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Article

Unexpected Formation of 6-(1H-Benzo[d]imidazol-2-yl)-1-phenyl-hexan-1-one and Its Structure in Solution and Solid State Analyzed in the Context of Tautomerism

by
Ryszard B. Nazarski
* and
Małgorzata Domagała
Department of Physical Chemistry, Faculty of Chemistry, University of Lodz, Pomorska 163/165, 90-236 Łódź, Poland
*
Author to whom correspondence should be addressed.
Crystals 2024, 14(8), 704; https://doi.org/10.3390/cryst14080704
Submission received: 30 June 2024 / Revised: 22 July 2024 / Accepted: 30 July 2024 / Published: 2 August 2024
(This article belongs to the Section Crystal Engineering)
Browse Figures
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Abstract

:
The structure of the title compound (4d), unexpectedly obtained in the reaction between o-phenylenediamine and 2-benzoylcyclohexanone instead of the target 3H-benzo[b][1,4]diazepine derivative 3d, was determined spectroscopically in solution and by a single-crystal X-ray diffraction (XRD) study. It involves two enantiomeric rotamers, called forms D and U, of which the structure was elucidated based on NMR spectra measured and predicted in DFT-GIAO calculations. An averaging of δCs for all tautomeric positions in the benzimidazole part of the 4d hydrate studied in wet (probably slightly acidic) CDCl3 unambiguously indicates tautomeric exchange in its imidazole unit. An XRD analysis of this material confirms the existence of only one tautomer in the solid phase. The non-covalent interactions forming between molecules of water and benzimidazole derivative are shorter than the sum of van der Waals radii and create an infinite-chain hydrogen bond motif along the b-axis. A possible mechanism for the observed cyclocondensation is also proposed.

Graphical Abstract

1. Introduction

The benzodiazepine moiety is a pharmaceutically important structure and constitutes the key subunit in many drugs used as anxiolytics, sedatives, muscle relaxants, and anticonvulsants, among others. They allosterically modulate the γ-aminobutyric acid (GABA) type A receptors, by increasing the apparent affinity of the major brain inhibitory neurotransmitter GABA to elicit the flow of Cl− ions through a central ligand-gated ion channel [1,2,3,4,5,6]. However, its long-term use can be problematic due to the gradual development of tolerance and dependency [7,8].
Unfortunately, synthetic studies on new modulators with higher selectivity for various subtypes of GABAA-receptor proteins are relatively rare [9,10,11,12,13,14]. Therefore, we tried to open a new route for species 3c–f (R1 = Ph, R2 = CH2) that have the 3H-1,5-benzodiazepine unit cyclo-condensed with carbocyclic systems, starting with o-phenylenediamine (1) and β-diketones 2c–f as electrophiles. An approach similar to that known to synthesize symmetric derivatives 3a,b (R1 = R2 = Me, But) [9,11] was used here; see Scheme 1. The isolated product was not the expected target system 3d, but a compound 2d. However, its spectroscopic data differed from those reported in the literature [15]. Therefore, we conducted a deeper structural study of 2d, including DFT-GIAO NMR calculations for the solution and XRD analysis for the solid phase.

2. Materials and Methods

2.1. Instrumentation and Chemicals

The 1H and 13C{1H} NMR spectra, including APT, COSY-45, and HETCOR correlations, were recorded in CDCl3 at ~21 °C on a Varian Gemini 200 BB spectrometer (Varian Inc., Palo Alto, CA, USA), operating at 200.11/50.33 MHz for 1H/13C nuclei, respectively. The δX values, in ppm, were referenced towards the high frequency (downfield, an obsolete term) from internal tetramethylsilane (TMS). The interproton coupling constants JHH are given in Hz (first-order analysis). IR spectra were recorded for the KBr pellet with a Nexus FT-IR instrument (Thermo Nicolet Corp., Madison, WI, USA); abbreviations were applied: s = strong, v = very, br = broad. The low- and high-resolution (HR) electron impact/chemical ionization mass spectra (EI-/CI-MS) were taken on a MAT 95 high-resolution mass spectrometer (Thermo Finnigan MAT GmbH, Bremen, Germany) at 70 eV ionizing energy; peaks > 10% rel. intensity are given only. Melting points (uncorrected) were determined with a Boëtius hot-stage apparatus. The solvents were dried according to standard procedures [16] and purified by distillation before use. Commercial reagents were provided by Sigma-Aldrich (St. Louis, MO, USA) and used as received. Substrate 2d was prepared using the literature method [17]. The crude product was vacuum distilled and recrystallized; bp ~195 °C/17 mmHg, mp 89–91 °C (from MeOH). Its NMR spectra were consistent with those reported [18]; the β-diketo form was only observed.

2.2. Synthesis and Spectral Data for 6-(1H-Benzo[d]imidazol-2-yl)-1-phenyl-hexan-1-one (4d)

The solution of o-phenylenediamine 1 (0.54 g; 5 mmol), 2-benzoylcyclohexanone 2d (1.01 g; 5 mmol), and 0.1 mL of conc. H2SO4 in 10 mL of EtOH was refluxed for 12 h, treated with 4 mL of cold water, and cooled to 5 °C. The precipitate resulting was separated and recrystallized to give product 4d as a monohydrate. Yield 0.66 g (45%). Colorless crystals, mp 134–135 °C (EtOH–H2O; 1:1, v/v). Anal. Calcd for C19H20N2O·H2O (M = 310.38): C, 73.52; H, 7.14; N, 9.03. Found: C, 73.71; H, 7.01; N, 9.39. IR: νmax 3544 s (N–Hfree), ~3435 vbr (N–Hassocd), ~3200 br, 1682 vs cm−1 (C=O). 1H NMR: δ 1.34–1.51 (m, 2H, C12-H2), 1.69 and 1.77 (2 × t, 2 × J ~7.1, 2H, C13-H2), 1.85 and 1.93 (2 × t, 2 × J ~7.5, 2H, C11-H2), 2.91 (t, J ~7.0, 2H, C14-H2), 2.98 (t, J ~7.4, 2H, C10-H2), 7.14–7.24 (m, 2H, C6-H and C7-H), 7.37–7.48 (m, 2H, C18-H and C20-H), 7.48–7.61 (m, 3H, C5-H, C8-H and C19-H), 7.85–7.93 (m, 2H, C17-H and C21-H), 8.90 (s, vbr, 1H, NH). 13C NMR: δ 23.32 (C13), 27.98 (C11), 28.51 (C12), 28.75 (C10), 38.10 (C14), 114.61 (br, C5 and C8), 122.01 (C6 and C7), 128.00 (C17 and C21), 128.59 (C18 and C20), 133.14 (C19), 136.73 (C16), 138.56 (br, C4 and C9), 155.23 (C2), 200.77 (C15). EI-MS m/z (%): 292 (M+•, 31), 187 ([M–PhCO]+, 56), 173 ([Ar(CH2)3]+, 14), 146 ([Ar(CH2)+1]+, 15), 145 ([Ar(CH2)]+, 85), 132 ([Ar+1]+•, 100), 131 (Ar+, 16), 105 ([PhCO]+, 21), 77 (Ph+, 24). CI-MS (isobutane) m/z (%): 293 ([M+H]+, 100). HR EI-MS: calcd for C19H20N2O M 292.1576, found M+• 292.1584.

2.3. Molecular Modeling and Vibrational Frequency Analysis in Solution

The molecular mechanics conformational search [19,20] was performed with random torsional searches of acyclic bonds combined with random shifts of subsets of atoms using the GMMX routine of PCMODEL [21]. Typically, 1500–2000 steps were employed within the energy window of 7 kcal/mol. The six resulting low-energy MMX force field [22] models of 4d were used as its promising candidates in further geometry optimizations carried out at two levels of the HF approach, followed by two levels of density functional theory (DFT), using Gaussian 16 [23]. Final optimizations were initially performed at the typical PCM(CHCl3)-B3LYP/def2-TZVPP level using the triple-ζ valence quality basis sets [24] and the IEF-PCM solvation model [25] for the simulation of the CDCl3 solution.
However, according to one reviewer, the failure to apply any dispersion correction during the modeling stage is inappropriate because of the presence of aromatic units in the structures under study. Therefore, it was logical to apply the B3LYP-GD3BJ approach, which includes the D3 version of Grimme’s dispersion correction with Becke–Johnson damping [26,27] already used previously [28]. Unexpectedly, these new calculations have led to a completely different conformer and energy landscape of the system 4d. Better results were achieved using the ωB97X-D functional [29] that contains Grimme’s D2 numerical correction for dispersion effects [30]. All details are presented in this paper’s Supplementary Materials (SM) part. The coordinates of all atoms in the two ‘best’ bent rotameric forms called downward and upward forms (D and U) determined in the last DFT method used are given in Table S6 of SM. These two forms are visualized in Figure 1 with Chemcraft [31] based on the Gaussian 16 output files.
Furthermore, harmonic vibrational frequencies were always calculated to characterize the localized stationary points on the energy surfaces as true minima (Nimag = 0) and to determine their standard Gibbs free energies, G°298.15, and, therefore, their contribution to the overall conformation in solution according to the Boltzmann distribution law [32,33,34]; for all details, see Section S1.1 of SM.

2.4. Prediction of NMR Spectra in Solution

Single-point DFT level calculations of absolute isotropic nuclear magnetic shieldings (σXs) were performed at the three series of the geometries of system 4d mentioned above, using Gaussian 16 [23]. The gauge-independent atomic orbital (GIAO) method [35], the hybrid density functional mPW1PW91 [36], and the pcSseg-2 NMR-specialized basis sets [37] were used, the latter retrieved from the Basis Set Exchange website [38,39,40]. In this recently applied DFT/NMR approach [41] the IEF-PCM solvation scheme was applied as above. The relative chemical shifts δX of a given NMR-active nucleus X were defined as δXcalc [ppm] = σXref − σXcalc, where σXref values found analogously for the NMR reference standard (TMS of the Td symmetry [42]) are given in Section S1.2 of the SM. Statistical analysis was carried out using the MS Excel 16 spreadsheet.

2.5. X-ray Diffraction Analysis for the Crystal

The X-ray measurement for 4d was performed on the Rigaku AFC5S diffractometer (Rigaku Corporation, Osaka, Japan) using graphite-monochromated CuKα radiation (λ = 1.54178 Å) with ω scans at 20(1) °C. Three standard intensities were monitored after each group of 150 reflections, and no evidence of crystal decay was observed. In the data reduction step [43,44], the intensities were corrected for Lorentz and polarization effects. The structure was solved by direct methods [45], which revealed the positions of all non-H atoms and refined on F2 by full-matrix least-squares calculations using SHELXL [46]. Non-H atoms were refined anisotropically. All H atoms bonded to C atoms were placed in geometrically calculated positions and refined with a riding model in which each H atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2Ueq of its parent C atom. The N- and O-bonded H atoms were found directly, however, hydrogen atoms of water were further refined with the application of DFIX restraints for stable refinement. Geometry analysis and molecular plots were obtained using PLATON [47] and Mercury [48].
Crystal data for the title compound, C19H20N2O·H2O (M = 310.38 g/mol): monoclinic, space group P 21/c (no. 14), a = 11.124(2) Å, b = 7.688(2) Å, c = 19.986(2) Å, β = 98.99(1)°, V = 1688.3(5) Å, Z = 4, T = 293(1) K, μ(MoKα) = 0.634 mm–1, Dcalc = 1.221 g/cm3, 2950 reflections measured (4.479 ≤ Θ ≤ 67.473), 1291 unique (Rint = 0.0144), which were applied in all calculations. The final R1 was 0.0356 and wR2 was 0.0873 (all data). More data collection and refinement parameters are given in Table S7 in the SM part, and the structure of the molecule with the atom-numbering scheme used is shown in Figure 2. The unit cell packing is depicted in Figure S5.
CCDC 2365642 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (accessed on 30 June 2024) or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033.

2.6. Theoretical Calculation for Hydrogen Bonds

All molecular systems were examined using the ωB97X-D functional [29] and the def2-TZVPP basis sets [24]. This density functional, which contains Grimme’s D2 numerical correction for dispersion [30], affords good results in the case of hydrogen bonds or other weak interactions with the contribution of dispersion effects and is appropriate for the calculation concerning relatively large systems [49,50,51]. Four molecular systems with the O–H…O, O–H…N, N–H…O, and C–H…O hydrogen bonds, (Figures S6–S9, respectively) were calculated using single-point DFT calculations in geometries taken from the crystal state. Only the positions of the H atoms were normalized according to neutron diffraction data [52], a standard procedure to model the system in geometries extracted from X-ray diffraction experiments. All calculations were carried out using Gaussian 16 [23]. The interaction energies of the systems analyzed were calculated as the difference between the total energy of the complex and the monomer energies and corrected for the basis set superposition error (BSSE) using the counterpoise procedure [53]. The monomers were in the same geometries as those of the dimer complex; thus, we excluded the deformation energy from our consideration.

3. Results and Discussion

3.1. Considerations for Solutions

In our efforts to exploit the cyclocondensation reaction according to the path shown in Scheme 1, β-diketone 2d was first investigated. Initially, it appeared that the resulting product was not the target 11-phenyl-2,3,4,11a-tetrahydro-1H-dibenzo[b,e][1,4]diazepine (3d) but compound 5, that is, the imine tautomer of enamine 6 (R2 = o-NH2C6H4), whose simpler analogs 6 (R1 ≠ R2) were reported by Letton et al. [54]; see Chart 1. The products of the exclusive attack of various amine systems on the carbonyl carbon atom of the aliphatic part of diketone 2d have long been known [9,54,55]. Consistent with this high chemoselectivity, the IR spectrum of our product revealed a single carbonyl band at 1682 cm−1 associated with the benzoyl group. Furthermore, the CI-MS spectrum with a base peak [M+H]+• at 293 amu was consistent with the stoichiometry of β-keto imine 5.
However, the 1H and 13C NMR spectra obtained did not confirm structure 5; the 2D COSY and HETCOR plots were the most informative. All of these data indicated the presence of two nitrogen-containing Y units in building block 7, the apparent symmetry of which was evident from the number and shape of the NMR signals observed; see Section 2.2. The presence of a cyclohexane fragment was ruled out because the COSY-45 experiment optimized to detect long-range JHH couplings did not reveal all the interproton connections required for such a cyclic moiety of 5; see Figure 3. Instead, the observed splittings ca. 7 Hz (indicating free rotation) strongly suggested the presence of the aliphatic chain –(CH2)5– in the system under study.
From the above NMR data, we deduced that the isolated product of the observed cyclocondensation is probably 2-substituted-1,3-benzimidazole 4d (an isomer of 5). This structure also agreed with the fragmentation patterns observed for the heteroaryl group of C7H5N2 in the EI-MS spectrum. Consequently, the two broad IR absorbance bands at ~3435 and ~3200 cm−1 were assignable to the -NH group and the water of hydration, respectively. Indeed, the presence of an H2O molecule was shown by microanalysis. The broadening of both IR bands mentioned above suggested the existence of some intermolecular hydrogen bonds. The absorbance at 3423 cm−1 due to the N–H stretching vibration (KBr disk) was reported for the parent benzimidazole [56].
A search in the literature revealed that Wang and Qin [15] described the waterless compound 4d, with an mp of 140–141 °C (from Me3CO2Et) synthesized at neutral pH. However, the reported physicochemical data of this product differed from those found for the monohydrate. The differences in the melting point value and the IR data could be explained by the water’s presence. However, there are also some large discrepancies in the NMR spectra recorded in CDCl3 that are difficult to explain. In particular, these latter differences prompted us to verify the validity of our structural conclusions about the species at hand. Therefore, we decided to perform its standard single-crystal XRD analysis of this material in addition to the usual DFT-GIAO NMR calculations [32,33,34,35,57].
Our structural assumptions about the product were confirmed by a prediction of its δH and δC values measured in CDCl3. Calculations of absolute isotropic nuclear magnetic shieldings, σX data, were performed with the GIAO method [35] at the DFT level for the lowest energy rotameric forms D and U obtained in geometry optimizations carried out at three DFT levels mentioned above; Figure 1 shows the ‘best’ forms obtained using the ωB97X-D functional [29]. They are, in fact, the enantiomeric rotamers that coexist in solution as a racemic mixture and therefore in a 1:1 ratio. Consequently, the D/U Boltzmann population ratio of ~2.7:1, ~1:5.8, or even ~9.1:1 (!) obtained standardly from the calculated ∆G values was not taken into account; see the in-depth discussion in Section S1.1 of SM. These two bent forms, with a fully extended aliphatic side chain C10–C15, are consistent with the stereochemical information emerging from the best fit of the δX data determined experimentally to those theoretically predicted in the CDCl3 solution simulated using the standard IEF-PCM solvation protocol [25], see Figure 4 and Figures S1–S3.
Of particular note is the intriguing averaging of δC data for the ‘tautomeric positions’ C4/C9, C5/C8, and C6/C7 (considering the parent benzimidazole [58] and using the atom numbering in harmony with that in our XRD analysis) in this moiety of compound 4d, which is consistent with its partially degenerate 13C{1H} NMR spectrum. The two signals mentioned above signals were broadened. However, GIAO calculations have provided quite different σC/δC values inside the above three pairs of carbon atoms for both forms D and U of its 1H-tautomer; a detailed discussion of these results is given in Section S1.2 of the SM. A similar case applies to the 1H NMR signals from protons H-C5/H-C8 and H-C6/H-C7 but is not as spectacular. The only explanation for such an δX data averaging is intermolecular proton transfer, resulting from a certain amount of H2O introduced and HCl present in a ‘wet’ CDCl3 (usually slightly acidic) [59,60]. This leads to 1,3-tautomeric equilibria between the 1H-form D and its 3H-counterpart D′ (and the related forms U and U′) with an H atom at the N3 atom, instead of at N1. The broadening of the two 13C signals above, indicating the presence of some dynamic processes, is fully consistent with this explanation. In turn, the broadening of the 1H triplet signal due to H2-C10 compared to H2-C14 (see Figure 3) strongly suggests that the former methylene protons are long-range coupled (4JHH) to the proton at N1/N3.
A representative scatter diagram with statistics for the highest correlation δCexp vs. δCcalc, evaluated using the root mean squared error (RMSE) value, found for the simulated CDCl3 solution of compound 4d using the GIAO results obtained for the best of three series of its DFT structures (vide supra) is given in Figure 4. The other relationships between the measured and calculated δX data, i.e., δH, δC, and δH,C [61] values, are discussed in Section S1.2 of the SM. The results found in this way can be taken as strong evidence of the correctness of this structural proposal for 4d, which was fully confirmed by X-ray crystallography of its monohydrate (see below and Section S2 of SM). At the same time, an unambiguous assignment of all its NMR signals was possible for the CDCl3 solution; see Section 2.2.
Interestingly, the averaged δC data found for all three tautomeric positions of the 4d hydrate are very close to analogous δC values measured in CDCl3 for 2-alkyl substituted 1H-benzo[d]imidazoles with methyl to hexyl alkyls [62,63,64,65], for which there is undoubtedly an imidazole tautomeric exchange in this solvent [66]. In the context of these facts, the ‘blocked tautomerism’ reported for some systems [58] and observed for the anhydrous product 4d studied by Wang and Qin [15] can only be explained by their use of very pure CDCl3 without any trace of H2O or HCl (vide supra). Unfortunately, these authors did not assign the 1H and 13C NMR signals observed for this material.
Now, we briefly turn to chemistry. It can be assumed that the unexpected observed cyclocondensation, which occurred under acidic conditions, involves an initial SN attack of amine 1 on the electrophilic carbonyl carbon atom of a cyclohexanone part of diketone 2d that provides an intermediate hemiaminal 8 with simultaneous cleavage of the adjacent C–C single bond in its alicyclic unit. The tautomerization of the formed enol 9 into ketone 10 and the subsequent dehydration process led to aromatization of the benzimidazole ring (Scheme 2). Interestingly, this would indicate that the two tautomers and two rotamers of product 4d could form in parallel in such a manner. This mechanism also explains the formation of 2-methylbenzoimidazole by treating amine 1 with diketone 2a (R1 = R2 = Me) in a hot acidic EtOH solution [67]. In this case, an acetone molecule is released.

3.2. Considerations for the Solid Phase

3.2.1. XRD Analysis

6-(1H-Benzo[d]imidazol-2-yl)-1-phenyl-hexan-1-one crystalize in the monoclinic system with the P21/c space group. Its molecular structure is shown in Figure 2. The asymmetric unit contains one molecule of title compound and one molecule of water.
All rings of the studied system are flat. A dihedral angle between the best planes of the benzimidazole rings is 1.2(2)°. The angle between the planes of the benzimidazole and the phenyl ring at the other end of the molecule is 81.4(1)°. A carbonyl group deviates from the best plane for the phenyl ring. The distance of the C15 carbon atom from the best plane for the phenyl ring is −0.021(2)Å, while the distance of the O22 oxygen atom deviates by −0.173(2)Å. The bond distances and angles of both molecules are in good agreement with the expected values [68]. The selected geometric parameters are listed in Table S8.
The crystal packing analysis for the investigated compound 4d has revealed the presence of different types of hydrogen bonds (H bonds). Both molecules, benzimidazole, and water, act as H-bond donors and acceptors. The O–H…N and N–H…O interactions generate an infinite chain motif along the b-axis, while the carbonyl oxygen atom O22 plays the role of a bifurcated acceptor in two O–H…O and C–H…O bonds. The latter holds every two chains, which are symmetry-related by the inversion that generates a centrosymmetric ring motif of the hydrogen bond (Figure 5b). All of these interactions together create a monoperiodic ribbon motif along the [010] direction (b-axis) shown in Figure S4. The geometric parameters of the H bonds are given in Table 1.
Looking at the geometry parameters of the H-bond bridges, it should be noticed that, for all of these contacts, the proton-acceptor distances are much shorter than the sum of van der Waals radii. The angles in hydrogen bridges for classical H bonds are almost equal, at about 160°.
To study the strength of the interactions mentioned above, we perform calculations at the ωB97X-D/def2-TZVPP level of theory. The energy parameters from the single-point calculations for each contact calculated separately are given in Table 1. For the centrosymmetric dimer with two C–H…O bonds the presented value, for a single C–H…O bond, is half of the energy value obtained for the dimer.
Looking at the obtained results, it can be seen that the O–H…N bond has the greatest interaction energy of −7.82 kcal/mol. The energies for dimers with O–H…O and N–H…O bonds are similar, about −5.5 kcal/mol. For the N–H…O interaction the energy is slightly higher by about 0.25 kcal/mol compared to those with O–H…O interaction. For the centrosymmetric dimer, the energy of the single C–H…O interaction is the lowest at −4.5 kcal/mol. This is expected since, in general, C–H is a relatively weaker donating group compared with O–H [69,70]. A very similar interaction energy for the optimized C–H…O motif (−4.2 kcal/mol) was found in [71] at the MP2/6-31+G** level of theory. The energy of N–H…O interactions is lower than the energy of this motif optimized on the MP2/6-31+G** level of theory only by about 0.5 kcal/mol [71] and about 1 kcal/mol less when optimized at the B3LYP/6-311++G(d,p) level investigated earlier in [72] (the energy of a single N–H…O bond was −6.63 kcal/mol). This difference is small taking into account different calculation methods. In our earlier research [49,50,51] we noticed that the ωB97X-D functional gives results similar to those of the MP2 method, so we use it here. However, the N–H…O motif of the H bond was also investigated in the work [73] where the energy of this interaction was up to −8 kcal/mol. In that article, we also used single-point calculations at the ωB97X-D/6-311++G(d,p) level for the geometry taken from the crystal state. It should be noted that this functional contains Grimme’s D2 numerical correction for dispersion effects [30]. Thus, additional effects included in this theory approximation may give a relatively larger interaction energy.
The Hirshfeld surface analysis [74,75] also indicates that all the contacts mentioned above are short. Figure 6a shows the Hirshfeld surface of the investigated compound mapped over dnorm. The red spots correspond to contacts with a length shorter than the sum of the van der Waals radii, and the white spots reflect contacts with a length equal to the sum of such radii.
The fingerprint plot [76,77], shown in Figure 6b, presents all molecular interactions and the most occurring interactions that were obtained from the Hirshfeld surface. Considering the formation of hydrogen bonds in the examined structure, the amount of O…H/H…O interactions is 9.6%, and for the N…H/H…N contacts the share is smaller, 6.3%. The most frequent interactions are H…H and C…H/H…C. The amount of H…H contacts is 54.4% of the total interactions, while the share of C…H/H…C contacts is 28.7%. The number of others is less than 0.4% for the individual type of contacts.

3.2.2. Tautomerism in a Solid State

The crystal structure of the monohydrate of system 4d does not confirm the existence of both its tautomeric forms. In fact, on the difference map, the position of one of the hydrogen atoms (H23B) is slightly blurred towards the nitrogen atom N3 (see Figure 7), which could suggest the existence of a tautomeric form.
However, the structure was refined without any disorder [78]. Geometric parameters of the structure studied also indicate the existence of one tautomeric form in a solid phase. A characteristic of the imidazole ring of the benzimidazole systems examined is that the internal angle about the N1 atom type is always larger than that about N3 by 2–3° [79]. In our case, the difference is 2.57°. The difference between the N1–C2 and N3–C2 bond lengths is another issue. In this study, the lengths of these bonds differ by 0.045 Å, they are not averaged. The above results are consistent with those obtained for 2-ethyl-1H-benzimidazole studied by Cabildo et al. [80].

4. Conclusions

According to the present DFT calculations of the structure of the title system 4d, supported by GIAO-based predictions of NMR chemical shifts, both of its bent rotational isomers, called forms D and U, which are simultaneously enantiomeric isomers, exist in a wet by necessity (and therefore probably slightly acidic, vide supra) CDCl3 solution as a racemic mixture. All these results were obtained for three series of geometries modeled at three different DFT levels. As expected, additional GIAO-based predictions of chemical shifts performed using structures modeled with a dispersion correction, using the ωB97X-D functional but not the B3LYP-GD3BJ approach, led to slightly better agreement with the experimental NMR data measured for the solution. The crucial δCcalc vs. δCexp correlation resulted in an RMSE of 0.83 ppm vs. 0.86 ppm initially found in the standard way using the B3LYP functional; a detailed discussion is presented in the SM. Closer analysis showed that, in such geometry reoptimizations with the correction for dispersion interactions, the imidazole part of the studied heteroaromatic moiety was slightly flattened; at the same time, the puckering of its benzene unit increased.
The harmonic frequency calculations performed for all the 18 forms of 4d under consideration showed a large physically unrealistic discrepancy in the associated ΔG values, which was explained by the approximations implemented in the software applied. This result sheds new light on the standard use of Boltzmann statistics to calculate the contribution of distinct conformational forms to their equilibrium mixture.
The averaged δX values (X = H, C) for the “tautomeric positions” in the benzimidazole unit of 4d, observed in all three series of NMR calculations, indisputably indicate that two tautomeric exchanges involving its imidazole moiety occur at the same time in the CDCl3 solution of the monohydrate of the system 4d analyzed here, namely D⇌D′ and U⇌U′, where in the forms signed with ′ the proton is located at the N3 atom. Thus, it can be considered that, in this CDCl3 solution, the two enantiomeric rotamers of this system co-exist side by side in whose imidazole parts the 1,3-tautomeric equilibrium exists. This interesting result, derived from a detailed analysis of the 13C NMR spectrum in our hand, is in sharp contrast to the blocked tautomerism observed for the anhydrous compound 4d dissolved in CDCl3, according to the NMR data reported by Wang and Qin [15].
In the context of possible prototropic tautomerism, the solid-state XRD analysis was especially focused on studying intermolecular hydrogen bonds. However, this investigation indicates the existence of only one tautomeric form in the solid phase of the monohydrate of the title system. Analysis of the crystal packing and the Hirshfeld surface for this system revealed the presence of different types of H bonds much shorter than the sum of van der Waals radii. The N atoms of the benzimidazole unit and the O atom of the water molecule act as excellent H-bond donors as well as acceptors by forming strong N–H…O and O–H…N hydrogen bonds. The O atom of the carbonyl group acts as a bifurcated acceptor and also participates in the formation of two short contacts of type O–H…O and C–H…O. All these interactions together create a 1D infinite chain hydrogen bond motif along the b-axis. The single-point calculations performed at the ωB97XD/def2-TVPP level indicate that the highest interaction energy is for the O–H…N bond, of −7.82 kcal/mol, and the lowest is for the C–H…O, of −4.5 kcal/mol. The energies of the O–H…O and N–H…O interactions are approximately in the middle of the above values.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cryst14080704/s1. Table S1: Energetic considerations for six forms of 4d in a simulated CDCl3 solution. Table S2: Torsional angles in four selected forms D and U. Table S3: GIAO-based σC/δC data and statistics for the best initial forms D and U. Table S4: GIAO-based σC/δC data and statistics for the best forms D and U (first reoptimization). Table S5: GIAO-based σC/δC data and statistics for the best forms D and U (second reoptimization). Figure S1: Scatter plots of δXcalc vs. δXexp (X = H, C) for form D (ωB97X-D, model 39922) of 4d in simulated CDCl3. Figure S2: The plot of δCcalc vs. δCexp using δCs averaged for the three tautomeric positions (ωB97X-D, D/U = 1:1). Figure S3: The plot of δH,Ccalc vs. δH,Cexp using averaged δXcalc data (ωB97X-D, D/U = 1:1). Table S6: The reoptimized (ωB97X-D) geometries for the two best forms D and U. Table S7: Crystal data for the title compound. Table S8: Selected geometric parameters for 4d. Figure S4: Projection along the [100]-direction of the molecular arrangement of the structure. Figure S5: Packing view of the unit cell. Figure S6: Dimer with O–H…O hydrogen bond. Figure S7: Dimer with O–H…N hydrogen bond. Figure S8: Dimer with N–H…O hydrogen bond. Figure S9: Dimer with C–H…O hydrogen bond. Table S9: Atomic coordinates used for calculations at the ωB97X-D/def2-TZVPP level of theory.

Author Contributions

Conceptualization, R.B.N.; methodology, R.B.N. and M.D.; software, R.B.N. and M.D.; formal analysis, R.B.N. and M.D.; investigation, R.B.N. and M.D.; writing—original draft preparation, R.B.N.; writing—review and editing, R.B.N. and M.D.; visualization, R.B.N. and M.D. All authors have read and agreed to the published version of the manuscript.

Funding

Part of the research (DFT molecular modeling and GIAO-based NMR calculations) was supported by Poland’s high-performance Infrastructure PLGrid (Ares supercomputer, ACC Cyfronet AGH, Kraków, Poland; https://www.cyfronet.pl/, accessed on 15 July 2024) within grant No. PLG/2023/016629 to R.B.N. Some calculations were carried out using resources provided by the Wroclaw Center for Networking and Supercomputing (https://wcss.pl, accessed on 15 July 2024), grant No. 68. Access to HPC machines and licensed software is gratefully acknowledged by M.D.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

The authors thank Lidia Turała for her participation in the synthetic part of the work. R.B.N. thanks Michał Piotrowicz (from this Faculty) for a mechanistic suggestion and especially Piotr Matczak (from this Department) for a very valuable discussion on DFT calculations.

Conflicts of Interest

The authors declare no conflicts of interest.

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Crystals 14 00704 sch001
Scheme 1. The assumed reaction course and the one encountered for diketone 2d.
Scheme 1. The assumed reaction course and the one encountered for diketone 2d.
Crystals 14 00704 sch001
Crystals 14 00704 g001
Figure 1. A 3D plot [31] of the two-part molecular structure (D/U = 1:1) of the 1H-tautomer of 4d in the CDCl3 solution, according to modeling at the IEF-PCM(CHCl3)/ωB97X-D/def2-TZVP theory level supported by subsequent DFT-GIAO NMR calculations; see the text for all details.
Figure 1. A 3D plot [31] of the two-part molecular structure (D/U = 1:1) of the 1H-tautomer of 4d in the CDCl3 solution, according to modeling at the IEF-PCM(CHCl3)/ωB97X-D/def2-TZVP theory level supported by subsequent DFT-GIAO NMR calculations; see the text for all details.
Crystals 14 00704 g001
Crystals 14 00704 g002
Figure 2. The molecular structure of 6-(1H-benzo[d]imidazol-2-yl)-1-phenyl-hexan-1-one monohydrate with the atom numbering scheme. Atomic displacement ellipsoids are drawn with a 50% probability level.
Figure 2. The molecular structure of 6-(1H-benzo[d]imidazol-2-yl)-1-phenyl-hexan-1-one monohydrate with the atom numbering scheme. Atomic displacement ellipsoids are drawn with a 50% probability level.
Crystals 14 00704 g002
Crystals 14 00704 ch001
Chart 1. Possible molecular systems and their units considered.
Chart 1. Possible molecular systems and their units considered.
Crystals 14 00704 ch001
Crystals 14 00704 g003
Figure 3. COSY-45 spectrum of 4d in the CDCl3 solution (aliphatic region only); pulse width 45 degrees, acquisition time 0.2 s, relaxation delay 1.0 s.
Figure 3. COSY-45 spectrum of 4d in the CDCl3 solution (aliphatic region only); pulse width 45 degrees, acquisition time 0.2 s, relaxation delay 1.0 s.
Crystals 14 00704 g003
Crystals 14 00704 g004
Figure 4. A scatter plot of the best δCcalc vs. δCexp relationship for the two-part structure of 4d (D/U = 1:1) found at the IEF-PCM(CHCl3)/ωB97X-D/def2-TZVP optimized geometries, by using δCcalc data averaged for the three tautomeric positions; see the text and SM for an explanation.
Figure 4. A scatter plot of the best δCcalc vs. δCexp relationship for the two-part structure of 4d (D/U = 1:1) found at the IEF-PCM(CHCl3)/ωB97X-D/def2-TZVP optimized geometries, by using δCcalc data averaged for the three tautomeric positions; see the text and SM for an explanation.
Crystals 14 00704 g004
Crystals 14 00704 sch002
Scheme 2. Proposed mechanism of the observed cyclocondensation reaction.
Scheme 2. Proposed mechanism of the observed cyclocondensation reaction.
Crystals 14 00704 sch002
Crystals 14 00704 g005
Figure 5. Molecular arrangement in the structure of the title compound: (a) view of infinite chains formed by the N1–H1…O23 and O23–H23B…N3 bonds and (b) b-axis view of the centrosymmetric ring formed by the O23–H23A…O22 and C8–H8…O22 bonds.
Figure 5. Molecular arrangement in the structure of the title compound: (a) view of infinite chains formed by the N1–H1…O23 and O23–H23B…N3 bonds and (b) b-axis view of the centrosymmetric ring formed by the O23–H23A…O22 and C8–H8…O22 bonds.
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Figure 6. (a) Hirshfeld surface of the title compound mapped over dnorm and (b) fingerprint plot showing all the interactions taken from the Hirshfeld surface.
Figure 6. (a) Hirshfeld surface of the title compound mapped over dnorm and (b) fingerprint plot showing all the interactions taken from the Hirshfeld surface.
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Crystals 14 00704 g007
Figure 7. Difference Fourier map associated with the O23–H23B…N3 hydrogen bond between the benzimidazole and water molecules. The map was calculated on the mean plane of N1/N3/O23 from a model containing all atoms except the H atoms in the hydrogen bonds. The contours are at 0.05 eÅ−3, and the dashed lines indicate negative contours. The electron density maxima corresponding to H atoms are marked in purple.
Figure 7. Difference Fourier map associated with the O23–H23B…N3 hydrogen bond between the benzimidazole and water molecules. The map was calculated on the mean plane of N1/N3/O23 from a model containing all atoms except the H atoms in the hydrogen bonds. The contours are at 0.05 eÅ−3, and the dashed lines indicate negative contours. The electron density maxima corresponding to H atoms are marked in purple.
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Table 1. Geometric parameters for hydrogen bonds and energy of interactions for two interacting molecules in crystal of 4d obtained at the ωB97X-D/def2-TZVPP level of theory.
Table 1. Geometric parameters for hydrogen bonds and energy of interactions for two interacting molecules in crystal of 4d obtained at the ωB97X-D/def2-TZVPP level of theory.
D–H [Å]H…A [Å]D…A [Å]D–H…A [°]Eint [kcal/mol]
O23–H23A…O220.82(2)2.28(2)3.063(3)160(3)−5.40
N1–H1…O23 I0.93(3)1.98(3)2.867(3)161(2)−5.64
O23–H23B…N3 II0.84(2)2.07(2)2.882(3)162(3)−7.82
C8–H8…O22 II0.932.543.217130−4.5
Symmetry codes: I 2-x, -y, 1-z; II 2-x, 1-y, 1-z.
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Nazarski, R.B.; Domagała, M. Unexpected Formation of 6-(1H-Benzo[d]imidazol-2-yl)-1-phenyl-hexan-1-one and Its Structure in Solution and Solid State Analyzed in the Context of Tautomerism. Crystals 2024, 14, 704. https://doi.org/10.3390/cryst14080704

AMA Style

Nazarski RB, Domagała M. Unexpected Formation of 6-(1H-Benzo[d]imidazol-2-yl)-1-phenyl-hexan-1-one and Its Structure in Solution and Solid State Analyzed in the Context of Tautomerism. Crystals. 2024; 14(8):704. https://doi.org/10.3390/cryst14080704

Chicago/Turabian Style

Nazarski, Ryszard B., and Małgorzata Domagała. 2024. "Unexpected Formation of 6-(1H-Benzo[d]imidazol-2-yl)-1-phenyl-hexan-1-one and Its Structure in Solution and Solid State Analyzed in the Context of Tautomerism" Crystals 14, no. 8: 704. https://doi.org/10.3390/cryst14080704

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