Dehydration in Aqueous Media

Par Sarah LE GUENIC

Dehydration in aqueous media

Thèse présentée pour l’obtention du grade de Docteur de l’UTC

Soutenue le 1er décembre 2015 Spécialité : Génie des Procédés Industriels et du Développement Durable D2238

Université de Technologie de Compiègne

Ecole Doctorale : Sciences pour l’ingénieur

Thèse présentée par

Sarah LE GUENIC

Pour le titre de Docteur en Génie des Procédés Industriels et du Développement Durable

Dehydration in aqueous media

Thèse dirigée par : Christophe LEN et Claire CEBALLOS

Soutenue le 1er décembre 2015 devant le jury composé de :

François JEROME Directeur de Recherche CNRS, Université de Poitiers Rapporteur

Rafael LUQUE Professeur, Universidad de Cordoba Rapporteur

Florent ALLAIS Professeur, AgroParisTech Examinateur

Stéphane OCTAVE Docteur, Université de Technologie de Compiègne Examinateur

Christophe LEN Professeur, Université de Technologie de Compiègne Directeur de thèse

Claire CEBALLOS Docteur, Ecole Supérieure de Chimie Organique et Directrice de thèse Minérale

Acknowledgements

This PhD work was done in the laboratory Transformations Intégrées de la Matière Renouvelable (TIMR, EA4297) of the Université de Technologie de Compiègne under the supervision of Pr. Christophe LEN and Dr. Claire CEBALLOS. I would like to thank Pr. André PAUSS, director of the laboratory, for giving me the opportunity to do this PhD. I would also like to thank Georges SANTINI, director of the Ecole Supérieure de Chimie Organique et Minérale (ESCOM) for letting me work in his school. I also thank the French Ministère de l’Enseignement Supérieur et de la Recherche for its financial support.

First of all, I would like to thank the Director and Co-director of my thesis, Pr. Christophe LEN and Dr. Claire CEBALLOS, for their scientific help, support and guidance during this PhD. I particularly thank Pr. LEN for his trust and for giving me the opportunities to present my work at international conferences.

I want to express my gratitude to the members of the jury that participated in my PhD defense. I would especially like to acknowledge the referees of my thesis, François JEROME and Rafael LUQUE. Thank you for the time you devoted and the feedback that you provided.

During my PhD work, I had the opportunity to do a Short Term Scientific Mission in the team of Pr. Herbert SIXTA, in the Department of Forest Products Technology, in Aalto University (Helsinki, Finland). I thank the COST program for the grant awarded and the Pr. SIXTA for his supervision. Thanks to Jean BUFFIERE, Olga ERSHOVA and Rita HATAKKA from the Biorefineries’ team for their help with the reactor, the HPLC and in the laboratory.

I would like to thank my colleagues from the OCAT team, with which I had the pleasure to collaborate: Carole, Claire, Denis, Estelle, Floriane, Frédéric, Gérald, Gwenaëlle, Muriel and Nicolas T. I particularly thank Nicolas T. and Denis for their many scientific advices, for their jokes and for the good times we spent together. Thanks to

Frédéric for the time he spent on my manuscript. I thank the interns, who participated on my project, for their work and implication: Quentin, Fabrice, David and Loïc. I thank Lysiane, from TIMR, for her help and the whole staff of ESCOM for their hospitality. Special thanks to France, Anissa, Bernard, Pierre-Yves, Joachim and Nathalie for the fun talks we had during coffee breaks.

This PhD would not have been the same without the fun and friendly atmosphere of the lab. Big thanks to Rémi, Nicolas G., Clément, Sophie, Audrey and Christina. Of course, I particularly thank Hasret and Nico who made this long journey with me, who suffered and laughed with me, who cheered me up when I was down and supported me through the important moments. The three PhD Babies have grown up and have become doctors. Now, one chapter in the story closes, but a whole new adventure begins! I would also like to thank all the PhD students that I have met during these 3 years for the nice moments: the RED² team – Christophe, Marina, Benjamin, Fabien, Florian, Pierre, Pierre, Tifenn, Tony, Rémy and Gaëtan, the Acoustic Boys – Antoine, Romain and Julien, and the TIMR Girls – Sylène, Maria and Atena.

A special thanks to my friends, Clémentine, Audrey, Marion, Claire, Tania and Ghania. Even if it was sometimes hard to find a date to see each other, spending time with you was always a good moment which cheered me up and made me forget (for a time!) the hard work waiting for me.

Of course, I would like to say a big and loving thanks to my parents and to my sister Marion and my brother Benjamin. Thank you for your support and your encouragements, thank you for trying to understand my work and for listening to me when I needed it. I know that I can always count on you. More broadly, I thank Dany, Evann, Gaële, Frédérique, Katia and the kids for their support.

And, last but not least: Yorick. Meeting you was one of the greatest things that happened to me during this PhD. Thank you for your daily support, for comforting me when I felt bad, for your jokes, for your delicious dishes, and for believing in me.

Table of contents

ACKNOWLEDGEMENTS ...... I

TABLE OF CONTENTS ...... III

ABBREVIATIONS ...... VII

LIST OF FIGURES ...... IX

LIST OF TABLES ...... XI

LIST OF SCHEMES ...... XII

GENERAL INTRODUCTION ...... 1

CHAPTER I ...... 5

CONTEXT AND LITERATURE REVIEW ...... 5

1. GREEN CHEMISTRY: DEFINITION AND TOOLS ...... 7 a. Green Chemistry: Origin and Twelve Principles ...... 7 b. Water as a green solvent ...... 10 i. General points on green solvents ...... 10 ii. Sub- and supercritical water ...... 14 c. Alternative activation methods ...... 17 i. An overview of the different methods ...... 17 ii. Microwave chemistry ...... 19 2. DEHYDRATION OF POLYHYDROXYLATED COMPOUNDS IN WATER ...... 25 a. Without a catalyst ...... 25 b. Homogeneous catalysis ...... 26 i. Mineral and organic acids ...... 26 ii. Metal sulphates ...... 27 iii. Metal chlorides ...... 29

iv. With the addition of CO2 ...... 30 c. Heterogeneous catalysis ...... 30 i. Modified silicates and aluminosilicates ...... 31 ii. Mixed oxides ...... 32 iii. Ion-exchange resins ...... 33 iv. Solid metal phosphates ...... 34 d. Enhancing selectivity ...... 34 3. ISSUE AND OBJECTIVES ...... 36 BIBLIOGRAPHY ...... 37

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CHAPTER II ...... 43

DEHYDRATION OF 1-PHENYLETHANE-1,2-DIOL IN WATER ...... 43

1. INTRODUCTION ...... 45 a. Phenylacetaldehyde: origin and applications ...... 45 b. Literature review ...... 45 c. Mechanism and structure of the by-product ...... 48 2. DEHYDRATION OF 1-PHENYLETHANE-1,2-DIOL UNDER CONVENTIONAL HEATING ...... 50 a. Variation of temperature and reaction time ...... 50 b. Influence of the diol concentration ...... 51 c. Conclusion ...... 52 3. DEHYDRATION OF 1-PHENYLETHANE-1,2-DIOL UNDER MICROWAVE IRRADIATION ...... 53 a. Optimisation of the phenylacetaldehyde yield in water ...... 53 i. Influence of temperature ...... 54 ii. Influence of reaction time ...... 55 iii. Influence of the catalyst nature ...... 56 iv. Conclusion ...... 57 b. Introduction of a co-solvent ...... 58 i. Choice of the co-solvent ...... 58 ii. Influence of the water/co-solvent ratio ...... 61 iii. Variation of the catalyst quantity ...... 63 iv. Variation of the reaction time ...... 64 v. Conclusion ...... 65 c. Recyclability of the aqueous phase ...... 66 d. Application to other alcohols ...... 67 i. 1-phenylethanol and 2-phenylethanol ...... 67 ii. 1-phenylpropan-1-ol ...... 68 iii. Hydrobenzoin ...... 69 e. Formation of phenylacetaldehyde from styrene oxide ...... 71 4. CONCLUSION ...... 73 BIBLIOGRAPHY ...... 76

CHAPTER III ...... 79

DEHYDRATION OF D-XYLOSE IN WATER ...... 79

1. INTRODUCTION ...... 81 a. From Biomass...... 81 i. Structure of lignocellulosic biomass ...... 82 ii. Structural diversity of hemicelluloses ...... 84 b. ... to Furfural ...... 87 i. Properties of furfural ...... 87 ii. Uses and applications of furfural ...... 88 iii. Industrial processes for furfural preparation ...... 90

c. Mechanistic aspects ...... 91 i. Mechanisms of furfural formation from D-xylose ...... 91 ii. Side and loss reactions ...... 94 d. Dehydration of D-xylose to furfural: a brief review of the literature ...... 95 i. Reactions in batch reactor under conventional heating ...... 96 ii. Reactions under microwave irradiation ...... 99 iii. Reactions in continuous flow reactor...... 100 e. Objectives of the Chapter ...... 101 2. DEHYDRATION OF D-XYLOSE UNDER MICROWAVE IRRADIATION WITH HOMOGENEOUS CATALYSIS ... 102 a. Reactions in biphasic medium ...... 102 i. Comparison of aqueous and biphasic media ...... 102 ii. Choice of the catalyst ...... 103 iii. Variation of temperature and reaction time ...... 105 iv. Kinetic study ...... 107 v. Variation of xylose concentration ...... 108 vi. Variation of catalyst quantity coupled with the addition of a salt ...... 109 b. Recyclability of the aqueous phase ...... 111 c. Conclusion ...... 112 3. DEHYDRATION OF D-XYLOSE UNDER MICROWAVE IRRADIATION WITH HETEROGENEOUS CATALYSIS . 114 a. Nafion NR50: properties and applications ...... 114 b. Reactions in biphasic medium ...... 115 i. Preliminary study ...... 115 ii. Comparison of aqueous and biphasic media ...... 116 iii. Variation of Nafion NR50 and salt quantities ...... 117 iv. Variation of xylose concentration ...... 118 v. Influence of temperature and reaction time ...... 119 c. Mechanism involved and comparison with HCl ...... 120 d. Regeneration and analyses of Nafion NR50 pellets ...... 121 e. Conclusion ...... 124 4. APPLICATION TO XYLAN AND HEMICELLULOSE SUGARS UNITS ...... 125 a. Dehydration of xylan into furfural ...... 125 i. By homogeneous catalysis ...... 125 ii. By heterogeneous catalysis ...... 127 b. Dehydration of other sugars composing hemicelluloses ...... 128 i. From L-arabinose to furfural ...... 129 ii. From D-glucose, D-mannose and D-galactose to 5-HMF ...... 130 c. Conclusion ...... 131 5. DEHYDRATION OF D-XYLOSE IN A CONTINUOUS FLOW REACTOR ...... 132 a. Reactor and operating conditions ...... 132 b. Reactions in water ...... 133 i. Influence of temperature and reaction time ...... 134 ii. Influence of the ratio between the inflows...... 135

iii. Influence of xylose concentration ...... 136 c. Conclusion ...... 138 6. CONCLUSIONS ...... 139 BIBLIOGRAPHY ...... 142

GENERAL CONCLUSIONS ...... 147

SCIENTIFIC COMMUNICATIONS ...... 151

RESUME ...... 155

EXPERIMENTAL SECTION ...... 165

1. GENERAL ...... 167 a. Chemical products and solvents ...... 167 b. Chromatography ...... 167 i. TLC ...... 167 ii. Flash-chromatography ...... 167 iii. HPLC ...... 167 c. NMR ...... 169 d. SEM-EDX ...... 169 e. ATR-FTIR ...... 169 2. CHAPTER II – DEHYDRATION OF 1-PHENYLETHANE-1,2-DIOL ...... 170 a. Thermal heating ...... 170 i. Equipment ...... 170 ii. General procedure ...... 170 b. Microwave reactor ...... 171 i. Equipment ...... 171 ii. Dehydration of 1-phenylethane-1,2-diol ...... 172 iii. Applications to other substrates...... 173 c. Identification of reaction products ...... 174 3. CHAPTER III - DEHYDRATION OF D-XYLOSE ...... 177 a. Microwave reactor ...... 177 i. Equipment ...... 177 ii. General procedures for homogeneous catalysis ...... 177 iii. General procedures for heterogeneous catalysis ...... 180 iv. Identification of reaction products ...... 182 b. Continuous flow reactor ...... 182 i. Equipment ...... 182 ii. Control of parameters ...... 184 iii. General procedure ...... 185 iv. Identification of reaction products ...... 185

APPENDICES ...... 187

Abbreviations

A A Frequency factor ATR-FTIR Attenuated Total Reflectance - Fourier Transform Infrared Spectroscopy C CPME Cyclopentyl methyl ether

[C]org/[C]aq Distribution ratio of a compound C D DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO Dimethyl sulfoxide E ε Dielectric constant ε’’ Dielectric loss

Ea Activation energy EDX Energy-Dispersive X-ray Spectroscopy EtOAc Ethyl acetate F FAME Fatty Acids Methyl Esters G GBL Gamma-butyrolactone GVL Gamma-valerolactone H 5-HMF 5-Hydroxymethyl furfural HPLC High Performance Liquid Chromatography K k Kinetic rate constant

Kw Ionic product of water M MAOS Microwave-Assisted Organic Chemistry MEK Methyl ethyl ketone Me-THF 2-Methyltetrahydrofuran MIBK Methyl isobutyl ketone mol% Molar percentage MSA Methanesulfonic acid MTBE Methyl tert-butyl ether MW Microwave

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N n/a Not available NMP N-Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance NOESY Nuclear Overhauser Effect SpectroscopY P P Pressure Pc Critical pressure S SCF Supercritical Fluids

scCO2 Supercritical CO2 scPropane Supercritical propane SCW Supercritical Water SEM Scanning Electron Microscopy T τ Residence time t Reaction time T Temperature tan δ Dissipation factor, or loss tangent Tc Critical temperature THF Tetrahydrofuran TLC Thin Layer Chromatography TOF Turnover frequency TON Turnover number

tR Retention time p-TSA para-Toluenesulfonic acid V VOC Volatile Organic Compound W wt% Weight percentage X X Conversion Y Y Yield

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List of figures

Figure 1: The Twelve Principles of Green Chemistry, from Anastas and Eghbali[3]...... 8 Figure 2: The Atom Economy and the E factor...... 9 Figure 3: Examples of renewable solvents...... 13 Figure 4: Phase diagram of water, from Saka et al.[18] ...... 15

Figure 5: Density, dielectric constant and ion dissociation constant (Kw) of water at 30 MPa as a function of temperature, from Peterson et al.[19] ...... 15 Figure 6: Two main heating mechanisms under microwave irradiation: (a) dipolar rotation; (b) ionic conduction mechanism. From Kappe, Dallinger & Murphree.[43] ...... 21 Figure 7: The temperature profile after 60 seconds by treatment ...... 22 Figure 8: Current pros and cons of microwave-assisted synthesis...... 24 Figure 9: By-products obtained during the dehydration of 1-phenylethane-1,2-diol in water[134,135] ...... 47 Figure 10: Comparison of the two possible structures of the by-product – 1H NMR...... 49 Figure 11: Configuration of the 2,4-diphenylbut-2-enal (3)...... 49 Figure 12: Influence of temperature for a) 8h and b) 16h of reaction...... 51 Figure 13: Influence of diol concentration...... 52 Figure 14: Influence of temperature...... 54 Figure 15: Influence of reaction time...... 55 Figure 16: Schematic process of a biphasic dehydration of 1-phenylethane-1,2-diol...... 58

Figure 17: Recyclability of the aqueous phase with a) FeCl3, b) HCl and c) H2SO4...... 66 Figure 18: Influence of reaction time on the synthesis of phenylacetaldehyde from styrene oxide...... 72 Figure 19: Schematic structure of lignocellulose. The hexagons represent the lignin subunits p-coumaryl alcohol (H), coniferyl alcohol (G) and sinapyl alcohol (S). From F. Streffer.[145] ...... 82 Figure 20: Cellulose structure...... 83 Figure 21: The three building blocks of lignin...... 84 Figure 22: Examples of (a) homoxylans and (b) (arabino)glucuronoxylan...... 85 Figure 23: Primary structure of galactomannan...... 86 Figure 24: Structures of the repeating units of the two main types of xyloglucans...... 86 Figure 25: Example of β-glucan structure with β-1,4 and β-1,3 bonds...... 87 Figure 26: Isomers, tautomers of D-xylose and their distribution in aqueous solution.[160] ...... 91 Figure 27: Comparison between aqueous and biphasic media...... 103 Figure 28: Efficacy of different catalysts on the dehydration of xylose...... 104 Figure 29: Effect of reaction temperature and time on a) xylose conversion and b) furfural yield...... 106 Figure 30: Effect of the initial xylose concentration on xylose conversion and furfural yield...... 109

Figure 31: Effect of the combination FeCl3/NaCl on a) xylose conversion and b) furfural yield...... 110

Figure 32: Reusability of the aqueous phase containing FeCl3 and NaCl for the xylose dehydration...... 112 Figure 33: Chemical structure of Nafion NR50...... 114 Figure 34: Images of a) a pristine pellet of Nafion NR50, ...... 115 Figure 35: Comparison between aqueous and biphasic media...... 116 Figure 36: Effect of the addition of NaCl on xylose conversion and furfural yield ...... 117 Figure 37: Effect of the initial xylose concentration on xylose conversion and furfural yield...... 118 Figure 38: Effect of reaction time on furfural yield for different temperatures...... 119 Figure 39: SEM images of Nafion NR50 (a) before reaction; (b) after a reaction without salt; ...... 122 Figure 40: Study of the recyclability of the Nafion NR50 pellets after regeneration steps in HCl...... 123 Figure 41: Xylose and furfural yield from xylan in function of ...... 126 Figure 42: Xylose and furfural yield from xylan as a function of temperature for t=60 min...... 128 Figure 43: Comparison of L-arabinose and D-xylose dehydration to furfural...... 129 Figure 44: Conversion of D-glucose, D-galactose and D-mannose to 5-HMF...... 131 Figure 45: Scheme of the reactor system, adapted from Tolonen et al.[210] ...... 132 Figure 46: Equation for calculating the residence time τ (s) of the reactions...... 133 Figure 47: Effect of reaction temperature and residence time on ...... 134 Figure 48: Scheme of the reactor body...... 135 Figure 49: Influence of the ratio φ “xylose solution flow”/ “heating water flow” on furfural yield...... 136 Figure 50: Influence of initial xylose concentration on a) xylose conversion and b) furfural yield...... 137 Figure 51: Calibration curve of phenylacetaldehyde, HPLC...... 168 Figure 52: Autoclave Parr used for the experiments...... 170 Figure 53: Microwave apparatus...... 171 Figure 54: Example of power, temperature and pressure profiles during a reaction...... 171 Figure 55: a) Schematic and b) picture of the reactor system...... 183

Figure 56: Enthalpy calculation for the determination of the temperature of the heating water TH...... 184

Figure 57: Enthalpy calculation for the determination of quenching water flow ṁQ...... 184 Figure 58: Equation for calculating the residence time τ (s) of the reactions...... 185

List of tables

Table 1: Overall ranking of solvents, adapted from Prat et al.[10]...... 11 Table 2: Dissipation factors (tan δ) of different solvents (2.45 GHz, 20°C)...... 21 Table 3: Examples of the effect of metal sulphates on the dehydration of biomass-derived polyols...... 28 Table 4: Physical properties of phenylacetaldehyde...... 45 Table 5: Effect of the salts on the dehydration of 1-phenylethane-1,2-diol under hydrothermal conditions. From Avola et al.[54] ...... 47 Table 6: Influence of the catalyst nature...... 56 Table 7: Choice of the co-solvent...... 59 Table 8: Physical properties of CPME. Data from Watanabe et al.[139] ...... 61 Table 9: Influence of the ratio water/co-solvent...... 62 Table 10: Variation of the catalyst quantity...... 63 Table 11: Variation of reaction time...... 64 Table 12: Values of TON and TOF for the three optimized catalysts...... 65 Table 13: Dehydration of 1-phenylethanol...... 67 Table 14: Dehydration of 2-phenylethanol...... 68 Table 15: Dehydration of 1-phenylpropan-1-ol...... 69 Table 16: Dehydration and pinacol rearrangement of hydrobenzoin...... 70 Table 17: Synthesis of phenylacetaldehyde from styrene oxide...... 71 Table 18: Cellulose, hemicelluloses and lignin content of selected biomass (wt%)...... 82 Table 19: Structure and physical properties of furfural...... 87 Table 20: Examples of furfural production processes...... 90 Table 21: Examples of studies on the dehydration of xylose using mineral and organic acids...... 96 Table 22: Examples of studies on the dehydration of xylose and hemicelluloses using metal chlorides...... 97 Table 23: Examples of studies on the dehydration of xylose and xylan with heterogeneous catalysts...... 98 Table 24: Dehydration of xylose, xylan and biomass under microwave irradiation...... 99 Table 25: Dehydration of xylose and xylan in continuous flow...... 100 -1 Table 26: Kinetic rate constants ki (min ) at each experimental temperature...... 108 -1 -1 Table 27: Frequency factors (Ai, min ), activation energies (Eai, kJ.mol ) and correlation factors R²...... 108 Table 28: ATR-FTIR absorption peaks of pristine and post-reaction Nafion NR50...... 123

List of schemes

Scheme 1: Dehydration of sorbitol to isosorbide in solvent-free conditions.[6] ...... 10 [13] Scheme 2: Formation of tetrahydrofuran, THF, from 1,4-butanediol in scCO2...... 12 Scheme 3: Dehydration of glycerol to acrolein with the addition of sulphuric acid.[63,64] ...... 26 [85] Scheme 4: Formation of 5-HMF from fructose in presence of AlCl3 under microwave irradiation...... 29 Scheme 5: Dehydration of cyclohexanol to cyclohexene in presence of carbon dioxide.[88] ...... 30 Scheme 6: Formation of methyl ethyl ketone from 2,3-butanediol with modified H-ZMS-5 zeolites.[94] ...... 31 Scheme 7: Formation of furfural from D-xylose with an ion-exchange resin, Amberlyst 70.[106] ...... 33 Scheme 8: Retrosynthetic scheme of phenylacetaldehyde...... 46 Scheme 9: Dehydration of 1-phenylethane-1,2-diol to phenylacetaldehyde...... 48 Scheme 10: Aldol condensation from phenylacetaldehyde...... 48

Scheme 11: Proposed action of AlCl3 in the dehydration of 1-phenylethane-1,2-diol...... 54 Scheme 12: Formation of styrene from 1-phenylethanol and 2-phenylethanol...... 67 Scheme 13: Formation of 1-phenylpropene from 1-phenylpropan-1-ol...... 69 Scheme 14: Dehydration and pinacol rearrangement of hydrobenzoin...... 70 Scheme 15: Formation of phenylacetaldehyde from styrene oxide...... 71 Scheme 16: Formation of furfural from hemicelluloses...... 88 Scheme 17: Examples of chemicals derived from furfural. Adapted from Hoydonckx et al.[150] ...... 89 Scheme 18: Xylose dehydration mechanism via enolisation, proposed by Marcotullio et al.[70] ...... 92 Scheme 19: Xylose dehydration mechanism involving both cyclic and acyclic pathways, ...... 93 Scheme 20: Mechanism of xylose dehydration into furfural proposed by Nimlos et al.[164] ...... 94 Scheme 21: Examples of side reactions occurring during the formation of furfural.[93,171] ...... 95 Scheme 22: Simplified reaction mechanism of furfural formation...... 107 Scheme 23: Cation exchange on the sulfonic acid groups of Nafion NR50...... 121 Scheme 24: Dehydration of xylan to furfural via xylose...... 125 Scheme 25: Dehydration of L-arabinose to furfural...... 129 Scheme 26: Formation of 5-HMF by the dehydration of D-glucose, D-galactose and D-mannose...... 130

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General introduction

For several years, environmental issues are in the centre of political, economic and industrial concerns. At the beginning of the 1990s, the first initiative of research to green chemistry was launched by the U.S. Environmental Protection Agency. Their objective was to set a framework for the prevention of the pollution linked to chemical industries. A few years later, the concept of Green Chemistry was developed by the American chemists Anastas and Warner. Green Chemistry was defined as the ―design of chemical products and processes to reduce or eliminate the use and generation of hazardous substances‖. In 1998, they introduced the Twelve Principles of Green Chemistry as a guiding framework for chemists. These principles contributed to the development and the popularisation of the concept of Green Chemistry:

1) Prevention. 2) Atom Economy. 3) Less Hazardous Chemical Synthesis. 4) Designing Safer Chemicals. 5) Safer Solvents and Auxiliaries. 6) Design for Energy Efficiency. 7) Use of Renewable Feedstocks. 8) Reduce Derivatives. 9) Catalysis. 10) Design for Degradation. 11) Real-Time Analysis for Pollution Prevention. 12) Inherently Safer Chemicals for Accident Prevention

Currently, one of the main challenges of the chemical industry is to synthesise molecules with high added value thanks to processes respecting the principles of Green Chemistry. The aim of this PhD work is to optimise green dehydration methods to form two target molecules: phenylacetaldehyde and furfural. Several keys issues were identified in order to design processes greener than the current ones. Experiments will be performed in water and when co-solvents will be necessary, green or eco-friendly solvents will be chosen. An activation method alternative to thermal heating, microwave irradiation, will be applied. A continuous flow reactor was also identified as an interesting alternative. When possible, reactions will be carried out without a catalyst, but, when needed, efficient, selective and reusable catalysts will be chosen.

General introduction

In the first Chapter, the context of the thesis will be described by developing the concept of Green Chemistry and the tools associated. A review of the literature on the dehydration of polyhydroxylated compounds in water will be discussed.

In Chapter II, the dehydration of 1-phenylethane-1,2-diol to form phenylacetaldehyde will be studied. After a brief introduction, thermal heating and microwave irradiation will be compared. Then, a procedure will be optimised under microwave irradiation by varying the nature of the catalyst, temperature, reaction time and initial reactant concentration. This optimised method will later be applied to other alcohols with similar structures.

Chapter III will focus on the dehydration of the biosourced D-xylose to produce furfural. First, an introduction to the reaction will be provided. A description of the lignocellulosic biomass structure and of the uses and applications of furfural will be given. The mechanistic aspects of the dehydration of xylose to furfural will be discussed. A brief state of the art of the reaction will be presented. Secondly, the optimisation of two methods with either homogeneous or heterogeneous catalysts under microwave irradiation will be discussed. The influence of reaction time, temperature and proportion of catalyst will be studied. Then, these two methods will be applied to xylan, a homopolymer of D-xylose, and to other sugar units. Finally, the formation of furfural from D-xylose will be studied in a flash continuous flow reactor, without any catalyst.

In the last part, after the concluding remarks, the experimental procedures will be described, as well as the compounds formed.

CHAPTER I

Context and literature review

Chapter I: Context and literature review

1. Green Chemistry: definition and tools

Green Chemistry is a concept which was introduced in the 1990s with the objective of helping chemists to improve the environmental performance and safety of their chemical processes. In the first part, the principles of sustainable and green chemistry will be developed. Alternative solvents represent one of the main entries in the green chemistry toolkit and are the subject of an enormous research effort. A description of these green solvents, and especially sub- and supercritical water, will be given in the second part. Finally, new activation techniques or the applications of established techniques in new ways represent important tools in the green chemistry toolkit. Then, the basic ideas of alternative activation methods such as sonochemistry or mechanochemistry will be described in the last part. More details will be given on microwave chemistry.

a. Green Chemistry: Origin and Twelve Principles

Green Chemistry is defined as the ―design of chemical products and processes to reduce or eliminate the use and generation of hazardous substances‖. This definition and the concept of Green Chemistry were first formulated at the beginning of the 1990s nearly 30 years ago.[1] In this definition, the concept of ―design‖ is the most important aspect of Green Chemistry. It induces novelty, planning and systematic conception. To help the chemists to achieve their goal of sustainability, Paul Anastas and John Warner introduced, in 1998, the Twelve Principles of Green Chemistry (Figure 1). They are a guiding framework for the design of new chemical products and processes, applying to all aspects of the process life-cycle from the raw materials used, to the efficiency and safety of the transformation, the toxicity and biodegradability of products and reagents used. Later, Poliakoff and co-workers proposed a mnemonic acronym, PRODUCTIVELY, which captures the spirit of the Twelve Principles of Green Chemistry in a single slide.[2]

Chapter I: Context and literature review

1) Prevention. It is better to prevent waste than to treat or clean up waste after it is formed. 2) Atom Economy. Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. 3) Less Hazardous Chemical Synthesis. Whenever practicable, synthetic methodologies should be designed to use and generate substances that pose little or no toxicity to human health and the environment. 4) Designing Safer Chemicals. Chemical products should be designed to preserve efficacy of the function while reducing toxicity. 5) Safer Solvents and Auxiliaries. The use of auxiliary substances (e.g. solvents, separation agents, etc) should be made unnecessary whenever possible and, when used, innocuous. 6) Design for Energy Efficiency. Energy requirements of chemical processes should be recognized for their environmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure. 7) Use of Renewable Feedstocks. A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable. 8) Reduce Derivatives. Unnecessary derivatization (use of blocking groups, protection/deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste. 9) Catalysis. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. 10) Design for Degradation. Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment. 11) Real-Time Analysis for Pollution Prevention. Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances. 12) Inherently Safer Chemicals for Accident Prevention. Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions, and fires.

Figure 1: The Twelve Principles of Green Chemistry, from Anastas and Eghbali[3].

Chapter I: Context and literature review

Over the years, several tools were introduced to help chemists measure the environmental impact of their chemical processes. The Atom Economy (AE) or Atom Efficiency concept, proposed by Trost in 1990, is one of the useful tools available for designing reactions with minimum waste.[4] It refers to the concept of maximizing the use of raw materials so that the final product contains the maximum number of atoms from the reactants. The ideal reaction would incorporate all of the atoms of the reactants. To sum up, the AE of a reaction is defined as the ratio of the molecular weight of the desired product over the sum of the molecular weights of all reactants used in the process (Figure 2). The Atom Economy (AE):

The E factor:

Figure 2: The Atom Economy and the E factor.

The concept of atom economy has been expanded usefully by Sheldon in 1992 by the introduction of the term ―E factor‖, or Environmental Impact Factor.[5] This metric can be defined as the actual amount of waste produced in the process (defined as everything but the desired product) (Figure 2). It takes the chemical yield into account and includes reagents, solvents losses, and all process aids. This concept is particularly useful for assessing the environmental impact of manufacturing processes.

Nowadays, despite the vast amount of research into the subject, it seems difficult to design a process respecting all the Twelve Principles. Therefore, the idea is to try to respect as many as we can. In this PhD work, we focused on six Principles: Atom Economy, Less Hazardous Chemical Synthesis, Safer Solvents and Auxiliaries, Use of Renewable Feedstocks, Reduce Derivatives and Catalysis. For instance, our experiments were performed with green solvents, in particular water. They were carried out under microwave irradiation, an activation method alternative to conventional heating. Efficient and reusable catalysts were preferred. In addition, in Chapter III, the sugar D- xylose, derived from biomass, was the raw material of the reactions.

Chapter I: Context and literature review

b. Water as a green solvent

i. General points on green solvents

Solvents are probably the most active area of Green Chemistry research. They represent an important challenge for Green Chemistry because they often account for the vast majority of mass wasted in synthesis and processes. Moreover, many conventional solvents are toxic, flammable and/or corrosive. Their volatility and solubility have contributed to air, water and land pollution, have increased the risk of workers’ exposure, and have led to serious accidents. Recovery and reuse, when possible, is often associated with energy-intensive processes like distillation. Thus, the ideal situation would be to not use any solvent. Efforts have been made to develop solvent-less conditions thanks, particularly, to the large amount of research done on heterogeneous catalysts. As a good example, the ion-exchange resin Amberlyst 35 proved to be efficient for the dehydration of sorbitol to isosorbide in a solvent-free system under microwave heating with a yield up to 70% (Scheme 1).[6]

Scheme 1: Dehydration of sorbitol to isosorbide in solvent-free conditions.[6]

However, in industrial processes, solvents are almost unavoidable. Homogeneous liquid phases are obtained thanks to their ability to dissolve solids and their influence on the solution viscosity. Furthermore, solvents facilitate mass and heat transfer and they have a crucial role in separation and purification steps. Thus, chemists needed to develop more sustainable alternatives than the conventional organic solvents. Two main routes towards green solvents have been developed: i) the substitution of hazardous solvents with ―eco-friendly‖ ones that show better EHS (Environmental, Health and Safety) properties, and ii) the substitution of petro-chemically derived solvents with ―bio- solvents‖ from renewable resources. The first strategy is based both on the use of safe and innocuous organic solvents, like acetone or alcohols, and on new generation solvents, such as ionic liquids and supercritical fluids. The second strategy relies on solvents produced from biomass such as ethanol by fermentation or glycerol derivatives obtained from triglycerides.

Chapter I: Context and literature review

Firstly, in order to substitute problematic solvents with ―eco-friendly‖ ones, several medicinal companies elaborated solvent selection guides in which the solvents are classified according to their compliance to the different safety principles: - workers’ safety (carcinogenicity, mutagenicity, skin and respiration absorption/sensitisation, toxicity, etc.) - process safety (flammability, explosiveness, peroxide formation, volatile organic compound – VOC – formation, etc.) - environmental safety (eco-toxicity, persistence, water contamination, ozone depletion potential, etc.). We can cite for instance the guides of Pfizer in 2008[7], GSK in 2011[8] and Sanofi in 2014.[9] From a survey of these different selection guides, an overall ranking of solvents was reported (Table 1).[10] Nevertheless, it has to be kept in mind that the criteria used corresponded to the needs and constraints of the pharmaceutical industry and may not fit with the criteria of other fields (academic or other type of industry).

Water, Ethanol, Isopropyl alcohol, n-Butanol, Ethyl acetate, Recommended Isopropyl acetate, n-Butyl acetate, Anisole, Sulfolane.

Methanol, tert-Butyl alcohol, Benzyl alcohol, Ethylene glycol, Recommended or problematic? Acetone, MEK, MIBK, Cyclohexanone, Methyl acetate, Acetic acid, Diethyl ether.

Me-THF, Heptanes, Methyl-cyclohexane, Toluene, Xylenes, Problematic Chlorobenzene, Acetonitrile, DMPU, DMSO.

Problematic or hazardous? MTBE, THF, Cyclohexane, DCM, Formic acid, Pyridine.

Diisopropyl ether, 1,4-Dioxane, Dimethoxyethane, Pentane, Hazardous Hexane, DMF, DMA, NMP, Methoxy-ethanol, Triethylamine.

Diethyl ether, Benzene, Chloroform, CCl4, Dichloroethane, Highly Hazardous Nitromethane.

Table 1: Overall ranking of solvents, adapted from Prat et al.[10].

Among them, we can focus on water which is probably the greenest alternative chemists have, beyond using solvent-free systems. It is the most abundant molecule on the planet and is referred to as a benign ―universal solvent‖. Indeed, water is a highly polar, cheap and safe solvent which does not induce any hazards, neither for humans nor for the environment. It is non-flammable and non-explosive. Therefore, water can be a

Chapter I: Context and literature review useful solvent for large scale process chemistry. The properties of water have even led to improved reaction rates and selectivity thanks to the hydrophobic effect, and to an easier separation since a lot of organic compounds did not dissolve in water. The main drawbacks of water as solvent are the risk of water contamination that can be energy- intensive to clean, the risk of deactivation of some catalysts or reagents and the low solubilisation of organic compounds that can limit the reactions. Surfactants[11], cage molecules such as cyclodextrin[12], or the use of sub- and supercritical conditions can be solutions for this last issue.

Other alternatives have been developed in order to replace traditional organic solvents. For example, the supercritical fluids (SCF) have been extensively studied in the past decades. Substances enter the supercritical phase above their critical pressures (Pc) and temperatures (Tc). Common SCF are generated from carbon dioxide, water, methane, methanol, ethanol or acetone. Carbon dioxide (scCO2) is one of the most widely used SCF thank to its readily accessible critical point: 304K (31°C) and 72.8 bar. It is a versatile solvent, safe and easy to handle. Supercritical fluids properties can be tuned by a simple change in temperature and pressure, and SCF have the advantage of having simplified experimental procedures: simply degassing the system allows the complete removal of the solvent. For example, Poliakoff and co-workers reported the formation of cyclic and acyclic ethers, acetals, and ketals by dehydration of alcohols using solid catalysts (Deloxan ASP and Amberlyst 15) in supercritical fluids (scCO2 and scPropane) as shown in Scheme 2.[13]

[13] Scheme 2: Formation of tetrahydrofuran, THF, from 1,4-butanediol in scCO2.

Another example of green solvents would be ionic liquids, pioneered in the last few decades by Seddon.[14] As their name highlights, ionic liquids, or sometimes called room temperature ionic liquids, are liquid salts at room temperature. They have no (or exceedingly low) vapour pressure, so volatile organic reaction products can be separated easily by distillation or under vacuum. They are thermally stable and can be used over a wide temperature range compared with conventional solvents, even if some recent studies have shown that they cannot be considered as non-flammable.[15] Their properties can be readily adjusted by varying the anion and cation. We can report, for example, the

Chapter I: Context and literature review work of Zhang et al. who worked on the dehydration of xylose to furfural in 1-butyl-3-

[16] methylimidazolium chloride with AlCl3. The best yield reached was 85%. However, ionic liquids have some drawbacks. Their synthesis from substances, that can be toxic

- - and hazardous, and the presence of perfluorinated counter-anions (PF6 and BF4 ), which can be released, raise the question of the greenness of these solvents. Besides, the reaction products often need to be extracted from the ionic liquid phase using standard organic solvents.

Secondly, the strategy was to develop new solvents derived from renewable resources to replace the conventional solvents derived from petroleum. The biomass feedstocks include waste materials, forest products, energy crops (starch crops, sugar crops, grasses, vegetable oils) and aquatic biomass. The variety of feedstocks can also be divided into three groups according to their chemical composition: cellulosic biomass, starch- and sugar-derived biomass and triglyceride-based biomass.[17] For instance, glycerol, which is a by-product of biodiesel production, is non-toxic and has promising physical and chemical properties as an alternative solvent (Figure 3). It has a very high boiling point and negligible vapour pressure and can dissolve many organic and inorganic compounds. It is poorly miscible with water, some ethers and hydrocarbons. Therefore, in addition to distilling products from this solvent, simple extractions with solvents such as ether and ethyl acetate are also possible.

Figure 3: Examples of renewable solvents.

2-Methyltetrahydrofuran (MeTHF) is also a promising renewable solvent obtained through a two-step hydrogenation of furfural, produced from lignocellulosic biomass (Figure 3). MeTHF has properties similar to conventional THF, which is used in many organometallic reactions, and can easily substitute it. Besides, contrary to THF, MeTHF has the advantage of being immiscible with water, and so provides clean organic–water phase separations. In addition to these two examples, many other renewable solvents have already proven their capacity to substitute hazardous ones: for instance, glycerol derivatives

Chapter I: Context and literature review

(esters, carbonates, acetals and ketals), gamma-butyrolactone (GBL), gamma- valerolactone (GVL), fatty acid methyl esters (FAME) or terpene derivatives. However, even if solvents obtained from renewable sources are technically green in terms of life-cycle analysis, the majority of them belongs to the group of VOCs and could be associated with atmospheric pollution and flammability.

In brief, even though the last couple of decades have seen a large development of these systems (SCF, ionic liquids, renewable solvents, etc) as clean alternatives for synthesis and catalysis, it also became increasingly clear that no single system will ever be able to completely replace all conventional solvents as a truly environmentally friendly alternative. It means that an ideal and universal ―green‖ solvent for all situations does not exist because there are drawbacks associated with all of these systems, both from the points of view of applicability and sustainability. Thus, for each situation, a balance has to be made between the solvent’s physical properties (boiling point, miscibility, solubility of the target compounds, etc), its green properties (low toxicity, recyclability, etc) and its possible drawbacks.

ii. Sub- and supercritical water

To combine the green properties of water and supercritical fluids, it was decided to perform the dehydration of alcohols in sub- and supercritical water.

Supercritical water (SCW) can be defined as water above its critical point (374°C, 22.1 MPa). For subcritical water, the definition is less strict and can describe several temperature and pressure windows. Other terms referring to subcritical water can be found in the literature, such as hot compressed water, superheated water or high- temperature water. The most practical definition denominates subcritical water as water above its boiling point at ambient pressure (> 100°C and 0.1 MPa) and below its critical point (374°C at 22.1 MPa). The different phases of water are represented in Figure 4.

Chapter I: Context and literature review

Figure 4: Phase diagram of water, from Saka et al.[18]

The chemistry in water differs significantly according to the temperature regions. Besides the sole ―temperature effect,‖ the major changes in physical and chemical properties of water decisively influence its properties as a solvent. Figure 5 illustrates the range of property variations that occur when the temperature increases from 0 to 500°C at 30 MPa.

Figure 5: Density, dielectric constant and ion dissociation constant (Kw) of water at 30 MPa as a function of temperature, from Peterson et al.[19]

Chapter I: Context and literature review

At temperatures below 300°C, water is fairly incompressible, which means that pressure has little effect on its physical properties, as long as it is sufficient to maintain water in its liquid state. In the region near the critical point, water is highly compressible. For example, the density decreases by nearly two orders of magnitude from liquid-like (about 800 kg.m-3) to dense gas-like value (about 150 kg.m-3) as the temperature increases from 300 to 450°C. These changes in density correlate with other macroscopic properties that reflect changes at the molecular level (solvation power, degree of hydrogen bonding, polarity, dielectric strength, molecular diffusivity and viscosity).[19]

With increasing temperature, the ion product of water (Kw) increases by three

-14 2 -2 -11 2 -2 orders of magnitude from Kw = 10 mol L at 25°C to Kw ≈ 10 mol L at 300°C, thus providing a source of hydronium and hydroxide ions. This means that water becomes both a stronger acid and a stronger base as the temperature increases to the subcritical water range. Thus, reactions typically promoted by either acid or base can be performed in high-temperature water without the addition of any catalyst. Above 300°C, Kw decreases again. Close to the supercritical point, the decrease is very sharp and leads to values below 10-20 mol2L-2 at 380°C. From this data, it can be clearly deduced that in subcritical water, ionic reactions will be enhanced while supercritical water will promote radical reactions. In addition, while chemical reactions in supercritical water have mainly been applied to break up bonds, the milder temperature region of subcritical water allows bond formation, i.e., synthesis of organic compounds.[20]

The dielectic constant of water ε is also largely influenced by the variation of temperature and pressure. It decreases from ε=80 at standard conditions of temperature and pressure to ε=31 at 225°C, P=100 bars, and finally to ε=6 at the critical point. Thus, water transforms from a polar, highly hydrogen-bonded solvent to behave more typically as a non-polar solvent like hexane. Consequently, with increasing temperature, the solubility of ionic molecules like organic salts strongly decreases, whereas the solubility of hydrophobic molecules increases.[21]

Recently, sub- and supercritical water have been applied intensively in different fields such as material synthesis[22], waste destruction[23], plastic recycling[24], and biomass processing[25,26]. Subcritical and supercritical water are suitable solvents for many chemical reactions such as alkylation reactions, condensations, oxidation or deprotection reactions.[21,27] Dehydration of alcohols can be performed in sub- and

Chapter I: Context and literature review supercritical water in good yields in pure water[28] or with the additions of catalysts such as metal sulphates.[29] Our team recently worked on the dehydration of glycerol to acrolein and on the synthesis of quinoline in subcritical water under conventional heating and microwave irradiation in batch[30] and in continuous flow.[31]

c. Alternative activation methods

Over the last three decades, significant effort has been put into in the development of environmentally friendly procedures as alternatives to conventional heating. The aim was to reduce energy consumption and chemical waste (due to inefficient chemical reactions or extensive purification). More energy-efficient activation methods such as microwaves, sonochemistry, photochemistry, electrochemistry or mechanochemistry were developed. First, a brief introduction into each of these clean technologies will be presented. As microwave irradiation is the alternative activation method applied during this PhD work, it will be described in more depth in the second paragraph.

i. An overview of the different methods

. Mechanochemistry

According to IUPAC, a mechano-chemical reaction is defined as ―a chemical reaction that is induced by the direct absorption of mechanical energy‖.[32] Nowadays, mechanochemistry refers to several areas of research: mechanical activation of solids, mechanical alloying and reactive milling of solids. During the mechanical grinding of two solids, there are a variety of changes that can take place: - grinding of the particles to a very small size, - increase of the surface area, - formation of defects and dislocations in the crystalline structure, - chemical reactions. The enhanced reactivity of chemicals can be explained by efficient mixing and an important increase of the surface area which induces a better contact between the reactants, but also by other factors such as increased temperature and pressure reached when the solids collide.

Chapter I: Context and literature review

Mechano-chemical methods have the advantage of offering solvent-free (or minimal solvent) routes to industrial materials and are therefore of great interest in designing more sustainable processes. The potential to access materials not available by other methods is also of great interest. In organic chemistry, mechanochemistry finds various applications including C-C bond formation, amine condensation, syntheses of heterocycles and fullerene modifications.[33,34]

. Sonochemistry

Sonochemistry is the application of ultrasound (20 kHz to 500 MHz) to chemical reactions and processes. The activation is induced by cavitation, which involves the creation, growth and collapse of micrometer-sized bubbles that are formed when an acoustic wave propagates through a liquid. Bubbles collapse in succeeding compression cycles (shock waves) and generate the energy for chemical and mechanical effects. Cavitational collapse also produces intense local heating (2000-5000 K) and high pressures (> 1000 bar). Therefore, sonication of a liquid medium can be thought of as generating high-energy ―hot spots‖ throughout the system. However, it should be noted that, in most cases, enhanced yields and reaction rates are due to the mechanical effects of shock waves (splitting of large molecules into smaller fragments, particle size reduction, surface cleaning and intensive mixing). Chemical effects of ultra-sound will occur only if high-energy species, released after the cavitational collapse, act as reaction intermediates. In these cases, changes in product distribution, switching of reaction mechanisms or changes in region- or diastereoselectivity may occur.[35] Sonochemistry includes different research areas such as material synthesis (preparation of micro- and nano-structured materials for example), environmental protection by degrading chemical and biological pollutants, and chemical synthesis.

. Electrochemistry

Electrochemistry concerns the transfer of charge, by the movement of ions, in liquid, solid or gaseous phases through which electrochemical transformation of species is achieved. Electrochemistry plays an important role in the commercial world and can be used for a wide range of applications: to synthesise chemicals and materials, to extract and produce metals, to generate power, to analyse compounds, etc. Therefore, electrochemistry has an important role to play for the development of greener and more efficient processes thanks to its many advantages. Indeed, electrons

Chapter I: Context and literature review are the cheapest, purest and most versatile redox agents able to perform clean and fast reactions. Thus, stoichiometric and hazardous reagents can be replaced. Water-based processes and products predominate in electrochemistry so organic solvents are avoided. New solvents and reaction media such as solid polymers or supercritical fluids can also be used. Besides, electrochemistry allows mild process conditions and ease of control. Syntheses are clean by direct oxidation or reduction.[36]

. Photochemistry

Photochemistry refers to the chemical effects of light. However, unlike electrochemistry, microwave irradiation or sonochemistry, photochemistry has long not been considered as an alternative technology for chemical synthesis. Its potential was mainly recognized for the clean-up of effluents. Nevertheless, photochemistry has three main advantages within the context of cleaner chemicals manufacturing. The first advantage is a reduced use of reagents. Indeed, photons can be regarded as ideal reagents: they activate reactions without directly generating any by-products as they are non-material and disappear in the process. Light sources can be switched on and off at will so photons do not need any storage and do not suffer degradation as conventional reagents do. The second advantage of photochemistry is the use of lower reaction temperatures. In a photochemical reaction, the activation energy is supplied by the photons directly to the molecules that absorb the light. Thus, photoreactions are often carried out at room temperature. Finally, photochemistry can help to control the selectivity of some types of reactions such as 2π + 2π cycloaddition or reactions involving singlet oxygen. However, nowadays, the exploitation of photochemistry in cleaner chemical manufacturing is limited by several problems: the need for a specialised processing plant, the problem of window fouling (deposition of by-product coatings on the lamp enclosures) that reduces the efficiency of the process or the high cost of protons linked to the lamp efficiency.[37]

ii. Microwave chemistry

The use of microwave heating in chemical applications emerged originally in 1986 with the work of the groups of Gedye and Giguere.[38,39] They both observed significant reaction rate enhancement using microwave irradiation. At that time, their equipment

Chapter I: Context and literature review was composed of domestic ovens and rudimentary reaction vessels. Over the years, technology evolved and research-grade instrumentation was introduced, improving the reproducibility of experiments and limiting the risk of fire and explosion. Then, since the late 1990s, the number of publications related to microwave-assisted organic synthesis (MAOS) increased dramatically (up to ≈ 5000). Microwave chemistry can be applied to a wide range of chemical reactions such as heterocyclic synthesis, transition-metal- catalysed reactions, N-acylations or esterifications.[40,41] In addition to organic synthesis, this technology penetrated also other fields such as polymer synthesis, material sciences, nanotechnology and biochemical processes.

. Principle

Microwave irradiation is an electromagnetic radiation in the frequency range of 30 GHz to 300 MHz, which corresponds to wavelengths of 1 cm to 1 m. A large fraction of the microwave spectrum is reserved for applications in telecommunication and radar technology. For microwave chemistry, the frequency of 2.45 GHz (corresponding to a wavelength of 12.2 cm) is used almost exclusively. Microwave chemistry relies on the ability of the reaction mixture to efficiently absorb microwave energy, by dielectric loss, and to convert it into heat. Briefly, the heating mechanism involves two main processes: dipole rotation and ionic conduction. Dipole rotation refers to the alignment of molecules that have permanent or induced dipoles with the electric field. At 2.45 GHz, the electric field oscillates 4.9 x 109 times per second. The oscillation of the molecules generates heat. The second main dissipation mechanism, ionic conduction, is the migration of dissolved ions with the oscillating electric field. Heat generation is due to frictional losses that depend on the size, charge and conductivity of the ions as well as on their interactions with the solvent. The two heating mechanisms are represented in Figure 6.[42]

Two parameters define the dielectric properties of a substance: (i) the dielectric constant (ε), describing the ability of molecules to be polarized by the electric field, and (ii) the dielectric loss (ε’’), indicating the efficiency with which electromagnetic radiation is converted into heat. The ratio of these two parameters defines the dielectric loss tangent, or dissipation factor, tan δ = ε’’/ε. This loss factor provides a measure of the ability of a material to convert electromagnetic energy into heat at a given frequency and temperature. A reaction medium with a high tan δ is required for a good absorption and, consequently, an efficient heating.

Chapter I: Context and literature review

Figure 6: Two main heating mechanisms under microwave irradiation: (a) dipolar rotation; (b) ionic conduction mechanism. From Kappe, Dallinger & Murphree.[43]

In general, solvents used for microwave synthesis can be classified as high (tan δ > 0.5), medium (0.1 < tan δ < 0.5) and low (tan δ < 0.1) microwave absorbing. Generally, solvents with high dielectric constants, such as water, ethanol or acetonitrile, tend to heat readily under microwave irradiation. Less polar substances, like aromatic and aliphatic hydrocarbons, or compounds with no permanent dipole moment (e.g. carbon dioxide, dioxan, or carbon tetrachloride) are poorly absorbing and are considered as ―microwave transparent‖. Table 2 shows the classification of common organic solvents according to their dissipation factor.[40]

Solvent tan δ Solvent tan δ

Ethylene glycol 1.350 Water 0.123 Ethanol 0.941 Chloroform 0.091 DMSO 0.825 Acetonitrile 0.062 Isopropanol 0.800 Acetone 0.054 Methanol 0.659 Tetrahydrofuran 0.047 Acetic acid 0.174 Dichloromethane 0.042 DMF 0.161 Toluene 0.040 1,2-Dichloroethane 0.127 Hexane 0.020

Table 2: Dissipation factors (tan δ) of different solvents (2.45 GHz, 20°C). Data from Dallinger & Kappe.[40]

Chapter I: Context and literature review

. Advantages/Drawbacks

Traditionally in organic synthesis, elevated temperatures are reached by using an external heat source such as an oil bath or a sand bath. Heat is transferred to the reaction medium by conduction and convection. This is a comparatively slow and inefficient method for transferring energy since it depends on the thermal conductivity of the materials used and wall effects can be observed (temperature of the reaction vessel higher than in the reaction medium). In contrast, microwave irradiation raises the temperature in the whole reaction volume simultaneously (core volumetric heating) by direct coupling of microwave energy with the molecules (solvents, reagents, catalysts) present in the reaction medium. As presented in Figure 7, an inverted temperature gradient can be observed by comparison with conventional heating. The very efficient internal heating transfer results in minimized wall effects which may lead to diminished catalyst deactivation for example.[40]

Figure 7: The temperature profile after 60 seconds by treatment in an oil bath (left) compared to microwave irradiation (right). From J. Schanche.[44] Temperature scale is in Kelvin. „0‟ on the vertical scale indicates the position of the meniscus.

As seen before, the question of solvent is an important topic in green chemistry. Solvent-free conditions can be employed while applying microwave irradiation. Reactions with neat reactants, using solid supports (e.g. silica, montmorillonite K10, zeolites) or phase-transfer catalysis can be performed using microwave heating. There are many benefits: avoidance of large volumes of solvent, simplified work-up, reduction

Chapter I: Context and literature review of the risks of over-pressure and explosion, recyclability of solid supports (when used). Besides, when solvents are unavoidable, it is possible to find green alternatives to hazardous solvents. Indeed, as seen in Table 2, while not all high-absorbing solvents may be classified as ―green‖, there are many desirable solvents that are excellent microwave- absorbing solvents.

The reaction rate of microwave-assisted organic reactions is 10- to 1000-fold faster than conventional synthesis. Besides, rapid heating to the target temperature inhibits the formation of by-products, leading to greater purity and to yield increase. From a green perspective, the remarkable improvement in conversion, yield and purity when using microwave heating is another great advantage. Indeed, these improvements induce less purification steps (less solvent/silica gel waste), and a smaller amount of reaction by-products that need to be disposed of.[45]

To summarise, microwave heating can provide the following advantages in comparison to conventional heating for chemical synthesis (Figure 8): (i) high heating rates, thus increased reaction rates; (ii) selective heating, if the reaction mixture contains compounds with different microwave absorbing properties; (iii) higher yields; (iv) better selectivity due to reduced side reactions; (v) improved reproducibility; (vi) no direct contact between the heating source and the chemicals; (vii) excellent control of the reaction parameters; and (viii) automation and high throughput synthesis. However, in addition to these advantages, microwave chemistry also has some significant limitations (Figure 8). One of the major drawbacks is the high costs for microwave reactors, which can easily be in the range of several thousands of Euros. The short penetration depth of microwave irradiation into the liquid medium limits the size of the reactors, which is a serious problem for scale-up. Finally, it is difficult to monitor reactions in situ.[46]

To overcome this scalability issue, the development of new reactors has been a challenge for engineers in the past few years. The main problem was how to design large- scale reactors such that the efficient and uniform application of dielectric heating can be achieved in a way similar to laboratory-scale reactors. Recently, flow reactors had attracted attention as a solution to these issues. This technology involves pumping a reaction mixture into a reactor where it undergoes microwave irradiation for a set time, and is subsequently pumped through a heat exchanger and into a receiving vessel.

Chapter I: Context and literature review

High heating rates

Short reaction times Expensive setup Selective heating

Improved reproducibility Microwave-Assisted Limited ‒ scale up + Organic Synthesis Contactless heating

Excellent control of Difficult in situ High yields with less reaction parameters monitoring side products

Automation and high throughput synthesis

Figure 8: Current pros and cons of microwave-assisted synthesis.

. Microwave Chemistry in Water

At 20°C, water can be considered only as a medium microwave absorbing solvent with a dissipation factor tan δ of 0.123 (Table 2). However, like many organic solvents, the tan δ of water is strongly influenced by temperature. As we saw before, the dielectric constant ε decreases drastically with temperature, from ε=80 at standard conditions of temperature and pressure to ε=31 at 225°C, P=100 bar, and finally to ε=6 at the critical point. Thus, the dielectric loss ε’’ and the loss tangent tan δ are also reduced. Consequently, water can be heated rather effectively by microwave irradiation from room temperature to 100°C, but it is difficult to superheat water in sealed vessels from 100 to 200°C and very difficult to reach 300°C by microwave heating. In fact, supercritical water can be considered as transparent to microwave radiation. Nevertheless, it should be noted that the dissipation factor of water can be significantly increased by the addition of small amounts of organic salts. Indeed, the introduction of ions in the solution leads to a marked increase in dielectric heating rates thanks to the ionic conduction mechanism. Besides, in most cases, the chemicals (substrates, reagents or catalysts) dissolved in the aqueous reaction mixture are strongly polar and therefore microwave absorbing, allowing a sufficient heating of the reaction mixture.[40]

Chapter I: Context and literature review

2. Dehydration of polyhydroxylated compounds in water

The dehydration of polyhydroxylated compounds can be performed in many different reaction media. Some studies reported the dehydration of polyols in gas phase without the addition of solvents.[47,48] This reaction can also be performed in organic solvents (classic or green)[49,50] or in alternative solvents such as ionic liquids[51,52] or supercritical fluids[13,53]. As we chose to perform our reactions in water, only the examples of dehydration in water will be reported in this chapter.

a. Without a catalyst

To start, we will focus on the reactions performed without any catalyst. It can be noticed that reactions are dependent on the temperature region used and so, on the water properties. For example, Avola et al. performed the dehydration of several activated alcohols at 180°C under pressure. As expected in the subcritical region, the researchers did not observe any radical reaction, such as oxidation, and all compounds underwent dehydration in moderate to high yields. The high concentration of H+ ions, due to the increase of the self-dissociation constant of water, promotes dehydration but also further transformations such as pinacol rearrangement and aldolic condensation.[54] Qadariyah et al. also observed a difference in the type of products formed during the dehydration of glycerol according to the temperature. Between 200 and 300°C, ionic reactions are favoured: acrolein and acetaldehyde are the main products, with, nevertheless, limited yields. At 400°C, in the supercritical region, the radical formation of allyl alcohol is promoted and reached 96%.[55] Dehydration of sugars can also be performed without the addition of any catalyst. From fructose and glucose, moderate temperatures (220°C) allow the formation of the target molecule, 5-hydroxymethylfurfural (5-HMF), with acceptable yields of 47% and 30% respectively, for a quantitative conversion.[56] The application of higher temperatures (350-400°C) to glucose produces 5-HMF in a limited yield (8%) while secondary and degradation products are mainly obtained.[57] The same observations can be made for the dehydration of xylose. Reactions performed in the subcritical region leads to the formation of furfural with moderate yields (50% at 220°C after 50 min in a batch reactor or after 30 min under microwave irradiation)[58,59] whereas reactions observed close to the critical point and in the supercritical region mainly formed retro-

Chapter I: Context and literature review aldol compounds, such as glyceraldehyde and glycoaldehyde due to the degradation of furfural or xylose.[60,61]

Thus, according to these studies, subcritical water seemed to be a suitable solvent for the dehydration of polyhydroxylated compounds. Supercritical water seemed to lead more to secondary products and to favour degradation.

b. Homogeneous catalysis

Secondly, we will focus on dehydration performed with homogeneous catalysis.

Classically, researchers used mineral acids such as H2SO4, HCl and H3PO4. However, since these acids are very corrosive, alternatives were investigated with the use of organic acids, soluble metal salts (metal sulphates, metal chlorides) or the addition of CO2.

i. Mineral and organic acids

Sulphuric acid gave good results on the dehydration of polyols. For example, 2,3- butanediol was successfully dehydrated in methyl ethyl ketone, MEK, (98% of

[62] conversion, 91% of yield) with the addition of H2SO4. This acid had also a positive effect on the dehydration of glycerol to acrolein. Ramayya et al. and Watanabe et al. both observed a limited yield of acrolein in pure water. The addition of H2SO4 increased conversion and yield. Ramayya et al. obtained 55% of conversion and 47% of yield at 350°C with 1 mol% of acid.[63] Watanabe et al. obtained 94% of conversion and 74% of yield (by-product was acetaldehyde) at 400°C with 10 mol% of acid.[64]

Scheme 3: Dehydration of glycerol to acrolein with the addition of sulphuric acid.[63,64]

Chapter I: Context and literature review

In industrial processes, hexoses and pentoses were mainly dehydrated by sulphuric acid. In addition, many articles reported the use of hydrochloric acid for the dehydration of sugars. Generally, researchers observed limited conversion and yield when using pure water and concluded that an acidic medium was necessary to perform the dehydration of sugars. Moreover, according to their studies, the dehydration of hexoses and pentoses was pH-dependent. A low concentration of H+ in the reaction medium (pH > 3) was not sufficient to catalyse the dehydration but a pH too acidic (pH < 1) led to the formation of by-products: levulinic and formic acid from hexoses and humins from both types of sugars. For the dehydration of fructose, a pH of 2-2.5 (HCl or

[65–67] H2SO4 solutions) seemed to maximise 5-HMF formation. A pH more acidic (1-1.5) was more adequate to dehydrate xylose and xylan.[68]

Alternative acids were tested to avoid the use of H2SO4 or HCl. Asghari et al. compared the effect of hydrochloric, sulphuric, phosphoric, citric, oxalic, maleic and p- toluenesulfonic (p-TSA) acids on the dehydration of fructose to 5-HMF. In an interesting way, they observed that phosphoric acid was more efficient than HCl and H2SO4: 65% of 5-HMF yield against 44 and 40% respectively. p-TSA gave a limited yield of 37%. Maleic acid led to a good yield of 60% while citric and oxalic acids promoted polymerization more than 5-HMF formation. Besides, these last three acids tended to degrade under subcritical conditions.[66] On their side, Yemis et al. compared three strong mineral acids (hydrochloric, sulphuric, and nitric acids) and three weak organic acids (phosphoric, acetic, and formic acids) on the dehydration of xylose and xylan to furfural. The furfural yields obtained from xylose in the presence of HCl, H2SO4, HNO3, H3PO4, CH3COOH and HCOOH were 59%, 50%, 5%, 43%, 25%, and 37%, respectively.[68] These differences in furfural yield could be attributed to the different anions generated in the reaction media. As highlighted by Marcotullio and De Jong, Cl- is the most effective anion favouring the conversion of xylose and xylan to furfural.[69,70] Good furfural yields can also be obtained by using formic acid[71] or maleic acid, even though maleic acid tended to degrade into malic acid when heated[72].

ii. Metal sulphates

Recently, the team of H. Vogel worked on the dehydration of biomass-derived polyols in sub- and supercritical water.[29,73–76] They mainly focused on the use of different metal sulphates (Na2SO4, CuSO4, ZnSO4, NiSO4, MgSO4) in order to replace

Chapter I: Context and literature review classic mineral acids. They performed their reactions using a continuous flow reactor. Some examples of their work are presented in Table 3.

Additive P Residence Conversion Yield Polyol (wt.%) T (°C) Ref. (ppm) (MPa) time τ (s) (%) (%)

1,2-Propanediol

5 - 34 360 60 31 20 [75]

5 ZnSO4 (400) 34 360 60 100 90

1,2-Butanediol

[74] 5 ZnSO4 (400) 34 340 120 100 70

Glycerol

[73] 1 ZnSO4 (790) 25 360 60 80 45

meso-Erythritol

5 - 34 360 120 75 48 [75]

5 ZnSO4 (4000) 34 360 120 100 60

Table 3: Examples of the effect of metal sulphates on the dehydration of biomass-derived polyols.

The dehydration of polyols was strongly influenced by the addition of salts. It was completely inhibited by sodium sulphate while bivalent transition metal cations increased both the conversion and the selectivity. One possible explanation for this effect was linked to the acidic properties of the used salts and to a possible pH shift. Depending on the substrate, copper and zinc sulphates were the best effective additives. However, copper salts may sometimes be too active and also promoted side reactions.

Chapter I: Context and literature review

iii. Metal chlorides

As an alternative to corrosive mineral acids, researchers performed dehydration of polyols in the presence of metal chlorides. Crittendon et al. compared the effects of

MnCl2, CuCl2 and SnCl2 for the dehydration of cyclohexanol to cyclohexene in supercritical water (375°C). MnCl2 and CuCl2 showed results similar to those obtained with HCl: an almost quantitative conversion and yields superior to 90% were obtained.[77]

The influence of ZnCl2 was studied by the team of Dai on the dehydration of diethylene glycol to 1,4-dioxane[78] and by the team of Tagaya on the dehydration of propylene glycol to 2-methyl-2-pentenal.[79] Both teams observed a limited yield in pure water, which was increased by the addition of ZnCl2 to 60% for 2-methyl-2-pentenal (300°C, 60 min, 1 wt% of ZnCl2) and 51% for 1,4-dioxane (340°C, 120 min, 0.5 wt% of ZnCl2).

For sugars, the addition of metal chlorides also proved to be efficient. In 2007, for the first time, Zhao et al. discovered that chromium (II) chlorides were very effective catalysts for the conversion of glucose to 5-HMF in ionic liquids with a yield near 70%.[80] This work inspired many studies on metal chlorides for the synthesis of furanic compounds. Chromium (III), for example, was used by Choudhary et al. to dehydrate

[81] xylose into furfural and led to a yield of 39% in water in combination with HCl. AlCl3 and FeCl3, being abundant and cheap, had received considerable attention for the production of 5-HMF and furfural[52,82,83] or for the pre-treatment of lignocellulosic material[84]. If we focus on the dehydrations performed in water, we can cite the work of De et al. who obtained moderate 5-HMF yields from fructose, glucose and sucrose (54%,

37% and 30% respectively) with the addition of AlCl3 under microwave irradiation (Scheme 4).[85] Recently, two studies compared the effect of different metal chlorides

(GeCl4, CrCl2, CrCl3, AlCl3, FeCl2, FeCl3, SnCl2, SnCl4, CeCl3, InCl3) on the dehydration of

[86] [87] xylan and of xylose and glucose . Both teams observed a superior effect of SnCl4. The effects of metal chlorides on the dehydration of xylose will be further discussed in Chapter III.

[85] Scheme 4: Formation of 5-HMF from fructose in presence of AlCl3 under microwave irradiation.

Chapter I: Context and literature review

iv. With the addition of CO2

In 2003, Hunter and Savage reported, for the first time, the acceleration of acid- catalysed reactions in high-temperature liquid water by the addition of carbon dioxide to the reaction medium. They examined the dehydration of cyclohexanol to form cyclohexene and obtained doubled yields when carbon dioxide was added to the aqueous medium (Scheme 5).[88] The basis of this rate enhancement was the reaction between carbon dioxide and water to yield carbonic acid, which subsequently dissociated. The pH of the reaction medium increased and dehydration was promoted. The same yield enhancement was observed for the formation of THF from 1,4-butanediol in high temperature water.[89]

Scheme 5: Dehydration of cyclohexanol to cyclohexene in presence of carbon dioxide.[88]

For Yamaguchi et al. who worked on the formation of cyclic ethers from polyols, the addition of CO2 did not lead to a higher yield of product at the end of the reaction but only enhanced the formation rates to reach the equilibrium yield.[90–92] The main advantage of an acid solvent composed of water and carbon dioxide is that it is environmentally-benign: both water and carbon dioxide are non-toxic, and separation and recycling of these two components are easily performed by depressurisation after reaction.

c. Heterogeneous catalysis

With comparison to homogeneous catalysis, heterogeneously catalysed processes have many advantages in the frame of green chemistry: they produce less waste, facilitate easy separation and recovery of the catalyst, and the elimination of mineral acids makes the reaction mixture less corrosive. However, finding an active and stable water-tolerant solid catalyst is still a challenge. Besides, during sugars dehydration, many undesired reactions take place and form humins, reducing selectivity and deactivating the catalyst.

Chapter I: Context and literature review

Some examples of heterogeneous catalysts used for dehydrating polyols and sugars are presented below.

i. Modified silicates and aluminosilicates

Two of the most commonly studied solid acids types are silicates and zeolites (aluminosilicates), modified or commercial. One of the main advantages of these materials is their shape selectivity and the possibility to control the pore size. In addition, the acidity of these materials can be controlled by varying the Si/Al ratio in the matrix.[93] Zhang et al. studied the effect of the variation of the Si/Al ratio of H-ZSM-5 zeolites and their further modification with boric acid on the dehydration of bio-based 2,3-butanediol to methyl ethyl ketone (MEK). The results showed that a high Si/Al ratio improved the conversion of 2,3-butanediol with a similar selectivity to MEK (conversion 100% and yield 69% at 300°C). The modification of the zeolite with boric acid allowed the researchers to obtain the same results but at a temperature of only 180°C (Scheme 6).[94]

Scheme 6: Formation of methyl ethyl ketone from 2,3-butanediol with modified H-ZMS-5 zeolites.[94]

Sulfonic acid and aluminium modified mesoporous shell silica beads were tested by Jeong et al. on the dehydration of xylose to furfural. Sulfonic acid modified catalysts gave limited conversion and yield (32% and 19% respectively). Because of their high

Lewis acidity (pKa > -5), the aluminium modified catalysts led to a higher conversion but to a lower selectivity in furfural. These catalysts were also tested for the dehydration of glycerol to acrolein and gave good results (conversion 79% and yield 48% with the sulfonic acid catalyst).[95] The H-MCM-22 zeolite was an effective and recyclable solid acid catalyst in the aqueous-phase dehydration of xylose, at 170°C. Up to 54% furfural yield was reached at 97% conversion in water. Besides, this solid acid catalyst was fairly stable (similar furfural yields were reached in recycling runs; no structural modifications and no leaching phenomena were detected).[96]

Chapter I: Context and literature review

You and Park carried out the dehydration of xylose into furfural over different H- zeolites in a continuous flow. Although all the used H-zeolites had similar surface areas, amounts of acid sites, and ratios of Brønsted acid sites/Lewis acid sites, the conversion of D-xylose decreased in the following order: H-Y > H-β > H-mordenite > H-ZSM-5 > H- ferrierite. For them, this indicated that xylose conversion increased with increasing channel size of the zeolite. The selectivity of furfural did not follow the same trend: the selectivity of furfural increased with increasing channel size, to a maximum value at a channel size of 5.5 Å (corresponding to H-ZSM-5), and then decreased with a further increase in channel size.[97]

ii. Mixed oxides

Metal oxides, especially ZrO2, TiO2, Fe2O3, and zirconia-containing mixed oxides modified by sulphate ions have been found to be promising catalysts for a wide variety of reactions (for example, esterification, isomerisation, alkylation, and cracking). Metal oxides are utilised both for their acid-base and redox properties and constitute one of the largest family of catalysts in heterogeneous catalysis.

Akizuki and Oshima studied the activity of a TiO2 catalyst with variable WO3 content on the dehydration of glycerol to acrolein in supercritical water. They observed that the reaction rate and the selectivity towards acrolein increased with an increase in

[98] WO3 content.

Qi et al. compared the activity of TiO2 (rutile and anatase) and ZrO2 on the dehydration of hexoses to 5-HMF under microwave irradiation. Rutile TiO2 had no significant effect on hexoses conversion but anatase TiO2 and ZrO2 led to moderate results starting from fructose (90% conversion and 41% yield with anatase TiO2) and

[99] limited yields starting from glucose. For Chareonlimkun et al., the presence of TiO2 and SO4–ZrO2 promoted the hydrolysis and dehydration of C5-sugars (xylose), C6-sugars (glucose), cellulose and lignocellulose to furfural and 5-HMF with less by-products

[100,101] formation, whereas ZrO2 strongly promoted the isomerisation reaction. Zirconium–tungsten (ZrW) mixed oxides were also relatively active catalysts in the aqueous phase reaction of xylose, at 170°C. The catalysts led to more than 90% conversion within 2 h reactions, but furfural yields were less than 35%. Results could be improved by using mesoporous ZrW with enhanced specific surface area and amount of accessible acid sites (41% yield at 100% conversion), and furthermore by doping the inorganic material with aluminium to give mesoporous ZrAlW (51% yield at 98%

Chapter I: Context and literature review conversion). Besides, catalyst recycling tests revealed that mesoporous ZrW and ZrAlW catalysts were fairly stable catalysts under the applied reaction conditions.[102] Graphene, graphene oxide, sulfonated graphene, and sulfonated graphene oxide (SGO) were prepared, characterized and tested for the dehydration of xylose to furfural in water by Lam et al. In particular, SGO was proven to be a rapid and water-tolerant solid acid catalyst even at very low catalyst loading, maintaining its initial activity after 12 tested repetitions at 200 °C, with an average furfural yield of 61% in comparison to 44% for the uncatalysed system.[103]

iii. Ion-exchange resins

Ion-exchange resins are sulfonated copolymers of styrene and divinyl benzene in which sulfonic acid groups act as active sites. Their maximum operating temperature is usually around 130°C, above which desulfonation of the acid sites starts to deactivate the catalyst. Ion-exchange resins have nevertheless been observed to work in a stable manner up to 150°C in the dehydration of monosaccharides.[93]

However, ion-exchange resins were mainly used in organic solvents (DMSO, acetonitrile, DMF, etc)[49,104,105] and not in pure water. We can report only two publications which investigate the use of Amberlyst 70 and Nafion SAC-13 for the dehydration of xylose in water. The first work led to moderate results with Amberlyst 70 (conversion 83% and yield 38%) which were increased by the use of a simultaneous stripping with nitrogen (conversion 99% and yield 70%, Scheme 7).[106] The second publication compared the activity of Amberlyst 70 and Nafion SAC-13 to HCl for the dehydration of xylose under microwave irradiation. Nafion SAC-13 led to lower results compared to HCl but Amberlyst 70 gave results similar to HCl. However, furfural yield stayed limited.[107]

Scheme 7: Formation of furfural from D-xylose with an ion-exchange resin, Amberlyst 70.[106]

Chapter I: Context and literature review

iv. Solid metal phosphates

Metal phosphates have a layered structure consisting of metal atom and phosphate species planes, and they exhibit both Lewis and Brønsted acidity. They are known for their ion-exchange and acid properties.[93] The team of Rusu performed sorbitol dehydration under hydrothermal conditions with metal (III)- and metal (IV)-phosphates as catalysts. The activity of the metal phosphates on the conversion of sorbitol and on the selectivity to isosorbide increased as follows: AlP < ZrP < FeP < LaP < CeP < BP. The presence of boron phosphate in the reaction medium led to a 100% conversion with an isosorbide selectivity of 70% (uncatalysed reaction gave 75% sorbitol conversion and 1,4-sorbitan as the main product). Sorbitol dehydration was favoured by moderate and strong acid sites, and not promoted by very strong and excessively strong acidity.[108] Zirconium phosphate obtained by hydrothermal methods using organic amines as templates had been examined as a solid catalyst for the dehydration reaction of xylose to furfural in aqueous-phase by Cheng et al. It presented good catalytic performance with conversions up to 96% and furfural yields up to 52% in short reaction times. Moreover, the catalyst was easily regenerated by thermal treatment in air and showed quite stable activity.[109]

d. Enhancing selectivity

As we have seen before, the easiest and most economical solvent for the dehydration of polyhydroxylated compounds is water. It is a non-toxic, non-flammable, safe and clean solvent. However, during the dehydration of monosaccharides, water also accelerates some of the consecutive reactions of furfural and 5-HMF, leading to a decrease in yield. Therefore, one of the solutions would be to isolate the product continuously from the catalyst-containing phase as soon as it has been formed, in order to avoid its consumption in consecutive reactions. This can be done, for example, by a simultaneous nitrogen stripping of furfural, transferring the furfural to a gas phase where it cannot react anymore since the catalyst and intermediates are not volatile.[110] Other approaches included adsorbing the formed 5-HMF from the reaction medium on activated carbon[111] or utilising a supercritical fluid,

[112] such as CO2, to concentrate furfural up to 95 wt%.

Chapter I: Context and literature review

More classically, the addition of a co-solvent allowed the furan to be transferred from the aqueous phase into the organic phase. Thus, the product was no longer in contact with water or with the catalyst, and suffered less side reactions. Toluene, THF or MIBK were often used as co-solvents[113,114] but recently, greener solvents such as Me-THF or cyclopentyl methyl ether (CPME) were introduced.[82,115] For example, Choudhary et al. doubled their furfural yield (from 39% to 76%) by introducing a toluene-phase.[81]

Chapter I: Context and literature review

3. Issue and objectives

The aim of this PhD work is to perform the dehydration of polyhydroxylated compounds in order to form target molecules with high added value with the idea to try to respect the Twelve Principles of Green Chemistry as much as we can. Despite common sense thinking that it will favour hydrolysis, water is a suitable medium for dehydration as it was described widely in the literature review. Thus, our reactions will be performed in sub- and supercritical water. When needed, catalysts will be chosen to be efficient, selective and recyclable. Several strategies will be tried in order to avoid batch reactions activated by thermal heating: the use of microwave reactors and the use of continuous flow reactors. In Chapter II, we will focus on the dehydration of a petro-sourced molecule, 1-phenylethane-1,2-diol, in water to form phenylacetaldehyde, a target molecule used in perfume compositions, in pharmaceuticals or as chemical intermediate. In Chapter III, the dehydration of biosourced D-xylose, as a model compound for hemicellulose, will be studied to form furfural, a bio-based platform molecule. The optimised methods will be extended to xylan and other sugar units present in hemicellulose.

Chapter I: Context and literature review

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[98] M. Akizuki, Y. Oshima, Ind. Eng. Chem. Res. 2012, 51, 12253–12257.

[99] X. Qi, M. Watanabe, T. M. Aida, R. L. Smith Jr., Catal. Commun. 2008, 9, 2244–2249.

[100] A. Chareonlimkun, V. Champreda, A. Shotipruk, N. Laosiripojana, Bioresour. Technol. 2010, 101, 4179–4186.

[101] A. Chareonlimkun, V. Champreda, A. Shotipruk, N. Laosiripojana, Fuel 2010, 89, 2873– 2880.

[102] M. M. Antunes, S. Lima, A. Fernandes, J. Candeias, M. Pillinger, S. M. Rocha, M. F. Ribeiro, A. A. Valente, Catal. Today 2012, 195, 127–135.

[103] E. Lam, J. H. Chong, E. Majid, Y. Liu, S. Hrapovic, A. C. W. Leung, J. H. T. Luong, Carbon N. Y. 2012, 50, 1033–1043.

[104] J. Tuteja, S. Nishimura, K. Ebitani, Bull. Chem. Soc. Jpn. 2012, 85, 275–281.

[105] A. Takagaki, M. Ohara, S. Nishimura, K. Ebitani, Chem. Lett. 2010, 39, 838–840.

[106] I. Agirrezabal-Telleria, A. Larreategui, J. Requies, M. B. Güemez, P. L. Arias, Bioresour. Technol. 2011, 102, 7478–7485.

[107] R. Weingarten, G. A. Tompsett, W. C. Conner Jr., G. W. Huber, J. Catal. 2011, 279, 174– 182.

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Chapter I: Context and literature review

[111] P. Vinke, H. van Bekkum, Starch - Stärke 1992, 44, 90–96.

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CHAPTER II

Dehydration of 1-phenylethane-1,2-diol in water

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

1. Introduction

a. Phenylacetaldehyde: origin and applications

Phenylacetaldehyde (1) is a colourless liquid with a sweet-green odour, similar to the one of hyacinths and narcissi. It has been identified in many essential oils[116] and as a volatile constituent of foods such as honey[117], chocolate[118] or buckwheat[119] for instance. Some of its physical properties are given in Table 4.

CAS number 122-78-1

Molar mass M = 120.15 g/mol

Density d = 1.079 g/mL (25°C)

Melting point mp = - 10°C

Phenylacetaldehyde (1) Boiling point bp = 195°C

Refractive index nD = 1.535

Table 4: Physical properties of phenylacetaldehyde.

Phenylacetaldehyde is used in perfume compositions, in particular for hyacinth and rose notes.[120] Further applications include the preparation of pharmaceuticals[121], insecticides[122], acaricides, disinfectants, and its use as a rate-controlling additive in the polymerization of polyesters with other monomers. Phenylacetaldehyde is also a useful intermediate in many organic syntheses. For example, phenylalanine, an intermediate for the sweetener aspartame, can be obtained by the reaction of phenylacetaldehyde with ammonia and hydrogen cyanide (via Strecker reaction).[123] Phenylacetic acid can also be obtained by the oxidation of the aldehyde.

b. Literature review

As represented on Scheme 8, phenylacetaldehyde can be synthesised by different ways. Firstly, it can be obtained in high yield by vapour-phase isomerisation of styrene oxide with heterogeneous catalysts such as borosilicate zeolite or magnesium silicate for instance.[124–127] Styrene oxide isomerisation can also be performed in organic solvents with the use of micro-organisms[128] or phosphotungstic heteropoly acids.[129]

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

Phenylacetaldehyde can also be synthesized by the direct oxidation of styrene by hydrogen peroxide in the presence of heterogeneous catalysts, by the catalytic dehydrogenation of 2-phenylethanol and by the Darzens glycidic ester synthesis from benzaldehyde and alkyl chloroacetates.[130–132]

Scheme 8: Retrosynthetic scheme of phenylacetaldehyde.

Finally, 1-phenylethane-1,2-diol (2) can be converted into phenylacetaldehyde by dehydration. In the vapour phase, the reaction is performed in high yield in the presence of heterogeneous catalysts.[127,133] For example, the use of H-ZSM-5 zeolite, silicalite or silica gel at 200-300°C led to high conversion and yield (> 96%).[133] Only three publications report the dehydration of 1-phenylethane-1,2-diol in water. In the first one, the reaction is performed at reflux and catalysed by mineral acids

(HCl, H2SO4 and H3PO4). Limited yields of phenylacetaldehyde were reached (< 20%) and a product with a higher boiling point was mainly obtained. According to the researchers, it could be a dimer of phenylacetaldehyde, 2-benzyl-4-phenyl-1,3-dioxane (structure on Figure 9). When steam was introduced into the reaction mixture in order to distil out the product, dimerisation was limited and yield of (1) increased to 70%.[134]

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

Figure 9: By-products obtained during the dehydration of 1-phenylethane-1,2-diol in water[134,135]

Katritzky and co-workers carried out the dehydration of 1-phenylethane-1,2-diol without a catalyst in cyclohexane and water at 200°C for 6h. In cyclohexane, conversion was low (14%) while it reached 93% in water. Main products were phenylacetaldehyde (24%) and an aldol condensation product, 2,4-diphenylbut-3-enal (41%, structure on Figure 9).[135] Finally, Avola et al. compared the dehydration of the diol in pure water and in NaCl and Na2SO4 solutions at 180°C for 16h. Their results are presented in Table 5. The addition of NaCl resulted in increased conversion and yield while the addition of

[54] Na2SO4 drastically reduced the conversion rates (2%).

Solvent Conversion (%) Yields (%)

H2O 43 22 21 1M NaCl 93 29 64

1M Na2SO4 2 1 0

Table 5: Effect of the salts on the dehydration of 1-phenylethane-1,2-diol under hydrothermal conditions. From Avola et al.[54]

However, through these publications, it can be noted that the selectivity towards phenylacetaldehyde was quite low in water: 26-53% in pure water, 31% in NaCl solution and less than 20% in acidic solutions. The aldol condensation product (3’) was formed in high yield. The reactivity of the aldehyde was high and it was difficult to avoid further reactions to happen. This issue is central in this Chapter II: how to maximise phenylacetaldehyde yield while limiting the secondary reactions?

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

c. Mechanism and structure of the by-product

The formation of phenylacetaldehyde from 1-phenylethane-1,2-diol is a simple dehydration. Its mechanism is presented on Scheme 9. The first step involves the protonation of the secondary alcohol by an acid, followed by loss of water to give a carbocation. Then, deprotonation of the adjacent carbon atom by a water molecule leads to the creation of the C=C double bond: an enol is formed. Finally, phenylacetaldehyde is formed by tautomerisation of the enol.

Scheme 9: Dehydration of 1-phenylethane-1,2-diol to phenylacetaldehyde.

The main by-product is produced by an aldol condensation of the phenylacetaldehyde on itself (Scheme 10). The first step is an aldol reaction. The enol is formed from the aldehyde by tautomerisation. It attacks a protonated molecule of aldehyde, leading to the aldol after deprotonation. The aldol then dehydrates to give the unsaturated carbonyl compound.

Scheme 10: Aldol condensation from phenylacetaldehyde.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

However, in contrast with previous reports,[54,135] the aldol condensation of aldehyde (1) led to the formation of the 2,4-diphenylbut-2-enal (3) instead of 2,4- diphenyl-but-3-enal (3’). The formation of compound (3) is favoured thanks to the formation of two conjugated double bonds (alkene and aldehyde) which stabilise the molecule. The structure of compound (3) was established by 1H and 13C NMR spectroscopy experiments. The 1H NMR spectrum showed that (i) the H[1] gave one singlet at 9.67 ppm indicating no coupling with another hydrogen atom; (ii) the H[2] gave one triplet at 6.88 ppm; and (iii) the H[3,4] gave one doublet at 3.71 ppm with an integral value for two hydrogen atoms. The coupling constant J = 7.6 Hz for H[2] and H[3,4] proved that the

1 CH and CH2 groups were neighbours. This H spectrum was not compatible with the structure (3’) previously described, since (i) a doublet would have been observed for the H[1]; (ii) H[2] and H[3] would have gave a doublet of doublets; and (iii) the H[3] and H[4] would have been integrated separately for 1 hydrogen atom each (Figure 10).

Figure 10: Comparison of the two possible structures of the by-product – 1H NMR.

The 13C NMR spectrum confirmed the structure (3) with chemical shifts of 153.47 ppm for the C[2], 138.02 ppm for the C[3] and 35.80 ppm for the C[4]. The comparison with the literature[136,137] also permitted validation that compound (3) had a 2,4- disubstituted-but-2-enal structure. Finally, the configuration Z or E of the enal 3 was assigned thanks to a NOESY (Nuclear Overhauser Effect SpectroscopY) NMR experiment. NOESY experiment affords a 2D chemical shift correlation map in which the cross peaks signals connect resonances from nuclei that are spatially close. In our case, the interaction between protons H[1] and H[2] indicated their spatial proximity and thus, an E configuration for the condensation product (Figure 11).

Figure 11: Configuration of the 2,4-diphenylbut-2-enal (3).

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

2. Dehydration of 1-phenylethane-1,2-diol under conventional heating

The first part of the study of the dehydration of 1-phenylethane-1,2-diol (2) into phenylacetaldehyde (1) has been carried out in a batch reactor under conventional heating without the addition of any catalyst. The experiments were done in a 316 stainless steel autoclave with an inner volume of 100 mL. The pressure during the reaction was the autogenous pressure of the solution at reaction temperature and was between 5 and 35 bar. The influence of temperature and reaction time on the phenylacetaldehyde yield was studied. The initial diol concentration was also varied in order to see its influence. However, because of the reactor alloy, the addition of a catalyst was not tested in order to avoid its corrosion.

a. Variation of temperature and reaction time

Firstly, the influence of temperature and reaction time was studied: several temperatures (160, 180, 200, 220 and 240°C) were tested for two reaction times (8 and 16h). Results are presented on Figure 12a (8h) and 12b (16h). As we can see, diol conversion increased both with temperature and reaction time. A quantitative conversion was reached after 16h at 200°C and after 8h at 220°C. However, the phenylacetaldehyde yield was very limited: it was between 9% and 13% regardless of the time or temperature used. As explained before, phenylacetaldehyde was very reactive and suffered an aldol condensation to form 2,4-diphenylbut-2-enal (3). The by-product yield was quite high, reaching 42% after 16h of reaction at 200°C. Nevertheless, it should be noticed that the formation of 2,4-diphenylbut-2-enal did not follow a linear trend: the yield increased to a maximum at 200 or 220°C depending on the reaction time, then decreased if the temperature continued to increase. Since the conversion was total, it suggested that other products were formed, from phenylacetaldehyde or from the condensation product, or that degradation occurred due to the high temperature. Avola et al. observed the formation of 3-phenylnaphtalene in diluted HCl at 180°C for 16h through an intramolecular Friedel-Crafts addition of the aldol condensation product.[138] In our case, we had not identified any additional compounds.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

Thanks to its properties (increase of ion product Kw, decrease of dielectric constant), subcritical water was a suitable medium to perform the dehydration of 1- phenylethane-1,2-diol without the addition of any catalyst. However, subcritical water also promoted the further condensation of phenylacetaldehyde.

a) % 100 90 80 Diol 70 conversion 60 50 Aldehyde 40 yield 30 By-product 20 yield 10 0 160 180 200 220 240 Temperature (°C)

b) % 100 90 80 Diol 70 conversion 60 50 Aldehyde 40 yield 30 20 By-product yield 10 0 160 180 200 220 240 Temperature (°C)

Figure 12: Influence of temperature for a) 8h and b) 16h of reaction. Autoclave, 1-phenylethane-1,2-diol concentration: 0.5 mol/L.

b. Influence of the diol concentration

In a second time, the influence of the initial 1-phenylethane-1,2-diol concentration (from 0.25 to 1 mol.L-1) was also studied at 200°C for 16h (Figure 13). Similar conversion

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water and yields were observed regardless of the diol concentration tested. Thus, the diol concentration did not seem to have a particular influence on its reactivity.

% 100 90 80 Diol 70 conversion 60 50 Aldehyde 40 yield 30 20 By-product 10 yield 0 0.25 0.5 1 Diol concentration (mol/L)

Figure 13: Influence of diol concentration. Autoclave, T = 200°C, t = 16h.

c. Conclusion

According to this study, using an autoclave as reactor was not the best option to produce phenylacetaldehyde in good yield and selectivity. The thermal inertia of the reactor induced a slow heating rate of the reaction medium: between 1 and 2h were required to reach the wanted temperature. Then, during this time interval, phenylacetaldehyde was formed and began to react on itself, thus decreasing yield and selectivity. Due to the reactor alloy, the use of catalysts was very limited in order to avoid its corrosion.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

3. Dehydration of 1-phenylethane-1,2-diol under microwave irradiation

From the results of the study under conventional heating, it appeared to us that the use of a microwave reactor could be an interesting alternative to autoclave. The fast heating rate of microwaves and the higher yields and selectivities usually obtained are ones of the many advantages of the microwave reactors. Thus, using microwave irradiation could be a tool to improve phenylacetaldehyde (1) yield while limiting the formation of 2,4-diphenylbut-2-enal (3). In a second part, we will focus on the dehydration of 1-phenylethane-1,2-diol (2) under microwave irradiation, in water and later, in biphasic medium.

a. Optimisation of the phenylacetaldehyde yield in water

In a first step, we will try to maximize the phenylacetaldehyde yield in water while limiting the formation of the aldol condensation product, 2,4-diphenylbut-2-enal, under microwave irradiation. The first experiment was carried out at 200°C for 30 minutes and led to a diol conversion and a phenylacetaldehyde yield of only 1%. Thus, a catalyst was necessary. The Lewis acid AlCl3 was selected as it had already given good results for promoting dehydration reactions.[85,113]

The dehydration reaction in the presence of AlCl3 in water is believed to be

2+ initiated by the hydrolysis of AlCl3 which formed the cationic species [Al(OH)(H2O)5] and H+. Then, these complexes can coordinate to the hydroxyls groups in order to form a chelate five-membered ring (Scheme 11). As metal cations draw off the electron density from the hydroxyl groups, an electron defect is created at the carbons. This means that the separation of either one of the hydroxyl groups is made easier.[75]

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

Scheme 11: Proposed action of AlCl3 in the dehydration of 1-phenylethane-1,2-diol.

i. Influence of temperature

Temperature is a significant factor in most chemical reactions. In order to see its influence, eight different temperatures (from 130 to 200°C) were tested on the dehydration of 1-phenylethane-1,2-diol during 30 minutes in the presence of AlCl3 (20 mol%) in water (Figure 14).

% 100 90 80 70 Diol conversion 60 50 Aldehyde 40 yield 30 By-product 20 yield 10 0 130 140 150 160 170 180 190 200 Temperature (°C)

Figure 14: Influence of temperature.

MW, t = 30 min, Catalyst: AlCl3 (20 mol%)

A temperature of 150°C was necessary to have a diol conversion superior to 10%. Conversion increased with temperature and reached 100% at 180°C. Phenylacetaldehyde yield increased with temperature to a maximum (55% at 170°C) and then decreased to

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

31% at 200°C. If the temperature exceeded 170°C, the aldol condensation product was formed to the detriment of phenylacetaldehyde. Consequently, the temperature selected for the rest of the study was 170°C.

ii. Influence of reaction time

Shorter reaction times are one of the many advantages of using microwave irradiation compared to thermal heating. Microwaves transfer their energy directly to the reactive species and therefore provide a highly efficient and fast heating of the reaction medium. Six reaction times, from 10 to 60 minutes, have been compared at 170°C in the presence of AlCl3 (20 mol%) in water (Figure 15). Experiments showed that the 1-phenyl-ethane-1,2-diol conversion increased with reaction time to reach a value of 98% after 60 minutes. Phenylacetaldehyde yield increased with time to a maximum of 55% after 30 minutes and then decreased if the reaction was continued. The selectivity towards the aldehyde decreased from 69% at 30 minutes to 49% at 60 minutes. Since the formation of 2,4-diphenylbut-2-enal was favoured if the reaction time exceeded 30 minutes, this reaction time was selected for the rest of the study.

% 100 90 80 70 Diol 60 conversion 50 Aldehyde 40 yield 30 20 By-product 10 yield 0 0 10 20 30 40 50 60 Reaction time (min)

Figure 15: Influence of reaction time.

MW, T = 170°C, Catalyst: AlCl3 (20 mol%)

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

iii. Influence of the catalyst nature

The activity of Lewis acids (AlCl3 and FeCl3), mineral Brønsted acids (HCl,

H2SO4), metal sulphates (MnSO4, ZnSO4, FeSO4 and Fe2(SO4)3), salts (NaCl and CaCl2) and solid acid catalysts (Montmorillonite K10, a clay, and Dowex, 50WX8, an ion- exchange resin) were compared on the dehydration of 1-phenylethane-1,2-diol. Reactions were carried out at 170°C for 30 minutes in water. The catalysts quantities were fixed at

20 mol%, except for NaCl and CaCl2 where 1 M solutions were used and solid catalysts where a mass ratio diol/catalyst of 1 was applied. Results are presented in Table 6.

Conversion Yield (%) Entry Catalyst (%) 1 3 1 - 1 1 0

2 AlCl3 80 55 3

3 FeCl3 99 59 6 4 HCl 96 63 4

5 H2SO4 97 62 4

6 MnSO4 1 1 0

7 ZnSO4 3 2 0

8 FeSO4 2 1 0

9 Fe2(SO4)3 54 26 0 10 NaCl a 1 1 0

a 11 CaCl2 4 4 0 12 Dowex 50WX8 b 100 45 13 13 Mont. K10 b 11 8 0

Table 6: Influence of the catalyst nature. MW, T = 170°C, t = 30 min, Catalyst: 20 mol%. a : Solution 1M, b : Ratio diol/catalyst = 1, wt/wt.

Firstly, in accordance with the literature[62,68,82,85], good phenylacetaldehyde yields were obtained with Lewis acids and mineral acids (from 55% with AlCl3 to 63% with

HCl). FeCl3 seemed to be a catalyst a little more active than AlCl3, leading to higher conversion and yields. The two Brønsted acids gave similar results.

In their experiments, Vogel’s group observed a positive effect of metal sulphates, especially ZnSO4, on the dehydration of biosourced polyols (1,2-propanediol, glycerol,

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water meso-erythritol, etc).[73–75] In our case, the use of metal (II) sulphates led to a very low conversion and yield, similar to those obtained without catalyst. Only iron (III) sulphate led to a 26% yield of phenylacetaldehyde for a 54% diol conversion. This difference with literature can be explained by an important difference in the reaction conditions: Vogel et coll. carried out their experiments close to the supercritical domain, between 320 and 360°C while our dehydration reaction was performed at 170°C.

Likewise, the use of salts such as NaCl and CaCl2 induced only a limited diol conversion (< 5%). These results did not follow the observation of Avola et al. For the same reaction, they observed a diol conversion of 93% and yields of 29% and 64% for the phenylacetaldehyde and the aldol condensation product respectively, with the use of a 1M solution of NaCl.[54] The activation method (thermal heating) and thus reaction times (16h) were different from our conditions and may explain this difference.

Finally, a total conversion was obtained with the ion-exchange resin Dowex

50WX8. Nevertheless, phenylacetaldehyde yield was lower than with AlCl3 (45 instead of 55%) due to the formation of more by-products (13%). On the other hand, the clay Montmorillonite K10 had a low efficiency on the dehydration of 1-phenylethane-1,2-diol with limited conversion and yield.

Therefore, it was decided to select the Lewis acids AlCl3 and FeCl3 and the mineral acids HCl and H2SO4 since they gave the best results.

iv. Conclusion

The optimisation of the phenylacetaldehyde formation in water was done under microwave irradiation. Best reaction conditions were a temperature of 170°C for a reaction time of 30 minutes. Mineral acids HCl and H2SO4 gave the highest phenylacetaldehyde yields (63 and 62% respectively). Nevertheless, Lewis acids AlCl3 and

FeCl3 proved to be a good alternative to these corrosive acids since they led to similar yields.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

b. Introduction of a co-solvent

Even if good phenylacetaldehyde yields were obtained in water, its selectivity was still inferior to 70% because of the formation of the aldol condensation product, 2,4- diphenylbut-2-enal, and others by-products. To solve this issue, a strategy widely used for the dehydration of monosaccharides[82,113] was applied: the introduction of a co- solvent (Figure 16).

Co-solvent Evaporator

Organic phase

Reaction medium Extractor Water

Aqueous phase

Figure 16: Schematic process of a biphasic dehydration of 1-phenylethane-1,2-diol.

In fact, 1-phenylethane-1,2-diol and the catalyst will have a better affinity with the aqueous phase whereas the partition coefficient of phenylacetaldehyde is in favour of the organic phase. Thus, in a biphasic system, the dehydration reaction will occur in the aqueous phase and the phenylacetaldehyde formed will be transferred into the organic phase and will not be able to react with itself.

i. Choice of the co-solvent

The first step was to choose a co-solvent. The selection criteria was (i) a solvent not miscible in water; (ii) which can resist the reaction conditions optimised in the first part of the study (170°C, 30 min of MW); and (iii) was efficient to transfer phenylacetaldehyde into the organic phase (low condensation product yield). The volumetric ratio water/co-solvent was first set to 1:1. It had been varied afterwards.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

Cyclopentyl methyl ether (CPME), ethyl acetate (EtOAc), toluene, methyltetrahydrofuran (Me-THF), tetrahydrofuran (THF), dimethyl carbonate and dioxolane were tested at 170°C for 30 minutes with AlCl3, FeCl3, HCl and H2SO4 (Table 7).

Conversion Yield (%) Entry Catalyst Co-solvent (%) 1 3

1 AlCl3 CPME 64 56 1 2 EtOAc 90 64 22 3 Toluene 80 78 0 4 Me-THF 71 62 9 5 THF 54 47 2

6 FeCl3 CPME 98 86 1 7 EtOAc 93 66 9 8 Toluene 99 88 0 9 Me-THF 88 72 1 10 THF 87 63 5

11 HCl CPME 97 94 1 12 EtOAc 94 79 15 13 Toluene 99 98 0 14 Me-THF 94 83 2 15 THF 91 67 8

16 H2SO4 CPME 98 95 2 17 EtOAc 99 70 25 18 Toluene 99 98 0 19 Me-THF 91 86 1 20 THF 93 70 8

Table 7: Choice of the co-solvent. MW, T = 170°C, t = 30 min, Catalyst: 20 mol%, Water/Co-solvent, 1:1, v/v

Dimethyl carbonate and dioxolane degraded under the reaction conditions. Thus, their results were not exploitable and do not appear in Table 7. Ethyl acetate was not an efficient solvent for the phenylacetaldehyde transfer. Indeed, at the end of the reaction, only one phase was observed. Thus, condensation product formation was not avoided and yields between 9 and 25% were obtained. As expected, since THF was partially

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water miscible with water, it did not capture efficiently phenylacetaldehyde which reacted with itself to form the condensation product with yields up to 8%.

Methyl-tetrahydrofuran, cyclopentyl methyl ether and toluene were efficient co- solvents since the by-product yields were inferior to 2%, except when Me-THF was combined with aluminium chloride (9%). Toluene gave the best results. It may be explained by the presence of the aromatic cycle which may favour the phenylacetaldehyde transfer into the organic phase. However, toluene is an organic solvent for which substitution is recommended, because of its environmental impact notably. Therefore, it would be wiser to opt for Me-THF or CPME which are considered as green solvents.[10] The use of Me-THF led to lower diol conversion and so lower phenylacetaldehyde yield than CPME. Thus, we chose CPME as co-solvent for the rest of the study.

Cyclopentyl methyl ether has many advantages as a solvent. It has (i) a high hydrophobicity and thus it is very easy to dry, (ii) a suppressed formation of peroxide by- products, (iii) a low vaporisation energy, (iv) a narrow explosion range and (v) it is relatively stable under acidic and basic conditions. Its physical properties are summarised in Table 8. Despite a petro-sourced origin and a high boiling point, CPME is an eco-friendly solvent considered as an alternative to other ethereal solvents such as THF, dioxan and 1,2-dimethoxyethane (DME), for a wide range of chemical reactions.[139,140]

CPME has been successfully used as a co-solvent in the dehydration of pentoses to furfural in the presence of sulphuric acid. Its use limited the formation of secondary products, usually formed in water, by transferring furfural into CPME. Xylose conversion and furfural yield were larger in the presence of CPME: after 60 minutes at 180°C, furfural yield reached a value close to 60% at 85% xylose conversion, whereas for the CPME free system, these values were 40 and 75%, respectively.[115]

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

Cyclopentyl methyl ether (CPME)

Density (20 °C) (g/cm3) 0.86 Melting point (°C) <-140 Boiling point (°C) 106 Viscosity (20 °C) (cP) 0.55 Surface tension (20 °C) (mN/m) 25.17 Vaporization energy (bp) (kcal/kg) 69.2 Specific heat (20 °C) (kcal/kg.K) 0.4346 Refractive index (20 °C) 1.4189 Dielectric constant (25 °C) 4.76 Dipole moment (D) 1.27 (calc) Azeotropic point with water (°C) 83a Solubility in water (g/100 g) 1.1 (23 °C) Flash point (°C) -1 Ignition point (°C) 180

log Pow 1.59 Explosion range (vol %) 1.1-9.9

a Composition Azeotrope (wt %) = CPME: 83.7, H2O: 16.3

Table 8: Physical properties of CPME. Data from Watanabe et al.[139]

ii. Influence of the water/co-solvent ratio

In their publication, Campos Molina et al. observed variations in conversion and yield according to the amount of CPME added to the aqueous phase. They varied the CPME/aqueous phase mass ratio from 0.67 to 2.33 and the best results were obtained for the ratio 2.33.[115] Thus, it was decided to vary the volumetric ratio water/CPME between the two phases while maintaining the value of total volume: the proportions 3:1, 2:1, 1:1,

1:2 and 1:3, v/v, were tested. The molar percentage of the four catalysts (AlCl3, FeCl3, HCl and H2SO4) was set at 20 mol%, the temperature at 170°C and the reaction time at 30 minutes. Results are presented in Table 9.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

Ratio water/co- Conversion Yield (%) Entry Catalyst solvent, v/v (%) 1 3

1 AlCl3 3:1 76 63 2 2 2:1 70 66 1 3 1:1 64 56 1 4 1:2 62 59 0 5 1:3 47 45 0

6 FeCl3 3:1 96 81 2 7 2:1 98 81 2 8 1:1 98 86 1 9 1:2 98 85 1 10 1:3 98 85 1

11 HCl 3:1 97 87 2 12 2:1 97 91 1 13 1:1 97 94 1 14 1:2 98 95 1 15 1:3 98 95 1

16 H2SO4 3:1 98 89 3 17 2:1 98 91 2 18 1:1 98 95 2 19 1:2 99 97 1 20 1:3 99 97 1

Table 9: Influence of the ratio water/co-solvent. MW, T = 170°C, t = 30 min, Catalyst: 20 mol%, Water/CPME, v/v

With FeCl3, HCl or H2SO4, the amount of organic solvent had no influence on the diol conversion. It was between 96 and 99%. Nevertheless, the more important the amount of CPME was, the higher the phenylacetaldehyde yield was, reaching 84%, 94% and 96% with FeCl3, HCl and H2SO4 respectively, with a water/CPME ratio of 1:3 (Table 9, entries 10, 15 and 20).

Among the different experiments, only AlCl3 gave a moderate diol conversion (< 76%) and a moderate phenylacetaldehyde yield (< 66%). Besides, results did not follow the same trend like for the other catalysts. With AlCl3, the more important the amount of CPME was, the lower conversion and yield were. Only 45% of aldehyde was obtained with a water/CPME ratio of 1:3. This decrease may be explained by the possible formation of

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water complexes between the aluminium cation and the ether CPME. In that case, the amount of free AlCl3 may not be enough to efficiently catalyse the dehydration. As shown in Table 9, the best results were obtained when the ratio of water/CPME was 1:2 or 1:3. Moreover, moderate aldehyde yields were obtained when using AlCl3 by comparison with the other catalysts. Therefore, it was decided that the dehydration of 1- phenylethanediol-1,2-diol will be done in the presence of FeCl3, HCl or H2SO4 (20 mol%) in a biphasic system water/CPME, 1:3, v/v at 170°C for 30 minutes under microwave irradiation.

iii. Variation of the catalyst quantity

Since diol conversions and aldehyde yields were almost total with 20 mol% of catalyst, we tried to decrease the catalyst quantity. The aim was to see if similar results could be obtained with a lower quantity of catalysts. Additional experiments were done with 5 mol% and 10 mol% of catalysts (FeCl3, HCl and H2SO4) at 170°C for 30 minutes in a biphasic system water/CPME, 1:3, v/v (Table 10).

Conversion Yield (%) Entry Catalyst mol% (%) 1 3

1 FeCl3 5 63 55 0 2 10 86 80 0 3 20 98 84 1

4 HCl 5 77 73 0 5 10 90 87 0 6 20 98 94 1

7 H2SO4 5 85 67 0 8 10 95 86 0 9 20 99 96 1

Table 10: Variation of the catalyst quantity. MW, T = 170°C, t = 30 min, Water/CPME, 1:3, v/v.

The decrease of the catalyst quantity led to a decrease of diol conversion and aldehyde yield. The latter went from 96 to 86% with H2SO4 and from 94 to 87% with HCl when the catalyst percentage decreased to 10 mol%. The difference was less important for

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

FeCl3: the yield only decreased from 84 to 80%. Thus, 20 mol% was necessary to obtain quantitative results.

iv. Variation of the reaction time

Because the optimisation of the reaction time was performed only with AlCl3

(paragraph 3.a.ii.), a new study was reproduced with the three other catalysts (FeCl3, HCl and H2SO4, 20 mol%) and the reaction conditions optimised so far (170°C, water/CPME, 1:3, v/v). The aim was to reduce the reaction time: four tests were carried out between 5 and 20 minutes for each catalyst (Table 11).

Reaction Conversion Yield (%) Entry Catalyst time (min) (%) 1 3

1 FeCl3 5 58 43 0 2 10 82 67 0 3 15 92 81 0 4 20 96 84 0 5 30 98 84 1

6 HCl 5 61 60 0 7 10 83 79 0 8 15 94 91 0 9 20 96 93 1 10 30 98 94 1

11 H2SO4 5 70 56 0 12 10 87 77 0 13 15 96 92 0 14 20 98 97 1 15 30 99 96 1

Table 11: Variation of reaction time. MW, T = 170°C, Catalyst: 20 mol%, Water/CPME , 1:3, v/v.

The decrease of the reaction time from 30 to 20 minutes led to almost no difference for 1-phenylethane-1,2-diol conversion and phenylacetaldehyde yield for the 3 catalysts (for example, 93% of aldehyde yield instead of 94% with HCl). Afterwards, if we continue to decrease the reaction time, diol conversion and aldehyde yield began to

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water decrease. Since similar results were obtained, it was decided to choose the shorter reaction time, 20 minutes, as an optimised value.

v. Conclusion

By comparison with the monophasic method (maximum yield: 63%), the introduction of a co-solvent allowed us to increase the phenylacetaldehyde yield up to 97% while limiting the formation of the aldol condensation product, 2,4-diphenylbut-2- enal. The operating conditions optimised under microwave irradiation were:

 Temperature: 170°C  Reaction time: 20 minutes  Biphasic medium: water/CPME, 1:3, v/v

 Catalysts: FeCl3, HCl, H2SO4  Catalyst quantity: 20 mol%

Best results were obtained with mineral acids (97% of yield with H2SO4 and 93% with HCl) but FeCl3 seemed to be a good alternative with an 84% yield.

The turnover number (TON), defined as the number of moles of product that a mole of catalyst can form before becoming inactivated, and the turnover frequency (TOF), referring to the turnover of the catalyst per unit of time, were calculated for each catalyst (Table 12).

Entry Catalyst TON TOF (s-1)

-3 1 FeCl3 4.2 3.5 x 10 2 HCl 4.6 3.9 x 10-3

-3 3 H2SO4 4.9 4.1 x 10

Table 12: Values of TON and TOF for the three optimized catalysts.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

c. Recyclability of the aqueous phase

In addition to activity and selectivity, one advantage of our system lay in the easy separation of the aqueous phase, containing the catalyst, and the CPME phase, containing the product. After a catalytic test, the organic phase could be treated to recover the aldehyde and the aqueous phase could be reused for a second catalytic cycle under the same conditions. For each catalyst, we performed 5 successive reactions with the same catalytic aqueous phase at 170°C during 20 minutes. The catalytic aqueous phase was recyclable for up to five cycles even if a progressive decrease in activity was observed for the acid catalysts FeCl3 and HCl (Figure 17a and 17b). No yield variation was observed with H2SO4

(Figure 17c). Therefore, it seemed that H2SO4 was the best acid catalyst to perform the dehydration of 1-phenylethane-1,2-diol in water/CPME biphasic system under microwave irradiation at 170°C for 20 minutes.

a) b) % % 100 100 By- By- 75 75 product product yield 50 yield 50 Aldehyde Aldehyde 25 25 yield yield 0 0 1 1 2 3 2 3 4 5 4 5 Run Run

c) % 100 By- product yield 50 Aldehyde yield 0 1 2 3 4 5 Run

Figure 17: Recyclability of the aqueous phase with a) FeCl3, b) HCl and c) H2SO4. MW, T = 170°C, t = 20 min Catalyst: 20 mol%, Water/CPME , 1:3, v/v.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

d. Application to other alcohols

In order to exemplify our optimised methods, several alcohols of structure similar to 1-phenylethane-1,2-diol were submitted for dehydration in biphasic and monophasic media. The dehydration of 1-phenylethanol, 2-phenylethanol, 1-phenyl-propan-1-ol and hydrobenzoin were compared.

i. 1-phenylethanol and 2-phenylethanol

Dehydration of 1-phenylethanol (4) and 2-phenylethanol (5) led to the formation of styrene (6) (Scheme 12). The experiments were carried out at 170°C for 20 minutes in presence of 20 mol% of catalysts (FeCl3, HCl and H2SO4) in a biphasic medium water/CPME, 1:3, v/v and in water. Results are presented in Table 13 and 14.

Scheme 12: Formation of styrene from 1-phenylethanol and 2-phenylethanol.

Conversion Styrene Entry Alcohol Catalyst Solvent (%) yield (%)

a 1 1-phenylethanol FeCl3 Water/CPME 79 54 2 HCl 74 74

3 H2SO4 70 70

4 FeCl3 Water 99 60 5 HCl 99 45

6 H2SO4 98 40

Table 13: Dehydration of 1-phenylethanol. MW, T = 170°C, t = 20 min, Catalyseur : 20 mol%. a : ratio Water/CPME = 1:3, v/v

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

The conversion of 1-phenylethanol was higher in water (98% with H2SO4 for example) than in biphasic medium (70%). However, selectivity towards styrene was much higher in biphasic medium than in water. With mineral acids for example, no secondary products were observed in biphasic medium (selectivity of 100%) whereas styrene selectivity in water did not exceed 45%. Styrene oligomers may be formed during the reaction, thus decreasing the yield. Therefore, once again, the presence of a co- solvent proved to be necessary to avoid the formation of by-products.

Conversion Styrene Entry Alcohol Catalyst Solvent (%) yield (%)

a 1 2-phenylethanol FeCl3 Water/CPME 9 0 2 HCl 7 0

3 H2SO4 9 0

4 FeCl3 Water 13 0 5 HCl 12 0

6 H2SO4 13 0

Table 14: Dehydration of 2-phenylethanol. MW, T = 170°C, t = 20 min, Catalyseur : 20 mol%. a : ratio Water/CPME = 1:3, v/v

By comparison, the dehydration of 2-phenylethanol was very limited under the reaction conditions, both in monophasic and biphasic media. A conversion inferior to 13% and a styrene yield close to zero were obtained. The difference of reactivity between the two alcohols can be explained by the stability of the carbocation formed during the dehydration. The secondary carbocation obtained from 1-phenylethanol was stabilised by the phenyl group and its formation was favoured, contrary to the primary one obtained from 2-phenylethanol.

ii. 1-phenylpropan-1-ol

Secondly, the dehydration of 1-phenylpropan-1-ol (7) in order to form 1- phenylpropene (8 and 8’, Scheme 13) was studied. Like previously, the experiments were carried out at 170°C for 20 minutes in presence of 20 mol% of catalysts (FeCl3, HCl and

H2SO4) in a biphasic medium water/CPME, 1:3, v/v and in water. Results are presented in Table 15.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

Scheme 13: Formation of 1-phenylpropene from 1-phenylpropan-1-ol.

Like it was observed for 1-phenylethanol, the dehydration of 1-phenylpropan-1-ol led to higher conversion in water than in biphasic medium (95% in water instead of 74% in water/CPME with FeCl3 for example). However, higher 1-phenylpropene yields were obtained in biphasic medium than in water. No secondary products were observed in biphasic medium (selectivity of 100%) whereas 1-phenylpropene selectivity did not exceed 51% in water. 1-Phenylpropene oligomers may be formed during the reaction in water, thus decreasing the yield. An NMR analysis showed that the main product was (E)-1-phenylpropene (94% (E), 6% (Z)). Therefore, the experiments showed that the presence of a co-solvent was necessary to avoid the formation of by-products.

Conversion 1-Phenyl- Entry Catalyst Solvent (%) propene (%)

a 1 FeCl3 Water/CPME 74 73 2 HCl 71 71

3 H2SO4 69 69

4 FeCl3 Water 95 33 5 HCl 93 45

6 H2SO4 92 47

Table 15: Dehydration of 1-phenylpropan-1-ol. MW, T = 170°C, t = 20 min, Catalyst: 20 mol%. a : ratio Water/CPME = 1:3, v/v

iii. Hydrobenzoin

Finally, the reaction of hydrobenzoin (9) in water was studied: it led to the formation of deoxybenzoin (10) by dehydration and diphenylacetaldehyde (11) by pinacol rearrangement (Scheme 14). Like for the other alcohols, the experiments were carried out at 170°C for 20 minutes in the presence of 20 mol% of catalysts (FeCl3, HCl

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

and H2SO4) in a biphasic medium water/CPME, 1:3, v/v and in water. Results are presented in Table 16.

Scheme 14: Dehydration and pinacol rearrangement of hydrobenzoin.

The main reaction was the pinacol rearrangement since we observed mostly the formation of diphenylacetaldehyde. The deoxybenzoin yield did not exceed 8% regardless of the reaction conditions.

In biphasic medium, hydrobenzoin conversion and diphenylacetaldehyde yield were moderate. For example, with H2SO4, 62% of hydrobenzoin were converted and 56% of diphenylacetaldehyde were obtained. In water, hydrobenzoin conversion was quantitative and the best diphenylacetaldehyde yield was 79%. However, it should be noticed that selectivity towards diphenylacetaldehyde was higher when using a co- solvent. Nevertheless, the introduction of CPME was not sufficient to promote only the pinacol rearrangement since a small amount of deoxybenzoin was still formed.

Yield (%) Conversion Entry Catalyst Solvent Diphenyl- (%) Deoxybenzoin acetaldehyde

a 1 FeCl3 Water/CPME 53 3 37 2 HCl 57 5 50

3 H2SO4 62 5 56

4 FeCl3 Water 99 6 67 5 HCl 99 8 76

6 H2SO4 100 8 79

Table 16: Dehydration and pinacol rearrangement of hydrobenzoin. MW, T = 170°C, t = 20 min, Catalyst: 20 mol%. a : ratio Water/CPME = 1:3, v/v

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

e. Formation of phenylacetaldehyde from styrene oxide

Lastly, the formation of phenylacetaldehyde directly from styrene oxide was tried. Styrene oxide (12) was hydrolysed to form 1-phenylethane-1,2-diol (2) which then underwent a dehydration to form phenylacetaldehyde (1) (Scheme 15).

Scheme 15: Formation of phenylacetaldehyde from styrene oxide.

The optimised methods were applied to styrene oxide: reactions were carried out under microwave irradiation at 170°C for 20 minutes in presence of 20 mol% of catalysts

(FeCl3, HCl and H2SO4) in a biphasic medium water/CPME, 1:3, v/v. Results are presented in Table 17, with the results from 1-phenylethane-1,2-diol for comparison.

Yield (%) Entry Substrate Catalyst 1 3

1 1-Phenylethane-1,2-diol FeCl3 84 0 2 Styrene oxide 86 0

3 1-Phenylethane-1,2-diol HCl 93 1 4 Styrene oxide 95 1

5 1-Phenylethane-1,2-diol H2SO4 97 0 6 Styrene oxide 94 0

Table 17: Synthesis of phenylacetaldehyde from styrene oxide. MW, T = 170°C, t = 20 min, Catalyst: 20 mol%, Water/CPME, 1:3, v/v.

Application of the optimised dehydration methods to styrene oxide produced the target aldehyde in yields comparable to those obtained from 1-phenylethane-1,2-diol: 86,

95 and 94% of phenylacetaldehyde were produced with FeCl3, HCl and H2SO4 respectively. Thus, additional experiments were performed at 170°C for 5, 10 and 15

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

minutes with H2SO4 (Figure 18). The hydrolysis of styrene oxide to 1-phenylethane-1,2- diol had a fast reaction rate since all styrene oxide was converted after 5 minutes.

% 100 90 Styrene oxide 80 conversion 70 60 Diol yield 50 40 Aldehyde 30 yield 20 By-product 10 yield 0 0 5 10 15 20 Reaction time (min)

Figure 18: Influence of reaction time on the synthesis of phenylacetaldehyde from styrene oxide.

MW, T = 170°C, Catalyst: H2SO4 (20 mol%), Water/CPME, 1:3, v/v.

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water

4. Conclusion

Phenylacetaldehyde (1) is a molecule used in perfume compositions, for the preparation of pharmaceuticals, insecticides, etc, or as a useful intermediate in many organic syntheses. Its synthesis by dehydration of 1-phenylethane-1,2-diol (2) was studied under thermal heating and under microwave irradiation. The formation of phenylacetaldehyde can be followed by an aldol condensation leading to the formation of an unwanted product, 2,4-diphenylbut-2-enal (3). The aim of our work was to produce phenylacetaldehyde in a good yield while limiting the formation of the condensation product.

According to our experiments, using an autoclave as reactor was not the best option to produce phenylacetaldehyde in good yield and selectivity. The slow heating rate of the reaction medium induced by the thermal inertia of the reactor and the long reaction times allowed the phenylacetaldehyde to react on itself to form the by-product. Low phenylacetaldehyde yields and selectivities were obtained. For example, only 9% of aldehyde was obtained at 200°C after 16h of reaction whereas the yield of condensation product reached 42%. Because of the reactor alloy, the use of catalysts was very limited in order to avoid its corrosion.

Therefore, it appeared to us that the use of microwave irradiation could be an interesting alternative to thermal heating. Among the many advantages of using microwave irradiation, the fast heating rate and the higher yields and selectivities usually obtained could help us to improve phenylacetaldehyde yield while limiting the formation of the by-product.

Firstly, the optimisation of the phenylacetaldehyde formation under microwave irradiation was done in water. Temperature, reaction time and nature of the catalyst were varied. Best reaction conditions were found to be a temperature of 170°C for a reaction time of 30 minutes. Mineral acids HCl and H2SO4 gave the highest phenylacetaldehyde yields (63 and 62% respectively). Nevertheless, Lewis acids AlCl3 and FeCl3 proved to be a good alternative to these corrosive acids since they led to similar yields. However, in water, the selectivity towards phenylacetaldehyde was still inferior to 70% because of the formation of the aldol condensation product. To solve this issue, it was decided to introduce a co-solvent, a strategy widely used for the dehydration of

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water monosaccharides. Since 1-phenylethane-1,2-diol and the catalyst had a better affinity with water, the dehydration reaction occurred in the aqueous phase. Then, the phenylacetaldehyde formed was transferred into the organic phase and was not able to react with itself into further reactions. First, the co-solvent, cyclopentyl methyl ether (CPME), was selected and then, the proportions between the aqueous and the organic phase were varied. The introduction of CPME had proven to be effective. Indeed, by comparison with the monophasic method, it allowed us to increase the phenylacetaldehyde yield from 63% up to 97% while limiting the formation of the aldol condensation product, 2,4-diphenylbut-2-enal, to 1% maximum. The operating conditions optimised under microwave irradiation were:

 Temperature: 170°C  Reaction time: 20 minutes  Biphasic medium: water/CPME, 1:3, v/v

 Catalysts: FeCl3, HCl, H2SO4  Catalyst quantity: 20 mol%

Best results were obtained with mineral acids (97% of yield with H2SO4 and 93% with HCl) but FeCl3 seemed to be a good alternative with a 84% yield.

Moreover, in addition to a higher selectivity, one advantage of our system lay in the easy separation of the two phases. After the reaction, the organic phase could be treated to recover the aldehyde and the aqueous phase, containing the catalyst, could be reused for a second cycle under the same conditions. The reusability of the catalytic aqueous phase was confirmed by performing 5 successive reactions. It was recyclable for up to five cycles even if a progressive decrease in activity was observed for the acid catalysts FeCl3 and HCl. No yield variation was observed with H2SO4.

In order to exemplify our optimised methods, several alcohols of structure similar to 1-phenylethane-1,2-diol were submitted to dehydration in biphasic and monophasic media. The dehydration of 1-phenylethanol and 2-phenylethanol to styrene, 1- phenylpropan-1-ol to 1-phenylpropene and hydrobenzoin to diphenylacetaldehyde (pinacol rearrangement was favoured) were compared. Except 2-phenylethanol which was not reactive, all alcohols tested gave the expected products in moderate to good yields. In general, alcohol conversion was higher in sole water but the yield and

Chapter II: Dehydration of 1-phenylethane-1,2-diol in water selectivity of the target products were higher in biphasic medium. Therefore, as for 1- phenylethane-1,2-diol, the presence of a co-solvent proved to be necessary to avoid the formation of by-products.

Finally, application of the optimised dehydration methods to styrene oxide as alternative substrate produced the target aldehyde in yields comparable to those obtained from 1-phenylethane-1,2-diol: 86, 95 and 94% of phenylacetaldehyde were produced with

FeCl3, HCl and H2SO4 respectively.

This study led to the publication of two articles in a peer-reviewed journals.[141,142]