Crystal structures of p-substituted derivatives of 2,6-dimethylbromobenzene with ½ ≤ Z′ ≤ 4

Four bromoarenes are characterized by different contents for their asymmetric units, with Z′ varying from ½ to 4, depending on the nature of a single functional group.


Chemical context
Our group is interested in the design of chemical model systems for studying polar-interactions (Cozzi et al., 2008). In order to achieve this objective, it is necessary to prepare a variety of arylboronic esters as suitable substrates for Suzuki-Miyaura cross-coupling reactions (Ishiyama et al., 1995;Kotha et al., 2002). We obtained these boronic derivatives starting from functionalized bromoarenes. The present communication is about the synthesis and crystallography of a series of such bromoarenes, namely, para-substituted derivatives of 2,6dimethylbromobenzene, for which the p-substituent is X = CN (1), X = NO 2 (2), X = NH 2 (3), or X = OH (4).
The crystallized molecules are closely related to one another from the chemical and structural points of view. However, very different crystal structures were obtained, with different compositions for the asymmetric units. Once again, this evidences that small chemical modifications for a given compound may induce dramatic changes in its crystal structure, even in the case of hydrogen/deuterium exchange, which is the smallest possible modification of a molecule (Vasylyeva ISSN 2056-9890 et al., 2010. As a consequence, the blind tests of organic crystal-structure prediction hosted by the CCDC (Reilly et al., 2016) certainly have a bright future ahead of them.

Structural commentary
No unusual bond lengths or angles are observed in the four molecules . For example, the C-Br bond lengths span a narrow range, from 1.900 (4) to 1.910 (2) Å . The substituent X in the position para to the C-Br bond thus has no influence on the geometry of the bromobenzene core, even if very different X groups are used, namely, strongly electronwithdrawing groups (X = CN, NO 2 ) and strongly electrondonating groups (X = NH 2 , OH). Another structural invariant over the studied series is the minimization of steric crowding effects between the Br atom and the methyl groups in ortho positions. The methyl groups are systematically rotated in such a way that the C-Br bond is staggered with a CH 2 fragment of the methyl group. As a consequence, the endocyclic angle at the Br-bearing C atom is always the largest one in the benzene ring, varying from 121.8 (3) in (3) to 123.9 (4) in (1).
The point of interest regarding the molecular structures is that four different values of Z 0 are obtained for the four compounds. Molecule (1) (X = CN) has the highest potential molecular symmetry, C 2v , assuming a linear C-C N group. Omitting H atoms, this symmetry is actually reached, with the C-Br and C-C N fragments lying on the mirror plane in space group P2 1 /m (Fig. 1). The asymmetric unit then contains a half-molecule, and Z 0 = 1 2 . In (2), with X = NO 2 , the latent symmetry C 2v is broken because the nitro group is tilted The molecular structure of (2), with displacement ellipsoids for non-H atoms at the 50% probability level.

Figure 3
The asymmetric unit of compound (3), with displacement ellipsoids for non-H atoms at the 30% probability level.

Figure 4
The asymmetric unit of compound (4), with displacement ellipsoids for non-H atoms at the 50% probability level.

Figure 1
The molecular structure of (1), with displacement ellipsoids for non-H atoms at the 50% probability level. Unlabelled atoms are generated by the symmetry operation (x, 3 2 À y, z).
slightly with respect to the benzene ring by an angle of 13.0 (4) . For this crystal, Z 0 = 1 in space group P1 (Fig. 2). Finally, for (3) and (4), which are isoelectronic molecules [X = NH 2 , (3) and X = OH, (4)], despite the molecular symmetry being close to C 2v , the asymmetric units contain more than one molecule: Z 0 = 2 for (3) (Fig. 3) and Z 0 = 4 for (4) (Fig. 4), in space groups P2 1 /n and Pbca, respectively. The increasing size of the asymmetric unit, reflected in the increasing value of Z 0 , may be rationalized on the basis of two key parameters. First, a higher molecular symmetry obviously favours the crystallization of low Z 0 crystals, as in (1). This has been observed in many symmetrically substituted benzene derivatives, for example, in 4-bromo-benzonitrile in space group Cm (Britton et al., 1977; see also Desiraju & Harlow, 1989), or 2,6-dibromo-4-chlorobenzonitrile in space group P2 1 /m (Britton, 2005). The standard asymmetric unit with Z 0 = 1 is obtained for (2), for which the molecular symmetry is lowered to C 1 . Secondly, the introduction of efficient donor groups for hydrogen bonding, such as NH 2 and OH groups, is an enabling factor for crystal structures having Z 0 > 1, as observed for (3) and (4). A search in the organic subset of the CSD (Groom et al., 2016) reflects such a trend: for example, comparing nitrobenzene and aniline derivatives, the former class is characterized by 12.5% of crystals with Z 0 > 1, and this fraction is increased to 15.6% in the latter. In the same way, phenol derivatives with Z 0 = 4 are not uncommon (Dey et al., 2005;Mukherjee & Desiraju, 2011).

Supramolecular features
As expected, compound (1) is featureless regarding the packing of the molecules. No short contacts such as halogen bonds are formed, andinteractions are insignificant, the shortest separation between benzene ring being defined by cell translations along the short cell axis, a = 4.0382 (1) Å .
For (2), two pairs of weak C-HÁ Á ÁO hydrogen bonds link the molecules to form two centrosymmetric first-level ring motifs of R 2 2 (10), with the participation of the nitro group as acceptor (Table 1). The nitro group participates with two contacts to two rings, generating a chain of R motifs along [110] (Fig. 5). As for (1), slipped -stacking interactions are insignificant, the benzene-to-benzene distance being, again, determined by the cell axis a = 4.0502 (5) Å .
Although compounds (3) and (4) are isoelectronic, they present different crystal structures. This is because their donor groups for hydrogen bonding are of a different nature: the N-H bond is a poorer donor compared to the O-H bond, on the basis of the polarity of these bonds, estimated with the differences of electronegativity N À H = 0.84 and O À H = 1.24 (Pauling's scale is used for ). Moreover, the NH 2 group is potentially involved in two hydrogen bonds, while the OH group is expected to form a single, stronger contact, at least as long as bifurcated hydrogen bonds are not considered.

Figure 5
Part of the crystal structure of (2), showing C-HÁ Á ÁO hydrogen bonds (dashed lines) forming R motifs in the crystals. Hydrogen bonds a (green) and b (red) correspond to entries 1 and 2 in Table 1. Atoms belonging to the asymmetric unit are labelled.

Figure 6
Part of the crystal structures of (3) (top) and (4)  contact oriented toward the lone pair of the acceptor N atom. A second level motif C 2 2 (4) is formed using the discrete contacts, and the chain of connected molecules runs along [010] (Fig. 6, top).
A similar framework of D and C motifs appears in (4), this time starting from a Z 0 = 4 asymmetric unit: three discrete motifs D(2) are formed within the asymmetric unit, and a fourth D(2) motif connects the first independent molecule with a symmetry-related molecule in the crystal (Table 3). As a consequence, C 4 4 (8) chains are formed, propagating parallel to [100] (Fig. 6, bottom). As mentioned above, the hydrogen bonds in (4) are much more efficient than those observed in (3): all O-HÁ Á ÁO bonds have short HÁ Á ÁO distances of ca 1.9 Å and O-HÁ Á ÁO angles are close to 180 (Table 3).
It is worth noting that none of the observed 1D supramolecular structures in (2)-(4) includeor C-HÁ Á Á contacts, nor C-BrÁ Á ÁBr halogen bonds. The arrangement of the molecules in the crystal over the studied series of compounds is thus mainly determined by the absence of, the presence of weak, or strong hydrogen bonds, respectively, in (1), (2) and (3), or (4).

Database survey
Polysubstituted benzene systems are ubiquitous in the crystallographic literature. Limiting a survey to 2,6-dimethylbromobenzene, only two derivatives closely related to the series we have studied may be found, with X = t Bu (Field et al., 2003) and X = I (Liu et al., 2008), which do not present obvious supramolecular features. Both form Z 0 = 1 2 crystals, as for (1).

Synthesis and crystallization
Compound (3) was purchased from Oakwood Chemical Co. and was the starting material for the synthesis of (2) by oxidation with m-CPBA, and (1) and (4) via a Sandmeyer reaction. Single crystals of (3) were obtained by slow evaporation of a CH 2 Cl 2 solution. Compound (1) was prepared by modification of the reported procedure (Xu et al., 2000). A solution of NaNO 2 (0.36 g, 5.2 mmol) in water (5 ml) was added dropwise to a suspension of 4-bromo-3,5-dimethylaniline (1 g, 5 mmol) in aqueous HCl (2 ml, 12 M), and water (2 ml) at 273 K. The mixture was stirred at 273 K for 30 min and then neutralized with NaHCO 3 . Separately, a solution of CuCN (0.54 g, 6 mmol), and KCN (0.81 g, 12 mmol) in water (10 ml) was heated at 343 K. This solution was added dropwise to the diazotization solution previously prepared. The mixture was kept at 343 K for 30 min with stirring and then cooled at room temperature. The product was extracted with toluene (3 Â 30 ml). The combined organic layers were dried over anh. Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc, 95:5) to obtain compound (1)  Compound (2) was prepared by modification of the reported procedure (Gilbert & Borden, 1979). A solution of 4-bromo-3,5-dimethylaniline and 3-chloroperoxybenzoic acid (4 g, 23 mmol) in CH 2 Cl 2 (35 ml) was heated at 323 K for 2 h. After cooling at room temperature, the precipitate was filtered off and the liquid phase was washed with NaOH (1 M, 3 Â 50 ml). The organic layer was dried over anh. Na 2 SO 4 and concentrated under reduced pressure. The residue was dissolved in glacial acetic acid (10 ml), and a solution of H 2 O 2 (5 ml, 33% aq. solution) and glacial acetic acid (5 ml) was added at room temperature. Then, conc. HNO 3 (0.5 ml) was slowly added and the mixture was heated to 363 K for 4 h. After cooling, the crude was treated with water (50 ml), and was extracted with CH 2 Cl 2 (3 Â 50 ml). The combined organic layers were dried over anh. Na 2 SO 4 and concentrated under reduced pressure. The crude was purified on a silica gel column chromatography (petroleum ether) to give compound (2) as bright-yellow crystals ( Preparation of (4): A solution of 4-bromo-3,5-dimethylaniline (1 g, 5 mmol) in conc. H 2 SO 4 (25 ml) and water (5 ml) was cooled to 273 K. Then a solution of NaNO 2 (0.35 g, 5 mmol) in water (10 ml) was added dropwise under stirring. After additional 30 min the solution was refluxed for 30 min. The mixture was cooled and extracted with EtOAc (3 Â 50 ml). The combined organic phases were dried over anh. Na 2 SO 4 and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc, 9:1) to provide the product (4) Table 2 Hydrogen-bond geometry (Å , ) for (3). (3) 3.365 (6) 157 (4) Symmetry codes: (i) Àx þ 1 2 ; y þ 1 2 ; Àz þ 1 2 ; (ii) x þ 1; y; z. Table 3 Hydrogen-bond geometry (Å , ) for (4).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. At room temperature, compound (3) decomposes after a few minutes under Mo K irradiation, but is stable for hours under Cu K irradiation. For compound (3), H atoms of NH 2 groups were located in a difference Fourier map and were refined with restraints of N-H = 0.89 (2) Å and HÁ Á ÁH = 1.52 (2) Å . For (4), H atoms of OH groups were found in a difference map and refined freely. All other H atoms in (1)-(4) were refined as riding.