A structural study of 2,4-dimethylaniline derivatives

The crystal structures of two aromatic amines are presented: a hydrogen-bonded brominated aniline, and a piperizine derivative.


Chemical context
Anilines are important building blocks for value-added chemicals such as indoles, which feature prominently in therapeutic agents (Humphrey & Kuethe, 2006). Polyaniline, formed by oxidative coupling of aniline, is a valuable conductive polymer used in advanced materials research (Kang et al., 1998). As they are prone to engage in hydrogen bonding, anilines have also been utilized in crystal engineering studies (Mukherjee et al., 2014). The piperazine functional group is present in a number of active pharmaceutical ingredients. In particular, the widely used antifungal agent itraconazole (Grant & Clissold, 1989), and antibacterial ciprofloxacin (Hooper & Wolfson, 1991) feature piperazine structural units with aryl-group substitution. We have an interest in constructing N-heterocyclic carbenes (NHCs) and NHC-derived ligands, which often feature N-aryl groups derived from substituted anilines. Halogenated NHCs can be utilized to fine-tune the steric and electronic properties of transition metal catalysts. It has been demonstated that the presence of fluorine on an aryl group of an NHC ligand influences the E/Z selectivity of a ruthenium cross-metathesis catalyst (Xu et al., 2017). In our efforts to prepare NHC ligands, anilines and N,N 0 -diaryldiamines are commonly used starting materials or synthetic intermediates.
In this study, we report the crystallographic characterization of two compounds derived from 2,4-dimethylaniline: 2-bromo-4,6-dimethylaniline (1) and N,N 0 -bis(2,4-dimethylphenyl)piperazine (2). Though available from many commercial suppliers, the crystal structure of 2-bromo-4,6-dimethylaniline (1) has not been previously disclosed. Only a few reports of compound 2 can be found in the literature. An early publication (Tikhomirova, 1971) describes the reaction of 2-(2,4dimethylanilino)ethanol with pyridinium chloride, which generates a mixture of 2,4-dimethylaniline and the piperazine ISSN 2056-9890 2, which was characterized only by elemental analysis, melting point, and boiling point. More recently, piperazine 2 was obtained as a trace by-product in the production of 2-(2,4dimethylanilino)ethanol via palladium-mediated hydrogen autotransfer between 2,4-dimethylaniline and ethylene glycol (Llabres-Campaner et al., 2017), and characterized by NMR and IR spectroscopy in addition to high resolution mass spectrometry. No X-ray structural data for compound 2 have been previously disclosed.

Structural commentary
The solid-state structure of 1 obtained by slow sublimation is depicted in Fig. 1. Two independent molecules are present in the asymmetric unit, which are hydrogen bonded (Table 1) to each other [d(NÁ Á ÁN) = 3.172 (5) Å ] within the P2 1 /c space group. The two independent molecules exhibit C-Br and C-N bond lengths that are equal within experimental error [1.910 (3)-1.912 (3) Å and 1.394 (4)-1.394 (5) Å , respectively]. The angle between the two mean planes passing through the aromatic rings of the two independent molecules is 80.6 (2) . The hydrogen atoms on each nitrogen centre that are not involved in the chains formed by the N-HÁ Á ÁN interactions are oriented towards the ortho bromine atoms on the aromatic rings. These intramolecular hydrogen bonds feature donor-acceptor distances of 3.082 (4) and 3.094 (4) Å .
X-ray diffraction analysis of 2 revealed a solvent-free structure in the P2 1 space group (Fig. 2). The asymmetric unit contains one pseudo-C i symmetric molecule. The central N 2 C 4 ring exhibits a chair conformation. Compound 2 represents the first crystallographically characterized diarylpiperazine with methyl groups on the aromatic substituents. The aromatic rings are twisted relative to the N 2 C 4 mean plane, forming angles of 46.8 (1) and 56.9 (1) for C5-C10 and C13-C18, respectively.

Supramolecular features
Each amino group in compound 1 provides one donor and one acceptor site for the hydrogen-bond interactions (Table 1), and chains are observed to form by translation along the crystallographic b axis (Fig. 3). Additionally, the bromine atoms from one of the two independent molecules exhibit weak van der Waals interactions to the equivalent sites on adjacent chains, related by an inversion centre (Fig. 4). The distance for this interaction is 3.537 (1) Å (sum of van der Waals radii for bromine: 3.70 Å ; Bondi, 1964). As the two C-BrÁ Á ÁBr bond angles are equal (ca 153 ), this classifies as a Type I halogen-halogen interaction (Cavallo et al., 2016). This type is generally accepted as a dispersion interaction, as opposed to Type II interactions which are weakly electrostatic in nature and require R-XÁ Á ÁX angles of 90 and 180 . Nointeractions are present in the structure. No significant intermolecular interactions are observed in the crystal packing motif of 2 (Fig. 5).

Database survey
The packing motif of compound 1 makes an interesting contrast to the structure of the less substituted analogue Table 1 Hydrogen-bond geometry (Å , ) for 1.

Figure 2
Displacement ellipsoid plot (50% probability) of the asymmetric unit of compound 2. Hydrogen atoms are omitted for clarity.

Figure 1
Displacement ellipsoid plot (50% probability) of the asymmetric unit of compound 1.
2-bromoaniline, which crystallizes from the melt in the trigonal P3 1 space group (Nayak et al., 2009). Helical arrangements are formed with each molecule involved in intermolecular N-HÁ Á ÁN hydrogen bonds [DÁ Á ÁA distance of 3.162 (6) Å ] and a weaker bromineÁ Á Ábromine interaction (BrÁ Á ÁBr distance of 3.637 (1) Å ), both observed along the 3 1 screw axes, and with additional intramolecular N-HÁ Á ÁBr interactions. In the case of the more sterically hindered derivative 1, this arrangement is not feasible and chains are instead adopted. Most of the crystallographically characterized diarylpiperazines feature the chair conformation; a few have been determined in the twist-boat form (Wirth et al., 2012). Whereas the phenyl groups of piperazine 2 are twisted relative to the N 2 C 4 mean plane, the structure of the less substituted N,N 0 -diphenylpiperazine, which crystallizes in the Pbca space group, exhibits phenyl groups closer to being in conjugation with the nitrogen lone pairs (Wirth et al., 2012;Safko & Pike, 2012). The sum of the bond angles around nitrogen is quite similar between the two structures (2: 338-341 ; N,N 0 -diphenylpiperazine: 343 ), though the N-C aryl bond lengths are slightly shortened in the phenyl-substituted analogue [2: 1.426 (3)-1.431 (3) Å ; N,N 0 -diphenylpiperazine: 1.4157 (15) Å ], indicating that resonance delocalization is a perhaps a minor effect, if present, while packing effects likely dominate. The structures of 2 and the phenyl analogue are overlaid in Fig. 6 for visual comparison.

Synthesis and crystallization
We prepared compound 1 by electrophilic aromatic bromination of the parent aniline, as reported previously for related compounds (Das et al., 2007). The resultant red-brown solid was reasonably pure by 1 H NMR, however it was easily sublimated to afford very pure colourless material, leaving behind oily reddish-brown impurities.
The piperazine compound 2 was unexpectedly obtained as a by-product during the synthesis of N,N 0 -bis(2,4-dimethylphenyl)ethylenediamine (3) via a condensation reaction. Compound 3 is evidently able to compete with 2,4-dimethylaniline as a nucleophile towards 1,2-dibromoethane, once formed. Both desired main product 3 and by-product 2 were isolated after separation by column chromatography. Packing diagram for compound 2. Hydrogen atoms are omitted for clarity.

Figure 3
Packing diagram for compound 1. Carbon-bound hydrogen atoms are omitted for clarity.

Figure 4
Type I bromine-bromine interaction in the packing of compound 1. Carbon-bound hydrogen atoms are omitted for clarity.
Synthetic protocols were conducted under ambient conditions using ACS-grade solvents. All chemicals were obtained from commercial sources and used as received. NMR spectra were collected using a Bruker 400 MHz Avance III spectrometer. 1 H and 13 C resonances are referenced to residual CHCl 3 or CDCl 3 , respectively, using the reported values relative to SiMe 4 (Fulmer et al., 2010).

Preparation of 2-bromo-4,6-dimethylaniline (1)
A 100 mL round-bottom flask equipped with a magnetic stir bar was charged with N-bromosuccinimide (3.4896 g, 19.607 mmol), ammonium acetate (0.1583 g, 2.054 mmol), and acetonitrile (60 mL). The reagent 2,4-dimethylaniline (2.4297 g, 20.050 mmol) was added slowly, by pipette. The resulting mixture was left to stir at room temperature for 90 min. The solvent was removed under vacuum to produce a reddish-brown solid. Water (45 mL) and dichloromethane (45 mL) were added, and the mixture was transferred to a separatory funnel. The organic layer was separated and washed with water (3 Â 30 mL), saturated sodium thiosulfate (30 mL), and brine (30 mL). After drying the organic layer with magnesium sulfate, the mixture was filtered and the volatiles removed under vacuum to afford a brown crystalline solid (3.2723 g, 83.42%). 1 H NMR (CDCl 3 , 400 MHz): 7.15 (s, 1H), 7.14 (s, 1H), 3.93 (s, 2H), 2.22 (s, 3H), 2.21 (s, 3H). The procedure was based on one reported for similar aniline derivatives (Das et al., 2007). The product can be purified by sublimation under static vacuum with heating to 308 K for 3 d. Large X-ray quality crystals of the product were obtained by slow sublimation under ambient conditions in a capped glass vial containing the crude product, over a period of months.
5.2. Preparation of N,N 0 0 0 -bis(2,4-dimethylphenyl)piperazine (2) and N,N 0 0 0 -bis(2,4-dimethylphenyl)ethylenediamine (3) A 100 mL round-bottom flask equipped with a magnetic stir bar was charged with 2,4-dimethylaniline (9.21 mL, 74.5 mmol), 1,2-dibromoethane (3.21 mL, 37.3 mmol), and N,N 0 -diisopropylethylamine (12.98 mL, 74.5 mmol), and fitted with a reflux condenser and drying tube. The mixture was heated to 403 K for 4 h, then cooled to room temperature affording a red solid mass. To this was added H 2 O (50 mL) before extraction with CH 2 Cl 2 (30 mL). The organic phase was washed with H 2 O (50 mL), and to the combined aqueous extracts was added 1 M NaOH(aq) (40 mL), and this mixture was extracted with CH 2 Cl 2 (50 mL). The combined organic extracts were washed with H 2 O (30 mL) and brine (30 mL), dried over MgSO 4 , decanted into a round-bottom flask, and dried under vacuum to afford a dark orange-red liquid. Addition of hexanes (40 mL) resulted in the precipitation of crystalline material. The solid material was redissolved by warming the hexanes, and the resultant clear red solution was stored overnight at 238 K. The mother liquor was decanted  research communications and the remaining solid material was washed with cold hexanes (3 Â 3 mL) and dried under vacuum to afford a beige solid (5.4730 g). NMR data indicated that the product was a 90:10 mol% mixture of 1,2-diamine 3 and piperazine 2, obtained with a 69% yield of products based on 1,2-dibromoethane. Separation of the compounds was achieved by silica gel flash chromatography. Elution of 1.3223 g of a mixture with CH 2 Cl 2 afforded piperazine 2 as a paletan crystalline solid (R f = 0.75, 124.0 mg, 60% recovery) and diamine 3 as a pale-yellow solid (R f = 0.21, 851.4 mg, 84% recovery  (Day et al., 2011). Crystals of piperazine 2 were grown by slow evaporation of a toluene solution of the compound, at room temperature.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 2. The N-H protons of compound 1 were located in the difference map and refined freely. The piperazine 2 crystallized in the non-centric group P2 1 ; no heavy atoms are present in the structure, therefore the Flack parameter was not calculated. Carbon-bound hydrogen atoms were placed in calculated positions (C-H = 0.95-0.99 Å ) and refined according to a riding model, with fixed U iso values of 1.2 times (CH and CH 2 groups) and 1.5 times (CH 3 groups) the parent atom. For both structures, data collection: APEX2 (Bruker, 2015); cell refinement: SAINT (Bruker, 2015); data reduction: SAINT (Bruker, 2015); program(s) used to solve structure: ShelXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

2-Bromo-4,6-dimethylaniline (1)
Crystal data 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Br1 0.97945 (2) 0.20330 (8)  where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.001 Δρ max = 0.20 e Å −3 Δρ min = −0.19 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.