Date of Award

December 2020

Document Type


Degree Name

Doctor of Philosophy (PhD)



Committee Member

Modi Wetzler

Committee Member

Brian Powell

Committee Member

Joseph S. Thrasher

Committee Member

William Pennington


The importance of the traditional 4-methylbenzenesulfonyl (tosyl) protecting groups in the widely used Richman-Atkins cyclization of azamacrocycles, in particular 1,4,7,10-tetraazacyclododecane (cyclen), is investigated through the systematic variation of groups, and the properties of the tosyl groups that contribute to successful cyclization are identified. The first experimental evidence of the Thorpe-Ingold effect contributing to cyclization, in the form of crystallographic overlays with low root-mean-square deviations, is presented and is further supported by a computational conformational study. In the absence of a bulky group on the center of one of the cyclic precursors contributing to the steric Thorpe-Ingold effect, an electronic gauche effect arising from the electron-withdrawing nature of sulfonamides is observed to also cause curvature of the cyclic precursor, leading to the desired cyclic product.Cyclens with a 3:1 substitution pattern of the amines find important applications particularly in medical imaging but suffer from inefficient and low-yielding synthesis. An efficient synthesis, installing the 3:1 substitution pattern prior to cyclization, is designed and attempted using 4-nitrobenzenesulfonyl (nosyl) protecting groups. Initial nosyl deprotection attempts were thwarted by what is hypothesized to be incomplete deprotection resulting in amine – sulfur dioxide complexes, but these difficulties were overcome via aqueous hydrolysis. The trifluorotosyl group was explored as a possible protecting group for Richman-Atkins cylization, and deprotection conditions were identified. Trifluorotosylated amines were highly crystalline, and while the lattice energies were calculated to be similar to those of their tosylated analogues, an in-depth study of the intermolecular close contacts via Hirshfeld surface, ratio of frequencies, and electrostatic potential energy map analyses showed that fluorine atoms form weak but numerous intermolecular interactions. These interactions resulted in a lack of isostructurality in nine out of ten pairs of tosyl/trifluorotosyl analogues indicating that the simple CH3 to CF3 modification could be a useful tool in crystal engineering, especially in sulfa drug formulations.



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