Flow Chemistry

Flow chemistry, continuous processing, or continuous flow chemistry, begins with two or more streams of different reactants pumped at specific flow rates into a single chamber, tube, or microreactor.  A reaction takes place, and the stream containing the resultant compound is collected at the outlet.  The solution may also be directed to subsequent flow reactor loops to generate the final product. Only small amounts of material are needed, which dramatically enhances process safety. Because of the inherent design of continuous flow technology, reaction conditions that cannot be safely achieved with batch reactions are possible. The result is product with higher quality, less impurity, and faster reaction cycle time.

Flow chemistry has been used for decades in the chemical industry. More recently, the pharmaceutical and fine chemical industries are increasingly adopting this technology. The inherent increased safety, improved product quality, cost efficiency, and overall production flexibility are drivers for the growing use of continuous flow chemistry. 

Flow Chemistry Basics

Generally, flow chemistry equipment consist of pumps that transport reactants, reagents, and solvent into reaction loops that introduce small volumes of reagents.  These feed into a mixing junction where reagent streams are combined and passed into a coil reactor to provide reaction residence time.  The reaction mixture may be fed into a column reactor that contains solid reagents, catalysts, or scavengers.  An inline back pressure regulator controls the system, pressure and inline analytics are often used to provide information about reaction performance.  Additionally, in situ FTIR spectroscopy can provide real-time feedback to proactively improve the reaction.  For example, data from in situ FTIR spectroscopy can be used to mitigate the effect of imperfect flow and control the addition rate of reagents for better mixing profile. 

Advantages of Flow Chemistry

• Better control and reproducibility of reactions.  Key reaction parameters such as mixing, heating, and residence time are more precisely controlled, leading to better product yield and impurity control.
  
  
• Wider range of reaction variable are accessible.  For example, running a continuous reaction under pressure allows reactions to be run at higher temperatures than possible in batch reactions, where solvent reflux at ambient pressures as is typical.  This can provide higher product yields.
  
  
• Modular, customizable workflow.  Flow chemistry equipment is highly modular.  This makes it easy to configure equipment to meet the requirements of specific reactions.  A range of task-specific modules are commercially available, and these are readily assembled into user-customized workflows.
  
  
• Improved process safety.  Reactions that are considered too hazardous to carry out in batch are often considered acceptable in continuous flow.  A hazardous reaction may be one that is very exothermic or otherwise energetic, and in flow reactions smaller amounts of reactants are in contact.  Also, exposure to toxic substrates and reagents are minimized by the smaller volumes required in continuous flow systems and the elimination of manual sampling for analysis.
  
  
• Rapid analysis, optimization, and scale-up of chemical reactions.  Testing a range of reaction variables is far faster in flow processes and less substrates and reagents are required.  Inline, real-time analysis provides immediate feedback on the effect of variables on reaction performance. 
  
  
• Increase product quality and yield.  Because of precise control over variables and the ability to safely execute reactions over a wider range of reaction conditions, overall yield is improved, while impurity levels are minimized. 

Key Applications of Flow Chemistry

In recent years, the number and types of reactions that performed with continuous flow chemistry have grown substantially, especially in pharmaceuticals, fine chemicals, green chemistry, catalytic reactions, and polymer chemistry.  Much of the growth is in chemistries that are too problematic to be handled on larger scale by batch reactions.  These include potentially hazardous reactions such as: 

• Hydrogenation Reactions
• Oxidations
• Halogenations
• Nitrations
• Diazotizations
• Grignards
• Reactions that use toxic gases

Reactions for which reactants may be human health hazards are more safely handled by flow chemistry.  Another growing use for continuous flow chemistry is to control stereochemistry, since reaction variables can be more carefully adjusted to control epimerization. 

Flow chemistry is used for reactions where starting materials are in limited supply and small scale reactions are preferable.

Improving Flow Chemistry with Process Analytical Technology

When coupled with process analytical technology (PAT), flow chemistry allows for rapid analysis, optimization, and scale-up of a chemical reaction. With continuous real-time analysis, researchers monitor steady state conditions, troubleshoot process mishaps, and identify reactive intermediates. When flow chemistry is analyzed with ATR-FTIR, each functional group of a given substance has a unique fingerprint which can be trended over time and provides continuous measurement of component concentration as a function or process conditions. This provides a means to track the time and conditions necessary to reach and maintain steady state. 

Continuous Flow Reaction Of Highly Exothermic Reaction

In this example, inline FTIR technology is used to analyze a continuous process that forms a thiomorpholine dioxide compound from the reaction of ethanolamine (EA) and divinylsulfone (DVS).  Inline FTIR was used in both the development of the continuous process and in the monitoring of the chemistry carried out at larger scale. The scientists found that in small scale batch testing, this reaction was highly exothermic and potentially problematic if run at larger scale. Additionally, they pointed out that DVS is a toxic alkylating agent and exposure should be avoided. 

To develop the continuous process, the reaction of EA with DVS was carried out in a 12 ml reactor, a ReactIR with flow cell was used to monitor the disappearance of DVS (1390 cm-1 band) and the appearance of the target compound (1195 cm-1 band). This reaction used water as a solvent, which did not interfere with the IR bands being tracked for DVS and compound 1.  As the trace of these bands vs. time shows, once pump B was started, the 1390 cm-1 band from DVS appears.  When pump A is actuated introducing EA, the DVS band disappears and the target compound appears and reaches steady state. The continuous flow reaction was adapted to larger equipment for kilogram scale production, and the ReactIR flow technology was employed to monitor the process in real-time. 

Development of a Safe and High-Throughput Continuous Manufacturing Approach to 4‑(2-Hydroxyethyl)thiomorpholine 1,1-Dioxide Neil A. Strotman, Yichen Tan, Kyle W. Powers, Maxime Soumeillant, and Simon W. Leung, Bristol-Myers Squibb, New Brunswick, New Jersey 08903, United States, Org. Process Res. Dev. 2018, 22, 721−727

The ReactIR 702L

Recently, a new FTIR spectrometer was introduced that is ideal for monitoring continuous flow chemistry in real time. 

Small and Lightweight
The streamlined profile fits easily into physically constrained areas, meaning the instrument can be placed along the reaction sequence to monitor where needed.

No Liquid-Nitrogen Required
Infrared measurements can be made continually and unattended for as long as necessary to accommodate a synthesis. 

iC IR 7 Software
Set up and monitoring trends is straightforward and intuitive. Data from the ReactIR 702L can be integrated with control systems to allow for proactive execution of the chemistry.  

In a flow chemistry example presented by a Contract Research Organization (CRO), NALAS Engineering, data-rich experimentation was used to develop a safer continuous flow method for a strongly exothermic chemical reaction.  This project used calorimetry for heat balance evaluation and in situ mid-infrared spectroscopy to monitor reaction components in real time and to develop kinetic models. 

Mid-infrared analysis was to used to define the fraction conversion at each stage of the multiple fluidic module system, as well as the overall conversion and yield as a function of residence time. Key variables such as dosing rate, catalyst loading, and temperature were screened and optimized rapidly based on real-time information provided by heat flow calorimetry and in situ mid-infrared spectroscopy.

These tools also provided an understanding of which step controls the overall process rate as well as the effect that mixing and mass transfer and catalyst have on the reaction rate.

Continuous Measurement of Structural Information

In situ FTIR spectroscopy provides continuous monitoring of key reaction species and provides continuous measurements of kinetics, mechanism, and pathway where offline sample and analysis difficult.

ReactIR fitted with a micro flow cell easily connects to a continuous flow reactor to provide a real-time “video” of the reaction chemistry as it takes place at any point in the flowing stream. 

Micro Flow Cell Optimized For

Continuous Flow Chemistry

In collaboration with leading scientists in continuous flow chemistry*, we have engineered an optimized flow cell for this important application.

The ReactIR Micro Flow Cell for continuous flow chemistry:

• Uses a multi-reflection ATR sensor with an effective pathlength that is the best balance between high sensitivity for the measurement of interest and minimum interference/saturation from solvents.
• Is optimized for infrared energy throughput, enabling use of thermoelectrically cooled MCT.  This both eliminates the need for liquid nitrogen and allows the detector to be “always on” and stable.
• Has an internal geometry that was developed and thoroughly tested to ensure no disruption in flow as the material moves across the sensor.
• Is designed to fit anywhere in the flow stream so you can monitor intermediates or product formation as required
• Offers diamond or silicon ATR sensor materials to optimize the spectral response based on the functional group of interest.

*ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing Carter,C., Lange, H., Ley,S., Baxendale, I.,Wittkamp, B., Goode,J., Gaunt, N., Org. Proc. R. & D., 2010, 14, 393–404

Flow Chemistry in Industry-Related Publications

Below is a selection of continuous flow chemistry publications.

Kobayashi, Shū. "Flow “fine” synthesis: high yielding and selective organic synthesis by flow methods." Chemistry–An Asian Journal (2015).
Published by the Synthetic Organic Chemistry Laboratory at the University of Tokyo, this paper focuses  the flow "fine" synthesis concept. The advantages of continuous flow methods over batch methods as well as the challenges presented by flow methods are described.

Sans, Victor, and Leroy Cronin. "Towards dial-a-molecule by integrating continuous flow, analytics and self-optimisation." Chemical Society Reviews 45.8 (2016): 2032-2043.
This paper focuses on the use and benefits of continuous flow platforms for synthetic chemistry in both industry and academic research, which highlighting significant contributions in this area.

Mallia, Carl J., and Ian R. Baxendale. "The use of gases in flow synthesis." Organic Process Research & Development 20.2 (2015): 327-360.
Published by the Department of Chemistry at the University of Durham, this paper describes the benefits of using flow chemistry for improved safety and increased efficiency in research. An overview of approaches to introduces gases into flow reactors along with different gaseous reactions already transferred into flow are discussed.

Ley, Steven V., et al. "Organic synthesis: march of the machines." Angewandte Chemie International Edition 54.11 (2015): 3449-3464.
Published by the Ley Research Group at the University of Cambridge Department of Chemistry, this paper describes how organic synthesis methods are changing and how these are helping to address challenges chemists face in research labs.

Baxendale, Ian R. "A short multistep flow synthesis of a potential spirocyclic fragrance component." Chemical Engineering & Technology 38.10 (2015): 1713-1716.
This paper describes how researchers are leveraging flow chemistry to aid in their synthesis challenges, which is making scale-up easier and safer.

Hafner, Andreas, and Steven V. Ley. "Generation of reactive ketenes under flow conditions through zincmediated dehalogenation." Synlett 26.11 (2015): 1470-1474.
This paper describes the generation of highly reactive monoalkyl and phenyl ketenes by using dehalogenation under flow conditions.

Puglisi, Alessandra, et al. "Organocatalysis chemistry in flow." Current Organocatalysis 2.2 (2015): 79- 101.
Recently, organocatalysis has become effective for performing stereoselective reactions in continuo. Stereoselective catalytic flow processes could be used in manufacturing of APIs and chiral intermediates. The paper discusses recent examples of continuous flow processes using organic molecules as catalysts. The paper highlights the potential of combining steroselective processes with solid-supported catalysis in catalytic reactors as well as with photoredox catalysis.

Mueller, Simon TR, et al. "Safe handling of diazo reagents through inline analytics and flow chemistry." Chimica Oggi-Chemistry Today 33 (2015): 5.
Through the use of flow chemistry in multistep processes, dangerous but useful diazo reagents can be accessed for large scale applications. The generation, isolation and use of diazo compounds can be performed continuously, so no large quantities of highly energetic material are accumulated.

Hu, Te, Ian R. Baxendale, and Marcus Baumann. "Exploring flow procedures for diazonium formation." Molecules 21.7 (2016): 918.
This paper describes how to use flow chemistry to for increased safety and continuous manufacturing to determine optimum condititions for the formation of diazonium compounds.

Atodiresei, Iuliana, Carlos Vila, and Magnus Rueping. "Asymmetric organocatalysis in continuous flow: Opportunities for impacting industrial catalysis." ACS Catalysis 5.3 (2015): 1972-1985.
This paper highlights advantages of organocatalytic transformations performed using continuous flow chemistry and which reactions have been successful. Batch and flow applications are compared.

Müller, Simon TR, et al. "Rapid generation and safe use of carbenes enabled by a novel flow protocol with in-line IR spectroscopy." Chemistry–A European Journal 21.19 (2015): 7016-7020. 
This paper describes a new continuous process for formation and use of donor/acceptor-substituted carbenes. The safety profile of diazo group transfer on methyl phenylacetate was determined including kinetic studies in batch and flow.

Continuous Flow Chemistry Development

Eric Fang, Ph.D., Snapdragon Chemistry

PAT is essential for developing robust continuous flow chemistry and providing full process understanding.  The utility of the application of continuous processing with various process analytical technologies is discussed, as well as case studies on developing flow chemistry processes.