Structure of 2-chloro-N-(p-tolyl)propanamide

Two independent samples of the title compound were studied using Cu Kα and Mo Kα radiation as part of a continuous crystallization study. In the crystal, chains along the a axis are formed via N—H⋯O hydrogen bonds between acetamide groups, as well as C—H⋯O interactions. These chains arrange themselves into parallel running stacks which display weak C—Cl⋯O=Chalogen bonding as well as weak C—H⋯π interactions.

Two independent samples of the title compound, alternatively 2-chloro-N-(4methylphenyl)propanamide, C 10 H 12 ClNO, 1, were studied using Cu K, 1a, and Mo K, 1b, radiation as part of a continuous crystallization study. The molecule crystallizes with disorder in the Cl/terminal methyl positions [occupancies for the major disorder component of 0.783 (2) in 1a and and 0.768 (2) in 1b] and exhibits N-C bond lengths of 1.3448 (19), 1.344 (2) Å , C O bond lengths of 1.2233 (18) and 1.2245 (19) Å and an acetamide moiety C-N-C-C torsion angle of 179.00 (13), 178.97 (14) for 1a and 1b, respectively. In the crystal, chains along the a axis are formed via N-HÁ Á ÁO hydrogen bonds between acetamide groups, as well as C-HÁ Á ÁO interactions. These chains arrange themselves into parallel running stacks which display weak C-ClÁ Á ÁO C halogen bonding as well as weak C-HÁ Á Á interactions.

Chemical context
The introduction of continuous processing has been a paradigm shift in safety and productivity in the synthesis and isolation of active pharmaceutical ingredients (APIs) in both industry and academic research (Mascia et al., 2013 andLee et al., 2015 and references contained therein). A major focus of our current research is developing design and optimization strategies to deliver robust, scalable and tunable continuous processes for API manufacturing, which can deliver specific API characteristics Zhao et al., 2015;O'Mahony et al., 2017;Simon et al., 2018). As part of this work we have been examining the continuous crystallization of 2-chloro-N-(p-tolyl)propanamide, 1, a key intermediate of -thio--chloroacrylamides, a class of compound that has shown importance in the literature as synthetically viable APIs (Murphy et al., 2007;Foley et al., 2011;) that can undergo transformations; such as Diels-Alder cycloadditions (Kissane et al., 2010a), 1,3-dipolar cycloadditions (Kissane et al., 2010b), sulfide group (Kissane et al., 2010c,d) and nucleophilic substitution . To design and understand a continuous crystallization process for 1, an extensive solubility study was conducted examining the compound's solubility characteristics in common organic solvents (Pascual et al., 2017). During this study, an improved bi-phasic synthesis was developed and crystals from two different continuous crystallization process runs were isolated to detect and characterize any variability of the crystalline material produced. These samples, 1a and 1b, of 2-chloro-N-(p-tolyl)propanamide, see Fig. 1, are described herein.
In the extended structure there is, as expected, a strong amide hydrogen bond, between the N-H group and the ketone oxygen (N8Á Á ÁO10 i , see Tables 2 and 3). This feature can be seen in many of the known phenylacetamides and the donoracceptor distance in similar congeners below range from 2.8175 (8) Å (XIHMOQ; Gowda et al., 2001) to the longer interaction in CEXPOK of 3.2576 (6) Å . The distance in IQOHOL is 2.8632 (6) Å , slightly longer than that found in 1.
There is also a weaker interaction between the methine group and the ketone (C11-H11Á Á ÁO10 i , see Tables 2 and 3). This type of chelate hydrogen bonding is also seen in Overlay image of both molecules of 2-chloro-N-(p-tolyl)propanamide (1a is shown in red and 1b in green) with an r.m.s. fit of 0.040 Å (no inversion). Displacement ellipsoids shown at the 50% probability level. Selected atom numbering only for clarity.

Figure 1
Molecular structures 1a and 1b showing the atom-numbering scheme. Only the major occupancy disorder components [1a 0.793 (4) and 1b 0.768 (2)] of the Cl1 and C12 positions are shown. Displacement ellipsoids drawn at the 50% probability level.

Figure 3
Hydrogen-bonding network represented by dotted lines of one layer in the cell viewed normal to the (001)  There are other supramolecular interactions that assist in the packing of 1. Complimenting the hydrogen bonding above, there is a weak C-ClÁ Á ÁO ii C ii halogen bond between the terminal chlorine and the ketone, with distances of 1a, 3.1761 (14) and 1b, 3.1734 (18) Å [symmetry code: (ii) 3 2 À x, À 1 2 + y, z]. A very weak example of a C-HÁ Á Á iii interaction is also present in 1, with the methyl group C12 directed towards the centroid of ring C1-C6 (see Tables 2 and 3).

Synthesis and crystallization
A solution of -chloropropionyl chloride (1.16 mL, 12mmol 1.2 equiv.) in toluene (30 mL) was added dropwise (with extreme caution) to a vigorously stirred bi-phasic suspension of p-toluidine (1.07 g, 10 mmol) in toluene (50 mL) and 40 mL of aqueous NaOH (1.20 g, 30 mmol, 3 equiv.) at 273 K. After the addition was complete, the biphasic suspension was warmed to room temperature and stirred vigorously for 1 h. The organic phase was separated, and the aqueous layer extracted with ethyl acetate (3 Â 15 mL). The organic layers were then combined, dried with Na 2 SO 4 , filtered and the solvent removed under vacuum. The resulting off-white solid was collected and washed with thoroughly with cold cyclohexane (1.89 g, 96%). Single crystals for X-ray analysis were grown by slow evaporation of a toluene solution at room temperature. Spectroscopic data for the obtained product matched that reported in the literature (Pascual et al., 2017).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. In both 1a and 1b, Cl1/Cl1a and C12/C12a were modelled as disordered over two positions using restraints (DFIX for C11-C12, C11-C12a distances) and constraints (EADP, Cl atoms). The occupancy was allowed to refine with a population parameter of 1a = 0.783 (2), and 1b = 0.768 (2). The amide N-H H atom was located in a difference-Fourier map and freely refined. H atoms bonded to carbon were placed with idealized geometry and refined using a riding model with C-H = 0.95 Å aromatic, C-H = 0.90 Å methine, with U iso (H) = 1.2U eq (C) and C-H = 0.98 Å methyl with U iso (H) = 1.5U eq (C).