Flow chemistry

Last updated

In flow chemistry, also called reactor engineering, a chemical reaction is run in a continuously flowing stream rather than in batch production. In other words, pumps move fluid into a reactor, and where tubes join one another, the fluids contact one another. If these fluids are reactive, a reaction takes place. Flow chemistry is a well-established technique for use at a large scale when manufacturing large quantities of a given material. However, the term has only been coined recently for its application on a laboratory scale by chemists and describes small pilot plants, and lab-scale continuous plants. [1] Often, microreactors are used. [2]

Contents

Batch vs. flow

Comparing parameter definitions in Batch vs Flow

Running flow reactions

Choosing to run a chemical reaction using flow chemistry, either in a microreactor or other mixing device offers a variety of pros and cons.

Advantages

Typical drivers are higher yields/selectivities, less needed manpower, or a higher safety level.

Disadvantages

The drawbacks have been discussed in view of establishing small scale continuous production processes by Pashkova and Greiner. [7]

Continuous flow reactors

reaction stages of a multi-cell flow reactor Coflore ACR.jpg
reaction stages of a multi-cell flow reactor

Continuous reactors are typically tube-like and manufactured from non-reactive materials such as stainless steel, glass, and polymers. Mixing methods include diffusion alone (if the diameter of the reactor is small e.g. <1 mm, such as in microreactors) and static mixers. Continuous flow reactors allow good control over reaction conditions including heat transfer, time, and mixing.

The residence time of the reagents in the reactor (i.e. the amount of time that the reaction is heated or cooled) is calculated from the volume of the reactor and the flow rate through it:

Therefore, to achieve a longer residence time, reagents can be pumped more slowly and/or a larger volume reactor used. Production rates can vary from nanoliters to liters per minute.

Some examples of flow reactors are spinning disk reactors; [8] spinning tube reactors; multi-cell flow reactors; oscillatory flow reactors; microreactors; hex reactors; and 'aspirator reactors'. In an aspirator reactor a pump propels one reagent, which causes a reactant to be sucked in. This type of reactor was patented around 1941 by the Nobel company for the production of nitroglycerin.

Flow reactor scale

The smaller scale of microflow reactors or microreactors can make them ideal for process development experiments. Although it is possible to operate flow processes at a ton scale, synthetic efficiency benefits from improved thermal and mass transfer as well as mass transport.

a microreactor LLNL-microreactor.jpg
a microreactor

Key application areas

Use of gases in flow

Laboratory scale flow reactors are ideal systems for using gases, particularly those that are toxic or associated with other hazards. The gas reactions that have been most successfully adapted to flow are hydrogenation and carbonylation, [9] [10] although work has also been performed using other gases, e.g. ethylene and ozone. [11]

Reasons for the suitability of flow systems for hazardous gas handling are:

Photochemistry in combination with flow chemistry

Continuous flow photochemistry offers multiple advantages over batch photochemistry. Photochemical reactions are driven by the number of photons that are able to activate molecules causing the desired reaction. The large surface area to volume ratio of a microreactor maximizes the illumination, and at the same time allows for efficient cooling, which decreases the thermal side products.

Electrochemistry in combination with flow chemistry

Continuous flow electrochemistry like continuous photochemistry offers many advantages over analogous batch conditions. Electrochemistry like Photochemical reactions can be considered as 'reagent-less' reactions. In an electrochemical reaction the reaction is facilitated by the number of electrons that are able to activate molecules causing the desired reaction. Continuous electrochemistry apparatus reduces the distance between the electrodes used to allow better control of the number of electrons transferred to the reaction media enabling better control and selectivity. [12] Recent developments in electrochemical flow-systems enabled the combination of reaction-oriented electrochemical flow systems with species-focused spectroscopy which allows a complete analysis of reactions involving multiple electron transfer steps, as well as unstable intermediates. [13] These systems which are referred to as spectroelectrochemistry systems can enable the use of UV-vis as well as more complex methods such as electrochemiluminescence. Furthermore, using electrochemistry allows another degree of flexibility since the user has control not only on the flow parameters and the nature of the electrochemical measurement itself but also on the geometry or nature of the electrode (or electrodes in the case of an electrode array). [14]

Process development

The process development change from a serial approach to a parallel approach. In batch the chemist works first followed by the chemical engineer. In flow chemistry this changes to a parallel approach, where chemist and chemical engineer work interactively. Typically there is a plant setup in the lab, which is a tool for both. This setup can be either commercial or noncommercial. The development scale can be small (ml/hour) for idea verification using a chip system and in the range of a couple of liters per hour for scalable systems like the flow miniplant technology. Chip systems are mainly used for a liquid-liquid application while flow miniplant systems can deal with solids or viscous material.

Scale up of microwave reactions

Microwave reactors are frequently used for small-scale batch chemistry. However, due to the extremes of temperature and pressure reached in a microwave it is often difficult to transfer these reactions to conventional non-microwave apparatus for subsequent development, leading to difficulties with scaling studies. A flow reactor with suitable high-temperature ability and pressure control can directly and accurately mimic the conditions created in a microwave reactor. [15] This eases the synthesis of larger quantities by extending reaction time.

Manufacturing scale solutions

Flow systems can be scaled to the tons per hour scale. Plant redesign (batch to conti[ clarification needed ] for an existing plant), Unit Operation (exchanging only one reaction step) and Modular Multi-purpose (Cutting a continuous plant into modular units) are typical realization solutions for flow processes.

Other uses of flow

It is possible to run experiments in flow using more sophisticated techniques, such as solid phase chemistries. Solid phase reagents, catalysts or scavengers can be used in solution and pumped through glass columns, for example, the synthesis of alkaloid natural product oxomaritidine using solid phase chemistries. [16]

There is an increasing interest in polymerization as a continuous flow process. For example, Reversible Addition-Fragmentation chain Transfer or RAFT polymerization. [17] [18] [19]

Continuous flow techniques have also been used for the controlled generation of nanoparticles. [20] The very rapid mixing and excellent temperature control of microreactors are able to give consistent and narrow particle size distribution of nanoparticles.

Segmented flow chemistry

As discussed above, running experiments in continuous flow systems is difficult, especially when one is developing new chemical reactions, which requires screening of multiple components, varying stoichiometry, temperature, and residence time. In continuous flow, experiments are performed serially, which means one experimental condition can be tested. Experimental throughput is highly variable and as typically five times the residence time is needed for obtaining steady state. For temperature variation the thermal mass of the reactor as well as peripherals such as fluid baths needs to be considered. More often than not, the analysis time needs to be considered.

Segmented flow is an approach that improves upon the speed in which screening, optimization, and libraries can be conducted in flow chemistry. Segmented flow uses a "Plug Flow" approach where specific volumetric experimental mixtures are created and then injected into a high-pressure flow reactor. Diffusion of the segment (reaction mixture) is minimized by using immiscible solvent on the leading and rear ends of the segment.

Composition of segment Segment Graphic 1.jpg
Composition of segment
Segment serial flow Segment Graphics.gif
Segment serial flow

One of the primary benefits of segmented flow chemistry is the ability to run experiments in a serial/parallel manner where experiments that share the same residence time and temperature can be repeatedly created and injected. In addition, the volume of each experiment is independent of that of the volume of the flow tube thereby saving a significant amount of reactant per experiment. When performing reaction screening and libraries, segment composition is typically varied by the composition of matter. When performing reaction optimization, segments vary by stoichiometry.

Segment serial/parallel Flow Segment Graphics2.gif
Segment serial/parallel Flow
Serial/Parallel Segments Serial-Parallel Segmented Flow Chemistry.jpg
Serial/Parallel Segments

Segmented flow is also used with online LCMS, both analytical and preparative where the segments are detected when exiting the reactor using UV and subsequently diluted for analytical LCMS or injected directly for preparative LCMS.

See also

Related Research Articles

<span class="mw-page-title-main">Hydrogenation</span> Chemical reaction between molecular hydrogen and another compound or element

Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically constitutes the addition of pairs of hydrogen atoms to a molecule, often an alkene. Catalysts are required for the reaction to be usable; non-catalytic hydrogenation takes place only at very high temperatures. Hydrogenation reduces double and triple bonds in hydrocarbons.

<span class="mw-page-title-main">Microreactor</span>

A microreactor or microstructured reactor or microchannel reactor is a device in which chemical reactions take place in a confinement with typical lateral dimensions below 1 mm; the most typical form of such confinement are microchannels. Microreactors are studied in the field of micro process engineering, together with other devices in which physical processes occur. The microreactor is usually a continuous flow reactor. Microreactors can offer many advantages over conventional scale reactors, including improvements in energy efficiency, reaction speed and yield, safety, reliability, scalability, on-site/on-demand production, and a much finer degree of process control.

<span class="mw-page-title-main">Chemical reactor</span> Enclosed volume where interconversion of compounds takes place

A chemical reactor is an enclosed volume in which a chemical reaction takes place. In chemical engineering, it is generally understood to be a process vessel used to carry out a chemical reaction, which is one of the classic unit operations in chemical process analysis. The design of a chemical reactor deals with multiple aspects of chemical engineering. Chemical engineers design reactors to maximize net present value for the given reaction. Designers ensure that the reaction proceeds with the highest efficiency towards the desired output product, producing the highest yield of product while requiring the least amount of money to purchase and operate. Normal operating expenses include energy input, energy removal, raw material costs, labor, etc. Energy changes can come in the form of heating or cooling, pumping to increase pressure, frictional pressure loss or agitation.

<span class="mw-page-title-main">Peptide synthesis</span> Production of peptides

In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl group of one amino acid to the amino group of another. Protecting group strategies are usually necessary to prevent undesirable side reactions with the various amino acid side chains. Chemical peptide synthesis most commonly starts at the carboxyl end of the peptide (C-terminus), and proceeds toward the amino-terminus (N-terminus). Protein biosynthesis in living organisms occurs in the opposite direction.

Micro process engineering is the science of conducting chemical or physical processes inside small volumina, typically inside channels with diameters of less than 1 mm (microchannels) or other structures with sub-millimeter dimensions. These processes are usually carried out in continuous flow mode, as opposed to batch production, allowing a throughput high enough to make micro process engineering a tool for chemical production. Micro process engineering is therefore not to be confused with microchemistry, which deals with very small overall quantities of matter.

<span class="mw-page-title-main">Chemical plant</span> Industrial process plant that manufactures chemicals

A chemical plant is an industrial process plant that manufactures chemicals, usually on a large scale. The general objective of a chemical plant is to create new material wealth via the chemical or biological transformation and or separation of materials. Chemical plants use specialized equipment, units, and technology in the manufacturing process. Other kinds of plants, such as polymer, pharmaceutical, food, and some beverage production facilities, power plants, oil refineries or other refineries, natural gas processing and biochemical plants, water and wastewater treatment, and pollution control equipment use many technologies that have similarities to chemical plant technology such as fluid systems and chemical reactor systems. Some would consider an oil refinery or a pharmaceutical or polymer manufacturer to be effectively a chemical plant.

<span class="mw-page-title-main">Trimethylsilyl group</span> Functional group

A trimethylsilyl group (abbreviated TMS) is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom [−Si(CH3)3], which is in turn bonded to the rest of a molecule. This structural group is characterized by chemical inertness and a large molecular volume, which makes it useful in a number of applications.

<span class="mw-page-title-main">Continuous stirred-tank reactor</span> Type of chemical reactor

The continuous stirred-tank reactor (CSTR), also known as vat- or backmix reactor, mixed flow reactor (MFR), or a continuous-flow stirred-tank reactor (CFSTR), is a common model for a chemical reactor in chemical engineering and environmental engineering. A CSTR often refers to a model used to estimate the key unit operation variables when using a continuous agitated-tank reactor to reach a specified output. The mathematical model works for all fluids: liquids, gases, and slurries.

<span class="mw-page-title-main">Plug flow reactor model</span> Reactor simulation model

The plug flow reactor model is a model used to describe chemical reactions in continuous, flowing systems of cylindrical geometry. The PFR model is used to predict the behavior of chemical reactors of such design, so that key reactor variables, such as the dimensions of the reactor, can be estimated.

<span class="mw-page-title-main">Aluminium hydride</span> Chemical compound

Aluminium hydride is an inorganic compound with the formula AlH3. Alane and its derivatives are part of a family of common reducing reagents in organic synthesis based around group 13 hydrides. In solution—typically in ethereal solvents such tetrahydrofuran or diethyl ether—aluminium hydride forms complexes with Lewis bases, and reacts selectively with particular organic functional groups, and although it is not a reagent of choice, it can react with carbon-carbon multiple bonds. Given its density, and with hydrogen content on the order of 10% by weight, some forms of alane are, as of 2016, active candidates for storing hydrogen and so for power generation in fuel cell applications, including electric vehicles. As of 2006 it was noted that further research was required to identify an efficient, economical way to reverse the process, regenerating alane from spent aluminium product.

<span class="mw-page-title-main">Reaction calorimeter</span> Apparatus for measuring reaction energy

A reaction calorimeter is a calorimeter that measures the amount of energy released (exothermic) or absorbed (endothermic) by a chemical reaction. These measurements provide a more accurate picture of such reactions.

Self-propagating high-temperature synthesis (SHS) is a method for producing both inorganic and organic compounds by exothermic combustion reactions in solids of different nature. Reactions can occur between a solid reactant coupled with either a gas, liquid, or other solid. If the reactants, intermediates, and products are all solids, it is known as a solid flame. If the reaction occurs between a solid reactant and a gas phase reactant, it is called infiltration combustion. Since the process occurs at high temperatures, the method is ideally suited for the production of refractory materials including powders, metallic alloys, or ceramics.

Operando spectroscopy is an analytical methodology wherein the spectroscopic characterization of materials undergoing reaction is coupled simultaneously with measurement of catalytic activity and selectivity. The primary concern of this methodology is to establish structure-reactivity/selectivity relationships of catalysts and thereby yield information about mechanisms. Other uses include those in engineering improvements to existing catalytic materials and processes and in developing new ones.

<span class="mw-page-title-main">Ammonium carbamate</span> Chemical compound

Ammonium carbamate is a chemical compound with the formula [NH4][H2NCO2] consisting of ammonium cation NH+4 and carbamate anion NH2COO. It is a white solid that is extremely soluble in water, less so in alcohol. Ammonium carbamate can be formed by the reaction of ammonia NH3 with carbon dioxide CO2, and will slowly decompose to those gases at ordinary temperatures and pressures. It is an intermediate in the industrial synthesis of urea (NH2)2CO, an important fertilizer.

Process chemistry is the arm of pharmaceutical chemistry concerned with the development and optimization of a synthetic scheme and pilot plant procedure to manufacture compounds for the drug development phase. Process chemistry is distinguished from medicinal chemistry, which is the arm of pharmaceutical chemistry tasked with designing and synthesizing molecules on small scale in the early drug discovery phase.

<span class="mw-page-title-main">Automated synthesis</span> Type of chemical synthesis

Automated synthesis or automatic synthesis is a set of techniques that use robotic equipment to perform chemical synthesis in an automated way. Automating processes allows for higher efficiency and product quality although automation technology can be cost-prohibitive and there are concerns regarding overdependence and job displacement. Chemical processes were automated throughout the 19th and 20th centuries, with major developments happening in the previous thirty years, as technology advanced. Tasks that are performed may include: synthesis in variety of different conditions, sample preparation, purification, and extractions. Applications of automated synthesis are found on research and industrial scales in a wide variety of fields including polymers, personal care, and radiosynthesis.

The residence time of a fluid parcel is the total time that the parcel has spent inside a control volume (e.g.: a chemical reactor, a lake, a human body). The residence time of a set of parcels is quantified in terms of the frequency distribution of the residence time in the set, which is known as residence time distribution (RTD), or in terms of its average, known as mean residence time.

Droplet-based microfluidics manipulate discrete volumes of fluids in immiscible phases with low Reynolds number and laminar flow regimes. Interest in droplet-based microfluidics systems has been growing substantially in past decades. Microdroplets offer the feasibility of handling miniature volumes of fluids conveniently, provide better mixing, encapsulation, sorting, sensing and are suitable for high throughput experiments. Two immiscible phases used for the droplet based systems are referred to as the continuous phase and dispersed phase.

Amol Arvindrao Kulkarni is an Indian research scientist at National Chemical Laboratory, Pune. He earned his PhD from the Institute of Chemical Technology, Mumbai in chemical engineering. His research expertise includes design and development of microreactors.

Heterogeneous metal catalyzed cross-coupling is a subset of metal catalyzed cross-coupling in which a heterogeneous metal catalyst is employed. Generally heterogeneous cross-coupling catalysts consist of a metal dispersed on an inorganic surface or bound to a polymeric support with ligands. Heterogeneous catalysts provide potential benefits over homogeneous catalysts in chemical processes in which cross-coupling is commonly employed—particularly in the fine chemical industry—including recyclability and lower metal contamination of reaction products. However, for cross-coupling reactions, heterogeneous metal catalysts can suffer from pitfalls such as poor turnover and poor substrate scope, which have limited their utility in cross-coupling reactions to date relative to homogeneous catalysts. Heterogeneous metal catalyzed cross-couplings, as with homogeneous metal catalyzed ones, most commonly use Pd as the cross-coupling metal.

References

  1. A. Kirschning (Editor): Chemistry in flow systems and Chemistry in flow systems II Thematic Series in the Open Access Beilstein Journal of Organic Chemistry.
  2. Guidi, Mara; Seeberger, Peter H.; Gilmore, Kerry (2020). "How to approach flow chemistry". Chemical Society Reviews. 49 (24): 8910–8932. doi: 10.1039/C9CS00832B . hdl: 21.11116/0000-0007-5D9A-4 . PMID   33140749. S2CID   226241802.
  3. Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio, C.; Ley, S. V.; Stevens, C. V. (2016-09-12). "Taming hazardous chemistry by continuous flow technology". Chemical Society Reviews. 45 (18): 4892–4928. doi:10.1039/C5CS00902B. ISSN   1460-4744. PMID   27453961.
  4. Fitzpatrick, Daniel E.; Battilocchio, Claudio; Ley, Steven V. (2016-02-19). "A Novel Internet-Based Reaction Monitoring, Control and Autonomous Self-Optimization Platform for Chemical Synthesis". Organic Process Research & Development. 20 (2): 386–394. doi: 10.1021/acs.oprd.5b00313 . ISSN   1083-6160.
  5. Smith, Christopher D.; Baxendale, Ian R.; Tranmer, Geoffrey K.; Baumann, Marcus; Smith, Stephen C.; Lewthwaite, Russell A.; Ley, Steven V. (2007). "Tagged phosphine reagents to assist reaction work-up by phase-switched scavenging using a modular flow reactor". Org. Biomol. Chem. 5 (10): 1562–1568. doi:10.1039/b703033a. PMID   17571185. S2CID   9891686.
  6. Boros, Zoltán; Nagy-Győr, László; Kátai-Fadgyas, Katalin; Kőhegyi, Imre; Ling, István; Nagy, Tamás; Iványi, Zoltán; Oláh, Márk; Ruzsics, György; Temesi, Ottó; Volk, Balázs (2019-06-01). "Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability". Journal of Flow Chemistry. 9 (2): 101–113. doi:10.1007/s41981-019-00036-x. ISSN   2063-0212. S2CID   155898388.
  7. Pashkova, A.; Greiner, L. (2011). "Towards Small-Scale Continuous Chemical Production: Technology Gaps and Challenges". Chemie Ingenieur Technik. 83 (9): 1337–1342. doi:10.1002/cite.201100037.
  8. Oxley, Paul; Brechtelsbauer, Clemens; Ricard, Francois; Lewis, Norman; Ramshaw, Colin (2000). "Evaluation of Spinning Disk Reactor Technology for the Manufacture of Pharmaceuticals" (PDF). Ind. Eng. Chem. Res. 39 (7): 2175–2182. doi:10.1021/ie990869u. Archived from the original (PDF) on 10 August 2017. Retrieved 10 May 2013.
  9. Csajági, Csaba; Borcsek, Bernadett; Niesz, Krisztián; Kovács, Ildikó; Székelyhidi, Zsolt; Bajkó, Zoltán; Ürge, László; Darvas, Ferenc (22 March 2008). "High-Efficiency Aminocarbonylation by Introducing CO to a Pressurized Continuous Flow Reactor". Org. Lett. 10 (8): 1589–1592. doi:10.1021/ol7030894. PMID   18358035.
  10. Mercadante, Michael A.; Leadbeater, Nicholas E. (July 2011). "Continuous-flow, palladium-catalysed alkoxycarbonylation reactions using a prototype reactor in which it is possible to load gas and heat simultaneously". Org. Biomol. Chem. 9 (19): 6575–6578. doi:10.1039/c1ob05808h. PMID   21850299.
  11. Roydhouse, M. D.; Ghaini, A.; Constantinou, A.; Cantu-Perez, A.; Motherwell, W. B.; Gavriilidis, A. (23 June 2011). "Ozonolysis in Flow Using Capillary Reactors". Org. Process Res. Dev. 15 (5): 989–996. doi:10.1021/op200036d.
  12. Noyhouzer, Tomer; Mandler, Daniel (2013). "A New Electrochemical Flow Cell for the Remote Sensing of Heavy Metals". Electroanalysis. 25: 109–115. doi:10.1002/elan.201200369.
  13. Noyhouzer T, Snowden M.E., Tefashe U.M., and Mauzeroll J., Modular Flow-Through Platform for Spectroelectrochemical Analysis, Analytical Chemistry 2017 89 (10), 5246-5253 DOI: 10.1021/acs.analchem.6b04649
  14. Noyhouzer T,Perry SC,Vicente-Luis A, Hayes PL and Mauzeroll J., The Best of Both Worlds: Combining Ultramicroelectrode and Flow Cell Technologies, Journal of the Electrochemical Society 2018 165 (2), H10-15 DOI: 10.1149/2.0641802jes
  15. Damm, M.; Glasnov, T. N.; Kappe, C. O. (2010). "Translating High-Temperature Microwave Chemistry to Scalable Continuous Flow Processes". Organic Process Research & Development. 14: 215–224. doi:10.1021/op900297e.
  16. Baxendale, Ian R.; Jon Deeley; Charlotte M. Griffiths-Jones; Steven V. Ley; Steen Saaby; Geoffrey K. Tranmer (2006). "A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly". Chemical Communications (24): 2566–2568. doi:10.1039/B600382F. PMID   16779479.
  17. Hornung, Christian H.; Guerrero-Sanchez, Carlos; Brasholz, Malte; Saubern, Simon; Chiefari, John; Moad, Graeme; Rizzardo, Ezio; Thang, San H. (March 2011). "Controlled RAFT Polymerization in a Continuous Flow Microreactor". Org. Process Res. Dev. 15 (3): 593–601. doi:10.1021/op1003314.
  18. Vandenbergh, Joke; Junkers, Thomas (August 2012). "Use of a continuous-flow microreactor for thiol–ene functionalization of RAFT-derived poly(butyl acrylate)". Polym. Chem. 3 (10): 2739–2742. doi:10.1039/c2py20423a. hdl: 1942/14216 . S2CID   98115101.
  19. Seyler, Helga; Jones, David J.; Holmes, Andrew B.; Wong, Wallace W. H. (2012). "Continuous flow synthesis of conjugated polymers". Chem. Commun. 48 (10): 1598–1600. doi:10.1039/c1cc14315h. PMID   21909518.
  20. Marek Wojnicki; Krzysztof Pacławski; Magdalena Luty-Błocho; Krzysztof Fitzner; Paul Oakley; Alan Stretton (2009). "Synthesis of Gold Nanoparticles in a Flow Microreactor". Rudy Metale. Archived from the original on 2016-08-18. Retrieved 2013-05-09.