Two Cocrystals of Phenazine with Different Phenylboronic Acids

Abstract

Boronic acids are an important class of molecules diversely used in organic synthesis, catalysis, medicinal chemistry, and for the design of functional materials. Particularly, aryl boronic acids in the solid state are known to exhibit pharmaceutical and photoluminescent properties for antimicrobial, sensing, and drug delivery applications. Furthermore, the phenazine molecule is known for its diverse pharmacological properties, including antibiotic activity. In the case of molecular crystalline solids, it is well established that understanding noncovalent interactions remains key to designing or engineering their functional properties. While both aryl boronic acids and phenazine molecules individually represent an important class of compounds, their co-assembly in the crystalline state is of interest within the context of supramolecular chemistry and crystal engineering. Herein, we report the supramolecular features of two newly synthesized cocrystals, which are composed of para-F/CF₃-substituted phenylboronic acids, respectively, and phenazine, as demonstrated by structure analysis by single-crystal X-ray diffraction.

1. Introduction

The structural features of aryl boronic acid derivatives always remain attractive to the chemical research community owing to their direct relevance in organic synthesis, catalysis, pharmaceutical development, topochemical reactions, sensing, and photoluminescence [1,2,3,4,5,6]. For instance, due to the empty p-orbital of the boron atom, aryl boronic acids can effectively interact with accepting electron pairs from nucleophilic residues of biomolecules [2,3]. Simultaneously, they can make reversible covalent bonds through two -OH groups with 1,2- or 1,3-diols such as sugars and glycoproteins, forming boronate esters under physiological conditions. [3] Although the self-association of organoboronic acids in the solid-state via hydrogen bonds is known, their structural diversification through cocrystallization with suitable coformer molecules has been less explored [7,8]. These investigations also show that the conformationally flexible -B(OH)₂ moiety in crystals can adopt various alignments depending on the relative orientations of the two -OH groups, such as syn-syn, syn-anti, and anti-anti.

The CSD database (version 5.46, November 2024) [9] and literature survey indicates no cocrystals have been reported for either (4-fluorophenyl)boronic acid (FBA) or (4-(trifluoromethyl)phenyl)boronic acid (TFBA) with the phenazine (PZ) molecule. However, the database reports two cocrystals of FBA, one with pyridin-1-ium-4-carboxylate (CSD refcode PUNZEG) [10] and another with a 1,8-naphthyridine ligand (CSD refcode TAZKUD) [7]. Moreover, the database also shows the presence of one cocrystal of TFBA with a boroxine-(N,N-dimethylmethanamine)-antimony complex (CSD refcode YUGSEA) [11]. In addition, a few cocrystals and their hydrates of (4-chloro/bromo/iodophenyl)boronic acids with PZ molecules have also been previously determined (CSD refcodes RORNOD, RORNUJ, RORPAR, and RORPEV) [8]. These cocrystals containing heavier halogen atoms (Cl, Br, I) were designed to evaluate the role of more polarizable halogen atoms in exhibiting halogen bonding, particularly in the presence of the self-association of phenylboronic acids via hydrogen bonding. As part of our ongoing project on designing various organoboron-based crystalline materials via noncovalent procedures [5,12], the focus of our work is to understand the supramolecular features of two newly synthesized cocrystals of the less polarizable fluorine-containing FBA (1) and TFBA (2) with the same PZ molecule, as provided in Figure 1 (see also Supplementary Materials).

2. Results and Discussion

Both cocrystals were synthesized via mechanochemical grinding (for 30 min) of the respective phenylboronic acid and phenazine, in a 2:1 molar ratio, using a mortar and pestle. The ground powders in both cases (100 mg in each) were recrystallized by slow evaporation from a toluene–acetone solution, at 20 °C, to obtain single crystals, suitable for single-crystal X-ray structure determination. In both cases, quantitative yields of cocrystals were obtained after recrystallization. The single crystals of cocrystals 1 and 2 appeared as elongated needles and relatively thicker needle shapes, respectively.

2.1. Crystal Structure Determination of Cocrystals 1 and 2

Detailed X-ray crystallographic data for cocrystals 1 and 2 are provided in

Table 1. Crystallographic data and refinement parameters. Values in parentheses () indicate the estimated standard deviation (ESD) for the corresponding parameter.

Identification Code	1	2
Empirical formula	C24H20B2F2N2O4	C26H20B2F6N2O4
CCDC no.	2455586	2455587
Formula weight/gmol−1	460.04	560.06
Temperature/K	293(2)	293(2)
Crystal system	monoclinic	triclinic
Space group	P21/n	P-1
a/Å	5.2892(3)	4.7792(3)
b/Å	18.7736(11)	11.4844(5)
c/Å	11.5458(6)	12.5192(7)
α/°	90	94.233(4)
β/°	102.544(6)	99.337(5)
γ/°	90	101.535(5)
Volume/Å3	1119.10(11)	660.31(7)
Z	2	1
ρcalcg/cm3	1.365	1.408
μ/mm−1	0.860	1.058
F(000)	476.0	286.0
Crystal size/mm3	0.42 × 0.07 × 0.03	0.19 × 0.09 × 0.07
Radiation	Cu Kα (λ = 1.54184 Å)	Cu Kα (λ = 1.54184 Å)
2Θ range for data collection/°	9.152 to 147.804	7.2 to 147.848
Index ranges	−6 ≤ h ≤ 6, −22 ≤ k ≤ 23, −14 ≤ l ≤ 14	−5 ≤ h ≤ 5, −14 ≤ k ≤ 14, −15 ≤ l ≤ 14
Reflections collected	10,272	12,224
Independent reflections	2231 [Rint = 0.0592, Rsigma = 0.0406]	2621 [Rint = 0.0800, Rsigma = 0.0449]
Data/restraints/parameters	2231/0/160	2621/141/224
Goodness-of-fit on F2	1.056	1.063
Final R indexes [I ≥ 2σ(I)]	R1 = 0.0579, wR2 = 0.1506	R1 = 0.0527, wR2 = 0.1331
Final R indexes [all data]	R1 = 0.0898, wR2 = 0.1815	R1 = 0.0806, wR2 = 0.1628
Largest diff. peak/hole/eÅ−3	0.14/−0.24	0.29/−0.18

(see also Supplementary Materials).

2.2. Supramolecular Features of Cocrystals 1 and 2

Cocrystal 1 crystallizes (as thin needles) in the monoclinic space group P2₁/n, with the asymmetric unit consisting of one FBA molecule and half a molecule of the PZ coformer (Figure 2a). A center of inversion generates the second half of the PZ molecule in the crystal structure. The FBA and PZ molecules are primarily connected via a strong O-H∙∙∙N hydrogen bond (O-H∙∙∙N distance and angle of 1.95(5) Å, and 167°, respectively). The -B(OH)₂ moiety of FBA in the crystal adopts a syn-anti conformation based on the relative orientation of two -O-H groups [8]. The packing arrangement of molecules in cocrystal 1 in the bc-crystallographic plane shows that FBA molecules form discrete dimers by two O-H∙∙∙O hydrogen bonds (each one of 1.91(5) Å, 170°) over an inversion center (dimeric motifs shaded in blue color, Figure 2b). Such FBA dimers are further linked with adjacent PZ molecules through the above-mentioned O-H∙∙∙N hydrogen bonds, assisted by weak C-H∙∙∙O hydrogen bonds (2.412(2) Å, 136°), linking the molecules together in the [001] direction (shaded in orange color, Figure 2b). Weak F∙∙∙π (3.316(3) Å) and displaced π∙∙∙π stacking (3.454(4) Å) interactions also assemble the FBA and PZ molecules (shaded in gray color, Figure 2b). This packing arrangement is further stabilized by multiple π-stacking interactions (segregated type) of the FBA and PZ molecules along the crystallographic a-direction (Figure 2c), forming the 3D supramolecular structure of cocrystal 1. Within these molecular π-stackings, the centroid (Cg)–centroid (Cg) distances remain the same (5.289(3) Å) for both the FBA and PZ molecules.

In contrast to cocrystal 1, the molecules of cocrystal 2 crystallize (as a long needle) in the triclinic space group P-1. Interestingly, the asymmetric unit of cocrystal 2 also includes one molecule of TFBA and half a molecule of PZ, assembled via a strong O-H∙∙∙N hydrogen bonding (1.98(5) Å, 165°), analogous to cocrystal 1 (Figure 2d). Again, a center of inversion generates the second half of the PZ molecule. In cocrystal 2, the -B(OH)₂ moiety of TFBA also exhibits syn-anti conformation. Owing to a comparable appearance of the asymmetric unit and molecular structural similarity of both cocrystals, the intermolecular interactions present in cocrystal 2 are anticipated to be similar to the ones observed for cocrystal 1. However, the overall molecular packing arrangement in cocrystal 2 seems to be different compared to cocrystal 1. This might be on account of the unique electronic environment around the phenyl rings (FBA vs. TFBA) in the presence of electron-withdrawing -F and -CF₃ substituents. In cocrystal 2, in the bc-crystallographic plane, the formation of discrete dimeric motifs of highly directional O-H∙∙∙O hydrogen bonds (1.87(6) Å, 179°) between the TFBA molecules is prevalent in the crystal packing (shaded in blue color, Figure 2e). These TFBA molecules are further noncovalently co-assembled with the PZ molecules, directed by weak C-H∙∙∙O (1.551(6) Å, 127 °), various C-H∙∙∙π, and strong O-H∙∙∙N bonding (shaded in orange color, Figure 2e). Multiple weak F∙∙∙π (ring-centroid) interactions (3.831(11) Å) also contribute toward the noncovalent association of the TFBA and PZ molecules. Finally, the overall crystal packing of cocrystal 2 is also stabilized via the segregated π-stacking interactions of the TFBA and PZ molecules, extending along the crystallographic a-direction (Figure 2f). The Cg∙∙∙Cg distances (4.779(3) Å) between the molecules in the π-stacked columns in cocrystal 2 remain shorter than the molecular stacking in cocrystal 1. Another unique structural feature of the two cocrystals is that the stacking pattern in cocrystal 2 generates a linear trajectory consisting of both the boronic acid and PZ molecules, whereas the molecular stacking mode in cocrystal 1 produces a wavy trajectory of molecules (as shaded in Figure 2c,f). Furthermore, the primary local supramolecular features, such as dimeric O-H∙∙∙O motifs, and O-H∙∙∙N and C-H∙∙∙O interactions, observed in both cocrystals (1 and 2), are also present in previously reported cocrystals of para-Cl/Br/I-substituted phenylboronic acids with PZ molecules [8]. In contrast, the presence of more polarizable heavier halogens originates additional directional halogen bonds (Cl/Br/I∙∙∙π) in the crystal packing of those cocrystals—which largely influences their supramolecular structures and differentiates them from the overall structural patterns found in cocrystals 1 and 2.

3. Materials and Methods

All the phenylboronic acids and phenazine were purchased from Sigma-Aldrich (Merck Life Science BV, Belgium, EU). These materials were directly used for cocrystallization without any further purification.

Single-crystal X-ray diffraction data were collected at 20 °C using a Rigaku Oxford Diffraction Supernova dual source diffractometer, using ω scans and Cu Kα radiation (λ = 1.54184 Å), and equipped with an Atlas CCD detector. Data integration was executed with the CrysAlisPro software [13]. Both structures were solved by Intrinsic Phasing, implemented in the ShelXT 2014/5 program [14]. The structures were refined by the full-matrix least-squares method within the Olex2 1.5 interface [15] using the ShelXL 2019/3 program [16]. All non-hydrogen atoms were refined anisotropically. Non-acidic hydrogen atoms (C-Hs) were geometrically placed and refined using a riding model. Acidic hydrogen atoms (O-Hs) were unambiguously identified from a Fourier difference electron density map and refined with a fixed U_iso of 1.5 times U_(eq) of the parent atoms. In each cocrystal, the asymmetric unit contains one full molecule of the corresponding phenylboronic acid and one half of a phenazine molecule. In case of cocrystal 2, the trifluoromethyl group was treated as two-component rotational disorder using geometric (SADI and FLAT) and displacement (SIMU) restraints.

4. Conclusions

Two new cocrystals of para-F/CF₃-substituted phenylboronic acids with the same phenazine coformer molecule are reported. Their crystal structures were determined through single-crystal X-ray diffraction. Both cocrystals are primarily stabilized by O-H∙∙∙O and O-H∙∙∙N hydrogen bonding. In addition, C-H∙∙∙O, F∙∙∙π, and π-stacking interactions contribute to their overall crystal packing. However, the overall structure of the two cocrystals appeared to differ in terms of their molecular packing mode.