Anodic Olefin Coupling Reactions: Experimental and Computational Methods for Investigating the Intramolecular Cyclization Reactions of Electrooxidatively-Generated Radicals and Radical Cations

Intramolecular anodic olefin coupling reactions represent the oxidative coupling of an electron rich double bond to an intramolecular nucleophile to generate new five- or six-membered rings from acyclic compounds. The reactions may proceed through radical or radical cation reactive intermediates and are initiated by a single electron oxidation of the starting material. This dissertation describes experimental and computational work towards elucidating the mechanisms for the coupling of electron rich olefins to a number of nucleophiles, including sulfonamides, alcohols, amidyl radicals, enol ethers, and allyl silanes. Methods employed include cyclic voltammetry, density functional theory (DFT) calculations, and competition experiments. The overarching goal of this work is to understand the reactions so that they may be better implemented and controlled in organic synthesis. This work describes methods for identifying cyclizations which are under thermodynamic and/or kinetic control, as well as cyclizations which may be reversible. The anodic olefin coupling reactions presented here represent two electron processes, and this work reveals the importance of the second single electron oxidation in terminating the reaction and permitting formation of the desired product.;Chapter 3 explores the coupling of sulfonamide anions and alcohols to electron rich olefins. When the two nucleophiles are in direct competition for coupling to the same olefin, sulfonamide cyclization is the thermodynamically preferred pathway and is promoted by high temperatures and slow rates of oxidation. Coupling of the alcohol to the double bond is the kinetically preferred pathway, and is promoted by the use of low temperatures and a fast rate of oxidation. Cyclic voltammetry and DFT calculations support a radical mechanism for sulfonamide cyclization. Experimental evidence demonstrates that alcohol trapping of a radical cation is reversible.;Chapter 4 discusses the anodic coupling of electron rich olefins to carboxylic acids to synthesize lactones. Cyclic voltammetry and DFT calculations support a mechanism in which a radical cation localized at the olefin is attacked by a carboxylate. Kolbe decarboxylation did not compete with the cyclization. Instead, the success of the cyclization depended strongly on the ability of the cyclized radical to be efficiently oxidized. Lastly, the importance of product stability with respect to the pH of the electrolysis, as well as changes in pH over the course of the reaction, was demonstrated.;Chapter 5 reports mechanistic details on the anodic generation of amidyl radicals and their use in intramolecular cyclizations to synthesize lactams. Cyclic voltammetry and DFT calculations support a radical mechanism. Computational and experimental results indicate that the reactions led to higher yields of the desired product when the cyclization was exothermic. However, efficient oxidation of the cyclized intermediate may be used to overcome problems associated with an endothermic cyclization. Finally, competition experiments indicate that amidyl radicals behave in a manner similar to sulfonamide radicals when in competition with an alcohol. That is, amidyl radical cyclization is the thermodynamically preferred pathway and is promoted by the use of high temperatures and slow rates of oxidation.;Chapter 6 describes preliminary results of an investigation into the use of allyl silanes and enol ethers as nucleophiles in anodic olefin coupling reactions. It was found that an enol ether may be successfully coupled to an electron rich olefin in the presence of an intramolecular alcohol. However, an allyl silane could not be coupled to the same electron rich olefin in the presence of an alcohol. Efforts to understand this behavior and manipulate the observed selectivity are ongoing.