C. Malla Reddy

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.

Kinematic and mechanical profile of the self-actuation of thermosalient crystal twins of 1,2,4,5-tetrabromobenzene: a molecular crystalline analogue of a bimetallic strip.

A paradigm shift from hard to flexible, organic-based optoelectronics requires fast and reversible mechanical response from actuating materials that are used for conversion of heat or light into mechanical motion. As the limits in the response times of polymer-based actuating materials are reached, which are inherent to the less-than-optimal coupling between the light/heat and mechanical energy in them, a conceptually new approach to mechanical actuation is required to leapfrog the performance of organic actuators. Herein, we explore single crystals of 1,2,4,5-tetrabromobenzene (TBB) as actuating elements and establish relations between their kinematic profile and mechanical properties. Centimeter-size acicular crystals of TBB are the only naturally twinned crystals out of about a dozen known materials that exhibit the thermosalient effect-an extremely rare and visually impressive crystal locomotion. When taken over a phase transition, crystals of this material store mechanical strain and are rapidly self-actuated to sudden jumps to release the internal strain, leaping up to several centimeters. To establish the structural basis for this colossal crystal motility, we investigated the mechanical profile of the crystals from macroscale, in response to externally induced deformation under microscope, to nanoscale, by using nanoindentation. Kinematic analysis based on high-speed recordings of over 200 twinned TBB crystals exposed to directional or nondirectional heating unraveled that the crystal locomotion is a kinematically complex phenomenon that includes at least six kinematic effects. The nanoscale tests confirm the highly elastic nature, with an elastic deformation recovery (60%) that is far superior to those of molecular crystals reported earlier. This property appears to be critical for accumulation of stress required for crystal jumping. Twinned crystals of TBB exposed to moderate directional heating behave as all-organic analogue of a bimetallic strip, where the lattice misfit between the two crystal components drives reversible deformation of the crystal.

Catalysis by molecular iodine: a rapid synthesis of 1,8-dioxo-octahydroxanthenes and their evaluation as potential anticancer agents.

Molecular iodine facilitated the reaction of 5,5-dimethyl-1,3-cyclohexanedione with aromatic aldehydes in iso-propanol affording a variety of 1,8-dioxo-octahydroxanthenes in high yields. Most of the compounds synthesized showed good anti-proliferative properties in vitro against three cancer cell lines and 9-(2-hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione possessing a 2-hydroxy phenyl group at C-9 position was found to be promising. Further structure elaboration of the same compound and the crystal structure analysis and hydrogen bonding patterns of another compound that is, 9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione prepared by using this methodology is presented.

Pd-mediated new synthesis of pyrroles: their evaluation as potential inhibitors of phosphodiesterase 4

A sequential Pd-mediated multi-component reaction followed by Suzuki or Heck or Sonogashira coupling in a single pot has been developed for the synthesis of functionalized pyrroles as potential inhibitors of PDE4.

A kinetically controlled crystallization process for identifying new co-crystal forms: fast evaporation of solvent from solutions to dryness

Fast evaporation of solvent from solutions to dryness by rotary evaporation is shown to be a useful technique for quick screening of APIs for possible new co-crystal forms. Faster crystallization kinetics of the process enhance the possibility of detecting metastable forms.

Direct correlation among crystal structure, mechanical behaviour and tabletability in a trimorphic molecular compound

Powder compaction data of three polymorphic Forms I (shearing), II (bending) and III (brittle) of 6-chloro-2,4-dinitroaniline demonstrates a direct relationship among mechanical properties, crystal structure and tableting behaviour, showing the essence of structure based assessment of mechanical properties of crystals, e.g., for identifying more efficient API formulation and manufacture processes.

Ultrasound mediated catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones leading to novel quinoline derivatives: their evaluation as potential anti-cancer agents.

A facile and catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones has been accomplished via the reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde with various aromatic amines in the presence of ultrasound. Some of these compounds were converted to the corresponding 2-(3-(hydroxymethyl)quinolin-2-yl)phenols and further structure elaboration of a representative quinoline derivative is presented. Molecular structure of two representative compounds was confirmed by single crystal X-ray diffraction study. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules.

A new route to indoles via in situ desilylation–Sonogashira strategy: identification of novel small molecules as potential anti-tuberculosis agents

A new Pd/C-mediated tandem reaction has been developed for the one pot synthesis of indoles containing an o-(RSO2NH)C6H4 group at the C-2 position. The methodology provided novel indoles as inhibitors of Mycobacterium tuberculosis H37Rv chorismate mutasein vitro representing the first example of chorismate mutase inhibition by a heteroarene based small molecule.