H-benzimidazole as a ligand with CK2 protein to make a protein−ligand complex.

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INTRODUCTION

indicated as potentially promising drugs for anticancer therapy. Up to now a number of inhibitors of CK2 have been discovered from various chemical groups, e.g., elagic acid,7 [5-oxo-5,6dihydroindolo-(1,2a)quinazolin-7-yl]acetic acid (IQA),8,9 4,5,6,7-tetrabromo-1H-benzotriazole (TBB, TBBt), 10,11 4,5,6,7-tetraiodo-1H-benzimidazole (TIBI), 4,5,6,7-tetrabro-

Protein casein kinase II (CK2) is a highly pleiotropic enzyme whose high constitutive activity is supposed to be instrumental in development and potentiation of tumor phenotype and spreading of infectious diseases. Abnormally high levels of CK2 have been documented in a number of cancers including kidney,1 mammary gland,2 lung,3 head4 and neck,5 and prostate,6 and coincidental arguments support the notion that CK2 promotes cell survival through oncogene regulation and plays global antiapoptotic role. Thus, CK2 inhibitors have been © 2014 American Chemical Society

Received: November 24, 2013 Revised: February 17, 2014 Published: March 5, 2014 2089

dx.doi.org/10.1021/jp411547z | J. Phys. Chem. A 2014, 118, 2089−2106

The Journal of Physical Chemistry A

Article

molecular fingerprint, provides the distribution of interactions of the molecule with its environment, and is convenient for comparison of different molecular systems. However, while the QTAIM based formalism reveals the nature and strength of the interactions between neighboring atoms, the Hirshfeld surfacebased approach detects which atoms, regardless of whether or not adjacent, are genuinely interacting with each other. The use of Laplacian or Hirshfeld surfaces enriches the X-ray methods to study the three-dimensional patterns at the atomic level. In our previous study some clues on the intermolecular interactions in the crystalline state and on the role of short halogen−halogen contacts competing against hydrogen bonding in crystal structure of organic compounds have been revealed for 4,5,6,7-tetraiodo-1H-benzimidazole and some other polyhalogenobenzimidazoles.24 The purpose of this study performed for a set of 4,5,6,7-tetrahalogeno-1Hbenzimidazoles, Figure 1, is a comparison of the weak

mo-1H-benzimidazole (TBBz, TBI);12 2,3,4,5-tetrabromocinnamic acid (TBCA),13 quinolones,14 anthraquinones, xanthenones, flavonoids,15,16 and hydroxycoumarines.17 A promising group is that of polyhalogenated benzimidazoles found to be valuable scaffold effectively competing with ATP binding site of CK2.18 The presence of four halogen atoms on the benzene ring of these heterocycles has been proved critical to fill the CK2 hydrophobic pocket at the ATP-binding site.14,19 Recently 4,5,6,7-tetraiodo-1H-benzimidazole (TIBI) was found to be about six times more potent than 4,5,6,7-tetrabromo-1Hbenzimidazole (TBI) as the inhibitor of rat liver CK2 (Ki 0.023 μM vs 0.139 mM, respectively).20 Halogen bonds have stabilizing effect in complexes of CK2 and its inhibitors.21,22 Although the above studies allowed prediction of binding of the inhibitor to the pocket in CK2, but they could not fully explain substantial differences between the biological activity of congeners. The knowledge of X-ray structure is vital for drug studies and understanding of formation of protein−ligand complex. Although some intermolecular interactions can change their character or play a different role in molecular crystals than in protein−ligand complexes, but in the absence of conformational effects the knowledge of crystal packing provides reliable preliminary information on the site and method of binding.23 Although some intermolecular interactions can change their character or play a different role in molecular crystals, but the susceptibility of certain sites in the molecule to formation of specific bonds in the crystal and in the complexes with ligands is similar. In this aspect, the environmental effect of the crystal mimics the effect of CK2 enzyme, i.e., influence the electron density of a single molecule of 4,5,6,7-tetrahalogeno-1Hbenzimidazole. In the environmental (packing) context, hydrogen bonds that cover the range between the covalent bonds, the van der Waals interactions, and stacking π−π interactions are assumed to play a key role.24 The common feature of all these polyhalogeno-1H-benzimidazoles studied so far was isostructurality, understood as the so-called 3D isostructurality, connected with the preservation of structural motives in 3D space.24 Three-dimensional isostructurality is an important factor in drug studies because it allows the search for more efficient alternatives or substrates for new drugs in pharmaceutical industry. Determination of 3D isostructurality requires careful examination of crystal structure, analysis of interatomic distances and nature and energy of intra- and intermolecular interactions. However, these factors are difficult to interpret in terms of the structure−biological properties relationship. Important progress in delivering methods suitable for investigation of molecules interaction with their direct environment was made by Bader, who developed Quantum Theory of Atoms in Molecules (QTAIM)25 and by Spackman, who proposed the Hirshfeld surface-based approach.26,27 Both formalisms allow visualization of various types of interactions coded by the shape, contour, and color with the use of Laplacian or Hirshfeld surfaces, respectively. The Laplacian surface of the electron density is a functional useful for characterization of the bonds pattern but also probing reactive sites in a molecule indicating the degree of susceptibility to electrophilic or nucleophilic attack. The Hirshfeld 3D surface delivers additional data as it allows a rigorous quantitative analysis of molecular properties for comparison with bulk measurements. Decomposition of the Hirshfeld surface allows obtaining a 2D map, which is called a

Figure 1. Chemical structure of 4,5,6,7-tetrahalogeno-1H-benzimidazoles.

interactions forcing differences in hydrogen bonds pattern and crystal packing, with a particular emphasis on the nature of halogen−halogen interactions in a set of congeners. We anticipate that this comparative study will contribute to understanding the fundamentals of biological activity of 4,5,6,7tetrahalogeno-1H-benzimidazoles at the molecular level and will provide a new methodology to discover improved CK2 inhibitors, effective in cancer prevention and treatment, thus will be helpful in planning the synthesis of new compounds of this class.

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EXPERIMENTS AND CALCULATIONS X-ray. 4,5,6,7-Tetrahalogenated-1H-benzimidazoles were prepared as single crystals suitable for X-ray study by the following method. The compounds were dissolved in hot absolute ethanol to obtain saturated solutions. Open vials with respective solutions were placed in hermetic vessels with hexane. After 2−4 days, single crystals were deposited on glass, then carefully filtered-off and dried. X-ray structural studies of 4,5,6,7-tetrahalogeno-1H-benzimidazoles were performed at room temperature (RT) using an Xcalibur R single crystal diffractometer from Oxford Diffraction. Monochromated CuKα radiation was applied. Monocrystals of the studied compounds were mounted on the goniometer, and reflections were collected up to a Bragg angle 2θ ≤ 140°. The intensities of the reflections were corrected for Lorenz-polarization effects and for absorption and extinction. The details of the experimental procedure are listed in Table 1. The structures were solved using direct methods from SHELXS-98 program28 and then refined by application of SHELXL-98 software.28 The structures have been deposited with Cambridge Structural Data Centre. Calculations. Quantum chemical calculations were carried out within the Gaussian09 code29 run on the CRAY supercomputer at the Supercomputer and Network Centre (PCSS) in Poznań, Poland. All calculations were performed 2090



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Table 1. Crystal Data and Structure Refinement for Orzesz20abs (4,5,6,7-Tetrabromo-1H- benzimidazole) and Orzesz19abs (4,5,6,7-Tetrachloro-1H-benzimidazole) identification code deposition number empirical formula formula weight temperature wavelength crystal system space group unit cell dimensions

volume Z density (calculated) absorption coefficient F(000) crystal size theta range for data collection index ranges reflections collected independent reflections completeness to theta = 70.61° absorption correction max. and min transmission refinement method data/restraints/parameters goodness-of-fit on F2 final R indices [I > 2σI] R indices (all data) extinction coefficient largest diff. peak and hole

orzesz20abs

orzesz19abs

CCDC 955361 C7H2Br4N2 433.75 293(2) K 1.54178 Å tetragonal I41/n a = 14.88460(10) Å b = 14.88460(10) Å c = 18.0113(2) Å 3990.43(6) Å3 16 2.888 Mg/m3 19.317 mm−1 3168 0.3379 × 0.2803 × 0.1375 mm3 3.85 to 70.61° −15 ≤ h ≤18, −15 ≤ k ≤17, −21 ≤ l ≤19 8248 1896 [R(int) = 0.0300] 98.9% analytical 0.210 and 0.030 full-matrix least-squares on F2 1896/0/127 1.055 R1 = 0.0270, wR2 = 0.0679 R1 = 0.0303, wR2 = 0.0694 0.000053(6) 0.545 and −0.354 e·Å−3

CCDC 955360 C7H2Cl4N2 255.91 293(2) K 1.54178 Å triclinic P1̅ a = 7.67020(10) Å, α = 108.783(2)° b = 15.1051(3) Å, β = 95.092(2)° c = 16.6774(4) Å, γ = 90.277(2)° 1820.96(6) Å3 8 1.867 Mg/m3 11.395 mm−1 1008 0.3663 × 0.2317 × 0.1862 mm3 2.81 to 70.99° −9 ≤ h ≤9, −18 ≤ k ≤ 18, −20 ≤ l ≤20 34482 6982 [R(int) = 0.0316] 98.8% analytical 0.273 and 0.061 full-matrix least-squares on F2 6982/0/502 1.061 R1 = 0.0268, wR2 = 0.0754 R1 = 0.0307, wR2 = 0.0771 0.00067(7) 0.260 and −0.246 e·Å−3

Poincare−Hopf relationship34 was used as a consistency check. At each extreme point, the topological parameters, the electron density, and its Laplacian were calculated. The surface of Laplacian of the electron density, which delivers better description of the reactive sites in molecule than electron density itself, was determined. The parameters characterizing each bonding or intermolecular interaction: the ellipticity of the bond, ε, the total electron energy density at BCP (HBCP), and its components, the local kinetic energy density (GBCP) and the local potential energy density (VBCP), and hydrogen bonding energy EE according to Espinosa35 were calculated. Hirshfeld Surface. Theoretical analysis of intermolecular interactions pattern was performed within the Hirshfeld surfaces approach.26 The crystal was partitioned into regions where the distribution of electron density from spherical atoms on the molecule (the promolecule) dominates over that of the crystal (the procrystal). This region, called the Hirshfeld surface,26,27 in a crystal is defined with the use of molecular weight-function w(r):

within the density functional theory (DFT) with exchangecorrelation hybrid functional: B3LYP (three-parameter exchange functional of Becke B330 combined with the Lee− Yang−Parr correlation functional LYP31) using the extended basis sets with polarization and diffuse functions 6-311+ +G(2d,p). The theoretical reactivity indices defined by Par and Pearson:32 the absolute electronegativity [χ = −(ELUMO + EHOMO)/2; eV]; absolute hardness [η = (ELUMO − EHOMO)/2; eV)]; electrophilicity index (reactivity) [ω = χ2/2η; eV]; and softness [S = 1/η; 1/eV] were calculated using Vargas et al.’s33 HOMO−LUMO approach. QTAIM and Laplacian Surface. Theoretical analysis of intermolecular interactions pattern was performed within the Bader’s quantum theory of atoms in molecules Quantum Theory of Atoms in Molecules (QTAIM).25,34 Within this approach the electron density distribution ρ(r) is treated as a scalar field and examined by the analysis of the accompanying gradient ∇ρ(r) vector field. Depending on the nature of the stationary points (maxima, saddle points, or minima in the electron density), it describes core-, bond-, ring-, and cagecritical points and denoted as nuclear attractor critical point (NACP), local maximum of electron density, bond critical point (BCP), minimum in the direction of the nucleus but it is a maximum in another main direction, ring critical point (RCP), minimum in two principal axes, and cage critical point (CCP), local minimum of electron density, respectively. The extreme point type was identified with the help of Hessian matrix composed of nine second-order derivatives of ρ(r). The

w(r ) =

∑A ∈ molecule ρA (r ) ∑A ∈ c rystal ρA (r )

(1)

where summation of spherically averaged atomic electron density centered on nucleus A, ρA(r), in eq 1 runs over the atoms belonging to the molecule (numerator) and to the crystal (denumerator), respectively. The Hirshfeld surface is separated using the condition w(r) ≥ 0.5, which limits the 2091



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Table 5. Hydrogen Bonds for Orzesz20abs (Å and deg)a

region where the promolecule contribution to the procrystal electron density exceeds that from all other molecules in the crystal.

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x

y

z

U(eq)

3813(1) 3325(1) 3446(1) 3874(1) 4328(2) 4088(2) 3857(2) 3644(2) 3664(2) 3864(2) 4067(2) 4287(2) 4429(3)

−3016(1) −1892(1) −81(1) 608(1) −2030(2) −1677(2) −1976(2) −1495(2) −718(2) −420(2) −906(2) −806(2) −1487(2)

48(1) 57(1) 56(1) 48(1) 40(1) 35(1) 35(1) 37(1) 37(1) 35(1) 35(1) 42(1) 45(1)

Br(1) Br(2) Br(3) Br(4) N(1) C(2) C(3) C(4) C(5) C(6) C(7) N(8) C(9)

U22

U33

U23

U13

U12

62(1) 44(1) 49(1) 61(1) 44(2) 44(2) 47(2) 40(2) 41(2) 49(2) 44(2) 45(2) 43(2)

61(1) 82(1) 79(1) 63(1) 51(2) 38(2) 37(2) 39(2) 40(2) 40(2) 41(2) 56(2) 59(2)

23(1) 45(1) 39(1) 20(1) 26(2) 23(2) 20(2) 31(2) 29(2) 17(1) 21(2) 24(2) 32(2)

−2(1) −5(1) 12(1) 4(1) 4(1) 2(1) 0(1) 0(1) 6(1) 5(1) 2(1) 2(1) 7(2)

6(1) 7(1) −9(1) 0(1) −2(1) 0(1) 6(1) 5(1) −3(1) 3(1) 2(1) 7(1) −2(2)

−1(1) 2(1) 0(1) −3(1) 2(1) −6(2) −6(2) −5(1) −5(2) −6(2) −5(2) 0(2) 2(2)

Table 4. Hydrogen Coordinates (× 10 ) and Isotropic Displacement Parameters (Å2 × 10 3) for Orzesz20abs H(8) H(9)

y

x

U(eq)

7740(30) 7050(30)

4290(30) 4630(30)

−480(30) −1520(30)

48(14) 45(12)

∠(DHA)

2.892(5)

175(5)

4,5,6,7‐tetraiodo (3.023 Å) > 4,5,6,7‐tetrabromo (2.892 Å)

4

x

d(D···A)

2.19(5)

tetrachloro-1H-benzimidazole, respectively. The refinement with anisotropic displacement parameters for all non-hydrogen atoms was performed, Tables 3 and 7, with the final R-factor of 3.07 and 3.03% for 4,5,6,7-tetrachloro- and 4,5,6,7-tetrabromo1H-benzimidazole, respectively. The crystalline packing of 4,5,6,7-tetrabromo-1H-benzimidazole and 4,5,6,7-tetrachloro1H-benzimidazole is shown in Figures 2 and 3. The hydrogen bond lengths are summarized in Tables 5 and 8 for 4,5,6,7tetrachloro- and 4,5,6,7-tetrabromo-1H-benzimidazole, respectively. Our previous studies have shown that 4,5,6,7-tetraiodo-1Hbenzimidazole, 4,6-dibromo-5,7-diiodo-1H-benzimidazole, and 4,6-dichloro-5,7-diiodo-1H-benzimidazole are isostructural.24 Surprisingly, the newly collected data for 4,5,6,7-tetrabromo1H-benzimidazole, and 4,5,6,7-tetrachloro-1H-benzimidazole, as well as for 4,5,6,7-tetrafluoro-1H-benzimidazole,36 clearly indicate that not all 4,5,6,7-tetrahalogeno-1H-benzimidazole crystals (halogen = F, Cl, Br, I) are isostructural; Table 9. While 4,5,6,7-tetrabromo-1H-benzimidazole is isostructural to the previously studied 4,5,6,7-tetraiodo-1H-benzimidazole and crystallizes in tetragonal space group I41/a, 4,5,6,7-tetrachloro-1H-benzimidazole and 4,5,6,7-tetrafluoro-1H-benzimidazole crystallize in triclinic P1̅ and monoclinic C2/c space groups, respectively. In all three previously studied compounds, the crystalline packing in tetragonal space group I41/a is forced by two competitive effects: intermolecular hydrogen bondings N1−H···N3′ and N1′···H−N3, which link each molecule with two neighboring ones (trimers), and van der Waals interactions between I···I atoms forcing almost perpendicular orientation of the molecules (the twist angles between the planes containing these molecules is close to 90°).24 This highly symmetric crystalline pattern is made by polar chains of the molecules arranged in one direction and accompanied by antiparallel chains arranged in the opposite direction (edge-to-face interactions). Although the molecules in 4,5,6,7-tetrachloro1H-benzimidazole (Figure 3 and Table 8) and 4,5,6,7tetrafluoro-1H-benzimidazole,36 linked by N1−H···N3′ and N1′···H−N3 intermolecular hydrogen bonds make trimers, and similarly to 4,5,6,7-tetraiodo-1H-benzimidazole24 and 4,5,6,7tetrabromo-1H-benzimidazole (Figure 2 and Table 5) but the packing pattern symmetry is much lower, the molecules of all 4,5,6,7-tetrahalogeno-1H-benzimidazoles are almost flat. According to decreasing average hydrogen bond length (and strength), the linking trimers of neighboring molecules of 4,5,6,7-tetrahalogeno-1H-benzimidazoles can be ordered as follows:

Table 3. Anisotropic Displacement Parameters (Å2 × 103) for Orzesz20abs; the Anisotropic Displacement Factor Exponent Takes the Form −2π2[h2a*2U11 + ... + 2hka*b*U12] U11

d(H···A)

0.71(5)

a

Table 2. Atomic Coordinates (× 104) and Equivalent Isotropic Displacement Parameters (Å2 × 103) for Orzesz20abs; U(eq) Is Defined As One Third of the Trace of the Orthogonalized Uij Tensor 9964(1) 11678(1) 11398(1) 9350(1) 8237(2) 9025(3) 9854(3) 10550(2) 10415(2) 9585(3) 8891(3) 8008(2) 7657(3)

d(D−H)

Symmetry transformations used to generate equivalent atoms: #1, y + 1/4, −x + 5/4, z + 1/4.

RESULTS AND DISCUSSION X-ray. The X-ray data for 4,5,6,7-tetrabromo-1H-benzimidazole and 4,5,6,7-tetrachloro-1H-benzimidazole collected at RT are listed in Tables 1−8. 4,5,6,7-Tetrabromo-1Hbenzimidazole crystallizes in I41/a space group with a = 14.88460(10) Å, b = 14.88460(10) Å, and c = 18.0113(2) Å and α = 90.0°, while 4,5,6,7-tetrachloro-1H-benzimidazole crystallizes in P1̅ space group with a = 7.67020(10) Å, b = 15.1051(3) Å, and c = 16.6774(4) Å and α = 108.783(2)°, β = 95.092(2)°, and γ = 90.277(2)°. The atomic positions are listed in Tables 2 and 6 for 4,5,6,7-tetrabromo- and 4,5,6,7-

Br(1) Br(2) Br(3) Br(4) N(1) C(2) C(3) C(4) C(5) C(6) C(7) N(8) C(9)

D−H···A N(8)−H(8)···N(1)#1

> 4,5,6,7‐tetrachloro (2.833 and 2.962 Å; 2.907 and 2.909 Å; average: 2.902 Å) > 4,5,6,7‐tetrafluoro (2.826 and 2.845 Å)

(2)

Although the trend (eq 2) is significant, it cannot explain the differences in packing. The twist angle between the planes containing the neighboring molecules is only about 6° in 2092



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Table 7. Anisotropic Displacement Parameters (Å2 × 103) for Orzesz19abs; the Anisotropic Displacement Factor Exponent Takes the Form −2π2[h2a*2U11 + ... + 2hka*b*U12]

Table 6. Atomic Coordinates (× 104) and Equivalent Isotropic Displacement Parameters (Å2 × 103) for Orzesz19abs; U(eq) Is Defined As One Third of the Trace of the Orthogonalized Uij Tensor Cl(1A) Cl(2A) Cl(3A) Cl(4A) N(1A) C(2A) C(3A) C(4A) C(5A) C(6A) C(7A) N(8A) C(9A) Cl(1B) Cl(2B) Cl(3B) Cl(4B) N(1B) C(2B) C(3B) C(4B) C(5B) C(6B) C(7B) N(8B) C(9B) Cl(1C) Cl(2C) Cl(3C) Cl(4C) N(1C) C(2C) C(3C) C(4C) C(5C) C(6C) C(7C) N(8C) C(9C) Cl(1D) Cl(2D) Cl(3D) Cl(4D) N(1D) C(2D) C(3D) C(4D) C(5D) C(6D) C(7D) N(8D) C(9D)

x

y

z

U(eq)

5912(1) 5419(1) 6771(1) 8499(1) 7634(2) 7339(2) 6589(2) 6408(2) 7007(2) 7760(2) 7914(2) 8562(2) 8354(3) 11287(1) 12922(1) 14104(1) 13643(1) 11079(2) 11730(2) 11920(2) 12644(2) 13184(2) 13011(2) 12305(2) 11999(2) 11289(3) 7153(1) 5851(1) 6386(1) 8213(1) 8999(2) 8294(2) 7443(2) 6867(2) 7118(2) 7951(2) 8556(2) 9434(2) 9661(3) 11081(1) 12812(1) 13800(1) 13092(1) 10377(2) 11205(2) 11584(2) 12377(2) 12832(2) 12512(2) 11690(2) 11162(2) 10390(3)

−1642(1) −2268(1) −962(1) 1021(1) 381(1) −50(1) −930(1) −1198(1) −601(1) 270(1) 544(1) 1339(1) 1199(2) 1683(1) −111(1) −1719(1) −1555(1) 1545(1) 842(1) 774(1) −16(1) −748(1) −685(1) 117(1) 393(1) 1240(1) 6465(1) 6218(1) 4339(1) 2695(1) 4670(1) 4717(1) 5443(1) 5321(1) 4473(1) 3745(1) 3880(1) 3326(1) 3835(1) 3083(1) 4969(1) 6540(1) 6207(1) 3092(1) 3831(1) 3958(1) 4795(1) 5503(1) 5377(1) 4539(1) 4220(1) 3367(1)

−2327(1) −730(1) 1077(1) 1326(1) −1789(1) −1199(1) −1313(1) −609(1) 214(1) 334(1) −380(1) −489(1) −1335(1) 6583(1) 6866(1) 5339(1) 3489(1) 4634(1) 4928(1) 5745(1) 5863(1) 5170(1) 4359(1) 4252(1) 3552(1) 3820(1) 6183(1) 4274(1) 2854(1) 3310(1) 6351(1) 5574(1) 5376(1) 4537(1) 3894(1) 4086(1) 4930(1) 5329(1) 6166(1) 8768(1) 8812(1) 10542(1) 12257(1) 10636(1) 10482(1) 9719(1) 9748(1) 10530(1) 11287(1) 11252(1) 11875(1) 11468(1)

57(1) 59(1) 65(1) 60(1) 44(1) 37(1) 39(1) 41(1) 43(1) 41(1) 38(1) 45(1) 49(1) 59(1) 63(1) 56(1) 55(1) 43(1) 37(1) 40(1) 42(1) 41(1) 39(1) 37(1) 43(1) 46(1) 56(1) 61(1) 62(1) 51(1) 40(1) 35(1) 39(1) 42(1) 41(1) 37(1) 35(1) 39(1) 41(1) 55(1) 56(1) 57(1) 59(1) 41(1) 36(1) 38(1) 40(1) 41(1) 39(1) 36(1) 41(1) 44(1)

Cl(1A) Cl(2A) Cl(3A) Cl(4A) N(1A) C(2A) C(3A) C(4A) C(5A) C(6A) C(7A) N(8A) C(9A) Cl(1B) Cl(2B) Cl(3B) Cl(4B) N(1B) C(2B) C(3B) C(4B) C(5B) C(6B) C(7B) N(8B) C(9B) Cl(1C) Cl(2C) Cl(3C) Cl(4C) N(1C) C(2C) C(3C) C(4C) C(5C) C(6C) C(7C) N(8C) C(9C) Cl(1D) Cl(2D) Cl(3D) Cl(4D) N(1D) C(2D) C(3D) C(4D) C(5D) C(6D) C(7D) N(8D) C(9D)

4,5,6,7-tetrafluoro-1H-benzimidazole forming hydrogenbonded flat tapes but increases to 17.62° and 53.55° as well as 10.08° and 49.33° for 4,5,6,7-tetrachloro-1H-benzimidazole in contradiction to 90° for 4,5,6,7-tetraiodo- or 4,5,6,7-

U11

U22

U33

U23

U13

U12

75(1) 64(1) 82(1) 74(1) 58(1) 41(1) 41(1) 41(1) 46(1) 43(1) 40(1) 57(1) 67(1) 83(1) 89(1) 62(1) 67(1) 54(1) 43(1) 47(1) 49(1) 43(1) 42(1) 42(1) 59(1) 59(1) 62(1) 57(1) 74(1) 69(1) 48(1) 38(1) 38(1) 39(1) 41(1) 42(1) 38(1) 48(1) 51(1) 75(1) 62(1) 63(1) 78(1) 52(1) 40(1) 41(1) 41(1) 39(1) 42(1) 41(1) 56(1) 58(1)

46(1) 47(1) 79(1) 67(1) 42(1) 37(1) 36(1) 39(1) 51(1) 48(1) 38(1) 37(1) 40(1) 51(1) 66(1) 42(1) 38(1) 36(1) 31(1) 37(1) 43(1) 34(1) 31(1) 34(1) 40(1) 41(1) 36(1) 55(1) 74(1) 44(1) 38(1) 33(1) 32(1) 38(1) 48(1) 36(1) 31(1) 32(1) 40(1) 54(1) 69(1) 44(1) 43(1) 36(1) 34(1) 40(1) 46(1) 36(1) 33(1) 35(1) 38(1) 38(1)

39(1) 72(1) 49(1) 30(1) 32(1) 31(1) 35(1) 47(1) 37(1) 29(1) 32(1) 35(1) 37(1) 36(1) 39(1) 70(1) 51(1) 40(1) 35(1) 31(1) 34(1) 47(1) 38(1) 32(1) 30(1) 40(1) 62(1) 80(1) 43(1) 33(1) 32(1) 33(1) 45(1) 52(1) 36(1) 32(1) 34(1) 34(1) 33(1) 32(1) 49(1) 73(1) 45(1) 34(1) 34(1) 31(1) 39(1) 50(1) 40(1) 32(1) 28(1) 37(1)

0(1) 28(1) 38(1) 4(1) 9(1) 7(1) 6(1) 17(1) 20(1) 7(1) 6(1) 3(1) 10(1) 2(1) 25(1) 26(1) 0(1) 11(1) 7(1) 4(1) 14(1) 15(1) 4(1) 6(1) 8(1) 15(1) 1(1) 34(1) 28(1) 2(1) 7(1) 7(1) 7(1) 19(1) 18(1) 8(1) 8(1) 9(1) 12(1) 5(1) 33(1) 28(1) 4(1) 9(1) 10(1) 9(1) 21(1) 19(1) 9(1) 10(1) 8(1) 13(1)

3(1) 13(1) 14(1) −3(1) 6(1) 6(1) 6(1) 9(1) 11(1) 4(1) 5(1) 2(1) 7(1) 17(1) 2(1) 5(1) 16(1) 9(1) 7(1) 7(1) 2(1) 4(1) 6(1) 7(1) 9(1) 8(1) 13(1) 3(1) −3(1) 4(1) 6(1) 7(1) 10(1) 5(1) 3(1) 6(1) 8(1) 7(1) 3(1) 9(1) 17(1) 13(1) 1(1) 5(1) 5(1) 6(1) 10(1) 6(1) 3(1) 4(1) 3(1) 7(1)

−14(1) −2(1) 16(1) 8(1) −5(1) 4(1) 2(1) 7(1) 14(1) 12(1) 6(1) −5(1) −8(1) 10(1) 0(1) 4(1) 8(1) 7(1) −1(1) −2(1) −6(1) −3(1) −1(1) −3(1) 5(1) 8(1) 5(1) 12(1) −1(1) −1(1) −3(1) −6(1) −3(1) 0(1) −5(1) −5(1) −4(1) 1(1) 0(1) −4(1) 8(1) −4(1) −17(1) −5(1) 2(1) 6(1) 9(1) 3(1) 0(1) 2(1) −4(1) −7(1)

tetrabromo-derivatives; Table 10. The ordering of 4,5,6,7tetrachloro-1H-benzimidazole molecules in crystal is intermediate between 4,5,6,7-tetrafluoro-1H-benzimidazole and 2093



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flat one of alpha 1H-benzimidazole suggests that hydrogen bonds play an important but not exclusive role in crystalline packing. Formation of very versatile hydrogen-bonding units in 1H-benzimidazole and its 4,5,6,7-tetrahalogeno-derivatives ensures the flexibility of the intermolecular interactions pattern. The intermolecular hydrogen bonds interfere with other possibly stabilizing interactions, mediated by short-range noncovalent forces, which can lead to formation of a variety of crystalline structures including polymorphs (as exemplified in parental 1H-benzimidazole). The variation in the twist angles in 4,5,6,7-tetrachloro-1H-benzimidazole indicates a possible polymorph coexistence. Thus, we performed differential scanning calorimetry (DSC), Figure 4, which revealed a phase transition without a change in enthalpy, a second order glassy one at Tg = 95 and 106 °C (heating and cooling, respectively), indicating the frozen disorder. According to Desiraju and Parthasarathy42 and Pedireddi,43 who studied 794 crystal structures, all possible Hal···Hal interactions can be classified as belonging to type I (both CHal···Hal angles equal to 180°) or type II (both angles close to 90° and 180°). Type I was assigned to the interactions across the crystallographic center of symmetry, while type II was assigned to the increasing polarizability of the halogen (F < Cl < Br < I). It is evident that 4,5,6,7-tetrahalogeno-1Hbenzimidazoles fall out of this classification because the respective angles are 126° and 177° for 4,5,6,7-tetraiodo-1Hbenzimidazole; 128° and 176° for 4,5,6,7-tetrabromo-1Hbenzimidazole; 171° and 142°, 170° and 139°, 136° and 141°, 146° and 150°, and 161° and 157° for 4,5,6,7-tetrachloro1H-benzimidazolel and 127° for 4,5,6,7-tetrafluoro-1H-benzimidazole; Table 10. While 4,5,6,7-tetraiodo-1H-benzimidazole and 4,5,6,7-tetrabromo-1H-benzimidazole can be considered as having approximate type II structure, 4,5,6,7-tetrachloro-1Hbenzimidazole and 4,5,6,7-tetrafluoro-1H-benzimidazole cannot be classified neither as having type II nor type I structure. The angles in 4,5,6,7-tetrachloro-1H-benzimidazole are mixtures of those observed for 4,5,6,7-tetrabromo-1H-benzimidazole/ 4,5,6,7-tetraiodo-1H-benzimidazole and 4,5,6,7-tetrafluoro-1Hbenzimidazole. The flat tape ordering in 4,5,6,7-tetrafluoro-1Hbenzimidazole coincides with the smallest C−Hal···Hal angles, the perpendicular orientation of the planes containing the neighboring molecules in 4,5,6,7-tetrabromo-1H-benzimidazole/4,5,6,7-tetraiodo-1H-benzimidazole coincides with approximate type II, while the orientation and angles in 4,5,6,7tetrachloro-1H-benzimidazole take intermediate values. To judge the role of hydrogen bonds and short-range noncovalent forces, the halogen containing crystals were studied. The most structurally related, 4,5,6,7-tetrahalogenophthalic anhydrides,44−49 are 3D isostructural (except 4,5,6,7tetraiodophthalic anhydride), Table 9, despite the lack of hydrogen bonds. Isostructural are also hexahalogenobenzenes (C6F6, C6Cl6, C6Br6, and C6I6),50−56 1,2-dibromo-1,3-dibromoand 1,4-dibromo-2,3,5,6-tetrachlorobenzene,52 and 1,4-dibro-

Figure 2. Crystal packing of 4,5,6,7-tetrabromo-1H-benzimidazole.

Figure 3. Crystal packing of 4,5,6,7-tetrachloro-1H-benzimidazole.

4,5,6,7-tetrabromo-1H-benzimidazole (Figure 2 versus Figure 3). Examination of the stable form (alpha) of parent compound, 1H-benzimidazole, which crystallizes in orthorhombic nonchiral P21nb space group,37−39 and its metastable form (beta), which transforms at room temperature to the alpha form40 and crystallizes in Pccn space group,41 leads to interesting conclusions. Although in both crystalline forms the molecules of 1H-benzimidazole are connected into polymeric chains via N−H···N hydrogen bonds, but the mode of aromatic ring interactions and the spatial arrangement differ significantly. While in the alpha form of the molecules show edge-to-face interactions,37−39 in the beta form, a sandwich−herringbone arrangement of the molecules is observed.40,41 The packing in 4,5,6,7-tetraiodo- and 4,5,6,7-tetrabromo-1H-benzimidazole crystals resemble that in alpha polymorph of 1H-benzimidazole, while that of 4,5,6,7-tetrachloro-1H-benzimidazole and 4,5,6,7tetrafluoro-1H-benzimidazole is close to that in beta polymorph of 1H-benzimidazole. According to the hydrogen bond length, 1H-benzimidazoles can be ordered as beta (2.884 Å) > alpha (2.853 Å), i.e., the hydrogen bond length in beta is close to that in 4,5,6,7-tetrabromo-1H-benzimidazole with perpendicular molecules, while in alpha to that in 4,5,6,7-tetrachloro-1Hbenzimidazole with skewed molecules. This indicates the effects opposite to those observed for 4,5,6,7-tetrahalogeno-substituted 1H-benzimidazoles. Thus, a comparison of the flat ordering of 4,5,6,7-tetrafluoro-1H-benzimidazole and the nonTable 8. Hydrogen Bonds for Orzesz19abs (Å and deg)a

a

D−H···A

d(D−H)

d(H···A)

d(D···A)

∠(DHA)

N(8A)-H(8A)···N(1D)#1 N(8B)-H(8B)···N(1A)#2 N(8C)-H(8C)···N(1B) N(8D)-H(8D)···N(1C)#3

0.82(3) 0.81(2) 0.86(2) 0.82(2)

2.14(3) 2.03(3) 2.06(2) 2.09(2)

2.962(2) 2.833(2) 2.909(2) 2.907(2)

173(2) 169(2) 173(2) 175(2)

Symmetry transformations used to generate equivalent atoms: #1, x, y, z − 1; #2, −x + 2, −y, −z; #3, −x + 2, −y + 1, −z + 2. 2094


90 90 90 22.655(3) 22.655(3) 9.136(1) 90 91.1(3) 90 13.39(3) 6.19(2) 12.66(3) 90 90.789(7) 90 13.422(3) 6.1794(14) 12.680(3) 90 91.18(1) 90 13.459(4) 5.789(1) 12.342(2) 90 91.182(3) 90 13.438(1) 5.7874(4) 12.332(1) 90 90 90 7.859 14.173(5) 5.911(3) 90 90 90 15.6273(2) 15.6273(2) 18.6297(3) 90 90 90 14.88460(10) 14.88460(10) 18.0113(2) 108.783(2) 95.092(2) 90.277(2) 7.67020(10) 15.1051(3) 16.6774(4) 90 91.1372(13) 90 18.3424(7) 7.2724(3) 21.4133(10)

I41/a P1̅ C2/c Pccn Pna21

90 90 90 13.507(10) 6.789(5) 6.940(5)

Pna21

90 90 90 13.492(3) 6.8053(14) 6.9388(15)

P21nb

5.2 5.31 4.5

R factor (%) space group α β γ a b c

2.67

4.0

mo-2,3,5,6-tetraiodobenzene,56 as well as p-halogenoethynylbenzenes (p-chloro-, p-bromo-, and p-iodoethynylbenzene).57 Although p-C6H4Cl2 and p-C6H4Br2 are isostructural,58,59 pC6H4I2 is not.60 While 1,3,5-trichlorobenzene, 1,3,5-tribromobenzene,61 and 1,3,5-triiodobenzene62 are isostructural, 1,3,5trifluorobenzene is not.63 It is also well-known that strong van der Waals forces between halogens keep iodine as solid, a bit weaker make bromine a liquid at RT, and much weaker make chlorine or fluorine gases. Thus, the weak van der Waals interaction plays an important role in forcing the symmetry and crystal packing motifs, which vary with the type of halogen atom in the molecule. The study of molecular dynamics of CH3Hal systems64,65 also suggests that an important factor in modulating the relaxation effects is van der Waals interactions between halogens. However, 4-chloroaniline66 and 4-bromoaniline,67 in which both van der Waals interactions and hydrogen bonds are present, are isostructural, while 4-iodoaniline is not.68 Similarly 5-fluoro-indol-3-ylacetic acid and 5-chloro-indol-3ylacetic acid are isostructural, but 5-bromo-indol-3-ylacetic acid is not.68,69 In 4,5,6,7-tetrahalogeno-1H-benzimidazoles the picture of the crystalline pattern is even more complicated. Small deviation of single molecules from planarity decreases in the order 4,5,6,7-tetraiodo (6.18°) > 4,5,6,7-tetrabromo(3.26°) > 4,5,6,7-tetrachloro (1.87°) > 4,5,6,7-tetrafluoro (0.46°), in agreement with a decrease in the Hal(7)−C(7)−C(6) and Hal(4)−C(4)−C(5) angles 4,5,6,7-tetraiodo (124.6°) > 4,5,6,7-tetrabromo (123.43°) > 4,5,6,7-tetrachloro (121.7°) > 4,5,6,7-tetrafluoro (120.3°). This implies that the repulsive contributions are largely compensated by attractive forces between the two neighboring closed-shell Hal atoms in a molecule. However, in 4,5,6,7-tetrahalogeno-1H-benzimidazoles the twist angle between the planes with neighboring molecules, interlayer distance, Table 10, and packing energy, Table 11a, also increase with increasing ionic/van der Waals radius, i.e., increasing repulsion, Figure 5a,b. For structurally related 4,5,6,7-tetrahalogenophthalic anhydrides, this tendency is not so clear (Tables 10 and Table 11b and red points in Figure 5a). Thus, the change in the type of halogen is associated with both elongation of hydrogen bonds (eq 2) and weakening of the van der Waals interactions between Hal···Hal, which disturb the almost perpendicular orientation of molecules and lower crystalline symmetry. The sigmoidal curve obtained as the best fit suggests a saturative character of the changes caused by the increase in ionic/van der Waals radius, Figure 5b , and the shortening of hydrogen bond, Figure 5c. QTAIM. Some light on the nature of the intra- and intermolecular interactions (hydrogen bonding, van der Waals contacts, and C−H···π interactions) forcing a specific crystal arrangement has been shed by the QTAIM approach, which permits their detection and distinction. The topology of these interactions can be described in terms of BCPs and RCPs and visualized with the help of molecular graphs and 3D Laplacian surfaces; Figures 6 and 7. The QTAIM calculations allowed getting the values of electron density ρ and the corresponding Laplacian Δρ for all BCPs of covalent bonds including the most interesting C−Hal ones. The strongest bond seems to be C−F, while the weakest is C−I, which is not surprising as the jump off effect of iodine is well-known. The QTAIM calculations yielded the average values of electron density ρC···Hal of 0.255, 0.207, 0.164, and 0.125 au for Hal = F, Cl, Br, and I, respectively. The corresponding Laplacian values ΔρC···Hal are

90 90 90 9.7257(11) 16.6879(17) 7.6056(11)

3.03 3.07

Cl F36 H41,42beta H40 alpha H39 alpha H38 alpha hydrogen/ halogen

Article

90 90 90 6.940(1) 13.498(1) 6.808(1)

I41/a P21/n P21/n P21/n P21/n Pna21

4.2 5 3.3 3.7 2.91

I24 Br

I41/a

11.2

3.7

I45 Br48 Br45 Cl47 Cl45,46 H44

4,5,6,7-tetrahalogenophthalic anhydrides 4,5,6,7-tetrahalogeno-1H-benzimidazoles and 1H-benzimidazole

Table 9. Comparison of Structural Data for a Set of 4,5,6,7-Tetrahalogeno-1H-benzimidazoles and Parental 1H-Benzimidazole (alpha and beta Polymorphic Forms) and 4,5,6,7-Tetrahalogenophthalic Anhydrides


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Table 10. Comparison of the Twist Angles between the Planes Containing Neighboring Molecules and C−Hal···Hal Angles for a Set of 4,5,6,7-Tetrahalogeno-1H-benzimidazoles and Parental 1H-Benzimidazole (alpha and beta Polymorphic Forms) hydrogen/halogen

twist angle (deg)

H (alpha) H (beta) F Cl

78.46/80.11 21.12/21.69 5.93 17.62/53.55 10.08/49.33

Br I

89.96 89.97

C−Hal···Hal angle (deg)

minimal Hal···Hal distance (Å)

interlayer distance (Å) (interlayer angle (deg))

127;127 142;171 139;170 136;141 146;150 157;161 128;176 126;177

2.821 3.275

3.235 (0.0) 3.487−3.514 (0.8)

3.581 4.045

3.458 (0.0) 3.908 (4.05)

Hal···Hal contacts can be classified as a closed-shell ionic interaction since the criterion proposed by Espinoza35 is fulfilled. In all 4,5,6,7-tetrahalogeno-1H-benzimidazoles, the Hal···Hal intermolecular contacts are shorter than the sum of van der Waals radius for Hal atom, which indicates the same repulsion/attraction compensative mechanism. For example, in 4,5,6,7-tetraiodo-1H-benzimidazole the intermolecular contacts I···I are 3.748 Å (I(6)···I(7)) and 3.905 Å (I(4)···I(4)), thus also longer than those intramolecular (3.531 Å) and those detected in hexaiodobenzene (3.77 Å55) or tetraiodophtalic anhydride (3.832 Å45). QTAIM confirmed the presence of intermolecular H-bonds. The value of electron density at hydrogen bond BCP ρN−H···N varies from 0.016 to 0.027 au, while the corresponding Laplacian ΔρNH···H is from 0.067 to 0.104 au. Close to zero values of ρ(r), small and positive values of Laplacian, relatively high values of ε (0.015−0.078), nearly zero values of total energy density HBCP (0.0025−0.0045 au), and values of |VBCP|/GBCP < 1, classify this bond as a border case between pure and transit closed-shell (according to Espinosa35 classification), while the Koch and Popelier’s70 topological criteria allow classification of N−H···N as a hydrogen bond. It is worth noting that for N−H···N bonds the H···N distance does not exceed 2.2 Å, thus its classification coincides with the classification by Jeffrey.71 The bond degree, HBCP/ρ, which measures the covalence degree and the strength of the N−H···N hydrogen bond (the stronger/shorter the interaction, the greater the bond degree) strongly depends on the substituted halogen and vary from 0.09 to 0.27 au. The ordering of 4,5,6,7-tetrahalogeno-1H-benzimidazoles according to the hydrogen bond strength is the same as eq 2 derived from hydrogen bonds length. Hirshfeld Surfaces. The hydrogen bonds, close and distant van der Waals Hal···Hal contacts, C−Hal···π interactions, and π−π stacking can be readily identifiable by means of molecular Hirshfeld surfaces.26,27 The Hirshfeld surface with the normalized contact distance dnorm, curvedness, and shape index mapped over this surface for each 4,5,6,7-tetrahalogeno1H-benzimidazole (Figure 8a−f) reveal some details on the interactions pattern, unavailable in QTAIM. The hydrogen bond N−H···N is visualized as red areas in the Hirshfeld surface, Figure 8a−f. The N···H/H···N intermolecular interactions, which comprise from 7.4 to 10.9% of the total

Figure 4. DSC for 4,5,6,7-tetrachloro-1H-benzimidazole, phase transition without a change in enthalpy, a second order glassy one at Tg = 95° and 106° (heating and cooling, respectively; 2°/min).

of 0.136, −0.317, −0.153, and 0.010 au for Hal = F, Cl, Br, and I, respectively. The QTAIM calculations revealed the presence of the Hal···Hal intramolecular contacts, only in 4,5,6,7tetraiodo-1H-benzimidazole, Figure 6, which is a unique feature. The QTAIM calculations yielded the value of electron density ρI···I of 0.016 au and the corresponding Laplacian value ΔρI···I of 0.004 au. These intramolecular I···I contacts are of the length 3.531 Å, thus longer than in hexaiodobenzene (3.50 Å55), but slightly shorter than in 4,5,6,7-tetraiodophtalic anhydride (3.545 Å45) or smaller than the sum of van der Waals radius. This implies the competition between repulsive/ attractive forces between the two closed-shell iodine atoms. The Hal···Hal intermolecular contacts, weaker than the intramolecular I···I, are present in 4,5,6,7-tetrahalogeno-1Hbenzimidazoles. The Hal···Hal intramolecular contacts occur only in 4,5,6,7-tetraiodo-1H-benzimidazole, while the intermolecular ones occur in all 4,5,6,7-tetrahalogeno-1H-benzimidazoles. The calculations yielded the values of electron density ρHal···Hal in the range of 0.015−0.017 au and the corresponding Laplacian values ΔρHal···Hal between 0.004 and 0.009 au. The

Table 11a. Comparison of the Packing Energy for 4,5,6,7-Tetrahalogeno-1H-benzimidazoles and Parental 1H-Benzimidazole (alpha and beta Polymorphic Forms) and 4,5,6,7-Tetrahalogenophthalic Anhydrides hydrogen/halogen

H38 alpha

H39 alpha

H40 alpha

H41,42 beta

F36

Cl

Br

I24

packing energy (kJ/mol)

−92.56

−41.94

−91.69

−102.93

−102.48

−108.55

−135.05

−160.42

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distinct spikes, Figure 9. The top left and bottom right of the 2D fingerprint plot reveal characteristic wings, which can be identified as a result of N−H···N interactions. The wings at the top left, di < de, can be assigned to the surface around the donor (N−H bond), whereas those at the bottom right, de > di, correspond to the surface around the acceptor (N). The smaller but also characteristic wings comprising from 12.9 to 24.2% of the total Hirshfed surfaces can be identified as a result of C− H···Hal interactions. The decomposed 2D fingerprint plot allows visualization of the contacts between the particular pairs of atoms. The regions in which one molecule in the crystal acts as a donor (de > di) and the other as an acceptor (de < di) are shown as complementary; Figure 9. The minimum value of de + di indicating the shortest contact changes with the change in halogen substitution for all 4,5,6,7-tetrahalogeno-1H-benzimidazoles. In general, all bonds/contacts in which a halogen atom is involved occupy 65.9, 77.4, 84.8, and 85.3% of the total Hirshfeld surface for F, Cl, Br, and I, respectively. The 2D fingerprint plot reveals the presence of Hal···Hal, Hal···C, and Hal···N contacts, which, depending on the type of halogen, occupy 26.1−33.5%, 8.4−20.5%, and 3.2−9.6% of the whole molecule area (Table 12). The percentage of interactions between the Hal atoms changes with increasing van der Waals radius, and the ordering F < Cl < Br < I is slightly disturbed only by chlorine F(26.8%) < Br(28.5%) < Cl(31.7/28.6/30.9/ 29.5%) < I(30.5%). The scattering in the percentage of interactions between Cl atoms results from the presence of four inequivalent molecules in tetrachloro crystal. (As far as tetrahalogenophtallic anhydrides are concerned, it increases in the order Cl(25.2%) < Br(26%) < I(36.9%), Table 12.) In 4,5,6,7-tetrahalogeno-1H-benzimidazoles, the change in halogen leads not only to changes in the percentage of Hal···Hal interactions but also in the number of halogens strongly involved, for fluorine only one, while for iodine, three (but they occupy four sites). The regions in the Hirshfeld surfaces corresponding to the strongest interactions are marked in red; see Figure 9. On the basis of these Hirshfeld surfaces, it is possible to identify the halogens that are the least important for associate formation. For 4,5,6,7-tetrafluoro-1H-benzimidazole the halogens that occupy the positions 4 and 5 are important, while that at position 7 is of much less importance and at position 6 of no importance, for 4,5,6,7-tetrachloro-1Hbenzimidazole the important halogens occupy positions 4 and 6, while that at position 5 is less important and that at position 7 is of no importancel for 4,5,6,7-tetrabromo-1H-benzimidazole the important halogens occupy positions 6 and 7, while that at position 5 is less important (participate in Br···N interaction) and that at position 4 is of no importance; for 4,5,6,7-tetraiodo1H-benzimidazole (which is considered the most active) the important halogens occupy positions 6, 7, and 4 (double), while that at position 5 is of no importance. Formation of molecular associations involves not only Hal···Hal but also C− H···Hal hydrogen bonds, Hal in which the proton at C(2) participates. Their contribution is small in planar and highly symmetric structures but increases with increasing structural disorder (F 20.5%, Cl 30.6%, Br 23%, and I 21.7%). In 4,5,6,7tetrafluoro-1H-benzimidazole all fluorine atoms that are involved in CH···F hydrogen bonds do not participate in F··· F interactions. In 4,5,6,7-tetrabromo-1H-benzimidazole, only the bromine atom in position 5 takes part in the CH···Hal bonds, while in 4,5,6,7-tetrachloro-1H-benzimidazole the halogen atom in position 4 (very weak bond) and the one in position 7

Figure 5. (a) Increase in packing energy with increasing ionic radius in a set of 4,5,6,7-tetrahalogeno-1H-benzimidazoles and 4,5,6,7-tetrahalogenophthalic anhydrides (solid lines, fit with sigmoidal curve; α, polymorph alpha; β, polymorph beta of 1H-benzimidazole). (b) Increase in twist angle with increasing ionic radius in a set of 4,5,6,7tetrahalogeno-1H-benzimidazoles (solid line. fit with sigmoidal curve; A,B,C,D letters have the same meaning as those in Figure 3). (c) An increase in twist angle with increasing hydrogen bond length, d(A···X), in a set of 4,5,6,7-tetrahalogeno-1H-benzimidazoles (solid line, fit with sigmoidal curve; A,B,C,D letters have the same meaning as those in Figure 3).

Hirshfeld surfaces for each molecule, Table 12, are also revealed in the 2D molecular fingerprint plot in the form of two sharp 2097



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Table 11b. Comparison of the Packing Energy for 4,5,6,7-Tetrahalogenophthalic Anhydrides hydrogen/halogen

H44

Cl45

Cl45

Cl47

Br45

Br48

I45

packing energy (kJ/mol)

−88.22

−110.39

−109.33

−109.23

−143.30

−142.12

−157.46

Figure 6. Molecular graphs of 4,5,6,7-tetrahalogeno-1H-benzimidazoles: (a) 4,5,6,7-tetrafluoro-1H-benzimidazole, (b) 4,5,6,7-tetrachloro-1Hbenzimidazole, (c) 4,5,6,7-tetrabromo-1H-benzimidazole, and (d) 4,5,6,7-tetraiodo-1H-benzimidazole).

Reactivity. Analysis of intermolecular bonds can provide detailed information on each 4,5,6,7-tetrahalogeno-1H-benzimidazole molecule behavior in a certain environment but is not able to provide information on its individual properties (reactivity). Some preliminary findings important for evaluation of biological activity come from the analysis of chemical reactivity descriptors for single molecules; Table 13. The narrowest highest occupied molecular orbital (HOMO)− lowest unoccupided molecular orbital LUMO gap (i.e., the smallest absolute hardness and largest softness) from among all 4,5,6,7-tetrahalogeno-1H-benzimidazole molecule has been established for 4,5,6,7-tetraiodo-1H-benzimidazole, which is the softest, the least stable, and the smallest energy, is required for its excitation. This feature is favorable for some unimolecular reactions such as isomerization, dissociation, or radical formation. An unusually high lying LUMO for 4,5,6,7tetraiodo-1H-benzimidazole suggests difficult participation in molecular reactions with nucleophiles; it is difficult to pump in an electron (poor electrophile). Conversely, a high lying HOMO level for 4,5,6,7-tetraiodo-1H-benzimidazole suggests difficult participation in molecular reactions with electrophiles (poor nucleophile). Detailed inspection of HOMO and LUMO orbitals indicates that the path of electron density transfer upon the excitation (from ground to first excited state) highly depends on the halogen type. The HOMO is located over the six-membered ring and both nitrogen atoms (similarly to 1Hbenzimidazole72,73) and changes only slightly upon the change in halogen in all 4,5,6,7-tetrahalogeno-1H-benzimidazoles

(stronger) take part in such bonds. In 4,5,6,7-tetraiodo-1Hbenzimidazole the iodine atoms at positions 5 and 6 take part in C−H···Hal hydrogen bonds. The Hal···Hal and C−H···Hal interactions compete, and only in 4,5,6,7-tetrachloro-1Hbenzimidazole are their percentage contributions the same. In general, the interactions in which Hal atoms participate comprise as much as 65.9, 77.4, 84.8, and 85.3% of the total Hirshfeld surface area of the molecule for F, Cl, Br, and I, respectively. A correlation between the percentage of occupation of the total H surface area of the molecule by the links in which a halogen atom is involved and the strength of hydrogen bonds suggests the balance effect between these interactions determining molecular aggregation in the crystal. When a halogen is involved in a greater number of bonds, then the hydrogen bond N−H···N linking neighboring molecules is stronger. The curvedness mapped on Hirshfeld surface shows that the largest regions of flat curvedness appear for 4,5,6,7tetrabromo-1H-benzimidazole. The shape index, which is sensitive to very subtle changes in surface shape, particularly in the regions where the curvedness is very low, is shown in Figure 8e. This analysis (the adjacent red and blue triangles) indicates that the crystal structures exhibit π···π stacking interactions (Figure 8a−f). The distances to the Hirshfeld surfaces from the nearest atoms outside (de) and inside (di) in the 2D fingerprint plots indicate decreasing efficiency of packing with the increase in van der Waals radius of halogen and decrease in N−H···N hydrogen bond strength. 2098



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Figure 7. Laplacian contour and surface for (a) 4,5,6,7-tetrafluoro-1H-benzimidazole, (b) 4,5,6,7-tetrachloro-1H-benzimidazole, (c) 4,5,6,7tetrabromo-1H-benzimidazole, and (d) 4,5,6,7-tetraiodo-1H-benzimidazole.

except for 4,5,6,7-tetraiodo-1H-benzimidazole, whereas the LUMO delocalization site changes from the atoms in heterocyclic ring for F, H, and Cl derivatives to halogen atoms at positions 5, 6, and 7 of the heterocyclic ring for 4,5,6,7-tetrabromo and 4,5,6,7-tetraiodo. The effect for 4,5,6,7tetraiodo-substitution is remarkable. (For 4,5,6,7-tetrahalogenophthalic anhydrides the tendency in HOMO/LUMO changes upon halogen change is kept; Table 13.) Because 4,5,6,7-tetraiodo-1H-benizmidazole has no charge, both HOMO and LUMO delivered relevant information about reactivity/stability of the specific regions of this molecule. Its HOMO is mostly located on the iodine substituted at position 4, i.e., the most reactive electrons are located at this position. The LUMO is oriented toward the iodine 7, 6, and, to a lesser degree, 5; thus, among all iodine atoms those at position 7 should take part in intermolecular interactions, which is in agreement with the conclusions derived from the Hirshfeld surfaces analysis. The ordering of 4,5,6,7-tetrahalogeno-1H-

benzimidazoles according to decreasing absolute electronegativity, χ, is correlated with the halogens electronegativity I < Br < Cl < F (Pauling scale). However, the most important descriptor, which measures the capacity of an electrophile to accept the maximal number of electrons in a neighboring reservoir of electron pool is the electrophilicity index, ω. The electrophilicity values, which are within the range 1.67−1.90 eV, Table 13, only for 4,5,6,7-tetariodo-1H-benzimidazole can be classified as low. Chemical substitution with halogen atoms (F, Cl, Br, or I) generating electron-withdrawing inductive effect and simultaneously electron donating by resonance effect, modifies the electrophilic properties of the molecule. It can be easily shown that a decrease in electron-withdrawing inductive effect (F > Cl > Br > I) and electron donating by resonance (F > Cl > Br > I) leads to a decrease in electrophilic activation (ω =1.898, 1.823, 1.765, 1.667 eV for F, Cl, Br, and I, respectively). The electronic activation is the weakest upon I and the strongest upon F substitution. The decrease in electrophilicity 2099



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Figure 8. Hirshfeld surface for each molecule: (left) the normalized contact distance dnorm, (middle) curvedness, and (right) shape index for (a) 1Hbenzimidazole (alpha); (b) 1H-benzimidazole (beta); (c) 4,5,6,7-tetrafluoro-1H-benzimidazole; (d) 4,5,6,7-tetrachloro-1H-benzimidazole; (e) 4,5,6,7-tetrabromo-1H-benzimidazole; and (f) 4,5,6,7-tetraiodo-1H-benzimidazole.

HOMO−LUMO gap) and difficult participation in molecular reactions (high lying both LUMO and HOMO) explains why 4,5,6,7-tetraiodo-1H-benzimidazole is more potent than 4,5,6,7tetrabromo- or 4,5,6,7-tetrachloro-1H-benzimidazole. An addi-

after 4,5,6,7-tetraiodo-substitution is remarkable. However, it is well-known that strongly electrophilic reagents lead to a low substrate selectivity,74,75 which for CK2 kinase inhibitors is crucial. This feature in combination with low stability (small 2100



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Table 12. Comparison of % of the Hirshfeld Surface, Total Hirshfeld Surface, and Volume Characterizing 4,5,6,7Tetrahalogeno-1H-benzimidazoles and 4,5,6,7-Tetrahalogenophthalic Anhydrides 4,5,6,7-tetrahalogeno-1H-benzimidazole

4,5,6,7-tetrahalogenophthalic anhydrides

hydrogen/ halogen

Hal···Hal (%)

Hal···C (%)

Hal···All (%)

surface (Å2)

volume (Å3)

Hal···Hal (%)

Hal···C (%)

Hal···All (%)

surface (Å2)

volume (Å3)

H F Cl Br I

26.7 28.8 28.6 30.5

8.3 12.8 23.4 24.2

65.9 77.4 84.8 85.3

163.6 181.45 218.14 232.58 255.24

154.82 171.63 218.04 243.56 277.07

25.2 26.0 36.9

21.8 22.1 12.3

78.3 79.5 74.5

233.11 249.03 270.61

244.87 260.91 300.33

Figure 9. Two-dimensional molecular fingerprint for each 4,5,6,7-tetrahalogeno-1H-benzimidazole studied: total interactions (left) and halogen− halogen interactions (hydrogen−hydrogen for 1H-benzimidazole) (right).

revealed that the longer (weaker) the hydrogen bond, the lower the electrophilicity, Figure 10a; moreover, the greater the van der Waals radius of a halogen (the greater the packing energy), the lower the electrophilicity, Figure 10b (Figure 10c). For 4,5,6,7-tetrahalogenophthalic anhydrides the tendency (the lower derivatives electrophilicity, the higher the energy of spatial packing in the crystal) is kept. The electrophilicity values for 4,5,6,7-tetrahalogenophthalic anhydrides seem larger as they are devoid of hydrogen bonds and contain three strongly electronegative oxygen atoms, Table 12, but their properties are

tional mechanism, the inhibition of electrophilic response leading to attenuated tumor cell survival76 (the inhibition of electrophilic groups derived from carcinogen activation), may be less important to much higher potency in vitro of 4,5,6,7tetraiodo-1H-benzimidazole in comparison to that of 4,5,6,7tetrabromo-1H-benzimidazole as far as antitumor activity is concerned. All above considerations were derived from the analysis of single molecules exclusively, thus omitting the role of intermolecular interactions. However, our intention was also to check the effect of spatial packing on reactivity. The results 2101



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Table 13. Comparison of Reactivity Descriptors Characterising 4,5,6,7-Tetrahalogeno-1H-benzimidazoles and 4,5,6,7-Tetrahalogenophthalic Anhydrides Calculated by B3LYP and HF hydrogen/ halogen H F Cl Br I H F Cl Br I

HOMO (eV)

LUMO (eV)

χ (eV)

η (eV)

4,5,6,7-Tetrahalogeno-1H-benzimidazoles −8.437 0.840 3.799 4.639 −9.376 0.652 4.362 5.014 −9.156 0.684 4.236 4.920 −9.042 0.734 4.154 4.888 −8.784 0.793 3.996 4.788 4,5,6,7-Tetrahalogenophthalic Anhydrides 0.719 4.904 5.624 −10.528 −11.872 0.237 5.475 5.712 −10.472 0.031 5.220 5.251 −10.100 0.039 5.030 5.069 −9.361 0.099 4.631 4.730

ω (eV)

S (eV)

1.555 1.898 1.824 1.765 1.667

0.216 0.199 0.203 0.205 0.209

2.139 2.624 2.595 2.496 2.267

0.178 0.175 0.190 0.197 0.211

much less prone to modification by a change in halogen type, which is indeed observed in vitro.8 From among all 4,5,6,7tetrahalogeno-1H-bezimidazoles, 4,5,6,7-tetraiodo-1H-benzimidazole molecule has the size best matching that of the CK2 binding pocket;14,19 thus, some light on the role of the intermolecular interactions in inhibition of CK2 should shed the analysis of the size of Hirshfeld surface/volume. To determine the total surface/volume−electrophilicity relationships, we checked a correlation of both values calculated using the Hirshfeld approach and the X-ray data with electrophilicity, Figure 11. The same character curve was also obtained as the best fit for the total Hirshfeld surface area assigned to all interactions in which Hal atoms participate in electrophilicity relationships. Thus, substrate selectivity is ensured not only by the electrophilicity but by the surface/volume size, and a combination of these factors provides a high effectiveness of 4,5,6,7-tetraiodo-1H-benzimidazole as CK2 kinase inhibitor. These conclusions, derived from combined X-ray and Hirshfeld analysis, are in good agreement with the results of molecular docking analysis performed for 4,5,6,7-tetrabromo- and 4,5,6,7tetraiodo-1H-benzimidazoles.14,19 The efficacy of 4,5,6,7tetrahalogeno-1H-benzimidazoles is supposed to be substantially dependent on hydrophobic interactions within a small cavity in CK2. 14,19 The potency of tetra-halogenated benzimidazoles was found to increase upon replacement of chlorine by bromine and, even more, by iodine, and to decrease if two unique bulky side chains on CK2 (Val66 and Ile174) are changed to alanines.19 The size of the cavity in which 4,5,6,7tetrahalogeno-1H-benzimidazoles dock was estimated as about 300 Å3. It is well-known that the hydrophobic cavity of CK2 prefers a ligand that is nonpolar and has a specific shape ensuring the largest possible area of contact between the surfaces of the ligand and the receptor (the hydrophobic surface inside the cavity of the receptor). The most effective filling of the hydrophobic cavity is achieved for possibly the largest and least polar molecule, that from among the 4,5,6,7tetrahalogeno-1H-benzimidazoles studied is 4,5,6,7-tetraiodo1H-benzimidazoles. Its Hirshfeld volume and surface are the largest, Table 12, and its dipole moment is the smallest (I (4.47 D) < Br (4.59 D) < Cl (5.02 D) < F (5.75 D), as follows from the presence of the large but the least polar halogen substituent, which is iodine. The iodine atoms are the least chemically reactive, which is reflected by low reactivity of 4,5,6,7-tetraiodo-

Figure 10. (a) Correlation between the hydrogen bond length, d(A·· X), and the electrophilicity, ω. (b) Correlation between the van der Waals radius of a halogen and the electrophilicity, ω (solid line, fit with sigmoidal curve). (c) Correlation between the packing energy and the electrophilicity, ω (solid line, fit with linear curve).

1H-benzimidazole. The neutral molecule of 4,5,6,7-tetrahalogeno-1H-benzimidazole tends to fill the cavity so that to achieve compensation of the potentials of the contacting surfaces of the ligand and the receptor. The protein−ligand interaction energy (van der Waals much smaller than steric) is greater for 4,5,6,7-tetraiodo-1H-benzimidazoles than for 4,5,6,7-tetrabromo-1H-benzimidazoles, but for both substances the interaction with CK2 leads to the complex stabilization; Table 14 and Figure 12. Although in the crystal van der Waals 2102



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only three iodine atoms I(4) of −26.42, I(6) of −26.9, and I(7) of −33.6 kJ/mol is attractive, while that of I(5) of 5.4 kJ/mol is repulsive. It is in agreement with the conclusions from Hirshfeld surface analysis that in 4,5,6,7-tetraiodo-1H-benzimidazole the halogens occupying positions 6, 7, and 4 (double) are important for the formation of interactions, while that at position 5 is of no importance, Figure 12. Moreover, the protein−ligand interaction analysis shows that in 4,5,6,7tetrabromo-1H-benzimidazole an important contribution to the interactions with the ligands is brought by the hydrogen bond in which both nitrogen atoms are involved, while in 4,5,6,7-tetraiodo-1H-benzimidazole only one nitrogen atom is involved so the interaction is nearly half weaker. A similar effect of hydrogen bond weakening has been observed in the 4,5,6,7tetraiodo-1H-benzimidazole crystal, eq 2. The water−ligand interaction in 4,5,6,7-tetrahalogeno-1H-benzimidazole-CK2 complex also has different character for the two compounds; in 4,5,6,7-tetraiodo-1H-benzimidazole it is repulsive, while in 4,5,6,7-tetrabromo-1H-benzimidazole it is attractive. Molecular docking of 4,5,6,7-tetrahalogeno-1H-benzimidazoles in CK2 cavity revealed that replacement of iodine with any other halogen, assuming the use of 4,5,6,7-tetraiodo-1H-benzimidazole template, leads not only to reduction in the contact area but also to water attraction instead of repulsion, which is undesirable from the point of view of activity. The removal of water molecules from the cavity and breaking of hydrogen bonds leads to an increase in entropy and is a driving force for the ligand, very effective for the 4,5,6,7-tetraiodo-1Hbenzimidazole and much less for 4,5,6,7-tetrabromo-1Hbenzimidazole. Thus, the ability to take part in the intermolecular interactions reflects the trend of chemical reactivity, which is based on the electronic properties in the 4,5,6,7-tetrahalogeno-1H-benzimidazoles. Such an analysis allows a fast prediction of the ability of 4,5,6,7-tetrahalogeno1H-benzimidazole to bind with CK2 kinase as its inhibitor.

Figure 11. Correlation between the Hirshfeld surface/volume and electrophilicity, for 4,5,6,7-tetrahalogeno-1H-benzimidazoles and 4,5,6,7-tetrahalogenophthalic anhydrides (solid lines, fit with linear curve).

interaction between two neighboring molecules is the greatest for 4,5,6,7-tetraiodo-1H-benzimidazole (−62.5 kJ/mol) and the lowest for 4,5,6,7-tetrafluoro-1H-benzimidazole (−38.9 kJ/ mol) and similarly the packing energy for 4,5,6,7-tetraiodo1H -benzimidazole (−184.24 kJ/mol) is much greater than for 4,5,6,7-tetrabromo-1H-benzimidazole (−147.97 kJ/mol), in the protein−ligand complex the effect is the reverse, that is the protein−ligand interaction is stronger for 4,5,6,7-tetrabromo1H-benzimidazole than for 4,5,6,7-tetraiodo-1H-benzimidazole. In the protein−ligand complex, the dominant is steric interaction whose order of magnitude, Table 14, is comparable with packing energy in the crystal. This effect, and in particular, the dominant steric contribution to the protein−ligand interaction, is well reproduced on docking of different 4,5,6,7tetrahalogeno-1H-benzimidazole with the use of 4,5,6,7tetraiodo-1H-benzimidazole template, which suggests that steric attraction is an important factor for binding. A comparison of contributions from particular halogens to the total protein−ligand energy in 4,5,6,7-tetrabromo-1H-benzimidazole and 4,5,6,7-tetraiodo-1H-benzimidazole shows that the interaction of all four bromide atoms with the ligand is attractive (Br(5) of −31.6 kJ/mol, Br(6) of −27.1 kJ/mol, Br(7) of −25.0 kJ/mol, and Br(4) of −22.7 kJ/mol), but that of

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CONCLUSIONS 1. The crystal structures of 4,5,6,7-tetrachloro- and 4,5,6,7tetrabromo-1H-benzimidazole have been determined by X-ray diffraction and refined to a final R-factor of 2.68 and 3.03%, respectively, at room temperature. 4,5,6,7Tetrabromo-1H-benzimidazole, crystallizes in the I41/a

Table 14. Comparison of Protein−Ligand and Internal Ligand Energies from Molecular Docking of 4,5,6,7-Tetrahalogeno-1Hbenzimidazoles energy (kJ/mol) protein−ligand ligand 4,5,6,7-tetrabromo-1Hbenzimidazole 2OXY 4,5,6,7-tetraiodo-1H-benzimidazole 3KXN 4,5,6,7-tetrafluoro-1H-benzimidazole 4,5,6,7-tetrachloro-1H-benzimidazole 4,5,6,7-tetrabromo-1Hbenzimidazole 4,5,6,7-tetraiodo-1H-benzimidazole

steric/piecewise linear potential

internal ligand van der Waals /Lennard-Jones

hydrogen bonding

Analysis of Structural Data Taken From Refs 15 and 19 −241.3 −62.9 −40.5

104.6

−40.5

−231.6

17.4

117.8

17.4

Docking Results Using 3KXN Template −57.2 52.3 −58.4 12.6 −57.8 −1.2

131.2 110.5 111.6

−234.3 −243.5 −239.7 −237.4

van der Waals /Lennard-Jones

−54.1

−58.1 2103

steric/piecewise linear Potential

water−ligand

−6.4

107.6



Article

Figure 12. 4,5,6,7-Tetraiodo-1H-benzimidazole-CK2 interactions pattern (the size of the atoms reflect the strength of interaction; protein atoms participating in 10 strongest interactions are depicted in green).

space group, while 4,5,6,7-tetrachloro-1H-benzimidazole is triclinic P1̅ with four molecules in elementary unit. 2. For 4,5,6,7-tetrachloro-1H-benzimidazole, DSC revealed a second order glassy phase transition at Tg = 95 °C/106 °C (heating/cooling), an indication of the frozen disorder and possible polymorphism. 3. The 3D packing in 4,5,6,7-tetrahalogeno-1H-benzimidazole crystals is forced by noncovalent, strongly directional, and mainly electrostatic interactions: N1−H···N3′ hydrogen bonds and much less directional, dispersion forces−van der Waals (Hal···Hal, Hal = H, F, Cl, Br, I) contacts. The particular arrangement of N1−H···N3′ hydrogen bonds depends strongly on the nature of the weaker interactions modulated by the type of halogen present in the molecule. The equilibration of electrostatic matching and dispersion van der Waals interactions between molecules is consistent with the crystal sitesymmetry (the weaker the van der Waals forces the stronger the hydrogen bonds) and forces different crystalline packing for different halogens. The increase in halogen electronegativity is associated with both the elongation of hydrogen bonds and weakening of van der Waals interactions between Hal···Hal, which disturb the almost perpendicular orientation of the molecules and lower the crystalline symmetry. 4. The decrease in electron withdrawing properties (F > Cl > Br > I) leads to a decrease in electrophilic activation (ω = 1.898, 1.823, 1.765, and 1.667 eV, respectively), which is much lower for 4,5,6,7-tetraiodo-1H-benzimidazole than for the other compounds. The 4,5,6,7-tetraiodo-1Hbenzimidazole derivative is the softest and thus should be less reactive than any other of the compounds studied in the unimolecular reactions. The ability to participate in weak intermolecular interactions is reflected by the trend

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of chemical reactivity following from the electronic properties of the molecule (electrophilicity). 5. The largest Hirshfeld surface and volume accompanied by the highest activity of 4,5,6,7-tetraiodo-1H-benzimidazole imply the best ability to fill the CK2 binding pocket. The drastic increase in potency of 4,5,6,7tetraiodo-1H-benzimidazole reflects drastic decrease in electrophilicity and in hydrogen bond strength as well as an increase in size and volume of Hirshfeld surface. 6. 4,5,6,7-Tetrahalogeno-1H-benzimidazoles can be classified as 3D bioisosteres, which enhance the desired biological properties of a compound without making significant changes in chemical structure of a single molecule but with significant changes in abilities to create intermolecular bonds.

AUTHOR INFORMATION

Corresponding Author

*(J.N.L.) Tel: +48-61-8295277. Fax: +48-61-8257758. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The study was supported by the Foundation for Development Diagnostics and Therapy, Warsaw, Poland (to J.N.L. and M.L.). Generous allotment of computer time from the Poznań Supercomputing and Networking Center (PCSS) in Poznań, Poland is gratefully acknowledged.

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