Defense Date


Document Type


Degree Name

Doctor of Philosophy



First Advisor

Scott Gronert

Second Advisor

Hani El Kaderi

Third Advisor

Katharine Tibbetts

Fourth Advisor

Matthew Hartman

Fifth Advisor

Marco Aldi


Halogenated heterocycles are common in pharmaceutical and natural products and there is a need to develop a better understanding of processes used to synthesize them. Although the halogenation of simple aromatic molecules is well understood, the mechanisms behind the halogenation of aromatic heterocycles have been more problematic to elucidate because multiple pathways are possible. Recently, new, radical-based mechanisms have been proposed for heterocycle halogenation. In this study, we examine and test the viability of possible nucleophilic substitution, SN2@X, mechanisms in the halogenation of anions derived from the deprotonation of aromatic heterocycles. All the experiments were done in a modified Thermo LCQ Plus equipped with ESI. The modifications allow a neutral reagent to be added to the helium buffer gas in the 3D ion trap. In this system, it is possible to monitor ion/molecule reactions over time periods up to 10 seconds. A variety of aromatic heterocyclic nucleophiles were chosen based on their inclusion of nitrogen and or sulfur as the heteroatoms. In addition to this, the halogenating molecules chosen included traditional halobenzenes and a new class of perfluorinated alkyl iodides. It was found that, experimentally, the SN2@X path is the likely mechanism in the halogenation of deprotonated heterocycles. With computational modeling, we have additional support for this substitution mechanism.

From this original study, two more studies were developed to look at the competing nucleophilic aromatic substitution reaction, SNAr. In the first of these studies, the focus was to look at how electron withdrawing substituents about an aromatic ring affect the ratio of SN2@X verses SNAr. As nucleophiles, 2-thiophenide and 5-thiazolide were used. The neutral reagents focus on trifluorobromobenzene derivatives along with pentafluorobromo- and -iodobenzene, and a two trifluoroiodobenzenes. What was found was that the ratio of the reactions depends on where the fluorines, or electron withdrawing substituents are in relation to the bromine or iodine on the ring. If the fluorines are in a close location to stabilize the resulting ionic product, SN2@X proceeds easily. However, the fluorines directly adjacent to the bromine or iodine also provide steric hinderance in the SNAr reaction.

In the final project, arylation and benzylation of bromopyridines was examined. The nucleophiles used were benzyl and phenyl anions as well as 5-thiazolide, and the neutral reagents were bromopyridines, with fluorines used as an electron withdrawing groups to help stabilize the transition state. In these experiments, steric hinderance highly affected the results between the phenyl and benzyl nucleophiles. With benzylic anions, the nucleophile is able to reach the aromatic ring with less steric interference and therefore can proceed with an SNAr reaction. In addition to this, with mono and difluorinated pyridine substrates, the nitrogen in the ring activated the ring yielding nucleophilic aromatic substitution losing fluoride rather than bromide in many cases.


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