Mesolytic Bond Cleavage and Proton-Coupled Electron Transfer in Organic Synthesis: Catalytic Carbocation Generation and Amide Functionalization

Abstract

Mesolytic bond cleavage is a bond-breaking event to yield a neutral radical and an ion from either a radical cation or a radical anion intermediate. The energy cost in mesolytic cleavage is significantly lower than bond homolysis of the neutral molecule. Though mesolytic bond cleavage has been extensively studied in electrochemistry and photochemistry, its synthetic application is less developed. In Chapter 2, a catalytic method for generating various carbocation intermediates under pH-neutral conditions is presented. The key mechanism is mesolytic bond cleavage of the radical cations derived from alkoxyamine substrates. This method had been applied to versatile C−C, C−O, and C−N bond formation.

In Chapter 3, 4, 5 and 6, a different type of bond cleavage strategy was exploited in organic synthesis, namely proton-coupled electron transfer (PCET). PCET generally describes chemical reaction involving movement of protons and electrons. Notably, a particularly intriguing type of PCET describes a concerted elementary step of an electron and proton transfer from one confined E−H -bond to different destinations and vice versa. Concerted PCET has been demonstrated to play a significant role in several biochemical transformations because of its facile kinetics compared to its stepwise analogues. In this thesis, synthetic applications of concerted PCET are presented in the aspects of strong E−H bond activation to yield highly reactive and valuable radical intermediates. PCET enabled homolytic cleavage of N−H bonds is revealed in the context of anti-Markovnikov hydroamination of alkenes in Chapter 3, as well as in Chapter 4, PCET enabled remote C(sp3)−H functionalization of amides in the courtesy of Hofmann–Löffler–Freytag reaction is illustrated. Moreover, in Chapter 5, a unique PCET mediated C−H activation/alkylation reaction was developed. The mechanistic studies proved that the ion pair interaction between the photo-oxidant and phosphate base are critical for this reactivity in the sense of reducing the kinetic barrier associated with classical multisite PCET pathways. Lastly, a reductive PCET was employed for a ketyl-olefin coupling reaction of unsaturated aldehyde substrates.