Tuan Zhao

Laurent Micouin

Riccardo Piccardi
email: riccardo.piccardi@parisdescartes.fr

Prof Renaud Philippe

Paul Knochel

Prof P Renaud

Prof O Baudoin

Claude Bernard Lyon

Synthesis of organometallic compounds in Flow

Keywords: Microreactor, organolithium, organomagnesium, organozinc, organoaluminum

Microreactor technology has proved to be an important technique in organic synthesis, especially when organometallic compounds are used, because it allows running rapid reactions with reactive and instable intermediates. This review will highlight the preparation of main-group organometallic compounds deriving from Lithium, Magnesium, Zinc and Aluminum and their applications in flow conditions.

Introduction

The development of microreactor technology has grown more and more in importance in the field of chemical synthesis. This technology offers many advantages like a great heat transfer and better mixing. The small reaction volume used in the reaction allows safe handling of highly exothermic or potentially explosive reactions, reagents or intermediates. Moreover, since the reactions are conducted in a continuous mode, scale-up can be simply obtained by running the reaction for longer time, or by numbering-up the reactors. [START_REF] Yoshida | Basics of Flow Microreactor Synthesis[END_REF][START_REF] Wiles | Micro Reaction Technology in Organic Synthesis[END_REF][START_REF] Wirth | Microreactors in Organic Chemistry and Catalysis[END_REF] Tuan ZHAO received his BSc in Chemical Engineering and Technology at Hefei University of Technology. After obtaining his MSc in Biomedical Engineering (Medicinal Engineering) from Dalian University of Technology in 2016, he joined the group of Dr. L. Micouin at University of Paris Descartes as a PhD student. He is currently working on chemistry of silylated diazoalkynes.

The objective of this review is to show the progresses that have been done in the last 2 decades in the synthesis of organometallic compounds in flow conditions; we will focus on the synthesis of derivatives of lithium, magnesium, zinc and aluminum and their sequential application in flow. An overview on organometallic chemistry in flow conditions has also been published by Noël in 2016. [START_REF] Noël | Organometallic Flow Chemistry[END_REF]

Lithium derivatives

Organolithium reagents are widespread used to generate new C-C bonds. [START_REF] Rappoport | The Chemistry of Organolithium Compounds volume 1[END_REF][START_REF] Rappoport | The Chemistry of Organolithium Compounds volume 2[END_REF] They can be prepared by reduction, halogen-metal exchange, or by metallation/deprotonation.

Halogen-metal exchange

Halogen-metal exchange is one of the most used methods to prepare aryllithium derivatives. These reactions are normally very fast and the lithiated species formed are often stable only at very low temperature. As a consequence, their use in very large scale is limited by the need of cryogenic temperatures. This problem can be circumvented performing the reaction in microreactors, since their heat-transfer characteristics allow an efficient dissipation of reaction's heat. This effect arises from the high ratio between the surface and the volume of the reactor. Moreover, the residence time can be adjusted in function of the volume of the channel and in function of the flow speed. Therefore degradation can be avoided and unstable intermediates, generated with very short residence time, can react in flow with different electrophiles.

Both Villani and Schwalbe reported the first examples of Br-Li exchange in microfluidic systems. The first one was the generation of lithiated species for the synthesis on tramadol. [START_REF] Zhang | Application of Microreactor Technology in Process Development[END_REF] The second one used a two-stage microreactor for the preparation of 3methoxybenzaldehyde at a kilogram scale. [START_REF] Schwalbe | Novel Innovation Systems for a Cellular Approach to Continuous Process Chemistry from Discovery to Market[END_REF] However the biggest contribution in this area was made by Yoshida, who developed what he called the Flash chemistry, that he defined as "a field of chemical synthesis where extremely fast reactions are conducted in a highly controlled manner to produce the desired compound with high selectivity". [START_REF] Yoshida | Flash Chemistry: Fast Organic Synthesis in Microsystems[END_REF][START_REF] Yoshida | Flash Chemistry: Fast Chemical Synthesis by Using Microreactors[END_REF][START_REF] Yoshida | Flash chemistry using electrochemical method and microsystems[END_REF] Monolithiation with n-BuLi of ortho-dibromobenzene (o-DBB) is very challenging because it can easily eliminate LiBr generating benzyne.

Yoshida showed that using a two-stage microreactor technology, monolithiated o-bromobenzene could be prepared without this side reaction, allowing the functionalization with different electrophiles (Figure 1a). [START_REF] Usutani | Generation and Reactions of o-Bromophenyllithium without Benzyne Formation Using a Microreactor[END_REF] Residence time was optimized by varying the length of the tube R1 with a fixed flow rate. Best results were obtained when conducting the reaction at -78 °C with a residence time of 0.8 s. The use of elevated flow rates combined with a T-mixer, leads to a better mixing that might explain the selective formation of the unstable lithiated species. [START_REF] Soleymani | Dimensionless Number for Identification of Flow Patterns inside a T-Micromixer[END_REF] Applying optimized conditions, different electrophiles were then used to prepare different o-bromo-substituted benzenes in good yields (Figure 1b). The sequential application of this system to prepare odisubstituted aromatics was then investigated using a multi-stage microreactor where each lithiation was followed by the reaction with an eletrophile (Figure 2). It is worth nothing that the second lithiation was conducted at 0 °C. The authors supposed that the second lithiated species were more stable than ortho-bromo phenyllithium, thus cryogenic temperatures were not necessary. This methodology was then generalized to the functionalization of pand m-dibromobenzenes, [START_REF] Nagaki | Integrated Micro Flow Synthesis Based on Sequential Br-Li Exchange Reactions of p-,m-, and o-Dibromobenzenes[END_REF] and bromobenzenes substituted with different reactive groups such as esters, [START_REF] Nagaki | Aryllithium Compounds Bearing Alkoxycarbonyl Groups: Generation and Reactions Using a Microflow System[END_REF][START_REF] Nagaki | A Flow Microreactor System Enables Organolithium Reactions without Protecting Alkoxycarbonyl Groups[END_REF][START_REF] Kim | A Flow-Microreactor Approach to Protecting-Group-Free Synthesis Using Organolithium Compounds[END_REF] carbamates or carbonates, [START_REF] Kim | Submillisecond organic synthesis: Outpacing Fries rearrangement through microfluidic rapid mixing[END_REF] cyano [START_REF] Nagaki | Generation and Reaction of Cyano-Substituted Aryllithium Compounds Using Microreactors[END_REF] and nitro [START_REF] Nagaki | Nitro-Substituted Aryl Lithium Compounds in Microreactor Synthesis: Switch between Kinetic and Thermodynamic Control[END_REF] or heteroaromatic systems such as dibromopyridines [START_REF] Nagaki | Flow Microreactor Synthesis of Disubstituted Pyridines from Dibromopyridines via Br/Li Exchange without Using Cryogenic Conditions[END_REF] .

Jia and coworkers reported the functionalization of bromoheterocycles via Br-Li exchange conducted at 10 °C using a similar approach. [START_REF] Liu | Generation and Reactions of Heteroaromatic Lithium Compounds by Using In-Line Mixer in a Continuous Flow Microreactor System at Mild Conditions[END_REF] In this case, the mixing efficiency was increased by a stainless steel in-line mixer (IM1) which is a splitting-andrecombining type micromixer, introduced after the first micromixer (M1) (Figure 3). Microreactors are perfectly adapted to handle gas and flow chemistry represents an important alternative to batch processes, especially in carbonylation reactions of lithiated species.

A good example is the synthesis of Amitriptyline 6 reported by Kirschning and Kupracz. The key intermediate of this synthesis is dibenzosuberone 5, which is prepared by a one-pot Parham cyclization. [START_REF] Kupracz | Multiple Organolithium Generation in the Continuous Flow Synthesis of Amitriptyline[END_REF] The batch synthesis, that was already reported in a previous work, [START_REF] Reames | A One-Pot Synthesis of Dibenzosuberones via the Parham Cycliacylation Reaction[END_REF] consists in the formation of the lithiated dimer 2, which is trapped with CO2, affording the carboxylate 4. Br/Li exchange generates a second lithiated species that attacks the carboxylate forming ketone 5 (Scheme 1). This process however presents different drawbacks: the first Br-Li exchange has to be conducted at very low temperature to avoid the formation of byproduct 3, thus a scale up is very problematic. Moreover the authors reported a lack of reproducibility for the second lithiation-cyclization step. For all these reasons they elaborated a new process based on microtechnology that allowed a better handling temperature conditions and gas (Figure 4). This set-up allowed the preparation of 6 in 76% yield from 1 with a residence time of 33 s.

Yoshida and coworkers reported another way to handle CO2 in carbonylation reactions. In particular they were interested in the synthesis of aromatic carboxylic acids or activated aromatic esters. [START_REF] Nagaki | Extremely Fast Gas/Liquid Reactions in Flow Microreactors: Carboxylation of Short-Lived Organolithiums[END_REF] In their set-up reactions occurred in a series of T-micromixers. The amount of CO2 introduced in the flow stream was regulated by a flow controller (FC). Before being introduced in the flow stream, CO2 was pressurized at 3 bar with a gas pressure regulator valve (Figure 5).

Once again, the lithiation step occurred at temperatures ranging between 0 and -60 °C and overall yields of carboxylic acids ranged from 59 to 89 % Jamison and coworkers reported the preparation of ketones from carbon dioxide and organolithium or Grignard reagents (Scheme 3). [START_REF] Wu | Continuous Flow Synthesis of Ketones from Carbon Dioxide and Organolithium or Grignard Reagents[END_REF] Scheme 3. Preparation of ketones from CO2 and organolithium reagents In this case the introduction of CO2 in the reaction stream was performed using a Mass Flow Controller (MCF) that allowed introducing the exact amount of gas (Figure 6). Biaryl derivatives can be prepared by carbolithiation of benzynes. In particular, Yoshida and coworkers showed that, starting from odibromobenzene it is possible to generate, via Br-Li exchange, benzyne. This one can then react with an aryllithium derivative obtained by halogen-Li exchange. The corresponding biaryllithium can be further functionalized with different electrophiles (Scheme 4a). [START_REF] Nagaki | Three-Component Coupling Based on Flash Chemistry. Carbolithiation of Benzyne with Functionalized Aryllithiums Followed by Reactions with Electrophiles[END_REF] This three-component transition metal-free coupling is extremely difficult to conduct in batch. The use of flow chemistry enables a precise control of the reaction conditions governed by the relative stabilities of the lithiated species. Organolithium derivatives can also be used in palladium catalyzed cross-coupling reactions, like in the Murahashi reaction. An example of this application in flow conditions was reported by Yoshida and coworkers. [START_REF] Nagaki | Cross-Coupling in a Flow Microreactor: Space Integration of Lithiation and Murahashi Coupling[END_REF] In this case, generated aryllithium was reacted in flow conditions with a mixture of the halide and PEPPSI-SIPr as soluble Pd catalyst (Scheme 4b).

Organolithium derivatives can also be used as precursors for the preparation of boronic acids. Since this class of compounds can be instable, they can be generated using microreactor technology and directly engaged in Suzuki-Miyaura coupling reactions without isolation.

The first example of preparation of boronic acids in flow conditions was reported by Buchwald and coworkers. [START_REF] Shu | Continuous-Flow Synthesis of Biaryls Enabled by Multistep Solid-Handling in a Lithiation/Borylation/Suzuki-Miyaura Cross-Coupling Sequence[END_REF] Aryllithium, generated by Br-Li exchange was reacted in a T-mixer with a diluted solution of B(i-PrO)3 (Figure 7). The combined stream was introduced in a tubular reactor that was heated at 60 °C and sonicated to generate the corresponding boronate. The solution of the boronate was then combined with a solution of KOH, and subsequently with a solution of the aryl halide and the precatalyst. These combined streams were then introduced in a tubular reactor that was heated at 60 °C and sonicated for the coupling step. A similar set-up can be used for the Rhodium catalyzed enantioselective 1,4 addition to enones. [START_REF] Shu | Enantioselective β-Arylation of Ketones Enabled by Lithiation/Borylation/1,4-Addition Sequence Under Flow Conditions[END_REF] Other examples of synthesis of boronic acids or boronic esters were reported by Ley and coworkers; [START_REF] Browne | A New Enabling Technology for Convenient Laboratory Scale Continuous Flow Processing at Low Temperatures[END_REF][START_REF] Newby | Investigation of a Lithium-Halogen Exchange Flow Process for the Preparation of Boronates by Using a Cryo-Flow Reactor[END_REF] in these cases the reactions were conducted at low temperature (-60 °C) using a Cryo-Flow reactor able to handle cryogenic conditions. Multijet Oscillating Disc (MJOD) reactors can also be used for the synthesis of phenylboronic acids. [START_REF] Sleveland | Synthesis of Phenylboronic Acids in Continuous Flow by Means of a Multijet Oscillating Disc Reactor System Operating at Cryogenic Temperatures[END_REF] The Miyaura borylation is an important reaction for the preparation of pharmaceutical intermediates. Usutani and Sedelmeier reported a flow process for the kilogram-scale synthesis of a boronic acid starting material for the synthesis of TAK-117, a selective PI3K inhibitor. [START_REF] Usutani | Development and Scale-up of a Flow Chemistry Lithiation-Borylation Route to a Key Boronic Acid Starting Material[END_REF] Trifluoroborates are very often a stable alternative to boronic acids in Suzuki-Miyaura reactions. The synthesis of bromomethyltrifluoroborates in flow conditions has been reported by Broom and coworkers. [START_REF] Broom | The Synthesis of Bromomethyltrifluoroborates through Continuous Flow Chemistry[END_REF] It is interesting to mention that the boronate obtained by reacting the lithiated species and B(i-PrO)3 was transformed in the trifluoroboronate using an aqueous solution of HF.

This was made possible since in a flow process the handling can be automated, making the operator exposition less of a concern.

Furthermore, although the preparation of potassium bromomethyltrifluoroborate was limited to batch sizes of 100 mg, the continuous flow process enabled the production of over 100 kg of this compound in less than one month.

Metalations

Lithium derivatives of aromatic compounds can be prepared also via metalation, especially when there is an ortho directing group. This method allows selective lithiation without the need to have a halogenated precursor.

An example of using microreactor technology for ortho-metalation was reported by Takasuka and coworkers. [START_REF] Takasuga | Pharmaceutical Industrial Experiments on Continuous Cryogenic Reactions Using Mini-Sized Multi-Stage Reactors[END_REF] They synthesized spirolactone 10, a precursor for the preparation of a neuropeptide Y receptor agonist. The batch synthesis of 10 involved ortho-lithiation of 7 at -60 °C to prepare 8, which was then added to a solution of 9 at the same temperature (Scheme 5). Ley and coworkers studied the ortho-lithiation of the fluoride 11 for the synthesis of boronic acid 12 (Figure 8). [START_REF] Newby | Reconfiguration of a Continuous Flow Platform for Extended Operation: Application to a Cryogenic Fluorine-Directed Ortho -Lithiation Reaction[END_REF] Metalation was performed at -40 °C using pre-cooled solution of the starting reagents, which were mixed in a Y-piece mixer. In order to improve the mixing at the exiting of the Y-mixer they used a 4 mm tube where they introduced some stirring bars. In proximity of the stirring bars they placed a magnet that was supported on a spinning disk that was moved by a stepped motor. Then the solution enters a 20 mL reactor and the intermediate was then mixed in another Y-piece mixer with B(OMe)3 at the same temperature, controlled by a thermocouple.

The collected boronate was then hydrolyzed into the boronic acids in a batch process. This system ran for 7 hours allowing isolating the desired product in 80% yield with a productivity of 15 g/h. Another example of how microreactors offer a better solution to a batch process was reported by Ryu Fukuyama and coworkers, who reported the carbonylation of 1-silyl-substituted organolithiums with CO. [START_REF] Fukuyama | Flow Update for the Carbonylation of 1-Silyl-Substituted Organolithiums under CO Pressure[END_REF] They adapted a previously reported batch process for the preparation of lithium enolates via rearrangement of instable acyllithiums that were produced by carbonylation of 1-silylsubstituted allyllithiums (Scheme 6). [START_REF] Murai | Acyllithium to Lithium Enolate Conversion by a 1,2-Silicon Shift. A Shortcut to Acylsilane Enolates[END_REF][START_REF] Ryu | Lithium Dienolate Generation by α-Regioselective Reaction of (1-Silylallyl)Lithiums with Carbon Monoxide[END_REF] Scheme 6. Carbonylation reaction of lithiated allylsilanes

Starting from the observation that the reaction proceeds faster and cleaner with pressurized CO, they decided to develop a process using microreactor technology. They developed the system depicted in Figure 9 where a solution of n-BuLi and a solution of TMEDA and the silane were mixed in a T-shaped mixer (M1). The resulting mixture was introduced in a tubular reactor (R1) that was maintained at 25 °C to ensure complete deprotonation. The formed allyllithium was mixed with pressurized CO (4 bar) in a T-mixer (M2) with a flow rate that was adjusted with a mass flow controller. The reaction mixture passed then through a tubular reactor (R2) that was heated at 80 °C for the carbonylation and rearrangement step. A back pressure regulator was placed behind the reactor to keep the system pressurized. The electrophile was then introduced in the flow stream and mixed in a T-mixer (M3). The resulting mixture was introduced in a tubular reactor (R3) that was maintained at 25 °C. Another interesting application of metalation in flow condition is the formation of oxyranyllithium derivatives. Metalation of epoxides generates an instable species that can be degraded by a second equivalent of lithiating agent. To circumvent this problem, Yoshida and his coworkers reported the use of microreactors for the generation and reaction of oxyranyllithium compounds. [START_REF] Nagaki | Generation and Reactions of Oxiranyllithiums by Use of a Flow Microreactor System[END_REF] Using a similar approach described in Scheme 1 and 2 they studied the deprotonation of styrene oxide with s-BuLi and the subsequent alkylation with MeI and different other electrophiles. They then extended the process to chiral disubstituted epoxides. In this case the challenge is the control of the configurational stability of the organolithium species. However, when the reactions were conducted under flow conditions, epimerization was avoided. This allowed the preparation of tetrasubstituted epoxides by a sequential stereospecific introduction of two electrophiles (Scheme 7). Another example in which flow conditions allowed generating stable enantioenriched carbanions was reported by Alezra and coworkers. [START_REF] Mambrini | Memory of Chirality in a Flow-Based System: Enantioselective Synthesis of Quaternary α-Amino Acids Using Flow Microreactors[END_REF] Based on their previous works on Memory of Chirality (MOC) [START_REF] Branca | Memory of Chirality of Tertiary Aromatic Amides: A Simple and Efficient Method for the Enantioselective Synthesis of Quaternary α-Amino Acids[END_REF][START_REF] Branca | Tertiary Aromatic Amide for Memory of Chirality: Access to Enantioenriched α-Substituted Valine[END_REF][START_REF] Mai | Memory of Chirality of Tertiary Aromatic Amide: Application to the Asymmetric Synthesis of (S)-α-MethylDOPA[END_REF][START_REF] Viswambharan | Substrate Control in Enantioselective and Diastereoselective Aldol Reaction by Memory of Chirality: A Rapid Access to Enantiopure β-Hydroxy Quaternary α-Amino Acids[END_REF] they developed a flow process for the generation of quaternary stereocenters with high selectivity. Chiral enolates, prepared using LDA, reacted with different electrophiles (Figure 10), leading to alkylations with an efficient memory of chirality. When the lithium derivatives are too instable, however, there is the possibility to generate a transient organolithium species in presence of an electrophile (Barbier's conditions) and control the two competitive pathways: degradation versus addition. An example of this approach has been reported by Knochel and coworkers who prepared carbamoyl and thiocarbamoyl lithium derivatives in presence of different carbonyl derivatives (Figure 11). [START_REF] Ganiek | Barbier Continuous Flow Preparation and Reactions of Carbamoyllithiums for Nucleophilic Amidation[END_REF] Figure 11. Generation and reaction of carbamoyl and thiocarbamoyl lithiums.

Microreactors allow the manipulation of very instable compounds, like for instance diazo compounds. Wirth and his collaborators showed that ethyldiazoacetate can be easily lithiated with LDA and reacted in situ with ketones. [START_REF] Müller | Ethyl Lithiodiazoacetate: Extremely Unstable Intermediate Handled Efficiently in Flow[END_REF] Figure 12. Generation and reaction of ethyl lithium diazoacetate.

The system applied for this synthesis is described in figure 12.

In order to avoid blockage, due to the instability of the lithiates species, all the reactants were pre-cooled at -78 °C before being mixed together. The collecting vial was also kept at this temperature for the same reason. LDA was prepared in a first reactor with a residence time of 0.8 mL, the flow exiting this coil was cooled down at -78 ° in a 0.25 mL coil before mixed with cooled ethyldiazoacetate.

The flow then entered a 0.03 mL reactor to afford the lithiated diazo derivative, which was then combined with a pre-cooled ketone in a Tmixer. The resulting mixture entered a third reactor of 12.4 mL where the addition of diazo onto the ketone occurred. The flow exiting the reactor was then collected and quenched with benzoic acid at -78 °C.

Microreactors technics can not only minimize side-products in linear synthesis, but are also excellent tools in divergent syntheses. As an example, Yoshida and coworkers studied the reactivity of trichlorovinyllithium in flow conditions. [START_REF] Nagaki | Flash Chemistry Using Trichlorovinyllithium: Switching the Reaction Pathways by High-Resolution Reaction Time Control[END_REF] This compound can be trapped with an electrophile, or eliminate LiCl to afford 1,2dichloroacetylene (Scheme 8). The latter can in turn be functionalized by a sequential Cl-Li exchange and reaction with an electrophile.

Scheme 8. Reactions of trichlorovinyl lithium.

Using similar set-up depicted in Schemes 1 and 3, it is possible to prepare trichlorovinyl-derivatives or unsymmetrical disubstituted alkynes starting from the same precursor using a very fine tuning of the reactions conditions.

Magnesium derivatives

Victor Grignard discovered organomagnesium compounds that took his name in 1900. [50] These compounds are one of the most important reagents for the formations of C-C bonds. [START_REF] Silverman | Handbook of Grignard Reagents[END_REF][START_REF] Wakefield | Grignard Reagents -New Developments[END_REF][START_REF] Rakita | Kirk-Othmer Encyclopedia of Chemical Technology[END_REF] They are used in many processes both at laboratory and industrial scale.

There are different methods to prepare Grignard reagents, among them the direct insertion of Mg metal into the C-Halogen bond, metalation or halogen-metal exchange. We will give an overview of the method of preparations and of their use.

Metal insertion

Grignard reported the preparation of MeMgI by treatment of Mg with MeI in diethyl ether. Industrial preparations in a continuous fashion of these reagents have already been reported long before the appearance of microreactors. [START_REF] Kollonitsch | Industrial use of organometallics in organic synthesis[END_REF]55] However since the reaction is very exothermic, the control of the reaction conditions is very important.

High heat release rates can led to vigorous boiling and result in overpressure and even explosions. [START_REF] Jones | Assessing a Runaway of a Grignard Reaction[END_REF] For production purpose, Continuous Stirred Tank Reactors (CSTR)

have been shown to better handle high exothermic reactions in which one or more of the reagents is a solid, as in the synthesis of Grignard reagents. [START_REF] Kopach | Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material[END_REF][START_REF] Braden | Development of a Commercial Flow Barbier Process for a Pharmaceutical Intermediate[END_REF] Other processes are based on the use of thermostated columns containing some rotating blades where granulated magnesium (diam.

1-3 mm) was inserted from the top and the halide pumped from the bottom. [START_REF] Klokov | Continuous and Batch Organomagnesium Synthesis of Ethyl-Substituted Silanes from Ethylchloride, Tetraethoxysilane, and Organotrichlorosilane for Production of Polyethylsiloxane Liquids. 2. Continuous One-Step Synthesis of Ethylethoxy-and Ethylchlorosilanes[END_REF][START_REF] Grachev | Continuous Synthesis of Organomagnesium Compounds[END_REF] The final Grignard reagent was collected from the top in a collecting vessel. However this reactor was used only for the production of alkyl Grignard derivatives.

One interesting feature with flow chemistry is the possibility to perform in-line analyses or quality control. Thus, Duchateau and his group reported the preparation of Grignard reagents in flow condition monitoring the quality of the reagents formed with on-line NMR (Figure 13). [START_REF] Goldbach | Preparation of Grignard Reagents from Magnesium Metal under Continuous Flow Conditions and On-Line Monitoring by NMR Spectroscopy[END_REF] For their set up, they filled a column with Mg particles ranging in size from 100 to 1000 m. The column was constituted by a stainless steel tube of 1.1 cm of diameter and a total volume of 75 mL and was kept in vertical position to keep the magnesium particles in a fluidized bed. The tube was equipped with a jacket for heating or cooling, and a thermostat for temperature control. The solution of the halide was introduced in the column by an HPLC pump with a flow of 5 mLmin -1 . The flow stream at the exit of the reactor was divided in two stream, one of which possessing a flow of 1 mLmin -1 that was connected to a low field bench NMR spectrometer, while the other part of the stream was collected in a flask for further analysis or reactions. The conversion of the reaction was followed by the registering every 10 to 15 s an NMR spectra of the solution flowing through the magnet. A similar approach was reported by Alcázar, de la Hoz and coworkers. [START_REF] Huck | Grignard Reagents on a Tab: Direct Magnesium Insertion under Flow Conditions[END_REF] For their process they filled a glass column with magnesium particles with a size of 20-230 mesh. The size of the particle was chosen with the purpose to avoid an elevated backpressure and at the same time ensuring a high surface area to maximize the contact between the metal and the halide. The solution of the halide was pumped into the column (Figure 14). The (trifluoromethyl)phenylmagnesium bromides in a safe and reproducible manner. [START_REF] Ashby | The Reaction of Benzotrihalides and Benzal Halides with Magnesium. Synthetic and Mechanistic Studies[END_REF][START_REF] Leazer | An Improved Preparation of 3,5-Bis(Trifluoromethyl)Acetophenone and Safety Considerations in the Preparation of 3,5-Bis(Trifluoromethyl)Phenyl Grignard Reagent[END_REF] Figure 14. Apparatus for Grignard preparation by metal insertion

Halogen/metal exchange

A mild method to generate Grignard is the halogen/metal exchange; however this reaction is often very exothermic and in large scale synthesis the control of the temperature can be difficult in batch processes. Yoshida and his group circumvented this problem developing a pilot plant with flow conditions for the preparation of pentafluorophenylmagnesium bromide (PFPMgBr) from bromopentafluorobenzene and ethylmagnesium bromide. [START_REF] Wakami | Grignard Exchange Reaction Using a Microflow System: From Bench to Pilot Plant[END_REF] This reaction was initially optimized on a laboratory scale. With the optimized conditions they developed a pilot reactor constituted from a shell tube of 20 cm long and with 17 mm of internal diameter. A heat exchanger constituted of 55 microtubes (i.d. 490 m, 200 mm long) was introduced into the shell tube. The solutions were mixed in a Toray Hi-mixer, before being introduced in the reactor shell that was kept at a constant temperature of 20 °C. The total residence time was 5s. This system was tested by running for 24 h and enabled a production of pentafluorophenylmagnesium bromide of 92 % yield (GC), corresponding to 14.7 Kg of product.

In the last decades different systems have been developed to monitor the advance of a reaction conducted in flow conditions.

Infrared spectroscopy has been used by Ley, Knochel and coworkers for Inline monitoring of the metal-halogen exchange reaction with i-PrMgBr. [START_REF] Brodmann | Continuous Preparation of Arylmagnesium Reagents in Flow with Inline IR Monitoring[END_REF] In this case the halide and i-PrMgBr were pumped in a tubular reactor that was kept at room temperature. At the exit of reactor an IR probe allowed registering the IR spectrum of the solution in real time (Figure 15). The halogen/metal exchange between the iodide 13 and i-PrMgCl . LiCl (Scheme can also be conducted with chip-based reactors. The corresponding Grignard reacted with different aldehydes and the reaction mixture was then hydrolyzed in flow. The two phases were separated in a flow liquid/liquid extractor. All the systeme was fully automated with pumps guided by a computer software program. [START_REF] Tricotet | Automated Generation and Reactions of 3-Hydroxymethylindoles in Continuous-Flow Microreactors[END_REF] Carboxylic acids can be prepared by reaction of a Grignard reagent and CO2. The group of Shen and Zhang reported the synthesis of 2,4,5-trifluorobenzoic acid via sequential Br-Mg exchange and carboxylation. [START_REF] Deng | The Continuous Flow Synthesis of 2,4,5-Trifluorobenzoic Acid via Sequential Grignard Exchange and Carboxylation Reactions Using Microreactors[END_REF] Figure 16. Set-up for the synthesis of 14.

The reaction of 1-bromo-2,4,5-trifluorobenzene with EtMgBr was conducted in a reactor made of a T-mixer and a delay loop at 30 °C, while the carboxylation reaction occurred at atmospheric pressure in a falling film microreactor (FFMR) (Figure 17). The stream of generated Grignard entered in the top of the FFMR while CO2 was introduced from the bottom. This reaction was conducted at 5 or 10 °C. In order to get high yields and selectivities, the reaction was performed using a flow rate of 0.4 mLmin -1 for the solutions of EtMgBr and 1-bromo-2,4,5-trifluorobenzene (total flow rate 0.8 mLmin -1 ) and a flow rate of 30 mLmin -1 for CO2.

Metalation

One of the limitations of metalation with lithium amides is the need to use very low temperatures, however this drawback has been circumvented with the use of magnesium amides, and in particular with the development of soluble R2NMgCl . LiCl. [START_REF] Krasovskiy | Mixed Mg/Li Amides of the Type R2NMgCl⋅LiCl as Highly Efficient Bases for the Regioselective Generation of Functionalized Aryl and Heteroaryl Magnesium Compounds[END_REF] Knochel and coworkers reported that TMPMgCl . LiCl can be used to metalate different heterocycles in flow conditions using a chip-based microreactor for the metalation step. [START_REF] Petersen | Continuous Flow Magnesiation of Functionalized Heterocycles and Acrylates with TMPMgCl⋅LiCl[END_REF] The generated organomagnesium then reacted with different electrophiles in another chip-based reactor followed by a coil reactor (Figure 18).

Both steps were realized at 25 °C with very short residence times. Acrylates are difficult to metalate since they can polymerize and the reaction needs very low temperature. This problem was solved by Knochel and his group using TMPMgCl . LiCl in flow conditions. [START_REF] Ganiek | Continuous Flow Magnesiation or Zincation of Acrylonitriles, Acrylates, and Nitroolefins. Application to the Synthesis of Butenolides[END_REF] The reactions were carried out in a tubular reactor made of PFA or PTFE and at a temperature ranging between room temperature and 50 °C (Figure 19). The metalated species exiting the reactor was mixed in flow condition with different electrophiles. This method was used to prepare different butenolides who could in turn be metalated and functionalized with different electrophiles (Figure 20).

Transmetalation

Organomagnesium compounds can be generated from transmetalation of lithiated species. Interestingly Knochel reported the possibility of in situ trapping transmetalation of aromatic or heteroaromatic lithium derivatives prepared by metalation [START_REF] Becker | Practical and Economic Lithiations of Functionalized Arenes and Heteroarenes Using Cy2 NLi in the Presence of Mg, Zn or La Halides in a Continuous Flow[END_REF][START_REF] Becker | Practical Continuous-Flow Trapping Metalations of Functionalized Arenes and Heteroarenes Using TMPLi in the Presence of Mg, Zn, Cu, or La Halides[END_REF][START_REF] Ketels | Selective Lithiation, Magnesiation, and Zincation of Unsymmetrical Azobenzenes Using Continuous Flow[END_REF] or halogen-lithium exchange. [START_REF] Ketels | Synthesis of Polyfunctional Diorganomagnesium and Diorganozinc Reagents through In Situ Trapping Halogen-Lithium Exchange of Highly Functionalized (Hetero)Aryl Halides in Continuous Flow[END_REF] They showed that acrylates could be deprotonated by lithium dicyclohexylamide (Cy2NLi) in presence of MgCl2 to afford the corresponding magnesium derivative that could then be quenched by different aldehydes (Figure 21). The same approach could be used for the lithiation with lithium 2,2,6,6-tetramethylpiperidine (LiTMP) of aromatic and heteroaromatic compounds (Figure 22).

Zinc derivatives

Since the discovery of diethylzinc in 1849 by Frankland, organozinc derivatives have been used in the formation of new C-C bonds. [START_REF] Frankland | Ueber die Isolirung der organischen Radicale[END_REF][START_REF] Frankland | Notiz über eine neue Reihe organischer Körper, welche Metalle, Phosphor u. s. w. enthalten[END_REF] Organozinc reagents are less reactive than organolithium or organomagnesium reagents. Because of their improved stability, they can tolerate many functional groups and are excellent precursors for transition-metal catalyzed reactions. [START_REF] Stahl | Comprehensive Organometallic Chemistry III[END_REF][START_REF] Boersma | Comprehensive Organometallic Chemistry[END_REF][START_REF] O'brien | Comprehensive Organometallic Chemistry II[END_REF][START_REF] Knochel | Comprehensive Organometallic Chemistry II[END_REF][START_REF] Knochel | Comprehensive Organometallic Chemistry III[END_REF] In this part we will discuss the different methods of their preparation in flow conditions together with some applications.

Insertion of zinc metal

Oxidative addition of zinc into organic halides is one of the most general methods to prepare organozinc halides. However this insertion requires activation of the metal, since zinc is prone to passivation. One of the best method of activation is to treat zinc consecutively with 1,2-dibromoethane and chlorotrimethylsilane (TMSCl). [START_REF] Knochel | Synthesis and Reactivity toward Acyl Chlorides and Enones of the New Highly Functionalized Copper Reagents RCu(CN)ZnI[END_REF] This type of activation was used by Alcázar and

McQuade in the first report of direct zinc insertion in flow conditions. [START_REF] Alonso | Continuous Synthesis of Organozinc Halides Coupled to Negishi Reactions[END_REF] This was done by filling a chromatography-type column (Omnifit® column) with zinc powder with a size of ~30 mesh. Once the zinc was activated and washed with dry THF, a solution of halide was passed through the zinc bed, while the column was heated at temperatures ranging between 30 to 110 °C for alkyl or cycloalkyl halides. Aryl halides didn't lead to the corresponding zinc derivatives, even at 110 °C and higher. This method allowed the preparation of different benzyl or alkyl zinc halides. The flow exiting this column was then mixed with another arylhalide and introduced in another packed column containing Silicat DPP-Pd catalyst which allowed a Negishi coupling. This coupling was performed at temperature ranging between 60 and 80 °C (Figure 24). Using the same system, Tissot and coworkers reported the synthesis of electro-deficient heteroaromatic 1,3-substituted cyclobutyls. [START_REF] Tissot | Synthesis of Electron-Deficient Heteroaromatic 1,3-Substituted Cyclobutyls via Zinc Insertion/Negishi Coupling Sequence under Batch and Automated Flow Conditions[END_REF] Zinc activation was carried out using 1M aqueous HCl solution. Using a completely automated system, they could create a library of compounds. The comparison between batch and flow synthesis demonstrated the complementarity of the two methods: batch process proved to be better suited for insertion reactions that require long reaction time while flow conditions are more appropriate if the generation of a variety of compounds is needed.

Alcázar and coworkers showed that organozinc halides can be engaged in visible light-induced nickel catalyzed Neghishi couplings.

In a first example a preformed organozinc halide was mixed in a Tjunction with a solution of aryl halide and a nickel catalyst (NiCl2 glyme + dtbbpy). The resulting stream was injected in a tubular PFA reactor that was irradiated at 450 nm. [START_REF] Abdiaj | Visible-Light-Induced Nickel-Catalyzed Negishi Cross-Couplings by Exogenous-Photosensitizer-Free Photocatalysis[END_REF] In a second work, these authors investigated the scale up of this synthesis. The optimized set up for the 2 reactions sequences (organozinc halide synthesis and Negishi coupling) is depicted in Figure 25. [START_REF] Abdiaj | Scalability of Visible-Light-Induced Nickel Negishi Reactions: A Combination of Flow Photochemistry, Use of Solid Reagents, and In-Line NMR Monitoring[END_REF] A first gear pump introduces the halide into the column filled with zinc powder. With this method, a productivity from 3.4 to 5.6 g/h could be reached with a perfect control of the whole process.

Ley and coworkers reported a Reformatsky like reaction with sulfinylimines under Barbier's conditions. [START_REF] Lau | Synthesis of a Precursor to Sacubitril Using Enabling Technologies[END_REF] A mixture of allylic bromide 15 (1.2 equiv), sulfinimine 16 (1.0 equiv) and LiCl (8.0 equiv) in i-PrOH was pumped through the zinc reactor, injected in a coil reactor of 10 mL and then passed through a scavenger cartridge filled with QP-SA and QP-TU. In these conditions they were able to obtain the final product 17 in 70 % yield and 99:1 dr (Figure 26). A similar Reformatsky reaction using Barbier's conditions was also reported by Alcázar and coworkers (Figure 27a). [START_REF] Huck | Reformatsky and Blaise Reactions in Flow as a Tool for Drug Discovery. One Pot Diversity Oriented Synthesis of Valuable Intermediates and Heterocycles[END_REF] This system was also applied to the Blaise reaction. In this case, full conversion could not be obtained with conditions developed for the Reformatzky reaction. So a reactor coil of 5 mL heated at 120 °C was inserted after the zinc column. This method allowed, after hydrolysis, the preparation of different -ketoesters (Figure 27b). The intermediate enamine generated in flow conditions could be trapped with different electrophiles in a batch reaction (Figure 28)

Metalation

Direct zincation using with zinc amides can be an alternative to lithiation-transmetalation for the preparation of organozinc derivatives.

Ganiek et al. reported the direct zincation of acrylonitriles and

nitroolefins with TMPZnCl (Figure 29). [START_REF] Ganiek | Continuous Flow Magnesiation or Zincation of Acrylonitriles, Acrylates, and Nitroolefins. Application to the Synthesis of Butenolides[END_REF] The corresponding zinc derivatives were coupled in-line with electrophiles in presence of Pd or copper catalysts.

Zincation of aromatic or heteroaromatic compounds can be also achieved with (Cy2N)2Zn . 2LiCl, prepared from Cy2NLi and ZnCl2. [START_REF] Becker | High-Temperature Continuous-Flow Zincations of Functionalized Arenes and Heteroarenes Using (Cy2N)2Zn•2LiCl[END_REF] Figure 29. Schematic set-up for of nitroalkenes or cyanoacrylates.

It is worth noting that the regioselectivity of metalation of substituted can be controlled by switching the metalation agent.

(Cy2N)2Zn . 2LiCl allowed thermodynamically controlled metalation, while TMPZn . 2LiCl afforded the kinetic controlled metalation product (Figure 30).

Transmetalation

Organozinc halides can be obtained by transmetalation of lithium derivatives in the same manner that has been described for Grignard reagents (Figures 21, 22 and 23). [START_REF] Becker | Practical and Economic Lithiations of Functionalized Arenes and Heteroarenes Using Cy2 NLi in the Presence of Mg, Zn or La Halides in a Continuous Flow[END_REF][START_REF] Becker | Practical Continuous-Flow Trapping Metalations of Functionalized Arenes and Heteroarenes Using TMPLi in the Presence of Mg, Zn, Cu, or La Halides[END_REF][START_REF] Ketels | Selective Lithiation, Magnesiation, and Zincation of Unsymmetrical Azobenzenes Using Continuous Flow[END_REF][START_REF] Ketels | Synthesis of Polyfunctional Diorganomagnesium and Diorganozinc Reagents through In Situ Trapping Halogen-Lithium Exchange of Highly Functionalized (Hetero)Aryl Halides in Continuous Flow[END_REF] This methodology was applied efficiently to the zincation of 1,2dicyanobenzene and other substituted benzonitriles. [START_REF] Ketels | Selective Zincation of 1,2-Dicyanobenzene and Related Benzonitriles in Continuous Flow Using In Situ Trapping Metalations[END_REF] Based on a previous work reported by Knochel, [START_REF] Sämann | Synthesis of Substituted Adamantylzinc Reagents Using a Mg-Insertion in the Presence of ZnCl 2 and Further Functionalizations[END_REF] Loren and his group prepared organozinc halides by transmetalation of transient Grignard reagents that were generated via a LiCl-mediated Mg insertion into the corresponding halide. [START_REF] Herath | Generation and Cross-Coupling of Organozinc Reagents in Flow[END_REF] The generation of the Grignard was performed using a column filled with magnesium particles with a size of ~50 mesh, that were activated using the same system described earlier by Alcazar. Better results were obtained by pumping separate solutions of LiCl and ZnCl2 with a solution of the halide into a T-mixer before passing through the Mg-packed column with a residence time of 5 min. The organozinc compounds can be telescoped downstream to a Negishi or decarboxylative Negishi cross-coupling reaction in glass chips.

Aluminum derivatives

Organoaluminum compounds have been discovered by Hallwachs and Schafarik in 1859. [94] Although aluminum is one of the most abundant metals in the earth's crust and is one of cheapest metal on the market, the use of organoaluminum reagents in organic transformations is rather limited. The covalent character of the Al-C bond is however expected to be a major advantage for the design of functional organometallic species. [START_REF] Micouin | The Chemistry of Organoaluminum Compounds[END_REF] One of the major limitations in the field is the need for a simple method to prepare these compounds without any transmetalation step, and in noncoordinating solvents since the reactivity of organoaluminum compounds is mostly driven by their Lewis acidity. [START_REF]Eisch In 'Comprehensive Organometallic Chemistry[END_REF] We reported a new procedure that allowed the preparation of dimethylalkynylaluminum reagents in non-polar solvents by direct metalation of terminal alkynes in presence of a catalytic amount of base, thus providing reagents with enhanced reactivity. [START_REF] Feuvrie | Synthesis and Reactivity of Mixed Alkynylalanes by Direct Triethylamine-Catalyzed Alumination of Terminal Alkynes[END_REF][START_REF] Zhou | Room Temperature Lewis Base-Catalyzed Alumination of Terminal Alkynes[END_REF] This protocol was adapted to a continuous flow process. The catalytic cycle is based on the lower affinity of the base for alkynylalanes than for trimethylaluminum. For this reason we suggested that an amine-supported complex of trimethylaluminum could metalate a terminal alkyne forming an alkynylaluminum complex that could be displaced by trimethylaluminum, regenerating the starting catalytic complex.

For this process a chromatography-type column was filled with methylpiperidine grafted on a polystyrene resin that was chosen as base catalyst. The complex with the base was obtained passing a 1.2 M solution of AlMe3 through the column. A solution containing the terminal alkyne (1.6 M) and AlMe3 (1.4 M) in toluene was then passed through the column at a flow rate of 20 Lmin -1 (residence time of 100 min) allowing the formation of the desired alkynylaluminum derivatives (Figure 31). This process enables the preparation of 1.2M to 1.4M toluene solutions of various dimethylalkynylaluminum reagents. [START_REF] Piccardi | Continuous Flow Synthesis of Dimethylalkynylaluminum Reagents[END_REF] Figure 31. Schematic preparation of dimethylalkynylaluminum reagents

Conclusions

The use of microreactor technology is constantly evolving and many synthetic transformations classically conducted in batch have been adapted to flow conditions. As a matter of fact, Roberge and coworkers identified three type of reactions that can be carried out in a microreactor: i) reactions that are very fast (less than 1 s) and that take place in the mixing zone; ii) reactions that are rapid (between 1 s and 10 min) and they are kinetically controlled; iii) slow reactions (more than 10 min) that can benefit of the increased safety deriving from this technology. [START_REF] Roberge | Microreactor Technology: A Revolution for the Fine Chemical and Pharmaceutical Industries?[END_REF] However, not all type of reactions can be performed in a microreactor. They showed that only % of the reactions that are carried out at Lonza could benefit from a continuous flow process, with 40 % of them using microreactor technology. The main restriction is the formation of insoluble materials during the process. This solubility problem associated with salt precipitation might be a psychological barrier to explore the preparation of organometallic compounds using microreactor technology.

In this review, we have showed that this technology is on the contrary very well adapted to the preparation and use of organometallic compounds, even on a large scale, and is a remarkable alternative to batch syntheses when cryogenic conditions are required. Moreover instable compounds can be generated and used in these systems, increasing the safety for the operator.

Automations and monitoring of a process are easier, making this technology suitable for both lab-scale and industrial applications.

Figure 1 .

 1 Figure 1. Microreactor system for Br-Li exchange of o-DBB and examples.

Figure 2 .

 2 Figure 2. Microreactor system for the sequential Br-Li exchange of o-DBB.

Figure 3 .

 3 Figure 3. Microreactor system for Br-Li exchange of bromopyridine.

Scheme 1 .

 1 Scheme 1. Batch synthesis of dibenzosuberone 5.

Figure 4 .

 4 Figure 4. Microreactor system for the preparation of 6. The system they developed consisted of a T-shaped micromixer M1 and a microtube reactor R1 in which the first step of the reaction took place at -50 °C. A tube-in-tube reactor allowing the introduction of carbon dioxide into the stream of the reactants was introduced directly behind R1. The carbonylation occurred at room temperature in a second microtube reactor R2. The excess of CO2 was then eliminated in a gas remover (GR) that consisted in a Teflon AF-2400 tube, and a back-pressure regulator. The solution was then mixed in a T-mixer with another equivalent of n-BuLi. Theses Br/Li exchange reaction and cyclisation were carried out at room temperature in R3.

Figure 5 .

 5 Figure 5. Microreactor system for the preparation of carboxylic acids.

Scheme 2 .

 2 Scheme 2. Preparation of activate esters from lithium carboxylates.

Figure 6 .

 6 Figure 6. Microreactor system for the preparation of ketones.

Scheme 4 .

 4 Scheme 4. a) Three component carbolithiation of benzyne in flow conditions; b) Murahashi coupling in flow conditions

Figure 7 .

 7 Figure 7. Microreactor system for Suzuki-Miyaura reaction.

Scheme 5 .

 5 Scheme 5. Reaction in batch of intermediate spirolactone 10.

Figure 8 .

 8 Figure 8. Microreactor system for ortho-lithiation.

Figure 9 .

 9 Figure 9. Microreactor system for carbonylation reaction of silyllithiums.

Scheme 7 .

 7 Scheme 7. Sequential stereospecific introduction of two electrophiles conducted in flow.

Figure 10 .

 10 Figure 10. Microreactor system for the generation of quaternary centers.

Figure 13 .

 13 Figure 13. Apparatus for Grignard preparation by metal insertion with In-line NMR monitoring.

  activation of the magnesium was done by pumping first a solution of DIBAL-H in toluene and then a solution of TMSCl and 1-bromo-2chloroethane in a solution of 0.5 M LiCl in THF. Once the column was activated, a 0.5 M solution of the halide in a 1:1 THF/toluene mixture was passed through the column at 50 °C with a residence time of 7.5 min. A 0.38 M solution of the corresponding Grignard was collected under nitrogen. The authors observed that the concentration of the reagent did not drop until ~70 % of the metal was consumed. The remaining metal was not disposed, but the column was refilled and reactivated. The Grignard reagent solution could then be used either in batch or directly by mixing the outcome of the column with different electrophiles. It is worth noting that this method was used to prepare potentially explosive

  It was possible to follow the generation of the Grignard in real time by integration of the intensities of the typical signal of the reagent. This system was extended to allow the reaction with different electrophiles. A second T-piece was introduced after the IR probe, allowing mixing the Grignard reagent to the electrophile. The IR monitoring enabled to control the time of electrophile addition.

Figure 15 .

 15 Figure 15. Set-up fpr the halogen/Mg exchange with IR monitoring.

Figure 17 .

 17 Figure 17. Set up for the carboxylation reaction with a FFMR.

Figure 18 .

 18 Figure 18. Set-up for heterocycles metalation with TMPMgCl.LiCl

Figure 19 .

 19 Figure 19. Schematic set-up for the metalation of acrylates.

Figure 20 .

 20 Figure 20. Schematic set-up for the functionalization of butenolides.

Figure

  Figure Schematic set-up for the in-situ trapping magnesiation of acrylates.

Figure 22 .

 22 Figure 22. Schematic set-up for the in-situ trapping magnesiation of lithium derivatives In a similar manner lithium-halogen exchange could be used to generate organomagnesium by trapping in situ the transient lithiated species with MgCl2 . LiCl (Figure 23).

Figure 23 .

 23 Figure 23. Schematic set-up for the in-situ trapping magnesiation of lithium derivatives

Figure 24 .

 24 Figure 24. a) Schematic set-up for generation of organozinc halides and subsequent Negishi coupling; b) Examples of product obtained

  photoreactor was a CORNING ® G1 reactor using a 405 nm LEDs.

Figure 25 .

 25 Figure 25. Schematic set-up for scaled up visible light catalyzed Negishi coupling.

Figure 26 .

 26 Figure 26. Schematic set-up for Reformatsky reaction with sulfylimines.

Figure 27 .

 27 Figure 27. Schematic set-up for a) Reformatsky reaction; b) Blaise reaction

Figure 28 .

 28 Figure 28. Trapping enamine intermediate with electrophiles

Figure 30 .

 30 Figure 30. Schematic set-up switching regioselectivity with (Cy2N)2Zn . 2LiCl.

Acknowledgements

One of us (T.Z.) thanks the China Scholarship Council for a scholarship.

obtained an engineer diploma in 1990. He obtained his PhD under the guidance of Professor J.-C

Author Contribution Statement

All the authors contributed equally to the redaction of this manuscript

Entry for the Table of Contents

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Jihye Choi

Valentin Valtchev

Masahiko Moteki

Masaru Ogura
email: oguram@iis.u-tokyo.ac.jp

Phase change material-containing mesoporous zeolite composite for adsorption heat recovery

A mesoporous zeolite is proposed as a phase change material (PCM) carrier. Owing to its physicochemical properties, the PCM-containing adsorbent has dual functions, namely simultaneous adsorption, and heat storage. In this study, the mesoporous chabazite-type zeolite SSZ-13, was prepared under various conditions to obtain optimized mesoporous SSZ-13 (MSSZ-13) as a PCM-containing adsorbent. The phase change material was then successfully introduced in the created mesopore space through vapor phase synthesis, and the micropores could be utilized as an adsorption field. The efficiency of the as-prepared PCMcontaining MSSZ-13 was evaluated by a dehumidification process. The afforded experimental results showed suppressed bed temperature ramping, owing to the recovery of the heat generated upon H 2 O adsorption through the PCM. Moreover, the relative amount of adsorbed water increased at the initial period of time-on-stream of the contacting humid fluid.

Introduction

Zeolite is a crystalline microporous material composed of silica and alumina. It is one of the representative catalysts that has achieved industrial application, owing to its high surface area, molecular shape-selectivity, high thermal and chemical stabilities, and chemical properties that can be controlled via chemical composition and ion-exchangeability tuning [START_REF] Valtchev | Hierarchical Zeolites[END_REF][START_REF] Davis | Zeolites and Molecular Sieves: Not Just Ordinary Catalysts[END_REF] . On the other hand, molecular diffusion, pore blocking, and deactivation of the active sites inside the small micropores limit diffusivity through this material [START_REF] Valtchev | Hierarchical Zeolites[END_REF][START_REF] Holm | Catalysis with Hierarchical Zeolites[END_REF] . One method to mitigate this limitation is to introduce larger pores in the zeolite crystal [START_REF] Holm | Catalysis with Hierarchical Zeolites[END_REF] . This type of zeolite material, which possesses the natures derived from both micro-and mesopores, is called mesoporous or hierarchical zeolite [START_REF] Koohsaryan | Nanosized and Hierarchical Zeolites: A Short Review[END_REF][START_REF] Hartmann | Hierarchical Zeolites: A Proven Strategy to Combine Shape Selectivity with Efficient Mass Transport[END_REF][START_REF] Tao | Mesopore-Modified Zeolites: Preparation, Characterization, and Applications[END_REF] . There are several methods to introduce mesopores in zeolite crystals, including acid leaching [START_REF] Yang | Bridging Dealumination and Desilication for the Synthesis of Hierarchical MFI Zeolites[END_REF][START_REF] Shetti | Assessment of the Mesopore Wall Catalytic Activities of MFI Zeolite with Mesoporous/Microporous Hierarchical Structures[END_REF] , alkaline leaching [START_REF] Sommer | Microporous and Mesoporous Materials Mesopore Formation in Zeolite H-SSZ-13 by Desilication with NaOH[END_REF][START_REF] Ogura | Formation of Uniform Mesopores in ZSM-5 Zeolite through Treatment in Alkaline Solution[END_REF] , and fluoride etching [START_REF] Du | A Non-Chemically Selective Top-down Approach towards the Preparation of Hierarchical TS-1 Zeolites with Improved Oxidative Desulfurization Catalytic Performance[END_REF][START_REF] Qin | The Mosaic Structure of Zeolite Crystals[END_REF][START_REF] Chen | The Preparation of Hierarchical SAPO-34 Crystals via Post-Synthesis Fluoride Etching[END_REF] . A method using a surfactant as a template for introducing mesopores in zeolite has also been reported [START_REF] Sachse | Surfactant-Templating of Zeolites: From Design to Application[END_REF][START_REF] Garcia-Martinez | Evidence of Intracrystalline Mesostructured Porosity in Zeolites by Advanced Gas Sorption, Electron Tomography and Rotation Electron Diffraction[END_REF] .

Owing to the above-mentioned advantages, zeolite is also widely used as an adsorbent in purification and separation processes [START_REF] Davis | Zeolites and Molecular Sieves: Not Just Ordinary Catalysts[END_REF] . In the adsorption process, the adsorption performance of the material is significantly affected by the increased adsorbent temperature due to the released heat of adsorption [START_REF] Hwang | Fixed-Bed Adsorption for Bulk Component System. Non-Equilibrium, Non-Isothermal and Non-Adiabatic Model[END_REF] . Therefore, methods to improve adsorption heat removal have been extensively studied [START_REF] Demir | A Review on Adsorption Heat Pump: Problems and Solutions[END_REF][START_REF] Wang | Performance Improvement of Adsorption Cooling by Heat and Mass Recovery Operation[END_REF][START_REF] Li | Applications of Organic Phase Change Materials Embedded in Adsorbents for Controlling Heat Produced by Charging and Discharging Natural Gas[END_REF][START_REF] Horstmeier | Performance Improvement of Vacuum Swing Adsorption Processes for CO2 Removal with Integrated Phase Change Material[END_REF] . Particularly, in short-time adsorption processes, the period for cooling the adsorbent is extremely short and hence, rapid removal of the heat of adsorption is essential to avoid degradation of the adsorption performance. Gas storage, adsorption heat pump (AHP), and pressure swing adsorption (PSA) processes are well-known examples of short-time adsorption processes [START_REF] Demir | A Review on Adsorption Heat Pump: Problems and Solutions[END_REF][START_REF] Wang | Performance Improvement of Adsorption Cooling by Heat and Mass Recovery Operation[END_REF][START_REF] Li | Applications of Organic Phase Change Materials Embedded in Adsorbents for Controlling Heat Produced by Charging and Discharging Natural Gas[END_REF][START_REF] Horstmeier | Performance Improvement of Vacuum Swing Adsorption Processes for CO2 Removal with Integrated Phase Change Material[END_REF] .

In many adsorption processes, the heat of adsorption is generally removed by a heat exchanger, a system that cools a process by transferring the released heat to heat transfer fluids. Another method uses the latent heat of a phase-change material (PCM) to remove the released heat of adsorption. One of the advantages of this latter method is that it allows the storage of the thermal energy within a narrow temperature range and its subsequent reutilization. Thus, the application of a PCM capsule or PCM-containing metallic void to the adsorption process prevents the drastic increase in temperature usually observed in this process [START_REF] Li | Applications of Organic Phase Change Materials Embedded in Adsorbents for Controlling Heat Produced by Charging and Discharging Natural Gas[END_REF][START_REF] Rady | Study of Heat and Mass Transfer in a Dehumidifying Desiccant Bed with Macro-Encapsulated Phase Change Materials[END_REF] . As a possible target of the PCM-containing adsorbent, a short-time adsorption process is considered, such as gas storage, PSA, and AHP, where adsorption heat recovery is required. Therefore, hydrogen, carbon dioxide, and water should be removed, via adsorption, by the PCM-containing adsorbent. In previous research using PCM in the adsorption process, heat transfer was reported to occur in two steps: the first one is from the adsorption site to the heat transfer medium, and the second one is from the medium to the PCM. A gaseous compound such as dried air or nitrogen is commonly employed as the heat transfer medium in the adsorption process. However, the slow heat transfer due to the small heat capacity of gaseous matter has been a major limitation for using PCM in adsorption processes [START_REF] Choi | Theoretical Evaluation of an Organic Phase Change Material (PCM)-Inserted Dual-Functional Adsorbent for the Recovery of Heat of Adsorption[END_REF] .

Recently, we have proposed a new concept for the application of a PCM-containing adsorbent [START_REF] Choi | Theoretical Evaluation of an Organic Phase Change Material (PCM)-Inserted Dual-Functional Adsorbent for the Recovery of Heat of Adsorption[END_REF] . By inserting a PCM molecule directly into the pores of the adsorbent, adsorption and adsorption heat recovery occur simultaneously in the same adsorbent particles. The inserted PCM is strongly confined in the porous space by the surface tension and thus, the amount of PCM leaked from the adsorbent pores during the operation is negligible. In this PCM-containing adsorbent concept, the heat of adsorption can be effectively removed by the confined PCM, owing to the extremely short heat transfer distance, without passing through the heat transfer medium. Moreover, the presence of the PCM increases the specific heat capacity of the material. This indicates that a PCM-containing adsorbent has the advantages of both latent and sensible heat storage. Therefore, rapid removal of the heat of adsorption can be expected by applying a PCM-containing adsorbent. Additionally, PCM can be homogenously distributed in the adsorption bed, as there is no density difference between the pelletized PCM-containing adsorbents. These facts indicate that an isothermal-adiabatic adsorption process can be realized by developing a PCM-containing adsorbent. Moreover, the adsorption performance of the short-time adsorption process could be upgraded simultaneously.

A specific concept of coexisting PCM and adsorbate inside the adsorbent is necessary to elaborate such a PCM-containing adsorbent. The host container for the PCM molecules should possess a large vacant space where a phase change, from solid to liquid, occurs. Furthermore, separation of the PCM and adsorbate inside the adsorbent is required in the specific concept to prevent the adsorbate from dissolving in the liquified PCM. We have reported PCM-containing mesoporous silica SBA-15 to exemplify a PCM-containing adsorbent. In this material, the mesoporous spaces are utilized as a heat storage field by the PCM, while the vacant spaces, where no PCM is present in the mesopores or external surface, are utilized as adsorption sites. Notably, PCM-containing SBA-15 exhibited isothermaladiabatic behavior and an improved adsorption performance during the initial few minutes of the dehumidifying process. This indicates the achievement of the developing objectives of the PCM-containing adsorbent. However, PCM-containing SBA-15 is just one example of a specific concept for PCM-containing adsorbent.

Herein, we propose the PCM-containing mesoporous zeolite SSZ-13 as another specific concept for the PCM-containing adsorbent. A schematic image of the concept, in which the adsorption site is located in the micropore and the mesoporous space is used as a heat storage field, is presented in Figure 1. One advantage of this concept is that the separation of the PCM and adsorbate in the zeolite crystal can be achieved by the size difference between the PCM molecule and adsorbate. Thus, by selecting a PCM molecule with a larger size than the micropore diameter, the PCM could only be accommodated in the mesopores. Using the data from our previous report [START_REF] Choi | Mesoporous Zeolite for Use as Dual-functional Heat-storage Adsorbent[END_REF] , we selected the chabazite (CHA)-type high-silica zeolite SSZ-13 with an ultra-small micropore (~0.4 nm) as the zeolite material, while paraffin was selected as the representative organic PCM. This as-synthesized PCM-containing mesoporous SSZ-13 (MSSZ-13) was then evaluated by monitoring the bed temperature and amount of adsorbed water in a fixed-bed dehumidifying adsorption process.

Experimental

Preparation of MSSZ-13

Two different methods were conducted to introduce the mesopores in zeolite SSZ-13, one using ammonium fluoride (NH 4 F) and the other sodium hydroxide (NaOH) aqueous solutions. The parent zeolite SSZ-13 (SiO 2 /Al 2 O 3 = 18) was supplied by a reference zeolite project of the Japan Zeolite Association.

Fluoride etching treatment of SSZ-13 was conducted in an ultrasonic (US) bath. Specifically, 1 g NH 4 + ion-exchanged SSZ-13 was added to 20 g of 40 wt% NH 4 F solution. The mixed slurry was subjected to different periods (20-120 min) of ultrasonic treatment at 25 and 40 ℃. The slurry was then filtered and washed threefold with deionized water (60 ℃, 500 mL). Subsequently, the filtrate was collected and dried overnight in air. The treatment was also carried out using double the zeolite/solution ratio (1 g NH 4 + -SSZ-13 zeolite in 40 g of 40 wt% NH 4 F solution), whereby the ultrasonic bath temperature was raised from 25 to 40 and 55 ℃, for 1 and 2 h.

Alkaline leaching treatment of SSZ-13 was conducted hydrothermally. Thus, 1 g Na + ionexchanged SSZ-13 was added to 30 mL of 0.6 M NaOH solution, and the slurry was stirred at 65 ℃ for several minutes (5, 15, 45, and 90 min) at a stirring speed of 400 rpm. After several minutes, the solution was filtered and washed threefold with deionized water (60 ℃, 500 mL). The filtrate was then allowed to dry overnight.

All the products prepared according to the above-described methods were labeled according to their preparation conditions, as summarized in Table 1. Finally, the prepared products were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and N 2 adsorption techniques.

Preparation and characterization of PCM-containing MSSZ-13

Paraffin (C22, docosane) was inserted into the mesopores of as-prepared MSSZ-13 (Section 2.1) via a vapor transportation method [START_REF] Choi | Confinement Effect on Enthalpy of Fusion and Melting Point of Organic Phase Change Materials in Cylindrical Nanospace of Mesoporous Silica and Carbon[END_REF] . Thus, MSSZ-13, was dried at 100 °C overnight and placed in an encapsulated desiccator. The PCM solid/liquid was separately placed in the same desiccator. Next, the desiccator was evacuated, sealed, and maintained at 150 °C in an air oven for several hours overnight until the adsorption of vaporized paraffin on MSSZ-13 reached equilibrium. The ratio of the volume by paraffin inside the mesopores, , was calculated by weighting the sample before and after inserting the paraffin, as follows:

(Eq. 1)

where represents the weight of PCM-containing SSZ-13, represents the weight of the dried MSSZ-13 before PCM vapor treatment, represents the PCM density, and represents the total pore volume of MSSZ-13 measured by N 2 adsorption. The value can be considered as the pore filling ratio of the PCM inside the mesopores.

The porous characteristics of the materials were measured by N 2 adsorption, while the melting point and enthalpy of phase changes of the PCM were measured by differential scanning calorimetry (DSC8230 Thermoplus, Rigaku). Each DSC measurement was repeated fivefold to determine whether any liquefied PCM leaked from the composite material. Additionally, water vapor adsorption isotherms were collected at different temperatures (293-318 K) to verify that the adsorption sites were still present after PCM insertion.

Dehumidifying adsorption process

Dehumidification using a packed bed of PCM-containing MSSZ-13 was carried out to evaluate the prepared PCM-containing MSSZ-13. As a reference, the dehumidification process was also performed using the parent SSZ-13. Thermal conductivity detection (TCD, GC8A, Shimadzu) was employed to detect water vapor throughout the packed bed of adsorption material. The pelletized adsorbent was sieved in the range 2-4 mm and then packed in the bed. Nitrogen was supplied by two different lines, one directly connected to the adsorbent column and the other connected to a bubbler in a water bath (50-80 °C) to create humid nitrogen. The humidified nitrogen was allowed to flow through the adsorbent bed column. The flow rate of each line was controlled by a flowmeter at 100 cm 3 /min. In all the experiments, the relative humidity at the inlet was fixed at 50%, while the initial temperature of the adsorption bed was maintained at 29.5 ℃. The adsorbent bed column was lagged with styrofoam to ensure adiabatic conditions. The temperature of the adsorbent bed was measured at two points, namely near the inlet and outlet of the column, using a K-type thermocouple. The length of the adsorbent bed was 2 cm, and the diameter of the bed was 1 cm. , The pretreatment of the adsorbent was performed at 60 ℃ for 3 h under dried nitrogen flow.

Results and discussion

Preparation of MSSZ-13

For the primary purpose of developing a PCM-containing adsorbent, a high storage capacity for latent heat is preferable. The storage capacity is determined by the enthalpy of fusion and the amount of PCM inserted inside the matter, which in turn are determined by the size and volume of the container space. Additionally, in the concept of the PCM-containing MSSZ-13, the microporous space is necessarily utilized for adsorption, and thus, preservation of the micropore volume of the SSZ-13 zeolite is another important factor for the establishment of the concept. Hence, for the development of a PCM-containing adsorbent, the MSSZ-13 must have a large mesopore diameter and volume, while maintaining the microporous volume. Thus, in this study, MSSZ-13 was prepared under various conditions to obtain the optimal MSSZ-13.

Effect of the treatment solution on the preparation

Aqueous NH 4 F and NaOH solutions were applied to the respective etching and leaching treatments employed in this study. The products prepared by fluoride etching and alkali leaching for various treatment periods were characterized by XRD, N 2 adsorption, and SEM techniques. The XRD patterns of the MSSZ-13 samples prepared by fluoride etching are depicted in Figure 2 (a), while those of the MSSZ-13 prepared by alkali leaching are presented in Figure 2 (b). The results revealed that the XRD patterns of all the MSSZ-13 samples were identical to those observed for SSZ-13. This indicates that the crystalline microporous structure of SSZ-13 is still retained after fluoride etching and alkali leaching. However, for both processes, the intensities of the XRD peaks gradually decreased with prolonged treatment. This suggests that both methods somewhat destroy the crystalline structure of the materials. Moreover, the intensities of the products formed by alkali leaching exhibited a greater decrease than those of the products prepared by fluoride etching. It is generally accepted that dissolved NH 4 F provides HF 2 -ions, which indiscriminately dissolve both the alumina and silica in the zeolite material [START_REF] Qin | The Mosaic Structure of Zeolite Crystals[END_REF][START_REF] Chen | The Preparation of Hierarchical SAPO-34 Crystals via Post-Synthesis Fluoride Etching[END_REF] . On the other hand, NaOH only extracts silica from the framework [START_REF] Sommer | Microporous and Mesoporous Materials Mesopore Formation in Zeolite H-SSZ-13 by Desilication with NaOH[END_REF] . Consequently, the preferential silica extraction from a silica-rich materialas SSZ-13 (Si/Al ratio ~9) leads to substantial crystallinity loss.

The nitrogen adsorption isotherms and their derived pore size distributions (BJH method) are respectively displayed in Figures 3 (a) and (b) for the products prepared by fluoride etching and in Figures 3 (c) and (d) for those obtained by alkali leaching. Additionally, the values of the micro-and mesopore volumes and average pore diameters are summarized in Table 2, and clearly demonstrate that both treatments successfully introduced mesopores. Specifically, in the samples prepared by fluoride etching, a gradual increase in the mesopore volume accompanied by a slight decrease in the micropore volume was observed with prolonged treatment. Comparatively, the products prepared by alkali leaching displayed a significant increase in the mesopore volume and a marked decrease in the micropore volume with increasing treatment time. This decrease in the micropore volume is in good agreement with the decrease in the crystallinity of zeolite, as illustrated in Figure 2. Notably, unlike the other samples, sample HT90 displayed a reduction in both the micro-and mesopore volumes with increasing treatment time. Compared to the products obtained by fluoride etching, the decrease in micropore volume was more significant than the increase in the mesopore volume for the products prepared by alkali leaching. For example, after 15 min alkali leaching, the sample (HT15) presented a 77% decrease from the original micropore volume and a mesopore volume of 0.15 cm 3 /g. On the other hand, no decrease in micropore volume and a mesopore volume of 0.10 cm 3 /g was observed after 20 min of fluoride etching (US20). Relatively wide pore size distributions, with mesopore sizes in the range of 2-50 nm, were observed for the products afforded by both techniques. This indicates that the mesopores were not uniformly introduced in the SSZ-13 material applied in this investigation.

The morphology features of SSZ-13 and the as-prepared MSSZ-13 are illustrated in Figure 4. As can be seen in Figure 4 (A), the parent SSZ-13 exhibits rectangular-shaped particles. The MSSZ-13 samples [Figures 4 (B)-(I)] displayed rectangular morphologies similar to those of the parent SSZ-13, even after fluoride etching and alkali leaching treatment. However, treatment slightly changed the edges of the particles, making them rounder in shape. Moreover, in the SEM image of HT90 [Figure 4 (I)], a crack was observed at the center of the particles, owing to the severe leaching. Such a drastic change in the morphology of the zeolite particles and the generation of surface cracks were also reported in the literature for ZSM-5 zeolite treated with a highly alkaline solution [START_REF] Ogura | Formation of Uniform Mesopores in ZSM-5 Zeolite through Treatment in Alkaline Solution[END_REF] .

At this stage, we could confirm that both methods were successful in introducing a large mesopore inside the microporous zeolite SSZ-13 particles. It was further suggested that alkali leaching is a destructive method against SSZ-13 zeolite, which resulted in a significant decrease in the micropore volume and crystallinity, compared to those attained with fluoride etching. As already mentioned, it is important to introduce a large mesopore while preserving the micropore of the mother zeolite crystal to be appropriate as a PCM-containing adsorbent. Therefore, fluoride etching was considered as the optimal method for the creation of MSSZ-13.

Effect of temperature on the preparation

The MSSZ-13 samples, namely US20, US40, US90, and US120, were prepared at 25 ℃ w ith a zeolite/solution ratio of 1/20 (Table 1). To investigate the effect of the treatment temperature on the material, fluoride etching was carried out at higher temperatures of 40 a nd 55 ℃. Additionally, the zeolite/solution ratio was doubled to obtain a larger mesopore volume, while the concentration of the fluoride solution was unchanged. The products prepared under these slightly more severe conditions were named according to their treatment temperature and time (US40d-1H, US40d-2H, US55d-1H, and US55d-2H; Table 1). The XRD patterns of the etched SSZ-13 samples prepared under the higher temperatures are presented in Figure 5. The same XRD patterns were observed for the products that originated from SSZ-13, indicating that the microporous crystalline structure of SSZ-13 was maintained after fluoride etching. However, with the increase in the treatment temperature and time, the intensities of the XRD patterns were drastically decreased. This indicates that the crystallinity of the SSZ-13 material decreases with increasing treatment temperature and time, owing to the more severe etching conditions.

The nitrogen adsorption-desorption isotherms and pore size distribution curves of the etched SSZ-13 samples are depicted in Figures 6 (a) and (b), respectively, while the physicochemical properties of etched materials are summarized in Table 3. A significant mesopore generation was observed in all the products. With the increase in the treatment temperature from 25 ℃ to 40 and 55 ℃ (i.e., from US60 to US40d-1H and US55d-1H), the mesopore volume largely increased. On the other hand, a further increase in the treatment time from 1 to 2 h led to a decrease in the mesopore volume, which seems to correlate with the results observed for HT90. Generally, with the increase in mesopore volume, the micropore volume decreased according to the treatment temperature and period, as summarized in Figure 7. However, for US40d-2H and US55d-2H, the mesoporous and microporous volumes decreased simultaneously. The pore size distribution became broader in the etched products. Similar to the changes in the mesopore volume, the mesopore diameter also decreased with increasing treatment time. This is possibly due to the formation of macropores that could not be detected by nitrogen adsorption or the presence of a relatively small amount of mesopores as a result of crystal destruction.

The scanning electron micrographs of the as-prepared MSSZ-13 samples are illustrated in Figure 8. All the MSSZ-13 materials obtained in this study displayed a morphology similar to that of the parent SSZ-13 [Figure 4 (A)], but with a relatively rounder shape along with the harder fluoride etching.

At this stage of the investigation, fluoride etching was determined as an effective method, over alkali leaching, to introduce mesopores in SSZ-13 while preserving the original micropores of SSZ-13. It is generally preferable to introduce a mesopore large enough to occlude the PCM, which corresponds to the heat storage capacity of perfect absorption of the released heat of adsorption. The latent heat storage capacity is determined from the amount of occluded PCM, since the enthalpy of fusion is a physical property of this material. A mesopore volume dozens of times larger than the micropore volume is required to completely absorb the released heat of adsorption, mainly due to the large quantity of the heat. On the other hand, preservation of the micropore volume while introducing mesopores is also important to maintain the adsorption capacity. A trade-off between maintaining the micropore volume and increasing the mesopore volume was, therefore, necessary, as illustrated in Figure 8. Thus, MSSZ-13 with a mesopore volume at least three-to fourfold larger than the micropore volume could be attained to utilize the material as a PCM container. Possible application of the PCM-containing adsorbent is by a rapid adsorption process, which runs before the adsorption system reaches adsorption equilibrium. Among the MSSZ-13 materials prepared in this study, US40d-1H displayed less crystallinity degradation, a large mesopore volume, and a relatively smaller decrease in micropore volume. Therefore, this material was selected for further investigation to determine its potential as a PCM-containing MSSZ-13.

The surface scanning electron micrographs of US40d-1H (Figure 9) confirm the introduction of non-uniform mesopores in this material. Indeed, various mesopore shapes were observed, including cheese-like holes ([Figures 9 (A) and (B)], honeycomb-like holes [Figure 9 (C)], and large crater-like holes [Figure 9 (D)] that indicated the introduction of not only mesopores but also macropores in some parts of the crystal.

Characterization of the as-prepared PCM-containing MSSZ-13 materials

In this study, paraffin was used as the PCM, which was inserted into the mesopores of MSSZ-13 via a vapor transportation method. First, it was necessary to confirm that paraffin could be used as the PCM in the concept of composite PCM-containing MSSZ-13. To utilize the microporous space as an adsorption field, the PCM molecule must be larger than the micropore size of MSSZ-13. The nitrogen adsorption isotherms of SSZ-13 and paraffinloaded SSZ-13 are demonstrated in Figure 10. Both porous materials displayed a drastic increase in the adsorbed amount of nitrogen in the low P/P 0 range, with no noticeable differences between them. This uptake of nitrogen in the P/P 0 range below 0.1 is derived from the nitrogen adsorbed in the microporous space. If paraffin were able to access the micropore, the microporous space would be occupied by the confined paraffin, and the nitrogen uptake would not be observed. Hence, the results confirmed that paraffin did not access the SSZ-13 micropores and thus the prepared material could be used as the PCM for this study.

The measured nitrogen adsorption isotherms of the MSSZ-13 and PCM-containing MSSZ-13 materials are presented in Figure 11. At the same time, the changes in the porous structure properties before and after PCM insertion are listed in Table 4. By inserting PCM into MSSZ-13, the mesopore volume was significantly decreased compared to that of the parent MSSZ-13. This indicated that PCM was successfully introduced solely into the mesopores of SSZ-13. However, nearly 40% of the MSSZ-13 micropore volume was simultaneously decreased. As confirmed in Figure 10, PCM does not occupy the microporous space of SSZ-13. Instead, PCM occupies the mesoporous space of MSSZ-13 and supposedly partially blocks diffusion to the micropores. Hence, separation of the adsorption site (micropores) and heat storage field of paraffin (phase change in the mesopores), was successfully achieved.

To investigate the adsorption properties of water vapor on SSZ-13 and PCM-containing MSSZ-13, H 2 O adsorption isotherms were measured at three different temperatures for SSZ-13 and at six different temperatures for PCM-containing MSSZ-13, as illustrated in Figure 12. Under the tested conditions, with x-axial relative pressure, the isotherms indicated that there was no apparent temperature dependency of the adsorption on SSZ-13 and PCM-containing MSSZ-13. For SSZ-13, the H 2 O adsorption isotherm was a Langmuir type I isotherm. On the other hand, PCM-containing SSZ-13 presented a Langmuir type I isotherm at the lower relative pressure range, while H 2 O condensation was observed at the higher pressure range at relative pressures above 0.8. This indicated that not all the mesoporous spaces were filled with PCM. Thus, after the PCM insertion process, the amount of adsorbed water vapor decreased at relative pressures lower than 0.7. This is because, as already discussed (Section 3.1.1), the micropore volume is reduced by fluoride etching, and some of the micropores become blocked after PCM insertion. However, even though a decrease in the amount of adsorbed H 2 O was detected, H 2 O adsorption sites were still clearly present in the prepared PCM-containing MSSZ-13.

Evaluation of the phase change and heat recovery of PCM-containing MSSZ-13

The melting properties and stability of the PCM inserted in MSSZ-13 were characterized by repeated DSC measurements. The phase change peak of the paraffin inserted in MSSZ-13 was observed (Figure 13), indicating the heat storage ability of the inserted paraffin. Moreover, the phase change (i.e., the phase change temperature and amount of heat recovery of the inserted paraffin) did not change during the repeated measurements, suggesting that the inserted PCM did not change physically or chemically. Moreover, the PCM did not seem to leak from the mesoporous space of MSSZ-13, even in the liquid state with thermal stability. The melting point of the inserted paraffin was 42.6 ℃, while its enthalpy of fusion was 156 J/g-PCM. These values were slightly lower than those of the original PCM (43.0 ℃ and 237 J/g-PCM, respectively), owing to the surface tension and interaction between the PCM molecules and the mesopore wall of MSSZ-13. These results confirmed that PCM-containing MSSZ-13 having dual functions of heat storage and adsorption was successfully prepared. These functions on the prepared PCM-containing MSSZ-13 were evaluated by a dehumidification process. The objective of developing PCM-containing MSSZ-13 was to achieve a performance upgrade of such a thermal process through absorption heat recovery. Therefore, the effectiveness was evaluated from the change in the amount of adsorbed water within the initial period of time-on-stream and by the difference in the system temperature. The temperature of the adsorbent was measured near the inlet and outlet of the fixed bed, as illustrated in Figures 14 (a) and (b), respectively. Additionally, the amount of H 2 O adsorbed on the adsorbent was calculated from the changes in the H 2 O concentration, which were detected by TCD [Figure 14 (c)]. The amount of adsorbed water relative to the equilibrium amount of adsorbed water is presented in Figure 14 (d). The relative humidity of the fluid at the inlet was fixed at 50%. Thus, the equilibrium amount of adsorbed water, q * , corresponds to the amount of adsorbed water on PCM-containing MSSZ-13 when P/P 0 is 0.5 [Figure 12 (b)]. As illustrated in Figures 14 (a) and (b), regardless of the position in the bed (near the inlet or outlet), the rapid increase in the bed temperature at the initial adsorption period was suppressed by the coexistence with the PCM. This proves that the PCM inserted in the adsorbent works successfully as a heat storage material. The value of q /q * on PCM-containing MSSZ-13 [Figure 14 (d)] was higher than that on SSZ-13 during the initial 5 minutes after flowing the humid fluid. Therefore, the PCM-containing MSSZ-13 can successfully recover the heat of adsorption, thereby resulting in an increased apparent rate of adsorption, as shown in the results. On the other hand, even though successful heat recovery through PCM was achieved, the amount of adsorbed water on the PCM-containing MSSZ-13 was slightly smaller than that on SSZ-13 [Figure 14 (c)]. This might be derived from the decrease in q * after PCM insertion (Figure 13), which has a more significant effect on the amount of adsorbed H 2 O than the heat recovery through the PCM. Additionally, the temperature dependence of the adsorbed water on SSZ-13 is relatively small. Therefore, as future perspectives, the use of a more temperature-sensitive zeolite, such as SAPO-34 [START_REF] Calabrese | Adsorption Performance and Thermodynamic Analysis of SAPO-34 Silicone Composite Foams for Adsorption Heat Pump Applications[END_REF] , as the mesoporous zeolitic container and application of PCM-containing MSSZ-13 to a more exothermic adsorption process should be considered to achieve drastic performance improvement in the adsorption processes.

In summary, a PCM-containing MSSZ-13 having simultaneous adsorptive and heat storage properties in the same material was successfully prepared. Additionally, the as-prepared PCM-containing MSSZ-13 was proven as a valid concept for the PCM-containing adsorbent.

Conclusions

As a new concept of PCM-containing adsorbent, a PCM-in-MSSZ-13 composite material was proposed as an adsorbent possessing simultaneous adsorptive and heat storage abilities in the same particles. An MSSZ-13 material with a large mesopore volume was used as the host material for inserting PCM solely in the mesopore. The mesopore was created by a fluoride etching method. Thus, PCM-containing MSSZ-13 was successfully prepared, and its mesoand microporosities were confirmed. The mesoporous space was utilized as a heat storage field, while the microporous space, originating from SSZ-13, was utilized as an adsorption field. The experimental results of the as-prepared PCM-containing MSSZ-13 revealed suppressed bed temperature ramping and an increase in the relative amount of adsorbed water vapor, q/q * . Therefore, it can be concluded that PCM-containing MSSZ-13 delivers an effective concept, namely that the performance can be upgraded through the heat adsorption recovery, and the composite can be another application for the utilization of mesoporous zeolite.

Acknowledgement

The authors would like to acknowledge Microtrac BEL Corporation for their support on the measurement of the H 2 O adsorption isotherms for a series of SSZ-13 materials. Observation of US40d-1H by surface SEM was conducted at the Advanced Characterization Nanotechnology Platform of the University of Tokyo, supported by "Nanotechnology Platform" of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. MO would like to thank Editage (www.editage.com) for English language editing. V.V. acknowledges the financial support from the ANR-TOTAL Industrial Chair 'NanoClean Energy".