Structural Analysis of 3,5-Bistrifluoromethylhydrocinnamic Acid

Abstract

The crystal structure of 3,5-bistrifluoromethylhydrocinnamic acid [systematic name: 3-[3,5-bis(trifluoromethyl)phenyl]propanoic acid], C₁₁H₈F₆O₂, has been determined and described. The structure was subject to the Hirshfeld surface-analysis and CE-B3LYP interaction-energies calculations. The title compound crystallises in the monoclinic P2₁/c space group with one molecule in the asymmetric unit. The propanoic acid side chain of the studied molecule has a bent conformation. The key supramolecular motif in the crystal structure is a centrosymmetric O–H∙∙∙O hydrogen-bonded dimer (R²₂(8) in the graph set notation). According to CE-B3LYP, the molecules involved in this motif exhibit the strongest pairwise interaction total energy (E_tot = −67.9 kJ/mol). On the other hand, there are seven other interacting molecular pairs with significant E_tot values in the range of −17 to −28 kJ/mol. In these, the energy is dominated by the dispersive contribution. A survey of the Cambridge Structural Database revealed that in other 3-phenylpropanoic acid structures, the middle dihedral angle of the propanoic acid side chain is always in the trans conformation. This contrasts the current structure where this dihedral angle is in the gauche conformation. According to the Density Functional Theory calculations in the gas phase (at the B3LYP/aug-cc-pvDZ level), the presence of the two CF₃ groups (strong electron-withdrawing character) increases the population of the gauche conformers by a substituent electronic effect, and this may be a minor factor contributing to the appearance of this conformation observed in the solid state.

1. Introduction

In the investigation centred around NK1 receptor ligands, we dealt, among others, with 3,5-bistrifluoromethylhydrocinnamic acid (Scheme 1a), which is a member of a wider family of hydrocinnamic acids (3-phenylpropanoic acids, 3-PPAs, Scheme 1b). Despite its commercial availability, the crystal structure of this compound has never been reported. This appears to be a gap since 3-PPAs have an important role in synthetic, medicinal, and structural chemistry.

As to the synthetic aspect, 3-PPAs are valuable reagents for constructing complex organic compounds of medicinal and agricultural significance [1], including those with heterocyclic substructures. The title compound itself was used to synthesise various active compounds [2,3,4,5,6].

Regarding bioactivity, many 3-PPAs and derivatives thereof were reported to have antimicrobial activities [7,8]. Such action is also common for closely related (unsaturated) cinnamic acids [9]. 3-(3,4-dihydroxyphenyl)propanoic acid was demonstrated to modulate brain synaptic plasticity and peripheral inflammation [10]. Several 3-PPAs substituted at the aromatic ring inhibit aromatic amino acid aminotransferase of Paracoccus denitrificans [11]. Some 3-PPAs were recently identified as L-lactate transport inhibitors [12]. More specifically to the topic of this report, we showed that the title compound is a weak ligand of the human NK1 receptor [13]. Other researchers reported some moderate antibacterial activity for its close analogue (3,5-bis(trifluoromethyl)cinnamic acid) [14]. 3-phenylpropanoic acid was used as a reference model to investigate the physicochemical properties of carboxylic acid bioisosteres that are relevant to medicinal chemistry [15]. Ronacaleret (containing a 3-PPA fragment) is a clinically considered investigational calcilytic for osteoporosis treatment [16]. Furthermore, if one takes into account more complicated (branched at the acid chain) derivatives of 3-PPAs, a list of their reported bioactivities is very long. Some very recent examples include p-(benzyloxy)phenylpropanoic acids as ligands of free fatty acid receptor 1 (GPR40) [17] or 2-(aryloxy)-3-phenylpropanoic acids as agonists of peroxisome proliferator-activated receptors α and γ [18].

As to the structural aspects, many crystal structures of 3-PPAs are deposited in the Cambridge Structural Database. If we restrict ourselves only to compounds without any modification in the propanoic acid chain, the available structures are those of the parent 3-phenylpropanoic acid [15,19] and of the analogues substituted in the aromatic ring with one [19,20,21,22,23,24,25,26,27,28], two [26,29,30,31,32] or three [33,34,35] substituents. Some 3-PPA derivatives were considered in co-crystal screening for a medicinally relevant compound [36]. The conformations of certain 3-PPAs were studied by spectroscopic and theoretical methods [37,38,39].

In light of these facts that show great interest in 3-PPAs for modern chemistry, we deemed it suitable to attempt a structure determination of 3,5-bistrifluoromethylhydrocinnamic acid by using a single-crystal X-ray diffraction method. The results thereof are reported in this contribution.

2. Materials and Methods

2.1. Synthesis and Crystallization

3,5-bis(trifluoromethyl)hydrocinnamic acid was obtained from a commercial source (Sigma-Aldrich, Burlington, MA, USA) and recrystallised from methanol for single-crystal structure measurements. The synthesis of this compound has been described several times [4,5].

2.2. Single-Crystal X-ray Diffraction

Diffraction data of a single crystal of the title compound were collected at a low temperature (100 K) using mirror-monochromated Cu Kα radiation (λ = 1.54184 Å) from a Rigaku SuperNova E (dual source) four-circle diffractometer equipped with an Eos CCD detector. CrysAlis PRO software (version 1.171.40.84a)_was used for all operations, including data collection, data reduction, and multi-scan absorption correction. The structure was solved by direct methods and refined by a full-matrix least-squares technique on F² data using SHELXTL programs [40] integrated with the OLEX2 crystallographic software [41]. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms bonded to carbon atoms were inserted in calculated positions and refined isotropically using standard parameters. The H atom of the hydroxyl group was located on a difference map, and its position was freely refined. The MERCURY program [42] was applied for the graphical presentation of the molecular and crystal structures.

2.3. Hirshfeld Surface and Pairwise Interaction Energy Analyses

The CrystalExplorer program, version 17.5, was used to calculate CE-B3LYP model energies and to perform Hirshfeld surface and energy-framework analyses [43]. The pairwise interaction energies were calculated for molecules within a 3.8 Å radius around the central molecule. The CE-B3LYP calculations were made with B3LYP/6-31G(d,p) electron densities. The default scaling factors, as reported by Mackenzie et al., were applied [44]. The wavefunctions were generated by Tonto [45]. Energy-framework representations were generated with the display threshold of 5 kJ/mol and the tube size set to 80.

2.4. Density Functional Theory Calculations

DFT calculations were performed by using the Gaussian 09 suite of programs [46]. Sets of plausible starting structures for conformers of the hydrocinnamic acid and the 3,5-bistrifluoromethylhydrocinnamic acid were manually prepared by rotating the flexible bonds in these molecules. The structures were optimised at the B3LYP/aug-cc-pvDZ level. The optimised geometries were used for harmonic frequency calculations at the same level to determine the character of the stationary points found. Duplicated minima and the structures with imaginary frequencies were discarded from further analysis. In the case of 3,5-bistrifluoromethylhydrocinnamic acid, it was possible to find many closely lying minima resulting from low-barrier rotation of the trifluoromethyl groups (in these structures, the conformation of the propionic side chain was identical). To simplify the analysis, in such cases, only one minimum (lowest energy) for a given side-chain conformation is discussed and shown. Partial atomic charges used in our discussion were those produced by the Natural Population Analysis [47], as implemented in Gaussian 09. Additional calculation variants, (1) with GD3 empirical correction for dispersion forces [48] and (2) in water with the PCM solvent model [49], were also performed, and their results and a brief discussion thereupon is given in Supplementary Materials Tables S1 and S2.

3. Results and Discussion

3.1. Crystal Structure and Hirshfeld Surface Analysis

The title compound crystallises in the monoclinic P2₁/c space group with one molecule in the asymmetric unit. Selected crystallographic data and refinement details are given in

Table 1. Crystallographic data and structure-refinement parameters for the title compound.

Chemical formula	C11H8F6O2
Formula weight	286.17
Crystal system	Monoclinic
space group	P21/c
a, b, c (Å)	5.00408(19), 13.7194(5), 16.6021(5)
α, β, γ (°)	90, 97.603(3), 90
V (Å)	1129.76(7)
Z	4
Dcalc (g∙cm−3)	1.682
μ (mm−1)	1.625
F (000)	576
Crystal size (mm)	0.12 × 0.06 × 0.04
Reflections collected	4063
Unique reflections	2090
Reflections I > 2σ(I)	1793
Rint	0.0197
Restraints/parameters	0/177
Goodness-of-fit	1.051
R1, wR2 (I > 2σ(I))	0.0340, 0.0820
R1, wR2 (all data)	0.0407, 0.0869
Max. peak/hole (e∙A−3)	0.304, −0.291

. The molecular structure is shown in Figure 1. All bond lengths and angles fall within normal ranges.

The benzene ring, carbon atoms of both CF₃ groups and one carbon atom (C9) of the propanoic acid chain lie in an almost ideal plane. The carbon atom of one of the trifluoromethyl substituents (C7) and the C9 atom are slightly displaced from this plane by 0.044(2) Å and 0.061(2) Å, respectively. In turn, the plane formed by the propanoic acid side chain is not perfect because the C9, C10, and O2 atoms are deflected from it by 0.117(2), 0.151(2), and 0.098(2) Å, respectively. This side-chain plane is close to perpendicular to the aromatic ring plane, and the angle between them is 84.16° (α_rsc). The propanoic acid part is skewed with the dihedral angles equal to 75.65° (θ₁, C2−C1−C9−C10), 67.31° (θ₂, C1−C9−C10−C11), and 17.39° (θ₃, C9−C10−C11−O1).

The Hirshfeld surface (HS) analysis, described in detail earlier [50,51], was used to explore the non-covalent interactions between neighbouring molecules in the crystal packing of the studied compound. HS mapped with d_norm helps to visualise areas around the molecule responsible for the strongest intermolecular interactions that influence the stabilization of the crystal lattice. This surface typically contains red, blue, and white colours corresponding to interatomic contacts, which are shorter, longer, and equal to the sum of the van der Waals radii, respectively [50,51].

The red spots in Figure 2 show places where there are hydrogen-bonding interactions between neighbouring molecules. The most intensively red spots are present around the carboxyl group, which interacts with the same neighbouring moiety to form centrosymmetric O–H∙∙∙O hydrogen-bonded dimers, with an O1∙∙∙O2 intermolecular distance of 2.655(1) Å and an O1∙∙∙H2–O2 bond angle of 173.4° (Figure 3). The adjacent dimeric units are separated by the C∙∙∙O contacts of 3.196(2) Å (Figure 3). Other red spots are connected with the formation of weaker C–H∙∙∙O and C–H∙∙∙F intermolecular interactions. The detailed parameters related to hydrogen-bonding contacts in the studied crystal structure are presented in

Table 2. Geometrical parameters (Å, °) for the hydrogen-bond interactions in the studied compound (symmetry codes are as in the caption to Figure 3).

D−H∙∙∙A	D−H	H∙∙∙A	D∙∙∙A	<(D−H∙∙∙A)
O2−H2∙∙∙O1 i	0.87(2)	1.794(1)	2.655(1)	173.4(1)
C2−H2A∙∙∙F3 ii	0.95	2.764	3.213(2)	109.8
C10−H10A∙∙∙O2 ii	0.99	2.672	3.577(2)	152.1
C6−H6∙∙∙F6 ii	0.95	2.755	3.281(2)	115.8
C10−H10A∙∙∙O1 iii	0.99	2.840	3.417(2)	117.9
C10−H10B∙∙∙F5 iv	0.99	2.517	3.439(2)	154.8
C4 iv−H4 iv∙∙∙O2	0.95	2.606	3.489(2)	154.9
C6 i−H6 i∙∙∙F1 iv	0.95	2.556	3.485(2)	165.9
C2 i−H2A i∙∙∙F4v	0.95	2.581	3.505(2)	164.3

Symmetry codes: (i) −x + 1, −y + 1, −z + 1; (ii) x – 1, y, z; (iii) −x, −y + 1, −z + 1; (iv) −x + 1, y – $\frac{1}{2}$, −z + $\frac{1}{2}$; (v) x + 1, −y + $\frac{3}{2}$, z + $\frac{1}{2}$.

. The molecular packing is also stabilised by weak π∙∙∙π stacking interactions between parallel aromatic rings of adjacent molecules (Figure 3). The shortest contacts between symmetry-related benzene rings are 3.603(2) (C1∙∙∙C4), 3.831(2) (C2∙∙∙C4), and 3.843(2) Å (C1∙∙∙C5). However, the shortest distance between centroids of aromatic rings is much longer and equal to 5.004 Å (Cg∙∙∙Cg), indicating the formation of very weak π∙∙∙π interactions. The presence of CF₃ groups further significantly affects the arrangement of the aromatic rings relative to each other. The shortest C∙∙∙F contact equals 3.651(2) Å (C6∙∙∙F5). In addition, the molecules in the crystal lattice are stabilised through C–H∙∙∙O and C–H∙∙∙F intermolecular interactions. The shortest distances between neighbouring F atoms are 3.001(2) (F2∙∙∙F2) and 3.038(2) Å (F3∙∙∙F6). Such interactions leading to the formation of specific channels between the CF₃ groups of neighbouring acid molecules, extending along the a axis, can also be considered stabilising for the crystal structure [52,53].

The percentage contributions of interatomic contacts to the HS area are shown in Figure 4. The most numerous interactions in the structure of 3,5-bistrifluoromethylhydrocinnamic acid belong to the F∙∙∙H and F∙∙∙F contacts, which both account for 57.2% of the total HS area. The other significant interatomic contacts are C∙∙∙H, O∙∙∙H and H∙∙∙H, contributing in sum 34.8%. The remaining interatomic interactions are negligible.

3.2. Intermolecular Interaction Energies and Energy Frameworks

In order to get insight into crystal packing on a ‘whole-of-molecules’ level, we performed a calculation of CrystalExplorer (CE) model energies [44,54] for the pairs present in the crystal structure. In the CE model, the interaction energy (E_tot) for selected pairs of molecules is constructed as a sum of four contributions scaled by scale factors (k):

E_tot = k_eleE_ele + k_polE_pol + k_disE_dis + k_repE_rep

The terms in the equation are those accounting for electrostatic (E_ele), polarization (E_pol), dispersion (E_dis), and repulsion (E_rep) contributions to energy. The scale factors (k) were calibrated so that the total energies agree with the quantum mechanical results at a selected level of theory [44,54].

Within a 3.8 Å radius from a central molecule with symmetry code x, y, z (marked as 0 in Figure 5), there are 13 neighbour molecules. Among these, it is possible to discern eight non-redundant pairs. The interaction energetics in these pairs are shown in

Table 3. CE-B3LYP interaction energies (kJ/mol) of the molecular pairs in the first coordination sphere of the title compound in the crystal structure (scaling factors for the energy contributions are k_ele = 1.057, k_pol = 0.740, k_disp = 0.871 and k_rep = 0.618).

Molecule Paired to Molecule 0	N	Sym op	R	Eele	Epol	Edis	Erep	Etot
a	1	−x + 1, −y + 1, −z + 1	9.26	−115.6	−25.3	−15.0	139.3	−67.9
b	2	x − 1, y, z; x + 1, y, z	5.00	−0.8	−2.0	−44.3	20.7	−28.1
c	2	−x + 1, y − $\frac{1}{2}$, −z + $\frac{1}{2}$; −x + 1, y + $\frac{1}{2}$, −z + $\frac{1}{2}$	7.23	−8.0	−0.8	−19.9	11.5	−19.3
d	1	−x, −y + 1, −z + 1	9.96	−8.7	−2.1	−15.9	9.2	−19.0
e	2	−x, y − $\frac{1}{2}$, −z + $\frac{1}{2}$; −x, y + $\frac{1}{2}$, −z + $\frac{1}{2}$	7.41	−4.2	−1.0	−21.9	11.2	−17.4
f	2	$\mathrm{x}-1,-\mathrm{y}+\frac{3}{2}$$, \mathrm{z}+\frac{1}{2}$; x, −$\mathrm{y}+\frac{3}{2}$, z −$\frac{1}{2}$	8.52	−0.2	−0.5	−12.6	5.2	−8.4
g	1	−x, −y, −z	10.13	−1.4	−0.1	−3.4	0.3	−4.3
h	2	$\mathrm{x},-\mathrm{y}+\frac{3}{2}$$, \mathrm{z}+\frac{1}{2}$; $\mathrm{x}-1,-\mathrm{y}+\frac{3}{2}$$, \mathrm{z}-\frac{1}{2}$	9.31	0.2	−0.2	−3.4	0.1	−2.8

N—number of pairs found in the first coordination sphere. Sym op—symmetry operation for the neighbouring molecules, as presented in Figure 5. R—distance between molecular centroids in Å. E_ele—electrostatic contribution to interaction energy. E_pol—polarization contribution to interaction energy. E_dis—dispersion contribution to interaction energy. E_rep—repulsion contribution to interaction energy. E_tot—total interaction energy.

. As expected, according to the CE-B3LYP calculation, the strongest pairwise interaction was found for the pair (molecules 0 and a in Figure 5), which is bonded by classical H-bonds between the carboxylic acid groups. Here, the total interaction energy amounts to −67.9 kJ/mol and is dominated by the electrostatic term. A much weaker but still significant interaction energy of −28.1 kJ/mol was found for two pairs of molecules from neighbouring unit cells, related by translation along the a-axis (molecules 0 and b₁ or b₂, Figure 5). In this case, the interaction energy comes almost exclusively from the dispersion term, with the electrostatic contribution of negligible magnitude. This is consistent with the type of contacts found in these pairs (weak π∙∙∙π, C6−H6∙∙∙F6ⁱⁱ, C10−H10A∙∙∙O2ⁱⁱ and C2−H2A∙∙∙F3ⁱⁱ contacts).

There are three further types of pairs (molecules 0 and c, 0 and d, and 0 and e) for which the total interaction energy is predicted to be slightly lower than −20 kJ/mol. The electrostatic contribution in these is cancelled out by the repulsion, and so, the dispersive term again dominates. In pairs (molecules 0 with c₁ and c₂ in Figure 5) related by a two-fold screw axis parallel to the b-axis and translation along this axis, the shortest contacts include the C_Ph−H∙∙∙O (i.e., C4^iv−H4^iv∙∙∙O2) and C−H∙∙∙F (i.e., C10−H10B∙∙∙F5^iv) interactions, and the total interaction energy is −19.3 kJ/mol. A very similar E_tot value of −19 kJ/mol is found for the pair of molecules (0 and d, Figure 5) that are related by inversion and translation along the a-axis. The shortest contacts between these molecules involve carboxyl groups (C11∙∙∙O1ⁱⁱⁱ and C10−H10A∙∙∙O1ⁱⁱⁱ). In turn, the shortest C−H∙∙∙F contact and the pairwise energy interaction equal to −17.4 kJ/mol are present for the two molecule pairs (0 with e₁ and e₂, Figure 5) related by the 2₁ screw axis and translation along the b-axis. The remaining three types of pairs (involving molecules f, g, and h, Figure 5) are characterised by a much lower E_tot value below −10 kJ/mol.

An energy-framework analysis (Figure 6) shows that the crystal packing energetics are anisotropic and dominated by electrostatic contribution. It is clearly seen that the thickest cylinders of the total energies are those corresponding to the thick cylinders of the Coulomb energies. On the other hand, the contribution of dispersion forces is still important, as it provides non-negligible stabilization (as judged by the relative thickness of the cylinders) in pairs with no electrostatic stabilization.

3.3. Comparison with Crystal Structures of Other 3-Phenylpropanoic Acids (3-PPAs)

For comparative purposes, we analysed the available structures of other 3-phenylpropanoic acids (

Table 4. Selected geometrical parameters of 3-PPAs crystal structures. The entries are sorted by ascending with the ring-plane/chain-plane α_rsc angle.

CSD Code	Substituent Pattern	Space Group	Molecule	Side-Chain Dihedral Angles 1			αrsc 2	Reference
				θ1	θ2	θ3
YASFUV	3-OMe	P21/a	A	0	180	0	0	[19]
YASFUV	3-OMe	P21/a	B	0	180	0	0	[19]
CUQBEW	4-C≡C−o-Tol	P21/n	A	−178	177	−2	1	[24]
BOPSOO	2-Me	P21/c	A	180	−178	0	1	[23]
CPPROP	4-Cl	P21/a	A	180	180	3	2	[21]
VOQLUJ	4-CF3	$P\overline{1}$	A	0	177	5	3	[25]
WIKRUE	4-OCH2CO2H	P1	A	180	−177	2	4	[27]
YASFIJ01	unsubstituted	P21/n	A	171	180	4	5	[15]
YARQIU	2,4-bis-Me	P21/c	A	−178	177	−3	5	[30]
YASFIJ02	unsubstituted	P21/n	A	−170	179	1	10	[55]
YABJUI	2-OMe	P21/c	A	178	−171	167	10	[26]
YASFIJ	unsubstituted	P21/a	A	177	−170	−177	11	[19]
MOWZEG	3,4-bis-Ph	$P\overline{1}$	A	−18	−179	−5	20	[31]
DITHPA10	3,5-bis-I, 4-OPh(4OH)	P21/c	A	−81	−177	65	23	[56]
VOXHOF	2-OH	P21/c	A	75	−174	118	34	[20]
YABJOC	2-OH, 4-Me	P21/c	A	142	−166	71	40	[26]
YASFOP	3-Me	P21/c	A	−96	173	−55	41	[19]
YASFOP	3-Me	P21/c	B	144	−151	166	42	[19]
AFUFIS	3,4-bis-OH	P21/c	A	−70	179	−175	67	[32]
YUYGEE	4-OH	P21/c	A	113	178	−2	68	[22]
YUYGEE01	4-OH	P21/c	A	−113	−178	1	68	[28]
YASFIJ	unsubstituted	P21/a	B	−100	156	−173	77	[19]
YOLPEW	3,5-bis-tBu, 4-F	P21/c	A	−91	−178	20	77	[35]
JUBKUP	3,5-bis-tBu, 4-OH	P21/c	A	−90	−178	19	77	[33]
UHUGUB	2,5-OMe	C2/c	A	84	−172	20	79	[29]
	3,5-bis-CF3	P21/c	A	76	67	17	84	this work
YASFIJ01	unsubstituted	P21/n	B	80	−178	3	85	[15]
LIWJEI	3,5-bis-tBu, 4-F	P21/c	A	88	−178	6	86	[34]
YASFIJ02	unsubstituted	P21/n	B	93	177	−2	88	[55]
YABKAP	4-OMe	P21/n	A	86	175	16	88	[26]
VASDOM	3-(CH=CH2CO2H), 4-OMe	C2/c	A	100	180	−14	88	[57]

¹ Dihedral angles θ₁, θ₂, θ₃ connected with the propanoic acid part defined analogously, as in the crystal structure presented in this paper; ² α_rsc—the angle between planes formed by the aromatic ring and propanoic acid chain.

). 3-phenylpropanoic acid salts (3-phenylpropionates and others), metal complexes, co-crystals, inclusion complexes, and solvates were excluded from this analysis.

The vast majority of the analysed derivatives, with only a few exceptions, crystallised in monoclinic space groups having a two-fold screw axis and differing only in the sliding plane. The crystal structures of the analysed 3-PPAs exhibit the R²₂(8) H-bond motif common for carboxylic acids [58,59], and the title compound is no exception here. In all but two structures, this motif is associated with the formation of cyclic dimers by the carboxylic groups of the propanoic acid side chains. The exceptions (WIKRUE and VASDOM) are structures of derivatives with two different carboxylic acid side chains in one molecule. In WIKRUE, the dimers are formed between the two different side chains located para to each other (propanoic acid to 2-oxyethanoic acid). In VASDOM, the cyclic dimer is formed by prop-2-enoic acid side chains, while the propanoic acid fragment is involved through its COOH group in noncentrosymmetric hydrogen-bond interactions with the C=CH−C=O moiety of the neighbouring prop-2-enoic acid part.

A second point for comparison is the overall molecule’s shape (mutual orientation of the ring and the side chain). In the structure presented herein, the side-chain plane is close to perpendicular to the aromatic ring’s plane. In the previously published 3-phenylpropanoic acids (Table 4), the mutual arrangement of the ring and side chain (α_rsc angle) is found to be either in one plane or almost perpendicular (as in the title structure) or in the middle between these two extremities. No clear pattern of a substituent effect on this behaviour is easily recognizable. Interestingly, in the crystal structures of the parent unsubstituted 3-phenylpropanoic acid (YASFIJ, YASFIJ01, and YASFIJ02), there are two crystallographically independent molecules (marked in Table 4 as A and B), and each has a different geometry.

Another point for analysis is the conformation of the propanoic acid side chain. In the structure presented herein, the side chain is bent and skewed, giving the (c,sc,sp) conformation of the θ₁, θ₂, and θ₃ dihedral angles, respectively. For the other 3-PPAs presented in Table 4, the conformations of the propanoic acid side chain are either (p,ap,p) or (c,ap,p), and the synclinal conformation of the θ₂ dihedral angle, as in the title compound’s structure, is not found.

3.4. Quantum Chemical Conformational Analysis

The quantum chemical (DFT) conformational analysis was performed for the title compound and its parent analogue, hydrocinnamic acid. The calculations were made in the gas phase at the B3LYP/aug-cc-pvDZ level (the results of the additional calculation variants are shown and briefly discussed in the Supplementary Materials, Tables S1 and S2). The aim of this modelling was to see if the appearance of the synclinal conformation of the dihedral angle θ₂ may be related to the substituent effect of the CF₃ groups on the conformational properties of the molecule. The conformers found for both molecules are shown in Figure 7, and their geometric and energetic parameters are displayed in

Table 5. Geometric and energetic parameters for the conformers of the unsubstituted hydrocinnamic acid and 3,5-bis-trifluoromethylhydrocinnamic acid (B3LYP/aug-cc-pvDZ level, gas phase).

hydrocinnamic Acid						3,5-Bistrifluoromethylhydrocinnamic Acid
			Side-Chain Dihedral Angles						Side-Chain Dihedral Angles
		ΔG [kJ/mol]	θ1	θ2	θ3			ΔG [kJ/mol]	θ1	θ2	θ3
1	trans-1 (c,ap,sp)	0.0	89	180	0	1	trans-1 (c,ap,sp)	0.0	90	180	0
2	trans-flat (sp,ap,sp)	2.7	0	180	0	2	gauche-1 (c,sc,sp)	3.3	93	−74	−17
3	trans-2 (c,ap,c)	3.6	89	−178	93	3	trans-2 (c,ap,c)	4.3	90	−178	92
4	gauche-1 (c,sc,sp)	5.0	92	−74	−24	4	trans-flat (sp,ap,sp)	5.6	0	180	0
5	gauche-2 (c,sc,ac)	8.3	99	−65	133	5	gauche-2 (c,sc,ac)	7.8	100	−63	137

.

In both cases, the trans-1 (c,ap,sp) conformer is the global minimum. The second most stable conformer in the unsubstituted hydrocinnamic acid is trans-flat (sp,ap,sp) (ΔG = 2.7 kJ/mol). The gauche-1 conformer (c,sc,sp) is fourth in the ranking, with ΔG = 5.0 kJ/mol. The introduction of 3,5-bis-CF₃ substitution reverses this order of conformer stabilities. In this substituted analogue, the gauche-1 is the second lowest in energy (ΔG = 3.3 kJ/mol), while the trans-flat conformer is fourth in the ranking (ΔG = 5.6 kJ/mol).

A possible explanation for this stability gain of the gauche-1 conformer may be derived from the fact that the CF₃ substituent strongly withdraws electrons from the C_ortho atom and increases the positive partial charge on the H_ortho atom (partial charges from the natural population analysis shown in Figure 8). This results in increased attractive interaction between the carbonyl oxygen and the H_ortho (shortening of the distance between these atoms, Figure 8) and adds some stabilization for the gauche-1 conformer. Such an explanation is consistent with another earlier experimental report (NMR measurements in solution), in which electron-withdrawing substituents were shown to increase the gauche population of 3-(para-substituted)phenylpropanoic acids [60].

It seems then that 3,5-bis-CF₃ substitution increases the population of the gauche-1 conformer and decreases the population of the trans-flat conformer in comparison with the unsubstituted hydrocinnamic acid. This could be one of the factors that favour the appearance of the gauche-1 conformer in the solid-state structure of the 3,5-bis-CF₃ analogue. On the other hand, since the discussed conformational energetic differences are relatively small, the substituent effect is likely not a key factor but rather one of the contributors here, with most of the influence coming from the supramolecular interactions.

Interestingly, in the previously published gas-phase spectroscopic and theoretical conformational investigations for 3-PPAs [37,39], only gauche-1 (a minor conformer) and trans-1 (a dominating conformer) conformations of the side chain were mentioned, and the trans-flat conformation was not reported at all. This is in contrast to the presence of the trans-flat conformer in solid-state structures of 3-PPAs and our gas-phase QM results, according to which this conformer is a significant low-energy minimum.

4. Conclusions

In the present work, we have structurally characterised 3,5-bistrifluoromethylhydrocinnamic acid, which is a member of the important family of 3-phenylpropanoic acids. The key structural motif in the analysed crystal is centrosymmetric O–H∙∙∙O hydrogen-bonded dimer (R²₂(8) motif). CE-B3LYP calculations show that the molecules involved in this motif exhibit the strongest pairwise interaction (E_tot = −67.9 kJ/mol), but seven other interacting molecular pairs have significant E_tot values in the range of −17 kJ/mol to −28 kJ/mol. In these latter pairs, the energy is dominated by the dispersive contribution. On surveying the CSD database, it has been found that other 3-PPA crystals do not exhibit the gauche conformation of the middle dihedral angle of the propanoic acid side chain, which in turn, is observed in the current structure. DFT calculations in the gas phase show that strong electron-withdrawing CF₃ substituents increase the population of the gauche conformation for the discussed dihedral angle, probably via the electronic substituent effect. It seems that this may be some minor factor contributing to the appearance of this conformation in the solid state. Experimental and theoretical work to systematically explore the substituent effect on the conformations of 3-PPAs is underway.