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Dissecting the Conformational and Interaction Topological Landscape of N-ethynylphenylbenzamide by the Device of Polymorphic Diversity Subhrajyoti Bhandary, Shivani Gonde, and Deepak Chopra Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01593 • Publication Date (Web): 27 Dec 2018 Downloaded from http://pubs.acs.org on January 3, 2019
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Crystal Growth & Design
Dissecting the Conformational and Interaction Topological Landscape of N-ethynylphenylbenzamide by the Device of Polymorphic Diversity Subhrajyoti Bhandary, Shivani Gonde, and Deepak Chopra* Crystallography and Crystal Chemistry Laboratory, Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal-By-Pass Road, Bhauri, Bhopal-462066, Madhya Pradesh, India ABSTRACT: Modern day crystal engineering approach aims at the exploration of the structural landscape of a molecule to perceive the phenomenon of crystallization event for that molecule. The present study focuses on the thorough experimental and computational investigations of the crystal landscape in conformationally flexible N-ethynylphenylbenzamide molecule. We have performed the chemical modification of the parent unsubstituted N-ethynylphenylbenzamide molecule on the benzoyl ring by different halogen substitutions (monofluoro/ difluoro/ trifluoromethyl/ chloro/ bromo) at ortho/ meta/ para positions and employed the device of polymorphophore concept to access a large number of experimentally viable structures in the landscape. In a total of eleven substituents as variants in molecules, the parent molecule displays monomorphic behaviour and the remaining ten molecules, each exists in several polymorphic forms resulting in a total of 28 single component crystal structures. Through the systematic analysis of their conformational preferences in the conformational landscape and classification of the prevalent supramolecular recognition patterns, the interaction topologies of all substituent modified polymorphic structures have been mapped by the quantification of interaction energies of supramolecular synthons followed by a crystal structure prediction study. The combination of all studies demonstrates that robustness of primary synthon topology (formed by N-H···O=C/ π···π stacking interaction) and local variation of structures by different secondary interaction preferences (weak C-H···O, C-H···π, C-H···F/ Cl/ Br and π···π interactions) construct a nearly similar global interaction topology of molecules in all crystal structures, and represents a general interaction topological landscape.
Introduction The event of crystallization is a complex phenomenon. For any given molecular compound, the crystal structure landscape represents a dynamic process as the final outcome of continuous structural as well as energetic perturbations. 1-3 So, the available scope of crystallization to form a stable crystal structure for a particular molecule is very large in number, and they can be structurally and energetically close to each other. The crystal structure (or energy) landscape highlights all such available crystallization possibilities for a molecule which includes polymorphs, pseudopolymorphs, and multicomponent crystals. 4-7 Hence, it is of sufficient importance to explore the crystal structure landscape of a compound using both computational methods and experimental interpretations, which is also one of the primary objectives of recent crystal engineering research. 1 The computational crystal structure prediction (CSP) method is a promising approach to compute the diverse crystallization plausibilities of a molecule within a small energy space via crystal lattice energy-density plot. 8 However, the main concern of the CSP approach is that it underestimates the kinetic factors associated with the route of crystallization, and hence, fails to predict on certain occasions the experimentally observed crystal structure. Also, this method often suffers from the obstacle of conformational degrees of freedom within the molecule, which increases the dimensionality of the energy landscape. 9 On the other hand, the appearance of multiple single-component crystal phases of a compound, i.e. polymorphs, clearly suggests
the existence of high energy structures (local minima) in the crystal energy landscape. 10-11 So, the phenomenon of polymorphism offers an excellent platform to explore the structural landscape of a molecule by means of the experimental findings. But, the accessibility of all such plausible structures in the landscape through experimental screening is a challenging task as it depends on the investment of sufficient ‘time and money'. 12 Interestingly, it has been already perceived that there are some families of molecules differing in minor substitution at the chemically harmless positions of the subject molecule keeping the main skeletal structure same, called polymorphophore, 13 such as sulphonamides, 14 ROY derivatives, 13 barbiturates, 15 carbamazepine derivatives, 16 Nphenylbenzamides 17 and fenamates , 18 that have strong tendency to exhibit polymorphism. At the heart of this notion of polymorphophore, it is deemed appropriate to map the crystal structure landscape of the native subject molecule by capturing all feasible (nearly equi-energetic) molecular conformations and a variety of packing modes of associations, through the access of a large number of substituent-variant but experimentally-equivalent polymorphic crystal structures which would not be obtained experimentally otherwise. 19 Furthermore, it is noteworthy that the subject of polymorphism itself is an attractive area of crystal engineering, materials science, and pharmaceutical research due to possible distinct solid-state properties (such as solubility, bioavailability, stabil ity, and compressibility) of each polymorphic form. 10, 20
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Figure 1. The molecular structure of monomorphic unsubstituted N-ethynylphenyl benzamide (30) and various halogens (fluoro, difluoro, trifluoromethyl, bromo and chloro) substituted polymorphic analogues with their codes based on the position of a substitution followed by the number of obtained polymorphic forms in individual families. The three conformational degrees of freedom (T1, T2, and T3 rotatable torsions) present in all molecules shown in red coloured bonds for the 30.
Although, the phenomenon of polymorphism in organic compounds was first recognized for benzamide long ago (1832), 21 and since then, a significant advancement in this field has already been achieved, it still stays to be a dynamic zone of organic solid-state research owing to the industrial demands. Recently, a few systematic analyses of crystal polymorphism on the basis of the Cambridge Structural Database (CSD) 22 statistics have concluded that in spite of the fact that polymorphism is a ubiquitous phenomenon, but still remains enigmatic towards our fundamental understanding, as every polymorphic system is unique and offers a new challenge to the practical accessibility of various structures because of contrasting thermodynamic and kinetic preferences through the process of crystallization. 10, 23 At this point, the fundamental basis towards the development of a gradual realization of this evergreen phenomenon can be certainly achieved to a certain extent by charting the polymorphic landscape of some iconic molecules like benzamide which has some rolling stories. 10, 24 Keeping in mind, all the above-mentioned facts, an extensive experimental and computational investigation has been performed into the polymorphic endeavour of conformationally flexible unsubstituted N-ethynylphenylbenzamide (30) molecule (a derivative of classical benzamide molecule) along with ten others structurally related substituted analogs to probe the crystal landscape of the parent molecule (see red square in Figure 1). A recent CSD survey (Version 5.39, Feb 2018) on the N-phenylbenzamide structural moiety yields 1500 hits, in which 102 structures belong to the polymorphic families (see Supporting Information). As a part of our continuous efforts towards the understanding of solid-state diversity present in the
N-phenylbenzamide derivatives, 25-31 and also motivated from the earlier study of Zipp et al. 17 and Matzger group 13, 23 regarding propensity for the existence of polymorphism in same classes of compounds, and directed towards the understanding of the structural landscape, herein we report seven new polymorphic families of substituted Nethynylphenylbenzamides. It has been recently observed by us that mono fluorination of the parent compound (30) at the ortho (o-F), meta (m-F) 28-30 and para (p-F) 31 positions resulted in polymorphic existences of all individual molecules. On the basis of these previous experiences, we have further functionalized the benzoyl ring systematically with the difluoro (23/ 24/ 25/ 26-F), trifluoromethyl (p-TF), bromo (o-Br) and chloro (p-Cl) substituents to create an electronic difference (depending on the electron withdrawing effect of various halogens) between two phenyl rings within the molecule, which can generate various arrays of both conformations and supramolecular structural adjustments by the subtle modulation of prevalent supramolecular constructs or synthons in the solid-state (Figure 1). 32-33 All the new compounds were synthesized in accordance with the procedure reported in the literature. 28, 31 Exploitation of this strategy of different halogen substitution at the benzoyl ring in a total of eleven equivalent molecules (three old and eight new) and explore their polymorphic forms experimentally allows to evaluate both conformational and supramolecular structural landscapes of the N-ethynylphenylbenzamides systematically. In the course of this study, the conformational landscape of the subject molecules has been quantified by the gas-phase potential energy surface calculations of the parent
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Crystal Growth & Design
molecule 30, and we introduce here a more general approach to describe the structural panorama associated with a molecule by the identification of common supramolecular units and quantification of overall intermolecular interaction topology based on the energetics of important supramolecular synthons. We named this method the “interaction topological landscape”.
with rotation about these bonds, (Figure 2), while single distribution maximum for T2
Results and Discussion The extensive crystallization screening of the unsubstituted compound 30 along with new substituted analogues (p-TF, 23F, 24-F, 25-F, 26-F, p-Cl, and o-Br) using various techniques and conditions (see Table S1, Supporting Information) from last few years yielded in monomorphic 30, dimorphic p-TF/ 24-F/ 26-F/ o-Br and trimorphic 23-F/ 25-F/ p-Cl substituted compounds (Figure 1). The three polymorphic monofluorinated equivalents, namely, o-F (dimorphic; LEBTIY/ o-FI and LEBTIY01/ o-FII), m-F (pentamorphic; LEBTAQ/ m-FI, LEBTAQ02/ m-FII, LEBTAQ03/ m-FIII, LEBTAQ01/ mFIV and LEBTAQ04/ m-FV) and p-F (trimorphic; GEKGOV/ p-FI, GEKGOV02/ p-FII and GEKGOV01/ p-FIII) were already reported in our previous studies. The numbers of polymorphs of all individual families were given after their code names in Figure 1. All the new crystalline forms were characterized by single crystal X-ray diffraction (SCXRD) along with the powder X-ray diffraction and differential scanning calorimetric techniques (see Table S2 and Figures S1S4). A total of 28 crystal structures (18 new) have been discussed 34 in this article in terms of their conformational preferences, adaptability of complimentary supramolecular recognition fragments (hydrogen bonding and stacking interactions), and overall intermolecular interactions topology of molecules in crystals by the quantification of interaction energies approach followed by the crystal structure prediction.
Conformational Landscape The final three-dimensional crystal structure is a mutual compromise of both the energy minimized molecular conformation and the stabilized intermolecular interactions (intra- and intermolecular energy). 35-36 In general, flexible neutral molecules adjust the flexible conformation in the crystal environment relative to their gas phase optimized geometries. 37 The penalty for this adjustment (conformational energy) is incurred usually to enhance the contribution from the crystal packing forces by the distortion of rotatable torsions (the occurrence of conformational polymorphism). Although, molecules often adopt relatively high energy conformers in the crystalline environment, but crystalline conformers are generally energetically close to the idealized molecular geometries (gas phase conformers). 9 So, in the context of crystal engineering, the energy minimized gas phase conformers of the flexible molecules can be very useful to predict the relatively high energy conformational space of molecules in their crystal structures. Usually, all 30 equivalent molecules have three conformational degres of freedom (T1, T2 and T3) in the molecular structure between two phenyl rings as shown in red coloured bond in Figure 1. A recent CSD survey of three torsions T1, T2 and T3 in all reported Nphenylbenzamides shows different distribution maxima for both the T1 and T3 torsion angles indicating the existence of different conformers, on account of the flexibility associated
Figure 2. Histograms of CSD occurrences for torsion angles associated with T1 (above) and T3 (below) in N-phenylbenzamide moiety showing two distribution maximum of each in between 2040° and 140-160°.
torsion clearly suggests a preference of only one conformer having torsion angles near to 180° (Figure S5). For this reason, here we have performed the gas phase potential energy surface (PES) calculations [computed at the M06-2X/ 6-311g++(d, p) level of theory] using the Gaussian 09 38 corresponding to the two most flexible torsions T1 and T3 of the representative unsubstituted molecule 30 to envisage the conformational landscape. The gas phase PES of parent molecule 30 for two torsions (T1 and T3) and the experimentally obtained torsional angles (in crystal) of individual symmetry-independent molecules in ten polymorphic differently substituted families including monomorphic 30 are depicted in Figure 3. The PES scan for torsions T1 (Figure 3a) and T3 (Figure 3c) each contain two distinct minima (two conformers) of similar energies. For T1-PES, the energy penalty for conformational change (ΔEgasgas) involving alteration of two gas phase conformers (energy barrier) is
