Iron(III)-catalyzed carbonyl-olefin ring-closing metathesis employs reactivity not typically observed in Lewis acid-catalyzed reactions. In converting a ketone with a pendant olefin into a cycloalkene and a simple carbonyl byproduct, the reaction requires the Lewis acid catalyst to differentiate between the carbonyl of the substrate and that of the byproduct. It is necessary to determine how this solution interaction imparts the desired reactivity to best employ this method. Herein, we report detailed kinetic, spectroscopic, and colligative measurements applied toward the identification of the solution structures of the active Fe(III) and Ga(III) carbonyl-olefin metathesis catalysts. These data are consistent with formation of Lewis acid-carbonyl pairs for both metal systems under stoichiometric conditions. However, they diverge in the presence of higher equivalents of carbonyl, with Fe(III) forming highly ligated complexes, and no observed change for Ga(III). These findings are consistent with the resting state identity of the Fe(III) metathesis catalyst changing over the course of the reaction.

Lewis acid-activation of carbonyl-containing substrates is broadly utilized in organic synthesis. In order to facilitate the development of novel reaction pathways and understand existing methods, it is necessary to determine the solution interactions between Lewis acids and Lewis bases. Herein, we report the application of in situ infrared spectroscopy and solution conductivity toward the identification of the solution structures formed when a range of carbonyl compounds are combined with catalytically active metal halide Lewis acids under synthetically relevant conditions. These data are consistent with formation of Lewis acid-dependent complexes, where metals of low relative Lewis acidity display no ground state interaction with carbonyls. Conversely, we observed the formation of polyligated complexes when stronger Lewis acids (SnCl 4 , TiCl 4 , ZrCl 4 , FeCl 3 , and AlCl 3 ) were treated with ketones, aldehydes, and esters. This collection of observations is intended to assist the synthetic chemist in the design of new catalysts and the development of novel methods.

The coordination of a carbonyl to a Lewis acid represents the first step in a wide range of catalytic transformations. In many reactions it is necessary for the Lewis acid to discriminate between starting material and product, and as a result, how these structures behave in solution must be characterized. Herein, we report the application of computational modeling to calculate properties of the solution interactions of acetone and benzaldehyde with FeCl3. Using these chemical models, we can predict spectral features in the carbonyl region of infrared (IR) spectroscopy. These simulated spectra are then directly compared to experimental spectra generated via titration-IR. We observe good agreement between theory and experiment, in that, between 0 and 1 equiv carbonyl with respect to FeCl3, a pairwise interaction dominates the spectra. When >1 equiv carbonyl is present, our theoretical model predicts two possible structures composed of 4:1 carbonyl to FeCl3, for acetone as well as benzaldehyde. When these predicted spectra are compared with titration-IR data, both structures contribute to the observed solution interactions. These findings suggest that the resting state of FeCl3-catalyzed carbonyl-based reactions employing simple substrates starts as a Lewis pair, but this structure is gradually consumed and becomes a highly ligated, catalytically less active Fe-centered complex as the reaction proceeds. An analytical model is proposed to quantify catalyst inhibition due to equilibrium between 1:1 and 4:1 carbonyl:Fe complexes.

Lewis acid-activation of carbonyl-containing substrates is a fundamental basis for facilitating transformations in organic chemistry. Historically, characterization of these interactions has been limited to models equivalent to stoichiometric reactions. Here, we report a method utilizing in situ infrared spectroscopy to probe the solution interactions between Lewis acids and carbonyls under synthetically relevant conditions. Using this method, we were able to identify 1:1 complexation between GaCl 3 and acetone and a highly ligated complex for FeCl 3 and acetone. The impact of this technique on mechanistic understanding is illustrated by application to the mechanism of Lewis acid-mediated carbonyl-olefin metathesis in which we were able to observe competitive binding interactions between substrate carbonyl and product carbonyl with the catalyst. Video Link The video component of this article can be found at https://www.jove.com/video/60745/ We believe this method is of general importance to chemists studying carbonyl-centered reactions catalyzed by Lewis acids. This detailed demonstration aims to help chemists apply this technique to their system of study.

Lipid peroxidation (LPO) is associated with a variety of pathologies and drives a form of regulated necrosis called ferroptosis. There is much interest in small-molecule inhibitors of LPO as potential leads for therapeutic development for neurodegeneration, stroke, and acute organ failure, but this has been hampered by the lack of a universal high-throughput assay that can identify and assess candidates. Herein, we describe the development and validation of such an approach. Phosphatidylcholine liposomes loaded with ∼10% phospholipid hydroperoxide and STY-BODIPY, a fluorescent signal carrier that co-autoxidizes with polyunsaturated phospholipids, are shown to autoxidize at convenient and constant rates when subjected to an optimized Fe 2+ -based initiation cocktail. The use of this initiation system enables the identification of each of the various classes of LPO inhibitors which have been shown to rescue from cell death in ferroptosis: radical-trapping antioxidants (RTAs), peroxidase mimics, and iron chelators. Furthermore, a limited dose−response profile of inhibitors enables the resolution of RTA and non-RTA inhibitors� thereby providing not only relative efficacy but mechanistic information in the same microplate-based experiment. Despite this versatility, the approach can still be used to estimate rate constants for the reaction of RTAs with chain-propagating peroxyl radicals, as demonstrated for a representative panel of RTAs. To illustrate the utility of this assay, we carried out a preliminary investigation of the 'off-target' activity of several ferroptosis suppressors that have been proposed to act independently of inhibition of LPO, including lipoxygenase inhibitors, cannabinoids, and necrostatins, the archetype inhibitors of necroptosis.