C-H Insertion in Dirhodium Tetracarboxylate-Catalyzed Reactions despite Dynamical Tendencies toward Fragmentation: Implications for Reaction Efficiency and Catalyst Design.

Rh-catalyzed C-H insertion reactions to form β-lactones suffer from post-transition state bifurcations, with the same transition states leading to ketones and ketenes via fragmentation in addition to β-lactones. In such a circumstance, traditional transition state theory cannot predict product selectivity, so we employed molecular dynamics simulations to do so and provide a framework for rationalizing the origins of said selectivity. Weak interactions between the catalyst and substrate were studied using energy decomposition and noncovalent interaction analyses, which unmasked an important role of the 2-bromophenyl substituent that has been used in multiple β-lactone-forming C-H insertion reactions.

Elucidating the role of catalytic amino acid residues in the peptide-mediated silica oligomerization reaction mechanism.

Understanding the detailed mechanism by which the proteins of marine diatoms such as silaffins are able to control the morphology of silica oligomers has eluded synthetic chemists and materials scientists for decades. In this study, we use DFT calculations to determine how individual amino acid residues of silaffin catalyze silica dimerization. The reaction network for formation of a silica dimer was explored using several different small molecules, including water, guanidinium ions, and methylammonium ions, the latter two molecules representing analogs of arginine and lysine, both of which are known to play critical roles in enabling the catalytic function of naturally occurring protein and synthetic analogs of silaffin.

Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking.

Simulating drug binding and unbinding is a challenge, as the rugged energy landscapes that separate bound and unbound states require extensive sampling that consumes significant computational resources. Here, we describe the use of interactive molecular dynamics in virtual reality (iMD-VR) as an accurate low-cost strategy for flexible protein-ligand docking. We outline an experimental protocol which enables expert iMD-VR users to guide ligands into and out of the binding pockets of trypsin, neuraminidase, and HIV-1 protease, and recreate their respective crystallographic protein-ligand binding poses within 5-10 minutes.

Low dimensional representations along intrinsic reaction coordinates and molecular dynamics trajectories using interatomic distance matrices.

Most chemical transformations (reactions or conformational changes) that are of interest to researchers have many degrees of freedom, usually too many to visualize without reducing the dimensionality of the system to include only the most important atomic motions. In this article, we describe a method of using Principal Component Analysis (PCA) for analyzing a series of molecular geometries (, a reaction pathway or molecular dynamics trajectory) and determining the reduced dimensional space that captures the most structural variance in the fewest dimensions. The software written to carry out this method is called , which permits (1) visualizing the geometries in a reduced dimensional space, (2) determining the axes that make up the reduced dimensional space, and (3) projecting the series of geometries into the low-dimensional space for visualization.

Post-transition state bifurcations induce dynamical detours in Pummerer-like reactions.

A post-transition state bifurcation (PTSB) involved in a Pummerer-type rearrangement is characterized using density functional theory (DFT) calculations on potential energy stationary points and direct dynamics simulations. A sensitivity of the ratio of products produced this PTSB to solvent dielectric constant is revealed and implications of such a dependence for selectivity control of organic reactions are discussed.

Rearrangement of Hydroxylated Pinene Derivatives to Fenchone-Type Frameworks: Computational Evidence for Dynamically-Controlled Selectivity.

An acid-catalyzed Prins/semipinacol rearrangement cascade reaction of hydroxylated pinene derivatives that leads to tricyclic fenchone-type scaffolds in very high yields and diastereoselectivity has been developed. Quantum chemical analysis of the selectivity-determining step provides support for the existence of an extremely flat potential energy surface around the transition state structure. This transition state structure appears to be ambimodal, i.

Synthesis of Highly Stereodefined Tetrasubstituted Acyclic All-Carbon Olefins via a Syn-Elimination Approach.

An efficient synthesis of stereodefined tetrasubstituted acyclic all-carbon olefins has been developed via a bis(2,6-xylyl)phosphate formation of stereoenriched tertiary alcohols, followed by in situ syn-elimination of the corresponding phosphates under mild conditions. This chemistry tolerates a wide variety of electronically and sterically diverse substrates and generates the desired tetrasubstituted olefins in high yields and stereoselectivities (>95:5) in most cases. This stereocontrolled olefin synthesis has been applied to the synthesis of anticancer drug tamoxifen in three steps from commercially available 1,2-diphenylbutan-1-one in 97:3 stereoselectivity and 78% overall yield.

Correction: Dynamic behavior of rearranging carbocations - implications for terpene biosynthesis.

[This corrects the article DOI: 10.3762/bjoc.12.

Navigating Past a Fork in the Road: Carbocation-π Interactions Can Manipulate Dynamic Behavior of Reactions Facing Post-Transition-State Bifurcations.

Dynamics calculations are described for carbocation rearrangements involving product-forming pathways with post-transition-state bifurcations. We show that noncovalent interactions with associated benzene rings (a simple model of aromatic amino acid side chains) can switch inherent dynamical tendencies for competing modes of disrotation, establishing that meaningful changes in dynamically controlled product selectivity can be achieved with few weak noncovalent interactions.

Cryptic post-transition state bifurcations that reduce the efficiency of lactone-forming Rh-carbenoid C-H insertions.

Byproducts of chemical reactions are generally thought to result from the competition between two reaction pathways, each with its own rate-determining transition state structure. We show here, however, that pathways with a single transition state structure followed by a post-transition state bifurcation may also be a source of undesired products, especially those whose appearance is unexpected. The viability of this scenario for intramolecular C-H insertion reactions affording β-lactones Rh-carbenoid intermediates is assessed through quantum chemical calculations on potential energy surfaces and quasi-classical molecular dynamics simulations.

Dynamic behavior of rearranging carbocations - implications for terpene biosynthesis.

This review describes unexpected dynamical behaviors of rearranging carbocations and the modern computational methods used to elucidate these aspects of reaction mechanisms. Unique potential energy surface topologies associated with these rearrangements have been discovered in recent years that are not only of fundamental interest, but also provide insight into the way Nature manipulates chemical space to accomplish specific chemical transformations. Cautions for analyzing both experimental and theoretical data on carbocation rearrangements are included throughout.

Experimental and computational mechanistic investigation of chlorocarbene additions to bridgehead carbene-anti-Bredt systems: noradamantylcarbene-adamantene and adamantylcarbene-homoadamantene.

Cophotolysis of noradamantyldiazirine with the phenanthride precursor of dichlorocarbene or phenylchlorodiazirine in pentane at room temperature produces noradamantylethylenes in 11% yield with slight diastereoselectivity. Cophotolysis of adamantyldiazirine with phenylchlorodiazirine in pentane at room temperature generates adamantylethylenes in 6% yield with no diastereoselectivity. (1)H NMR showed the reaction of noradamantyldiazirine + phenylchlorodiazirine to be independent of solvent, and the rate of noradamantyldiazirine consumption correlated with the rate of ethylene formation.