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Benzothiophenes, activated by oxidation to the correspondingS‐oxides, undergo C−H/C−H‐type coupling with phenols to give C4 arylation products. While an electron‐withdrawing group at C3 of the benzothiophene is important, the process operates without a directing group and a metal catalyst, thus rendering it compatible with sensitive functionalities—e.g. halides and formyl groups. Quantum chemical calculations suggest a formal stepwise mechanism involving heterolytic cleavage of an aryloxysulfur species to give a π‐complex of the corresponding benzothiophene and a phenoxonium cation. Subsequent addition of the phenoxonium cation to the C4 position of the benzothiophene is favored over the addition to C3; Fukui functions predict that the major regioisomer is formed at the more electron‐rich position between C3 and C4. Varied selective manipulation of the benzothiophene products showcase the synthetic utility of the metal‐free arylation process.

We report that O‐selective arylation of 2‐ and 4‐pyridones with arylboronic acids is affected by a modular, bismacycle‐based system. The utility of this umpolung approach to pyridyl ethers, which is complementary to conventional methods based on S_NAr or cross‐coupling, is demonstrated through the concise synthesis of Ki6783 and picolinafen, and the formal synthesis of cabozantib and golvatinib. Computational investigations reveal that arylation proceeds in a concerted fashion via a 5‐membered transition state. The kinetically‐controlled regioselectivity for O‐arylation—which is reversed relative to previous Bi^V‐mediated pyridone arylations—is attributed primarily to the geometric constraints imposed by the bismacyclic scaffold.

The importance of modified peptides and proteins for applications in drug discovery, and for illuminating biological processes at the molecular level, is fueling a demand for efficient methods that facilitate the precise modification of these biomolecules. Herein, we describe the development of a photocatalytic method for the rapid and efficient dimerization and site-specific functionalization of peptide and protein diselenides. This methodology, dubbed the photocatalytic diselenide contraction, involves irradiation at 450 nm in the presence of an iridium photocatalyst and a phosphine and results in rapid and clean conversion of diselenides to reductively stable selenoethers. A mechanism for this photocatalytic transformation is proposed, which is supported by photoluminescence spectroscopy and density functional theory calculations. The utility of the photocatalytic diselenide contraction transformation is highlighted through the dimerization of selenopeptides, and by the generation of two families of protein conjugates via the site-selective modification of calmodulin containing the 21^stamino acid selenocysteine, and the C-terminal modification of a ubiquitin diselenide.

AQME, automated quantum mechanical environments, is a free and open‐source Python package for the rapid deployment of automated workflows using cheminformatics and quantum chemistry. AQME workflows integrate tasks performed across multiple computational chemistry packages and data formats, preserving all computational protocols, data, and metadata for machine and human users to access and reuse. AQME has a modular structure of independent modules that can be implemented in any sequence, allowing the users to use all or only the desired parts of the program. The code has been developed for researchers with basic familiarity with the Python programming language. The CSEARCH module interfaces to molecular mechanics and semi‐empirical QM (SQM) conformer generation tools (e.g., RDKit and Conformer–Rotamer Ensemble Sampling Tool, CREST) starting from various initial structure formats. The CMIN module enables geometry refinement with SQM and neural network potentials, such as ANI. The QPREP module interfaces with multiple QM programs, such as Gaussian, ORCA, and PySCF. The QCORR module processes QM results, storing structural, energetic, and property data while also enabling automated error handling (i.e., convergence errors, wrong number of imaginary frequencies, isomerization, etc.) and job resubmission. The QDESCP module provides easy access to QM ensemble‐averaged molecular descriptors and computed properties, such as NMR spectra. Overall, AQME provides automated, transparent, and reproducible workflows to produce, analyze and archive computational chemistry results. SMILES inputs can be used, and many aspects of tedious human manipulation can be avoided. Installation and execution on Windows, macOS, and Linux platforms have been tested, and the code has been developed to support access through Jupyter Notebooks, the command line, and job submission (e.g., Slurm) scripts. Examples of pre‐configured workflows are available in various formats, and hands‐on video tutorials illustrate their use.

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Data Science > Chemoinformatics

[3+2] cycloadditions of nitroolefins have emerged as a selective and catalyst‐free alternative for the synthesis of 1,2,3‐triazoles from azides. We describe mechanistic studies into the cycloaddition/rearomatization reaction sequence. DFT calculations revealed a rate‐limiting cycloaddition step proceeding via an asynchronous TS with high kinetic selectivity for the 1,5‐triazole. Kinetic studies reveal a second‐order rate law, and¹³C kinetic isotopic effects at natural abundance were measured with a significant normal effect at the conjugated olefinic centers of 1.0158 and 1.0216 at the α and β‐carbons of β‐nitrostyrene. Distortion/interaction‐activation strain and energy decomposition analyses revealed that the major regioisomeric pathway benefits from an earlier and less‐distorted TS, while intermolecular interaction terms dominate the preference for 1,5‐ over 1,4‐cycloadducts. In addition, the major regioisomer also has more favorable electrostatic and dispersion terms. Additionally, while static DFT calculations suggest a concerted but highly asynchronousEi‐type HNO₂elimination mechanism, quasiclassical direct‐dynamics calculations reveal the existence of a dynamic intermediate.

A bifunctional iminophosphorane (BIMP)‐catalysed enantioselective synthesis of α,β‐unsaturated cyclohexenones through a facially selective 1,3‐prototropic shift of β,γ‐unsaturated prochiral isomers, under mild reaction conditions and in short reaction times, on a range of structurally diverse substrates, is reported. α,β‐Unsaturated cyclohexenone products primed for downstream derivatisation were obtained in high yields (up to 99 %) and consistently high enantioselectivity (up to 99 %ee). Computational studies into the reaction mechanism and origins of enantioselectivity, including multivariate linear regression of TS energy, were carried out and the obtained data were found to be in good agreement with experimental findings.