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Article

Halogens On, H-Bonds Off—Insights into Structure Control of Dihalogenated Imidazole Derivatives

by
Luca Mensing
,
Marcus Layh
and
Marian Hebenbrock
*
Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstr. 28/30, 48149 Münster, Germany
*
Author to whom correspondence should be addressed.
Crystals 2025, 15(11), 1000; https://doi.org/10.3390/cryst15111000
Submission received: 31 October 2025 / Revised: 14 November 2025 / Accepted: 15 November 2025 / Published: 20 November 2025
(This article belongs to the Special Issue Analysis of Halogen and Other σ-Hole Bonds in Crystals (2nd Edition))
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Abstract

Halogen bonds play an important role in the targeted generation of solid-state structures, with polyhalogenated compounds enabling the simultaneous formation of various interactions. In this manuscript, we investigate the interactions of dihalogenated compounds in the solid state. Unlike investigated in previous studies, the introduction of protective groups in these compounds prevents the formation of dominant hydrogen bonds. The structures of diiodo imidazole derivatives are compared with the analogous dibromo compounds. A total of four different protective groups (two benzylic and two oxycarbonyl protective groups) are introduced and the respective compounds are characterized by X-ray crystallography. The significance of the protective groups for the solid-state structure can be distinguished on the basis of the additional donor atoms and functional groups. It can be seen that the iodo compounds in particular are capable of forming halogen bonds and that additional structural motifs can be generated by suitable protective groups.

Graphical Abstract

1. Introduction

Over the past few decades, halogen bonding has gained substantial interest due to a wide range of applications in supramolecular chemistry [1], crystal engineering [2,3], (organo)catalysis [4] and medicinal chemistry [5]. Probably the first halogen-bonded complex was synthesized in 1814 by J. J. Colin [6], who synthesized an I2···NH3 adduct that was characterized about 50 years later by F. Guthrie [7]. Foundational insights into halogen bonding were supported by the theoretical work of R. S. Mulliken [8], who introduced the general concept of donor–acceptor (charge-transfer) interactions between molecules, and by O. Hassel [9], whose X-ray crystallographic studies provided early experimental evidence for interactions between halogen atoms and electron donors. However, the term ‘halogen bonding’ was coined in 1978 by Dumas et al. [10,11]
In general, halogen bonding is a non-covalent bond and is defined as an interaction between a halogen atom as an electron acceptor and a Lewis base, such as nitrogen, oxygen or sulfur as an electron donor. The typical halogen atoms involved are iodine, bromine, or chlorine. The halogen bond is a result of the anisotropic electron density on the halogen atom, called the σ-hole, in which the Lewis base is able to donate electrons and thus form a relatively strong non-covalent interaction. This interaction leads to typical features such as a near-linear angle (∠C-X···Donor: ~180°) and the sum of the van der Waals radii of donor and acceptor exceeding the interatomic distance. Other arrangements and geometries are also possible, depending on the nature of donor and acceptor. The strength depends on the halogen atoms involved with F < Cl < Br < I, due to their different polarizability. Variation of electron donor and acceptor can be used for targeted structural control in crystal engineering [12,13].
Imidazole derivatives play a crucial role in many biological systems such as hemoglobin, nucleic acid bases (purines) and the neurotransmitter histamine but are also important in areas such as supramolecular ligand chemistry [14,15,16]. Due to the relevance of imidazole derivatives, including halogen-substituted imidazole derivatives, and the ability of their nitrogen atoms to function as electron donors, many studies have focused on (halogen-)substituted imidazole derivatives in various research areas. In medicinal chemistry, polyhalogenated imidazole nucleosides were evaluated as antiviral drugs [17]. Furthermore, polyhalogenated benzimidazole nucleosides were also investigated as antiviral agents and were active against the HCMV virus [18]. Even in anticancer therapies, polyhalogenated benzimidazoles were investigated [19]. In different materials studies the influence of the direct substitution of the heterocycle at position C2, but also the influence of the halogen-substitution on the backbone of an imidazole derivative, regarding their potential as corrosion inhibitors, have been studied [20,21]. Furthermore, halogenated imidazole linkers are considered as ligands in metal–organic frameworks (MOFs), a field recently awarded the Nobel Prize hereby emphasizing the importance of MOFs. Halogenated imidazole derivatives are capable of enhancing the stiffness of MOFs [22], introducing a permanent dipole, and facilitating responses to electric fields [23] as well as increasing gas-uptake properties [24].
With a focus on supramolecular structures of halogen-containing imidazole derivatives, various studies were undertaken. Portilla et al. investigated the influence of halogen atoms and hydrogen bonds in the crystal structures of 1,2,4-trisubstituted imidazoles with haloaryl groups based on the presence of imidazole derivatives with haloaryl groups in several commercial antifungals [25,26]. Furthermore, Macías, Portilla et al. have investigated compounds with either two fluorine or two chlorine atoms on N-substituted 4-arylimidazoles or with only one chlorine atom, but with an unprotected N atom. Structural differences in the solid state could be attributed to different chain orientations, which are stabilized by different hydrogen bonds and halogen···halogen interactions [27].
Furthermore, the direct halogen-substitution of imidazole derivatives was also investigated in the context of supramolecular chemistry. The di- and tri-halogen-substitution of imidazole with Cl, Br, and I, and the intermolecular interactions showed that NH···N interactions are the main structural feature. Chains are formed, but the molecules are also stabilized by halogen···halogen bonds, and these interactions can have a major impact on structural control [28]. In addition, the influence of substituents (in this case, a benzyl protective group) on the N1 atom of the imidazole derivative was analyzed. The protection prevents the formation of NH···N bonds. The imidazole derivatives were monoiodinated at C2 (imidazole and benzimidazole) or C4 (imidazole). It was concluded that the C2 derivatives are capable of forming halogen bonds [28].
Beyond imidazole derivatives the literature on supramolecular chemistry shows that the balance between hydrogen bonding and halogen bonding can be adjusted and influenced by substituents and parameters during the crystallization process. Competition between both types of interactions has been reported, with evidence suggesting a direct relationship between molecular architecture and the ratio between both interactions in different cocrystals [29]. Stoichiometric control can transform a given assembly from one dominated by hydrogen bonding (C–H···O ‘tapes’) to one dominated by halogen bonding with short I···O contacts, despite the two-component systems being otherwise identical, thereby highlighting direct switching between both types [30]. Similarly, solvent polarity influences competitive co-crystallization: less polar solvents favor hydrogen bonding products, whereas more polar solvents favor halogen bonding networks. In addition to the polarity of the solvent, the relative strengths of the donors and the crystallization pathways influence the ratio of hydrogen bonds to halogen bonds [31]. Trimorphic co-crystals further demonstrate the orthogonality of halogen and hydrogen bonded synthons [32]. Systematic surveys with bifunctional donors/acceptors reveal hierarchies in which geometry and electrostatics (MEP) determine which bonding type becomes the primary synthon [33,34]. In related systems, iodine frequently engages in X-N/O contacts and can even capture acceptor sites that are usually involved in NH···N hydrogen bonds. This demonstrates the ability of halogen bonding to alter packing arrangement [35]. Multifunctional donors demonstrate that hydrogen and halogen bonding can coexist or exclude each other, depending on donor geometry. These precedents justify strategies that attenuate hydrogen bonding donors and enhance halogen bonding (e.g., the use of heavier halogens or tailored conditions) when targeting structural control in halogenated imidazoles [36]. Related oxime systems show halogen bonding at O/N sites and illustrate the influence of halogen substitution on the number of hydrogen bonds [37].
In this paper, we have investigated the influence of dihalogenation of imidazoles in their C4 and C5 positions with either bromine or iodine with a focus on halogen bond formation. Furthermore, we have protected the N1 position with various protecting groups to create different electronic and steric environments, which may be essential for further considerations in supramolecular chemistry using halogen bonding as a key to structural control. In total, eight different compounds were synthesized and characterized by X-ray crystallography.

2. Materials and Methods

2.1. General Aspects

All chemicals used in this study were of p.a. grade and were obtained from ABCR (Karlsruhe, Germany), Acros Organics (Geel, Belgium), Alfa Aesar (Ward Hill, MA, USA), AppliChem (Darmstadt, Germany), BLDpharm (Shanghai, China), Carl Roth (Karlsruhe, Germany), Fisher Scientific (Waltham, MA, USA), Fluorochem (Glossop, UK), Merck (Darmstadt, Germany) Sigma-Aldrich (Burlington, MA, USA), TCI (Tokyo, Japan) or VWR (Radnor, PA, USA) and used, if not stated otherwise, without further purification.
NMR spectra were recorded on AVANCE NEO 400 (Bruker Biospin, Ettlingen, Germany) and AVANCE NEO 500 (Bruker Biospin, Ettlingen, Germany) NMR spectrometers. Chemical shifts are reported as δ, parts per million (ppm), and referenced to internal solvent residues. Coupling constants J are stated in Hertz (Hz). The following abbreviations were used for spin multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), m (multiplet). High-resolution ESI-MS spectra were recorded on an Impact II VIP QTOF ESI-MS (Bruker).
Elemental analysis was performed on a vario EL III CHNS (Elementar Analysensysteme GmbH, Langenselbold, Germany).

2.2. Synthetic Procedures

The synthesis procedures and the associated analytical data can be found in the SI. Some of the procedures are taken from the literature or serve to compare the analytical data obtained with that of known compounds [38,39,40,41,42].

2.3. X-Ray

Intensity data were collected using monochromated MoKα radiation on a Bruker D8 Venture diffractometer with a Photon III detector using either APEX5 or APEX6 software suite [43,44,45]. The collection method involved ω scans. Data reduction was performed using the program SAINT [44]. The crystal structures were solved by Intrinsic Phasing using SHELXT [46]. Non-hydrogen atoms were first refined isotropically, followed by anisotropic refinement by full-matrix least-squares calculation based on F2 using SHELXL [47]. H atoms were positioned geometrically and allowed to ride on their respective parent atoms. The co-crystallized solvent molecules in compounds 3d (n-pentane) and 4d (THF) were treated as a diffuse contribution to the overall scattering without specific atom positions by SQUEEZE/PLATON [48]. Crystallization attempts of 3d from other solvents resulted in the same structure with voids for co-crystallized solvents (CCDC 2499425 with co-crystallized diethylether, not further discussed). The structure of compound 3c is disordered over two positions with a ratio of 70:30. The same crystal structure with a disordered molecule was also obtained from various other solvents (methanol, ethanol, diethyl ether, THF, toluene, ethyl acetate, n-hexane) and under different crystallization conditions. Further details of the crystal structure determinations are available from the Cambridge Crystallographic Data Center on quoting the depository number CCDC 2499326–2499331, 2499334–2499335 and 2499425. Table 1 with the crystallographic details were created using WinGX [49,50].

3. Results

3.1. Synthesis of Halogenated and Protected Imidazole Derivatives

The synthesis of the halogenated imidazole derivatives was carried out either starting from imidazole or from the commercially available, tribromo derivative (Scheme 1). The dibromo derivative was prepared by dehalogenation of 2,4,5-tribromoimidazole. The dehalogenation reaction was carried out with ethylmagnesium bromide and yielded the dibromo derivative 1 in good yield. For the iodo derivatives, imidazole was reacted with iodine and iodide under basic conditions, resulting in the diiodo species 2.
The protective groups were introduced by deprotonation of the respective imidazole derivative with sodium hydride and subsequent reaction with di-tert-butyl dicarbonate, 4-methoxybenzyl chloride, benzyl bromide, or benzyl chloroformate. The protected compounds were obtained in moderate to good yields of 41% to 91%.

3.2. Molecular Structures of the Dihalogenated Derivatives

All compounds were obtained as single crystals and examined using X-ray crystallography. Despite the different protective groups, there are common structural features in the molecular structures within a halogen. The dibromo derivatives are characterized by bond lengths between 1.853(1) Å and 1.864(3) Å of the two carbon-bromine bonds. Although the bond lengths of these C–Br bonds vary slightly in each derivative, they are within the range of typical carbon-bromine bond lengths (1.875(11) Å, [51]). In particular, there are no significant deviations in bond lengths compared to related compounds such as functionalized monobromo and dibromo imidazoles [52,53,54]. The only striking feature is that unfunctionalized dibromo imidazoles have significantly shorter C–Br bonds [28]. Other intermolecular structural features of 3a, 3b, and 3d are unexceptional. However, despite several attempts to crystallize compound 3c from different solvents and under different crystallization conditions, only a disordered structure over two positions with a ratio of 70:30 could be obtained.
The molecular structures of the analogous iodo imidazole derivatives (Figure 1, compounds 3, Figure S9, are similar) also exhibit similar structural features. The bond lengths of the two carbon-iodine bonds for compounds 4a, 4b, and 4d range from 2.062(2) Å and 2.080(2) Å. As with the bromo derivatives, the differences in bond lengths between the two C–I bonds in each structure are negligible. The values are within the range of typical CAr–I bond lengths [51]. They also do not differ from functionalized monoiodoimidazoles and protonated diiodoimidazoles. However, the bond lengths are also significantly longer here than in unfunctionalized diiodoimidazoles. The structure of compound 4c differs due to the presence of four molecules in its asymmetric unit, compared to one in the others. Here, the bond lengths are significantly more widely distributed, with very long C-I bond lengths (2.107(1) Å) to short bond lengths corresponding to those of the unfunctionalized diiodoimidazoles (2.023(1) Å).

3.3. Supramolecular Features of the Dihalogenated Derivatives

While other studies on the structures of halogenated imidazole derivatives have primarily identified hydrogen bonds formed by the N–H bond of the imidazoles as the main structural elements, these interactions are not possible in the present compounds due to the protective group. Possible halogen bonds that occur should be identified and discussed on the basis of the distance criterion (smaller than the sum of the van der Waals radii [55] of the atoms involved). The distances 3.40 Å (N···Br), 3.37 Å (O···Br) and 3.70 Å (Br···Br) are used as a basis for the bromo compounds and 3.53 Å (N···I), 3.50 Å (O···I) and 3.96 Å (I···I) for the iodo compounds. In addition, the alignments of the atoms involved with each other are discussed and the formation of a halogen bond is assessed. Selected structural features of the connections are presented and discussed below.
The supramolecular structure of the Boc-protected bromine derivative 3a features short distances between the nitrogen and the bromine atoms (Figure 2). The distance between the two atoms (3.242(1) Å) is shorter than the sum of the van der Waals radii of the atoms involved. Although the alignment of the two molecules is coplanar, the C–N···Br angles differ significantly from 120° (90.63(9)° and 165.2(1)°). For the interaction of an sp2-hybridized nitrogen atom, however, this would be expected for efficient interaction of the free electron pair. This interaction continues in one plane, which is supported by an interaction of the carbonyl oxygen atom of the protective group with a methyl group of the tert-butyl unit, forming a strand of co-directional imidazole units. The second bromine atom is not directly involved in any interaction with a specific atom but interacts with the methyl groups above and below the antiparallel strands. The distance between the antiparallel strands is 3.39 Å, which indicates possible π–π interactions between the only slightly offset, stacked aromatic rings. In addition, the strands interact with neighboring strands via van der Waals interactions between the methyl groups.
The structure of the analogous iodo derivative 4a exhibits similar features to the bromine derivative 3a (Figure 3). In addition to a short distance between the iodine atom and a neighboring nitrogen atom, the compound also features close contacts (3.141(1) Å) between the iodine atom and an adjacent oxygen atom, which is smaller than the sum of the van der Waals radii. The carbon-iodine bond is also oriented towards the oxygen atom (∠C–I···O 156.81(6)°). The halogen bond formed between the nitrogen and the iodine atom is similar to the interaction of the bromine derivative 3a described above, but the bond is now almost directly aligned with the free electron pair of the nitrogen atom (∠C–N-I 124.0(1)° and 125.7(1)°). The distance between the nitrogen atom and the iodine atom is 2.890(2) Å and therefore significantly shorter than the sum of the van der Waals radii and falling within the typical range of corresponding halogen bonds [56]. In addition to these two short contacts, the molecules interact via hydrogen bonds (Figure 3B), with a geometry and bond length that indicates moderately strong hydrogen bonds (hydrogen bond geometry (C5–H5···O2’) d(D–H): 0.95 Å, d(H···A): 2.38 Å, <DHA: 153.4°, d(D···A): 3.257 (2) Å, A: O2‘ −x + 1, −y + 1, −z + 1) [57].
The structure of the PMB-protected derivative 3b exhibits additional structural features compared to 3a (Figure 4). On the one hand, there are short bromine···oxygen contacts (3.087(2) Å), which are significantly shorter than the sum of the van der Waals radii and the C–Br bond is aligned in an almost linear fashion with the oxygen atom (∠C–Br···O 165.6(1)°). The distance is however larger than in strong halogen bonds (2.98 Å [58]). On the other hand, the bromine atom of the other C–Br bond has a short contact to the proton of a C–H bond of a neighboring imidazole (2.92 Å) in an almost linear arrangement. It is only slightly offset and aligned with the imidazole ring of another molecule at a distance of 3.37 Å from the plane of the imidazole ring (Figure 4B). The iodo PMB compound 4b is structurally similar to compound 4a and also has short iodine···nitrogen contacts in which the nitrogen atom is perfectly aligned for interaction with the iodine atom (distance (I···N): 2.818(4) Å, ∠C–I···N: 177.8(2)°). The optimal interaction with the free electron pair of the nitrogen atom is also evident from the orientation of the C–I bond relative to the sp2-hybridized nitrogen atom (120.0(3)° and 134.8(3)°). Similar to the bromo derivative 3a, one C–I bond is also aligned with a neighboring aromatic phenyl ring (Figure 4C), with a distance of 3.59 Å between the iodine atom and the aromatic ring. A similar structural motif was also found for monoiodo imidazole [59,60,61]. Due to the mutual interaction, the two imidazoles stack slightly offset from each other, with a distance of 3.70 Å between the two imidazole ring planes.
The most interesting structure is probably that of the two CBZ-protected compounds 3d and 4d, both of which crystallize in the trigonal space group R-3. In both compounds, the co-crystallized solvent is arranged in channels that run through the crystal (Figure 5). While the unit cell of compound 3d contains three pentane molecules, the unit cell of compound 4d contains three THF molecules. The structure of both molecules is very similar, indicating intrinsic interactions between the common molecular parts. The electron density of the solvent molecules is completely distributed across the channels, so that the molecules were treated as diffuse electron density. In the case of the bromo species 3d, a cavity with a volume of 226 Å3 has formed, and in the case of the iodo species 4d, a cavity with a volume of 252 Å3. Since the two structures differ only slightly, crystallize in the same space group with similar cell parameters, and are similarly packed, these two structures can be described as isotypic.
Both supramolecular structures feature interactions between the halogens and the nitrogen atoms of the imidazole unit with distances (I···N: 2.936(2) Å (4d), Br···N: 2.921(1) Å (3d)) smaller than the sum of the van der Waals radii indicating an attractive interaction (Figure S10A). The orientation of the C–X bond is almost linear with respect to the nitrogen atom (∠C–I···N: 169.48(7)° (4d), ∠C–Br···N: 171.03(4)° (3d)). The imidazole moiety is also perfectly aligned with the halogen atom with respect to the free electron pair of the nitrogen atom (∠C–N···X, I: 124.1(1)° and 116.1(1)° (4d); Br: 112.51(9)° and 121.88(8)° (3d)). Additional molecular contacts are formed by intermolecular interactions between two carbonyl groups of adjacent molecules. The molecules of 4d (Figure S10B) arrange themselves in such a way that the C···O distance is 2.905(2) Å (3d: 2.803(1) Å) and the C = O double bond points at a slight angle to the carbonyl carbon (∠C = O···C, 4d: 133.1(1)°, 3d: 136.08(8)°). In addition, phenyl and imidazole rings are stacked on top of each other (distance, 4d: 3.45 Å, 3d: 3.42 Å) in such way that π-π interactions can be formed due to the planar (angle between the planes, 4d: 5°, 3d: 4°) slightly offset arrangement of the aromatic rings [62].
The Hirshfeld surface analysis (Figure 6) also shows the high similarity of the two structures. The fingerprint plots (generated with the CrystalExplorer 21 [63] software) for the reciprocal interactions for carbon and hydrogen are shown as examples. It is evident that a large part of the interactions takes place via van der Waals interactions (cf. H···H plot). The pattern is strongly reminiscent of the interaction of alkanes with characteristic short interactions (de = di ≈ 1.2 Å). It can also be seen that the disordered solvent was treated as a uniform electron density, resulting in very long interactions via the channel formed. The typical wing-like pattern of the reciprocal C···H interactions indicates the presence of C–H···π interactions, such as those formed in aromatic systems arranged orthogonal to each other [64,65]. The presence of π-π stacking interactions is illustrated by the plot of reciprocal C···C interactions which shows a strong signal reflecting the typical distance of 3.6 Å (de = di ≈ 1.8 Å) [62]. A proportional overview of all selected interactions in the totality of intermolecular contacts shows that the differences between compounds 3d and 4d are also negligible in terms of the individual proportions.

4. Discussion

Comparison of Halogen-Bonding Related Effects

The correlation between the halogen bonds and the various protective groups is determined based on the distances between potential donor–acceptor combinations. The shortest contact distance observed in all crystal structures are used as basis for a comparison (Table 2). Fundamentally, the electron density of the aromatic compound should play a significant role in the strength of the halogen bond [66,67]. Carbamate protective groups should therefore reduce the electron density in the ring whereas benzylic protective groups should not have a strong influence on the electron density. If anything, the PMB protective group should be less electron-withdrawing than the Bn protective group.
For contact distances up to 4.0 Å there are hardly any interactions. Among the presented examples for interactions in bromo compounds, the O···Br interaction (3.6241(4) Å) in 3a is more likely to be a result of the stacking of corresponding molecular parts due to the orientation. The same applies to the Br···Br interaction (3.9404(7) Å) in compound 3d. The bonds in the N···Br interaction (3.458(3) Å) of compound 3b, which are aligned nearly orthogonal to each other, make it difficult for the atoms to interact in an optimal way. The suboptimal alignment of the free electron pair of the nitrogen atom in the N···Br interaction (3.242(1) Å) in compound 3a is also evident in compound 3d, although the distance is significantly shorter (2.921(1) Å). Only the Br···O interactions (3.087(2) Å) of compound 3b indicate a real interaction and are in the range of reported Br···O interactions of various compounds [68,69]. The fact that halogen bonds play a greater role in more polarizable atoms is evident as the number of analogous halogen bonds is greater in the iodo derivatives.
More attractive interactions can be identified in the iodo compounds and are attributed to σ-hole interactions. Only the interaction of the two iodine atoms with a distance of 3.866(1) Å in compound 4c appears to be the result of a pure packing effect, especially since the value is only slightly below the sum of the van der Waals radii [55]. In compound 4a, an attractive I···O interaction can be identified (3.141(1) Å) and is in the range of reported I···O interactions of various compounds [67,70]. I···N interactions that indicate halogen bonds can be determined for all compounds. The observed distances increase in the order PMB < Boc < Cbz < Bn. This is however not expected from the electron-withdrawing properties and may be the result of additional interactions, which are not solely attributable to the halogens.
Although no single effect can be identified that influences halogen bonds, the set of compounds clearly shows the differences between the individual halogens in terms of their potential to form halogen bonds and the effects of these bonds. Strong interactions with the σ-hole of the halogens can only be detected in the iodo compounds, which is also reflected in the orientation of the nitrogen atoms involved. These interactions have a strong structure-determining effect and allow for the formation of molecular networks. The fact that halogen bonds never determine a structure on their own is clearly demonstrated by the example of the isotypic compounds 3d and 4d, which have the same structural arrangement, so that neither the bromo nor the iodo compound exhibits optimal interaction of the nitrogen atoms with the halogen atoms.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cryst15111000/s1. NMR data, synthetic procedures and additional figures.

Author Contributions

Conceptualization, M.H.; Formal analysis, M.L. and M.H.; Investigation, L.M. and M.H.; Data curation, L.M., M.L. and M.H.; Writing—original draft, L.M. and M.H.; Writing—review and editing, L.M., M.L. and M.H.; Visualization, M.H.; Supervision, M.H.; Project administration, M.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by University of Münster. MH would like to express his gratitude to the Fonds der Chemischen Industrie (VCI) for its financial support.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
aq.aqueous
Boctert-butyloxycarbonyl
Bnbenzyl
Cbzbenzyloxycarbonyl
Cmpdcompound
DCMdichloromethane
DMSOdimethyl sulfoxide
EtOAcethyl acetate
nanot available
PMBp-methoxybenzyl
sat.saturated
THFtetrahydrofuran

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Crystals 15 01000 sch001
Scheme 1. Synthesis of the dihalogenated imidazole derivatives and introduction of the protective groups. (a): 1.0 eq. 2,4,5-tribromoimidazole, 2.0 eq. ethylmagnesium bromide in Et2O, THF, 3 h, 50 °C; (b): 1.0 eq. imidazole, 2.0 eq. iodine, 3.0 eq. KI, 3.0 eq. NaOH, water, 18 h, rt; (c): (R = Boc) 1.0 eq. 1 or 2, 1.1 eq. NaH, 1.1 eq. di-tert-butyl dicarbonate, THF, 18 h, rt; (R = PMB) 1.0 eq. 1 or 2, 1.1 eq. NaH, 1.1 eq. 4-methoxybenzyl chloride, THF, 18 h, rt; (R = Bn) 1.0 eq. 1 or 2, 1.1 eq. NaH, 1.1 eq. benzyl bromide, THF, 18 h, rt; (R = Cbz) 1.0 eq. 1 or 2, 1.1 eq. NaH, 1.1 eq. benzyl chloroformate, THF, 18 h, rt.
Scheme 1. Synthesis of the dihalogenated imidazole derivatives and introduction of the protective groups. (a): 1.0 eq. 2,4,5-tribromoimidazole, 2.0 eq. ethylmagnesium bromide in Et2O, THF, 3 h, 50 °C; (b): 1.0 eq. imidazole, 2.0 eq. iodine, 3.0 eq. KI, 3.0 eq. NaOH, water, 18 h, rt; (c): (R = Boc) 1.0 eq. 1 or 2, 1.1 eq. NaH, 1.1 eq. di-tert-butyl dicarbonate, THF, 18 h, rt; (R = PMB) 1.0 eq. 1 or 2, 1.1 eq. NaH, 1.1 eq. 4-methoxybenzyl chloride, THF, 18 h, rt; (R = Bn) 1.0 eq. 1 or 2, 1.1 eq. NaH, 1.1 eq. benzyl bromide, THF, 18 h, rt; (R = Cbz) 1.0 eq. 1 or 2, 1.1 eq. NaH, 1.1 eq. benzyl chloroformate, THF, 18 h, rt.
Crystals 15 01000 sch001
Crystals 15 01000 g001
Figure 1. (A) Molecular structure of compound 4a. (B) Molecular structure of compound 4b. (C) An exemplary molecular structure of compound 4c of the four molecules from the asymmetric unit. (D) Molecular structure of compound 4d (Displacement ellipsoids are shown at the 50% level, hydrogen atoms at an arbitrary radius of 0.135 Å. Color coding: H: ○, C: Crystals 15 01000 i001, N: ●, O: ●, I: ●).
Figure 1. (A) Molecular structure of compound 4a. (B) Molecular structure of compound 4b. (C) An exemplary molecular structure of compound 4c of the four molecules from the asymmetric unit. (D) Molecular structure of compound 4d (Displacement ellipsoids are shown at the 50% level, hydrogen atoms at an arbitrary radius of 0.135 Å. Color coding: H: ○, C: Crystals 15 01000 i001, N: ●, O: ●, I: ●).
Crystals 15 01000 g001
Crystals 15 01000 g002
Figure 2. (A) Partial packing diagram of compound 3a with highlighted Br···N interactions and interactions of a methyl group with an oxygen atom of the Boc protecting group (symmetry code: ‘ 1 + x, y, z; ’’ 2 + x, y, z). (B) Partial packing diagram of compound 3a with close contacts between the methyl groups and a bromine substituent, as well as between the methyl groups of the protective groups (symmetry codes: ’ 1 − x, ½ + y, 1 − z; ’’ ½ − x, ½ + y, ½ + z; ’’’ 1 − x, 1 − y, 1 − z; ’’’’ ½ − x, 1 − y, ½ + z). (Displacement ellipsoids are shown at the 50% level, hydrogen atoms except for the imidazole protons (arbitrary radius of 0.135 Å) are omitted for clarity. Selected distances are shown in orange. Color coding: H: ○, C: Crystals 15 01000 i001, N: ●, O: ●, Br: ●).
Figure 2. (A) Partial packing diagram of compound 3a with highlighted Br···N interactions and interactions of a methyl group with an oxygen atom of the Boc protecting group (symmetry code: ‘ 1 + x, y, z; ’’ 2 + x, y, z). (B) Partial packing diagram of compound 3a with close contacts between the methyl groups and a bromine substituent, as well as between the methyl groups of the protective groups (symmetry codes: ’ 1 − x, ½ + y, 1 − z; ’’ ½ − x, ½ + y, ½ + z; ’’’ 1 − x, 1 − y, 1 − z; ’’’’ ½ − x, 1 − y, ½ + z). (Displacement ellipsoids are shown at the 50% level, hydrogen atoms except for the imidazole protons (arbitrary radius of 0.135 Å) are omitted for clarity. Selected distances are shown in orange. Color coding: H: ○, C: Crystals 15 01000 i001, N: ●, O: ●, Br: ●).
Crystals 15 01000 g002
Crystals 15 01000 g003
Figure 3. (A) Partial packing diagram of compound 4a with highlighted I···N and I···O interactions (symmetry code: ‘ x, 3/2−y, −½ + z; ’’ −½ + x, y, ½−z). (B) Partial packing diagram of compound 4a with highlighted hydrogen bonds between the imidazole proton and the carbonyl oxygen of a protective group (symmetry code: ‘ 1 − x, 1 − y, 1 − z). (Displacement ellipsoids are shown at the 50% level, hydrogen atoms except for the imidazole protons (arbitrary radius of 0.135 Å) are omitted for clarity. Selected distances are shown in orange. Color coding: H: ○, C: Crystals 15 01000 i001, N: ●, O: ●, I: ●).
Figure 3. (A) Partial packing diagram of compound 4a with highlighted I···N and I···O interactions (symmetry code: ‘ x, 3/2−y, −½ + z; ’’ −½ + x, y, ½−z). (B) Partial packing diagram of compound 4a with highlighted hydrogen bonds between the imidazole proton and the carbonyl oxygen of a protective group (symmetry code: ‘ 1 − x, 1 − y, 1 − z). (Displacement ellipsoids are shown at the 50% level, hydrogen atoms except for the imidazole protons (arbitrary radius of 0.135 Å) are omitted for clarity. Selected distances are shown in orange. Color coding: H: ○, C: Crystals 15 01000 i001, N: ●, O: ●, I: ●).
Crystals 15 01000 g003
Crystals 15 01000 g004
Figure 4. (A) Partial packing diagram of compound 3b with highlighted Br···O interaction (symmetry code: ‘ −½ + x, 3/2−y, 1 − z; ’’ ½ + x, 3/2−y, 1 − z). (B) Partial packing diagram of compound 3b with close contacts of an imidazole proton and a bromine substituent, as well as interaction of a bromine substituent with a neighboring aromatic (symmetry codes: ‘ −x, ½ + y, 3/2−z; ’’ 1 − x, ½ + y, 3/2−z). (C) Partial packing diagram of compound 4b with highlighted interaction of the iodine atoms with neighboring aromatic atoms (symmetry code: ‘ 1 − x, 1 − y, 1 − z). (Displacement ellipsoids are shown at the 50% level, hydrogen atoms except for the imidazole protons (arbitrary radius of 0.135 Å) are omitted for clarity. Selected distances are shown in orange. Color coding: H: ○, C: Crystals 15 01000 i001, N: ●, O: ●, Br: ●, I: ●).
Figure 4. (A) Partial packing diagram of compound 3b with highlighted Br···O interaction (symmetry code: ‘ −½ + x, 3/2−y, 1 − z; ’’ ½ + x, 3/2−y, 1 − z). (B) Partial packing diagram of compound 3b with close contacts of an imidazole proton and a bromine substituent, as well as interaction of a bromine substituent with a neighboring aromatic (symmetry codes: ‘ −x, ½ + y, 3/2−z; ’’ 1 − x, ½ + y, 3/2−z). (C) Partial packing diagram of compound 4b with highlighted interaction of the iodine atoms with neighboring aromatic atoms (symmetry code: ‘ 1 − x, 1 − y, 1 − z). (Displacement ellipsoids are shown at the 50% level, hydrogen atoms except for the imidazole protons (arbitrary radius of 0.135 Å) are omitted for clarity. Selected distances are shown in orange. Color coding: H: ○, C: Crystals 15 01000 i001, N: ●, O: ●, Br: ●, I: ●).
Crystals 15 01000 g004
Crystals 15 01000 g005
Figure 5. (A) Packing diagram of compound 3d viewed along the c-axis. (B) Packing diagram of compound 4d viewed along the c-axis. (The molecules are shown in stick model. The channels formed by the disordered solvent are outlined in yellow. Color coding: H: ○, C: ●, N: ●, O: ●, Br: ●, I: ●).
Figure 5. (A) Packing diagram of compound 3d viewed along the c-axis. (B) Packing diagram of compound 4d viewed along the c-axis. (The molecules are shown in stick model. The channels formed by the disordered solvent are outlined in yellow. Color coding: H: ○, C: ●, N: ●, O: ●, Br: ●, I: ●).
Crystals 15 01000 g005
Crystals 15 01000 g006
Figure 6. Fingerprint plot of the reciprocal H···H interactions of compound 4d (A) and compound 3d (B), fingerprint plot of the reciprocal C···H interactions of compound 4d (C) and compound 3d (D), fingerprint plot of the reciprocal C···C interactions of compound 4d (E) and compound 3d (F), and overview of the proportions (rounded to integers) of selected interactions in the total intermolecular interactions for compounds 3d (top) and 4d (bottom) (G) (The proportion of X···O contacts (purple) is <0.5%).
Figure 6. Fingerprint plot of the reciprocal H···H interactions of compound 4d (A) and compound 3d (B), fingerprint plot of the reciprocal C···H interactions of compound 4d (C) and compound 3d (D), fingerprint plot of the reciprocal C···C interactions of compound 4d (E) and compound 3d (F), and overview of the proportions (rounded to integers) of selected interactions in the total intermolecular interactions for compounds 3d (top) and 4d (bottom) (G) (The proportion of X···O contacts (purple) is <0.5%).
Crystals 15 01000 g006
Table 1. Crystallographic data of compounds 3a–4d.
Table 1. Crystallographic data of compounds 3a–4d.
Cmpd 3aCmpd 3bCmpd 3cCmpd 3dCmpd 4aCmpd 4bCmpd 4cCmpd 4d
CCDC24993262499330249933124993272499329249933424993282499335
Empirical formulaC8H10Br2N2O2C11H10Br2N2OC10H8Br2N2C11H8Br2N2O2C8H10I2N2O2C11H10I2N2OC10H8I2N2C11H8I2N2O2
Formula weight326.00346.03316.00360.01419.98440.01409.98453.99
Crystal systemOrthorhombicOrthorhombicOrthorhombicTrigonalOrthorhombicOrthorhombicMonoclinicTrigonal
Space groupPnmaP212121P212121R-3PbcaPbcaP21R-3
a, Å7.2871(2)4.82760(10)6.64120(10)28.4883(3)13.8801(2)14.1428(8)11.5334(17)29.2203(6)
b, Å6.7709(2)10.0063(3)12.3670(3)28.4883(3)11.0928(2)8.4991(5)14.1707(19)29.2203(6)
c, Å21.5274(5)24.5484(6)12.6667(3)8.38630(10)15.9440(2)21.0899(12)14.215(3)8.5898(3)
α, deg.9090909090909090
β, deg.90909090909092.286(6)90
γ, deg.909090120909090120
V, Å31062.17(5)1185.85(5)1040.34(4)5894.32(14)2454.88(6)2535.0(3)2321.5(7)6351.6(3)
Z4441888818
ρcalc, g cm−32.0391.9382.0181.8262.2732.3062.3462.136
μ(MoKα), mm−17.6086.8157.7516.1805.1044.9435.3834.448
Crystal size, mm30.19 × 0.17 × 0.06 0.19 × 0.13 × 0.080.22 × 0.17 × 0.070.29 × 0.17 × 0.120.19 × 0.18 × 0.130.21 × 0.07 × 0.050.13 × 0.07 × 0.040.56 × 0.05 × 0.05
Temperature (K)100(2)100(2)100(2)100(2)100(2)123(2)145(2)145(2)
θ range, deg2.951–30.1172.198–30.0442.302–30.0902.477–30.1052.555–34.6692.409–27.4881.767–30.0482.504–27.500
hkl range, deg−10:10, −9:9, −30:30−6:6, −14:14, −34:34−9:9, −17:17, −17:17−40:40, −40:40, −11:11−22:22, −17:17, −25:25−18:18, −11:11, −27:27−16:15, −19:19, −20:19−37:37, −37:37, −11:11
Total/unique data/Rint18227/1687/0.024819884/3466/0.046318798/3053/0.030035924/3854/0.0298141626/4969/0.042322199/2906/0.03427011/7011/0.020130218/3229/0.0276
Data/restraints/parameters1687/0/843466/0/1463053/475/2003854/0/1544969/0/1302906/0/1467011/1/5053229/0/154
R1/wR2 [I > 2σ(I)]0.0123/0.03110.0237/0.05560.0134/0.03150.0150/0.03590.0187/0.04860.0312/0.08540.0434/0.10650.0129/0.0314
R1/wR2 [all data]0.0129/0.03140.0261/0.05640.0140/0.03170.0166/0.03630.0240/0.05060.0339/0.08680.0446/0.10730.0135/0.0316
Flack parameterna0.004(6)0.003(5)nanana0.12(5)na
S1.1221.0311.0471.0741.0961.2491.1331.100
Min./max. res. dens., eÅ−30.464/−0.2990.945/−0.4230.211/−0.2310.463/−0.3850.596/−1.3511.070/−1.0462.498/−1.2330.561/−0.568
Table 2. Overview of the shortest contacts found in the respective compounds.
Table 2. Overview of the shortest contacts found in the respective compounds.
CompoundN···X
[Å]		O···X
[Å]		X···X
[Å]
3a3.242(1)3.6241(4)nd a
4a2.890(2)3.141(1)nd a
3b3.458(3)3.087(2)nd a
4b2.818(4)nd and a
3cnd ana bnd a
4c2.96(1)na b3.866(1)
3d2.921(1)nd a3.9404(7)
4d2.936(1)nd and a
a no corresponding contact found up to a distance of 4.0 Å. b the compound does not contain any oxygen atoms.
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Mensing, L.; Layh, M.; Hebenbrock, M. Halogens On, H-Bonds Off—Insights into Structure Control of Dihalogenated Imidazole Derivatives. Crystals 2025, 15, 1000. https://doi.org/10.3390/cryst15111000

AMA Style

Mensing L, Layh M, Hebenbrock M. Halogens On, H-Bonds Off—Insights into Structure Control of Dihalogenated Imidazole Derivatives. Crystals. 2025; 15(11):1000. https://doi.org/10.3390/cryst15111000

Chicago/Turabian Style

Mensing, Luca, Marcus Layh, and Marian Hebenbrock. 2025. "Halogens On, H-Bonds Off—Insights into Structure Control of Dihalogenated Imidazole Derivatives" Crystals 15, no. 11: 1000. https://doi.org/10.3390/cryst15111000

APA Style

Mensing, L., Layh, M., & Hebenbrock, M. (2025). Halogens On, H-Bonds Off—Insights into Structure Control of Dihalogenated Imidazole Derivatives. Crystals, 15(11), 1000. https://doi.org/10.3390/cryst15111000

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