Kimberley M. Christopher

Per‐ and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants resistant to degradation due to strong C─F bonds. Efficient, energy‐saving methods for PFAS remediation remain a critical challenge. Here, we develop a computational framework revealing that radical anions of perfluorosulfonic acids serve as key intermediates where electron attachment weakens C─F and C─S bonds by up to 80 kcal/mol, enabling degradation pathways inaccessible to neutral or deprotonated species. Electrons and hydrogen atoms emerge as the dominant agents of defluorination, while hydroxyl radicals play a secondary role. Coupled with experimental validation in a nonthermal plasma reactor, we demonstrate that electron upconversion facilitates catalytic defluorination cycles through radical–anion cross‐reactions, enhancing fluoride release up to four‐fold. These findings unify plasma, photoredox, and electrochemical approaches under an electron‐catalytic mechanism, suggesting broadly applicable, greener strategies for destroying persistent fluorinated pollutants.

Electron upconversion, the promotion of a single electron into a higher-energy orbital as the direct consequence of an exergonic chemical step, has been studied mainly as a way to generate transient “super-reductants” that hand off a high-energy electron to an external acceptor. Here, we explore a different application of this phenomenon. Using density functional theory calculations in combination with a survey of enzyme-catalyzed processes, we show that the same upconverted radical anions can act intramolecularly to expel otherwise recalcitrant leaving groups, accomplishing transformations that are formally two-electron, heterolytic eliminations. Taking redox dehydratases as the starting inspiration, we compare the energetics of hydroxide elimination from a ketyl radical anion against the classical, stereoelectronically favorable enolate route. Elimination through the upconverted ketyl is thermodynamically preferred by ~10 kcal/mol, and although this preference diminishes, it does not disappear even for a remote, non-activated γ-hydroxyl group. The orbital picture is simple: occupation of a high-energy antibonding orbital is relieved when electron density flows into the σ* orbital of the scissile bond, so that bond cleavage demotes the electron into a lower-energy, non-bonding orbital. Thus, upconversion is not only a route to strong reductants; it is a general activation mode for bond cleavage. The same logic applies to the C–O, C–N, and C–S eliminations carried out by diol dehydratases, 4-hydroxybutyryl-CoA dehydratase, certain glycyl radical enzymes, and ribonucleotide reductase under mild, metal-sparing, anaerobic conditions, and it suggests design principles for synthetic eliminations that avoid strong acids, strong bases, and pre-activated substrates.

Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (-)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.

We report an unusual transformation where the transient formation of a nitrene moiety initiates a sequence of steps leading to remote oxidative C–H functionalization (R–CH₃ to R–CH₂OC(O)R’) and the concomitant reduction of the nitrene into an amino group. No external oxidants or reductants are needed for this formal molecular comproportionation. Detected and isolated intermediates and computational analysis suggest that the process occurs with pyrazole ring opening and recyclization.

We report an unusual transformation where a transient formation of a nitrene moiety initiates a sequence of steps where leading to a remote oxidative C-H functionalization (R-CH3 to R-CH2OC(O)R’) and concomitant reduction of the nitrene into an amino group. No external oxi-dants or reductants are needed for this formal molecular com-proportionation. Detected and iso-lated intermediates and computational analysis suggest that the process occurs with pyrazole ring opening and recyclization.

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.