Optimization of the Synthesis of Glycerol Derived Monoethers from Glycidol by Means of Heterogeneous Acid Catalysis

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Article Optimization of the Synthesis of Glycerol Derived Monoethers from Glycidol by Means of Heterogeneous Acid Catalysis

Elisabet Pires 1,2,* , José Ignacio García 1, Alejandro Leal-Duaso 1, José Antonio Mayoral 1,2, José Ignacio García-Peiro 2 and David Velázquez 2

1 Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-University of Zaragoza-Calle Pedro Cerbuna, 12, E-50009 Zaragoza, Spain; [email protected] (J.I.G.); [email protected] (A.L.-D.); [email protected] (J.A.M.) 2 Departmento de Química Orgánica, Facultad de Ciencias, University of Zaragoza, Calle Pedro Cerbuna, 12, E-50009 Zaragoza, Spain; [email protected] (J.I.G.-P.); [email protected] (D.V.) * Correspondence: [email protected]; Tel.: +34-876-553501

Received: 7 October 2018; Accepted: 3 November 2018; Published: 6 November 2018

Abstract: We present an efﬁcient and green methodology for the synthesis of glycerol monoethers, starting from glycidol and different alcohols, by means of heterogeneous acid catalysis. A scope of Brønsted and Lewis acid catalysts were applied to the benchmark reaction of glycidol and methanol. The selected catalysts were cationic exchangers, such as Naﬁon NR50, Dowex 50WX2, Amberlyst 15 and K10-Montmorillonite, both in their protonic form and exchanged with Al(III), Zn(II) and Fe(III). Thus, total conversions were reached in short times by using 1 and 5% mol catalyst loading and room temperature, without the need for excess glycidol or the presence of a solvent. Finally, these conditions and the best catalysts were successfully applied to the reaction of glycidol with several alcohols such as butanol or isopropanol.

Keywords: green solvent; glycerol; glycidol; glycerol ether; heterogeneous catalysis; acid catalyst; Bronsted acid; Lewis acid

1. Introduction The vast majority of chemical industry processes rely on the use of conventional organic solvents. Although there are undisputable advantages in the use of these kinds of solvents, there are also important drawbacks, such as their (eco)toxicity, volatility and flammability. For this reason, developing cost-effective, harmless and environmentally benign alternative solvent systems is a research area of great interest. Among the different proposals, glycerol itself and its derivatives are attracting a lot of attention as green and renewable solvents [1–4]. In particular, glycerol-derived monoethers (GMEs) have arisen as a promising option due to their chemical stability, tunable physical-chemical properties by just adjusting the nature of the substituent [5], relatively low ecotoxicology [6–8] and also due to the possibility of forming low melting mixtures (LMM) or Deep Eutectic Solvents (DES) [9]. When doing a search for potential applications for glycerol ethers in Scifinder Database, more than 7000 records dealing with patents involving the use of these compounds can be found. Thus, focusing on GMEs, the most common uses for these compounds are as additives in cosmetics or pharmaceuticals [10], and also in the formulation of dry-cleaning [11], cement formulation [12], cutting fluids [13], corrosion inhibitors [14], detergents [15], inks [16], herbicides and lubricants [17].

Molecules 2018, 23, 2887; doi:10.3390/molecules23112887 www.mdpi.com/journal/molecules Molecules 2018, 23, 2887 2 of 10

Particularly, 3-[(2-ethylhexyl)oxy]-1,2-propanediol, known as Sensiva®SC50, is one of the GMEs used in skin creams. For all these reasons, it is of great importance to develop sustainable methodologies for obtaining glycerol monoethers (GMEs). Lemaire and co-workers have beautifully reviewed the synthesis of glycerol ethers, starting from both glycerol and platform molecules, such as glycidol, epichlorohydrin and 3-chloropropane-1,2-diol, which can in turn be prepared from glycerol [18]. As mentioned in this work, scarce data on the production of GMEs is found despite the numerous potential applications of glycerol alkyl ethers [19–21]. Addressing the synthesis of GMEs, the direct synthesis from glycerol has been envisaged but the difficulty in selectively reacting just one of the hydroxyl groups of glycerol is the main drawback of this approach. Thus, the best results described until now in the reaction of glycerol with several alcohols were presented by Jerôme et al. [22]. They described 70% selectivity towards GMEs using homogeneous Lewis catalysts, such as Bi(OTf)3. Recently Henriques et al. [23] described a similar selectivity in the reaction of glycerol and ethanol using a heterogeneous catalyst, namely USY, HZSM-5 and H-Beta zeolites. In both cases, obtaining high selectivity of GMEs is achieved by the use of high reaction temperatures and an excess of glycerol, which can be difficult to separate after the reaction is completed. Thus, the use of building blocks usually improves the selectivity of the process and allows to obtain mono-, di- and triethers with different alkyl chains in a controlled way without the need for excess of starting reagent. Some works have been published where GMEs have been obtained from glycidol with excellent conversions and selectivities by using homogeneous Lewis acids as catalysts [24,25]. The authors described high glycidol conversions and product selectivities over 90% with the use of Bi(OTf)3 and Al(OTf)3 as catalysts. A very low catalyst loading of 0.01% is used and the reaction is carried out at 80 ◦C. The use of these catalysts avoided the oligomerization of glycidol to a major extent, which could be an advantage compared to the use of basic catalysis [26], but the elimination of the catalyst from the reaction medium can be considered as a drawback as it implies the loss of parts of the GMEs that possess a non-negligible water solubility. This methodology has been improved by the same authors by using heterogeneous acid catalysts, namely Nafion NR50 [27]. Total glycidol conversions are described with a low catalytic loading (0.5%) and product yields in between 86% for isopropanol and 6% for 2-ethylhexan-1-ol. We recently presented a work dealing with the synthesis of GMEs starting from glycidol and several alcohols in the presence of both homogeneous and heterogeneous basic catalysts [26]. Although very good yields were achieved, we can consider some drawbacks that should be overcome in order to improve the sustainability of the process. First, the best results were described with the use of 20% mol of alkaline hydroxides that have to be neutralized in reaction media with subsequent salt formation. Also in the case of using more hindered alcohols or less reactive ones, the oligomerization of glycidol took place in a non-negligible extent. That is why we envisaged the possibility of exploring the use of heterogeneous acid catalysts as an alternative to our previous results. Here, we propose an efficient and green methodology for the synthesis of glycerol monoethers starting from glycidol and different alcohols (methanol, butanol and isopropanol) by means of heterogeneous acid catalysis. This methodology intends to overcome some drawbacks of previously described synthetic procedures such as the use of excess glycidol or the use of homogeneous catalyst, thus improving the sustainability of the synthesis.

2. Results and Discussion

2.1. Reaction of Glycidol and Methanol by Means of Heterogeneous Brønsted Acid Catalysis First, the reaction conditions were optimized in the benchmark reaction of glycidol (1) with methanol (2a) by using Dowex 50WX2 as catalyst (Scheme 1). Dowex 50WX2 is a sulfonic resin that has Molecules 2018, 23, x FOR PEER REVIEW 3 of 10

conversion and product selectivity (3a and 3b) was studied by modifying the loading of catalyst (5, 10 and 20% mol in respect to glycidol) and the reaction temperature (25 and 65 °C). In all cases methanol was used as the solvent (methanol: glycidol molar ratio 15:1). The reaction was monitored Moleculesby means2018 of, 23 Gas, 2887 Chromatography (GC) using diglyme as the internal standard. 3 of 10

Molecules 2018, 23, x FOR PEER REVIEW 3 of 10 been commonly and successfully used in catalysis [28–30]. The inﬂuence on both glycidol conversion conversionand product and selectivity product (3aselectivityand 3b) ( was3a and studied 3b) was by modifyingstudied by themodifying loading the of catalyst loading (5, of 10catalyst and 20% (5, 10mol and in respect20% mol to glycidol)in respect and to theglycidol) reaction and temperature the reaction (25 andtemperature 65 ◦C). In (25 all casesand 65 methanol °C). In wasall cases used methanolas the solvent was used (methanol: as the solvent glycidol (methanol: molar ratio glycid 15:1).ol Themolar reaction ratio 15:1). was monitoredThe reaction by was means monitored of Gas byChromatography means of Gas Chromatography (GC) using diglyme (GC) as using the internal diglyme standard. as the internal standard. Scheme 1. Reaction of glycidol (1) with methanol (2a) used as the benchmark reaction.

When using 10% or 20% mol catalyst loading, total conversions of glycidol were reached in less than 2 h regardless of the reaction temperature (Figure 1). Thus, using 20% of Dowex 50WX2, glycidol was totally converted in only 0.5 h. When lowering the catalyst loading to 5%, the reaction was dramatically slowed down, and 24−48 h was necessary to complete the reaction. ApartScheme from glycidol 1. ReactionReaction conversion, of glycidol yields ( 1)) with with of methanol methanol both products ( (2a)) used 3a as and the 3bbenchmark were determined reaction. (Figure 1). As can be seen, the ratio 3a/3b is almost constant (70/30) and not dependent on the reaction conditions.When using using But the 10% 10% selectivity or or 20% 20% mol of mol thecatalyst catalyst reaction, loading, loading, and thustotal total theconversions conversionsformation of of glycidol ofby-products glycidol were were (mostlyreached reached glycidol in less in thanlessoligomers), than2 h regardless 2 h is regardless greatly of the influenced ofreaction the reaction temperatureby the temperature reaction (Figure temperature (Figure 1). Thus,1 ).and using Thus, catalyst 20% using of loading. Dowex 20% of 50WX2,Thus Dowex the glycidol 50WX2, optimal wasglycidolconditions totally was convertedin totally order convertedto in obtain only a in0.5 higher only h. When 0.5selectivity h. lowering When is lowering to the use catalyst a the10% catalyst catalyst loading loading loading to 5%, to andthe 5%, 25reaction the °C reaction reaction was wasdramaticallytemperature. dramatically slowed These slowed down,conditions down, and were24 and−48 24 applied h− was48 h necessary wasto the necessary rest to of complete the to catalysts. complete the reaction. the reaction. Apart from glycidol conversion, yields of both products 3a and 3b were determined (Figure 1). As can be seen, the ratio 3a/3b is almost constant (70/30) and not dependent on the reaction conditions. But the selectivity of the reaction, and thus the formation of by-products (mostly glycidol oligomers), is greatly influenced by the reaction temperature and catalyst loading. Thus the optimal conditions in order to obtain a higher selectivity is to use a 10% catalyst loading and 25 °C reaction temperature. These conditions were applied to the rest of the catalysts.

Figure 1. Influence of catalyst loading and reaction temperature in glycidol (1) conversion and product Figure 1. Influence of catalyst loading and reaction temperature in glycidol (1) conversion and yields in the reaction of glycidol and methanol catalyzed with Dowex 50WX2. product yields in the reaction of glycidol and methanol catalyzed with Dowex 50WX2. Apart from glycidol conversion, yields of both products 3a and 3b were determined (Figure 1). Once the best reaction conditions were established (10% mol catalyst and 25 °C), a selection of As can be seen, the ratio 3a/3b is almost constant (70/30) and not dependent on the reaction conditions. solid Brønsted acid catalysts was made in order to study the influence of the nature of the acid site in But the selectivity of the reaction, and thus the formation of by-products (mostly glycidol oligomers), the reaction results. For this purpose, synthetic resins with aryl, alkyl and perfluoroalkyl sulfonic is greatly influenced by the reaction temperature and catalyst loading. Thus the optimal conditions in groups (Amberlyst A15, Dowex 50WX2, Deloxan I/9, Nafion NR50 and Aquivion PW79S) and orderFigure to obtain 1. Influence a higher of selectivity catalyst loading is to use and a reaction 10% catalyst temperature loading in and glycidol 25 ◦C (1 reaction) conversion temperature. and carboxylic sites (Dowex CCR-2) were selected, together with a natural clay K10-H+ Montmorillonite. Theseproduct conditions yields were in the applied reaction to of theglycidol rest ofand the methanol catalysts. catalyzed with Dowex 50WX2. Catalyst with carboxylic groups Dowex CCR-2 provided very poor glycidol conversions (14%) Once the best reaction conditions were established (10% mol catalyst and 25 ◦C), a selection in long reactions times (24 h), this catalyst being discarded. Comparing the rest of the catalysts, an of solidOnce Brønsted the best acid reaction catalysts conditions was made were in established order to study (10% themol influence catalyst and of the 25 nature°C), a selection of the acid of increase in oligomers formation was observed when using more acidic solids such as Nafion NR50 solidsite in Brønsted the reaction acid catalysts results. was For thismade purpose, in order syntheticto study the resins influence with aryl,of the alkyl nature and of perfluoroalkylthe acid site in or Aquivion PW79S compared to the results obtained with Dowex 50WX2 (Figure 2b). The use of thesulfonic reaction groups results. (Amberlyst For this A15, purpose, Dowex synthetic 50WX2, Deloxan resins with I/9, Nafionaryl, alkyl NR50 and and perfluoroalkyl Aquivion PW79S) sulfonic and Amberlyst 15, a more crosslinked resin, also worsened the selectivity of the reaction towards 3a and groupscarboxylic (Amberlyst sites (Dowex A15, CCR-2) Dowex were 50WX2, selected, Deloxan together I/9, with Nafion a natural NR50 clay and K10-H Aquivion+ Montmorillonite. PW79S) and 3b, and the activity of the alkyl sulfonic resin Deloxan I/9 was lower as expected (Figure+ 2a), thus 6 h carboxylicCatalyst sites with (Dowex carboxylic CCR-2) groups were selected, Dowex CCR-2 together provided with a natural very poor clay glycidol K10-H conversions Montmorillonite. (14%) were necessary to achieve total glycidol conversion. With all of these catalysts, a ratio 3a/3b of 70:30 in longCatalyst reactions with times carboxylic (24 h), grou thisps catalyst Dowex being CCR-2 discarded. provided Comparing very poor glycidol the rest ofconversions the catalysts, (14%) an was achieved and the product selectivity was maintained along the reaction. inincrease long reactions in oligomers times formation (24 h), this was catalyst observed being when discarded. using more Comparing acidic solidsthe rest such of the as Nafion catalysts, NR50 an increaseor Aquivion in oligomers PW79S compared formation towas the observed results obtained when using with more Dowex acidic 50WX2 solids (Figure such as2b). Nafion The useNR50 of Amberlystor Aquivion 15, PW79S a more compared crosslinked to resin,the results also worsened obtained thewith selectivity Dowex 50WX2 of the reaction(Figure towards2b). The 3auseand of Amberlyst3b, and the 15, activity a more of crosslinked the alkyl sulfonic resin, resinalso wo Deloxanrsened I/9 the was selectivity lower as of expected the reaction (Figure towards2a), thus 3a and 6 h 3b, and the activity of the alkyl sulfonic resin Deloxan I/9 was lower as expected (Figure 2a), thus 6 h were necessary to achieve total glycidol conversion. With all of these catalysts, a ratio 3a/3b of 70:30 was achieved and the product selectivity was maintained along the reaction.

Molecules 2018, 23, 2887 4 of 10 were necessary to achieve total glycidol conversion. With all of these catalysts, a ratio 3a/3b of 70:30 Molecules 2018, 23, x FOR PEER REVIEW 4 of 10 was achieved and the product selectivity was maintained along the reaction.

（a）

（b）

FigureFigure 2. Inﬂuence 2. Influence of of thethe nature nature of ofthethe catalyst catalyst on glycidol on glycidol (1) conversion (1) conversion (a) and products (a) and selectivity products selectivity(b). (b).

Finally,Finally, acidic acidic K10 MontmorilloniteK10 Montmorillonite provided provided very very good good results, results, as as 80% 80% yield yield of of the the products products was achievedwas in achieved only 1 hin reaction only 1 h time, reaction and time, with and a higher with a regioselectivity higher regioselectivity (ratio 3a(ratio/3b 3a80:20)./3b 80:20). This This catalyst catalyst was the best of the tested solids in activity and product selectivity. Above this, its natural was the best of the tested solids in activity and product selectivity. Above this, its natural origin origin improves the sustainability of the process. improves the sustainability of the process. 2.2. Reaction of Glycidol and Methanol by Means of Heterogeneous Lewis Catalysis 2.2. Reaction of Glycidol and Methanol by Means of Heterogeneous Lewis Catalysis Based on the studies presented by Cuccinello et al. [24,25], we decided to test some Basedheterogeneous on the studies Lewis presented acid catalysts by Cuccinello in order to et explore al. [24, 25the], possibility we decided of toimproving test some the heterogeneous product Lewisselectivity acid catalysts with inrespect order to to the explore ones obtained the possibility with Brønsted of improving solid K10-H the product+. As it has selectivity been mentioned, with respect to thethe ones fact obtained of obtaining with two Brønsted regioisomers, solid K10-H3a and +3b., As should it has be been addressed mentioned, as an advantage the fact ofif the obtaining mixture two regioisomers,is used as3a a andsolvent3b, due should to the be similar addressed physical-che as an advantagemical characteristics if the mixture of both is products, used as abut solvent it is a due to thegreat similar drawback physical-chemical if only one of characteristics the products is ofintend bothed products, for use, due but to it the is adifficulty great drawback of the separation if only one of theof products these compounds is intended due for to use,their duechemical to the similari difﬁcultyty. The of good the separation results obtained of these by using compounds K10-H+ dueas to a catalyst prompted us to try the same catalysts exchanged with Al+3 (K10-Al), Zn+2 (K10-Zn) or Fe+3 their chemical similarity. The good results obtained by using K10-H+ as a catalyst prompted us to try (K10-Fe), both dried at 120 °C and calcined at 550 °C. Previous IR studies of adsorbed pyridine, as a the same catalysts exchanged with Al+3 (K10-Al), Zn+2 (K10-Zn) or Fe+3 (K10-Fe), both dried at 120 ◦C ◦ and calcined at 550 C. Previous IR studies of adsorbed pyridine, as a probe molecule, on exchanged Molecules 2018, 23, 2887 5 of 10

Molecules 2018, 23, x FOR PEER REVIEW 5 of 10 Montmorillonites, showed the presence of both Brønsted and Lewis sites in dried solids at 120 ◦C andprobe an increase molecule, of Lewison exchanged acidity uponMontmorillonites, calcination at showed 550 ◦C[ the31 ].presence An approximate of both Brønsted comparison and Lewis of the relativesites in acidity dried ofsolids several at 120 clays °C hasand beenan increase carried of out Lewis by comparingacidity upon the calcination intensity ofat the550 IR°C peaks[31]. An of pyridineapproximate coordinated comparison to Brø nstedof the andrelative Lewis acidity sites. of several clays has been carried out by comparing theThe intensity possibility of the of IR using peaks 10% of pyridine mol of these coordinated catalysts, to as Br inønsted the case and of Lewis K10-H sites.+, was ﬁrst considered, + but theThe lower possibility functionalization of using 10% of K10-Al mol of these (0.18 mmolcatalysts, Al as g− in1), the K10-Fe case of (0.2 K10-H mmol, was Fe g first−1) andconsidered, K10-Zn but the lower functionalization of K10-Al (0.18 mmol Al g−1), K10-Fe (0.2 mmol Fe g−1) and K10-Zn (0.28 mmol Zn g−1) in respect to K10-H+ (0.59 mmol H+ g−1) implies the use of an amount of solid (0.28 mmol Zn g−1) in respect to K10-H+ (0.59 mmol H+ g−1) implies the use of an amount of solid that that makes the work up of the reaction difﬁcult. That is why we decided to start the catalytic test with makes the work up of the reaction difficult. That is why we decided to start the catalytic test with 5% 5% mol catalyst. mol catalyst. Table 1 gathers the results of the reaction of glycidol (1) with methanol (2a) at room temperature, Table 1 gathers the results of the reaction of glycidol (1) with methanol (2a) at room temperature, and as it can be seen, the lower activity and higher regioselectivity of calcined solids (entry 4 to 6) and as it can be seen, the lower activity and higher regioselectivity of calcined solids (entry 4 to 6) agree with the lower number of acid sites and the increase of the Lewis/Brønsted sites ratio. agree with the lower number of acid sites and the increase of the Lewis/ Brønsted sites ratio.

Table 1. Results of the reaction of glycidol (1) with methanol (2a) at room temperature catalyzed by Table 1. Results of the reaction of glycidol (1) with methanol (2a) at room temperature catalyzed by exchanged K10-Montmorillonites 1. exchanged K10-Montmorillonites 1. ◦ 2 EntryEntry CatalystCatalyst TT ( (°C)C) Activation Activation Time (h)(h) 2 ProductsProducts Yield 3a/3b 3a/3b 11 K10-AlK10-Al 120 120 0.5 0.5 94 82:1882:18 22 K10-FeK10-Fe 120 120 0.5 86 70:3070:30 3 K10-Zn 120 18 91 93:7 3 K10-Zn 120 18 91 93:7 44 K10-Al-calcK10-Al-calc 550 550 1.5 1.5 84.984.9 89:1189:11 5 K10-Fe-calc 550 1.5 74.8 91:9 5 K10-Fe-calc 550 1.5 74.8 91:9 6 K10-Zn-calc 550 24 79.1 90:10 6 K10-Zn-calc 550 24 79.1 90:10 1 A ratio 2a/1 of 15 mol and 5% mol catalyst are used, 1 added dropwise; 2 time for total conversion of glycidol 1 2 is considered.A ratio 2a/1 of 15 mol and 5% mol catalyst are used, 1 added dropwise; time for total conversion of glycidol is considered. Thus, a different behavior is observed for each catalyst but with a common trend, upon calcination Thus, a different behavior is observed for each catalyst but with a common trend, upon the reaction was slowed down in all the cases. Thus, the presence of Brønsted acid sites accelerates calcination the reaction was slowed down in all the cases. Thus, the presence of Brønsted acid sites the reaction. It is also noteworthy that K10-Zn (entry 3) and calcined clays (entries 4–6) greatly accelerates the reaction. It is also noteworthy that K10-Zn (entry 3) and calcined clays (entries 4–6) improved the regioselectivity (3a/3b) with respect to K10-H+. In this case, Lewis acid sites favor the greatly improved the regioselectivity (3a/3b) with respect to K10-H+. In this case, Lewis acid sites attackfavor of the methanol attack of to methanol the less to substituted the less substituted carbon of carbon the epoxide of the epoxide ring. This ring. is This also is observed also observed when ◦ comparingwhen comparing the 3a/3b theratio 3a/3b in theratio reactions in the reactions where the where catalysts the catalysts are activated are activated at 120 C at (Table 120 °C1 entries(Table 1 1 to 3).entries As Lewis/Br 1 to 3). Asønsted Lewis/ increases Brønsted (K10-Zn increases > K10-Al (K10-Zn > K10-Fe)> K10-Al [31 > ],K10-Fe) the 3a/ [31],3b ratio the also3a/3b follows ratio also the samefollows trend. the same trend. TheThe good good results results obtained obtained with with these these solids solids prompted prompted us us toto trytry toto reducereduce the amount of of catalyst. catalyst. ThusThus the the reactions reactions were were tested tested using using 1% 1% mol mol of of solid. solid. A A comparison comparison ofof thethe resultsresults with 1% and 5% 5% catalystcatalyst are are shown shown in in Figure Figure3. 3.

FigureFigure 3. Reaction3. Reaction of of glycidol glycidol (1 ()1 with) with methanol methanol ( 2a(2a)) catalyzed catalyzed by by 1% 1% molmol andand 5%5% molmol K10.K10.

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As it can be seen in Figure 3, a reduction in the amount of catalyst increases the time for total glycidol conversions in all the cases. It is noteworthy that in the case of K10-Zn, low glycidol Molecules 2018, 23, 2887 6 of 10 conversions are achieved even at 24 h reaction time when using 1% catalyst. In the case of K10-Fe and K10-Al, a higher amount of byproducts are formed when reducing the amount of catalyst. Finally, productAs it yields can be are seen also in affected. Figure 3Thus, a reduction for K10-Al, in the yield amount of 3a of + catalyst 3b is reduced increases from the 94% time when for using total glycidola 5% mol conversions catalyst to 80% in all when the cases.using 1% It ismol. noteworthy For K10-Zn that the in effect the caseis even of K10-Zn,more dramatic low glycidol with a conversionsdrastic decrease are achieved in yields even from at 91% 24 hyield reaction to 36%. time when using 1% catalyst. In the case of K10-Fe and K10-Al,The a analysis higher amount of the data of byproducts in Figure 3 areshows formed that whenthe best reducing results for the the amount reaction of catalyst. of glycidol Finally, with productmethanol yields are areachieved also affected. when usin Thusg for5% K10-Al, mol K10-Al the yield treated of 3a +at3b 120is reduced°C, both from in terms 94% whenof glycidol using aconversion 5% mol catalyst and product to 80% selectivity. when using Thus, 1% mol.these Forreac K10-Zntion conditions the effect were is even applied more in dramatic the study with of the a drasticrecoverability decrease of in the yields catalyst from (Figure 91% yield 4). to 36%. TheWhen analysis recovering of the K10-Al data two in Figure consec3utiveshows runs that can thebe done best with results no forloss the of activity. reaction But of from glycidol run with3, a progressive methanol are loss achieved of activity when is observed. using 5% molHowe K10-Alver, total treated conversions at 120 ◦C, of both glycidol in terms are achieved of glycidol at conversionroom temperature and product in moderate selectivity. reaction Thus, time. these Finally, reaction it conditionsis noteworthy were that applied in all the in the cases study a product of the recoverabilityselectivity over of 90% the catalystis maintained. (Figure 4).

FigureFigure 4.4. RecoverabilityRecoverability ofof K10-AlK10-Al (5%(5% mol)mol) inin thethe reactionreaction ofof glycidolglycidol (1(1)) with with methanol methanol ( 2a(2a).).

When recovering K10-Al two consecutive runs can be done with no loss of activity. But from run 2.3. Reaction of Glycidol with Several Alcohols for the Synthesis of GMEs 3, a progressive loss of activity is observed. However, total conversions of glycidol are achieved at roomIn temperature order to demonstrate in moderate the reaction applicability time. Finally,of these itcatalytic is noteworthy systems that to the in allsynthesis the cases of GMEs, a product the selectivityreaction of over glycidol 90% iswith maintained. other alcohols was performed (Scheme 2). Again, K10 Montmorillonites were chosen due to the good results provided in the reaction with methanol. 2.3. Reaction of Glycidol with Several Alcohols for the Synthesis of GMEs In order to demonstrate the applicability of these catalytic systems to the synthesis of GMEs, the reaction of glycidol with other alcohols was performed (Scheme 2). Again, K10 Montmorillonites were chosen due to the good results provided in the reaction with methanol.

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Scheme 2. ReactionReaction of glycidol ( 1)) with with several several alcohols ( 2).

Unfortunately, reactions using triﬂuoroethanoltrifluoroethanol (2d)) provided very poor yields in a long long reaction reaction + time (e.g., withwith K10-HK10-H+,, 5% yieldyield waswas achievedachieved in in 6 6 h h reaction reaction time). time). These These results results are are attributed attributed to the to thelow low nucleophilicity nucleophilicity of this of this alcohol. alcohol. However, However, as it as can it becan seen be seen in Table in Table2, the 2, catalysts the catalysts provided provided good goodresults results when when using using isopropanol isopropanol or butanol. or butanol. These These results results being thebeing best the described best described up to now up to for now the forsynthesis the synthesis of GMEs of withGMEs heterogeneous with heterogeneous catalysis. catalysis.

Table 2. Results of the reaction of glycidol with other alcohols at room temperature catalyzed by Table 2. Results of the reaction of glycidol with other alcohols at room temperature catalyzed by exchanged K10-Montmorillonites 1. exchanged K10-Montmorillonites 1. Alcohol Catalyst 2 Products Yield 4–5a/4–5b Alcohol Catalyst TimeTime (h) (h) 2 Products Yield 4–5a/4–5b + 2b 2b K10-HK10-H+ 0.50.5 70 70 83:17 83:17 2b K10-Al 0.5 79 76:24 2b K10-Al 0.5 79 76:24 2b K10-Zn 24 65 3 88:12 2b K10-Zn 24 65 3 88:12 2c K10-H+ 2 78 91:9 2c K10-H+ 2 78 91:9 2c K10-Al 1 75 85:15 2c 2c K10-ZnK10-Al 1 24 75 72 85:15 95:5 1 A ratio 2/1 of 15 mol2c are usedK10-Zn and 5% mol catalyst24 is used in the 72 case of K10-Al and 95:5 K10-Zn and 10% in the 1case A ratio of K10-H 2/1 of+, 115added mol are dropwise; used and2 time 5% for mol total catalyst conversion is used of glycidol in the case is considered; of K10-Al3 85% and glycidol K10-Zn conversion and 10% inafter the 24 case h. of K10-H+, 1 added dropwise; 2 time for total conversion of glycidol is considered; 3 85% glycidol conversion after 24 h. 2.4. Comparison of Synthetic Methodologies for Obtaining GMEs 2.4. ComparisonIn order to of be Synthetic able to selectMethodologies the best for methodology Obtaining GMEs for the synthesis of the glycerol monoethers startingIn order from glycidolto be able for to each select alcohol the best (2a –methodology2c), we have gatheredfor the synthesis in Table 3ofthe the best glycerol results monoethers reported in startingthis manuscript from glycidol together for witheach thealcohol best results(2a–2c), published we have gathered up to now in for Table these 3 the reactions. best results reported in this manuscript together with the best results published up to now for these reactions. Table 3. Comparison of the synthetic methodologies for the synthesis of GMEs (3–5a and 3–5b). This comparative table can be a useful tool for designing or scaling up the synthesis of GMEs. In Catalyst Loading Alcohol/Glycidol Reaction Conversion addition,Alcohol severalCatalyst parameters can be tuned in order to obtainTime (h)either better conversions ora/b selectivities, Ref. (% mol) Molar Ratio T(◦C) (Selectivity) or to prioritize lower reaction temperatures or catalyst loading depending on its price and 2a KOH 1 20 15 2 65 100 (93) 100:0 [26] recoverability.2a Al(OTf) 3 0.01 9 1 80 100 (94) 66:34 [24] 2a Nafion NR50 0.5 9 1 80 85 (79) 77:23 [27] 2a Nafion NR50 10 9 2 25 100 (67) 72:28 2aTable 3.K10-H Comparison+1 of the10 synthetic method15 ologies for 0.5the synthesis 25 of GMEs 100 (83)(3–5a and 80:20 3–5b). 2a K10-Al 1 5 15 0.5 25 100 (94) 82:18 Catalyst Loading Alcohol/Glycidol Time Reaction T Conversion Alcohol2a CatalystK10-Zn 1 5 15 24 25 100 (91) 93:7 a/b Ref (% mol) Molar Ratio (h) (°C) (Selectivity) 2b KOH 1 20 15 1.5 65 100 (60) 100:0 2a KOH 1 20 15 2 65 100 (93) 100:0 [26] 2b Al(OTf)3 0.01 9 1 80 94 (91) 66:34 [24] 2a2b Al(OTf)Nafion3 NR50 0.01 0.5 9 9 1 1580 80 39 100 (37) (94) 72:2866:34 [27[24]] 2b NafionK10-H +1 10 15 0.5 25 100 (70) 83:13 2a 1 0.5 9 1 80 85 (79) 77:23 [27] 2b NR50K10-Al 5 15 0.5 25 100 (79) 76:24 1 2c NafionK10-Zn 5 15 24 25 85 (65) 88:12 2a 10 9 2 25 100 (67) 72:28 2c NR50KOH 1 20 15 2 65 100 (30) 100:0 2a2c K10-HAl(OTf)+1 3 10 0.01 15 9 0.51 25 80 85100 (87) (83) 66:3480:20 [24] 2c Nafion NR50 0.5 9 15 80 95 (86) 78:22 [27] 1 2a2c K10-AlK10-H +1 5 10 1515 0.52 25 25 100100 (78) (94) 91:982:18 2a2c K10-ZnK10-Al 1 1 5 5 1515 241 25 25 100100 (75) (91) 85:1593:7 2b2c KOHK10-Zn 1 1 20 5 1515 1.524 65 25 100100 (72) (60) 95:5100:0 2b Al(OTf)3 0.01 1 Glycidol 9 ( 1) is added dropwise. 1 80 94 (91) 66:34 [24] Nafion 2b 0.5 9 15 80 39 (37) 72:28 [27] NR50 2b K10-H+1 10 15 0.5 25 100 (70) 83:13 2b K10-Al 1 5 15 0.5 25 100 (79) 76:24

Molecules 2018, 23, 2887 8 of 10

This comparative table can be a useful tool for designing or scaling up the synthesis of GMEs. In addition, several parameters can be tuned in order to obtain either better conversions or selectivities, or to prioritize lower reaction temperatures or catalyst loading depending on its price and recoverability. As it can be seen, results provided by K10 Montmorillonites can improve the sustainability of the synthetic process for the obtaining of GMEs as good yields and selectivities can be achieved at room temperature. Although a higher loading of the catalyst is needed, the possibility of its reuse is also an advantage compared to the use of homogeneous catalysts such as KOH or Al (OTf)3.

3. Materials and Methods Gas chromatography was carried out in a Hewlett Packard 5890 and 7890 series II Gas Chromatograph using a column Zebron ZB-Wax 30 m × 0.25 mm × 0.25 µm for the determination of the results of the reaction of glycidol with methanol, and for the rest of the alcohols, a column of phenyl silicone 5.5% (Zebron ZB-5HT Inferno 30 m × 0.25 mm × 0.25 µm) was used. Helium was used as a carrier gas, and the detection was done with a flame ionization detector (FID). Glycidol, diglyme, Dowex 50WX2, K10 Montmorillonite, Aquivion PW79S and Amberlyst 15 were purchased from Sigma-Aldrich (St. Louis, MO, USA). Methanol and isopropanol, were purchased from Scharlab (Barcelona, Spain). Butanol, 2,2,2-trifluoroethanol and Nafion NR50 were purchased from Alfa Aesar (Haverhill, MA, USA).

3.1. Preparation of the Catalysts Prior to the reaction, commercial sulfonic resins were dried under vacuum at 50 ◦C for two days and K10 clays were dried at 120 ◦C overnight or calcined at 550 ◦C. Preparation and activation of K10-Al, K10-Fe and K10-Zn is described elsewhere [31].

3.2. Reaction Procedure for the Synthesis of Glycerol Monoethers The appropriate amount of alcohol (15:1 with respect to glycidol), the catalyst (5, 10 or 20% mol with respect to glycidol) and diglyme as internal standard (15% w/w with respect to glycidol) were placed into a round bottomed flask. The reaction was stirred and heated at the desired temperature (65 or 25 ◦C) under argon. Then, glycidol (4.35 mmol) was added dropwise for 15 min. The reaction was monitored at different times by extracting samples that were filtered and diluted with methanol prior to injection in GC. After total consumption of glycidol, the heterogeneous catalysts were just filtered off. Conversions and yields were determined by GC. All the alcohols were dried and distilled over calcium hydride prior to use.

4. Conclusions A simple methodology for the synthesis of glycerol monoethers from glycidol and several alcohols has been presented. The use of heterogeneous catalysts, such as exchanged Montmorillonites, room temperature, the lack of need for any excess glycidol or additional solvents, and obtaining good yields and selectivities makes this process comply with the principles of green chemistry. The inﬂuence of catalyst loading and the reaction temperature was studied, as well as the inﬂuence of the nature of the catalyst and the alcohol. Brønsted catalysts provided good glycidol conversions in short times, but selectivity towards GMEs strongly depended on the catalyst. Thus, Dowex 50WX2 and K10-H+ provided the best yields. Exchanged K10 Montmorillonites showed a good activity in the reaction of glycidol and several alcohols, these results being comparable to previous results in the literature. Elimination of Bronsted acidity by calcination in exchanged K10 clays slowed down the reactions but a slight increase in regioselectivity was obtained. Molecules 2018, 23, 2887 9 of 10

Author Contributions: conceptualization, J.I.G. and E.P., methodology, A.L.-D.; investigation: A.L.-D., J.I.G.-P. and D.V.; writing—original draft preparation, E.P., writing—review A.L.-D. and J.A.M. supervision, E.P., project administration, J.I.G.; funding acquisition, J.I.G. and J.A.M. Funding: This research was funded by MINECO (project CTQ2014-52367-R), Gobierno de Aragón (Group E37_17R) and the European Regional Development Funds. A. Leal-Duaso acknowledges the MECD for a FPU grant. Conﬂicts of Interest: The authors declare no conﬂicts of interest.

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Sample Availability: Samples of the compounds are available from the authors.

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