Synthesis in flow

In this Issue, we focus on reaction outcomes which are unique to flow setups and their application in synthesis.

Francesca Paradisi, Professor of Sustainable Pharmaceutical Chemistry at the University of Bern, talks to Nature Synthesis about the reactivity of biocatalysts in flow.

Anna Slater, Professor of Chemistry and Royal Society University Research Fellow at the University of Liverpool, talks to Nature Synthesis about developing supramolecular and materials synthesis in flow chemistry.

David Ford, Senior Director of Chemistry at Snapdragon Chemistry, talks to Nature Synthesis about using flow chemistry in process development and reaction scale-up.

Gabriela Oksdath-Mansilla, an INFIQC-CONICET researcher and Professor of Chemistry in the Facultad de Ciencias Químicas at the Universidad Nacional de Córdoba, talks to Nature Synthesis about performing photochemistry in flow.

Flow chemistry enables efficient generation and improved reactivity of sulfuryl fluoride for sulfur fluoride exchange click chemistry.

Regio- and stereoselective boryllithiation and borylsodiation of alkynes in a flow microreactor yields functionalized borylated alkenes.

The use of gaseous sulfuryl fluoride in sulfur(VI) fluoride exchange reactions is a challenge. Now, a flow set-up for the on-demand generation and onward reaction of sulfuryl fluoride, from sulfuryl chloride, is reported. The process produces fluorosulfate and sulfamoyl fluoride analogues of small molecules, peptides and proteins.

A flow microreactor-enabled method is reported for the stereo- and regioselective synthesis of multisubstituted alkenes by reductive syn-boryllithiation and syn-borylsodiation of arylacetylenes. Reaction of the alkyne substrate with a naphthalenide reductant and a boron electrophile generates a syn-β-borylalkenyl alkali metal intermediate, which can react with a range of electrophiles.

The high stability of THF and rapid cleavage of α-anionic THF make the direct generation and use of α-anionic THF challenging. Now, a flow synthetic method is used to control the metallation of unstable α-anionic THF, allowing a range of functionalization reactions to be carried out directly on THF.

The synthesis of aryl C-glycosides often requires manipulation of protecting groups. Here a general method to prepare aryl C-glycosides from unprotected and stable starting materials has been achieved by photoredox, Ni-catalysed cross-coupling. The protocol was also applied in the synthesis of several sugar–drug conjugates and gliflozin drug molecules.

Preventing metal deposition by cathodic reduction under direct current electrolysis conditions is a formidable challenge in transition-metal-catalysed electrosynthesis. Now, an asymmetric-waveform alternating current (a.c.) electrolysis approach is developed for silver-catalysed C–H phosphorylation where this a.c.-based approach regenerates the silver catalyst and keeps the catalyst loading balanced during the reaction.

Controlling diastereodivergent light-driven processes remains synthetically challenging. Here, we disclose how the light source and steric parameters can be used to control the diastereoselectivity of [2 + 2] heterocycloaddition processes, such as in Paternò–Büchi reactions, and provide access to previously inaccessible stereochemical variants.

Self-driving labs (SDLs) combine machine learning with automated experimental platforms, enabling rapid exploration of the chemical space and accelerating the pace of materials and molecular discovery. In this Review, the application of SDLs, their limitations and future opportunities are discussed, and a roadmap is provided for their implementation by non-expert scientists.

Timothy Noël, a professor at the University of Amsterdam and Chair of Flow Chemistry, talks to Nature Synthesis about how flow technologies and photocatalytic methods enable C(sp³)–H functionalization reactions.

Scalable and efficient chemical recycling of commodity polymeric materials remains a challenge as the materials continually accumulate in the environment. Now, upcycling of polystyrene into benzoic acid and other value-added chemicals is realized under mild photooxidation conditions, with hydrogen atom transfer as the key step.