Kévin Cousin

Frédéric Hapiot

Eric Monflier
email: eric.monflier@univ-artois.fr

Selective ruthenium-catalyzed hydroaminomethylation of unsaturated oleochemicals

Keywords: ruthenium, hydroaminométhylation, triolein, methyl undecenoate, amines T, triolein, MO, methyl oleate, ML, methyl linoleate, MU, methyl

Rhodium-catalyzed hydroaminomethylation (HAM) was recently described as an innovative way to functionalize triglycerides. In our search to reduce production costs, we sought to replace rhodium by ruthenium whose price is currently more than 20 times lower. In this study, we proceeded to HAM of unsaturated oleochemicals using ruthenium precursors under phosphine-free conditions. The experimental conditions were optimized by changing the nature of the solvent, the reaction temperature, and the CO/H2 pressure. While rhodium led to good catalytic activity and low chemoselectivity (mixture of hydroxyl and amino groups), ruthenium proved to be less active but more chemoselective as amino-substituted products were mainly formed. Of interest, HAM of methyl undecenoate (MU) occurred in a highly chemo-and regioselective fashion using acetonitrile as solvent.

Practical applications

Selective Ru-catalyzed hydroaminomethylation could be implemented on an industrial scale for the conversion of unsaturated oleochemicals into amines. This finding is of importance as the obtained aminoproducts can be used in many industrial areas such as surfactants, polymers, or lubricants.

Introduction

Hydroaminomethylation (HAM) has recently gained increasing interest within the field of green chemistry as the reaction provides biosourced amines (which may be used as monomers or quaternized to form surface active compounds) with high atom economy and low environmental impact. [START_REF] Crozet | Recent Advances in Amine Synthesis by Catalytic Hydroaminomethylation of Alkenes[END_REF][START_REF] Kalck | Tandem Hydroaminomethylation Reaction to Synthesize Amines from Alkenes[END_REF] HAM is a homogeneously catalyzed reaction, employing transition metal catalysts, which consists in three consecutive reactions involving hydroformylation of carbon-carbon double bonds into aldehydes, condensation of amines, and hydrogenation of the resulting imines/enamines into amines. These tandem reactions occur under CO/H2 pressure in a one-pot procedure, which is very appealing from a synthetic viewpoint. However, the economic viability of such reaction on an industrial scale is compromised by the high price of the rhodium catalyst and utilization of phosphines. [START_REF] Behr | Hydroformylation and related reactions of renewable resources[END_REF][START_REF] De Oliveira Dias | Sustainable route to biomass-based amines: rhodium catalyzed hydroaminomethylation in green solvents[END_REF][START_REF] Chen | Recent progress in rhodium-catalyzed hydroaminomethylation[END_REF] Effective recyclability and low catalyst loading are thus required. To prevent utilization of phosphines, alternatives emerged such as Rh/amine combinations. [START_REF] Behr | Hydroaminomethylation of fatty acids with primary and secondary amines -a new route to interesting surfactant substrates[END_REF] For example, we recently showed that phosphine-free HAM of triolein (T) and commercial oils resulted in the functionalization of fatty chains by amino and hydroxyl groups in various proportions depending on the applied experimental conditions. [START_REF] Vanbésien | A hydroaminomethylation/hydrohydroxymethylation sequence for the one pot synthesis of aminohydroxytriglycerides[END_REF][START_REF] Hapiot | Aminoalcools gras et procédé de préparation de ceux-ci[END_REF] To overcome the pricing hurdle of rhodium catalysts, ruthenium-based approaches were developed. Ruthenium was envisaged as an interesting surrogate because it is currently more than 20 times cheaper than rhodium. Ruthenium-catalyzed HAM have already been described for petrosourced substrates. [START_REF] Jachimowicz | Scope and Pathway of Catalytic Aminomethylation of Olefins[END_REF][START_REF] Schaffrath | Regio control in ruthenium catalysed aminomethylation[END_REF][START_REF] Srivastava | Ruthenium carbonyl-complex catalyzed hydroaminomethylation of olefins with carbon dioxide and amines[END_REF][START_REF] Wu | Efficient and Regioselective Ruthenium-catalyzed Hydroaminomethylation of Olefins[END_REF][START_REF] Gülak | Phosphine-and Hydrogen-Free: Highly Regioselective Ruthenium-Catalyzed Hydroaminomethylation of Olefins[END_REF][START_REF] Wu | Using Aqueous Ammonia in Hydroaminomethylation Reactions: Ruthenium-Catalyzed Synthesis of Tertiary Amines[END_REF][START_REF] Liu | From Internal Olefins to Linear Amines: Ruthenium-catalyzed Domino Watergas Shift/Hydroaminomethylation Sequence[END_REF][START_REF] Ali | Carbon Dioxide Transformation in Imidazolium Salts: Hydroaminomethylation Catalyzed by Ru-Complexes[END_REF][START_REF] Oda | Diene hydroaminomethylation via ruthenium-catalyzed C-C bond forming transfer hydrogenation: beyond carbonylation[END_REF] To our knowledge, nothing was reported so far on utilization of ruthenium catalysts in HAM of unsaturated oleochemicals. In the present study, we describe pros and cons of ruthenium as a metal catalyst in HAM of unsaturated fatty chains (Figure 1) and compare the observed catalytic performances to those obtained with rhodium.

Materials and methods

Reagents and solvents

Triolein (T, 97% C18:1), methyl oleate (MO), methyl linoleate (ML), methyl undecenoate (MU), Ru3CO12, amines, and solvents were received from Aldrich (France) in their highest purity. VHOSO (Very High Oleic Sunflower Oil, 86% C18:1, 6% C18:2, 4% C18:3, 3% C18:0, 1% C20:0) was a gift from Novance (Venette, France). T, MO, ML, MU and VHOSO were deperoxidized over basic alumina before use. Syngas (CO/H2 = 1/1) and hydrogen were supplied from Air Liquide (France). CDCl3 (99.50% isotopic purity) was purchased from Eurisotop.

General procedure of HAM experiments

All hydroaminomethylation experiments were carried out in laboratory reactors equipped with a mechanical stirrer, pressure regulators and a safety rupture valve from Parr Instrument Company (USA). In a typical experiment, triolein (1 mL, 1 mmol), Ru3CO12 (3.2 mg, 0.015 mmol), and HNBu2 (3 mmol) were dissolved in toluene (6 mL). The solution was then poured into the stainless-steel autoclave. After it had been heated to reaction temperature, the reactor was pressurized under CO and H2 pressures and the solution was stirred at 1500 rpm. After 18 h, the reactor was cooled down to RT and depressurized. The crude reaction mixture was filtered on Celite®545 to remove the ruthenium catalyst and the products were analyzed.

Products analysis

After evaporation of toluene, an aliquot of the organic phase was dissolved in 500 L CDCl3 and analyzed at RT by NMR spectrometry using a Bruker DRX300 spectrometer operating at 300 MHz for 1 H nuclei and 75 MHz for [START_REF] Gülak | Phosphine-and Hydrogen-Free: Highly Regioselective Ruthenium-Catalyzed Hydroaminomethylation of Olefins[END_REF] C nuclei. Conversions and selectivities were determined by 1 H NMR by comparing the integrations of signals (see supporting information). Conversions and selectivities were also confirmed by GC-MS for MU. The GC-MS analyses were performed using a Shimadzu QP2010 gas chromatograph with a split/splitless injection port and coupled with mass spectrometer. The separation was performed with a silica capillary column Zebron ZB-SemiVolatils (5% polysilarylene-95% dimethylsiloxane, 30 × 0.25 mm, internal diameter 0.25 µm) (see supporting information). Crude reaction mixtures were also purified on a silica column (heptane/ethyl acetate 90/10 v/v) and the isolated products were fully characterized by NMR spectroscopy (see supporting information).

Results

In an initial exploratory study to assess the performances of ruthenium in HAM of biosourced substrates, we chose T as a model substrate and Ru3CO12 as a ruthenium precursor as its efficacy was recently proven in HAM of petrosourced substrates. [START_REF] Liu | From Internal Olefins to Linear Amines: Ruthenium-catalyzed Domino Watergas Shift/Hydroaminomethylation Sequence[END_REF][START_REF] Ali | Carbon Dioxide Transformation in Imidazolium Salts: Hydroaminomethylation Catalyzed by Ru-Complexes[END_REF] Reaction conditions were similar to previous studies on rhodium catalysts. [START_REF] Vanbésien | A hydroaminomethylation/hydrohydroxymethylation sequence for the one pot synthesis of aminohydroxytriglycerides[END_REF] The first set of experiments concerned the amine nature (Table 1). Indeed, during the course of the HAM reaction, amines may act as both reactants and ruthenium ligands. It is thus of importance to define the ideal amine structure capable of i) coordinating to ruthenium to form hydroformylating and hydrogenating catalysts, and ii) condensing with aldehydes to form imine/enamine intermediates. To reach T-grafted tertiary amines, we made use of secondary amines.

Insert Table 1 Acyclic secondary amines led to moderate conversions (Table 1, entries 1-3) and high selectivity in amino-derivatives (amine selectivity up to 94%) while pyrrolidine gave lower conversion (entry 4) and higher proportion of aldehydes (S. Ald = 10%). Diethanolamine, for its part, was dissolved in THF as it was insoluble in toluene. It was basically inactive under such experimental conditions. A set of batch experiments was then carried out to optimize the experimental conditions using dibutylamine, the best secondary amine of Table 1 in terms of catalytic performances. Changing the nature of the solvent greatly affected the catalytic activity. The conversion dropped to 18% with THF (Table 1, entry 6) and to 6% with isopropanol (entry 7), suggesting that the solvent has an influence on the catalytic performances. Conversely, the selectivity in amino-derivatives were slightly higher (96% and 97% with THF and isopropanol, respectively, vs 94% with toluene). Only hydrogenated products were detected as sideproducts whatever the solvent. Under otherwise identical conditions, no reaction took place using Nmethyl-2-pyrrolidone (NMP) as a solvent (entry 8). Logically, reducing the catalyst loading by a factor 2 halved the conversion without altering the selectivities (Table 2, entry 3).

Insert Table 2.

As expected, variations of the reaction temperature greatly influenced both the conversion and selectivities. At 90 °C, the conversion is only 6%, indicative of the higher activation energy required with ruthenium compared to rhodium. Raising the temperature to 120 °C speeded up the catalytic activity as 31% C=C were converted over 18 h at 120 °C. No aldehydes or alcohols were identified irrespective of the temperature. The proportion of amino-derivatives was high (up to 98%) but slightly decreased when increasing the temperature, to the benefit of small amounts of hydrogenated products.

Insert Table 3 Attempts to enhance the performance of the Rucatalyst through variation of the CO/H2 pressure from 40 to 100 bar resulted in a significant increase in the conversion from 9 to 29%, respectively, in line with previous results from the literature (Table 3). [START_REF] Srivastava | Ruthenium carbonyl-complex catalyzed hydroaminomethylation of olefins with carbon dioxide and amines[END_REF] However, contrary to what was observed when increasing the reaction temperature, the proportion of amino-derivatives slightly increased at the expense of the percentage of hydrogenated products. The best results were obtained at 100 bar of CO/H2 (entry 4). The pressure ratio of CO and H2 was varied to 1/2 while keeping the total pressure at 100 bar (entry 5). The slight increase in conversion (31%) was compensated by a significant decrease of amine selectivity. Under such experimental conditions, less amino-derivatives were formed to the benefit of hydrogenated products.

Insert Table 4

After a clearly positive effect of temperature and pressure was established, the study was then further extended to Ru-catalyzed HAM of other unsaturated oleochemicals. Converting MO was slightly easier than T, and a better selectivity in amino-derivatives was obtained as well (Table 4, entry 1). Conversely, the presence of a multiple C=C bonds on the fatty alkyl chains turned out to have a deleterious influence on both the conversion and selectivity. For example, conversions lower than 5% were measured for ML and VHOSO, suggesting that the presence of at least two C=C might inhibit the Ru-catalyst. As already stated for Rh-catalyst, [START_REF] Vanbésien | A hydroaminomethylation/hydrohydroxymethylation sequence for the one pot synthesis of aminohydroxytriglycerides[END_REF] C=C double bonds probably isomerize to form a -allyl Ru-complex displaying reduced catalytic activity towards internal alkenes. However, no conclusive statement can be made at this stage. HAM of MU was regarded with great attention, as it contains a terminal alkene that would behave very differently from the other studied substrates. Increasing the reaction time from 6 to 36 h improved the amine selectivity from 47 to 96% while the proportion of alkene isomers dropped from 47 to 0% (Table 4, entries 4-6). However, the l/b ratio slightly decreased. A nearly stoichiometric proportion of linear and branched amino derivatives was obtained over 36 h. Lowering the reaction temperature to 80 °C resulted in both a poor 14% conversion over 6 h, and an increase in the selectivity in linear products, which is expected due to the lower energy barrier for the hydroformylation of the terminal position (entry 7). Conversely, increasing the temperature to 120 °C resulted in substantial proportions of alkenes isomers (up to 60%, entry 9). Similar effects were observed by lowering the pressure of CO/H2 (1/1) (entry 10). Changing the CO/H2 from 1/1 to 1/2 gave the highest alkene isomers proportion found in this study (80%, entry 11). As confirmed by GC-MS, alkenes isomers showed their carbon-carbon double bond in 2-or 3-position. Utilization of THF instead of toluene as a solvent resulted in a lower conversion (from 100 to 74%) and chemoselectivity (from 47 to 40%) while the l/b ratio was improved form 62/38 to 75/25. The effect was even more pronounced when MU was subjected to HAM in CH3CN. The conversion dropped to 41% but the l/b ratio raised 96/4, the highest value found herein (entry 13). Over 18 h in CH3CN, the conversion reached 74% and the proportion of amino derivatives was significantly improved to 38% without affecting the regioselectivity (entry 14). Over 66 h, both the conversion and the chemoselectivity were increased (entry 15). The proportion of isomers decreased to 30% while the percentage of hydrogenated products remained constant. Similar results were obtained over 18 h at 140 °C (entry 16). Satisfyingly, isomers were no longer detected when the reaction proceeded over 66 h at 140 °C (entry 17). Amino-derivatives represented 96% of the final mixture, alongside 4% of hydrogenated products. Additionally, the regioselectivity remained constant with a l/b of 96/4. A further increase in reaction temperature to 160 °C did not alter the relative proportion of products but substantially altered the regioselectivity (entry 18).

Generally speaking, we notice a lower catalytic activity of the Ru/amine combination by comparison with the Rh/amine couple in HAM of internal C=C bonds. [START_REF] Vanbésien | A hydroaminomethylation/hydrohydroxymethylation sequence for the one pot synthesis of aminohydroxytriglycerides[END_REF] For example, under 80 bar CO/H2 (1/1) at 110 °C in toluene with HNBu2 as amine, the turn-over frequency (TOF) is of 0.88 h -1 in HAM of T using Ru-catalyst while we obtained TOF of 3.7 h -1 with Rh-catalyst in our previous study. [START_REF] Vanbésien | A hydroaminomethylation/hydrohydroxymethylation sequence for the one pot synthesis of aminohydroxytriglycerides[END_REF] Amongst the studied amines, acyclic ones are the more appropriate, probably because of their -donating ability towards ruthenium and the flexibility of their structure to fit the ruthenium coordination sphere. Both electronic and steric effects can be distinguished using pyrrolidine and diethanolamine as reactants and potential Ruligands. In the presence of pyrrolidine, the presence of aldehyde intermediates (aldehyde selectivity = 10%) shows that the conversion of C=C bonds is incomplete within 18 h. Pyrrolidine being more rigid than acyclic amines, the bulky pyrrolidinecoordinated Ru-catalyst probably experiences more difficulty to reach bulky internal C=C bonds. This assumption is supported by previous studies by Beller et al. [START_REF] Gülak | Phosphine-and Hydrogen-Free: Highly Regioselective Ruthenium-Catalyzed Hydroaminomethylation of Olefins[END_REF] They showed that pyrrolidine is more appropriate for HAM of terminal alkenes than internal C=C bonds. As an indirect proof of the lower reactivity of internal C=C bonds, the less hindered terminal C=C bond of MU is converted over 6 h (Table 4, entry 4). The ineffectiveness of diethanolamine in combination with ruthenium clearly informs that inductive effects also affect the amine coordination towards the Ru center. Compared with acyclic amines, the lower donating ability of the diethanolamine nitrogen is undoubtedly responsible for the lack of reactivity of the Ru-catalyst, and the subsequent absence of aldehydes. Note that, apart for pyrrolidine, no aldehyde intermediates are detected over the course of the HAM reaction, indicative of their fast conversion into enamines by condensation with amines (see Figure S24, Supporting Information). Enamines then undergo fast hydrogenation to give saturated amino-derivatives. We conclude that the hydroformylation step seems to be ratedetermining in the Ru-catalyzed HAM process (Table 1), as already observed throughout the literature. [START_REF] Schaffrath | Regio control in ruthenium catalysed aminomethylation[END_REF][START_REF] Gülak | Phosphine-and Hydrogen-Free: Highly Regioselective Ruthenium-Catalyzed Hydroaminomethylation of Olefins[END_REF] Increases in both conversion and selectivity in amino-derivatives are observed in HAM of T on increasing the CO/H2 pressure (Table 3). Of interest, the selectivity in amino derivatives reaches 95% upon operating at 100 bar of CO/H2. This trend agrees well with those obtained in former studies on HAM of terminal alkenes. [START_REF] Wu | Efficient and Regioselective Ruthenium-catalyzed Hydroaminomethylation of Olefins[END_REF] The effect of the reaction temperature is typical of what is usually observed for HAM reaction of internal C=C bonds (Table 2). Rising the temperature leads to higher catalytic activity but lower selectivity. [START_REF] Crozet | Recent Advances in Amine Synthesis by Catalytic Hydroaminomethylation of Alkenes[END_REF][START_REF] Vanbésien | A hydroaminomethylation/hydrohydroxymethylation sequence for the one pot synthesis of aminohydroxytriglycerides[END_REF] Herein, the proportion of amino-derivatives decreases to the benefit of unwanted hydrogenated products. However, the effect of increasing the temperature is less pronounced with terminal alkenes such as MU as the selectivities remain rather constant up to 160 °C (Table 4, entry 17). Only the regioselectivity is slightly affected. The nature of the solvent also greatly affect the catalytic performances of the Ru-catalyzed HAM reaction. Regarding the coordination capability of the solvents, polar solvents such as THF, isopropanol, or NMP lead to low conversions, suggesting that they modify the ruthenium coordination sphere to such an extent that the coordination of the substrate is rendered difficult. The effect is amplified in CH3CN as this solvent can strongly coordinate ruthenium. The resulting Rucatalyst is then more prone to react with the terminal position, as exemplified by the high l/b of 96/4 reported in Table 4 (entry 13). This observation is in line with results reported by Keim et al. who showed that more strongly coordinating polar solvents favor high selectivities. [START_REF] Schaffrath | Regio control in ruthenium catalysed aminomethylation[END_REF] The crucial role played by the bulkiness of both the Ru-catalyst and the substrate is also revealed upon HAM of MU. Indeed, the results from Table 4 show that isomers are formed alongside the expected amino-derivatives. However, the proportion of isomers is clearly reduced over time while the proportion of branched amino-derivative increases (entries 13-15 and entries 16-17). The effect is especially spectacular in CH3CN at 140 °C over 66 h as internal isomers are fully converted into aminoderivatives with high chemo-and regioselectivities (Table 4, entry 17). This clearly indicates internal C=C are less reactive than terminal ones because of the lower accessibility towards the catalyst. As the isomerization process continues over the course of the reaction, internal C=C bonds isomerize into terminal ones, which then undergo HAM to yield amino derivatives.

Conclusions

To summarize, we investigated Ru-catalyzed HAM of unsaturated oleochemicals with a cost-cutting goal in mind. Throughout this study, we show that one of the main advantage of ruthenium over rhodium lies in the high selectivity in aminoderivatives and the absence of hydroxylated products. While alcohols are formed in nonnegligible proportions upon Rh-catalyzed HAM of unsaturated oleochemicals such as triglycerides, no alcohol is detected with Ru3CO12 as a catalytic precursor. Note that upon Ru-catalyzed HAM of terminal alkene such as MU, alkene isomers may be formed in non-negligible proportion. However, increasing the temperature and reaction time suffices to reduce their proportion. Interestingly, utilization of CH3CN as a solvent leads to both high conversion and selectivities. --

Figure 1 .

 1 Figure 1. Ru-catalyzed hydroaminomethylation of unsaturated oleochemicals.

  (3 mmol), Ru3CO12 (6.4 mg, 0.030 mmol), HNBu2 (3 mmol), toluene (6 mL), pressure of CO/H2 (1/1) = 100 bar. b pressure of CO/H2 (1/1) = 80 bar c pressure of CO/H2 (1/2) = 100 bar d in THF. e in CH3CN.

Table 1 .

 1 Ruthenium-catalyzed HAM of triolein using various amines and solvent a

	Entry	Amine	Conv. (%)	S. Ald (%)	S. Amine (%)	S. Hydro (%)
	1	HNEt2	37	0	86	14
	2	HNBu2	45	0	94	6
	3	HNHex2	45	0	90	10
	4	pyrrolidine	25	10	80	10
	5	HN(CH2CH2OH)2 b	0	0	0	0
	6	HNBu2 b	18	0	96	4
	7	HNBu2 c	6	0	97	3
	8	HNBu2 d	0	0	0	0
	a Triolein (1 mL, 1 mmol), Ru3CO12 (6.4 mg, 0.030 mmol), amine (3 mmol), toluene (6 mL), 110 °C, 100 bar
	CO/H2 (1/1), 18 h.

b

In THF. c in isopropanol. d In NMP.

Table 2 .

 2 of the temperature in ruthenium-catalyzed HAM of triolein a

	Entry	Temperature (°C)	Conv. (%)	S. Amine (%)	S. Hydro (%)
	1	90	6	98	2
	2	100	10	97	3
	3	110	24	94	6
	4	120	31	92	8
	a Triolein (1 mL, 1 mmol), Ru3CO12 (3.2 mg, 0.015 mmol), HNBu2 (3 mmol), toluene (6 mL), 80 bar CO/H2 (1/1),
	18 h.

Table 3 .

 3 Influence of the CO and H2 pressures in ruthenium-catalyzed HAM of triolein a

	Entry	(bar)	CO/H2	Conv. (%)	S. Amine (%) S. Hydro (%)
	1	40	1/1	9	90	10
	2	60	1/1	16	92	8
	3	80	1/1	24	94	6
	4	100	1/1	29	95	5
	5	100	1/2	31	86	14
	a Triolein (1 mL, 1 mmol), Ru3CO12 (3.2 mg, 0.015 mmol), HNBu2 (3 mmol), toluene (6 mL), 110 °C, 18 h.

Table 4 .

 4 Ruthenium-catalyzed HAM of other unsaturated oleochemicals. a

	Entry Substrate	Temp. (°C)	Reaction time (h)	Conv. (%)	S. Amine (%) (l/b)	S. Hydro (%)	S. Iso (%)
	1	MO	110	18	52	97	3	-
	2	ML	110	18	<5	-	-	-
	3	VHOSO	110	18	<5	-	-	-
	4	MU	110	6	100	47 (62/38)	5	47
	5	MU	110	18	100	70 (57/43)	3	27
	6	MU	110	36	100	96 (53/47)	4	0
	7	MU		6	14	(86/14)	4	29
	8	MU	100		52	54 (73/27)		40
		MU	120	6	100	38 (73/27)	2	60
	10 b	MU	110	6	79	21 (77/23)	6	63
	11 c	MU	110	6	97	18 (67/33)	2	80
	12 d	MU	110	6	74	40 (75/25)	3	57
	13 e	MU	110	6	41	29 (96/4)	2	69
	14 e	MU	110	18	74	38 (96/4)	6	56
	15 e	MU	110	66	100	67 (96/4)	3	30
	16 e	MU	140	18	100	64 (96/4)	2	34
	17 e	MU	140	66	100	96 (95/5)	4	0
	18 e	MU	160	18	100	64 (89/11)	6	30
	a C=C bonds

This work was performed, in partnership with the SAS PIVERT, within the frame of the French Institute for the Energy Transition (Institut pour la Transition Energétique (ITE) P.I.V.E.R.T. (www.institutpivert.com) selected as an Investment for the Future ("Investissements d'Avenir"). This work was supported, as part of the Investments for the Future, by the French Government under the reference ANR-001-01.

The authors have declared no conflict of interest.


D Liu

O Monfret

Y Bourdreux

D Urban

D Guianvarc'

G Doisneau

Fast Access to 5-Hydroxymethyl Derivatives of 2′-Deoxyuridine Promoted by Acidic Amberlyst 15 Resin

5-Hydroxymethyl derivatives of pyrimidine nucleosides are an important class of biologically relevant compounds. In addition, such derivatives and related compounds can be functionalized for various applications. To enable fast, economical, and efficient access to 5hydroxymethylated derivatives of 2′-deoxyuridine, we report a method for the O-5 chemoselective transformation of unprotected 5-(hydroxymethyl)-2′-deoxyuridine through selective etherification in the presence of an alcohol promoted by acidic Amberlyst 15 resin at room temperature. These mild conditions constitute a significant improvement compared with the harsh conditions previously described. Applied to various primary or secondary alcohols, the reaction showed a broad substrate scope, and 24 C(5)-modified derivatives of 5hmdU were synthesized with good isolated yields. Notably, this efficient procedure represents a straightforward method for preparing (i) several useful building blocks for subsequent chemical ligation by using CuAAC reactions; (ii) natural hypermodified thymidines and analogues, including glycosylated derivatives; and (iii) cyanoethyl-protected 5hmdU, useful for solid-phase oligonucleotide syntheses.

C(5)-Modified pyrimidine nucleosides have been extensively studied due to their antiviral, antibacterial, and anti-tumoral activities. [1][2][3][4][5][6] Furthermore, the discovery of oxidative lesions 7 or enzymatically catalyzed modifications at the C(5) position of pyrimidines within DNA [8][9][10][11][12] have prompted the development of efficient routes to the corresponding nucleoside building blocks for subsequent incorporation into oligonucleotides. [13][14][15][16] Moreover, the C(5) position is a popular site for the internal introduction of various labels and reactive groups into either synthetic oligonucleotides or natural nucleic acids, with applications in detection and quantification. 17 These various fields of investigation related to C(5)-modified pyrimidines explain the many synthetic approaches that have been developed to provide access to 5-substituted pyrimidine nucleosides and for their functionalization. 2,18 Most of these methods rely on easily accessible 5-iodo-2′deoxyuridine (5IdU) 19 which has been extensively used in Sonogashira, Heck, Stille, Suzuki-Miyaura, and Buchwald-Hartwig-Migita cross-coupling reactions. [START_REF]Palladium-Catalyzed Modification of Nucleosides, Nucleotides and Oligonucleotides[END_REF] Interestingly, in recent years, a repertoire of Pd-catalyzed reactions that proceed in water under mild conditions have been developed for applications in the functionalization of nucleobases and have revealed a potential for the biorthogonal labeling of nucleic acids. [START_REF] Omumi | [END_REF][22][23][24][25] 5-Bromomethyl-2′deoxyuridine (5BrmdU) has also often been used as key intermediate for the preparation of 5-modified derivatives of deoxyuridine; 26,27 nucleophilic substitutions of the bromine atom with alcohols or amines gives rapid access to such products. However, the preparation of the 5BrmdU requires radical bromination at the 5-methyl position of thymidine by using Nbromosuccinimide in benzene or CCl4, and strict control of this reaction is necessary to avoid the formation of secondary products through dibromination. 28 Other drawbacks are its modest yields, the need to work with the fully protected thymidine, and the requirement to engage the product in subsequent reactions without purification to avoid its degradation. 5-(Hydroxymethyl)-2′-deoxyuridine (5hmdU, 1) is also an interesting precursor for the introduction of functionalization at the C(5) position, as exemplified by esterification or glycosylation reactions with appropriately activated sugar derivatives. [28][29][30] However, the preparation of 5′,3′-protected 5-hydroxymethyl derivatives requires the aforementioned 5BrmdU. In the present study, we focused our attention on the unprotected 5hmdU (1) as a precursor providing rapid and selective access to 5-odified 2′-deoxyuridine compounds. 5h dU is a che ica stab e co pound, easi prepared fro 2′-deoxyuridine by using a scalable single-step reaction without protecting groups. Indeed, h drox eth ation of 2′deoxyuridine can be accomplished in aqueous formaldehyde or paraformaldehyde solutions with potassium hydroxide or triethylamine as a base. 31 The resulting 5hmdU (1) can be isolated by silica gel column chromatography in 60-80% yield. Further selective reactions of the 5-h drox group are i ited due to the presence of the second 5′ pri ar a coho group on the deoxyribose unit. However, the pseudobenzylic position makes it possible to envisage selective transformations.

However, only a few selective O(5) chemical transformations of 5hmdU (1) have been reported. Following the initial works of Cline et al. in 1959 on 5-substituted pyrimidines 32 and that of Scheit in 1966 33 on uridine derivatives, Sowers and Beardsley accomplished an O(5)-selective reaction of 1 in refluxing glacial acetic acid in the presence of trifluoroacetic acid to furnish the corresponding acetylated derivative in a good yield under S N 1 conditions. 34 Later, the Sowers group selectively prepared a 5-cyanoethyl derivative by trifluoroacetic acid-catalyzed etherification in refluxing 2-cyanoethanol (Scheme 1A). 35 It has also been reported by Sekine and co-workers 36 that the 5-hydroxy group of 5hmdU reacts selectively with sodium azide in chloro(trimethyl)silane with the incorporation of an azido group through the formation of a chloromethyl intermediate. 30,37 As shown in Scheme 1B, these selective 5hmdU transformations take advantage of the allylic position of the alcohol functionality allowing the formation of stable cat-ionic intermediates that react with nucleophiles to give either the ester 2 or the ether 3. These reactions were found to be fully selective, as proven by NMR analysis and comparison of the chemical shift of the respective C(5) methylene protons.

Scheme 1 (A) Previous works and our approach to the selective transformation of 5hmdU. (B) Proposed mechanism for the acid-catalyzed selective transformation.

Because of our interest in preparing ether derivatives of 5hmdU, we (and others) observed that these harsh conditions of etherification give rise to moderate yields 13,14,16 and, in our hands, subsequent cleavage of the glycosidic bond occurred. To identify milder conditions for forming the allylic cation intermediate suitable for the O(5)-selective etherification of 5hmdU by an S N 1-type reaction, we then considered the use of a polystyrene sulfonic resin as a catalyst at room temperature. Acidic resins are widely used as catalysts in organic reactions, and they have been found to be useful for the activation of hydroxy groups to access ester, alkene, or ether functionalities. [38][39][40] Use of such resins facilitates the workup of reactions, as simple filtration can be used to remove the acidic reagent. Allylic and benzylic alcohols form stable electrophilic intermediates that react readily with nucleophiles to form ether products, even at room temperature, and for this purpose, Amberlyst 15 proved to be very efficient. 41,42 Amberlyst 15 has even been used to induce the selective iodination of primary alcohols with sodium iodide, further demonstrating its usefulness in promoting the formation of electrophilic intermediates. 43 Here, we report a selective transformation of unprotected 5hmdU (1) by using acidic Amberlyst 15 resin as a promoter for the formation of the intermediate allylic cation and its reaction with several alcohols. This procedure permits rapid and efficient syntheses of several 5-(alkoxymethyl)-2′-deoxyuridines (including some that are useful as building blocks for subsequent functionalization), as well as natural hypermodified thymidines and their ana-logues, such as glycosylated derivatives, or cyanoethyl-protected 5hmdU, useful in solid-phase oligonucleotide syntheses.

Initially, we tested the selective etherification of 5hmdU (1) at room temperature by using Amberlyst 15 resin as a catalyst in the presence of several primary alcohols, which also served as solvents (Table 1). Due to the large excess of alcohol used in these preliminary reactions, low-boiling methanol, ethanol, and propan-1-ol were initially selected as reactants to facilitate the purification of the final products. Under these reaction conditions, total conversion of the starting material was observed within 24 hours. After removal of the residual alcohol, the resulting products were purified by flash column chromatography on silica gel, and the C(5) methyl ethers 4a-c were isolated in yields of 80-88% (Table 1, entries 1, 3, and 4). Interestingly, by using these mild conditions, we did not observe any glycosidic bond cleavage. Switching from Amberlyst 15 to acidic Dowex 50W resin did not improve either the time required for the reaction or the yield of the isolated products (entry 2).

Because of these encouraging results, we then attempted to perform the reaction in acetonitrile as the solvent to decrease the amount of alcohol required. Interestingly, we found that reactions in such conditions were also efficient and allowed the amount of the alcohol to be reduced to just five equivalents with no significant difference in yield (entries 5-7). Etherification reactions with various alcohols were then examined. A range of 2substituted ethanols, including several derivatizable alcohols (2-bromo-, 2-chloro-, and 2azidoethanol) were then used in etherification reaction (Scheme 2). 44 Moreover, 2cyanoethanol, commonly used to attach a protecting group to 5-(hydroxymethyl)pyrimidines for solid-phase oligonucleotide syntheses, 35 was assayed. The ether products 4d-i were obtained in good yields and with similar efficiencies, except for the reactions with 2bromoethanol and ethane-1,2-diol, which gave 4e and 4g, respectively, in yields of only 36 and 57%. Interestingly, the introduction of the azido group in 4i and 4j provided two useful building blocks for subsequent chemical ligation with alkynes through copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reactions. Importantly, the cyanoethyl-protected 5hmdU 4h was obtained in an excellent 90% yield. The synthesis of the cyanoethyl ether from unprotected 5hmdU previously required the use of harsh conditions involving the presence of TFA at 100 °C, and gave only a 50% yield. 13,14,16 The present procedure therefore provides easy access to a valuable starting precursor for the preparation of phosphoramidite building blocks for the synthesis of DNA containing 5hmdU or 5hmdC residues, as cyanoethyl ether-protected pyrimidines are widely used in automated DNA synthesis.

The procedure was then tested with several unsaturated ethenyl or propargyl alcohols (Scheme 2). We found an excellent reactivity, as 5hmdU was efficiently converted into the ethenyl derivatives 4k-m in yields from 87 to 97% in the case of pent-4-en-1-ol; the propargyl and homopropargyl ethers 4n and 4o, respectively, were also obtained in yields of 90 and 89%. These two propargyl derivatives are also potential versatile building blocks for further derivatization of nucleoside analogues by using CuAAC reactions.

Secondary alcohols were also high-yielding substrates, giving products 4r-u in yields of 63-81%. Finally, as expected, the bulky tertiary alcohol tert-butanol did not give the corresponding ether; likewise, adamantan-1-ol gave only the 5-N-(acetamido)methyl derivative product, due to a itter's reaction of the cationic inter ediate with acetonitrile. 45,46 By using benzylic alcohols in acetonitrile, ethers 4p and 4q were obtained in lower yields of 71 and 28% respectively. Unfortunately, we observed that a 4-methoxy substituent dramatically influenced the efficiency of the reaction. Interestingly, the transformation leading to the benzyl ether 4p can be seen as a selective masking reaction for the O(5) hydroxy group of 5hmdU. The alcohol functionality can then be easily recovered by a previously described protocol using anhydrous FeCl 3 in dichloromethane. 47,48 Next, to further investigate the scope of this protocol, we considered the synthesis of several C(5)-odified 2′-deoxyuridine derivatives of biological interest. Because oligonucleotide glycosylation has been shown to enhance cellular uptake, 49 we attempted to apply this method to the introduction of glycopyranosyl alcohol derivatives (Figure 1). Unfortunately, reactions of 1 with five equivalents of such derivatives were much less efficient, as exemplified by the low yields of 4v (17%) and 4w (33%) obtained by reactions with tri-O-benzyl--methylglucoside and diisopropylgalactoside respectively, [START_REF] Sun | Tri-O-benzyl--methylglucopyranoside was prepared according to[END_REF] presumably due to the increased steric bulk of these reactants. We were, however, pleased to isolate the thioglucopyranoside 4x in 74% yield, [START_REF]Diiso-propylgalactopyranoside was purchased from Acros Organics BVBA (Geel, Belgium). (Thioglucopyranoside 4x Isolated as a white solid; yield: 74%. 1 H NMR (360 MHz[END_REF] from a reaction conducted in the presence of five equivalents of -2,3,4,6-tetra-O-acetylthioglucopyranose. 52 Product 4x is a thio analogue of  -D-glucopyranosyl-5-hydroxymethyl-2′-deoxyuridine (glc-5hmdU) or the base J motif, a rare DNA modification identified in Trypanosoma brucei in 1993. 11

Figure 1 Structures of O-and S-glycoside derivatives

As an example to demonstrate the usefulness of this etherification protocol for the synthesis of other natural hypermodified thymidines, we applied our approach to a rapid preparation of 5-(2-aminoethoxy)methyl-2′-deoxyuridine (5; 5-NeOmdU), a 5hmdU derivative reported as a thymidine hypermodification, replacing 40% of thymidine nucleotides in the Salmonella phage ViI. 12,53 Reaction of 2-azidoethanol (easily prepared in 92% yield from 2chloroethanol) with 5hmdU in acetonitrile in the presence of Amberlyst 15 for 24 hours at room temperature gave the (2-azido-ethoxy)methyl derivative 4k in 81% yield. The final conversion of the azide group into a primary amine by the Staudinger reaction with 1.1 equivalents of triphenyl-phosphine in 1:1 water-methanol at 50 °C for three hours gave product 5 in 83% isolated yield (Scheme 3). We also prepared the aminopropoxy derivative 6 by a similar two-step transformation (Scheme 3). The previously reported synthesis of 5-NeOmdU (5) involved nucleophilic substitution of the bromine atom of the 5-bromomethyl derivative of 3′,5′-di-O-acetyldeoxyuridine with an N-protected 2-aminoethanol as a nucleophile. 53 By using our protocol, the target compound 5 was obtained in only two steps from 5hmdU, without any protection steps, in 67% overall yield (Scheme 3). Finally, we were pleased to find that the Amberlyst 15-based procedure was highly efficient for the preparation of the 5-iodomethyl derivative 7 by reaction of 1 with one equivalent of sodium iodide in acetonitrile. Under these conditions, the formation of a new product and the total disappearance of the 5hmdU starting material was observed within one hour. After filtration of the resin, evaporation of the acetonitrile, and flash chromatography on silica gel, we obtained the iodide intermediate 7, which was found to be stable enough for 1 H and 13 C NMR analysis. 54 Interestingly, compound 7 is a valuable intermediate for the rapid syntheses of various derivatives with different groups at the C(5)-position of the pyrimidine nucleoside, as exemplified with the synthesis of 5-{[(2-hydroxyethyl)amino]-methyl}-2′-deoxyuridine (5-heNmdU; 8) 12 in two steps and 70% overall yield (Scheme 4). The intermediate 7 was also used in a preparation of the base J analogue 4x by nucleophilic substitution using 1.7 equivalents of the isothiourea derivative 9. [55][56][57][58] Reaction for four hours at room temperature in acetonitrile in the presence of triethylamine gave the -linked thioglucoside 4x in 59% isolated yield (Scheme 4).

In conclusion, a selective reaction of unprotected 5-(hydroxymethyl)-2′-deoxyuridine with various alcohols promoted by acidic Amberlyst 15 resin at room temperature was successfully developed for the preparation of a large number of 5-odified 2′-deoxyuridine derivatives in high yields. This procedure is an important improvement on the previous method, which required harsh conditions, and gave lower yields due to substantial cleavage of the glycosidic bond. Under our mild conditions for etherification, a broad scope of functionalities, including alkene, alkyne, alcohol, amino, and azido groups, can be easily and selectively introduced at the C(5) position of pyrimidine bases, thereby permitting further transformations by click reactions. By using this procedure, we also succeeded in preparing 5-(iodomethyl)-2′-deoxyuridine, useful in nucleophilic substitutions, as exemplified by the rapid preparation of the thio analogue of the base J nucleoside 4x. Work is in progress to extend this procedure to access more elaborate structures of biological relevance.

2 ,

 2 R=OAc, ref x 3, R= O(CH 2 ) 2 CN, ref y Previous work -ROH in MeCN acidic resin room temperature -ROH, acidic resin, room temperature

Scheme 3

 3 Scheme 3 Rapid preparation of 5-(2-aminoethoxy)methyl-2′-deoxyuridine (5) and 5-(2-aminopropoxy)methyl-2′-deoxyuridine (6). Reagents and conditions: (a) Azido alcohol (5 equiv), Amberlyst 15, MeCN, (b) Ph 3 P (1.1 equiv), 1:1 MeOH-H 2 O, 50 °C, 3 h

Scheme 4

 4 Scheme 4 Reagents and conditions: (a) NaI (1.0 equiv), Amberlyst 15, MeCN, r.t., 1 h; (b) 2-aminoethanol, KOH, r.t. 70% (two steps); (c) 9 (1.7 equiv), Et 3 N, MeCN, r.t., 4 h, 59% (two steps)

Table 1

 1 Optimizations of the conditions for the etherification reaction

	Entry	Resin H +	Solvent	Alcohol	R	Product	Yield c (%)
	1 a	Amberlyst 15		MeOH	Me	4a	87
	2 a	Dowex 50W		MeOH	Me	4a	76
	3 a	Amberlyst 15		EtOH	Et	4b	88
	4 a	Amberlyst 15		PrOH	Pr	4c	87
	5 b	Amberlyst 15 CH 3 CN	MeOH	Me	4a	76
	6 b	Amberlyst 15 CH 3 CN	EtOH	Et	4b	83
	7 b	Amberlyst 15 CH 3 CN	PrOH	Pr	4c	80

a Carried out at r.t. for 12-24 h. b Carried out with ROH (5 equiv) at r.t. for 12-24 h. c Isolated yield after flash chromatography (silica gel).

Scheme 2 Scope of the etherification reaction promoted by Amberlyst 15 acidic resin. Reagents and conditions: nucleoside 1, Amberlyst 15 (1 g/mmol 1), ROH (5 equiv), MeCN, r.t., 12-24 h. Isolated yields after flash chromatography (silica gel)


Claudia Prestigiacomo

Martina Biondo

Alessandro Galia
email: alessandro.galia@unipa.itrudina.bleta@univ-artois.fr

Eric Monflier

Anne Ponchel

Dominique Prevost

Onofrio Scialdone

Sébastien Tilloy

Rudina Bleta

Sebastien Tilloy

Interesterification of triglycerides with methyl acetate for biodiesel production using a cyclodextrin-derived SnO@-Al 2 O 3 composite as heterogeneous catalyst

Keywords: tin oxide, alumina, cyclodextrin, interesterification, methyl esters, biodiesel

teaching and research institutions in France or abroad, or from public or private research centers.

Interesterification of triglycerides with methyl acetate for biodiesel production using a cyclodextrin-derived SnO@γ-Al2O3 composite as heterogeneous catalyst

Introduction

The current energy system for transportation is still based on fossil fuels whose utilization is not sustainable in the long term due to limited resources and negative impact on climate change related to the accumulation of CO2 in the atmosphere [START_REF] Esan | A concise review on alternative route of biodiesel production via interesterification of different feedstocks[END_REF]. For these reasons, fossil fuels must be gradually substituted by other CO2 neutral renewable energetic sources. In this context, biodiesel can be an interesting renewable alternative to fossil diesel as it has similar performances, but lower emissions of particulate matter and greenhouse gases [START_REF] Liu | Emissions of regulated pollutants and PAHs from waste-cookingoil biodiesel-fuelled heavy-duty diesel engine with catalyser[END_REF].

The conventional industrial route to biodiesel (fatty acid methyl esters or FAME) production is by transesterification of triglycerides (TG) contained in fatty feedstocks, such as vegetable oils or animal fats, with excess methanol [START_REF] Lin | Fuel structure and properties of biodiesel produced by the peroxidation process[END_REF] using acid or base chemical catalysts [START_REF] Enweremadu | Technical aspects of production and analysis of biodiesel from used cooking oil. A review[END_REF], as well as enzymes [START_REF] Ranganathan | An overview of enzymatic production of biodiesel[END_REF].

Although transesterification has been widely used for FAME production, this technology presents some drawbacks, such as the generation of glycerol as a byproduct, which is usually managed as a waste. In fact, the vast amount of crude glycerol generated each year largely exceeds the current demand for chemical production in the market and the disposal of waste glycerol has become a serious environmental issue that needs to be resolved within the next decade. Another drawback of the transesterification is that methanol, which is used as acyl acceptor, is insoluble in the reaction media; therefore the alcoholysis generally starts with high interfacial mass transfer resistances that require accurate mixing. Recently, it was also found that methanol could be incompatible with the long-term stability of several heterogeneous catalytic systems, therefore making the overall process less effective [START_REF] Esan | A concise review on alternative route of biodiesel production via interesterification of different feedstocks[END_REF].

To overcome those limitations, other biodiesel production technologies have been developed so far [START_REF] Estevez | Biodiesel at the Crossroads: A Critical Review[END_REF][START_REF] Abbaszaadeh | Current biodiesel production technologies: A comparative review[END_REF]. In particular, the interesterification of triglycerides has been identified as a promising alternative to the transesterification route since methanol is substituted with methyl or ethyl acetate as acyl donors, which are perfectly miscible with the reactive mixture [START_REF] Casas | Methanol-enhanced chemical interesterification of sunflower oil with methyl acetate[END_REF]. In addition, the triacetylglycerol (triacetin, TA) generated as the main co-product, has a higher market value compared to glycerol since it can be added to the biodiesel formulation up to 10 wt.%, without changing the fuel quality [START_REF] Casas | Effects of triacetin on biodiesel quality[END_REF], and can also be used as green plasticiser for polymers and as additive in cosmetic and pharmaceutical industries [START_REF] Borges | Recent developments on heterogeneous catalysts for biodiesel production by oil esterification and transesterification reactions: a review[END_REF].

Many studies were conducted in the last years to investigate the potentiality of the interesterification in order to optimize the operative parameters and the performances of the catalytic system. Some of them evidence that this reaction could be performed without added catalysts, using supercritical methyl acetate [START_REF] Esan | A concise review on alternative route of biodiesel production via interesterification of different feedstocks[END_REF][START_REF] Campanelli | Synthesis of biodiesel from edible, non-edible and waste cooking oils via supercritical methyl acetate transesterification[END_REF][START_REF] Saka | A new process for catalyst-free production of biodiesel using supercritical methyl acetate[END_REF][START_REF] Goembira | Biodiesel production from rapeseed oil by various supercritical carboxylate esters[END_REF][START_REF] Goembira | Advanced supercritical methyl acetate method for biodiesel production from Pongamia pinnata oil[END_REF][START_REF] Goembira | Factors affecting biodiesel yield in interesterification of rapeseed oil by supercritical methyl acetate[END_REF] or ethyl acetate [START_REF] Sootchiewcharn | Biodiesel production from refined palm oil using supercritical ethyl acetate in a microreactor[END_REF][START_REF] Sakdasri | Lipid-based biofuel synthesized from palm-olein oil by supercritical ethyl acetate in fixed-bed reactor[END_REF] as acyl donnors, but the high-temperature and highpressure conditions reduce the process flexibility. Other studies report that the interesterification can be conducted at room temperature using alkaline hydroxide and/or alkoxides as homogeneous catalysts [START_REF] Abelniece | Biodiesel production by interesterification of rapeseed oil with methyl formate in presence of potassium alkoxides[END_REF][START_REF] Kampars | Interesterification of rapeseed oil with methyl acetate in the presence of potassium tert-butoxide solution in tetrahydrofuran[END_REF][START_REF] Kampars | The Unanticipated Catalytic Activity of Lithium tert-Butoxide/THF in the Interesterification of Rapeseed Oil with Methyl Acetate[END_REF][START_REF] Medeiros | Chemical interesterification of cotton oil with methyl acetate assisted by ultrasound for biodiesel production[END_REF][START_REF] Casas | Kinetics of chemical interesterification of sunflower oil with methyl acetate for biodiesel and triacetin production[END_REF][START_REF] Casas | New trends in biodiesel production: chemical interesterification of sunflower oil with methyl acetate[END_REF][START_REF] Miesiac | Transesterification of triglycerides with ethyl acetate[END_REF][START_REF] Kusumaningtyas | A new route of biodiesel production through chemical interesterification of jatropha oil using ethyl acetate[END_REF]. However, as alkaline compounds are only partially soluble in the reaction mixture, low molecular weight poly(ethyleneglycol) is usually employed as complexing agent, or hazardous solvents, such as tetrahydrofuran, are added to the reaction mixture to improve the reaction kinetics [START_REF] Kampars | Interesterification of rapeseed oil with methyl acetate in the presence of potassium tert-butoxide solution in tetrahydrofuran[END_REF][START_REF] Kampars | The Unanticipated Catalytic Activity of Lithium tert-Butoxide/THF in the Interesterification of Rapeseed Oil with Methyl Acetate[END_REF]. In another study, tin (II) octoate was identified as an efficient homogeneous catalyst in the interesterification of rapeseed oil with ethyl acetate acieving 61% fatty acid ethyl esters (FAEE) yield after 20 h at 210 °C [START_REF] Galia | Interesterification of rapeseed oil catalyzed by tin octoate[END_REF]. Although tin (II) octoate was completely soluble in the reaction system, its recovery was a serious drawback for the practical use of the process. In addition, enzymes have also been extensively employed as biocatalysts in the interesterification of vegetable oils with different acyl donors [START_REF] Dicosimo | Industrial use of immobilized enzymes[END_REF][START_REF] Jenab | Performance of two immobilized lipases for interesterification between canola oil and fully-hydrogenated canola oil under supercritical carbon dioxide[END_REF][START_REF] Pacheco | Optimization of reaction conditions in the enzymatic interesterification of soybean oil and fully hydrogenated soybean oil to produce plastic fats[END_REF][START_REF] Bharathiraja | The kinetics of interesterfication on waste cooking oil (sunflower oil) for the production of fatty acid alkyl esters using a whole cell biocatalyst (Rhizopus oryzae) and pure lipase enzyme[END_REF][START_REF] Mendes | Simulation of process inter-esterification in fluidized bed bioreactor for production of biodiesel[END_REF][START_REF] Xu | Study on the kinetics of enzymatic interesterification of triglycerides for biodiesel production with methyl acetate as the acyl acceptor[END_REF]. Enzymes offer the advantage of conducting the reaction under mild conditions, giving near quantitative FAME yields with almost no activity loss upon reuse, but they fail to achieve high yields in short reaction times [START_REF] Xu | Study on the kinetics of enzymatic interesterification of triglycerides for biodiesel production with methyl acetate as the acyl acceptor[END_REF][START_REF] Du | Comparative study on lipase-catalyzed transformation of soybean oil for biodiesel production with different acyl acceptors[END_REF].

In this context, chemical heterogeneous interesterification has aroused as an interesting alternative since it offers the advantage of producing high FAME yields in short reaction times and the possibility to regenerate and reuse the catalyst, therefore reducing the operation costs. From the literature on this field, it seems however that interesterification usually requires longer reaction times with respect to transesterification to reach equivalent FAME yields [START_REF] Esan | A concise review on alternative route of biodiesel production via interesterification of different feedstocks[END_REF]. Phenyl-sulfonic acid-functionalized SBA-15 catalyst [START_REF] Usai | Sulfonic acid-functionalized mesoporous silicas: microcalorimetric characterization and catalytic performance toward biodiesel synthesis[END_REF], nobium phosphate, nobium oxide, γ-alumina and zeolite HY [START_REF] Ribeiro | Efficiency of heterogeneous catalysts in interesterification reaction from macaw oil (Acrocomia aculeata) and methyl acetate[END_REF][START_REF] Ribeiro | Synthesis of methyl esters and triacetin from macaw oil (Acrocomia aculeata) and methyl acetate over γalumina[END_REF], together with mixed oxides [START_REF] Simões | Heterogeneous catalyst screening for fatty acid methyl esters production through interesterification reaction[END_REF] and hydrotalcites [START_REF] Dhawan | Interesterification of triglycerides with methyl acetate for the co-production biodiesel and triacetin using hydrotalcite as a heterogenous base catalyst[END_REF], were investigated as heterogeneous catalysts in the interesterification of several raw materials at different operational conditions. In particular, 48% FAME yield was obtained in the interesterification of olive oil with ethyl acetate after 6 h at 130 °C in the presence of phenyl-sulfonic acid-functionalized SBA-15 [START_REF] Usai | Sulfonic acid-functionalized mesoporous silicas: microcalorimetric characterization and catalytic performance toward biodiesel synthesis[END_REF], while 52.5% and 49.8 % FAME yields could be reached in the interesterification of macaw oil with methyl acetate after 1 h at 250 °C using γ-alumina and nobium phosphate, respectively, as heterogeneous catalysts [START_REF] Ribeiro | Efficiency of heterogeneous catalysts in interesterification reaction from macaw oil (Acrocomia aculeata) and methyl acetate[END_REF].

Recently, commercial Sn(II)O has been identified as a promising heterogeneous catalyst in the interesterification of rapeseed oil with methyl acetate [START_REF] Interrante | Interesterification of rapeseed oil catalysed by a low surface area tin (II) oxide heterogeneous catalyst[END_REF]. Unfortunately, this material was composed of agglomerated particles with extremely low surface area (0.7 m 2 /g) and pore volume (0.0022 cm 3 /g) which may cause inevitable mass transfer limitations during the catalytic process, leading to a decrease of the catalyst utilization efficiency. Therefore, finding a way to control the morphology and surface properties of Sn(II)O and at the same time increase the availability of catalytic active sites is of significant importance for optimizing the catalyst performance.

In this context, the application of γ-alumina (γ-Al2O3) as support material is an attractive option for increasing metal-support interactions owing to the great number of γ-Al2O3 surface defects that are known to play an important role as binding sites for catalytic particles and clusters [START_REF] Kwak | Coordinatively unsaturated Al 3+ centers as binding sites for active catalyst phases of platinum on gamma-Al2O3[END_REF][START_REF] Kwak | Understanding the nature of surface nitrates in BaO/γ-Al2O3 NOx storage materials: A combined experimental and theoretical study[END_REF]. In a previous study [START_REF] Bleta | Robust mesoporous CoMo/γ-Al2O3 catalysts from cyclodextrin-based supramolecular assemblies for hydrothermal processing of microalgae: effect of the preparation method[END_REF], we have proposed for the first time an efficient cyclodextrin (CD)-assisted colloidal self-assembly strategy to synthesize γ-Al2O3-supported CoMo catalysts with excellent catalytic activity and stability in the hydrothermal liquefaction (HTL) of microalgae. In particular, randomly methylated β-cyclodextrin (RaMeβCD) with an average degree of methylation of 1.8 methoxy groups per glycopyranose unit and surface active properties [START_REF] Bleta | Understanding the role of cyclodextrins in the self-assembly, crystallinity, and porosity of titania nanostructures[END_REF] was found to be particularly effective in directing the assembly of AlO(OH) colloids around the metallo-supramolecular assemblies, giving rise to robust and reutilisable composites with high energy recovery capacity and promising oxygen removal efficiency.

Herein, we explore the capacity of γ-Al2O3 nanoparticles to adsorb preferentially on the (001) facets of square-like SnO crystals and trigger their stacking into octahedron-like particles with well-defined mesoporous core-shell micro-/nano-structure. The resulting composites demonstrate a remarkable improvement in the efficiency of interesterification of rapeseed oil with methyl acetate at 210°C with respect to commercial SnO, showing an increase by 42% in FAME yield. This study highlights a novel function of γ-Al2O3 to act not only as support material for dispersion of active elements, but also to modulate the shape of micron-sized SnO crystals and construct composites with new architectures and improved catalytic activity.

Materials and Methods

Materials

Tin (II) chloride dehydrate (SnCl2•2H2O, Mw 225.65 g mol -1 ), aluminum tri-sec-butoxide ASB (Al[OC(CH3)3]3, Mw 246.32 g mol -1 ) and Pluronic F127 (PEO106PPO70PEO106 : PEO = poly(ethylene oxide) and PPO = poly(propylene oxide)) (Mw 12600 g mol -1 ) were purchased from Sigma Aldrich.

Randomly methylated β-cyclodextrin (denoted RaMeβCD, average degree of molar substitution (DS) 1.8, Mw 1310 g mol -1 ) was a gift from Wacker Chemie GmbH. Refined rapeseed oil was purchased from a local supermarket and its fatty acid composition was determined by quantitative transesterification as reported by Koohi Kamali et al. [START_REF] Kamali | Optimization of Sunflower Oil Transesterification Process Using Sodium Methoxide[END_REF], using sodium methoxide (98%) from Alfa Aesar as homogeneous catalyst, methanol (HPLC grade 99.8%) from Sigma Aldrich as alcohol and citric acid (99%) from Sigma Aldrich as neutralizing agent. Methyl acetate (HPLC grade > 99.8%) from Carlo Erba Reagents was used as acyl donor in the interesterification reaction and as solvent to prepare samples for GC analyses. For the GC calibration, methyl palmitate (C 16:0, ≥99%), methyl stearate (C 18:0, ̴ 99%), methyl oleate (C 18:1, ≥99%), methyl linoleate (C 18:2, ≥99%), triacetin (≥99%) and methyl heptadecanoate (≥99%) were purchased from Sigma Aldrich.

Determination of the composition of rapeseed oil

Fatty acid composition of adopted rapeseed oil is reported in Table 1. It was determined by quantitative conversion of an oil sample to FAMEs by transesterification with methanol in the presence of sodium methoxide that is the most active homogeneous catalyst for this reaction [START_REF] Kamali | Optimization of Sunflower Oil Transesterification Process Using Sodium Methoxide[END_REF].

Loading procedure and product separation were performed according to procedure reported in the literature [START_REF] Kamali | Optimization of Sunflower Oil Transesterification Process Using Sodium Methoxide[END_REF]. The reaction was carried out dissolving 200±5 mg of sodium methoxide in 20.00±0.01 g of methanol. This solution was mixed with 10.00±0.01 g of the rapeseed oil. To obtain quantitative conversion of all triglycerides, the alcohol was in strong stoichiometric excess compared to the oil.

The reaction was performed at the normal boiling point of methanol with a reaction apparatus and experimental procedure described elsewhere [START_REF] Interrante | Interesterification of rapeseed oil catalysed by a low surface area tin (II) oxide heterogeneous catalyst[END_REF]. Transesterified rapeseed oil must contain also methyl esters of C 20:1 and C 22:1 fatty acids, however these FAMEs could not be detected and quantified because of the lack of suitable pure standards.

Anyway, their cumulative concentration in our rapeseed oil must be lower than 2% w/w as assessed by the summation of the mass fractions reported in Table 1, and FAME yields should be little affected by their presence.

Preparation of tin based oxides

Three different approaches were used for the preparation of tin-based oxides. In a first approach, called complexation [START_REF] Abreu | New multi-phase catalytic systems based on tin compounds active for vegetable oil transesterification reaction[END_REF], urea (1.5 g, 25 mmol) and NaOH (0.34 g, 8.5 mmol) were dissolved in 20 mL of distilled water, then added to 20 mL of an aqueous solution of tin (II) chloride SnCl2•2H2O (0.65 g, 2.9 mmol). The mixture was refluxed at 40 °C for 30 min, then put it in a refrigerator at 4°C overnight. The resulting precipitate was isolated by filtration, then washed several times with water and ethanol and finally calcined at 500 °C for 4 h. This sample was denoted Sn-CM. In a second procedure, named hydrothermal method [START_REF] Sun | Solvothermal synthesis and characterization of ultrathin SnO nanosheets[END_REF], SnCl2•2H2O (1.128 g) was first dissolved in 10 mL of absolute ethanol, then 30 mL of ammonia solution (25-28 wt%) was added. After homogenization, the mixture was sealed in a Teflon-lined stainless-steel autoclave at 130 °C for 15 hours. The solid precipitate was collected by centrifugation, washed several times with deionized water, then rinsed with ethanol and finally dried in an oven at 80°C overnight. This sample was denoted Sn-HT. In a third approach named alkaline method [START_REF] Huda | New route in the synthesis of Tin(II) oxide micro-sheets and its thermal transormation[END_REF], SnCl2•2H2O (0.5 g, 2.2 mmol) was dissolved in 20 mL of distilled water at 75 °C and maintained under stirring for 30 minutes. Afterwards, varying amounts of NaOH (1.0 to 2.0 g) were added and mixtures were heated at 95 °C under reflux for additional 3 hours. The obtained precipitates were collected by centrifugation, washed with deionized water and ethanol by several centrifugation/redispersion cycles, and finally calcined at 300 °C for 3 hours.

Samples were identified according to the following notation: Sn-alk-x where x represents the NaOH concentration in the reaction medium varying from 0.25M to 0.75M.

Preparation of mesoporous -Al2O3

-Al2O3 was prepared using boehmite AlO(OH) as precursor was synthesized according to a previously reported sol-gel method [START_REF] Bleta | An efficient route to aqueous phase synthesis of nanocrystalline γ-Al2O3 with high porosity: From stable boehmite colloids to large pore mesoporous alumina[END_REF]. Typically, 185 mL of hot distilled water (85 °C) was added rapidly to 25.3 g (0.1 mol) of ASB at a hydrolysis ratio (h = [H2O]/[Al]) of 100. Afterwards, 0.47 mL of nitric acid ([HNO3]/[Al] = 0.07) was added dropwise to peptise the hydroxide precipitate. The mixture was refluxed at 85 °C for 24 h, then allowed to cool down naturally to room temperature.

The resulting hydrosol was a stable transparent suspension of AlO(OH) nanoparticles (pH 4.5) having an aluminum concentration of 0.5 mol L -1 . Afterwards, Pluronic F127 (10 wt %) and RaMeβCD (50 mg mL -1 ) were added successively to 150 mL of the above boehmite sol. After an equilibrium time of 24 h at room temperature, the hybrid sol was dried at 80 °C, then the recovered xerogel was calcined at 500 °C for 2 h giving a mesoporous -Al2O3 material.

Preparation of SnO-based composites

SnO-based composites were prepared by co-assembly of -Al2O3 nanoparticles with as-synthesized SnO microcrystals in an aqueous RaMeβCD solution. Typically, for an aluminum-tin equimolar composition, 1.5 g of as-synthesized SnO was dispersed in 40 mL of an aqueous solution of RaMeβCD (30 mg mL -1 ), to which 565 mg of -Al2O3 was added. The suspension was exposed to ultrasonic irradiation for 15 minutes (120W power, 80% amplitude, 3s pulse on, 1s pulse off), then maintained under stirring at 75 °C until water was completely evaporated. Finally, the recovered solid was calcined at 300 °C for 3 hours under air flow. Catalysts were denoted SnO@-Al2O3y where y indicates the Al/Sn molar ratio varying from 0.5 to 2.0.

Characterization methods

N2-adsorption isotherms were collected at -196 °C using an adsorption analyzer Micromeritics Tristar 3020. The specific surface areas were evaluated by the Brunauer-Emmet-Teller (BET) method [START_REF] Brunauer | Adsorption of gases in multimolecular layers[END_REF] and pore size distributions were determined using the Barrett-Joyner-Halenda (BJH) method assuming a cylindrical pore structure [START_REF] Barrett | The determination of pore volume and area distributions in porous substances. I. computations from nitrogen isotherms[END_REF]. Powder X-ray Diffraction (XRD) patterns were recorded using a Siemens D5000 X-ray diffractometer equipped with a Cu Kα radiation source in a Bragg-Brentano configuration. XRD scans were run with a 2θ angle in the range of 10° < 2θ < 80° using a 0.02° step size and a counting time of 2 s per step. Scanning electron microscopy (SEM) observations were recorded on a field emission gun scanning electron microscope (FE-SEM) (model Hitachi S-4700) equipped with an Energy Dispersive X-ray (EDX) detector. An acceleration voltage of 5.0 kV was used to minimize the accumulation of charges in the sample.

Analytical methods

The concentrations of methyl esters and triacetin in the samples were measured using a Agilent 7890B

Gas Chromatograph (GC) equipped with a RESTEK Superchrom FAMEWAX capillary column (length 30 m, external diameter 0.32 mm, internal diameter 0.25 mm) and a Flame Ionization Detector (FID). Helium 5.0 was used as carrier gas. The GC oven temperature was set at 165 °C for 22 min, then it was increased with a heating rate of 5 °C min -1 up to 220 °C and maintained at that temperature for 5 min. Calibration was accomplished for FAMEs and triacetin by preparing solutions of known concentration of pure alkyl esters (C 16:0, C 18:0, C 18:1, C 18:2, C 18:3) and TA, using methyl heptadecanoate as internal standards. Cumulative yields in fatty acid methyl esters YFAME and in triacetin YTA were computed according to equation 1:

𝑌 = 𝑌 = (1)
where MFAME and MTA are the masses of free fatty acid methyl esters and triacetin determined through GC calibration and M 0 oil is the initial mass of rapeseed oil loaded in the reactor.

Experimental procedures for interesterification

Interesterification experiments were conducted in a stainless steel autoclave reactor with an internal volume of 20 mL. A needle valve was used to insulate the reactor during the reaction. In a typical experiment, 1.5±0.01 g of rapeseed oil and 5.1±0.01 g of methyl acetate were loaded in the reactor to obtain an oil/methyl acetate molar ratio of 1:40. The reactor was sealed and Argon was used to purge and pressurize it at a final pressure of about 2.5 bar. The reactor was heated with a heating rate of about 12 °C min -1 by two heating cartridges inserted in an aluminum block. Reaction time was computed after the reaction temperature was reached. To stop the interesterification, the reactor was rapidly cooled to room temperature by immersion in an ice-water bath.

The system was opened and the products, including the catalyst, were recovered by adding about 3 g of methyl acetate. The monophasic solution was separated from the catalyst by centrifugation at 4000 rpm for 30 min. The liquid phase was recovered with a Pasteur pipette and stored in a glass vial. The catalyst was washed several times with methyl acetate to remove traces of wetting oil mixture, then dried in an oven at 60 °C overnight.

Results and discussion

Interesterification of rapeseed oil with bulk SnO catalysts

Initially, three different approaches were employed to prepare tin-based oxides with the goal to evaluate the effect of the preparation method on the crystalline properties and interesterification activity of the catalysts.

In a first approach, using urea as the complexing agent [START_REF] Abreu | New multi-phase catalytic systems based on tin compounds active for vegetable oil transesterification reaction[END_REF][START_REF] Abdel-Naby | Effect of cyanoguanidine-metal and urea-metal complexes on the thermal degradation of poly(vinyl chloride)[END_REF], cassiterite tetragonal Sn(IV)O2

(JCPDS card 77-0450) was exclusively produced after calcination at 500 °C (Figure 1, Aa). On the other hand, the hydrothermal synthesis carried out at 130°C for 16 hours [START_REF] Sun | Solvothermal synthesis and characterization of ultrathin SnO nanosheets[END_REF]

SnO

As pointed out by Gulo et al. [START_REF] Huda | New route in the synthesis of Tin(II) oxide micro-sheets and its thermal transormation[END_REF], the synthesis of SnO in alkaline media consists of three consecutive reactions: first, SnCl2 is hydrolyzed in water producing Sn4(OH)2Cl6 (Equation 2); then, the HCl released is neutralized by the NaOH, while Cl -ions from Sn4(OH)2Cl6 are gradually replaced by hydroxide ions yielding Sn4(OH)6Cl2 (Equation 3); finally, the SnO crystals are produced via dissolution-precipitation from Sn4(OH)6Cl2 during aging at 95°C (Equation 4). Meanwhile, the presence of HCl in the reaction medium, even in small amounts, is likely to promote oxidation of SnO to SnO2 (Equation 5), consistent with the observation at 0.25 M NaOH.

4 𝑆𝑛𝐶𝑙 ( ) + 2 𝐻 𝑂 ( ) ↔ 𝑆𝑛 (𝑂𝐻) 𝐶𝑙 ( ) + 2 𝐻𝐶𝑙 ( ) (2)
𝑆𝑛 (𝑂𝐻) 𝐶𝑙 ( ) + 2 𝐻𝐶𝑙 ( ) + 6 𝑁𝑎𝑂𝐻 ( ) → 𝑆𝑛 (𝑂𝐻) 𝐶𝑙 ( ) + 6 𝑁𝑎𝐶𝑙 ( ) + 2 𝐻 𝑂 ( ) (3)

𝑆𝑛 (𝑂𝐻) 𝐶𝑙 ( ) + 2 𝑁𝑎𝑂𝐻 ( ) → 4 𝑆𝑛𝑂 ( ) + 2 𝑁𝑎𝐶𝑙 ( ) + 4 𝐻 𝑂 ( ) (4)
2 𝑆𝑛𝐶𝑙 ( ) + 𝑂 ( ) + 2 𝐻 𝑂 ( ) ↔ 2 𝑆𝑛𝑂 ( ) + 4 𝐻𝐶𝑙 ( ) (5)
To gain further insights into the morphological changes on Sn-based crystals with the NaOH concentration, FE-SEM observations were carried out. Representative micrographs revealed a shape evolution from spherical particles to square-plate crystals (Figure 2). Indeed, the Sn-alk-0.25M solid was composed mainly of angular clasts with rough surfaces and irregular boundaries with dimensions ranging from 5 µm to more than 100 µm (Figure 2A Indeed, as reported by Casas et al. [START_REF] Casas | Kinetics of chemical interesterification of sunflower oil with methyl acetate for biodiesel and triacetin production[END_REF], triglycerides can be totally converted using a MA/TG molar ratio of 18. However, a molar ratio of 50 was needed to completely transform the monoacetindiglyceride, while a MA/TG molar ratio as high as 100 was not enough to completely remove the diacetinmonoglyceride. This is a clear indication of the high degree of reversibility of the interesterification reaction where the conversion of diacetinmonoglyceride to triacetin is the ratelimiting step. It is important to point out that, using methyl acetate in large excess is also an effective way to reduce the viscosity of triglycerides and dissolve the monoacetindiglyceride and diacetinmonoglyceride intermediates as well as triacetin [START_REF] Dhawan | Interesterification of triglycerides with methyl acetate for the co-production biodiesel and triacetin using hydrotalcite as a heterogenous base catalyst[END_REF].

In our study, the interesterification reaction was set at 210 °C, using a methyl acetate-to-oil molar ratio (MA/TG) of 40 and a catalyst-to-oil molar ratio (SnO/TG) of 0.65 [START_REF] Interrante | Interesterification of rapeseed oil catalysed by a low surface area tin (II) oxide heterogeneous catalyst[END_REF]. The results obtained after 30 minutes of reaction time are presented in Table 1, together with those obtained in a control experiment performed with commercial SnO under the same conditions.

Similarly to the experiment carried out without catalyst (entry 1), the activities achieved with the SnO2-based solids were extremely low giving only 1% (entry 2) and 2% (entry 4) FAME yields for the Sn-CM and the Sn-alk-0.25M catalysts respectively. Moreover, triacetin was found only in form of traces. The catalytic activity was slightly improved with the SnO-SnO2 mixture, reaching 7.4% yield in FAME (entry 3). Noticeably, under identical conditions, pure SnO prepared by the alkaline method displayed the highest performance in this reaction, that was quite similar to that of commercial SnO [START_REF] Interrante | Interesterification of rapeseed oil catalysed by a low surface area tin (II) oxide heterogeneous catalyst[END_REF]. Indeed, 24.2% yield in FAME and 0.3% yield in TA were reached with the Sn-alk-0.38M catalyst (entry 5), while 17.4% FAME and 0.2% TA were achieved with the Sn-alk-0.50M one (entry 6). Although Sn(IV)O2 has proved to be catalytically active in the transesterification of tryglicerides [START_REF] Xie | Silica-Supported Tin Oxides as Heterogeneous Acid Catalysts for Transesterification of Soybean Oil with Methanol[END_REF], our results clearly revealed that the Sn(II)O was more suitable for the interesterification reaction. As both SnO-alk-0.38M and SnO-alk-0.50M catalysts had very similar surface areas (<1 m 2 /g), the superior interesterification activity of the former probably results from its different crystalline properties, in particular the preferential orientation of crystals along the (001) planes, consistent with XRD analysis (Figure 1, B-b) and FE-SEM observations (Figure 2 C,D).

Interesterification of rapeseed oil with SnO@γ-Al2O3 composites

Encouraged by results obtained with bulk SnO catalysts prepared by the alkaline method and taking into account that they had very low specific surface areas (less than 1 m 2 /g) (Table 2), we then decided to disperse SnO particles over a large-pore mesoporous -Al2O3 matrix prepared by the colloidal approach [START_REF] Bleta | An efficient route to aqueous phase synthesis of nanocrystalline γ-Al2O3 with high porosity: From stable boehmite colloids to large pore mesoporous alumina[END_REF].

The procedure used for the preparation of SnO@-Al2O3 composites is illustrated in Scheme 2. First, a boehmite (AlO(OH)) sol was synthesized in aqueous phase by sol-gel process at 85 °C using aluminum tri-sec butoxide (ASB) as precursor (hydrolysis ratio H2O/Al ~ 100) [START_REF] Bleta | An efficient route to aqueous phase synthesis of nanocrystalline γ-Al2O3 with high porosity: From stable boehmite colloids to large pore mesoporous alumina[END_REF]. Then, boehmite nanoparticles were allowed to self-assemble around the supramolecular template formed between the randomly methylated β-CD (RaMeβCD) and the Pluronic F127. After calcination at 500 °C, a mesoporous nanofiber-like -Al2O3 solid was recovered. In parallel, micrometric quadrilateral SnO particles were prepared by dissolution-precipitation in alkaline medium (0.38M NaOH) as previously described, then redispersed in a RaMeβCD aqueous solution (30 mg/mL). The obtained hybrid RaMeβCD@SnO--Al2O3 material was subsequently subjected to ultrasonic irradiation for 15 minutes. By varying the -Al2O3 loading in the RaMeβCD@SnO suspension, mesoporous SnO@-XRD patterns (Figure 3) revealed that the intensity of ( 001) and (002) peaks was greatly enhanced upon increasing the -Al2O3 loading, indicating that alumina can modulate the orientation growth of SnO crystals in a direction parallel to the (001) plane. Indeed, it is possible that -Al2O3 particles adsorb preferentially on the (001) facets of SnO, which are actually the most thermodynamically stable and possess the lowest surface energy [56]. Such adsorption could facilitate stacking of SnO crystals and promote their growth into polyhedral-shaped particles with well-developed (001) facets.

Note that among the four catalysts, SnO@-Al2O31.0 prepared with an equimolar Sn/Al composition showed the highest reflexion intensities at 18.3° and 37.2° indicative of development of structures with most abundant exposed (001) facets. From the N2-adsorption analysis (Figure 4), it can be seen that all SnO@γ-Al2O3 composites displayed type-IV isotherms with a type H3 hysteresis loop, characteristic of mesoporous materials with wide pore size distributions. As a general trend, upon increasing the γ-Al2O3 loading, a significant increase in the specific surface area (from 35 to 173 m 2 /g) and pore volume (from 0.103 to 0.307 cm 3 /g) was noticed. Bimodal pore size distributions were developed for the composites prepared with the lowest Al/Sn molar ratios, while monomodal structures were obtained for the highest alumina loadings. The largest pores with an average diameter of 19-24 nm probably resulted from the high degree of freedom of γ-Al2O3 nanoparticles deposited on the surface of SnO microcrystals, enabling the formation of a fibrous network, while the smallest ones (9-11 nm) were characteristic of bare γ-Al2O3 with a higher degree of particle aggregation (Figure S5, ESI). This means that in our composites, -Al2O3 particles are either assembled into fibbers or densely packed in more compact structures, on the surface of the SnO crystals, as aggregates. SnO@-Al2O30.5, (b) SnO@-Al2O30.67, (c) SnO@-Al2O31.0, (d) SnO@-Al2O32.0. dV/dlog(w) Pore Volume (cm³/g•Å)

Relative pressure (P/P0) Pore width (nm)

Quantity adsorbed (cm 3 /g STP)

dV/dlog(w) Pore Volume (cm 3 /g . Å)

Table 2. Structural and textural characteristics of -Al2O3 supports and SnO@-Al2O3 composites after thermal treatment at 300 °C.

Sample XRD

N2-adsorption Evidence for the shape evolution from squares (bare SnO) to truncated octahedral-like particles (SnO@-Al2O3 composites) was provided by FE-SEM observations, which confirmed that -Al2O3 nanoparticles assembled almost exclusively on the surface of SnO promoting the growth of microcrystals in a direction parallel to the (001) plane (Figures S6-S10, ESI). Representative FE-SEM images of the SnO@-Al2O31.0 composite (Figure 5) indicated that this solid was composed mainly of individual non-aggregated structures with octahedral shapes and smooth boundaries (Figure 5 A-D) having a typical length of 20 to 30 µm and a thickness of about 2 µm (Figure 5 E-F).

SBET a (m 2 /g) Vp b (cm 3 /g) Dp c (nm) Sol-gel -Al2O3 -Al2O3 219
EDX elemental mapping (Figure 5 G) also confirmed that Al, O and Sn atoms were uniformly distributed on the microplatelets. Locally, some aggregation of alumina nanoparticles was also observed on the surface of SnO microcrystals. It is worth noting that those composite particles also presented some surface damages due to partial eradication of SnO crystals caused by the ultrasonic irradiation, which resulted in formation of holes in the center of the polyhedra and, in some cases, fragmentation of the crystals. Nevertheless, upon increasing the -Al2O3 loading, this phenomenon was attenuated, consistent with the increase in the plate thickness, thus providing greater improvement of the impact resistance (Figures S6-S10, ESI). The catalytic activity of SnO@-Al2O3 composites was then evaluated in the interesterification of rapeseed oil under the same conditions as with bare SnO. FAME and triacetin yields obtained with the different supported catalysts are shown in Table 3. Clearly, the overall activity was dependent on the -Al2O3 loading. While mesoporous -Al2O3 was almost inactive after 30 min at 210°C (entry 1), the addition of a small amount of -Al2O3 to the SnO catalyst (Al/Sn molar ratio = 0.5) resulted in an increase in the FAME yield to 24.9% (entry 3), which represents, however, only a slight improvement (by ~0.7%) with respect to bare SnO (entry 2). As shown previously by several authors, -Al2O3 may catalyze efficiently interesterification of triglycerides, however, higher temperatures and pressures are required compared to our conditions. Indeed, Ribeiro et al. [START_REF] Ribeiro | Synthesis of methyl esters and triacetin from macaw oil (Acrocomia aculeata) and methyl acetate over γalumina[END_REF] obtained 82.5% conversion efficiency with macaw oil using -Al2O3 as catalyst at a temperature of 300 °C under autogenous pressure, while a 60.2% FAME yield was reported by Visioli et al.

[57] at a temperature of 275 °C and 20 MPa pressure. Interestingly, we noticed cooperative effects upon increasing the -Al2O3 loading, which not only resulted in increased conversion of rapeseed oil, but also promoted the reaction of monoacetindiglyceride and diacetinmonoglyceride intermediates with methyl acetate towards triacetin formation (entries 4-6). As reported in many studies [START_REF] Casas | Effects of triacetin on biodiesel quality[END_REF][START_REF] Saka | A new process for catalyst-free production of biodiesel using supercritical methyl acetate[END_REF][START_REF] Casas | New trends in biodiesel production: chemical interesterification of sunflower oil with methyl acetate[END_REF]58], triacetin can be used as a fuel additive or included in the biodiesel formulation up to 10 wt % since it enhances the biodiesel quality. However, above this limit threshold, it tends to reduce the cetane number of biodiesel below the minimum limit fixed by the EN 14214 guidelines [START_REF] Casas | Effects of triacetin on biodiesel quality[END_REF]. The FAME yields obtained with our catalysts after 30 minutes at 210 °C were 27.2% for SnO@Al2O30.75 (entry 4), 30.9% for SnO@Al2O31.0 (entry 5) and 33.5% for SnO@Al2O32.0 (entry 6), giving triacetin yields of 1.0%, 2.0% and 1.5% respectively. Among the different composites, SnO@Al2O3 2.0 appeared to be the most suitable for rapeseed biodiesel production, achieving a global yield of 35.0% after 30 minutes and 82.5 % after 120 minutes (Figure S11, ESI). Interestingly, this catalyst was also more active than the commercial SnO (entry 7). Time course analysis (Figure S11, ESI) also indicated that the reaction kinetics were faster with SnO@Al2O32.0, showing almost 10 wt.% differences in FAME yields on consecutive 30-min time intervals.

Based on the characterization results, it is clear that the catalytic performance of SnO@-Al2O3 composites results from a combined effect of textural, structural and morphological characteristics.

Thus, the largest surface area obtained with SnO@-Al2O32.0 catalyst (173 m 2 /g) should provide a greater number of adsorption sites and active centers, facilitating the adsorption properties of the composite towards both triglycerides and methyl acetate. Moreover, its high pore volume (0.307 cm 3 /g) should improve the diffusion of both reactants and products during the catalytic process and reduce the mass transfer limitations, which are critical issues for microporous catalysts. Finally, the mesoporous -Al2O3 material can also modify or reshape the SnO microcrystals and promote their growth along the (001) planes, which appear to be the most active in the interesterification reaction.

Overall, these results showed that -Al2O3 may be a suitable material for preparing SnO-based composites with enhanced interesterification activities; however, when this oxide was used in a large excess to SnO (Al/Sn molar ratio of 2.0) a drop in TA yield was also observed (from 2.0% to 1.5%), which is probably due to parallel undesired decomposition reactions catalyzed by the aluminaenriched composite [START_REF] Simões | Heterogeneous catalyst screening for fatty acid methyl esters production through interesterification reaction[END_REF].

Our results can be compared with those of Nunes and Castilhos [START_REF] Nunes | Chemical interesterification of soybean oil and methyl acetate to FAME using CaO as catalyst[END_REF] who obtained 62.3 wt.% FAME yield in the interesterification of soybean oil with methyl acetate using calcium oxide (CaO) as heterogeneous catalyst. The optimum conditions found by the authors were a MA:oil molar ratio of 40:1, 10 wt.% catalyst, 325°C temperature and 4 hours reaction time. In addition, the authors found that CaO was the most efficient catalyst in comparison with Y-zeolite, MgO, Nb2O5 and mixed oxides [START_REF] Simões | Heterogeneous catalyst screening for fatty acid methyl esters production through interesterification reaction[END_REF].

It is generally reported that high water concentration in the reaction mixture decreases the activity of homogeneous and heterogeneous catalysts preventing the utilization of cheap feedstocks, such as waste cooking oil [START_REF] Endalew | Inorganic heterogeneous catalysts for biodiesel production from vegetable oils[END_REF]. To this end, the SnO@-Al2O32.0 composite was selected to investigate the effect of water as impurity. An additional run was performed under the same operating conditions as in the preceding experiments, with the only exception that 2 wt.% water was deliberately added in the reaction medium. We noticed that FAME and TA yields were greatly enhanced upon addition of water, reaching 47.5% and 2.4% respectively (entry 8, Table 3), thus reproducing the behavior obtained with commercial bulk SnO [START_REF] Interrante | Interesterification of rapeseed oil catalysed by a low surface area tin (II) oxide heterogeneous catalyst[END_REF]. Such effect could be related to a possible modification of the reaction mechanism, where interesterification, transesterification and esterification reactions could be combined in a consecutive continuous process. Indeed, as illustrated in Scheme 3, in the presence of water, SnO may catalyze first the hydrolysis of methyl acetate to acetic acid and methanol, then this latter may react with triglycerides through a transesterification reaction yielding glycerol and FAME. In parallel, glycerol could also react with acetic acid through an esterification reaction yielding triacetin, diacetinmonoglyceride and monoacetindiglyceride.

As pointed out by Casas et al. [START_REF] Casas | Kinetics of chemical interesterification of sunflower oil with methyl acetate for biodiesel and triacetin production[END_REF], transesterification has faster kinetics when compared to interesterification since it uses methanol as acyl receptor, which usually requires milder conditions to achieve higher yields. Farobie and Matsumura [START_REF] Farobie | Continuous production of biodiesel under supercritical methyl acetate conditions: experimental investigation and kinetic model[END_REF] have explained this difference by the lower reactivity of supercritical methyl acetate producing an unstable intermediate, which requires higher activation energy when compared to supercritical methanol. Supporting evidence in favor of the proposed mechanism was provided by the chromatographic profiles (Figure S12, ESI), where the ratio of the peak areas corresponding to diacetinmonoglyceride and monoacetindiglyceride increased with respect to the internal standard peak upon addition of 2 wt.% water in the reaction medium. In contrast, in the absence of added water, those ratios were very low, suggesting the formation of only traces of MADG and DAMG. An important issue in the perspective of utilization of heterogeneous catalysts in industrial application is their long term stability. To assess this aspect we evaluated the recyclability of SnO@-Al2O32.0 under the same reaction conditions (MA/TG molar ratio of 40, a catalyst content of 10 wt.%, and a reaction temperature of 210°C for 30 minutes). The FAME and triacetin yields obtained during the reuse tests, with and without water, are shown in Figure 6. In the absence of water, FAME content decreased from 33.5 % in the first run to 19.0% in the second run and then was stabilized to 18.0% in the third run, representing a catalytic efficiency decay of 45.6% (Figure 6, A). However, in the presence of 2 wt.% water, a more pronounced catalytic efficiency loss (72.3 %) was observed (Figure 6, B). We identified that washing the catalyst with methyl acetate between consecutive runs did not produced any significant improvement in the catalytic activity (Figure S13, ESI), therefore excluding a possible blockage of catalyst active sites by the reactants. One of the factors at the origin of such activity decay may be the instability of -Al2O3 under our reaction conditions, especially in the presence of water [START_REF] Macdonald | The thermodynamics of the aluminium-water system at elevated temperatures[END_REF][START_REF] Ravenelle | Structural changes of γ-Al2O3-supported catalysts in hot liquid water[END_REF]. Indeed, the XRD diagram of the catalyst recovered after the third run in the experiment conducted with 2 wt.% water showed that tin was still in the oxidation state +2, but -Al2O3 was hydrolyzed into boehmite (Figure S14, ESI). Such a transformation would probably be accelerated by the acetic acid formed during the hydrolysis of methyl acetate, implying partial dissolution of the support and loss of a part of catalyst particles. Despite that decay, the activities obtained in the third run are still higher than some reported in literature in interesterification reaction with other heterogeneous catalysts, such as Nb2O5 and Y zeolite as well as Mg-Al and Ca-Mg-Al mixed oxides, tested at a temperature similar to that used in our study [START_REF] Simões | Heterogeneous catalyst screening for fatty acid methyl esters production through interesterification reaction[END_REF].

Conclusions

In summary, pure romarchite tetragonal Sn(II)O, prepared under alkaline conditions at 75 °C via dissolution-precipitation from Sn4(OH)6Cl2, was found to be more suitable catalyst in the interesterification of rapeseed oil with methyl acetate with respect to the cassiterite tetragonal Sn(IV)O2 and the Sn(II)O/Sn(IV)O2 mixture, achieving 24.2 % yield in FAME after 30 minutes at 210 °C. To further improve the morphological and surface properties of Sn(II)O, mesoporous Sn(II)O@γ-Al2O3 core-shell octahedral composites were prepared through a hierarchical selfassembly process triggered by randomly methylated β-cyclodextrin (RaMeβCD)-based assemblies.

In this approach, RaMeβCD can regulate the orientation of rod-like γ-Al2O3 nanoparticles on the

  yielded a mixture of Sn(II)O and Sn(IV)O2 composed in majority of Sn(II)O crystals (Figure 1, Ab). Finally, the alkaline method under mild conditions (75 °C and ambient pressure) produced pure romarchite tetragonal Sn(II)O (JCPDS card 06-0395) via dissolution-precipitation from Sn4(OH)6Cl2 (Figure 1, Ac) [47]. However, to maintain Sn in the oxidation state of +2, a minimum amount of NaOH was necessary in order to neutralize the HCl released during the SnCl2 dissolution. Indeed, a detailed investigation on the effect of NaOH concentration revealed that at 0.25 M NaOH (Sn/NaOH = 0.44), the conditions favored maximum formation of cassiterite tetragonal SnO2 (Figure 1, B a), while at 0.38 M (Sn/NaOH = 0.30) (Figure 1, B b) and 0.5 M NaOH (Sn/NaOH = 0.22) (Figure 1, B c), a shiny black solid was recovered, characteristic of tetragonal romarchite Sn(II)O. Notably, the SnO particles prepared with 0.38 M NaOH displayed the most intense reflexion peaks of the (001) and (002) facets, located at 18.3° and 37.2° respectively, indicating preferential growth of the crystal planes along the (001) direction. However, further increase in the NaOH concentration to 0.75 M (Sn/NaOH = 0.15) was found to be detrimental since it caused total dissolution of the oxide into Na2[Sn(OH)6]2.

Figure 1 .

 1 Figure 1. XRD patterns of Sn-based oxides prepared by different methods and with different NaOH concentrations. (A) Effect of the preparation method: complexation (a), hydrothermal (b) and alkaline (c). (B) Effect of NaOH concentration on the crystallinity of Sn-based solids prepared by the alkaline method: 0.25 M NaOH (a), 0.38 M NaOH (b) and 0.50 M NaOH (c).

  , Figure S1 A-C ESI). These clasts consisted mainly of fine-grained and densely-packed spherical particles with smooth surfaces and an average 50-100 nm diameter (Figure 2B, Figure S1 D,E, ESI). Conversely, stacked structures comprised mainly of quadrilateral microplatelets with exposed (001) facets were obtained with the Sn-alk-0.38M catalyst (Figure 2C,D; Figure S2, ESI) in agreement with the XRD data. Microplatelets were about 10-100 µm long and 0.5-2.0 µm thick (Figure S4, ESI). Further increase in the NaOH concentration to 0.5M (Sn-alk-0.50M solid) led to reduction of the average particle sizes to 10-30 µm and to formation of aggregates with 3D flower-like architectures which consisted mainly of interpenetrating micro-sheets (Figure 2E-F, Figure S3, ESI). Noticeably, the (001) facets of Sn-alk-0.50M crystals were less exposed due to the formation of perpendicularly oriented microsheets pointing at different directions, which were at the origin of the attenuation of reflexions at 18.3° and 37.2° in the XRD patterns (Figure 1, B c).

Figure 2 .Scheme 1 .

 21 Figure 2. FEG-SEM micrographs of Sn-based oxides prepared by the alkaline method with different NaOH concentrations: 0.25 M NaOH (A, B), 0.38 M NaOH (C, D) and 0.50 M NaOH (E, F).

Figure 3 .

 3 Figure 3. XRD patterns of SnO@-Al2O3 composites: (a) SnO@-Al2O30.5, (b) SnO@-Al2O30.67, (c) SnO@-

Figure 4 .

 4 Figure 4. N2 adsorption isotherms (A) and corresponding pore size distributions (B) of SnO@-Al2O3 composites: (a)

Figure 5 .

 5 Figure 5. FE-SEM images (A-F) of SnO@-Al2O31.0 composite and corresponding EDX elemental mapping distribution

Scheme 3 .

 3 Scheme 3. Schematic illustration of biodiesel production in the presence of methyl acetate (MA) and water by simultaneous interesterification and transesterification.

Figure 6 .

 6 Figure 6. Catalytic recyclability of SnO@-Al2O32.0 catalyst in the absence (A) and in the presence of 2 wt.% water (B).

  -synthesized micron-size Sn(II)O crystals yielding mesoporous composites with unique properties. Particulate composites were composed of a functional SnO microcrystal core with high catalytic activity and a mesoporous alumina shell with good pore accessibility. Importantly, the γ-Al2O3 shell was found to promote stacking of square-like SnO particles along the (001) direction and resulted in formation of single octahedron-like crystals with highly exposed facets that were particularly active in the interesterification of rapeseed oil with methyl acetate. The best results were obtained with the composite prepared with an Al/Sn molar ratio of 2.0 achieving a total FAME and triacetin yield of 35.0% after 30 minutes and 82.5 % after 120 minutes at 210 °C. This novel approach based on γ-Al2O3-controlled growth of SnO microcrystals assisted by RaMeβCD provides a brand new way to construct functional composites with new architectures and improved catalytic performance in interesterification reactions.

Table 1 .

 1 Fatty acid composition of the rapeseed oil used in this study.

	Fatty acid	Symbol (C-length : no.=bonds)	% w/w
	Palmitic acid	16:0	4.5
	Stearic acid	18:0	1.5
	Oleic acid	18:1	65.1
	Linoleic acid	18:2	16.5
	Linolenic acid	18:3	10.8

Table 1 .

 1 Catalytic performance of Sn-based catalysts in the interesterification of rapeseed oil. a Reaction conditions: 1.5 g rapeseed oil, 10 wt.% SnO/oil, 5 g methyl acetate (MA/TG = 40), initial pressure inside reactor: 2 bar, vapor pressure MA: 30 bar, temperature 210 °C, reaction time 30 minutes.

				Interesterification tests
	Entry	Catalyst	Crystal phase (XRD)	YFAME (w/w %)	YTA (w/w %)
	1	no catalyst	-	0.8	n.d.
	2	Sn-CM	SnO2	1.0	n.d.
	3	Sn-HT	SnO-SnO2	7.4	n.d.
	4	Sn-alk-0.25M	SnO2	1.22	n.d.
	5	Sn-alk-0.38M	SnO	24.2	0.3
	6	Sn-alk-0.50M	SnO	17.4	0.2
	7	SnO (Alfa Aesar)	SnO	23.6	0.4
	a

  specific surface area determined in the relative pressure range 0.1-0.25, b cumulative pore volume and c average pore diameter resulting from BJH calculations.

				0.276	4.2
	-Al2O3	-Al2O3	236	0.674	11.2
	Sn-alk-0.38M	SnO	<1	nd	nd
	SnO@-Al2O30.5	SnO	35	0.103	11.0/23.6
	SnO@-Al2O30.75	SnO	56	0.174	11.0/18.6
	SnO@-Al2O31.0	SnO	88	0.261	10.8
	SnO@-Al2O32.0	SnO	173	0.307	7.5

a

Table 3 .

 3 Catalytic performance of Sn-based catalysts in the interesterification of rapeseed oil to biodiesel and triacetin. a Reaction conditions: 1.5 g rapeseed oil, 10 wt.% SnO/oil, 5 g methyl acetate (MA/TG = 40), initial pressure inside reactor: 2 bar, vapor pressure MA: 30 bar, temperature 210 °C, reaction time 30 minutes.

			Interesterification tests
	Entry	Catalyst	YFAME	YTA
			(w/w %)	(w/w %)
	1	Mesoporous -Al2O3	2.0	n.d.
	2	SnO-alk-0.38M	24.2	0.3
	3	SnO@Al2O30.5	24.9	n.d.
	4	SnO@Al2O30.75	27.2	1.0
	5	SnO@Al2O31.0	30.9	2.0
	6	SnO@Al2O32.0	33.5	1.5
	7	SnO-comm (Alfa Aesar)	23.6	0.4
	8	SnO@Al2O32.0-water	47.5	2.4

a

Acknowledgments

Chevreul Institute (FR 2638), Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation, FEDER and University of Palermo are acknowledged for supporting and funding this work. We are grateful to A. Addad and L. Burylo for technical assistance with FE-SEM and XRD respectively. The electron microscopy facility in Lille is supported by the Conseil Regional des Hauts-de-France and the European Regional Development Fund (ERDF).

Appendix A. Supplementary Material FE-SEM images of bare SnO and SnO@γ-Al2O3 composites, kinetics of interesterification of rapeseed oil with methyl acetate catalyzed by the SnO@γ-Al2O32.0 composite, chromatographic profiles of reaction products, catalytic recyclability of SnO@γ-Al2O3 with intermittent washing between runs, XRD patterns of SnO@γ-Al2O32.0 after catalytic test in 2 wt.% water.


The production of MIR gas sensors on PICs requires Sb-based light sources. The growth on inexpensive and large-sized mismatched substrates (~8% with GaAs) introduces dislocations. They create deep levels in the gap and act as trap defects, impacting laser performances. It's crucial to have an active zone tolerant to dislocations, which is achievable with interband cascade lasers (ICL).

Introduction:

III-Sb

Fig. 2 .GaSb

 2 Fig. 2. Band structure of 1 stage of the ICL active zone

FigFig. 7 .Fig. 6 .▪

 76 Fig. 4. ICL structure

Fig. 8 .

 8 Fig. 8. (a) LIV curves of a 10 µm x 2 mm AlGaAsSb ICL on GaSb and GaAs (b) Spectra

Fig. 9 .

 9 Fig. 9. (a) LIV curves of a 8 µm x 2 mm SLs ICL on GaSb and GaAs (b) Spectra

Fig. 10 .

 10 Fig. 10. Ageing of an ICL on GaAs