An integrated self-optimizing programmable chemical synthesis and reaction engine.

Robotic platforms for chemistry are developing rapidly but most systems are not currently able to adapt to changing circumstances in real-time. We present a dynamically programmable system capable of making, optimizing, and discovering new molecules which utilizes seven sensors that continuously monitor the reaction. By developing a dynamic programming language, we demonstrate the 10-fold scale-up of a highly exothermic oxidation reaction, end point detection, as well as detecting critical hardware failures. We also show how the use of in-line spectroscopy such as HPLC, Raman, and NMR can be used for closed-loop optimization of reactions, exemplified using Van Leusen oxazole synthesis, a four-component Ugi condensation and manganese-catalysed epoxidation reactions, as well as two previously unreported reactions, discovered from a selected chemical space, providing up to 50% yield improvement over 25-50 iterations. Finally, we demonstrate an experimental pipeline to explore a trifluoromethylations reaction space, that discovers new molecules.

Metal-free reductive cleavage of C-N and S-N bonds by photoactivated electron transfer from a neutral organic donor.

A photoactivated neutral organic super electron donor cleaves challenging arenesulfonamides derived from dialkylamines at room temperature. It also cleaves a) ArCNR and b) ArNC bonds. This study also highlights the assistance given to these cleavage reactions by the groups attached to N in (a) and to C in (b), by lowering LUMO energies and by stabilizing the products of fragmentation.

Overturning established chemoselectivities: selective reduction of arenes over malonates and cyanoacetates by photoactivated organic electron donors.

The prevalence of metal-based reducing reagents, including metals, metal complexes, and metal salts, has produced an empirical order of reactivity that governs our approach to chemical synthesis. However, this reactivity may be influenced by stabilization of transition states, intermediates, and products through substrate-metal bonding. This article reports that in the absence of such stabilizing interactions, established chemoselectivities can be overthrown. Thus, photoactivation of the recently developed neutral organic superelectron donor 5 selectively reduces alkyl-substituted benzene rings in the presence of activated esters and nitriles, in direct contrast to metal-based reductions, opening a new perspective on reactivity. The altered outcomes arising from the organic electron donors are attributed to selective interactions between the neutral organic donors and the arene rings of the substrates.

Reactions of triflate esters and triflamides with an organic neutral super-electron-donor.

The bis-pyridinylidene 13 converts aliphatic and aryl triflate esters to the corresponding alcohols and phenols respectively, using DMF as solvent, generally in excellent yields. While the deprotection of aryl triflates has been seen with other reagents and by more than one mechanism, the deprotection of alkyl triflates is a new reaction. Studies with (18)O labelled DMF indicate that the C-O bond stays intact and hence it is the S-O bond that cleaves, underlining that the cleavage results from the extraordinary electron donor capability of 13. Trifluoromethanesulfonamides are converted to the parent amines in like manner, representing the first cleavage of such substrates by a ground-state organic reducing reagent.