High-Resolution Charge Density Studies on Electronic Nature of Weak Interactions and Correlation of Molecular Conformation with Packing in Solid State

Abstract

The thesis entitled “High-Resolution Charge Density Studies on Electronic Nature of Weak Interactions and Correlation of Molecular Conformation with Packing in Solid State” consist of five chapters. Chapter 1 is a brief introduction to the methodologies and techniques utilized in modelling electron densities and the topics relevant to the work. The subsequent four chapters are divided into two parts-Part A and Part B. Part A has two chapters that discusses the electronic nature of unexplored weak intermolecular interactionspnicogen bonding in nitrogen atom and hydrophobic interactions between methyl groups in molecular crystals. Part B also contains two chapters that investigates the symbiotic relation of molecular conformation and packing in solid state in two unique cases-hybridized induced polymorphism observed in sulfa drug acetazolamide and unusual asymmetry observed in overcrowded Octachloronaphthalene molecule Part A: Electronic Nature of Weak Interactions Chapter 2 discusses the electron density features of pnicogen bond between nitrogen as an electrophile and chlorine as a nucleophile from experimental and theoretical charge density analyses of 2-amino-5-nitropyridine and chloroacetic acid complex. The charge transfer nature of pnicogen bonding due to overlap between donor lone pair orbitals of Cl atom and antibonding N-C sigma star orbital has been demonstrated from gas phase NBO calculations. Presence of sigma hole on N atom is further confirmed from 3D deformation maps and electrostatic maps. Topological description from AIM analysis and energy estimation based on EML method proves this interaction to be weak in nature and comparable to the strength of carbon bonding, type II F•••F halogen bonding. Detailed Cambridge Structural Database (CSD) analysis reveals that planar N atoms have the maximum propensity to participate as electrophile in pnicogen bonding. Chapter 3 reports the frequent occurrence of methyl•••methyl hydrophobic interactions in the solid-state from CSD study with a detailed analysis of these interactions in a series of cocrystals of biologically active molecules such as caffeine, theophylline and tetramethylpyrazine using experimental X-ray charge density analysis, variable-temperature crystallography and solidstate NMR. The visualization of accurate electron density distribution in the interaction region reveals that they are stabilized by the minimized electrostatic repulsion and maximized dispersion forces. This chapter further proves methyl•••methyl HI as a group•••group interaction with a pronounced torsional vibration for the hydrophobic methyl groups which leads to a significant entropic contribution towards its stability. A characteristic C-13 ssNMR up-field chemical shift was found to be associated with these methyl•••methyl interactions in the crystal state. Part B: Correlation of Molecular Conformation with Packing Chapter 4 discusses a new type of polymorphism called hybridized induced polymorphism in connection with the unusual phenomenon of the formation of kinetic form as against the thermodynamic form on slow cooling of boiling aqueous solution of diuretic drug Acetazolamide. Experimental charge density analysis aided with ab initio calculations have investigated the local electron density at the amino region of both polymorphs. A series of crystallization experiments of AZM in aqueous medium were conducted. The boiling solution was ramped down at different rates of cooling; rapid cooling in liquid nitrogen, ambient cooling to room temperature, controlled cooling at (10°C/hr, 7°C/hr and 5°C/hr) to room temperature. PXRD analysis reveals the kinetic form occurs only when the cooling rate is quite slow (7°C/hr and 5°C/hr). The occurrence of both polymorphs from aqueous solution of AZM under different crystallization conditions is rationalized in terms of hybridization induced polymorphism. Chapter 5 investigates electron density distribution in an overcrowded aromatic molecule, Octachloronaphthalene (OCN) by charge density analysis to unravel several unexplored factors responsible for steric hindrance. The topological features of the enigmatic peri interactions contributing to steric overcrowding are qualified and quantified from experimental and theoretical charge density studies. A new facet in the fundamental understanding of peri interactions is revealed by NCI (Non-Covalent Interaction) analysis. The potential role of these interactions in deforming the molecular geometry and subsequent effect on aromaticity are substantiated from NICS (Nuclear Independent Chemical Shift) and QTAIM (Quantum Theory of Atoms in Molecules) calculations. The eye-catching dissimilarity in the out-of-plane twisting of OCN renders the molecule in an asymmetric geometry in the crystalline phase as compared to symmetric geometry in the optimized solvated phase. This is uniquely characterised by their molecular electrostatic potential (MESP) respectively and is explained in terms of conflict between two opposing forces- peri interactions and symbiotic intermolecular Cl•••Cl and Cl••• contacts.