Aryl chlorides are numerous in drug discovery as synthetic handles and initial steps for functionalization. Electrophilic aromatic substitution (EAS) is a common method of synthesizing such aryl chlorides. However, this method of synthesis of C-H functionalization is hindered by harsh reaction conditions, reduced reactivity towards electron poor substrates and an inability to control the regioselectivity of the products. Regioselectivity is still an unsolved problem to the innate electronic properties of various substrates. Regioselectivity of the electrophilic halogenation is controlled primarily by the substrates, commonly resulting in a mixture of constitutional isomers. It would be synthetically useful, especially in the field of medicinal chemistry, to have access to a mild catalytic-controlled halogenation methodology.<br/>In our lab, we have recently developed a Lewis base catalyst-controlled regiodivergent method for the regioselectivity of simple phenols. Triphenylphosphine sulfide was our most reactive catalyst and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP)-disulfide both gave para-selectivity. While investigating the mechanism of action, we observed the formation of catalytic intermediates such as a triphenylphosphine dimer. We hypothesize that these intermediates could possess catalytic activity to primarily drive product formation. To investigate the true catalytic species, we performed kinetic experiments via nuclear magnetic resonance (NMR) spectroscopy to measure the initial rate of reaction across a variety of substrates comparing all four proposed catalytic species. Across all substrates, the triphenylphosphine monomer catalyst was, on average, 3-4 times faster than the dimer, with the fastest being 15 times faster, indicating that the dimer, as previously hypothesized, is not the primary catalytic species and its formation during the reaction is likely a factor in slowing down the rate. As such, we suspect that being able to prevent the dimer formation would yield even faster rates of reaction, and we hypothesize that the sterics of the catalyst may impact the intermediate formation.<br/>To gain more insight into the structure and electronic properties of the catalytic intermediates, future studies include the isolation of crystal structures and utilization of computational calculations and models such as Gaussian.

Mechanistic studies of Lewis base catalyst-controlled regioselective chlorination of arenes and heterocycles

2019 Spring National Meeting

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