Date on Master's Thesis/Doctoral Dissertation

12-2018

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Chemistry

Degree Program

Chemistry, PhD

Committee Chair

Hammond, Gerald

Committee Co-Chair (if applicable)

Nantz, Michael

Committee Member

Nantz, Michael

Committee Member

Ramezanipour, Farshid

Committee Member

Ng, Chin

Author's Keywords

hydrogen halides; chlorothiolation; metal-free; homoallylic amines; dimethylsulfoxide; DMPU

Abstract

The addition of hydrogen halides to carbon-carbon unsaturated systems is a classic synthetic transformation that gives rise to a variety of halogenated products as well as building blocks.1 The different routes to achieve hydrohalogenation make use of the hydrogen halides either in the gaseous form2 or in solution3, or their surrogates4. Only second to dihalogens, hydrogen halides are the most atom efficient source of halogenation. However, hydrogen halides are reactive gases at ambient temperature, posing a major challenge in their application. Handling gaseous hydrogen halide reagents requires expert knowledge and specialized equipment. We have investigated the formulation of environmentally benign organic aprotic hydrogen halide solutions to address this challenge. The properties of these formulations have been investigated in reactions with unsaturated systems. Given that hydrogen bonding may play a role in the formation of stable HX solutions, we sought to screen and investigate various solvents with strong hydrogen bonding capabilities that do not adversely jeopardize the intrinsic properties the HX molecules. The few commercially available aprotic HX-solutions have low concentrations of HX and therefore offer few synthetic advantages.5 The formulation of stable HX solutions with higher concentrations and better reactivity in hydrohalogenation was our goal. Inspired by Laurence et al’s concept of hydrogen bond basicity6 and their classification of organic molecules based on their basicity (pKBHX scale), we found that 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) formed a stable complex with HF molecules. Our newly formulated solution of hydrogen fluoride in DMPU has exhibited higher reactivity than its predecessors in a wide scope of transformations.7 We are pleased to report novel DMPU solutions of HCl and HBr. The advantages of these solutions are their relatively higher HX concentrations (12.6 M HCl and 10 M HBr) and bench stable over long periods of time compared to the commercially available organic solutions. Another unique quality of these solutions is their compatibility with water and/or base-sensitive reactions. In addition, DMPU is non-nucleophilic, so it won’t compete with halides in nucleophilic reactions. These new organic-based solutions of hydrogen halides have been applied in a metal-free hydrobromination of alkynes8 and a homogenous gold-catalyzed hydrochlorination of alkynes9. In addition, the combination of our new HCl reagent (HCl/DMPU) with sulfoxides forms a unique chlorothiolation system for alkenes with high regioselectivity.10 Under mild and transition-metal-free conditions, dimethylsulfoxide (DMSO) undergoes a one-carbon homologation to afford 4-chloropiperidines from homoallylic amines via a Pummerer fragmentation mechanism. The reactions are scalable and have broad substrate scope.

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