The past, present and potential for microfluidic reactor technology in chemical synthesis

TLDR: The utility of microfluidic reactor technology as a tool in chemical synthesis in both academic research and industrial applications and the current roadblocks hindering the widespread use are assessed.

Abstract: The successes and failures of past research in the development of microfluidic reactors for chemical synthesis are highlighted. Current roadblocks are assessed and a series of challenges for the future of this area are identified.

Figures

Figure 1 – Microfluidic reactors for industrial processes. a, The Lonza FlowPlate Lab microfluidic reactor can be used for

Figure 5 – Microfluidic reactor size considerations. A plot of Reynolds number versus residence time for microfluidic reactors of 5 metres in length and channel diameters ranging between 100 μm and 5 mm. Data show that, for a wide range of flow rates,

Figure 4 – Microfluidic reactors for reaction optimisation with continuous monitoring. Continuous online IR analysis of the 625 product of a Paal-Knorr reaction allowed for reaction optimisation using several different multi-trajectory optimisation strategies. a, Experimental setup showing both fluid flow (solid lines) and data flow (dashed lines). b, Three different methods were assessed (from top to bottom): steepest gradient, conjugate gradient and Armijo conjugate gradient. The colour scale shows the value of the objective function, X/τ, where X is the conversion fraction and τ is the residence time. The black box denotes the initial conditions in each case and the optimal conditions are highlighted by a red box. The Armijo conjugate 630 gradient method is shown to be the most efficient.113

Figure 3 – Microfluidic reactors for reaction optimisation. Reaction optimisation was performed on a microfluidic reactor using

Figure 7 – Microfluidic reactors for discovery catalyst research. A microfluidic reactor and genetic algorithms were used to find new catalysts for the oxidation of methane. a, Hundreds of reaction conditions were assayed in droplets. The authors took

Figure 2 – Microfluidic reactors for integrated synthesis. On-chip, integrated synthesis of the imaging probe 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) with subsequent testing of the probe in mice. The multi-step synthesis was performed in a PDMS microfluidic reactor and is shown in steps (i) to (v) in a. The PDMS valve mechanism used to dose and extract reagents

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Citation for this paper:
Elvira, K.S., Casadevall I Solvas, X. Wootton, R.C.R. & deMello, A.J. (2013). The
past, present and potential for microfluidic reactor technology in chemical
synthesis. Nature Chemistry, 5, 905-915. https://doi.org/10.1038/nchem.1753
UVicSPACE: Research & Learning Repository
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This is a post-review version of the following article:
The past, present and potential for microfluidic reactor technology in chemical
synthesis
Katherine S. Elvira, Xavier Casadevall i Solvas, Robert C. R. Wootton and Andrew J.
deMello
2013
The final published version of this article can be found at:
https://doi.org/10.1038/nchem.1753

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The past, present and potential for
microfluidic reactor technology in chemical
synthesis
Katherine S. Elvira,
*
Xavier Casadevall i Solvas, Robert C. R. Wootton and Andrew J.
5
deMello
*
Department of Chemistry and Applied Biosciences, Institute for Chemical and Bioengineering, ETH Zürich,
Wolfgang-Pauli Strasse 10, Zürich, 8093, Switzerland
10
(*katherine.elvira@chem.ethz.ch and *andrew.demello@chem.ethz.ch)
The past two decades have seen far-reaching progress in the development of microfluidic systems for
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use in the chemical and biological sciences. Herein we assess the utility of microfluidic reactor
technology as an essential tool in chemical synthesis in both academic research and industrial
applications. We highlight the successes and failures of past research in the field and provide a
catalogue of chemistries performed in a microfluidic reactor. Subsequently, we assess the current
roadblocks hindering the widespread use of microfluidic reactors from the perspective of both synthetic
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chemistry and industrial application. Finally, we will set out seven challenges that we hope will inspire
the future research in this field.
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The advent of microfluidic technology as a basic tool for chemical synthesis is slowly coming of age,
particularly in industrial settings. As with many new techniques, initial claims regarding performance,
uniqueness and applicability were optimistic and wide ranging. The field has now had time to mature and
it is time to look back on some of these early claims and compare them to actual progress, with a view to
predicting how and if microfluidic reactors can reach their full potential in the field of chemical research.
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Microfluidic systems manipulate and control fluids that are geometrically constrained within
environments having internal dimensions, or hydrodynamic diameters, most easily measured in microns.
Although the first example of a microfluidic device can be traced back to 1940,
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work by Terry and co-
workers describing the fabrication and testing of a chip-based gas chromatograph,
2
and later studies by
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Manz
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, Mathies
4
and others in the early 1990s in the field of chip-based separations, better define the
origins of mainstream microfluidic total analysis systems (μTAS) as they are understood today. At a similar
time, the field of microfluidic reaction technology for chemical synthesis was developing quickly with
notable contributions from researchers at GlaxoSmithKline (UK),
5
Massachusetts Institute of Technology
(USA),
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the Institut für Mikrotechnik Mainz (Germany)
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and Imperial College London (UK),
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amongst
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others.
The intrinsic advantages associated with performing chemistry in microfluidic devices have been discussed
extensively elsewhere, but in simple terms are due to the scale-dependent processes of heat and mass
transfer.
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Small fluidic volumes dictate that low Reynolds number regimes are the norm, with fluids being
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increasingly influenced by viscosity rather than inertia. In addition, large surface area-to-volume ratios
ensure thermal homogeneity across the reactor and rapid heat transfer between the device and the
contained fluid. These basic properties give rise to the following broad advantages that have made the
technology attractive (in principle) for chemical synthesis in both industry and academia.
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3
Small reagent volumes. There is a distinct cost advantage in using small volumes of precious reagents
where minimal amounts may be available for testing or processing. Particularly when used for informatics
rather than for product synthesis, microfluidic reactors consume far less reagent than bulk systems to
gather the same, and in most cases more chemical information.
10,11
Selectivity. Many chemical and biological reactions generate more than one product from the same
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reactant pool depending on the local conditions. This phenomenon is often ascribed to kinetic versus
thermodynamic control of the reaction pathway.
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In microfluidic reactors the degree of control over local
conditions is such that it is often possible to select one product over another with high precision.
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Green credentials. Since heat transfer becomes more efficient as reaction volumes shrink, the amount of
energy consumed per unit temperature rise can be made extremely small, leading to significant
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environmental benefits.
14
Similarly the improved selectivity
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mentioned above leads to less stringent
reaction clean-up, and thus simpler chemistry than is typical on the macroscale.
Rapid reactions. It has often been claimed that microfluidic reactors produce “faster reactions” than
those performed on the macroscale.
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Specifically, space-time yields (product formed per reactor volume
and time) in microfluidic reactors are consistently reported to be higher than those in bulk reactors.
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It is,
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however, difficult to make direct comparisons, as bulk reactions are rarely optimised to terminate exactly
at the final equilibrium position of the reaction (reaction completion or endpoint), but often incorporate
extra time to ensure completion has been reached. Reactions performed in microfluidic reactors are
rarely run for longer than the time required to reach the reaction endpoint, since they can be closely
monitored to determine reaction completion. Accordingly, reaction times from literature syntheses are
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almost always incompatible with times associated with microfluidic formats. It is also important to note
that there is no reason to expect the intrinsic rate of rate-limited reactions to increase within a
microfluidic device compared to a similar “bulk” reaction unless a wall-mediated mechanism is invoked.
This is simply because reaction kinetics do not rely on large-scale diffusion. Despite this issue, the rate of
mass-transfer limited reactions (i.e. reactions operating in the diffusive domain) will typically be increased
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4
by the small characteristic dimensions of microfluidic reactors, since in mass-transfer limited systems
diffusive effects are significant with respect to the overall rate.
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Small footprints. Flow reactors almost always have a smaller footprint per kilogram of product than
macroscale reactors.
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Adoption of microfluidic formats allows this scale to be further reduced since more
efficient heat transfer means that requirements for heat exchange equipment are minimised.
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Safe reactions. Microfluidic reactors have several intrinsic properties that make them safe environments
in which to perform dangerous chemistry. Firstly, the small instantaneous volumes involved mean that
reactions involving reactive, toxic or explosive intermediates can be carried out in safety.
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Furthermore,
the high surface area-to-volume ratios within the channel allow the rapid transport of heat when
performing exothermic reactions
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and the enhancement of wall quenching in radical mediated systems.
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That said, scientists are not prophets. The predictions made and the hype generated around early stage
technology is often wide of the mark when examined with the benefit of hindsight. Accordingly, some of
the initial predictions relating to the development of chemical microfluidic systems bear inspection. Below
are a few of the standout predictions that have been made, or questions that have been posed, around
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microfluidic reaction technology, together with the current answer to these questions.
Will microfluidic technology replace the flask? This was a question posed often enough to become a
review title.
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The notion was that a microfluidic reaction system could be used for as wide a range of
chemical operations as the venerable round-bottomed flask. To be fair, most people asking this question
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came to the same conclusion: there are areas where the application of microfluidic reaction technology
makes sense, and others where the flask will remain the modality of choice.
Numbering up not scaling up.
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It has long been suggested that the way to transform microfluidic
chemistry into an industrial tool is to massively parallelise the reactors (numbering up or scaling out)
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