Anastasios Polyzos

The continuous-flow synthesis of carboxylic acids using CO2 in a tube-in-tube gas permeable membrane reactor.

The use of flow chemistry methods, and immobilized reagents and scavengers is leading to recognizable advances in the praxis of molecular assembly. The operation of these processes can bring wide-ranging benefits, not the least of which releases human resources so necessary for the intellectual design and planning of the synthesis pathways. The increasingly competitive climate of chemical research in industrial and academic programs has necessitated a shift from the previous inefficient downstream chemical processing methods towards more sustainable approaches that better reflect the challenges of the discovery process. To address these issues, we have advocated the use of tools and techniques that facilitate more of a “machine-assisted” approach, of which flow chemistry has been particularly useful for conducting efficient, multistep sequences leading directly to a drug molecule or even natural products. When these methods are coupled with the use of immobilized reagents, scavengers, catch and release, and phase switching methods, our group has shown that flow chemistry can lead to demonstrable improvements particularly as they relate to reaction work-ups by avoiding conventional methods of chromatography, crystallization, distillation and aqueous extractions or pH adjustments. Furthermore, flow chemistry methods can accommodate improved safety through incorporation of appropriate monitoring and remote control methods. The use of reactive gases in organic synthesis provides advantages in terms of cost efficiency and work-up. Reactive gases can often be used in excess and are readily removed from the reaction mixture, affording cleaner synthesis processes. However, there is a general reluctance to use reactive gases in research laboratories largely owing to problems related to the containment of pressurized gases, associated safety factors, and the high capital costs and infrastructure requirements of large scale gas-liquid reactors. Flow chemical methods may overcome some of the obstacles to their adoption in useful synthetic transformations. The introduction of gases into flow streams can be achieved through plug-flow techniques, microreactors, or mechanical mixing of gas-liquid phases, however, the resulting ambient pressures or low throughput can restrict these approaches. We have previously reported upon the use of gas permeable membrane tubing (Teflon AF-2400) as a particularly effective method of delivering gas to a liquid flow stream in a controlled manner. Teflon AF-2400 is a chemically inert copolymer of tetrafluoroethylene (TFE) and 2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole (Figure 1). The resulting polymer is an extensively microporous, amorphous material with high gas permeability.

Hydrogenation in flow: Homogeneous and heterogeneous catalysis using Teflon AF-2400 to effect gas–liquid contact at elevated pressure

A Tube-in-Tube reactor/injector has been developed, based on a gas-permeable Teflon AF-2400 membrane, which allows both heterogeneous and homogeneous catalytic hydrogenation reactions to be efficiently carried out at elevated pressure in flow, thereby increasing the safety profile of these reactions. Measurements of the gas permeation through the tubing and uptake into solution, using both a burette method and a novel computer-assisted ‘bubble counting’ technique, indicate that permeation/dissolution follows Henrys law and that saturation is achieved extremely rapidly. The same gas-permeable membrane has also been shown to efficiently effect removal of excess unreacted hydrogen, thus enabling further downstream reaction/processing.

Flow Chemistry: Intelligent Processing of Gas–Liquid Transformations Using a Tube-in-Tube Reactor

CONSPECTUS: The previous decade has witnessed the expeditious uptake of flow chemistry techniques in modern synthesis laboratories, and flow-based chemistry is poised to significantly impact our approach to chemical preparation. The advantages of moving from classical batch synthesis to flow mode, in order to address the limitations of traditional approaches, particularly within the context of organic synthesis are now well established. Flow chemistry methodology has led to measurable improvements in safety and reduced energy consumption and has enabled the expansion of available reaction conditions. Contributions from our own laboratories have focused on the establishment of flow chemistry methods to address challenges associated with the assembly of complex targets through the development of multistep methods employing supported reagents and in-line monitoring of reaction intermediates to ensure the delivery of high quality target compounds. Recently, flow chemistry approaches have addressed the challenges associated with reactions utilizing reactive gases in classical batch synthesis. The small volumes of microreactors ameliorate the hazards of high-pressure gas reactions and enable improved mixing with the liquid phase. Established strategies for gas-liquid reactions in flow have relied on plug-flow (or segmented flow) regimes in which the gas plugs are introduced to a liquid stream and dissolution of gas relies on interfacial contact of the gas bubble with the liquid phase. This approach confers limited control over gas concentration within the liquid phase and is unsuitable for multistep methods requiring heterogeneous catalysis or solid supported reagents. We have identified the use of a gas-permeable fluoropolymer, Teflon AF-2400, as a simple method of achieving efficient gas-liquid contact to afford homogeneous solutions of reactive gases in flow. The membrane permits the transport of a wide range of gases with significant control of the stoichiometry of reactive gas in a given reaction mixture. We have developed a tube-in-tube reactor device consisting of a pair of concentric capillaries in which pressurized gas permeates through an inner Teflon AF-2400 tube and reacts with dissolved substrate within a liquid phase that flows within a second gas impermeable tube. This Account examines our efforts toward the development of a simple, unified methodology for the processing of gaseous reagents in flow by way of development of a tube-in-tube reactor device and applications to key C-C, C-N, and C-O bond forming and hydrogenation reactions. We further describe the application to multistep reactions using solid-supported reagents and extend the technology to processes utilizing multiple gas reagents. A key feature of our work is the development of computer-aided imaging techniques to allow automated in-line monitoring of gas concentration and stoichiometry in real time. We anticipate that this Account will illustrate the convenience and benefits of membrane tube-in-tube reactor technology to improve and concomitantly broaden the scope of gas/liquid/solid reactions in organic synthesis.

The Oxygen‐Mediated Synthesis of 1,3‐Butadiynes in Continuous Flow: Using Teflon AF‐2400 to Effect Gas/Liquid Contact

In recent years, as the ecological impact of technology and industrial processes has become clearer, there has been a growing demand for more environmentally benign and sustainable chemical processes. One noteworthy example of this ongoing trend has been the development of oxidative processes that use molecular oxygen as the reagent, either directly or in conjunction with catalysis. As well as for typical functional group oxidations, molecular oxygen is seeing significant and increasing use in several synthetically important carbon carbon bond forming reactions. Of these, the Glaser–Hay oxidative acetylene coupling reaction to form 1,3-butadiynes is an important example. The intense research interest in this reaction is largely due the importance of the conjugated diyne and polyyne products, which have very interesting electronic, optical, and material properties. Being completely ecologically compatible, the use of molecular oxygen is clearly advantageous when compared with other common metal-based oxidants (e.g. , chromium(VI) reagents, permanganate). The latter have significant toxicity and their use necessitates expensive and energy-intensive clean-up procedures. Importantly, the gaseous nature of oxygen facilitates its separation from products, thereby permitting the use of excess oxidant in order to drive reactions to completion. However, this also leads to severe complications from a process standpoint, in that gas/liquid phase-transfer phenomena have to be considered. Whilst several practical methods exist to increase the dissolution rate of oxygen (and other gases) into solution (e.g. , sparging, agitation, vortex mixing), the accurate control of these processes is by no means trivial. In addition, owing to changes in physical parameters such as surface-to-volume ratios, the scale-up of batch chemical processes that involve a gas/liquid interface is often much more complex than simply using a bigger reaction vessel. An obvious further consideration with gaseous reagents such as oxygen is that the high pressures often required to obtain adequate solution concentrations (according to Henry’s law) call for specialized and expensive containment vessels, and raise safety concerns. Flow chemistry (and related continuous processing techniques) has emerged recently as an alternative paradigm of synthesis chemistry that offers solutions to some of the problems associated with batch processing. In particular, as the physical parameters of the processing zones are fixed (and small), the scale-up of reaction processes is greatly simplified and can be achieved either by increasing the running-time of a reaction, or by parallelization of the reaction through multiple identical paths (“scale-out”). This is especially advantageous for processes that involve hazardous intermediates or conditions (e.g. , high pressures or temperatures), as the total hazard present at any one time is kept to a minimum. Additionally, mixing processes (including interfacial transfer) are often enhanced due to the small physical scale (and, hence, increased surface-to-volume ratio) of the reaction zones. Notwithstanding the potential benefits of conducting gas/ liquid chemistry in flow, development in this area has been relatively slow, perhaps due to the difficulty of achieving accurate and reliable control of the interfacial processes. Until recently, approaches to solve these problems have focused on “mechanical mixing” of the two phases in order to achieve greater interfacial surface areas, and this has resulted in some interesting engineering developments. However, the relationship between the morphology of the interface (hence, reaction conversion) and flow rate is often non-linear, and this can cause severe difficulty with reaction optimization. Seeking a more generally applicable, consistent, and wellcontrolled method of gas/liquid contact, we conceived the use of semi-permeable membranes to generate homogeneous gas solutions. We have shown that Teflon AF-2400 (a co-polymer of tetrafluoroethene and a perfluorodimethyldioxolane) is very well suited to this purpose as it is extremely permeable to a wide range of gases but practically impermeable to liquids, and exhibits much of the chemical resistance associated with polytetrafluoroethylene (PTFE). By using a simple “jar” reactor we demonstrated the use of this material for the ozonolysis of alkenes, and more recently we have developed a “tube-intube” reactor that has been used to effect carboxylations and hydrogenations at elevated pressures. Herein, we present our initial findings on the use of oxygen in such a reactor to effect Glaser–Hay couplings of terminal alkynes in continuous flow. The permeability of the AF-2400 tubing to molecular oxygen can be demonstrated by using a visual indicator that changes color in the presence of the gas. Shown in Figure 1 are photographs of a coil of the AF-2400 tubing in a sealed glass vessel, the contents of which were continuously flushed with either air, oxygen, or argon (all at [a] T. P. Petersen, Dr. A. Polyzos , Dr. M. O’Brien, Dr. I. R. Baxendale, Prof. S. V. Ley Whiffen Laboratory, Department of Chemistry University of Cambridge Lensfield Road, Cambridge (UK) E-mail : svl1000@cam.ac.uk [b] T. P. Petersen, Dr. T. Ulven Department of Physics and Chemistry University of Southern Denmark, Odense (Denmark) [c] T. P. Petersen Discovery Chemistry and DMPK H. Lundbeck A/S, Valby (Denmark) [d] Dr. A. Polyzos CSIRO, Materials Science and Engineering Bayview Avenue, Clayton South, VIC 3169 (Australia) Sp eial Isu e: lo w C h em itry

Versatile, High Quality and Scalable Continuous Flow Production of Metal-Organic Frameworks

Further deployment of Metal-Organic Frameworks in applied settings requires their ready preparation at scale. Expansion of typical batch processes can lead to unsuccessful or low quality synthesis for some systems. Here we report how continuous flow chemistry can be adapted as a versatile route to a range of MOFs, by emulating conditions of lab-scale batch synthesis. This delivers ready synthesis of three different MOFs, with surface areas that closely match theoretical maxima, with production rates of 60 g/h at extremely high space-time yields.

Flow synthesis using gaseous ammonia in a Teflon AF-2400 tube-in-tube reactor: Paal–Knorr pyrrole formation and gas concentration measurement by inline flow titration

Using a simple and accessible Teflon AF-2400 based tube-in-tube reactor, a series of pyrroles were synthesised in flow using the Paal-Knorr reaction of 1,4-diketones with gaseous ammonia. An inline flow titration technique allowed measurement of the ammonia concentration and its relationship to residence time and temperature.

Porous, functional, poly(styrene-co-divinylbenzene) monoliths by RAFT polymerization

Herein we provide the first report of a new method for the preparation of porous functional poly(styrene-co-divinylbenzene) monoliths by use of reversible addition–fragmentation chain transfer (RAFT) polymerization. The method, exemplified by styrene–divinylbenzene copolymerization in the presence of 2-cyano-2-propyl dodecyl trithiocarbonate, provides control over polymerization kinetics, monolith morphology and surface functionality. Kinetic studies of monolith formation show a period of slow copolymerization, with a rate similar to RAFT homopolymerization of styrene, followed by rapid copolymerization, with a rate similar to that observed in conventional styrene–divinylbenzene copolymerization. The time to onset of rapid polymerization (gelation) and the monolith morphology depend strongly on the RAFT agent concentration. The RAFT-synthesized monoliths show a modified morphology with smaller pores and polymer globules when compared to non-RAFT monoliths, but importantly retain good flow properties. Retention of the thiocarbonylthio group within the monolith structure in an active form for surface-functionalization of the polymeric monoliths is demonstrated by the successful RAFT “grafting from” polymerization of (4-vinylphenyl)boronic acid. These functional monoliths have potential applications in chromatography and flow chemistry.

Continuous flow based catch and release protocol for the synthesis of α-ketoesters

Summary Using a combination of commercially available mesofluidic flow equipment and tubes packed with immobilised reagents and scavengers, a new synthesis of α-ketoesters is reported.

Cubic phases of ternary amphiphile–water systems

The reversed cubic phases (QII) are a class of self-assembled amphiphile–water structures that are rich in diversity and structural complexity. These nanostructured liquid crystalline materials are generating much interest owing to their unique surface morphology, biological relevance and potential technological and medical applications. The structure of QII phases in binary amphiphile–water systems is affected by the molecular structure of surfactant, water content, temperature and pressure. The presence of additives also plays an important role. The structure and phase behaviour of ternary QII phases, which are comprised of two miscible amphiphiles and water, significantly differ from the binary system alone. The modulation of the phase behaviour through the addition of a second amphiphile offers an opportunity to control the size and shape of the nanostructures using a ‘bottom-up’ approach. In this mini-review, we discuss the structure of reversed cubic phases of amphiphile–water systems and highlight the modulation of cubic-phase structure in ternary-phase systems. We also extend this review to bulk cubic phases and the corresponding nanoscale dispersions, cubic-phase nanoparticles.

Surface immobilization of bio-functionalized cubosomes: sensing of proteins by quartz crystal microbalance.

A strategy for tethering lipid liquid crystalline submicrometer particles (cubosomes) to a gold surface for the detection of proteins is reported. Time-resolved quartz crystal microbalance (QCM-D) was used to monitor the cubosome-protein interaction in real time. To achieve specific binding, cubosomes were prepared from the nonionic surfactant phytantriol, block-copolymer, Pluronic F-127, and a secondary biotinylated lipid, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[biotinyl(polyethyleneglycol)-2000], which enabled attachment of the particles to a neutravidin (NAv)-alkanethiol monolayer at the gold surface of the QCM sensor chip. A second set of cubosomes was further functionalized with addition of the glycolipid (G(M1)) to facilitate a specific binding uptake of the protein, cholera toxin B subunit (CT(B)), from solution. QCM-D confirmed the specificity of the cubosome-NAv binding. The analysis of titration experiments, also performed with QCM, suggests that an optimal concentration of cubosomes is required for the efficient packing of the particles at the surface: high cubosome concentrations lead to chaotic cubosome binding onto the surface, sterically inhibiting surface attachment, or require significant reorganization to permit uniform cubosome coverage. The methodology enabled the straightforward preparation of a complex nanostructured edifice, which was then used to specifically capture analyte proteins (cholera toxin B subunit or free NAv) from solution, supporting the potential for development of this approach as a biosensing platform.