Abstract
We have identified the most likely reaction mechanism for oxidizing heptafulvenes to the corresponding tropones by experimental and theoretical investigations. The experimental studies were done by coupling a three-dimensional printed miniaturized reactor with an integrated electrospray ionization needle to a mass spectrometer. Using the experimentally observed ions as a basis, nine alternative reaction pathways were investigated with density functional theory calculations. The lowest energy reaction pathway starts with the formation of an epoxide that is opened upon the addition of a second equivalent of the oxidizing species meta-chloroperoxybenzoic acid. The adduct formed then undergoes a Criegee-like rearrangement to yield a positively charged hemiketal, which on deprotonation dissociates into acetone and tropone. Overall, the reaction mechanism resembles a Hock-like rearrangement.
Highlights
Tropones and troponoids are interesting compounds due to their anticancer properties,[1,2] antimicrobial activity,[3,4] and antifungal effects.[5]
The experiment was performed as follows: at t = 0, acquisition of mass spectra was started; immediately after this, compound 1 from one syringe and meta-chloroperoxybenzoic acid (mCPBA) from another syringe were infused into the miniaturized reactor at flow rates of 125 μL/min each
Based on the mass spectrometrically detected ions and their temporal profiles, the reaction pathways for density functional theory (DFT) investigation were drafted
Summary
Tropones and troponoids are interesting compounds due to their anticancer properties,[1,2] antimicrobial activity,[3,4] and antifungal effects.[5]. Examples highlighting the capability of online MS to detect short-lived reaction intermediates include the Negishi reaction,[12] microdroplet studies of the cycloaddition between diethyl azodicarboxylate and quadricyclane,[13] as well as of hydrazone formation,[14] and monitoring of visible-light-mediated [3 + 2] annulation.[15] Microreactors and flow chemistry systems combined with MS have been used for probing reaction mechanisms.[16]. MS provides only limited structural information, and the species observed may not be unambiguously identifiable by MS In these scenarios, computational chemistry can be used in synergy with the experimental results. The combination of computational chemistry and microreactors coupled online with MS detection for probing reaction mechanisms seems to be a concept hitherto unexplored. Meta-Chloroperoxybenzoic Acid (mCPBA)Mediated Oxidation of Heptafulvene 1 into Tropone 5 density functional theory (DFT) calculations were performed (M06-2X/6-311++G(d,p)) to assess the various mechanisms that would explain the appearance of the species observed. The energies obtained from these calculations are given as Gibbs free energies, unless explicitly noted otherwise
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