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Redox catalysis has been broadly utilized in electrochemical synthesis due to its kinetic advantages over direct electrolysis. The appropriate choice of redox mediator can avoid electrode passivation and overpotential, which strongly inhibit the efficient activation of substrates in electrolysis. Despite the benefits brought by redox catalysis, establishing the precise nature of substrate activation remains challenging. Herein, we determine that a Co(i) complex bearing two N,N,N-tridentate ligands acts as a competent redox catalyst for the reduction of benzyl bromide substrates. Kinetic studies combining electroanalytical techniques with multivariable linear-regression analysis were conducted, disclosing an outer-sphere electron-transfer mechanism, which occurs in concert with C–Br bond cleavage. Furthermore, we apply a pattern recognition platform to distinguish between mechanisms in the activation of benzyl bromides, found to be dependent on the ligation state of the cobalt(i) center and ligand used., Through kinetic studies combining electroanalytical techniques with multivariable linear-regression (MLR) analysis, a pattern recognition platform is established to determine the electron-transfer mechanism (inner-sphere or outer-sphere) of an electrochemical reduction of benzyl bromides, mediated by different cobalt complexes.

A range of electroanalytical tools can be applied to studying redox reactions, probing key mechanistic questions in synthetic chemistry., Monitoring reactive intermediates can provide vital information in the study of synthetic reaction mechanisms, enabling the design of new catalysts and methods. Many synthetic transformations are centred on the alteration of oxidation states, but these redox processes frequently pass through intermediates with short life-times, making their study challenging. A variety of electroanalytical tools can be utilised to investigate these redox-active intermediates: from voltammetry to in situ spectroelectrochemistry and scanning electrochemical microscopy. This perspective provides an overview of these tools, with examples of both electrochemically-initiated processes and monitoring redox-active intermediates formed chemically in solution. The article is designed to introduce synthetic organic and organometallic chemists to electroanalytical techniques and their use in probing key mechanistic questions.

A regioselective and enantioselective palladium-catalyzed relay Heck alkenylation of alkenylbenzene derivatives to construct remote stereocenters is disclosed. Various β-substituted styrenes were readily obtained in moderate yields with good to excellent levels of enantioselectivity. This strategy provides rapid access to enantioenriched δ, e, ζ, and η-alkenyl aryl compounds from simple starting materials. Mechanistic studies suggest that termination of the relay reaction is controlled by affinity of the arene for the Pd complex during migration.

Quantitative structure–activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst.

The utilization of physical organic molecular descriptors for the quantitative description of reaction outcomes in multivariate linear regression models is demonstrated as an effective tool for a priori prediction and mechanistic interrogation., Multivariate Linear Regression (MLR) models utilizing computationally-derived and empirically-derived physical organic molecular descriptors are described in this review. Several reports demonstrating the effectiveness of this methodological approach towards reaction optimization and mechanistic interrogation are discussed. A detailed protocol to access quantitative and predictive MLR models is provided as a guide for model development and parameter analysis.

This work combines the thermostable alcohol dehydrogenase D (AdhD) from Pyrococcus furiosus and the organic electrocatalyst TEMPO to create a bifunctional catalyst that selectively oxidizes primary and secondary alcohols. The active sites function independently, can be switched on by changing reaction conditions, and can selectively oxidize a mixture of 1- and 2-butanol. The NAD+-dependent enzyme catalyses the secondary alcohol oxidation at a rate 3-fold faster than the primary alcohol, while the covalently attached 4-glycidyl-TEMPO oxidizes 1-butanol and has negligible activity toward 2-butanol. This hybrid catalytic approach has potential value for selective alcohol oxidations as well as other electrochemical and enzymatic multistep processes in energy conversion and chemical synthesis.

The development of a hybrid, tri-catalytic architecture is demonstrated by immobilizing MWCNTs, TEMPO-modified linear poly(ethylenimine) and oxalate decarboxylase on an electrode to enable enhanced electrochemical oxidation of glycerol. This immobilized, hybrid catalytic motif results in a synergistic 3.3-fold enhancement of glycerol oxidation and collects up to 14 electrons per molecule of glycerol.

A mild palladium-catalyzed ligand-controlled regioselective 1,3-arylfluorination of 2[H]-chromenes has been developed. The products with a syn-1,3 substitution pattern were obtained with high enantiomeric excess using a PyrOx ligand, wherein the utility of these pyranyl-fluorides was further demonstrated through their participation in a diastereoselective C-C bond forming reaction. Ligand dependent divergent formation of both the 1,3- and 1,2- alkene difunctionalization products was observed. The nature of this bifurcation was investigated through experimental studies in combination with computational and statistical analysis tools. Ultimately, the site selectivity was found to rely on ligand denticity and metal electrophilicity, the electronics of the boronic acid, and the donor ability of the directing group in the substrate.

The intermolecular enantioselective C–H functionalization with acceptor-only metallocarbenes is reported using a new family of Ir(III)-bis(imidazolinyl)phenyl catalysts, developed based on the interplay of experimental and computational insights. The reaction is tolerant of a variety of diazoacetate precursors and is found to be heavily influenced by the steric and electronic properties of the substrate. Phthalan and dihydrofuran derivatives are functionalized in good yields and excellent enantioselectivities.

Achieving selective C–H functionalization is a significant challenge that requires discrimination between many similar C–H bonds., Achieving selective C–H functionalization is a significant challenge that requires discrimination between many similar C–H bonds. Yet, reaction systems employing Rh2(DOSP)4 and Rh2(BPCP)4 were recently demonstrated to afford high levels of selectivity in the C–H insertion of carbenes into toluene-derived substrates. Herein, we explore the origin of this selectivity through a systematic analysis of substrate and reagent features that alter levels of selectivity from 20 : 1 to 1 : 610 for secondary (or tertiary)-to-primary benzylic C–H functionalization of toluene derivatives. Describing this variation using infrared vibrations and point charges, we have developed a mathematical model from which are identified features of the systems that determine levels of site-selectivity and are applied as predictive factors to describe the selectivity behavior of new substrate/reagent combinations.

Palladium-catalyzed 1,4-difunctionalizations of isoprene that produce skipped polyenes are reported., Palladium-catalyzed 1,4-difunctionalizations of isoprene that produce skipped polyenes are reported. Complex isomeric product mixtures are possible as a result of the difficult-to-control migratory insertion of isoprene into a Pd–alkenyl bond, but good site selectivity has been achieved using easily accessible pyrox ligands. Mechanistic studies suggest that the control of insertion is the result of the unique electronic asymmetry and steric properties of the ligand.

Pd-catalyzed allylic relay Suzuki cross-coupling reactions of secondary alkyl tosylates, featuring a sterically-hindered oxidative addition and precise control of β-hydride elimination, are reported. The identification of a linear free energy relationship between the relative rates of substrate consumption and the electronic nature of the substrate alkene suggests that the oxidative addition requires direct alkene involvement. A study of the effect of alkyl chain length on the reaction outcome supports a chelation-controlled oxidative addition.

Alkene difunctionalization, the addition of two functional groups across a double bond, exemplifies a class of reactions with significant synthetic potential. This emerging area examines recent developments of palladium-catalyzed difunctionalization reactions, with a focus on mechanistic strategies that allow for functionalization of a common palladium alkyl intermediate.

Palladium(II)-catalyzed oxidations constitute a paramount reaction class but have remained immature over the past few decades. Recently, this field has reappeared at the forefront of organometallic catalysis. This emerging area article outlines recent developments in palladium(II)-catalyzed oxidation chemistry with discussion of potential future growth.