Regioselective aliphatic C-H functionalization using frustrated radical pairs.

Frustrated Lewis pairs (FLPs) are well documented for the activation of small molecules such as dihydrogen and carbon dioxide1-4. Although canonical FLP chemistry is heterolytic in nature, recent work has shown that certain FLPs can undergo single-electron transfer to afford radical pairs5. Owing to steric encumbrance and/or weak bonding association, these radicals do not annihilate one another, and they have thus been named frustrated radical pairs (FRPs). Notable preliminary results suggest that FRPs may be useful reagents in chemical synthesis6-8, although their applications remain limited. Here we demonstrate that the functionalization of C(sp3)-H bonds can be accomplished using a class of FRPs generated from disilazide donors and an N-oxoammonium acceptor. Together, these species undergo single-electron transfer to generate a transient and persistent radical pair capable of cleaving unactivated C-H bonds to furnish aminoxylated products. By tuning the structure of the donor, it is possible to control regioselectivity and tailor reactivity towards tertiary, secondary or primary C-H bonds. Mechanistic studies lend strong support for the formation and involvement of radical pairs in the target reaction.

Photocatalytic Anti-Markovnikov Hydroamination of Alkenes with Primary Heteroaryl Amines.

We report a light-driven method for the intermolecular anti-Markovnikov hydroamination of alkenes with primary heteroaryl amines. In this protocol, electron transfer between an amine substrate and an excited-state iridium photocatalyst affords an aminium radical cation (ARC) intermediate that undergoes C-N bond formation with a nucleophilic alkene. Integral to reaction success is the electronic character of the amine, wherein increasingly electron-deficient heteroaryl amines generate increasingly reactive ARCs. Counteranion-dependent reactivity is observed, and iridium triflate photocatalysts are employed in place of conventional iridium hexafluorophosphate complexes. This method exhibits broad functional group tolerance across 55 examples of N-alkylated products derived from pharmaceutically relevant heteroaryl amines.

A Physical Organic Approach towards Statistical Modeling of Tetrazole and Azide Decomposition.

Nitrogen atom-rich heterocycles and organic azides have found extensive use in many sectors of modern chemistry from drug discovery to energetic materials. The prediction and understanding of their energetic properties are thus key to the safe and effective application of these compounds. In this work, we disclose the use of multivariate linear regression modeling for the prediction of the decomposition temperature and impact sensitivity of structurally diverse tetrazoles and organic azides. We report a data-driven approach for property prediction featuring a collection of quantum mechanical parameters and computational workflows. The statistical models reported herein carry predictive accuracy as well as chemical interpretability. Model validation was successfully accomplished via tetrazole test sets with parameters generated exclusively in silico. Mechanistic analysis of the statistical models indicated distinct divergent pathways of thermal and impact-initiated decomposition.

Electrocatalysis as an enabling technology for organic synthesis.

Electrochemistry has recently gained increased attention as a versatile strategy for achieving challenging transformations at the forefront of synthetic organic chemistry. Electrochemistry's unique ability to generate highly reactive radical and radical ion intermediates in a controlled fashion under mild conditions has inspired the development of a number of new electrochemical methodologies for the preparation of valuable chemical motifs. Particularly, recent developments in electrosynthesis have featured an increased use of redox-active electrocatalysts to further enhance control over the selective formation and downstream reactivity of these reactive intermediates. Furthermore, electrocatalytic mediators enable synthetic transformations to proceed in a manner that is mechanistically distinct from purely chemical methods, allowing for the subversion of kinetic and thermodynamic obstacles encountered in conventional organic synthesis. This review highlights key innovations within the past decade in the area of synthetic electrocatalysis, with emphasis on the mechanisms and catalyst design principles underpinning these advancements. A host of oxidative and reductive electrocatalytic methodologies are discussed and are grouped according to the classification of the synthetic transformation and the nature of the electrocatalyst.

Working at the interfaces of data science and synthetic electrochemistry.

Electrochemistry is quickly entering the mainstream of synthetic organic chemistry. The diversity of new transformations enabled by electrochemistry is to a large extent a consequence of the unique features and reaction parameters in electrochemical systems including redox mediators, applied potential, electrode material, and cell construction. While offering chemists new means to control reactivity and selectivity, these additional features also increase the dimensionalities of a reaction system and complicate its optimization. This challenge, however, has spawned increasing adoption of data science tools to aid reaction discovery as well as development of high-throughput screening platforms that facilitate the generation of high quality datasets. In this Perspective, we provide an overview of recent advances in data-science driven electrochemistry with an emphasis on the opportunities and challenges facing this growing subdiscipline.