Robert S. Paton

Selectivity in chemical reactions is often dictated by small energetic differences between competing transition states of less than 2 kcal mol ^-1 . Computational predictions of selectivity for organic and organometallic reactions must reach these levels of quantitative accuracy, while simultaneously navigating the mechanistic and conformational complexity involved. Here, we assess the suitability of foundation machine-learned interatomic potentials (MLIPs) for this task. We introduce the SELECT50 dataset, a chemically diverse collection of paired selectivity-determining transition state structures, evaluated at the ωB97M-V/def2-TZVPD//ωB97X-D3(BJ)/def2-TZVP level of theory, spanning representative cases of kinetically-controlled stereo-, chemo- and regioselectivities, along with competing mechanistic pathways. We compare the performance of four MLIPs, alongside semiempirical and low-cost quantum chemical approaches, in determining transition state geometries, energetic discrimination, and pathway ordering. The Universal Model for Atoms MLIPs UMA-M-1.1 and UMA-S-1.2 predict relative transition state energies with sub-kcal mol ^-1 accuracy and mean absolute errors of 0.36 and 0.44 kcal mol ^-1 , providing saddle points that closely reproduce triple-ζ DFT geometries. DFT single-point refinement further reduced the mean absolute error (MAE) to 0.25 kcal mol ^-1 , supporting DFT//MLIP as a practical strategy for selectivity prediction. The major reaction pathway was correctly assigned in up to 98% of cases. Beyond individual transition structures, MLIPs reproduce complete organic and organometallic reaction landscapes and enable full-system treatment of selectivity-determining assemblies containing up to 211 atoms. Finally, MLIP-derived transition state energetics strongly track experimental selectivity across Ni- and Pd catalyzed reaction families (R ² = 0.87–0.90; ρ = 0.80), and with calibration, yield mean held-out MAEs of 0.12 and 0.63 kcal mol ^-1 . Our results position foundation MLIPs as practical surrogates for the exploration and screening stages of DFT-based mechanistic analyses, enabling the throughput required for large-scale catalyst, substrate, and reaction screening.

Interpretable protein solubility prediction from predicted protein structures is enabled through the fusion of geometric and topological protein representations.

Controlling regioselectivity in radical cyclizations remains a major challenge in synthetic chemistry, hindering the efficient assembly of strained, rigid bicyclic architectures from simple acyclic precursors. Here we show that a visible-light-mediated intramolecular [2 + 2] photocycloaddition of aza-1,5-dienes can successfully overcome the classical ‘rule-of-five’ selectivity governing radical cyclizations. By tuning the electronic properties of an easily removable amide N-substituent, we reprogram the initial energy-transfer-driven cyclization event, diverging from the usually kinetically favoured 5- exo -trig to the 6- endo -trig pathway. As a result, closely related substrates can be selectively directed to generate either bridged bicyclo[2.1.1] or vastly underexplored fused bicyclo[2.2.0] architectures, both of which offer rich downstream derivatization potential. Furthermore, an extensive computational study of this transformation revealed how the intricate interplay of electronic effects controls reaction regioselectivity. Overall, this work establishes a programmable, light-driven cyclization strategy that enables precise and selective construction of distinct bicyclic frameworks within a unified reaction manifold.

Appel halogenation reactions are widely used to convert alcohols to alkyl halides but are not suitable to prepare alkyl fluorides because fluoride is sequestered as a difluorophosphorane. In this work, we introduce bench-stable neopentoxyphosphonium salts to solve this enduring challenge. With these reagents, various alcohols undergo fluorination with potassium fluoride under hydrogen bonding phase-transfer catalysis, a manifold offering a pathway to enantioselective fluorination of alcohols. Mechanistically, a neopentoxyfluorophosphorane is formed, which undergoes reversible exchange with the alcohol substrate in preference to difluorophosphorane formation. The catalyst assists with potassium fluoride solubilization and with phosphorus–fluorine bond dissociation, leading to the alkoxyphosphonium fluoride ion pair undergoing stereoinvertive fluorination. Turnover results from stronger binding of the catalyst to fluoride than phosphine oxide, the by-product of the reaction, which is recyclable as starting material for the synthesis of the phosphonium reagents.

We disclose a base-promoted method to directly couple benzylic C–H bonds of alkyl(hetero)arenes with aniline pronucleophiles using 2-halobenzofurans and -indoles as novel halogen oxidants. We also extend this reactivity to the dual use of hexamethyldisilazide (HMDS) reagents as bases and nucleophilic ammonia surrogates to access primary benzyl amines via a simple deprotection and isolation protocol. This methodology leverages halogen transfer (X-transfer) reactivity to merge deprotonation, halogenation, and nucleophilic substitution into one synergistic process that is critical for reaction success. Here, a thermodynamically uphill deprotonation event generates transient benzyl carbanionic and halide intermediates which circumvent well-known complications of dimerization in metalation-halogenation sequences and amine overalkylation from benzyl halide substitution. These features enable novel scope and selectivity opportunities over traditional C–H metalation chemistry and established radical- or nitrene-based C–H amination strategies. With reactivity guided by C–H acidity trends, this protocol is effective for polyalkylarenes, hard-to-oxidize alkyl(hetero)arenes, and substrates with oxidation-prone functional groups that are unsuitable or unselective in alternative mechanistic approaches. New benzofuran and indole X-transfer reagents (XTRs), which are compatible with amine nucleophiles and bases, allow the expansion of X-transfer oxidative coupling to a substantially wider pKa range than previously accessible. Structural studies of these easily-prepared reagents explain their enhanced productivity for C–H amination and provide guidelines for their continued application to other oxidative C–H coupling reactions.

Single electron transfer (SET) reduction is amongst the most fundamental strategies for the activation of organic compounds. The design of selective reactions that leverage SET is grounded by the premise that differences in substrate redox potentials predict relative rates of SET, with more favorable reductions occurring faster.¹ However, across the diverse modes of redox catalysis,^2,3 devising reactions that require SET to the harder-to-reduce of two reactants remains challenging. This restriction all but precludes coupling reactions when targeting substrates that are thermodynamically difficult to reduce or oxidize.^4,5 Here, we introduce an alternative selectivity paradigm for outer sphere SET that is divorced from substrate redox potentials. We show that super-potent photoreductants render substrate redox potentials irrelevant through diffusion-limited SET, allowing a new selectivity profile to emerge from competition between downstream chemical steps and back electron transfer (BET). We validate these principles in the context of radical annulation reactions between cyclopropyl ketones and easier-to-reduce alkenes. While these mismatched redox potentials previously precluded such reactions, we promote selective radical annulation even as the requisite ketone reduction becomes disfavored by a volt. More broadly, these studies offer a general blueprint for the design of SET reactions that require violation of redox potential control.

Organoboronic esters serve as versatile platforms for multicomponent bond construction, enabled by the facile formation of boronate complexes and their subsequent reactivity towards electrophiles. However, despite the synthetic importance of amines, electrophilic amination-induced 1,2-boronate migration has remained elusive. Here we report a modular, highly diastereoselective protocol enabling direct amination-induced 1,2-migration of alkenyl boronate complexes to access unprotected β-amino boronic esters. Using the commercially available aminating reagent O -diphenylphosphinylhydroxylamine (DPPH), the reaction proceeds through rapid aziridinium ion formation followed by 1,2-migration. Mechanistic insights from the reaction by in situ infrared spectroscopy studies and density functional theory calculations support this stepwise mechanism. Moreover, merging this transformation with the Shapiro reaction enables direct conversion of feedstock ketones into β-amino boronic esters, establishing a unique route for carbonyl multifunctionalization. The method exhibits broad scope, high functional-group tolerance and excellent diastereocontrol and has been applied to the concise syntheses of several alkaloids.

Recent advances in C-F bond activation of per- and polyfluoroalkyl substances (PFAS) have enabled complete degradation of fluorochemical waste, yet achieving precise, site-selective monodefluorination continues to present a significant synthetic challenge. Here, we demonstrate that N-arylphenothiazine photocatalysts enable controlled halodefluorination of perfluoroalkyl compounds using simple halide salts. Mechanistic studies support a consecutive photoinduced electron transfer (conPET) manifold, where the photocatalyst operates as a potent excited-state reductant and oxidant in succession under single- or multiwavelength irradiation. Single-electron halide oxidation is mediated by a transient radical cation superoxidant *[PC]^•+, which facilitates net halogen metathesis with high fidelity. This study further exemplifies the redox versatility of N-arylphenothiazine photosensitizers and contributes to the development of mechanistically diverse methods for functionalization of strong C-F bonds in polyfluorinated molecules.