Flow chemistry streamlines amide synthesis.

Unlock Amide Synthesis: Flow Chemistry's Game-Changing Solution

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Soraya Malik in Science & Nature December 2025 • 4 min read.

"A streamlined approach to amide creation overcomes limitations of traditional methods, offering a practical and general route with enhanced efficiency and scalability."


Amides are fundamental components in a vast range of molecules, finding critical applications in pharmaceuticals, agrochemicals, and various other chemical industries. Consequently, there's a continuous drive to refine and improve amide formation methods, specifically those that minimize the use of stoichiometric activating agents, which can be wasteful and generate unwanted byproducts.

While much attention has been given to catalysts that facilitate the condensation of amines with carboxylic acids, alternative strategies, particularly those leveraging isocyanates, have emerged as efficient routes to amides. Isocyanates offer a reactive, mass-efficient synthon for the amide unit. However, traditional methods involving isocyanates often suffer from limitations such as narrow substrate tolerance and the need for harsh reaction conditions.

Recent research introduces a novel approach that overcomes these challenges by employing flow chemistry and substoichiometric amounts of CuBr2 to facilitate the reaction between Grignard reagents and isocyanates. This innovative method boasts high yields, excellent scalability, and broad functional group tolerance, making it a valuable tool for chemists seeking efficient and reliable amide synthesis.

The Flow Chemistry Advantage: A Practical and General Amidation Method

Flow chemistry streamlines amide synthesis.

The limitations of traditional methods for reacting carbon nucleophiles with isocyanates stem from narrow substrate tolerance and unfavorable reaction conditions. To combat these issues, researchers explored the use of flow chemistry—a technique where reactions occur in a continuous stream within a confined space. This allows for precise control over reaction parameters, enhanced mixing, and efficient heat transfer.

The key findings of this research highlight the effectiveness of flow chemistry in amide synthesis:

  • High Yields: The flow chemistry approach, combined with substoichiometric amounts of CuBr2, consistently produced high yields of desired amides.
  • Scalability: The method proved scalable, allowing for the production of amides in larger quantities without compromising yield or efficiency.
  • Functional Group Tolerance: The reaction tolerated a wide range of functional groups on both the isocyanate and Grignard reagent, expanding the scope of applicable substrates.
  • Versatility: Both sterically hindered and unhindered isocyanates, as well as sp²- and sp³-hybridized coupling partners, could be used successfully, showcasing the method's broad applicability.
These advantages stem from the enhanced control and efficiency afforded by flow chemistry. The fast mixing and precise temperature control minimize side reactions and promote the formation of the desired amide product. Furthermore, the use of substoichiometric CuBr2 acts as a catalyst, accelerating the reaction without the need for large amounts of potentially hazardous reagents.

The Future of Amide Synthesis: Streamlining Chemical Processes

This research marks a significant advancement in amide synthesis, providing a practical, general, and scalable method for creating these essential chemical building blocks. By leveraging the power of flow chemistry and substoichiometric catalysis, this approach overcomes the limitations of traditional methods, offering chemists a versatile tool for a wide range of applications.

The implications of this development extend beyond the laboratory, potentially impacting the pharmaceutical, agrochemical, and materials science industries. The ability to efficiently synthesize amides with diverse functionalities opens doors to the discovery and development of novel compounds with improved properties and enhanced performance.

As flow chemistry continues to evolve and find new applications, we can expect further breakthroughs in chemical synthesis, leading to more efficient, sustainable, and innovative processes for creating the molecules that shape our world.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1002/ange.201807393, Alternate LINK

Title: A Practical And General Amidation Method From Isocyanates Enabled By Flow Technology

Subject: General Medicine

Journal: Angewandte Chemie

Publisher: Wiley

Authors: Jason D. Williams, William J. Kerr, Stuart G. Leach, David M. Lindsay

Published: 2018-08-17

Everything You Need To Know

1

What is amide synthesis, and why is it important?

Amide synthesis is the process of creating amides, which are fundamental building blocks in many important molecules. These molecules are essential for pharmaceuticals, agrochemicals, and other industrial chemicals. The methods of creating amides are always improving, and this is important because the traditional methods can be inefficient and create unwanted byproducts.

2

What is flow chemistry, and how does it improve amide synthesis?

Flow chemistry is a technique where reactions occur in a continuous stream within a confined space. This allows for precise control over reaction parameters, enhanced mixing, and efficient heat transfer. Flow chemistry provides high yields, scalability, and functional group tolerance in amide synthesis. This means that the reaction can produce large quantities of amides efficiently, and it works well with a wide variety of chemical compounds. The fast mixing and precise temperature control in Flow Chemistry minimizes side reactions, accelerating the reaction without hazardous reagents.

3

What is the role of CuBr2 in this amide synthesis method?

CuBr2 is a catalyst used in the described process to facilitate the reaction between Grignard reagents and isocyanates. It is used in substoichiometric amounts, meaning that less of the catalyst is needed. The use of CuBr2 allows for a more efficient reaction without the need for large amounts of potentially hazardous reagents. It helps to accelerate the reaction in a controlled environment, leading to high yields of the desired amide product.

4

What are Grignard reagents, and how are they used in the amide synthesis?

Grignard reagents are carbon nucleophiles that react with isocyanates to form amides. This reaction is improved by using flow chemistry. By using flow chemistry the limitations of traditional methods are avoided. This leads to high yields, scalability, and functional group tolerance, expanding the scope of applicable substrates. Both sterically hindered and unhindered isocyanates, as well as sp²- and sp³-hybridized coupling partners, could be used successfully.

5

How do isocyanates contribute to amide synthesis, and what are the benefits of the new method?

Isocyanates are a key component in the amide synthesis process. They are used as a reactive building block for the amide unit. Flow chemistry and substoichiometric amounts of CuBr2 are used to overcome the limitations of traditional methods. This approach allows the reaction to proceed efficiently and with high yields, and the process is scalable.

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