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“How strong is this Lewis acid?” is a question researchers often approach by calculating its fluoride ion affinity (FIA) with quantum chemistry. Here, we present FIA49k, an extensive FIA dataset with 48,986 data points calculated at the RI‐DSD‐BLYP‐D3(BJ)/def2‐QZVPP//PBEh‐3c level of theory, including 13 differentp‐block atoms as the fluoride accepting site. The FIA49k dataset was used to train FIA‐GNN, two message‐passing graph neural networks, which predict gas and solution phase FIA values of molecules excluded from training with a mean absolute error of 14 kJ mol⁻¹(r²=0.93) from the SMILES string of the Lewis acid as the only input. The level of accuracy is notable, given the wide energetic range of 750 kJ mol⁻¹spanned by FIA49k. The model's value was demonstrated with four case studies, including predictions for molecules extracted from the Cambridge Structural Database and by reproducing results from catalysis research available in the literature. Weaknesses of the model are evaluated and interpreted chemically. FIA‐GNN and the FIA49k dataset can be reached via a free web app (www.grebgroup.de/fia‐gnn).

 

Bond dissociation energetics underpin the thermodynamics of chemical transformations where bonds are broken or formed and can also be used to predict reaction rates and selectivities.

 

Abstract The control of tetrahedral carbon stereocentres remains a focus of modern synthetic chemistry and is enabled by their configurational stability. By contrast, trisubstituted nitrogen 1 , phosphorus 2 and sulfur compounds 3 undergo pyramidal inversion, a fundamental and well-recognized stereochemical phenomenon that is widely exploited 4 . However, the stereochemistry of oxonium ions—compounds bearing three substituents on a positively charged oxygen atom—is poorly developed and there are few applications of oxonium ions in synthesis beyond their existence as reactive intermediates 5,6 . There are no examples of configurationally stable oxonium ions in which the oxygen atom is the sole stereogenic centre, probably owing to the low barrier to oxygen pyramidal inversion 7 and the perception that all oxonium ions are highly reactive. Here we describe the design, synthesis and characterization of a helically chiral triaryloxonium ion in which inversion of the oxygen lone pair is prevented through geometric restriction to enable it to function as a determinant of configuration. A combined synthesis and quantum calculation approach delineates design principles that enable configurationally stable and room-temperature isolable salts to be generated. We show that the barrier to inversion is greater than 110 kJ mol −1 and outline processes for resolution. This constitutes, to our knowledge, the only example of a chiral non-racemic and configurationally stable molecule in which the oxygen atom is the sole stereogenic centre. 

Opening and reclosing pyridines enables selective halogenation at the 3-position of the ring. 

Abstract Biaryl scaffolds are privileged templates used in the discovery and design of therapeutics with high affinity and specificity for a broad range of protein targets. Biaryls are found in the structures of therapeutics, including antibiotics, anti-inflammatory, analgesic, neurological and antihypertensive drugs. However, existing synthetic routes to biphenyls rely on traditional coupling approaches that require both arenes to be prefunctionalized with halides or pseudohalides with the desired regiochemistry. Therefore, the coupling of drug fragments may be challenging via conventional approaches. As an attractive alternative, directed C−H activation has the potential to be a versatile tool to form para -substituted biphenyl motifs selectively. However, existing C–H arylation protocols are not suitable for drug entities as they are hindered by catalyst deactivation by polar and delicate functionalities present alongside the instability of macrocyclic intermediates required for para -C−H activation. To address this challenge, we have developed a robust catalytic system that displays unique efficacy towards para -arylation of highly functionalized substrates such as drug entities, giving access to structurally diversified biaryl scaffolds. This diversification process provides access to an expanded chemical space for further exploration in drug discovery. Further, the applicability of the transformation is realized through the synthesis of drug molecules bearing a biphenyl fragment. Computational and experimental mechanistic studies further provide insight into the catalytic cycle operative in this versatile C−H arylation protocol.