Crystal Structure and Hirshfeld Surface Analysis of Hexakis(acetoxymethyl)benzene

Abstract

Representatives of the hexasubstituted benzene derivatives, also known as hexa-hosts, have been the subject of extensive studies in solution and in the solid state, including the investigation of their ability to act as artificial receptors for various substrates, as well as detailed conformational analyses. In this paper, we describe the X-ray crystal structure of hexakis(acetoxymethyl)benzene (1), a member of the above class of compounds. The molecules of 1 adopt an aaabbb conformation, in which three side-arms point to the same face of the central benzene ring, while the other three point in the opposite direction. As the compound lacks strong hydrogen bond donors, C–H···O hydrogen bonds connect the molecules to a three-dimensional supramolecular network. According to the Hirshfeld surface analysis, the H∙∙∙O/O∙∙∙H interactions represent the major contribution of the molecular Hirshfeld surface.

1. Introduction

Hexasubstituted benzene derivatives, in their function as hexa-hosts [1,2,3], were shown to have interesting binding properties towards various substrates [4,5,6,7,8,9,10]. The potential of these compounds to act as artificial receptors was evaluated both in the solution and in the solid state. Analyses of the conformations of various hexasubstituted benzenes [6,7,8,9,10,11,12,13,14,15] revealed that the ababab conformation, with an alternating arrangement of the side-arms above (a) and below (b) the plane of the benzene ring, is frequently observed in crystal structures. In addition, such conformations as aaabbb, aaabab, and even aaaaaa have also been observed. In the case of hexakis(acetoxymethyl)benzene (1; see Figure 1), the crystal structure of which is described in this paper, the molecules adopt an aaabbb conformation.

Since compound 1 has no strong hydrogen bond donors, the crystal is stabilized by numerous C–H···O hydrogen bonds. It should be noted that the C–H···O interaction has long been the subject of controversial discussions. Intensive studies revealed its hydrogen bonding character and its important role in crystal packing [16,17,18,19,20,21,22] and in various recognition processes in artificial and biological systems. There are many examples of the involvement of C–H···O hydrogen bonds in such processes [23,24,25,26,27], ranging from the molecular recognition of carbohydrates by artificial receptors [25] to protein–ligand interactions [26] and participation in the interactions of adjacent strands of parallel and antiparallel β-sheets in proteins [27].

2. Results and Discussion

2.1. Synthesis

Hexakis(acetoxymethyl)benzene (1) was synthesized according to Backer’s procedure [28], in which hexakis(bromomethyl)benzene (4) is reacted with potassium acetate in acetic anhydride. The synthesis of compound 4 started with the bromomethylation of mesitylene (2) to give 1,3,5-tris(bromomethyl)-2,4,6-trimethylbenzene (3), followed by the bromination of the methyl groups of 3 [29]. All reaction steps are summarized in Scheme 1.

The formation of hexakis(acetoxymethyl)benzene (1) has also been described for the reaction of diisopropylacetylene and 1,4-diacetoxy-2-butyne in the presence of Hg[Co(CO)₄]₂, yielding a mixture of products, including compound 1 (formed by the trimerization of 1,4-diacetoxy-2-butyne) [30,31].

2.2. Structure Elucidation

The crystal structure of the hexapodal compound 1, the molecular structure of which is shown in Figure 2a, was solved in the monoclinic space group P2₁/c (Table S1 in Supporting Information). The asymmetric unit of the elementary cell contains one complete molecule and one half of the molecule, i.e., one of the molecules is found in a general position, whereas the second one is located on a crystallographic symmetry center. Nevertheless, both molecules adopt similar geometries with a three-up/three-down orientation (aaabbb pattern) of the substituents around the perimeter of the aromatic ring. The torsion angles of the C_aryl–C–O–C sequences in molecule A range from 130.6(1) to 179.7(1)°, while those of molecule B are 120.1(1)–175.7(1)° (Table S2 in Supporting Information). In molecule A, two of the substituents exist in an elongated conformation, while the other four show a high degree of twisting. In the case of the inversion-symmetric molecule (B), four of the branches adopt a fully extended conformation, while the remaining ones are considerably twisted. These conformational differences are also obvious from the superposition of the independent molecules displayed in Figure 2b. As can be seen from Table S3 (Supporting Information), the crystal is stabilized by a variety of intermolecular C–H···O hydrogen bonds [16] [d(H···O) 2.41–2.57 Å, ∢(C–H···O) 119.7–171.2°]. With the exception of O10, all carbonyl oxygen atoms are involved in molecular association, either by acting as single or bifurcated acceptors. A packing excerpt showing the mode of intermolecular interactions is depicted in Figure 3a. The scheme shown in Figure 3b represents a part of the C–H···O bonds occurring in the crystal structure, in which the methylene hydrogen atoms are primarily involved due to packing effects. However, it should be noted that the more acidic methyl hydrogen atoms also contribute, but to a lesser extent, to the formation of the hydrogen bonding pattern.

2.3. Hirshfeld Surface Analysis

To visualize and quantify the intermolecular contacts present in the crystal structure, the CrystalExplorer 17.5 software [32] was used to generate the Hirshfeld surfaces [33] and the associated two-dimensional fingerprint plots [34] of the independent molecules. At this point, it should be noted that the standard C–H bond lengths given by SHELXL are biased by 0.1–0.15 Å and are replaced here by a more realistic value of 1.083 Å.

In the Hirshfeld surface plotted over d_norm, the blue-, white- and red-colored regions represent intermolecular contacts with distances longer than, equal to, or shorter than the sum of the van der Waals radii [35] of the atoms. The bright red spots on the d_norm surfaces shown in Figure 4 arise from short H∙∙∙O contacts, resulting from C–H···O bonds. They are visible in the fingerprint plots of the molecules as a pair of symmetrical short spikes with a minimum value of d_e + d_i ≈ 2.35 Å (see Figure S1, Supporting Information). The decomposition of the 2D fingerprint plots reveals that H∙∙∙O/O∙∙∙H interactions represent the main contribution (49.2 and 48.3%) of the molecular Hirshfeld surface (see Figure 5). H∙∙∙H contacts, which correspond to van der Waals interactions, appear as the next largest region, making up 39.6 and 41.4% of the Hirshfeld surfaces. They can be recognized in the fingerprint plots as a region of widely scattered points with a closest distance of d_e + d_i ≈ 2.24 Å. The H∙∙∙C/C∙∙∙H interactions cover a range of 10.2 and 9.1%.

3. Materials and Methods

3.1. Synthesis

Hexakis(bromomethyl)benzene (4; 2.00 g, 3.15 mmol) and potassium acetate (3.13 g, 31.89 mmol) were suspended in acetic anhydride (25 mL) and stirred under reflux for 4 h. The reaction mixture was poured into water (350 mL), forming a brown precipitate. After stirring at room temperature for 2 h, the solid was filtered off and washed with water. Recrystallization of the crude product from ethanol yielded colorless crystals of 1 (1.16 g, 72%). M.p. 159–160 °C. TLC: R_f = 0.21 [SiO₂; eluent: toluene/ethyl acetate 3:1 v/v]. ¹H NMR (500 MHz, CDCl₃, ppm): δ = 2.06 (s, 18 H, CH₃), 5.38 (s, 12 H, CH₂). ¹³C NMR (125 MHz, CDCl₃, ppm): δ = 20.9 (CH₃), 60.0 (CH₂), 137.6 (C_Ar), 170.3 (C=O). LC-MS (ESI) m/z calcd. for C₂₄H₃₀O₁₂Na: 533.16 [M + Na]⁺, found 533.13. Anal. calc. for C₂₄H₃₀O₁₂: C, 56.47; H, 5.92%; found: C, 56.41; H, 5.82%.

The synthesis of the starting material, hexakis(bromomethyl)benzene (4), was carried out according to the literature [29].

3.2. Crystallization and X-Ray Structure Determination

Crystals of the compound were grown by the slow evaporation of toluene from a corresponding solution at room temperature. The crystal suitable for the X-ray diffraction experiment was selected under the microscope and mounted on a glass fiber. The intensity data were collected on a Bruker APEX II diffractometer [36] with MoK_α radiation (λ = 0.71073 Å) using ω and φ scans. Data integration and reduction were processed with SAINT [36]. Absorption correction was carried out by using SADABS [37]. Preliminary structure models were derived by the application of direct methods [38] and refined by full-matrix least-squares calculation based on F² for all reflections [39]. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included in the models in calculated positions and were refined as constrained to bonding atoms. The crystallographic data are given below and in the Supplementary Materials (Table S1).

Crystal data for C₂₄H₃₀O₁₂ (M = 510.48 g/mol): monoclinic; space group P2₁/c (no. 14); a = 16.6400(7) Å; b = 8.1525(3) Å; c = 27.577(1) Å; β = 101.902(1)°; V = 3660.6(2) ų; Z = 6; T = 100(2) K; µ(MoK_α) = 0.112 mm⁻¹; D_calc = 1.389 g/cm³; 8914 reflections measured (1.5° ≤ θ ≤ 28.1°); 8202 unique reflections (R_int = 0.0184), which were used in all calculations. The final R₁ was 0.0379 (I > 2σ(I)) and wR₂ was 0.1029 (all data), with GOF = 1.019.

4. Conclusions

This paper describes the X-ray crystal structure of hexakis(acetoxymethyl)benzene (1), a representative of the class of hexasubstituted benzenes (some of them also known as hexa-hosts). The crystals of 1 obtained from toluene have the monoclinic space group P2₁/c and the molecules adopt a conformation in which the side-arms are arranged in aaabbb fashion around the central benzene ring. A large number of intermolecular C–H···O hydrogen bonds are responsible for the stabilization of the crystal structure. The carbonyl oxygen atoms of 1 are involved in these hydrogen bonding interactions, either by acting as single or bifurcated acceptors. As revealed by Hirshfeld surface analysis, the H∙∙∙O/O∙∙∙H interactions represent the largest contribution (49.2 and 48.3%) of the molecular Hirshfeld surface.