Application of Computational Chemical Shift Prediction Techniques to the Cereoanhydride Structure Problem-Carboxylate Complications.

Despite the vast array of techniques available to modern-day chemists, structural misassignments still occur. These misassignments are often only realized upon attempted synthesis, when the spectra of synthesized products do not match previously reported spectra. This was the case with marine natural product cereoanhydride. The originally proposed 7-membered ring anhydride (1) was shown to be incorrect, although a likely precursor to the correct structure (2) in both its laboratory synthesis and biosynthesis. Herein, in addition to showing how NMR computations could have been used to arrive at the correct structure, we show that the conversion of 1 to 2 is indeed energetically viable, and we highlight complications in predicting NMR chemical shifts for molecules with acidic protons

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 via Rh-carbenoid intermediates is assessed through quantum chemical calculations on potential energy surfaces and quasi-classical molecular dynamics simulations. It appears that, in these cases, the rhodium catalyst is to blame for the accessibility of a second, unintended, pathway following the transition state structure for β-lactone formation that leads to fragmentation to a ketene and carbonyl compound. If an unexpected product is formed via a post-transition state bifurcation, conventional strategies for suppressing its formation are unlikely to succeed. Guidelines for recognizing the presence of a post-transition state bifurcation are described here, along with hints at means for controlling product distributions

Tipping the balance: theoretical interrogation of divergent extended heterolytic fragmentations.

Herein we interrogate a type of heterolytic fragmentation reaction called a 'divergent fragmentation' using density functional theory (DFT), natural bond orbital (NBO) analysis, ab initio molecular dynamics (AIMD), and external electric field (EEF) calculations. We demonstrate that substituents, electrostatic environment and non-statistical dynamic effects all influence product selectivity in reactions that involve divergent fragmentation pathways. Direct dynamics simulations reveal an unexpected post-transition state bifurcation (PTSB), and EEF calculations suggest that some transition states for divergent pathways can, in principle, be selectively stabilized if an electric field of the correct magnitude is oriented appropriately

Modulation of inherent dynamical tendencies of the bisabolyl cation via preorganization in epi-isozizaene synthase.

The relative importance of preorganization, selective transition state stabilization and inherent reactivity are assessed through quantum chemical and docking calculations for a sesquiterpene synthase (epi-isozizaene synthase, EIZS). Inherent reactivity of the bisabolyl cation, both static and dynamic, appears to determine the pathway to product, although preorganization and selective binding of the final transition state structure in the multi-step carbocation cascade that forms epi-isozizaene appear to play important roles

Carbocations and the Complex Flavor and Bouquet of Wine: Mechanistic Aspects of Terpene Biosynthesis in Wine Grapes.

Computational chemistry approaches for studying the formation of terpenes/terpenoids in wines are presented, using five particular terpenes/terpenoids (1,8-cineole, α-ylangene, botrydial, rotundone, and the wine lactone), volatile compounds (or their precursors) found in wine and/or wine grapes, as representative examples. Through these examples, we show how modern computational quantum chemistry can be employed as an effective tool for assessing the validity of proposed mechanisms for terpene/terpenoid formation

Stereodivergent, Diels-Alder-initiated organocascades employing α,β-unsaturated acylammonium salts: scope, mechanism, and application.

Chiral α,β-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels-Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic γ- and δ-lactones from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe extensions of stereodivergent DAL organocascades to other racemic dienes bearing pendant secondary and tertiary alcohols, and application to a formal synthesis of (+)-dihydrocompactin is described. A combined experimental and computational investigation of unsaturated acylammonium salt formation and the entire DAL organocascade pathway provide a rationalization of the effect of Brønsted base additives and enabled a controllable, diastereodivergent DAL process leading to a full complement of possible stereoisomeric products. Evaluation of free energy and enthalpy barriers in conjunction with experimentally observed temperature effects revealed that the DAL is a rare case of an entropy-controlled diastereoselective process. NMR analysis of diene alcohol-Brønsted base interactions and computational studies provide a plausible explanation of observed stabilization of exo transition-state structures through hydrogen-bonding effects

Pushing the limits of concertedness. A waltz of wandering carbocations.

Among the array of complex terpene-forming carbocation cyclization/rearrangement reactions, the so-called "triple shift" reactions are among the most unexpected. Such reactions involve the asynchronous combination of three 1,n-shifts into a concerted process, e.g., a 1,2-alkyl shift followed by a 1,3-hydride shift followed by a second 1,2-alkyl shift. This type of reaction so far has been proposed to occur during the biosynthesis of diterpenes and the sidechains of sterols. Here we describe efforts to push the limits of concertedness in this type of carbocation reaction by designing, and characterizing with quantum chemical computations, systems that could couple additional 1,n-shift events to a triple shift leading, in principle to quadruple, pentuple, etc. shifts. While our designs did not lead to clear-cut examples of quadruple, etc. shifts, they did lead to reactions with surprisingly flat energy surfaces where more than five chemical events connect reactants and plausible products. Ab initio molecular dynamics simulations demonstrate that the formal minima on these surfaces interchange on short timescales, both with each other and with additional unexpected structures, allowing us a glimpse into a very complex manifold that allows ready access to great structural diversity

Visualization without Vision – How Blind and Visually Impaired Students and Researchers Engage with Molecular Structures

This article examines the tools and techniques currently available that enable blind and visually impaired (BVI) individuals to visualize three-dimensional objects used in learning chemistry concepts. How BVI individuals engage with and visualize molecular structure is discussed and recent tactile (or haptic) and auditory methods for visualization of various chemistry concepts are summarized. Remaining challenges for chemistry education researchers are described with the aim of highlighting the potential value of educational research in further enabling BVI students to pursue careers in science, technology, engineering, and mathematics (STEM) fields

Switching on a Nontraditional Enzymatic Base—Deprotonation by Serine in the ent-Kaurene Synthase from Bradyrhizobium japonicum

Terpene synthases often catalyze complex carbocation cascade reactions. It has been previously shown that single-residue switches involving replacement of a key aliphatic residue with serine or threonine can “short-circuit” such reactions that are presumed to act indirectly via dipole stabilization of intermediate carbocations. Here a similar switch was found in the structurally characterized ent-kaurene synthase from Bradyrhizobium japonicum. Application of a recently developed computational approach to terpene synthases, TerDockin, surprisingly indicates direct action of the introduced serine hydroxyl as a catalytic base. Notably, this model suggests an alternative interpretation of previous results and potential routes toward reengineering terpene synthase activity more generally