Date

2017

Document Type

Dissertation

Degree

Doctor of Philosophy

Department

Chemistry

First Adviser

Vicic, David

Other advisers/committee members

Flowers, Robert; Syvret, Robert; Landskron, Kai

Abstract

This thesis details the author’s contributions to the fields of difluoromethylation and polydifluoromethylation chemistries. State-of-the-art methodology in difluoromethylation is achieved in our lab either by nickel-catalyzed conventional cross-coupling between electrophiles and the nucleophile (DMPU)2Zn(CF2H)2 or by reductive cross-coupling to join HCF2Cl and aryl halides with a nickel catalyst. Chapter 1 introduces the benefits of incorporating fluorinated moieties in drug candidates and general methods to install CF3, (CF2)n and CF2H moieties into arenes and heteroarenes. Chapter 2 details the first nickel-catalyzed difluoromethylation of aryl halides with a novel difluoromethyl zinc reagent. The new method displays broad substrate scope (aryl iodide, bromide and triflate are well-tolerated) and operational simplicity (reaction is performed at room temperature). Preliminary mechanistic studies reveal that the oxidative addition of alkylated aryl iodides is not taking place under reaction conditions, shutting down the reactivity of this type of substrate. Chapter 3 presents our attempts to construct a proposed intermediate in fluorinated olefin metathesis, namely a perfluorometallacyclobutane. After several failures, the first example of a platinum perfluorometallacyclobutane is successfully synthesized via halogen exchange between [(COD)Pt(Me)2] and 1,3-diiodoperfluoropropane. The ligand substitution reaction enabled the preparation of a family of platinum perfluorometallacyclobutanes, which could be systematically characterized by single crystal X-ray diffraction, as well as 1H, 19F and 195Pt NMR spectroscopies. Chapter 4 discusses the discovery of a halogen-bonded adduct from the reaction of 1,4-diiodooctafluorobutane with potassium tert-butoxide in dioxane. Crystallography reveals an extended two-dimensional network held together by strong iodine-oxygen interactions, which display the shortest iodine-oxygen distance and the longest iodine-carbon distance thus far reported for any perfluoroalkyl iodide substrate. An iron-mediated perfluoroalkylation of benzene is developed using α,ω-diiodoperfluoroalkanes and t-BuOK in DMF at room temperature. Chapter 5 describes our development of preliminary catalyst and reaction conditions for the nickel-catalyzed reductive cross-coupling of aryl iodides and bromides with HCF2Cl. Early investigations into the mechanism of this new method were undertaken, and we proposed that a radical process is likely taking place during reaction. The new protocol provides a much cheaper way to difluoromethylate aryl halides compared with the strategy outlined in Chapter 2.

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Chemistry Commons

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