Continuous Manufacturing for the Simmons-Smith Reaction: A Step Forward in Flow Chemistry

We are excited to share a new publication in Organic Process Research & Development that demonstrates how continuous manufacturing can unlock more efficient and safer ways to perform traditionally challenging reactions.

The collaboration with RCPE, TU Graz, and Thermo Fisher Scientific, “Enhancing the Simmons-Smith Reaction Including Post-Reaction Processing. A Continuous Manufacturing Line Generating Organozinc Species in Flow” (DOI: 10.1021/acs.oprd.5c00230), showcases how the Simmons-Smith reaction, well known for transforming alkenes into cyclopropanes, can be implemented in a fully continuous process.

Traditionally, this transformation has been carried out in batch with several limitations, including:

• Handling of sensitive organozinc intermediates
• Challenges in controlling heat transfer and reaction safety
• Scale-up difficulties in industrial settings
• Time-consuming filtration and extraction steps to remove zinc salts and impurities

By transferring the chemistry into flow, the researchers demonstrate:

• A packed-bed zinc-copper reactor, activated in flow, that eliminates the need for post-reaction filtration.
• A two-stage cross-flow extraction, enabling simultaneous quenching and efficient removal of zinc salts.
• At-line monitoring using chromophoric reagents, allowing real-time tracking of extraction efficiency and process control.
• Improved safety, since organozinc reagents are generated and consumed continuously rather than accumulated in bulk.
• Enhanced efficiency and reproducibility through tighter process control.

This publication not only provides a scalable and integrated solution for a fundamental reaction in organic synthesis but also underscores the broader potential of flow chemistry to modernize pharmaceutical and fine chemical manufacturing. Continuous processes like this one are paving the way for safer, more sustainable, and more economical chemical production.

This study successfully demonstrates a fully integrated continuous flow strategy for the Simmons–Smith cyclopropanation reaction, including not only the core reaction step but also downstream processing (workup and purification).

Key take-home messages:

• The authors show that generating the reactive organozinc species in flow can be reliably coupled with subsequent transformations, achieving a robust manufacturing line rather than discrete batch steps.
• This continuous approach yields improved reproducibility, control over reaction conditions (e.g., mixing, residence times), and potential scalability relative to traditional batch protocols.
• Importantly, the authors also integrate post-reaction processing steps (e.g., quenching, separations) into the flow sequence, thereby bridging reaction and workup in a single streamlined line.
• The work provides a blueprint for translating complex, multi-step chemistries into continuous manufacturing, particularly for sensitive organometallic intermediates such as organozinc carbenoids used in Simmons–Smith reactions.
• From a practical standpoint, this strategy helps mitigate issues typical in batch processing (e.g., manual transfer, scale-up inconsistencies, heat/mass transfer limitations) and points toward more efficient, safer, and sustainable synthetic operations.

In sum, this publication marks a meaningful advance in continuous. Flow organometallic chemistry: not only can the reactive species be generated and consumed in flow, but the entire downstream sequence can be embedded in a continuous line, making such processes more amenable to industrial adoption.