Visible-Light-Promoted C–S Cross-Coupling via Intermolecular Charge Transfer

Disclosed is a mild, scalable, visible-light-promoted cross-coupling reaction between thiols and aryl halides for the construction of C–S bonds in the absence of both transition metal and photoredox catalysts. The scope of aryl halides and thiol partners includes over 60 examples and therefore provides an entry point into various aryl thioether building blocks of pharmaceutical interest. Furthermore, to demonstrate its utility, this C–S coupling protocol was applied in drug synthesis and late-stage modifications of active pharmaceutical ingredients. UV–vis spectroscopy and time-dependent density functional theory calculations suggest that visible-light-promoted intermolecular charge transfer within the thiolate–aryl halide electron donor–acceptor complex permits the reactivity in the absence of catalyst

Mechanism of Homogeneous Reduction of CO₂ by Pyridine: Proton Relay in Aqueous Solvent and Aromatic Stabilization

We employ quantum chemical calculations to investigate the mechanism of homogeneous CO₂ reduction by pyridine (Py) in the Py/p-GaP system. We find that CO₂ reduction by Py commences with PyCOOH⁰ formation where: (a) protonated Py (PyH⁺) is reduced to PyH⁰, (b) PyH⁰ then reduces CO₂ by one electron transfer (ET) via nucleophilic attack by its N lone pair on the C of CO₂, and finally (c) proton transfer (PT) from PyH⁰ to CO₂ produces PyCOOH⁰. The predicted enthalpic barrier for this proton-coupled ET (PCET) reaction is 45.7 kcal/mol for direct PT from PyH⁰ to CO₂. However, when PT is mediated by one to three water molecules acting as a proton relay, the barrier decreases to 29.5, 20.4, and 18.5 kcal/mol, respectively. The water proton relay reduces strain in the transition state (TS) and facilitates more complete ET. For PT mediated by a three water molecule proton relay, adding water molecules to explicitly solvate the core reaction system reduces the barrier to 13.6–16.5 kcal/mol, depending on the number and configuration of the solvating waters. This agrees with the experimentally determined barrier of 16.5 ± 2.4 kcal/mol. We calculate a p<i>K</i> _a for PyH⁰ of 31 indicating that PT preceding ET is highly unfavorable. Moreover, we demonstrate that ET precedes PT in PyCOOH⁰ formation, confirming PyH⁰’s p<i>K</i> _a as irrelevant for predicting PT from PyH⁰ to CO₂. Furthermore, we calculate adiabatic electron affinities in aqueous solvent for CO₂, Py, and Py·CO₂ of 47.4, 37.9, and 66.3 kcal/mol respectively, indicating that the anionic complex PyCOO^– stabilizes the anionic radicals CO₂ ^– and Py^– to facilitate low barrier ET. As the reduction of CO₂ proceeds through ET and then PT, the pyridine ring becomes aromatic, and thus Py catalyzes CO₂ reduction by stabilizing the PCET TS and the PyCOOH⁰ product through aromatic resonance stabilization. Our results suggest that Py catalyzes the homogeneous reductions of formic acid and formaldehyde en route to formation of CH₃OH through a series of one-electron reductions analogous to the PCET reduction of CO₂ examined here, where the electrode only acts to reduce PyH⁺ to PyH⁰

C–N Cross-Coupling via Photoexcitation of Nickel–Amine Complexes

C–N cross-coupling is an important class of reactions with far-reaching impacts across chemistry, materials science, biology, and medicine. Transition metal complexes can elegantly orchestrate diverse aminations but typically require demanding reaction conditions, precious metal catalysts, or oxygen-sensitive procedures. Here, we introduce a mild nickel-catalyzed C–N cross-coupling methodology that operates at room temperature using an inexpensive nickel source (NiBr₂·3H₂O), is oxygen tolerant, and proceeds through direct irradiation of the nickel–amine complex. This operationally robust process was employed for the synthesis of diverse C–N-coupled products (40 examples) by irradiating a solution containing an amine, an aryl halide, and a catalytic amount of NiBr₂·3H₂O with a commercially available 365 nm LED at room temperature without added photoredox catalyst and the amine substrate serving additional roles as the ligands and base. Density functional theory calculations and kinetic isotope effect experiments were performed to elucidate the observed C–N cross-coupling reactivity

Predicting Hydride Donor Strength via Quantum Chemical Calculations of Hydride Transfer Activation Free Energy

We propose a method to approximate the kinetic properties of hydride donor species by relating the nucleophilicity (<i>N</i>) of a hydride to the activation free energy <i>Δ<i>G</i></i>^⧧ of its corresponding hydride transfer reaction. <i>N</i> is a kinetic parameter related to the hydride transfer rate constant that quantifies a nucleophilic hydridic species’ tendency to donate. Our method estimates <i>N</i> using quantum chemical calculations to compute <i>Δ<i>G</i></i>^⧧ for hydride transfers from hydride donors to CO₂ in solution. A linear correlation for each class of hydrides is then established between experimentally determined <i>N</i> values and the computationally predicted <i>Δ<i>G</i></i>^⧧; this relationship can then be used to predict nucleophilicity for different hydride donors within each class. This approach is employed to determine <i>N</i> for four different classes of hydride donors: two organic (carbon-based and benzimidazole-based) and two inorganic (boron and silicon) hydride classes. We argue that silicon and boron hydrides are driven by the formation of the more stable Si–O or B–O bond. In contrast, the carbon-based hydrides considered herein are driven by the stability acquired upon rearomatization, a feature making these species of particular interest, because they both exhibit catalytic behavior and can be recycled

Roles of the Lewis Acid and Base in the Chemical Reduction of CO₂ Catalyzed by Frustrated Lewis Pairs

We employ quantum chemical calculations to discover how frustrated Lewis pairs (FLP) catalyze the reduction of CO₂ by ammonia borane (AB); specifically, we examine how the Lewis acid (LA) and Lewis base (LB) of an FLP activate CO₂ for reduction. We find that the LA (trichloroaluminum, AlCl₃) alone catalyzes hydride transfer (HT) to CO₂ while the LB (trimesitylenephosphine, PMes₃) actually hinders HT; inclusion of the LB increases the HT barrier by ∼8 kcal/mol relative to the reaction catalyzed by LAs only. The LB hinders HT by donating its lone pair to the LUMO of CO₂, increasing the electron density on the C atom and thus lowering its hydride affinity. Although the LB hinders HT, it nonetheless plays a crucial role by stabilizing the active FLP·CO₂ complex relative to the LA dimer, free CO₂, and free LB. This greatly increases the concentration of the reactive complex in the form FLP·CO₂ and thus increases the rate of reaction. We expect that the principles we describe will aid in understanding other catalytic CO₂ reductions

Reduction of CO₂ to Methanol Catalyzed by a Biomimetic Organo-Hydride Produced from Pyridine

We use quantum chemical calculations to elucidate a viable mechanism for pyridine-catalyzed reduction of CO₂ to methanol involving homogeneous catalytic steps. The first phase of the catalytic cycle involves generation of the key catalytic agent, 1,2-dihydropyridine (<b>PyH</b>_<b>2</b>). First, pyridine (Py) undergoes a H⁺ transfer (PT) to form pyridinium (PyH⁺), followed by an e^– transfer (ET) to produce pyridinium radical (PyH⁰). Examples of systems to effect this ET to populate PyH⁺’s LUMO (<i>E</i>⁰_calc ∼ −1.3 V vs SCE) to form the solution phase PyH⁰ via highly reducing electrons include the photoelectrochemical p-GaP system (<i>E</i>_CBM ∼ −1.5 V vs SCE at pH 5) and the photochemical [Ru­(phen)₃]²⁺/ascorbate system. We predict that PyH⁰ undergoes further PT–ET steps to form the key closed-shell, dearomatized (<b>PyH</b>_<b>2</b>) species (with the PT capable of being assisted by a negatively biased cathode). Our proposed sequential PT–ET–PT–ET mechanism for transforming Py into <b>PyH</b>_<b>2</b> is analogous to that described in the formation of related dihydropyridines. Because it is driven by its proclivity to regain aromaticity, <b>PyH</b>_<b>2</b> is a potent recyclable organo-hydride donor that mimics important aspects of the role of NADPH in the formation of C–H bonds in the photosynthetic CO₂ reduction process. In particular, in the second phase of the catalytic cycle, which involves three separate reduction steps, we predict that the <b>PyH</b>_<b>2</b>/Py redox couple is kinetically and thermodynamically competent in catalytically effecting hydride and proton transfers (the latter often mediated by a proton relay chain) to CO₂ and its two succeeding intermediates, namely, formic acid and formaldehyde, to ultimately form CH₃OH. The hydride and proton transfers for the first of these reduction steps, the homogeneous reduction of CO₂, are sequential in nature (in which the formate to formic acid protonation can be assisted by a negatively biased cathode). In contrast, these transfers are coupled in each of the two subsequent homogeneous hydride and proton transfer steps to reduce formic acid and formaldehyde

Visible-Light Organic Photocatalysis for Latent Radical-Initiated Polymerization via 2e^–/1H⁺ Transfers: Initiation with Parallels to Photosynthesis

We report the latent production of free radicals from energy stored in a redox potential through a 2e^–/1H⁺ transfer process, analogous to energy harvesting in photosynthesis, using visible-light organic photoredox catalysis (photocatalysis) of methylene blue chromophore with a sacrificial sterically hindered amine reductant and an onium salt oxidant. This enables light-initiated free-radical polymerization to continue over extended time intervals (hours) in the dark after brief (seconds) low-intensity illumination and beyond the spatial reach of light by diffusion of the metastable leuco-methylene blue photoproduct. The present organic photoredox catalysis system functions via a 2e^–/1H⁺ shuttle mechanism, as opposed to the 1e^– transfer process typical of organometallic-based and conventional organic multicomponent photoinitiator formulations. This prevents immediate formation of open-shell (radical) intermediates from the amine upon light absorption and enables the “storage” of light-energy without spontaneous initiation of the polymerization. Latent energy release and radical production are then controlled by the subsequent light-independent reaction (analogous to the Calvin cycle) between leuco-methylene blue and the onium salt oxidant that is responsible for regeneration of the organic methylene blue photocatalyst. This robust approach for photocatalysis-based energy harvesting and extended release in the dark enables temporally controlled redox initiation of polymer syntheses under low-intensity short exposure conditions and permits visible-light-mediated synthesis of polymers at least 1 order of magnitude thicker than achievable with conventional photoinitiated formulations and irradiation regimes

Organocatalyzed Atom Transfer Radical Polymerization Using <i>N</i>‑Aryl Phenoxazines as Photoredox Catalysts

<i>N</i>-Aryl phenoxazines have been synthesized and introduced as strongly reducing metal-free photoredox catalysts in organocatalyzed atom transfer radical polymerization for the synthesis of well-defined polymers. Experiments confirmed quantum chemical predictions that, like their dihydrophenazine analogs, the photoexcited states of phenoxazine photoredox catalysts are strongly reducing and achieve superior performance when they possess charge transfer character. We compare phenoxazines to previously reported dihydrophenazines and phenothiazines as photoredox catalysts to gain insight into the performance of these catalysts and establish principles for catalyst design. A key finding reveals that maintenance of a planar conformation of the phenoxazine catalyst during the catalytic cycle encourages the synthesis of well-defined macromolecules. Using these principles, we realized a core substituted phenoxazine as a visible light photoredox catalyst that performed superior to UV-absorbing phenoxazines as well as previously reported organic photocatalysts in organocatalyzed atom transfer radical polymerization. Using this catalyst and irradiating with white LEDs resulted in the production of polymers with targeted molecular weights through achieving quantitative initiator efficiencies, which possess dispersities ranging from 1.13 to 1.31

Structure–Property Relationships for Tailoring Phenoxazines as Reducing Photoredox Catalysts

Through the study of structure–property relationships using a combination of experimental and computational analyses, a number of phenoxazine derivatives have been developed as visible light absorbing, organic photoredox catalysts (PCs) with excited state reduction potentials rivaling those of highly reducing transition metal PCs. Time-dependent density functional theory (TD-DFT) computational modeling of the photoexcitation of <i>N</i>-aryl and core modified phenoxazines guided the design of PCs with absorption profiles in the visible regime. In accordance with our previous work with <i>N</i>,<i>N</i>-diaryl dihydrophenazines, characterization of noncore modified <i>N</i>-aryl phenoxazines in the excited state demonstrated that the nature of the <i>N</i>-aryl substituent dictates the ability of the PC to access a charge transfer excited state. However, our current analysis of core modified phenoxazines revealed that these molecules can access a different type of CT excited state which we posit involves a core substituent as the electron acceptor. Modification of the core of phenoxazine derivatives with electron-donating and electron-withdrawing substituents was used to alter triplet energies, excited state reduction potentials, and oxidation potentials of the phenoxazine derivatives. The catalytic activity of these molecules was explored using organocatalyzed atom transfer radical polymerization (O-ATRP) for the synthesis of poly­(methyl methacrylate) (PMMA) using white light irradiation. All of the derivatives were determined to be suitable PCs for O-ATRP as indicated by a linear growth of polymer molecular weight as a function of monomer conversion and the ability to synthesize PMMA with moderate to low dispersity (dispersity less than or equal to 1.5) and initiator efficiencies typically greater than 70% at high conversions. However, only PCs that exhibit strong absorption of visible light and strong triplet excited state reduction potentials maintain control over the polymerization during the entire course of the reaction. The structure–property relationships established here will enable the application of these organic PCs for O-ATRP and other photoredox-catalyzed small molecule and polymer syntheses