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School of Chemical Sciences, Dublin City University, D09 V209 Dublin, Ireland
Author to whom correspondence should be addressed.
Molbank 2024, 2024(1), M1771;
Submission received: 21 December 2023 / Revised: 22 January 2024 / Accepted: 31 January 2024 / Published: 4 February 2024
(This article belongs to the Section Structure Determination)


The title compound N-(2,4-difluorophenyl)-2-fluorobenzamide (Fo24) was synthesized in high yield (1.09 g; 87%) using standard synthetic procedures from the condensation reaction of 2-fluorobenzoyl chloride with 2,4-difluoroaniline. Crystals of Fo24 were grown from CH2Cl2 at room temperature. The Fo24 crystal structure was determined using single-crystal X-ray diffraction methods at 294 (1) K in space group Pn (No. 7). Fo24 is the second regular tri-fluorinated benzamide with the formula C13H8F3N1O1 to be reported and contrasts with the more common difluorinated and tetra-fluorinated analogues. In Fo24, both aromatic rings are effectively coplanar with an interplanar angle of 0.7(2)°. The central amide group plane is oriented by 23.04(18)° and 23.69(17)° from both aromatic rings, forming an intramolecular contact with an ortho-F12 atom with H1⋯F12 = 2.12(4) Å. The primary hydrogen bonds are 1D amide–amide interactions that form along the b-axis direction. In addition, weaker C-H⋯F/O interactions are noted: a R22(12) synthon involving two C-H, a N-H and two C-F groups, with C-F⋯C ring–ring stacking contacts completing the interactions.

1. Introduction

Fluorinated molecules have attracted extensive research interest in medicinal chemistry and pharmaceuticals over the past several decades, with the development of new drugs and therapies [1,2]. Moreover, structural analyses of fluorinated benzamides have increased, with advances demonstrated in the enormous increase in benzamide datasets, structures and published papers [3,4,5,6,7,8,9], as archived on databases and repositories such as the Cambridge Structural Database (CSD) [3].
In this short study, we expand on the structural knowledge of halogenated benzamides and report the chemistry and crystal structure of N-(2,4-difluorophenyl)-2-fluorobenzamide, (Fo24), an isomer of the recently reported 2,3-difluorinated analogue Fo23 [10].
Fo24 is a compound of the larger 18 isomer grid containing three sets of six FpXY, FmXY and FoXY isomers (where p, m, o are the para-, meta-, ortho- substitution of the monofluoro-substituted aromatic ring). The XY labels (X = 2 or 3; Y = 3, 4, 5 or 6) represent the six disubstituted fluorinated aromatic groups as 2,3-; 2,4-; 2,5-; 2,6-; 3,4- and 3,5-F2. Additionally, the amide reversed series represent 18 more compounds, resulting in a 36-isomer grid. Beyond this, more isomers are possible where trifluoro-aromatic substitution results in another 20 isomers. As such, completion of entire isomer grids is desirable for a thorough physicochemical analysis and full representation of the 3D structural space around a particular compound. In reporting the Fo24 crystal structure herein, we highlight once again the gap that exists in the available structural data for tri-fluorinated benzamides. This contrasts with their di-fluorinated and tetra-fluorinated counterparts which have been well documented to date [3,4,5,6,9].

2. Experimental

2.1. Materials and Characterisation

The chemicals, materials, spectroscopic, X-ray diffraction methods and analytical equipment are as reported in previous research [7,8,9]. Chemicals in the Fo24 synthesis (Scheme 1) were used as purchased from Sigma Aldrich. The synthetic approaches are standard, (ESI) [4,5,6,7,8,9]. The single crystal X-ray diffraction methods and data collection procedures for the Fo24 crystal structure (Scheme 1, Figure 1) are routine [9,11]. Data collection, reduction, structure solution and refinement were performed using the CrysAlisPro [11] and SHELXS, SHELXL14 programs [12]. The molecular structure and hydrogen bonding diagrams (Figure 1, Figure 2, Figure 3 and Figure 4) were made using the Mercury program [13]. Geometric analysis of Fo24 was accomplished using the SHELXL14 output [12] and CALC ALL function in the PLATON package [14]. CSD structural analyses and comparisons were performed with version 5.45 [Conquest 2023.3.0—Build 392256] on 19 December 2023 [3].

2.2. Reaction Procedure and Characterisation: Experimental and Spectroscopic Data

Synthetic yield (%) = 87%. Melting point range of 110–112 °C.
Experimental (Calculated) CHN Analysis (%): C = 62.4% (62.2); H = 3.1% (3.2); N = 5.9% (5.6).
1H NMR data (CDCl3): 6.85 (2H, m), 7.14 (1H, dd, 3J = 8.5, 4J = 1), 7.26 (1H, td, 3J = 7.6, 4J = 1), 7.48 (1H, m) 8.11 (1H, td, 3J = 7.6, 4J = 1.8), 8.37 (1H, td, 3J = 8.5, 4J = 6), 8.61 (1H, d, 3J = 16.4).
1H NMR data (d6-DMSO): 7.13 (1H, t, 3J = 8.5), 7.36 (3H, m), 7.60 (1H, q, 3J = 7.1, 4J = 1.5), 7.73 (2H, m), 10.16 (1H, br. s). 19F NMR data (d6-DMSO) (ppm): −114, −115, −118. IR (ATR): 3375 (m), 3070 (m), 1656 (m), 1610 (m), 1481 (m), 1285 (m), 1216 (m), 1086 (m), 961 (m), 846 (s). The 13C spectral data diagrams are available in the supplementary information (ESI).
Figure 3. (i) A view of the C-H⋯O/F interactions between three Fo24 molecules involving O1, F12 and F22 and (ii) a view with atoms drawn as their van der Waals spheres.
Figure 3. (i) A view of the C-H⋯O/F interactions between three Fo24 molecules involving O1, F12 and F22 and (ii) a view with atoms drawn as their van der Waals spheres.
Molbank 2024 m1771 g003aMolbank 2024 m1771 g003b
Figure 4. A view of the overlap between Fo23 [10] and Fo24, highlighting the similar molecular geometry.
Figure 4. A view of the overlap between Fo23 [10] and Fo24, highlighting the similar molecular geometry.
Molbank 2024 m1771 g004
Fo24 crystal structure data collected using a Xcalibur Sapphire 3 (Gemini Ultra) [11].
Chemical formula: C13H8F3O1N1; Mr 251.20; crystal system and space group, monoclinic Pn (No. 7); T = 294 (2) K; a = 5.6756(3), b = 4.9829(2), c = 19.3064(12) Å, β = 91.197(5)°, V = 545.88 (5) Å3; radiation Mo-Kα; μ = 0.13 mm−1; crystal size 0.93 × 0.39 × 0.07 mm; analytical absorption correction, Tmin,max = 0.933, 0.991; number of measured, independent, observed [I > 2σ(I)] reflections and parameters, 3717, 1799, 1615 and 168, with 2 restraints; Rint = 0.019; R[F2 > 2σ(F2)] = 0.038, wR(F2) = 0.091, Goodness of fit = 1.04; hydrogen atoms treated by a mixture of independent (N-H) and constrained (C-H) refinement; Δρmax, Δρmin (as e Å−3) = 0.18, −0.14; the absolute structure = −0.5(7).

3. Results and Discussion

The Fo24 compound was synthesized in high yield using standard condensation procedures as reported for Fo23 and related compounds [9,10]. The spectroscopic data are as predicted, and inspection of the 1H NMR spectrum of Fo24 attests to its overall high purity. The 13C and 19F spectra are as expected when compared with similar fluorinated compounds. For the 19F NMR, the peaks at −114, −115 and −118 ppm are typical of the fluorine substitution patterns expected in aromatic systems [15,16].
The Fo24 crystal structure is notable (Figure 1) in that it is essentially isomorphous with its Fo23 isomer (they crystallize in the same space group Pn). The unit cell dimensions (with an a- and b-axis swap) and cell volumes are similar. The overlay of Fo23 [10] and Fo24 molecules, therefore, attests to the structural similarity (Figure 4). The Fo24 molecular structure is essentially planar with respect to the aromatic rings, with both C6 rings mutually oriented at an interplanar angle of 0.7(2)° (Figure 1). The amide group (C = ONH) is at an interplanar angle with the aromatic ring planes of 23.04(18)° and 23.69(17)° and arises with 1D amide–amide hydrogen bonding in the b-axis direction (Figure 2). An intramolecular contact is present between the amido N1 and ortho-F12, with N1⋯F12 = 2.745(3) Å. The amide H1 was refined with isotropic displacement parameters and results in an intramolecular H1⋯F12 distance = 2.12(4) Å, with N1-H1⋯F12 angle = 132(3)°. This distance is short [3], but not as short as the intramolecular H⋯F distances of ca. 1.95 Å from CSD datasets [3,17], and as reported by Leckta et al. in several naphthalenylbenzamide structures [18]. In this study of Fo24, an auxiliary intramolecular C26-H26⋯O1 interaction is also noted, with a C26⋯O1 distance of 2.858(5) Å.
The primary intermolecular hydrogen bond is the amide–amide interaction linking Fo24 molecules into 1D chains along the b-axis direction (N1⋯O1i = 3.092(3) Å; symmetry code: i = x, 1 + y, z) (Figure 2). There is also a synthon with longer intermolecular C-H⋯Fii contacts involving two C-Hs (H25, H26) forming a cyclic hydrogen-bonded R22(12) motif with the F12 and F22 atoms on a nearby Fo24 molecule (symmetry code: ii = x − 1,y − 1,z; H⋯Fii = 2.49, 2.57 Å. This involves the N-H group positioned syn- to the F12 and F22 atoms (Figure 3). This type of composite interaction is noted in N,N’-(2-fluoro-5-methylbenzene-1,2-diyl)-bis(2-fluorobenzamide), PIHQUT [3,19] with H⋯F distances of 2.54 Å, and YAZBOT (N-(2,4-difluorophenyl)-2,5-difluorobenzamide) [6] (H⋯F = 2.42, 2.49 Å). In Fo24, the non-hydrogen atoms in the cyclical hydrogen-bonded arrangement are coplanar and parallel to the (1 −1 2) plane.
The molecular similarity with Fo23 is remarkable, with an RMSD of 0.02 Å and a maximum deviation = 0.05 Å (Figure 4). This is not surprising, and the differences between the molecules involves the peripheral F23 (Fo23) and F24 (Fo24) atoms that have little impact on the molecular geometries in their respective structures. This demonstrates the similarities and differences that can arise in closely related structures. Acquiring as many crystal structures as possible in molecular series is desirable to fill known gaps in the CSD [3]. Rationalizing why similarities and differences in series of molecules (isomers) requires entire, completed structural sequences at different temperatures and polymorphic grids assessed so as to gain a systematic insight into the overall structural behaviour.
It is noted from a CSD review that 2-chloro-N-(4-chloro-2-fluorophenyl)benzamide or XEHZOD crystallizes in space group Pna21 and differs by replacing the two F atoms (in Fo24) with two Cl atoms [3,20]. The 2-bromo-N-(2,4-dichlorophenyl)benzamide or ZAJWUF structure in space group Pbca is another related crystal structure [21]. Both structural examples are the only equivalent halo-substituted structures available on the CSD, where the three F atoms in Fo24 are replaced by any X = halogen atoms [3]. However, in terms of isostructural behaviour, the crystal structures that are noted for being similar to Fo24 are Fo23 [10], YAZBIN (in space group Pn) and YAZBOT (in space group P21) [6].

4. Overall Structural Results and Related Literature

Tri-fluorinated benzamides with the C6CONHC6 skeleton are relatively rare on the CSD [3,10]. Analysis using the formula C13H8F3O1N1 reveals that only Fo23 (with which it is essentially isomorphous) [3,10] is available for direct comparisons with Fo24. It does not matter if the compound 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-; 3,5-F2] on the second ring. These tri-fluorinated aromatic crystal structures of the formula C13H8F3O1N1 have not been reported. In contrast, many di- and tetra-fluorinated analogues are available for structural comparisons [3,4,5,6,9]. Analysis of a benzamide search [C13H8X3O1N1 formula; X = F, Cl, Br, I and C6CONHC6 skeleton] and reviewing various trihalide (X) combinations shows that the majority are chloro-derivatives. The chloro-derivatives provide ten CSD structural ‘hits’ and structures, as listed by CANYAV, CANYEZ [3,22], ENUKAA [23], JOFHAO [24], KODTUT [25], LAQDOY [26], XEHZOD [20], YODDUR [27], YOVMIG [28] and ZAJWUF [21].
We anticipate that many tri-fluorinated benzamide structures will be reported in the literature shortly and archived in the CSD [3]. The crystal structure of Fo24 is the second tri-fluorinated crystal structure reported by our group [10].

5. Conclusions and Future Work

The benzamide crystal structures reported in the Cambridge Structural Database [3] facilitate analysis of physicochemical research trends and patterns. Ongoing research is directed towards the development of larger n × m benzamide isomer grids and correlating properties such as melting points, spectroscopic and structural data [3,4,5,6,7,8,9,10,20,21,22,23,24,25,26,27,28]. Even when analyzing relatively small molecules such as benzamides, there are gaps in our structural knowledge where crystal structure prediction can potentially be used to fill the spaces [29]. However, it is better if the structural data become available for as many compounds as possible as this is the definitive structural proof. As in any broad structure class of organic compound, there are gaps in the published/archived structural data, as noted for tri-fluorinated and mixed halogenated benzamides [3]. Given the frequency of disorder and crystallographic twinning [9] that occurs in benzamides, it is not surprising that there is a lack of datasets with many structures not reported due to high R-factors, etc. [3]. We hope to substantially increase the number of benzamide structures in the near future. This approach and the developing computational methods [29] will assist the scientific community in future endeavors regarding structural systematics [3].

Supplementary Materials

The following are available online: the 1H, 13C and 19F NMR spectral data, supplementary diagram, CSD analyses, Interaction Table and the Fo24 CheckCIF report.

Author Contributions

N.H. synthesized, characterized, crystallized Fo24 and collated the preliminary data; J.F.G. performed the single-crystal X-ray diffraction experiment and analyzed the crystallographic data; J.F.G. edited and submitted the Fo24 manuscript and supplementary ESI. All authors have read and agreed to the published version of the manuscript.


Internal funding was made available from Dublin City University and Meath VEC.

Data Availability Statement

CCDC Deposition number 2320603 contains the supplementary crystallographic data for this paper. All other data in this paper are in the supplementary information section.


J.F.G. thanks Dublin City University for grants in aid of research while N.H. thanks Dublin City University and Meath VEC for funding a postgraduate fellowship.

Conflicts of Interest

The authors declare no conflicts of interest.


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Scheme 1. Fo24 or (N-(2,4-difluorophenyl)-2-fluorobenzamide).
Scheme 1. Fo24 or (N-(2,4-difluorophenyl)-2-fluorobenzamide).
Molbank 2024 m1771 sch001
Figure 1. An ORTEP diagram of the Fo24 structure with displacement ellipsoids at the 30% probability level and highlighting the intramolecular N1-H1⋯F12 interaction.
Figure 1. An ORTEP diagram of the Fo24 structure with displacement ellipsoids at the 30% probability level and highlighting the intramolecular N1-H1⋯F12 interaction.
Molbank 2024 m1771 g001
Figure 2. A view of the amide⋯amide interaction along the b-axis direction in Fo24 with unit cell axes.
Figure 2. A view of the amide⋯amide interaction along the b-axis direction in Fo24 with unit cell axes.
Molbank 2024 m1771 g002
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Hehir, N.; Gallagher, J.F. N-(2,4-Difluorophenyl)-2-fluorobenzamide. Molbank 2024, 2024, M1771.

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Hehir N, Gallagher JF. N-(2,4-Difluorophenyl)-2-fluorobenzamide. Molbank. 2024; 2024(1):M1771.

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Hehir, Niall, and John F. Gallagher. 2024. "N-(2,4-Difluorophenyl)-2-fluorobenzamide" Molbank 2024, no. 1: M1771.

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