Matthew N. Grayson

• PhD
• Senior Lecturer (Associate Professor) at University of Bath

The calculation of transition state (TS) geometries is essential for understanding reaction mechanisms and rational synthetic methodology design. However, traditional methods like density functional theory (DFT) are often too computationally expensive for large-scale TS identification and are significantly slower than high-throughput experimental s...

Correction for ‘Distortion/interaction analysis via machine learning’ by Samuel G. Espley et al., Digital Discovery, 2024, 3, 2479–2486, https://doi.org/10.1039/D4DD00224E.

The calculation of transition state (TS) geometries is essential for understanding reaction mechanisms and rational synthetic methodology design. However, traditional methods like density functional theory (DFT) are often too computationally expensive for large-scale TS identification and are significantly slower than high-throughput experimental s...

The calculation of transition state (TS) geometries is essential for understanding reaction mechanisms and rational synthetic methodology design. However, traditional methods like density functional theory (DFT) are often too computationally expensive for large-scale TS identification and are significantly slower than high-throughput experimental s...

Machine learning (ML) models have provided a highly efficient pathway to quantum mechanical accurate reaction barrier predictions. Previous approaches have, however, stopped at prediction of these barriers instead of developing predictive capabilities in reactivity analysis tasks such as distortion/interaction–activation strain analysis. Such metho...

Machine learning (ML) models have provided a highly efficient pathway to quantum mechanical accurate reaction barrier predictions. Previous approaches have, however, stopped at prediction of these barriers instead of developing predictive capabilities in reactivity analysis tasks such as distortion/interaction-activation strain analysis. Such metho...

Machine learning (ML) can deliver rapid and accurate reaction barrier predictions for use in rational reactivity design. However, model training requires large data sets of typically thousands or tens of thousands of barriers that are very expensive to obtain computationally or experimentally. Furthermore, bespoke data sets are required for each re...

Machine learning (ML) models can, once trained, make reaction barrier predictions in seconds, which is orders of magnitude faster than quantum mechanical (QM) methods such as density functional theory (DFT). However, these ML models need to be trained on large datasets of typically thousands of expensive, high accuracy barriers and do not generalis...

The synergistic use of (organo)photoredox catalysts with hydrogen-atom transfer (HAT) cocatalysts has emerged as a powerful strategy for innate C(sp3)-H bond functionalization, particularly for C-H bonds α- to nitrogen. Azide ion (N3-) was recently identified as an effective HAT catalyst for the challenging α-C-H alkylation of unprotected, primary...

Quaternary benzylic centers are accessed with high atom and step economy by Ir-catalyzed alkene hydroarylation. These studies provide unique examples of the use of non-polarized 1,1-disubstituted alkenes in branch selective Murai-type hydro(hetero)arylations. Detailed mechanistic studies have been undertaken, and these indicate that the first irrev...

Current models for oxazaborolidine-catalyzed transition-state structures are determined by C-H···O-B and C-H···O═S formyl hydrogen bonding between the electrophile and catalyst. However, selectivity in the oxazaborolidine-catalyzed Mukaiyama aldol cannot be fully rationalized using these models. Combined density functional theory and noncovalent in...

Modern QM modelling methods, such as DFT, have provided detailed mechanistic insights into countless reactions. However, their computational cost inhibits their ability to rapidly screen large numbers of substrates and catalysts in reaction discovery. For a C-C bond forming nitro-Michael addition, we introduce a synergistic semi-empirical quantum m...

Plastic pollution continues to worsen globally in volume and complexity. The complexity in plastic production, use and disposal is significant, highlighting the importance of clear communication to consumers. Yet despite this, poor plastic labelling is clear, evident from poor waste management metrics even in the most equipped countries. Plastic la...

Here, we compare the relative performances of different force fields for conformational searching of hydrogen-bond-donating catalyst-like molecules. We assess the force fields by their predictions of conformer energies, geometries, low-energy, nonredundant conformers, and the maximum numbers of possible conformers. Overall, MM3, MMFFs, and OPLS3e h...

A synthetic study into the catalytic hydrogen/deuterium (H/D) exchange of 1° silanes, 2° silanes, and 3° siloxanes is presented, facilitated by iron-β-diketiminato complexes (1a and 1b). Near-complete H/D exchange is observed for a variety of aryl- and alkyl-containing hydrosilanes and hydrosiloxanes. The reaction tolerates alternative hydride sour...

Application of machine learning (ML) to the prediction of reaction activation barriers is a new and exciting field for these algorithms. The works covered here are specifically those in which ML is trained to predict the activation energies of homogeneous chemical reactions, where the activation energy is given by the energy difference between the...

Communication of information through the global switching of conformation in synthetic molecules has hitherto entailed the inversion of chirality. Here, we report a class of oligomer through which information may be communicated through a global reversal of polarity. Ethylene-bridged oligoureas are constitutionally symmetrical, conformationally fle...

Manipulating the stereochemistry of polymers is a powerful method to alter their physical properties. Despite the chirality of monosaccharides, reports on the impact of stereochemistry in natural polysaccharides and synthetic carbohydrate polymers remain absent. Herein, we report the cocrystallisation of regio‐ and stereoregular polyethers derived...

The mechanism of the asymmetric BINOL-derived hydroxyl carboxylic acid catalyzed allylboration of benzaldehyde was investigated using density functional theory calculations. A new reaction model is proposed, and the roles of the two Brønsted acidic sites of the catalyst elucidated. Catalyst distortion was found to be a key factor in determining ste...

This review aims to examine literature where different force fields are compared by their performances in conformational analysis and searching of organic molecules. Conformational analysis studies are those where energies and/or geometries of conformers are evaluated with force fields; the closer the values are to experiment or ab initio calculati...

Animal testing remains a contentious ethical issue in predictive toxicology. Thus, a fast, versatile, low-cost quantum chemical model is presented for predicting the risk of Ames mutagenicity in a series of 1,4 Michael acceptor type compounds. This framework eliminates the need for transition state calculations, and uses an intermediate structure t...

Synthetic carbohydrate polyethers, which are polysaccharide mimics, are synthesised by regioregular anionic ring‐opening polymerisation of oxetanes produced from d‐ or l‐xylose. By exploiting the chirality of xylose and varying stereochemical composition, the crystallinity of the resulting materials can be controlled. Mixing together homochiral pol...

Fasamycin natural products are biosynthetic precursors of the formicamycins. Both groups of compounds are polyketide natural products that exhibit potent antibacterial activity despite displaying different three-dimensional topologies. We show here that transformation of fasamycin into formicamycin metabolites requires two gene products and occurs...

A practical, catalytic entry to α,α,α‐trisubstituted (α‐tertiary) primary amines by C−H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100 % atom‐economy. Our strategy, wh...

The first example of enantioselective S−H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee) and yields (up to 97 %) are achieved for 31 examples in S−H insertion reactions of aryl thiols and α‐carbonyl sulfoxonium ylides.

Catalytic strategies for the α‐C−H functionalisation of primary amines are a major challenge in organic synthesis. A photocatalytic protocol for the α‐C−H alkylation of unprotected primary amines that is amenable to the direct synthesis of α‐tertiary primary amines is reported. This process is readily scalable in continuous flow to provide access t...

A method has been developed to reliably quantify the isotopic composition of liquid water, requiring only immersion of a ‘ReactIR’ probe in the sample under test. The accuracy and robustness of this method has been extensively tested using a deuterium/protium system, and substantial improvements in sensitivity were obtained using highly novel chemi...

The first enantioselective S−H insertion reaction of α‐carbonyl sulfoxonium ylides was developed under thiourea catalysis. Up to 95 % ee and 97 % isolated yields were obtained in 31 examples. Abstract The first example of enantioselective S−H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellen...

A practical, catalytic entry to α,α,α‑trisubstituted (α‑tertiary) primary amines by C–H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100% atom-economy. Our strategy, whi...

The Sondheimer dialkyne reagent has previously been employed in strain-promoted double-click cycloadditions with bis-azide peptides to generate stapled peptide inhibitors of protein–protein interactions. The substituted variants of the Sondheimer dialkyne can be used to generate functionalized stapled peptide inhibitors with improved biological pro...

Assessing the safety of new chemicals, without introducing the need for animal testing, is a task of great importance. The Ames test, a widely used bioassay to assess mutagenicity, can be an expensive, wasteful process with animal-derived reagents. Existing in silico methods for the prediction of Ames test results are traditionally based on chemica...

Alkenyl boronic esters are important reagents in organic synthesis. Herein, we report that these valuable products can be accessed by the homologation of boronic esters with lithiated epoxysilanes. Aliphatic and electron‐rich aromatic boronic esters provided vinylidene boronic esters in moderate to high yields, while electron‐deficient aromatic and...

Auf verschiedenen Wegen: Vinylidenborsäureester können durch Homologisierung von Borsäureestern mit lithiiertem Epoxysilan in einem Prozess erhalten werden, bei dem die Selektivität für den Vinylborsäureester oder das Vinylsilanprodukt von der Anionenstabilisierungsfähigkeit der R‐Gruppe abhängt. Die Methode wurde für eine kurze stereoselektive Syn...

The first catalytic enantioselective pinacol rearrangement was reported by Antilla and co-workers in 2010. The reaction was catalyzed by a chiral phosphoric acid and resulted in high levels of enantioselectivity (up to 96% ee). The present study uses Density Functional Theory to investigate the mechanism and origins of stereoselectivity of this imp...

The Ames mutagenicity assay is a long established in vitro test to measure the mutagenicity potential of a new chemical used in regulatory testing globally. One of the key computational approaches to modelling the Ames assay relies on the formation of chemical categories based on the different electrophilic compounds that are able to react directly...

The 50-year-old allylboration reaction has seen dramatic developments since the dawn of the new century after the first catalytic asymmetric versions came into play. In the past decade alone, several methodologies capable of achieving the desired homoallylic alcohols in over 90% ee have been developed. This review focuses on the chiral Brønsted aci...

CH···O hydrogen bonds involving formyl groups have been invoked as a crucial factor controlling many asymmetric transformations. We conducted quasi-classical direct molecular dynamics simulations on the phosphoric acid-catalyzed allylboration of benzaldehyde to understand the synergy between the phosphoric acid OH···O hydrogen bond and the secondar...

CH···O hydrogen bonds involving formyl groups have been invoked as a crucial factor controlling many asymmetric transformations. We have conducted quasi-classical direct molecular dynamics simulations on the phosphoric acid-catalyzed allylboration of benzaldehyde to understand the synergy between the phosphoric acid OH···O hydrogen bond and the sec...

We report density functional theory calculations which examine the mechanism and origins of stereoselectivity of Soós’ landmark discovery from 2005 that cinchona thioureas catalyze the asymmetric Michael addition of nitroalkanes to enones. We show that the electrophile is activated by the catalyst’s protonated amine and that the nucleophile binds t...

The cinchona alkaloid-derived urea-catalyzed asymmetric conjugate addition of aromatic thiols to cycloalkenones was studied using density functional theory (DFT). Deprotonation of the thiol gives a protonated amine that activates the electrophile by Brønsted acid catalysis while the urea group binds the nucleophilic thiolate by hydrogen bonding. Th...

Modern density functional theory and powerful contemporary computers have made it possible to explore complex reactions of value in organic synthesis. We describe recent explorations of mechanisms and origins of stereoselectivities with density functional theory calculations. The specific functionals and basis sets that are routinely used in comput...

Chiral Brønsted acid-catalyzed allyl(propargyl)boration of ortho-alkynyl benzaldehydes gives rise to ω-alkynyl homoallylic(homopropargylic)alcohols that can be further transformed to complex molecular scaffolds via subsequent hydroalkoxylation, RCEYM or intramolecular PKR. Optimizations of each two-step transformation is reported. A strong dependen...

Wynberg's report from 1977 that natural cinchona alkaloids catalyze the asymmetric conjugate addition of aromatic thiols to cycloalkenones is a landmark discovery in hydrogen bonding organocatalysis. Wynberg proposed that this reaction proceeded via the formation of a thiolate-alkylammonium tight ion pair and activation of the enone electrophile by...

Aurovertins are fungal polyketides that exhibit potent inhibition of ATP synthase. Aurovertins contain a 2,6-dioxabicyclo[3.2.1]-octane ring that is proposed to be derived from a polyene precursor through regioselective oxidations and epoxide openings. In this study, we identified only four enzymes are required to produce aurovertin E 4. The core p...

The catalyst generated in situ from RuH2(CO)(PPh3)3, (S)-SEGPHOS, and a chiral phosphoric acid promotes asymmetric hydrohydroxyalkylation of butadiene and affords enantioenriched α-methyl homoallylic alcohols. The observed diastereo- and enantioselectivities are determined by both the chiral phosphine and chiral phosphate ligands. Density functiona...

The reaction of tryptamine and (2-oxo-cyclohexyl)-acetic acid can be catalyzed by 3,3'-Bis(triphenylsilyl)-1,1'-bi-2-naphthol phosphoric acid to give an asymmetric beta-carboline. This reaction was first studied by Holloway et al. but their mechanistic work did not explain the high stereoselectivity achieved. This study uses density functional theo...

Density functional theory calculations suggest that asymmetric boronate addition to o-quinone methides proceeds via a Lewis-acid catalyzed process through a closed six-membered transition structure. The BINOL-derived catalyst undergoes an exchange process with the original ethoxide boronate ligands. This activation mode successfully accounts for th...

Two base mediated cascade rearrangement reactions of diallyl ethers were developed leading to selective [2,3]-Wittig-oxy-Cope and isomerization-Claisen rearrangements. Both diaryl and aryl-silyl substituted 1,3-substituted propenyl substrates were examined and each exhibits unique reactivity and different reaction pathways. Detailed mechanistic and...

1,1'-Bi-2-naphthol (BINOL)-derived catalysts catalyze the asymmetric propargylation of ketones. Density functional theory (DFT) calculations show that the reaction proceeds via a closed six-membered transition structure (TS) in which the chiral catalyst undergoes an exchange process with the original cyclic boronate ligand. This leads to a Lewis ac...

BINOL-derived phosphoric acids catalyze the asymmetric propargylation of aldehydes. DFT calculations showed that the reaction proceeds via a six-membered TS in which the catalyst Brønsted acidic site interacts with the pseudoaxial cyclic boronate oxygen and the phosphoryl oxygen interacts with the formyl proton. This model accurately predicts the s...

BINOL-derived phosphoric acids catalyze the asymmetric allylboration of aldehydes. DFT and QM/MM hybrid calculations showed that the reaction proceeds via a transition state involving both a hydrogen-bonding interaction from the catalyst hydroxyl group to the pseudoaxial oxygen of the cyclic boronate and a stabilizing interaction from the phosphory...