Sajesh P. Thomas

Unusually short chalcogen bonds involving organoselenium: Insights into the Se-N bond cleavage mechanism of the antioxidant ebselen and analogues

Structural studies on the polymorphs of the organoselenium antioxidant ebselen and its derivative show the potential of organic selenium to form unusually short Se⋅⋅⋅O chalcogen bonds that lead to conserved supramolecular recognition units. Se⋅⋅⋅O interactions observed in these polymorphs are the shortest such chalcogen bonds known for organoselenium compounds. The FTIR spectral evolution characteristics of this interaction from solution state to solid crystalline state further validates the robustness of this class of supramolecular recognition units. The strength and electronic nature of the Se⋅⋅⋅O chalcogen bonds were explored using high-resolution X-ray charge density analysis and atons-in-molecules (AIM) theoretical analysis. A charge density study unravels the strong electrostatic nature of Se⋅⋅⋅O chalcogen bonding and soft-metal-like behavior of organoselenium. An analysis of the charge density around Se-N and Se-C covalent bonds in conjunction with the Se⋅⋅⋅O chalcogen bonding modes in ebselen and its analogues provides insights into the mechanism of drug action in this class of organoselenium antioxidants. The potential role of the intermolecular Se⋅⋅⋅O chalcogen bonding in forming the intermediate supramolecular assembly that leads to the bond cleavage mechanism has been proposed in terms of electron density topological parameters in a series of molecular complexes of ebselen with reactive oxygen species (ROS).

Polymorphism and tautomeric preference in fenobam and the utility of NLO response to detect polymorphic impurities

Crystal structures of polymorphs and solvatomorphs of the potential anxiolytic drug fenobam exhibit an exclusive preference for one of the two possible tautomeric structures. A novel methodology based on nonlinear optical response has been successfully employed to detect the presence of a polymorphic impurity in a mixture of polymorphs.

Organic alloys of room temperature liquids thiophenol and selenophenol

The first examples of organic alloys of two room temperature liquids, obtained and characterized via in situ cryo-crystallography, are presented. Thiophenol and selenophenol, which exhibit isostructurality and similar modes of S⋯S and Se⋯Se homo-chalcogen interactions along with weak and rare S–H⋯S and Se–H⋯Se hydrogen bonds, are shown to form solid solutions exhibiting Veggards law-like trends.

The Elusive Structural Origin of Plastic Bending in Dimethyl Sulfone Crystals with Quasi-isotropic Crystal Packing

Bending in molecular crystals is typically associated with the anisotropy of intermolecular interactions. The intriguing observation is reported of plastic bending in dimethyl sulfone, which exhibits nearly isotropic crystal packing and interaction topology, defying the known structural models of bending crystals. The origin of the bending phenomenon has been explored in terms of intermolecular interaction energies, experimental X-ray charge density analysis, and variable temperature neutron diffraction studies. H⋅⋅⋅H dihydrogen interactions and differences in electrostatic complementarity between molecular layers are found to facilitate the bending behavior.

Energy frameworks and a topological analysis of the supramolecular features in in situ cryocrystallized liquids: tuning the weak interaction landscape via fluorination

Weak intermolecular interactions observed in crystalline materials are often influenced or forced by stronger interactions such as classical hydrogen bonds. Room temperature liquids offer a scenario where such strong interactions are absent so that the role and nature of the weak interactions can be studied more reliably. In this context, we have analyzed the common organic reagent benzoyl chloride (BC) and a series of its fluorinated derivatives using in situ cryocrystallography. The intermolecular interaction energies have been estimated and their topologies explored using energy framework analysis in a series of ten benzoyl chloride analogues, which reveal that the ππ stacking interactions serve as the primary building blocks in these crystal structures. The crystal packing is also stabilized by a variety of interaction motifs involving weak C-HO/F/Cl hydrogen bonds and FF, FCl, and ClCl interactions. It is found that fluorination alters the electrostatic nature of the benzoyl chlorides, with subsequent changes in the formation of different weak interaction motifs. The effects of fluorination on these weak intermolecular interactions have been systematically analyzed further via detailed inputs from a topological analysis of the electron density and Hirshfeld surface analysis.

High throughput profiling of molecular shapes in crystals

Molecular shape is important in both crystallisation and supramolecular assembly, yet its role is not completely understood. We present a computationally efficient scheme to describe and classify the molecular shapes in crystals. The method involves rotation invariant description of Hirshfeld surfaces in terms of of spherical harmonic functions. Hirshfeld surfaces represent the boundaries of a molecule in the crystalline environment, and are widely used to visualise and interpret crystalline interactions. The spherical harmonic description of molecular shapes are compared and classified by means of principal component analysis and cluster analysis. When applied to a series of metals, the method results in a clear classification based on their lattice type. When applied to around 300 crystal structures comprising of series of substituted benzenes, naphthalenes and phenylbenzamide it shows the capacity to classify structures based on chemical scaffolds, chemical isosterism, and conformational similarity. The computational efficiency of the method is demonstrated with an application to over 14 thousand crystal structures. High throughput screening of molecular shapes and interaction surfaces in the Cambridge Structural Database (CSD) using this method has direct applications in drug discovery, supramolecular chemistry and materials design.

Accurate Lattice Energies for Molecular Crystals from Experimental Crystal Structures

Using four different benchmark sets of molecular crystals, we establish the level of confidence for lattice energies estimated using CE-B3LYP model energies and experimental crystal structures. [ IUCrJ 2017 , 4 , 575 - 587 10.1107/S205225251700848X .] We conclude that they compare very well with available benchmark estimates derived from sublimation enthalpies, and in many cases they are comparable with, and sometimes better than, more computationally demanding approaches, such as those based on periodic DFT plus dispersion methodologies. The performance over the complete set of 110 crystals indicates a mean absolute deviation from benchmark energies of only 6.6 kJ mol-1. Applications to polymorphic crystals and larger molecules are also presented and critically discussed. The results highlight the importance of recognizing the consequences of different sets of crystal/molecule geometries when different methodologies are compared, as well as the need for more extensive benchmark sets of crystal structures and associated lattice energies.

The Polymorphs of ROY: A Computational Study of Lattice Energies and Conformational Energy Differences*

The remarkable structural diversity observed in polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (commonly known as ROY) challenges computational attempts to predict or rationalize their relative stability. This modest study explores the applicability of CE-B3LYP model energy calculation of lattice energies (using experimental crystal structures), supplemented by a systematic approach to account for conformational energy differences. The CE-B3LYP model provides sensible estimates of absolute and relative lattice energies for the polymorphs, provided care is taken to achieve convergence in the summation of pairwise terms. Conformational energy differences based on density functional theory (DFT) energies are shown to be unreliable, but MP2 energies based on DFT-optimized structures show considerable promise.

2-Amino-4-methyl-pyrimidinium dihydrogen phosphate.

A charge-assisted hydrogen-bonding network involving N—H⋯O and O—H⋯O hydrogen bonds stabilizes the crystal of the title salt, C5H8N3 +·H2PO4 −. The dihydrogen phosphate anions form one-dimensional chains along [100], via O—H⋯O hydrogen bonds. The 2-amino-4-methylpyrimidinium cations are linked to these chains by means of two different kinds of N—H⋯O hydrogen bonds. Neighbouring chains are linked via C—H⋯N and C—H⋯O hydrogen bonds forming two-dimensional slab-like networks lying parallel to (01-1).

Quantitative approaches to crystal engineering: applications to mechanical properties

Over the last two decades, crystal engineering has evolved from its early stage of attempting to understand the grammar of crystal packing into applying such insights for the design of useful crystal forms. Nevertheless, the pursuit of crystal engineering is still largely based on qualitative structural intuitions and trial-and-error approaches. In this context, the ‘energy framework’ analysis, [1] a method we recently introduced, has been found useful for the visualization and understanding of crystal packing in terms of intermolecular interaction topology – leading to a more quantitative approach to crystal engineering. I will demonstrate the utility of this technique in crystal engineering and applications in various contexts such as the identification of supramolecular recognition units, understanding isostructurality, polymorphism and enantiomorphism. Moreover, we show that mechanical properties such as bending/shearing in molecular crystals [2,3] can also be correlated with the topology of intermolecular interactions as manifested in their energy frameworks.[1] The anisotropy in the strengths of crystal packing can be visualized as the anisotropy in the ‘energy frameworks’, making it an efficient tool to predict bending/ shearing behaviour in crystals. To demonstrate this, several crystals that exhibit interesting mechanical properties have been analyzed in terms of energy frameworks. In addition, we also present an intriguing observation of plastic-bending in dimethyl sulfone crystal that defies this common trend, showing nearly isotropic energy frameworks. In order to rationalize the observed bending behaviour of the crystal, we performed X-ray charge density studies and variable temperature neutron crystallography. H···H dihydrogen interactions and differences in electrostatic complementarity between molecular layers have been found to facilitate the bending behaviour in this case.