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

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Quantitative Investigation of Polymorphism in 3(trifluoromethyl)-N-[2-(trifluoromethyl)phenyl]benzamide Deepak Chopra, Piyush Panini, and Subhrajyoti Bhandary Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b01638 • Publication Date (Web): 05 Apr 2016 Downloaded from http://pubs.acs.org on April 9, 2016

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Crystal Growth & Design

Quantitative Investigation of Polymorphism in 3-(trifluoromethyl)-N-[2(trifluoromethyl)phenyl]benzamide Piyush Paninia#,Subhrajyoti Bhandarya#, Deepak Chopraa* a

Crystallography and Crystal Chemistry Laboratory, Department of Chemistry, Indian Institute

of Science Education and Research Bhopal, Madhya Pradesh, India-462066. #: Both the authors have contributed equally. Email: [email protected]; Fax: 91-0755-6692370.

Abstract: The occurrence of concomitant dimorphism has been observed in the case of trifluromethyl 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, P-1, Form I) to non-centrosymmetric, Z' = 4 structure (monoclinic, Cc). Both the 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, C-H···π hydrogen bonds) in their crystal packing while difference in their crystal packing is mainly on account of the presence of weak C-H···F-C(sp3) hydrogen bond and C(sp3)-F···F-C(sp3) interactions.

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 is

ACS Paragon Plus Environment


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increasing at a rapid rate (approximately 40000 per year) [1]. This also includes the compounds which crystallized with multiple number 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 search [11] shows that around 12.5% of total organic crystal structures consist of Z′ > 1. This percentage is now increased from 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) psuedosymmetry, (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] (vii) Supramolecular synthon frustration [15] as highlighted by J. W. Steed [2-4 ] 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 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 stable [18] and also t h e 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 calculations [19] concluded that about 55-60% structures consists of the highest stabilized molecular pairs in the asymmetric unit [6]. It was observed by the author that structures with space group P1, P21 and P-1 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 amongst polymorphs are of special interest in the research area which is directly related to pharmaceuticals [22-23]. Concomitant polymorphism [24] is a phenomenon when two or more forms crystallize simultaneously from the same solvent and crystallization flask under


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identical crystal growth conditions. The physical or chemical properties which may vary amongst different polymorphs are unequivocally characterized by different techniques such as melting point measurements [differential scanning calorimetry (DSC)], thermo gravimetric 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 amongst 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, Dunitz and Gavezzotti [31] and the authors observed that the high Z′ polymorph exhibits a minor tendency to have a lower density and corresponds to high- temperature form while in cases where the high Z′ polymorph has the higher density, corresponds to the low-temperature 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 on performing the lattice energy calculations of different forms gives insignificant information about the reason for the occurrence of the high Z′ structure. In this manuscript, we report a dimorphic system (crystallized concomitantly) in case of trifluomethyl substituted

benzanilide

namely,

3-(trifluoromethyl)-N-[2-(trifluoromethyl)

phenyl]benzamide (T-1-2), wherein one form crystallizes in the centrosymmetric triclinic space group P-1with two molecules in the asymmetric unit (Z = 4) (T- 1-2 Form I] while the other (T1-2 Form II) crystallizes in the non-centrosymetric 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-



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F” group), namely the weak C-H···F-C hydrogen bond [35-39] and C-F···F-C [40] interaction in polymorph formation [41].

Experimental section: The synthesis of the compound 3-(trifluoromethyl)-N-[2-(trifluoromethyl)phenyl]benzamide (T1-2) is already reported in our previous work [37]. The compound T-1-2 crystallized in two morphologies (needle and plate; Fig. 1 & S1) from methanol+hexane (1:1) and observed to exhibit concomitant polymorphism [22-23]. 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 P-1with two molecules in the asymmetric unit (Z = 4) while the plate form (T-1-2 Form II) crystallizes in the non-centrosymmetric 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 (Figs. 2-5 and 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 PerkinElmer DSC 6000 instrument. Each of the polymorphs along with the bulk powder was subjected to two heatingcooling cycles. The results of the DSC experiments on the needle crystals (Form I) displays two endothermic peaks adjacent to one other: the first peak is observed at 109°C (∆Ht = -15.4 J/g) while the second is at 112°C (∆Ht = -69.8 J/g) with the scanning rate of 5°C/min [Fig. 2(a)]. In the subsequent heating cycle only one endothermic peak at 111.5 °C was observed. Further, DSC experiments @ 5°C/min on the plate crystals (Form II) displays an endothermic peak at 112°C (∆Ht = -98.2 J/g) and remained invariant in the second heating cycle [Fig. 2(b)]. Hence, the study suggests that there is a phase transition of Form I to Form II near at 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 Linkam LTS420 connected with a Leica polarising microscope. From this experiment (Fig. 4) an interesting phenomenon was observed, the solid to


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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 Fig. 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 the events of solid-to-solid phase transition and melting happens 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 rate were performed on the crystal of Form I [Fig. 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 [Fig. 3]. So, it can be concluded that 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°C/min and 10°C/min) whereas at lower scanning rates (1°C/min and 3°C/min), the first endothermic peak ‘a’ is small and the second endothermic peak ‘b’ is more prominent. [Fig. 2(b) & 3]. These unusual [42-43] 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 [∆Ht ('b')= -95.5 J/g for 1°C/min.] for this process is very similar to what was observed for melting of Form II [Fig. 2(b), ∆Ht = 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 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 case of Form I. Wherein, the Form I is more stable below the transition point and Form II is more stable at higher temperature and Form II does not convert to Form I on cooling since it is not kinetically accessible [44]. Moreover, DSC traces for the bulk powder @



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5°C/min shows an endothermic peak at 111°C for the two heating cycles [Fig. 2(c)]. It thus suggests that it is representative of Form II (having a similar melting point). In all DSC traces, 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° to 50°, step size- 0.013103°, time per step- 200 sec, scan speed- 0.0167 °/sec and 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 (Fig. 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 JANA2000 [45] [Fig. S3]. In comparison of IR spectra of bulk powder with two polymorphic forms [Fig. S4], small blue shifts in N-H and C=O bond stretching frequencies were observed ongoing from Form I to Form II.


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

Figure 2: DSC traces, recorded @ 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.



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


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Figure 4: Hot Stage microscope snapshots @ 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) .



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

Theoretical calculations To investigate the relative stability of these polymorphs, the lattice energies were calculated from atom-atom method in the CLP module [46-47] (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. Interaction energy of molecular pair was calculated from the PIXELC module [19] 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 [48].The output file (mlc file), after PIXEL calculation, 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 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 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 the possible molecular pairs could be obtained in the case of T-1-2 Form II [49]. In case of 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


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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 (SC)’, are then identified by the program. The central molecule in the cluster is called the ‘kernel molecule’ and all the molecules surrounding it thus leads 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 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). 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 like 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, better is the structural match.

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 Formula Weight

C15H9F6NO 333.23

C15H9F6NO 333.23

CCDC No.

1043499

1043500

Crystal System; Space group a (Å) b (Å) c (Å) α (⁰)/ β (⁰)/ γ (⁰)

Triclinic, P-1

Monoclinic, Cc 12.658(2) 9.6582(16) 45.734(7) 90/ 94.585(4)/ 90

Volume /Density (g/cm3) Z/ Z' F (000)/ µ (mm-1) θ (min, max)

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

hmin,max, kmin,max, lmin,max

-10, 9; -10, 10; -30, 30

No. of ref. No. unique ref./ obs. ref. No. of parameters

25934 6359, 4261 415

5573.1(16)/ 1.589 16/ 4 2688/ 0.155 2.66/ 28.43 -16, 16; -12, 12; -61, 61


64803 14033, 12466 880


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R_all, R_obs wR2_all, wR2_obs ∆ρmin,max(eÅ-3)

0.0862, 0.0457 0.1104, 0.0973 -0.304, 0.350

0.0438, 0.0359 0.0865, 0.0829 -0.225, 0.322

G. o. F

1.032

1.036

Table 2: List of selected torsion angles (°). Torsion 1(º)a Torsion 2(º)a Torsion 3(º)a C2-C1- C13- N1 C13-N1- C7-C12 C7-N1- C13-C1 n n 165.96/ 168.08 63.66/ 62.84 177.80/ 175.55n T-1-2 Form I T-1-2 Form II -162.95/ -166.84/ 164.22/ 167.85n 116.99/ 114.40/ 67.08/ 63.50n -178.22/ -173.16/ 178.95/ 176.95n a also corresponds to the similar torsions in the nth molecule in the asymmetric unit of the two forms; n = 1/ 2/ 3/ 4 respectively.

Table 3: Lattice energy (kJ/mol) partitioned into Coulombic, polarization, dispersion and repulsion contribution by atom-atom CLP method. Code

ECoul

EPol

EDisp

ERep

1. -32.9 -29.9 -141.2 74.2 T-1-2 Form I -30.1 -139.6 74.7 2. T-1-2 Form II -33.0 # Reported experimental sublimation energy for benzanilide = 125.4 kJ/mol [32]

ETot# -129.8 -127.9

Table 4: Intra- and intermolecular Interactions along with interaction energies (I.E. in kJ/mol) obtained from the PIXEL method. Neutron values are given for all D-H···A interactions.

CentroidCentroid ECoul EPol EDisp ERep ETot Distance (Å) T12 Form I (P-1, Z = 4, Z' = 2)

Involved Interactions

Geometry (Å/ °)

N1-H1···O2=C28 C6-H6···O2=C28 C29-F7···C13=O1 N2-H2···O1=C13 C21-H21···O1=C13 C14-F2···C28=O2

1.95, 142 2.72, 127 3.103(2), 140(1) 1.94, 143 2.62, 127 3.082(2), 144(1)

Motifs

Symmetry code

I 1···2

x, y, z

4.187

-37.9 -13.8

-62.4

59.2

-54.9

II 1···2

x-1, y, z

4.207

-37.4 -13.9

-60.4

57.1

-54.7

x, y-1, z

7.988

-8.6

-5.4

-19.1

14.4

-18.7

C20-H20···O2=C28

2.37, 149

x-1, y+1, z

9.062

-12.8

-6.1

-18.3

19.7

-17.5

C26-H26···O1=C13

2.22, 167

x, y-1, z

6.964

0.2

-3.0

-21.4

10.1

-14.1

C5-H5···F7 C5-H5···C21

2.74, 122 2.89, 142

III 2···2 IV 1···2 V 1···2


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VI 2···2 VII 1···1 VIII 1···1 IX 1···2 X 1···1 XI 2···2 XII 1···2 XIII 1···2 XIV 1···2


-x+1, -y-1, -z+1

12.485

-7.1

-1.8

-11.7

7.8

-12.7

C19-H19···F12

2.46, 167

x, y-1, z

7.988

-1.1

-2.4

-17.9

9.2

-12.2

C11-H11···F2 C12-H12···C5

2.48, 135 2.87, 149

-x+1, -y+1, -z+2

12.608

-4.3

-0.9

-7.7

3.6

-9.3

C4-H4···F6

2.63, 138

-x+1, -y+1, -z+2

13.879

-4.1

-0.9

-6.9

4.0

-7.9

-x+2, -y, -z+1

12.299

-2.7

-0.5

-6.9

3.7

-6.4

-x+1, -y, -z+1

10.185

0.2

-0.4

-9.5

3.5

-6.2

-x+2, -y+1, -z+1

14.055

-2.5

-0.4

-3.8

1.5

-5.2

C10-H10···F10

2.66, 131

-x+1, -y, -z+2

11.825

-0.1

-0.2

-3.3

0.6

-2.9

C15-F6···F8-C29

3.001(2), 127(1), 114(1)

-x+2, -y, -z+1

12.034

0.1

-0.1

-2.4

1.1

-1.3

C14-F1···F11-C30

2.845(2), 142(1), 144(1)

N2-H2···O1=C13 C21-H21···O1=C13 C14-F2···C28=O2 N3-H3···O4-C58 C32-H32···O4=C38 C60-F23···C43=O3 N1-H1···O2=C28 C6-H6···O2=C28 C29-F7···C13-O1 N4-H4···O3=C43 C51-H51···O3=C43 C44-F13···C58-O4

1.90, 148 2.58, 128 3.129(2), 145(1) 1.93, 142 2.77, 126 3.137(2), 142(1) 1.94, 143 2.71, 123 3.074(2), 142(1) 1.95, 141 2.64, 126 3.081(2), 143(1)

C24-H24···F5 C25-H25···F5 C9-H9···F1 C14-F1···F1-C14

2.62, 121 2.62, 122 2.66, 138 2.932(2), 130(1), 130(1)

C30-F11···F12-C30 2.999(2), 134(1), 100(1)

T12 Form II (Cc, Z = 16, Z' = 4) I 1···2

x+1/2, y+1/2, z

4.297

-39.7 -15.9

-56.2

55.4 -56.3

II 3···4

x, y, z

4.224

-38.5 -14.8

-60.9

58.4 -55.8

III 1···2

x, y, z

4.188

-35.5 -14.0

-62.0

58.3 -53.2

IV 3···4

x-1/2, y-1/2, z

4.290

-35.0 -13.6

-56.2

52.4 -52.5

x-1/2, y+1/2, z

7.961

-8.9

-5.5

-19.3

15.1 -18.7

C50-H50···O4=C58

2.36, 148

x+1/2, y-1/2, z

7.961

-7.8

-5.1

-18.3

13.2 -18.0

C20-H20···O2=C28

2.37, 149

x, y+1, z

9.031

-11.8

-6.1

-17.7

18.4 -17.3

x, y-1, z

9.023

-13.2

-6.3

-18.4

20.9 -17.0

x-1/2, y+1/2, z

6.908

-0.3

-3.3

-23.2

12.0 -14.7

x+1/2, y-1/2, z

6.936

-0.2

-3.0

-21.4

10.0 -14.6

x+1/2, y-1/2, z

12.433

-7.5

-1.9

-11.9

8.5 -12.8

x-1/2, y+1/2, z

7.961

-1.7

-2.4

-17.7

9.1 -12.7

x+1/2, y-1/2, z

7.961

-1.0

-2.7

-18.7

10.3 -12.0

x+1/2, -y+1/2, z+1/2

13.081

-3.9

-1.3

-7.8

4.5

-8.6

x, y, z

10.128

-0.2

-0.5

-9.9

3.7

-6.9

XVI 1···3

x-1/2, y-1/2, z

12.255

-2.8

-0.5

-7.0

3.8

-6.4

XVII 2···3

x-1/2, -y+3/2, z+1/2

13.306

-2.3

-0.8

-5.7

3.0

-5.7

V 4···4 VI 2···2 VII 1···2 VIII 3···4 IX 1···2 X 3···4 XI 2···4 XII 3···3 XIII 1···1 XIV 1···4 XV 2···4

2.24, 167 C24-H24···O1=C13 2.74, 160 C23-H23···C11 2.21, 164 C54-H54···O3=C43 2.74, 153 C53-H53···C41 2.70, 122 C5-H5···F7 2.82, 143 C5-H5···C21 2.74, 123 C33-H33···F23 2.92, 139 C33-H33···C51 2.43, 167 C19-H19···F20 2.44, 167 C49-H49···F12 2.48, 134 C41-H41···F13 2.90, 150 C42-H42···C33 2.46, 135 C11-H11···F2 2.85, 148 C12-H12···C5 2.55, 133 C55-H55···F6A 2.73, 132 C56-H56···F5A C30-F10···F20-C59 2.985(2), 133(1), 101(1) C30-F12···F21-C59 2.994(2), 92(1), 132(1) 2.68, 136 C9-H9···F14 2.65, 136 C39-H39···F1 C14-F1···F14-C44 2.932(2), 129(1), 128(1) C25-H25···F16A


2.60, 143


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XVIII 2···3 XIX 1···4 XX 1···4 XXI 2···3 XXII 1···4 XXIII 2···3 XXIV 1···3 XXV 1···3

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x, y+1, z

14.031

-2.5

-0.4

-3.7

1.3

-5.4

C40-H40···F11

2.70, 131

x, y-1, z

13.984

-2.5

-0.4

-4.0

1.7

-5.2

C10-H10···F19

2.66, 128

x, -y+1, z+1/2

11.960

-0.5

-0.1

-3.3

1.1

-2.8

x, -y+1, z+1/2

11.737

0.8

-0.5

-4.2

2.0

-2.0

x-1/2, y-1/2, z

11.992

0.2

-0.1

-2.3

1.0

-1.3

C14-F1···F21-C59

x-1/2, y-1/2, z

12.051

0.1

-0.1

-2.4

1.2

-1.2

C30-F10···F14-C44 2.830(2), 143(1), 145(1)

x-1/2, -y+1/2, z+1/2

11.553

3.3

-0.5

-5.0

2.1

-0.1

C15-F5A···F18A-C45 2.784(2), 167(1), 112(1)

x-1, -y+1, z+1/2

13.154

1.5

-0.2

-1.7

0.4

-0.0

C15-F6A···F17A-C45 2.987(2), 173(1), 135(1)

C15-F4A···F24-C60 2.979(2), 153(1), 110(1) C15-F4A···F22-C60 2.995(2), 144(1), 104(1) C29-F8···F18A-C45 2.890(2), 101(1), 145(1) C29-F9···F18A-C45 2.972(2), 97(1), 126(1) 2.863(2), 141(1), 146(1)

Figure 6: ORTEP of (a) T-1-2 Form I, (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 3.3[55]) of six molecules (two molecules in the asymmetric unit of Form I and 4 in Form II) in the two polymorphs at solid state geometry. Color code for C atoms in figure: Gray: T-1-2 Form I molecule 1, Purple: T-1-2 Form I


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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 and Cyan: T-1-2 Form II molecule 4.

Results and Discussion: ORTEPs of the two forms were presented in Figure 6(a) and 6(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 [Fig. 6(a)]. This is most stabilized molecular motif in the T-1-2 Form I (I.E =54.9 kJ/mol, Table 4). However, in 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 pair of molecules [molecule 1 with molecule 2, I.E = -53.2 kJ/mol; molecule 3 with molecule 4, I.E = -55.8 kJ/mol, these belong amongst four most stabilized motifs in Form II, Table 4] in the asymmetric unit. Further, the two of the most stabilized motifs are observed to be connected via dimeric weak C(sp3)-F···F-C(sp3) interactions [Fig. 6(b), motif XV, I.E = -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 molecule 1 and 2 of Form II [color code: Black and orange; Fig. 6(c)-S5] has a different molecular conformation than the rest four molecules (including two molecules in the 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 to 54° for these molecules, Table 2) in comparison with the molecules 1 and 2 of Form II with the remaining four molecules [Fig. 6(c)-S5]. In addition, a slight difference in the torsion associated with the phenyl ring on the carbonyl side (torsion 1) is also observed in case of the molecules 1 and 2 of Form II while the remaining four molecules have nearly invariant molecular conformation [Fig. 6(c)- Fig. 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.



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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 [(supramolecular constructs (SC)]. The first one is the presence of 2D SC (similar molecular sheet) with dissimilarity index of 1.5 whereas the second one consists of 1D SC (similar molecular chain) with dissimilarity index of 4.8 in there crystal packing [Figs. 7 – 8 & S2]. It clearly indicates that the two polymorphs have a similar molecular chain (red colored circle in Fig. 7) consisting of N-H···O=C hydrogen bond in the crystal packing [Fig. 7 & 8]. Such chains are interconnected with the presence of weaker interactions (marked with circles of different color: yellow, green, purple in Fig. 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 presents in the crystal packing.

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.


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Analysis of the Lattice energy and the Molecular pairs The results of the lattice energy calculations suggest that both the 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 the forms have 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 towards the total stabilization energy is highest (approximately 70% in the two forms) in case of organic crystals. Comparison of the molecular pairs extracted from the crystal packing of T-1-2 Form I and Form II [Figs. 9 - 10, 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 & II in Form I and motifs I – IV in Form II, Fig. 9] with the I.E in the range of 52 – 57 kJ/mol (Table 4) in the two forms. In case of Form I, two symmetry independent molecules (both shows different molecular conformation) alternate with each other in the formation of the molecular chain along a-axis (Table 4), utilizing motif I & II. Further, in case of Form II, the formation of a similar molecular chain, but along the [110] direction, wherein two molecules with different molecular conformation alternate with each other (motif I with III and motif II with IV) in the crystal packing [Figs 9 & 11]. It is to be noted that the next set of stabilized motifs (similar in both forms) were observed to involve in a short C-H···O=C hydrogen bond [less than 2.37Å, motifs III & IV in Form I and motifs V – VIII in Form II, Fig. 9, I.E lie (-17 to -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 the 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 (2.46Å, 167°) in Form I and motif XI (2.43Å, 167° & 2.44Å, 167°) in Form II] having similar stabilization energy (Table 4, Fig. 10) with significant electrostatic (coulombic + polarization) contribution (~ 43 - 44%). Molecular motifs in Figures 10 and 11 shows the presence of interactions involving organic fluorine, like C-H···F- C(sp3)



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Page 18 of 30

hydrogen bond and C(sp3)-F···F-C(sp3) interactions, in the crystal packing of two forms of T-1-2. Most of the molecular motifs were observed to be similar in the two forms. All the molecular motifs in Form I were observed to be present in Form II (Fig. 10 – S6) with similar 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, I.E lies (-8 to -0.1 kJ/mol)] in the T-1-2 Form II were not observed in Form I. Figures 11 - 13 displays the comparative view of the molecular packing in Form I and Form II with the shaded region showing the similar part in their crystal packing. The similar part of the crystal packing in the two forms involves the formation of a molecular chain with the utilization of a strong N-H···O=C hydrogen bond along with weak C-H···O=C hydrogen bond and C(sp3)F···C=O interactions [along the a-axis, motifs I & II in Form I and along [110] direction, motifs I – IV in Form II, Fig. 11]. ]. A weak dimeric C-H···F-C(sp3) hydrogen bond (motif VI in form I and motif XI in form II) along with a 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 box in Fig. 11]. The crystal packing in the two forms was observed to be different in terms of the orientation of the shaded box (Fig. 12), although they are connected with the presence of weak, hence flexible, C-H···F-C(sp3) hydrogen bond and C(sp3)-F···F-C(sp3) intermolecular interactions in both the forms of T-1-2 [Fig. 11 & 12] with the stabilization energy ranging from 0.1 – 8 kJ/mol. These boxes orient parallel to each other in the Form I while the formation of the herringbone pattern by these (Fig. 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 like C-H···F-C(sp3) hydrogen bond and C(sp3)-F···F-C(sp3) intermolecular interactions in the third crystallographic direction (Fig. 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 surfaces [57] and two-dimensional fingerprint plots [58], obtained by the


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the CrystalExplorer software [59]. This was observed to be very important tools to comparing crystal packing, particularly in 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 [Fig. 14]. Most of the intermolecular interactions are similar in the both forms of T-1-2, the dissimilarity in their 2D fingerprint plots will only be visualized through careful analysis of same. The differences were mainly observed on the tail of fingerprint plots which are associated with mainly weak interactions like H···F, H···H, and F···F. This is also visible in the shape of corresponding decomposed 2D fingerprint plots for these interactions [Fig. 14]. In case of H···O interactions, contribution from the strong H···O interactions (observed as pair of spikes) is 4% more in case of molecule 2 than molecule 1. This was also observed with molecules 2 and 4 when compare 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 strong NH···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 decomposed 2D fingerprint plot for F···F contacts corresponds to presence these interactions at short distances in their crystal packing.



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Page 20 of 30

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 color of C-atoms corresponds to different molecules in the asymmetric unit.


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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].



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Page 22 of 30

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 depicts the intermolecular interactions and different colors for C-atoms have been used for Z' >1. Shaded region shows the similar part in their crystal packing.


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Figure 12: Schematic display of crystal packing in T-1-2 Form II. Shaded box indicates the similar 2D molecular packing in the two forms of T-1-2.

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 depicts the intermolecular interactions and different colors for C-atoms have been used for Z' >1. Shaded box indicates the similar part in their crystal packing.



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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.


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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 finger print analysis. In the present case this could be one of the possible explanation for the appearance of Z' > 1 structures in the two forms. Further, it is interesting to observe that one form exhibits rotational disorder of -CF3 group whereas the other form does not exhibit any disorder. A rare case of phase transition from Z' = 2 centrosymmetric structure (triclinic, P-1) to the Z' = 4 non- centrosymmetric (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 case of Form I while this packs as a herringbone pattern in Form II. The weak and flexible C-H···FC(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 describe in this work can be extended to study the polymorphic behavior of compounds of 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. Acknowledgements: We acknowledge IISER Bhopal for research facilities and infrastructure. SB thanks Prof. G. W. H. Höhne for invaluable suggestions on interpretation of DSC curves. DC thanks SERB-DST for research funding.



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For Table of Contents Use Only and Synopsis

Quantitative Investigation of Polymorphism in 3-(trifluoromethyl)-N-[2(trifluoromethyl)phenyl]benzamide Piyush Paninia#,Subhrajyoti Bhandarya#, Deepak Chopraa*

An extremely rare occurrence of simultaneous melting and solid-to-solid phase transition has been observed at the same temperature for concomitant dimorphs in the case of 3(trifluoromethyl)-N-[2-(trifluoromethyl)phenyl]benzamide. Interestingly, both the forms contain multiple molecules in the asymmetric unit. Quantitative analysis of the crystal packing reveals 2D isostructurality between the two forms, wherein the difference in crystal packing arises due to the presence of weak C-H···F-C(sp3) hydrogen bonds and C(sp3)-F···F-C(sp3) interactions.


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

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