Unique applications of dearomative strategies: I) arene-oxides/oxepines through a dearomative epoxidation of non-activated arenes Ii) arenophile-mediated dearomatization of pyridines Iii) solution-state electrochemical dearomatization of polystyrene

Siddiqi, Zohaib R.

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Description

Title

Unique applications of dearomative strategies: I) arene-oxides/oxepines through a dearomative epoxidation of non-activated arenes Ii) arenophile-mediated dearomatization of pyridines Iii) solution-state electrochemical dearomatization of polystyrene

Author(s)

Siddiqi, Zohaib R.

Issue Date

2023-05-26

Director of Research (if dissertation) or Advisor (if thesis)

Sarlah, David

Doctoral Committee Chair(s)

Sarlah, David

Committee Member(s)

• White, Christina
• Silverman, Scott
• Moore, Jeffrey

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Dearomatization

Abstract

The utility of aromatic compounds extends far beyond the field of synthetic chemistry and are commonplace molecules in biological systems, chemical engineering, and daily life. Whether in the form of small molecules or macromolecular systems, a vast amount of research effort has been placed into the synthetic functionalization of these compounds – which has led to the development of numerous mild and highly efficient transformations on aromatic compounds. As a result, incredible libraries of aromatic compounds exist – where the strategic use of dearomatization carries the molecular diversity of aromatics into the 3-dimensional realm. This thesis discusses the four major strategies that were developed to dearomatize and functionalize non-activated arenes to efficiently build molecules that cannot be prepared readily through alternative means. Three of these methodologies rely on the use of the arenophile MTAD – which can perform a dearomative formal [4+2]-cycloaddition upon irradiation with visible light. These arene-MTAD cycloadducts, as they are referred to in this thesis, were used as reactive intermediates in these methodologies. The last chapter discusses an electrochemical Birch-type reduction on the commodity polymers. Chapter 1 describes the development of the formal dearomative oxidation of arenes to arene-oxides and benzoxepines. Arene-oxides are highly reactive intermediates that are notable for their importance in human metabolism – but are generally not studied directly due to their short lifetimes in biological systems. Benzoxepines are a class of heterocycles that have been prepared only sparingly in the literature but could be useful as building blocks in medicinal chemistry. As a result, a method for the construction of both families was developed, which utilized the photo-mediated dearomatization of arenes with MTAD, followed by olefin epoxidation, whereupon cycloreversion yielded arene-oxides and benzoxepines. This method proved to be mild enough to where arene-oxides could be isolated and observed directly, without any observation of phenols. Chapter 2 describes the application of this dearomative methodology to pyridines. The overall goal of this project was to develop a methodology capable of accessing multiple classes of substituted piperidines, which is an unsolved challenge in the literature. Such a methodology would have utility in medicinal chemistry where piperidines are both common motifs in pharmaceuticals and are non-trivial to prepare in large libraries. Direct dearomative methodologies of pyridines currently suffer from the inability to bring in multiple points of functionality, which is a highlight of this MTAD-mediated methodology. A large portion of this project is devoted to the derivitization and functionalization of the functionalized pyridine-cycloadducts, which can build a large array of complexity from just three reactions. Chapter 3 describes a copper-catalyzed carboamination of arene-cycloadducts using Grignard nucleophiles. While a similar method was previously developed which utilized a nickel catalyst, only vinyl and aryl Grignard reagents were tolerated. This methodology, which utilizes alkyl Grignard reagents, both expands methodologies and highlights a new metal that is competent in these transformations. Chapter 5 describes a synthesis of MTAD that is both simple and efficient. The previous synthesis of MTAD has suffered from the isolation and generation of toxic intermediates, irreproducible protocols, and poor overall yields. This new methodology can be performed on mol scale without issue and has been used to produce hundreds of grams of MTAD to date. Chapter 6 describes the development of an electrochemical dearomatization on polystyrene – a commercial polymer prepared on 20 million ton scale and encountered every day. This dearomative methodology acts as a new mode of polystyrene functionalization that functions orthogonally to previous methods for polymer post-synthetic modification. With the failure of more traditional methods for arene-dearomatization, electrochemical reduction proved to not only be a mild means for polystyrene dearomatization but allowed for the complete dearomatization of the polymer. Some mechanistic studies identified that since polymer chains must diffuse to the cathode for reactivity, this reaction behaves under mass transport kinetics – an uncommon finding even in the realm of macromolecular reactions.

Graduation Semester

2023-08

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Zohaib Siddiqi

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