Synthesis and Structure of Fluorinated (Benzo[d]imidazol-2-yl)methanols: Bench Compounds for Diverse Applications

A simple and general approach to the synthesis (from commercial precursors) of eight out of nine possible (benzo[d]imidazol-2-yl)methanols fluorinated on the benzene ring is reported. Molecular and crystalline structures of most compounds were solved by X-ray diffraction analysis. This made it possible to reveal the influence of the number and arrangement of fluorine atoms in the benzene cycle on the formation of intermolecular hydrogen bonds. It was found that the more fluorine atoms are present in a compound, the higher the dimensionality of the H-bonded structure is. Moreover, the presence of fluorine atoms in the synthesized compounds leads to the emergence of C–F…π interactions affecting crystal packing. The synthesized fluorinated (benzo[d]imidazol-2-yl)methanols may serve as excellent bench compounds for the synthesis of a systematic series of fluorine-containing derivatives to study structure–property correlations in various fields of research from medicine to materials science.


Results and Discussion
The chemical transformations leading to the target fluorinated and polyfluorinated (benzo[d]imidazol-2-yl)methanols are shown in Scheme 1. Commercially available fluorinated anilines 2d,e,g and nitrobenzenes 5b,c,i were used as starting substrates. Anilines 2d,e,g were acylated to obtain corresponding acetanilides 3, which were then nitrated by means of a mixture of HNO3 (70%) with conc. H2SO4 (1:1) to prepare nitroacetanilides 4d,e,g. Boiling of these nitroacetamides in conc. HCl led to nitroanilines 6d,e,g with good yields (80-90%). The range of the nitroanilines thus obtained was expanded via the aminodefluorination reaction of fluorinated nitrobenzenes 5b,c,i with aqueous ammonia in EtOH. The reaction gave rise to nitro anilines 6b,c,i, which, just as 6d,e,g and commercially available 6a, were reduced to corresponding o-phenylenediamines 7a-e,g,i by the action of SnCl2 in HCl.
A special synthetic route was employed to prepare trifluoro-o-phenylenediamine 7h; the route is based on a reduction in corresponding 4,5,7-trifluoro-2,1,3-benzothiadiazole 9, which was synthesized by transformation of tetrafluoroaniline 8 into corresponding Ar-N=S=NSiMe3 with its subsequent fluoride-induced nucleophilic ortho-cyclization [53]. Finally, the interaction of fluorinated o-phenylenediamines 7a-e and 7g-i with glycolic acid in hydrochloric acid led to target benzo[d]imidazol-2-yl)methanols 1a-e,g-i with good yields (70-85%). All fluorinated benzimidazoles 1 as well as their precursors were fully characterized by spectral methods (Experimental section and Supplementary Materials).
As for difluorobenzimidazole 1f, within the framework of this work, we failed to design a route for its preparation. The only thing we can say is that this route cannot be based on the use of known 6-nitro-2,5-difluoroaniline or 1,4-difluoro-2,3-dinitrobenzene because these compounds form only in trace amounts during the nitration of 2,5-difluoroacetanilide or 1,4-difluoro-2-nitrobenzene, respectively [54,55]. In addition, we showed that according to X-ray diffraction analysis, the number and arrangement of fluorine atoms in (benzo[d]imidazol-2-yl)methanols sufficiently influence on their crystal packing. It was found that the more fluorine atoms are present in a compound, the higher the dimensionality of the H-bonded structure is. Moreover, the presence of fluorine atoms in the synthesized compounds leads to the emergence of C-F . . . π interactions affecting the crystal packing.

Results and Discussion
The chemical transformations leading to the target fluorinated and polyfluorinated (benzo[d]imidazol-2-yl)methanols are shown in Scheme 1. Commercially available fluorinated anilines 2d,e,g and nitrobenzenes 5b,c,i were used as starting substrates. Anilines 2d,e,g were acylated to obtain corresponding acetanilides 3, which were then nitrated by means of a mixture of HNO 3 (70%) with conc. H 2 SO 4 (1:1) to prepare nitroacetanilides 4d,e,g. Boiling of these nitroacetamides in conc. HCl led to nitroanilines 6d,e,g with good yields (80-90%). The range of the nitroanilines thus obtained was expanded via the aminodefluorination reaction of fluorinated nitrobenzenes 5b,c,i with aqueous ammonia in EtOH. The reaction gave rise to nitro anilines 6b,c,i, which, just as 6d,e,g and commercially available 6a, were reduced to corresponding o-phenylenediamines 7a-e,g,i by the action of SnCl 2 in HCl.
A special synthetic route was employed to prepare trifluoro-o-phenylenediamine 7h; the route is based on a reduction in corresponding 4,5,7-trifluoro-2,1,3-benzothiadiazole 9, which was synthesized by transformation of tetrafluoroaniline 8 into corresponding Ar-N=S=NSiMe 3 with its subsequent fluoride-induced nucleophilic ortho-cyclization [53]. Finally, the interaction of fluorinated o-phenylenediamines 7a-e and 7g-i with glycolic acid in hydrochloric acid led to target benzo[d]imidazol-2-yl)methanols 1a-e,g-i with good yields (70-85%). All fluorinated benzimidazoles 1 as well as their precursors were fully characterized by spectral methods (Experimental section and Supplementary Materials).
As for difluorobenzimidazole 1f, within the framework of this work, we failed to design a route for its preparation. The only thing we can say is that this route cannot be based on the use of known 6-nitro-2,5-difluoroaniline or 1,4-difluoro-2,3-dinitrobenzene because these compounds form Crystals 2020, 10, 786 4 of 16 only in trace amounts during the nitration of 2,5-difluoroacetanilide or 1,4-difluoro-2-nitrobenzene, respectively [54,55]. Well-shaped crystals of compounds 1b-e, 1g, and 1i were obtained upon crystallization from acetonitrile or a mixture of acetonitrile with toluene. As to compound 1h, upon crystallization from various mixtures of solvents, it gave strongly supersaturated solutions with subsequent avalanche-like formation of fine-needle crystals in the form of intergrown hedgehogs.
Molecular and crystal structures of benzimidazoles 1b-e, 1g, and 1i were solved by single-crystal X-ray diffraction. The X-ray crystallographic analyses revealed that 1b and 1e crystallize in triclinic P-1 space groups, 1c and 1g both crystallize in the monoclinic C2/c space group, whereas 1d in the P21/c space group, and 1i in the tetragonal P41212 space group. ORTEP diagrams of dimer H-bonded structures drawn with 50% ellipsoid probability and numbering schemes for these compounds are depicted in Figure 2 below. The diagrams confirm the expected substitution patterns for the synthesized fluorinated benzimidazole series.
In the investigated benzimidazoles, aromatic nuclei are perfectly planar, and the bond lengths and bond angles are very close to or the same as statistical means [56]. Torsion angles between the aromatic cycle and hydroxymethyl group are in the broad range from 8.12° to 84.45°. These conformation differences are due to dissimilarities in the binding of the molecules through intermolecular H-bonds N-H…O, O-H…N, and C-H…F (Table 1). Well-shaped crystals of compounds 1b-e, 1g, and 1i were obtained upon crystallization from acetonitrile or a mixture of acetonitrile with toluene. As to compound 1h, upon crystallization from various mixtures of solvents, it gave strongly supersaturated solutions with subsequent avalanche-like formation of fine-needle crystals in the form of intergrown hedgehogs.
Molecular and crystal structures of benzimidazoles 1b-e, 1g, and 1i were solved by single-crystal X-ray diffraction. The X-ray crystallographic analyses revealed that 1b and 1e crystallize in triclinic P-1 space groups, 1c and 1g both crystallize in the monoclinic C2/c space group, whereas 1d in the P2 1 /c space group, and 1i in the tetragonal P4 1 2 1 2 space group. ORTEP diagrams of dimer H-bonded structures drawn with 50% ellipsoid probability and numbering schemes for these compounds are depicted in Figure 2 below. The diagrams confirm the expected substitution patterns for the synthesized fluorinated benzimidazole series. Well-shaped crystals of compounds 1b-e, 1g, and 1i were obtained upon crystallization from acetonitrile or a mixture of acetonitrile with toluene. As to compound 1h, upon crystallization from various mixtures of solvents, it gave strongly supersaturated solutions with subsequent avalanche-like formation of fine-needle crystals in the form of intergrown hedgehogs.
Molecular and crystal structures of benzimidazoles 1b-e, 1g, and 1i were solved by single-crystal X-ray diffraction. The X-ray crystallographic analyses revealed that 1b and 1e crystallize in triclinic P-1 space groups, 1c and 1g both crystallize in the monoclinic C2/c space group, whereas 1d in the P21/c space group, and 1i in the tetragonal P41212 space group. ORTEP diagrams of dimer H-bonded structures drawn with 50% ellipsoid probability and numbering schemes for these compounds are depicted in Figure 2 below. The diagrams confirm the expected substitution patterns for the synthesized fluorinated benzimidazole series.
In the investigated benzimidazoles, aromatic nuclei are perfectly planar, and the bond lengths and bond angles are very close to or the same as statistical means [56]. Torsion angles between the aromatic cycle and hydroxymethyl group are in the broad range from 8.12° to 84.45°. These conformation differences are due to dissimilarities in the binding of the molecules through intermolecular H-bonds N-H…O, O-H…N, and C-H…F (Table 1). In the investigated benzimidazoles, aromatic nuclei are perfectly planar, and the bond lengths and bond angles are very close to or the same as statistical means [56]. Torsion angles between the aromatic cycle and hydroxymethyl group are in the broad range from 8.12 • to 84.45 • . These conformation differences are due to dissimilarities in the binding of the molecules through intermolecular H-bonds N-H . . . O, O-H . . . N, and C-H . . . F (Table 1).
To visualize how molecules 1b-e, 1g, and 1i are assembled into corresponding crystal structures through H-bonds and short intermolecular contacts, it is reasonable first to choose low-dimensional substructures, for example dimers presented in Figure 2, and then to perform their supramolecular assembly. In 1b, the propagation of dimers {1b . . . 1b} via a pair of intermolecular H-bonds N1-H . . . O9 generates parallel chains running along the [100] direction ( Figure 3a). As illustrated in Figure 3b, the final structure is formed due to the binding of chains via H-bonds of type C8-H . . . F1 and π-π interactions giving rise to short intermolecular contacts C7 . . . The compounds 1c and 1g are highly isostructural; they both contain a fluorine atom at position 4, also participating in the crosslinking of molecules into layers (Figure 4a). Then, the layers are combined similarly through intermolecular C CH 2 -H . . . F hydrogen bonding and π-π stacking interactions into the final structure (Figure 4b and Supplementary Materials). As for compound 1d, in its crystals, the supramolecular self-organization of layers is implemented through interlayer short contacts between atoms F2 and C5 ( Figure 5). To visualize how molecules 1b-e, 1g, and 1i are assembled into corresponding crystal structures through H-bonds and short intermolecular contacts, it is reasonable first to choose low-dimensional substructures, for example dimers presented in Figure 2, and then to perform their supramolecular assembly. In 1b, the propagation of dimers {1b…1b} via a pair of intermolecular H-bonds N1-H…O9 generates parallel chains running along the [100] direction ( Figure 3a). As illustrated in Figure 3b, the final structure is formed due to the binding of chains via H-bonds of type C8-H…F1′ and π-π interactions giving rise to short intermolecular contacts C7′…C7′ (3.384 Å). Difluorobenzimidazole 1e is isostructural to monofluoro-derivative 1b; in its solid state, dimers {1e…1e} are linked into chains via H-bonds of two types: N1-H…O9 and C8-H…F2 (Supplementary Materials). The latter set the orientation of molecules 1e in the chains and prevent the disordering observed in compound 1b. The final supramolecular assembly of chains, as in 1b, is realized via intermolecular H-bonds C8-H…F1′ and π-π interactions (Supplementary Materials). In 1c, 1d, and 1g containing two or three adjacent fluorine atoms on the benzene ring, the binding of dimeric synthons via N-H…O and O-H…N hydrogen bonds causes the formation of layers. The compounds 1c and 1g are highly isostructural; they both contain a fluorine atom at position 4, also participating in the crosslinking of molecules into layers (Figure 4a). Then, the layers       A further increase in the number of fluorine atoms on the benzene ring gives rise to additional intermolecular interactions, and the tetrafluoro-derivative prefers to bind into a framework ( Figure 6). Thus, it is noteworthy that the compounds containing one fluorine atom or not containing neighboring fluorine atoms (1b and 1e) form hydrogen-bonded chains. Compounds 1c, 1d, and 1g, in which benzimidazoles bear two or three adjacent fluorine atoms, form a layered polymeric structure in the solid phase, whereas tetrafluoro-derivative 1i upon crystallization yields a framework.
Crystals 2020, 10, x FOR PEER REVIEW 8 of 17 A further increase in the number of fluorine atoms on the benzene ring gives rise to additional intermolecular interactions, and the tetrafluoro-derivative prefers to bind into a framework ( Figure  6). Thus, it is noteworthy that the compounds containing one fluorine atom or not containing neighboring fluorine atoms (1b and 1e) form hydrogen-bonded chains. Compounds 1c, 1d, and 1g, in which benzimidazoles bear two or three adjacent fluorine atoms, form a layered polymeric structure in the solid phase, whereas tetrafluoro-derivative 1i upon crystallization yields a framework.  In addition to the preceding discussion of how fluorinated (benzo[d]imidazol-2-yl)methanols are bound through H-bonds, their forced mutual orientation is also of interest. Benzimidazole  In addition to the preceding discussion of how fluorinated (benzo[d]imidazol-2-yl)methanols are bound through H-bonds, their forced mutual orientation is also of interest. Benzimidazole moieties of neighboring molecules are arranged into slipped-parallel stacks with head-to-tail or head-to-head orientations. The distances between planes of aromatic rings are in the range 3.25 to 3.60 Å, and the Crystals 2020, 10, 786 9 of 16 intercentroid distances (Cg . . . Cg) are 3.44 to 3.98 Å; both are characteristic of π-stacking interactions ( Figure 7a). In addition to the π-π interactions, nonvalent contacts between the F atoms and π-systems of neighboring molecules (C-F . . . π interactions, Figure 7b) are present in all the compounds except for 1d in which H . . . π interactions take place. Atom-to-plane distances F . . . Cg and H . . . Cg are 3.25-3.89 and 2.70-2.97 Å, respectively. The energy of these interactions is an order of magnitude or more inferior to the energy of classic H-bonds [57,58]; however, the finding that they take place suggests that they also affect the packing of the fluorinated (benzo[d]imidazol-2-yl)methanols. This observation is worth noting because it indicates that interactions of the C-F . . . π type are capable of exerting some influence even on such structures rigidly cross-linked by H-bonds.
Crystals 2020, 10, x FOR PEER REVIEW 9 of 17 moieties of neighboring molecules are arranged into slipped-parallel stacks with head-to-tail or head-to-head orientations. The distances between planes of aromatic rings are in the range 3.25 to 3.60 Å, and the intercentroid distances (Cg…Cg) are 3.44 to 3.98 Å; both are characteristic of π-stacking interactions ( Figure 7a). In addition to the π-π interactions, nonvalent contacts between the F atoms and π-systems of neighboring molecules (C-F…π interactions, Figure 7b) are present in all the compounds except for 1d in which H…π interactions take place. Atom-to-plane distances F…Cg and H…Cg are 3.25-3.89 and 2.70-2.97 Å, respectively. The energy of these interactions is an order of magnitude or more inferior to the energy of classic H-bonds [57,58]; however, the finding that they take place suggests that they also affect the packing of the fluorinated (benzo[d]imidazol-2-yl)methanols. This observation is worth noting because it indicates that interactions of the C-F…π type are capable of exerting some influence even on such structures rigidly cross-linked by H-bonds.

Conclusions
In organic chemistry and interdisciplinary research, the identification of correlations between the structure and properties of compounds is of great importance. Given that fluoro-organic derivatives play an important role in the development of new drugs and in the creation of materials with unique properties, basic fluorinated derivatives including heterocyclic compounds are in high demand. The fluorinated (benzo[d]imidazol-2-yl)methanols and their key precursors described in this paper can serve as compounds at the bench that will help to obtain a wide variety of products in the fields of medicinal chemistry and materials science. In particular, in our further studies, the synthesized compounds will be utilized for the preparation of benzimidazolyl-substituted nitronyl nitroxide radicals and magnetically active 2D complexes of Mn(II) with these radicals. We hope that a comparative study of magnetic properties of these manganese-nitroxide complexes will enable us to find a way to increase the temperature of transition of the complexes into a magnetically ordered state and will be valuable for further research on the cooperative valence tautomerism phenomenon [32,33,59].
In addition to the synthetic potential of the obtained series of fluorinated (benzo[d]imidazol-2-yl)methanols, interesting results were obtained in their X-ray structural analysis. It turned out that weak H-bonds C-H…F can actively intervene into the interaction of such strong donors and acceptors of H-bonds as the imidazole moiety and hydroxyl group, thus radically changing the nature of the binding of molecules and causing an increase in the resulting structures' dimensionality. Moreover, the presence of fluorine atoms in the synthesized compounds leads to the

Conclusions
In organic chemistry and interdisciplinary research, the identification of correlations between the structure and properties of compounds is of great importance. Given that fluoro-organic derivatives play an important role in the development of new drugs and in the creation of materials with unique properties, basic fluorinated derivatives including heterocyclic compounds are in high demand. The fluorinated (benzo[d]imidazol-2-yl)methanols and their key precursors described in this paper can serve as compounds at the bench that will help to obtain a wide variety of products in the fields of medicinal chemistry and materials science. In particular, in our further studies, the synthesized compounds will be utilized for the preparation of benzimidazolyl-substituted nitronyl nitroxide radicals and magnetically active 2D complexes of Mn(II) with these radicals. We hope that a comparative study of magnetic properties of these manganese-nitroxide complexes will enable us to find a way to increase the temperature of transition of the complexes into a magnetically ordered state and will be valuable for further research on the cooperative valence tautomerism phenomenon [32,33,59].
In addition to the synthetic potential of the obtained series of fluorinated (benzo[d]imidazol-2-yl)methanols, interesting results were obtained in their X-ray structural analysis. It turned out that weak H-bonds C-H . . . F can actively intervene into the interaction of such strong donors and acceptors of H-bonds as the imidazole moiety and hydroxyl group, thus radically changing the nature of the binding of molecules and causing an increase in the resulting structures' dimensionality. Moreover, the presence of fluorine atoms in the synthesized compounds leads to the emergence of other competing and concerted weak intermolecular interactions, like C-F . . . π [58,60,61], which to some extent affect the crystal packing too. It is obvious that such interactions can also exist in crystals of derivatives of the synthesized benzimidazoles and thereby affect their properties. Furthermore, it is expected that such derivatives carrying different fluorinated benzimidazole moieties will interact differently with biological molecules and biological targets.

Interaction of o-Phenylenediamines with Glycolic Acid: The General Procedure
Each o-phenylenediamine 7a-e or 7g-i (10.0 mmol) was added to an aqueous 4N HCl solution (20 mL) containing glycolic acid (10.0 mmol). Then, the reaction mixture was refluxed for 8 h, cooled to 0 • C, and alkalized with a~40% NaOH aqueous solution up to pH ≈ 8. The precipitate was filtered off and washed with ice-cold water to obtain corresponding (benzo[d]imidazol-2-yl)methanols 1a-e and 1g-i [62]

Single-Crystal X-ray Diffraction Analyses
These analyses of 1b-1e, 1g, and 1i were performed on a Bruker Kappa Apex II CCD diffractometer using ϕ,ω-scans of narrow (0.5 • ) frames with Mo Kα radiation (λ = 0.71073 Å) and a graphite monochromator. The structures were solved by direct methods in the SHELX-97 software [63] and were refined by the full-matrix least-squares method against all F2 in anisotropic approximation using SHELXL-2014/7 [64]. Absorption corrections were applied via the empirical multiscan method by means of the SADABS software [65]. The hydrogen atoms' positions, except for H atoms in NH and OH groups, were calculated with the riding model. Nitrogen-bound and oxygen-bound H atoms were located on a difference Fourier map and refined freely. The resultant crystal structures were analyzed for short contacts between nonbonded atoms using PLATON [66,67] and MERCURY [68]. General crystallographic data for these compounds are summarized in Table 2. CCDC 2016713-2016718 contain the supplementary crystallographic data for benzimidazoles 1b-e, 1g, and 1i, respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac. uk/cgi-bin/catreq.cgi or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (+44)-1223-336-033 or by e-mail: deposit@ccdc.cam.ac.uk.