Charlotte Wiles

Continuous flow reactors: a perspective

With aspects of continuous processing featuring heavily in efforts towards increasing the ‘green’ prospects of pharmaceutical and fine chemical manufacturing, this article focuses on the developments made into the application of continuous flow reactors for sustainable chemical research and production.

Recent advances in synthetic micro reaction technology

Although in its infancy, the field of micro reaction technology is growing rapidly, with many research groups investigating the practical advantages associated with reaction miniaturisation. With this in mind, the following Feature Article aims to provide an overview of the progress made in the past decade, paying particular attention to the field of synthetic organic chemistry.

Continuous process technology: a tool for sustainable production

Reviewing the open literature, the authors give their perspective on if continuous process technology has a role to play in sustainable production within the chemical industry.

Micro reaction technology in organic synthesis

Introduction to Micro Reaction Technology What is Micro Reaction Technology? Fabrication/Construction of Micro Reactors Manipulation of Reactants and Products within Flow Reactors Advantages of Micro Reaction Technology Disadvantages of Micro Reactors Process Intensification In Situ Reaction Monitoring Commercial Availability of Continuous Flow Outlook References Micro Reactions Employing a Gaseous Component Gas-Phase Micro Reactions Gas-Liquid-Phase Micro Reactions Gas-Liquid-Solid Micro Reactions References Liquid-Phase Micro Reactions Nucleophilic Substitution Electrophilic Substitution Nucleophilic Addition Elimination Reactions Oxidations Reductions Metal-Catalyzed Cross-Coupling Reactions Rearrangements Multistep/Multicomponent Liquid-Phase Reactions Summary References Multi-Phase Micro Reactions Nucleophilic Substitution Electrophilic Substitution Nucleophilic Addition Elimination Reactions Oxidation Reactions Metal-Catalyzed Cross-Coupling Reactions Rearrangements Enantioselective Reactions Multistep/Multicomponent Reactions Summary References Electrochemical and Photochemical Applications of Micro Reaction Technology Electrochemical Synthesis under Continuous Flow Photochemical Synthesis under Continuous Flow Multiphase Photochemical Reactions References The Use of Microfluidic Devices for the Preparation and Manipulation of Droplets and Inorganic/Organic Particles Droplet Formation using Continuous Flow Methodology Preparation of Inorganic Nanoparticles under Continuous Processing Conditions Formation of Organic Particles within Continuous Flow Devices The Use of Micro Reactors for the Postsynthetic Manipulation of Organic Compounds Mixed Particle Formation Summary References Industrial Interest in Micro Reaction Technology MRT in Production Environments Synthesis of Fine Chemicals Using Micro Reactors Synthesis of Pharmaceuticals and Natural Products using Continuous Flow Methodology Synthesis of Small Doses of Radiopharmaceuticals Summary References Microscale Continuous Separations and Purifications Introduction Liquid-Liquid Extractions Gas-Liquid Separation Solvent Exchange and Solvent Removal The Use of Scavenger Resins for Product Purification under Flow Continuous Flow Resolutions Product Isolation Summary References

The aldol reaction of silyl enol ethers within a micro reactor

We have demonstrated the use of silyl enol ethers in the aldol reaction within a micro reactor. Quantitative conversion of the silyl enol ether to a beta-hydroxyketone was observed in a 20 min period compared to traditional batch systems, where quantitative yields were only obtained when extended reaction times of 24 h were employed.

Solution phase synthesis of β-peptides using micro reactors

Abstract The synthesis of β-peptides has been successfully performed using a borosilicate glass micro reactor, in which a network of channels has been produced using a photolithographic and wet etching method. The reagents were mobilised by electroosmotic flow (EOF). The micro reactor was initially evaluated using a carbodiimide coupling reaction to form a dipeptide. The methodology has been extended such that the peptides may also be produced via the pentafluorophenyl ester derivatives of amino acids. It was found that performing the pentafluorophenyl ester reactions in the micro reactor resulted in an increase in the reaction efficiency over the traditional batch method. We postulate that the enhancement in rate of reaction is an electrochemical phenomenon, due to the reaction being performed in an electric field, which is unique to micro reactor systems. It has also been demonstrated that selective deprotection of the resultant dipeptides can be achieved. This approach has been used in the synthesis of a tripeptide.

Improved method for kinetic studies in microreactors using flow manipulation and noninvasive Raman spectrometry

A novel method has been devised to derive kinetic information about reactions in microfluidic systems. Advantages have been demonstrated over conventional procedures for a Knoevenagel condensation reaction in terms of the time required to obtain the data (fivefold reduction) and the efficient use of reagents (tenfold reduction). The procedure is based on a step change from a low (e.g., 0.6 μL min(-1)) to a high (e.g., 14 μL min(-1)) flow rate and real-time noninvasive Raman measurements at the end of the flow line, which allows location-specific information to be obtained without the need to move the measurement probe along the microreactor channel. To validate the method, values of the effective reaction order n were obtained employing two different experimental methodologies. Using these values of n, rate constants k were calculated and compared. The values of k derived from the proposed method at 10 and 40 °C were 0.0356 ± 0.0008 mol(-0.3) dm(0.9) s(-1) (n = 1.3) and 0.24 ± 0.018 mol(-0.1) dm(0.3) s(-1) (n = 1.1), respectively, whereas the values obtained using a more laborious conventional methodology were 0.0335 ± 0.0032 mol(-0.4) dm(1.2) s(-1) (n = 1.4) at 10 °C and 0.244 ± 0.032 mol(-0.3) dm(0.9) s(-1) (n = 1.3) at 40 °C. The new approach is not limited to analysis by Raman spectrometry and can be used with different techniques that can be incorporated into the end of the flow path to provide rapid measurements.

A microreactor for the study of biotransformations by a cross‐linked γ‐lactamase enzyme

A (+)-gamma-lactamase was precipitated, cross-linked and the resulting solid crushed prior to immobilisation within a capillary column microreactor. The microreactor was subsequently used to study enzyme stability, activity, kinetics and substrate specificity. The thermophilic (+)-gamma-lactamase retained 100% of its initial activity at the assay temperature, 80 degrees C, for 6 h and retained 52% activity after 10 h, indicating the advantage of immobilisation. This high stability of the immobilised enzyme provided the advantage that it could be utilised to screen many compounds in the microreactor system. This advantage overcame the fact that the immobilisation process affected enzyme kinetics and activity, which was reduced (by 70%) compared to the free enzyme. In general, the enzyme displayed similar substrate specificity to that found in a previous study for the free enzyme; however, enhanced activity was seen towards one substrate, acrylamide. The system developed correlates well with the free enzyme in batch assay and indicates the suitability of the system for enzyme substrate screening, allowing a significant reduction in cost, due to the reduced amounts of enzyme, substrates and other assay constituents required.

1,4-Addition of enolates to α,β-unsaturated ketones within a micro reactor

We demonstrate the formation of a series of diketone enolates and their subsequent reaction with alpha,beta-unsaturated carbonyl compounds in order to prepare a variety of Michael adducts. In all cases, the conversions observed within a micro reactor were greater than those obtained in batch.

The use of solid-supported reagents for the multi-step synthesis of analytically pure α,β-unsaturated compounds in miniaturized flow reactors

Micro reaction technology offers a safe, controllable and information rich technique suitable for the long-term production of pharmaceutical agents and fine chemicals. To date however, few of the syntheses performed using this technology have addressed the problems associated with product purification. With this in mind, we report herein the incorporation of multiple supported reagents into EOF-based miniaturized flow reactors for the two-step synthesis of analytically pure compounds. Using this approach, the successful synthesis of 20 α,β-unsaturated compounds in excellent yields (>99.1%) and purities (>99.9%) has been achieved, illustrating significant improvements compared to traditional batch techniques.