Sumy Joseph

IR spectroscopy as a probe for C–H⋯X hydrogen bonded supramolecular synthons

Weak hydrogen bonds of the type C–H⋯X (X: N, O, S and halogens) have evoked considerable interest over the years, especially in the context of crystal engineering. However, association patterns of weak hydrogen bonds are generally difficult to characterize, and yet the identification of such patterns is of interest, especially in high throughput work or where single crystal X-ray analysis is difficult or impossible. To obtain structural information on such assemblies, we describe here a five step IR spectroscopic method that identifies supramolecular synthons in weak hydrogen bonded dimer assemblies, bifurcated systems, and π-electron mediated synthons. The synthons studied here contain C–H groups as hydrogen bond donors. The method involves: (i) identifying simple compounds/cocrystals/salts that contain the hydrogen bonded dimer synthon of interest or linear hydrogen bonded assemblies between the same functionalities; (ii) scanning infrared (IR) spectra of the compounds; (iii) identifying characteristic spectral differences between dimer and linear; (iv) assigning identified bands as marker bands for identification of the supramolecular synthon, and finally (v) identifying synthons in compounds whose crystal structures are not known. The method has been effectively implemented for assemblies involving dimer/linear weak hydrogen bonds in nitrobenzenes (C–H⋯O–NO), nitro-dimethylamino compounds (NMe2⋯O2N), chalcones (C–H⋯OC), benzonitriles (C–H⋯NC) and fluorobenzoic acids (C–H⋯F–C). Two other special cases of C–H⋯π and N–H⋯π synthons were studied in which the band shape of the C–H stretch in hydrocarbons and the N–H deformation in aminobenzenes was examined.

Crystal packing and melting temperatures of small oxalate esters: the role of C—H⋯O hydrogen bonding

The simple dialkyl oxalates are generally liquids at room temperature except for dimethyl and di-tert-butyl oxalate which melt at 327 and 343 K. The crystal structures of diethyl, di-iso-propyl, di-n-butyl, di-tert-butyl and methyl ethyl oxalates were determined. The liquid esters were crystallized using the cryocrystallization technique. A comparison of the intermolecular interactions and packing features in these crystal structures was carried out. The crystal structure of dimethyl oxalate was redetermined at various temperatures. The other compounds were also studied at several temperatures in order to assess the attractive nature of the hydrogen bonds therein. A number of moderate to well defined C-H···O interactions account for the higher melting points of the two solid esters. Additionally, a diminished entropic contribution ΔS(m) in di-tert-butyl oxalate possibly increases the melting point of this compound further.

Exploring the salt–cocrystal continuum with solid-state NMR using natural-abundance samples: implications for crystal engineering

The salt–cocrystal continuum is a well known phenomenon in crystal engineering and has been studied here in several multicomponent solids with solid-state NMR (700 MHz) using 15N-1H heteronuclear dipolar coupling. The measurement is made at ultrafast (60–70 kHz) magic angle spinning (MAS) frequency. The experiment is sensitive enough to determine the proton position even in a continuum situation and can be performed on minimal amounts of microcrystalline or even amorphous solids with natural-abundance 15N samples. Such a measurement gives reliable values of N—H distances and is therefore a direct indication of the position of the proton in the salt–cocrystal continuum. The crystal structures of the relevant solids have also been determined at a high level of accuracy and the results of the X-ray and NMR experiments are compared.

Succinate esters: odd-even effects in melting points

Dialkyl succinates show a pattern of alternating behavior in their melting points, as the number of C atoms in the alkane side chain increases, unlike in the dialkyl oxalates [Joseph et al. (2011). Acta Cryst. B67, 525-534]. Dialkyl succinates with odd numbers of C atoms in the alkyl side chain show higher melting points than the immediately adjacent analogues with even numbers. The crystal structures and their molecular packing have been analyzed for a series of dialkyl succinates with 1-4 C atoms in the alkyl side chain. The energy difference (ΔE) between the optimized and observed molecular conformations, density, Kitaigorodskii packing index (KPI) and C-H...O interactions are considered to rationalize this behavior. In contrast to the dialkyl oxalates where a larger number of moderately strong C-H...O interactions were characteristic of oxalates with elevated melting points, here the molecular packing and the density play a major role in raising the melting point. On moving from oxalate to succinate esters the introduction of the C2 spacer adds two activated H atoms to the asymmetric unit, resulting in the formation of stronger C-H...O hydrogen bonds in all succinates. As a result the crystallinity of long-chain alkyl substituted esters improves enormously in the presence of hydrogen bonds from activated donors.

Probing the Crystal Structure Landscape by Doping: 4‐Bromo, 4‐Chloro, and 4‐Methylcinnamic Acids

Accessing the data points in the crystal structure landscape of a molecule is a challenging task, either experimentally or computationally. We have charted the crystal structure landscape of 4-bromocinnamic acid (4BCA) experimentally and computationally: experimental doping is achieved with 4-methylcinnamic acid (4MCA) to obtain new crystal structures; computational doping is performed with 4-chlorocinnamic acid (4CCA) as a model system, because of the difficulties associated in parameterizing the Br atom. The landscape of 4CCA is explored experimentally in turn, also by doping it with 4MCA, and is found to bear a close resemblance to the landscape of 4BCA, justifying the ready miscibility of these two halogenated cinnamic acids to form solid solutions without any change in crystal structure. In effect, 4MCA, 4CCA and 4BCA form a commutable group of crystal structures, which may be realized experimentally or computationally, and constitute the landscape. Unlike the results obtained by Kitaigorodskii, all but two of the multiple solid solutions obtained in the methyl-doping experiments take structures that are different from the hitherto observed crystal forms of the parent compounds. Even granted that the latter might be inherently polymorphic, this unusual observation provokes the suggestion that solid solution formation may be used to probe the crystal structure landscape. The influence of π⋅⋅⋅π interactions, weak hydrogen bonds and halogen bonds in directing the formation of these new structures is also seen.

Exploring the salt–co-crystal continuum with ssNMR using natural abundance samples

There is a significant recent interest in differentiating multi-component solid forms such as salt, cocrystal, and their continuum, owing to the direct relationship of property to clinical, regulatory and legal requirements for an active pharmaceutical ingredient (API). In this context, detection of the H-atom position in a hydrogen bond X–H•••A–Y is a matter of fundamental and practical importance.[1] In the present study, solid forms of simple cocrystals/salts were investigated by high field (700 MHz) solid-state NMR (ssNMR) technique using the samples with naturally abundant 15N nuclei. Several model compounds in a series of prototypical salt/cocrystal/continuum systems exhibiting the {PyN•••H–O–}/{PyN+–H•••O-} type of hydrogen bonds were selected and prepared. The crystal structures were determined at low temperature and room temperature using X-ray diffraction. Accurate H-atom positions were determined by measuring the 15N–1H distances through 15N-1H dipolar interactions using 2D inversely proton-detected cross-polarization with variable contact-time (invCP-VC) 1H→15N→1H experiments at ultra-fast (νR ≥ 60–70 kHz) magic angle spinning (MAS) frequency.[2] The experiment is sensitive enough to determine the proton position even in a continuum where an ambiguity of terminology for the solid form often arises[3] and can be performed on minimum amounts of microcrystalline or even amorphous solids with natural abundance 15N samples. The crystal structures of the relevant solids have also been determined at a high level of accuracy and the results of the X-ray and NMR experiments are compared. This work has implications in the pharmaceutical industry where the salt/cocrystal/continuum condition of the APIs is seriously considered.

Crystal engineering of multifunctional materials

The study of mechanical properties (elasticity/plasticity/brittleness) of molecular crystals has gained much importance since the advent of its practical use in different fields. The structural features, molecular packing and interaction hierarchies in bendable organic crystals are studied and documented.[1] Multiple properties in the same material is advantageous since it provides a broad spectrum in regulating the industrial application of such materials.[2] Elastically bendable organic single crystals with efficient luminescence property are important since it may be used as a material in the fields of organic light–emitting diodes (OLEDs), bio-imaging and optical communications.[3] In the present study the packing features and elastically bending property of a family of structurally related organic compounds are analysed and correlated. They are designed with the consideration of crystal engineering of multi-functional materials. The present study also demonstrates the ability of elastically bendable small organic molecular materials to display remarkable luminescence and photomechanical property such as bending of thin needles upon illumination with UV light.

Exploring the structural landscape by chloro–methyl exchange

The crystal structure landscape is a mapping of the various dynamic events occurring during the process of crystallization, and these correspond to multitudes of structural and energetic transformations. Polymorphism and solvation being recurrent issues in organic crystal engineering, the relevance of the idea of the crystal structure landscape– in both the academic and the industrial contexts– is undeniable. Experimentally, fluorine substitution augmented by computational crystal structure prediction has proven to be a handy technique in the exploration of the crystal structure landscape of benzoic acid and the benzoic acidisonicotinamide cocrystal. The device of fluoro substitution works well in the study of the crystal structure landscape of the unsubstituted compound because of the closeness in the sizes of the fluorine atom and the hydrogen atom.The relationship between the chlorine atom and the methyl group are somewhat similar to that between the fluorine and hydrogen atoms, in that both sets of atoms have similar volumes, and both sets of atoms are exchangeable in crystal structures of compounds that are analogous in terms of molecular structure, because the interactions they participate in are largely isotropic. The current work explores this possibility using chlorinated aromatic acids and their methyl analogues, and attempts to chart the crystal structure landscape of the subject compound.