Olefin Autoxidation in Flow

Handling hazardous multiphase reactions in flow brings not only safety advantages but also significantly improved performance, due to better mass transfer characteristics. In this paper, we present a continuous microreactor setup, capable of performing olefin autoxidations with O₂, under solvent-free and catalyst-free conditions. Owing to the transparent reactor design, consumption of O₂ can be visually followed and exhaustion of the gas bubbles marks a clear end point along the channel length coordinate. Tracking the position of this end point enables measuring effective rate constants. The developed system was calibrated using the well-studied β-pinene substrate, and was subsequently applied to the synthetically interesting transformation of (+)-valencene to (+)-nootkatone. For the latter, a space-time yield was obtained that is at least 3 orders of magnitude larger than that realized with established biotechnology approaches

A Clock Reaction Based on Molybdenum Blue

Clock reactions are rare kinetic phenomena, so far limited mostly to systems with ionic oxoacids and oxoanions in water. We report a new clock reaction in cyclohexanol that forms molybdenum blue from a noncharged, yellow molybdenum complex as precursor, in the presence of hydrogen peroxide. Interestingly, the concomitant color change is reversible, enabling multiple clock cycles to be executed consecutively. The kinetics of the clock reaction were experimentally characterized, and by adding insights from quantum chemical calculations, a plausible reaction mechanism was postulated. Key elementary reaction steps comprise sigmatropic rearrangements with five-membered or bicyclo[3.1.0] transition states. Importantly, numerical kinetic modeling demonstrated the mechanism’s ability to reproduce the experimental findings. It also revealed that clock behavior is intimately connected to the sudden exhaustion of hydrogen peroxide. Due to the stoichiometric coproduction of ketone, the reaction bears potential for application in alcohol oxidation catalysis

Origin of Regioselectivity in α-Humulene Functionalization

Humulene is a sesquiterpene with an important biochemical lead structure, consisting of an 11-membered ring, containing three nonconjugated CC double bonds, two of them being triply substituted and one being doubly substituted. As observed by many groups, one of the two triply substituted CC double bonds is significantly more reactive. In order to rationalize this peculiar regioselectivity, the conformational space of humulene has been explored computationally using various DFT functionals. Four different conformations were identified. Each conformation is chiral and has two enantiomeric forms, yielding a total of eight conformers. The potential energy surface for the interconversion of these conformers was characterized via intrinsic reaction coordinate analyses. Furthermore, an evaluation of the microcanonical partition functions allowed for a quantification of the entropy contributions and the calculation of the temperature dependent equilibrium composition. The results strongly suggest that the high regioselectivity is related to a strong, hyper-conjugative σ_Cα–Cβ–π_CC orbital overlap in the predominant conformations that discriminates one triply substituted double bond from the other. Furthermore, the order of magnitude of the calculated activation energies for the interconversions of the conformers is supported by NMR measurements at different temperatures

Optimization of Grignard Addition to Esters: Kinetic and Mechanistic Study of Model Phthalide Using Flow Chemistry

The kinetics of sequential addition of a distinct Grignard species onto a lactone is studied by flow chemistry. The experimental data are shown to be consistent with a kinetic model based on four reaction steps, reaction of ester to magnesium hemiacetal, rearrangement to ketone (forward and backward), and reaction of ketone to tertiary alcohol upon quenching. The experimental derived reaction mechanism is supported by ab initio molecular computations, and the predicted activation energy is in good agreement with the experimental observations. The Grignard reaction follows a substrate-independent, reductive [2 + 2] cycloaddition of the Meisenheimer/Casper type. Moreover, the rearrangement equilibrium between magnesium hemiacetal and ketone is characterized and found to be feasible. Monoaddition of the ester carbonyl group is demonstrated for fluorophenyl­magnesium bromide but at reaction conditions at −40 °C with several hours of residence time. Working under cryogenic temperature conditions is essential to realizing monoaddition of the ester carbonyl group with Grignard reagents