Catalysis by neutral, organic, small molecules capable of binding and activating substrates solely via noncovalent interactions—particularly H-bonding—has emerged as an important approach in organocatalysis. The mechanisms which such molecule catalysts induce high enantioselectivity may be quite different from those used that rely on covalent interactions with substrates. Attractive are weaker, less distance dependent, directional, more affected entropy than interactions. However, the...

ConspectusRedox events in which an electron and proton are exchanged a concerted elementary step commonly referred to as proton-coupled transfers (PCETs). PCETs known operate numerous important biological redox processes, well recent inorganic technologies for small molecule activation. These studies suggest that PCET catalysis might also function general mode of substrate activation organic synthesis. Over the past three years, our group has worked advance this hypothesis demonstrate...

The first highly enantioselective catalytic protocol for the reductive coupling of ketones and hydrazones is reported. These reactions proceed through neutral ketyl radical intermediates generated via a concerted proton-coupled electron transfer (PCET) event jointly mediated by chiral phosphoric acid catalyst photoredox Ir(ppy)2(dtbpy)PF6. Remarkably, these radicals appear to remain H-bonded conjugate base Brønsted during course subsequent C-C bond-forming step, furnishing syn 1,2-amino...

We report a new photocatalytic protocol for the redox-neutral isomerization of cyclic alcohols to linear ketones via C–C bond scission. Mechanistic studies demonstrate that key alkoxy radical intermediates in this reaction are generated direct homolytic activation alcohol O–H bonds an unusual intramolecular PCET process, wherein electron travels proximal cation concert with proton transfer weak Brønsted base. Effective strength considerations shown accurately forecast feasibility generation...

Hydroamination gets a light push uphill of olefins is broadly useful method for making carbon-nitrogen bonds. However, when both the amine and olefin have multiple alkyl substituents, reaction can become energetically unfavorable. Musacchio et al. used energy in blue to surmount this obstacle (see Perspective by Buchanan Hull). A photo-excited iridium complex oxidized amine, which turn bonded efficiently olefin, after thiophenol cocatalyst shuttled electron back. The could operate across...

A new thiourea catalyst is reported for the enantioselective cationic polycyclization of hydroxylactams. Both yield and enantioselectivity this transformation were found to vary strongly with identity a single aromatic residue on common framework, more expansive polarizable arenes proving optimal. Evidence presented mechanism in which stabilizing cation−π interactions are principal determinant enantioselectivity.

Concerted proton-coupled electron transfer is a key mechanism of substrate activation in biological redox catalysis. However, its applications organic synthesis remain largely unexplored. Herein, we report the development new catalytic protocol for ketyl-olefin coupling and present evidence to support concerted being operative ketyl formation. Notably, reaction outcomes were correctly predicted by simple thermodynamic formalism relating oxidation potentials pKa values specific Brønsted...

Here we describe a dual catalyst system comprised of an iridium photocatalyst and weak phosphate base that is capable both selectively homolyzing the N–H bonds N-arylamides (bond dissociation free energies ∼ 100 kcal/mol) via concerted proton-coupled electron transfer (PCET) mediating efficient carboamination reactions resulting amidyl radicals. This manner PCET activation, which finds its basis in numerous biological redox processes, enables formal homolysis stronger amide bond presence...

Here we report a ternary catalyst system for the intramolecular hydroamidation of unactivated olefins using simple N-aryl amide derivatives. Amide activation in these reactions occurs via concerted proton-coupled electron transfer (PCET) mediated by an excited state iridium complex and weak phosphate base to furnish reactive amidyl radical that readily adds pendant alkenes. A series H-atom, electron, proton events with thiophenol cocatalyst product regenerate active forms photocatalyst base....

While olefin amination with aminium radical cations is a classical method for C-N bond formation, catalytic variants that utilize simple 2° amine precursors remain largely undeveloped. Herein we report new visible-light photoredox protocol the intramolecular anti-Markovnikov hydroamination of aryl olefins proceeds through catalytically generated intermediates. Mechanistic studies are consistent process involving oxidation via electron transfer, turnover-limiting and second transfer step to...

Charging through the looking glass Asymmetric catalysis is a commonly applied technique to prepare just one of two mirror-image products in chemical reaction. But what if you already have compound want, stuck mixture left- and right-handed enantiomers? Shin et al. now show that light-induced electron transfer can trigger favorable succession proton hydrogen-atom steps, both which are susceptible biasing by catalysts, preferentially convert cyclic urea enantiomers into (see Perspective...

While interest in the synthetic chemistry of radical cations continues to grow, controlling enantioselectivity reactions these intermediates remains a challenge. Based on recent insights into oxidation tryptophan enzymatic systems, we report photocatalytic method for generation indole as hydrogen-bonded adducts with chiral phosphate anions. These noncovalent open-shell complexes can be intercepted by stable nitroxyl TEMPO· form alkoxyamine-substituted pyrroloindolines high levels...

We report a general protocol for the light-driven isomerization of cyclic aliphatic alcohols to linear carbonyl compounds. These reactions proceed via proton-coupled electron-transfer activation alcohol O–H bonds followed by subsequent C–C β-scission resulting alkoxy radical intermediates. In many cases, these redox-neutral isomerizations in opposition significant energetic gradient, yielding products that are less thermodynamically stable than starting materials. A mechanism is presented...

Epoxy thermosets are high-volume materials that play a central role in wide range of engineering applications; however, technologies to recycle these polymers remain rare. Here, we present catalytic, light-driven method enables chemical recycling industrially relevant thiol epoxy their original monomer at ambient temperature. This strategy relies on the proton-coupled electron transfer (PCET) activation hydroxy groups within polymer network generate key alkoxy radicals promote fragmentation...

Here we report a catalytic method for the intermolecular anti-Markovnikov hydroamination of unactivated alkenes using primary and secondary sulfonamides. These reactions occur at room temperature under visible light irradiation are jointly catalyzed by an iridium(III) photocatalyst, dialkyl phosphate base, thiol hydrogen atom donor. Reaction outcomes consistent with intermediacy N-centered sulfonamidyl radical generated via proton-coupled electron transfer activation sulfonamide N–H bond....

The mechanism of a recently reported aldehyde alpha-oxyamination reaction has been studied using combination kinetic, spectrometric, and spectrophotometric techniques. Most crucially, the use validated cyclopropane-based radical-clock substrate demonstrated that carbon-oxygen bond formation occurs predominantly through an enamine activation manifold. mechanistic details herein indicate that, as proposed for previously alcohol oxidations, complexation between TEMPO simple metal salt leads to...

A total synthesis of the marine natural product diazonamide (1) has been accomplished. This work features a highly stereoselective C(10) quaternary center and central furanoindoline core enabled by an iminium-catalyzed alkylation–cyclization cascade. Additionally, magnesium-mediated intramolecular macroaldolization palladium-catalyzed tandem borylation/annulation were developed to enable closure two 12-membered macrocycles A. involves 20 steps in its longest linear sequence proceeds 1.8%...

Aminium radical cations have been extensively studied as electrophilic aminating species that readily participate in C–N bond forming processes with alkenes and arenes. However, their utility synthesis has limited, generation required unstable, reactive starting materials harsh reaction conditions. Visible-light photoredox catalysis emerged a platform for the mild production of aminium from either unfunctionalized or N-functionalized amines. This Perspective covers recent synthetic methods...

Elbasvir is a potent NS5A antagonist for the treatment of chronic hepatitis C. A seemingly trivial indoline oxidation en route to target compound was complicated by epimerization stereogenic hemiaminal center under most standard conditions. To address this issue, novel visible light photoredox process developed involving an iridium photosensitizer and environmentally-benign perester oxidant. The reaction discovered through high-throughput experimentation campaign optimized demonstrated on...

The direct, site-selective alkylation of unactivated C(sp3)-H bonds in organic substrates is a long-standing goal synthetic chemistry. General approaches to the activation strong C-H include radical-mediated processes involving highly reactive intermediates, such as heteroatom-centered radicals. Herein, we describe catalytic, intermolecular that circumvents species via new elementary step for cleavage multisite-proton-coupled electron transfer (multisite-PCET). Mechanistic studies indicate...

An enantioselective, radical-based method for the intramolecular hydroamination of alkenes with sulfonamides is reported. These reactions are proposed to proceed via N-centered radicals formed by proton-coupled electron transfer (PCET) activation sulfonamide N-H bonds. Noncovalent interactions between neutral sulfonamidyl radical and a chiral phosphoric acid generated in PCET event hypothesized serve as basis asymmetric induction subsequent C-N bond forming step, achieving selectivities up...