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International audience; Bioorthogonal click and release reactions are powerful tools for chemical biology allowing, for example, the selective release of drugs in biological media, including inside animals. Here we developed two new families of iminosydnone mesoionic reactants that allow a bioorthogonal release of electrophilic species under physiological conditions. Their synthesis and reactivities as dipoles in cycloaddition reactions with strained alkynes have been studied in detail. Whereas the impact of the pH on the reaction kinetics was demonstrated experimentally, theoretical calculations suggest that the newly designed dipoles display reduced resonance stabilization energies compared to previously described iminosydnones explaining their higher reactivity. These mesoionic compounds react smoothly with cycloalkynes under physiological, copper-free reaction conditions to form a click pyrazole product together with a released alkyl-or aryl-isocyanate. With kinetic constants up to 1000 M-1 s-1 , this click and release reaction is among the fastest described to date, and represents the first bioorthogonal process allowing the release of isocyanate electrophiles inside living cells offering interesting perspectives in chemical biology.

The synthesis of quaternary homoallylic halides and trichloroacetates from cyclopropylcarbinols, as reported by Marek in 2020 (J. Am. Chem. Soc. 2020, 142, 5543-5548), is one of the few reported examples of stereospecific nucleophilic substitution involving chiral bridged carbocations. However, for the phenyl-substituted substrates the stereoselectivity of the reaction is poor and a mixture of diastereomers is obtained. In order to understand the nature of the intermediates involved in this transformation and explain the loss of selectivity for certain substrates, we have performed a Density Functional Theory investigation of the reaction mechanism at the DLPNO-CCSD(T)/Def2TZVPP level of theory. Our results indicate that cyclopropylcarbinyl cations are stable intermediates in this reaction, while bicyclobutonium structures are high-energy transition structures and as such are not involved, regardless of the substitution pattern on the substrate. Instead, multiple rearrangement pathways of cyclopropylcarbinyl cations have been located, including rotations around their π-bonds and ring openings to homoallylic cations. Importantly, the relative energies of these homoallylic cations and of the activation barriers to reach them are correlated to the nature of the substituents. While direct nucleophilic attack on the chiral cyclopropylcarbinyl cation is kinetically favored for most systems, the rearrangements become competitive with nucleophilic attack for the phenyl-substituted systems, leading to a loss of selectivity through a mixture of rearranged carbocation intermediates. As such, it appears that stereospecific reactions of chiral cyclopropylcarbinyl cations depend on the ability of these cations to access homoallylic structures, from which selectivity is not guaranteed.

The reactions of elemental sulfur (S8) and polysulfides with nucleophiles are relevant to organic synthesis, materials science and biochemistry, but the mechanisms by which they operate are still unknown. Depending on the nature of the nucleophile, a broad variety of products can be obtained, but reaction pathways are difficult to probe experimentally due to the inherent thermodynamic and kinetic instability of polysulfide intermediates. Using Density Functional Theory (DFT) calculations at the ωB97X-D/aug-cc-pV(T+d)Z/SMD(MeCN) // ωB97X-D/ aug-cc-pVDZ/SMD(MeCN) level of theory, this study provides the first comprehensive picture of the mechanisms behind the reaction of elemental sulfur and polysulfides with cyanide and phosphines, which quantitatively generate the monosulfide products thiocyanate and phosphine sulfides, respectively. These reactions are prototypical of the reactions of sulfur with other strong nucleophiles including carbon-based systems, and are important for the titration and detection of elemental sulfur in complex media. We first demonstrate that from the two mechanisms proposed more than 60 years ago, the Foss-Bartlett hypothesis is the most likely nucleophilic decomposition pathway for polysulfide intermediates containing good leaving groups. Importantly, we find that unimolecular decomposition pathways, either cyclizative or not, have the lowest activation barriers for most polysulfide intermediates. This indicates that such intermediates are fleeting in solution as they rapidly decompose even without an external nucleophile. Other bimolecular decomposition pathways were also located, including scrambling reactions and attack on thiosulfoxides, which are less likely to intervene as they require larger concentrations of highly-reactive intermediates. Overall, our results indicate that for long polysulfides intramolecular cyclization is the most favorable decomposition pathway. For short polysulfides, a mixture of unimolecular decomposition and nucleophilic attack can be expected, in addition to scrambling pathways if the concentration of nucleophile is low. Overall, this work highlighted the various pathways available for polysulfide decomposition, allowing the study of polysulfide reactivity in more complex settings such as organic transformations or biochemical pathways.

The synthesis of quaternary homoallylic halides and trichloroacetates from cyclopropylcarbinols, as reported by Marek in 2020 (J. Am. Chem. Soc. 2020, 142, 5543-5548), is one of the few reported examples of stereospecific nucleophilic substitution on chiral non-classical carbocations. However, for the phenyl-substituted substrates the stereoselectivity of the reaction is lost and a mixture of diastereomers is obtained. In order to understand the nature of the intermediates in-volved in this transformation and explain the loss of selectivity for certain substrates, we have performed a Density Func-tional Theory investigation of the reaction mechanism at the ωB97X-D/Def2TZVPP and M06-2X/Def2TZVPP levels of theory. Our results indicate that non-classical cyclopropylcarbinyl cations are stable intermediates in this reaction, while bicyclobutonium structures are high-energy transition structures and as such are not involved, regardless of the substitu-ent pattern on the substrate. Instead, multiple rearrangement pathways of cyclopropylcarbinyl cations have been located, including rotations around their π-bonds and ring openings to classical homoallylic cations. Importantly, the relative energies of these homoallylic cations and of the activation barriers to reach them are correlated to the nature of the sub-stituents. While direct nucleophilic attack on the chiral cyclopropylcarbinyl cation is kinetically favored for most sys-tems, the rearrangements become competitive with nucleophilic attack for the phenyl-substituted systems, leading to a loss of selectivity through a mixture of rearranged carbocation intermediates. As such, it appears that stereospecific reac-tions of chiral non-classical cyclopropylcarbinyl cations depend on the ability of these cations to access classical homoallylic structures, from which selectivity is not guaranteed.