Protein Kinase CK2 Inhibitors - American Chemical Society

J. Phys. Chem. A 2010, 114, 563–575

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Structural Study of Selected Polyhalogenated Benzimidazoles (Protein Kinase CK2 Inhibitors) by Nuclear Quadrupole Double Resonance, X-ray, and Density Functional Theory J. N. Latosin´ska* and M. Latosin´ska Faculty of Physics, Adam Mickiewicz UniVersity Umultowska 85, 61-614 Poznan´, Poland

J. Seliger†,‡ and V. Zˇagar† “Jozef Stefan” Institute, JamoVa 39, 1000 Ljubljana, SloVenia, and Faculty of Mathematics and Physics, UniVersity of Ljubljana, Jadranska 19, 1000 Ljubljana, SloVenia

J. K. Maurin National Medicines Institute, Chelmska 30/34, 00-750 Warsaw, Poland, and Institute of Atomic Energy, 05-400 Otwock-Swierk, Poland

A. Orzeszko Institute of Chemistry, Warsaw UniVersity of Life Sciences, 159C Nowoursynowska Street, 02-787 Warsaw, Poland, and Military UniVersity of Technology, 2 Kaliskiego Street, 00-908 Warsaw, Poland

Z. Kazimierczuk Institute of Chemistry, Warsaw UniVersity of Life Sciences, 159C Nowoursynowska Street, 02-787 Warsaw, Poland ReceiVed: August 5, 2009; ReVised Manuscript ReceiVed: NoVember 2, 2009

Protein kinase CK2 inhibitors, polyhalogenated benzimidazoles, have been studied experimentally in solid state by NMR-NQR double resonance and X-ray and theoretically by the density functional theory (DFT). Six resonance frequencies on 14N have been detected and assigned to particular nitrogen sites in each polyhalogenated benzimidazole molecule. The effects of prototropic annular tautomerism and polymorphism related to stable cluster formation due to intermolecular hydrogen bonding interactions on the 14N NQR parameters have been analyzed within the DFT and AIM (atoms in molecules) formalism. The studies suggest that all polyhalogenobenzimidazoles are isostructural and can exhibit polymorphism and that 14N NQR is very sensitive to hydrogen bondings but less sensitive to the specific arrangement of the hydrogen bonded molecules. NQDR and DFT results suggest the presence of the prototropic annular tautomerism 50:50, which is in a good agreement with the X-ray and 1H NMR data. Introduction In the late 1980s polyhalogenated benzimidazoles were found to be valuable scaffolds effectively competing with ATP binding site of casein kinase II (CK2).1 Their structural analogue 4,5,6,7-tetrabromo-1H-benzotriazole (TBB) was later demonstrated to be one of the most powerful and selective cell permeable inhibitors of CK2.2,3 The presence of four bromine atoms on the benzene ring of these heterocycles was proved critical to fill the CK2 hydrophobic pocket to the ATP-binding site.4,5 A comparative analysis of selected tetrabromobenzimidazole derivatives revealed the presence of some highly conserved water molecules at the ATP-binding site.4 It is worth noting the important role of the stabilizing effect of halogen bonds in complexes of CK2 and its inhibitors.4 * Author for correspondence. Tel.: +48-61-8295277. Fax: +48-618257758. E-mail: [email protected]. † “Jozef Stefan” Institute. ‡ University of Ljubljana.

Protein kinase CK2 is a highly pleiotropic enzyme whose high constitutive activity is suspected to be instrumental in enhancement of the tumor phenotype and infectious diseases. CK2 inhibitors have been indicated as potentially promising drugs for anticancer therapy. We have found recently that 4,5,6,7-tetraiodo-1H-benzimidazole (TIBI) (Ki ) 0.023 µM) is a several times more potent inhibitor of CK2 than TBB (Ki ) 0.4 µM) or 4,5,6,7-tetrabromo-1H-benzimidazole (TBI) (Ki ) 0.5 µM).6 Structural studies of 4,5,6,7-tetrabromo-1H-benzimidazole and some of its derivatives by means of solid state 13C, 15N NMR spectroscopy have been reported.7 In this work we pay more attention to the structural (including electron-density distribution) aspects of other polyhalogenated benzimidazoles using the crystallography, NQDR spectroscopy and DFT calculations. While the X-ray studies provide the information on the crystalline packing, NQDR provides more detailed information on the local distribution of electron density, whereas the results of DFT calculations reveal global distribution of electron density in the whole molecule. We expect that this combined study will

10.1021/jp9075492  2010 American Chemical Society Published on Web 12/01/2009

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J. Phys. Chem. A, Vol. 114, No. 1, 2010

Figure 1. 1H-3H tautomeric equilibrium in polyhalogenobenzimidazoles.

facilitate the understanding of the detailed structural features of polyhalogenobenzimidazoles and contribute to the further explanation of the role of CK2 inhibitors on the molecular level, especially the functional implications of tautomerism for recognition and binding of these molecules to CK2. Experimental Section Materials. The following halogenobenzimidazoles Figure 1, were prepared by the condensation of respective halogenated 1,2-phenylenediamine with formic acid according to the method of Phillips:8 5-chloro-1H-benzimidazole, 4,6dibromo-1H-benzimidazole, 4,6-dichloro-1H-benzimidazole, 5,6-dichloro-1H-benzimidazole. 4,5,6,7-tetrachloro-1H-benzimidazole was synthesized by the method of Burton et al.9 Iodinated benzimidazoles 4,6-dichloro-5,7-diiodo-1H-benzimimidazole, 4,6-dibromo-5,7-diiodo-1H-benzimidazole and 4,5,6,7-tetraiodo-1H-benzimidazole were synthesized by iodination of respective benzimidazole with mixture of iodineperiodic acid in sulfuric acid solution.6 4,6-Dibromo-5,7-dichloro-1H-benzimidazole was obtained by exhaustive bromination according the following procedure. To the stirred and refluxed solution of 4,6-dichloro-1Hbenzimidazole (1.87 g, 10 mmol) in water (70 mL) bromine (2.7 mL, 50 mmol) was added portionwise within 6 h. The reflux was continued for 30 h. The reaction mixture was cooled and the orange precipitate was filtered off to be dissolved in MeOH-aqueous ammonia (3:1, v/v) treated with charcoal and cellite. The pale-yellow filtrate was brought to pH 4-5 with acetic acid and the precipitate formed was crystallized from EtOH to give colorless crystals (2.61 g, 76%); mp> 300 °C (with decomp.). UV (MeOH): 261 nm (8400), 269 nm (8000), 289 nm (3700), 298.5 nm (3400). 1 H NMR (Me2SO-d6) δ (ppm): 8.49 (s, H-C), 13.49 and 13.63 (2 bs, H-N). MS, m/z: 348 (32, M+ + 4), 346 (86, M+ + 2), 344 (100, M+), 342 (40, M+ - 2), 265 (14, M+ 79). Anal. Calcd for C7H2N2Br2Cl2 (344.82): C, 24.38; H 0.58; N, 8.12. Found: C, 24.29; H, 0.67; N, 8.01. Methods. X-ray structural studies of halogenated imidazoles were performed using an Xcalibur R single crystal diffractometer from Oxford Diffraction. Monochromated Cu KR radiation was applied in all experiments. Monocrystals of the compounds studied were mounted on the goniometer and reflections were collected up to Bragg angles 2θ e 140°. The intensities of the reflections were corrected for Lorenzpolarization effects and for absorption and extinction.

Latosin´ska et al. Structures were solved using direct methods from SHELXS98 program10 and then refined by application of SHELXL98 software.11 The crystallographic data for the respective structures are given in Table 1. The crystal packing of 4,5,6,7tetraiodo-1H-benzimidazole and the disordered iodine and bromine positions in 4,6-dibromo-5,7-diiodo-1H-benzimidazole are shown in Figures 2 and 3. All structures have been deposited with Cambridge Structural Data Centre. The respective deposit numbers are shown in Table 1. Different double resonance techniques based on magnetic field cycling were used to detect 14N NQR frequencies. The proton spin system was polarized in B0 ) 0.75 T for 30 s. Then the sample was pneumatically transferred within 0.1 s into another magnet where it was left for 0.3 s. In this other magnet the magnetic field can be varied continuously between zero and 0.1 T. After the stay in this magnet, the sample was pneumatically transferred within 0.1 s back into the first magnet and the proton NMR signal was measured immediately after the sample had been stopped in the first magnet. As the first method we used the 1H-14N cross relaxation spectroscopy.12-14 In this method the sample is left to relax in a low magnetic field for 0.3 s and the low magnetic field varied between the magnetic field cycles in steps of approximately 0.5 mT corresponding to the step in the proton Larmor frequency νL of 20 kHz. When the proton Larmor frequency νL matches the 14N NQR frequency νQ, the proton spin-lattice relaxation time shortens, which results in a decrease in the proton NMR signal after the cycle. In some cases, especially at higher proton Larmor frequencies, the step of 40 kHz can be used. On the other hand, around νL ) νQ the step is reduced to 10 kHz to improve the resolution. In the second step, we used the solid-effect technique.15 In this method the low magnetic field is fixed and the sample is in the low magnetic field irradiated for 0.5 s with a strong rf magnetic field at variable frequencies. When the frequency ν of the rf magnetic field is ν ) νQ ( νL, simultaneous spin flips take place in both 1H and 14N spin systems and, as a result, the proton magnetization drops to a lower value. The experiment was repeated for a few values of the low magnetic field to clarify the spectrum and to get rid of the signal artifacts caused by the direct proton absorption of the rf power at multiples of the proton Larmor frequency and the level crossing signals produced by the higher harmonics of the rf magnetic field. As the final technique, combining the three 14N NQR frequencies from a given nitrogen site, we used the twofrequency irradiation technique.16 Here, the proton Larmor frequency νL is set in resonance with the lowest 14N NQR frequency ν0 and the sample is irradiated with two rf magnetic fields at the frequencies ν1 ) ν and ν2 ) ν + ν0. When ν1 ) ν- and ν2 ) ν- + ν0 ) ν+, the proton relaxation rate in the low magnetic field increases and, as a result, the proton NMR signal at the end of the magnetic field cycle drops to a low value. In total, six resonance lines for each halogenobenzimidazole were detected to the accuracy of 10 kHz. The typical spectra are shown in Figure 4. Calculations. Quantum chemical calculations were carried out within the GAUSSIAN03TM code17 run on the CRAY supercomputer at the Supercomputer and Network Centre (PCSS) in Poznan, Poland. All calculations were performed using the density functional theory (DFT) with B3-LYP exchange-correlation hybrid functional (three-parameter exchange functional of Becke B318 combined with the

Structure of Selected Polyhalogenated Benzimidazoles

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TABLE 1: Crystal Data and Structure Refinement for the Studied Structures CCDC number empirical formula formula weight temperature wavelength crystal system space group unit cell dimensions volume Z density (calculated) absorption coefficient F(000) crystal size θ range for data collection index ranges no. of reflections collected independent reflections completeness to θ ) 70.39° absorption correction max. and min transmission refinement method data/restraints/parameters goodness-of-fit on F2 final R indices [I > 2σ(I)] R indices (all data) extinction coefficient largest diff peak and hole

739732 C7H2Cl2I2N2 438.81 293(2) K 1.54178 Å tetragonal I41/a a ) 15.1126(6) Å, R ) 90° b ) 15.1126(6) Å, β ) 90° c ) 18.2395(7) Å, γ ) 90° 4165.7(3) Å3 16 2.799 Mg/m3 52.117 mm-1 3168 0.4181 × 0.2860 × 0.2101 mm3 3.80 to 70.39° -17 e h e 18, -18 e k e 17, -18 e l e 21 49149 1964 [R(int) ) 0.0802] 98.4% analytical 0.055 and 0.003 full-matrix least-squares on F2 1964/34/156 1.122 R1 ) 0.0783, wR2 ) 0.2312 R1 ) 0.0871, wR2 ) 0.2365 0.000054(14) +0.601 and -0.639 e Å-3

Lee-Yang-Parr correlation functional LYP19), using the extended basis set with polarization and diffuse functions 6-311++G(d,p). The efficiency of the DFT calculations performed at the above-mentioned level of theory for reproduction of NQR parameters was earlier proved.20,21 The calculations were carried out under the assumption of the crystallographic as well as the partially optimized geometry (Berry algorithm), where in optimization only the positions

739733 C 7 H 2 I 4N 2 621.71 293(2) K 1.54178 Å tetragonal I41/a a ) 15.6273(2) Å, R ) 90° b ) 15.6273(2) Å, β ) 90° c ) 18.6297(3) Å, γ ) 90° 4549.61(11) Å3 16 3.631 Mg/m3 84.408 mm-1 4320 0.4829 × 0.4081 × 0.2801 mm3 3.69 to 70.13° -15 e h e 17, -18 e k e 17, -22 e l e 21 9617 2075 [R(int) ) 0.0365] 95.4% analytical 0.028 and 0.001 full-matrix least-squares on F2 2075/0/126 1.075 R1 ) 0.0291, wR2 ) 0.0763 R1 ) 0.0305, wR2 ) 0.0773 +0.939 and -1.141 e Å-3

739734 C7H2Br2I2N2 527.73 293(2) K 1.54178 Å tetragonal I41/a a ) 15.2873(5) Å, R ) 90° b ) 15.2873(5) Å, β ) 90° c ) 18.3089(3) Å, γ ) 90° 4278.8(2) Å3 16 3.277 Mg/m3 55.415 mm-1 3744 0.3398 × 0.2588 × 0.1719 mm3 3.77 to 70.35° -14 e h e 17, -17 e k e 17, -21 e l e 21 8654 1937 [R(int) ) 0.0343] 94.6% analytical 0.067 and 0.006 full-matrix least-squares on F2 1937/8/156 1.076 R1 ) 0.0645, wR2 ) 0.1705 R1 ) 0.0751, wR2 ) 0.1794 0.000065(9) +1.183 and -1.515 e Å-3

of hydrogen atoms were allowed to relax while those of all other atoms remained frozen. For all optimized structures the minima were verified using frequency calculations. The principal components of the EFG tensor, qii (i ) x, y, and z), were used to obtain the 14N NQR parameters: the nuclear quadrupole coupling constants (e2qQh-1), asymmetry parameters (η), and NQR frequencies (ν) which are interrelated by the equations:22

Figure 2. Crystal packing of 4,5,6,7-tetraiodo-1H-benzimidazole shown along the tetragonal c-axis. All the non-hydrogen atoms are shown as 30% probability ellipsoids. The nitrogen atoms are shown in dark blue, whereas the iodine atoms are shown in magenta. The N-H · · · N hydrogen bonds are shown as the thin dashed lines.

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Latosin´ska et al. TABLE 2: Experimental 14N NQR Parameters for 1H-Benzimidazole and Polyhalogenobenzimidazoles

e2Qq (3 + η) 4h e2Qq (3 - η) ν-(14N) ) 4h

ν+(14N) )

ν0(14N) ) ν+(14N) - ν(14N) )

(1) e2Qq η 2h

The nuclear quadrupole moment for 14N equal to 2.044 fm2 was assumed. The values of the hydrogen bond energies were determined according to the supermolecular approach,23 while the appropriated corrections were performed by means of the zero point energy (ZPE)24 calculations. Analysis of the topological parameters such as bond critical points, Laplacian of the electron density, and ellipiticity of the bonds was performed within the atoms in molecules theory (AIM).25 Atomic charges and bond populations were calculated using the natural population (NPA) and natural bond orbital (NBO) analysis methods developed by Reed et al.26

compound

site

1H-benzimidazolea

-NH-Nd

1H-benzimidazoleb

-Nd

5,6-dichloro1H-benzimidazole

-NH-Nd

4,6-dichloro1H-benzimidazole

Results and Discussion The number of the resonance lines (six) detected experimentally for each polyhalogenobenzimidazole, except for 5-chloro1H-benzimidazole for which no signal could be recorded (Table

-NH-

-NH-Nd

4,6-dibromo1H-benzimidazole

-NH-Nd

4,6-dibromo-5, 7-dichloro1H-benzimidazole

-NH-Nd

4,6-dichloro-5, 7-diiodo1H-benzimidazole

-NH-Nd

Figure 3. Hydrogen bonded chain of the 4,6-dibromo-5,7-diiodo-1Hbenzimidazole. The disordered iodine and bromine positions are visualized (bromine atoms are shown in red whereas iodine in magenta). All non-hydrogen atoms are shown as 30% probability ellipsoids. The hydrogen bonds are marked as the thin dashed lines.

4,6-dibromo-5, 7-diiodo1H-benzimidazole

-NH-Nd

4,5,6,7-tetrachloro1H-benzimidazole

4,5,6,7-tetraiodo1H-benzimidazole

-NH-Nd -NH-Nd

a

Figure 4. 1H-14N solid effect double resonance spectra of 4,6dichloro-5,7-diiodo-1H-benzimidazole (top), 4,6-dibromo-5,7-diiodo1H-benzimidazole (middle), and 4,5,6,7-tetraiodo-1H-benzimidazole (bottom). The spectra are measured at T ) 198 K in magnetic field B ) 2.5 mT.

ν + , ν- , ν0 (MHz)

e2qQh-1 (MHz)

η

temp (K)

1.885 1.100 0.770 2.590 2.115 0.475 1.863 1.167 0.694 2.573 2.150 0.422 1.880 1.100 0.780 2.515 2.205 0.31 1.900 1.080 0.820 2.640 2.165 0.475 1.900 1.079 0.820 2.570 2.150 0.42 1.965 1.105 0.860 2.660 2.110 0.550 1.955 1.120 0.835 2.650 2.115 0.545 1.970 1.195 0.775 2.660 2.110 0.550 2.050 1.190 0.860 2.670 2.000 1.330 0.670 2.640 2.170 0.470

2.021

0.687

77

3.149

0.268

1.976

0.786

3.140

0.303

1.985

0.785

3.145

0.197

1.985

0.826

3.205

0.297

1.984

0.826

3.145

0.267

2.045

0.840

3.180

0.346

2.050

0.815

3.175

0.343

2.110

0.735

3.180

0.346

2.160

0.796

198

2.220

0.604

198

3.210

0.293

291

149

141

198

183

198

203

experimental data from ref 27. b experimental data from ref 28.

2, Figure 4), suggests that similarly to benzimidazole27,28 there are no crystallographically inequivalent molecules in the elementary cell, which is consistent with the X-ray data available for some polyhalogeno derivatives; see Table 1 in this paper and ref 5. However, the measurements have been performed in slightly different temperatures because the suitable conditions, especially a long enough proton relaxation time T1, in the low magnetic field were required, the temperature dependence of the NQR frequencies in these compounds is weak, so the results of measurements taken at different temperatures do not change the general conclusions. Admittedly, the knowledge of ν0 ) ν+ - ν- facilitates grouping the resonance lines and a comparison with benzimi-



Figure 5. Trimers in the structure of benzimidazole (a) R and (b) β polymorphic forms. Green lines indicate the intermolecular hydrogen bonds.

TABLE 3: Calculated 14N NQR Parameters for Polyhalogenobenzimidazoles (Assumed X-ray Structures, Proton Positions Optimized) monomer X-ray compound 1H-benzimidazole R form

a

1H-benzimidazole β formb 4,6-dichloro-5,7-diiodo-1H-benzimidazolec 4,6-dichloro-5,7-diiodo-3H-benzimidazolec 4,6-dibromo-5,7-diiodo-1H-benzimidazolec 4,6- dibromo -5,7-diiodo-3H-benzimidazolec 4,5,6,7-tetraiodo-1H-benzimidazolec a

trimer X-ray

site

e2qQh-1 (MHz)

η

-NH-Nd -NH-Nd -NH-Nd -NH-Nd -NH-Nd -NH-Nd -NH-Nd

3.465 4.064 3.154 3.816 3.120 4.541 3.120 4.457 2.934 4.261 2.934 4.211 3.087 4.176

0.174 0.097 0.140 0.060 0.477 0.010 0.477 0.003 0.421 0.023 0.421 0.013 0.256 0.058

e2qQh-1 (MHz) 2.499 3.516 2.456 3.808 2.682 4.130 2.714 4.090 2.522 3.852 2.511 3..834 2.707 3.783

tetramer X-ray η

e2qQh-1 (MHz)

η

0.483 0.287 0.798 0.153 0.877 0.117 0.852 0.106 0.783 0.158 0.796 0.146 0.540 0.172

2.498 3.515 2.454 3.806 2.673 4.114 2.713 4.089 2.489 3.818 2.504 3.842 2.699 3.749

0.491 0.296 0.803 0.162 0.879 0.131 0.847 0.115 0.805 0.162 0.789 0.172 0.547 0.184

X-ray structure from ref 38. b X-ray structure from ref 39. c X-ray structures, this paper.

dazole facilitates their assignment to nitrogen sites, but the DFT calculations permit unambiguous assignment of the lines to the particular -Nd and -NH- nitrogen sites in the molecules. The assignment is not straightforward because of the possible tautomerism and participation of each nitrogen atom in intermolecular hydrogen bond of the same NH · · · N pattern. The 14N NQR parameters: e2qQh-1, η, and frequencies ν+, ν-, ν0 at all nitrogen atoms have been calculated at the B3LYP/6311++G(d,p) level assuming different tautomers (Figure 1) and polymorphic forms, which differ in molecular aggregations formed by the intermolecular interactions (Figure 5). The results are collected in Tables 3 and 4. Tautomerism. Because it is known that the 1H a 3H tautomerization plays an important role in enzymatic reactions, inspection of the most stable tautomeric forms of the following polyhalogenobenzimidazoles, 5-chloro-1H-benzimidazole, 4,6dibromo-1H-benzimidazole, 4,6-dichloro-1H-benzimidazole, 5,6dichloro-1H-benzimidazole, 4,6-dichloro-5,7-diiodo-1H-benzimimidazole, 4,6-dibromo-5,7-dichloro-1H-benzimidazole and 4,6-dibromo-5,7-diiodo-1H-benzimidazole, allows further discussion of the functional implications of tautomerism for recognition and binding of these molecules to CK2. The calculations performed for the 1H and 3H tautomers at the B3LYP/6-311++G(d,p) level of theory predicted the stability of 1H slightly higher than that of 3H tautomeric form for all above-mentioned polyhalogenobenzimidazoles. Accord-

ing the intrinsic stability measured by the tautomerization barrier height, ∆E3H-1H (Table 5) halogenobenzimidazoles could be ordered as follows:

5-Cl < 4,6-diCl < 4,6-diBr < 4,6-diBr-5,7-diCl < 4,6-diBr-5,7-diI < 4,6-diCl-5,7-diI Generally, the ∆E3H-1H values suggest that mono- and disubstituted benzimidazoles have generally much lower intrinsic stability than tetrasubstiuted ones. The increase in ∆E3H-1H upon trimer formation indicates that the tautomerization process can hardly occur in solid and polar media. The low intrinsic stability of 5-chloro-1H-benzimidazole explains the problems with NQDR measurements connected with the fast relaxation characterized by a very short proton spin-lattice relaxation time T1 observed for this sample. With increasing number and weight of the halogen (iodine/chlorine/bromine) atoms in halogenobenzimidazole, the intrinsic stability and elongation of the proton relaxation time increase permitting NQDR experiment. The relatively low tautomerization barriers for polyhalogenobenzimidazoles are in a good agreement with the prototropic annular tautomerism observed in X-ray experiment as a superposition, i.e., 50:50 mixture of two tautomers 1H and 3H in the crystal structure. Such an effect is assumed as typical of centrosymmetric structures in which the N-H hydrogen atom can be disordered over two ring N atoms;29,30 therefore it can be expected for the other halogenobenzimidazoles.

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TABLE 4: Calculated 14N NQR Parameters for Polyhalogenobenzimidazoles (r Polymorphic Form Assumed) monomer 1H compound

site

-NH-Nd 5,6-dichloro-1H-benzimidazole -NH-Nd 4,6-dichloro-1H-benzimidazole -NH-Nd 4,6-dibromo-1H-benzimidazole -NH-Nd 4,6-dibromo-5,7-dichloro-NH1H-benzimidazole -Nd 4,6-dichloro-5,7-diiodo-NH1H-benzimidazole -Nd 4,6-dibromo-5,7-diiodo-NH1H-benzimidazole -Nd 4,5,6,7-tetrachloro-NH1H-benzimidazole -Nd 4,5,6,7-tetraiodo-NH1H-benzimidazole -Nd 5-chloro-1H-benzimidazole

3H

3H

η

e2qQh-1 (MHz)

η

e2qQh-1 (MHz)

η

e2qQh-1 (MHz)

η

3.454 4.086 3.499 4.097 3.501 4.157 3.494 4.134 3.443 4.123 3.406 4.121 3.398 4.099 3.452 4.143 3.388 4.051

0.163 0.127 0.148 0.128 0.123 0.15 0.148 0.121 0.131 0.164 0.127 0.163 0.134 0.162 0.132 0.168 0.130 0.163

3.499 4.082 3.499 4.097 3.434 4.046 3.419 4.038 3.430 4.135 2.429 3.339 3.413 4.071 3.452 4.143 3.388 4.051

0.156 0.099 0.148 0.128 0.154 0.153 0.120 0.153 0.135 0.167 0.127 0.163 0.128 0.164 0.132 0.168 0.130 0.163

2.498 3.534 2.542 3.527 2.563 3.582 2.556 3.563 2.579 3.426 2.548 3.436 2.476 3.395 2.588 3.446 2.429 3.339

0.494 0.319 0.523 0.325 0.543 0.323 0.546 0.321 0.546 0.452 0.612 0.432 0.594 0.446 0.623 0.452 0.586 0.467

2.534 3.516 2.542 3.527 2.545 3.371 2.537 3.355 2.578 3.423 2.568 3.385 2.538 3.418 2.588 3.446 2.429 3.339

0.518 0.291 0.523 0.325 0.558 0.430 0.561 0.426 0.615 0.461 0.623 0.452 0.617 0.431 0.623 0.452 0.586 0.467

µ (D) 1H-benzimidazole (R polymorph) 1H-benzimidazole (β polymorph) 5-chloro-1H-benzimidazole 5,6-dichloro-1H-benzimidazole 4,6-dichloro-1H-benzimidazole 4,6-dibromo-1H-benzimidazole 4,6-dibromo-5,7-dichloro1H-benzimidazole 4,6-dichloro-5,7-diiodo1H-benzimidazole 4,6-dibromo-5,7-diiodo1H-benzimidazole 4,5,6,7-tetrachloro-1H-benzimidazole 4,5,6,7-tetraiodo-1H-benzimidazole

1H

e2qQh-1 (MHz)

TABLE 5: Relative Stability (∆E3H-1H) and Dipole Moments (µ) of Polyhalogenobenzimidazoles compound

tetramer

∆E3H-1H (kJ/mol)

0.4 1.1 4.8 4.9

1H 3.70 3.52 5.19 5.16 4.93 4.88 4.69

3H

3.58 3.82 3.78 4.68

23.9

4.41 4.56

18.4

4.26 4.41 4.84 4.09

The correlation between the 14N NQR frequencies obtained in the experiment and those calculated by DFT, assuming the monomers of 1H and 3H tautomeric forms, is only fairly good (the correlation coefficients are as low as 0.897 and 0.895 and standard deviations as high as 0.554 and 0.556 MHz, respectively). The calculated 14N NQR frequencies deviate much more from the experimental ones for -NH- (correlation coefficient 0.765 and standard deviation 0.776) than for -Nd sites (correlation coefficient 0.984, standard deviation 0.259), which suggests that the formation of hydrogen bond accompanied with the proton transfer requires the rearrangement of electron density, and consequently the NQR frequencies are shifted. The reproduction of the e2qQh-1 under the assumption of monomer presence is surprisingly good (correlation coefficients 0.981 and 0.986 and standard deviations 0.067 and 0.055 MHz for 1H and 3H tautomers, respectively); however, these values are highly overestimated, but that of the asymmetry parameters is very poor (correlation coefficients 0.174 and 0.389 and standard deviations 0.022 and 0.021, respectively, for 1H and 3H tautomers) and these values are highly underestimated. Separate analyses of the asymmetry parameters for each kind of nitrogen site -NH- and -Nd (correlation coefficients 0.960 and 0.979 and standard deviations 0.004 and 0.006 for the 1H tautomer) revealed that the source of the significant error in η is the interchange of the x and y axes of the EFG tensor caused by

the protonation of the nitrogen -Nd, which, however, because of the form of eqs 1, does not directly influence the 14N NQR frequencies. In Figure 6, the change in the orientation of EFG tensor axes at both nitrogen sites upon hydrogen bonds formation was shown. The differences in the orientation of the EFG tensor principal axes for monomer and trimer are greater for -NH- than for the -Nd site (35, 15, and 39 versus 39, 15, and 10 deg, for x, y, and z axes, respectively). This observation additionally confirms the necessity of taking into account the proton transfer in hydrogen bondings in polyhalogenobenzimidazoles. Upon trimer formation, the decrease in e2qQh-1, whose magnitude depends on the nitrogen site type: 70% for -NH- and 80% for -N- and the increase in η by about 2.5 times for -Nd and by about 5 times for -NH- is observed (Table 4). At the -Nd site the changes in e2qQh-1 are directly proportional to the changes in η with the positive sign, while at the -NH- site the changes in e2qQh-1 are proportional to those in η but with the negative sign. The correlation between the 14N NQR frequencies obtained in the experiment and those calculated by DFT, assuming the trimers of 1H and 3H tautomeric forms (which corresponds to having taken into regard the hydrogen bond formation) is very good (the correlation coefficients are 0.980 and 0.978 and standard deviations 0.178 and 0.173 MHz for 1H and 3H tautomers, respectively), Figure 7a. The reproduction of the e2qQh-1, under the assumption of trimer consisting of 1H or 3H tautomers, is also very good (correlation coefficients 0.979 and 0.982 standard deviations 0.101 and 0.087 MHz for 1H and 3H tautomers, respectively), Figure 7b, and the asymmetry parameters only slightly worse (correlation coefficients 0.881 and 0.883 and standard deviations 0.055 and 0.050 MHz for 1H and 3H tautomers, respectively), Figure 7c, which makes it difficult to verify the presence of the specific tautomeric form using 14N NQR and DFT results. Direct comparison of the. 14 N NQR frequencies calculated for trimers consisting of 1H and 3H tautomers, leads to a conclusion that the differences in the frequencies are lower than10 kHz (i.e., within the experimental error) and the presence of different tautomers can be easily masked by line width. Similar quality of correlations of the 14N NQR frequencies and e2qQh-1 obtained in the experiment and those calculated by DFT, assuming the monomers and trimers of 1H and 3H, supports this conclusion.



Figure 6. Orientation of the EFG tensor axes at both nitrogen atoms -Nd and -NH- sites in polyhalogenobenzimidazoles: (A) 1Hbenzimidazole R monomer; (B) 1H-benzimidazole β monomer; (C) 1H-benzimidazole R trimer; (D) 1H-benzimidazole β trimer; (E) 5,6dichloro-1H-benzimidazole trimer; (F) 4,6-dichloro-1H-benzimidazole trimer; (G) 4,6-dibromo-5,7-dichloro-1H-benzimidazole trimer; (H) 4,5,6,7-tetraiodo-1H-benzimidazole trimer.

570


Figure 7. Correlations between the experimental (exp) and calculated (calc) (A) 14N-NQR frequencies, (B) quadrupole coupling constants, (C) asymmetry parameters under assumption of monomers and trimers of 1H and 3H tautomers of polyhalogenobenzimidazoles (fit: 1H, solid line; 3H, dashed line).

The correlation between the 14N NQR frequencies, e2qQh-1 and η obtained in the experiment and those calculated by DFT, assuming the trimers of 1H-benzimidazole, 4,5,6,7-tetraiodo1H-benzimidazole, 4,6-dichloro-5,7-diiodo-1H-benzimidazole, and 4,6-dibromo-5,7-diiodo-1H-benzimidazole, constructed on the basis of the available X-ray data, is very good (the

Latosin´ska et al. correlation coefficients are 0.979, 0.944, and 0.878 and standard deviations are 0.206, 0.242 MHz, and 0.138, for 14N NQR frequencies, e2qQh-1, and η, respectively) and much better than those obtained assuming the predicted structures or the monomers, Table 3, Figure 8a,b. A comparison of the results for monomer, trimer, and tetramer shows a systematic improvement in the reproduction of NQR parameters to a degree proportional to the strength of the interactions (the weaker the interaction the smaller the correction). The slightly lower scattering (by 0.022 MHz) and slope of the line (by 3.6%) for tetramers in comparison to results obtained for trimers suggests that contact interaction only slightly influences the 14N-NQR frequencies. The improvement in reproduction of the NQR parameters for 1H-benzimidazole, 4,5,6,7-tetraiodo-1H-benzimidazole, and 4,6dichloro-5,7-diiodo-1H-benzimidazole after taking into account the next neighbor interactions in clusters (tetramers) is small and hence seems unworthy against the drastic increase in the computational cost. The next neighbor interactions only insignificantly influence the orientation of the EFG tensor axes and the values of the EFG tensor components and so also the asymmetry parameter at the hydrogen bonded sites. This conclusion is in a good agreement with the results of our recent studies of 6-thioguanine and 6-mercaptopurine.31 Moreover, the correlation between the 14N NQR frequencies obtained in the experiment and those calculated by DFT, assuming the 1H and 3H tautomeric forms prepared on the basis of X-ray structures is similarly good (the correlation coefficients are 0.979 and 0.971 standard deviations 0.206 and 0.211 MHz for 1H and 3H tautomers, respectively), Figure 7a, and the negligible differences in the frequencies (within the experimental error), Table 3, leads to the conclusion that both tautomers can be present. Additionally, the 1H NMR signals detected at about 13.0 ppm and assigned to NH in polyhalogenobenzimidazoles show an asymmetric doublet structure for 4,6-dichloro-5,7-diiodo-6 and 4,6-dibromo-5,7-diiodo-1H-benzimidazole due to the coupling to the two nitrogen atoms but an asymmetric broad line for 4,5,6,7-tetraiodo-1H-benzimidazole,6 which cannot be explained by proton exchange with the solvent, conformational changes, or the formation of closed and open structures but only by the presence of interconverting tautomers, i.e., the occurrence of the proton transfer. Such a double proton transfer between hydrogen bonded nitrogen atoms in many nucleobase pairs was observed by 1H NMR in solution as well as solid state.32-35 Structural Pattern. Benzimidazole. Specific structural pattern minimizing the dipole moment, typical of R (stable) polymorph of unsubstituted benzimidazole, was studied using X-ray by DikEdixhoven et al., Escande and Galigne, and Stibrany et al.36-39 The β polymorph of benzimidazole, which differs from R in the melting point (445 versus 431 K) was recently found to be metastable; it transforms at room temperature to the R form.39 Although in both crystalline forms the benzimidazole molecules are connected into polymeric chains via N-H · · · N hydrogen bonds, the modes of aromatic ring interactions and the spatial arrangements differ in these two molecules significantly. While in the R form the molecules show edge-to-face interactions,38 in the β form, a sandwich-herringbone arrangement of the aromatic molecules is observed.39 The R form, which is energetically more stable than β, has slightly higher effective dipole moment (14.4 versus 13.3 D), which suggest that the polarization of the neighboring layers forces the specific arrangement. In the benzimidazole structure each molecule links two neighboring ones via two intermolecular hydrogen bonds: N1-H · · · N3′′ (rN1 · · · N3′′ ) 2.853 Å, ∠(N1-H · · · N3′′) ) 166°



Figure 8. Correlation between the experimental (exp) and calculated (calc, under assumption of X-ray structure) 14N-NQR frequencies for different clusters of (A) 1H-benzimidazole, 4,6-dichloro-5,7-diiodo-1H-benzimidazole, 4,6-dibromo-5,7-diiodo-1H-benzimidazole, and 4,5,6,7-tetraiodo-1Hbenzimidazole and (B) 1H-benzimidazole, 4,6-dichloro-5,7-diiodo-1H-benzimidazole, 4,6-dibromo-5,7-diiodo-3H-benzimidazole, and 4,5,6,7-tetraiodo3H-benzimidazole. Symbols: open, monomers; solid, trimers; crossed, tetramers. Lines: dotted, monomers; solid, trimers; dashed, tetramers.

and rN1 · · · · N3′′ ) 2.884 Å, ∠(N1-H · · · N3′′) ) 174° for R and β forms, respectively) and N1′ · · · H-N3 (rN1′ · · · N3 ) 2.853 Å, ∠(N1′ · · · H-N3) ) 157° and rN1′ · · · N3 ) 2.885 Å, ∠(N1′ · · · H-N3) ) 178° for R and β forms, respectively) (Figure 5). These intermolecular hydrogen bonds can be detected and characterized using the AIM theory which describes the molecular topology through the determination of bond critical points (BCP) between two neighboring atoms. The topological parameters used to characterize the H-bonds (bond length r, electron density F, its Laplacian ∆F, and ellipiticity ε) collected in Table 6, describe the molecular stability and characterize the internuclear pathways, which can be classified as shared or closed-shell. The AIM calculations yielded the value of electron densities of 0.024-0.035 au (N-H · · · N) (it falls within a certain range of values, typically between 0.001 and 0.035 au) markedly lower

than for the covalent bonds. The corresponding Laplacian values ∆FN · · · N are positive and amount to 0.091-0.098 au (typically between 0.006 and 0.130 au), which is indicative of the closedshell interaction. These results confirm the existence of intermolecular hydrogen bonds in the benzimidazole crystal structure, since the topological criteria proposed by Koch and Popelier40 are fulfilled and DFT predicts the N-H · · · N bonds in benzimidazole generally much stronger than typical (13 kJ/mol). Moreover, the N-H · · · N bonds in the R form are 60% stronger than those in β form (36.3 and 36.7 versus 22.6 and 22.7 kJ/ mol, for R and β polymorph, respectively), which is in a good agreement with the observed differences in melting points and stability of both forms. Comparison of the hydrogen bonds strength and electron density at the hydrogen bond critical points (Table 6) suggests that both hydrogen bonds in R and β

0.036

36.5

0.036

0.036

0.036

36.5

36.4

0.036

36.5

4,5,6,7-tetrachloro1H-benzimidazole 4,5,6,7-tetraiodo1H-benzimidazole

0.036

36.4

36.5

0.036

36.2

4,6-dibromo-5,7-diiodo3H-benzimidazole

0.035

36.9

0.036

0.036

35.9

36.4

0.035 0.024 0.036 0.036 0.036 0.035 0.036

36.3 22.6 36.6 36.4 36.6 35.8 36.9

E (kJ/mol) F (au)

4,6-dibromo-5,7-diiodo1H-benzimidazole

1H-benzimidazole (R) 1H-benzimidazole (β) 5-chloro-1H-benzimidazole 5-chloro-3H-benzimidazole 5,6-dichloro-1H-benzimidazole 4,6-dichloro-1H-benzimidazole 4,6-dichloro3H-benzimidazole 4,6-dibromo1H-benzimidazole 4,6-dibromo3H-benzimidazole 4,6-dibromo-5,7-dichloro1H-benzimidazole 4,6-dibromo-5,7-dichloro3H-benzimidazole 4,6-dichloro-5,7-diiodo1H-benzimidazole 4,6-dichloro-5,7-diiodo3H-benzimidazole

compound 0.031 0.084 0.032 0.032 0.033 0.031 0.031

ε

0.098 0.029

0.098 0.029

0.098 0.028

0.098 0.030

0.098 0.028

0.098 0.030

0.098 0.028

0.097 0.029

0.099 0.030

0.098 0.031

0.098 0.092 0.099 0.098 0.099 0.098 0.098

∆(F) (au)

N · · · H-N (N1 · · · H-N3′′)

36.2

36.1

36.4

36.1

36.3

36.2

36.1

35.8

36.6

36.0

36.7 22.7 36.6 36.7 36.4 36.2 36.6

0.036

0.036

0.036

0.036

0.036

0.036

0.035

0.036

0.035

0.036

0.036 0.024 0.036 0.036 0.036 0.036 0.036

E (kJ/mol) F (au) 0.032 0.081 0.032 0.032 0.033 0.031 0.031

ε

0.097 0.029

0.097 0.028

0.097 0.027

0.097 0.030

0.097 0.027

0.097 0.030

0.097 0.027

0.097 0.029

0.099 0.030

0.097 0.031

0.099 0.091 0.098 0.098 0.098 0.099 0.097

∆(F) (au)

N-H · · · N (N3-H · · · N1′)

5.1

12.8

0.008

0.015

0.017

0.007 0.062

4.6 4.2

15.1

0.016

0.016

0.006

0.017

0.005

13.8

12.8

14.4

13.2

11.9

0.015

0.004 0.004 0.004 0.004 0.013

2.6 2.6 2.6 2.6 11.0 2.6

0.004

2.7

E (kJ/mol) F (au) ε

0.513 0.522 0.570 0.519 0.728

0.023 1.208

0.056 0.55

0.061 0.400

0.021 1.094 0.022 2.610

0.059 0.457

0.051 4.016

0.020 2.370

0.060 0.684

0.017 2.547

0.050 0.977

0.012 0.012 0.012 0.012 0.049

0.012 0.475

∆(F) (au)

N· · ·X

0.018 0.015

14.3 11.2

0.017

15.0

0.017

0.019 0.016 0.017

16.9 12.4 13.9

12.6

0.015

14.1

E (kJ/mol) F (au) ε

2.05

0.83

2.96

1.92

2.28

1.42

1.33

1.39

0.23

0.12

0.004

0.002

0.005

0.004

0.004

0.003

0.003

0.003

0.001

0.001

E (kJ/mol) F (au)

ε

0.011 0.234

0.005 0.354

0.016 0.231

0.011 0.252

0.013 0.237

0.009 0.261

0.009 0.275

0.009 0.270

0.001 0.167

0.001 0.246

∆(F) (au)

Y · · · Z (different rings)


0.044 0.224 0.038 0.607

0.041 0.219

0.052 0.449

0.055 0.280 0.049 0.609 0.048 0.511

0.047 0.738

∆(F) (au)

Y · · · Z (the same ring)

TABLE 6: Bond Critical Point Properties (G, the Electron Density; ∆(G), Laplacian of the Electron Density; ε, Ellipticity; E, Energy; X-Proton or Halogen, Y, Z-halogen) for the Trimers of Polyhalogenobenzimidazoles (r Polymorphic Form Assumed)

572 Latosin´ska et al.



Figure 9. Correlation between the experimental (exp) and calculated (calc, under assumption of R and β polymorphic forms) 14N-NQR frequencies for polyhalogeno-1H-benzimidazoles.

polymorphic forms of benzimidazole are of similar strength (the differences are equal to 8.7 × 10-5 and 3.4 × 10-4 kJ/mol for R and β forms, respectively). The correlation between the 14N-NQR frequencies obtained in the experiment and those calculated by DFT, assuming the presence of trimers of R and β polymorphic forms, is very good (Table 3, Figure 9); the differences in the correlation coefficients (0.989 and 0.991 for R and β forms, respectively) and standard deviations (0.159 and 0.157 MHz for R and β forms, respectively) are negligibly small. The slightly lower slope of the line (1.13 versus 1.24) suggests the presence of the R rather than the β form, but the differences are very small and unambiguous determination is not possible, which means that 14N NQR is very sensitive to hydrogen bondings but less sensitive to the specific arrangement of the hydrogen bonded molecules. Polyhalogenobenzimidazoles. According to the crystallographic data, all halogenobenzimidazole crystals are isostructural and have the same space group I41/a. The intermolecular hydrogen bondings N1-H · · · N3′ and N1′ · · · H-N3 (Figure 5a), which link each molecule with two neighboring ones, occur between the molecules related by the 4-fold screw symmetry axis along the c direction of the tetragonal cell. As the compound crystallizes in the centrosymmetric group, the polar chains of

the molecules arranged in one direction are accompanied by antiparallel chains arranged in the opposite direction and this spatial ordering is very close to that observed in the R form of 1H-benzimidazole. This suggests that this kind of polymorphism can be expected in polyhalogenobenzimidazoles. The correlation between the 14N-NQR frequencies obtained in the experiment and those calculated by DFT, assuming the trimers of polymorphic forms R (constructed on the basis of available X-ray data) and β (constructed on the basis of X-ray data for the β form of 1H-benzimidazole) of polyhalogenobenzimidazoles is very good, Figure 7. The differences in the correlation coefficients 0.980 and 0.978 for R and β forms, respectively, and standard deviations of 0.170 and 0.202 MHz for R and β forms, respectively, are rather small. Slightly better correlation coefficient and lower scattering as well as lower slope of the line (1.08 versus 1.22) suggest the presence of the R rather than β form and confirm our previous conclusion that 14N NQR is very sensitive to hydrogen bondings but less sensitive to the specific arrangement of the hydrogen bonded molecules. The differences in the orientation of the EFG tensor principal axes for R and β polymorphs of polyhalogenated-1H-benzimidazole are much greater for -NH- than for the -Nd site, Figure 6c,d, which is reflected by the differences in the asymmetry parameters at both sites. The hydrogen bondings in polyhalogenobenzimidazoles structures, similarly as in 1H-benzimidazole can be detected and characterized in terms of the AIM theory (Table 6). The AIM calculations yielded the value of electron densities of 0.035-0.036 au (N-H · · · N) (which falls within a certain range of values, typically between 0.001 and 0.035 au) markedly lower than for the covalent bonds. The corresponding Laplacian values ∆FN · · · N are 0.097 and 0.099 au (typically between 0.006 and 0.130 au), which is indicative of closed-shell interaction. These results confirm that in the crystal structures of polyhalogenobenzimidazoles the intermolecular hydrogen bonds exist since the topological criteria proposed by Koch and Popelier40 are fulfilled and that DFT predicts the N-H · · · N bonds in polyhalogenobenzimidazoles generally stronger than typical. Moreover, the N-H · · · N bonds formed by both nitrogen atoms (N1 and N3) differ insignificantly in strength (less than 0.4 kJ/mol), which is in good agreement with the differences in their lengths. Comparison of the HB strength and electron density at the hydrogen bond critical points in polyhalogenobenzimidazoles (Table 6) suggests that all hydrogen bonds are of

TABLE 7: Ring Critical Point Properties (G, the Electron Density; ∆(G), Laplacian of the Electron Density) for the Trimers of Polyhalogenobenzimidazoles N1-C2-N3-C8-C9

C4-C5-C6-C7-C8-C9

compound

F (au)

∆(F) (au)

F (au)

∆(F) (au)

1H-benzimidazole (R) 5-chloro-1H-benzimidazole 5-chloro-3H-benzimidazole 5,6-dichloro-1H-benzimidazole 4,6-dichloro-1H-benzimidazole 4,6-dichloro-3H-benzimidazole 4,6-dibromo-1H-benzimidazole 4,6-dibromo-3H-benzimidazole 4,6-dibromo-5,7-dichloro-1H-benzimidazole 4,6-dibromo-5,7-dichloro-3H-benzimidazole 4,6-dichloro-5,7-diiodo-1H-benzimidazole 4,6-dichloro-5,7-diiodo-3H-benzimidazole 4,6-dibromo-5,7-diiodo-1H-benzimidazole 4,6-dibromo-5,7-diiodo-3H-benzimidazole 4,5,6,7-tetrachloro-1H-benzimidazole 4,5,6,7-tetraiodo-1H-benzimidazole

0.057 0.057 0.057 0.057 0.057 0.057 0.057 0.057 0.057 0.057 0.057 0.057 0.057 0.057 0.057 0.057

0.400 0.400 0.400 0.401 0.399 0.399 0.399 0.399 0.398 0.398 0.398 0.398 0.398 0.398 0.398 0.398

0.023 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.023 0.023 0.023 0.023 0.022 0.023

0.166 0.164 0.164 0.162 0.162 0.162 0.163 0.163 0.159 0.159 0.160 0.160 0.161 0.161 0.158 0.162

574


similar strength. The differences in e2qQh-1 and η observed for both nitrogen sites suggests that hydrogen bonds are asymmetric and should be described by a proton double minimum potential, which confirms the AIM analysis. AIM calculations revealed also additional to HB closed-shell interactions in polyhalogenobenzimidazoles structures, i.e., N · · · X (X ) H, Cl, Br or I) and two kinds of Y · · · Z (Y, Z ) Cl, Br or I) contacts, which are much weaker than hydrogen bondings (Table 6). The AIM calculations yielded for N · · · X interactions the values of electron densities of 0.004-0.062 au and the corresponding Laplacian values of about 0.012-0.022 au, while for Y-Z contacts, the values of electron densities of 0.015-0.018 au and the corresponding Laplacian values about 0.038-0.055 au (Y, Z from the same ring). For Y-Z contacts (Y, Z from the different rings) the values of electron densities were 0.001-0.005 au and the corresponding Laplacian values 0.001-0.016 au. In each case the values of these two parameters were markedly lower than for the hydrogen bonds and thus indicative of closed-shell interactions. On the basis of the calculated local potential energy density at BCPs (the following ordering of the intermolecular interactions according to increasing bond strength (E) can be proposed: N1-H · · · N3 ∼ N1-H · · · N3 < N1 · · · X < X · · · Y (X, Y from the same ring) < X · · · Y (X, Y from the different rings), which is in a good agreement with that obtained on the basis of density at the critical points, with the lower F value meaning the weaker bond. The electron density at the ring critical points (RCP) calculated by AIM (Table 7) differs only insignificantly upon substituent additions/changes; however, some trends are evident. As a result of substitution of strongly electron withdrawing substituents (chlorine, bromine, or iodine atoms) at the 4, 5, 6, and/or 7 positions of the benzimidazole ring, the electron density at the ring critical point (RCP) located on the benzene ring decreases. The changes in the electron density at the RCP located on heterocyclic ring are more poorly manifested, but the increase in electron density at RCP and increase in the e2qQh-1 on both nitrogen atoms are observed; i.e., EFG tends toward nonspherical symmetry, which is also reflected by the changes in asymmetry parameter. The direction of changes in the electron density suggests delocalization of electron density from nitrogen to halogen atoms. Conclusions 1. Reproduction of the 14N NQR parameters at the DFT level assuming the X-ray structure with optimized proton positions and taking into account hydrogen bonds and nitrogen-halogen and halogen-halogen contacts for polyhalogenobenzimidazoles is very good. 14N NQR is very sensitive to hydrogen bondings but less sensitive to the specific arrangement of the hydrogen bonded molecules. 2. A comparison of the results for monomer, trimer, and cluster (tetramer) shows systematic improvement in the reproduction of NQR parameters to a degree proportional to the strength of the interactions (the weaker the interaction the smaller the correction). 3. Comparison of the results (NQDR and DFT) suggests the presence of both 1H and 3H tautomers, which is in good agreement with the 1H NMR results. According to increasing intrinsic stability, the polyhalogenobenzimidazoles studied could be ordered as follows:

Latosin´ska et al.

5-Cl < 4,6-diCl < 4,6-diBr < 4,6-diBr-5,7-diCl < 4,6-diBr-5,7-diI < 4,6-diCl-5,7-diI This ordering is in good agreement with that obtained on the basis of the splitting of the doublets assigned to NH from the 1H NMR spectra. 4. The combined NQDR and DFT studies confirmed that all polyhalogenobenzimidazoles studied are isostructural and can exhibit polymorphism. The R form with the molecules showing edge-to-face interactions is predicted for all polyhalogenbenzimidazoles. 5. On the basis of the calculated local potential energy density at BCPs, the following ordering of the intermolecular interactions according to increasing bond strength can be proposed:

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