Salts and Cocrystals of Furosemide with Pyridines - ACS Publications

Subscriber access provided by UB + Fachbibliothek Chemie | (FU-Bibliothekssystem)

Article

Salts and Cocrystals of Furosemide with Pyridines: Differences in #-Stacking and Color Polymorphism Ekta Sangtani, Suman Kumar Mandal, Sreelakshmi A. S., Parthapratim Munshi, and Rajesh G. Gonnade Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 24 Apr 2017 Downloaded from http://pubs.acs.org on April 29, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Crystal Growth & Design is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Salts and Cocrystals of Furosemide with Pyridines: Differences in π−Stacking and Color Polymorphism Ekta Sangtani,a,b Suman Kumar Mandal,c A. S. Sreelakshmi,a Parthapratim Munshi,c and Rajesh G. Gonnade* a,b a

Centre for Materials Characterisation, CSIR-National Chemical Laboratory, Dr. Homi Bhabha

Road, Pune 411008, India. b

Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg,

New Delhi 110001, India c

Chemical & Biological Crystallography Laboratory, Department of Chemistry, School of

Natural Sciences, Shiv Nadar University, Tehsil Dadri, UP 201314, India. KEYWORDS: Cocrystal, Color Polymorphism, Conformation, Hydrogen Bonding, Molecular Salts, Stacking Interactions ABSTRACT Furosemide (FS), a loop diuretic drug exhibits polymorphism not only in pure entity, but also in cocrystal/salt forms. In continuation of our previous report of color cocrystals polymorphism of FS and 4,4’-Bipyridine (4BPY), FS was further screened for color cocrystals by cocrystallization with other pyridines using slow evaporative solution crystallization method. Interestingly, 2:1 molecular salt of FS and 1, 2-bis(4-pyridyl)ethylene (4BPE) displayed color polymorphism in 1 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 51

isopropanol yielding an orange (form 1I, plates) and the yellow (form 1II, blocks) crystals concomitantly. The yield of orange crystals, which appeared within 10-15 hours have been always more compared to the later formed yellow crystals, thus signifying the preference for orange crystals. The cocrystallization experiment once also yielded yellow colored 2:3 molecular salt (form 1III); however these crystals could not be reproduced later. Further, cocrystallization of FS and 4BPE from THF, dioxane and their mixture produced comparatively unstable solvates, form 1IV, form 1V and form 1VI crystals respectively. Cocrystallization of FS with other pyridines like 1,2 bis(4-pyridyl)ethane (4BPA), 1,2 bis(4-pyridyl)propane (4BPP) 1,2 bis(2-pyridyl)ethylene (2BPE), and 1,10-Phenanthroline (Phen) also gave colorless molecular salts 2, 4 and cocrystals 3 and 5 respectively. The single crystal structure analysis revealed the formation of common sandwich motif between FS and pyridines through varying geometry π−stacking interactions in all the crystals. The significant color difference between the polymorphs could be attributed to the different level of conjugation generated by dissimilar π−stacking patterns between the two components. Investigation on the origin of the color difference using DFT calculations revealed the decrease in the HOMO−LUMO gap for orange crystals compared to yellow crystals.

INTRODUCTION Development of multicomponent crystals1-5 and the study of their chemical-physical properties have evolved into a contemporary area of research comprising pharmaceutical solids,610

agrochemicals,11 high energy materials,12-15 functional solids,16-17 and so on in the last one-two

decades. Cocrystals with suitable cocrystal former are being deliberately made because of its exploitation in optimizing the physico-chemical properties of these materials that include 2 ACS Paragon Plus Environment

Page 3 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


density, solubility, stability, sensitivity, compatibility, fluorescence, elasticity, color etc.18-21 Molecules in cocrystals are primarily held together by non-covalent interactions including hydrogen bonding, halogen bonding, charge-transfer interactions (π−stacking) and van der Waals forces.22-26 Association of constituent molecules through charge-transfer interactions can result in the formation of color cocrystals depending on the conjugation level, even though individual components are colorless.19-21 The π−overlap between the constituent molecules facilitate charge-transfer from HOMO to LUMO in visible region and the extent of this overlap determines (energy difference between HOMO-LUMO) the bathochromic shift. These color materials are industrially important due to their extensive application in optoelectronic field of photoconductivity,27-28 photovoltaics,29 tunable light emitters,30-31 nonlinear optics,32 and lightdriven actuators.24 There are few reports in literature wherein color of a compound is successfully altered and tuned via cocrystallization.33-36 Increasing interest in the development of cocrystals in recent time have resulted in the reporting of large number of polymorphic cocrystals.37 While it might be proposed that cocrystal formation may restrict polymorphism,38-40 our previous encounter showed that molecules which have a tendency to display polymorphism can reveal polymorphism in their cocrystals too.21 The cocrystals of furosemide (FS) with 4,4'-bipyridine (4BPY) displayed color cocrystal polymorphism, orange and yellow, albeit both the constituent molecules were colorless. The difference in the color between the dimorphs was attributed to the differences in the π···π* separation between the benzene ring of FS and the pyridine ring of 4BPY further substantiated by DFT calculations. In a pursuit of obtaining new cocrystals of FS and their polymorphs, its cocrystallization studies were undertaken with other pyridines in order to investigate the possible formation of cocrystals through π−stacking assemblies and its consequences on the development

3 ACS Paragon Plus Environment


Page 4 of 51

of color. The cocrystallization of FS was carried out with 1, 2-bis(4-pyridyl)ethylene (4BPE), 1,2-bis(4-pyridyl)ethane (4BPA), 1,2-bis(2-pyridyl)ethylene (2BPE), 1,2-bis(4-pyridyl)propane (4BPP) and 1,10-Phenanthroline (Phen). Interestingly, cocrystallization of FS with 4BPE also yielded molecular salt polymorphs, orange and yellow, in the stoichiometric ratio 2:1. Additionally, yellow colored disappeared molecular salt (stoichiometric ratio 2:3) and unstable salts solvates with dioxane and THF were also produced. The colorless cocrystals/salts of FS with 4BPA, 2BPE, 4BPP and Phen were also obtained. Crystal structure analysis of the molecular salt dimorphs revealed differences in the π−stacking patterns of molecules along with their hydrogen bonding interactions. Further, the estimation of the gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) helped us to arrive at a possible reason for their color difference.


Page 5 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 1. Molecular structures for components used for salt and cocrystal synthesis, furosemide (FS), 1, 2-Bis(4-pyridyl) ethylene (4BPE), 1, 2-Bis(4-pyridyl)ethane (4BPA), 1, 2-Bis(2pyridyl)ethylene (2BPE), 1,3-Bis(4-pyridyl)propane (4BPP) and 1,10-Phenanthroline (Phen). EXPERIMENTAL SECTION Materials: The furosemide (FS) and all other cocrystal components were obtained from SigmaAldrich: furosemide (FS) (99%), 1,2-Bis(4-pyridyl)ethylene (4BPE) (97%), 1,2-Bis(4pyridyl)ethane

(4BPA)

(99%),

1,2-Bis(2-pyridyl)ethylene

(2BPE)

(97%),

1,3-Bis(4-

pyridyl)propane (4BPP) and 1,10-Phenanthroline (Phen) (≥ 99%). All the solvents used for the crystallization were of HPLC grade. Cocrystallization: Cocrystallization of equimolar amount of FS and 4BPE, 4BPA, 2BPE, 4BPP and Phen was attempted by grinding as well as slow evaporation methods. The grinding experiments were carried out manually using mortar and pestle. The 1:1 stoichiometric molar ratios of FS and respective cocrystal formers (CCF) were ground for about 15-20 minutes using both neat and liquid assisted grinding (or kneading)41 methods in separate experiments. In liquid assisted grinding, small (catalytic) amount ethanol was added to the grinding mixture. Although, the PXRD analysis of the ground samples indicated the formation of cocrystals; it also showed the presence of diffraction peaks of individual components. Solution cocrystallization was carried out using slow evaporation method from a variety of common organic solvents like methanol, ethanol, iso-propanol, methanol-water, ethanol-water, methanol-ethanol, iso-propanol-water mixtures, 1propanol, 1-butanol, tetrahydrofuran (THF), dioxane, acetone, acetonitrile, acetonitrilewater mixture, dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO) (Table S1, 5 ACS Paragon Plus Environment


Page 6 of 51

SI). A clear solution obtained by warming of the components in the required solvent was allowed to evaporate for 1-3 days at room temperature. Cocrystallization of FS and 4BPE was attempted at ambient conditions from almost all the common organic solvents as well as solvent mixtures (Table S1, SI). Cocrystallization of FS with 4BPE from isopropanol yielded molecular salt polymorphs in the stoichiometric ratio 2:1, form 1I crystals (orange, figure 1a) within 10-15 h and form 1II crystals (yellow, figure 1b) after one day in the same flask concomitantly (figure 1c). The quantity of form 1I had been always more compared to the form 1II crystals in all the crystallization experiment, thus specifying the preference for form 1I crystals. In addition, new yellow colored molecular salt (form 1III, figure 1d) of FS and 4BPE in the stoichiometric ratio 2:3 was once produced concomitantly with form 1I and 1II crystals, however these form 1III crystals could not be reproduced later. Formation of form 1III crystals with different stoichiometry of FS and 4BPE (2:3) could be the consequence of the presence of extra quantity of 4BPE in the mother liquor after the initial crystallization of form 1I and form 1II crystals. Crystallization of 1 from THF and 1,4-dioxane produces their respective molecular salt solvates [form 1IV (figure 1e) and form 1V (figure 1f)] containing one molecule of each FS and 4BPE along with one molecule of solvent. Both solvates were unstable and started gradually converting to orange crystals (form 1I) after exposed to an open atmosphere. Cocrystallization of 1 from the mixture of THF-1,4-dioxane (1:1, v/v) again yielded the molecular salt solvates, form 1VI (figure 1g) containing one FS and half molecule of 4BPE along with one molecule of THF, 1/4th molecule of 1,4-dioxane and a molecule of water. Storage of the form 1VI crystals for longer duration in the crystallization flask revealed nucleation of tiny orange crystals on its surface (figure 1h).


Page 7 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The crystal structure determination of one such crystals revealed it to be the form 1I crystals, thus suggesting the conversion of form 1VI crystals to form 1I crystals after the escape of solvent molecules. Cocrystallization of FS with other pyridines like 4BPA and 4BPP yielded colorless molecular salts 2 and 4 respectively (Figure 1i, 1k) and with coformers 2BPE and Phen it yielded colorless cocrystals 3 and 5 respectively (Figure 1j, 1l).

Figure 1. Photomicrographs of salts and cocrystals of FS with pyridines (a) form 1I, (b) form 1II, (c) forms 1I and 1II obtained concomitantly, (d) form 1III, (e) form 1IV (THF solvate), (f) form 1V (dioxane solvate), (g) form 1VI (dioxane-THF-water solvate), (h) form 1VI crystals displaying the crystallization of orange crystals on its surface after exposing to the open atmosphere for one day, (i) 2, (j) 3, (k) 4 and (l) 5.



Page 8 of 51

DSC and PXRD Studies Differential scanning calorimetry (DSC) analysis of forms 1I, 1II and 1III showed only the single endotherm attributed to their melting at 236.6 °C, 237.3 °C and 197.6 °C respectively (Figure 2a and S2a) and thus ruled out any phase transition during heating unlike previous case.21 The DSC analysis of crystals of 2, 3 and 4 also revealed the single endotherm corresponding to their melting at 240.6°C, 236.5°C and 187°C (Figure S4a, S5a, S6a, SI). However, the DSC measurements showed lower melting point (86.5 °C) for crystals of 5 (Figure S7a, SI). The DSC analysis of crystals of forms 1IV, 1V and 1VI could not be carried out because of their instability. The overlay of the experimental PXRD patterns of form 1I, 1II, 1III, 2, 3, 4 and 5 crystals with their respective PXRD profile simulated from the single-crystal X-ray data matched well, thus confirming the homogeneity of the sample (Figures S1, S2b, S4b, S5b, S6b, S7b, SI). Overlay of the experimental PXRD of both polymorphs forms 1I and 1II showed significant difference that confirmed their polymorphic nature (Figure 2b). The PXRD measurements of forms 1IV, 1V and 1VI crystals recorded after 24 hours revealed the diffraction peaks of form 1I crystals along with peaks of solvates (Figure S3, SI).


Page 9 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(a)

(b)

Figure 2. (a) Overlay of DSC profiles of form 1I (blue) and form 1II (red) molecular salts showing slight difference in their melting and (b) overlay of experimental PXRD patterns of form 1I (black) and form 1II (red) molecular salts displaying differences in crystal structures. See Supporting Information (SI) for

1

H NMR spectroscopy (Figures S8-S21),

crystallization details (Table S1), details of X-ray diffraction data collection, structure solution and refinement details (Table S2), DSC and PXRD details for other forms of 1 and compounds 2 – 5, density functional theory (DFT) calculations, lattice energy and intermolecular potential calculations, solid state UV, scanning electron microscopic studies, etc. RESULTS AND DISCUSSION Molecular Salt Polymorphs and Solvates of FS and 4BPE (1). Single crystal X-ray analysis revealed that the form 1I and form 1II crystals belong to monoclinic P21/c and triclinic P-1, space groups, respectively (Figures 3a-3b, Table S2, SI). The asymmetric unit of form 1I contains one molecule of FS and half molecule of 4BPE, thus the



Page 10 of 51

stoichiometry of FS and 4BPE is 2:1. Actually, the 4BPE molecule acquires a special position (inversion center), therefore only half the molecule is present in the asymmetric unit and the other half is generated by inversion operation. Similarly, in form 1II crystals the asymmetric unit contains two molecules of FS and one molecule of 4BPE, therefore the ratio of FS to 4BPE is 2:1. As the ratio of both components is same in forms 1I and 1II crystals, both can be termed as polymorphs. Crystals of form 1III salt and comparatively unstable solvates i.e. form 1IV (THF solvate), form 1V (dioxane solvate) and form 1VI (THF-dioxane-water solvate) belongs to triclinic P-1 space group (Figures S22, Table S2, SI). The asymmetric unit of forms 1III crystals contained two molecules of FS and three molecules of 4BPE, therefore the stoichiometry of FS and 4BPE is 2:3. The asymmetric unit of forms 1IV and 1V crystals contained one molecule of each FS and 4BPE along with a molecule of solvate THF and dioxane respectively. The asymmetric unit of form 1VI solvate contained a molecule of FS, half molecule of 4BPE along with one molecule of THF, 1/4th molecule of dioxane and a molecule of water. The 4BPE and dioxane molecules occupy the inversion center, therefore only half 4BPE and 1/4th dioxane molecule is present in the asymmetric unit. Thus, the stoichiometry of all the five components, FS: 4BPE: THF: dioxane: H2O in form 1VI crystal is 2 : 1 : 2 : 0.5 : 2. The stoichiometry of FS and 4BPE molecules in dimorphs and form 1III is also confirmed by 1H NMR spectroscopy (Figure S8-S13, SI). Both pyridine rings of 4BPE molecule in forms 1II, 1III and 1V crystals showed slight deviation from the planarity (~10-13°), however the conformation difference in form 1IV crystals is significant (28°). In form 1I and form 1VI crystals, 4BPE molecule has planar conformation. The ethylene carbons in two of the planar 4BPE molecules in form 1III crystals showed statistical disorder over two positions with occupancies 0.90 and 0.10. Similarly in form 1VI solvate, the furan as well as carboxyl group of FS showed statistical disorder over


Page 11 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


two positions with major and minor occupancies roughly around 80% and 20%. The C–O bond lengths [1.230 –1.297 Å] in the COOH group of FS in all crystal forms of 1 show that proton transfer has occurred (except in primed FS molecule of form 1II crystals, 1.232(2) –1.311(2) Å) from an acid O−H group of FS to the N-atom of the 4BPE thus revealing these to be the molecular salts. In form 1I crystals both N-atoms of the 4BPE are protonated whereas in form 1II crystals only one N-atom of the 4BPE is protonated. The intramolecular geometry of the FS as observed in these crystal forms revealed formation of intramolecular N−H···O hydrogen bonding interactions [graph set (6)] with comparative geometry engaging N−H of the amine moiety and the carbonyl oxygen of the carboxyl group (Entries 1, 4-5, 9-10, 14, 17, 20, Table S3, Figure 3a and 3b), similar to the polymorphs and other cocrystals of FS.21,42-49 Additionally, intramolecular short halogen bonding interaction between the Cl and the sulfonyl oxygen (C−Cl···O=S) is also observed in FS molecules (Entries 3, 7, 8, 12, 13, 15, 18, 21 Table S3, SI). In some of the structures (form 1I, unprimed FS in form 1II), intramolecular N−H···Cl hydrogen bond between the amide N−H and Cl of the FS molecules (Entries 2, 6, Table S3, SI) is also observed while in some cases (primed FS in form 1III, forms 1IV-1V) short intramolecular N···Cl halogen bond between amide N and Cl is seen. (Entries 11, 16, 19, Table S3, SI) The structural overlay of the FS molecules in all crystal forms of 1 showed significant change in the orientation of furan ring due to the free rotation about N1−C8 bond (C1−N1−C8−C9 torsion) as well as sulfonamide moiety (Figure 3c, Table S4, SI). In form 1I crystals, the furan ring takes extended conformation whereas it adopts folded conformation in all other crystal forms of 1 with respect to the basal plane of the benzene ring. Moreover, the conformation of sulfonyl amide group is similar in all the crystal forms of 1 except the unprimed FS molecule of form 1II crystals wherein the conformation of sulfonyl amide moiety differ by almost by 110°.



Page 12 of 51

(a)

(b)

(c) Figure 3. ORTEPs50 of (a) form 1I and (b) form 1II molecular salts of 1. The formation of intramolecular N−H···O and short N−H···Cl and C−Cl···O=S bond in FS is also depicted by 12 ACS Paragon Plus Environment

Page 13 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


dotted line. The displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii. (c) The structure overlay of the molecules of FS in all the crystal forms of 1. The conformation difference of furan moiety in polymorphs, form 1I (orange) and form 1II [green (primed) and yellow (unprimed)] is clearly seen. For the ORTEPs of forms 1III – 1VI, please see supporting informations (Figure S22). Formation of Common Sandwich Structure The common structural feature observed in all the molecular salts of FS-4BPE is the formation of sandwich motif. In form 1I, 1II and 1VI crystals the sandwich motif comprises two molecules of FS and one molecule of 4BPE (Figure 4 (a-c)). Both FS and 4BPE molecules interact through aromatic π···π stacking interactions (entries 1 and 11, Table S5, entry 1, Table S6, SI) involving benzene ring of FS and pyridine ring of 4BPE. However, there are differences in the orientation of FS and 4BPE within the sandwich motif. In forms 1I and 1VI crystals both pyridines rings of 4BPE and benzene rings of two FS molecules involved in π−stacking interactions are arranged across the inversion center (Figure 4a and 4c). Conversely, in form 1II crystals, only one pyridine ring of 4BPE is involved in π−stacking interactions with the benzene ring of the unprimed FS molecule. The primed FS being different in orientation with respect to the unprimed FS, its benzene ring is not engaged in π−stacking interactions with other pyridine ring of 4BPE. However, this difference in orientations brings the π−cloud of its carbonyl group (C=O) in stacking mode with respect to the π−electron cloud of the other pyridine ring of 4BPE to generate the C=O···π contact (Figure 4b, entry12, Table S5, SI). Thus, in forms 1I and 1VI, both 4BPE pyridine rings in centrosymmetric sandwich assembly are engaged in π−stacking interactions whereas in form 1II crystals, one pyridine ring is involved in π−stacking interactions while the other pyridine ring is forming C=O···π contact. The extent of overlap is more in form 13 ACS Paragon Plus Environment


Page 14 of 51

1I crystals compared to form 1II crystals. The sandwich association in form 1II crystals also paves the way for the generation of C−H···π interactions (entry13, Table S5, SI) between the 4BPE H-atom and the π−electron cloud of the furan ring of unprimed FS. The C−H of the same furan ring is also engaged in generating quite long and nonlinear C−H···O, C−H···Cl and marginal C−H···π contacts (entries 14-16, Table S5, SI) with the primed FS molecule. In the sandwich motifs of forms 1III, 1IV and 1V, two molecules of FS accommodate two 4BPE molecules. Both 4BPE molecules within the sandwich assembly are interacting with each other as well as with FS molecules through π−stacking interactions, thus generating a chain via π···π contacts involving FS-4BPE-4BPE-FS tetramer (Figure 4d-4f, entries 1-3, Table S8, entries 1-2 and 19-20, Table S9). Both FS and 4BPE molecules in forms 1IV and 1V, which are involved in π−stacking interactions within the sandwich motif are related to the other pair through center of symmetry, whereas in form 1III crystals, no inversion symmetry exist within the sandwich assembly. The sandwich assembly in all the three forms is further supplemented by short C−H···N contact between 4BPE C−H and amide N atom of FS (Figure 4d-4f, entry 4, Table S8, entries 3 and 21, Table S9, SI).

(a)

(b)


Page 15 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(c)

(e)

(d)

(f)



Page 16 of 51

Figure 4. View of sandwich motifs in (a) form 1I, (b) form 1II, (c) form 1VI, (d) form 1III, (e) form 1IV and (f) form 1V. Molecular salts and cocrystals of FS with other pyridines (2-5) Crystals of 2, 3, 4 and 5 were crystallized in monoclinic P21/c, P21/n space groups, triclinic P-1 and monoclinic C2/c space groups respectively. Unit cell dimensions suggest that molecular salt 2 is isostructural with form 1I crystals (Table S2). Asymmetric unit of 2 and 3 contained one molecule of FS and half molecule of coformers 4BPA and 2BPE respectively, which occupies the special position (inversion center) (figure 5a-5b). The asymmetric unit of 4 contained two different conformers of FS having full occupancy along with one full molecule of 4BPP (figure 5c). Thus, the stoichiometry of FS and coformers in crystals of 2, 3 and 4 is 2:1. In contrast, one molecule of each FS and coformer Phen is present in the asymmetric unit of 5 (stoichiometry 1:1) along with two molecules of water (figure 5d). The stoichiometry of FS and coformers in 2, 3, 4 and 5 has also been confirmed using 1H NMR spectroscopy (Figures S14-S21, SI). The furan moiety in 3 and 5 displayed statistical disorder over two positions with equal occupancies (50% for both unprimed and primed) in 3 while 0.65 (unprimed FS) and 0.35 (primed FS) in 5. One of the carbon atom (C18) of the propane spacer of 4BPP molecule in 4 showed significant thermal disorder which has been modeled over two positions having occupancies of 0.55 (C18A) and 0.45 (C18B). The C–O bond lengths [1.248–1.276 Å] in the COOH group of FS in 2 and 4 (primed conformer 2) shows that proton transfer has occurred from an acid O−H group to the pyridine N-atom of the 4BPA and 4BPP respectively suggesting these to be the molecular salts. Conversely, the C–O bond lengths [1.226–1.318 Å] in the COOH group of FS molecule in 3 and 5 shows that proton transfer has not taken place revealing these be the cocrystals. The intramolecular geometry of the FS in all these crystals reveals the formation of intramolecular 16 ACS Paragon Plus Environment

Page 17 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


N−H···O hydrogen bond [graph set, 6] engaging amine N−H and the carboxyl oxygen (Figure 5a-5d, entry 24, 26, 28, 29, 32, Table S3). Additionally, intramolecular short halogen bonding interaction C−Cl···O=S between Cl and the sulfonyl O is also observed in all these crystals (Figure 5a-5d, entry 25, 27, 30, 31, 33, Table S3). Two major orientations of furan moiety of FS are observed in these crystals due to the free rotation about the N1−C8 bond (C1−N1−C8−C9 torsion). In crystals of 2 and 5, the furan rings takes extended conformation with respect to the orientations of benzene ring similar to the form 1I crystals, whereas in crystals of 3 and 4 furan moiety takes folded conformations (Figure 5e)

(a)

(b)



Page 18 of 51

(c)

(d)

(e) Figure 5. ORTEPs50 of (a) molecular salt 2, (b) cocrystal 3, (c) molecular salt 4 and (d) cocrystals 5 with atom numbering scheme showing association of pyridines with FS. The displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii. The formation of intramolecular N−H···O and short C−Cl···O=S bond 18 ACS Paragon Plus Environment

Page 19 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


in FS is also depicted. (e) Structure overlay of the FS molecules, 2 (cream), 3(purple), 4 (unprimed- yellow, primed-magenta) and 5 (cyan). Formation of Common Sandwich Structure in 2, 3, 4 and 5 Both FS and the coformers (pyridines) in all these structures generate the sandwich assembly, however with a difference. Both molecules in salt 2 form a sandwich assembly similar to form 1I crystals, comprising two molecules of FS and one molecule of 4BPA arranged across the inversion center through π−stacking interactions between the benzene ring of FS and pyridine ring of 4BPA (Figure 6a, entry 1, Table S10, SI). The sandwich assembly is further supported by two C−H···O interactions formed between ethane C−H and carbonyl and furan oxygens (Figure 6a, entries 2-3, Table S10, SI). Similarly, two FS molecules and a molecule of 2BPE also constitute the sandwich assembly across the inversion center in cocrystal 3 (Figure 6b). However, both molecules within the sandwich motif do not associate via π−stacking interactions but purely through van der Waals forces (the distance between the two closest carbon atoms; C···C = 3.157(4) Å). The sandwich assembly formation seems to be merely the packing consequence (entry 1, Table S11, SI) in this crystal. Molecules in 4 were also involved in the sandwich assembly formation comprising two symmetry independent molecules of FS and one molecule of 4BPP. Similar to form 1II crystals, only one pyridine ring is involved in π−stacking interactions with the benzene of the prime FS molecule, whereas the other pyridine ring is protruding away from the sandwich assembly (Figure 6c, entry 1, Table S12, SI). The pyridine ring which is involved in π−stacking interactions with a benzene ring of prime FS molecules is also making off-centered C−H···π interaction (entry 2, Table S12, SI) with furan ring of the primed FS molecule. The benzene ring of the unprimed FS molecule is somewhat engaged



Page 20 of 51

through C−H···π interactions involving propane CH of 4BPP (entry 3, Table S12, SI). Both coformers (primed and unprimed) within the sandwich assemblies are also connected through C−H···O interactions formed between furan C−H of primed FS and sulfonyl oxygen of the unprimed FS (entry 4, Table S12, SI). Molecules in cocrystal hydrate 5 also constitute a sandwich motif comprising two FS molecules that accommodate two molecules of Phen (Figure 6d). Molecules in sandwich assembly are strongly held by parallel displaced π···π interactions between FS benzene ring and both pyridine and benzene rings of Phen (Entries 1-2, Table S13, SI). The two Phen moieties within the sandwich assemblies are also involved in centrosymmetric π−stacking interactions between its pyridine and benzene rings (Entries 3-4, Table S13, SI). Thus, the π−stacking interactions between FS - Phen and Phen - Phen moieties generate a finite chain of π···π interactions involving FS-Phen-Phen-FS tetramer within the sandwich assembly. The sandwich motif is further strengthened by centrosymmetric N−H···N hydrogen bond between amide N−H and pyridine N of Phen as well as centrosymmetric C−H···O interaction between Phen C−H and furan oxygen (Entries 5-6, Table S13, SI).


Page 21 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(a)

(c)

(b)

(d)

Figure 6. View of sandwich motifs in (a) molecular salt 2, (b) cocrystal 3 (c) molecular salt 4 and (d) cocrystal 5.



Page 22 of 51

Correlation of Molecular Packing with Color Difference in Molecular Salts Polymorphs (form 1I and form 1II) The molecular packing in polymorphs of 1 is correlated with their color difference with respect to the linking of common sandwich assemblies. The crystal structure analysis revealed that the sandwich motifs in forms 1I and 1II crystals are stitched differently. In form 1I crystals, the neighboring sandwich assemblies are unit translated along the a-axis to generate the monolayer structure comprising linear chains of FS that accommodates chain of 4BPE molecules (Figure 7a). Along the monolayer the unit-translated FS molecules are connected through strong N−H···O hydrogen bond engaging N−H of sulfonyl amide and C=O of the carboxyl group to create a molecular string (entry 2, Table S5, SI). Each 4BPE molecule of adjacent unit-translated sandwich motifs are also engaged in π−stacking assemblies (entry 4, Table S5, SI) across the inversion center to generate the extended chain within the monolayer. Additionally, the 4BPE molecules are interacting with the chain of FS through strong and linear N−H···O hydrogen bond involving N−H of the pyridine and carbonyl oxygen of the carboxyl group (entry 3, Table S5, SI). The assembly of FS and 4BPE molecules in the monolayer structure somewhat resembles a ladder structure where molecular strings of FS can be considered as the rails and the 4BPE molecules as rungs similar to the yellow cocrystal polymorph of FS and 4BPY21 (Figure 7a and S23, SI). These two assemblies, i.e. sandwich and linear, are part of an extended monolayer structure created by the unit-translated arrangement of molecules along the a-axis. The closely associated sandwich assemblies in form 1II crystals are arranged centrosymmetrically along the ac diagonal to generate the monolayer structure however, with a difference. The FS molecules within the monolayer are not connected directly, instead they are joined through 4BPE molecules of the adjacent sandwich motif via 22 ACS Paragon Plus Environment

Page 23 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


centrosymmetric N−H···O and O−H···N hydrogen bonds (Figure 7b, entries 17 and 18, Table S5, SI) engaging the pyridine N atom and carboxyl group. Both symmetry independent FS molecules are arranged alternately along the monolayer structure. Unlike, form 1I crystals, the 4BPE molecules do not associate with each other within the monolayer.

(a)

(b) Figure 7. Molecular arrangement displaying association of adjacent sandwich motifs in (a) form 1I and (b) form 1II crystals.



Page 24 of 51

The adjacent c-glide related monolayers, in form 1I crystals, are loosely connected along the b-axis through C−H···O and C−H···Cl interactions involving C−H of the benzene and oxygen of the sulfonyl and C−H of furan and Cl of benzene of FS molecule respectively (entries 5 and 6, Table S5, SI) to generate the bilayer structure (Figure 8a). In contrast, the neighboring monolayers in form 1II crystals are unit-translated along the b-axis to generate the bilayer structure. The monolayers within the bilayer are linked through FS molecules via strong N−H···O hydrogen bond between N−H of the sulfonyl amide and oxygen of the carboxyl group supplemented by the C−H···O interactions between C−H of the furan and oxygen of the carboxyl group (Figure 8b, entries 19-21, Table S5, SI).

(a)


Page 25 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(b) Figure 8. View of molecular packing showing the association of monolayers through weak interactions like C−H···O and C−H···Cl in form 1I crystals (a) and via strong N−H···O and C−H···O interactions in form 1II crystals (b). Molecular packing along the c-axis in form 1I crystals revealed formation of a monolayer structure through tight binding of the neighboring unit-translated sandwich assemblies. Within the monolayers both FS and 4BPE molecules are strongly associated through N−H···O and C−H···O interactions (Figure S24a, entries 7-10, Table S5, SI). However, the sandwich assemblies along the b-axis are loosely connected only via C−H···O contact (entry 5, Table S5, SI). Conversely, the adjoining unit translated sandwich assemblies in form 1II crystals, are in comparison loosely connected to generate a monolayer and bilayer structure (Figure S24b, SI) through N−H···O and C−H···O interactions (entries 19- 23, Table S5, SI). In our previous finding,21 the color difference between the cocrystal dimorphs was endorsed to the differences in the π−stacking pattern of two components, the maximum overlap between the FS and 4BPY molecule resulted in the orange cocrystals compared to the yellow



Page 26 of 51

cocrystal which witnessed largely displaced π−stacking interactions between these moieties. Similarly, the color difference in both polymorphs in the present case can be rationalized based on the molecular packing of FS and 4BPE and its conjugation level. The orange color of the form 1I molecular salt can be attributed to the maximum overlap between FS and 4BPE molecules that are interacting via π−stacking interactions supplemented by π−stacking interactions between the pyridine rings thus generating more highly conjugated system (figure 7a). On the other hand, the overlap between the FS and 4BPE molecules in form 1II molecular salt is only partial and limited only to FS and 4BPE molecules. No π−stacking interactions between the pyridine rings were observed, unlike form 1I crystals to extend the conjugation. Thus amongst the two polymorphs, form 1I crystals revealed a maximum degree of conjugation compared to form 1II crystals that resulted in the color difference between them. Although the association of sandwich motifs in form 1I (FS-4BPE, present case) and form 1I of FS and 4,4' bipyridine (previous report)21 are similar (ladder structure), however the color of both crystals differs. The form 1I crystals of 1 are orange whereas the form 1I of FS and 4,4' bipyridine21 were light yellow. This color difference could be rationalized based on the conjugation level along the ladder structure (figure S23, SI). The red shift in form 1I crystals (FS-4BPE) could be because of the extended conjugation due to the presence of an extra double bond in coformer 4BPE compared to 4,4' bipyridine. The computation of packing energies51-52 for form 1I and form 1II gave the values of 540.7 kJ/mol and -528.9 kJ/mol, respectively, indicating that the form 1I crystals are more stable compared to form 1II crystals. The values of crystal densities of 1.564 g cm−3 (form 1I) and 1.553 g cm−3 (form 1II) are also consistent with their packing energies. This also corroborates the formation of form 1I crystals exclusively in all of the crystallization experiments either 26 ACS Paragon Plus Environment

Page 27 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


separately or concomitantly with form 1II crystals (the quantity of form 1I crystals were always more compared to form 1II crystals). The estimation of the intermolecular potential51-52 between the molecules involved in the sandwich motif formation (considering one benzene and one pyridine rings) revealed a slightly higher value for form 1II crystals (−66.7 kJ/mol; Figure 4b) than that of form 1I crystals (−63.1 kJ/mol; Figure 4a), could be because of the shorter π···π distance in the former compared to the later. However, considering the sandwich assembly as a whole in both forms, form 1I crystals showed maximum overlap because of its centrosymmetric arrangement engaging both pyridine rings of 4BPE in π-stacking interactions with benzene rings of FS with total intermolecular potential value −126.2 kJ/mol. Conversely, in form 1II, only one pyridine ring of 4BPE is involved in π−stacking interactions with a benzene ring of FS having intermolecular potential value −66.7 kJ/mol and the other pyridine ring of 4BPE is occupied with C=O group of FS through C=O···π interactions having intermolecular potential value of −18.4 kJ/mol, thus the total intermolecular potential value of molecules assembled in sandwich motif is -85.1 kJ/mol. The intermolecular potential values for the linking of the sandwich assemblies in all the three dimensions in both polymorphs revealed similar values (see ESI, page no. S53). This suggests that molecules in form 1I crystals form stronger sandwich assembly compared to the form 1II crystals. This also establishes the preferential formation of form 1I crystals in all the crystallization experiments. The intermolecular interactions in different molecular environments of the cocrystals polymorphs of 1 were visualized and quantified via fingerprint plots as generated from Hirshfeld surface analysis53-55 (Figure S25, SI) using the program Crystal Explorer.56 The intermolecular interactions were evaluated with respect to their contribution to the overall stability of the dimorphs. The dissimilarity in the Hirshfeld fingerprint images for both polymorphs are 27 ACS Paragon Plus Environment


Page 28 of 51

distinguishable, thus revealing a different molecular environment in the two cocrystals polymorphs (Figure S26, SI) and also confirms the high sensitivity of this method for the comparison of polymorphic structures.57 Among the interactions present in both forms, H···H, H···O and H···C made major contributions to the Hirshfeld surface areas (Figure S26c, SI). The solid-state UV−Vis spectrum in absorbance mode reveals absorption for form 1I and form 1II crystals at different wavelengths. Crystals of form 1I showed λmax value at 600 nm whereas form 1II crystals at 522 nm suggesting a red shift of the absorption in form 1I crystals compared to the form 1II crystals (Figure 9). To rationalize the orange (form 1I) and yellow (form 1II) colors of the molecular salt dimorphs and to estimate the HOMO-LUMO gap, crystal coordinates of both structures were optimized using DFT58 method and Gaussian09.59 The calculations were performed using B3LYP functional and 6-311G** basis set. The HOMOLUMO gap values estimated from theoretical calculations compare reasonably well with the experimental UV-vis experiments (Figures S27, Table S7, SI). Similar observation was noticed in an earlier study by some of us.60 The calculated value of λmax for form 1I crystals is 749 nm (over estimated by 20%) while, for the form 1II, the value is 369 nm (under estimated by 41%). The ~50% lower band gap in form 1I crystals (0.06084 Hartree) compared to form 1II crystals (0.12388 Hartree) revealed optimization of the donor−acceptor interactions, which essentially leading to the color change of form 1II crystals from yellow to orange in the form 1I crystals. It is to be also noted that the molecular dipole moment of orange form is higher (14.2D) than that of yellow form (10.2D).


Page 29 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 9. UV−Vis spectra of the solid sample of form 1I (black) and form 1II (red) crystals in absorption mode. Similarity in molecular packing of form 1I and form 1VI crystals The sandwich assemblies in form 1VI crystals generate the monolayer structure similar to the form 1I crystals. The unit-translated sandwich assemblies along the a-axis are connected through N−H···O and C−H···O interactions involving pyridine N−H and C−H moieties and carboxyl oxygens of the FS molecule to generate the monolayer structure (Figure 10, entries 2-4, Table S6, SI). This arrangement also brings the 4BPE molecules of neighboring sandwich motifs in close proximity along the monolayer to generate π−stacking interactions between its pyridines rings, similar to form 1I crystals (Figure 10, entry 5, Table S6, SI). However, the joining of the neighbouring monolayers differs in both forms. In form 1I crystals, the neighbouring monolayers are loosely connected along the b-axis through C−H···O and C−H···Cl interactions to generate the bilayer structure (Figure 8a). Conversely, the adjacent monolayers in form 1VI solvate are bridged through furan moieties using C−H···O interactions (Figures 10, S28a, entry 6, Table S6, 29 ACS Paragon Plus Environment


Page 30 of 51

SI). The linking of the four sandwich assemblies roughly along the c-axis creates an open channel between them to accommodate the solvent molecules. The included water, THF and dioxane molecules are interacting with the host molecules using O−H···O, N−H···O, C−H···O, C−H···Cl and van der Waals interactions (Figure S28b, entries 13-20, Table S6, SI). The estimation of the voids calculated using contact surface with default probe radius 1.2 Å after removing the solvent molecules revealed open channels amounting to 343.16 Å3 per unit cell (26.5% of the cell volume) suggesting the easy escape route for the solvent molecules (Figure S28c, SI). Hence, the release of the solvent molecules from the channel enables the host molecules to reorient and adjust themselves with their cooperative and concerted movement to achieve the packing similar to the form 1I crystals. The conversion of form 1VI crystals to form 1I crystals after the release of the solvent molecules from the open channel substantiates this assumption (Figures 1h, S3, SI). The SEM image of the crystals of form 1VI showed development of cracks on the crystal surface, probably indicating the escape of solvent molecules (Figure S29, SI).


Page 31 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 10. An association of sandwich assemblies in form 1VI crystals down b-axis displaying open channels that accommodate the solvent molecules. All the solvent molecules in the open channel are loosely held to the host as well as with each other. For the packing of molecules in other direction see supporting information (Figure S28). Similarity in Molecular Packing of Forms 1III, 1IV and 1V Crystals The sandwich assemblies in forms 1III, 1IV and 1V have similar molecular arrangement. The neighboring sandwich motifs in these crystals create a monolayer structure, along a-axis in form 1III and along b-axis in forms 1IV and 1V (Figures 11a-11c). The unit-translated sandwich assemblies are held diagonally along the monolayer structure through strong N−H···O hydrogen 31 ACS Paragon Plus Environment


Page 32 of 51

bond between the sulfonyl amide N−H and carbonyl oxygen. The only difference is that in form 1III crystals the symmetry independent FS molecules (primed and unprimed) which are linked through N−H···O hydrogen bonds are pseudo-centrosymmetrically related (entries 5-6, Table S8) whereas in forms 1IV and 1V crystals, the diagonally linked FS molecules have inversion symmetry (entries 4 and 22, Table S9, SI). The stitching of the sandwich motifs along the monolayers are further supplemented by several C−H···O interactions between the 4BPE C−H and sulfonyl and carbonyl oxygens of the FS molecules thereby strengthening the association of molecules along the monolayer (entries 7-14, Table S8, entries 5-9 and 23-26, Table S9, SI). The joining of these adjacent monolayers in forms 1III, 1IV and 1V crystals also reveals similarity. In all the crystals the monolayers are loosely connected to generate an open channel to accommodate third 4BPE molecule in form 1III and THF and dioxane molecules in forms 1IV and 1V solvates respectively. In form 1III crystals two adjoining sandwich motifs along the baxis are connected through C−H···O interaction between furan C−H and sulfonyl oxygen to create an open channel of approximate dimensions 6 x 7 Å2 that houses the third 4BPE molecule on its top and bottom surface (Figure 11a, entry 15, Table S8). Similarly, in forms 1IV and 1V, the adjacent monolayers are glued centrosymmetrically via off-centered C−H···π interactions between the furan C−H and pyridine ring of 4BPE molecules and C−H···O interaction between C−H (CH2) and furan oxygen of FS (Figure 11b-11c, entries 10, 15, 27-28 Table S9). The joining of the four such sandwich motifs on the bc plane in both solvates generates an open space of approximate area 8 x 12 Å2 that accommodates two molecules of the solvents. The only noticeable difference in the packing of form 1III and forms 1IV and 1V crystals is that the solvent molecules occupy the position of the third 4BPE molecule (Figures S30-S32). The third 4BPE molecule in form 1III and solvent molecules in forms 1IV and 1V crystals are associated


Page 33 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


with the host molecules via N−H···N, C−H···N, C−H···O and C−H···Cl contacts (entries 17, 18, 21-23, Table S8, entries 16-18 and 32-35, Table S9, SI). The estimation of the voids calculated using contact surface with the default probe radius 1.2 Å after removing the solvent molecules revealed voids amounting to 276.89 Å3 per unit cell (20.2% of the cell volume) for Form 1IV (THF solvate, Figure S33a) and 293.35 Å3 per unit cell (21.1% of the cell volume) for form 1V (dioxane solvate, Figure S33b). The molecular packing viewed down the a-axis also revealed the thorough, open channel in both solvates displaying the escape route of these solvent molecules.

(a)



Page 34 of 51

(b)

(c) 34 ACS Paragon Plus Environment

Page 35 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 11. View of molecular packing in crystals of (a) form 1III, (b) form 1IV and (c) 1V crystals. Packing of molecules in other directions are given in supporting informations (figures S30-S32).

Similarity in the crystal structures of form 1I and 2 The correlation of the crystal structures of form 1I and salt 2 revealed similarities due to the similarities in the coformer structure. The coformer (4BPE) in compound 1 has ethylene spacer (−CH=CH−) whereas in compound 2 the coformer (4BPA) comprises ethyl spacer (−CH2−CH2−) that link the two pyridines rings. Similar to form 1I crystals, the neighboring sandwich assemblies along the a-axis generate the monolayer structure (Figure 12). Along the monolayer the unit-translated FS molecules are connected through strong N−H···O hydrogen bond engaging amide N−H and carbonyl oxygen (entry 4, Table S10, SI). Each 4BPA molecule of adjacent unit-translated sandwich motifs are also interacting with FS molecules within the monolayer structure through N−H···O hydrogen bond, engaging 4BPA N−H and carbonyl oxygen (entry 5, Table S10, SI). The association of the adjacent sandwich motifs along the monolayer also brings pyridine rings of 4BPA molecules in proximity to generate parallel displaced π−stacking interactions, like form 1I crystals, however the centroid···centroid distance is longer (entry 6, Table S10, SI). The neighboring sandwich assemblies along the b-axis are connected via weak C−H···O and C−H···Cl interactions engaging FS molecules (entries 7-9, Table S10, SI). Although the packing of molecules in 2 is isostructural with form 1I crystals (Figures S24a and S34 entries 10-16, Table S10, SI), its crystals are colorless, unlike form 1I orange crystals. This could be due to the discontinuity in the conjugation within the sandwich assembly because of the ethane spacer present in 4BPA molecules, unlike 4BPE molecule which 35 ACS Paragon Plus Environment


Page 36 of 51

has ethylene spacer that helps in the extension of conjugation. Furthermore, the stacking distance between the two 4BPA molecules is more than 4.5 Å, thus ruling out the charge-transfer between its pyridines rings

Figure 12. Joining of the adjacent sandwich assemblies on the ab plane through N−H···O, C−H···O, C−H···Cl and π···π interactions (between pyridine rings) to generate the twodimensional arrangement. The computation of packing energies51-52 for 2 revealed value −527.7 kJ/mol constituted by two clusters, one is of FS and other one is of 4BPA and each cluster having individual packing energies −194.47 kJ/mol and −138.71 kJ/mol. The estimation of the intermolecular potential gave the first rank to the molecules involved in sandwich motif formation with revealed a highest rank (-57.7 kJ/mol) albeit in the presence of stronger N−H···O hydrogen bonds which connects the adjacent sandwich assemblies gets rank second (-55.1 kJ/mol). The loose association of the neighboring sandwich assemblies along the b-axis through C−H···O and C−H···Cl contacts gets third rank with intermolecular potential value -46.6 kJ/mol. 36 ACS Paragon Plus Environment

Page 37 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Molecular packing in crystals of 3, 4 and 5 The linking of adjacent sandwich motifs in all these structures generates the monolayer structures although in different fashion. In cocrystal 3, the lack of π-stacking interaction in the sandwich assembly (Figure 6b) could be the reason of its colorless nature. The joining of the neighbouring sandwich assemblies generate the monolayers wherein FS molecules are linked via strong N−H···O hydrogen bond involving N−H and oxygen of the sulfonyl amide group (Figure 13, entry 2, Table S11, SI). This association also brings the C=O of carboxyl group in stacking distance with the benzene of FS to create short C=O···π interaction (Figure 13, entry 3, Table S11, SI). The N−H···O linked 1D molecular string of FS is further strengthened by C−H···Cl interaction between furan C−H and Cl (entry 4, Table S11, SI). The 2BPE molecules of the neighbouring sandwich motif within the monolayer do not associate via π···π interactions, although it has a comparable stacking arrangement to create the one-dimensional extended chain structure within the monolayer. The arrangement of molecules of FS and 2BPE within the monolayer resembles a ladder-like structure wherein the chain of FS molecules can be judged as the rails and the 2BPE molecules as rungs (Figure S35). One can also envisage the separate linear assembly of FS and 2BPE through short and linear O−H···N hydrogen bond within the monolayer engaging carboxyl O−H group of FS of the next sandwich motif and the pyridine N atom of the 2BPE of the preceding sandwich motif (Figure 13, entry 5, Table S11, SI). Each linear assembly gets support from weak C−H···O interactions between 2BPE and FS molecules (entries 6-7, Table S11, SI). These two motifs, i.e., sandwich and linear, are part of an extended monolayer structure created by the arrangement of FS and 2BPE molecules along the a-axis. The neighboring monolayers along the ac-diagonal are related by n-glide symmetry and are firmly held together via two N−H···O hydrogen bonds between sulfonyl amide with carboxyl 37 ACS Paragon Plus Environment


Page 38 of 51

oxygen and amine N−H with sulfonyl oxygen to generate the compact 2D packing (Figure S36, entries 8-9, Table S11, SI). Molecular packing viewed down the monolayer (a-axis) reveals joining of the crystallographic 21-screw related sandwich assemblies through bifurcated C···O (C···O = 2.880 (3) Å and 3.019(3) Å, Figure S37, SI) contacts to generate the corrugated sheet structure on the bc plane. The n-glide related FS molecules within the sheets are connected via N−H···O and C−H···O interactions (entries 8-10, Table S11, SI) to affirm the tight binding of molecules within the sheet.

Figure 13. Molecular arrangement reveals monolayer formation in cocrystal 3 In molecular salt 4, the neighbouring sandwich assemblies along the ab diagonal are joined through FS (primed and unprimed) molecules to generate the monolayer structure via pseudo-centrosymmetric N−H···O hydrogen bonds and short C−Cl···N halogen bond (Figure 14, entries 5-9, Table S12, SI). The closely associated monolayers roughly along the c-axis are tightly held through C−H···O interactions (Figure 14, entries 10-12, 15, Table S12, SI) to


Page 39 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


generate the compact bilayer structure. The adjoining bilayers are further extended along the caxis centrosymmetrically through C−H···O interactions leading to compact 2D packing (Figure S38, SI). The neighbouring monolayers along the ab diagonals are further stitched through N−H···O and O−H···N hydrogen bonds involving 4BPP and FS molecule thereby strengthening association between FS and 4BPP molecules (Figure S39 entries 13-14, Table S12, SI). The colorless appearance of molecular salt 4 could be explained on the basis of geometry of association of both constituents within the sandwich assembly and its subsequent packing. Although one of the pyridine ring of the 4BPP is involved in π−stacking interaction with benzene ring of FS but the other pyridine ring which is separated by propyl spacer is not involved in π−stacking interaction within the sandwich motif that resulted in the breaking of conjugation.



Page 40 of 51

Figure 14. Adjacent sandwich motifs in 4 generate the monolayer structure through pseudocentrosymmetric N−H···O and unit-translated C−Cl···N interactions. Adjoining monolayers are stitched together along the c-axis through C−H···O contacts to yield two-dimensional packing. The sandwich assemblies in cocrystals 5 also generate the monolayer structure along the a-axis through the centrosymmetric π−stacking interactions between furan rings (Figure 15, entry 7, Table S13, SI). The adjacent unit-translated monolayers along the b-axis are connected through C−H···O interactions to generate the bilayer structure on the ab plane (Figure 15, entry 8, Table S13, SI). Along the c-axis the adjacent monolayers are joined through N−H···O hydrogen bond engaging FS’s amide N−H and the carbonyl oxygen (Figure S40, entry 9, Table S13, SI). The association is further reinforced by short Cl···O=C halogen bonding contact (entry 10, Table S13, SI). Although both constituent molecules in cocrystal 5 generate proper sandwich assemblies facilitated through π···π interactions between them, the colorless appearance of it could be attributed to the breaking of π−stacking conjugation during the association of neighbouring sandwich assemblies. The open space created between the sandwich assemblies along the c-axis has been occupied by two water molecules. Actually, the water molecules bridged the gap between the sandwich assemblies along the c-axis which are interacting with FS and Phen molecules through O−H···O and O−H···N hydrogen bonds as well as with other water molecule via O−H···O hydrogen bond (Figures S40-S41, entries 11-15, Table S13, SI). The estimation of the voids calculated using contact surface with default probe radius 1.2 Å after removing the water molecules revealed voids amounting to 270.61 Å3 per unit cell (5.7% of the cell volume). Molecular packing viewed down the b-axis also revealed thorough open channel that occupies the water molecules (Figures S42, SI). This significant decrease in the melting


Page 41 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


point of 5 (86.5 °C) compared to its components FS (206 °C) and Phen (117 °C) could be due to the escape of water molecules from the crystals resulted in the collapse of a lattice.

Figure 15. Adjacent sandwich motifs in cocrystal 5 generate the monolayer structure through π···π interactions between furan rings. The adjoining monolayers are stitched together along the b-axis through C10−H10···O1 contact to yield two-dimensional packing.

The computation of packing energies51-52 for the 3, 4 and 5 revealed value −535.7 kJ/mol, −496.3 kJ/mol and −396.3 kJ/mol respectively. Intermolecular potential associated with sandwich motifs in 3 has very less value (−24. 9 kJ/mol) compared to the sandwich assemblies in crystals 4 (-66.6 kJ/mol) and 5 (-68.16 kJ/mol) (Figure 6b-6d). This suggests the stronger association between the FS and coformer molecules within the sandwich motifs in crystals of 4 and 5 compared to crystals of 3. Further, the sandwich assembly is not the strongest association in crystals of 3 and 4. Association of FS molecules generating the monolayers structure through N−H···O and C=O···π interactions within the monolayer in crystals of 3 has highest intermolecular value (−74.7 kJ/mol) whereas association of FS molecules through C=O···π



Page 42 of 51

contact in crystals of 4 gets intermolecular potential having value (-86.8 kJ/mol). The intermolecular potential values for the linking of the sandwich assemblies in other dimensions in these crystals have similar intermolecular potential values (-25 − -40 kJ/mol). CONCLUSIONS In summary, molecular salts/cocrystals of a loop diuretic drug, furosemide (FS) and the next batch of pyridines have been prepared and thoroughly characterized using appropriate solidstate characterization techniques. Molecular salts of FS with 1,2-bis(4-pyridyl)ethylene (4BPE) in stoichiometric ratio 2:1 exhibited color polymorphism, orange (form 1I) and yellow (form 1II). Furthermore, both constituent molecules also produced form 1III crystals in stoichiometric ratio 2:3 along with relatively unstable solvates with THF and/or dioxane (form 1IV, 1V, 1VI). Solvates form 1IV, 1V and 1VI converted to form 1I crystals after the escape of the solvent molecules from the lattice, confirmed by PXRD and single crystal X-ray analysis. Additionally, FS also produced colorless salts with 4BPA (2) and 4BPP (4) and cocrystals with 2BPE (3) and Phen (5), however none of these exhibited polymorphism. The common structural features observed in all of the salts/cocrystals is the formation of sandwich motifs comprised of two FSs and one pyridine or two FSs and two pyridines connected mostly through π−stacking interactions. The variation in the color between the polymorphs (forms 1I and 1II) could be attributed to the differences in the π···π* separation between the benzene ring of FS and pyridine ring of 4BPE. The HOMO–LUMO gaps estimated from theoretical calculations compare reasonably well with the experimental UV-Vis values. The preferential formation of form 1I crystals in large quantity compared to form 1II crystals as well as conversion of all the molecular salt solvates to form 1I crystals after the release of solvent molecules revealed the importance of π−stacking assemblies in driving the self-assembly and subsequently governing the nucleation 42 ACS Paragon Plus Environment

Page 43 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


process.61 The highest rank of intermolecular potential values for sandwich assemblies in most of the crystals, revealed that it is the preferred mode of associations between FS and pyridines and could have formed first during pre-nuclei clustering. Crystal structure of molecular salt 2 although similar to form 1I crystals, its colorless nature could be attributed to the discontinuity in the conjugation. On the similar note, the colorless appearance of cocrystals 3 and molecular salt 4 could be because of the absence of proper sandwich assembly and extension of the conjugation. Further the colorless nature of cocrystals 5 can be explained on the basis of discontinuity in the extension of conjugation in the linking of the sandwich assemblies. The conformational flexibility of furan and sulfonamide moieties of FS contributed greatly for the formation of salt polymorphs and other molecular cocrystals and salts. The results further show the versatility of furosemide in developing the color cocrystals other than its therapeutic efficiency. Additionally, our studies show that stacking pattern in crystals can be tuned or altered by developing cocrystals and hence can be utilized for designing functional materials which can found applications in optoelectronic devices. The cocrystallization studies of FS with other coformers are currently being strategies and explored in our laboratory to obtain cocrystals/salts covering a wide range of the visible region by tuning the molecular arrangement. ASSOCIATED CONTENT Supporting Information. Characterization data for all salts and cocrystals 1-5 including 1H NMR, DSC, PXRD, crystallization details, intramolecular and intermolecular interactions, torsion angle tables, structural overlay, packing diagrams, hirshfeld surface plots, HOMOLUMO orbital view, solid-state UV spectra and SEM images. This material is available free of charge via the Internet at http://pubs.acs.org.



Page 44 of 51

AUTHOR INFORMATION Corresponding Author *[email protected] No. 020-25902225, Fax No. 020-25902642 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources This work was made possible by financial support from CSIR (ORIGIN) Notes The authors declare no competing financial interest. ACKNOWLEDGMENT ES thanks CSIR and SKM thanks UGC for fellowship. We gratefully acknowledge Dr. Ms. S. Mule for her kind support in carrying out the DSC measurements. We also thank Mr. Sagar Janampelli for recording the solid-state UV spectra, Mr. Chitikeshi Harshavardhan for providing SEM images and Mr. Yashpal Yadav for grabbing the crystal photographs. ABBREVIATIONS FS: Furosemide 4BPE: 1, 2-bis(4-pyridyl)ethylene 4BPA:1,2 bis(4-pyridyl)ethane 2BPE: 1,2 bis(2-pyridyl)ethylene 44 ACS Paragon Plus Environment

Page 45 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4BPP: 1,2 bis(4-pyridyl)propane Phen:1,10-Phenanthroline THF: Tetrahydrofuran REFERENCES 1. Etter, M. C.; Frankenbach, G. M. Chemistry of Materials 1989, 1, 10-12. 2. Etter, M. C. Acc. Chem. Res. 1990, 23, 120–126. 3. Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem. Int. Ed. 2001, 40, 3240– 3242. 4. Bond, A. D. CrystEngComm 2007, 9, 833–834. 5. Stahly, G. P. Cryst. Growth Des. 2007, 7, 1007–1026. 6. Aakeröy, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439−448. 7. Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950–2967. 8. Sekhon, B. S. Ars Pharm 2009, 50, 99–117. 9. Aakeröy, C. B., Fasulo, M. E., Desper, J. Mol. Pharm. 2007, 4, 317–322. 10. Morissette, S. L.; Almarsson,Ö.; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R.. Adv. Drug Deliv. Rev. 2004, 56, 275–300. 11. Nauha, E.; Nissinen, M. J. Mol. Struct. 2011, 1006, 566–569. 12. Bolton, O.; Simke, L. R.; Pagoria, P. F.; Matzger, A. J. Cryst. Growth Des. 2012, 12, 4311–4314. 13. Millar, D. I. A.; Maynard-Casely, H. E.; Allan, D. R.; Cumming, A. S.;Lennie, A. R.; Mackay, A. J.; Oswald, L. D. H.; Tang, C. C.; Pulham, C. R. CrystEngComm 2012, 14, 3742–3749. 14. Bolton, O.; Matzger, A. J. Angew. Chem. Int. Ed. 2011, 50, 8960–8963.



Page 46 of 51

15. Spitzer, D.; Risse, B.; Schnell, F.; Pichot, V.; Klaumünzer, M.; Schaefer, M. R. Sci. Rep. 2014, 4, 1–6. 16. Gabriel, G. J.; Sorey, S.; Iverson, B. L. J. Am. Chem. Soc. 2005, 127, 2637−2640. 17. Nakano, T. Polym. J. 2010, 42, 103−123. 18. Almarsson, Ö.; Zaworotko, M. J. Chem. Commun. 2004, 7, 1889−1896. 19. Sander, J. R. G.; Bucar, D. K.; Rodger, F. H.; Baltrusaitis, J.; Zhang G. G. Z.; Macgillivray, L. R. J. Pharm. Sci. 2010, 99, 3676–3683. 20. Biswas, S.; Saha, R.; Steele, I. M.; Kumar, S.; Dey, K. J. Chem. Crystallogr. 2013, 43, 493–501. 21. Sangtani, E.; Sahu, S. K.; Thorat, S. H.; Gawade, R. L.; Jha, K. K.; Munshi, P.; Gonnade, R. G. Cryst. Growth Des. 2015, 15, 5858−5872. 22. Park, S. K.; Varghese, S.; Kim, J. H.; Yoon, S. J.; Kwon, O. K.; An, B. K.; Gierschner, J.; Park, S. Y. J. Am. Chem. Soc. 2013, 135, 4757–4764. 23. Nguyen, H. L.; Horton, P. N.; Hursthouse, M. B.; Legon, A. C.; Bruce, D. W. J. Am. Chem. Soc. 2004, 126, 16– 17. 24. Morimoto, M.; Irie, M. J. Am. Chem. Soc. 2010, 132, 14172 –14178. 25. Bolton, O.; Lee, K.; Kim, H. J.; Lin, K. Y.; Kim, J. Nat. Chem. 2011, 3, 205–210. 26. Pan, F.; Wong, M. S.; Gramlich, V.; Bosshard, C.; Günter, P. J. Am. Chem. Soc. 1996, 118, 6315–6316. 27. Tsutsumi, J. Y.; Yamada, T.; Matsui, H.; Haas, S.; Hasegawa, T. Phys. Rev. Lett. 2010, 105, 226601(1−4). 28. Vincent, V. M.; Wright, J. D. J. Chem. Soc., Faraday Trans.1 1974, 70, 58−71.


Page 47 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


29. Kang, S. J.; Ahn, S.; Kim, J. B.; Schenck, C.; Hiszpanski, A. M.; Oh, S.; Schiros, T.; Loo, Y.-L.; Nuckolls, C. J. Am. Chem. Soc. 2013, 135, 2207−2212. 30. Yan, D.; Delori, A.; Lloyd, G. O.; Friščić, T.; Day, G. M.; Jones, W.; Lu, J.; Wei, M.; Evans, D. G.; Duan, X. Angew. Chem., Int. Ed. 2011, 50, 12483−12486. 31. Yan, D.; Yang, H.; Meng, Q.; Lin, H.; Wei, M. Adv. Funct. Mater. 2014, 24, 587−594. 32. Bosshard, C.; Wong, M. S.; Pan, F.; Günter, P.; Gramlich, V. Adv. Mater. 1997, 9, 554−557. 33. Zhu, W.; Zheng, R.; Zhen, Y.; Yu, Z.; Dong, H.; Fu, H.; Shi, Q.; Hu, W. J. Am. Chem. Soc. 2015, 137, 11038−11046. 34. Bučar, D.-K.; Filip, S.; Arhangelskis, M.; Lloyd, G. O.; Jones, W. CrystEngComm, 2013, 15, 6289–6291. 35. Pallipurath, A.; Skelton, J. M.; Delori, A.; Duffy, C.; Erxlebenb A.; Jones, W. CrystEngComm, 2015, 17, 7684–7692. 36. Delori, A.; Urquhart, A. J.; Oswald, I. D. H. CrystEngComm, 2016, 18, 5360–5364. 37. Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2014, 16, 3451–3465. 38. Vishweshwar, P.; McMahon, J. A.; Peterson, M. L.; Hickey, M. B.; Shattocka, T. R.; Zaworotko; M. J. Chem. Commun. 2005, 4601–4603. 39. Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun., 2006, 1369–1371. 40. Dubey, R.; Desiraju, G. R. Angew. Chem. Int. Ed. 2014, 53, 13178 –13182. 41. Karki, S.; Friščić, T.; Jones, W.; Motherwell, W. D. S. Mol. Pharm. 2007, 4, 347–354. 42. Goud, N. R.; Gangavaram, S.; Suresh, K.; Pal, S.; Manjunatha, S. G.; Nambiar, S.;Nangia, A. J. Pharm. Sci. 2012, 101, 664–680.



Page 48 of 51

43. Ueto, T.; Takata, N.; Muroyama, N.; Nedu, A.; Sasaki, A.; Tanida, S.; Terada, K. Cryst. Growth Des. 2012, 12, 485–495. 44. Stepanovs, D.; Mishnev, A. Acta Cryst. 2012, C68, o488–o491. 45. Harriss, B. I.; Vella-Zarb, L.; Wilson, C.; Evans, I. R. Cryst. Growth Des. 2014, 14, 783−791. 46. Khandavilli, U. B. R.; Gangavaram, S.; Goud, N. R.; Cherukuvada, S.; Raghavender, S.; Nangia, A.; Manjunatha, S. G.; Nambiarc, S.; Pal, S. CrystEngComm 2014, 16, 4842– 4852. 47. Srirambhatla, V. K.; Kraft, A.; Wattb, S.; Powell, A. V. CrystEngComm 2014, 16, 9979– 9982. 48. Banik, M.; Gopi, S. P.; Ganguly, S.; Desiraju, G. R. Cryst. Growth Des. 2016, 16, 5418–5428. 49. Babu, N. J.; Cherukuvada, S.; Thakuria, R.; Nangia, A. Cryst. Growth Des. 2010, 10, 1979–1989. 50. Farrugia, L. J. J. Appl. Cryst. 2012, 45, 849–854. 51. Gavezzotti, A., Acc. Chem. Res. 1994, 27, 309–314. 52. Gavezzotti, A.; Filippini, G. J. Phys. Chem. 1994, 98, 4831–4837. 53. McKinnon, J. J.; Spackman, M. A.; Mitchell, A. S. Acta Crystallogr. Sect. B2004, B60, 627– 668. 54. McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Chem. Commun. 2007, 3814– 3816. 55. Spackman, M. A.; Jayatilaka, D. CrystEngComm 2009, 11, 19– 32.


Page 49 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


56. Wolff, S. K.; Grimwood, D. J.; McKinnon, J. J.; Jayatilaka, D.; Packman, M. A. Crystal Explorer;University

of

Western:

Perth,

Australia,

2007;

http://hirshfeldsurface.net/CrystalExplorer. 57. Munshi, P.; Skelton, B. W.; McKinnon, J. J.; Spackman, M. A. CrystEngComm 2008, 10, 197–206. 58. Kohn, W.; Sham, L. J. Phys. Rev. A 1965, 140, 1133–1138. 59. Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, M. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009. 60. Shaikh, A. C.; Ranade, D. S.; Thorat, S.; Maity, A.; Kulkarni, P. P.; Gonnade, R. G.; Munshi, P.; Patil, N. T. Chem. Commun., 2015, 51, 16115–16118.



Page 50 of 51

61. Gawade, R. L.; Chakravarty, D. K.; Kotmale, A.; Sangtani, E.; Joshi, P. V.; Ahmed, A.; Mane, M. V.; Das, S.; Vanka, K.; Rajamohanan, P. R.; Puranik, V. G.; Gonnade, R. G. Cryst. Growth Des. 2016, 16, 2416–2428.


Page 51 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


For Table of Contents Use Only

Salts and Cocrystals of Furosemide with Pyridines: Differences in π-Stacking and Color Polymorphism

Ekta Sangtani,a,b Suman Kumar Mandal,c A. S. Sreelakshmi,a Parthapratim Munshi,c and Rajesh G. Gonnade* a,b Furosemide, a loop diuretic drug has a potential to exhibit polymorphism, produced color polymorphs orange (form 1I) and yellow (form 1II) concomitantly with coformer 1, 2-bis(4pyridyl)ethylene (4BPE). However, cocrystallization of FS with other pyridines yielded colorless salts (2 and 4) and cocrystals (3 and 5). The significant color difference between the two polymorphs (forms 1I and 1II) could be attributed to the dissimilar π-stacking patterns between the two components and differences in their HOMO-LUMO gap. The molecular packing of form 1I and 2 are very similar but 2 is colorless due to lack of extended πconjugation.


Salts and Cocrystals of Furosemide with Pyridines - ACS Publications

Recommend Documents