Soumyajit Ghosh

Elastic and Bendable Caffeine Cocrystals: Implications for the Design of Flexible Organic Materials

Molecular crystals are among the most ancient and highly investigated materials in chemistry. However, mechanical properties of these materials have remained relatively unexplored despite their unique applications in optoelectronics, mechanical actuators, artificial muscles, pharmaceuticals, and explosives. Conserving the orientational order of molecules and bonds is important for efficient charge transport and for the lifetime of organic light-emitting diodes, transistors, and solar cells. Hence, the realization of high-performance materials with excellent self-healing capabilities or efficient stress dissipating behaviors is attractive. For this reason, the remarkable properties displayed by natural fibres such as spider silk, muscle protein titin, cytoskeleton microtubules, etc. have recently sparked tremendous interest in establishing a reliable structure–property correlation to guide the design of their mimics for various applications. A good starting point for achieving such a goal is to study much simpler and easy-to-characterize organic crystals, which selfassemble through the same noncovalent interactions. It remains a challenge to simultaneously achieve both flexibility and crystallinity in organic materials because crystallinity positively correlates with brittleness. For example, compared to highly ordered molecular crystals, liquid crystals show greater flexibility, but are less crystalline. Desiraju and co-workers showed irreversible mechanical bending in organic crystals as mediated by the movement of molecular sheets through weak interactions between them. The plastic deformation disrupts the long-range order permanently. It was also shown that reversible molecular movements in organic crystals (e.g., in photomechanical bending), can perform work in devices. Herein we report a remarkably flexible, elastically bendable cocrystal solvate 1, formed from caffeine (CAF), 4-chloro-3-nitrobenzoic acid (CNB), and methanol in a 1:1:< 1 ratio (Figure 1). The cocrystal solvate 1 retains a high internal order through an efficient stress dissipation mechanism, and hence is important in the context of crystal engineering and for the design of flexible organic materials. The single crystals of 1 could be obtained from a 1:1 molar solution of CAF and CNB in methanol by using a slow evaporation method (Figure 1). H NMR and thermogravimetric (TG) analyses have confirmed the presence of CAF, CNB, and methanol molecules in a 1:1:< 1 ratio within the lattice (see Figures S1 and S2 in the Supporting Information). The typically long needle crystals of 1 grow along the a axis (Figure 1 and Figure S4). When a straight crystal, having about a 0.1 mm thickness and 5 mm length, was pushed with a metal pin while being held with a pair of forceps (tweezers) from the opposite end, it transformed into a bent shape without breaking (Figure 2a–d and Figure S5). Further, it could be made into a loop by joining the two ends with a smooth curve (see Videos S1–S3 in the Supporting Information). Upon withdrawal of the force, the crystal quickly Figure 1. Single-crystal preparation of the cocrystal solvate 1 from a methanol solution of caffeine and 4-chloro-3-nitrobenzoic acid.

Mechanical properties of molecular crystals—applications to crystal engineering

We present an overview of very recent advances in the understanding of structure–mechanical property correlations in molecular crystals. After the introductory part on some classical two-dimensional structures from the literature, we survey recent reports (mostly since 2005) pertinent to the mechanical properties of molecular crystals studied by application of external stress using a range of techniques. This includes both qualitative (shearing, bending and brittle crystals) and quantitative (nanoindentation, powder compaction and high-pressure) studies on establishing the correlation of anisotropic mechanical behaviour with the underlying crystal structure. Section 9, emphasizes on the usefulness of crystal engineering approach to improve the mechanical properties of molecular crystals, particularly the active pharmaceutical ingredients for their better tabletability properties. The parallels of the phenomena in other class of well studied materials are also appropriately drawn and discussed in the context of structure-mechanical property relationship. In the final part we comment on the prospects and ramifications of this emerging field.

Spatially resolved analysis of short-range structure perturbations in a plastically bent molecular crystal

The exceptional mechanical flexibility observed with certain organic crystals defies the common perception of single crystals as brittle objects. Here, we describe the morphostructural consequences of plastic deformation in crystals of hexachlorobenzene that can be bent mechanically at multiple locations to 360° with retention of macroscopic integrity. This extraordinary plasticity proceeds by segregation of the bent section into flexible layers that slide on top of each other, thereby generating domains with slightly different lattice orientations. Microscopic, spectroscopic and diffraction analyses of the bent crystal showed that the preservation of crystal integrity when stress is applied on the (001) face requires sliding of layers by breaking and re-formation of halogen-halogen interactions. Application of stress on the (100) face, in the direction where π···π interactions dominate the packing, leads to immediate crystal disintegration. Within a broader perspective, this study highlights the yet unrecognized extraordinary malleability of molecular crystals with strongly anisotropic supramolecular interactions.

Dual Stress and Thermally Driven Mechanical Properties of the Same Organic Crystal: 2,6-Dichlorobenzylidene-4-fluoro-3-nitroaniline.

An elastic organic crystal, 2,6-dichlorobenzylidine-4-fluoro-3-nitroaniline (DFNA), which also shows thermosalient behavior, is studied. The presence of these two distinct properties in the same crystal is unusual and unprecedented because they follow respectively from isotropy and anisotropy in the crystal packing. Therefore, while both properties lead from the crystal structure, the mechanisms for bending and thermosalience are quite independent of one another. Crystals of the low-temperature (α) form of the title compound are bent easily without any signs of fracture with the application of deforming stress, and this bending is within the elastic limit. The crystal structure of the α-form was determined (P21/c, Z = 4, a = 3.927(7) Å, b = 21.98(4) Å, c = 15.32(3) Å). There is an irreversible phase transition at 138 °C of this form to the high-temperature β-form followed by melting at 140 °C. Variable-temperature X-ray powder diffraction was used to investigate the structural changes across the phase transition and, along with an FTIR study, establishes the structure of the β-form. A possible rationale for strain build-up is given. Thermosalient behavior arises from anisotropic changes in the three unit cell parameters across the phase transition, notably an increase in the b axis parameter from 21.98 to 22.30 Å. A rationale is provided for the existence of both elasticity and thermosalience in the same crystal. FTIR studies across the phase transition reveal important mechanistic insights: (i) increased π···π repulsions along [100] lead to expansion along the a axis; (ii) change in alignment of C-Cl and NO2 groups result from density changes; and (iii) competition between short-range repulsive (π···π) interactions and long-range attractive dipolar interactions (C-Cl and NO2) could lie at the origin of the existence of two distinctive properties.

Co-crystals of caffeine with substituted nitroanilines and nitrobenzoic acids: Structure–mechanical property and thermal studies

Nine new 1 : 1 co-crystals of caffeine with some halogenated nitroanilines and two nitrobenzoic acids have been synthesized. These new caffeine (CAF) co-crystals, with 4-nitroaniline (4NA), 4-fluoro-3-nitroaniline (4F3NA), 4-chloro-3-nitroaniline (4Cl3NA), 4-iodo-3-nitroaniline (4I3NA), 2-fluro-5-nitroaniline (2F5NA), 2-chloro-5-nitroaniline (2Cl5NA), 2-iodo-4-nitroaniline (2I4NA), 2,4-dinitrobenzoic acid (24DNB), 2-fluoro-5-nitrobenzoic acid (2F5NB), are characterized by single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and infrared spectroscopy. The co-crystals adopt a range of structures, namely two-dimensional (2D) flat layer, corrugated layer and 3D interlocked structures. The series of crystals allowed us to establish a structure–mechanical property relationship by using a simple mechanical deformation (qualitative) method. The 2D flat layer crystals (CAF/24DNB, CAF/2Cl5NA and CAF/2I4NA), which have strong intralayer and weak interlayer interactions show shear deformation behaviour, while those with weak intralayer interactions (CAF/4Cl3NA and CAF/4I3NA) show brittle fracture on application of a mechanical stress. The structures with corrugated layers (CAF/2F5NA) or 3D interlocked packing (CAF/NA, CAF/2F5NB and CAF/4F3NA) also show brittle behaviour. We also show the need for a wide initial search, targeting even the least expected synthons, to improve the efficiency of co-crystal screening.

Drug–drug salt forms of ciprofloxacin with diflunisal and indoprofen

Two salt forms of a fluoroquinolone antibacterial drug, ciprofloxacin (CIP), with non-steroidal anti-inflammatory drugs, diflunisal (CIP/DIF) and indoprofen (CIP/INDP/H2O), were synthesized and characterized by PXRD, FTIR, DSC, TGA and HSM. Crystal structure determination allowed us to study the drug–drug interactions and the piperazine-based synthon (protonated piperazinecarboxylate) in the two forms, which is potentially useful for the crystal engineering of new salt forms of many piperazine-based drugs.

Tuning mechanical behaviour by controlling the structure of a series of theophylline co-crystals

Six new co-crystals of theophylline with some substituted carboxylic acids, amides and one active pharmaceutical ingredient (API) have been synthesized. These new theophylline (THP) co-crystals with picolinamide (PIC), 3,4-dichlorobenzoic acid (DCB), 4-chloro-3-nitrobenzoic acid (4Cl3NB), 4-fluoro-3-nitrobenzoic acid (4F3NB), p-hydroxybenzamide (HBEN) and acetazolamide (ACZ) were characterized by single crystal X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. THP–PIC, THP–DCB, THP–4Cl3NB and THP–4F3NB adopt 2D flat structures, while the other two, THP–ACZ and THP–HBEN, are 3D interlocked structures. The co-crystals having a 2D structure show shearing behaviour on application of a mechanical stress in a qualitative sense, whereas the interlocked crystals are associated with brittleness in nature. This series of co-crystals give a better picture of the structure–property correlation on the basis of inherent crystal packing. The presence of strong intralayer interactions and weak interlayer interactions in 2D layered crystals is crucial in imparting softness in THP–DCB, THP–PIC, THP–4Cl3NB and THP–4F3NB.

In situ high pressure study of an elastic crystal by FTIR spectroscopy

We performed an in situ high pressure FTIR spectroscopic study on a 2,3-dichlorobenzylidine-4-bromoaniline (DBA) crystal at pressures ranging from ambient pressure to 13.8 GPa at room temperature. The variations in the stretching frequency of the aromatic C–H, H–CN and C–Cl bands on compression showed significant molecular movement in the DBA crystal. Decompression was monitored on the aliphatic and aromatic C–H stretches which clearly show the reversibility of the molecular movements in the crystal lattice.

Design of elastically bendable molecular crystals: implications for smart actuators

Imparting both flexibility and crystallinity in organic solids pose a great challenge because it defies the common perception of brittle nature of organic crystals. Mechanical properties of molecular crystals are less explored by scientific community though it has a wide array of applications including optoelectronics, mechanical actuators, artificial muscles etc.[1] Recently, Ghosh and Reddy demonstrated first example of excellent shape recovery of elastic bendable co-crystal solvate of caffeine4-chloro-3-nitrobenzoic acid.[2] This behaviour is attributed to interlocked host structure with weak and dispersive interactions in all three directions. There was no design strategy yet even after this serendipitious discovery. Later Ghosh et al. addressed this through designing a series of seven halogenated N-benzylidineanilines crystals.[3a] It has been observed that following two features are mainly responsible: 1) Presence of weak and dispersive interactions including peripheral halogen bonds that can act as structural buffers for easy breakage and reformation during bending. 2) interlocked corrugated pattern which prevents easy slippage of molecular planes. The crystals are highly flexible and even when it breaks down in two pieces, individual pieces show excellent shape recovery indicating its self-healing nature. Also, there is recent report of dual stress and thermally driven mechanical properties of same organic crystal 2,6-dichlorobenzylidine-4-fluoro-3nitroaniline.[3b] Two properties are not related to each other and arise from simultaneous isotropy and anisotropy in crystal packing. These materials have immense potential for smart hybrid actuating devices in future. [1] a) John, G. et al. (2012). Angew. Chem. Int. Ed. 51, 1760-1762. b) Cui, Q. H. et al. (2012). J. Mater. Chem. 22, 41364140. c) Horiuchi, S. et al. (2008). Nat. Mater. 7, 357-366. [2] Ghosh, S. & Reddy, C. M. (2012). Angew. Chem. Int. Ed. 124, 10465-10469. [3] a) Ghosh, S. et al. (2015). Angew. Chem. Int. Ed. 54, 2674-2678. b) Ghosh, S. et al. (2015). J. Am. Chem. Soc. 137, 9912-9921.