In dead biological tissues such as human hair, the ability of antioxidants to minimise autoxidation is determined by their chemical reactions with reactive oxygen species. In order to improve our understanding of factors determining such antioxidant properties, the mechanistic chemistry of four phenolic antioxidants found in tea and rosemary extracts (epicatechin, epigallocatechin gallate, rosmarinic and carnosic acids) has been investigated. The degradation of N-acetyl alanine by photochemically generated hydroxyl radicals was used as a model system. A relatively high concentration of the antioxidants (0.1 equivalent with respect to the substrate) tested the ability of the antioxidants to intercept both initiating hydroxyl radicals (preventive action) and propagating peroxyl radicals (chain-breaking action). LC-MS data showed the formation of hydroxylated derivatives, quinones and hydroperoxides of the antioxidants. The structure of the assignment was aided by deuterium exchange experiments. Tea polyphenolics (epicatechin and epigallocatechin gallate) outperformed the rosemary compounds in preventing substrate degradation and were particularly effective in capturing the initiating radicals. Carnosic acid was suggested to act mostly as a chain-breaking antioxidant. All of the antioxidants except for rosmarinic acid generated hydroperoxides which was tentatively ascribed to the insufficient lability of the benzylic C-H bond of rosmarinic acid.

Despite considerable advances in the well-established benzoin reaction, cross-benzoin reactions remain challenging often due to limited substrate scope, generation of undesired products, and engineered catalysts. Here we outline an entirely new entry path into this useful reaction by demonstrating that hydroxycarbenes (R––OH) can serve as alternative synthons for benzoin reactions. We do so by trapping the hydroxycarbene intermediates to avoid their rapid quantum-mechanical tunneling [1,2]H-shifts to the corresponding aldehydes. By extending the pyridine probe technique, nascent hydroxycarbenes are intercepted to form persistent zwitterionic intermediates. These intermediates subsequently react with a variety of aldehydes, enabling cross-benzoin reactions in high yields and chemoselectivities. We provide the first characterization of hydroxycarbene-derived zwitterionic intermediates, using advanced mass spectrometric analyses and support their formation and reactivity with computational studies. Our findings establish nucleophilic trapping as a practical tool for taming hydroxycarbene reactivity and expanding their synthetic utility.

Chemical reactions are traditionally depicted as linear equations optimized toward a single product, with other outcomes treated as minor side products. However, advances in reaction automation now allow systematic exploration of reaction “hyperspaces”—that is, multidimensional landscapes of conditions—showing that even archetypal transformations can yield previously unrecognized dominant products. Using the Robowski robotic platform with low‐cost NMR detection, we scanned nearly 1000 conditions for the bromination of 1,1‐diphenylethylene (DPE) and benzylideneacetone (BDA). These maps revealed new major products, condition‐dependent switchovers between addition and substitution pathways, and novel substitution patterns with potential for derivatization into biologically active scaffolds. In turn, correlations and anticorrelations in product distributions across the hyperspace facilitated reconstruction of mechanistic networks connecting different outcomes. Together, our findings show that even foundational reactions, long considered mechanistically complete, harbor hidden complexity and behave as dynamic, switchable networks embedded in conditions’ space.

Despite considerable advances in the well-established benzoin reaction, cross-benzoin reactions remain challenging often due to limited substrate scope, generation of undesired products, and engineered catalysts. Here we outline an entirely new entry path into this useful reaction by demonstrating that hydroxycarbenes (R––OH) can serve as alternative synthons for benzoin reactions. We do so by trapping the hydroxycarbene intermediates to avoid their rapid quantum-mechanical tunneling [1,2]H-shifts to the corresponding aldehydes. By extending the pyridine probe technique, nascent hydroxycarbenes are intercepted to form persistent zwitterionic intermediates. These intermediates subsequently react with a variety of aldehydes, enabling cross-benzoin reactions in high yields and chemoselectivities. We provide the first characterization of hydroxycarbene-derived zwitterionic intermediates, using advanced mass spectrometric analyses and support their formation and reactivity with computational studies. Our findings establish nucleophilic trapping as a practical tool for taming hydroxycarbene reactivity and expanding their synthetic utility.

Chemical reactions are traditionally depicted as linear equations optimized toward a single product, with other outcomes treated as minor side products. However, advances in reaction automation now allow systematic exploration of reaction “hyperspaces”—that is, multidimensional landscapes of conditions—showing that even archetypal transformations can yield previously unrecognized dominant products. Using the Robowski robotic platform with low‐cost NMR detection, we scanned nearly 1000 conditions for the bromination of 1,1‐diphenylethylene (DPE) and benzylideneacetone (BDA). These maps revealed new major products, condition‐dependent switchovers between addition and substitution pathways, and novel substitution patterns with potential for derivatization into biologically active scaffolds. In turn, correlations and anticorrelations in product distributions across the hyperspace facilitated reconstruction of mechanistic networks connecting different outcomes. Together, our findings show that even foundational reactions, long considered mechanistically complete, harbor hidden complexity and behave as dynamic, switchable networks embedded in conditions’ space.