N-(2,3-Difluorophenyl)-2-fluorobenzamide

Abstract

The title compound N-(2,3-difluorophenyl)-2-fluorobenzamide or (Fo23) was obtained at high yield (88%) from the condensation reaction of 2-fluorobenzoyl chloride with 2,3-difluoroaniline using standard synthetic procedures. The crystal structure of Fo23 was determined at 294 (1) K using single crystal X-ray diffraction methods and represents the first regular tri-fluorinated benzamide with formula C₁₃H₈F₃NO compared to the difluorinated and tetra-fluorinated analogues. In the structure, both aromatic rings are effectively co-planar, with an interplanar angle of 0.5(2)°; however, the central amide group plane is oriented by 23.17(18)° and 23.44(17)° from the aromatic rings as influenced by 1D amide⋯amide hydrogen bonds along the a-axis direction. Longer C-H⋯F/O interactions and the arrangement of a R²₂(12) synthon involving two C-F, a N-H and two C-H, together with C-F⋯C ring⋯ring stacking contacts, complete the interactions in the Fo23 crystal structure.

1. Introduction

Benzamides continue to attract considerable research attention (and especially in structural science) as a key area in the much wider field of amide research [1,2,3,4,5]. Consequently, benzamides have seen applications in organic synthesis and pharmaceuticals, and through biopolymers and biochemistry [1,2,3,4,5]. Therefore, in terms of amide-based structural chemistry, the exponential increase in organic (bio)materials and pharmaceuticals has been noted in the literature and as archived on databases such as the Cambridge Structural Database (CSD) [3]. Fluorine derivatives continue to attract extensive attention in medicinal chemistry and pharmaceuticals, with the on-going development of new drugs and therapies [6,7]. Fluorinated benzamides, carboxamides and their structures, both solid-state and gas-phase, have been investigated over the past three decades [3,8,9,10,11,12,13]. The advances in structural research are reflected in the huge increase in published and archived benzamide datasets [3,8,9,10,11,12,13]. Of further note is our experience with both halogenated benzamides and carbamates. The crystallization of benzamides tends to be easier and form better quality single crystals compared to the carbamate analogues. The additional -O- spacer in the central OCONH gives additional flexibility to the carbamates in solution, perhaps ultimately contributing to poorer crystal growth [12,14].

In this paper, we expand on the structural knowledge of halogenated benzamides and report the chemistry and crystal structure of N-(2,3-difluorophenyl)-2-fluorobenzamide or (Fo23). The o notation refers to ortho-substitution on the mono-substituted fluorobenzoyl ring, whereas the 23 refers to di-fluoro substitution on the N-substituted benzene ring. The crystal and molecular structure of Fo23 forms part of an 18-molecule series comprising three sets of six FpXY, FmXY and FoXY isomers, where p, m and o refer to para-, meta- and ortho-substitution and XY represent the six disubstituted fluorinated aromatic isomers 2,3-; 2,4-; 2,5-; 2,6-; 3,4-; and 3,5- (X = 2 or 3 and Y = 3, 4, 5 or 6). In reporting the first compound in a series of papers of this type, we also highlight that a gap exists in the structural data for trisubstituted (fluorinated) benzamides. This contrasts with their di-fluorinated and tetra-fluorinated counterparts, which have been described well [3,8,9,10,13]. This is also highlighted in the ESI, where the relative numbers of halogenated (fluorinated) benzamides are compared.

2. Experimental Section

2.1. Materials and Characterisation

The chemicals and materials, spectroscopy, X-ray diffraction methods and analytical equipment are as described previously [12,13,14]. Chemicals utilised in the synthesis of Fo23 (Scheme 1) were used without purification, as purchased from Sigma Aldrich (Ireland). The synthetic approaches are standard and have been used previously by us and other research groups [8,9,10,11,12,13]. The single crystal X-ray diffraction methods and data collection procedures for the Fo23 crystal structure (Scheme 1) are routine for data collected at 294(2) K [14]. Data collection, reduction, structure solution and refinement used the SHELXS, SHELXL14 programs [15]. The molecular and hydrogen bonding diagrams (Figure 1, Figure 2 and Figure 3) were generated using the Mercury graphics program [16] and with geometric analysis using both SHELXL14 [15] and PLATON [17]. CSD analyses were performed with version 5.42+4 updates on 21 July 2023 [3]. The CSD analyses and hydrogen bond/contact data (Table S1, Supplementary Materials) are included in the supplementary information.

2.2. Reaction Procedure and Characterisation: Experimental and Spectroscopic Data

Synthetic yield (%) = 88%. Melting point range of 100–102 °C.

Experimental (Calculated) CHN Analysis (%): C = 62.5% (62.2); H = 3.0% (3.2); N = 6.0% (5.6). ¹H NMR data (CDCl₃): 6.88 (1H, qd, ³J = 8.88, ⁴J = 1.5), 7.05 (1H, ddd, ³J = 8.7, ⁴J = 2.1), 7.15 (1H, dd, ³J = 8.2, ⁴J = 1), 7.27 (1H, td, ³J = 7.6, ⁴J = 1), 7.50 (1H, m, ³J = 7.6), 8.12 (1H, td, ³J = 8.2, ⁴J = 1.7), 8.20 (1H, tt, ³J = 7.5, ⁴J = 1.5), 8.73 (1H, d, ³J = 16.4). ¹H NMR data (d⁶-DMSO): 7.30 (4H, m), 7.57 (1H, ddd, ³J = 6.9), 7.62 (1H, ddd, ³J = 6.5, ⁴J = 1.7), 7.73 (1H, td, ³J = 7.5, ⁴J = 1.65), 10.39 (1H, br. s). ¹⁹F NMR data (d⁶-DMSO) (ppm): −114, −139, −147. IR (ATR): 3370 (m), 2924 (w), 1661 (m), 1610 (m), 1546 (m), 1469 (s), 1289 (m), 1215 (m), 1134 (m), 820 (m). The ¹³C spectral data are presented in the supplementary information (ESI).

Fo23 crystal structure data were collected on an Oxford Diffraction Xcalibur Sapphire 3 (Gemini ultra) diffractometer.

Chemical formula: C₁₃H₈F₃ON; Mr 251.20; crystal system and space group, monoclinic Pn (No. 7); T = 294 (2) K; a = 4.9556 (2), b = 5.6718 (3), c = 19.6250 (15) Å, β = 96.618(6)°, V = 547.93 (6) ų; radiation Mo-K_α; μ = 0.13 mm⁻¹; crystal size 0.14 × 0.06 × 0.04 mm; analytical absorption correction with T_min,max = 0.965, 0.988; number of measured, independent, observed [I > 2σ(I)] reflections and parameters, 4269, 1600, 1334 and 167 with 2 restraints; R_int = 0.021; R[F² > 2σ(F²)] = 0.038, wR(F²) = 0.079, Goodness of fit = 1.09; hydrogen atoms treated by a mixture of independent (N-H) and constrained (C-H) refinement; ∆ρ_max, ∆ρ_min (as e Å⁻³) = 0.12, −0.09; the absolute structure = −1.5(8); and the inverted structure = 2.5(8) (Flack).

3. Results and Discussion

The Fo23 compound was synthesized at high yield using standard condensation procedures. The spectroscopic data were as expected, and an inspection of the ¹H NMR spectrum of Fo23 attests to its overall purity; the ¹³C and ¹⁹F spectra were as predicted; for the ¹⁹F NMR, the three peaks were located at −114, −139 and −147 ppm and are typical of the fluorine substitution patterns expected on the two substituted aromatic rings.

The molecular structure of Fo23 is largely planar with respect to the aromatic rings and these C₆ rings have an interplanar angle of 0.5(2)° (Figure 1). The amide group (C=ONH) is oriented from the aromatic planes at angles of 23.17(18)° and 23.44(17)°. This arises with the formation of 1D amide⋯amide hydrogen bonds in the a-axis direction. There is intramolecular contact between N1 and F12, with N1⋯F12 = 2.745(3) Å. The amide H1 was refined with isotropic displacement parameters and this resulted in a H1⋯F12 distance of 2.17(3) Å and with a N1-H1⋯F12 angle = 126(3)°. This intramolecular distance is reasonably short [3], but not as short as the intramolecular H⋯F distances of ca. 1.95 Å as reported on the CSD [3,18] and predicted by Leckta and co-workers in a series of naphthalenylbenzamide structures [19]. In the present structural study of Fo23, an auxiliary intramolecular C26-H26⋯O1 interaction was also present, with a C26⋯O1 distance of 2.853(5) Å.

Figure 1. An ORTEP diagram of the Fo23 structure with displacement ellipsoids at the 30% probability level.

Figure 1. An ORTEP diagram of the Fo23 structure with displacement ellipsoids at the 30% probability level.

The primary intermolecular hydrogen bonding interaction is the N1⋯O1ⁱ = 3.054(4) Å as an amide⋯amide interaction linking Fo23 molecules into 1D chains along the a-axis direction (symmetry code: i = 1+x,y,z) (Figure 2). In addition there is a notable synthon involving longer intermolecular C-H⋯Fⁱⁱ contacts, such that two C-Hs (H25, H26) form a cyclic hydrogen bonded R²₂(12) motif with fluorine atoms F12 and F22 on an adjacent Fo23 molecule (symmetry code: ii = x-1,1+y,z). The H⋯Fⁱⁱ distances are 2.51 and 2.56 Å. This involves the N-H group as positioned syn- to the two fluorine atoms (Figure 3). The non-hydrogen atoms in this cyclic arrangement are co-planar and effectively parallel to the (112) plane. There are C-F⋯C ring⋯ring stacking contacts involving C12-F12⋯C26 with F12⋯C26ⁱⁱⁱ = 3.151(4) Å and F12⋯Cg1ⁱⁱⁱ = 3.399 (2) Å (symmetry code: iii = x,y-1,z; Cg1 is the C₆ ring centroid; Table S1, ESI). The cyclic type of composite interaction in Fo23 as noted in Figure 3 is also observed in PIHQUT [3,5], where the H⋯F distances are 2.54 Å and YAZBOT [10] (H⋯F distances of 2.42 and 2.49 Å). The YAZBIN structure (or N-(2,4-difluorophenyl)-2-4-difluorobenzamide) with X-ray data collected at 100 K is effectively isomorphous with Fo23 and the molecular conformations show a good overlap [17]. Differences between the interactions in the Fo23 and YAZBIN structures can be attributed to the different fluorine substitution pattern, data collection temperatures and disorder in one of the benzene rings in YAZBIN [10]. Of further note is that the four related crystal structures [RUXZOB in P2₁2₁2₁, RUXZUH in P2₁/n [9]; YAZBAF in P2₁/c, YAZBEJ in Pna2₁ [10] differ from Fo23 by changing a C-H for C-F (a H for F swap). The four crystal structures are quite different to Fo23 and use different packing arrangements in three different space groups. Only YAZBEJ of the four related structures [9,10] displays a similar but more asymmetric R²₂(12) synthon, but with the C=O positioned syn- to the two C-F groups. This highlights once again the differences that can arise in closely related structures and why a thorough and up to date analysis is needed, with additional crystal structures archived to fill the known gaps in the CSD [3]. Rationalizing why similarities and differences in series of molecules (isomers) require complete series of crystal structures, preferably at different temperatures, and their polymorphs allowed us to gain a thorough insight into crystallization behaviour.

Figure 2. A view of the amide⋯amide interaction along the a-axis in Fo23.

Figure 2. A view of the amide⋯amide interaction along the a-axis in Fo23.

Figure 3. (i) A view of the C-H⋯O/F interactions in Fo23 involving O1, F12 and F22 (with the interaction distances in Å) and (ii) a similar view with atoms depicted as their van der Waals spheres.

Figure 3. (i) A view of the C-H⋯O/F interactions in Fo23 involving O1, F12 and F22 (with the interaction distances in Å) and (ii) a similar view with atoms depicted as their van der Waals spheres.

From the CSD [3], it is noted that JOFHAO is 2-chloro-N-(2,3-dichlorophenyl)benzamide [20] and is the trichloro-equivalent crystal structure of Fo23. Indeed, JOFHAO crystallizes in space group Pc (No. 7), but unlike Fo23 (in space group Pn) has Z’=2. The two molecules adopt different conformations, with one molecular conformation similar to that of Fo23 and the second with the ortho-chlorobenzene ring rotated by ca. 180° degrees and positioned syn to the amide C=O group. The beauty of the JOFHAO structure is that it shows that both conformations are easily accessible and crystallize in the structure in equal numbers without disorder [20].

4. Overall Structural Results and Related Literature

There are no tri-fluorinated benzamide structures available of the type C₆CONHC₆ with chemical formula C₁₃H₈F₃ON for direct comparisons with Fo23 [3]. This is regardless of whether the structure is trisubstituted fluorine on one C₆ aromatic ring or in any combination of o-/m-/p-monosubstituted F and disubstituted F₂ as [2,3-; 2,4-; 2,5-; 2,6-; 3,4- and 3,5-F₂] on the second aromatic ring. It is noted there are many di- and tetra-fluorinated analogues present on the CSD for comparisons [3,8,9,10,13]. In expanding the general CSD search and reviewing all combinations of trihalides (X = F, Cl, Br, I), the majority of structures are chloro-derived and have 10 structural ‘hits’ and 10 structures available on the CSD [3].

For the difluorinated benzamide analogues (formula = C₁₃H₉F₂ON), there are 30 crystal structure ‘hits’ with 19 individual molecules. The discrepancy arises whereby some crystal structures have datasets collected at different temperatures, datasets, polymorphs, etc. The expanded halide series (from using only fluorine) has 89 structural ‘hits’ and 74 individual structures. For the tetra-fluorinated benzamides there are 29 structural ‘hits’ and 27 individual structures using C₁₃H₇F₄ON [3,9,10]. Interestingly, thus far, there are no other Cl, Br, I combinations available [3]. In addition, the mono-fluorinated N-phenylbenzamides (as C₁₃H₁₀FON) reveals a total of eight structural ‘hits’ and six crystal structures, although UXEZIH is a mixed 1:1 molecular system with a methyl/F 50:50 present (site occupancies of 0.5) [21]. Expanding the CSD search to include all halides X (X = F, Cl, Br, I) provides 24 structural ‘hits’ and 16 individual crystal structures. In the analysis, all searches were conducted using the latest CSD version [3]. Therefore, the crystal structure of Fo23 is unique (thus far) in terms of it being the first structural report of a regular tri-fluorinated benzamide of chemical formula C₁₃H₈F₃ON. However, it can be stated that the tri-fluorinated benzamide group of unpublished crystal structures will soon be reported and available for larger analyses using both CSD and AI approaches.

5. Conclusions and Future Work

The sheer number of simple benzamide structures that are now available on structural databases such as the Cambridge Structural Database [3] means that both structural and physicochemical research has a rich base from which to develop and expand. Future work is aimed at developing larger n × m isomer grids with a view to correlating melting points, spectroscopic and structural data based on halogenated benzamides [3,10,13]. However, as noted in the crystal structure of Fo23, there are a number of gaps in the currently available structural data, especially for tri-fluorinated benzamide analogues and mixed halogenated benzamides [3]. This could develop into a rich vein of structural research, as halogenated benzamide and their mixed halide analogue datasets are reported and archived [3]. However, often a reason for the lack of reporting on some crystal structures is the prevalence of group and molecular disorder, as seen in many benzamide structures [3,13]. Work is on-going by our group to increase the number of benzamides communicated to augment the data already available and to assist in the future endeavours of crystal structure analysis for structural systematics [3,12,13,21]. Our future research will complement that of on-going fluorine chemical research and developments in benzamide chemistry and related compounds [22,23,24,25,26].