Université de Toulouse, INP, LCA (Laboratoire de Chimie Agro-Industrielle), ENSIACET, 4 Allée

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1 Electronic Supplementary Material (ESI) for Green Chemistry. This journal is The Royal Society of Chemistry 2014 Electronic Supplementary Material (ESI) - Manuscript - ID is GC-ART Glycerol Acetals and Ketals as Bio-based Solvents: Positioning in Hansen and COSMO-RS spaces, Volatility and Stability towards Hydrolysis and Autoxidation Laurianne Moity (1), Valérie Molinier (1), Adrien Benazzouz (1), Véronique Nardello-Rataj (1), Mohammed Kamal Elmkaddem (2,3), Pascale de Caro (2,3), Sophie Thiébaud-Roux (2,3), Vincent Gerbaud (4), Philippe Marion (5), Jean-Marie Aubry (1) * (1) Université Lille Nord de France, Université de Lille 1, ENSCL, E.A Chimie Moléculaire et Formulation, Cité Scientifique, Villeneuve d'ascq Cedex, France, Jean-Marie.Aubry@univlille1.fr (2) Université de Toulouse, INP, LCA (Laboratoire de Chimie Agro-Industrielle), ENSIACET, 4 Allée Emile Monso, Toulouse, France (3) INRA, UMR 1010 CAI, Toulouse, France (4) Université de Toulouse, INP, CNRS, LGC (Laboratoire de Génie Chimique), ENSIACET, 4 Allée Emile Monso, Toulouse, France (5) Solvay Recherches & Innovation, Centre de Lyon, 85 rue des Frères Perret, Saint-Fons Cedex, France

2 Table 1: Number, name and structure of the glycerol acetals/ketals and of the various oxygenated solvents studied in this work. The experimental boiling points (b.p.) at atmospheric pressure reported in SciFinder are given. For 4, the value reported at reduced pressure has been extrapolated at atmospheric pressure (in italics) using the Pressure-Temperature nomograph based on the Clausius-Clapeyron equation. T 50% is the temperature at which half of the sample has vaporised during an ATG experiment (see text). It allows predicting a b.p. value, also indicated (see text). The Hansen solubility parameters d, p and h are the ones provided by Hansen 50 or calculated using the Yamamoto Molecular Breaking (Y-MB) method implemented in the HSPiP software (HSPiP, version ). The F1, F2, F3, F4 coordinates in the COSMO-RS are also provided, as described in references 51 and 7. N Name Structure experimental b.p. ( C) T 50% ( C) estimated b.p. ( C) d (MPa 1/2 ) p (MPa 1/2 ) h (MPa 1/2 ) F F2 F3 F4 1a Glycerol formal (dioxolane) b Glycerol formal (dioxane) Solketal Methylisobutylidene glycerol n.d a Benzaldehyde glycerol acetal (dioxolane) b Benzaldehyde glycerol acetal (dioxane) ,3-Dioxolane

3 6 2-Methyl-1,3-dioxolane ,2-Dimethyl-1,3- dioxolane ,2,4-Trimethyl-1,3- dioxolane ,4-Dioxane Methylal Ethylal n-butyl acetate Ethylene glycol n-butyl ether (C 4 E 1 ) Propylene glycol n-butyl ether (C 4 P 1 ) Diethylene glycol ethyl ether (C 2 E 2 )

4 16 Diethylene glycol butyl ether (C 4 E 2 ) Diethylene glycol hexyl ether (C 6 E 2 ) Tetrahydrofurfuryl alcohol Dimethyl isosorbide

5 Synthesis of Benzaldehyde Glycerol Acetal (BGA) 4a + 4b Material and methods For syntheses of 4a + 4b, glycerol (Sigma-Aldrich, 98%), benzaldehyde (Sigma-Aldrich, 98%) and cyclohexane (Sigma-Aldrich, 99%) were used. The cation exchange resin catalyst, Amberlyst-15, commercially available from Fluka, had a capacity of 4.7 meq H + /g and an average particle size of m. As a pre-treatment before the experiments, the resin was washed with distilled water, methanol then ether. It was dried under vacuum for 10 h at 40 C. Gas Chromatography analysis Chromatograms were obtained using Varian 3800 GC instrument coupled to a flame ionisation detector (FID). The silica capillary column (Stabilwax, 30 m) was supplied by Restek Corporation. The carrier gas was helium (Air Liquide, France) delivered at a flow rate of 1.7 ml/min. The injector and detector temperatures were set at 250 C. The oven temperature was held at 60 C for 1 min, ramped up to 240 C at 20 C/min and held for 10 min at this temperature. The retention times for the relevant compounds are 2 min, for cyclohexane, 3.8 min for dodecane, 6.3 min for benzaldehyde, 10.4 min for glycerol, 12.4 min for cis-4b, 12.8 min for cis-4a, 13.5 min for trans-4a, 16.1 min for trans-4b. 4b as the 6-member ring is a 1,3-dioxane derivative called 2-phenyl-(1,3)dioxan-5-ol and 4a as the 5-member ring is a 1,3-dioxolane derivative called (2-phenyl-(1,3)dioxolan-4-yl)-methanol. Dodecane was added in samples of reaction mixture as an internal standard before analysis by gas chromatography. Benzaldehyde conversion (X B ), acetals yield (Y BGA ) and products selectivity (S i ) were calculated according to the following expressions: X B (%) 1 n reacted benzaldehyde,,, initial n 100 Y BGA (%) n BGA n 100 S initial 4a (%) 4a 100 benzaldehyde n benzaldehyde n 4a n 4b S 4b (%) n 4b n 4a n 4b 100 Preparation of benzaldehyde glycerol acetal (BGA) Acetalisation reactions of glycerol with benzaldehyde were carried out in a 100 ml glass multi-reactors device equipped with a magnetic stirrer, a thermometer and a heating controller. Dean Stark apparatus was used to remove continuously the water via its hetero-azeotrope with cyclohexane (69.5 C, 91.6% wt./wt. cyclohexane). The magnetically stirring was fixed at 150 rpm for all the experiments to avoid external diffusion limitation. In a typical experiment, an equimolar mixture of glycerol (6.3 g, 68.5 mol) and benzaldehyde (7.3 g, 68.5 mol) was stirred with pre-activated Amberlyst-15 (4% mol, 4.7 mmol H + /g) and cyclohexane (10 ml). The reaction was conducted under reflux for 3 hours. At the end of the reaction, the medium was diluted with ethyl acetate, filtered immediately and concentrated under vacuum to remove the solvent. Results and discussion As described by Deutsch et al., 43 acetalisation of glycerol and benzaldehyde yields cyclic acetals composed of 1,3-dioxolane and 1,3-dioxane derivatives. The authors have identified several factors that govern the yield and selectivity of acetal isomers among which temperature, reaction time and nature of solvent. The influence of these different parameters on the synthesis of benzaldehyde glycerol acetal (BGA) 4a + 4b was investigated by using Amberlyst-15. Cyclohexane has been selected as solvent because it matches the requirements of compatibility with the medium and equilibrium shift by forming an azeotropic mixture with water. First, the effect of reaction temperature was investigated in order to control the isomers ratios (Table 2). Table 2: Effect of reaction temperature (T) and time (t) on benzaldehyde conversion (X B ), yield (Y BGA ) and selectivity of benzaldehyde glycerol acetal isomers 4a and 4b. Conditions: molar ratio glycerol:benzaldehyde 1:1, 4% Amberlyst-15, 10 ml cyclohexane, 150 rpm.

6 T ( C) t (h) X B (%) Y BGA (%) 4a (%) 4b (%) Reflux Reflux (a) Reflux (b) (a) + overnight at room temperature in the presence of Amberlyst-15 resin, (b) + overnight at room temperature after removing catalyst The results in Table 2 show that the selectivity of acetal isomers is quite dependent on the temperature / catalyst couple. The highest proportion of 1,3-dioxolane derivative 4a is 56% after a reaction conducted for 3 hours at reflux temperature, and decreases when lower temperatures are used. Therefore, the formation of the six-membered cyclic acetal seems to be enhanced under mild temperatures (30 C in cyclohexane), which is compliant with the results reported by Deutsch, under refluxing dichloromethane as a low boiling point solvent. 43 We also found that the 1,3-dioxane derivative 4b slightly predominates (58%), by keeping the reaction mixture overnight at room temperature, in the presence of Amberlyst-15 resin, while the ratio 4a:4b does not change in the same conditions without catalyst. In fact, a ring-transformation process occurs according to the acidcatalysed equilibrium previously described. 43 As expected, increased temperature improved the conversion of benzaldehyde into acetals, therefore the azeotropic reflux temperature was kept for the following experiments. Table 3 shows the effect of varying the solvent amount and the catalyst loading on the production of glycerol acetals. The results for the three cyclohexane volumes tested presented in Table 3 show that an increase of solvent content in the reaction mixture does not significantly change the selectivity towards five/six-membered cyclic acetals. The best acetals yield of 82% was obtained for 10 ml, meaning that the maximum of water was removed by azeotropic distillation. The increase in catalyst loading from 1 to 5 mol % has a slight effect on the reaction kinetics since acetals yields vary from 80 to 84%. From 4 mol %, the number of available active catalytic sites is enough to ensure an adsorption process of reactant on catalyst surface. The results illustrate that the varying amounts of solvent and of resin always direct the selectivity in favor of the 5-membered ring isomer 4a, which is the kinetic product. Finally, 10 ml of solvent and 4% of Amberlyst-15 were kept for kinetic studies. Table 3: Effect of catalyst loading (Cat) and solvent amount (V cyclo ) on benzaldehyde conversion (X B ), yield (Y BGA ) and selectivity of benzaldehyde glycerol acetal isomers 4a and 4b. Catalyst loading is given in mol. % towards glycerol. Conditions: molar ratio glycerol:benzaldehyde 1:1, refluxing temperature, 3h, 150 rpm. Cat (%) V cyclo (ml) X B (%) Y BGA (%) 4a 4b While keeping these experimental conditions, acetalisation reaction was monitored over time. The results are given in Figure 1.

7 Figure 1: Kinetics of the Amberlyst-15-catalysed condensation of glycerol with benzaldehyde. Left: evolution of the total benzaldehyde glycerol acetal 4 (triangles), isomers 4a (black dots) and 4b (empty dots); right: evolution of the ratio of isomers 4a (black dots) and 4b (empty dots) in the product formed. Conditions: molar ratio glycerol:benzaldehyde 1:1, 4 mol.% Amberlyst-15, 10 ml refluxing cyclohexane, 150 rpm Figure 1 (left) confirms that a maximum yield in BGA (84%) is reached after 3 h of reaction. On the other hand, the percentage of isomers presented in Figure 2 (right) indicates that the five-membered cyclic acetal 4a is the major product during the whole reaction; the initial ratio 65/35 4a/4b tends towards an equilibrium corresponding to about 50% of each isomer, reached after 4 h reaction time. This result confirms that 1,3-dioxolane 4a is the kinetic product. We have checked that the maximal yield was obtained after 3 h, corresponding to a 56/44 ratio for 1,3-dioxolane 4a / 1,3-dioxane 4b. After a distillation under vacuum of this mixture, the distribution switched towards 66/34, due to an enrichment in 1,3-dioxolane derivative 4a, of lower boiling point. This fraction enriched in 1,3- dioxolane compound 4a has been selected for hydrolysis studies. Finally, the experimental conditions proposed allow a quick acetalisation reaction with a high yield. Moreover, factors acting on the selectivity have been identified. It is thus possible to design a specific composition by tuning parameters during the reaction (reaction time or temperature), as well as during the post-reaction treatments (contact with acid catalyst or distillation).

8 Table 4: Name, CAS number, Hansen solubility parameters and coordinates in COSMO-RS space of the 88 traditional solvents of Hansen s work 50. Name CAS δ d δ p δ h F1 F2 F3 F4 1-Bromonaphthalene Butanol Chlorobutane Pentanol Propanol ,1,1-Trichloroethane ,3-Butanediol ,4-Dioxane Ethyl-1-Butanol Ethyl-Hexanol Nitropropane Acetic Acid Acetic Anhydride Acetone Acetonitrile Acetophenone Aniline Benzaldehyde Benzene Butyl Lactate Butyric Acid Butyronitrile Carbon Disulfide Carbon Tetrachloride Chlorobenzene Chlorocyclohexane Chloroform Cyclohexane Cyclohexanol

9 Cyclohexanone Cyclohexylamine Di-(2-Chloroethyl) Ether Di-Isobutyl Ketone Diacetone Alcohol Diethyl Amine Diethyl Ether Diethyl Sulfide Diethylene Glycol Diethylene Glycol Monobutyl Ether Diethylene Glycol Monomethyl Ether Dimethyl Formamide Dimethyl Sulfoxide Dipropyl Amine Dipropylene Glycol Ethanol Ethanolamine Ethyl Acetate Ethyl Benzene Ethyl Lactate Ethylene Dichloride Ethylene Glycol Ethylene Glycol Monobutyl Ether Ethylene Glycol Monoethyl Ether Ethylene Glycol Monoethyl Ether Acetate Ethylene Glycol Monomethyl Ether Formic Acid Furan Glycerol Hexane Isoamyl Acetate Isobutyl Isobutyrate

10 Isophorone m-cresol Mesityl Oxide Methanol Methyl Ethyl Ketone Methyl Isoamyl Ketone Methyl Isobutyl Carbinol Methyl Isobutyl Ketone Methylal Methylene Dichloride Morpholine n-butyl Acetate Nitrobenzene Nitroethane Nitromethane o-dichlorobenzene o-xylene p-xylene Propylene Carbonate Propylene Glycol Pyridine Styrene Tetrahydrofuran Tetrahydronaphthalene Toluene Trichloroethylene γ-butyrolactone

11 Table 5: Ranking of the 88 traditional solvents of Hansen s work 50 as regards to their proximity to acetals 1 to 4 according to the Hansen approach. Classical solvents Ranking from acetal/ketal 1a 1b 2 3 4a 1-Bromonaphthalene Butanol Chlorobutane Pentanol Propanol ,1,1-Trichloroethane ,3-Butanediol ,4-Dioxane Ethyl-1-Butanol Ethyl-Hexanol Nitropropane Acetic Acid Acetic Anhydride Acetone Acetonitrile Acetophenone Aniline Benzaldehyde Benzene Butyl Lactate Butyric Acid Butyronitrile Carbon Disulfide Carbon Tetrachloride Chlorobenzene Chlorocyclohexane Chloroform Cyclohexane Cyclohexanol Cyclohexanone Cyclohexylamine Di-(2-Chloroethyl) Ether Di-Isobutyl Ketone Diacetone Alcohol

12 Diethyl Amine Diethyl Ether Diethyl Sulfide Diethylene Glycol Diethylene Glycol Monobutyl Ether Diethylene Glycol Monomethyl Ether Dimethyl Formamide Dimethyl Sulfoxide Dipropyl Amine Dipropylene Glycol Ethanol Ethanolamine Ethyl Acetate Ethyl Benzene Ethyl Lactate Ethylene Dichloride Ethylene Glycol Ethylene Glycol Monobutyl Ether Ethylene Glycol Monoethyl Ether Ethylene Glycol Monoethyl Ether Acetate Ethylene Glycol Monomethyl Ether Formic Acid Furan Glycerol Hexane Isoamyl Acetate Isobutyl Isobutyrate Isophorone m-cresol Mesityl Oxide Methanol Methyl Ethyl Ketone Methyl Isoamyl Ketone Methyl Isobutyl Carbinol Methyl Isobutyl Ketone Methylal Methylene Dichloride Morpholine n-butyl Acetate Nitrobenzene

13 Nitroethane Nitromethane o-dichlorobenzene o-xylene p-xylene Propylene Carbonate Propylene Glycol Pyridine Styrene Tetrahydrofuran Tetrahydronaphthalene Toluene Trichloroethylene γ-butyrolactone

14 Table 6: Ranking of the 88 traditional solvents of Hansen s work 50 as regards to their proximity to acetals 1 to 4 according to the COSMO-RS approach. Classical solvents Ranking from acetal/ketal 1a 1b Bromonaphthalene Butanol Chlorobutane Pentanol Propanol ,1,1-Trichloroethane ,3-Butanediol ,4-Dioxane Ethyl-1-Butanol Ethyl-Hexanol Nitropropane Acetic Acid Acetic Anhydride Acetone Acetonitrile Acetophenone Aniline Benzaldehyde Benzene Butyl Lactate Butyric Acid Butyronitrile Carbon Disulfide Carbon Tetrachloride Chlorobenzene Chlorocyclohexane Chloroform Cyclohexane Cyclohexanol Cyclohexanone Cyclohexylamine Di-(2-Chloroethyl) Ether Di-Isobutyl Ketone Diacetone Alcohol Diethyl Amine Diethyl Ether

15 Diethyl Sulfide Diethylene Glycol Diethylene Glycol Monobutyl Ether Diethylene Glycol Monomethyl Ether Dimethyl Formamide Dimethyl Sulfoxide Dipropyl Amine Dipropylene Glycol Ethanol Ethanolamine Ethyl Acetate Ethyl Benzene Ethyl Lactate Ethylene Dichloride Ethylene Glycol Ethylene Glycol Monobutyl Ether Ethylene Glycol Monoethyl Ether Ethylene Glycol Monoethyl Ether Acetate Ethylene Glycol Monomethyl Ether Formic Acid Furan Glycerol Hexane Isoamyl Acetate Isobutyl Isobutyrate Isophorone m-cresol Mesityl Oxide Methanol Methyl Ethyl Ketone Methyl Isoamyl Ketone Methyl Isobutyl Carbinol Methyl Isobutyl Ketone Methylal Methylene Dichloride Morpholine n-butyl Acetate Nitrobenzene Nitroethane Nitromethane o-dichlorobenzene

16 o-xylene p-xylene Propylene Carbonate Propylene Glycol Pyridine Styrene Tetrahydrofuran Tetrahydronaphthalene Toluene Trichloroethylene γ-butyrolactone

17 Possible intramolecular hydrogen bonding in solketal In the manuscript, the surprising high stability towards hydrolysis of solketal is justified by the plausible stabilization of the molecule via an intramolecular hydrogen bonding. These results and conclusion are in agreement with the results of Bruice and Piszkiwicz 1. We had a closer look at the molecular conformers of solketal with COSMO-RS (BP-TZVP, C30_1301). The profiles of the 2 most stable conformers (A and B) are shown in Figure 2. The σ- profile of the first conformer (A) exhibits a characteristic region for σ values below e.å -2 showing its ability to interact as a hydrogen-bond donor. This feature is absent from conformer B because it performs intramolecular hydrogen bond (Figure 2, red dotted line) Conformer A Conformer B p(σ) ,03-0,02-0,01 0,0 0,01 0,02 0,03 σ / e.å -2 Figure 2. σ-profiles of the 2 mains conformers of solketal according to COSMO-RS, including one (B) with an intramolecular hydrogen bonding. The predominance of conformers A or B depends on the environment of the molecule (Table 7). For instance, the low chemical potential of conformer B in n-hexane (µ B (hexane) = kj.mol -1 ) indicates that the intramolecular hydrogen-bonding is favored against interactions with the solvent. Conversely, the open form (conformer A) is favored in water (µ A (water) = kj.mol -1 ). This conclusion seems to be contradictory with our experimental observations which are in perfect agreement with those of Bruice and Pszkiwics for the hydrolysis of solketal. A more solid hypothesis for the experimental deviation observed would probably require a deeper computational study, including kinetic aspects and explicit solvation, but for sure this falls out of the scope of the paper. Table 7. Chemical potential of 2 conformers of solketal in water and n-hexane. Conformer Chemical potential of solketal (kj.mol -1 ) Water n-hexane A B This kind of arguments can be used for the fast estimation of the potential intramolecular hydrogen bonding in molecules, even in complex cases such as pharmaceutical molecules 2, and to discuss the effect of the solvent. 1 J. Am. Chem. Soc., 1967, 89 (14), pp J. Med. Chem., 2013, 56 (12), pp