Abhijeet S. Sinha

A versatile and green mechanochemical route for aldehyde-oxime conversions.

A robust, facile and solvent-free mechanochemical path for aldehyde-oxime transformations using hydroxylamine and NaOH is explored; the method is suitable for aromatic and aliphatic aldehydes decorated with a range of substituents.

Impact and importance of electrostatic potential calculations for predicting structural patterns of hydrogen and halogen bonding

The way in which differences in electrostatic potential values can govern how ditopic hydrogen/halogen-bond acceptors form supramolecular interactions in the solid state has been examined using two heterocycles, [1,2,3]triazalo-[3,5-α]quinoline and, [1,2,3]triazalo-[3,5-α]pyridine. In general, the “better” donor (as ranked by electrostatic potential values) preferentially binds to the acceptor atom that carries the higher electrostatic potential value but the outcome is crucially dependent on the magnitude of the potential-energy differences, and structural selectivity can be fine-tuned to generate specifically targeted supramolecular architectures. DFT calculations on [1,2,3]triazalo-[3,5-α]quinoline and [1,2,3]triazalo-[3,5-α]pyridine indicate that the differences in electrostatic potential between the competing sites on the molecules are 38 kJ mol−1 and 26 kJ mol−1, respectively. In order to establish how the nature of the electrostatic potential differences impact the structural landscape around these molecules both heterocycles were co-crystallized with twelve hydrogen-bond (HB) donors, five halogen-bond (XB) donors, and four mixed HB/XB donors. A total of 42 new co-crystals were obtained (as determined by IR spectroscopy), eight of which yielded crystals suitable for single-crystal X-ray diffraction. Results indicate that an electrostatic potential difference greater than 38 kJ mol−1 leads to a pronounced intermolecular preference for the best acceptor but no selectivity is obtained with a smaller difference. This study shows that electrostatic factors play important roles for defining the structural landscape around molecules capable of engaging in a numerous and competing intermolecular interactions as long as the difference between potentially competing sites is large enough.

Synthesis of ketoximes via a solvent-assisted and robust mechanochemical pathway

A versatile and robust mechanochemical route to ketone–oxime conversions has been established for a broad range of ketones via a simple mortar–pestle grinding method. The relative reactivity of aldehydes vs. ketones under these conditions has also been explored, along with an examination of the possible connection between reactivity and electronic substituent effects.

Novel co-crystals of the nutraceutical sinapic acid

Sinapic acid (SA) is a nutraceutical with known anti-oxidant, anti-microbial, anti-inflammatory, anti-cancer, and anti-anxiety properties. Novel co-crystals of SA were prepared with co-formers belonging to the category of GRAS [isonicotinic acid (INC), nicotinamide (NIA)], non-GRAS [4-pyridinecarbonitrile (PYC)], and active pharmaceutical ingredients (APIs) [6-propyl-2-thiouracil (PTU)] list of compounds. Structural study based on the X-ray crystal structures revealed the intermolecular hydrogen-bonded interactions and molecular packing. The crystal structure of sinapic acid shows the anticipated acid–acid homodimer along with discrete hydrogen bonds between the acid carbonyl and the phenolic moiety. The robust acid–acid homodimer appears to be very stable and is retained in the structures of two co-crystals (SA·NIA and SA·PYC). In these cases, co-crystallization occurs via intermolecular phenol O–H⋯Naromatic hydrogen bonds between the co-formers. In the SA·PTU·2MeCN co-crystal the acid–acid homodimer gives way to the anticipated acid–amide heterodimer, with the phenolic moiety of SA hydrogen-bonded to acetonitrile. Attempts at obtaining the desolvated co-crystal led to lattice breakdown, thus highlighting the importance of acetonitrile in the formation of the co-crystal. Among the co-crystals examined, SA·INC (5 weeks), SA·NIA (8 weeks) and SA·PYC (5 weeks) were found to be stable under accelerated humidity conditions (40 °C, 75% RH), whereas SA·PTU·2MeCN decomposed after one week into individual components due to solvent loss.

Modulating the physical properties of solid forms of urea using co-crystallization technology

The solid-form landscape of urea was explored using full interaction maps (FIMs) and data from the CSD to develop optimum protocols for synthesizing co-crystals of urea. As a result, 49 of the 60 attempted reactions produced new co-crystals, and the crystal structures of four of these are presented. Moreover, the goal of reducing the solubility and lowering the hygroscopicity of the parent compound was achieved, which in turn offers new opportunities for application as a slow-release fertilizer with limited hygroscopicity, thereby reducing many current problems of transport, handling, and storage of urea.

Exploring binding preferences in co-crystals of conformationally flexible multitopic ligands

A series of conformationally flexible, bipyridine-based ligands were co-crystallized with nine aliphatic dicarboxylic acids of varying carbon chain lengths. Multiple hydrogen-bond acceptor and donor sites on both the ligands and the dicarboxylic acids increased the potential for cocrystal formation. The calculated molecular electrostatic potential surface (MEPS) of each bipyridine species was used to predict hydrogen-bond preferences in two ways. First, a comparison of different conformations of the same ligand revealed which conformation had the lowest total energy and, second, the maxima and minima on the potential surfaces allowed the potential hydrogen-bonding sites to be ranked with respect to each other. Pre-screening by infrared spectroscopy (IR) showed that all 36 experiments produced co-crystals and thirteen of these were crystallographically characterized. Structures were grouped by ligand, hydrogen bonds identified and analyzed for patterns within structures and within ligand groups. Direct comparison of the electrostatic potential charges of ligands with propensity of formed hydrogen bonds underscores that the vast majority of intermolecular hydrogen bonds tend to take place between best hydrogen-bond donor and acceptor sites (as ranked by the electrostatic potentials).

Competition between hydrogen bonds and halogen bonds: a structural study

The competition and balance between intermolecular hydrogen bonds (HBs) and halogen bonds (XBs) were explored by co-crystallizing tetra-functionalized (2 × HB (–OH) and 2 × XB (–CC–I)) molecules, trans-1,4-bis(iodoethynyl)cyclohexane-1,4-diol (D1) and cis-1,4-bis(iodoethynyl)cyclohexane-1,4-diol (D2), with six ditopic nitrogen based acceptor molecules. The crystal structures of both D1 and D2 showed non-covalent interactions between HB/XB donors and available acceptor sites (oxygen/triple bond/negative region of iodine). In three co-crystals of D1 the HB and XB donors act in similar ways as both activated iodine and hydroxyl hydrogen bind to the nitrogen acceptors in the solid state. In contrast, in a co-crystal of D2, a geometric isomer of D1, there were only hydrogen bonds to the co-former and the halogen-bond donor interacted with the hydroxyl oxygen atoms of D2. A stronger tendency for linear XB interactions (as well as greater van der Waals radii reduction) was observed with nitrogen atoms as acceptors (average reduction = 21%) compared to those involving an oxygen atom as an acceptor (average reduction = 16%). A control molecule, trans-1,4-diethynylcyclohexane-1,4-diol (D3), which has only HB donors (–OH and –CC–H) was also examined to get a better understanding of the balance between XB and HB intercations. The ethynyl hydrogen atom did not form hydrogen bonds to the nitrogen atoms in acceptors, and only O–H⋯N and –CC–H⋯O hydrogen bonds were observed in these structures.

Chapter 1:Co-crystals: Introduction and Scope

In this chapter, we briefly discuss the history of co-crystals as well as some of the complications that have surrounded the definitions and nomenclature of co-crystals. We attempt to shed some light on the challenges associated with achieving predictable and targeted supramolecular synthesis, and we also examine the role of robust hydrogen- and halogen-bond-based supramolecular synthons on the directed assembly of extended supramolecular architectures. These synthons are analyzed with respect to both geometric and electrostatic considerations, and multiple case studies on the sequential design and assembly of higher-order molecular co-crystals (four- and five-component assemblies) are presented. Furthermore, the use of cheminformatics-based methods such as the Cambridge Structural Database (CSD), IsoStar and hydrogen bond propensity (HBP) are also discussed. Lastly, some of the most common applications of co-crystals are highlighted in brief.

Structural Examination of Halogen-Bonded Co-Crystals of Tritopic Acceptors

A series of tritopic N-heterocyclic compounds containing electrostatically and geometrically equivalent binding sites were synthesized and subjected to systematic co-crystallizations with selected perfluoroiodoarenes in order to map out their structural landscapes. More than 70% of the attempted reactions produced a co-crystal as indicated by IR spectroscopy. Four new crystal structures are reported and in all of them, at least one potential binding site on the acceptor is left vacant. The absence of halogen bonds to all sites can be ascribed primarily due to deactivation of the σ-hole on the iodo-arene donors and partially due to steric hindrance. The tritopic acceptors containing 5,6-dimethylbenzimidazole derivatives yield discrete tetrameric aggregates in the solid state, whereas the pyrazole and imidazole analogues assemble into halogen-bonded 1-D chains.