xv, 219 p. : ill. (some col.) / Chemists have long recognized the potential of the BN bond to mimic CC double bonds in aromatic systems. Phenyl and indole are two of the most important arenes in natural systems, as well as medicine, applied chemistry, and materials science. Despite the potential of BN arenes as phenyl and indole mimics in biomolecules, few isoelectronic and isostructural BN biomolecules have been synthesized. Substitution of BN for C=C imparts tunability to aromatic systems, giving new and potentially valuable properties to the resulting molecules. Our group has sought to expand the utility of BN arenes by developing the synthetic arsenal available to chemists seeking to incorporate the BN bond into biological and other organic molecules of importance. The scope of this dissertation is twofold: (1) development of the first "fused" BN indole, including a survey of its reactivity towards electrophiles, synthesis of the parent N -H compound with complete characterization, and a comparison to natural indole and (2) expansion of the synthetic methodologies for constructing 1,2-dihydro-1,2-azaborine derivatives, including complete structural characterization of a family of "pre-aromatic" and aromatic compounds and a protection-free synthesis of azaborines. The contributions outlined in this dissertation expand both the fundamental understanding of BN isosterism in aromatic molecules and the synthetic toolbox for chemists seeking to incorporate BN arenes into biological and other organic motifs. This dissertation includes previously published and unpublished coauthored material. / Committee in charge: Professor Kenneth M. Doxsee, Chair; Professor Shih-Yuan Liu, Advisor; Professor Victoria J. DeRose, Member; Professor Michael M. Haley, Member; Professor Janis Weeks, Outside Member

Thesis advisor: Shih-Yuan Liu / Described herein are two projects on the application and effects of BN/CC isosterism on indole-containing compounds. In the first chapter, the synthetic route to an unnatural boron and nitrogen-containing analogue of tryptophan (BN-tryptophan) via late-stage functionalization of BN-indole is disclosed and its spectroscopic properties are reported with respect to the natural amino acid, tryptophan. The incorporation of BN-tryptophan into proteins expressed in E. coli using selective pressure incorporation, a residue specific method of unnatural amino acid incorporation, is then reported and its reactivity and fluorescence in the proteins characterized. In the second chapter, the synthesis of a BN-indole-containing aromatic scaffold is reported and the cation-π binding ability characterized by nuclear magnetic resonance (NMR) monitored titrations is disclosed. The resulting chemical shifts were analyzed using a non-linear curve fitting procedure and the extracted association constants (Ka’s) compared with the natural indole scaffold. Computations were also performed to support the titration results. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Selective Mu Opioid Receptor (MOR) antagonists possess immense potential in the treatment of opioid abuse/addiction. Utilizing the “message-address” concept, our laboratory reported a novel, reversible, non-peptide MOR selective antagonist 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4՛-pyridyl)carboxamido]morphinan (NAP). Molecular modeling studies revealed that the selectivity of NAP for the MOR is because of a π-π stacking interaction of its pyridine ring with the Trp318residue in theMOR. Pharmacological characterization showed that NAP is a P-glycoprotein substrate, thereby limiting its use in the treatment of opioid abuse/addiction. Thus, to modify NAP, we replaced the pyridine ring with its isosteric counterpart thiophene. Isosteric replacement could lead to development of compounds with different pharmacologic properties. Additionally, exploring other ring systems would diversify and enrich our library of compounds and aid in establishing a comprehensive structure-activity relationship. Therefore, newly synthesized compounds included thiophene derivatives of 6α/β-naltrexamine with potential to be used in the treatment of opioid abuse/addiction. Preliminary in vivo screening revealed that compounds 8 and 11 could be acting as antagonists. To aid in the design and synthesis of newer generation of MOR selective analogs, a 3-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Comparative Molecular Field Analysis (CoMFA) on 6β-N-heterocyclic substituted naltrexamine derivatives was conducted. After rigorous optimizations, the best CoMFA model possessed low predictive power. Results obtained suggested that small structural changes could lead to significant change in binding modes of these ligands. To further validate this observation, molecular docking studies were performed which revealed that these ligands indeed possessed multiple distinct binding modes thereby offering rationale for the CoMFA results. Thus, overall this study furnished useful information about the complexity of protein-ligand interactions which will aid in designing more potent and selective MOR ligands.

The thesis entitled “Organic fluorine in crystal engineering: Consequences on molecular and supramolecular organization” consists of six chapters. The main theme of the thesis is to address the role of substituted fluorine atoms in altering the geometrical and electronic features in organic molecules and its subsequent consequences on crystal packing. The thesis is divided into three parts. Part I deals with compounds that are liquids under ambient conditions, crystal structures of which have been determined by the technique of in situ cryocrystallography. Part II demonstrates the utilization of in situ cryocrystallography to study kinetically trapped metastable crystalline phases that provide information about crystallization pathways. In part III, crystal structures of a series of conformationally flexible molecules are studied to evaluate the consequences of fluorine substitution on the overall molecular conformation. The genesis and stabilization of a particular molecular conformation has been rationalized in terms of variability in intermolecular interactions in the crystalline state. Part I. In situ cryocrystallography: Probing the solid state structures of ambient condition liquids. Chapter 1 discusses the crystal structures of benzoyl chloride and its fluorinated analogs. These compounds have been analysed for the propensity of adoption of Cl···O halogen bonded dimers and catemers. The influence of conformational and electronic effects of sequential fluorination on the periphery of the phenyl ring has been quantified in terms of the most positive electrostatic potential, VS,max (corresponding to σ-hole) on the Cl-atom. It is shown that fluorine also exhibits “amphoteric” nature like other heavier halogens, particularly in presence of electron withdrawing groups. Although almost all the derivatives pack through C–H···O, C–H···F, C–H···Cl, Cl···F, C–H···π and π···π interactions, the compound 2,3,5,6-tetrafluorobenzoyl chloride exhibited a not so commonly observed Cl···O halogen bonded catemer. On the other hand, the proposed Cl···O mediated dimer is not observed in any of the structures due to geometrical constraints in the crystal lattice. Chapter 2 presents the preferences of fluorine to form hydrogen bond (C–H···F) and halogen bonds (X···F; X= Cl, Br, I). Crystal structures of all three isomers of chloro-, bromo-and iodo-fluorobenzene have been probed in order to gain insights into packing interactions preferred by fluorine and other heavier halogens. It has been observed that homo halogen…halogen (Cl···Cl, Br···Br and I···I) contacts prevail in most of the structures with fluorine being associated with the hydrogen atom forming C–H···F hydrogen bond. The competition between homo and hetero halogen bonds (I···I vs I···F) is evident from the packing polymorphism exhibited by 4-iodo fluorobenzene observed under different cooling protocols. The crystal structures of pentafluoro halo (Cl, Br, I) benzenes were also determined in order to explore the propensity of formation of homo halogen bonds over hetero halogen bonds. Different dimeric and catemeric motifs based on X···F and F···F interactions were observed in these structures. Chapter 3 focuses on the effect of different cooling protocols in generating newer polymorphs of a given liquid. The third polymorph (C2/c, Z'=6) of phenylacetylene was obtained by sudden quenching of the liquid filled in capillary from a hot water bath (363 K) to the nitrogen bath (< 77 K). Also, different polymorphs were obtained for both 2¬fluoro phenylacetylene (Pna21, Z'=1) and 3-fluoro phenylacetylene (P21/c, Z'=3) when crystallized by sudden quenching in contrast to the generally followed method of slow cooling which results in isostructural forms (P21, Z'=1). The rationale for these kinetically stable “arrested” crystalline configurations is provided in part II of the thesis. Part II. Tracing crystallization pathways via kinetically captured metastable forms. Chapter 4 explains the utilization of the new approach of sudden quenching of liquids (detailed in chapter 3) to obtain kinetically stable (metastable) crystalline phases that appear to be closer to the unstructured liquids. Six different examples namely, phenylacetylene, 2-fluorophenylacetylene, 3-fluorophenylacetylene, 4-fluorobenzoyl chloride, 3-chloro fluorobenzene and ethyl chloroformate are discussed in this context. In each case, different polymorphs were obtained when the liquid was cooled slowly (100 K/h) and when quenched sharply in liquid nitrogen. The relationship between these metastable forms and the stable forms (obtained by slow cooling) combined with the mechanistic details of growth of stable forms from metastable forms provides clues about the crystallization pathways. Part III. Conformational analysis in the solid state: Counterbalance of intermolecular interactions with molecular and crystallographic symmetries. Chapter 5 describes the crystal structures of a series of conformationally flexible molecules namely, acetylene and diacetylene spaced aryl biscarbonates and biscarbamates. While most of the molecules adopt commonly anticipated anti (transoid) conformation, some adopt unusual cisoid and gauche conformations. It is shown that the unusually twisted conformation of one of the compounds [but-2-yne-bis(2,3,4,5,6¬pentafluorocarbonate)] is stabilized mainly by the extraordinarily short C–H···F intermolecular hydrogen bond. The strength of this rather short C–H···F hydrogen bond has been authenticated by combined single crystal neutron diffraction and X-ray charge density analysis. It has also been shown that the equi-volume relationship of H-and F-atoms (H/F isosterism) can be explored to access various possible conformers of a diacetylene spaced aryl biscarbonate. While biscarbonates show variety of molecular conformations due to absence of robust intermolecular interactions, all the biscarbamates adopt anti conformation where the molecules are linked with antiparallel chains formed with N–H···O=C hydrogen bonds. Chapter 6 presents a unique example where the commonly encountered crystallographic terms namely, high Z' structure, polymorphism, phase transformation, disorder, isosterism and isostructuralism are witnessed in a single molecular species (parent compound benzoylcarvacryl thiourea and its fluorine substituted analogs). The origin of all these phenomenon has been attributed to the propensity of formation of a planar molecular dimeric chain mediated via N–H···O [R2 (12)] and N–H···S [R2 (8)] dimers.