'-Azoxydiphenol Pbqi P-Benzoquinone

Nitrosophenol '-

Pph

monoliths PAD 4,4'-Azodiphenol PAP p-aminophenol

Keywords:

Chemical groups and molecules

APTS (3-Aminopropyl)-triethoxysilane ASM Aminopropyl silica monoliths CPL ε-Caprolactam DPTS 3-(2,4-Dinitrophenylamino)-propyltriethoxysilane FA Formic acid MCM Mobil Composition of Matter MMA Methylmethacrylate MPTS (3-Mercaptopropyl)-trimethoxysilane MSM Mercaptopropyl silica monoliths NSM Native silica

Introduction

Nowadays, the fine chemical and pharmaceutical industry must satisfy the demand of the increasing market requirements, meanwhile, respond specific needs of customer and social, such as environmental friendly production and energy savings. The microreactor technology, which has been proposed and investigated for two decades, which has a great potential for improving the current production mode: 50% of reactions in the fine chemical/pharmaceutical industry could benefit from a continuous process based mainly on microreactor technology. 1 The role of catalysis in industry is irreplaceable. Over 90% of all industrial chemicals are produced in a catalytic process. 2 Compared with homogeneous catalysis, heterogeneous catalyst, particularly solid catalyst, are widely used in industrial production because it can be separated in the process and recycled. Moreover, it can be implemented in fixed-bed reactor to improve the production efficiency. 3 Hence, the combination of heterogeneous catalysis and continuous-flow microreactors has drawn attention recently.

Among different microreactors with heterogeneous catalysts, packed-bed microreactor is the most mentioned and investigated, because of its easy fabrication and high catalyst loading. [START_REF]Experimental condition range •••••reaction parameters on conversion under stationary conditions ••••Evaluation of catalyst stability••••••••Influence of temperature and flow rate on the PNP conversion•••••••••••Influence of concentrations of reactants on the PNP conversion ••••••••••••Kinetic analysis of the reaction in the monolithic reactor •••••••of packed-bed and monolith microreactors •Catalyst performance in transfer hydrogenation reaction •••••••••Pressure drop and permeability[END_REF] It is commonly composed by a micro-channel randomly filled with powders or small pellets catalyst.

The applications of microreactors with powder catalysts are largely limited in industry because the pressure drop could be significant and the possible catalyst aging could lead to the risk of clogging of microchannels. The monolithic microreactor is a rather new field and is currently in very rapid expansion in laboratory researches, due to its intrinsic advantages such as high porosity and large specific surface of catalyst support. 5 However, the lack of effective preparation method of monolithic catalyst in industrial-grade reactor immensely limits its development. Thus, the key issue of this thesis resides in mastering the synthesis of monolithic microreactors, understanding the nature properties and differences between packed-bed and monolithic microreactor, and evaluating their industrial potentials.

Hence, the general objective of this study is to prepare the microreactors with mechanically stable monolithic catalyst. To prove the concept, the immobilization of a hybrid inorganic-organic monolithic will be realized in stainless-steel tube. Therefore, its performance will be compared to a packed-bed microreactor by a convenient model reaction.

This investigation is interdisciplinary: the chemical engineering contributes to the kinetic analysis and modelisation of the reaction tested in the microreactor, and the chemistry serves in the monolithic catalyst preparation and characterization. For this reason, the project has been supervised by two researchers, respectively of chemical engineering and chemistry, who can well handle the emerged problems from their respective fields. This work takes also into account the parallel studies of internship students who have been involved in the synthesis of monolith notably. This thesis is divided in five chapters, and the organization is as follows:

The first one "Bibliographic study" gives an overview of the background knowledge of microreactors, emphasizing industrial applications and classification of reactions that take advantage of microreactor technology. The combination of heterogeneous catalysts with microreactors is discussed. Afterwards, the investigations on the reduction of p-nitrophenol in neutral, alkaline and acidic conditions are presented. The transfer hydrogenation of p-nitrophenol with formic acid is chosen as the model reaction of this thesis, because it seems a simple, clean and safe reaction, the reactive and product have important applications in chemical industry.

The second chapter "Study of p-nitrophenol hydrogenation as model reaction in a packed-bed microreactor" presents the investigations of model reaction catalyzed with a commercial Pd@alumina powder. First of all, the set-up is developed, as well as an analytical method precise enough to get quantitative information about the concentrations of p-nitrophenol and p-aminophenol, because published analytical methods didn't work in our experimental conditions. Then, the commercial catalyst is tested, and the effect of reaction parameters on conversion such as temperature, flow rate, initial concentration of reactants and time on flow are observed, with a special attention to the beginning of each run (dynamic study) and to their steady-state.

The third chapter "Modelisation of the reaction in packed-bed microreactor with heterogeneous catalyst" describes the modeling investigations based on the experimental observations in chapter 2. The ideal plug flow model is adopted to describe the packed-bed microreactor. The modelisation under transient conditions is firstly established for the rationalization of experimental observations, and then the model under stationary conditions is investigated to determine the reaction rate expression.

The fourth chapter "Preparation and characterization of monolithic microreactor" is dedicated to the preparation and characterization of the silica-based monolith with incorporated palladium nanoparticles. General research status about the preparation method of monolithic catalyst is firstly introduced, with the highlight of silica-based monolith. Then, series of silica-based monoliths have been prepared in cylinder PP-PE polymer tubes (syringe), for optimizing the preparation conditions of the stable, well-formed, hierarchically porous and functionalized silica monoliths. Thereafter, the functionalized silica monolith is prepared in a stainless-steel reactor tube with the optimized preparation conditions, and the palladium nanoparticles are immobilized by continuous flow method. A series of characterization methods are investigated to evaluate the monolith properties and confirm the effectiveness of preparation method.

The last chapter "Study of p-nitrophenol hydrogenation as model reaction in the monolithic microreactor and comparison with packed-bed microreactor" includes the catalytic test of monolithic catalyst with model reaction and the comparison of its properties with that of the commercial powder catalyst in packed-bed microreactor. The first experimental section presents the influence of reaction parameters such as temperature, flow rate and initial concentration of reactants on the conversion of p-nitrophenol in monolithic microreactor. Then the kinetic model of the reaction under stationary conditions is established, and the dynamic study of the reaction is presented. Finally, the performances of monolithic microreactor and packed-bed microreactor are compared, including their catalytic performances, the differences in dynamic study and kinetic model, and their pressure drop and permeability comparison.

Chapter 1 -Bibliographic study

This chapter concerns the background knowledge about heterogeneous catalyst in microreactor. At first, general introduction of microreactors and different types of microreactors with heterogeneous catalyst are presented; secondly, the model reaction chosen for catalytic tests: transfer hydrogenation of p-nitrophenol with formic acid is introduced, including the methods of the reduction and the mechanism of the reaction.

Microreactor with heterogeneous catalyst

Overview of microreactor

Over the past two decades, microfluidic technology has been advanced as means of process intensification 6 . Microreactor (MR) is currently burgeoning and is an interdisciplinary field that combines science and engineering 7 . The chemical industry 8 , biotechnology 9 , pharmaceutical industry 10 and energy 11 are just some of the fields where this new concept in production, analysis and research could find applications 12 .

A "microreactor" is a miniaturized reaction system with dimensions in the millimeter and submillimeter range, that is operated under flow conditions. Other names that are rarely used are nano-, mili-and mini-reactors. 7(b) Most of the currently used microstructured devices take advantage of microfluidics and nanofluidics, which ensure high efficiency as well as repeatability of chemical processes 13 , due to high heat and mass transfer properties. More precisely, their thermal Peclet numbers 14 are below 1,000 under operation and their Reynolds numbers are below 250, corresponding to laminar flow conditions. 7 (a) The history of microfluidic devices dates back to 1940s when a millimeter scale electrophoretic separator has been studied by Philpot 15 . Then, in 1979, Terry 16 realized a miniaturized gas chromatography apparatus on a silicon wafer, including fluid propulsion within microchannels of sub-millimeter cross section. The fabrication of the first high performance liquid chromatography (HPLC) device (a 5 x 5 mm chip containing an open-tubular column of 6 μm x 2μm x 15 cm) using Si-Pyrex technology published by Manz 17 greatly boosts the development of microfluidic technology. The first micro-valves 18 and micro-pumps 19 based on silicon micro-machining have been studied and presented in the end of 1980s. Then in the 1990s, Manz 20 , Mathies 21 and others have studied the microfluidic systems in the field of chip-based separations. Following these pioneer works, new microfluidic components were developed for fluid transport, fluid metering, fluid mixing, valving, or concentration and separation of molecules within miniaturized quantities of fluids 22 . Meanwhile, the research fields of continuous flow microreactors have been also well exploited in catalysis 23 , nanoparticle synthesis 24 , sensing 25 , electrochemistry 26 , polymerization 27 among a lot of applications.

Microreactors are often compared with batch reactors. The characterization of the performances of reactors includes the conversion (for simple reaction), the yield (or selectivity) and the productivity. The ideal reactor models show that the performance equations, which reflect the effect of the operating conditions, are the same in a batch reactor and in a perfect plug flow reactor, which well represent microreactor. That is to say a reaction should follow identical reaction sequences, conversion rate and yield in an "ideal" microreactor and in an "ideal" batch reactor.

The implementation in real reactors brings out differences. Compared with conventional batch reactors, microreactors exhibit numerous advantages that have been discussed extensively. [6][7][8][9] -Advantages of a flow-reaction: (1) in a batch reactor, the reactants are initially charged, and left to react for a certain period, then the final reaction mixture is discharged. So, under continuous operation, the productivity can be improved, by eliminating the steps related to loading and discharge; (2) the continuous operation can be automated more easily.

-Advantages related to the small dimensions of microreactors: (1) the reagent consumption is low, and changes in operating conditions are fast and easy to do, so microreactors are attractive during the process development phase; (2) the amount of reaction product is reduced, which is interesting in the case of synthesis of hazardous intermediate compounds.

-Advantages related to the geometry of microreactors, that offers great control of the reaction conditions such as concentrations and temperatures: (1) the control of temperature is obtained with the high surface area-to-volume ratio of microreactor, in the range of 10000 to 50000 m -1 in microreactor while it is usually less than 100 m -1 in traditional reactors 28 . This allows to use the full potential of temperature during highly exothermic reactions and avoids hot-spots formation 29 . According to their efficient heat transfer and small volume, the reactions involving reactive, toxic or explosive intermediates can be carried out in safety in microreactors 6 ; (2) the control of concentrations in microreactors is achieved by an efficient micro-mixing and a short radial diffusion time, leading to a narrow residence time distribution (RTD) which give them a behavior close to the ideal plug flow model 28 . This behavior allows usage of minimal amounts of reagent to precisely control the reaction and provide high selectivity towards the desired product. 7 (b) The quality of mixing is especially important in the case of fast biphasic reactions or fast competitive reactions.

Application of microreactors and industrial examples

Although most of microreactors applications have been studied in academia, industry has also taken an inquisitive interest in this new technology. As proposed by Roberge, 50% of the reaction in pharmaceutical and fine chemical industry would benefit from a continuous process, and microreactor technology could be preferred reaction device in 44% of these reactions 1 . The question remaining is whether these microreactor devices are able to meet the expectations for industrial use raised in the academic environment. In the last fifteen years, a lot of companies, especially some microreactor builders such as BASF, Lonza, Corning, IMM, have studied microstructured devices as tools for process intensification, and they conclude that, not all chemical reactions can profit from microreactors. Hence, in the following part, the different types of reactions that take advantage in microreactors and some examples of industrial interest are presented.

Contribution of microreactors to different types of reactions

Among the great number of reactions carried out in microreactors in the lab or in the chemical industry 30 , three main types of reactions emerge clearly.

Fast and exothermic reactions

The batch reactors have many obvious advantages because they are easy to be handled, and also it is easy to visualize how a reaction proceeds, when a reagent or a catalyst is added into a flask or when heat is added to initiate a reaction. However, chemists usually slow-down organic synthesis because it is very difficult or practically impossible to conduct some extremely fast or/and exothermic reactions in a flask due to the lack of control of the side reactions. The three following examples show how microreactors technology could contribute to the development of fast organic synthesis. a-More than ten years ago a concept called "flash chemistry" was presented by Yoshida 31 . It is defined as a field of chemical synthesis where extremely fast reactions are conducted in a highly controlled manner to produce desired compounds with high selectivity. Among a number of studies conducted by Yoshida group on the potential of microreactors, an impressive example concerning the control of the fast organolithiums isomerization is presented here 32 . A chip microreactor (CMR), characterized by a submillisecond range reaction time even at cryogenic temperature has been designed. It allowed the formation of the desired product 2 from 1 with a 86% yield, without isomeric byproducts 3 (as shown in Figure 1) at a total flow rate of 4.5 mL/min corresponding to a residence time of 0.33 ms.

The competitive very rapid anionic Fries rearrangement has been avoided, and a high chemoselectivity was observed. For a comparison, the reaction conducted in a conventional flask generated only the isomer 3. The rapid continuous flow nature of the CMR delivered a throughput of 5.3 g/hour, which show a great potential for scalable industrial chemical synthesis. b-Wolf investigated the quite exothermic selective oxidation of primary alcohols to the aldehyde with oxygen using silver as the catalyst (Figure 2(A)) 33 . The microreactor developed for this reaction is a cube of 1 cm edge length and having 200 crossed channels for the reactants and for the coolant (Figure 2(B)). Because of the efficient heat transfer, the reaction temperature could be controlled accurately, avoiding hot spots. Compared to traditional reactor consisting of thick catalyst layer placed on a gas-permeable plate, the reactor volume has been greatly reduced so that the residence time is largely decreased, and the selectivity could be increased from 40% and 85% to 96%, moreover, the hot spot has been reduced from 160℃ to 0℃. b) . At the laboratory scale, the synthesis was conducted at 273K in a Cytos® microreactor with an internal volume of 1.1 mL with 88% yield, 28% higher than the yield obtained in a batch reactor. For the industrial scale, the numbering-up method has been chosen. The Cytos® Pilot System used was composed of 11 microreactors in parallel. The product mass flow of 0.06 kg/h per microreactor was the same on both scales. With same yield of 88%, the microreactor is at 273K while the reaction temperature of batch process should be held under 193K. Various indicators of life cycle assessment (LCA) showed that the application of microreactor could gain significant ecological advantages in comparison to the batch reactor, and the total CED (Cumulative Energy Demand) of microreactor is 500 GJ/FU (functional unit, 1 t m-anisaldehyde) lower than that of batch reactor. The highly toxic or explosive nature of reactants or byproducts in some reactions can make it difficult to handle and control in a conventional lab or industrial scale. Indeed, the process involving hydrazine, diazo compounds, azides or cyanides can be problematic in the industrial production. However, the safe usage of these "dangerous materials" is recommended, especially if their applications offer better atom economy and process intensification. The reduction of risk and improvement of reactions have been demonstrated with the use of flow microreactor 34 .

a-Hydrazine (N 2 H 4 ) is a well-known powerful bi-functional nucleophile and a readily available reducing agent. However, its utilization on a large scale has been limited because of the high toxicity and the high corrosiveness. The explosive and gaseous hydrazine in the batch reactor also makes the safety issues quite important 35 . For example, hydrazine is used in Wolff-Kishner reaction to reduce ketones and aldehydes to the corresponding alkane. The hydrazone intermediate could lead to formation of heterocycles such as insoles and azine by-products that should be discarded. In batch process, the reaction proceeds in the high temperature boiling solvent, in order to remove the hydrazone from the reactor. The method requires several hours of operation and a large excess of hydrazine. The microreactor could overcome these limitations, because its small volume and the improved mass and heat transfer reduce the risk of thermal runaway and explosions. Jensen 35 (a) has investigated the Wolff-Kishner reductions in a novel silicon carbide microreactor that prevents the hydrazine from boiling out of the reactor. Compared with typical batch conditions, the reaction time has been reduced by two orders of magnitude, and a high yield was obtained without requiring a large amount of hydrazine (Figure 4). ) is one of the most versatile and powerful reagents available for the preparation of carbon-carbon and carbon-heteroatom bonds in chemistry 36 . Nevertheless, diazomethane is an extremely volatile, poisonous, carcinogenic and explosive gas. Furthermore, it is extraordinary reactive and high sensitive to light, heat and mechanical shock 34 . The batch preparation of the diazomethane is always performed in specialized glass equipment without ground glass joints to avoid the light and shock. Purification and transportation of the diazomethane generated are also quite complicated 37 . Kim 36 has investigated a dual-channel microreactor containing a highly hydrophobic poly (dimethylsiloxane) (PDMS) membrane that separated a channel for diazomethane generation and channel for synthesis. In the bottom channel, diazald® and KOH generate diazomethane, the PDMS membrane allow the transfer of diazomethane to the top channel while leaving water and other ionic salts behind. In the top channel, the gaseous diazomethane could react with various substrates with excellent yield (> 81%). Although the productivity in lab is only 0.58-2.88 mmol/day, this continuous in-situ generation, separation and reaction of high toxic reagents could be potentially useful for large-scale production.

Reactions with unstable intermediates or consecutive products

The reduction and elimination of short-lived intermediate and the consecutive product are always an important issue to deal with not only in laboratory but also in industrial production, in order to improve the productivity and purity of target product and to cut down the manufacturing cost. The continuous flow microreactor systems is an effective solution to this problem, which can greatly reduce the residence time to the order of milliseconds, keeping the flexibility of the addition order of reaction components. Moreover, the connection of different steps in microreactor could be much tighter in some reactions to reduce the undesired side or consecutive products, thereby to increase the purity of final product.

a-During the conversion from aryl and alkyl Grignard reagents to aryl and alkyl boron compounds, a number of elemental reactions give rise to side products which reduce the yield of the target product and generate purification problems. Hessel38 have investigated the replacement of a batch process by a continuous-flow process composed of a micromixer and a tubular reactor for the phenyl boronic acid 6 production. It results in notable process intensification: the best yield of microreactor investigations was 89%, about 24% more than the industrial batch-wise process. In addition, the energy expenditure was also reduced, due to operation at ambient temperature while the batch process was carried out at cryogenic temperatures. A pilot-scale configuration was achieved with a throughput of about 6kg of phenyl boronic acid per day, equivalent to a production of 20 tons of product per year. Last but not least, as intermediates may precipitate in the course of reaction, the results show that microreactors may adapt to fouling-sensitive reactions. b-ε-caprolactam(CPL) 16 is a commercially important chemical product, mainly used in the production of nylon 6 fibers and resins. Nevertheless, among the traditional methods of CPL synthesis, the CPL selectivity is usually lower than 90% in industrial process using consecutive continuous stirred tank reactors, on account of the several side products and the inefficient pre-mixing process. Wang 39 has developed a system containing two consecutive microreactors and a stirred vessel to improve the selectivity of the synthesis of CPL. The first microreactor was used to conduct the reaction of cyclohexanecarboxylic acid 13 and oleum 14, and then the intermediate product named mixed anhydride was obtained with 97% selectivity. The mixed anhydride then reacted quickly with nitroso-sulfuric acid 15 in the second microreactor, and then the reaction was finished in the vessel. The selectivity of CPL can reach 93.9%, much higher than that achieved in a batch reactor they investigated (84.6%).

.2.1 Scale-up methods

After the demonstration of the performance of microreactor in laboratory, the challenge is how to get benefits of microreactor in chemical industry while increasing the throughput for production. Two approaches to increase the production rate of microreactor are possible Figure 8 : scale-up by increasing the setup size and flow rates or numbering-up by parallelization of units.

Scale-up method can be more easily realized, while taking the risk of losing mass and heat transfer performance. Numbering-up could require hundreds of units to achieve the large-scale production and more complex and expensive control systems, but the desired features of a basic unit could be guaranteed40 .

Applications of microreactors in industrial productions

Industry is not very active in publishing not only because of confidentiality reasons. This may also be caused by the fact that many aspects of this new technology were covered by patents 42 . Scarce publications are probably the tip of the iceberg, and as several of the earlier patents have now expired, known examples of applications of microreactors in industrial productions will increase.

Initiated in 2005 in Germany, the DEMiS projet (Degussa, Uhde, TU Chemnitz, TU Darmstadt, MPI Mulheim) is the first and most often mentioned example for microreactor industrial process up to now 43 . A microstructured reactor has been used for the epoxidation of propylene to propylene oxide with H 2 O 2 on a TS-1 zeolite. The production capacity of this process approximates 5-10 t/year. A nitroglycerin pilot plant with the productivity 10kg/h has been installed at Xi'an site in China and has started up in 2005 with the collaboration from Germany's Institute for microtechnology Mainz (IMM) 44 . Microreactor technology is the key to this production process and the plant is foreseen to operate safely and fully automated 8 .

Figure 12 Nitroglycerin microstructured reactor based pilot plant (Xi'an/ China)

An industrial scale plant for the free radical polymerisation of methylmethacrylate (MMA) was designed by Iwasaki and Yoshida. This pilot plant was installed in Japan, at the Idemitsu Company and its capacity of production is 10t/year 8 . Eight micro-reactor blocks are arranged in a parallel manner. Each of these blocks contains three micro-tube reactors of 11.8 mL (500 μm internal diameter, 60 cm length) in series. It should be noticed that the performance of this pilot plant was similar to that of a single micro-reactor tube, which demonstrates that external numbering-up of microreactors is able to be successfully applied to industrial production.

Another impressive industrial production with microreactor is the process development for pharmaceutical production under cGMP (current Good Manufacturing Practices) conditions, developed by DSM, a manufacturer of fine chemicals and active pharmaceutical ingredients, and Corning Inc. 45 . The goal of this project was to develop a safe and highly selective nitration process using pure nitric acid, and get the desired amount and quality of product at full GMP level. A commercially viable approach to a cGMP nitration reaction was investigated with individual reactor modules, then the numbering-up concept was applied. After nine months, the production process had a capacity of approximately 100 kg/h which corresponds to nearly 800 tons per year.

Figure 14 Production bank with four identical reactors and distribution 45

Research status of microreactor with heterogeneous catalyst

The role of catalysis in industry is irreplaceable. Over 90% of all industrial chemicals are produced in a catalytic process 2 . Both homogeneous and heterogeneous catalysis find wide application in chemicals production. Compared with homogeneous catalysis, heterogeneous catalysts, especially the solid catalysts, gain more attention in the industrial production because they are easily separated in the process, and they can be implemented in fixed-bed reactor to improve the production efficiency 3 . In addition, they are cheap, easy to get, and have good thermal stability.

However, heterogeneous catalysts are difficult to implement in microreactor. So, this combination has drawn attention only recently. The potential advantages of the microreactor with heterogeneous catalysts have been discussed in some recent reviews [3][START_REF]Experimental condition range •••••reaction parameters on conversion under stationary conditions ••••Evaluation of catalyst stability••••••••Influence of temperature and flow rate on the PNP conversion•••••••••••Influence of concentrations of reactants on the PNP conversion ••••••••••••Kinetic analysis of the reaction in the monolithic reactor •••••••of packed-bed and monolith microreactors •Catalyst performance in transfer hydrogenation reaction •••••••••Pressure drop and permeability[END_REF][5]46 : ultra-low catalyst consumption, more efficient use of resources and generation of less waste, high specific surface areas of catalysis and so on. In the following part, we present different types of microreactors with heterogeneous catalyst and their applications.

Different types and comparison of microreactors with heterogeneous catalysts

Methods of immobilization of heterogeneous catalyst in microreactors

Heterogeneous catalytic microreactors can be classified into three main types as shown in Figure 15: (i) packed-bed microreactor, (ii) wall-coated microreactor and (iii) monolithic microreactor. Packed-bed microreactor is among the most studied, commonly composed by a micro-channel randomly filled with powders or small pellets catalyst. The support of the catalyst is an insoluble solid, either a polymeric or inorganic particle. The particles are generally smaller than 50μm, less than 1/20 of the bed diameter to avoid the channeling or misdistribution of flow [START_REF]Experimental condition range •••••reaction parameters on conversion under stationary conditions ••••Evaluation of catalyst stability••••••••Influence of temperature and flow rate on the PNP conversion•••••••••••Influence of concentrations of reactants on the PNP conversion ••••••••••••Kinetic analysis of the reaction in the monolithic reactor •••••••of packed-bed and monolith microreactors •Catalyst performance in transfer hydrogenation reaction •••••••••Pressure drop and permeability[END_REF] . Catalyst can be loaded into the microchannel either by manual filling, or by applying a pump or vacuum at the reactor outlet. Besides, the packed catalyst should be retained inside the microchannel by sinters at both ends. The possibility to use either commercial or synthesized bulk catalysts greatly expands the application areas 46 (a) .

Wall-coated microreactor has inner wall with a uniform and thin layer thickness (usually in the 1-10 μm range) of catalytic coating. Several reviews 5,[46][47] have discussed the methods of the immobilization of catalytic wall coatings into capillary-or chip-based microreactors, such as the sol-gel deposition 48 , electrophoretic deposition 49 and electroless plating, chemical vapor deposition technique 50 . The general steps of the immobilization often involves 46 : i) pre-treatment of the microreactor wall surface; ii) application of a porous coating of the catalyst support; iii) immobilization of the catalyst itself (usually noble metal like Pt, Pd or Au) onto the catalyst support.

Monolithic microreactor is a microreactor in the form of column with monolith inside. Monolith is the solid material polymeric 51 or inorganic 52 , structured with interconnected pores that are both macropores (larger than 50nm in diameter) and mesopores (2-50nm) or micropores (less than 2nm) [START_REF]According to IUPAC definition 54[END_REF] . Different from the mature packed-bed technology, monolithic microreactor is a rather new field, which is currently in very rapid expansion, due to the huge interest and spread in organic flow synthesis 5 .

Characteristic and comparison of different microreactors with heterogeneous catalysts

The relative advantages and disadvantages of heterogeneous catalytic microreactors have been discussed in several publications [START_REF]Experimental condition range •••••reaction parameters on conversion under stationary conditions ••••Evaluation of catalyst stability••••••••Influence of temperature and flow rate on the PNP conversion•••••••••••Influence of concentrations of reactants on the PNP conversion ••••••••••••Kinetic analysis of the reaction in the monolithic reactor •••••••of packed-bed and monolith microreactors •Catalyst performance in transfer hydrogenation reaction •••••••••Pressure drop and permeability[END_REF]46,54 .

Generally speaking, packed-bed microreactors can be made easily because the catalysts can be directly introduced into the microreactors after suitable size reduction. This approach gives access to a large range of catalytic supports. Advantages of such packed-bed are high catalyst loading and fairly easy characterization and quantification of the catalyst. However, limitations can be the poorly controlled fluid dynamics and the significant pressure drops along the microchannel. In addition, the presence of solid catalyst may limit heat transfer and lead to hot-spot formation.

Unlike packed-bed microreactors, the mass transfer resistance is minimized in wall-coated microreactors to ensure smooth flow of reagents, without leading significant pressure drops or blockage of microchannels. Moreover, the fluid dynamics, the heat and mass transfer properties inside the wall-coated microreactors can be well predicted due to the well-defined flow geometries. Despite of the good flow-through properties, the major disadvantage is the low catalyst loading, owing to the thin layer of catalyst supported on the inner walls.

Monolithic catalysts are designed to have quite high void volume and a large specific surface area, leading to efficient contact of the catalyst, allowing high productivity and selectivity. The drawbacks of monolithic microreactors could be the compromise between the pressure drop and the flow rate, the preparation of the catalyst inside the microreactor channels, leading to difficulty of modelization and the risk of pore clogging or non-uniformity of radial permeability 5 .

Applications of microreactors with heterogeneous catalyst

In the recent review by Alhooshani 4 , applications of heterogeneous catalytic microreactors have been discussed. We present some examples of applications of microreactors with heterogeneous catalyst with impressive performance in pharmacy.

The pharmaceutical industry is going through a change from batch systems to continuous-flow systems. During each stage of the development of a drug, the quantities of active compound required increase: for the initial tests during discovery, only 5-10 mg is required; for the toxicology and pharmacokinetics studies, 500 mg-2 g are required; finally, kilogram-amounts are required for larger trials. The microreactors with heterogeneous catalyst are easily compatible with the aim of small amounts production. In addition, with the scale-up or numbering-up method, they have great potential in the pharmaceutical production.

Recently, applications of continuous flow processes in pharmaceutical industry such as the preparation of fine chemicals, active pharmaceutical ingredients (API) and finished dosage forms have been gained much attention, especially in academia 55 .

a-Recently, the Novartis/MIT partnership demonstrates an excellent example of industry/academic collaboration in a fully automated integrated continuous flow synthesis apparatus 55(e)(f),56 . The instrument is not bigger than a kitchen refrigerator (as shown in Figure 16) and can be easily adapted to produce a variety of target molecules meeting U.S. pharmacopeia standards, for example the Aliskiren (drug for hypertension) with a productivity of 41g/h. The continuous-flow system contains four types of microreactors, types I and II without catalyst, types III and IV with catalyst, as illustrated in Figure 17. In type I, all the reagents are passed through the reactor, and the exiting mixture contains target products with the unreacted reagents or by-products and a further separation step is necessary. In type II, one of the reagents, saying B, is supported and confined into the reactor. If an excess amount of supported B is used, the exiting reaction mixture will contain the target product only. However, the reactor must be changed frequently due to the consumption of B. In type III, a homogeneous catalyst is employed; similar to type I, the further separation step is necessary. In type IV, the heterogeneous catalyst is immobilized into the reactor, so the catalyst can be reused easily. According to authors, this type of reactor is regarded as the most convenient for continuous-flow synthesis because the catalytic methodologies are nowadays imperative for the development of sustainable and efficient processes 55(b)(g) .

Figure 17 Four types of continuous-flow microreactors b-An impressive, complete and chiroselective synthesis of an API, (R)-Rolipram 18, using heterogeneous catalytic continuous-flow system has been described by Kobayashi 55(g) (j) . The starting materials and related reagents have been passed through a sequence of chiral and achiral solid catalysts as shown in Figure 18. Moreover, the (S)-Rolipram 19 was obtained simply by replacing the chiral heterogeneous catalyst in reactor II with the opposite enantiomer catalyst. The yield is 50% from commercially available aldehyde 17, the productivity is 1g per 24 h and the enantiomeric excess is 96% for both of the products 18 and 19.

Conclusion

The overview of microreactors and their advantages related to continuous operation, small dimension and geometry have been introduced. Microreactors have been applied in different types of reactions, in order to control the reaction rate, reduce the release the highly toxic products and reduce the side-products. Compared to related traditional batch processes, the heat and mass transfer, mixing efficiency, residence time control, process safety, production costs and environmental conservation of continuous manufacturing with microreactors are much improved. The combination of heterogeneous catalysts with microreactors has been discussed, and three different methods of immobilization of heterogeneous catalyst in microreactors have been summarized: (i) packed-bed microreactor, (ii) wall-coated microreactor and (iii) monolithic microreactor.

Reduction of p-nitrophenol as model reaction

In order to test and compare the performance of heterogeneous catalytic microreactors with various supports, a model reaction should be selected, which should be simple, safe, easy to handle and to analyze.

In this thesis, we have focused on the transfer hydrogenation of p-nitrophenol (PNP) with formic acid (FA) on palladium catalyst. This reaction starts only in presence of catalysts in a low temperature range 57 and satisfies all the above conditions. In addition, it has a particular environmental interest:

-All the reagents (PNP and FA) and product p-aminophenol (PAP) are commercial, so the study of the reaction is convenient; -The PNP is among the most common nitrophenolic compounds that widely used in chemical industry. It is listed as the priority pollutant by the United States Environmental Protection Agency due to its water solubility, chemical stability and toxicity to human health 58 . Compared to the current methods of pollutant treatment such as biological treatment 59 , catalytic reduction method of PNP is more efficient and more sustainable, because it converts PNP to more environmental friendly products 58 (a) . -The PAP is an important intermediate in fine and pharmacy industry for the synthesis of several important analgesic and antipyretic drugs, such as paracetamol, acetanilide, phenacetin 60 . Besides, PAP can be also applied in the field of dyes, anticorrosive lubricants and pharmaceuticals 57(b -The transfer hydrogenation provides an attractive option for the reduction of nitrophenol. This method avoids the use of dihydrogen gas under high temperature and high pressure, therefore is beneficial to reduce the energy consumption, and reduce the additional cost of transport and storage of dihydrogen gas 62 ; -Among the available hydrogen donors 63 , FA is a safe, cheap and plentiful hydrogen source with high stability and low toxicity, and could be derived from biomass 62 (c),64 . By biological or chemical method, the only byproduct of dehydrogenation reaction of FA, CO 2 , could be regenerated to FA in large quantities 64 , completing the sustainable cycles for the potential use of FA as hydrogen source; -In the nanoparticle state, palladium is a distinct material with a strong affinity to hydrogen owing to both its catalytic and hydrogen absorbing properties, which makes it a good catalyst for various hydrogenation reactions 65 . Pd nanoparticles have an excellent activity 62 (c) in the catalytic hydrogenation reactions and in the decomposition of FA 57(2),62(c),66 .

Reduction of p-nitrophenol in heterogeneous conditions

Methods of reduction

In current researches, the catalytic reduction of PNP is mainly carried out with reducing agents in neutral, alkaline and acidic conditions, such as dihydrogen (H 2 ), sodium borohydride (NaBH 4 ), and FA. In this part, several studies of different hydrogenation methods in heterogeneous conditions with Pd, Ni etc. are introduced.

Reduction in neutral condition

In neutral condition, the direct catalytic hydrogenation of PNP is mainly done by dihydrogen. The only byproduct is H 2 O and usual catalysts are noble metals.

Figure 19 Hydrogenation of PNP with H2

This reaction has been studied in both continuous and batch reactor. Sá67 has investigated this reaction in a continuous-flow flooded-bed microreactor (ThalesNano H-Cube Mini®) where the PNP solution and H 2 flow upward through the catalyst bed. The hydrogen gas was generated in situ through electrolysis of water. It was the first time that the novel nano-Cu 2 O catalysts grafted on polymeric resins was found active in hydrogenation, without the promotion of a noble metal. Yin68 has investigated the influence of supports on catalytic activity of Ni catalysts in this reaction, and demonstrated that the catalytic activity increased in the order of Ni@kieselguhr >> Ni@TiO 2 > Ni@Al 2 O 3 . The surface acidities of these catalysts are critical to their catalytic activity.

Parida 60 (b) has used palladium supported mesoporous silica as catalyst in the flask at room temperature. The influence of catalyst loading and the reaction time on hydrogenation of PNP have been studied and a mechanism of this reaction was proposed as follows: PNP is firstly reduced to p-nitrosophenol (PNS) then to p-hydroxylaminophenol (PHx), and the intermediate p-benzoquinone imine (PBQI) is formed between the reduction of PHx to PAP.

Reduction in alkaline condition

The reduction of PNP in alkaline condition is mainly investigated with NaBH 4 , and also with KBH 4 and N 2 H 4 as reducing agents, owing to their low prices, efficient reducibility and good solubility in water 69 . Moreover, there is no side reaction and the mechanism has been well described. The progress of this reaction can be easily followed by UV-vis. spectroscopy.

The characteristic absorption band of PNP was observed at 317 nm. In alkaline conditions, after adding the NaBH 4 , the shifted peak at 400 nm corresponding to the p-nitrophenolate anion (PNP -) is observed as show in Figure 21. After the reaction begins, the decrease in absorption of PNP - was observed on the time scale, meanwhile the formation of a new peak at 300 nm corresponding to PAP. Thus the consumption of PNP and appearance of PAP can be monitored easily. (Reaction conditions: CPNP 0 =1mM, CNaBH4 0 =26.4 mM, Pd 0 =50μg, time=16 min)

However, a large excess of NaBH 4 is usually used for the complete reduction and hydrogen gas bubbles are formed during the process because of the self-hydrolysis of NaBH 4 in water 70 , which can become a problematic issue for this reaction.

The reduction with NaBH 4 has been widely utilized for investigating the new heterogeneous catalyst. Pal 71 has studied this reaction with Ag nanoparticles formed in situ and Esumi 72 has utilized this reaction as model reaction to compare the catalytic activity of their dendrimer-Au nanocomposites. Liz-Marzán 73 has summarized the investigations from 2004-2011 of the reduction of PNP in aqueous solution with NaBH 4 utilizing different metal nanoparticles as catalysts such as Pd, Pt, Au, Ag in various supports such as spherical polyelectrolyte brush (SPB), TiO 2 , Al 2 O 3 and so on that demonstrated that this reaction is extensively adopted in the study of catalyst. He proposed that the Langmuir-Hinshelwood model could well represent the kinetic of this reaction.

This reaction was also studied in microreactors with heterogeneous catalysts 70,74 . Recently Cornelissen 70 has successfully fabricated a wall-coated microreactor by the immobilization of protein cages on the inner surface. The reduction of PNP with NaBH 4 has demonstrated the stability of the virus-like particle catalyst and its high efficiency. Ballauff has investigated the full kinetic analysis of the catalytic reduction of PNP with sodium borohydride by metallic nanoparticles in some publications 76 . Because of the large excess of BH 4 -(40-300), the reaction follows a pseudo-first order reaction rate with respect to PNP 76 (c) . The mechanism of the reduction of PNP by metallic nanoparticles was proposed as shown in Figure 23: In step A, PNP was first reduced to the PNS which was quickly converted to PHx, which was the only stable intermediate; in step B, PHx could be reduced to the final product PAP. There was an adsorption/desorption equilibrium for all compounds in all steps and all reactions were assumed to take place solely at the surface of the metal nanoparticles (Langmuir-Hinshelwood model). The established full kinetic equations had good agreements with the experimental data.

The kinetic constants obtained from this analysis indicated that the step B is the rate-determining step 76 (b) . However, neither PNS nor PHx was detected or isolated during these studies.

Reduction in acidic condition

The researches about the reduction of PNP in acidic condition are much fewer than in alkaline condition. The main acidic reducing agent is formic acid 57 (b),62(c),66 (b) .

Javaid 57 (b) has investigated a wall-coated microreactor and examined the transfer hydrogenation of PNP with aqueous formic acid. Different catalysts such as Pd, porous Pd, Pd-Ag, PdO and porous PdO were coated into the inner surface of a metallic tube (inner volume 196 μL). No side reaction occurred and no hydrogen gas was found during the process. The reaction concentration of PNP is 10mM, and the evolution of CO 2 gas bubbles was observed during the reaction. The porous catalysts showed better catalytic activity than non-porous equivalents, and porous PdO demonstrated the best catalytic activity. The effect of the concentration of FA on the conversion of PNP was studied as shown in Figure 24.

Mechanism of reduction in formic acid

The mechanism of the reduction of p-nitrophenol in formic acid on Pd catalyst has been rarely studied. Nevertheless, the mechanism of the reduction of aromatic nitro compound such as nitrobenzene to the corresponding aniline has been well discussed 77 . Combining these investigations, the complete mechanism of the reduction of p-nitrophenol in formic acid with Pd catalyst has been proposed as shown in Figure 25.

The reduction occurs in several steps along two routes: The first steps are the same as the routes in neutral or alkaline conditions: the PNP is first reduced to the PNS and then further reduced to PHx in two very fast steps 77 . The PNP and PNS are strongly adsorbed on the catalyst surface. Then, in direct route, the product PAP could be formed via a disproportionation pathway: 2 PHx -> PAP+PNS. The PHx reduction is slow because of the cleavage of an O-N bond.

In the condensation route, the b) for p-nitrophenol)

The reaction routes are strongly influenced by the catalyst support and promoters added. For example, a large amount of PHx may accumulate in the direct route 77(b) if the catalyst is not active enough and/or if the step for the reduction of PHx is slow, but this accumulation of PHx has not been known on the support or not, and has not been proved directly. This accumulation can be reduced through the addition of promoters, especially of vanadium compounds [77][78] . In spite of the lack of direct evidence about this mechanism, the group of Studer 78 has detected the accumulation of the corresponding hydroxylamine in the catalytic hydrogenation of nitroarene (benzenesulfonamide-N-cyclohexyl-N-methyl-2-nitro) with Pd@C catalyst and acetic acid as reducing agent. They reduced the accumulation by adding vanadium promoters such as VOSO 4 , V 2 O 5 and so on. They also suggested a mechanism which could be called a "catalytic by-pass": the hydroxylamine is not directly hydrogenated to the corresponding aniline but disproportionate rapidly so that the nitroso intermediate could re-enter the catalytic cycle and the amine formation is accelerated. The same principle as the disproportionation of PHx of the direct route is shown in Figure 25.

The group of Cai 79 has investigated the products distribution during the transfer of hydrogenation of nitrobenzene, and detected the formation and decomposition of azoxybezene (Ph-N=NO-Ph) and hydrazobenzene (Ph-NH-NH-Ph), which demonstrated the condensation route.

Among the majority of the studies of the reduction of PNP, the direct route is mainly concerned. On the basis of the work of Ebitani 64 (a) and Jiao 80 , we propose the catalytic cycle corresponding to the direct route of the mechanism in Figure 26.

Methods of analysis

The most commonly used identification and quantitative analysis method of this reaction is the ultraviolet-visible (UV-vis.) spectroscopy, which is usually utilized in the alkaline and acidic conditions 57,60,76,81 . In alkaline conditions, the consumption of PNP and formation of PAP can be monitored easily as discussed in the part of 1.2.1.1.2. However, in acidic conditions, the pH value can impact the UV-vis. spectra of PNP as shown in Figure 27. The peak of PNP varies to lower wavelength when the pH value decreases and the overlap of the spectra of PNP and PAP makes the formation of PAP difficult to be monitored 57 (b) . High performance liquid chromatography (HPLC) is also used to determine the quantity of PNP and PAP in order to calculate the conversion yield of reaction. In both of the investigations of Hart 82 and Hanna 83 , a C18 packed column has been utilized in the HPLC system. Hart 82 has adopted a mobile phase consisted of 40% acetonitrile and 60% water, containing

Conclusion

Due to the advantages discussed, the transfer hydrogenation of p-nitrophenol with formic acid on palladium catalyst has been chosen as the model reaction. The investigations of the reduction of p-nitrophenol in neutral, alkaline and acidic conditions have been introduced and the mechanism of the reduction in formic acid has been discussed. The methods of analysis of the reduction such as UV-vis and HPLC analysis have been summarized.

In the following experimental analysis part, the model reaction will be tested in both packed-bed microreactor and monolithic microreactor mainly analyzed by UV-vis and HPLC methods.

Chapter 2 -Study of p-nitrophenol hydrogenation as model reaction in a packed-bed microreactor

In this part, investigations about p-nitrophenol (PNP) hydrogenation catalyzed with a commercial Pd@alumina powder are presented. Chapter 2 is devoted to experimental observations and chapter 3 to models, both in transient and stead-state conditions for the establishment of a reaction rate equation. Chapter 2 is divided in 4 sections. A first experimental section presents the set-up and three analysis protocols more and more sophisticated. A second section presents different ways of characterization of reaction: Nuclear Magnetic Resonance (NMR) and Mass Spectroscopy (MS) analysis of the reaction mixture, comparison of batch and flow-reactor experiments and measurements of PNP and PAP adsorption and desorption in the batch reactor.

Thirdly, the effect of reaction parameters on conversion such as temperature, flow rate and initial concentration of reactants are summarized. Last but not least, the dynamic studies of the reaction are presented; this part presents the attempts to identify the intermediate products detected in our investigations but never reported in publications.

Experimental section

Experimental condition

As discussed in 1.2, the model reaction chosen in order to compare the performance of different catalysts is the transfer hydrogenation of p-nitrophenol (PNP) by formic acid (FA) with Pd catalyst. The commercial catalyst is powder Pd@alumina catalyst, containing 5% Pd (Strem Chemicals). All reagents are commercial.

The packed-bed microreactor is a stainless-steel tube, with sinters at both ends and that is filled with commercial catalyst powder. The characteristics of microreactor are listed in Table 1.

Protocol 1: off-line UV analysis

Three different analytical protocols, more and more sophisticated, were developed for testing the properties of the reaction in packed-bed microreactor. The preliminary experiments have been carried out with off-line UV-visible analysis of samples leaving the reactor.

Experimental set-up

The scheme of the experimental set-up is shown in Figure 28. The solutions of PNP and FA are pre-mixed before reaction, as it was preliminary checked that there is no reaction between PNP and FA without catalyst

Off-line UV-vis spectroscopy Calibration

The aim of this part is to find the range of wavelength giving the most precise analysis of the reaction mixture. The method was developed in 3 steps. In the figure above we can see that the spectra of PNP and PAP overlap between 200-330 nm and that only PNP absorbs above 330 nm. So, we can calculate the conversion of PNP in this range. It should be noted that the maximum concentration of PAP or PNP solution that can be measured in off-line UV-vis is about 0.2 mmol/L, so for the further reactions with more concentrated solutions, the product should be diluted before the off-line UV-vis. analysis.

(b) Calibration solutions were prepared in order to define the absorbance range where the response factor is constant. The response factor (RF) of PNP in each wavelength is calculated as follows: RF = Absorbance/Concentration of PNP If in a certain range of wavelength, the RF of different calibration solutions remains the same, that means the concentration of PNP follows a linear relation with the absorbance without the impact of FA and PAP, so we can choose this range of wavelength as the effective absorption wavelength to calculate the conversion.

The composition of calibration solutions, reported in table 2, corresponds to different degrees of conversion of a mixture containing initially 0.1 mmol/L of PNP. In the first series of experiments, the concentration of FA is always stoichiometric (C FA 0 /C PNP 0 = 3), and in the second series experiment, C FA 0 /C PNP 0 was varied from 1.2 to 18 to eliminate the influence of FA. As a result, the response factor is quite constant in the wavelength range 325-349nm, the standard deviation is 6%. The variation of standard deviation of RF at different wavelength is plot in Annex A-1 Figure A1.

(c) In order to improve the precision of the concentrations measurements, a multilinear regression method was used. We assume that the absorbance () at a given wavelength in the 325-349 nm range can be regarded as a function of concentration of PNP, FA and PAP as:

Absorbance  = a  × 𝐶 𝑃𝑁𝑃 + b  × 𝐶 𝐹𝐴 + c  × 𝐶 𝑃𝐴𝑃
The coefficients a λ , b λ and c λ are calculated from UV spectra of calibration solutions, and then the theoretical absorbance is calculated with the multilinear relation. Coefficients b and c are very low, indicating that the contribution of FA and PAP is not significant. The deviation between measurements and calculations is minimum in the range 330-337 nm. The average deviation over the set of calibration solutions is about 3.4%.

In conclusion, the range of 330-337 nm is chosen to calculate the PNP conversion in the further reaction studies with off-line UV-vis. measurements. The PNP conversion is calculated from the average value over the 330-337 nm range of the absorbance ratio at the exit of the microreactor and in the tank containing the feed mixture. It is notable that the disappearance of PAP cannot be observed nor quantitatively analyzed with UV method.

Protocol 2: on-line UV analysis

Acquisition of a new UV-visible Photo-Diode Array (PDA) detector (MD-4010 Diode-array Detector, Jasco) allows combining the reaction and spectroscopic detection under the same continuous flow. The software of the detector monitors three dimension spectra (time-wavelength-intensity), and offers the possibility to plot either complete UV-visible spectrum at a given time, or intensity-time profile at a given wavelength, or a 3D-representation.

Experimental set-up

The new experimental set-up with integrated on-line PDA detector is shown in Figure 30. The 6 port valve is added in order to analysis both feed and reacted mixture. The valve can be switched to direct the flow toward the bypass (blue), where the feed solution is directly pumped into the PDA detector, or the route of reaction (red) where the solution is pumped through the microreactor and then through the PDA detector. In this way, we can know the variation of the product composition as the function of time. The pump and the oven are the same as in the first set-up.

The reaction protocol includes a 5-10 min sequence for analysis of feed mixture, followed by an 80-120 min sequence for the continuous analysis of the reactor effluent. The sequence ends when steady-state is clearly established. Calibration method used for PNP-conversion calculation is similar as presented for off-line UV vis. calibration. The concentrations of calibration solutions are listed in Annex A-2 Table A1. The calculations on the response factor and regression are in Annex A-2 Figure A2 and Figure A3, respectively. The final range for the calculation of PNP conversion with online UV PDA is 357-367 nm.

A three dimension spectrum (Time-Wavelength-Intensity) obtained by the software of the detector is shown in Figure 31. Further experiments have shown that this peak is not an artefact, but it corresponds to a real component that is neither PNP nor PAP. We name it intermediate I250. Attempts to identify I250 are presented in part 2.4.2. It was also observed that the intensity of I250 depends on the reaction conditions and on the history of the catalyst. Hence, in order to ensure repeatable catalyst conditions, a washing protocol was developed, as discussed in the following part.

Washing protocols

In order to assess the effect of catalyst washing on the UV intensity of I250, a series of experiments with different washing temperatures have been carried out. In all these experiments, the condition of reaction remains the same, with flow rate Q = 1mL/min, reaction temperature T reaction = 30℃, C PNP 0 =0.4mmol/L, C FA 0 =1.2mmol/L. After each reaction sequence, we wash the microreactor set-up with distilled water during about 2 hours. The washing temperature varies from 30 to 80℃. Figure 32 shows the absorbance profiles of reaction sequence at 250nm realized after washing at different temperatures. Figure 32 indicates: (i) the intensity returns to the level of the feed solution after 2 hours, which means I250 no longer flows out of the microreactor. (ii) After a higher washing temperature, the I250 peak appears later, it is lower and wider. In addition, the surface areas under the peaks are roughly the same whatever the washing temperature (75. 4, 77.8, 78.7, 77.1 for 30℃, 50℃, 70℃, 80℃, respectively), indicating that approximately the same quantity of I250 is formed and desorbed at the beginning of the reaction sequence. In order to have a better insight on the washing process, the 250 nm-absorbance was also measured during washing process (Figure 33). At higher temperature, I250 flows out of the reactor faster, and the quantities of I250 washed out, estimated from the surface area under the peak, seems to be higher. It should be noted that the I250 amount washed out is about 10 times lower than the amount desorbed during the reaction sequence.

Figure 33 Variation of intensity of I250 with time during the washing process after reactions

These experiments indicate that the amount of I250 produced during reaction sequence is little dependent on the temperature of washing, even if I250 seems to be more strongly retained on the catalyst surface when it has been washed at higher temperature.

It is noteworthy that the I250 disappears if the packed-bed microreactor is left unused for about 1 month after washing, and it reappears after about five reactions-washing sequences I250 returns again. This probably indicates that, small quantity of I250 can be adsorbed and "stored" on the catalyst support. I250 amounts above this "stored I250" could be transformed to PAP or desorbed, but this stored I250 still remains on the support even after reaction and washing, unless the long-time immersion in water.

Finally, the washing protocol was fixed as follows: washing with distilled water, at 40°C and during 60 minutes. This protocol was applied after each reaction sequence.

Analysis with off-line HPLC

As neither off-line nor on-line UV vis. can analyze quantitatively the PAP, analysis with off-line HPLC has been investigated to prepare the next protocol.

Two publications (Hart 82 and Hanna 83 ) have reported HPLC analysis in studies of PNP hydrogenation. In both cases, chromatography is made on a reverse-phase C18 column, with a mixture of acidified acetonitrile and water as the mobile phase, at flow rate between 0.5 mL/min -1 mL/min.

In our study, we used a C18 reversed phase HPLC column (3.5 μm, 4.6100mm, XBridge®, WATERS), and a mixture of deionized water and acetonitrile acidified by 0.05% FA as the mobile phase, at a 0.5 mL/min flow rate. As shown in the UV-visible absorption spectra in Figure 29, both PNP and PAP have significant absorption intensity around 225nm and 300nm, here we have chosen 225 nm as the UV detection wavelength. The proportion of acetonitrile and FA was varied in order to optimize the quality of the resolution, results are reported in Table 3. It indicates that the retention time of PAP does not change a lot, while the retention time of PNP increases with the increase of the proportion of water. In order to insure the good separation of PNP and PAP meanwhile cut down the analysis time, we adopt the following mobile phase composition: 60% water, 40% acetonitrile, both acidified by 0.05% FA.

The calibration of the method has shown excellent linear correlation between PNP or PAP concentration as a function of the surface area of chromatographic peaks, in the range of concentrations below 0.4 mmol/L, typical of experiments with protocol 2 (see Annex A-3 ).

Protocol 3: on-line UV analysis coupled with HPLC

The aim of the third protocol is to get a quantitative analysis of both PNP and PAP by HPLC directly at the outlet of the microreactor.

Experimental set-up with PDA and HPLC

As discussed before, HPLC is an effective quantitative analysis method of PNP and PAP, but with off-line HPLC we have to collect samples at the outlet of microreactor and then carry out HPLC analysis. The delay between reaction and analysis may lose the opportunity to analyze some unstable intermediates. Hence, the experimental set-up with on-line reactor and HPLC equipment (i.e. injection valve, chromatographic column and PDA detector) has been developed as shown in Figure 34. The reactants mixture is pumped by Pump 1, and the mobile phase is pumped by Pump 2. Valve 1 directs the reactants mixture either towards the by-pass (blue), or toward the reactor (red), as previously. With Valve 2, in load position (orange), the reaction mixture fills in the injection loop (20μL); in inject position (red), the mixture is injected into the HPLC column and then components are detected in the PDA after separation in the column.

Analysis and washing protocols

The full protocol includes the following sequences:

-Analysis of the reactor feed mixture: valve 1 on by-pass, valve 2 in load position, thus the reactant flows in the by-pass and then fills the loop of Valve 2, meanwhile the HPLC column is washed by eluent; Then valve 2 is switched to inject position, for HPLC analysis. -Reaction sequence: valve 1 on reactor, in order that reaction mixture reacts on the catalyst, and valve 2 in load position. Every 10-20 minutes, the effluent of the reactor is analyzed by manual switch of valve 2 (load/inject). -After the reaction, the washing process is carried out by distilled water of 40℃ for 1 hour.

Calibration and corrections

First calibration curves were obtained with PNP and PAP mixtures in the concentration range 0.04-0.4 mmol/L. As experiments were done with concentrations up to 5 mmol/L, the calibration should be done again. In this new series of calibration solutions indicated in Figure 35, the FA concentration is always 3 times of that of PNP, there is not FA in the PAP solutions. From this figure, we conclude that the PNP and PAP concentrations have a polynomial relation (calculated by OriginPro 8.5 software) with the surface area of chromatographic peaks:

C PNP = 1.55 × 10 -6 × S PNP 2 + 0.00253 × S PNP (R 2 = 0.99867) (1

Reaction characterization

Identification of products

Analysis by nuclear magnetic resonance (NMR)

In order to identify the product of reaction, we utilized D 2 O as the solvent of the reaction in microreactor, and then the product of reaction has been analyzed by off-line UV-vis. spectroscopy and 1 H NMR. The conversion measured by off-line UV is 0.938. For comparison, the mixed solution of commercial PNP, FA and PAP (C PNP : C FA : C PAP = 1:3:9) has been prepared and analyzed by 1 H NMR (detailed information of NMR in Annex A-5 ). As we can see from Figure 36, only PNP and PAP are visible on the reaction product spectra. The FA has disappeared during the reaction, perhaps because of proton exchange with D 2 O. RMN integration confirms exactly the PNP conversion determined by UV.

Analysis by mass spectrometry (MS)

The MS analysis (3100 Mass Detector, WATERS) has been utilized to confirm the product of reaction and to identify the intermediate I250. As we can see in Figure 37, analysis with ES-mode of a reaction mixture whose PNP conversion measured by UV is 61% exhibits only the peak at m/z = 109 corresponding to PAP produced and the peak at m/z = 138 corresponding to residual PNP. The evolution of PAP and PNP concentrations in the reactor effluent has also been observed by MS analysis. 1 mL-Samples of product are collected at 10-12 min, 23-25 min and 44-46 min after the beginning of the reaction sequence, and then analyzed by MS in ES+ and ES-mode. Figure 38 shows that the peak corresponding to PNP decreases while the peak corresponding to PAP increases simultaneously. Reaction condition: CPNP 0 =0.5 mmol/L, CFA 0 =3 mmol/L, T=25℃, Q = 0.5mL/min

Comparison between batch and continuous conditions

The reaction has also been investigated in a batch reactor in order to get a better insight on the course of the reaction and on possible by-products. Two batch experiments at different initial concentrations are compared with flow experiments, under conditions where the conversion should be the same in both reactors, i.e. with the flow rate values equal to the batch reaction volume divided by the batch reaction time, and with the same local reaction conditions (catalyst amount, concentrations and temperature). Theoretical justifications are presented in chapter 3, section 3.1.2.

The batch set-up consists in a flask, magnetic stirrer and oil heating bath. The aqueous solution of PNP and FA is prepared, degassed and poured into the flask under stirring and heating, then the Pd@Al 2 O 3 catalyst is added. The reaction product is analyzed by off-line UV-vis. and NMR. For NMR analysis, the solvent is D 2 O.

The turnover frequency (TOF), defined as the turnover number (TON, the moles of substrate converted per the moles of catalyst used) per unit time, quantifies the activity of catalyst and is often used to compare catalyst performances. They are calculated as: This comparison indicates a slightly better activity of the catalyst in flow reactor, but without precision because of the shape of the spectra. Actually, Figure 39 shows that the products of , indicating the PAP in the batch product is partially in a carbonated form. It is probably due to the accumulation in the flask of the CO 2 evolved by the reaction, while in microreactor, the continuous flow remove the product off the reactor and avoid the accumulation of CO 2 .

TOF batch = V batch . C 0 PNP. X batch /(t batch .n Pd ) , TOF flow = Q MR . C 0 PNP. X MR /n Pd

Study of adsorption and desorption phenomena

In order to understand the difference between reaction products in batch and continuous flow reactor, check the effect of adsorption of PNP or PAP in the support on the decrease of UV spectrum, a series of adsorption-desorption tests have been carried out in batch conditions. In a typical adsorption experiment, a given amount of catalyst is contacted with a given volume of PNP or PAP aqueous solution of known concentration. The flask is stirred at temperature controlled with heating bath throughout the duration of the test. 1ml of sample is taken after a given contact time and analyzed by UV spectroscopy. For desorption test, the catalyst is filtered and then desorbed with a given amount of ethanol at 40℃ for 1 hour. The liquid is analyzed by UV and MS.

Adsorption of PNP

The adsorption isotherm is used to describe the equilibrium established between the concentration of component adsorbed and the concentration of the component in solution. In our tests, concentration in solution is measured by UV-vis., and adsorbed concentration is calculated by difference with initial solution:

𝑞 𝑒 = (𝐶 0 -𝐶 𝑒 ) × 𝑉 𝑚 𝑐𝑎𝑡
where C e : Solution concentration (mmol/L) q e : Adsorbed solute by adsorbent (mmol/g) V : volume of solution

The adsorption isotherm of PNP is measured at 30℃ in 1 hour, with 0.05 g catalyst and 10 mL solution in each test, and initial concentration PNP varied from 1 to 25 mmol/L. At first, it was checked that concentration are stable after 1 hour, this indicates that equilibrium is established. More detailed experimental results are listed in Annex A-6 Table A2.

The plot of the results exhibits a linear part at low concentration and a slower augmentation of q e with C e at high concentration. This trend characterizes a Langmuir adsorption model: Pd@Al2O3 catalyst at 30°C.

𝑞 𝑒 = 𝐾𝑐 𝑒 1 + 𝐾′𝑐 𝑒

Adsorption and desorption of PAP

The adsorption experiments of PAP are measured in the same way as for PNP. Detailed experimental results are listed in Annex A-6 Table A3.

The measurements are really dispersed (Figure 42). In spite of the bad experimental precision, it should be noted that in the same concentration range, the PAP adsorption seems to be 10 times higher than PNP adsorption.

Figure 42 Adsorption equilibria of PAP onto Pd@Al2O3 catalyst at 30°C, contact time 1h.

With the goal to improve the precision measurements, evolution of adsorption equilibria was measured for a period of 19h and a very significant decreased in the concentration of PAP in the liquid above the catalyst was observed in Figure 43. Two hypotheses might be considered to explain the disappearance of PAP: a reaction of PAP leading to form a solid substance or a precipitation of PAP due to the low solubility. The product after 19h corresponds to an unknown product, which was explored in the following desorption test. The main conclusion of this part is that off-line UV spectroscopy is not a convenient method to know the composition of a reaction mixture. Hence, in the following part, most of the reported results are measured by HPLC. Other experimental observations may be pointed out:

-The influence of CO 2 on PAP UV-vis spectrum.

-The difference of reaction course in batch and flow catalytic reactor, despite of the predictions of ideal models of reactors. Along all these experiments, it was also observed that fresh catalyst has specific properties and it should be "aged" by some reaction cycles to give reproducible results.

Effect of reaction parameters on conversion

Preliminary results

The experimental conditions are varied in the range indicated in Table 5, in order to establish the reaction rate expression. Before this, some preliminary check-in were made. 85 On the other hand, the maximum concentration expected in our experimental range is 30 mmol/L in case of total conversion of 10 mmol/L of PNP. This indicates that CO 2 evolved by the reaction remains dissolved in the reaction mixture.

b-As reaction onto the catalyst sites involves mass transfer from bulk liquid to the surface of the catalyst particle and then diffusion inside the porous structure up to the catalytic sites, the mass transfer criteria should be evaluated in order to know if reactant transport slow down the reaction process. Determination of rate-controlling step is particularly important in case of kinetics determination. Mass transfer criteria are calculated in Annex A-7.

Mears external mass transfer criterion is in the 10 -8 -10 -9 range, indicating that mass transfer from bulk to particle surface in much more faster than chemical reaction. For internal mass transfer, the Weisz-Prater criterion is in the 10 -7 -10 -9 range, signifying that the influence of internal pore diffusion is also negligible.

c-As reported by Maschmeyer 86 , stainless steel could catalyze hydrogenation reactions with formic acid. In order to investigate the effect of the stainless steel wall on the model reaction, sand has been filled into the tube to replace the catalyst. A series of tests with different reaction conditions have been carried out as summarized in Table 6. In a very intense reaction condition (high initial concentration, high temperature and low flow rate), the conversion is about 12%. However, our experimental range never reaches so strong reaction conditions, therefore the effect of stainless steel wall can be ignored.

In summary, the bulk diffusion and the internal pore diffusion can be neglected; the inner wall of tube has no effect on the catalytic reaction; the CO 2 produced are all dissolved therefore no bubbles can be produced.

Influence of temperature and flow rate on the PNP conversion

Influence of temperature and flow rate on the conversion was studied. The results are summarized in the following Figure 46. The repeatability has been verified. It indicates that the temperature and flow rate do not have effect on the conversion of PNP in packed-bed microreactor.

Influence of the concentrations of reactants

The effect of initial concentration of PNP and FA has been investigated with all three protocols, that give the same pattern, i.e. a strong effect of initial concentration on the conversion, as shown in Figure 47.

Dynamic studies

As explained in the first part of this chapter, as soon as we observed the dependence of measurements on the history of the catalyst leading to a lack of reproducibility of experiments, we implement a protocol involving alternation of reaction sequences and catalyst washing sequences. This protocol induces a transient behavior of the catalyst during the first period of the reaction sequences.

Experimental observations

Concentration profiles

On-line analysis, either with UV-vis. PDA (protocol 2) or with HPLC (protocol 3) allows to observe the variations of composition of the reaction mixture flowing out of the reactor. The appearance and disappearance of a component, we call it intermediate I250, have been clearly detected as shown in Figure 48 (A).

Different experiments were performed with protocol 2 (PDA on-line analysis), in order to relate the amount of I250 to experimental conditions. This amount is roughly estimated from the surface area of the 250 nm UV-band. It is observed that the amount of I250 flowing out of the reactor is the same when the initial concentration of PNP or the flow rates are varied (figures and data in Annex A-8 ). This could indicate that this amount is related to the catalyst surface area, unchanged during tests. Both off-line and on-line HPLC analysis confirms the profiles of PNP and PAP concentrations: as we can see from Figure 48 (B), at the outlet of reactor, the concentration of PNP exhibits a shoulder at the beginning and then decreased continuously and finally stabilized; meanwhile the concentration of PAP increased and reaches the stationary value after a long time, as compared to residence time.

Actually, the period of unsteady-state behavior of a flow-reactor is normally in the range of the residence time, i.e. the time interval necessary to fill in the reactor with reactants mixture. In homogeneous reactor, it is simply the fluid volume divided by the flow rate. In our microreactor, this time is about 20 s at a 1 mL/min flow rate. With heterogeneous catalyst, a certain amount of reacting mixture is stored by adsorption onto the catalyst surface (support and sites). From adsorption experiments, the time on feed necessary to saturate the catalyst with PNP is roughly estimated about 15-20 min at 1 mL/min flow rate 87 .

Several attempts were made to observe I250. With on-line HPLC analysis, we can also observe the presence of I250, but not with off-line HPLC. Figure 49 shows the series of chromatograms measured directly at the exit of the reactor: the first peak (purple) corresponding to PAP increases, while the last peak (blue) of PNP decreases. Moreover, at the time corresponding to maximum of 250 nm-UV band attributed to I250, a HPLC peak (red) appears between PAP and PNP peaks, then disappeared quickly. This peak is attributed to the intermediate I250. This peak was not detected with traditional off-line HPLC which involves a step of collection of product, i.e. a delay between reaction and analysis. This could indicate that the intermediate I250 is quite unstable in air or under light, which means it could be easily oxidized or photodecomposed.

Effect of formic acid on intermediate amount

It was noted that neither C PNP 0 nor Q have an effect on the amount of I250 flowing out of the reactor. When the initial concentration of FA is varied, with on-line PDA UV analysis, the variation of I250 profile is observed as shown in Figure 50. Based on these observations, we could conclude that there two reaction routes exist: one could be the direct route discussed in 1.2.1; the other one could be promoted by the deficit of FA, in which I250 is produced and transformed to PAP.

Attempts for the identification of intermediate product

Test of possible intermediate according to plausible mechanism

According to the plausible mechanism discussed in 1.2.1 in Figure 25, the possible intermediates are p-nitrosophenol (PNS), p-hydroxylaminophenol (PHx), 4,4'-Azoxydiphenol (PAXD), 4,4'-Azo diphenol (PAD) 4,4'-hydrazobisphenol (PHB) or p-Benzoquinone imine (PBQI). On considering the possible photosensitivity or instability of I250, we studied PNS, PHx , PAD and PBQI in this part.

PNS is a commercial product. PAD is successfully synthetized by modifying a method described in literature 88 (detailed synthesis information in Annex A-10 ). PHx is not commercial and there is not any synthesis method published, so that we modified the protocol of synthesis of hydroxylaminobenzene from nitrobenzene 89 . But we failed to synthetize PHx : the final product is the PAP according to the 1 H NMR analysis. Similar to PHx, PBQI is not commercial either and cannot be synthesized steadily 90 .

As a first element of comparison, the UV-spectra of PNS and PAD, shown on Figure 51, do not exhibit a hug adsorption band around 250 nm. T=25℃. After the reaction begins, the samples are collected each 10-12 minutes (Figure 52) and analyzed by MS in order to acquire the variation of the constitution of the product. The time of collection is 2 minutes. Another similar experiment is carried out with D 2 O solvent, so that the samples can be analyzed by 1 H NMR. As we can see in Figure 52, the curve of I250 reaches its maximum in the sample taken at 25 minutes, which is then compared with PNS and PAD.

(b) Results of NMR analysis

The reaction product with maximum I250 concentration, sampled at 25 minutes, is analyzed by 1 H NMR and compared with PNS and PAD. As shown on Figure 54, in the sample of reaction containing I250, PNP, FA and PAP are well identified, and there are several small peaks with δ between 6.89 and 7.22 which could corresponds to I250. The repeatability of these peaks is verified by repeating the same experiment. However, the 1 H NMR spectra of PNS and PAD do not match with these peaks detected.

Hence, UV-spectra as well as NMR indicate that I250 is neither PAD nor PNS.

Figure 54 Comparison of 1 H NMR of PNS, PAD with the sample containing I250.

Evaluation of stability of intermediate

Several observations question the I250 stability : the peak corresponding to I250 is visible with on-line HPLC, but not with off-line HPLC ; with RMN as well as with MS, the signal that could be attributed to I250 is very weak. To evaluate the stability of I250, a special experiment was made with on-line PDA. The normal reaction is started according to protocol 2, and when I250 reaches its maximum, the pump is stopped and reaction mixture containing I250 still remains in the UV cell. We continue to store the variation of I250 in the UV cell till to the stabilization.

The instability of I250 is clearly demonstrated by Figure 55: after the stop of flow, the curve of 250 nm decreases rapidly, and the half-life time is just about 2 minutes. It explains that only traces of I250 are detected by methods involving a delay between reaction and analysis.

Conclusion

In this part, three protocols differing by the analysis methods are presented : with off-line UV analysis, the set-up is quite simple and the conversion of PNP can be calculated, but the quantitative analysis of PAP cannot be carried out; with on-line UV analysis, the variation of composition of the reaction mixture can be easily detected, for example the appearance and diminution of intermediate I250, but the quantitative analysis of PAP is still a problem; with on-line HPLC analysis, the quantitative analysis of both PNP and PAP can be realized, so that we can get the time-concentration profile of these components. Compared with traditional HPLC analysis, this protocol eliminates the step of collection of products, and can allow the detection of quite unstable intermediates such as I250.

The main reaction product, PAP, is confirmed by NMR and MS. The comparison between batch reactor and microreactor demonstrate that the microreactor limits the adsorption phenomena and formation of byproduct by successive reaction, because of its continuous-flow mode.

The effect of temperature and flow rate is not demonstrated in our study, but the strong effect of initial concentration of reactants has been found, which could indicate a second-order reaction kinetic.

Several possible intermediates PNP, PAD and PHx according to plausible mechanism have been investigated, but neither PNP nor PAD does not match with the nature of I250 according to the UV, MS and NMR analysis, and PHx and PBQI are not commercial and could not be synthetized. The I250 is quite unstable, but it could be transformed to the PAP without catalyst. Hence, we suppose that I250 is PBQI, by the following reasons: a) PBQI is not stable and can generate PAP quickly. 91 Based on the mechanism proposed by Hart 82 and Bols 84 , the reaction mechanism proposed in Figure 25 could be modified as follows: d) In the former researches discussed, Parida 60 (b) and Saleh 75 have proposed the mechanism including PBQI as the intermediate. Saleh has observed a change of color during the reduction of PNP by hydrazine and attributed green color to PBQI. However, we have also observed the change of color of the product: the yellow color of PNP aqueous solution became colorless after the addition of FA; during the reaction, when the peak of I250 was intense, the color of product changed to blue purple; after the stable state of reaction arrived, the color was brownness (attributed to PAP). As we know that the green color can obtained by mixing yellow and blue, therefore the green color observed by Saleh could be the yellow color of PNP mixed by the color of PBQI, i.e. I250 (blue color in our investigations).

Further investigations are needed to confirm these hypotheses.

Chapter 3 -Modelisation of the reaction in packed-bed microreactor with heterogeneous catalyst

The reactor with solid catalyst can be classified as a fixed bed catalytic reactor. Models of such reactors range from the very simple one to some very sophisticated, depending on the type of convective heat and mass transfer, and on the objective of the modeling. We are interested in two objectives: (i) to find a model that mimics the dynamic behavior experimentally observed, in order to understand what happens onto the catalyst; (ii) to establish a kinetic model of the reaction under stationary conditions. For both objectives, the influence of flow pattern on the PNP conversion is much lower than that of reaction kinetics. Hence, the basic one-dimensional model, i.e. the ideal plug flow model, is adopted.

Ideal models of reactors and methods of calculation

Steady-state plug flow model

The ideal plug-flow model assumes that all the fluid elements move with a uniform velocity on a cross-section, so concentration and temperature gradients only occur in the axial direction. As the temperature of the catalytic reactor is controlled, constant temperature within the reactor is assumed. Volumetric flow rate Q is also considered as constant because of liquid incompressibility.

The reaction that takes place on the catalyst can be simplified as: PNP + 3 FA ----> PAP + 3 CO 2 + 2 H 2 O

Figure 58 Schematic presentation of plug flow reactor

The steady-state continuity equation is written as the mass balance over a differential volume element of catalyst dV CAT for PNP reactant: As the reaction rate r only depends on concentrations, the differential equation ( 4) can be solved by analytical or numerical integration of dC PNP /r, depending on the form of the kinetic law. The steady-state relation (4) is used for kinetic analysis of the reaction (see 3.3).

Q C PNP = Q(C PNP + dC PNP ) + r • dV CAT <==> -Q • dC PNP dV CAT = r

Ideal batch reactor model

As we have compared experiments in flow reactor and in batch reactor, it is necessary to present a model of batch reactor. The simplest model, i.e. ideal batch reactor model is chosen. It is supposed to be perfectly mixed, so at any instant the composition throughout the reactor is uniform. The reactants are initially charged into a flask, are well mixed, and are left to react for a certain period. Hence, composition changes with time. The material balance for PNP reactant about the whole reaction mixture is:

V LIQ dC PNP dt + r • V CAT = 0 (𝟓)
with:

V LIQ , volume of the reaction mixture in batch reactor X, conversion of PNP, calculated as X = 1-C PNP /C PNP °

The time t necessary to obtain a conversion X is:

t = V LIQ V CAT ∫ -dC PNP r X 0
Whereas in a catalytic flow reactor the same conversion is reached after a "contact time":

τ = V CAT Q = ∫ -dC PNP r X 0
Hence, at the same initial concentration and same temperature, the dependence of the reaction rate r on the concentration is the same in both reactors. If the same amount of catalyst is involved, the condition to get the same conversion is simply Q FLOW = V LIQ /t BATCH .

Amount of PNP accumulated within the reactor per unit time + Amount of PNP consumed within the reactor per unit time = 0

Unsteady-state catalytic plug flow model

Changes in operating conditions result in step perturbation at the entrance of the reactor: at first, the catalyst is under pure water; then, at time 0, the reactant mixture is fed at constant flow rate and composition the mixture reacts in the reactor according to the time evolved since its entrance. As a result, at least during a time equal to the residence time, both composition of fluid and composition on the catalyst surface vary all along the reactor. Hence, the unsteady-state mass balance over a differential volume element of reactor containing a volume of catalyst dV CAT and a volume of fluid ε/(1-ε) dV CAT , during an elementary time interval dt, results in a partial differential equation. For example for PNP:

Q C PNP = Q(C PNP + dC PNP ) + r • dV CAT + [ ε 1 -ε dC PNP dt + dq PNP dt ] dV CAT <==> -Q • dC PNP dV CAT = r + ε 1 -ε dC PNP dt + dq PNP dt (𝟔)
with: q PNP , molar concentration of PNP adsorbed on the catalyst surface ε, void fraction in the catalyst bed = V LIQ /(V LIQ +V CAT ) Boundary conditions: t=0, C PNP =q PNP =0 within the reactor t>0, C PNP = C PNP 0 at the reactor entrance (V=0)

Resolution method of the unsteady-state catalytic plug flow model

Except for a first order simple reaction and linear adsorption equilibrium, the resolution of the partial differential equation (PDE) (6) involves numerical calculation method. The finite difference method was selected because it gives the possibility to easily change the kinetic and the adsorption model.

The method is illustrated in Figure 59. As the evolution of concentration observed in the experimental reactor is quite slow in comparison with the fluid residence time, the number of cells has a little influence on the shape of the response curve. The results calculated with 1 cell or 16 cells differ in only a few percent.

On the contrary the number of time intervals should be high (typically 100-200) to obtain a smooth response curve.

Simulation of reactor under transient conditions

In this section, we try to reproduce the concentration profiles observed when the flow reactor experiment starts with new operating conditions. For the record, catalyst bed is washed with water between each test; and after the beginning of the test, a peak of unknown compound (I250), appears in the reactor effluent during a quite long time before the achievement of steady-state conditions, as shown below.

Figure 60 Intensity profile of 4 wavelengths by UV PDA.

I250 is at 250nm and PNP is around 360 nm.

Reaction model with successive reactions

Model hypothesis and resolution method

As a first model to account for the observations, a simple reaction with one intermediate species I is considered: PNP ---> I ---> PAP This model gives a simplified picture of the mechanism of the reaction presented in Chapter 1, as long as the rate of decomposition of one intermediate is slower than the others.

It is also supposed that all the reactions take place on the catalyst surface and that Langmuir hypothesis apply 92 : -Uniformly energetic adsorption sites -Monolayer coverage -No interaction between adsorbed molecules In addition, -

The adsorption phenomenon is supposed much faster than chemical reactions, so liquid and adsorbed phases are at equilibrium, -First order reaction rates are considered

The elementary steps of reaction corresponding to these hypotheses are:

(1) Fast adsorption equilibrium of PNP, with the equilibrium constant K PNP = q PNP /(sC PNP ) PNP + s = PNP ads (2) Formation of intermediate I, with a first order reaction rate r 1 = k 1 q PNP 92 Hofmann, H., Chemie Ingenieur Technik 1991, 63 (2), 103-103.

PNP ads -> I ads (3) Fast adsorption equilibrium of I, with the equilibrium constant K I = q I /(sC I )

I+s=I ads (4) Formation of PAP, with a first order reaction rate r 2 = k 2 q I I ads -> PAP with:

PNP ads , I ads , PNP or I species adsorbed on a catalytic site, q PNP and q I , the corresponding adsorbed concentrations s, the concentration of free catalyst sites q T , the total concentration of catalyst sites r i , the rate of reaction i (i=1,2) expressed on the catalyst volume basis.

The Langmuir-Hinshelwood model gives the total concentration of sites: q T = s+q PNP +q I ; Because of the adsorption equilibria, it is possible to express adsorbed concentrations as function of fluid concentration, as well as their time-derivatives :

q J = K J • q T • C J 1 + K PNP C PNP + K I C I J = PNP, I dq PNP dt = ∂q PNP ∂C PNP dC PNP dt + ∂q PNP ∂C I dC I dt = K PNP q T (1 + K I C I ) dC PNP dt -K I C PNP dC I dt (1 + K PNP C PNP + K I C I ) 2 (𝟕)
The same expression holds for I, by inversion of PNP and I subscripts.

The mass balances equations (6) are expressed for components PNP, I and PAP, with the rates of consumption: r PNP = r 1 r I = -r 1 +r 2 r PAP = -r 2 The mass balance equations constitute a system of 2 coupled linear equations, whose variables are the time-derivatives of fluid concentrations dC PNP /dt and dC I /dt. So, these derivatives are computed for each cell. Then, the concentrations at time t+∆t are calculated as C J (t)+ dC J /dt∆t . It should be noted that the PAP mass balance is independent because PAP was supposed to immediately desorb.

Results of simulation

In order to reduce the number of parameters to handle, dimensionless groups of parameters are used. Time is divided by fluid residence time, and concentrations and adsorption equilibrium constants are divided by initial PNP concentration (c j =C j /C PNP 0 and K' j =K j C PNP 0 ). An adsorbed phase Damkholer number is introduced to express the reaction rates constants. A capacity ratio θ between liquid and catalyst phase is defined. It could be noted that the "traditional" Damkholer number, i.e. the product of the rate constant by the residence time, is simply aDa j . θ = tQ(1-ε)/(εV CAT ) Da j = k j q T V CAT /(QC PNP 0 ) a = εC PNP 0 /((1-ε)q T ) Typical concentration profile of this model is illustrated on The influence of the parameters was studied, and it was observed that an increase in the first reaction rate (Da 1 ), in PNP adsorption (K PNP ') or in fluid relative capacity (a), or a decrease in I adsorption (K I '), are favorable to the extent of the reaction (decrease of PNP and increase of PAP), while an increase in the 2nd reaction rate (Da 2 ) has a low effect on PNP, and leads to a decrease of I for the benefit of PAP.

The parameters were largely varied and it was never observed a maximum on the I concentration profile. This result might seem surprising because it is well-known that in a batch reactor, successive reaction will lead to a maximum of intermediate concentration. Actually, during the course of the reaction, the rate of formation of the intermediate decreases while its rate of decomposition increases. In a steady-state flow reactor, this maximum also exists but it depends on the residence time. In conclusion, this simple model predicts that, under unsteady-state conditions, the compositions evolve regularly toward steady-state values, the intermediate just produces a delay before the product exit. Such model is not able to mimic the observations.

Reaction model with change in the catalyst surface

Model hypothesis and resolution method

In order to reproduce the appearance and then the disappearance of an intermediate, it is necessary to imagine a change in the mechanism of reaction. Hence, as the catalyst covered at first with water, and then with the reaction mixture, it is supposed that the properties of surface change, let's say from state s to state σ and that the intermediate is formed only on s and is not involved in PAP formation when PAP is formed on surface. The change in surface properties could be due to the decomposition of FA on the catalyst surface as proposed in section 1.2.1.2 Figure 26 or H-adsorption on Pd or Al 2 O 3 support.

The simplest steps of reaction corresponding to these hypotheses are:

(1) Adsorption of FA and PNP on initial surface s, transformation to σ surface with adsorbed intermediate I, with reaction rate r 3 = k 3 s C PNP FA+ PNP + s -> I ads

(2) Fast adsorption equilibrium of I, with equilibrium constant K I = q I /(σC I )

I ads = I + σ (3) Fast adsorption equilibrium of PNP on σ surface, with the equilibrium constant K PNP = q PNP /(σC PNP )

PNP + σ = PNP ads (4) Formation of product PAP, with a first order reaction rate r 1 = k 1 q PNP PNP ads -> PAP ads (5) Fast desorption equilibrium of PAP on σ surface, with the equilibrium constant K PAP = q PAP /(σC PAP )

PAP ads = PAP + σ As in the previous case, adsorption equilibrium is supposed and Langmuir-Hinshelwood model is used. The unsteady state mass balance equations are considered for each component with the following production reaction rates:

(1) Reactant PNP : r PNP = -r 1 -r 3 (2) Product PAP : r PAP = r 1 (3) Intermediate I : r I = r 3 Additional relations concerning the catalyst surface are :

(4) Sites s :

-ds/dt = r 3 (5) Catalyst surface : σ + s + q I + q PNP + q PAP = q T = const.

Initial conditions : At t=0, s = q T and C J =0 for J= PNP, PAP, I At t>0, V = 0: C PNP = C PNP 0 and C J =0 for J≠ PNP

The same dimensionless parameters and the same resolution method are used as for the previous model: analytical derivation of adsorption concentrations (Eq. 7), calculation of derivative values at time t by resolution of the system of mass-balance equations, and calculation of concentration values at time t+ ∆t from first order series expansion. 26 that the first step of reaction is the decomposition of FA on the catalyst surface, which could lead the change of catalyst surface.

Results of simulation

3 Kinetic model of reaction under stationary conditions

The kinetics of the reaction is established with experimental results obtained with on-line HPLC analysis (protocol 3), at the end of a reaction sequence of 60-100 min, i.e. at steady-state. The data set is composed of 55 points, all of them measured at 40°C, most of them at a stoechiometric ratio C FA 0 /C PNP 0 =3, with a 1 mL/min flow rate. The range of variation of parameters is the following : C PNP 0 = 0.3 -5 mmol/L, C FA 0 = 0.9 -10 mmol/L, corresponding to m = 0.45 -1.4, Q = 0.5 -2 mL/min. The repetition of the same "base point" at C PNP 0 =0.6 mmol/L allows to check the stability of the catalyst over a 8 months period : the standard deviation of 15 measurements is about 12%, indicating a poor reproducibility as well as a slow deactivation (Figure 64). The table of measurement is presented in Annex A-11 . The quality of the measurements is evaluated by comparison of initial PNP concentration measured by weighing and calculation from HPLC calibration curves, and by the material balance, i.e. the deviation between initial PNP concentration and final PNP plus PAP concentrations. The mean value of the deviation on material balance is 4.0%, and the deviation between the methods of evaluation of initial concentration is 3.0%.

Second order kinetics

As the strong dependence of PNP conversion on initial concentration was observed, a second-order kinetics was tested at first. Its main advantage is that it involves only one adjustable parameter, the rate constant k, unlike the models that take into account adsorption of reactant on the catalyst such as Langmuir-Hinshelwood model. The reaction rate r is expressed for an element of catalyst volume: r = kC PNP C FA In order to integrate the PNP material balance expression for an ideal plug-flow model ( 4), both concentrations have to be expressed as functions of PNP conversion:

V CAT Q = ∫ -dC PNP r 𝐶𝑓 𝐶° (𝟒) With C PNP = C PNP 0 (1-X), C FA = C FA 0 -3 C PNP 0 X = 3 C PNP 0 (m-X) with m = C FA 0 /(3 C PNP 0 ), from (4)
we can obtain:

Da = 3 k V CAT C PNP 0 Q = ∫ dX (1 -X)(m -X) X 0
The result of integration differs according to the value of the reactant ratio m. It can be noted that we never get the exact equality m=1. So, the result of integration is:

Da = 3 k V CAT C PNP 0 Q = 1 m -1 Ln( 1 - X m 1 -X ) (𝟖)
The relation (8) indicates that the plot of 1/(m-1) Ln[(1-X/m) /(1-X)] versus C PNP 0 /Q, when C PNP 0 , Q and m are varied, should be a straight line passing by the origin, whose slope is 3kV CAT . With the whole set of points, we obtain 3kV CAT ≈ 2.9 L 2 /(molmin), i.e. the rate constant k ≈ 3020.8 L/(molmin), as V CAT ≈ V MR /2= 0.32 mL in the microreactor.

The pertinence of the model is evaluated from the comparison of the PNP conversion calculated with the rate constant and the experimental conversion, as shown in Figure 65. The correlation of the results, as shown in Figure 65 is not perfect, but the wide dispersion of data has to be considered. Nevertheless, the mean deviation between second order model and experiments is not acceptable (about 35%): the model fails at low conversion, where the model predicts higher reaction rate than observed.

Although the wide dispersion of data, the plot of the mean reaction molar flow rate over the catalyst bed, calculated as Q C PNP 0 X, as a function of the mean PNP concentration (C PNP 0 + C PNP f )/2 clearly shows that the reaction rate is lower when there is a deficit in FA (Figure 66). And integration of the PNP mass balance equation becomes:

Da = 9 k V CAT C PNP 0 Q = ∫ dX (m -X) 2 X 0 = X m(m -X) (𝟗)
The plot of X/(m-X) as a function of m C PNP 0 /Q should be a straight line when m, C PNP 0 and Q are varied. The rate constant thus obtained is 9kV CAT ≈ 7.5 L 2 /(molmin), i.e., k ≈ 2604 L/(molmin). The comparison between experimental and calculated values is slightly better than with the previous model, with a mean error of 16%, but the trend is still the same (higher calculated reaction rate at low conversion).

Comparison with possible mechanism of reaction

Despite the poor precision of experimental results, we tried to exploit the reaction mechanism presented in Chapter 1 (Figure 25), which involves two concurrent paths to form PAP. The reaction steps are:

(1) PNP + FA -> PNS + CO 2 + H 2 O PNS = p-nitrosophenol : HO-ϕ-N=O (2) PNS + FA -> PHx + CO 2 PHx = p-hydroxylaminophenol : HO-ϕ-NHOH (3) PHx + FA -> PAP + CO 2 + H 2 O In case of FA deficit, the following steps could be favored:

(4) 2 PHx + FA -> PHB + CO 2 + 2 H 2 O PHB = 4,4'-hydrazobisphenol (PHB) : HO-ϕ-NH-NH-ϕ-OH (5) PHB + FA -> 2 PAP + CO 2
It should be noted that only PNP and PAP are analyzed, so it is not possible to make a difference between two reaction paths having the same partial orders of reaction. Moreover, in case of successive steps, it is the slowest one that regulates the reaction rate. Hence, the model tested is as simple as possible : only steps (1) and ( 4) are considered, with different forms of kinetics law, and they are supposed to be much slower than the others. The reactions rates tested are:

(1) r 1 = k 1 C PNP . C FA (4) r 4 = k 4 C FA Integration of these reaction rates in PNP material balance leads to a non-linear equation involving both rate constant as adjustable parameters. The values of these parameters that minimize the deviation between experimental and calculated PNP conversion are calculated by a Matlab program. We obtain a flat minimum, i.e. a zone where the residue ∑(X calc -X exp ) 2 varies a few, with k 1 ≈ 729.2-1038.4 L/(molmin) and k 4 ≈ 69.4-121.5 L/(molmin). The adjustment is slightly better than with only one reaction, but the general trend with poor representation of low conversion results, remains the same despite the use of two adjustable parameters.

Conclusion

In this chapter, firstly, in the simulation of reactor under transient conditions, the model has been established with the hypothesis of the change of catalyst surface, which can well feature the dynamic behavior experimentally observed: the intermediate profile exhibits a maximum, the PNP profiles a shoulder more or less pronounced and PAP increases and stabilizes after a longer time than PNP.

Secondly, the kinetic models of reaction under stationary conditions have been investigated. The second order kinetics has been explored as r = K c PNP C FA and r = k C FA 2 . Both of them could basically reflect the experimental PNP conversion. But large deviation is observed in the low PNP conversion range, i.e. when reactant concentrations are low.

Chapter 4 -Preparation and characterization of monolithic microreactor

In this part, a microreactor with silica-based monolith incorporated palladium nanoparticles will be prepared in a brand-new method and characterized. Before that, the general research status about the monolithic catalysts will be firstly introduced, emphasizing the preparation method of monolithic catalysts. Then series of silica-based monoliths have been prepared in cylinder PP-PE polymer tubes (syringe), for optimizing the preparation conditions of the stable, well-formed, hierarchically porous and functionalized silica monoliths. With the optimized preparation conditions, the hybrid monolith is prepared in a stainless-steel tube pre-coated with glass successfully. Afterwards, by means of continuous flow, palladium nanoparticles have been immobilized with success in the tube containing monolith and confirmed by a series of characterization methods.

Monolithic catalyst

Generality properties of monolithic materials

According to the definition by IUPAC, a monolith is "a shaped, fabricated, intractable article with a homogeneous microstructure that does not exhibit any structural components distinguishable by optical microscopy". The most monolith families applied in catalysis under continuous flow for fine chemical production have a polymer, or inorganic matrices skeleton (such as silica, zeolites) exhibiting mesopores or/and macropores (typically inferior to 10μm). 54 (a), 93 It exists also other monoliths made of ceramic or metal foils, but they present the very large flow-through pore or channels (>50μm) and their applications in the field of fine chemical synthesis is rare.

Upon most cases, monoliths are synthesized in one-step process, and exhibit a large pore volume (1-2 mL/g), which imparts these materials an excellent catalytic efficiency due to the large amount of active surface available, 54 (a), 94 and therefore pose an attractive alternative to traditional catalyst powders or pellets. 95 In recent years, the research on complex and hierarchically organized monolithic materials has been greatly improved and is still evolving rapidly. Various preparation techniques have been reported 96 for the hierarchically organized porous materials. This type of monolithic materials has a multi-level porous architecture, and offers unique properties with combination of pore sizes: micro-and mesopores offer the large interfacial areas and pore volumes; in the mesoporous dimension, either well-structured pores (e.g. 2D-hexagonal) or disorganized arrangements are possible (Figure 68); while macropores promote the mass transport to the active sites and decrease transport limitations within the materials.

Preparation of monolithic catalyst

There are mainly three types of monolithic catalysts used for application in catalysis for fine chemical production in continuous processes, whose skeleton consist of organic polymer, silica or zeolite materials. As the researches of zeolite monolithic catalyst are quite limited, here we mainly present the organic polymer monolithic catalyst and silica-based monolithic catalyst.

Organic polymer based monolithic catalyst

Polymers can be easily modified with a wide variety of functionalities; in consequence they are outstanding substrates for catalytic functions and allow a wide range of possible applications. Kirschning 54 (b) and Galarneau 54 (a) have discussed their preparation and applications. Three main methods for the preparation of polymer monolithic catalyst have emerged.

The first approach is developed by the group of Fréchet, based on the "molding" process. 97 The general procedure is shown in Figure 69: the mixture of monomers and porogenic solvent was transported into a stainless-steel column tube acting as a mold, and then the column was sealed and heated for the polymerization, following by the washing process. Thus, the macroporous organic polymer monoliths with large flow-through macropores (0.7-2 μm) and a connected network of mesopore (10 nm) were obtained. Different monoliths, such as polyacrylamide, polystyrene etc. have been made.

Figure 69 Scheme of the method of Fréchet for the preparation of macroporous polymer monoliths 97 (a) Thereafter, based on this method, the group of Steven 98 has loaded Pd 0 nanoparticles into the monolith by pumping sodium tetrachloropalladate (K 2 PdCl 4 ) and sodium borohydride (NaBH 4 ) for Pd reduction, and then performed series of Heck reactions (cross-coupling between aryl halides and alkenes) in continuous flow mode. The reactor was a 6.6 mm (ID)  70 mm glass column filled with monolithic catalyst, but the quantity of Pd loaded was not mentioned. They obtained Heck products in high purity with good yields (> 80%), and shorter reaction times (2h) than in corresponding batch equivalent (16-20h). 99 Despite of the improvement of production brought by Fréchet-type macroporous polymer monoliths, the defect of these materials is that the swelling of the skeleton, leading to variations of the pressure drop and residence time, can largely impact on their applications.

A second strategy has been introduced by Kirschning 100 to overcome this limitation. The polymer/glass monolith was prepared by synthesizing the polymers inside the porosity of a glass rod with macropores between 50-300 μm. This polymer/glass monolith, with macropores of 1-2 μm, can maintain the same versatility for functionalization as classical polymers; moreover, the rigid macroporous matrix can well limit the swelling of skeleton. On the basis of the polymer/glass monoliths, the same group has incorporated the Pd 0 nanoparticles into the materials by circulating the aqueous solution sodium tetrachloropalladate (Na 2 Cl 4 Pd) and then NaBH 4 for Pd reduction 102 . Thus, the catalytic monolith with a palladium content of 0.03 wt % has been prepared in a 5.3 (ID)  110 mm stainless-steel column, and the Suzuki-Miyaura coupling reactions have been performed, with the yields up to 99%.

The third preparation method is based on the high internal phase emulsions (HIPE), which is defined as an emulsion containing more than 74% of internal phase and external phase 103 . After the pioneer work of Bartl 104 and Lissant 105 , the polymer HIPE (polyHIPE) has drawn widespread attention in monolithic catalyst. The typical preparation strategy of polyHIPE is presented in Figure 72. PolyHIPE is characterized by the presence of open-cell structure, pore sizes of which are normally in the millimeter-scale, but the majority of polyHIPE have pores that are tens of micrometers in diameter 106 , with a low density from around 0.1 to as low as 0.0126 g/cm 3 and a porosity up to 0.94. 107 Afterwards the polyHIPE has been functionalized with various organic groups and immobilized palladium nanoparticles on its surface by batch method with reduction of K 2 PdCl 4 or Pd(OCH 2 CH 3 ) 2 . 108 With the functionalization of primary amine group (-NH 2 ), the Pd loading could reach 8 wt %, and exhibits good catalytic performance in a Suzuki-Miyaura coupling reaction.

Thanks to the polymer-based monoliths, the first time a functionalized monolith can exhibit key advantages when used as a catalytic microreactor. However, the challenges still remain for these materials, particularly from the viewpoint of engineering: most of polymers are sensitive to mechanical forces and may show a limited thermal and chemical stability, and their properties may vary by shrinking or swelling. 54(a)

Silica monoliths

The silica monoliths with either micro, meso, or macropores have been well known for several years. However, there are only two main types of silica hierarchically organized monolithic materials have been reported for catalytic reactions. One family was firstly synthesized by the group of Imhof109 by using an oil-in-water emulsion (for example, dodecane in water stabilized by quaternary ammonium surfactant) as a template. Then, it has been well developed for catalytic reactions by the group of Backov110 , by using emulsions stabilized by silica particles and sol-gel process in acidic condition (Figure 73(A)). The emulsifiers (surfactants), which allow the formation of polar and apolar regions, were mainly used to form the well-ordered nanostructure. These native silica porous monoliths are named Si(HIPE) for "silica high internal phase emulsion". They feature poly-dispersed macropores from 0.5 to 5 μm 110 (b) , and mainly microporous and mesopores (Figure 73(B)), with about 700-800 m 2 /g of surface area and 70-92% porosity, and a density as low as 0.08 g/cm 3 . The general mechanism of sol-gel process in acidic condition is presented in Figure 74. There are two main steps. The hydrolysis step of the alkoxide of silicon in acidic condition is intended to initiate the formation of hydroxyls groups around Si for the following condensation step. The condensation step allows the growth of the chains by formation of siloxane bridges (Si-O-Si), and there are two possible reactions during this step: alkoxylation reaction between an alkoxide of silicon and another partially hydrolyzed alkoxide; oxolation reaction between two partially hydrolyzed alkoxides.

Figure 74 Mechanism of silica-based sol-gel process in acidic condition

In order to benefit the hybrid organic-inorganic chemistry versatility, the functionalization of native Si(HIPE) monoliths have been investigated subsequently with organically derived silane such as 3-(2,4-dinitrophenylamino)-propyltriethoxysilane (DPTS), (3-Mercaptopropyl)trimethoxysilane (MPTS), (3-aminopropyl)-triethoxysilane (APTS) etc. to prepare hybrid organic-inorganic porous silica-based monoliths. 110(e) (f) Two methods of functionalization have been carried out: direct synthesize by mixing the organosilane, tetraethylorthosilane (TEOS) and the emulsifier tetradecyltrimethylammonium bromide (TTAB) at the beginning of sol-gel process (co-condensation), or by grafting the organo-functional groups by immersing the prepared Si(HIPE) in the organosilane solution under vacuum.

It should be noted that, as shown in Figure 75, the mesoporosity of mercapto-Si(HIPE) (functionalized by MPTS), was characteristic of randomly dispersed pores, while that of the dinitro-Si(HIPE) (functionalized by DPTS) exhibits a hexagonal organization. Backov explained this difference by the aromatic structure of DPTS inducing an orderly arrangement, that would not be offered by the mercapto derivative. 110(e) Then the Pd 0 nanoparticles are incorporated by immersing the functionalized support in a palladium acetate (Pd(OAc) 2 ) solution and then reduced by NaBH 4 . In order to compare these monolithic catalysts, the Mizoroki-Heck coupling reaction has been carried out in a batch reactor. 110 (c) The Pd loadings are similar (3.9-4.1 wt%) for all monoliths, but the monolithic catalyst functionalized by MPTS and prepared by co-condensation method (mercapto-Si(HIPE)) have the best turnover and cycling performances, as compared in Table 7. The high TOF of MPTS indicates that the co-condensation method is more effective for functionalization than the grafting method; moreover, the silica monolith modified with a mercapto group provides a fairly good scavenging power toward Pd nanoparticles. A second family of silica monoliths was developed by the group of Galarneau 111 , featuring a well-defined hierarchical porosity (macropores 2-10 μm and mesopores 7-20 nm) with high surface areas up to 600 m 2 /g, on the basis of the monoliths first synthesized by Nakanishi 112 in 1997 for chromatographic applications. A typical synthesis involves an alkoxysilane and a polyethylene oxide (PEO) with water as porogenic solvent. A particular phase separation named spinodal decomposition occurred between the silica rich phase and PEO rich phase, which produced a homogeneous bi-continuous network of PEO/water and silica. Then this material was treated by alkaline, giving rise to the mesoporosity within the structures 111(e) . It is worth noting that the well-ordered mesopores cannot be obtained by this method, unless the preparation based on the skeleton of MCM-41 (Mobil Composition of Matter No.41), a well-known mesoporous material. 111(e) The resulting monoliths were cladded by heat-shrinkable polytetrafluoroethylene (PTFE) and ended by two glass tubes, which allow the connection to the pump for further continuous-flow processes. 111(a) (c) An aqueous solution of palladium nitrate (Pd(NO 3 ) 2 ) was pumped through the cladded monolith, that was then washed and reduced by the H 2 flow, generating the catalytic monolith with 6 mm diameter, 1 cm length, 4.6 wt % Pd. The catalytic partial hydrogenation reaction of 3-hexyn-1-ol demonstrated an excellent yield (80%) and productivity (0.8 mol/g Pd /h) compared to a commercial Pd@SiO 2 grain catalyst (32%yield, 0.3 mol/g Pd /h productivity).113 Other bimodal meso and macro porous silica monoliths combined with SBA-15 (Stanta Barbara Amorphous-15) have been reported recently,114 they bear a monolithic character and open macro-porosity while offering a highly ordered mesoporous network, but their applications in catalytic microreactors are rare.

In conclusion, each of these types owns its unique properties and limitations. With respect to polymer monoliths, key advantages like mechanical and thermal stability are offered by silica monoliths, which are also more resistant to a wider range of solvents. The obstacle of the development of silica monolith is the lack of reliable route between academic laboratories to industrial application, for example, the seamless cladding of the silica monolithic rods into microreactor. Up to now, preparation of silica catalytic monoliths in microreactors is mainly by the batch-continuous process: for example, the silica monolith is firstly prepared and functionalized in batch process, and then cladded by PTFE and ended with glass tube to be immobilized Pd nanoparticle in continuous process. However, this type monolithic microreactor is not enough attractive to the industry, because the PTFE materials do not allow the same range of operating conditions (in terms of resistance to pressure and solvents) as stainless-steel tube, hence they cannot meet the demand of industrial application. Hence, the following research on the preparation method of silica-based monolithic microreactor with Pd nanoparticle is quite unique and more convenient for the industrial purposes.

Experimental section

Preparation of functionalized monolithic catalyst

The procedure of preparation was based on the method of Backov 110 (b) , and the proportion of reagent was varied to optimize the condition of preparation, in order to synthesize the mechanically stable hybrid monolithic catalyst in a PP-PE polymer tube (syringe) and in a stainless-steel tube, without shrinkage phenomenon. The chemicals utilized in this section are all commercial products.

Direct synthesis of functionalized monolith in polymer tube

The Native Silica Monoliths (NSM), Aminopropyl Silica Monoliths (ASM) and Mercaptopropyl Silica Monoliths (MSM) were prepared in similar procedure. The functionalization of NSM was carried out by co-condensation method, and it should be mentioned that the direct synthesis of ASM by co-condensation method has not been reported yet.

(1) The aqueous solution of TTAB was prepared in the mortar in a given concentration, followed the adding of concentrated HCl (37%).

(2) This step depends on the substrate: for NSM synthesis, a given amount of TEOS was added dropwise in the former mixture along with the vigorous agitation by pestle for approximately 5 minutes in order to perform TEOS hydrolysis. For ASM and MSM, TEOS was pre-mixed with (3-aminopropyl)-triethoxysilane (APTS) or with (3-mercaptopropyl)trimethoxysilane (MPTS) before addition to TTAB solution.

(3) The emulsion was formed by adding of dodecane drop by drop on maintaining the vigorous agitation continually for about 7 minutes. (4) The final step was the transfer of the emulsion into a plastic syringe, and then the syringe is sealed and left for 10 days for aging. (5) The resulting materials were then washed dropwise with THF/Acetone (1:1) for 5 days and then with ethanol for two days in Soxhlet.

Growing of Pd nanoparticles within functionalized monolith in batch mode

On the basis of the researches of Backov 110(c) (f) , the catalytic performance of mercapto functionalized monolith is better than that of amino functionalized monolith. It was also demonstrated that addition of triphenylphosphine (PPh 3 ) during the impregnation step in the grafted hybrid monolith in a molar ratio 4:1 relative to palladium offer better catalytic performances. Thus in the following monolith preparation and characterization, the MSM is mainly investigated, and addition of PPh 3 is tested.

Hence, the Pd nanoparticles are impregnated by three ways: The preparation procedures are similar:

(1) MSM (0.1 g) was added in a flask under argon atmosphere.

(2) (a) Pd(PPh 3 ) 4 (0.15 mmol) was then added, or, (b) 3 mL of Pd(OAc) 2 (0.15 mmol) solution containing PPh 3 (0.6 mmol) was added, or, (c) 3 mL of Pd(OAc) 2 (0.15 mmol) solution was added (3) 3 ml of dry THF was added into the flask. The solution was left in dark under stirring for 2 days. ( 4) A fresh solution NaBH 4 (1.5 mmol) prepared in THF/H 2 O (v/v, 3mL) was degassed by argon bubbling for 30 minutes then quickly added into the previous solution. ( 5) After the sufficient reduction within 1 hour, the resulting matrix was then washed in ethanol for 2 days then dried in air at room temperature.

Direct synthesis of functionalized monolith in stainless-steel tube

As the preparation of functionalized monolith immobilized by Pd nanoparticles has been explored successfully, the Pd@monolith has been synthesized in the stainless-steel tube with the optimized preparation condition (detailed in Annex A-12 ).

The emulsion was transposed into a special stainless-steel tube (internal diameter D MM =4 mm, length L MM =100 mm, GLT®(Glass Lined Tubing), TRAJAN), which has a layer of glass coated on the interior surface of tube. Then both ends of the tube were sealed up with the pre-sheared polytetrafluoroethylene (PTFE) sheets and Swagelok plugs, then left to age for 10 days at room temperature.

The tube containing the resulting material was connected with the micro flow pump and washed by pumping THF/acetone (v/v) for 3 hours with the flow rate 0.1 mL/min under 40℃, then washed with ethanol for 2 hours. The color of the effluent on the outlet of the tube changed from pale yellow to colorless at the beginning of washing process. Each hour, the outflow was collected, evaporated and analyzed by 1 H NMR for following and insuring the effectiveness of washing. This hybrid monolith is labeled MSM-T.

Continuous growing of Pd nanoparticles within functionalized monolith in stainless-steel tube

The continuous flow has been applied for the washing and in-situ growing of Pd nanoparticles, to prepare the microreactor with silica-based monolithic catalyst.

A solution of palladium acetate (20 mmol/L) in water was pumped through the tube containing monolith at 0.15 mL/min for 1 hour. The color of the outflow changed from colorless to brown.

And then the distilled water was pumped for 20 minutes at 0.15 mL/min in order to wash the redundant palladium acetate. Then the same procedure was repeated: after palladium acetate was pumped for another 1 hour at the same flow rate, the tube was washed by water for 20 minutes again. A fresh solution of NaBH 4 in water/2-propanol (1:59) (2-propanol was used to reduce the bubble formed by NaBH 4 in water, dissolved oxygen was removed from water by ultrasonic degassing for 30 min) was prepared and then pumped through the tube at 1 mL/min for 4 hours. Finally, the tube was conditioned by washing with water at 1 mL/min for 2 hours, and ethanol at 1 mL/min for 2 hours. The functionalized monolithic catalyst was labeled Pd@MSM-T.

Two tubes have been prepared in exactly the same conditions: one was sampled and dried for analysis and the other one was used as a monolithic microreactor for catalytic reactions. In order to prevent the shrinkage phenomena of MSM, the monolith in the tube for catalytic reaction was maintained wet in water.

The general preparation strategy of functionalized monolithic catalyst in stainless-steel tube is illustrated in Figure 79.

Characterization method

Several methods were utilized to characterize the monoliths.

a-Degree of condensation and types of silicate species

The functionalization of monolith can be measured qualitatively by Cross Polarization Magic Angle Spinning (CP-MAS) NMR analysis 115 . 29 Si and 13 C CP-MAS NMR spectra were obtained by solid-state NMR spectroscopy on a Bruker Avance-400 MHz NMR spectrometer operating at 29 Si resonance frequency of 79.5MHz. About 80mg of samples were placed in zirconium dioxide rotors of 4-mm outer diameter and spun at a Magic Angle Spinning rate of 10 kHz in a commercial Bruker Double Channel probe. 29 Si CPMAS experiments was performed with Cross Polarization (CP) technique using a ramped 1H-pulse starting at 100% power and decreasing until 50% during the contact time (5 ms) in order to circumvent Hartmann-Hahn mismatches. To improve the resolution, a dipolar decoupling GT8 pulse sequence was applied during the acquisition time.

To obtain a good signal-to-noise ratio, between 1K and 10K scans were accumulated using a delay of 2.5s. The 29 Si chemical shifts were referenced to tetramethylsilane.

29 Si CP-MAS NMR appears as a straightforward tool to detect the local chemical environment around the Si atoms, so that it allows to identify different siloxane species. The assignments of 29 Si NMR signals to the silicate species 110(e) that could be formed during monolith synthesis are illustrated in Figure 80. hysteresis loop H 3 is normally observed if the adsorbent forms aggregates, and it is not characteristic of mesoporosity. The hysteresis loop H 4 indicates that the adsorbent bears essentially a microporous structure associated with some residual mesoporosity.

Characterization and discussion

Optimization of preparation conditions of NSM, ASM and MSM in polymer tube

In this part, the aim of optimization of the preparation conditions is to synthesize the mechanically stable monolith in tube without shrinkage. Hence, NSM, ASM and MSM were synthesized in PP-PE polymer tube (syringe), which allows rough estimation of the shrinkage ratio.

The CP-MAS NMR analysis was used to characterize the condensation degree and the effectiveness of functionalization.

Optimization of preparation conditions of NSM

Our first concern was to elaborate mechanically stable aerogel after drying in preformed tube, so the first aim of the preparation of NSM was just to confirm the convenient condition for preparation of monoliths in the PP-PE polymer tube (syringe). Thus, several conditions of preparation are tested, the criteria are the shrinkage ratio, that might be as low as possible and the degree of condensation and the degree of functionalization, both expected high.

As discussed in publication 110 (b) , in the preparation of Si(HIPE) by sol-gel process, the volume ratio of aqueous phase and oil phase could affect the properties of emulsion, and the quantity of TTAB and TEOS could have effect on hydrolysis and condensation steps. Hence, three coefficients have been considered when varying the preparation conditions: R 1 is the total aqueous phase volume/dodecane volume R 2 is the mass of TTAB/mass of total aqueous phase R 3 is the mass of TEOS/mass of total aqueous phase X SR is the shrinkage ratio, corresponding to the ratio of decreased volume aerogel monolith to the volume of initial emulsion. The volume of shrunken monolith is estimated from the scale on the polymer tube by visual inspection, so estimation of X SR is not precise.

The detailed preparation conditions were listed in Annex A-15 Table A9 and the variation of preparation parameters of NSM were summarized in Table 8, marked by the grey color. The preparation condition of NSM-B was the same as in publication of Backov 110 (b) . The NSM have been successfully prepared, which demonstrated the feasibility of our concern.

The 29 Si CP-MAS NMR spectra of NSM are summarized Figure 83 and the condensation degree %C.D.Q has been calculated as presented in section 4.2.2 (Table of values in Annex A-16 Table A12). The significant Q 3 type Si peak has been detected in all NSM samples, and weak Q 2 and Q 4 peaks have been found in some samples. The 90% X SR of NSM-1, in which R 1 was the lowest, corresponds a prodigious shrinkage as shown in Figure 84 (A), compared with NSM-2 in Figure 84 (B). This is in accordance with the conclusion of Backov 110 (b) : as the condensation step started at the oil-water interface, the increase in oil (dodecane) fraction would destabilize the oil-water interface, going against the silica condensation and thus leading to the shrinkage of monoliths. In the sample NSM-4 with the highest amount of emulsifier R 2 = 0.35, the X SR was -10%, indicating that the final volume of monolith was larger than the volume of starting emulsion.

Poor condensation is indicated by the only slight Q 3 peak in 29 Si CP-MAS NMR analysis. The high quantity of emulsifier TTAB might destabilize emulsion, thus reducing hydrolysis and/or condensation step, so, it still exists some -Si-OH groups that did not bond to each other, leading to the augmentation of volume and the decrease of mechanical stability.

Comparison of X SR of NSM-3, NSM-4 and NSM-7, shows that higher or lower TTAB quantities were both not favorable conditions in the preparations of NSM. The effect of quantity of TEOS was not obvious on the preparation of NSM in the range of 0.1< R 3 < 0.3, by comparing NSM-5, NSM-6 and NSM-7. All the NSM samples had similar degrees of condensation %C.D.Q lying in the range about 73%-75%, as expected. 13 C spectrum of NSM was just used to demonstrate the effectiveness of washing process. The peaks of TTAB have been detected in some samples of NSM (results in Annex A-17 ), corresponding the residual TTAB in the monolith after washing.

To sum up, the preparation conditions of NSM-2, NSM-6, NSM-7 and NSM-B are all favorable, considering their small shrinkage ratio and good condensation degree. By summarizing the above investigations on the effect of preparation conditions, it could be roughly concluded that with R 1 > 0.36, 0.15 < R 2 < 0.35 and 0.1 < R 3 < 0.3, the NSM could be prepared steadily with little shrinkage phenomena.

Optimization of preparation conditions of ASM

In fact, the direct synthesis of ASM by co-condensation method has not been reported yet. Hence, the major aim of the synthesis of ASM in this thesis was mainly to verify the feasibility of the co-condensation method on the preparation of ASM and to compare with MSM.

To explore this synthesis method, preparation conditions have been largely tuned, which was different from the synthesis of NSM. The detailed preparation conditions were listed in Annex A-15 Table A10 and the variation of preparation conditions of ASM were summarized in Table 9, marked by the grey color. R 4 represents the n(TEOS)/n(organosilane) (APTS in this synthesis). The shrinkage phenomena of ASM-2 was associated the low R 1 during the preparation. The similar phenomenon was also observed in NSM-1, which gave the evidence of our previous explanation: the increase of quantity of dodecane in the starting emulsions could lead the shrinkage of monoliths. The effect of augmentation of R 1 in ASM-1 was not obvious on the shrinkage.

The high emulsifier ratio R 2 led the high volume of ASM-5, and the low R 2 could give rise to the shrinkage phenomena (ASM-4). These results perfectly matched with the NSM syntheses.

Similar to NSM preparation, effect of TEOS (R 3 ) was not obvious to be observed. As for the effect of R 4 , it was difficult to draw a general conclusion in current synthesis of ASM. However, the object is to functionalize the NSM, so with the high R 4 of ASM-7, perhaps we could obtain more functionalized monolith, which will be verified in the following CP-MAS NMR analysis.

The 29 Si CP-MAS NMR spectra for ASM are illustrated in Figure 85. With the deconvolution of spectra, the area proportion of T and condensation degree of ASM samples are listed in Table 9 (table of detailed values in Annex A-16 Table A13). The presence of T type proves the successful functionalization of monolith. T 3 , Q 2 , Q 3 and Q 4 existed in all samples, and T 2 was not as obvious as other peaks. The condensation degree T varies in the range of 92.3% -100% and %C.D.Q varies in the range of 77.4% -80.4%, higher than that of NSM, which demonstrates the effectiveness of co-condensation method to synthesize ASM. It is worth noting that with high value of R 4 , ASM-7 exhibits the high proportion of T type, compared to other samples. It indicates that the high quantity of APTS in the emulsion is beneficial to functionalize the monolith, and also favorable to the condensation process. The peak TTAB (30.4 and 67 ppm) cannot be found, this confirms the monoliths were all well washed. In ASM-1, the proportion of amino group can be hardly found, but the -CH 2 CH 3 group is significant, indicating the week functionalization with -NH 2 group and strong condensation with -CH 2 CH 3 . Considering the high R 1 value of ASM-1, we can conclude that the too little quantity of oil phase in the emulsion is not favorable to the co-condensation functionalization, because it could prevent the formation of stable oil-water interface during the condensation.

By combining the results of shrinkage ratio and NMR analyses, we can see that the best range for preparation of NSM was also applicative in the preparation of ASM. And we can define more precise condition range for ASM synthesis: 0.41 < R 1 < 6.46, 0.15 < R 2 < 0.28, and 0.1 < R 3 < 0.3.

Optimization of preparation conditions of MSM

The preparation conditions of MSM were basically based on the favorable range for monolith synthesis concluded in NSM investigations, with slight change of R 1 and R 2 in the safe range, and vast variation of R 4 to explore the convenient proportion of MPTS in the co-condensation process.

The detailed preparation conditions were listed in Annex A-15 Table A11 and the variation of preparation conditions of MSM were summarized in Table 10, marked by the grey color. R 4 represents the n(TEOS)/n(organosilane) (MPTS in this synthesis). The MSM-B was the preparation condition of Backov 110 (b) . The X SR augmented with the increase of 1/R 4 , which indicated the excessive of MPTS could not promote the co-condensation process, because too much organo-groups which could not react in the condensation, might destabilize the emulsion. Hence, the R 4 =9 was the favorable condition for the MSM synthesis by co-condensation method.

The 29 Si CP-MAS NMR spectra of MSM in Figure 87 exhibit the presence of T 2 , T 3 , Q 2 , Q 3 and Q 4 peak, and T 2 type was not always obvious. A14). With overall consideration, the preparation conditions of MSM-1, MSM-7 and MSM-B are all favorable for the synthesis of MSM in tube.

In the 13 C CP-MAS NMR spectra for MSM illustrated in Figure 88, the peak of around 27 ppm in the 13 C NMR spectra demonstrates directly the existence of -SH group in the MSM prepared 118 . The other peaks around 30 ppm could be attributed to the surfactant. In conclusion, in this part, by co-condensation method, the optimizations of preparation conditions for NSM, ASM and MSM have been explored in the polymer tube (syringe). The shrinkage ratio and CP-MAS NMR analyses have been carried out to characterize the shrinkage phenomena, condensation degree and the functionalization results. The effects of preparation parameters such as ratio of aqueous phase (R 1 ), TTAB quantities (R 2 ), TEOS quantities (R 3 ) and MPTS or APTS quantities (R 4 ) in reactants have been investigated, and a favorable preparation condition range is proposed: R 1 > 0.3, 0.15 < R 2 < 0.35 and 0.1 < R 3 < 0.3. As for ASM and MSM, this range is 0.41 < R 1 < 6.46, 0.15 < R 2 < 0.28, and 0.1 < R 3 < 0.3. The functionalized monoliths with low shrinkage ratio and good condensation degree such as ASM-7, MSM-1, MSM-7 and MSM-B have been prepared with success.

According to the work of Backov 110(c) (f) , mercapto group provides good stabilizing power toward Pd nanoparticles, therefore the catalytic performance of mercapto functionalized monolith should be better than that of amino functionalized monolith. Hence, in the following catalytic monolith preparation and characterization, the MSM was mainly investigated, due to lack of time to test all samples.

Characterization of the hierarchy of pores

Here the macroporosity and mesoporosity of monoliths prepared in polymer tube are characterized by SEM and TEM, and the microporosity and specific surface of monoliths are characterized by BET analysis through N 2 adsorption-desorption isotherm. The functionalized monolith used for characterization is MSM-7, owing to its low shrinkage ratio, successful functionalization and good condensation degree.

SEM and TEM analysis

For the characterization of macroporosity of MSM, SEM analysis of MSM-7 (Figure 89 The TEM analysis was investigated to observe the mesoporosity of MSM prepared. Because Backov 110(e) did not observe the organization in the prepared mercapto-fonctionalized monolith as we discussed in the part 4.1.2.2, we will compare the TEM of MSM-7 and MSM-B (prepared with the conditions of Backov), to confirm the difference of MSM prepared.

As shown in Figure 90 (A)-(C), the typical 2D-hexagonal organization has been observed in the MSM-7, with the interval about 5 nm, therefore the mesoporosity of MSM-7 can be verified.

With regard to MSM-B (Figure 90 (D)-(F)), there are only randomly dispersed pores, and the hexagonal organization cannot be observed, just as the published results. Backov explained that this difference of organization was because the mercapto derivative did not offer high organization. However, based on our investigations, with a favorable preparation condition of MSM such as that of MSM-7, the typical 2D-hexagonal organization could be clearly observed.

N2 Adsorption-desorption isotherm

For the further confirmation of the meso-and the micro-porosity of MSM-1, and for the measurement of specific surface, the N 2 adsorption-desorption isotherm analysis has been investigated. As shown in Figure 91 (A), a weak hysteresis loop can be observed between the adsorption and desorption curves, which matches with hysteresis loop H 4 as discussed in 4.2.2, and indicates microporosity with fewer numbers of mesopores 110 (c) . The hysteresis loop of MSM investigated by Backov (Figure 91 (B)) marches with hysteresis loop H 2 , indicating the existence of only the mesoporosity not microporosity. With the BET analysis, the specific surface area of MSM-1 is 1260 m 2 /g. Compared with other monoliths in publications summarized in Table 11, our prepared MSM has an impressive surface area, perhaps thanks to its well-ordered 2D-hexagonal organization. This work MSM-1 1260 -Backov 110 (d) SiO 2 foam 1450 Backov 110 (b) SiO 2 830 Backov 110 (g) SBA-SiO 2 760 Backov 119

Imidazole-SiO 2 462 Backov 110 (e) Methyl-SiO 2 450 Backov 110 (e) Pyrrol-SiO 2 392 Backov 110 (e) Mercapto-SiO 2 53 Bakker 120

Polymer 482 Barbaro 113

ArSO 3 -SiO 2 322 Barbaro 111 (f) TiO 2 148 Debecker 121

Al-SiO 2 900 Galarneau 111 (d) BMIM-TFSI-SiO 2 a 761 Galarneau 111 (a) SiO 2 750 Galarneau

Characterization of Pd growing in batch mode within functionalized monolith

In the following catalytic monolith characterizations, hybrid monolith MSM-7 was chosen to carry out the immobilization of Pd nanoparticles because it was well functionalized, bearing the hierarchy macro-, meso-and micro-porosity, with typical hexagonal organization in mesoscale, and it has the high specific surface. The monolith MSM-B was also loaded with Pd nanoparticles for the comparison. As described in section 4. The main target of the immobilization synthesis is to incorporate the Pd nanoparticles into the monolith structure, with good dispersion. With the TEM analysis, the dispersion situation of Pd nanoparticles could be observed easily.

The Figure 92 demonstrates that, by direct immobilization of Pd nanoparticles in monolith MSM with Pd(0)(PPh 3 ) 4 , the Pd nanoparticles with diameter about 3 -10 nm have been deposed inside the interior of grains, but the clustering phenomena is observed. Due to the poor dispersity, this method is not favorable for the immobilization of Pd nanoparticles. In conclusion, by reducing Pd(II)(OAc) 2 without addition of PPh 3 in MSM-7, Pd nanoparticles are well dispersed and incorporated in the grains, this is an ideal preparation method. Therefore, in the following investigation of monolithic catalyst in the stainless-steel tube, the same method is adopted.

Characterization of functionalized monolith prepared in the stainless-steel tube

As the preparation of MSM immobilized by Pd nanoparticles has been explored successfully, the hybrid monolith has been synthesized in the stainless-steel tube, it is labeled MSM-T. The preparation parameters of reactants are those of MSM-7. The difference is that the condensation step of MSM-T is performed in stainless-steel tube and its washing step and impregnation of Pd The condensation degree and proportion of each type peak of MSM-T is summarized in Table 12 with the comparison of MSM-7 (detailed values in Annex A-16 Table A15). The higher %C.D.T indicates the functionalization of MSM-T is more effective compared with MSM-7. The scheme of co-condensation steps in the tube is presented in Figure 96. When the prepared emulsion was transferred into the tube, we assume that the glass wall was activated by the acidic solution, therefore the co-condensation was conducted between the hydroxylated silica wall, the hydrolyzed MPTS and TEOS. The MSM-T (Figure 97 (A) and (B)) exhibits the same well-ordered 2D-hexagonal structuration as MSM-7, with the interval of meso-organization about 5 nm. It indicates that the co-condensation conducted well in the stainless-steel tube. The Pd nanoparticles have been successfully incorporated into the monolith as demonstrated in Figure 97 (C) and (D). Although the dispersion was not as ideal as the Pd@MSM-7 because in some areas the Pd nanoparticles have aggregated, none the less, the Pd nanoparticles are reasonably dispersed in the monolith.

The aggregation phenomenon of Pd nanoparticles might be explained by the Oswald ripening, which describes the phenomenon of coarsening -the large particles grow at the expense of small particles124 . This phenomenon has been observed in the growth of Pd nanoparticles125 . In our case, the continuous flow might promote the Oswald ripening, because once some Pd nanoparticles have been immobilized in the monolith, the following small Pd nanoparticles in the continuous flow could continue to aggregate on the former larger Pd fixed. The atomic ratios of O on Si measured by EDS in three samples are all a little higher than 2: O/Si for MSM-7 is about 2.12 and for MSM-T is 2.3. With the deconvolution calculations of NMR analyses of MSM-7 and MSM-T, the estimated O/Si ratio for MSM-7 is 2.24 and for MSM-T is 2.18 (detailed calculation in Annex A-18 Table A16). Thus, the high O/Si ratio is entirely reasonable. The Pd incorporated in MSM-T by continuous flow method was up to 19.6% in weight, much higher than the commercial catalyst Pd@Al 2 O 3 (5.3 wt %, confirmed by EDS analysis) we used in the packed-bed microreactor. The characteristics of Pd@MSM-T are summarized Table 14 and compared with different monolithic catalysts in publications in recent years. It is obvious that Pd@MSM-T has a quite high porosity and Pd loading, proving that the MSM prepared and the continuous immobilization method in our work are extraordinary effective. monolithic catalyst in the industrial grade continuous flow reactor makes it only applied in lab scale application.

In order to make a breakthrough over this, the optimized preparation condition range for native silica monolith and functionalized monolith has been investigated. Then the mechanically stable mercapto-functionalized silica monolith has been prepared with success in polymer tube and characterized, demonstrating it possesses the flow-through macropores, typical hexagonal organization of mesopores and micropores, high specific surface and scarcely any shrinkage.

Same monolith then was synthesized by co-condensation method in a stainless-steel tube with the inner wall pre-coated by glass. Afterwards, palladium nanoparticles have been immobilized within the monolith in this tube by a continuous flow method. The high content of Pd in the monolithic catalyst highlights the effectiveness of the continuous in-situ incorporation of Pd nanoparticles. The practicability of prepared microreactor with monolithic catalyst will be verified by the following catalytic test.

Chapter 5 -Study of p-nitrophenol hydrogenation as model reaction in the monolithic microreactor and comparison with packed-bed microreactor

In this chapter, the monolithic catalyst Pd@MSM-T in the microreactor prepared in the chapter 4 is tested on the transfer hydrogenation of p-nitrophenol (PNP) with formic acid (FA), and then its properties are compared with that of the commercial catalyst in packed-bed microreactor. A first experimental section presents the influence of reaction parameters such as temperature, flow rate and initial concentration of reactants, then a kinetic model of the reaction under stationary conditions is established and the dynamic study of the reaction is presented. Last but not least, the performances of monolithic catalyst and commercial catalyst (Pd@alumina powder) are compared, including the catalyst performance, the dynamic and kinetic study and the pressure drop.

Experimental section

Experimental conditions

The same transfer hydrogenation of PNP by FA is chosen to compare the performance of the new Pd@silica based monolith catalyst with commercial Pd@alumina powder presented in Chapters 2 and 3. The characteristics of microreactor are listed in Table 15.

Experimental set-up and protocol

The on-line HPLC analysis (protocol 3 described in the section 2.1.4), which allows the quantitative analysis of both PNP and PAP directly at the outlet of the microreactor, is adopted. The experimental set-up is similar to the set-up in Figure 34 of Chapter 2; the only difference is that the monolithic microreactor replaces the packed-bed microreactor. Some experiments with on-line PDA analysis (protocol 2) are performed in order to observe the dynamic behavior of the new catalyst.

The full protocol is the same as presented in the section 2.1.4.2, including the analysis of the feed reactor mixture, a reaction sequence of 60-200 min with periodic analysis of the reactor effluent, and the washing process with water at 40℃ after each reaction.

Experimental condition range

The experimental conditions vary in the range summarized in

Effect of reaction parameters on conversion under stationary conditions

Evaluation of catalyst stability

The establishment of steady-state was checked during dynamic study (see 5.4). The evolution of monolithic catalyst in the microreactor is verified by repeating the reaction under the same "base" condition over about 50 days period. The results on Figure 98 show an evident dispersion, with a standard deviation of the PNP conversion X about 18.3% (C PNP 0 =0.6 mmol/L) and 9% (C PNP 0 =1 mmol/L). The conversion of the final point (53 days after the first point) is 0.46, still superior to the average value of X (0.38). It indicates that, in spite of the poor reproducibility, the activity of the new monolithic catalyst is stable with time.

Figure 98 Catalyst evolution over 53 days period. CPNP 0 = 0.6 or 1 mmol/L, CFA 0 /CPNP 0 =3, Q = 1 mL/min, T=40℃

Influence of temperature and flow rate on the PNP conversion

The effect of temperature and the flow rate on the conversion of PNP were studied and the results are summarized in Figure 99. Graph (A) shows that the temperature does not have any effect on the conversion of PNP in monolithic microreactor. A significant effect of flow rate is observed clearly on Graph (B). As expected, the conversion increased with the decrease of flow rate, i.e. with increasing residence time.

Influence of concentrations of reactants on the PNP conversion

The influence of initial concentration of PNP and FA on conversion of PNP has been investigated. As shown in Figure 100

Kinetic analysis of the reaction in the monolithic reactor

The kinetics model of the reaction in monolithic microreactor is based on the experimental results of on-line HPLC analysis at the end of a reaction sequence of 60-200 min (steady-state). The data set is composed of 45 points: -Temperature = 40℃, except 3 points at 60℃ and 2 at 80℃; -Flow rate 1 mL/min except 2 points at 0.2 mL/min and 2 at 0.5 mL/min -Concentrations C PNP 0 = 0.6 mmol/L and C FA 0 = 1.8 mmol/L (i.e. stoichiometric ratio, m = C FA 0 /3 C PNP 0 =1) at base point, C PNP 0 varied between 0.6 and 4 mmol/L, and m varied between 0.5 and 2.

For reminding, the steady-state plug flow reactor model is used to represent the operation in the monolith reactor. The PNP material balance on an elementary slice of reactor containing a volume of catalyst dV CAT is :

Q C PNP = Q(C PNP + dC PNP ) + r • dV CAT <==> -Q • dC PNP dV CAT = r <==> V CAT Q = ∫ -dC PNP r 𝐶𝑓 𝐶° (𝟒)
with the r, the volumetric reaction rate expressed per catalyst volume unit.

The first order reaction rate, relative to FA concentration is: r = k C FA (𝟏𝟏)

FA concentration depends on PNP conversion X :

C FA = 3 C PNP 0 (m -X)
with the stoichiometric ratio m= C FA 0 /3C PNP 0 .

V CAT C PNP 0 • Q = ∫ dX r X 0 = ∫ dX 3kC PNP 0 (m -X) Da = 3 k V CAT Q = ∫ dX (m -X) = -Ln ( 1 - X m ) (𝟏𝟐) <==> X CALC = m(1 -exp ( 3 k V CAT Q )) (𝟏𝟑)
Because of the strong dispersion of data, the mean values of measurements made in the same experimental conditions are considered for the first kinetics trials, they compose a reduced data set (Annex A-19 ). The rate constant 3kV CAT is calculated onto reduced data using Eq.( 12), we obtain 0.486 mL/min. As the porosity of monolithic materials is about 0.987 (estimated in chapter 4), so k ≈ 9.94 min -1 , with V CAT ≈ V ML *(1-0.987) = 0.0163 mL. The conversions calculated with this value and Eq.( 13) are compared with experimental ones for all data in Figure 101. As all experimental conditions except temperature are the same on red and green points, their comparison on Figure 101 confirms the absence of temperature influence noted in 5.2.2. This could indicate that adsorption phenomenon is rate determining. Actually, when the reaction rate is proportional to the quantity of adsorbed molecules, at low surface coverage, the kinetic expression reduces to r = kKC129 . Thus, the experimentally observed rate constant k EXP equals kK,

where k is the reaction rate constant for the surface reaction and K the adsorption equilibrium constant. K decreases with increased temperature by the factor e λ/RT . As k = Ae -E/RT , therefore, the apparent activation energy E app = E-λ, is lower than the true activation energy of the surface reaction E.

It could be noted that X EXP is slightly higher than predicted by the model when the reaction rate is high, i.e. at high FA concentration. This deviation cannot be attributed to the saturation of the surface, that would lead to an opposite trend, as indicated by a Langmuir Hinshelwood model.

Dynamic studies

The sequence washing-reaction results in a step perturbation at the entrance of the reactor: at first, the catalyst is under pure water. Then, the reactant mixture is fed at constant flow rate and composition: the mixture reacts in the reactor according to the time evolved since its entrance. The deviation between PAP formed and PNP consumed was calculated for each experiments, at the end of the reaction sequence, i.e. at steady state. The average of the absolute value of deviation is 7%, while the average deviation is less than 1 %, indicating random deviations. So, it can be concluded that, at steady-state, PAP is the only product of PNP hydrogenation, at least within the limits of analytical precision.

However, on-line HPLC analysis has allowed the detection of I250 during the washing sequence with water (red line in Figure 105). This indicates that I250 is indeed formed during the reaction as an intermediate, but in monolithic microreactor, it is adsorbed on the catalyst support and probably a part is quickly converted into the final product, therefore it does not flow out of the reactor during the reaction sequence. The purple and blue dashed lines correspond to the decrease of PAP and PNP, respectively. The first HPLC chromatogram is that of the mixture after 10 min washing. PNP concentration is reduced by a factor 7 and PAP concentration by 20. Hence, the washing sequence is quite effective for PNP and PAP. However, concentration of I250 decreases very slowly, indicating a difficult desorption of I250. Figure 103 shows that there is no catalyst deactivation during a reaction sequence, therefore I250 could be adsorbed on silica support rather on Pd nanoparticles.

Comparison of packed-bed and monolith microreactors

The main subject of comparison of commercial Pd@alumina powder catalyst and new Pd@silica monolithic catalyst concerns their activity towards transfer hydrogenation of PNP reaction. The catalyst performances are firstly compared by calculating the turnover frequency. A subsidiary comparison concerns the pressure drop and permeability of the catalyst, which is an important criterion for industrial applications. The differences in dynamic studies and kinetic models are discussed afterwards.

Catalyst performance in transfer hydrogenation reaction

TOF (turnover frequency), defined as the TON (the turnover number, the moles of substrate converted per the moles of catalyst used) per unit time, is used to compare the catalyst performance of the commercial catalyst in packed-bed microreactor (Pd@Al 2 O 3 ) with the catalytic monolith Pd@MSM-T in the monolithic microreactor. In flow reactor, TOF is calculated as: The TOF of monolithic catalyst Pd@MSM-T is about 3 -6 times larger than that of commercial catalyst Pd@Al 2 O 3 , that demonstrates the excellent activity of Pd@MSM-T. When initial concentration of PNP increases, the ratio of TOF monolith /TOF pack-bed decreases, as expected from the difference in reaction order.

TOF flow = Q MR C PNP 0 X /
The highlighted catalytic performance of monolithic catalyst probably owes to the following reason: as shown in Figure 106(A), the monolith skeleton is heavily loaded by Pd nanoparticles (19.6 wt%), and the large surface area of monolith (1260 m 2 /g) give large accessible surface between reactants and Pd, while in the commercial Pd@Al 2 O 3 powder catalyst, the poor loading of Pd (5.3 wt%) and the small surface area (110 m 2 /g) could limit the sufficient contact between reactants and Pd.

Figure 106 TEM images of (A) monolithic catalyst Pd@MSM-T and (B) commercial Pd@Al2O3 powder catalyst (Pd pointed by white circle)

Pressure drop and permeability

Mechanical stability and hydraulic permeability of the packed-bed and monolithic microreactor are determined by analyzing the pressure drop -flow rate relationship, which characterizes the resistance to hydraulic flow and provides additional information in assessing process economics. For comparison, pressure drop at 1 mL/min is 25 bar for packed-bed microreactor, and 5 bar for monolithic microraector.

According to Darcy's law, the pressure drop over the reactor length (p/L) is related to the permeability as follows 130 :

∆p L =  K D Q A c (𝟏𝟒)
where  is the viscosity of liquid (water in our study, with dynamic viscosity 0.89 mPas at 25℃) K D is the Darcy permeability Q is the volumetric flow rate A c is the cross-sectional area of tube (A c,PB = 0.157 cm 2 for packed-bed microreactor and A c,ML = 0.126 cm 2 for monolithic microreactor)

Hence, the pressure drop over the reactor length (p/L) is in a linear relation with the volumetric flow rate (Q), with slope of /(K D  A c ).

The pressure drop is measured by KELLER digital Manometer LEO 2. The measurement is repeated three times for each flow rate of each reactor and the average value is utilized. The pressure drop (p) divided by tube length (L PB = 4 cm for packed-bed microreactor and L ML = 10 cm for monolithic microreactor) is summarized in Figure 107 with the variation of flow rate (Q). With equation ( 14), the permeability of packed-bed microreactor is K D,PB = 1.5310 -14 m 2 , and that of monolithic microreactor is K D,ML = 2.5710 -13 m 2 , about 17 times higher. The high permeability of monolithic catalyst matches well with its highly porous nature, which can enhance the through-flows of fluid in macropores.

The typical linear relationship between p/L and flow rate indicates the mechanically stable bed morphology of monolithic catalyst, resistant to time and use 131 . It is also obvious that the pressure drop over the reactor length of monolithic microreactor is about 10 times smaller than that of packed-bed microreactor. It reveals that the monolithic microreactor have an advantage over pack-bed microreactor from an economic perspective, especially in industrial application. the reaction with monolithic catalyst is first order with respect to C FA (r = kC FA ). Both involve the influence of FA, and the step of FA dissociation should be rate determining. As effect of temperature is absent in both commercial and monolithic catalysts, it indicates the reaction rate depends on concentration of FA adsorbed on the catalyst as discussed in section 5.3. c-Concentration profile at the beginning of reaction sequence is very sharp with monolithic microreactor, and much smoother with packed-bed microreactor. This indicates a very narrow residence time distribution (RTD) in monolith. This probably can be attributed to the high porosity combined to a very regular structure, like a foam, of monolith. Actually, the large specific surface of monolith MSM (1260 m 2 /g) compared to Pd@Al 2 O 3 powder (110 m 2 /g), allows efficient contact between flowing fluid (in the macropores) and stagnant fluid (in the mesopores and micropores), which intensifies mass transport from and to the active surface sites in the mesopores and micropores 131 .

Difference in dynamic behavior and kinetic model

Finally, in monolith, the narrow RTD and the easy access to Pd sites seems to favor selectively the main reaction path.

Conclusion

In this chapter, monolithic microreactor is firstly tested by the model reaction, with on-line UV PDA and on-line HPLC analysis. The reaction parameters on conversion under stationary conditions have been investigated: the reaction temperature and initial concentration of PNP have no effect on conversion; the effects of flow rate and the initial concentration of FA have been found. The first order reaction rate with respect to FA has been established successfully, it gives a good representation of variation of PNP conversion with experimental conditions. The absence of temperature effect reveals that the reaction rate depends on concentration of FA adsorbed on the catalyst.

In dynamic studies, the intermediate I250 is not observed with the monolith supported catalyst, confirmed by on-line PDA UV analysis, but it is detected during the washing process. It demonstrates that the I250 is formed on the catalyst support. It can be either transformed to PAP quickly or stay adsorbed.

Last but not least, the comparison of packed-bed and monolith microreactors has been investigated. The catalyst performances are first compared by calculating the turnover frequency, and the outstanding activity of monolithic catalyst has been demonstrated. The comparison of pressure drop demonstrates the mechanical stability of monolithic microreactor and its industrial potential. The comparison of dynamic study and kinetic model highlights the large specific surface of monolith and the specific texture of the hierarchical porosity.

General conclusion and outlook

The main purpose of this thesis was to explore the preparation of microreactors with monolithic catalyst, and to compare its performance to a packed-bed microreactor by a convenient model reaction. Thus, the transfer hydrogenation of p-nitrophenol (PNP) by formic acid (FA) catalyzed by palladium has been chosen as the model reaction.

First of all, concerning the analysis of this reaction, among the three developed protocols, the on-line analysis exhibits instinct advantages. In our investigations, despite the off-line UV analysis is easy to access and can analysis the conversion of PNP, the quantitative analysis of the main product, p-aminophenol (PAP) cannot be carried out, whereas it is possible in transfer hydrogenation with NaBH 4 . With on-line UV analysis, the variation of composition of the reaction mixture can be easily detected. We were also able to detect the appearance and diminution of an unstable intermediate I250, which has never been done. With on-line HPLC analysis, the quantitative analysis of both PNP and PAP can be realized, therefore we can get the time-concentration profile of these components. The simultaneous quantification of PNP and PAP indicates that, within the experimental error range, PAP is the only product of reaction at steady-state. Compared with traditional HPLC analysis, this protocol eliminates the step of collection of products, and can allow the detection of quite unstable intermediates I250.

Secondly, conjunction of experimental observations and numerical simulation of the reactor under transient conditions give some insight about the reaction mechanism. Briefly, pertinent observations concern : -The differences between batch and continuous flow modes : flow reaction seems to limit adsorption phenomena and formation of by-product by successive reaction. -The numerical simulation of the microreactor, showing that only a change in the catalyst surface can produce the transient formation of a reaction product. -Experimental observations about I250, notably analytical investigations and effect of reaction parameters, lead to the conclusion of 2 simultaneous reaction paths. The path involving I250 would be favored by acid deficit. The successful hypothesis of the change of catalyst surface can well support the proposed reaction mechanism: the first step of reaction is the decomposition of FA on the surface of Pd catalyst, which could lead to the change of catalyst surface. Finally, from these observations, we suppose that I250 could be p-Benzoquinone imine (PBQI). Thirdly, a breakthrough has been made in the preparation of mechanically stable hybrid inorganic-organic silica monolith, notably the mercapto-functionalized silica monolith in the stainless-steel tube with the inner wall pre-coated by glass. With our methodologie, for the first time, we optimized and characterized the preparation condition range of monolith in stainless-steel tube (4mm diameters). The prepared mercapto-functionalized silica monolith possesses the flow-through macropores, typical hexagonal organization of mesopores and micropores, high specific surface and scarcely any shrinkage. Afterwards, a high content of palladium nanoparticles (4.4 mg/22.5mg) have been immobilized within the monolith in this tube by a continuous flow method.

After the comparison of packed-bed and monolith microreactors, some points have to be highlighted: a-The outstanding activity of monolithic catalyst in the transfer hydrogenation of PNP with FA reaction has been demonstrated with a TOF of monolithic catalyst Pd@MSM-T about 3 -6 times larger than that of commercial catalyst Pd@Al 2 O 3 , demonstrating the large accessible surface of Pd catalyst in monolithic catalyst. The chemical stability is proved by a campaign of reaction during several weeks; b-The mechanical stability of monolithic catalyst in microreactor is proved by a much lower pressure drop of monolithic microreactor than packed-bed microreactor. This is very important for an industrial application; c-The differences of dynamic study and kinetic model reveal the differences of catalyst properties: the large specific surface and specific texture of the hierarchical porosity of monolithic catalyst favor a narrow residence time distribution (RTD) in monolithic microractor.

The outlook of this project mainly consists of two aspects:

The hybrid inorganic-organic monolithic catalyst in the stainless-steel tube offers a new tool for that can be largely expanded in different applications.

The proof of concept with mercapto-functionalized silica monolith opens methods for the immobilization of other organic functions such as metal nanoparticles ligands (for example amine which to be fully studied), chiral or achiral ligands and chiral selectors.

The prepared microreactor with monolithic catalyst offers particular industrial interests, because of its low pressure drop, good mechanical stability, high specific surface and excellent catalytic performance. With the same preparation method, the scale-up and numbering-up methods can be taken into consideration, to increase the throughput for pilot scale and industrial scale production.

Annex

A-1 Calibration of UV-Visible analysis of PNP (protocol 1)

As shown in Figure A1, the response factor is quite constant in the wavelength range 325-349nm, the standard deviation is 6%. The concentrations of calibration solutions are listed in Table A1. The calculations on the response factor and regression are shown in Figure A2 and Figure A3, respectively. The final range for the calculation of PNP conversion with online UV PDA is 357-367 nm.

A-3 Calibration of off-line HPLC analysis

In order to ensure the feasibility of HPLC method in quantitive analysis of PNP and PAP, several calibration solutions with different concentrations of PNP and PAP in the range of concentrations below 0.4 mmol/L have been prepared for that. The plots of PNP or PAP concentration as a function of the surface area of chromatographic peak S exhibit excellent linear correlation as shown in Figure A4.

A-4 Effect of pH values on PAP chromatogram

The effect of pH values on the PAP chromatogram has been observed. In order to improve the precision of measurements, the effect of pH, varied either with hydrochloric acid (HCl) or FA has been investigated and summarized in the following tables.

PAP with

A-6 Adsorption isotherm results of PNP and PAP

The results of adsorption investigations of PNP and PAP are summarized in Table A2 and Table A3.

A-7 Mass transfer criteria

The external mass transfer can be analyzed by the mass transfer coefficient k D (m/s), and the internal mass transfer can be analyzed by the effective diffusion coefficient D eff (m 2 /s).

External mass transfer

To obtain the mass transfer coefficient, the Reynolds number Re, the diffusion coefficient D m (m 2 /s), the Schmidt number Sc and the Sherwood number Sh must be calculated as follows.

The Reynolds number Re: where 𝑀𝐵 (g/mol) the molecular weight of solvent B, here is 18 g/mol, ∅ the association factor of solvent, for water ∅=2.6, T (℃) the temperature, μ (Pa.s)the viscosity of solvent V A (ml/mol) the molar volume of solute A at its normal boiling temperature, for PNP, V A = 151 mL/mol

The Schmidt number Sc:

Sc = μ (ρ • D m ) ⁄
The Sherwood number Sh can be estimated by a large number of correlations. We utilize the most widely used correlation here: Sh = 2 + 0.6 Re 1/2 𝑆𝑐 1/3 From Sh, the mass transfer coefficient k D can be estimate: k 𝐷 = 𝑆ℎ • 𝐷 𝑚 /𝐷 𝑐𝑎𝑡 For investigating the external mass diffusion, Mears proposed a criterion, Mears' criterion f E , the ratio of the rate of reaction to the external diffusion rate. If this criterion is less than 0.05, it means that the external diffusion resistance is low and can be neglected.

f E = r exp r diffusion = Q • X/V k D • S cat /V cat
where S cat the external surface of catalyst and V cat the volume of catalyst.

The related calculation results are listed in the following table: In fact in all the experiments, the Mears' criterion f E << 0.05. Therefore, the bulk diffusion can be neglected.

Internal mass transfer

The effective diffusion coefficient D eff is calculated by diffusion coefficient D m , the porosity ε and the tortuosity τ :

D E = D m • ε/τ
The porosity ε can be calculated by the correlation proposed by Tsotsas and Schlünder 133 which were adapted from the empirical formula of Dixon 134 . ε = 0.37 + 0.05 N + 0.5344 N 2

N = D D cat

We can get the porosity ε = 0.371

The tortuosity τ can be calculated by the correlation reported by Puncochar and Drahoš 135 : τ = 1 √𝜀 so τ = 1.64 133 Tsotsas, E.; Schlünder, E. U., Wärme -und Stoffübertragung 1990, 25 (4), 245-256. 134 Dixon Anthony, G., Canadian Journal of Chemical Engineering 1988, 66 (5), 705-708. 135 Punčochář, M.;Drahoš, J., Chemical Engineering Science 1993, 48 (11), 2173-2175. For investigation of internal mass diffusion effect inside the catalyst pellet, the Weisz-Prater criterion Θ w is used to determine whether internal mass transfer is limiting the reaction.

Θ w = QX/V (S cat /V cat ) 2 D E If Θ w <0.1, the internal pore diffusion can be negligible.

From Table A5, the Weisz-Prater criterion is much smaller than 0.1, signifying that internal pore diffusion is also negligible.

A-8 Estimation of the quantity of I250 in different experimental conditions

Different experiments were performed with protocol 2 (PDA on-line analysis), in order to relate the amount of I250 to experimental conditions. This amount is roughly estimated from the surface area of the 250 nm UV-band. Figure A5 shows the variation of I250 on time under different conditions. A mixture of KOH (23g, 0.38 mol), PNP (5.2g, 0.038 mol), and water (6,25mL) is heated to 120℃ and maintained for 1h, then the mixture is heated slowly to 200℃ and left to reactor for 12h.

During the heating, the mixture changed into a brown viscous liquid along with the appearance of large numbers of bubbles. The products in the flask is then dissolved by adding water in maintaining the heating, and then acidified with 2 mol/L HCl 40ml. The dark red solution is extracted with ethyl acetate and dried with Na 2 SO 4 overnight, and then the solvent was removed under reduced pressure. The residue is purified by silica gel column chromatography eluting with dichloromethane and then ethyl acetate. The tawny solid of 0.429g (10.55% yield) is obtained after the evaporation of solvent. 1 H NMR (400 MHz, DMSO): δ=7.71 (d, J HH = 12 Hz, 4H), 6.90 (d, J HH = 12 Hz, 4H).

A-11 Experimental steady-state results measured for kinetics determination

The results of experiments of steady-state with packed-bed microreactor are summarized in Table A8. A concentrated hydrochloric acid (37%, 0.36 mL) was rapidly added to aqueous solution of TTAB (0.336 g, 1 mmol) of 26% mass concentration in the mortar. Then, TEOS (0.27 g, 1.3 mmol) and MPTS (0.028 g, 0.143 mmol) were mixed uniformly, and added in the former solution drop by drop along with the vigorous agitation by pestle for approximately 5 minutes in order to perform TEOS hydrolysis. Then the emulsion was formed and dodecane (2.82 mL) was added drop by drop for 7 minutes along with the vigorous agitation continually.

A-13 Preparation of TEM analysis samples

Before the TEM analysis, the EMBed-812 epoxy resin (Electron Microscopy Science) was prepared freshly: the EMBed-812 (22.6 g), DDSA (16 g), NMA (9.8 g) DMP-30 (0.7 g) were mixed and stirred for 2 hours. All these reagents were from EMBed-812 EMBEDDING KIT. Then the mixture was transferred into the BEEM® embedding capsules (Electron Microscopy Science). Samples of monoliths were grinded vigorously in the mortar then added into the prepared resin mixture in the capsules, following the heating of 60℃ for 24 hours in the oven. The specimens for TEM then prepared.

A-14 Detail calculation of V m and BET constant of BET analysis

The BET equation can be plotted as a straight line with p/V (p 0 -p) on the y-axis and p/p 0 on the x-axis based on the experimental results. This linear relationship of BET plot can be only maintained in the range of 0.05 < p/p 0 < 0.35. The slope and intercept of the line are used to calculate the monolayer adsorbed gas quantity V m and BET constant c as follows:

V m = 1 slope + intercept c = 1 + slope intercept

A-15 Preparation conditions of monoliths in polymer tube

The preparations conditions of Native Silica Monoliths (NSM), Aminopropyl Silica Monoliths (ASM) and Mercaptopropyl Silica Monoliths (MSM) are varied as in the following tables.

A-16 Detailed information of calculation of condensation degree for NSN, AMS and MSM

The detailed information of area proportions of each type peak is summarized in the following tables for condensation degree calculation. The O/Si ratio is calculated on the basis of deconvolution of CP-MAS NMR analysis. The material PNP balance over the reactor with a mean value of the reaction rate is:

Q (C PNP 0 -C PNP f ) = Q • C PNP 0 • X = r m • V CAT

Figure 1

 1 Figure 1 Reaction of unrearranged intermediates 1 to desired product 2 in CMR

Figure 2

 2 Figure 2 Comparison of different reactors in the work of Wolf with the oxidative dehydrogenation

Figure 3 4 1

 34 Figure 3 Two-step synthesis of m-anisaldehyde 5 from m-bromoanisole 4

Figure 4

 4 Figure 4 Comparison of batch and microreactor with the Wolff-Kishner reaction

Figure 5

 5 Figure 5 Illustration of the microreactor (60 μL in volume with the 45 μm thick membrane) for in-situ generation, separation, and reactions of diazomethane 36

Figure 6

 6 Figure 6 Main reaction of the Phenyl Boronic Acid Process and side/consecutive products (target poduct 6, side/consecutive products 7-12) and comparison of microreactor and batch reactor in the Phenyl Boronic Acid 6 Process

Figure

  Figure 7 Caprolactam 16 synthesis from cyclohexanecarboxylic acid 13

Figure 8

 8 Figure 8 Simplified scheme illustrating scale-up versus numbering-up strategies

Figure 9

 9 Figure 9 The internal volume and throughput of Corning Advanced-Flow Reactors

Figure 11

 11 Figure 11 Research of lithiation reaction with Lonza microreactor. (A) Reaction scheme of Li-H exchange and coupling; (B) Different Lonza microreactors (left: Lab-Plate 0.4-3 mL, Right: plate A6 (3-12 mL) or A5 (7-33 mL)); (C) Comparison of different reactors and flow rates for scale-up of the lithiation reaction

Figure 13

 13 Figure 13 Industrial pilot plant (10 t/year ) with three micro-reactor blocks for radical polymerisation in Japan 8

Figure 15

 15 Figure 15 Schematic representation of the cross-section of a microchannel in (a) packed-bed, (b)wall-coated, and (c) monolithic microreactors 46(b)

Figure 16

 16 Figure 16 Reconfigurable system for continuous production and formulation of APIs developed by a Novartis/MIT group 55(f) (a: Labeled photograph of the stack of upstream synthesis modules; b: Labeled photograph of the downstream purification and formulation modules.)

Figure 18 Flow

 18 Figure 18 Flow synthesis of the anti-inflammatory drug (R)-Rolipram and (S)-Rolipram with four reactors (D: 5-10mm, L: 50-300 mm) packed with solid catalysts

Figure 20

 20 Figure 20 Mechanism of hydrogenation of PNP to PAP with H2 proposed by Parida 60(b)

Figure 21

 21 Figure 21 Time dependent evolution of UV-vis. spectra showing the catalytic reduction of p-nitrophenol (PNP, pic at 317 nm) to p-aminophenol (PAP) by sodium borohydride 57(a)

Figure 22

 22 Figure 22 Reduction of PNP with NaBH4 has been used as the model reaction to test a wall-coated microreactor immobilized by catalytic virus-like particles with Au nanoparticles encapsulated inside 70

Figure 23

 23 Figure 23 Proposed mechanism of the reduction of PNP with sodium borohydride by metallic nanoparticles by Ballauff 76 .

Figure 24

 24 Figure 24 Effect of the concentration of FA on the conversion of PNP (0.01 M). The formic acid concentration varied: 0.01 M, 0.03 M, 0.05 M and 0.1 M. Porous-PdO-coated reactor was used at30 °C, with a residence time of 14.7 s. 57(b)

Figure 25

 25 Figure 25 Proposed mechanism of hydrogenation of p-nitrophenol with formic acid on Pd (adapted from Blaser 77(b) for p-nitrophenol)

Figure 26

 26 Figure 26 Direct route of the mechanism for transfer hydrogenation of PNP by FA over supported Pd catalyst

Figure 27

 27 Figure 27 Example of UV-vis. spectra of final product by use of different concentrations of formic acid. Measured pH (a)pH = 2.5 and (b) pH = 5.0. CPNP 0 =10 mM, Pd 0 =67.3mg, reaction time=14.7 ms.

  . The aqueous solution containing PNP and FA is degassed and then pumped by a micro flow pump (1μl/min-10ml/min, Thermo Fisher, Model ISO-3100SD) via the reservoir, and the flow rate can be changed by the micro flow pump. The reaction temperature is controlled in a column-oven (High Standard Performances, 39~99℃, Interchim). Samples of the microreactor effluent are collected in flasks and then analyzed by the off-line UV-vis spectroscopy (UVIKON 933, Kontron Instrument).

Figure 28

 28 Figure 28 Schematic representation of the experimental set-up of protocol 1 with off-line UV-vis. analysis

( a )

 a Figure 29 UV-vis absorption spectra of PNP (0.1mmol/L) and PAP (0.1mmol/L)

Figure 30 (

 30 Figure 30 (A) Photo and (B) Schematic representation of the experimental set-up of protocol 2 with on-line UV-vis. detector

Figure 31

 31 Figure 31 Example of 3D (Time-Wavelength-Intensity) PDA UV-vis. spectrum A: measurement of the feed concentration; B: measurement of the product concentration (Condition: CPNP 0 = 0.4 mmol/L, CFA 0 = 1.2 mmol/L, T = 40°C, Q = 0.5 mL/min)

Figure 32

 32 Figure 32 Variation of intensity of I250 of the reaction with time after different washing temperatures measured by PDA UV-vis. at 250 nm wavelength

Figure 34

 34 Figure 34 Experimental set-up with PDA and HPLC

Figure 35

 35 Figure 35 Calibration of PNP and PAP with on-line HPLC: concentration of different calibration solutions and polynomial fit of concentration of PNP and PAP as a function of S (integration of peak)

Figure 36

 36 Figure 36 1 H NMR spectra of PNP, FA and PAP the reference solution (CPNP=1, CFA=3, CPAP =9 mmol/L) and product of reaction (condition: CPNP 0 =10 mmol/L, CFA 0 =30 mmol/L, T=30°C, Q=1mL/min calculated concentrations : CPNP=0.6, CFA=1.8, CPAP =9.4 mmol/L).

Figure 37

 37 Figure 37 MS analysis (ES-) of reaction product. Reaction condition: CPNP 0 =0.5 mmol/L, CFA 0 =1.5 mmol/L, T=30℃, Q = 1mL/min, Conversion X=0.61(measured by off-line UV).

Figure 38

 38 Figure 38 Change of PNP and PAP in the product of reaction analyzed by MS.

  t batch : time of reaction in batch reactor V batch : total volume of the reactant Q MR: flow rate in microreactor n Pd : moles of palladium in the reactor C 0 PNP : initial concentration of PNP, at time 0 in batch or in the feed of microreactor X : conversion in batch at time t batch or at the outlet of microreactor The conditions of the reaction in microreactor and batch reactor are listed in the following table:

  reaction differ in batch and flow reactor: at low concentration (Figure39 (A)), the absorption band around 225 nm is very low in batch, while at high concentration (Figure39(B)), a new band at 400 nm appears on the batch spectrum.

Figure 39

 39 Figure 39 Comparison of UV spectrum of product in batch reactor and in microreactor under different reaction conditions. (A) CPNP 0 =0.5 mmol/L (B) CPNP 0 =10 mmol/L

Figure 40

 40 Figure 40 1 H NMR spectra of (A) sole PAP solution (B) mixed solution of PAP and PNP (C) mixed solution of PAP and CO2 and (D) reaction product in batch reactor with CPNP 0 =10 mmol/L (solvent D2O δ=4.7(s,H))

Figure 41

 41 Figure41shows that experimental points are in reasonable agreement with the following correlation (calculated by OriginPro 8.5 software) :𝑞 𝑒,𝑃𝑁𝑃 = 0.037 × 𝑐 𝑒,𝑃𝑁𝑃 /(1 + 0.04 × 𝑐 𝑒,𝑃𝑁𝑃 )Although the correlation is not very strong (R 2 =0.887), the Langmuir model is acceptable to represent PNP adsorption onto Pd@Al 2 O 3 catalyst.

Figure 41

 41 Figure 41 Experimental points and Langmuir model fitting of adsorption equilibria of PNP onto

Figure 43

 43 Figure 43 Adsorption of PAP for a longer period (19h)

Figure 44

 44 Figure 44 Example of desorption of PAP by UV-vis. analysis (adsorption condition: molar ratio Pd/PAP=0.1, V=1.51ml, CPAP 0 =10 mmol/L, adsorbed fraction 0.31, desorption with 1.51 mL ethanol)

Figure 45

 45 Figure 45 Mass Spectrometry of the supernatant of desorption solution of PAP (ES+ mode)

Figure 46

 46 Figure 46 Effect of temperature and flow rate on the conversion. (A) Effect of temperature (condition: CPNP 0 =0.4 mmol/L, CFA 0 =1.2 mmol/L, Q=0.5 mL/min) (B) Effect of flow rate (condition: CPNP 0 =0.6 mmol/L, CFA 0 =1.8 mmol/L, T=40℃)

Figure 47

 47 Figure 47 Effect of initial concentration on the conversion. Condition: protocol 3: CPNP 0 =0.3-5 mmol/L, CFA 0 /CPNP 0 =3, T=40℃, Q=1mL/min)

Figure 48

 48 Figure 48 Concentration profile detected by (A) Protocol 2 with on-line PDA UV-vis. (condition of example: CPNP 0 = 0.4 mmol/L, CFA 0 = 1.2 mmol/L, T = 40°C, Q = 0.5 mL/min) (B) Protocol 3 with off-line and on-line HPLC analysis (condition of example: CPNP 0 = 0.6 mmol/L, CFA 0 = 1.8 mmol/L, T = 40°C, Q = 1 mL/min)

Figure 49

 49 Figure 49 Investigation with on-line HPLC analysis before integration of peak (condition of example: CPNP 0 = 0.6 mmol/L, CFA 0 = 1.8 mmol/L, T = 40°𝐶, Q = 1 mL/min)

Figure 50

 50 Figure 50 Effect of m = CFA 0 /3 CPNP 0 on the I250 profile (CPNP 0 = 0.5 mmol/L, T=25℃, Q=0.5 mL/min)

Figure 51 UV

 51 Figure 51 UV-vis. spectrum of PNS and PAD

Figure 52

 52 Figure 52 Samples collected at different reaction time then analyzed by MS and 1 H NMR

Figure 53

 53 Figure 53 Relative intensity of MS peak of samples taken at the outlet of the reactor at different time. (A) Peaks corresponding to PAP (m/z= 108 in ES-mode, m/z= 110 in ES+ mode). (B) Peaks whose intensity changes in time (m/z= 107 in ES-mode, m/z= 108 in ES+ mode).

Figure 55

 55 Figure 55 Evaluation of stability of I250 in the reaction media without catalyst measure by UV-vis. PDA at 250 nm (condition: CPNP 0 = 0.6 mmol/L, CFA 0 = 1.8 mmol/L, T = 40°C, Q = 1 mL/min)

Figure 56

 56 Figure 56 Comparison of final product from the stability test of I250 in the UV cell and THE usual product of the reaction in the same condition (condition: CPNP 0 = 0.6 mmol/L, CFA 0 = 1.8 mmol/L, T = 40°C, Q = 1 mL/min)

Figure 57

 57 Figure 57 Modified mechanism of hydrogenation of p-nitrophenol in formic acid with Pd (black:proposed mechanism; grey: academic mechanism 77(b) )

  illustrated in Figure58: C i , molar concentration of component i in the liquid phase within the reactor, C i ° the feeding concentration Q, volumetric flow rate V, volume of catalyst between entrance of reactor and point under consideration, V CAT the total volume of catalyst r, rate of reaction of PNP per unit of catalyst volume

Figure 59

 59 Figure 59 Schematic representation of finite difference method

  Figure 61: all concentrations increase and reach a constant value (steady state) after a time depending on the parameters values, and longer for PAP than for I. Two points could be highlighted: (i) the PNP concentration increases just because the reactor is full of water at time 0; (ii) the residence time is calculated as the time necessary to treat the fluid volume, i.e. εV/Q and does not take into account the storage capacity of the catalyst (support and Pd).

Figure 61

 61 Figure 61 Dimensionless concentration profiles at the exit of reactor for model of reaction with one intermediate species. Values of parameters: Da1=1, Da2=0.06, a=5, KPNPCPNP°=1, KI/KPNP=4

Figure 62

 62 Figure 62 Schematic representation of the reaction model with properties surface change

  Concentration profiles are drawn over a time from the beginning of the experiment equal to 20 times of residence time, and with different values of parameters. The typical shape of the concentration profiles is shown in Figure 63. For every data set, the intermediate profile exhibits a peak and the PNP profiles a shoulder more or less pronounced.

Figure 63

 63 Figure 63 Concentration profiles at the exit of reactor for model of reaction with surface change.Values of parameters: Da1=1, Da2=2, a=1, KPNPCPNP 0 =3, KI/KPNP=0

Figure 64

 64 Figure 64 Catalyst evolution between the first measurement (january 2017) and last one (april 2018) with a slow desactivation (blue dashed line). Base point conditions : CPNP 0 = 0.6 mmol/L, CFA 0 = 1.8 mmol/L, Q = 1 mL/min, T=40°C.

Figure 65

 65 Figure 65 Comparison of the PNP conversion experimental versus calculated with the second order kinetics, with the rate constant k ≈ 3020.8 L/(molmin). Color code: FA deficit (black m≈0.45, red m≈0.65), FA stoichiometry (blue Q=0.5 mL/min, grey Q=1mL/min, green Q=2 mL/min), FA excess (orange m≈1.4)

Figure 66

 66 Figure 66 Plot of the mean reaction rate versus the mean PNP concentration. FA deficit (Red m≈0.45, blue m≈0.65), black all other points.

Figure 67

 67 Figure 67 Comparison of the PNP conversion experimental versus calculated with the 2nd order kinetics relative to FA, with the rate constant k ≈ 2604 L/(molmin). Color code: FA deficit (black m≈0.45, red m≈0.65), FA stoichiometry (blue Q=0.5 mL/min, grey Q=1mL/min,5 green Q=2 mL/min), FA excess (orange m≈1.4)

Figure 68

 68 Figure 68 Concept of hierarchy in a porous material: micropores in purple circle and mesopores in grey circle. For the mesoporous regime, either well-organized pores with monomodal character as hexagonal organization or non-ordered arrangements are possible. Figure is modified from Husing 96(c)

  97(a) Peters, E. C.; Svec, F.; Fréchet, J. M. J., Advanced Materials 1999, 11 (14), 1169-1181. (b) Svec, F.; Fréchet, J. M. J., Analytical Chemistry 1992, 64 (7), 820-822.

Figure 70 (

 70 Figure 70 (A) SEM picture of the macroporous polymer before immobilization of Pd 0 ; (B) TEM image of immobilization of Pd 0 on monolith 98

Figure 71

 71 Figure 71 Structure of the polymer/glass monolith: (A) left: the picture of monolith inserted into a stainless-steel tube, right: SEM image of porous glass support structure with polymer 54(b),101 (B) TEM images of Pd(0) nanoparticles immobilized on the monolith 102

Figure 72

 72 Figure 72 Schematic synthesis strategy of polyHIPE (modified from Kaskel 107(c) )

Figure 73

 73 Figure 73 Preparation of Si(HIPE) by Backov: (A): Schematic of emulsions and high internal phase emulsions (HIPE). top: Normal oil-in-water (O/W) and the reverse (W/O) emulsion, bottom: high-internal-phase emulsion 95 ; (B): SEM image of hierarchical well-organized monolith Si(HIPE) 110(b)(e)

Figure 75

 75 Figure 75 TEM pictures of the functionalized monoliths 110(e) (A) dinitro-Si(HIPE) (B) mercapto-Si(HIPE)

Figure 76

 76 Figure 76 TEM images of Pd(0) nanoparticles immobilized on the grafted Si(HIPE): Left: Typical monolith after the Pd nanoparticles immobilization by grafting method (the white arrow indicates the monolith inner part);Right: Pd nanoparticles observed through TEM 110(c)

Figure 77

 77 Figure 77 Photo of cladded monolith and SEM images of silica-based monolith prepared by the phase separation method 111(a)(e)

Figure 78

 78 Figure 78 Left: Photo of monolith incorporated Pd 0 ; Middle: SEM image of monolith incorporated Pd 0 ; Right: TEM image with the arrows indicating the Pd nanoparticles in the skeleton of silica monolith 113

  (a) Direct immobilization of Pd nanoparticles in MSM with Pd(0)(PPh 3 ) 4 . (b) Immobilization of Pd nanoparticles in MSM by reducing Pd(II)(OAc) 2 with addition of PPh 3 (c) Immobilization of Pd nanoparticles in MSM by reducing Pd(II)(OAc) 2 without addition of PPh 3

Figure 79

 79 Figure 79 Schematic presentation of the preparation strategy of functionalized monolithic catalyst in stainless-steel tube

Figure 80 29

 80 Figure 80 29 Si NMR assignments (center Si)

Figure 83

 83 Figure 83 Stack plot of 29 Si CP-MAS NMR spectra for NSM in different preparation conditions

Figure 84

 84 Figure 84 Example of shrinkage phenomena of monoliths (A) NSM-1 with 90% shrinkage; (B) NSM-2 with 20% shrinkage

Figure 85

 85 Figure 85 Stack plot of 29 Si CP-MAS NMR spectra for ASM in different preparation conditions

Figure 86

 86 Figure 86 Stack plot of 13 C CP-MAS NMR spectra for ASM in different preparation conditions

Figure 87

 87 Figure 87 Stack plot of 29 Si CP-MAS NMR spectra for MSM in different preparation conditions

Figure 88

 88 Figure 88 Stack plot of 13 C CP-MAS NMR spectra for MSM in different preparation conditions

  (A) and (B)) was investigated and compared with the NSM-6 before functionalization (Figure 89 (C) and (D)).The typical interconnected macroporous textures of high internal phase emulsion have been observed in both MSM and NSM, which indicates that the functionalization of mercapto group does not destroy the intrinsic structure of NSM, even if the spherical structure of foam in MSM is smoother, probably due to its organic functionalization. The polydisperse opened cells are connected with the "external junction" pointed by the white arrows. The "cell windows" are the holes in the cells marked by the black arrows in the image Figure89(A) and (C), and there are also holes between different cells. All these holes are in the micrometer range, about 2μm-10μm, revealing the macro-porosity of the NSM and MSM prepared.

Figure 89

 89 Figure 89 SEM images of (A)(B)MSM-7 and (C)(D) NSM-6. The white arrows show the example of the "external junction" between cells and the black arrows show the typical cell windows

Figure 90

 90 Figure 90 TEM images of (A)-(C): MSM-7 and (D)-(F): MSM-B

Figure 91 N2

 91 Figure 91 N2 Adsorption-desorption isotherm analysis of (A) MSM-1 and (B) MSM-B (from Backov 110(e) )

  2.1.2, the Pd nanoparticles were impregnated by three ways: (a) Direct immobilization of Pd nanoparticles in MSM-7 with Pd(0)(PPh 3 ) 4 , labeled Pd@MSM-7-D. (b) Immobilization of Pd nanoparticles in MSM-7 or MSM-B by reducing Pd(II)(OAc) 2 with addition of PPh 3 , labeled Pd@ MSM-7-P or Pd@ MSM-B-P, respectively. (c) Immobilization of Pd nanoparticles in MSM-7 or MSM-B by reducing Pd(II)(OAc) 2 without addition of PPh 3 , labeled Pd@ MSM-7-NP or Pd@ MSM-B-NP, respectively.

Figure 92

 92 Figure 92 TEM images of Pd@MSM-7-D

Figure 93

 93 Figure 93 TEM images of (A) (B)Pd@MSM-B-P and (C) (D)Pd@MSM-B-NP. Effect of PPh3

Figure 94

 94 Figure 94 TEM images of (A) (B)Pd@MSM-7-P and (C) (D)Pd@MSM-7-NP. The white arrows pointed out the Pd nanoparticles on the boundary of monoliths

  step are conducted with continuous flow. The prepared MSM-T was analyzed by CP-MAS NMR firstly to characterize the result of co-condensation in the tube. The 29 Si NMR of MSM-T (Figure 95 (A)) indicated the similar results to MSM-7. T 3 and T 2 proved the successful functionalization, which was confirmed by the peak of C-SH group in 13 C NMR (Figure 95 (B)). The peak around 60 ppm and 15 ppm reveals the presence of SiO-CH 2 CH 3 group in resulting monolith.

Figure 95

 95 Figure 95 CP-MAS NMR analysis of MSM-T and comparison with MSM-7: (A) 29 Si CP-MAS NMR of MSM-T and MSM-7 (B) 13 C CP-MAS NMR of MSM-T and MSM-7

Figure 96

 96 Figure 96 Co-condensation step of sol-gel process in the stainless-steel tube pre-coated with glass

Figure 97

 97 Figure 97 TEM images of (A)(B)MSM-T before impregnation and (C)(D)Pd@MSM-T after impregnation of Pd nanoparticles

Figure 99

 99 Figure 99 Effect of (A) reaction temperature and (B) flow rate on the PNP conversion. (Condition: A : CPNP 0 =0.6 mmol/L, CFA 0 =1.8 mmol/L , Q = 1mL/min ; B : CPNP 0 =2 mmol/L, CFA 0 = 6 mmol/L ,T=40℃)

  (A), despite of the dispersion of the results, the conversion of PNP always varies in the range of 0.3-0.5, regardless of the large variation of C PNP 0 from 0.5 mmol/L to 4.5 mmol/L. This indicates the conversion of PNP is independent of the initial concentration of PNP. In Figure 100 (B), the conversion of PNP increases along with the augmentation of C FA 0 , exhibiting roughly a linear relation. It could indicate a first order reaction with respect to FA.

Figure 100

 100 Figure 100 Effect of initial concentration of (A) PNP and (B) FA on the PNP conversion. (Reaction conditions : A : CFA 0 /CPNP 0 =3, T=40℃, Q = 1mL/min ; B : CPNP 0 =0.6 mmol/L, T=40℃, Q = 1mL/min)

Figure 101

 101 Figure 101 Comparison of calculated X and experimental X. (X calculated with first order reaction rate with respect to FA with k= 9.94 min -1 . Q=1mL/min except black points; T=40℃ except green points. Red: base points; Grey m1. Bleu FA excess (m>1); Purple FA deficit (m<1))

Figure 102

 102 Figure102Comparison of calculated X with mean values of experimental X. CFA varies from 0.9 to 3.5 mmol/L; CPNP 0 = 0.6 mmol/L, Q=1 mL/min, T=40°C.

  Both on-line PDA UV and on-line HPLC were used to observe and quantify the variation of the composition of reaction mixture flowing out of the reactor. The profiles of concentration are shown on Figure 103 and Figure 104. On both figures, the concentration of PNP exhibits a slight shoulder at the beginning of the sequence and then stabilizes rapidly. Meanwhile, the concentration of PAP increases and reaches the stationary value after a little longer time than PNP, as shown by on-line HPLC analysis (Figure 103). Unlike with the commercial catalyst, it is noteworthy that the intermediate I250 or other intermediate have not been detected neither at 250 nm nor at other wavelengths, as illustrated by red line at 250 nm in Figure 104(A) and by 3D-PDA UV in Figure 104(B).

Figure 103

 103 Figure 103 Concentration profile of PNP and PAP at outlet of reactor detected by on-line HPLC (Reaction condition: CPNP 0 =0.6 mmol/L, CFA 0 =1.8 mmol/L,T=40℃, Q = 1mL/min)

Figure 105

 105 Figure 105 On-line HPLC analysis of the washing process of the reactor (purple dashed line: PAP, blue dashed line: PNP. Washing condition: 40℃ with water for 1h)

Figure 107

 107 Figure 107 Pressure drop-flow rate in packed-bed and monolithic microreactors

Figure

  Figure A1 Standard deviation (SD) of response factor (RF) in each wavelength with the results of off-line UV-vis. of different calibration solutions

Figure

  Figure A2 Standard deviation (SD) of response factor (RF) in each wavelength with the results of on-line UV-vis. of different calibration solutions

Figure

  Figure A4 Calibration of PNP and PAP with off-line HPLC: concentration of different calibration solutions and linear fit of concentration of PNP and PAP as a function of S (integration of peak)

  s) the superficial flow velocity of the fluid, d cat (m) the catalyst average diameter, ρ (g/m 3 ) the density of the fluid μ (Pa.s) the viscosity of the fluid D m is the mutual diffusion coefficient of solute A at very low concentrations in solvent B. It exist many correlations to estimate the diffusion coefficient. A widely used correlation called Wilke-Chang 132 estimation method is adopted here:

Figure

  Figure A5 (A) Variation of I250 on time with different initial concentrations CPNP 0 . Y-axis is the intensity/ CPNP 0 for clearer comparison. Reaction condition: CFA 0 /CPNP 0 = 3, Q=0.5 mL/min, T=25 ℃ (B) Variation of I250 on time with different flow rates Q. Reaction condition: CPNP 0 =0.5 mmol/L, CFA 0 /CPNP 0 = 6 , T=25 ℃

A- 17

 17 13 C CP-MAS NMR of NSMThe 13 C CP-MAS NMR of NSM is just used to confirm the effectiveness of washing process. The following figure indicates the presence of TTAB (main at 30.4 ppm) in the NSM, which was not totally washed out.

Figure

  Figure A6 13 C CP-MAS NMR of NSM

  of PNP and PAP in the final product.Mean value of concentration C m is calculated as (C 0 +C f )/2. As the experimental variation of C PNP 0 is much wider than that of the conversion, we compare r m V CAT / C PNP 0 plots clearly show that the reaction rate is roughly first order with respect to FA, and not to PNP.

Figure

  Figure A7 Comparison of mean reaction rate (rmVCAT/CPNP 0 ) to mean dimensionless concentration of (A) PNP and (B) FA at T=40°C. Q=1mL/min except black points. Red m=1, Blue FA excess (m>1), Purple FA deficit (m<1)

  25 mM o-phosphoric acid. The injection volume was 50 L with a flow rate of 0.5 mL/min and UV detection wavelength of 254 nm. The conditions of Hanna's work 83 are: the mobile phase was a mixture of 50% deionized water, 50% acetonitrile and 1% acetic acid. The flow rate was 1 mL/min and the PNP and PAP were measured at wavelengths of 317 nm and 273 nm, respectively.

81 (a) Venkatesan, P.; Santhanalakshmi, J., Nanoscience and Nanotechnology 2012, 1 (2),

43-47. (b)

Sharma, M.; Hazra, S.; Basu, S., Advanced Powder Technology 2017, 28 (11), 3085-3094. (c) Liu, K.; Wang, Y.; Chen, P.; Zhong, W.; Liu, Q.; Li, M.; Wang, Y.; Wang, W.; Lu, Z.; Wang, D., Applied Catalysis B: Environmental 2016, 196, 223-231. 82 Honeychurch, K. C.; Hart, J. P., Electroanalysis 2007, 19 (21), 2176-2184. 83 Bae, S.; Gim, S.; Kim, H.; Hanna, K., Applied Catalysis B: Environmental 2016, 182, 541-549.

Table 1

 1 Characteristics of the packed-bed microreactor

	Symbol	Parameter	Unit	Dimension
	D PB	Internal diameter of packed-bed microreactor	mm	4.47
	L PB	Length of packed-bed microreactor	mm	40
	V PB	Volume of tube of packed-bed microreactor	mL	0.64
	m cat,PB	Catalyst mass	mg	639.5
	D cat, PB	Catalyst average diameter	mm	0.07
	m pd, PB	Palladium mass	mg	32

Table 2

 2 Summary of conditions of calibration experiments of off-line UV

	Assumed C PNP ° mmol/L	C FA	0 0 /C PNP	Assumed conversion	Composition of calibration solution C PNP C FA C PAP mmol/L mmol/L mmol/L
				0	0.1	0.3	0
				0.9	0.01	0.03	0.09
			3	0.7 0.5	0.03 0.05	0.09 0. 15	0. 07 0.05
				0.3	0.07	0.21	0.03
	0.1			0	0.01	0.03	0.09
			18	0	0.01	0.18	0.09
			1.2 3	0.5	0.05 0.05	0.06 0.15	0.05 0.05
		2 4.67	0.1	0.09 0.09	0.18 0.42	0.01 0.01

Table 3

 3 Optimization of proportion of mobile phase and the retention time of PAP and PNP

	Proportion Water (acidified by Acetonitrile (acidified by 0.05 % FA) 0.05 % FA)	Retention time of PAP (min)	Retention time of PNP (min)
	50%	50%	0.76	1.29
	60%	40%	0.80	1.80
	70%	30%	0.85	3
	80%	20%	0.85	4.5
	90%	10%	0.88	11.14

Table 4

 4 Comparison of reaction in microreactor and batch reactor (n Pd = 0.3 mmol, T=30℃)

		V batch (mL)	t batch (min)	Q (mL/min)	C 0 mmol/L PNP	C 0 mmol/L FA	X	TOF (h -1 )
	Batch Microreactor	20 /	20 /	/ 1	10	30	0.92 0.96	1.84 1.92
	Batch Microreactor	20 /	20 /	/ 1	0.5	1.5	0.49 0.72	0.049 0.072

Table 5

 5 Range of experimental conditions for flow reaction with commercial Pd@Al2O3 catalyst

	Symbol	Parameter	Unit	Dimension
	Q	Flow rate	mL/min	0.1-4
	T	Temperature	°C	30 -60
	C PNP °	Initial concentration of p-nitrophenol	mmol/L	0.1-10
	C FA °	Initial concentration of formic acid	mmol/L	(1.5~6)  C PNP °

a-As the reaction produces 3 mol of CO 2 per mol of PNP reacted, CO 2 bubbles were expected in first experiments, but never observed. Actually, the solubility of CO 2 under 1 bar is 38.4 mmol/L at 20 ℃ and 28.6 mmol/L at 30 ℃ .

Table 6

 6 Effect of tube wall

	C PNP °, mmol/L	C FA °, mmol/L	T, °C	Q, mL/mn	X
	0,5 10	1,5 30	30 50 70	1 0,5	0,019 0,012 0,088 0,064 0,119

  At this point, the model with change in the catalyst surface properties is satisfactory because it represents roughly the pattern of experimental results. To go further, it should be necessary to adjust the model parameters values with experiments. The effect of variation of parameters on the maximum value of intermediate concentration, on PNP conversion and on the magnitude of the PNP shoulder expressed as C PNP,MAX /C PNP,f are studied in this objective. -The main influence of the phases ratio a appears on the intermediate concentration, which increases while the catalyst capacity increases. -An increase in the PNP adsorption equilibrium constant leads to an increase in the PNP storage on the surface, and a clear decrease in the intermediate concentration. -An increase in the rate constant of PAP formation increases the PNP conversion and slightly decreases the intermediate concentration. In conclusion, in order to simulate the concentrations profiles of PNP, PAP and intermediate I observed when the reactor is under transient conditions, two models have been investigated. With the hypothesis of the change of catalyst surface, the model established can well mimic the dynamic behavior observed in experiments. This successful simulation could also support the mechanism we proposed in Figure

Table 7

 7 Comparison of different functionalized Si(HIPE) monoliths incorporated with Pd 0 in the

	Mizoroki-Heck coupling reaction
	Names of samples Pd@mercaptoFunctionalization organosilane MPTS	MPTS	APTS

-Si(HIPE) Pd@g-mercapto-Si(HIPE) Pd@g-amino-Si(HIPE)

Table 8

 8 Variation of preparation conditions of NSM and resulting shrinkage ratio and Q%

		NSM-1 NSM-2 NSM-3 NSM-4 NSM-5 NSM-6 NSM-7 NSM-B
	R 1	0,30	0,60	0,47	0,47	0,47	0,47	0,47	0,36
	R 2	0,24	0,24	0,15	0,35	0,24	0,24	0,24	0,32

Table 9

 9 Variation of preparation conditions of ASM and resulting shrinkage ratio and C.D.

		ASM-1 ASM-2 ASM-3 ASM-4 ASM-5 ASM-6 ASM-7 ASM-8	ASM-9
	R 1	6.46	0.41	0.82	0.64	0.64	0.64	0.64	0.64	0.64
	R 2	0,18	0,18	0,18	0,10	0,28	0,15	0,18	0,18	0,18
	R 3	0,23	0,23	0,23	0,23	0,23	0,30	0,23	0,23	0,22
	R 4	21.5	19	19	19	19	19	10	15	19
	X SR	10%	80%	40%	60%	-60%	20%	20%	70%	60%
	%C.D.T 100.0%	98.0%	96.4%	95.8%	95.8%	92.3%	94.7%	95.5%	98.2%
	%C.D.Q 80.1%	77.4%	78.4%	78.5%	77.4%	78.9%	80.4%	79.5%	78.4%

Table 10

 10 Variation of preparation conditions of MSM and resulting monolith characteristics

		MSM-1 MSM-2 MSM-3 MSM-4 MSM-5 MSM-6 MSM-7 MSM-B
	R 1	0.40	0.55	0.47	0.47	0.47	0.47	0.47	0.36
	R 2	0.24	0.24	0.19	0.24	0.24	0.24	0.24	0.31
	R 3	0.21	0.21	0.21	0.22	0.22	0.22	0.21	0.28
	R 4	9	9	9	2.3	4	19	9	9
	X SR	15%	30%	10%	80%	50%	20%	10%	10%
	%C.D.T	93.0%	96.1%	89.9%	92.8%	90.4%	94.3%	92.1%	93.2%
	%C.D.Q 77.4%	76.1%	77.2%	79.3%	80.8%	76.6%	78.4%	77.1%

Table 10

 10

(table of detailed values in Annex A-16 Table

Table 11

 11 Specific surface area of monoliths in recent publications

	Reference	Monolith	Surface area (m 2 /g)	Published year

Table 12

 12

	Comparison of condensation degree of MSM-T and MSM-7
		MSM-T	MSM-7
	%C.D.T	93.9%	92.1%
	%C.D.Q 78.5%	78.4%

  Table13EDS analysis of MSM-7, MSM-T and Pd@MSM-T

	Sample name	MSM-7	MSM-T	Pd@MSM-T
	Elements	Atomic%	Atomic%	Atomic%
	O	65.5	68.7	68.3
	Si	30.9	29.6	23.2
	S	3.6	1.7	3.8
	Pd	-	-	4.7

Table 14

 14 Monolithic catalysts with Pd on different supports published in recent years

	Monolithic catalyst support	Immobilization method a	V tube (ml) b	Density (g/cm 3 )	Porosity	Content Pd (wt %)	Specific Surface (m 2 /g)
	MSM-T			continuous	1.256	0.0179	0.987 c	19.6	1260
	Al 2 O 3 (powder)	batch	-	3.97	-	5.3	110
	ASM-gB d 110(c)	batch	-	0.14	0.92	3.9	300
	MSM-gB e 110(c)	batch	-	0.10	0.88	4.1	400
	MSM-B f 110(c)	batch	-	0.09	0.93	3.9	53
	SiO 2 -Pyrrol 110(f)	batch	-	0.07	0.962	3.9	392
	SiO 2 -ArSO 3	113	continuous	0.283	-	-	4.6	322
	SiO 2 -PMHS g 126	continuous	1.256			0.9	220
	SiO 2 -[Bmim]BF 4	h 119	batch		0.16	0.89	0.99	187
	Polymer 127		batch	-	-	-	0.3	305
	Polymer 120		batch	-	-	-	5	482
	CGO i 128			batch	-	-	-	4.73	-
	TiO 2	111(f)			continuous	0.377	-	-	0.24	148
	a: Immobilization of Pd are either in the flask (batch) or in continuous flow (continuous)
	b: V tube is the volume of continuous flow reactor
	c: Porosity of MSM-T is estimated approximately by density(MSM-T)/skeletal density, the skeletal density for
	MSM is 1.36 g/cm 3 110(e)
	d: ASM-gB is silica monolith functionalized by amino group by grafting method
	e: MSM-gB is silica monolith functionalized by mercapto group by grafting method
	f: MSM-B is silica monolith functionalized by mercapto group by co-condensation method
	g: PHMS: Polymethylhydrosiloxane
	h: [Bmim]BF 4 : 1-Butyl-3-methylimidazolium tetrafluoroborate
	i: CGO: Carbon based graphene oxide
	4.4 Conclusion
	In the light of the state of the art of monolithic catalyst, the silica-based monoliths exhibit distinct
	advantages; nevertheless, the lack of effective means for synthesizing porous silica-based
	126 Pelisson, C. H.; Nakanishi, T.; Zhu, Y.; Morisato, K.; Kamei, T.; Maeno, A.; Kaji, H.; Muroyama, S.; Tafu, M.;
	Kanamori, K.; Shimada, T.; Nakanishi, K., ACS Applied Materials & Interfaces 2017, 9 (1), 406-412. 127 Jumde, R. P.; Marelli, M.; Scotti, N.; Mandoli, A.; Psaro, R.; Evangelisti, C., Journal of Molecular Catalysis A:
	Chemical 2016, 414, 55-61.

128

Nakhate, A. V.; Yadav, G. D., ChemistrySelect 2016, 1 (13), 3954-3965.

Table 15

 15 Characteristics of the monolithic microreactor

	Symbol	Parameter	Unit	Dimension
	D ML	Internal diameter of monolithic microreactor	mm	4
	L ML	Length of monolithic microreactor	mm	100
	V ML	Volume of tube of monolithic microreactor	mL	1.256
	m cat,ML	Catalyst mass	mg	22.5
	m pd,ML	Palladium mass	mg	4.4

Table 16

 16

	, in order to establish the

Table 16

 16 Range of experimental conditions for flow reaction with monolithic catalyst

	Symbol	Parameter	Unit	Dimension
	Q	Flow rate	mL/min	0.2 -1
	T	Temperature	°C	40 -80
	C PNP °	Initial concentration of p-nitrophenol	mmol/L	0.6 -4.5
	C FA °	Initial concentration of formic acid	mmol/L	(1.5 -6)  C PNP °

  The comparison of TOF is listed in Table17. The n Pd of Pd@Al 2 O 3 is 0.301 mmol and the n Pd of Pd@MSM-T is 0.042 mmol. The conversion of PNP is the average value of all measurements in the same condition.

		n Pd
	with
	Q MR: flow rate in microreactor
	n Pd : moles of palladium in the reactor
	C PNP	0 : initial concentration of PNP in the feed of microreactor
	X : conversion of PNP at the outlet of microreactor

Table 17 TOF

 17

	C PNP 0 mmol/L	C FA mmol/L 0	X packed-bed	X monolith	TOF packed-bed TOF monolith h -1 h -1	𝐓𝐎𝐅 𝐦𝐨𝐧𝐨𝐥𝐢𝐭𝐡 𝐓𝐎𝐅 𝐩𝐚𝐜𝐤𝐞𝐝-𝐛𝐞𝐝
	0.6	1.8	0.625	0.382	0.075	0.327	4.360
	0.6	0.9	0.161	0.122	0.019	0.104	5.474
	0.6	3.6	1	0.846	0.120	0.725	6.042
	1	3	0.787	0.384	0.157	0.549	3.497
	2	6	0.916	0.408	0.366	1.167	3.189
	4	9	0.959	0.398	0.765	2.274	2.973

of commercial catalyst and monolithic catalyst (Q = 1 mL/min, T = 40°C)

  The main difference of dynamic behavior concerns the formation of intermediate I250. With commercial catalyst Pd@Al 2 O 3 , I250 exits massively from the reactor a few minutes after the beginning of the reaction sequence. Conjunction of observation indicates that hydrogenation of PNP involves two distinct reaction paths, the main classic one and another one with I250 as intermediate in PAP formation, slower and favored when there is not enough FA (Figure57). With monolith, exit of I250 is not observed during reaction sequence, but it appears in washing sequence. b-Another difference concerns the reaction rate models. In the kinetic model established, the reaction with commercial catalyst is in second order (either r = kC PNP C FA or r = k C FA 2 ), while

a-131 Kohns, R.; Haas, C. P.; Höltzel, A.; Splith, C.; Enke, D.; Tallarek, U., Reaction Chemistry & Engineering 2018, 3 (3), 353-364.

C FA 0 /C PNP 0 Assumed conversion Composition of calibration solution

		Table A1 Calibration conditions for on-line UV PDA
	Assumed
	C PNP ° mmol/L			C PNP mmol/L	C FA mmol/L	C PAP mmol/L
	0.1	3	0.9	0.01	0.03	0.09
	0.1	2.1	0.1	0.09	0.18	0.01
	0.1	4.5	0.1	0.09	0.42	0.01
	0.3	3	0.5	0.15	0.45	0.15
	0.5	3	0.9	0.05	0.15	0.45
	0.5	4.5	0.9	0.05	0.9	0.45
	0.5	2.1	0.5	0.25	0.3	0.25
	0.5	2.1	0.1	0.45	0.9	0.05
	0.5	4.5	0.1	0.45	2.1	0.05

  TableA2The adsorption isotherm of PNP

	Molar ratio Pd/PNP	X ads,PNP	V/mL	C PNP 0 mmol/L	m cat /g	c e,PNP mmol/L	q e,PNP mmol/g
	0.0940	0.082	10	25	0.05	22.94345 0.41131
	0.1566	0.124	10	15	0.05	13.13499 0.373003
	0.2349	0.159	10	10	0.05	8.41371 0.317258
	0.2936	0.108	10	8	0.05	7.133543 0.173291
	0.3915	0.109	10	6	0.05	5.382284 0.123543
	0.5873	0.110	10	4	0.05	3.561901 0.08762
	1.1746	0.03	10	2	0.05	1.934446 0.013111
	2.3492	0.068	10	1	0.05	0.931608 0.013678
	0.1992	0.104	10	10	0.0424	8.9621	0.24479
		Table A3 The adsorption isotherm of PAP
	Molar ratio Pd/PAP	X ads,PAP	V/mL	C PAP 0 mmol/L	m cat /g	c e,PAP mmol/L	q e,PAP mmol/g
	0.1000	0.3059	1.51	10	0.003	6.941	1.539697
	0.1000	0.1553	6.08	10	0.0124	8.447	0.761471
	0.1000	0.2733	10	10	0.0212	7.267	1.289151
	0.1000	0.4781	10	10	0.0212	5.219	2.255189
	0.2000	0.4058	10	10	0.0424	5.942	0.957075
	0.2000	0.4126	10	10	0.0424	5.874	0.973113

  Table A4 Parameters of external mass transfer

		0.14869	7.56182E-10	1322.43	4.54	4.90E-05	2.37E-08
	8	0.18586	7.56182E-10	1322.43	4.84	5.23E-05	2.78E-08
	9	0.29737	7.56182E-10	1322.43	5.59	6.04E-05	3.83E-08
	10	0.07434	7.56182E-10	1322.43	3.80	4.10E-05	1.37E-08
	11	0.07434	7.81126E-10	1280.20	3.78	4.21E-05	1.33E-08
	12	0.07434	7.56182E-10	1322.43	3.80	4.10E-05	8.78E-10
	13	0.07434	7.81126E-10	1280.20	3.78	4.21E-05	8.60E-10
	14	0.03717	7.56182E-10	1322.43	3.27	3.53E-05	6.55E-10
	15	0.05947	7.56182E-10	1322.43	3.61	3.90E-05	4.65E-10
	16	0.07434	7.56182E-10	1322.43	3.80	4.10E-05	5.21E-10
	17	0.03717	7.56182E-10	1322.43	3.27	3.53E-05	6.21E-09
	18	0.05947	7.56182E-10	1322.43	3.61	3.90E-05	9.00E-09
	19	0.07434	7.56182E-10	1322.43	3.80	4.10E-05	1.07E-08
	20	0.07434	7.56182E-10	1322.43	3.80	4.10E-05	4.23E-09
	21	0.07434	8.0607E-10	1240.59	3.76	4.33E-05	3.86E-09
	Entry	Re	D m (m 2 /s)	Sc	Sh	k D (m/s)	f E
	1	0.03717	7.81126E-10	1280.20	3.26	3.63E-05	8.11E-09
	2	0.03717	7.56182E-10	1322.43	3.27	3.53E-05	8.23E-09
	3	0.03717	7.81126E-10	1280.20	3.26	3.63E-05	8.09E-09
	4	0.03717	8.0607E-10	1240.59	3.24	3.73E-05	7.86E-09
	5	0.03717	8.31014E-10	1203.35	3.23	3.84E-05	7.67E-09
	6	0.07434	7.56182E-10	1322.43	3.80	4.10E-05	1.42E-08

Table A5

 A5 Parameters of internal mass transfer

	Entry	D eff (m 2 /s)	Θ w
	1	1.76E-10	3.90E-08
	2	1.71E-10	3.97E-08
	3	1.76E-10	3.89E-08
	4	1.82E-10	3.76E-08
	5	1.88E-10	3.66E-08
	6	1.71E-10	7.93E-08
	7	1.71E-10	1.59E-07
	8	1.71E-10	1.98E-07
	9	1.71E-10	3.16E-07
		1.71E-10	7.68E-08
		1.76E-10	7.44E-08
		1.71E-10	4.92E-09
		1.76E-10	4.79E-09
		1.71E-10	3.16E-09
		1.71E-10	2.47E-09
		1.71E-10	2.92E-09
		1.71E-10	2.99E-08
		1.71E-10	4.79E-08
		1.71E-10	6.01E-08
		1.71E-10	2.37E-08
		1.82E-10	2.14E-08

Effect of FA on the intermediate I250 In

  TableA6Quantity of I250 with variation of CNP 0 and Q TableA7it is clear to see the quantity of I250 (S I250 ) increases with m, and the quantity of I250 is correlated to 1/C FA 0 . FA pumped is calculated by C FA 0 *Q*t 0 , where t 0 is the reaction time before the appearance of FA.

				With variation of C NP 0
	C NP	0 mmol/l	0.5	0.45	0.4	0.3	0.25
	Q I250 a.u.*mL	27.99	30.07	33.00	34.19	33.87
				With variation of Q
	Q mL/min	0.5	1	2	4
	Q I250 a.u.*mL	33.98	27.15	30.61	35.94
	A-9

  Table A7 Effect of concentration of FA on the intermediate

	m	t 0 , min	FA pumped	S I250	S I250 *m
	0.67	35	17.7	138.8	93.0
	1	18	13.5	104.2	104.2
	1.67	10	12.5	62.2	103.9
	A-10 Synthesis of 4,4'-Azodiphenol (PAD)

Table A8 Table

 A8 of experimental steady-state results measured for kinetics determination

		1		8	4.47	2.76	1.75	-0.16	0.609	0.596
	16	1		8	4.27	2.91	1.73	0.40	0.594	0.625
	17	1		10	5.57	3.43	1.81	-1.27	0.675	0.598
	18	1		10	5.51	3.62	2.07	-0.32	0.625	0.605
	19	1		0.9	0.26	0.07	0.15	0.59	0.401	1.170
	20	1		0.9	0.32	0.07	0.25	0.67	0.233	0.926
	21	1		0.9	0.33	0.08	0.25	0.67	0.234	0.920
	22	1		1.8	0.60	0.34	0.19	0.56	0.688	0.997
	23	1		1.8	0.64	0.41	0.20	0.48	0.689	0.941
	24	1		1.8	0.59	0.34	0.29	0.89	0.510	1.015
	25	1		1.8	0.63	0.32	0.24	0.64	0.613	0.949
	26	1		1.8	0.61	0.33	0.28	0.83	0.533	0.990
	27	1		1.8	0.59	0.34	0.27	0.84	0.545	1.017
	28	1		1.8	0.59	0.34	0.29	0.89	0.510	1.015
	29	1		1.8	0.62	0.42	0.21	0.54	0.670	0.961
	30	1		1.8	0.62	0.41	0.20	0.53	0.678	0.961
	31	1		1.8	0.57	0.38	0.14	0.52	0.755	1.058
	32	1		1.8	0.61	0.39	0.21	0.60	0.659	0.984
	33	1		1.8	0.56	0.45	0.17	0.62	0.696	1.064
	34	1		1.8	0.65	0.36	0.22	0.51	0.664	0.926
	35	1		1.8	0.61	0.36	0.19	0.55	0.685	0.989
	36	1		1.8	0.63	0.32	0.26	0.68	0.593	0.949
	37	1		3	1.02	1.09	0.18	0.49	0.821	0.980
	38	1		3	0.97	0.81	0.20	0.66	0.799	1.026
	39	1		3	0.99	0.84	0.25	0.79	0.744	1.011
	40	1		3	1.00	0.87	0.22	0.65	0.784	1.003
	41	1		6	1.93	2.16	0.14	0.65	0.926	1.039
	42	1		6	1.93	2.11	0.18	0.76	0.906	1.038
	Entry 43	Q 1	T	C FA 0 12	C PNP 0 4.59	C PAP f 4.34	C PNP 0.23 f	C FA f -1.09	X 0.950	m= C FA 0 /3 C PNP 0 0.871
	44	ml/min 1	°C	mmol/L mmol/L mmol/L mmol/L mmol/L 12 4.03 4.63 0.13 0.30	0.969	0.993
	45	0.5 1	40	1.8 15	0.59 4.88	0.41 5.81	0.12 0.19	0.41 0.93	0.791 0.961	1.023 1.025
	46	0.5 1	40	1.8 15	0.62 4.89	0.40 6.11	0.22 0.20	0.58 0.92	0.652 0.959	0.961 1.022
	47	0.5 1	40	1.8 1.2	0.62 0.28	0.40 0.14	0.20 0.12	0.52 0.72	0.682 0.570	0.961 1.411
	48	0.5 1	40	1.8 1.2	0.52 0.29	0.38 0.14	0.12 0.14	0.62 0.75	0.762 0.527	1.160 1.397
	49	0.5 1	40	3 10	0.99 2.57	0.77 4.15	0.23 0.00	0.74 2.28	0.766 0.990	1.014 1.295
	50	1 1	40	0.9 10	0.61 2.45	0.07 3.76	0.51 0.00	0.60 2.66	0.161 0.990	0.490 1.362
	51	1 1	40	3.75 3	2.69 0.99	1.04 0.78	1.81 0.17	1.10 0.56	0.328 0.824	0.465 1.013
	52	1 1.5	40	3.75 1.8	2.69 0.65	1.04 0.42	1.77 0.21	0.99 0.48	0.342 0.681	0.465 0.930
	53	1 2	40	6 1.8	4.31 0.65	2.13 0.41	2.42 0.21	0.34 0.48	0.438 0.681	0.464 0.930
	10 54	1 2	40	6 1.8	4.40 0.59	2.10 0.39	2.31 0.18	-0.27 0.57	0.475 0.696	0.455 1.017
	11 55	1 2	40	1.2 1.8	0.60 0.61	0.22 0.39	0.41 0.20	0.65 0.57	0.306 0.673	0.669 0.986
	12	1	40	1.2	0.61	0.20	0.44	0.68	0.281	0.652
	13	1	40	5	2.55	1.59	1.32	1.30	0.482	0.653
	14	1	40	5	2.54	1.63	1.41	1.62	0.443	0.656

A-

12 Detailed direct synthesis of functionalized monolith in stainless-steel tube

  Table A9 Preparation conditions of NSM

			Table A10 Preparation conditions of ASM
		ASM-1 ASM-2 ASM-3 ASM-4 ASM-5 ASM-6 ASM-7 ASM-8	ASM-9
	m TEOS (g)	0,201	0,201	0,201	0,201	0,201	0,201	0,201	0,201	0,201
	m (APTES) (g)	0,0102	0,011	0,011	0,011	0,011	0,011	0,021	0,015	0,011
	V H2O (mL)	0,639	0,642	0,642	0,642	0,642	0,418	0,674	0,652	0,696
	V HCl (37%)(mL)	0,24	0,24	0,24	0,24	0,24	0,24	0,24	0,24	0,24
	m TTAB (g)	0,1631 0,1639 0,1635 0,0968 0,2574 0,1068	0,172	0,1667	0,1776
	V dodecane (mL)	0,136	9,4	9,4	9,4	1,88	0,892	1,88	1,88	1,88
			Table A11 Preparation conditions of MSM
		MSM-1 MSM-2 MSM-3 MSM-4 MSM-5 MSM-6 MSM-7 MSM-B
	m TEOS (g)		0.18	0.18	0.18	0.1488 0.8335 0.9895	0.9	0.9
	m (MPTES) (g)	0.019	0.019	0.019	0.059	0.196	0.049	0.094	0.094
	V H2O (mL)		0.64	0.64	0.64	0.64	3.2	3.2	3.2	2,145
	V HCl (37%)(mL)	0.24	0.24	0.24	0.24	1.2	1.2	1.2	1.2
	m TTAB (g)		0.224	0.224	0.176	0.224	1.12	1.12	1.12	1.12
	V dodecane (mL)	2.2	1.6	1.88	1.88	9.4	9.4	9.4	9.4
	Sample name	NSM-1 NSM-2 NSM-3 NSM-4 NSM-5 NSM-6 NSM-7 NSM-B
	m TEOS (g)	1	1	1	1	0.46	1.39	1	1
	V H 2 O (mL)	3.2	3.2	3.2	3.2	3.2	3.2	3.2	2.145
	V HCl (37%)(mL)	1.2	1.2	1.2	1.2	1.2	1.2	1.2	1.2
	m TTAB (g)	1.12	1.12	0.69	1.61	1.12	1.12	1.12	1.155
	V dodecane (mL)	14.7	7.3	9.4	9.4	9.4	9.4	9.4	9.4

  Table A12 Condensation degree of NSM samples and area proportions of each type peak Table A13 Condensation degree of ASM samples and area proportions of each type peak Table A14 Condensation degree of MSM samples and area proportions of each type peak

		ASM-1 ASM-2 ASM-3 ASM-4 ASM-5	ASM-6 ASM-7 ASM-8 ASM-9
	%T 2	0.0%	6.0%	10.8%	12.6%	12.5%	23.0%	16.0%	13.4%	5.4%
	%T 3	100.0% 94.0%	89.2%	87.4%	87.5%	77.0%	84.0%	86.6%	94.6%
	%Q 2	11.4%	5.4%	13.9%	10.7%	11.5%	11.8%	11.1%	6.8%	6.4%
	%Q 3	56.7%	79.5%	58.7%	64.4%	67.3%	60.7%	56.4%	68.3%	73.6%
	%Q 4	31.8%	15.1%	27.4%	24.9%	21.2%	27.5%	32.5%	24.9%	20.0%
	%C.D.T 100.0% 98.0%	96.4%	95.8%	95.8%	92.3%	94.7%	95.5%	98.2%
	%C.D.Q 80.1%	77.4%	78.4%	78.5%	77.4%	78.9%	80.4%	79.5%	78.4%
		MSM-1	MSM-2		MSM-3	MSM-4	MSM-5	MSM-6	MSM-7	MSM-B
	%T 2	21.1%	11.7%		30.2%	21.5%		28.7%	17.1%	23.8%	20.5%
	%T 3	78.9%	88.3%		69.8%	78.5%		71.3%	82.9%	76.2%	79.5%
	%Q 2	12.9%	14.3%		11.6%	10.0%		3.9%	11.4%	14.8%	13.0%
	%Q 3	64.6%	67.0%		68.0%	62.7%		69.0%	70.9%	57.0%	65.8%
	%Q 4	22.6%	18.7%		20.3%	27.3%		27.1%	17.8%	28.3%	21.2%
	%C.D.T	93.0%	96.1%		89.9%	92.8%		90.4%	94.3%	92.1%	93.2%
	%C.D.Q	77.4%	76.1%		77.2%	79.3%		80.8%	76.6%	78.4%	77.1%
	Table A15 Detailed information of condensation degree of MSM-T compared to MSM-7
							MSM-7	MSM-T
					%T 2		23.8%	18.3%
					%T 3		76.2%	81.7%
					%Q 2		14.8%		9.3%
					%Q 3		57.0%	67.5%
					%Q 4		28.3%	23.2%
					%C.D.T	92.1%	93.9%
					%C.D.Q 78.4%	78.5%
		NSM-1	NSM-2	NSM-3 NSM-4 NSM-5	NSM-6	NSM-7	NSM-B
	%Q 2	5.9%	8.5%		12.6%	-		6.5%	3.9%	16.3%	18.5%
	%Q 3	87.6%	83.7%		81.8%	-		86.7%	95.9%	71.3%	66.0%
	%Q 4	6.5%	7.8%		5.6%	-		6.8%	0.2%	12.4%	15.5%
	%C.D.Q	75.1	74.8		73.2	-		75.1	74.1	74.0	74.3

19 Test of kinetics with mean values over the reactor

  Table A16 Calculation of O/Si ratio by CP-MAS NMR analysisBecause of the strong dispersion of data, the mean values of measurements made in the same experimental conditions are considered for the first kinetics trials (reduced data are listed below). This approach allows the direct plot between volumetric reaction rate and reactant concentrations. Table A17 Reduced data set for the first kinetics trials

	1 2 3 4 5 6 7 8 9 10 11 A-Entry 12	O/Si 2 1.5 3 2.5 2 ml/min °C mmol/L mmol/L mmol/L mmol/L mmol/L MSM-T MSM-7 O/Si of MSM-T T 2 5.4% 5.8% 0.108 T 3 24.1% 18.5% 0.362 Q 2 6.6% 11.2% 0.198 Q 3 47.5% 43.2% 1.188 Q 4 16.4% 21.4% 0.328 Sum 2.18 Q T C FA 0 C PNP 0 C PAP f C PNP f C FA f 0,2 40 4,841 1,852 1,538 0,699 1,385 0,5 40 4,653 1,725 1,077 0,899 2,770 1 40 1,748 0,628 0,207 0,388 1,179 1 40 3,553 0,629 0,531 0,097 2,006 1 40 2,700 0,662 0,356 0,262 1,631 1 40 0,900 0,669 0,060 0,588 0,721 1 40 2,502 0,908 0,308 0,559 2,077 1 40 4,410 1,649 0,767 0,975 3,699 1 40 11,420 4,106 2,236 2,472 5,293 1 60 1,783 0,636 0,184 0,443 1,248 1 80 1,717 0,621 0,198 0,413 1,205	O/Si of MSM-7 0.116 0.278 0.336 1.080 0.428 2.24 X m= C FA 0 /3 C PNP 0 0,623 1,080 0,479 1,159 0,382 0,956 0,846 1,909 0,605 1,359 0,122 0,448 0,384 1,102 0,408 1,213 0,398 0,974 0,303 0,944 0,334 0,966

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Acknowledgements

First of all, I would like to express my deepest gratitude towards my PhD supervisor Pr. Françoise DUPRAT for her enthusiastic and strong support to my PhD achievement, and Dr. Damien HÉRAULT for his kindness and his precise assistance all along this work. Although this thesis is interdisciplinary and its complexity is beyond expectation, thanks to Françoise and Damien, the emerged problems are well handled. They gave me great help not only in academic filed but also in general life. It is a really great privilege for me to work with them and I have realized how

Moreover, deconvolution of the 29 Si resonances and integration of the areas allowed an estimation of the degree of condensation in the network; they are calculated by MestReNova V9.0 software. Figure 81 gives an example of deconvolution on a 29 Si CP-MAS spectrum. Hence, the condensation degree of T type (%C.D.T) and Q type (% C.D.Q) the materials could be evaluated by applying the formula: %C. D. T = 2 × %T 2 + 3 × %T 3 3 (𝟏𝟎 -𝟏) %C. D. Q = 2 × %Q 2 + 3 × %Q 3 + 4 × %Q [START_REF]Experimental condition range •••••reaction parameters on conversion under stationary conditions ••••Evaluation of catalyst stability••••••••Influence of temperature and flow rate on the PNP conversion•••••••••••Influence of concentrations of reactants on the PNP conversion ••••••••••••Kinetic analysis of the reaction in the monolithic reactor •••••••of packed-bed and monolith microreactors •Catalyst performance in transfer hydrogenation reaction •••••••••Pressure drop and permeability[END_REF] 4 (𝟏𝟎 -𝟐)

where %T n and %Q n (n=2,3 or 4) are the ratio of integration of each peak to the sum of integration of T and Q peaks, respectively. The higher C.D. of T and Q indicates a more complete condensation; it must be high enough to insure a good mechanical resistance. Transmission electron microscope (TEM) was used to capture the internal structure of monoliths prepared, and normally requires an ultrathin specimen (less than 100 nm thick) on a grid. Thus, before the TEM analysis, an epoxy resin was prepared according to a protocol described in Annex A-13 , and then samples of monoliths finely grinded are incorporated into the resin, and cut in extremely thin slices (60-90 nm) with the ultramicrotomy (LBK BROMMA 8800 Ultrotome® III) equipped by a diamond knife (DiATOME Ultra Diamond Knife, Electron Microscopy Science). TEM was performed using a FEI Tecnaï G2 operating at 80 kV -200 kV equipped with CCD TVIPS (1k*1k) camera.

Scanning electron microscopy (SEM) was used to observe the sample's surface topography, which was performed with Zeiss Gemini SEM 500 operating at 20 KV.

c-Elemental analysis

Energy-dispersive X-ray spectroscopy (EDS) was coupled with SEM, to perform the elemental analysis of samples. For EDS analysis, the specimens were grinded vigorously in the mortar and then carbon-coated before examination. At least 3 points of detection for each sample have been analyzed with EDS and the elemental composition of each material was the average of measurements of these points. The carbon was not taken into account because the samples were carbon-coated and fixed on the observation base by a conducting resin, a material rich in carbon.

d-Surface area

Surface areas and pore characteristics were obtained through nitrogen isotherm adsorption-desorption experiments using an ASAP 2020 Micromeritics automatic adsorption analyzers at 77 K. The Brunauer-Emmett-Teller (BET) theory was used to take into account the multilayer adsorption characteristic of the physical adsorption of gas molecules on a solid surface 116 . The resulting BET equation is

where p and p 0 are the equilibrium and the saturation pressure of adsorbates at the temperature of adsorption, V a (cm 3 /g) is the adsorbed gas quantity per unit of solid and and V m (cm 3 /g) are the monolayer adsorbed gas quantity per unit of solid. c is the BET constant. Detailed calculation of V m and c is presented in Annex A-14 . The specific surface areas of solids S s are calculated as:

where N A is the Avogadro's number, s c is the adsorption cross section of the adsorbing species, V g is the molar volume of the adsorbate gas. Nitrogen is the commonly employed gaseous adsorbate used for surface probing by BET methods.

The different forms of the hysteresis loop in adsorption-desorption isotherms have been schematized and classified by the IUPAC (Figure 82). The hysteresis loop H 1 and H 2 are observed in the mesoporous adsorbents. H 1 presents the narrow distribution of mesopores, and H 2 presents the mesopores in intercommunication. The

Heterogeneous catalysis in microreactors: study of the performance of various supports

Abstract :

This study presents the preparation and the evaluation of performance of a new monolithic catalyst in microreactor. The transfer hydrogenation of p-nitrophenol by formic acid is chosen as the model reaction for the comparison of the monolith with a traditional packed-bed microreactor containing commercial catalyst. This thesis includes an important experimental part. On the one hand, experimental set-up and protocols involving on-line analysis have been developed in order to study quantitatively the model reaction; On the other hand, the conditions of preparation of functionalized silica monolith in a stainless steel tube with the inner wall pre-coated by glass were optimized, and the palladium nanoparticles were immobilized by a continuous flow method. The monolith possesses the flow-through macropores, typical hexagonal organization of mesopores and micropores, and scarcely any shrinkage.

The comparison of the two types of catalysts mainly focuses on the activity of catalysts in the model reaction, their kinetic model and their dynamic behavior in the start-up phase of the flow microreactor. In the theoretical part, the modelisation of reactor has been investigated both under stationary conditions for kinetics determination and under transient conditions for the rationalization of experimental observations. Pd@silica monolith and commercial Pd@alumina powder have different behavior and gives different kinetic laws. A reaction model with change in the catalytic surface properties could explain the unusual profile of concentrations observed with commercial catalyst. The superior performance of monolithic catalyst is demonstrated, which also exhibits particular industrial interests.

Key words :

Microreactor, Heterogeneous catalyst, Transfer hydrogenation, Kinetics modelisation, Catalyst synthesis

Catalyse hétérogène en microréacteur : Etude de performance de differents catalyseurs Résumé : Cette étude présente la préparation et l'évaluation de l'activité d'un nouveau catalyseur monolithique en microréacteur. La réaction d'hydrogénation du p-nitrophénol par transfert d'hydrogène avec l'acide formique a été choisie comme réaction modèle pour comparer les performances du monolithe à celles d'un catalyseur commercial en lit fixe. Cette thèse comporte une partie expérimentale importante. D'un côté, un montage expérimental et des protocoles d'analyse en ligne ont été mis au point pour faire une étude quantitative précise de la réaction modèle. De l'autre côté, les conditions de préparation d'un monolithe de silice fonctionnalisée dans le tube-réacteur en acier chemisé de verre ont été optimisées. Il a été chargé en nanoparticules de Pd par une méthode en écoulement. Le monolithe comporte un réseau de macropores pour l'écoulement et une organisation hexagonale typique de mésopores et micropores, et cela presque sans retrait au séchage. L'activité des 2 types de catalyseurs dans la réaction modèle a été comparée par leur cinétique de réaction et leur comportement dynamique dans la phase de mise en régime du microréacteur. Une partie théorique présente la modélisation du microréacteur en régime stationnaire pour l'établissement des cinétiques et en régime transitoire pour rationaliser les observations expérimentales. Le monolithe Pd@silice et le catalyseur commercial Pd@alumine ont des comportements différents et obéissent à des lois cinétiques différentes. Un modèle réactionnel impliquant un changement de propriétés de la surface catalytique pourrait expliquer le profil de concentration inhabituel observé avec le catalyseur commercial. La comparaison démontre la supériorité du nouveau catalyseur monolithe, et lui ouvre de bonnes perspectives industrielles.