Structural landscape guided exploration of a new polymorph of 4

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Structural landscape guided exploration of a new polymorph of 4-nitrobenzoic acid. Sibananda G. Dash, Shiv Shankar Singh, and Tejender S. Thakur Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01509 • Publication Date (Web): 04 Jan 2019 Downloaded from http://pubs.acs.org on January 5, 2019

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Crystal Growth & Design

Structural landscape guided exploration of a new polymorph of 4nitrobenzoic acid. Sibananda G. Dash,1, 2 Shiv Shankar Singh,1, 2 and Tejender S. Thakur1, 2* 1Academy

of Scientific and Innovative Research (AcSIR), CSIR-Central Drug Research

Institute (CSIR-CDRI) Campus, Lucknow 226 031, INDIA 2Molecular

and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow

226 031 INDIA

Email: [email protected]

Abstract A structural landscape approach can be advantageous in the identification and assessment of the most probable polymorphs of a given compound. However, the experimental realization of these putative polymorphs remains a challenging endeavor. In this report, we present the utilization of a structural landscape study in the identification and characterization of a new polymorph (form III) of 4-nitrobenzoic acid, which was obtained after 38 years. The reported polymorph was first predicted from the CSP computation, then validated by the fluorosubstitution method and was finally realized experimentally by utilizing the information deduced from the landscape study. Additionally, the role of crystallizing solvent in promoting the crystal growth of new polymorph was studied from the FT-IR and fluorescence spectroscopic data, which sheds some light on the polymorph selection in the solution.

Keywords: Crystal Structure landscape, Crystal Structure Prediction, Lattice energy calculations, and π···π stacking Interactions.

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Introduction According to classical nucleation theory, the crystallization proceeds through molecular recognition, nucleation and crystal growth steps. It is generally assumed that molecules associate to form large size clusters or nuclei that may subsequently transform into distinct crystal forms (polymorphs, solvate, and cocrystals) from the solution.1,

2

A more accurate

description of the crystallization process has been recently provided by the two-step crystallization mechanism.3 This mechanism considers the formation of stable, dense liquidlike molecular clusters in solution followed by the formation of a structured nucleus inside the cluster. The growing nuclei inside the molecular clusters are considered to possess the characteristic structural features of the crystal form they eventually evolve into in the final stage of crystallization. 4 It is the relative stability of these nuclei and the growth kinetics that decides which crystal form will subsequently appear, in a crystallization experiment.5 An optimal choice of crystallization conditions (pressure, temperature, concentration, etc.), solvents and additives can help in modulating the growth of a particular polymorph. Several experimental approaches to polymorph selection and control have been proposed earlier in the literature.6-10 These include crystallization from solvent7, 8 melt, sublimation, by polymerinduced hetero-nucleation10 and by the use of additives4 as nucleation promotor or inhibitor for a specific polymorph. On the other hand, better control over crystallization processes can be achieved if the information on all experimentally viable crystal forms of a compound is available beforehand.11 Crystal structure prediction (CSP) has become an indispensable tool for the identification of potential polymorphs of a given compound and to establish the stability relationships between them.12 A CSP run generates thousands of energy ranked crystal forms for a given compound. However, not all of them are observables under ambient conditions. The assessment of experimental viability each of these computer-generated structures even within a few kJ/mol energy window is still a challenge. To get a reliable stability order it is crucial also to consider the thermal and entropic contributions at given temperature in the computation especially for some polymorphs.13,

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Additionally, the

inclusion of kinetic factors, which may play a crucial role in deciding the outcomes of a crystallization reaction directly into the computation, is yet to be realized in CSP. In this situation, a structural landscape study can be beneficial in the validation of CSP generated structures and isolation of the possible crystal forms.15 A landscape study involves the characterization of all structural endpoints (polymorphs and solvates) for a given compound, 2


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identification of the viable crystallization routes and their validation with the help of a combined computational and experimental approach. 16, 17 H O

O

H

H

H

H

4-Nitrobenzoic acid (4NBA) 2-FluoroBenzoic acid (2F-4NBA) 3-FluoroBenzoic acid (3F-4NBA)

NO2

4NBA

2F-4NBA

3F-4NBA

1a Form I

2a Form I

3a Form I

1b Form II

2b Form II

3b DMF solvate

1c

2c

3c

Form III

DMF solvate

DMSO solvate

1d NMF solvate

2d DMSO solvate

1e

DMF solvate

2e

p-Xylene solvate 3e

Pyridine salt

1f

DMA solvate

2f

Pyridine salt

Aniline salt

1f

DMSO solvate 2g Aniline salt-I

1h TEA salt

2h Aniline salt-II

1i

2i

Aniline salt-III

2j

Aniline salt-IV

Aniline salt-I

3d p-Xylene solvate 3f

Scheme I Herein, we present a structural landscape guided strategy for the exploration of a new polymorph of 4-nitrobenzoic acid (4NBA, Scheme I). A new polymorph, of 4NBA (Form III: P21/c, a = 6.4, b= 7.6, c =14.1; β = 90.8) which was predicted as the potential polymorph by CSP, was obtained in the experiment from the aniline-dioxane solvent mixture. Further, we have tried to understand the role played by the aniline in promoting the growth of the new polymorph in solution through spectroscopic measurements.

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Results and Discussion Crystal structure prediction and structural landscape of 4-Nitrobenzoic acid 4-nitrobenzoic acid (4NBA) is known to exist in two polymorphic forms (Form I, 1a: C2/c, a = 20.9, b = 5.0, c = 12.8; β = 97.1 and form II, 1b: P21/c, a = 5.4, b = 5.1, c = 24.7; β = 96.9). 18, 19

In the past 38 years, it has been used many a time in the crystallization studies, and about

100 crystal structures of this compound have been reported in the Cambridge structural database.20 However, none of these studies indicates the presence or isolation of new polymorphs for this compound. Recently, we had also studied the role played by the various dipole-dipole type interactions present in the 4NBA (form I) using experimental charge density analysis.21 A CSP study performed by us on this compound reveals several putative polymorphs within few kcal/mol packing energy differences (Table S7, Supporting Information). The experimental viability of some of these predicted polymorphs was assessed by employing a combined experimental and computational approach. Firstly, a classification of these putative structures (top 50 ranked structures) based on probable growth pathway was performed using the methodology described by us in a previous study.

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Primary molecular recognition units (0-D growth units) were identified from the packing analysis of the predicted structures. The relative stability of these 0-D growth units was assessed from the gas phase quantum chemical calculations (Table S9, Supporting Information). All the structures were then clustered into groups based on structural similarity at 1-D, 2-D, and 3-D growth unit levels. A structural interrelationship between predicted structures was then derived based on observed similarity at the different growth unit levels (0-D through 3-D). Twenty-two 0-D growth units, five 1-D growth units, seven 2D growth units were identified that are grouped under 22 distinct pathways (Table S8-S15, Supporting Information). The experimentally observed structures (polymorphs and solvates) were used for validating the prominent growth pathways and constitutes the landscape for the compound. The crystallization endpoints for some of these growth pathways were also validated indirectly by utilizing the fluoro-substitution approach, 23 i.e., by studying the polymorphs of its structural analogues, i.e. 2-fluoro-4-nitrobenzoic acid (2F4NBA) and 3-fluoro-4-nitrobenzoic acid (3F-4NBA) in the present case. In principle, a mono-fluoro-substitution prompts small chemical perturbation in the molecular packing and thus, provide a handle to explore putative, high-energy polymorphs, which are inaccessible 4


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for the parent compound, 4NBA under ambient conditions. The polymorph screening studies performed by us on the 2F-4NBA yielded two polymorphs (2a: C2/c, a = 21.3, b = 5.1, c = 13.3; β = 97.1 and 2b: P–1, Z’= 2; a = 6.9, b = 7.4, c = 14.3; α = 80.6, β = 89.7, γ = 76.2). Interestingly, an isostructural variant for 2F-4NBA form II, 2b exhibiting noticeable variation in the cell angles (2b1: P–1, Z’= 2, a = 6.9, b = 7.5, c = 14.7; α = 98.8, β = 90.5, γ = 101.3) with an RMSD of 1.81 was also observed in the experimental screening.24 In the case of 3F4NBA, only one polymorph (3a: P21/n, a = 7.2, b = 5.9, c = 16.9; β = 93.1) was isolated in the screening studies. The comparison of the crystal structures of 4NBA analogues reveals isostructurality between 1a (4NBA, form I) and 2a (2F-4NBA, form I) having an RMSD of 0.26. Whereas, no isostructural analogues were identified in the case of 2b (2F-4NBA, form II) and 3a (2F-4NBA, form I.

Figure 1 Schematic depiction of the polymorph landscape of 4NBA showing structural evolution from 0-D, 1-D and 2-D growth units. A comparison of the experimental forms 1a, 1b, 2b and 3a with the CSP generated structures for 4NBA shows the closest match at 1st, 3rd, 12th and 133rd rank respectively (Table S7, Supporting Information). A putative structural landscape of 4NBA polymorphs was anticipated based on analysis of these structures (shown in Figure 1). The structural 5



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landscape analysis shows that 1b and 2b can be considered as the two phenotypic variation of 4NBA that originates from the same ‘1D’ growth unit (a 1-D tape built from the 0-D growth units ‘0A’, ‘0C’ and ‘0H’). However, the two structures differ in the arrangement of these tapes in 2-D and 3-D. A criss-cross 3-D network arrangement of these tapes was observed in case of 1b. Whereas, a planar 2-D arrangement of these tapes resulting in a layered structure (2F) is observed in the case of 2b (see Figure 2).

Figure 2. Two distinct phenotypic structural variations of 4NBA originating from the same 1-D growth unit ‘1D’. Table 2. Comparison of lattice energies of 4NBA polymorphs (1a-1c) reported in the study with its plausible polymorphs 2bhyp and 3ahyp (that are isostructural with 2b and 3a) obtained from the periodic DFT calculation.

Form

Space Group

Z’

α(º)

β(º)

γ(º)

Lattice energy (kcal mol–1)

1a

C2/c

1

20.954 5.022 12.837

90

97.13

90

–33.9

1b

P21/c

1

5.404

5.141 24.689

90

96.88

90

–32.9

2bhyp

P-1

2

6.924

7.452 14.260 80.574 89.742 79.198

–32.6

3ahyp

P21/n

1

7.298

5.863 16.923

–19.4

a(Å)

b(Å)

c(Å)

90

93.106

90

Finding appropriate experimental conditions suitable for the isolation of these putative 4NBA polymorphs that are isostructural to 2b and 3a was the next obvious challenge. Before proceeding further, we revalidated the experimental viability of these putative polymorphs by 6


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assessing the stability order for 1a, 1b and the two hypothetical polymorphs (isostructural to 2b and 3a) using the more accurate periodic-DFT calculations (see Table 2). The lattice energies for the hypothetical 4NBA polymorphs 2bhyp and 3ahyp were found –32.6 and –19.4 kcal/mol respectively. Which indicates that a new polymorph isostructural to 2b could be experimentally more accessible than a polymorph, isostructural to 3a. Considering this we attempted an extensive screening of 4NBA polymorphs by varying experimental conditions, which however, led us to isolation of several new solvated forms of 4NBA analogues with NMF (1d), DMF (1e, 2c and 3b), DMA(1f) and DMSO (1g, 2d and 3c) (Figure 3). Unfortunately, no new 4NBA polymorph was obtained in these experiments. The inclusion of solvent molecules in the crystal lattice in these cases was not surprising, as the heteromeric, solute-solvent interaction energies in these cases, were found comparable to the carboxylic acid homodimer. On the other hand, solvents, which resulted in either form I or II (e.g., Acetone, acetonitrile, methanol, ethanol, ethyl acetate, dioxane, and formamide) showed lower solute-solvent interaction energy than the homodimer (see Table 3, Table S9 and Figure S4). Crystallization of 4NBA from solvents acetone, ethanol, methanol, acetonitrile, 1-propanol and 2-propanol gave form I, 1a. Whereas, form II, 1b was obtained from dioxane solvent. Crystallization of 4NBA from trimethylamine (TEA) resulted in the isolation of a salt form, 1h. Table 3 Stabilization energies (corrected for BSSE) obtained for the most stable solventsolute molecular pairs of 4NBA, 2F4NBA, and 3F4NBA.

Coformer

Interaction 4NBA

Homodimer

O–H···O dimer

–16.69

Dimethyl sulfoxide N,N’-Dimethylformamide N-methylformamide N-methylacetamide N,N’-Dimethylacetamide Formamide Methanol Acetone Ethyl acetate Dioxane Acetonitrile

O–H···O, S···O O–H···O, C–H···O O–H···O O–H···O, C–H···O O–H···O O–H···O, C–H···O O–H···O, O–H···O O–H···O, C–H···O O–H···O O–H···O O–H···N

–17.26 –14.44 –14.08 –13.78 –13.73 –13.55 –12.18 –11.52 –11.10 –10.88 –8.31

Form 1a, 1b, 1c 1g 1e 1d 1f -

ΔEBSSE (kcal/mol) 2F-4NBA –16.00 –17.11 –14.34 –13.97 –13.71 –13.67 –13.45 –12.05 –11.41 –11.00 –10.86 –9.11

Form 2a, 2b 2d 2c -

3F-4NBA

Form

–16.45

3a

–17.71 –14.92 –14.54 –14.29 –14.23 –13.48 –12.38 –11.85 –10.92 –11.18 –9.51

3c 3b -

The 2F-4NBA molecules in 2b adopt a stacked layered packing having a short interplanar distance of 3.38 Å, resulting from the strong π···π stacking interactions (see 7



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Table S6). We assumed that a new 4NBA polymorph isostructural to 2b, can be achieved by modulating the π···π stacking interactions in solution. Considering this, we attempted crystallization of 4NBA in the solvent mixtures containing a small amount of an aromatic cosolvent. We expected that a π···π stacked layered structure will be favoured, and consequently, the growth of form II having criss-cross arrangement of 1-D tapes (growth unit ‘1D’) could be inhibited. However, the crystallization of 4NBA in the presence of an aromatic solvent (benzene, toluene, and p-xylene) still resulted in the isolation of form II. Whereas, in the case of 2F-4NBA and 3F-4NBA, a p-xylene solvate (2e and 3d) was obtained from the solvent mixture. The relative stability of heteromeric π···π stacked dimer complexes in the case of 2F-4NBA and 3F-NBA was found comparable to the respective homomeric π···π stacked dimers which might have favored their incorporation in the crystal (Table 4). Interestingly, a 2-D layer packing was observed in all these solvated forms (see Figure 3 and Table S6). However, in the case of 4NBA, all heteromeric π···π stacked complexes with aromatic solvent (benzene, toluene, and p-xylene) were found weaker than the homomeric complexes (Table 4 and Figure S5). Table 4 Stabilization energies of molecular pairs of 4NBA analogues with aromatic solvents.

Co-solvent Molecular pair Benzene Toluene Xylene Pyridine

Aniline

BenDim1 TolDim1 TolDim2 XylDim1 PyDim1 PyDim2 PyDim3 AnDi1 AnDi2 AnDi3

Interaction π···π stacking π···π stacking-syn π···π stacking-anti π···π stacking π···π stacking-syn π···π stacking-anti O–H···N π···π stacking-syn π···π stacking-anti O–H···N

ΔEBSSE (kcal/mol) 4NBA 2F-4NBA 3F-4NBA –6.15 –6.99 –6.61 –7.47 –8.32 –8.17 –7.59 –8.68 –8.19 –8.95 –10.00 –9.63 –4.63 –6.48 –5.59 –6.10 –6.76 –6.70 –13.85 –13.99 –14.40 –13.43 –14.40 –14.87 –12.86 –14.09 –11.37 –16.76 –16.66 –17.05

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Figure 3 Structure landscape depicting the various 1-D and 2-D growth units identified from the solvate forms of 4NBAs. We also attempted crystallization of 4NBA in the presence of pyridine considering that a heteroaromatic solvent will further enhance the formation of π···π interactions in the case of 4NBA. However, no new form was isolated in the case of parent 4NBA. Although, the 2F-4NBA and 3F-4NBA resulted in the pyridine salt crystals (2f and 3e) probably due to their higher ΔpKa differences (Table S16, Supporting Information).

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Figure 4. Packing adopted by the anilinium salts of 4NBA, 2F-4NBA, and 3F-4NBA (phenyl ring atoms are not shown for clarity). We further attempted crystallization of 4NBA in the presence of 1-2 drops of aniline in dioxane solvent which finally gave the anticipated polymorph, form III, 1c isostructural with the previously noted 2F-4NBA form II, 2b (RMSD = 1.81). This led us to assume that aniline might be acting as a promoter of the third polymorph of 4NBA in solution. Interestingly, computations also indicated high relative stability for heteromeric π···π stacked dimer complexes in comparison to homomeric π···π stacked dimer in this case (and Table S6). The relative stability of all the three polymorphs was established from DSC melting point measurements. Form I and II show higher melting endotherm peaks at 241.0 and 240.2 °C respectively whereas, the form III show a phase transition at 98.7 °C followed by the melting endotherm at 225.3 °C. Form III crystals was found unstable at room temperature and convert to amorphous form within 1-2 days. To explore the role of aniline in the crystallization of 4NBA, form III we attempted crystallization of 2F-4NBA and 3F-4NBA under the same experimental conditions, which, however, led to the isolation of several anilinium salts (2g-2j and 3f, see Figure 4). The crystallization of 2F-4NBA in the presence of aniline resulted in the five salt forms (2g-2j). Amongst them, two of 2F-4NBA‒aniline salts 2g and 2g1 were found isostructural (with an RMSD of 0.19). Additionally, two distinct 1:1 salt form (2h and 2i) and a 2:1 aniline salt form, 2j was also obtained from the aniline-dioxane mixture. The 3F-4NBA gave only a 1:1 salt form (3f). Formation of these salt forms in the fluoro-substituted 4NBAs may be attributed to their high acidity and stronger heteromeric π···π stacking interactions in crystals (Table 4 and Supporting Information, Table S4). Interestingly, the two 2F-4NBA-aniline 1:1 salt forms (2g and 2h) were found adopting a layered packing (Figure 5), which led us to presume that, the formation of a similar 4NBA-aniline salt layer in a small amount in solution may facilitate the growth of form III. To investigate it further we performed crystallization of 4NBA in an aniline-dioxane solvent mixture by varying the solvent ratio from 1:20 to 1:5 (v/v). At the low concentration of aniline (v/v < 1/20) 4NBA form II, 1b was isolated whereas, a higher concentration of aniline in the solvent mixture (v/v > 1/10) resulted in the formation of 4NBA-aniline salt (1i) having a layered structure. Incidentally, the formation of small amount 4NBA-aniline salt in the aniline-dioxane solvent mixture (v/v 1/10) was also 10


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observed by FT-IR spectroscopy. Which led us to believe that there may be a possible involvement of aniline salt formation in facilitating the growth of form III, from the anilinedioxane solvent mixture.

Figure 5. Molecular packing in (a) 4NBA‒aniline, 1i and (b) 2F-4NBA‒aniline salts (2g and 2h) showing the arrangement of π···π stacking layers. The FT-IR analysis of the saturated solution of 4NBA analogues in dioxane shows the presence of a strong C=O stretching peak at 1725-1729 cm-1 indicating its involvement in hydrogen bonding. The formation of a carboxylic acid homodimer in solution was confirmed only in the case of 2F-4NBA and 3F-4NBA (as evident from the out of plane O‒H wagging peaks appearing near 945 cm-1). Additionally, a broad carboxylic O‒H stretching peak was also observed in the case of 2F-4NBA and 3F-4NBA at 2965 and 2969 cm-1 respectively. Whereas, no such peaks were observed in the case of 4NBA.21 FT-IR studies performed in the aniline-dioxane solvent mixture (v/v 1/10) show a further shift in the C=O stretching to lower wavenumbers indicating a strengthening of hydrogen bonding by the salt formation in solution for all 4NBA analogues. A reduction in the O‒H wagging peak intensity was also observed on aniline addition, which is considered indicative of the reduced population of carboxylic acid dimers in solution for 2F-4NBA and 3F-4NBA. The FT-IR spectra for 4NBA 11



also showed a slight redshift in the C=O stretching frequency in the aniline-dioxane solvent mixture indicating its participation in hydrogen bonding. Formation of the ionic complex with aniline in the solution was also supported by the blue shift in the N‒H asymmetric and symmetric stretching in the case of all three acids (Table S17, Supporting information). We also studied the effect of aniline in the solvent mixture by using the fluorescence spectroscopy. The emission spectra of 4NBA (λe = 347 nm) were studied in pure dioxane and the aniline‒dioxane solvent mixture (v/v 1/100) at variable concentrations. The emission spectra showed gradual fluorescence quenching with an increase in 4NBA concentration in the dioxane solution indicating a molecular aggregation in solution through ··· stacking interactions. A further enhancement in the fluorescence quenching was observed in the aniline‒dioxane (v/v 1/100) solvent mixture (see Figure S6). Thus, point towards the probable role of aniline in promoting the aggregation of 4NBA molecules through ··· stacking interactions in solution. Aniline acts as fluorescence quencher in solution by complexation with 4NBA i.e. by salt formation. However, it is important to note that the extent of quenching increase noticeably at the higher 4NBA concentration. Whereas, the amount of aniline in solution was kept constant throughout. Therefore, the observed quenching effect was attributed to a higher aggregation of 4NBA molecules probably facilitated through the ··· stacking interactions modulated by the presence of aniline-4NBA complexes present in the solution. Finally, to establish the role played by aniline-4NBA salt in the growth of form III we performed crystallization of 4NBA in the presences seeds of aniline-salt crystals of 4NBA analogues. The form III was successfully regenerated from solution by seeding with aniline2F-4NBA salt (2g) crystals in the solvents, which previously gave the other polymorphs of 4NBA. These results confirmed that the formation of an aniline–4NBA salt layer might be assisting the crystal growth of form III in solution.

Conclusion The structural landscape of 4-Nitrobenzoic acid was explored using CSP and fluorosubstitution method in the present study. Two new polymorphs, 2bhyp (isostructural with 2F12


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4NBA form II, 2b) and 3ahyp (isostructural with 3F-4NBA form I, 3a) were identified for 4NBA. Amongst the two plausible polymorphs, a 4NBA polymorph isostructural to the 2F4NBA form II, 2bhyp showed lattice energy comparable with the known polymorphs (differing in lattice energy with 4NBA form II, 1b by 0.3 kcal/mol). However, the other putative polymorph, 3ahyp showed poor stability and hence was considered experimentally less feasible. The third polymorph of 4NBA was successfully grown from an aniline-dioxane solvent mixture after extensive screening from various solvents. Aniline-4NBA salt was found acting as a promoter for the growth of 4NBA form III at low concentration. A higher concentration of aniline in solution, however, leads to the isolation of the 4NBA-aniline salt crystals. The FT-IR study indicates the formation of 4NBA-anilinium salt in solution even at low concentration of aniline in the solvent mixture. The enhanced molecular aggregation of 4NBA molecules was observed in the fluorescence studies in the presence of aniline in the solvent mixture. Spectroscopic studies and the seeding experiments performed using the 2F4NBA-aniline salt crystals both points toward the formation of a 4NBA-anilinium salt layer in solution, which is probably favoring the growth of the third polymorph in solution. Our study presents the utilization of structural landscape in the rational polymorph screening which can also be used to attain better control over the crystallization processes.

Supporting Information Tables: Crystallization, crystallographic data collection and refinement details (Table S1– S4); Geometrical analysis of intermolecular interactions (Table S5-S6); Crystal structure prediction details (Table S7); Structure landscape analysis of predicted structures (Table S8– S15); Lattice energy computation details; ΔpKa calculation data (Table S16) and FT-IR measurement details (Table 17). Figures: ORTEP of crystal structures (Figure S1); Optimized geometries of homo and hetero dimers (Figure S2, S4 and S5); Packing energy vs. crystal density plot (Figure S3); Fluorescence spectra (Figure S6); DSC thermogram of 4NBA polymorphs (Figure S7). The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/XXX.XXXX

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Acknowledgments SGD and SSS thanks the Council of Scientific and Industrial Research for the award Fellowships. TST thanks, Science and Engineering Research Board (SERB) Department of Science and Technology (DST), Government of India for financial assistance under Extra Mural Research (EMR) Funding (project no. EMR/2016/005154). CSIR-CDRI manuscript communication number 9790.

References (1) Volmer, M., Kinetik der Phasenbildung. Ed.; Dresden und Leipzig : Steinkopff: 1939. (2) Davey, R. J.; Allen, K.; Blagden, N.; Cross, W. I.; Lieberman, H. F.; Quayle, M. J.; Righini, S.; Seton, L.; Tiddy, G. J. T., Crystal engineering – nucleation, the key step. CrystEngComm 2002, 4, 257-264. (3) Vekilov, P. G., The two-step mechanism of nucleation of crystals in solution. Nanoscale 2010, 2, 2346-2357. (4) Weissbuch, I.; Popovitz-Biro, R.; Lahav, M.; Leiserowitz, L.; Rehovot, Understanding and control of nucleation, growth, habit, dissolution and structure of two- and threedimensional crystals using `tailor-made' auxiliaries. Acta Cryst. 1995, B51, 115-148. (5) Desgranges, C.; Delhommelle, J., Insights into the Molecular Mechanism Underlying Polymorph Selection. J. Am.Chem. Soc. 2006, 128, 15104-15105. (6) Thakuria, R.; Thakur, T. S., 5.13 - Crystal Polymorphism in Pharmaceutical Science. In Comprehensive Supramolecular Chemistry II, Atwood, J. L., Ed. Elsevier: Oxford, 2017; pp 283-309. (7) Davey, R. J., The role of the solvent in crystal growth from solution. J. Cryst. Growth 1986, 76, 637-644. (8) Threlfall, T., Crystallisation of Polymorphs: Thermodynamic Insight into the Role of Solvent. Org. Proc. Res. Dev. 2000, 4, 384-390. (9) Diao, Y.; Whaley, K. E.; Helgeson, M. E.; Woldeyes, M. A.; Doyle, P. S.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., Gel-Induced Selective Crystallization of Polymorphs. J. Am.Chem. Soc. 2012, 134, 673-684. (10) Lang, M.; Grzesiak, A. L.; Matzger, A. J., The Use of Polymer Heteronuclei for Crystalline Polymorph Selection. J. Am.Chem. Soc. 2002, 124, 14834-14835. (11) Neumann, M. A.; van de Streek, J.; Fabbiani, F. P. A.; Hidber, P.; Grassmann, O., Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening. Nat. Commun. 2015, 6, 7793. (12) Braun, D. E.; Gelbrich, T.; Wurst, K.; Griesser, U. J., Computational and Experimental Characterization of Five Crystal Forms of Thymine: Packing Polymorphism, Polytypism/Disorder, and Stoichiometric 0.8-Hydrate. Cryst. Growth Des. 2016, 16, 3480-3496. (13) Reilly, A. M.; Tkatchenko, A., Role of Dispersion Interactions in the Polymorphism and Entropic Stabilization of the Aspirin Crystal. Phys. Rev. Lett. 2014, 113, 055701. 14


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(14) Wen, S.; Beran, G. J. O., Accidental Degeneracy in Crystalline Aspirin: New Insights from High-Level ab Initio Calculations. Cryst. Growth Des. 2012, 12, 21692172. (15) Desiraju, G., Approaches to crystal structure landscape exploration. Acta Cryst. 2017, B73, 775-778. (16) Mukherjee, A.; Grobelny, P.; Thakur, T. S.; Desiraju, G. R., Polymorphs, Pseudopolymorphs, and Co-Crystals of Orcinol: Exploring the Structural Landscape with High Throughput Crystallography. Cryst. Growth Des. 2011, 11, 2637-2653. (17) Thakur, T. S.; Dubey, R.; Desiraju, G. R., Crystal Structure and Prediction. Annu. Rev. Phys. Chem. 2015, 66, 21-42. (18) Tavale, S. S.; Pant, L. M., Further refinement of the structure of p-nitrobenzoic acid. Acta Cryst. 1971, B27, 1479-1481. (19) Groth, P., The Crystal Structure of a New Modification of p-Nitrobenzoic Acid at 150 C. Acta Chem. Scand. 1980, 34, 229-230. (20) Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C., The Cambridge Structural Database. Acta Cryst. 2016, B72, 171-179. (21) Thakur, T. S.; Singh, S. S., Studying the Role of C═O···C═O, C═O···N–O, and N– O···N–O Dipole–Dipole Interactions in the Crystal Packing of 4-Nitrobenzoic Acid and 3,3′-Dinitrobenzophenone Polymorphs: An Experimental Charge Density Study. Cryst. Growth Des. 2015, 15, 3280-3292. (22) Singh, S. S.; Vasantha, K. Y.; Sattur, A. P.; Thakur, T. S., Experimental and computational crystal structure landscape study of nigerloxin: a fungal metabolite from Aspergillus niger. CrystEngComm 2016, 18, 1740-1751. (23) Dubey, R.; Pavan, M. S.; Desiraju, G. R., Structural landscape of benzoic acid: using experimental crystal structures of fluorobenzoic acids as a probe. Chem. Commun. 2012, 48, 9020-9022. (24) Coles, S. J.; Threlfall, T. L.; Tizzard, G. J., The Same but Different: Isostructural Polymorphs and the Case of 3-Chloromandelic Acid. Cryst. Growth Des. 2014, 14, 1623-1628.

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For Table of Contents Use Only

Structural landscape guided exploration of a new polymorph of 4nitrobenzoic acid. Sibananda G. Dash, Shiv Shankar Singh, and Tejender S. Thakur*

TOC Graphics

Synopsis: A new polymorph of 4-nitrobenzoic acid, Form III was realized experimentally from a rational polymorph screening approach guided by the structural landscape study.

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A new polymorph of 4-nitrobenzoic acid, Form III predicted form CSP was realized experimentally from a rational polymorph screening guided by the structural landscape study. 250x124mm (150 x 150 DPI)


Structural landscape guided exploration of a new polymorph of 4

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