Microwave-assisted flow processing in heterogeneously copper nano-catalyzed reactions

In the last decades, micro-processing and microwave technology have been established as mature technologies, however, mainly instigated by academia. Many advances in micro-process technology have led to novel routes and/or process windows to replace batch operations by more efficient continuous processes, both at lab and at industrial scales. Especially, the fine-chemicals industry has been recognized for realistic implementation of these technologies with respect to both scale as well as cost. In this thesis, the major hurdles to combine microwave and micro-processing technology for organic syntheses have been addressed. In comparison to gas-phase reactions, metal-catalyzed liquid-phase organic synthesis requires different operational process windows to realize successful implementation of micro-processing. Major issue here is to avoid solid bases and slurry catalysts by including pre-treatment steps and depositing catalysts onto structured supports. In addition, the use of metals as catalysts under microwave irradiation is known for rapid energy absorption and, therefore, requires special attention regarding temperature control. The Ullmann-type coupling reaction and the Simmons-Smith type cyclopropanation are both intensively employed in the fine-chemicals industry and were, therefore, investigated over various novel heterogeneous Cu catalysts in this project. The Cu-catalyzed coupling of aromatic compounds is not only an excellent example to investigate the benefits of integrated microwave and micro/milli-reactor technologies, but also for its potential applications in the production of pharmaceutically active molecules, such as antivirals and antibiotics (e.g. Vancomycin). This type of organic reactions provides considerable challenges to overcome, both with respect to the severe reaction conditions and, undoubtedly, the sustainability of heterogeneous catalysis which substantially contributes to the cost in flow processing. More importantly, however, was the use of heterogeneous CuZn nano-colloids which, as oxidative stable "metallic microwave-absorber", provide an additional benefit (but also point of attention) regarding the higher temperatures at the locus of the reaction. Therefore, monometallic and bimetallic Cu-based nanoparticles with a narrow size-distribution and a high resistance against oxidation and agglomeration were developed. The chemical and colloidal stability of these Cu-based nanoparticles, including their purity and morphology, could be significantly improved by coating the copper nanoparticles with poly(N-vinylpyrrolidone). These nano-catalysts were then tested for their performance in the Ullmann-type coupling reaction and the Simmons-Smith cyclopropanation. Subsequently, these novel nano-catalysts were immobilized onto a microwave-transparent TiO2 support and used in a fixed-bed reactor. Novel routes for the preparation of highly active TiO2-supported Cu and CuZn catalysts were proposed and applied in Cu-catalyzed organic reactions. The copper oxidation was significantly suppressed by using CuZn/TiO2 catalytic films and a strong relation between the catalyst composition and activity was found for the Ullmann C O coupling reaction. This novel preparation method was based on titania dip-coating onto glass beads, obtaining either structured mesoporous or non-porous titania thin films, which could be loaded with the catalyst nanoparticles by deposition onto the calcined films. These catalysts were analyzed using various characterization techniques and in operando synchrotron X-ray absorption spectroscopy, giving a better understanding of their catalytic behavior. Besides catalyzing a reaction, the energy supply towards the catalyst surface is obviously as important and has been also investigated in this project. This issue has been addressed separately, because in traditional reactors the energy supply is particularly governed by classical heat transfer limitations. Furthermore, the troubleshooting of the major obstacles for continuous operations to synergize the benefits of microwave systems and micro/milli-processing in flow synthesis has been targeted. A micro fixed-bed reactor was designed, using packed spherical glass beads coated with the catalyst and support, for kg-scale flow operations in the Ullmann C-O coupling. In addition, the influence of reactor shape and dimensions for effective microwave irradiation was studied. Experimental evidence of complete microwave penetration in the radial direction was found, allowing rapid and controlled heating without significant radial temperature gradients in the flow-through reactors. The above mentioned developments in chemistry, nano-catalysis and reactor engineering were the basis for an extended cost study, consisting of 14 process scenarios. In this way, the cost-impact of micro-processing and microwave heating for liquid-phase reactions in fine-chemicals synthesis could be envisaged. Two examples were studied, i.e. the Ullmann-type coupling reactions and the Aspirin synthesis. It could be concluded that the operating costs in the Ullmann-type processes compared to those of the Aspirin synthesis can be defined as either material based (e.g. reactant excess, pretreatment and catalyst synthesis) or downstream processing based (e.g. work-up, waste treatment) processes. The impact of integrating microwave heating and micro-processing systems on profitability was evaluated with respect to operational costs and chemical productivity. This techno-economic evaluation provided a route map, highlighting feasible routes to combine different technologies, chemical processes and catalyst systems

Scale-up of an RF heated micro trickle bed reactor to a kg/day production scale

The scale-up of a radiofrequency (RF) heated micro trickle bed reactor for hydrogenation of 2-methyl-3-butyne-2-ol (MBY) over a Pd/TiO2 catalyst has been performed. The axial and radial temperature profiles were calculated using a 2D convection and conduction heat transfer model. The effect of the reactor length, tube diameter and number of parallel tubes on the temperature non-uniformity parameter has been studied. The axial scale-up was achieved by repeating a single periodic unit consisting of one heating and one catalytic zone along the reactor length. The catalyst loading can be increased by an order of magnitude following this approach. A radial temperature difference of 2 K was developed in a reactor with an inner diameter of 15 mm. The scale-up by numbering up allows the accommodation of seven parallel tubes inside a single RF coil. It creates a 7 K difference in the average temperature between the central and the outer tubes which results in a 5% difference in MBY conversion. An overall scale-up factor of near 700 is achieved which corresponds to a production rate of 0.5 kg of product/day

Scale-up of Microwave Assisted Flow Synthesis by Transient Processing through Monomode Cavities in Series

A new scale-up concept for microwave assisted flow processing is presented where modular scale-up is achieved by implementing microwave cavities in series. The scale-up concept is demonstrated for case studies of a packed-bed reactor and a wall-coated tubular reactor. With known kinetics and reaction temperature, a packed-bed reactor gave a conversion of 99% with the highest production rate of 170 kgprod/kgcat·h for esterification of acetic acid and ethanol catalyzed by ion-exchange resin in 18 cavities. A similar approach for a multicomponent reaction of benzaldehyde, piperidine, and phenylacetylene catalyzed by a thin Cu film in a wall-coated tubular reactor gave 99% conversion with the highest production rate of 7740 kgprod/kgcat·h in 28 cavities. In both cases, the pseudo first order reaction rate with respect to the limiting reactant yielded a typical rise in conversion and production rate. In a packed-bed reactor-heat exchanger operated at a temperature between 343 and 348 K, the conversion in the esterification reaction increased from 22% to 88% when the number of cavities was increased from one to eight. The experimental conversions matched the predictions of a packed bed reactor model within 5%. The production capacity in flow reactors, restricted to smaller sizes due to a limited microwave penetration depth and dominated mainly by the reaction kinetics, was increased by modular scale-up with implementation of the microwave multicavity assembly

Microwave-assisted Cu-catalyzed Ullmann ether synthesis in a continuous-flow milli-plant

The combination of milli-scale processing and microwave heating has been investigated for the Cu-catalyzed Ullmann etherification in fine-chemical synthesis, providing improved catalytic activity and selective catalyst heating. Wall-coated and fixed-bed milli-reactors were designed and applied in the Cucatalyzed Ullmann-type CAO coupling of phenol and 4-chloropyridine. In a batch reactor the results show clearly increased yields for the microwave heated process at low microwave powers, whereas high powers and catalyst loadings reduced the benefits of microwave heating. Slightly higher yields were found in the Cu/ZnO wall-coated as compared to the Cu/TiO2 fixed-bed flow-reactor. The benefit here is that the reaction occurs at the surface of the metal nanoparticles confined within a support film making the nano-copper equally accessible. Catalyst deactivation was mainly caused by Cu oxidation and coke formation; however, at longer process times leaching played a significant role. Catalyst activity could partially be recovered by removal of deposited by-product by means of calcination. After 6 h on-stream the reactor productivities were 28.3 and 55:1 kgprod=ðm3 R hÞ for the fresh Cu/ZnO wall-coated and Cu/TiO2 fixed-bed reactor, respectively. Comparison of single- and multimode microwaves showed a threefold yield increase for single-mode microwaves. Control of nanoparticles size and loading allows to avoid high temperatures in a single-mode microwave field and provides a novel solution to a major problem for combining metal catalysis and microwave heating. Catalyst stability appeared to be more important and provided twofold yield increase for the CuZn/TiO2 catalyst as compared to the Cu/TiO2 catalyst due to stabilized copper by preferential oxidation of the zinc. For this catalyst a threefold yield increase was observed in single-mode microwaves which, to the best of our knowledge, led to a not yet reported productivity of 172 kgprod=ðm3 R hÞ for the microwave and flow Ullmann CAO coupling

New routes to Cu(l)/Cu nanocatalysts for the multicomponent click synthesis of 1,2,3-triazoles

An array of copper and copper–zinc based nanoparticles (NPs) have been fabricated employing a variety of polymeric capping agents. Analysis by TEM, XRPD and XPS suggests that by manipulating reagent, reductant and solvent conditions it is possible to achieve materials that are mono-/narrow disperse with mean particle sizes in the ≤10 nm regime. Oxidative stability in air is achieved for monometallic NPs using poly(methyl methacrylate) (PMMA) anti-agglomerant in conjunction with a variety of reducing conditions. In contrast, those encapsulated by either poly(1-vinylpyrrolidin-2-one) (PVP) or poly(4-vinylpyridine) (PVPy) rapidly show Cu2O formation, with all data suggesting progressive oxidation from Cu to Cu@Cu2O core–shell structure and finally Cu2O. Bimetallic copper–zinc systems, reveal metal segregation and the formation of Cu2O and ZnO. Catalysts have been screened in the synthesis of 1,2,3-triazoles through multicomponent azide–alkyne 1,3-dipolar cycloaddition. Whereas PMMA- and PVPy-coating results in reduced catalytic activity, those protected by PVP are highly active, with quantitative triazole syntheses achieved at room temperature and with catalyst loadings of 0.03 mol% metal for Cu and CuZn systems prepared using NaH2PO2, N2H4 or NaBH4 reductants.This work was generously supported by the Spanish Ministerio de Ciencia e Innovación (MICINN; CTQ2007-65218 and Consolider Ingenio 2010-CSD2007-00006), the Generalitat Valenciana (GV; PROMETEO/2009/039), and FEDER. Y. M. and B. R. K. thank the ISO of the Universidad de Alicante, the UK EPSRC and the University of Cambridge for grants