Trevor A. Hamlin

We present PyOrbb, an open‐source, user‐friendly Python‐based program that automates the analysis and visualization of orbital interaction mechanisms between molecular fragments or reactants, based on quantum‐chemical computations with the Amsterdam Density Functional (ADF) program. PyOrbb extracts the essential mixing patterns, presents them in an interactively adjustable orbital interaction diagram, and summarizes all relevant quantitative data in a convenient Excel spreadsheet for further analysis. The tool enables efficient interpretation of chemical bonding across a broad range of systems, including examples from organic, inorganic, and supramolecular chemistry. The application runs on macOS and Windows operating systems. PyOrbb is shown to accurately and rapidly visualize relevant bonding mechanisms from the often‐overwhelming output of density functional computations.

Catch bonds—dynamic molecular interactions whose lifetimes increase under mechanical load—are central to biological mechanotransduction but remain challenging to replicate synthetically. Here, we report a covalent catch-bonding mechanism in a low-molecular-weight motif based on hydroxyethyl phosphate (HEP) triesters. Our design uses force-mediated inhibition of a neighboring group participation (NGP) pathway: mechanical tension suppresses intramolecular assistance, thereby increasing the reaction barrier and prolonging bond lifetimes. Density Functional Theory calculations confirm that tensile force hinders the geometric contraction required for NGP, providing a mechanistic basis for catch-bond behaviour. Single-molecule force spectroscopy reveals that HEP triester lifetimes increase over threefold at 400 pN. This work establishes a molecular mechanism for engineering covalent catch bonds, offering opportunities to design force-responsive polymer networks. By translating a biological concept into a synthetic framework, our findings open new avenues for adaptive materials and mechanochemical sensing.

We have quantum chemically analyzed how substituents R affect the carboncarbon bond strength in 1,2‐disubstituted ethane, RH ₂ CCH ₂ R (R = H, CH ₃ , NH ₂ , OH, F), using density functional theory. Our quantitative MO bonding analyses reveal that the CC bond between the two RH ₂ C ^• radicals progressively weakens as the electron‐donating ability of the R group increases because of the occurrence of a lone‐pair shielded radical on RH ₂ C ^• . The lone‐pair type orbital amplitude on the carbon center arises from the interaction with a lone pair on the substituent R. The shielding of the carbon radical center and, thus, CC bond weakening is more pronounced as the substituent becomes less electronegative. Contrary to the commonly accepted rationale that electron‐donating groups R weaken the CC bond by stabilizing the resulting radical RH ₂ C ^• , our analyses show that all substituents, except R = F, destabilize the radical. The present findings demonstrate that the lone‐pair shielded radical features in a broader variety of organic radicals than previously assumed and can be used as a handle for tuning the bond strengths.

Radical addition reactions have become an indispensable tool for constructing carbon-carbon bonds in organic chemistry. Given the significance of these processes, it is imperative that the underlying rules governing odd electron C-C bond forming processes be better understood. This study explores the fundamental case of methyl radical addition reaction (MRAR) to monosubstituted ethylene derivatives (H₂C_β═C_αHR, with R = H, CHO, and NMe₂) using Density Functional Theory at ZORA-(U)OLYP/TZ2P. We quantitatively analyzed the factors governing regioselectivity and substituent effects using the Activation Strain Model and Energy Decomposition Analysis. Regarding regioselectivity, radical addition@β is universally favored over addition@α due to reduction in the buildup of unfavorable Pauli repulsion (ΔE_Pauli) and maximization of orbital interactions (ΔE_oi) with the β-carbon. Substituents modulate reactivity through electronic effects: NMe₂ (a representative electron-donating group) and CHO (a representative electron-withdrawing group) lower activation barriers with respect to the unsubstituted reactions due to improved orbital interactions. Among the substituents, CHO lowers the activation barrier for radical addition more than NMe₂ due to a change in the orbital interaction mechanism. By linking qualitative theories like Frontier Molecular Orbital Theory with detailed computational insights, this work advances the mechanistic understanding of radical addition reactions and provides a physically sound and intuitive basis for understanding these key transformations.

The binding affinities for a series of Lewis acids (LAs) to acrolein and azabutadiene were investigated using density functional theory calculations at ZORA-BLYP-D3(BJ)/TZ2P. In all systems, LAs favor σ-binding to the lone pair of nitrogen or oxygen, rather than π-binding to the C=C double bond. Activation strain and energy decomposition analyses reveal that σ-binding is preferred over π-binding due to reduced steric (Pauli) repulsion between the LA and the substrate. Furthermore, LAs σ-bind more strongly to the nitrogen of azabutadiene than to the oxygen of acrolein due to enhanced electrostatic and orbital interactions. In addition, the role of solvation in the σ-binding versus π-binding preference was also examined: the preference for σ-binding clearly remains and even increases for strong LAs, but for weak LAs such as I2, the preference for σ-binding diminishes in solvent, though σ-binding remains dominant. Lastly, analysis of I2 catalysis of a model Diels-Alder reaction indicates that the preferred transition state features σ-binding. Overall, π-binding appears to be more of a (theoretical) curiosity and is unlikely to play a dominant role in catalysis.

Radical addition reactions have become an indispensable tool for constructing carbon-carbon bonds in organic chemistry. Given the significance of these processes, it is imperative that the underlying rules governing odd electron C-C bond forming processes are better understood. This study explores the fundamental case of methyl radical addition reaction (MRAR) to monosubstituted ethylene derivatives (H2C=CHR, with R = H, CHO, and NMe2) using Density Functional Theory at ZORA-(U)OLYP/TZ2P. We quantitatively analyzed the factors governing regioselectivity and substituent effects using the Activation Strain Model and Energy Decomposition Analysis. Regarding regioselectivity, radical addition@ is universally favored over addition@ due to reduction in the buildup of unfavorable Pauli repulsion (ΔEPauli) and maximization of orbital interactions (ΔEoi) with the -carbon. Substituents modulate reactivity through electronic effects: both electron-donating groups (EDGs) like NMe2 and electron-withdrawing groups (EWGs) like CHO lower activation barriers with respect to the unsubstituted reactions due to improved orbital interactions. Among the substituents, the EWG lowers the activation barriers more than the EDG due to a change in the orbital interaction mechanism. By linking qualitative theories like Frontier Molecular Orbital Theory with detailed computational insights, this work advances the mechanistic understanding of radical addition reactions and provides a physically sound and intuitive basis for understanding these key transformations.

The enantioselective construction of small ring carbocycles provides organic chemists with an enduring challenge.¹ Despite their commercial importance, enantioselective synthetic routes towards alkylidenecyclopropanes (ACPs), a class of small ring carbocycles, remain underdeveloped.^2,3 Importantly, ACPs can be converted into cyclopropanes, a common feature in drug molecules (e.g. Nirmatrelvir, 1),⁴ as well as both naturally occurring and synthetic agrochemicals (e.q. permethrin 2).^5,6 We now describe the facile synthesis of highly enantioenriched alkylidenecyclopropanes through the use of a bifunctional iminophosphorane (BIMP) catalysed, stereo-controlled, strain-relieving deconjugation. Small modifications to the basic catalyst system were used to broaden the scope of the reaction to substrates containing ester, amide, phosphine oxide, and ketone functionalities. Through the design of a suitable substrate and re-tuning of the catalyst's iminophosphorane moiety, the transformation was effectively applied to the synthesis of a single stereoisomer of the commonplace insecticide permethrin as well as a range of cyclopropane-based insecticide cores. State-of-the-art computational studies were performed to provide detailed insight into the mechanistic pathway and origin of both diastereo- and enantioselectivities.

Radical additions to olefins and related π-systems are essential tools in the modern synthetic toolbox for forging C-C and C-X bonds. We report a systematic DFT study (ZORA-(U)OLYP/TZ2P) on methyl radical (H₃C^•) additions to H₂C═X substrates, where X is varied across elements from the tetrel (group 14: C, Si, Ge), pnictogen (group 15: N, P, As), and chalcogen (group 16: O, S, Se) groups. Our analysis reveals clear periodic trends: addition barriers at carbon decrease, and those at X increase from tetrels to chalcogens; reaction energies become less favorable across a period but more favorable down a group. Regioselectivity favors addition at X except for X = CH₂, NH, and O, where carbon attack dominates─consistent with experimental data. These trends arise from a balance of orbital interactions and Pauli repulsion, with the latter emerging as a key, yet underappreciated, factor governing radical reactivity and regioselectivity in π-systems.

The activation of small molecules is a crucial step in advancing sustainable chemistry, enabling key transformations in fine chemical synthesis and energy storage. While transition metals have traditionally dominated this field, main‐group elements—specifically metallylenes, which are heavier analogs of carbenes (silylenes, germylenes, stannylenes, and plumbylenes)—have emerged as viable alternatives due to their unique electronic properties and tunable reactivity. This review explores the mechanisms by which metallylenes activate small molecules, highlighting the influence of ligand design, electronic structure, and geometric factors. We discuss recent advances in the field, including computational insights into metallylene‐mediated bond activation and experimental demonstrations of their catalytic potential. Additionally, we examine follow‐up reactions such as hydrogenation and hydroboration, which illustrate the versatility of metallylenes in small‐molecule transformation. By providing a comprehensive overview of the latest developments, this review aims to bridge fundamental principles with potential applications, paving the way for metallylene‐based catalysis in sustainable chemistry.