Anna C. Brezny

Reactive organic intermediates─particularly radical cations and dications─possess unique structural and electronic properties significant for the advancement of fundamental chemistry and materials. However, stabilizing motifs for these highly reactive species have limited synthetic accessibility and tunability. N-Heterocyclic carbene-carbodiimide (NHC-CDI) adducts are a promising platform to stabilize these intermediates due to their tunability and synthetic accessibility. Herein, we report a simple NHC-CDI framework─containing substituted diphenyl CDIs with one radical stabilizer (4-dimethylamino) and one tunable handle─that can stabilize distonic radical cation and dication species. We synthesized six systematically varied adducts that undergo two sequential oxidations with half-wave potentials (E1/2,1 = −0.528 to −0.205 V; E1/2,2 = −0.005 to +0.115 V) correlating strongly to the electronics of the CDI (i.e., Hammett (σp) parameters). Electrochemical studies confirmed each redox event as a reversible, one-electron, and diffusion-controlled process. Additionally, spectroscopic experiments of a chemically oxidized NHC-CDI support the formation and stability of the radical cation and dication species. The facile synthetic tunability and accessibility make this platform promising for the study and development of reactive intermediates for catalysis and energy materials.

Oxygen atom transfer (OAT) is a useful reaction in chemical synthesis, but because of the low reactivity of O₂ with organic substrates, harsh oxidants are often required. In contrast, metalloenzymes such as Cytochrome P450 catalyze a wide range of OAT reactions under mild conditions with O₂ as the source of the O atoms. In this work, we use a synthetic manganese porphyrin catalyst to mimic this reactivity. Our method enables electrochemical epoxidation of styrenes using O₂ through the generation of a Mn-superoxo intermediate. We report the reactivity of 12 styrene derivatives, with yields impacted by the position and electronic properties of the substituents. Spectroelectrochemical analyses indicate the generation of high-valent intermediates that enable epoxidation under these mild conditions.

Ferric porphyrins catalyse the aerobic oxidative cleavage of 2,3-dimethylindole, mimicking dioxygenase enzymes. The indole itself first reduces Fe ^III (porphyrin) to Fe ^II (porphyrin) via a proton-coupled electron transfer mechanism.

2-Fluorenyl benzoates were recently shown to undergo C–H bond oxidation through intramolecular proton transfer coupled with electron transfer to an external oxidant. Kinetic analysis revealed unusual rate-driving force relationships. Our analysis indicated a mechanism of multi-site concerted proton–electron transfer (MS-CPET) for all of these reactions. More recently, an alternative interpretation of the kinetic data was proposed to explain the unusual rate-driving force relationships, invoking a crossover from CPET to a stepwise mechanism with an initial intramolecular proton transfer (PT) (Costentin, Savéant, Chem. Sci., 2020, 11, 1006). Here, we show that this proposed alternative pathway is untenable based on prior and new experimental assessments of the intramolecular PT equilibrium constant and rates. Measurement of the fluorenyl 9-C–H pK_a, H/D exchange experiments, and kinetic modelling with COPASI eliminate the possibility of a stepwise mechanism for C–H oxidation in the fluorenyl benzoate series. Implications for asynchronous (imbalanced) MS-CPET mechanisms are discussed with respect to classical Marcus theory and the quantum-mechanical treatment of concerted proton–electron transfer.

Multiple H₂O₂-forming mechanisms are accessible in Fe(porphyrin)-catalysed oxygen reduction, a key reaction in both fuel cell technologies and oxygen-utilizing enzymes.

Electrons added to TiO₂ and other semiconductors often occupy trap states, whose reactivity can determine the catalytic and stoichiometric chemistry of the material. We previously showed that reduced aqueous colloidal TiO₂ nanoparticles have two distinct classes of thermally equilibrated trapped electrons, termed Red/e^– and Blue/e^–. Presented here are parallel optical and electron paramagnetic resonance (EPR) kinetic studies of the reactivity of these electrons with solution-based oxidants. Optical stopped-flow measurements monitoring the reactions of TiO₂/e^– with substoichiometric oxidants showed a surprising pattern: an initial fast (seconds) decrease in TiO₂/e^– absorbance followed by a secondary, slow (minutes) increase in the broad TiO₂/e^– optical feature. The analysis revealed that the fast decrease is due to the preferential oxidation of the Red/e^– trap states and the slow increase results from the re-equilibration of electrons from Blue/e⁻ to Red/e⁻ states. This kinetic model was confirmed by freeze-quench EPR measurements. Quantitative analysis of the kinetic data demonstrated that Red/e^– react ∼5 times faster than Blue/e^– with the nitroxyl radical oxidant 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxyl (4-MeO-TEMPO). Similar reactivity patterns were also observed in oxidations of TiO₂/e^– by O₂, which like 4-MeO-TEMPO is a proton-coupled electron transfer (PCET) oxidant, and by the pure electron transfer (ET) oxidant potassium triiodide (KI₃). This suggests that the faster intrinsic reactivity of one trap state over another on the seconds–minutes time scale is likely a general feature of reduced TiO₂ reactivity. This differential trap-state reactivity is likely to influence the performance of TiO₂ in photochemical/electrochemical devices, and it suggests an opportunity for tuning catalysis.

The selectivity of the oxygen reduction reaction (ORR) for water over hydrogen peroxide is important for fuel cells and other technologies. Iron porphyrin catalysts have long been studied for the ORR, but the origins of their selectivity are not well understood because the selectivity-determining step(s) usually occur after the rate-determining step. We report here the effects of acid concentration, as well as other solution conditions such as of acid pKa, on the H2O2/H2O selectivity in electrocatalytic ORR by iron tetramesitylporphyrin Fe(TMP) in DMF. The results show that selectivity reflects a kinetic competition in which the dependence on [HX] is one order greater for the production of H2O than H2O2. Based on such experimental results and computational studies, we propose that the selectivity is governed by competition between protonation of the hydroperoxo intermediate, Fe^III(TMP)(OOH), to produce water versus dissociation of the HOO^– ligand to yield to H2O2. The data rule out a bifurcation based on the regioselectivity of protonation of the hydroperoxide, as suggested in the enzymatic systems. Furthermore, the analysis developed in this study should be generally valuable to the study of selectivity in other multiproton/multielectron electrocatalytic reactions.

The catalytic reduction of O₂ to H₂O is important for energy transduction in both synthetic and natural systems. Herein, we report a kinetic and thermochemical study of the oxygen reduction reaction (ORR) catalyzed by iron tetraphenylporphyrin (Fe(TPP)) in N,N′-dimethylformamide using decamethylferrocene as a soluble reductant and para-toluenesulfonic acid (pTsOH) as the proton source. This work identifies and characterizes catalytic intermediates and their thermochemistry, providing a detailed mechanistic understanding of the system. Specifically, reduction of the ferric porphyrin, [Fe^III(TPP)]⁺_, forms the ferrous porphyrin, Fe^II(TPP), which binds O₂ reversibly to form the ferric-superoxide porphyrin complex, Fe^III(TPP)(O₂^•–). The temperature dependence of both the electron transfer and O₂ binding equilibrium constants has been determined. Kinetic studies over a range of concentrations and temperatures show that the catalyst resting state changes during the course of each catalytic run, necessitating the use of global kinetic modeling to extract rate constants and kinetic barriers. The rate-determining step in oxygen reduction is the protonation of Fe^III(TPP)(O₂^•–) by pTsOH, which proceeds with a substantial kinetic barrier. Computational studies indicate that this barrier for proton transfer arises from an unfavorable preassociation of the proton donor with the superoxide adduct and a transition state that requires significant desolvation of the proton donor. Together, these results are the first example of oxygen reduction by iron tetraphenylporphyrin where the pre-equilibria among ferric, ferrous, and ferric-superoxide intermediates have been quantified under catalytic conditions. This work gives a generalizable model for the mechanism of iron porphyrin-catalyzed ORR and provides an unusually complete mechanistic study of an ORR reaction. More broadly, this study also highlights the kinetic challenges for proton transfer to catalytic intermediates in organic media.

In the nearly 80 years since catalytic hydroformylation was first reported, hundreds of billions of pounds of aldehyde have been produced by this atom efficient one-carbon homologation of alkenes in the presence of H₂ and CO. Despite the economy and demonstrated scalability of hydroformylation, the enantioselective process (asymmetric hydroformylation, AHF) currently does not contribute significantly to the production of chiral aldehydes and their derivatives. Current impediments to practical application of AHF include low diversity of chiral ligands that provide effective rates and selectivities, limited exploration of substrate scope, few demonstrations of efficient flow reactor processes, and incomplete mechanistic understanding of the factors that control reaction selectivity and rate. This Account summarizes developments in ligand design, substrate scope, reactor technology, and mechanistic understanding that advance AHF toward practical and atom-efficient production of chiral α-stereogenic aldehydes. Initial applications of AHF were limited to activated terminal alkenes such as styrene, but recent developments enable high selectivity for unactivated olefins and more complex substrates such as 1,1′- and 1,2-disubstituted alkenes. Expanded substrate scope primarily results from new chiral phosphine ligands, especially phospholanes and bisdiazaphospholanes (BDPs). These ligands are now more accessible due to improved synthesis and resolution procedures. One of the virtues of diazaphospholanes is the relative ease of derivatization, including attachment to heterogeneous supports. Hydroformylation involves toxic and flammable reactants, a serious concern in pharmaceutical production facilities. Flow reactors offer many process benefits for handling dangerous reagents and for systematically moving from research to production scales. New approaches to achieving good gas–liquid mixing in flow reactors have been demonstrated with BDP-derived catalyst systems and lend assurance that AHF can be practically implemented by the pharmaceutical and fine chemical industries. To date, progress in AHF has been empirically driven, because hydroformylation is a complex, multistep process for which the origins of chemo-, regio-, and enantioselectivity are difficult to elucidate. Mechanistic complexity arises from three concurrent catalytic cycles (linear and two diastereomeric branched paths), significant pooling of catalyst as off-cycle species, and multiple elementary steps that are kinetically competitive. Addressing such complexity requires new approaches to collecting kinetic and extra-kinetic information and analyzing these data. In this Account, we describe our group’s progress toward understanding the complex kinetics and mechanism of AHF as catalyzed by rhodium bis(diazaphospholane) catalysts. Our strategy features both “outside-in” (i.e., monitoring catalytic rates and selectivities as a function of reactant concentration and temperature) and “inside-out” (i.e., building kinetic models based on the rates of component steps of the catalytic reaction) approaches. These studies include isotopic labeling, interception and characterization of catalytic intermediates using NMR techniques, multinuclear high-pressure NMR spectroscopy, and sophisticated kinetic modeling. Such broad-based approaches illuminate the kinetic and mechanistic origins of selectivity and activity of AHF and the elucidation of important principles that apply to all catalytic reactions.