Semester

Summer

Date of Graduation

2022

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Brian Popp

Committee Co-Chair

Jessica Hoover

Committee Member

Jessica Hoover

Committee Member

Bjorn Soderberg

Committee Member

Kung Wang

Committee Member

Mark Mclaughlin

Abstract

The synthesis of carboxylic acids is important to the chemistry community, owing to the broad applicability of these compounds as fine chemicals and pharmaceuticals. Method development over the last decade has focused on the preparation of carboxylic acids through transition metal catalysis utilizing CO2 as a C1 synthon. Copper-catalyzed heteroelement(bora and sila)-carboxylation protocols provide functional group rich carboxylic acid products, yet remain underdeveloped and thus underutilized. Consequently, catalytic reductive difunctionalization methodologies in which CO2 and B(pin) (pin = pinacolate: 2,3-dimethyl-2,3-butanediolate) are installed across the double bond of a vinyl arene were recently developed. These boracarboxylation protocols provided novel, pharmaceutically relevant, α-aryl propionic acids bearing a β-boryl functionality in good to excellent yields; however, the alkene scope was limited. Here, solutions to substrate scope limitations and methods to improve reaction efficiency will be presented. Reactivity studies of sterically challenging α-substituted vinyl arene substrates revealed a complex kinetic interplay between catalytic reduction of CO2 and alkene migratory insertion reaction pathways. These results have impacted the ways in which the catalytic boracarboxylation system is altered to allow for transformation of challenging alkene substrates. The method in which the α-substituted vinyl arenes were boracarboxylated led to a glovebox-free benchtop synthesis of borylated Ibuprofen. Moreover, the benchtop method circumvents the need to use a prefunctionalized copper(I)-precatalyst through in-situ generation of the active catalytic species from readily available and easily synthesized starting materials. Guided by previous experimental studies, a catalytic phosphine additive, Xantphos, led to expansion of the boracarboxylation scope to unactivated alkenes. Insights from these studies are expected to contribute to increased use of Xantphos as a catalytic additive in copper(I)-boryl catalysis.

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