Conformational polymorphism of 3-(azido­meth­yl)benzoic acid

Three conformational polymorphs of 3-(azido­meth­yl)benzoic acid are reported. All three structures maintain similar carb­oxy­lic acid dimers and π–π stacking. Crystal structure analysis and com­putational evaluations highlight the azido­methyl group as a source of conformational polymorphism, thus having potential implications in the design of solid-state reactions.

Abstract

Three conformational polymorphs of 3-(azido­meth­yl)benzoic acid, C₈H₇N₃O₂, are reported. All three structures maintain similar carb­oxy­lic acid dimers and π–π stacking. Crystal structure analysis and com­putational evaluations highlight the azido­methyl group as a source of conformational polymorphism, thus having potential implications in the design of solid-state reactions.

Introduction

Polymorphism is a long-standing focus of crystal engineering with wide-ranging implications towards functional solids (Price, 2013 ▸; Chung & Diao, 2016 ▸; Aitipamula et al., 2014 ▸). Different crystal forms exhibit distinct physical properties, such as solubility, stability, melting point, and color, yet maintain the same chemical com­position and connectivity (Desiraju, 2008 ▸; Brog et al., 2013 ▸). This is especially relevant in the pharmaceutical industry where product control is critical (Lee et al., 2011 ▸; Singhal & Curatolo, 2004 ▸). Polymorphism can be considered common, as highlighted by a >50% occurrence within a pharmaceutical database (Cruz-Cabeza et al., 2015 ▸). More recently it was reported that 37–66% of com­pounds exhibit polymorphism (Cruz-Cabeza et al., 2020 ▸). These facts, among various others, continue to drive fundamental and functional polymorphism studies.

Consequently, this has driven further categorization of polymorphs; conformational polymorphs are a subtype of polymorphism whereby the unique crystal structures are a result of different conformers of a mol­ecule (Cruz-Cabeza & Bernstein, 2014 ▸; Nangia, 2008 ▸). In fact, one of the most famous polymorphic mol­ecules studied, colloquially known as ROY, has structures that are conformational polymorphs (Yu, 2010 ▸; Thomas & Spackman, 2018 ▸; Cruz-Cabeza & Bernstein, 2014 ▸). A discussion of conformational polymorphs requires specific definitions and here we will use the classification detailed by Cruz-Cabexa & Bernstein (2014 ▸): Any change in a given single rotatable bond of a mol­ecule always affords a new conformation, but it affords a new conformer only if the conformational change goes through a potential energy barrier into a different potential energy well. As such, the transition from one conformational polymorph to another necessitates crossing a conformational energy barrier. If no energy barrier exists between solid-state conformations identified, they are simply related by adjustment and will be considered here as simply a polymorph.

Conformational changes maintain an energetic magnitude that falls within the range of inter­molecular inter­actions (Bernstein, 2007 ▸). Thus, torsion angles (i.e. rotations about bonds) are a common mol­ecular feature altered in polymorphic crystal structures. In fact, 36% of polymorphic mol­ecules exhibit conformational polymorphism (Cruz-Cabeza & Bernstein, 2014 ▸). A theoretical analysis of these conformational polymorphs showed that 80% of the conformational changes maintained an (gas phase) energy barrier of 2.4 kcal mol⁻¹. The identification and evaluation of functional groups that drive conformational polymorphism will continue to provide valuable fundamental crystal engineering knowledge.

One functional group that is surprisingly understudied in the solid state is the azide group; there are <1800 organic azides reported in the Cambridge Structural Database (Groom et al., 2016 ▸). The conformational flexibility of the azide group has been noted within the context of crystal engineering solid-state reactions (Madhusudhanan et al., 2021 ▸). Identifying packing tendencies of the azide group is critical to rationally designing azide-containing solids (Bhandary et al., 2022 ▸). Only recently have intra­molecular inter­actions between the azide and various Lewis bases been considered (Bursch et al., 2021 ▸). Here we contribute to the fundamental knowledge of organic azides in the solid state by reporting three conformational polymorphs of 3-(azido­meth­yl)benzoic acid (see Scheme 1). Our single-crystal X-ray diffraction studies motivated theoretical conformational analysis and crystal packing evaluations.

Experimental

Materials and crystallization

3-(Azido­meth­yl)benzoic acid was purchased from Combi-Blocks and used without further purification. Crystals of polymorphs A, B, and C were obtained by slow evaporation of 3-(azido­meth­yl)benzoic acid solutions of tert-butyl methyl ether, chloro­form, and methanol, respectively.

Single-crystal X-ray diffraction

Crystal data, data collection, and structure refinement details are summarized in Table 1 ▸. The H atoms of the investigated structures were located from difference Fourier maps. H atoms bound to O atoms were placed and refined. H atoms bound to C atoms were placed in geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of the placed H atoms were fixed at 1.2 times the U _eq values of the atoms to which they were linked. For polymorph B, the TWINROTMAT routine within PLATON (Spek, 2020 ▸) indicated twinning. The twin law was found to be ( 00, 0 0, 101). The BASF value refined to 0.5471 (16).

Table 1. Experimental details.

For all three structures: C₈H₇N₃O₂, M _r = 177.17. Experiments were carried out at 100 K with Mo Kα radiation using a Bruker D8 VENTURE DUO diffractometer. Absorption was corrected for by multi-scan methods (SADABS; Krause et al., 2015 ▸). H atoms were treated by a mixture of independent and constrained refinements.

	A	B	C
Crystal data
Crystal system, space group	Monoclinic, P21/c	Monoclinic, P21/n	Triclinic, P
a, b, c (Å)	7.6327 (5), 9.5561 (6), 11.2899 (7)	3.7712 (3), 6.1229 (5), 34.868 (3)	3.8029 (2), 9.9199 (5), 11.5709 (6)
α, β, γ (°)	90, 104.095 (3), 90	90, 93.099 (3), 90	66.828 (2), 82.168 (3), 82.245 (2)
V (Å3)	798.68 (9)	803.96 (11)	395.96 (4)
Z	4	4	2
μ (mm−1)	0.11	0.11	0.11
Crystal size (mm)	0.16 × 0.12 × 0.04	0.28 × 0.06 × 0.02	0.31 × 0.12 × 0.01
Data collection
T min, T max	0.675, 0.746	0.682, 0.745	0.692, 0.745
No. of measured, independent and observed [I > 2σ(I)] reflections	21950, 1988, 1496	10613, 1656, 1411	10604, 1405, 1196
R int	0.059	0.036	0.039
(sin θ/λ)max (Å−1)	0.669	0.625	0.596
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.041, 0.101, 1.03	0.043, 0.085, 1.13	0.036, 0.096, 1.05
No. of reflections	1988	1656	1405
No. of parameters	122	123	122
Δρmax, Δρmin (e Å−3)	0.32, −0.23	0.25, −0.23	0.28, −0.22

Computer programs: APEX4 (Bruker, 2021 ▸), SAINT (Bruker, 2016 ▸), SHELXT2018 (Sheldrick, 2015a ▸), SHELXS (Sheldrick, 2008 ▸), SHELXL2018 (Sheldrick, 2015b ▸), and OLEX2 (Dolomanov et al., 2009 ▸).

Computational methods

Conformational and relative energy analysis

Gas-phase density functional theory (DFT) com­putations were carried out at the B97-D/ccpVTZ level of theory using the GAUSSIAN16 (Frisch et al., 2016 ▸) package and GaussView6 inter­face (Dennington et al., 2016 ▸). B97-D/ccpVTZ was se­lect­ed based on what was used in a conformational polymorph review (Cruz-Cabeza & Bernstein, 2014 ▸). Potential energy scans were conducted using the relaxed scan method contained within GAUSSIAN16. Optimizations were con­duct­ed using the ‘tight’ keyword. Frequency calculations were also conducted on the unrestricted optimizations to ensure a local minimum.

Hirshfeld surface analysis and fingerprint plots

Hirshfeld surfaces and fingerprint plots were com­puted using CrystalExplorer21 (Version 21.5; Spackman et al., 2021 ▸). The Hirshfeld surfaces are plotted as d _norm. Contacts closer than the sum of the van der Waals radii are highlighted in red, longer contacts in blue, and contacts near the sum of the van der Waals radii in white.

Database evaluations

Evaluation of the Cambridge Structural Database (CSD, Version 5.43, updates through November 2022; Groom et al., 2016 ▸) was conducted using ConQuest (Version 2022.3.0; Bruno et al., 2002 ▸). A search of organic azides (R–CH _x –N₃), either organic or as organic ligands bound to metals, resulted in 2102 hits. Search restrictions of only organic structures, no powder structures, and 3D coordinates provided resulted in 1751 hits, which is less than 0.15% of the structures reported in the CSD as of March 2023. Of these 1751 structures, only 26 structures in the CSD contain a benzyl azide group (Ph–CH₂–N₃).

Results and discussion

Mol­ecular structures

Fig. 1 ▸ highlights the asymmetric units of polymorphs A, B, and C. Direct com­parison of the structures was conducted using Mercury (Macrae et al., 2020 ▸) and the imbedded mol­ecule and structure overlay tools. The different conformations of the benzyl azide group are also featured in an overlay diagram (Fig. 1 ▸) generated by matching up the arene rings of each structure. The clear differences between the structures are changes in two torsion angles shown in Fig. 2 ▸, identified as dihedrals τ₁ and τ₂. The question then becomes are these structures related as polymorphs or as conformational polymorphs? As mentioned above, to be true conformational polymorphs there must be an appreciable energy barrier between the conformations in question. If there is no appreciable energy barrier, the relationship between the species is then considered a conformational adjustment and the structures will be considered as polymorphs.

Figure 1.

The asymmetric units of the 3-(azido­meth­yl)benzoic acid polymorphs A, B, and C, viewed perpendicular to the arene ring. The displacement ellipsoids are drawn at the 50% probability level. The far right image is an overlay of the polymorphs by matching up the arene ring; color code: A = yellow, B = pink, and C = black. The r.m.s. deviation values are as follows: A and B = 0.913 Å, A and C = 1.266 Å, and B and C = 1.135 Å.

Figure 2.

ChemDraw figure (left) depicting the two torsion angles of inter­est, i.e. τ₁ and τ₂. The highlighted pink sections indicate the atoms that make up the dihedral angle. The X _gas conformations are shown to the right of the ChemDraw image.

However, before conducting theoretical conformational analysis, there are a few measurable parameters shown to have a high probability for indicating a conformational polymorph relationship (Cruz-Cabeza & Bernstein, 2014 ▸). For example, measuring torsion angles and com­puting a Δθ (Table 2 ▸) can provide an initial measure to classifying the structures. Between the three unique pairs, there is at least one Δθ value that is >96°, providing an initial indication that all three are likely conformational polymorphs. Another metric used initially to evaluate the structures is to com­pare the r.m.s. deviation values of the atomic positions found from crystal structures. The r.m.s. deviation values for pairs of structures are listed in the Fig. 1 ▸ caption. With each of the r.m.s. deviation values being >0.375 Å, the data further suggest that the mol­ecules are conformational polymorphs.

Table 2. Computational values.

	ΔE crys–crys(X) (kcal mol−1)	ΔE crys–gas(X) (kcal mol−1)	ΔE gas–gas(A–X) (kcal mol−1)	τ1-gas (°)	τ1-crys (°)	τ1-Δθ (°)	τ2-gas (°)	τ2-crys (°)	τ2-Δθ (°)
A	0.00	0.02	0.00	−95.81	−95.76		62.01	59.93
B	1.66	0.57	1.11	140.58	52.06	147.82	172.31	−146.85	153.22
C	1.29	1.25	0.06	−85.58	−131.44	35.68	−62.15	−108.21	168.14

Notes: τ₁-gas and τ₂-gas are the torsion angles obtained from X _gas. τ₁-crys and τ₂-crys are the torsion angles obtained from X _crys. Δθ is taken as the difference between the dihedral angle in A _crys and the dihedral angle in B _crys or C _crys.

Conformational analysis

Single point energy analysis

After evaluating the crystal structures in a topical manner, we proceeded to con­duct an in-depth analysis of conformational energetics using com­putational methods. To begin, we utilized an approach described by Cruz-Cabeza & Bernstein (2014 ▸). We calculated six relative energy values for the structures reported (vide infra) from two different mol­ecular optimizations. A restricted optimization is denoted X _crys (X = A, B, or C), where the dihedrals τ₁ and τ₂ (Fig. 2 ▸) were constrained to the values observed in the crystal structure, while optimizing all other parameters. The associated energy (or relative energy) for this restricted optimization is denoted as E _crys(X) (X = A, B, or C). Conversely, X _gas and E _gas(X) (X = A, B, or C) denotes an unrestricted optimization from the crystal structure coordinates to a minimum, and the associated energy (or relative energy). From these we then applied the following equations:

The ΔE _crys–gas(X) value represents the adjustment energy, i.e. the energy needed to go from the crystal conformation to an optimized configuration. The ΔE _gas–gas(X–X) value re­pre­sents the energy difference between the specified conformers in the gas phase. ΔE _crys–crys(X–X) is simply the relative energy between the mol­ecules under the solid-state configuration. Table 2 ▸ com­piles all the values.

Both A _crys and A _gas are the most energetically favorable in their respective optimization conditions (Table 2 ▸). Under the restrained optimization, the trend was B _crys < C _crys < A _crys in terms of stability. A _crys was 1.66 and 1.29 kcal mol⁻¹ more favorable than B _crys and C _crys, respectively. The minimal adjustment energy value for A _crys suggested a very similar mol­ecular geometry between the restricted and unrestricted gas-phase optimization, which is confirmed by the similar torsion angles (Table 2 ▸). Polymorph B has an adjustment energy of just over 0.5 kcal mol⁻¹, which is a result of repositioning of the azide group roughly 90° about the τ₁ dihedral and 25° about the τ₂ dihedral. This shifting eliminates an unfavorable eclipsed conformation between an H atom and the arene ring. Notably, even when optimized with no restrictions, B _gas is 1.1 kcal mol⁻¹ higher in energy than A _gas. The C polymorph undergoes the most significant adjustment, with a value of 1.25 kcal mol⁻¹. The optimization procedure adjusted τ₁ of C _gas by 46° to be like polymorph A (≃10° difference). Given that the τ₁ of C _crys was only 35.68° different than that of τ₁ of A _crys, this shift is not entirely surprising. In fact, the value of τ₁-Δθ would suggest that C _crys and A _crys are related by conformational adjustment, but τ₂ also changes. The largest difference between C _gas and A _gas is the τ₂ value positioning the azide group in a different direction with respect to the carb­oxy­lic acid group; with A _gas, the azide group is pointed toward the carb­oxy­lic acid group, while C _gas is directed away, pointing toward the C—H group para to the carb­oxy­lic acid group. Ultimately C _gas and A _gas represent two distinct conformations, which are very similar in terms of their energetic conformational changes, differing by only 0.06 kcal mol⁻¹. The adjustment energies [ΔE _crys–gas(X)] and conformational energies [ΔE _gas–gas(X–X)] listed here fall within the most common range of values observed by Cruz-Cabeza & Bernstein (2014 ▸).

Potential energy scans

As mentioned previously, true conformational polymorphs are identified based on the presence of appreciable energy barriers. Thus, we calculated relaxed potential energy scans (PES) for both the τ₁ and τ₂ (for τ₂, we only scanned using the low energy A _gas conformation as a starting point) dihedral angles and plotted the relative energy of X _gas and X _crys on a PES profile. The scans started from the crystal structure conformation of each and involved 36 steps of 10°. Each polymorph scan is shown in Fig. 3 ▸. As expected, there are energetically favorable basins. The diamonds represent X _gas, while the triangles represent the X _crys relative to the most favorable A _gas. Each of the diamonds (X _gas) are in local potential energy basins.

Figure 3.

PES profile (a) of A, B, and C about τ₁, and (b) of A about τ₂ (right).

Both scans (Fig. 3 ▸) immediately highlight the global minimum, showing that A _gas is in the most favorable energy basins. When considering the τ₁ scan of A, we note the very minimal adjustment energy of A _crys. In contrast to the favorable A arrangement, the τ₁ scan of B highlights an overall higher energy conformation. The τ₂ torsion angle of B _gas is 172.31°, which essentially points the linear-like azide group away from the arene ring; in addition, the τ₁ torsion angle is much less perpendicular than A _gas and C _gas. The combination here leads to this energetically elevated conformation. As expected, B _gas resides in the energy basin for the τ₁ scan and B _crys is elevated from this position, showing that B _crys is an adjustment of the B _gas conformation. The τ₁ scan of C looks remarkably like that of A, which is expected due to the similar τ₁ starting values. However, the position of the azide group (vide infra) causes the change in the PES profile. Following a pattern similar to B, the C _crys species is quite elevated from the basin in which the C _gas resides [ΔE _crys–gas(C) = 1.25 kcal mol⁻¹]; however, the mol­ecular arrangement of C _crys would still be considered a conformational adjustment of C _gas. C _crys is roughly 0.2 kcal mol⁻¹ above the PES at the τ₁ dihedral of −131.44°. When considering the τ₁ PES profiles, it certainly suggests that the relationship between B and both A and C is that of conformational polymorphism. In contrast, the τ₁ PES scans do not make it clear that A and C are of this relationship; does the re-positioning of the azide group progress through an appreciable energy barrier? The scan of τ₂ highlights that this prerequisite is met. Specifically, the energy barrier to change τ₂ from A _gas to C _gas is ≃ 1.27 kcal mol⁻¹. Thus, we can conclude that the relationship between all three species is that of conformational polymorphism.

Crystal packing and inter­molecular inter­actions

The most prominent inter­molecular packing feature is the (8) carb­oxy­lic acid dimer (see parameters in Table 3 ▸), which is preserved among all three polymorphs (Fig. 4 ▸). Thus, the long-range crystal packing of each of the polymorphs is dictated by an inter­play between the mol­ecular conformation and the inter­molecular forces (π–π stacking and C—H hydrogen bonds) between these dimers.

Table 3. Table of germane noncovalent parameters.

Parameter	A	B	C
O—H⋯O hydrogen-bond parameters*
O—H (Å)	0.96 (3)	0.89 (3)	0.90 (3)
H⋯O (Å)	1.68 (3)	1.74 (3)	1.73 (3)
O⋯O (Å)	2.6334 (15)	2.619 (2)	2.6346 (15)
D—H⋯A (°)	175 (3)	172 (3)	176 (2)
π–π stacking parameters
Distance between planes (Å)	3.361	3.414	3.406
	3.353
Centroid–centroid distance (Å)	3.6568 (12)	3.7712 (3)	3.8029 (2)
	4.0950 (12)
Closest C⋯C distance (Å)	3.3714 (19)	3.414 (3)	3.419 (2)
	3.367 (2)

Note: (*) symmetry transformations used to generate equivalent atoms for carb­oxy­lic acid dimer hydrogen bonds. Mol­ecule A: −x + 2, −y + 2, −z + 1; mol­ecule B: −x + 2, −y + 1, −z; mol­ecule C: −x, −y + 2, −z + 1.

Figure 4.

The carb­oxy­lic acid dimers of polymorphs A, B, and C. The red dotted lines indicate hydrogen bonds and the displacement ellipsoids are drawn at the 50% probability level.

Crystal packing of A

Diffraction-quality crystals of A were grown by slow evaporation of a tert-butyl methyl ether solution of 1, producing colorless plates. The com­plex crystallizes in the space group P2₁/c, with a single mol­ecule in the asymmetric unit. π–π stacking within A is anti­parallel and offset leading to two unique π–π stacking inter­actions [Fig. 5(b) ▸]. The offset and anti­parallel packing is noted when viewing a packing diagram down the crystallographic a axis [Fig. 5 ▸(d)]. The π–π dimer with greater overlap has a 3.361 Å distance between the mean planes generated from the arene rings. The closest contact between the C atoms of these rings is 3.3714 (19) Å [two purple lines in Fig. 5(b) ▸ are symmetrically the same], with a centroid–centroid distance of 3.6568 (12) Å. The dimer with less overlap has 3.353 Å between the mean planes generated from the arene rings. The closest contact between the C atoms of these rings is 3.367 (2) Å [two lines in Fig. 5(b) ▸ are related by symmetry and are thus the same], while the centroid–centroid distance is 4.0950 (12) Å.

Figure 5.

(a) The Hirshfeld surface for polymorph A shown as d _norm and (b) the π–π stacking. The purple dotted lines indicate the closest C⋯C inter­actions. (c) The C—H hydrogen bonding between adjacent mol­ecules. The red dotted lines indicate C—H hydrogen bonds with oxygen acceptors, while the blue lines indicate inter­actions with nitro­gen acceptors. (d) A packing diagram, viewed down the crystallographic a axis, with displacement ellipsoids drawn at the 50% probability level.

Inspection of the Hirshfeld surface indicated two locations of close C—H hydrogen-bonding contacts [Fig. 5 ▸(c)]. The first is a C—H hydrogen bond between a methyl­ene group and the acid O atom, with H8B⋯O2 = 2.7123 (11) Å and C8—H8B⋯O2 = 139.80 (9)°. This inter­action likely assists the π–π dimer that maintains greater overlap. However, the π–π dimer with less overlap maintains a slightly closer contact parameter. The terminal N atom of the azide group also acts as a hydrogen-bond acceptor. The aryl C—H group para to the carb­oxy­lic acid group forms an inter­molecular hydrogen bond with the terminal azide N atom of an adjacent mol­ecule. The hydrogen-bond parameters are H4⋯N3 = 2.6827 (15) Å and C4—H4⋯N3 = 150.15 (10)°.

Crystal packing of B

Diffraction-quality crystals of B were grown by slow evaporation of a chloro­form solution of 1, producing colorless plates. The mol­ecule crystallizes in the space group P2₁/n, with a single mol­ecule in the asymmetric unit. Mol­ecules participating in π–π stacking are arranged in an offset parallel manner observed when viewing the crystal packing down the crystallographic a axis [Figs. 6(b) ▸ and 6(d) ▸]. The distance between the planes formed by the arene rings is 3.414 Å, with a centroid–centroid distance of 3.7712 (3) Å. The closest C⋯C distance is 3.414 (3) Å.

Figure 6.

(a) The Hirshfeld surface for polymorph B shown as d _norm and (b) the π–π stacking. The purple dotted lines indicate the closest C⋯C inter­actions. (c) A packing diagram, viewed down the crystallographic a axis, with displacement ellipsoids drawn at the 50% probability level. (d) The C—H hydrogen bonding between adjacent mol­ecules. The red dotted lines indicate C—H hydrogen bonds with oxygen acceptors, while the blue dotted lines indicate inter­actions with nitro­gen acceptors.

Again, assisted by the Hirshfeld surface, we identified a few significant (i.e. close contact) C—H hydrogen bonds of B [Fig. 6 ▸(d)]. Like polymorph A, the methyl­ene H atoms in polymorph B assist in the construction of π–π stacking. The hydrogen-bond parameters from the methyl­ene C—H group to the first N atom of an adjacent azide group are H8B⋯N1 = 2.6444 (19) Å and C8—H8B⋯N1 = 147.90 (11)°. The aryl C—H group ortho to the carb­oxy­lic acid group and para to the benzyl azide group forms a C—H hydrogen bond with the carboxyl hydroxy group, with parameters of H6⋯O2 = 2.5545 (15) Å and C6—H6⋯O2 = 157.78 (14)°. The C—H group meta to the carb­oxy­lic acid group forms a C—H hydrogen bond to an adjacent mol­ecule that has hydrogen-bond parameters of H5⋯O1 = 2.6414 (14) Å and C5—H5⋯O1 = 140.59 (13)°.

Crystal packing of C

Diffraction-quality crystals of C were grown by slow evaporation of a methanol solution of 1, producing colorless plates. The mol­ecule crystallizes in the space group P , with a single mol­ecule in the asymmetric unit. A carb­oxy­lic acid dimer is present and, like polymorph B, the π–π stacking adopts an offset parallel manner [Fig. 7 ▸(b)], with a distance between the planes formed by the arene rings of 3.406 Å and a centroid–centroid distance of 3.8029 (2) Å. The closest C⋯C distance is 3.419 (2) Å.

Figure 7.

(a) The Hirshfeld surface for polymorph C shown as d _norm and (b) the π–π stacking. The purple dotted lines indicate the closest C⋯C inter­actions, while the blue lines are C—H hydrogen bonds with nitro­gen acceptors. (c) A packing diagram, viewed down the crystallographic a axis, with displacement ellipsoids drawn at the 50% probability level. (d) C—H hydrogen bonding between adjacent mol­ecules. The red dotted lines indicate C—H hydrogen bonds with oxygen, while the blue dotted lines indicate inter­actions with nitro­gen acceptors.

The significant C—H hydrogen bond contacts identified by Hirshfeld surface analysis are shown in Fig. 7 ▸(c). Like the other structures, the methyl­ene C—H group participates in hydrogen bonding. One of the methyl­ene H atoms is a bifurcated C—H hydrogen-bond donor that inter­acts with the first N atom (N1) of an adjacent azide, as well as the carboxyl O atom. The contact parameters are H8A⋯N1 = 2.6437 (15) Å and C8—H8B⋯N1 = 132.41 (9)°, and form with a mol­ecule that also participates in π–π stacking. The other contact of atom H8A is to O1, with hydrogen-bond parameters of H8B⋯O1 = 2.5197 (10) Å and C8—H8B⋯O1 = 140.87 (8)°. The other C—H hydrogen of the methyl­ene C atom, H8A, also hydrogen bonds to atom O1 of a different adjacent mol­ecule, with parameters H8B⋯O1 = 2.6335 (11) Å and C8—H8B⋯O1 = 132.51 (11)°. The other significant C—H hydrogen bond is formed between the aryl C—H group para to the carb­oxy­lic acid group and the terminal N atom of an azide group. The hydrogen-bond parameters are H4⋯N3 = 2.7353 (15) Å and C4—H4⋯N3 = 127.56 (10)°.

Fingerprint plot analysis

Fingerprint plot analysis offers an additional avenue to evaluate and visually communicate differences in solid-state structures, effectively highlighting variations (Spackman & McKinnon, 2002 ▸). The plots for each of the polymorphs are displayed side-by-side in Fig. 8 ▸. There are striking similarities between polymorphs A and C, while B is quite distinct, which aligns with the conformational analysis. The element-to-element breakdown of each species is presented in the supporting information (Figs. S1–S3).

Figure 8.

Fingerprint plots of polymorphs A, B, and C.

Conclusion

Three unique structures of 3-(azido­meth­yl)benzoic acid are presented. The relationship between the trifecta of structures has been demonstrated through conformational analysis to be conformational polymorphism. The in silico conformational analysis showed an appreciable energy barrier between mol­ecular arrangements observed in the crystal structures. The data further demonstrated that the different conformations observed are not simply adjustments of the same local minima conformers. Despite the different conformations, several packing features were preserved across all three structures, namely, the carb­oxy­lic acid dimer and π–π stacking. Inter­estingly, the methyl­ene C—H hydrogens also participate in C—H hydrogen bonding across the series. The identification of the methyl azide group as a potential source of conformational polymorphism, as well as a C—H hydrogen-bond donor, has potential implications in the construction of solid-state reaction design and builds on the limited number of crystal structures containing organic azides.

Supplementary Material

CCDC references: 2241209, 2241210, 2241211

Funding Statement

Funding for this research was provided by: National Institutes of Health, National Institute of General Medical Sciences (grant No. P30GM103546); National Science Foundation (grant No. CHE1337908); M. J. Murdock Charitable Trust (grant No. 202119871:02/24/2022).