Crystal structure and Hirshfeld surface analysis of 1-carboxy-2-(3,4-dihydroxyphenyl)ethan-1-aminium chloride 2-ammonio-3-(3,4-dihydroxyphenyl)propanoate: a new polymorph of l-dopa HCl and isotypic with its bromide counterpart

The crystal structure of new monoclininc polymorph of l-dopa HCl is reported, and hydrogen-bonding interactions are discussed.

The title molecular salt, C 9 H 12 NO 4 + ÁCl À ÁC 9 H 11 NO 4 , is isotypic with that of the bromide counterpart [Kathiravan et al. (2016). Acta Cryst. E72, [1544][1545][1546][1547][1548]. The title salt is a second monoclinic polymorph of the l-dopa HCl structure reported earlier in the monoclinic space group P2 1 [Jandacek & Earle (1971). Acta Cryst. B27, 841-845; Mostad & Rømming (1974). Acta Chemica Scand. B28, 1161-1168]. In the title compound, monoclinic space group I2, one of the dopa molecules has a positive charge with a protonated -amino group and the -carboxylic acid group uncharged, while the second dopa molecule has a neutral charge, the -amino group is protonated and the -carboxylic acid is deprotonated. In the previously reported form, a single dopa molecule is observed in which the -amino group is protonated and the -carboxylic acid group is uncharged. The invariant and variations of various types of intermolecular interactions present in these two forms of dopa HCl structures are discussed with the aid of two-dimensional fingerprint plots.

Chemical context
The aromatic amino acid enzyme, tyrosine-3-hydroxylase, catalyses the conversion of the amino acid l-tyrosine to l-dopa (l-3,4-dihydroxyphenylalanine). After successful conversion, the l-dopa molecule acts as a precursor for neurotransmitter molecules, such as dopamine, norepinephrine and epinephrine. The l-dopa molecule is found to be an effective drug in the symptomatic treatment of Parkinson's disease (Chan et al., 2012). Polymorphism is very common amongst pharamaceutically important molecules and is responsible for differences in many properties (Bernstein, 2002(Bernstein, , 2011Nangia, 2008;Guranda & Deeva, 2010). The first monoclinic form (I) [space group P2 1 and z 0 = 1] of l-dopa HCl was reported in the 1970s (Jandacek & Earle, 1971;Mostad & Rømming, 1974). Herein, we report on the crystal and molecular structure of a second monoclinic polymorph, form (II) (space group I2) of l-dopa HCl. The hydrogen-bonding patterns and the relative contributions of various intermolecular interactions present in forms (I) and (II) are compared. ISSN 2056-9890

Structural commentary
The asymmetric unit of the title compound, (II), is illustrated in Fig. 1. It consists of two dopa molecules, and a Cl À anion located on a twofold rotation axis. As observed in the isotypic l-dopa HBr molecular salt (III) (Kathiravan et al., 2016), one of the dopa molecules is in the zwitterionic form and the other in the cationic form. In the cationic dopa molecule, the -amino group is protonated and carries a positive charge and the hydrogen atom (H4O) of the -carboxylic acid group is located in a general position and was refined with 50% occupancy.
The crystal structures of l-dopa (Mostad et al., 1971), its hydrochloride form (I) (Jandacek & Earle, 1971;Mostad & Rømming, 1974), the hydrobromide form (III) (Kathiravan et al., 2016) and the dihydrate form (André & Duarte, 2014), have been reported. The dihydrate form of dopa crystallizes in the orthorhombic space group P2 1 2 1 2 1 with a single dopa molecule in its zwitterionic form. The free dopa molecule and its hydrochloride form (I) crystallized in the monoclinic space group P2 1 . In the l-dopa structure, the dopa molecule is in the zwitterionic form, while in the latter the -amino group is protonated and the -carboxylic acid is neutral. As mentioned earlier (Kathiravan et al., 2016), the deposited coordinates of the l-dopa HCl structure belong to the R configuration. Therefore, the l-dopa HCl structure was inverted and the inverted model used for superposition. As shown in Fig. 2, one of the dopa molecules of the title molecular salt (II) is superimposed with the inverted model of l-dopa HCl (I) and one of the dopa molecules of the isotypic Br compound (III). The r.m.s. deviation of the former pair is 0.105 Å while for the latter pair it is calculated to be 0.094 Å .

Supramolecular features
The crystal structure of the title molecular salt (II) displays a network of intermolecular N-HÁ Á ÁCl, N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds (Table 1), producing a three-dimensional framework (Fig. 3). It is of interest to note that the N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen-bonding geometries in the title compound are slightly different when compared to its isotypic bromide counterpart (III) (Kathiravan et al., 2016) The molecular structure of the title molecular salt, (II), showing the atom labelling scheme [symmetry code: ($) Àx + 3, y, Àz + 1]. Displacement ellipsoids are drawn at the 50% probability level.

Figure 3
Crystal packing of the title molecular salt, (II), viewed along the b axis. The hydrogen bonds are shown as dashed lines (see Table 1), and Cbound H atoms have been omitted for clarity. carboxylic acid group of a dopa molecule with the carboxylate group of an adjacent dopa molecule. This interaction produces dopa dimers that are arranged as ribbons propagating along the b axis (Fig. 3). As observed in the bromide counterpart (III), the protonated amino group acts as a threefold donor for three intermolecular hydrogen bonds, two of them with Cl À anions and one with the carbonyl oxygen atom, O3, of the dopa acid group. One of the characteristic features observed in many amino acid-carboxylic acid/metal complexes (Sharma et al., 2006;Selvaraj et al., 2007;Balakrishnan, Ramamurthi, Jeyakanthan et al., 2013;Sathiskumar et al., 2015a,b,c;Revathi et al., 2015) is that the amino acid molecules aggregate in headto-tail sequences of the type Á Á ÁNH 3 + -CHR-COO À Á Á ÁNH 3 + -CHR-COO À Á Á Á in which -amino andcarboxylate groups are brought into periodic hydrogenbonded proximity in a peptide-like arrangements. Similar arrangements (as layers) are observed in the title compound, in which -amino (atom N1) and -carboxylate (atom O3) groups interact via an N-HÁ Á ÁO hydrogen bond. Adjacent layers are interconnected by strong O-HÁ Á ÁO hydrogen bonds. The former N-HÁ Á ÁO and the latter O-HÁ Á ÁO interactions collectively form an R 4 4 (18) ring motif (Fig. 4). Similar interactions are presented in dopa and the HCl form (I).
As shown in Table 1, the amino group (via H1A and H1B) of the dopa molecule participates in N-HÁ Á ÁCl interactions with two different Cl À anions. As observed in the bromide counterpart (III), these interactions interconnect the cations and anions into a chain of cyclic motifs that enclose R 4 2 (8) rings and runs parallel to the b axis (Fig. 5a). Forms (I) and (II) of the dopa HCl structures differ in the formation of cyclic motifs. In form (I), two N-HÁ Á ÁCl hydrogen bonds link the cations and anions into a chain. Adjacent chains are interconnected through O-HÁ Á ÁCl interactions (carboxylic acidÁ Á ÁCl). Collectively, these interactions generate cyclic motifs (Fig. 5b).
The side-chain hydroxy groups (O1-H1O and O2-H2O) of the dopa molecules are involved in O-HÁ Á ÁO hydrogenbonding interactions, the former with the carbonyl oxygen atom (O3) and the latter in a bifurcated mode with two different hydroxy (O1 and O2) oxygen atoms of adjacent dopa Part of the crystal structure of (II) showing the R 4 4 (18) motifs formed through N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds (see Table 1).

Figure 6
Adjacent dopa layers are interlinked by side chain-side chain interactions in (II) through intermolecular O-HÁ Á ÁO hydrogen bonds (see Table 1).

Figure 5
(a) Part of the crystal structure of (II) showing the R 4 2 (8) motif formed by intermolecular N-HÁ Á ÁCl hydrogen bonds (see Table 1 layers (Fig. 6). These interactions are invariant in the dopa structures reported earlier.

Hirshfeld surface analysis
The Hirshfeld surfaces (HS) and the decomposed twodimensional fingerprint plots have been generated, using the program CrystalExplorer (Wolff et al., 2012), to investigate the similarities and differences in the crystal packing amongst polymorphs. The two different views of the HS diagram for the complete unit of dopa molecules along with the Cl À anion and the two-dimensional fingerprint plots are shown in Fig. 7.
The analysis suggests that the OÁ Á ÁH contacts contribute more (41.6%) to the crystal packing when compared to other contacts with respect to the dopa molecules in the title compound. The relative contributions of HÁ Á ÁH, CÁ Á ÁH and HÁ Á ÁCl contacts are 29, 18.6 and 6.2%, respectively, with respect to the complete unit of dopa molecule. These contacts are nearly identical in the case of the bromide counterpart. The HÁ Á ÁCl and OÁ Á ÁCl contacts contributions to the Hirshfeld surface area for the Cl ion are 71.9 and 13.7%, respectively. In the bromide counterpart (III), the corresponding contacts are found to be 64.1 (HÁ Á ÁBr) and 10.2% (OÁ Á ÁBr). It is clearly seen that these contacts are lower in the bromide counterpart (III) when compared to the title salt (II).
In form (I) of the dopa HCl structure, the relative contributions of OÁ Á ÁH, HÁ Á ÁH, CÁ Á ÁH and HÁ Á ÁCl contacts are 40.5, 25.2, 17.1 and 14.1%, respectively, with respect to the cationic dopa molecule. It is worthy to note that OÁ Á ÁH and HÁ Á ÁH contacts are reduced by 1.1-3.8% when compared to form (II). The HÁ Á ÁCl contact is increased by 7.9% in (I) when compared to (II) of the dopa HCl structure. In (I) anionic Cl À , the relative contribution of HÁ Á ÁCl contacts is found be 90.4%. This is approximately 18.5 and 26% higher when compared to (II) and its bromide counterpart (III). These contacts are used to discriminate between forms (I) and (II).

Synthesis and crystallization
l-dopa and HCl (1:1 molar ratio) were dissolved in doubledistilled water and stirred well for 6 h. The mixture was filtered and the filtrate left to evaporate slowly. Colourless block-shaped crystals of the title molecular salt (II) were obtained after a growth period of 15 days.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Since the title molecular salt (I) is isotypic with its bromide counterpart (III) (Kathiravan et al., 2016), it was refined with the coordinates of the dopa molecule of the latter as a starting model. The Cl À anion was located from a difference Fourier map. The amino and carboxylic acid H atoms were located from a difference Fourier map and freely refined. The OH groups of the dopa side chain and Cbound H atoms were treated as riding atoms and included in geometrically  Computer programs: APEX2, SAINT and XPREP (Bruker, 2004), Mercury (Macrae et al., 2006), SHELXL2014/7 (Sheldrick, 2015) and publCIF (Westrip, 2010). Structure solution -isomorphous replacement.