catalysts Article Reaction of Glycerol with Trimethyl Orthoformate: Towards the Synthesis of New Glycerol Derivatives Roberto Calmanti, Emanuele Amadio , Alvise Perosa * and Maurizio Selva * Department of Molecular Sciences and Nanosystems, Università Ca’ Foscari Venezia, Via Torino 155, 30172 Venezia Mestre, Italy; [email protected] (R.C.); [email protected] (E.A.) * Correspondence: [email protected] (A.P.); [email protected] (M.S.); Tel.: +39-041-234-8958 (A.P.); +39-041-234-8687 (M.S.) Received: 29 May 2019; Accepted: 9 June 2019; Published: 14 June 2019 Abstract: The reactivity of glycerol with trimethyl orthoformate is here described with an emphasis on developing a reliable synthetic approach for glycerol valorization. The glycerol based orthoester 4-(dimethoxymethoxy)methyl)-2-methoxy-1,3-dioxolane (3) was synthesized, under catalytic as well as catalyst-free conditions, by taking advantage of the thermodynamically controlled equilibrium between intermediates. Both Brønsted and Lewis acid catalysts accelerated the attainment of such an equilibrium, particularly Brønsted acidic ionic liquids BSMImHSO4 and BSMImBr were the most effective compounds for this reaction. The kinetic profiles allowed the proposal of a mechanism that accounts for the selectivity of the reaction. Keywords: glycerol; orthoesters; Brønsted acid; ionic liquids; trimethyl orthoformate 1. Introduction Glycerol (Glyc) is one of the most important biomass-derived platform chemicals [1]. Over the last few decades, the overabundance of this bio-diesel by-product stimulated academic and industrial interests towards its conversion into renewable high value-added chemicals [2–7]. Some of the most promising processes are summarized in Figure1. In this field, our research group has explored different thermal and catalytic synthetic approaches by reacting Glyc with formaldehyde, acetone, dimethyl carbonate, and enol esters to yield acetals, ketals, and other sustainable derivatives [8–13]. In a search to further expand this chemistry and to identify new bio-building blocks, we considered orthoesters (OEs) as another family of electrophilic partners for the upgrading of Glyc. The impressive reactivity of OEs—up to 20,000 times higher than of the above cited ketones and aldehydes [14]—has stimulated significant studies for their applications as protecting groups for carboxylic acids and esters [15] (owing to their stability towards strong nucleophiles and bases), as dehydrating agents [16,17], and as copolymers for the synthesis of polyorthoesters [18,19]. More recently, a fascinating use of OEs in the synthesis of dynamic cryptands has been proposed, employed for the controlled release of metal ion guests [20,21]. Catalysts 2019, 9, 534; doi:10.3390/catal9060534 www.mdpi.com/journal/catalysts Catalysts 2019,, 99,, 534x FOR PEER REVIEW 22 of of 13 H yd ro ge no lysi Oligomerization s R n e o fo ti rm sa li in yc g C or oxidative carbonylation Transesterification Figure 1. Glycerol conversion routes. Figure 1. Glycerol conversion routes. Some pioneering research dating back to the ‘60s and ‘80s highlighted the potential of the reaction of GlycSome with pioneering OEs. In 1964, research Crank dating and Eastwoodback to the were ‘60s the and first ‘80s to investigatehighlightedthe the reaction potential between of the triolsreaction and of triethylorthoformate Glyc with OEs. In to1964, obtain Crank bicyclic and orthoestersEastwood were (BOEs) the [22 first], demonstrating to investigate the the formation reaction ofbetween several triols BOEs and from triethylorthoformate 1,2,4- 1,2,5- and to 1,3,5-triols. obtain bicyclic By usingorthoesters Glyc as(BOEs) reagent, [22], theydemonstrating observed the formation of aseveral mixture BOEs of the from pentacyclic 1,2,4- 1,2,5-cis -and/trans 1,3,5-triols.-2-ethoxy-4-hydroxymethyl-1,3-dioxolane By using Glyc as reagent, they observed (1) and itsthe hexacyclic formation isomerof a mixturecis-/trans of -2-ethoxy-5-hydroxy-1,3-dioxanethe pentacyclic cis-/trans-2-ethoxy-4-hydroxymet (4) (Figure2a) inhyl-1,3-dioxolane a 9:1 ratio with 67% (1) ofand yield, its hexacyclic which could isomer thermally cis-/trans- decomposed2-ethoxy-5-hydroxy-1,3-dioxane to ethanol, CO2 and (4 allyl) (Figure alcohol 2a) [in23 ].a 9:1 The ratio bicyclic with compound67% of yield, 2,6,7-trioxabyciclo which could thermally [2.2.1] decomposed heptane (2) was to ethanol, not observed. CO2 and A allyl few yearsalcohol ago, [23]. Thshibalonza The bicyclic andcompound Monbaliu 2,6,7-trioxabyciclo revisited the reaction [2.2.1] by heptane focusing (2 on) was the not formic observed. acid-catalyzed A few years synthesis ago, of Thshibalonza allyl alcohol underand Monbaliu continuous-flow revisited conditionsthe reaction (Figure by focusing2b) [24 on]. the formic acid-catalyzed synthesis of allyl alcohol underIn continuous-flow the late 1970s, Hall conditions et al. successfully (Figure 2b) accomplished [24]. the synthesis of 2 (Figure2c, Yield 70%) and ≈ its furtherIn the polymerization late 1970s, Hall to et five-membered al. successfully rings accomplished polyorthoesters the synthesis [25,26]. of Since 2 (Figure then, the 2c, ring-openingYield ≈ 70%) polymerizationsand its further polymerization of BOEs (including to five2)-membered have been extensivelyrings polyorthoesters investigated [25,26]. and reviewed Since then, [27 –the29]. ring- openingFurthermore, polymerizations diglycerol-OEs of BOEs (including were used 2 also) have to been develop extensively acid-labile investigated polymers and for drug-deliveryreviewed [27– applications29]. [18,30]. InFurthermore, this work, diglycerol-OEs the thermal andwere catalytic used also reaction to develop between acid-labile Gly andpolymers HC(OMe) for drug-delivery3 is studied withapplications the aim [18,30]. to develop new reliable synthetic protocols for glycerol exploitation. The selective formation (up to 95% of yield) of a new glycerol-based 5-membered ring di-orthoester (the cis-/trans-4-(dimethoxymethoxy)methyl)-2-methoxy-1,3-dioxolane; 3, Figure2d) was accomplished by using HC(OMe)3 as model OE via a dynamic and thermodynamically-controlled synthetic strategy. A variety of homogeneous and heterogeneous acids (PPTS, DBUHBr, sulfuric acid, Amberlyst-15, amberlyst-36, FeCl3, and AlF3) and ionic liquids (BSMImHSO4, BSMImBr) were used as Brønsted/Lewis-acidic catalysts. In this context, the ionic liquids (ILs) were tested as they are known to give better yields, turnover numbers, and frequencies, and improved catalysts recyclability [31]. The effect of basic catalysts (such as K2CO3 and trioctylmethylphosphonium methylcarbonate: [P1888]CH3OCO2−) was also investigated for comparison. Catalysts 2019, 9, 534 3 of 13 Catalysts 2019, 9, x FOR PEER REVIEW 3 of 13 Figure 2. Reactions between Gly and OEs. Figure 2. Reactions between Gly and OEs. 2. Results and Discussion In this work, the thermal and catalytic reaction between Gly and HC(OMe)3 is studied with the The reactivity between Glyc and HC(OMe) was first tested in the absence of any catalyst, in aim to develop new reliable synthetic protocols for3 glycerol exploitation. The selective formation (up analogy to the reaction conditions previously reported in literature [22,25,26]. The reaction was carried to 95% of yield) of a new glycerol-based 5-membered ring di-orthoester (the cis-/trans-4- out in the absence of added solvents at 90 C with a reagent molar ratio Q = 1 (Q = HC(OMe) :Glyc) (dimethoxymethoxy)methyl)-2-methoxy-1,3-dioxolane;◦ 3, Figure 2d) was accomplished by3 using for 1 h. The products were isolated and fully characterized by GC-MS, 1H, 13C, and 2D-NMR analyses HC(OMe)3 as model OE via a dynamic and thermodynamically-controlled synthetic strategy. A (see Material and Methods or Supplementary Materials for further details) revealing the formation variety of homogeneous and heterogeneous acids (PPTS, DBUHBr, sulfuric acid, Amberlyst-15, of the five-membered ring OE 1, the bicyclic compound 2,6,7-trioxabyciclo [2.2.1] heptane 2, and the amberlyst-36, FeCl3, and AlF3) and ionic liquids (BSMImHSO4, BSMImBr) were used as di-orthoester 3 (1 and 3 as mixtures of diastereomers) in 82/11/7 selectivity respectively (Figure3). Brønsted/Lewis-acidic catalysts. In this context, the ionic liquids (ILs) were tested as they are known Figure4 shows the gaschromatogram of the crude reaction mixture. toCatalysts give better 2019, 9, xyields, FOR PEER turnover REVIEW numbers, and frequencies, and improved catalysts recyclability4 of 13 [31]. The effect of basic catalysts (such as K2CO3 and trioctylmethylphosphonium methylcarbonate: [P1888]CH3OCO2−) was also investigated for comparison. 2. Results and Discussion The reactivity between Glyc and HC(OMe)3 was first tested in the absence of any catalyst, in analogy to the reaction conditions previously reported in literature [22,25,26]. The reaction was carried out in the absence of added solvents at 90 °C with a reagent molar ratio Q = 1 (Q = HC(OMe)3:Glyc) for 1 h. The productsFigure 3. wereReaction isolated of Gly and with fully HC(OMe) characterized. by GC-MS, 1H, 13C, and Figure 3. Reaction of Gly with HC(OMe)3. 3 2D-NMR analyses (see Material and Methods or Supplementary Materials for further details) revealingThe six-membered the formation ring of the isomers five-membered4 and the correspondent ring OE 1, the3 derivativebicyclic compound were not observed.2,6,7-trioxabyciclo This was 1250000 unexpected, since previous results for the reaction between Glyc and triethyl orthoformate reported [2.2.1] heptane1200000