Quantitative Investigation of Polymorphism in 3-(Trifluoromethyl)-N-[2

Article pubs.acs.org/crystal

Quantitative Investigation of Polymorphism in 3‑(Trifluoromethyl)‑N‑[2-(trifluoromethyl)phenyl]benzamide Piyush Panini,† Subhrajyoti Bhandary,† and Deepak Chopra* Crystallography and Crystal Chemistry Laboratory, Department of Chemistry, Indian Institute of Science Education and Research, Bhopal, Madhya Pradesh 462066, India S Supporting Information *

ABSTRACT: The occurrence of concomitant dimorphism has been observed in the case of trifluoromethyl substituted benzanilide, namely, 3-(trifluoromethyl)-N-[2-(trifluoromethyl)phenyl]benzamide, wherein both forms show the presence of a multiple number of molecules in the asymmetric unit (Z′ > 1). Thermal studies confirm the “extremely rare occurrence” of simultaneous melting and solid-to-solid phase transition at the same temperature from centrosymmetric, Z′ = 2 structure (triclinic, P1,̅ form I) to noncentrosymmetric, Z′ = 4 structure (monoclinic, Cc). Both forms exhibit similar density and lattice energy. Conformationally different molecules in the asymmetric unit in both the high-Z′ structures are observed to be connected with strong N−H···OC and weak C−H···OC hydrogen bonds. The dissimilarities in the crystal packing were analyzed by Xpac method, and the molecule−molecule interaction energies were evaluated by the PIXEL method. The results revealed the presence of 2D isostructurality between the two forms which mainly consists of the most stabilized intermolecular interactions (namely, strong N- H···OC, C−H···OC, and C−H···π hydrogen bonds) in their crystal packing while differences in their crystal packing are mainly on account of the presence of weak C−H···F−C(sp3) hydrogen bond and C(sp3)−F···F−C(sp3) interactions.

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a compound.5 This has also been observed in the case of polymorphism by many researchers where higher Z′ structures were less stable than the lower Z′ structures, showing phase transition from the higher Z′ structure to the lower Z′ > 1 structure.16,17 However, there are reports wherein the higher Z′ structures are more thermodynamically stable18 and also the phase transition from lower Z′ to the more stable Z′ > 1 structures have been observed. The most comprehensive and comparative work on Z′ = 1 and Z′ = 2 structures by Gavezzotti with detailed inputs from PIXEL energy calculations19 concluded that about 55−60% of structures consists of the highest stabilized molecular pairs in the asymmetric unit.6 It was observed by the author that structures with space groups P1, P21, and P1̅ are more likely to show Z′ = 2. Polymorphism is a phenomenon of occurrence of two molecular arrangements of the same compound in the solid state and may lead to changes in many physical properties such as melting point, particle size, stability, tableting, bioavailability, dissolution rates, and pharmacological activity among polymorphs.20,21 The changes in physiochemical activity and other related properties among polymorphs are of special interest in the research area which is directly related to pharmaceuticals.22,23 Concomitant

INTRODUCTION In recent years, the number of crystal structure determinations for solids and also for compounds which are liquids at room temperature deposited in the Cambridge Structural Database has been increasing at a rapid rate (approximately 40000 per year).1 This also includes the compounds which crystallized with multiple numbers of molecules in the asymmetric unit (Z′ > 1). Structures with Z′ > 1 have always been of interest to the scientific community, and the possible reasons for their existence are still not fully understood.2−10 The current CSD search11 shows that around 12.5% of total organic crystal structures consist of Z′ > 1. This percentage is now increased from the previously reported number (8.8% of total structure).3 It was postulated that the Z′ > 1 structures are metastable forms of a compound which are obtained under kinetic conditions. There have been many reasons, for example (i) pseudosymmetry, (ii) modulation,12 (iii) awkward molecular shape, (iv) equi-energetic conformation,4 (v) molecules having many functional groups which can form strong hydrogen bonds (for example, alcohols, steroids, nucleoside, and nucleotides) or can form charge assisted interactions,13 (vi) melt or sublimation crystallization,14 and (vii) supramolecular synthon frustration15 as highlighted by Steed2−4 and other researchers for the observed phenomenon. It was also stated that it is a crystal “on the way” or “fossil relics” which just had started and can be a consequence of incomplete or interrupted crystallization, hence actually a metastable form of © 2016 American Chemical Society

Received: November 20, 2015 Revised: March 30, 2016 Published: April 5, 2016 2561

DOI: 10.1021/acs.cgd.5b01638 Cryst. Growth Des. 2016, 16, 2561−2572

Crystal Growth & Design

Article

Table 1. Crystallographic and Refinement Data of the Two Forms of T-1-2 data

T-1-2 form I

T-1-2 form II

formula fw CCDC No. cryst syst, space group a (Å) b (Å) c (Å) α (deg)/β (deg)/γ (deg) vol (Å3)/density (g/cm3) Z/Z′ F(000)/μ (mm−1) θ(min)/θ(max) hmin,max; kmin,max; lmin,max no. of reflecns no. unique reflecns/obs reflecns no. of params R(all), R(obs) Rw2(all), Rw2(obs) Δρmin,max (e Å−3) GOF

C15H9F6NO 333.23 1043499 triclinic, P1̅ 7.8491(7) 7.9883(8) 23.143(2) 88.435(3)/82.971(3)/75.095(3) 1391.7(2)/1.590 4/2 672/0.155 2.64/27.48 −10, 9; −10, 10; −30, 30 25934 6359, 4261 415 0.0862, 0.0457 0.1104, 0.0973 −0.304, 0.350 1.032

C15H9F6NO 333.23 1043500 monoclinic, Cc 12.658(2) 9.6582(16) 45.734(7) 90/94.585(4)/90 5573.1(16)/1.589 16/4 2688/0.155 2.66/28.43 −16, 16; −12, 12; −61, 61 64803 14033, 12466 880 0.0438, 0.0359 0.0865, 0.0829 −0.225, 0.322 1.036

Figure 1. Crystals obtained after crystallization from methanol and hexane. Concomitance [crystals of two morphologies (needles and plates)] was observed.

polymorphism24 is a phenomenon when two or more forms crystallize simultaneously from the same solvent and crystallization flask under identical crystal growth conditions. The physical or chemical properties which may vary among different polymorphs are unequivocally characterized by different techniques such as melting point measurements [differential scanning calorimetry (DSC)], thermogravimetric analysis (TGA), spectroscopic tools [IR, Raman, and solid-state (SS) NMR], and X-ray diffraction (powder and crystal) techniques.25 Moreover, polymorphs provide a platform to study and understand the differences in crystal packing which may arise due to (i) Z′ > 1, if it occurs; (ii) two polymorphs may have different molecular conformation, a phenomenon defined as conformational polymorphism;26−30 (iii) different intermolecular interactions occur among two or more polymorphs. An extensive database analysis with inputs from molecule−molecule energy calculations by the atom−atom potential method on polymorphs of organic compounds in which at least one member has Z′ > 2 has been performed by Bernstein et al.,31 and the authors observed that the high-Z′ polymorph exhibits a minor tendency to have a lower density and corresponds to a

Figure 2. DSC traces, recorded at 5 °C/min for (a) T-1-2 form I crystals (b) T-1-2 form II crystals, and (c) T-1-2 bulk powder (obtained after synthesis) for two heating and cooling cycles.

high-temperature form while in cases where the high-Z′ polymorph has the higher density, it corresponds to the lowtemperature form. The crystallization method (i.e., the procedure from which the crystal has been obtained) was also observed to influence the process of obtaining the high-Z′ polymorph. Furthermore, they observed that performing the lattice energy calculations of different forms gives insignificant information about the reason for the occurrence of the high-Z′ structure. In this work, we report a dimorphic system (crystallized concomitantly) in the case of a trifluomethyl substituted benzanilide, namely, 3-(trifluoromethyl)-N-[2-(trifluoromethyl)phenyl]benzamide (T-1-2), wherein one form crystallizes in the 2562



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The synthesis of compound T-1-2 is already reported in our previous work.37 Compound T-1-2 crystallized in two morphologies (needle and plate; Figure 1 and Supporting Information Figure S1) from methanol + hexane (1:1) and was observed to exhibit concomitant

polymorphism.24 Single crystal data collection and subsequent structure solution results indicate that the needle form (T-1-2 form I) crystallizes in the centrosymmetric triclinic space group P1̅ with two molecules in the asymmetric unit (Z = 4) while the plate form (T-1-2 form II) crystallizes in the noncentrosymmetric monoclinic space group Cc with four molecules in the asymmetric unit (Z = 16) [Table 1]. Characterizations of Polymorphs. The two polymorphs have been characterized using thermal techniques such as differential scanning calorimetry (DSC), hot stage microscopy (HSM), powder X-ray diffraction (PXRD), and also solid-state FTIR techniques (Figures 2−5 and Figure S4). DSC experiments were performed on the bulk powder (obtained after synthesis and purification by column chromatography)37 and the two polymorphs of T-1-2 with a PerkinElmer DSC 6000 instrument. Each of the polymorphs along with the bulk powder was subjected to two heating−cooling cycles. The results of the DSC experiments on the needle crystals (form I) display two endothermic peaks adjacent to one other: the first peak is observed at 109 °C (ΔHt = −15.4 J/g) while the second is at 112 °C (ΔHt = −69.8 J/g) with the scanning rate of 5 °C/min (Figure 2a). In the subsequent heating cycle only one endothermic peak at 111.5 °C was observed. Further, DSC experiments at 5 °C/min on the plate crystals (form II) displays an endothermic peak at 112 °C (ΔHt = −98.2 J/g) and remained

Figure 3. Overlay of DSC traces for T-1-2 form I crystals, recorded at different scan rates.

Figure 5. Overlay of experimental PXRD patterns of two forms of T-1-2 with the bulk powder, obtained after synthesis and purification.

centrosymmetric triclinic space group P1̅ with two molecules in the asymmetric unit (Z = 4; T-1-2 form I) while the other (T-1-2 form II) crystallizes in the noncentrosymetric monoclinic space group Cc with four molecules in the asymmetric unit (Z = 16) [Table 1]. These exhibit an extremely rare occurrence of melting along with solid-to-solid phase transition, occurring at the same temperature from form I (Z′ = 2) to form II (Z′ = 4), and this feature is not investigated in the literature. Further, these polymorphs have been extensively studied by inputs from Xpac method,32−34 and the role of different intermolecular interactions has been analyzed by molecule−molecule interaction energy calculations by the PIXEL method.19 In addition, this system provides opportunities to analyze the role of interactions involving organic fluorine (“C−F” group), namely, the weak C−H···F−C hydrogen bond35−39 and C−F···F−C40 interaction in polymorph formation.41

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EXPERIMENTAL SECTION

Figure 4. Hot stage microscope snapshots at 2 °C/min heating rate of form I (needle) and form II (plate). Purple circle indicates the initiation of melting for form I and solid-to-solid-phase transition from form I to form II together at 109 °C. Red arrow shows the appearance of plate-like crystals (form II). 2563



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was observed, the solid-to-solid phase transition from form I to form II (appearance of plate-like crystal) and initiation of the melting of form I occurs simultaneously at around 109 °C followed by the further completion of melting of form I and form II (shown by purple circle and red arrow in Figure 4). Therefore, it may be difficult to conclude that the two polymorphic forms are either “monotropically” or “enantiotropically” related as in the case of form I; both events of solid-to-solid phase transition and melting happen at the same temperature (109 °C). To get further insights into the simultaneous occurrence of melting and solid-to-solid phase transition at the same temperature, DSC experiments with different scanning rates were performed on the crystal of form I [Figure 3]. The experiment shows that neither the onset temperature of the first endotherm (a) nor the second (b) one are affected significantly by the presence of different scanning rates [Figure 3]. So, it can be concluded that the melting event happens in both the endothermic peaks. Further, it was observed that the phase transition (peak a) endothermic peak is more visible and prominent at a higher scan rates (5 and 10 °C/min) whereas, at lower scanning rates (1 and 3 °C/min), the first endothermic peak a is small and the second endothermic peak b is more prominent. (Figures 2b and 3). These unusual42,43 results suggest that, at the higher scanning rates, the sample partly underwent solid-to-solid phase transition (form I to form II) along with the melting of pure form I in the first endotherm (peak a) followed by the melting of the converted form II and the remaining form I in the second endotherm (peak b). Lowering the scanning rate may provide enough time for solid-to-solid second order transition to the former phase along with melting of a small amount of form I in the first endotherm due to kinetic reasons. So, the second endothermic peak corresponds to melting of form II as the heat of transition [ΔHt(b) = −95.5 J/g for 1 °C/min] for this process is very similar to what was observed for melting of form II (Figure 2b; ΔHt = −98.2 J/g). From the thermal characterizations it can be concluded that kinetics play a very important role on the relative stability of the two polymorphs; for the slower scanning rates (e.g., 1 °C/min) form I is converted to form II to near completion along with the negligible amount of melting of form I

Figure 6. ORTEP diagrams of (a) T-1-2 form I and (b) T-1-2 form II, drawn with 50% ellipsoidal probability with the atom numbering scheme. Dotted lines indicate the presence of different intermolecular interactions in the asymmetric unit. (c) Molecular overlay (drawn with Mercury 3.355) of six molecules (two molecules in the asymmetric unit of form I and four in form II) in the two polymorphs at solid-state geometry. Color code for C atoms: gray, T-1-2 form I molecule 1; purple, T-1-2 form I molecule 2; black, T-1-2 form II molecule 1; orange, T-1-2 form II molecule 2; green, T-1-2 form II molecule 3; cyan, T-1-2 form II molecule 4. invariant in the second heating cycle (Figure 2b). Hence, the study suggests that there is a phase transition of form I to form II near 109 °C, which remained unchanged in the subsequent heating cycles. In order to monitor the visualization processes on the occurrence of the phase transition, HSM experiments have been performed on a Linkam LTS420 instrument connected with a Leica polarizing microscope. From this experiment (Figure 4) an interesting phenomenon

Table 2. List of Selected Torsion Angles (deg) torsion 1 (deg)a C2−C1−C13−N1 T-1-2 form I T-1-2 form II a

n

165.96/168.08 −162.95/ −166.84/164.22/167.85n

torsion 2 (deg)a C13−N1- C7−C12 n

63.66/62.84 116.99/114.40/67.08/63.50n

torsion 3 (deg)a C7−N1- C13−C1 177.80/175.55n −178.22/−173.16/178.95/176.95n

Also corresponds to similar torsions in the nth molecule in the asymmetric unit of the two forms; n = 1/2/3/4, respectively.

Figure 7. Presence of 2D SC in form I and form II of T-1-2.

Figure 8. Presence of 1D SC in form I and form II of T-1-2. 2564



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in the first endothermic peak. So, they are most likely to be enantiotropically related as an endothermic phase transition (form I to form II) observed before melting in the case of form I. Wherein form I is more stable below the transition point and form II is more stable at higher temperature, form II does not convert to form I on cooling since it is not kinetically accessible.44 Moreover, DSC traces for the bulk powder at 5 °C/min shows an endothermic peak at 111 °C for the two heating cycles (Figure 2c). It thus suggests that it is representative of form II (having a similar melting point). In all DSC traces, the exothermic peak corresponds to recrystallization of the material while cooling. The experimental powder pattern of the bulk powder of T-1-2 and the two forms were recorded on a PANalytical Empyrean X-ray diffractometer (angle, 0−50°; step size, 0.013103°; time per step, 200 s; scan

speed, 0.0167°/s; number of steps, 4189). For that, the two forms were carefully separated from the crystallization beaker and crushed to make a powdered sample using a grinder. The results show the similarity in peaks of the corresponding 2θ position for the experimental PXRD pattern of the bulk with the recorded PXRD pattern of T-1-2 form II (Figure 5). Therefore, the bulk is representative of the form II of T-1-2. This has also been concluded from the experiments on thermal characterization and further confirmed by profile fitting refinement by JANA200045 (Figure S3). In comparison of IR spectra of bulk powder with two polymorphic forms (Figure S4), small blue shifts in N−H and CO bond stretching frequencies were observed on going from form I to form II. Theoretical Calculations. To investigate the relative stability of these polymorphs, the lattice energies were calculated from the atom− atom method in the CLP module46,47 (Table 3). This is on account of the fact that the PIXEL method cannot work when more than two molecules are present in the asymmetric unit. The obtained lattice energy was observed to be comparable with the experimental sublimation energy of benzanilide. The interaction energy of the molecular pair was calculated from the PIXELC module19 in the CLP program package. For this purpose hydrogen atoms were moved to their neutron value and an accurate electron density of the molecules was obtained at MP2/6-31G** with Gaussian 09.48The output file (mlc file), after PIXEL calculation,

Table 3. Lattice Energy (kJ/mol) Partitioned into Coulombic, Polarization, Dispersion, and Repulsion Contributions by Atom−Atom CLP Method 1 2

code

Ecoul

Epol

Edisp

Erep

Etota

T-1-2 form I T-1-2 form II

−32.9 −33.0

−29.9 −30.1

−141.2 −139.6

74.2 74.7

−129.8 −127.9

a

Reported experimental sublimation energy for benzanilide = 125.4 kJ/mol.32

Figure 9. Similar molecular pairs in the two forms of T-1-2 along with their interaction energy [(numbers in red), kJ/mol, Table 4]. Dotted lines indicate the intermolecular interactions. Different colors of C atoms correspond to different molecules in the asymmetric unit. 2565



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Figure 10. Molecular pairs, involving fluorine interactions in the two forms of T-1-2 along with their interaction energies [(numbers in red), kJ/mol, Table 4]. consists of molecule−molecule interaction energy along with the symmetry elements which relate to the molecules. The interaction energy of a selected molecular pair (from the mlc file), extracted from the crystal packing along with the involved intermolecular interactions, were listed in Table 4, with the total energies being partitioned into their Coulombic, polarization, dispersion, and repulsion contributions. Since PIXEL cannot handle more than two molecules in the asymmetric unit, hence in the case of T-1-2 form II (having four molecules in the asymmetric unit), a total of six calculations were performed taking two molecules at a time and keeping the crystal lattice invariant. In this way, the interaction energies of all of the possible molecular pairs could be obtained in the case of T-1-2 form II.49 In case of the disordered -CF3 group in form II, the molecules with the maximum population of F atoms was considered for the calculations. It was observed that the results obtained by the PIXEL energy calculations are comparable with those which are calculated at high-level MP2 and DFT-D quantum mechanical calculations.50−53 XPAC Analysis. The similarities or dissimilarities that exist in the crystal packing of the two polymorphs of T-1-2 were analyzed by Xpac method.32−34 The advantage of the Xpac method is its flexibility in allowing the comparison of structures with Z′ > 1, polymorphs, multicomponent systems and families of related compounds. In this program, a set of neighboring molecules is generated around a central molecule from the symmetry operations of the space group of each structure.54 The common supramolecular motifs, termed as “supramolecular constructs (SCs)”, are then identified by the program. The central molecule in the cluster is called the “kernel molecule” and all the molecules surrounding it thus lead to the generation of the coordination sphere. Then the crystal packing of the compounds

(taking two at a time) is compared solely on the basis of the relative geometric conformations and position of the molecules. In the program the molecule is represented by selecting the atoms in the molecule which best represent the molecular shape. This is called the “corresponding ordered set of points” (COSP). The parameter based on angular, planar, and distance relationships between the kernel molecule and the molecule in the cluster is now compared between the two crystal structures. It may be 3D (exactly similar arrangement or isostructural), 2D (layer of molecules is similar), 1D (a row of molecules is similar), or 0D similarity (isolated units such as dimers are identical in the packing). The measure of the extent to which the two crystal structures deviate from the perfect geometrical similarity is defined as the “dissimilarity index (X)”.34 Lower the value of X, the better is the structural match.

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RESULTS AND DISCUSSION ORTEPs of the two forms were presented in Figure 6a,b. It is noteworthy that the two molecules in the asymmetric unit in form I are connected by the strong N−H···OC hydrogen bond along with weak C(sp3)−F···CO interactions (Figure 6a). This is the most stabilized molecular motif in the T-1-2 form I (IE = 54.9 kJ/mol, Table 4). However, in the case of T-1-2 form II (Z′ = 4), the strong N−H···OC hydrogen bond along with weak C(sp3)−F···CO interactions linked two pairs of molecules (molecule 1 with molecule 2, IE = −53.2 kJ/mol; molecule 3 with molecule 4, IE = −55.8 kJ/mol; these belong among the four most stabilized motifs in form II, Table 4) in the 2566



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Table 4. Intra- and Intermolecular Interactions along with Interaction Energies (IE, kJ/mol) Obtained from the PIXEL Method (Neutron Values Given for All D−H···A Interactions)

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Table 4. continued

Figure 11. Comparative view of the packing of molecules in (a) T-1-2 form I down the ac plane and (b) form II down the ac plane. Dotted lines depict the intermolecular interactions, and different colors for C atoms have been used for Z′ > 1. Shaded regions show the similar parts in their crystal packing.

asymmetric unit. Further, two of the most stabilized motifs are observed to be connected via dimeric weak C(sp3)−F···F−C(sp3) interactions (Figure 6b, motif XV, IE = −6.9 kJ/mol, Table 4) in the asymmetric unit in T-1-2 form II. Overlay of the six molecules (two molecules in the asymmetric unit of form I and four in form II) shows that molecules 1 and 2 of form II [color code, black and orange; Figure 6c and Figure S5] have a different molecular conformation than the rest of the four molecules (including two molecules in form I) in the solid. The direction of the -CF3 group on the aniline side of the molecule is observed to be oppositely oriented

(the difference in the associated torsion 2 lies between 47 and 54° for these molecules; Table 2) in comparison with molecules 1 and 2 of form II with the remaining four molecules (Figure 6c and Figure S5). In addition, a slight difference in the torsion associated with the phenyl ring on the carbonyl side (torsion 1) is also observed in the case of molecules 1 and 2 of form II while the remaining four molecules have nearly invariant molecular conformation (Figure 6c and Figure S5). Hence, it is noteworthy to mention that in both the forms, the molecules in the asymmetric unit possess different molecular conformations which are connected with the strong N−H···OC hydrogen bond. 2568



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Figure 12. Schematic display of crystal packing in T-1-2 form II. The shaded box indicates the similar 2D molecular packing in the two forms of T-1-2.

similar density. The obtained lattice energy is observed to be comparable with the experimental sublimation energy of benzanilide.56 Partitioning of the lattice energy into different energy components revealed that contribution from the dispersion energy toward the total stabilization energy is highest (approximately 70% in the two forms) in the case of organic crystals. Comparison of the molecular pairs extracted from the crystal packing of T-1-2 form I and form II (Figures 9 and 10 and Figure S6) further confirms the 2D similarities associated in their crystal packing. Except a few motifs, all were observed involving similar intermolecular interactions. In both cases, the most stabilized molecular pairs were observed to consist of strong N−H···OC hydrogen bond along with weak C−H··· OC hydrogen bond and C(sp3)−F···CO interactions (motifs I and II in form I and motifs I−IV in form II; Figure 9) with IE in the range of 52−57 kJ/mol (Table 4) in the two forms. In the case of form I, two symmetry independent molecules (both show different molecular conformation) alternate with each other in the formation of the molecular chain along the a-axis (Table 4), utilizing motifs I and II. Further, in the case of form II, the formation of a similar molecular chain, but along the [110] direction, wherein two molecules with different molecular conformations alternate with each other (motif I with III and motif II with IV) in the crystal packing (Figures 9 and 11). It is to be noted that the next set of stabilized motifs (similar in both forms) was observed to be involved in a short C−H···OC hydrogen bond (less than 2.37 Å, motifs III and IV in form I and motifs V−VIII in form II; Figure 9; IE lies between −17 and −19 kJ/mol). The total interaction energy has significant contribution (42−52%) from electrostatics (Table 4). Further motifs V and VII (involving weak C−H···F−C and C−H···π hydrogen bonds) in the form I were found to be similar to motifs IX, X, XII, and XIII in form II. Dimeric motifs involving short and directional C−H···F−C(sp3) hydrogen bond were also observed in both forms [motif VI (2.46 Å, 167°) in form I and motif XI (2.43 Å, 167° and 2.44 Å, 167°) in form II] having similar stabilization energy (Table 4 and Figure 10) with significant electrostatic (Coulombic + polarization) contribution (∼43−44%). Molecular motifs in Figures 10 and 11 show the presence of interactions involving organic fluorine, such as C−H···F−C(sp3) hydrogen bond and C(sp3)−F···F−C(sp3) interactions, in the crystal packing of the two forms of T-1-2. Most of the molecular motifs were observed to be similar in the two forms. All of the molecular motifs in form I were observed to be present in form II (Figure 10 and Figure S6) with similar

Figure 13. Packing of molecules in (a) T-1-2 form I down the bc plane and (b) form II down the (110) plane. Dotted lines depict the intermolecular interactions, and different colors for C atoms have been used for Z′ > 1. Shaded boxes indicate the similar parts in their crystal packing.

Comparison of Crystal Packing. For the current Xpac analysis, atoms with labels C1−C15, N1, and O1 in molecule 1 of T-1-2 form I were considered for “corresponding ordered sets of points” (COSPs). The filter setting was set to low [a/p/d, 7/10/1.50] for tight tolerance in the comparison of the two polymorphs. The comparison of the crystal packing of T-1-2 form I with form II gave two independent similar fragments (SCs). The first one is the presence of a 2D SC (similar molecular sheet) with dissimilarity index of 1.5 whereas the second one consists of a 1D SC (similar molecular chain) with dissimilarity index of 4.8 in the crystal packing (Figures 7 and 8 and Figure S2). It clearly indicates that the two polymorphs have a similar molecular chain (red colored circle in Figure 7) consisting of a N−H···OC hydrogen bond in the crystal packing (Figures 7 and 8). Such chains are interconnected with the presence of weaker interactions (marked with circles of different color, yellow, green, and purple in Figure 7) present between molecules. To get further insights into the similarities and dissimilarities associated with the two forms of T-1-2, it is of interest to investigate the nature and energetics of these interactions, which are present in the crystal packing. Analysis of the Lattice Energy and the Molecular Pairs. The results of the lattice energy calculations suggest that both polymorphs have similar lattice energies (the difference between form I and form II is 1.9 kJ/mol; Table 3), and hence in this case this accounts for the observance of concomitance polymorphs. It is to be also noted here that both forms have 2569



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Figure 14. Comparison of full fingerprint plots and decomposed fingerprint plots for various intermolecular interactions in the two forms of T-1-2. The number indicates the percentage contribution of the interaction over the Hirshfeld surface.

with the presence of a weak, hence flexible, C−H···F−C(sp3) hydrogen bond and C(sp3)-F···F−C(sp3) intermolecular interactions in both forms of T-1-2 (Figures 11 and 12) with the stabilization energy ranging from 0.1 to 8 kJ/mol. These boxes orient parallel to each other in the form I while the formation of the herringbone pattern by these (Figure 12) was observed in form II. Figure 13 further displays the differences associated with the crystal packing of the two forms which is mainly stabilized by the presence of weaker interactions such as C−H···F−C(sp3) hydrogen bond and C(sp3)−F···F−C(sp3) intermolecular interactions in the third crystallographic direction (Figure 11). It is to be noted that, in the molecular pairs, which consist of weak C(sp3)−F···F−C(sp3) intermolecular interactions, the total interactions energy is mainly dominated by dispersion energy contribution (more than 85%, Table 4). Fingerprint Plots Analysis. Analysis of crystal packing and involved intermolecular interactions are widely performed by Hirshfeld surfaces57 and two-dimensional fingerprint plots,58 obtained by the CrystalExplorer software.59 These were observed

stabilization energy. Motifs XIV, XVII, XX, and XXI [involving mainly weak C−H···F−C(sp3) hydrogen bond and C(sp3)− F···F−C(sp3) interactions; IE lies between −8 and −0.1 kJ/mol] in T-1-2 form II were not observed in form I. Figures 11−13 display the comparative views of the molecular packing in form I and form II with the shaded regions showing the similar parts in their crystal packing. The similar parts of the crystal packing in the two forms involve the formation of a molecular chain with the utilization of a strong N−H···OC hydrogen bond along with a weak C−H···OC hydrogen bond and C(sp3)−F···CO interactions [along the a-axis, motifs I and II in form I and along the [110] direction and motifs I − IV in form II; Figure 11]. A weak dimeric C−H···F−C(sp3) hydrogen bond (motif VI in form I and motif XI in form II) along with weak C−H···F−C(sp3) hydrogen bonds (motif in XII in form I while motif XIX in form II) were observed to connect such chains, thus forming a molecular layer down the ac plane (shaded boxes in Figure 11). The crystal packing in the two forms was observed to be different in terms of the orientation of the shaded box (Figure 12), although they are connected 2570



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interest in the pharmaceutical industry and to exploit subtle differences in polymorph formation which can be ascribed to the effects of weak intermolecular interactions in crystal formation.

to be very important tools for comparing crystal packing, particularly in the case of polymorphs. The fingerprint plots of all molecules in the two forms of T-1-2 display similar features about intermolecular interactions, since they have very little difference in their crystal packing [Figure 14]. Most of the intermolecular interactions are similar in both forms of T-1-2; the dissimilarity in their 2D fingerprint plots will only be visualized through careful analysis of the same. The differences were mainly observed on the tail of the fingerprint plots which are associated with mainly weak interactions such as H···F, H···H, and F···F. This is also visible in the shape of corresponding decomposed 2D fingerprint plots for these interactions (Figure 14). In the case of H···O interactions, contribution from the strong H···O interactions (observed as a pair of spikes) is 4% more in the case of molecule 2 than in molecule 1. This was also observed with molecules 2 and 4 when compared with 1 and 2 in form II for the H···O interactions. The variation in the contribution from H···O contacts for the two molecules in the two forms which correspond to differences in their respective crystal structures. This may be related to the observance of high Z′ in the two forms, as molecules in their asymmetric units are connected with a strong N−H···OC hydrogen bond along with the presence of weak C−H···OC hydrogen bonds. The contributions from weaker interactions were found to be similar (difference is 1−3%) in all cases. The weak H···F contacts were observed to be a major contributor (more than 37%) in all cases, followed by H···H contacts. The spikes in the decomposed 2D fingerprint plot for F···F contacts corresponds to the presence of these interactions at short distances in their crystal packing.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01638. Crystal images of different batches, description of data collection and structure solution and refinement, space group determinations, Xpac plots, description and results of profile fitting refinement, FTIR spectra, molecular overlay of independent molecules of the two forms, and diagram of interactions of the two forms with their interaction energies (PDF) Accession Codes

CCDC 1043499−1043500 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: 91-0755-6692370. Author Contributions †

P.P. and S.B. have contributed equally to this work.

Notes

The authors declare no competing financial interest.

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CONCLUSIONS Concomitant polymorphs of 3-(trifluoromethyl)-N-[2(trifluoromethyl)phenyl]benzamide have been observed which display the presence of Z′ > 1 in their crystal structures. Unique molecules (possessing different molecular conformation) in the asymmetric unit in the two forms were observed to be connected with strong N−H···OC along with weak C−H···OC hydrogen bonds. The differences in the contribution from H···O contacts for the two molecules in the two forms were also observed from 2D fingerprint analysis. In the present case this could be one of the possible explanations for the appearance of Z′ > 1 structures in the two forms. Further, it is interesting to observe that one form exhibits rotational disorder of the -CF3 group whereas the other form does not exhibit any disorder. A rare case of phase transition from the Z′ = 2 centrosymmetric structure (triclinic, P1̅) to the Z′ = 4 noncentrosymmetric (monoclinic, Cc) structure has been characterized by thermal experiments. Similarity in density and lattice energies of the two forms could be the possible reason for concomitant crystallization. The two forms consist of similar 2D packing arrangement with similar intermolecular interactions of similar stabilization as observed from the Xpac analysis and supported from PIXEL energy calculations. The common 2D molecular layer is found to be arranged in parallel in the case of form I while this packs as a herringbone pattern in form II. The weak and flexible C−H···F−C(sp3) hydrogen bond and C(sp3)−F···F−C(sp3) intermolecular interactions were observed to stabilize the changes in the crystal packing of two forms; however the magnitudes of their total lattice energies are similar. The methodologies described in this work can be extended to study the polymorphic behavior of compounds of

ACKNOWLEDGMENTS We acknowledge IISER Bhopal for research facilities and infrastructure. S.B. thanks Prof. G. W. H. Höhne for invaluable suggestions on interpretation of DSC curves. D.C. thanks SERB-DST for research funding.

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REFERENCES

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Quantitative Investigation of Polymorphism in 3-(Trifluoromethyl)-N-[2

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