Polymorphism of an Organic System Effected by the Directionality of Hydrogen-Bonding Chains

Four polymorphs of 2-[methyl(phenyl)amino]nicotinic acid were discovered, and their single crystal structures were obtained at 90 K. In addition, one monohydrate and one salt were also crystallized and measured. Among the crystal structures, there are 17 crystallographically independent conformations. More interestingly, the four anhydrate forms are tessellated similarly by stacking of onedimension hydrogen-bonding chains and, yet, the directionalities of the hydrogen-bonding chains are unique in each polymorph. Polymorphism, as defined in McCrone’s words, is “the ability of a given element or compound to crystallize as more than one distinct crystal species.” Some crystals are conformational polymorphs because of conformational variations of molecules in the solid state. Because of the dissimilarity in solid-state structures, polymorphs of the substance can vary significantly in their physicochemical properties. An understanding of the structureproperty relationships in polymorphs has been an impetus of polymorphism studies as epitomized by the fast growing number of crystal structures in the Cambridge Structural Database (CSD) as well as a vast amount of research reports including several recent books on polymorphism. The polymorphic formation of a given substance lies in a compromise between interand intramolecular interactions which can be affected by crystallization conditions. A number of diarylamines are known to be polymorphic. During our systematic investigation of these compounds, we have discovered four polymorphs (I, II, III, and IV), one monohydrate, and one hydrochloride salt of 2-[methyl(phenyl)amino]nicotinic acid (2-MPNA), shown in Figure 1a, from different growth conditions. Single crystal structures were solved at 90 K with R1 values smaller than 0.059 and the crystallographic data are listed in Table 1. For the details of experimental procedures, see Supporting Information. It is known that organic systems with four or more well-characterized polymorphs are scarce. 2-MPNA is particularly unusual not only in the exhibition of extensive polymorphism, but also in the total number of crystallographically independent conformations in the four polymorphs, which stands at 17 (Z′ ) 1, 3, 3, 10 for forms I, II, III, and IV, respectively). The number increases to 19 if the monohydrate (Z′ ) 1) and salt (Z′ ) 1) are included. Furthermore, all of the crystal structures consist of respectively equal numbers of R and S enantiomeric conformations that stem from the chirality of the tertiary amino group (N7). In all the structures except form IV, the R and S conformations are mirror images (e.g., Figure 1c) that are directly related by crystallographic symmetry operations (i.e., glide plane). In the case of form IV, there are five different R and five different S enantiomeric conformations presented in the asymmetric unit (Z′ ) 10); however, no R/S mirror pair can be identified and no reflection symmetry is present in the space group (P21). Organic crystals with high Z′ are not commonly seen; a survey of crystal structures with Z′ g 10 in the 2008 CSD resulted in 30 hits; 20 were organic and 10 organometallic. The 19 symmetry-independent conformations differ in three torsion angles designated as τ1, τ2 and τ3 (Figure 1b and Table 2). An R enantiomeric conformation has all three angles negative while an S has them positive. As a result of glide-reflection symmetry, the absolute values of τ1-τ3 of each R/S pair in all but form IV are exactly the same; the slightly different values in form IV are due to the lack of reflection symmetry relating the R and S molecules, probably caused by subtle variations in the local intermolecular interaction environment. In all molecules, the C-C bond between COOH and the pyridinyl ring is single as indicated by the bond length (average distance: 1.488 (5) Å). This suggests rotation about the C-C bond is permitted. In addition, due to the steric hindrance caused by the methyl group, the atom N7, which bridges the two aromatic rings, is no longer conjugated with either ring. Figure 2 illustrates conformational energy scans of single R enantiomeric conformer versus the three torsion angles respectively. It appears that each angle has two energy minima. For τ1, the global energy minimum is located at -157.5° and the second minimum at 35.0° (7 kJ/mol higher). For τ2, the two values are -142.5° and 62.5° with the latter being 35 kJ/mol higher in energy. For τ3, because of the 2-fold symmetry of the phenyl ring along N7-C8, the two iso-energetic values are 45.0° and -137.5° despite a small energy difference seen in the figure, which is an artifact caused by the calculations where only τ3 was allowed to change while other angles and bond distances were kept constant (this is also the case for evaluating τ1 and τ2, respectively). The torsion angles of all R conformers as listed in Table 2 clearly show the molecules reside very closely in the basin defined by the energy minima of the three torsion angles. The similarity in their conformations is further illustrated by the inset figure in Figure 2. The monohydrate form indicates similar yet noticeably different τ1 from those in the anhydrate forms, plausibly a result of change in the molecular energy and hydrogen bonding pattern thanks to the relocation of * To whom correspondence should be addressed. Phone: (859) 257-1472. Fax: (859) 257-7585. E-mail: [email protected]. † Department of Pharmaceutical Sciences. ‡ Department of Chemistry. Figure 1. R-2-[methyl(phenyl)amino]nicotinic acid (a) with atoms labeled as in the crystals and torsion angles marked (b) and superimposed enantiomeric conformers found in form I indicating their mirror symmetry (c). Note that the lone pair of electrons on N7 points inward in (b). CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 9 3137–3140 10.1021/cg800339h CCC: $40.75  2008 American Chemical Society Published on Web 07/29/2008 the acidic proton and participation of water molecules. Moreover, the salt form takes a significant adjustment in the conformation as indicated by τ1. The crystal structures of forms I-IV exhibit the same hydrogenbonded acid-to-pyridine catemer; forms I-III show a C(6) motif and form IV a C2(12) according to the graph-set analysis of hydrogen bonds. In form I, molecules with alternating absolute configuration organize themselves as one-dimensional chains perpendicular to the (101) plane (Figure 3a). In form II, the R/S enantiomers of each conformer form one-dimensional chains along the a axis (Figure 3b); similarly, in form III, the one-dimensional chains are along the c axis (Figure 3c). In form IV, each enantiomeric pair forms a one-dimensional chain along the c axis, resulting in five unique chain packing motifs in the unit cell (Figure 3d). Despite strong similarities among the four crystal structures, these are four distinct polymorphs as demonstrated by the hydrogenbonding patterns in the crystal structures. Because each 2-MPNA molecule accepts (due to the pyridinyl N1) and donates (due to the hydroxyl O17) protons along every one-dimensional hydrogenbonding network, the flow direction of protons may be regarded Table 1. Crystallographic Data of Crystal Structures Identified of 2-MPNA I II III IV monohydrate HCl salt formula C13H12N2O2 C13H12N2O2 C13H12N2O2 C13H12N2O2 C13H12N2O2 ·H2O C13H12N2O2 ·HCl morphology colorless needle colorless plate colorless block colorless needle colorless needle colorless block melting point (onset) (°C) 133.0 125.0 127.0 129.0 82.0 220.0 space group Cc Pca21 Pc P21 P21/n P21/n a/Å 11.711(2) 14.3290(2) 13.316(3) 8.6871(7) 7.155(1) 6.896(1) b/Å 8.644(2) 8.9360(3) 8.841(2) 44.926(4) 7.595(1) 13.5839(3) c/Å 11.664(2) 26.5210(7) 14.282(3) 14.238(1) 21.868(4) 13.7170(3) R/° 90 90 90 90 90 90 /° 104.17(3) 90 91.60(3) 90.113(4) 90.73(1) 102.60(3) γ/° 90 90 90 90 90 90 Z′ 1 3 3 10 1 1 Z 4 12 6 20 4 4 V/Å 1144.8(4) 3395.9(2) 1680.7(6) 5556.9(8) 1188.3(3) 1253.9(4) Dcal/g · cm 1.324 1.339 1.353 1.364 1.377 1.402 R1 0.0587 0.0539 0.0537 0.0488 0.0388 0.0493 wR2 0.1914 0.1244 0.1060 0.1620 0.1090 0.1485 T/K 90.0(2) 90.0(2) 90.0(2) 90.0(2) 90.0(2) 90.0(2) a Please see Supporting Information for more thermal data of the crystal systems. b Strictly speaking, this should be the dehydration temperature. Table 2. Torsion Angles, τ1 (O17-C15-C3-C2), τ2 (C3-C2-N7-C8), and τ3 (C2-N7-C8-C9/C13), in Forms I-IV, Monohydrate (H), and Salt (S)