The Relevance of Experimental Charge Density Analysis in Unraveling Noncovalent Interactions in Molecular Crystals.

The work carried out by our research group over the last couple of decades in the context of quantitative crystal engineering involves the analysis of intermolecular interactions such as carbon (tetrel) bonding, pnicogen bonding, chalcogen bonding, and halogen bonding using experimental charge density methodology is reviewed. The focus is to extract electron density distribution in the intermolecular space and to obtain guidelines to evaluate the strength and directionality of such interactions towards the design of molecular crystals with desired properties. Following the early studies on halogen bonding interactions, several "sigma-hole" interaction types with similar electrostatic origins have been explored in recent times for their strength, origin, and structural consequences. These include interactions such as carbon (tetrel) bonding, pnicogen bonding, chalcogen bonding, and halogen bonding. Experimental X-ray charge density analysis has proved to be a powerful tool in unraveling the strength and electronic origin of such interactions, providing insights beyond the theoretical estimates from gas-phase molecular dimer calculations. In this mini-review, we outline some selected contributions from the X-ray charge density studies to the field of non-covalent interactions (NCIs) involving elements of the groups 14-17 of the periodic table. Quantitative insights into the nature of these interactions obtained from the experimental electron density distribution and subsequent topological analysis by the quantum theory of atoms in molecules (QTAIM) have been discussed. A few notable examples of weak interactions have been presented in terms of their experimental charge density features. These examples reveal not only the strength and beauty of X-ray charge density multipole modeling as an advanced structural chemistry tool but also its utility in providing experimental benchmarks for the theoretical studies of weak interactions in crystals.

Exploring the different environments effect of piperine via combined crystallographic, QM/MM and molecular dynamics simulation study.

Piperine is a pungent alkaloid, largely present in the skin of pepper. It is the most active component of pepper and being used as a medicine in many Asian countries. The effect of piperine on memory impairment and neurodegeneration in Alzheimer's disease model has been investigated. In the present study, we aim to investigate the effect of piperine molecule in different environments (crystal and active site of proteins) from crystallography, molecular docking, QM/MM based charge density analysis and molecular dynamic simulation. The crystal structure of piperine has been used to determine the topological electron density of intermolecular interactions. The O-atoms of piperine is forming C-H⋅⋅⋅O interactions with the neighboring molecules in the crystal, these interactions also confirmed from the Hirshfeld surface. Further, to understand the nature of interactions and the conformational flexibility of piperine in the active site of recombinant human acetylcholinesterase (rhAChE), molecular docking analysis has been performed. The selected docked complex suggests favorable hydrogen bonding and hydrophobic interactions with rhAChE enzyme; notably, the O3 atom of piperine molecule forms strong hydrogen bonding interaction with Glu202 at 1.8 Å. To determine the charge density distribution and the electrostatic properties of piperine molecule in the active site of rhAChE, the piperine-rhAChE complex was minimized at QM/MM energy level; in which, the binding pocket with piperine was considered as QM region. The charge density analysis of piperine and the interacting amino acid groups have been carried out. The topological analysis of O3⋯H-O/Glu202 hydrogen bonding interaction exhibits strong interactions and the electron density ρcp(r): 0.242 eÅ-3 and the Laplacian ∇2ρcp(r): 3.176 eÅ-5 respectively. These results were compared with the corresponding molecule present in the crystal and gas phase environments of piperine. The comparison of active site structure with the corresponding crystal phase and gas phase structures reveal that piperine exhibits large conformational modification in the active site. The molecular dynamics simulation and binding free energy calculations were performed, this gives the stability, binding affinity of the molecule in the active site of rhAChE. The O3⋯H-O/Glu202 interaction shows the high stability (89.2%), this was confirmed from the stability of hydrogen bond analysis. The binding free energy was used to measure the rate of inhibition of enzyme in the presence of ligand molecule. The comparative study allows to understand the nature of piperine molecule in the gas and crystal phases, and amino acids environment.

Do halogen bonds dictate the packing preferences in solid solutions?

The isomeric compounds, 4-bromo-2-chloro benzoic acid (4Br) and 2-bromo-4-chlorobenzoic acid (2Br), crystallize in entirely different space groups, P21/n and P1[combining macron] respectively. Both structures are stabilized by a strong O-HO hydrogen bonds generating a carboxylic acid dimer along with an unusual triangular halogen bonded motif in the former and a well-defined halogen bond in the latter. Charge density analysis establishes the nature of halogen bonds by bringing out significant changes in the packing features of the two structures as well as the quantification of the interaction energies involved in the formation of the motifs. Cocrystallization efforts lead to the formation of solid solutions of varied stoichiometric ratios among the two entirely different crystalline forms, a feature which is observed for the first time, and depends on the nature of the halogen bonds. Despite the significant variations in the charge density distribution in intermolecular space, the triangular motif, with two type II BrCl and ClBr and one type I BrBr contact in the structure of 4Br dictates the packing preferences in the solid solution as established by accurate single crystal diffraction studies supported by cognate powder diffraction analysis (PXRD) and differential scanning calorimetric (DSC) studies. A systematic study of the solid solution by varying the stoichiometric ratios establishes the hierarchy in halogen bonded motifs and consequently its directional influence to form the resultant supramolecular assembly.

Exploring the rare S-H...S hydrogen bond using charge density analysis in isomers of mercaptobenzoic acid.

Experimental and theoretical charge density analyses on isomers of mercaptobenzoic acid have been carried out to quantify the hydrogen bonding of the hitherto less explored thiols, to assess the strength of the interactions using the topological features of the electron density. The electron density study offers interesting insights into the nature of the S-H...S interaction. The interaction energy is comparable with that of a weak hydrogen bond. The strength and directionality of the S-H...S hydrogen bond is demonstrated to be mainly due to the conformation locking potential of the intramolecular S...O chalcogen bond in 2-mercaptobenzoic acid and is stronger than in 3-mercaptobenzoic acid, which lacks the intramolecular S...O bond. The para-substituted mercaptobenzoic acid depicts a type I S...S interaction.

Topological characterization of electron density, electrostatic potential and intermolecular interactions of 2-nitroimidazole: an experimental and theoretical study.

An experimental charge density distribution of 2-nitroimidazole was determined from high-resolution X-ray diffraction and the Hansen-Coppens multipole model. The 2-nitroimidazole compound was crystallized and a high-angle X-ray diffraction intensity data set has been collected at low temperature (110 K). The structure was solved and further, an aspherical multipole model refinement was performed up to octapole level; the results were used to determine the structure, bond topological and electrostatic properties of the molecule. In the crystal, the molecule exhibits a planar structure and forms weak and strong intermolecular hydrogen-bonding interactions with the neighbouring molecules. The Hirshfeld surface of the molecule was plotted, which explores different types of intermolecular interactions and their strength. The topological analysis of electron density at the bond critical points (b.c.p.) of the molecule was performed, from that the electron density ρbcp(r) and the Laplacian of electron density ∇2ρbcp(r) at the b.c.p.s of the molecule have been determined; these parameters show the charge concentration/depletion of the nitroimidazole bonds in the crystal. The electrostatic parameters like atomic charges and the dipole moment of the molecule were calculated. The electrostatic potential surface of the molecule has been plotted, and it displays a large electronegative region around the nitro group. All the experimental results were compared with the corresponding theoretical calculations performed using CRYSTAL09.

Is CH3NH3PbI3 Polar?

In view of the continued controversy concerning the polar/nonpolar nature of the hybrid perovskite system, CH3NH3PbI3, we report the first investigation of a time-resolved pump-probe measurement of the second harmonic generation efficiency as well as using its more traditional form as a sensitive probe of the absence/presence of the center of inversion in the system both in its excited and ground states, respectively. Our results clearly show that SHG efficiency, if nonzero, is below the limit of detection, strongly indicative of a nonpolar or centrosymmetric structure. Our results on the same samples, based on temperature dependent single crystal X-ray diffraction and P-E loop measurements, are entirely consistent with the above conclusion of a centrosymmetric structure for this compound in all three phases, namely the high temperature cubic phase, the intermediate temperature tetragonal phase and the low temperature orthorhombic phase. It is important to note that all our experimental probes are volume averaging and performed on bulk materials, suggesting that basic material properties of CH3NH3PbI3 are consistent with a centrosymmetric, nonpolar structure.

Acetazolamide polymorphism: a case of hybridization induced polymorphism?

The unusual phenomenon of the formation of the kinetic form as against the thermodynamic form upon slow cooling of boiling aqueous solution in the case of diuretic drug acetazolamide is rationalized in terms of "hybridization induced polymorphism" based on extensive experimental and theoretical investigations.

Halogen Bonding and Chalcogen Bonding in 4,7-Dibromo-5,6-dinitro-2,1,3-benzothiadiazole.

An organic solid, 4,7-dibromo-5,6-dinitro-2,1,3-benzothiadiazole, has been designed to serve as an illustrative example to quantitatively evaluate the relative merits of halogen and chalcogen bonding in terms of charge density features. The compound displays two polymorphic modifications, one crystallizing in a non-centrosymmetric space group (Z' = 1) and the other in a centrosymmetric space group with two molecules in the asymmetric unit (Z' = 2). Topological analysis based on QTAIM clearly brings out the dominance of the chalcogen bond over the halogen bond along with an indication that halogen bonds are more directional compared to chalcogen bonds. The cohesive energies calculated with the absence of both strong and weak hydrogen bonds as well as stacking interaction are indicative of the stabilities associated with the polymorphic forms.

Experimental validation of 'pnicogen bonding' in nitrogen by charge density analysis.

The participation of a nitrogen atom acting as an electrophile in pnicogen bonding, a hitherto unexplored interaction has been established by experimental charge density analysis. QTAIM and NBO analyses ratify this observation.

Crystal landscape in the orcinol:4,4'-bipyridine system: synthon modularity, polymorphism and transferability of multipole charge density parameters.

Polymorphism in the orcinol:4,4'-bipyridine cocrystal system is analyzed in terms of a robust convergent modular phenol⋯pyridine supramolecular synthon. Employing the Synthon Based Fragments Approach (SBFA) to transfer the multipole charge density parameters, it is demonstrated that the crystal landscape can be quantified in terms of intermolecular interaction energies in the five crystal forms so far isolated in this complex system. There are five crystal forms. The first has an open, divergent O-H⋯N based structure with alternating orcinol and bipyridine molecules. The other four polymorphs have different three-dimensional packing but all of them are similar at an interaction level, and are based on a modular O-H⋯N mediated supramolecular synthon that consists of two orcinol and two bipyridine molecules in a closed, convergent structure. The SBFA method, which depends on the modularity of synthons, provides good agreement between experiment and theory because it takes into account the supramolecular contribution to charge density. The existence of five crystal forms in this system shows that polymorphism in cocrystals need not be considered to be an unusual phenomenon. Studies of the crystal landscape could lead to an understanding of the kinetic pathways that control the crystallization processes, in other words the valleys in the landscape. These pathways are traditionally not considered in exercises pertaining to computational crystal structure prediction, which rather monitors the thermodynamics of the various stable forms in the system, in other words the peaks in the landscape.

Experimental evidence for 'carbon bonding' in the solid state from charge density analysis.

The validity of the newly proposed 'carbon bonding', an interaction where a carbon atom acts as an electrophilic site towards a variety of nucleophiles, has been investigated in the solid state. X-ray charge density analysis provides experimental evidence for this hitherto unexplored interaction and unravels its nature and strength.

Halogen bonding in fluorine: experimental charge density study on intermolecular F···F and F···S donor-acceptor contacts.

The enigmatic type II C-F···F-C and C-F···S-C interactions in pentafluorophenyl 2,2'-bithiazole are shown to be realistic "σ-hole" interactions based on high resolution X-ray charge density analysis.

Structural landscape of benzoic acid: using experimental crystal structures of fluorobenzoic acids as a probe.

Experimental crystal structures of mono and polyfluorinated benzoic acids correspond to high energy computed crystal structures of benzoic acid itself, thereby permitting access to its structural landscape.

Extending the supramolecular synthon based fragment approach (SBFA) for transferability of multipole charge density parameters to monofluorobenzoic acids and their cocrystals with isonicotinamide: importance of C-H···O, C-H···F, and F···F intermolecular regions.

An extension of the supramolecular synthon-based fragment approach (SBFA) method for transferability of multipole charge density parameters to include weak supramolecular synthons is proposed. In particular, the SBFA method is applied to C-H···O, C-H···F, and F···F containing synthons. A high resolution charge density study has been performed on 4-fluorobenzoic acid to build a synthon library for C-H···F infinite chain interactions. Libraries for C-H···O and F···F synthons were taken from earlier work. The SBFA methodology was applied successfully to 2- and 3-fluorobenzoic acids, data sets for which were collected in a routine manner at 100 K, and the modularity of the synthons was demonstrated. Cocrystals of isonicotinamide with all three fluorobenzoic acids were also studied with the SBFA method. The topological analysis of inter- and intramolecular interaction regions was performed using Bader's AIM approach. This study shows that the SBFA method is generally applicable to generate charge density maps using information from multiple intermolecular regions.