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Doctor of Philosophy / Chemistry / Christer B. Aakeroy / A series of co-crystallizations between four biimidazole based compounds with nine symmetric aliphatic di-acids and fifteen perfluorinated halogen-bond donors were carried out to determine if a MEPS based ranking can be used to effectively assign selectivity in hydrogen- and halogen-bond interactions. The results suggested that a simple electrostatic view provides a reliable tool for successfully implementing the practical co-crystal synthesis with desired connectivity. MEPS based selectivity guidelines for halogen-bond interactions were explored in co-crystallizations between twelve asymmetric ditopic acceptors and nine halogen-bond donors. If the difference between the two acceptor sites is below 35 kJ/mol, no selectivity was observed; above 65 kJ/mol halogen bond selectivity dominates and mid ΔE range was recognized as the grey area where predictions cannot be made. To examine competition between hydrogen and halogen bonds, five heteroaryl-2-imidazoles were co-crystallized with fifteen halogen-bond donors. It was found that halogen bonds prefer best the acceptor site, demonstrating that a suitably activated halogen-bond donor can compete with a strong hydrogen-bond donor. The benefits of ‘double activation’ for promoting halogen bond effectiveness was explored with nine haloethynylnitrobenzenes. The positive potential on halogen atoms was enhanced through a combination of an sp-hybridized carbon and electron-withdrawing nitro group(s). Iodoethynylnitrobenzenes were identified as the most effective halogen-bond donors reported to date and the compounds were exploited for the interaction preferences of nitro group and nitro⋯X-Csp interactions were identified as synthetic tools for energetic co-crystal assembly. A synthetic strategy for the deliberate assembly of molecular polygons was developed utilizing bifurcated halogen bonds constructed from N-oxides and complementary halogen-bond donors via co-crystallization. A convenient, effective, and scalable protocol for stabilizing volatile liquid chemicals with co-crystallization was achieved. Through the use of halogen-bonding, liquid iodoperfluoroalkanes were transformed into crystalline materials with low-vapor pressure, considerable thermal stability and moisture resistance. To stabilize the energetic compound ethylenedinitramine, a co-crystallization approach targeting the acidic protons was employed. Eight co-crystals were obtained and the acceptors were identified as supramolecular protecting groups leading to diminished reactivity and enhanced stability while retaining the desirable energetic properties.

The thesis entitled “Intermolecular Interactions in Molecular Crystals: Quantitative Estimates from Experimental and Theoretical Charge Densities” consists of four chapters and an Appendix. Chapter 1 highlights the principles of crystal engineering from charge density point of view. Chapter 2 (Section I - III) deals with the evaluation of weak intermolecular interactions and in particular related to the features of concomitant polymorphism. Chapter 3 describes the co-operative role of weak interactions in the presence of strong hydrogen bonds in small bioactive molecules in terms of topological properties. Chapter 4 unravels the inter-ion interactions in terms of charge density features in an ionic salt. The general conclusions of the works presented in this thesis are provided at the end of the chapters. Appendix A explores the varieties of hydrogen bonds in a simple molecule. Identification of intermolecular interactions based purely on distance-angle criteria is inadequate and in the context of ‘quantitative crystal engineering’, recognition of critical points in terms of charge density distribution becomes extremely relevant to justify the occurrence of any interaction in the intermolecular space. The results from single crystal X-ray diffraction data at 90K (compound in chapter 4 at 113K) have been compared with those from periodic theoretical calculations via DFT method at high-level basis set (B3LYP/6-31G**) in order to establish a common platform between theory and experiment. Chapter 1 gives a brief review on crystal engineering to analyze intermolecular interactions along with the description of both experimental and theoretical approaches used in the analysis of charge densities in molecular crystals. The eight of Koch and Popelier’s criteria, defined using the theory of “Atoms in Molecules”, to characterize hydrogen bonds have also been discussed in detail. Chapter 2 (I) presents the charge density analysis in coumarin, 1-thiocoumarin, and 3-acetylcoumarin. Coumarin has been extensively studied as it finds applications in several areas of synthetic chemistry, medicinal chemistry, and photochemistry. The packing of molecules in the crystal lattice is governed by weak C−HLO and C−HLπ interactions only. The variations in charge density properties and derived local energy densities have been investigated in these regions of intermolecular interactions. The lacuna of the identification of a lower limit for the hydrogen bond formation has been addressed in terms of all eight of Koch and Popelier’s criteria, to bring out the distinguishing features between a hydrogen bond (C−HLO) and a van der Waals interaction (C−HLπ) for the first time. Chapter 2 (II) highlights the nature of intermolecular interactions involving sulfur in 1-thiocoumarin, 2-thiocoumarin, and dithiocoumarin. These compounds pack in the crystal lattice mainly via weak C−HLS and SLS interactions. The analysis of experimental and theoretical charge densities clearly categorizes these interactions as pure van der Waals in nature. The distribution of charge densities in the vicinity of the S atom has been analyzed to get better insights into the nature of sulfur in different environments. Chapter 2 (III) provides a detailed investigation of the charge density distribution in concomitant polymorphs of 3-acetylcoumarin. The electron density maps in the two forms demonstrate the differences in the nature of the charge density distribution particularly in the features associated with C−HLO and C−HLπ interactions. The net charges derived based on the population analysis via multipole refinement and also the charges evaluated via integration over the atomic basins and the molecular dipole moments show significant differences. The lattice energies calculated from experimental charge density approach clearly suggest that form A is thermodynamically stable compared to form B. Mapping of electrostatic potential over the molecular surfaces also bring out the differences between the two forms. Chapter 3 describes the analysis of charge density distribution in three small bioactive molecules, 2-thiouracil, cytosine monohydrate, and salicylic acid. These molecules pack in the crystal lattice via strong hydrogen bonds, such as N−HLO, N−HLS, and O−HLO. In spite of the presence of such strong hydrogen bonds, the weak interactions like C−HLO and C−HLS also contribute in tandem to the packing features. The distribution of charge densities in intermolecular space provides a quantitative comparison on the strength of both strong and weak interactions. The variations in electronegativity associated with the S, O, and N atoms are clearly seen in the electrostatic potential maps over the molecular surfaces. Chapter 4 deals with study of intermolecular interactions in N,N,N´N´-tetramethylethlenediammonium dithiocyanate, analyzed based on experimental charge densities from X-ray diffraction data at 113 K and compared with theoretical charge densities. The packing in the crystal lattice is governed mainly by a strong N+−H…N− hydrogen bond along with several weak interactions such as C−HLS, C−HLN, and C−HLπ. The charge density distribution in the region of inter-ionic interaction is also highlighted and the electrostatic potential map clearly provides the insights in to its interacting feature. Appendix A describes the experimental and theoretical charge density studies in 1-formyl-3-thiosemicarbazide and the assessment of five varieties of hydrogen bonds.

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