Structure of 1,5-benzodiazepinones in the solid state and in solution: Effect of the fluorination in the six-membered ring

Summary Two novel tetrafluorinated 1,5-benzodiazepinones were synthesized and their X-ray structures determined. 6,7,8,9-Tetrafluoro-4-methyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one crystallizes in the monoclinic P21/c space group and 6,7,8,9-tetrafluoro-1,4-dimethyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one in the triclinic P−1 space group. Density functional theory studies at the B3LYP/6-311++G(d,p) level were carried out on these compounds and on four non-fluorinated derivatives, allowing to calculate geometries, tautomeric energies and ring-inversion barriers, that were compared with the experimental results obtained by static and dynamic NMR in solution and in solid state.

As a continuation of our research program on the synthesis, spectroscopic and biological properties of 1,5-benzodiazepine derivatives as well as their calculated parameters, we report in the present publication the experimental and theoretical studies of 1,5-benzodiazepinones 1-6; note that only compounds 1 and

Geometries
The geometries of two related structures together with their codes as reported in the Cambridge Structural Database [8,9] are shown in Figure 2.
Compound 1 crystallizes in the monoclinic P2 1 /c space group containing one molecule per asymmetric unit ( Figure 3; the numbering used in the crystallographic part is different from that of Figure 1). The bonding distances and angles agree with the electronic distribution according to one amide group on the C1 atom and one double bond, C3-N2, (tautomer a in Figure 7). The molecule is not planar due to the folding of the sevenmembered ring with C1, C2 and C3 out of the plane defined by the aromatic ring and the nitrogen atoms. The dihedral angles between this plane and those formed by the C1N1O1 and N2C3C8 atoms are 35.4(2)º and 41.7(2)º, respectively.
These molecules are linked forming dimers by symmetric hydrogen bonds between the amide group and the carbonyl oxygen atom of an adjacent one (distances N1H1···O1' 1.932(2) Å and N1···O1' 2.877(2) Å; angle NHO 162.7(1)º). These dimers interact by double intermolecular F-F contacts between the F5 of a molecule and the F6 of a neighboring one (distance 2.875(2) Å) giving rise to a zigzag chain in the [10-1] direction ( Figure 4). These chains are stacked by a partial π-π overlapping between the aromatic rings with a shortest distance of 3.19(1) Å.  Compound 2 crystallizes in the triclinic P-1 space group containing one molecule per asymmetric unit ( Figure 5). As for compound 1, the molecular geometry corresponds to tautomer a. The seven-membered ring is also folded with dihedral angles between the aromatic ring and C1N1O1 of 44.1(3)º and with N2C3C8 of 43.2(3)º. This higher values compared to compound 1 indicate a greater deformation in the seven-membered ring owing to the presence of the N-methyl substituent.
The N-methylation prevents the dimerization by hydrogen bonding leading to a very different packing. Therefore, the most significant intermolecular interaction is the F-F contact between the F4 and F7 atoms of adjacent molecules (distance 2.669(3) Å) giving rise to chains along the b axis ( Figure 6). Each chain is placed antiparallel to the following one in order to minimize the steric hindrance of the groups out of plane. The two chains interact by π-π overlapping between their aromatic rings, with a shortest distance of 3.35(1) Å. The so formed double chains are isolated because of the above-mentioned steric reasons.
We compared the geometries of compounds 3 (TUPSAZ) [8,10] and 5 (EFARUA) [8][9][10] (Figure 2) with those determined in the present work, 1 and 2. To describe the folding of the sevenmembered ring we used the distance d in Å between the methylene carbon and the plane defined by the benzene ring. These values are 1.36 Å (3), 1.26 Å (5), 1.33 Å (1) and 1.57 Å (2), thus the 1,5-benzodiazepinone with a 4-methyl ring, 3, is more bent than that with a 4-phenyl ring, 5. More significant for the present work, the N-methyl substituent folded considerably the ring, compare 2 with 1, this being related to the inversion process discussed below.

Energies and tautomerism
For the 1H-derivatives five possible tautomers exist while for the N-methyl ones only three different tautomers are possible ( Figure 7).
Mannschreck et al. already concluded in 1967 that 3 has the structure 3a based on a methylene signal at 3.14 ppm [11]. This is also compatible with tautomer 3d but considering that amides never exist as imidic acids, Mannschreck's conclusion is certainly right. Varma et al. reported in 2008 that the reaction between o-phenylenediamine and methyl acetylacetate yields the methoxy derivative 7 ( Figure 8) without any reported proof [12]. In a subsequent paper they reported that the reaction of o-phenylenediamine using ethyl acetylacetate instead of methyl acetylacetate yielded the expected diazepinone that they represent using the tautomer 3d again without any reported proof, neither in the main text nor in the supplementary data [13]. A comprehensive theoretical study of the tautomerism of 3 was carried out by Okovytyy et al. in 2010, including monoethanol and diethanol solvates as well as dimeric forms [14] (they do not consider tautomer 3e). In the gas phase their relative energies (in kJ mol −1 ) are: 3a (0.0) > 3b (14.6) > 3d (48.5) > 3c (93.4) and with an ethanol molecule they are: 3a (0.0) > 3b (0.6) > 3d (51.3) > 3c (70.0). The great stabilization of 3b due to ethanol does not correspond to that observed by Mannschreck in CDCl 3 [11]. Our calculations (gas phase) are reported in Table 1. Table 1: Relative stabilities in kJ mol -1 of the different tautomers of compounds shown in Figure 1 and Figure 7. The tautomerism between a and b implies the breaking/formation of a C-H bond. This is similar to the case of acetylacetone (diketo and ketoenol tautomers) that when both tautomers are present, both can be observed by NMR because the tautomerization barrier is high enough. Therefore, if a CH 2 group is observed in 1 H or in 13 C NMR in the case of 1,5-benzodiazepinones only tautomer a is present in solution.
We report in Table 2 ( 1 H and 19 F NMR data) and There are several interesting results concerning the data reported in Table 2. One of them is the J HF coupling constant present in the N-methyl group of compound 2. This coupling constant, of about 4.5 Hz, identifies unambiguously F9, i.e. it is a 5 J HF9 because all the calculated values for the coupling constants between the N-methyl protons and the fluorine atoms are very small (about 0.1 Hz) except that with F9 (calculated 6.6 Hz). In the literature (Figure 9), there is a related coupling constant present in 2-fluoroacetophenone (8) [18]. Note that this 1 H-19 F coupling can be through-bonds, i.e. a 5 J or throughspace, a common problem involving 19 F [19,20]. Starting from the F9 assignment, the ( 19 F-19 F) COSY experiments permitted to establish the correlation F9-F8-F7-F6, in both compounds. Another interesting coupling is the geminal 2 J HH ≈ 12 Hz of the methylene group in the case of compound 2. This coupling is well reproduced by the calculations ≈ −10.5 Hz. Next, we compared the experimental and calculated chemical shifts (   Table 3 reports the 13 C and 15 N NMR data; here the situation is more difficult because the 13 C NMR signals of the benzene ring carbons are coupled with all the fluorine atoms giving rise to multiplets, which have been analyzed using the Mnova 8.1.0 NMR software [21] for spin simulation, and when needed by irradiation of the 1 H nuclei to simplify the spectra. In the gs-HMBC ( 1 H-13 C) spectra, a correlation between the C4-CH 3 protons and C4 permitted to assign to the latter the chemical shifts at 168.7 ppm for 1 and 170.9 for 2, in accordance with the calculated values. However, the 13 C CPMAS signals corresponding to carbon atoms C6 to C9 could not be properly analyzed, and only the centers of the multiplets are given (138.1 and 138.6 ppm for 1 and 2, respectively). Some couplings involving the fluorine atoms are not well reproduced by the calculations, this is particularly apparent for the 1 J CF , that are overestimated, in absolute value, by about 68 Hz. The overestimation and difficulty to calculate coupling constants involving 19 F has been reported several times [20,22,23].
Concerning the 15 N experimental spectra all nitrogen atoms appear as singlets in solution as well as in the solid state, only small coupling constants with the fluorine substituents have been theoretically calculated so most probably the width of the experimental signals mask them.
In Barriers (all in kJ mol −1 ) The experimental inversion barriers of 3a, 5a (twice) and 6a have been determined and are given in Table 4. We have calculated those of 1a and 2a. The barriers for an AB system that become an A 2 one depend on three values: i) the coalescence temperature T C ; ii) the difference in Hz of the protons of the AB  system (Δν AB ), and iii) the geminal coupling constant, J AB (or J ae ). The inversion rate at the coalescence temperature for an AB system is given by k C = π/√2·√Δν 2 + 6 J AB 2 [11] and the barrier by the modified Eyring equation [24][25][26], ΔG ‡ = 19.12·T C (10.32 + log T C /k C ) [18][19][20]. From the values in Table 4 we have determined the corresponding experimental inversion barriers.
The agreement between experimental and calculated values is satisfactory: using for 2a the 75.0 kJ mol −1 and for 5a the 41.8 kJ mol −1 values we obtained by linear regression (no intercept) ΔG ‡ exp. = (0.99 ± 0.04) ΔG ‡ calcd , n = 5, R 2 = 0.993. This equation predicts for 4a 61.0 kJ mol −1 . Note the increase between toluene and DMSO that corresponds to the raise of inversion barriers with that of the solvent polarity; a similar behavior has been reported for diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one) [27].    X-ray data collection and structure refinement. Data collection for all compounds was carried out at room temperature on a Bruker Smart CCD diffractometer using graphitemonochromated Mo Kα radiation (λ = 0.71073 Å) operating at 50 kV and 30 mA for 1 and 2. In all cases, data were collected over a hemisphere of the reciprocal space by combination of three exposure sets. Each exposure was of 20 s covered 0.3 in ω. The cell parameter were determined and refined by a leastsquares fit of all reflections. The first 100 frames were recollected at the end of the data collection to monitor crystal decay, and no appreciable decay was observed. A summary of the fundamental crystal and refinement data is given in Table 5. The structures were solved by direct methods and refined by full-matrix least-square procedures on F 2 (SHELXL-97) [28]. All non-hydrogen atoms were refined anisotropically.
The hydrogen atoms were included in their calculated positions and refined riding on the respective carbon atoms with the exception of hydrogen H1 bonded to N1 for 1 that was located in a Fourier synthesis and refined riding on the respective bonded atom. Theoretical calculations. The geometry of the molecules has been fully optimized with the hybrid HF/DFT B3LYP [29][30][31] computational method and the 6-31G(d) basis set [32]. Frequency calculations have been carried out at the same computational level to verify that the structures obtained correspond to energetic minima. A further optimization has been carried out at the B3LYP/6-311++G(d,p) level [33,34]. These geometries have been used for the calculations of the absolute chemical shieldings with the GIAO method [35,36] and the B3LYP/6-311++G(d,p) computational level. All the calculations have been carried out with the Gaussian-09 package [37].
The literature equations shown in Figure 11 have been used to transform absolute shieldings into chemical shifts.

Supporting Information
Variable temperature 1 H NMR spectra, 13 C, 15 N, 19 F solid state NMR spectra; Table S1 containing calculated and some experimental 1 H, 13 C and 15 N chemical shifts (δ, ppm) of compounds 3a to 6a; Geometry (Å), energy (hartree) and number of imaginary frequencies of the different tautomers calculated at the B3LYP/6-311++G(d,p) computational level.

Supporting Information File 1
Additional material.