Redox-Controlled Shunts in a Synthetic Chemical Reaction Cycle

Abstract

Shunts, alternative pathways in chemical reaction networks (CRNs), are ubiquitous in nature, enabling adaptability to external and internal stimuli. We introduce a CRN in which the recovery of Michael-accepting species is driven by oxidation chemistry. Using weak oxidants can enable access to two shunts within this CRN with different kinetics and a reduced number of side reactions compared to the main cycle that is driven by strong oxidants. Furthermore, we introduce a strategy to recycle one of the main products under flow conditions to partially reverse the CRN and control product speciation throughout time. These findings introduce new levels of control over artificial CRNs, driven by redox chemistry, narrowing the gap between synthetic and natural systems.

Chemical reaction networks based on conjugate additions on β′-substituted Michael acceptors

“…Starting from exploring the separate steps of this network, we found that proline, as well as other primary and secondary amines, can recover the amine-functionalised MA from the sulfoxide- and sulfone-MAs with yields of 55 to 83%. 76 Combining all reactions in a signal-induced cycle, we found that in the presence of the strong oxidant oxone, sulfone-MA forms and subsequently proline-MA recovers in a yield of 55% ( Fig. 7 , full cycle).…”

“…Along those lines, extensive studies from the group of S. Thayumanavan, as well as in our lab, showed that both the electron-withdrawing group (EWG) and leaving group on the MA, as well as the characteristics of the nucleophile strongly impact the overall kinetics of the reactions and stability of the involved species. 13,63,68,76,84,90 While allylic amides were relatively unreactive, diethyl(α-acetoxymethyl)vinylphosphonate (DVP) was found to have intermediate reactivity and allylic esters were found to be most reactive, with the acetate leaving group leading to slower addition-substitution reactions than the bromide leaving group (Scheme 4B, top). Among nucleophiles, we found aliphatic tertiary amines to react fastest, at comparable rates to thiols, which react faster than aromatic tertiary amines, secondary amines, primary amines, and lastly alcohols, which do not show any meaningful reactivity with β′-substituted MAs (Scheme 4B, bottom).…”

“…Although this cycle works in a signal-induced manner, it cannot be run autonomously due to cross-reactivity of free thiol and oxidant. Even in the signal-induced sulfone cycle, we observed a range of side reactions such as oxidation of proline and proline-MA, 76 which made us wonder whether some of these reactions can be mitigated by employing weaker oxidants. Studying medium-strength oxidants such as NaClO 2 , we found that indeed, proline-MA can also be recovered in yields of up to 83% with fewer oxidative side reactions occurring ( Fig.…”

“…Furthermore, the kinetics of the sulfide shunt are significantly slower than those found in the full cycle or the sulfoxide shunt. 76 …”

“…Despite their versatile applications, β′-substituted MAs also suffer from some downsides, such as a loss of double bond functionality upon double additions. 76 Furthermore, the reactivity and high reversibility of these species may lead to a decreased stability of the desired products. 58,76 Lastly, double bonds typically tend to be relatively labile groups and may degrade over time thermally, in light, or in the presence of radical sources, making the addition of inhibitors necessary for prolonged storage.…”