Synthesis, molecular and crystal structures of 4-amino-3,5-difluorobenzonitrile, ethyl 4-amino-3,5-difluorobenzoate, and diethyl 4,4′-(diazene-1,2-diyl)bis(3,5-difluorobenzoate)

Two intermediates, 4-amino-3,5-difluorobenzonitrile, C7H4F2N2 (I), and ethyl 4-amino-3,5-difluorobenzoate, C9H9F2NO2 (II), along with a visible-light-responsive azobenzene derivative, diethyl 4,4′-(diazene-1,2-diyl)bis(3,5-difluorobenzoate), C18H14F4N2O4 (III), obtained by four-step synthetic procedure, were studied using single-crystal X-ray diffraction. In the crystals of I and II, the molecules are connected by N—H⋯N, N—H⋯F and N—H⋯O hydrogen bonds, C—H⋯F short contacts, and π-stacking interactions. In the crystal of III, only stacking interactions between the molecules are found.


Chemical context
Azobenzene and its derivatives have different absorbance depending on the molecular conformation (trans or cis) around the central N N bond (Mostad & Rømming, 1971;Harada et al., 1997) and molecular architecture.Recently, derivatives of azobenzene, known as pharmacophores, whose activity can be altered via the application of excitation sources with different wavelengths, started being used as molecular tools for controlling biological processes (Aggarwal et al., 2020;Gutzeit et al., 2021).The development of new pharmacophores can be achieved via alteration of the molecular properties by changing the chemical structure, shape, polarity, and other molecular characteristics.
It was indicated (Ble ´ger et al., 2012;Knie et al., 2014) that fluorination of benzene rings in azobenzene in ortho positions to the N N group along with the introduction of electronwithdrawing groups in a para position can help to achieve higher isomer conversion to the cis form when compared to other azobenzene derivatives.In addition, it was observed that the thermal stability of the cis isomers of ortho fluorinated azobenzenes compared to non-fluorinated materials was significantly increased from 5 h to 700 days (Ble ´ger et al., 2012).
Another interesting application of azobenzene-based organic materials was presented by Peng and co-workers (Peng et al., 2022), who demonstrated that the non-centrosymmetric 2-amino-2 0 ,4,4 0 ,6,6 0 -pentafluoroazobenzene was a single-component ferroelectric.In that publication, it was stated that the above-mentioned material was the first single-component organic ferroelectric that opened the way to the design and exploration of azobenzene-based ferroelectrics with promising applications in biofriendly ferroelectric devices.
Herein, the synthetic protocols for two intermediates, 4amino-3,5-difluorobenzonitrile (I), ethyl 4-amino-3,5-difluorobenzoate (II), and an azobenzene derivative with the fluorine atoms in ortho-positions and ester group in a paraposition, namely, diethyl-4,4 0 -(2,2 0 ,6,6 0 -tetrafluoro)azobenzene dicarboxylate (III) obtained in four-step synthesis using a modified synthetic procedure (Appiah et al., 2017) are reported along with the comprehensive X-ray structural study of these materials in the solid state.The synthesized azobenzene derivative might be used as a precursor for further development and application in photopharmacological studies.It has been shown that fluorinated azobenzenes can be used also for the synthesis of photoresponsive main-chain oligomers with azobenzene moieties incorporated in linear unsaturated or saturated polyolefins on a gram scale (Appiah et al., 2017).

Structural commentary
The geometric parameters of molecule I (Table 1, Fig. 1) are very similar to those found in related structures lacking fluorine substituents.For example, a comparison of the geometrical parameters of I with those of 4-aminobenzonitrile (Merlino & Sartori, 1982;Heine et al., 1994;Islor et al., 2013;Alimi et al., 2018) in which there are no fluorine substituents, shows their similarity.However, while in 4-aminobenzonitrile (Alimi et al., 2018), the angles in the phenyl ring are almost the same (from 118.5 to 120.8 � ), in I, the C6-C5-C4 angle with the value 114.5 (1) � is more acute than the C7-C6-C5 [124.4 (1) � ] and C5-C4-C3 [124.2 (1) � ] angles, mainly due to the influence of highly electronegative fluorine substituents.It also can be noted, that the cyano group bond length C1 N1 [1.146 (2) A ˚] is slightly longer than the literature value (1.136A ˚; Allen et al., 1987).Increased conjugation can lead to a slight reduction in bond order, potentially lengthening and somewhat weakening the triple bond compared to a nonconjugated nitrile (Allen et al., 1987).
Likewise, the bond lengths and angles in II (Table 1, Fig. 1) are very similar to those reported previously for related structures, for instance, for the molecule of ethyl-4-aminobenzoate (similar to molecule II, without fluorine substit-uents) that was reported in several publications (Lynch & McClenaghan, 2002;Chan & Welberry, 2010 The geometric parameters of molecule III (Table 1, Fig. 1) are very similar to those found in related structures.There are few structures reported in the literature (Kerckhoffs et al., 2022;Hermann et al., 2017;Bushuyev et al., 2016;Saccone et al., 2014, andAggarwal et al., 2020) featuring trans-azobenzene with halogen substituents at the 2-and 6-positions.However, there are two structures that have been found to incorporate the diethyl-4,4 0 -azobenzene dicarboxylate moiety (Niu et al., 2011;Gajda et al., 2014).In both those structures, the molecules are planar.The title structure III is centrosymmetric, the phenyl rings are planar.The N1 N1 0 distance [1.252 (3) A ˚] is very close to the distances presented in the literature.In the molecule of II, the C7 O1 distance is 1.212 (4) A ˚, and in the molecule of III the distance C7 O1 is equal to 1.211 (2) A ˚.Those values are close to the statistical mean value of 1.221 A ˚ (Allen et al., 1987).
For a convenient comparison of the molecular geometries of I-III, some bond lengths and their notations are presented in Scheme 1 and Table 1.From Table 1, it is clear that in all molecules the C-F bonds are characterized by very similar Molecular structures of I, II, III with the atomic numbering schemes.Displacement ellipsoids are drawn at the 50% probability level.Symmetry code: ( 0 ) 1 À x, 1 À y, 2 À z for III.
bond lengths.As a result of the para position of the donor and acceptor substituents of the phenyl rings, it is expected that this ring should have quinoid character (Zyss, 1994).Indeed, bond lengths 1 and 2 (see Scheme 1 and Table 1) are reduced if compared with the other bond lengths in the phenyl rings (see supporting information).
The length of the double N N bond in molecule III corresponds to a standard value for this series of compounds.The molecule of III, in contrast to the previously studied molecule of diethyl 4,4 0 -(diazenediyl)dibenzoate (DDB; Niu et al., 2011) without F substituents, is not planar.The torsion angle that characterizes the position of the phenyl rings relative to the central C-N N-C fragment is equal to 17.2 (3) � in III and 0.2 (2) � in DDB.It can be explained by the intramolecular steric interactions between F and N atoms in III, N1� � �F1 = 2.644 (2) A ˚and N1� � �F2 = 2.945 (2) A ˚, which are slightly shorter than sum of van der Waals radii (Batsanov, 2001).An overlay of molecules III and DDB demonstrates the molecular similarity with the exception of the orientation of the terminal Me groups (See Fig. 3).

Supramolecular features
The packing in the crystal of I is defined by weak N-H� � �N and N-H� � �F H-bonds (Fig. 4 and Table 2), and �-stacking interactions with interplanar distances between the overlapping phenyl rings equal to 3.3573 (8) A ˚and distances between the ring centroids equal to 3.7283 (4) A ˚.The parameters of the short contacts correspond to the average D� � �A distances for specific interactions [N-H� � �N = 2.9-3.0A (Prasad & Govil, 1980) and N-H� � �F = 2.427 A ˚ (Taylor, 2017)].Interplanar distances for stacking interactions are slightly shorter than the interplanar distance in graphite (3.42A ˚), indicating the significant role of stacking interactions in this crystal.As a result of the hydrogen bonding, molecules of I form chains along the (101) direction.
In the crystal of II, N-H� � �O hydrogen bonds and C-H� � �F short contacts are found (Fig. 5, Table 3) as well as �-�-stacking interactions with interplanar distances between phenyl rings equal to 3.325 (3) A ˚and distances between ring centroids of 3.490 (3) A ˚.The parameters of the short contacts correspond to the average D� � �A distances for specific inter-  C 7 H 4 F 2 N 2 , C 9 H 9 F 2 NO 2 and C 18 H 14 F 4 N 2 O 4 869 Figure 2 Histogram of N N bond-length distribution in azobenzene derivatives.

Figure 4
The packing in the crystal of I. Hydrogen bonds are shown as dotted lines.
Hydrogen atoms not participating in hydrogen bonding are omitted for clarity.
actions (N-H� � �O = 2.7-3.3A ˚ (Bakker et al., 2023) and N-H� � �F = 2.427 (6) A ˚ (Taylor, 2017)].As a result of hydrogen bonding, molecules of II form chains along the baxis direction.In the structures of both I and II, short intramolecular contacts of the type N-H� � �F are observed.
The relative orientations of the molecular cores in structure III (Fig. 6) and in the analogous crystal structure of trans-1,2bis(4-bromo-2,6-difluorophenyl)diazene (Broichhagen et al., 2015) are similar.In the crystal of III, the interplanar distance between the molecular core containing the phenyl rings and the N N bond is 3.324 (13) A ˚and intercentroid distance is 4.6106 (17) A ˚.The nearest distance of the azo group N atom to the carbon atom in the phenyl ring N1� � �C6 is 3.184 (3) A ˚, and the distance to the ring centroid is 3.465 (19) A ˚.The distance between carbonyl atom O1 and the nearest C atom in the phenyl ring is 3.316 (2) A ˚and to the ring centroid is 3.351 (18) A ˚.As a result of �-� stacking, the molecules of III form chains along the [011] direction.
The novelty of 4-amino-3,5-difluorobenzoate (II) was also confirmed by the lack of this structure in the CSD.The closest analogue without fluorine substituents in the phenyl ring is ethyl 4-amino-benzoate (benzocaine), an anesthetic applied in medicine and the pharmaceutical industry and described as 19 database entries.Eight of the structures were reported by Patyk-Kaz ´mierczak & Kaz ´mierczak (2020) (QQQAXG11-18), which represent several polymorphs in the same P2 1 /c space group but with different cell parameters.Other structures were reported by Patel et al. (2017) (QQQAXG09-10) where two polymorphs of benzocaine were described in space groups P2 1 2 1 2 1 and P2 1 /c.Earlier, these structures were mentioned by Chan & Welberry (2010) and Lynch & McClenaghan (2002).
The structure of diethyl-4,4 0 -(2,2 0 ,6,6 0 -tetrafluoro)azobenzene dicarboxylate (III) had also not been deposited in the CSD.However, similar tetra-halogenated molecules with the halogens in ortho positions have been described (Kerckhoffs et al., 2022;TETROD).It should be mentioned that molecules of cis and trans (Z and E) isomers were structurally characterized when it was possible to separate them and when the cis isomers had a long half-life to facilitate their isolation.The authors showed that it was possible to modify the stability of the cis isomers by introducing larger halogen atoms in the ortho positions and a heavier element substituent in the para position.If the azo-benzene molecules with small substituents (H, F) in the ortho positions are planar, with larger halogens (I) they are non-planar, and their cis isomers are more stable.It is important to mention that the ortho-tetrafluoroazobenzenes (DIQBOX; Hermann et al., 2017) resulting from isomerization of the molecule, resulted in significant shape changes, with the trans isomer exhibiting elongation and the cis isomer adopting a more spherical shape.In addition, diethyl-4,4 0 -azobenzene dicarboxylate, which represents the non-halogenated analogue of compound III [Niu et   The packing in the crystal of II.Hydrogen bonds are shown as dashed lines.Hydrogen atoms not participating in hydrogen bonding are omitted for clarity.

Figure 6
The packing in the crystal of III.Stacking short contacts are shown as dashed lines.Hydrogen atoms are omitted for clarity.N1� � �C6(À x, 1 À y, arrangement in the trans isomers.However, if the ortho positions are occupied by bulky iodine substituents, such as in diethyl 4,4 0 -diazenediylbis(3,5-diiodobenzoate), the molecule is non-planar in the trans form (TETROD; Kerckhoffs et al., 2022).In addition, some non-halogenated and halogenated azobenzenes, both cis and trans isomers, have been studied [Hampson & Robertson,1941

Synthesis and crystallization
The synthesis of molecules I-III is shown in the reaction scheme, and follows a slight modification of the procedure described previously (Appiah et al., 2017).Starting materials were purchased from Ambeed Inc. and Sigma-Aldrich and used without further purification.To obtain 4-amino-3,5-difluorobenzonitrile (I), 4-bromo-2,6-difluoroaniline (50.0 g, 240 mmol, 1 eq.) and CuCN (64.5 g, 720 mmol, 3 eq.)were suspended in dimethylformamide (DMF, 500 mL) and refluxed for 24 h.The mixture was cooled to room temperature and NH 4 OH (2 L, 18%) was added, and the resulting solution was filtered.The mixture (filtrate) was extracted with EtOAc (4 � 750 mL) and the organic phase was washed with NH 4 OH 18%, de-ionized water, brine, dried with Na 2 SO 4 , and filtered.The residue was purified through a silica gel plug with CH 2 Cl 2 /n-hexane 2:1, to yield a dark-brown solid (15.7 g, 102 mmol, 42% yield).
ethanol (300 mL) and H 2 SO 4 (6 mL) and refluxed for 10 h.The reaction was neutralized using a saturated solution of sodium bicarbonate, followed by extraction with dichloromethane (DCM, 4 � 300 mL).The organic phase was dried using sodium sulfate (Na 2 SO 4 ), filtered, and concentrated under reduced pressure, yielding the intermediate product (14.99 g, 75 mmol, 77% yield).
Crystallization of all compounds for diffraction studies was performed using the slow evaporation method.All solutions were prepared by dissolving compounds I-III in DCM (2 mL) and sonicating them for 10 min.Then they were capped with cotton plugs and left in the hood for 4 days.Thereafter transparent plate-like crystals of I and II, and dark-red needlelike crystals of III were obtained.

Refinement
Crystal data, data collection and structure refinement details for compounds I, II, and III are summarized in Table 4.The acidic N-H protons in I and II were localized from the residual electron-density map and refined freely.All other H atoms were positioned geometrically (C-H = 0.95-0.99A ˚) and refined as riding with U iso (H) = 1.2U eq (C) or 1.5U eq (Cmethyl).

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.Hydrogen-bond geometry (Å, º)

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.28 e Å −3 Δρ min = −0.29 e Å −3

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.
Using CSD Version 5.45 (update of June 2024; Groom et al., 2016), a statistical analysis of the N N bonds in 2261 Ph-N N-Ph fragments from 1733 crystal structures was carried out.A histogram of the bond-length distribution with a mean bond value of 1.246 A ˚, median 1.253A ˚and su 0.034 A ˚is presented in Fig. 2. It clearly demonstrates that the central bond length in molecule III corresponds to the median value of such bonds.

Table 1
Selected bond lengths (A ˚) in molecules of I-III.

Table 4
Experimental details.