Reaction of Glycerol with Trimethyl Orthoformate: Towards the Synthesis of New Glycerol Derivatives

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 2, and the di-orthoester 3 (1 and 3 as mixtures of diastereomers) in 82/11/7 selectivity respectivelya ﬁve- and1150000 six-membered (Figure 3). Figure ring 4 isomeric shows the ratio gaschromatogram of 3:1 [26] or 9:1 of [22 the] for crude compounds reaction 1:4mixture.. A reasonable 1100000 explanation is that, under our conditions, the reaction15.05915.823 between glycerol and HC(OMe)3 is kinetically 1050000 rather than1000000 thermodynamically controlled. Indeed, the ring strain energy of ﬁve-membered ring

1,3-dioxolane950000 (7.3 kcal/mol) is higher than the six-membered ring 1,3-dioxane analogs (2.9 kcal/mol) [32], while the900000 stabilization energy due to their formation was 4.4 and 13.2 respectively [33]. These trends 850000 of energies show that 1,3-dioxane are more stable than 1,3-dioxolane. This explanation is also in 800000

750000

700000

650000 600000 550000

500000 19.777 450000

400000 11.757 19.634 350000

300000

250000

200000

150000

100000

50000

0 Time--> 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00

Figure 4. Gaschromatogram of the reaction between HC(OMe)3 and Gly with Q = 1, 90 °C, 1 h.

The six-membered ring isomers 4 and the correspondent 3 derivative were not observed. This was unexpected, since previous results for the reaction between Glyc and triethyl orthoformate reported a five- and six-membered ring isomeric ratio of 3:1 [26Error! Bookmark not defined.] or 9:1 [22] for compounds 1:4. A reasonable explanation is that, under our conditions, the reaction between glycerol and HC(OMe)3 is kinetically rather than thermodynamically controlled. Indeed, the ring strain energy of five-membered ring 1,3-dioxolane (7.3 kcal/mol) is higher than the six-membered ring 1,3-dioxane analogs (2.9 kcal/mol) [32], while the stabilization energy due to their formation was 4.4 and 13.2 respectively [33]. These trends of energies show that 1,3-dioxane are more stable than 1,3-dioxolane. This explanation is also in agreement with the results reported by Yokohama et al. for the ring-opening polymerization of 2 that under kinetical control, leads to the almost exclusive formation of the five-membered ring product [26]. Further experiments were then carried out at different temperatures and Glyc:HC(OMe)3 molar ratios by following the product distribution over the time. At 90 °C, under reactive distillation conditions to remove methanol continuously during the reaction, the kinetic profile of the reaction was studied for 24 h at two different molar ratios Q = 1 and Q = 10 (Figure 5a,b). In both cases, within the first minutes of reaction the initial biphasic mixture turned homogeneous and vigorous distillation of methanol was observed. For both ratios Q = 1 and Q = 10, the Glyc conversion was almost quantitative after 0.5 h (based on GC analysis) towards formation of 1 and 3 respectively, thus proving that the formation of the glycerol-OEs is basically instantaneous, yielding a statistical

Catalysts 2019, 9, x FOR PEER REVIEW 4 of 13

Catalysts 2019, 9, 534 4 of 13

agreement with the results reported by Yokohama et al. for the ring-opening polymerization of 2 that under kinetical control, leads toFigure the almost 3. Reaction exclusive of Gly formation with HC(OMe) of the3 ﬁve-membered. ring product [26].

1250000

1200000

1150000

1100000 15.05915.823

1050000

1000000

950000

900000

850000

800000

750000

700000

650000

600000

550000

500000 19.777 450000

400000 11.757 19.634 350000

300000

250000

200000

150000

100000

50000

0 Time--> 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00

Figure 4. Gaschromatogram of the reaction between HC(OMe)3 and Gly with Q = 1, 90 ◦C, 1 h. Figure 4. Gaschromatogram of the reaction between HC(OMe)3 and Gly with Q = 1, 90 °C, 1 h.

Further experiments were then carried out at different temperatures and Glyc:HC(OMe)3 molar The six-membered ring isomers 4 and the correspondent 3 derivative were not observed. This ratios by following the product distribution over the time. At 90 ◦C, under reactive distillation was unexpected, since previous results for the reaction between Glyc and triethyl orthoformate conditions to remove methanol continuously during the reaction, the kinetic profile of the reaction reported a five- and six-membered ring isomeric ratio of 3:1 [26Error! Bookmark not defined.] or 9:1 was studied for 24 h at two different molar ratios Q = 1 and Q = 10 (Figure5a,b). In both cases, [22] for compounds 1:4. A reasonable explanation is that, under our conditions, the reaction between within the first minutes of reaction the initial biphasic mixture turned homogeneous and vigorous glycerol and HC(OMe)3 is kinetically rather than thermodynamically controlled. Indeed, the ring distillation of methanol was observed. For both ratios Q = 1 and Q = 10, the Glyc conversion was strain energy of five-membered ring 1,3-dioxolane (7.3 kcal/mol) is higher than the six-membered almost quantitative after 0.5 h (based on GC analysis) towards formation of 1 and 3 respectively, ring 1,3-dioxane analogs (2.9 kcal/mol) [32], while the stabilization energy due to their formation was thus proving that the formation of the glycerol-OEs is basically instantaneous, yielding a statistical 4.4 and 13.2 respectively [33]. These trends of energies show that 1,3-dioxane are more stable than product distribution. After 24 h, a relatively slow dynamic covalent exchange reaction yielded a 1,3-dioxolane. This explanation is also in agreement with the results reported by Yokohama et al. for thermodynamically controlled product distribution which is influenced by the reaction conditions. the ring-opening polymerization of 2 that under kinetical control, leads to the almost exclusive For example, with Q = 1, after 1 h the selectivity was shifted towards 1, but prolonging the reaction formation of the five-membered ring product [26]. time, 1 and 3 slowly decreased in favor of the formation of 2 (39% after 24 h) via an intramolecular Further experiments were then carried out at different temperatures and Glyc:HC(OMe)3 molar reaction favored by the continuous removal of methanol. When using an excess of HC(OMe)3 (Q = 10) ratios by following the product distribution over the time. At 90 °C, under reactive distillation the initial selectivity was shifted towards the formation of 3 (80%, 1 h), as expected; after 24 h the conditions to remove methanol continuously during the reaction, the kinetic profile of the reaction reaction slowly proceeded further favoring conversion of 1 into 3 (97%, 24 h). It is worth noting that, was studied for 24 h at two different molar ratios Q = 1 and Q = 10 (Figure 5a,b). In both cases, within under these conditions, 3 could be isolated by simply evaporating the excess of HC(OMe)3 without the first minutes of reaction the initial biphasic mixture turned homogeneous and vigorous any further purification step (95% isolated yield with 98% purity by GC). distillation of methanol was observed. For both ratios Q = 1 and Q = 10, the Glyc conversion was almost quantitative after 0.5 h (based on GC analysis) towards formation of 1 and 3 respectively, thus proving that the formation of the glycerol-OEs is basically instantaneous, yielding a statistical

Catalysts 2019, 9, x FOR PEER REVIEW 5 of 13

Catalysts 2019, 9, x FOR PEER REVIEW 5 of 13 product distribution. After 24 h, a relatively slow dynamic covalent exchange reaction yielded a thermodynamicallyproduct distribution. controlled After 24 producth, a relatively distribution slow dynamicwhich is covalentinfluenced exchange by the reaction yieldedconditions. a Forthermodynamically example, with Q =controlled 1, after 1 producth the selectivity distribution was which shifted is towardsinfluenced 1, bybut the prolonging reaction conditions. the reaction time,For 1example, and 3 slowly with Q decreased = 1, after 1in h favorthe selectivity of the formation was shifted of 2towards (39% after 1, but 24 prolongingh) via an intramolecular the reaction reactiontime, 1 favoredand 3 slowly by the decreased continuous in favor removal of the of formation methanol. of When 2 (39% using after an24 h)excess via an of intramolecular HC(OMe)3 (Q = 10)reaction the initial favored selectivity by the was continuous shifted towardsremoval theof methanol. formation When of 3 (80%, using 1 anh), excess as expected; of HC(OMe) after 243 (Q h the= reaction10) the slowlyinitial selectivity proceeded was furt shiftedher favoring towards conversion the formation of 1 of into 3 (80%, 3 (97%, 1 h), 24 as h). expected; It is worth after noting 24 h the that, underreaction these slowly conditions, proceeded 3 could further be favoringisolated conversionby simply ofev aporating1 into 3 (97%, the 24 excess h). It ofis worthHC(OMe) noting3 without that, Catalystsanyunder further2019 these, 9purification, 534conditions, step 3 could (95% be isolated isolated yield by simply with 98% evaporating purity by the GC). excess of HC(OMe)3 without5 of 13 any further purification step (95% isolated yield with 98% purity by GC).

Figure 5. Conversion of Gly and products selectivity for the catalyst-free reaction between Gly and Figure 5. Conversion of Gly and products selectivity for the catalyst-free reaction between Gly and HC(OMe)3.3. ReactionReaction conditions: Gly [5.43 mmol] and HC(OMe)33 with Q = 11 ( (aa)) or or Q Q = 1010 ( (bb)) at at 90 90 °C.◦C. HC(OMe)3. Reaction conditions: Gly [5.43 mmol] and HC(OMe)3 with Q = 1 (a) or Q = 10 (b) at 90 °C. The experimental results indicated that—likewise to the known glycerol-orthoformate TheThe experimental experimental results results indicate indicatedd that—likewisethat—likewise toto thethe known known glycerol-orthoformate glycerol-orthoformate reactivity reactivity reactivity[22–24,26] [and22– 24the,26 alkoxy-exchange] and the alkoxy-exchange reactivity of OEs reactivity [34]—the of OEs initial [34 fast]—the reaction initial of fastHC(OMe) reaction3 with of [22–24,26] and the alkoxy-exchange reactivity of OEs [34]—the initial fast reaction of HC(OMe)3 with HC(OMe)GlycGlyc gives gives3 1with 1which which Glyc is is in givesin equilibrium equilibrium1 which iswithwith in equilibrium 22 andand 3, the latterlatter with formed2formedand 3 ,by by the reaction reaction latter formedwith with another another by reaction molecule molecule with anotherofof orthoformate. orthoformate. molecule Interconversion of Interconversion orthoformate. of of Interconversion 22 andand 33 goesgoes through of 2 and aa3 dynamicdynamicgoes through covalent covalent a dynamic reaction reaction covalent involving involving reaction 1 as1 as involvingthethe intermediate. intermediate.1 as the Scheme intermediate.Scheme 1 1 shows shows Scheme thethe hypothesizedhypothesized1 shows the reaction hypothesizedreaction pathways.pathways. reaction pathways.

O OHOH O HOHO OH OO OO

Fast

O O O O OHOH O 1 O OO OO

O OO O O CH OH OOO O O CH OH CH OH3 O O 3 3 O O O CH3OH O O O

Dynamic Covalent Pathway Covalent Dynamic 2 3

SchemeScheme 1. 1.Pathways Pathways forfor thethe Gly and HC(OMe) 33 reaction.reaction. Scheme 1. Pathways for the Gly and HC(OMe)3 reaction.

The reaction was further investigated by varying Q between 1 and 10, at T = 90 ◦C and 25 ◦C, for 24 h. As shown in Table1, 3 was formed selectively at 90 ◦C only with a large excess of HC(OMe)3 (Q = 10) (entry 5, Table1). At lower Q values instead (entries 1–4, Table1), the selectivity-determining dynamic equilibrium resulted in a statistical products distribution. Catalysts 2019, 9, x FOR PEER REVIEW 6 of 13

The reaction was further investigated by varying Q between 1 and 10, at T = 90 °C and 25 °C, for 24 h. As shown in Table 1, 3 was formed selectively at 90 °C only with a large excess of HC(OMe)3 (Q = 10) (entry 5, Table 1). At lower Q values instead (entry 1–4, Table 1), the selectivity-determining dynamic equilibrium resulted in a statistical products distribution. A less pronounced exchange equilibrium between the products was observed for the reactions conducted at 25 °C respect to the ones conducted at 90 °C. In fact, at 25 °C and Q = 1 the reaction was very slow and after 24 h, conversion reached only 63% (90% conversion after 48 h), with 79% selectivity towards formation of 1 (entry 6, Table 1 and Figure S32 for the reaction profile). At higher Q = 10, the reaction rate increased reaching almost quantitative conversion, but the product distribution was not shifted towards the formation of 3, as was the case for the reaction conducted at 90 °C. Instead, a high (88%) selectivity towards 1 was observed after 1 h, while after 24 h the dynamic equilibrium promoted a 74/5/21 selectivity towards 1/2/3 respectively (entry 7 and Figure S33 for the Catalystsreaction2019 profile)., 9, 534 6 of 13

Table 1. Q and T effect on products distribution for the catalyst-free reaction of Gly with HC(OMe) Table 1. Q and T eﬀect on products distribution for the catalyst-free reaction of Gly with HC(OMe).

Conversion SelectivitySelectivity (%) a(%) a EntryEntry Q Q T( T (°C)C) Conversion (%) a ◦ (%) a 11 22 3 3 1 1 90 96 58 39 3 1 1 90 96 58 39 3 2 2 1.51.5 9090 9696 56 56 99 35 35 3 3 22 9090 9696 51 51 33 46 46 4 4 55 9090 9999 24 24 22 74 74 5 5 1010 9090 100100 3 3 0 0 97 97 6 6 11 2525 6363 79 79 88 13 13 7 7 1010 2525 9595 74 74 55 21 21 Reaction conditions: Gly (5.43 mmol) and HC(OMe) with Q = 1–10, T = 90 C, t = 24 h. a Conversion of Gly and Reaction conditions: Gly (5.43 m mol) and HC(OMe)3 3 with Q = 1–10, T ◦= 90 °C, t = 24 h. a Conversion products selectivity determined by GC. of Gly and products selectivity determined by GC.

AOverall, less pronounced the catalyst-free exchange reaction equilibrium between Gly between and HC(OMe) the products3 lead wasto the observed selectivefor synthesis the reactions of conductedthe thermodynamically-favored at 25 ◦C respect to the product ones conducted 3—a new atorthoester 90 ◦C. In derivative fact, at 25 of◦C glycerol—after and Q = 1 the 24 reaction h and was veryin the slow presence and after of an 24 excess h, conversion of OE. reached only 63% (90% conversion after 48 h), with 79% selectivity towardsWith formation the aim to of accelerate1 (entry 6,attainment Table1 and of the Figure dynamic S32 for equilibrium the reaction among profile). 1, 2, and At higher3, and to Q direct= 10, the reactionselectivity, rate different increased acid reaching catalysts almost were then quantitative tested at conversion,Q = 10 and T but = 90 the °C. product The results distribution are listed was in not shiftedTable 2. towards In the thepresence formation of PPTS of 3 ,(10%w/w as was thegly), case known for theto reactioncatalyze conductedthe reaction at of 90 diglycerol◦C. Instead, with a high (88%)triethyl selectivity orthoformate towards [30],1 thewas reaction observed reached after 1qu h,antitative while after conversion 24 h the and dynamic 97% selectivity equilibrium towards promoted a374 in/ 51/ 21h (entry selectivity 3 and towards4; Table 2).1/2 No/3 respectively further products (entry were 7 and observed Figure even S33 forafter the 24 reaction h, indicating profile). that 3 is stable under the reaction conditions (Figure S34 for the reaction profile). As shown in Table 2, all Overall, the catalyst-free reaction between Gly and HC(OMe)3 lead to the selective synthesis of thethe thermodynamically-favoredother acid catalysts favored product the formation3—a new of orthoester 3 already derivative after 1 h. of Only glycerol—after for diazabicyclo- 24 h and in undecenium bromide (DBUHBr, entry 5–6, Table 2) a slower dynamic equilibrium—in line with the the presence of an excess of OE. uncatalyzed reaction—was observed (75% and 93% selectivity after 1 and 24 h, respectively) likely With the aim to accelerate attainment of the dynamic equilibrium among 1, 2, and 3, and to direct due to the lower acidity [35]. Brønsted and Lewis acidic catalysts such as H2SO4, amberlyst-15, selectivity, different acid catalysts were then tested at Q = 10 and T = 90 C. The results are listed amberlyst-36, iron chloride and aluminum fluoride promoted moderate-to-good◦ selectivity (84, 79, in Table2. In the presence of PPTS (10%w /w ), known to catalyze the reaction of diglycerol with 87, 91, 87%, respectively; entries 7, 9, 11, 13, 15, glyTable 2) towards 3 after 1 h along with small amount triethylof ill-defined orthoformate products [30 (e.g.,], the alde reactionhydes, reached ethers, or quantitative oligomers). conversion The latter andwere 97% probably selectivity formed towards by 3 incatalytic 1 h (entries decomposition 3 and 4; Table of 32 ).as No already further described products in were the literature observed for even OEs after [26,36,37]. 24 h, indicating The reaction that 3 is stablebecame under evident the after reaction 24 h. conditions In particular, (Figure the use S34 of forsulfuric the reaction acid caused profile). formation As shown of a large in Table quantity2, all the other(≈41%) acid of four catalysts major favored undefined the products formation (see of Figu3 alreadyres S35–S39 after for 1 h. the Only gas-chromatography for diazabicyclo-undecenium trace and bromide (DBUHBr, entries 5 and 6, Table2) a slower dynamic equilibrium—in line with the uncatalyzed reaction—was observed (75% and 93% selectivity after 1 and 24 h, respectively) likely due to the lower acidity [35]. Brønsted and Lewis acidic catalysts such as H2SO4, amberlyst-15, amberlyst-36, iron chloride and aluminum fluoride promoted moderate-to-good selectivity (84%, 79%, 87%, 91%, 87%, respectively; entries 7, 9, 11, 13, 15, Table2) towards 3 after 1 h along with small amount of ill-defined products (e.g., aldehydes, ethers, or oligomers). The latter were probably formed by catalytic decomposition of 3 as already described in the literature for OEs [26,36,37]. The reaction became evident after 24 h. In particular, the use of sulfuric acid caused formation of a large quantity ( 41%) of ≈ four major undefined products (see Figures S35–S39 for the gas-chromatography trace and MS spectra) after 24 h at 90 ◦C. Instead, when using the ionic liquids butylsulfonylmethylimidazolium bromide (BSMImBr) and hydrogensulfate (BSMImHSO4) as catalyst (entries 17–20, Table2) the fast reaction rates were always accompanied by the quantitative and selective formation of 3 (98%) and by the absence of side reactions (99% also after 24 h). The same acidic ionic liquids allowed to perform the reaction at 25 ◦C, still with appreciable selectivity towards 3 (81–87%; entries 21–22; Table2). Finally, no Catalysts 2019, 9, x FOR PEER REVIEW 7 of 13

MS spectra) after 24 h at 90 °C. Instead, when using the ionic liquids butylsulfonylmethylimidazolium bromide (BSMImBr) and hydrogensulfate (BSMImHSO4) as catalyst (entries 17–20, Table 2) the fast

Catalystsreaction2019 rates, 9, 534 were always accompanied by the quantitative and selective formation of 3 (98%) and7 of 13 by the absence of side reactions (99% also after 24 h). The same acidic ionic liquids allowed to perform the reaction at 25 °C, still with appreciable selectivity towards 3 (81–87%; entries 21–22; Table 2). conversionFinally, no of conversion Glyc was observed of Glyc when was usingobserv basiced when catalysts, using such basic as K 2catalysts,CO3 or [P 1888such]CH as3 OCOK2CO2−3 [or38 ], owing[P1888]CH to the3OCO stability2− [38], ofowing OEs towardsto the stability bases. of OEs towards bases. ToTo rationalize rationalize the the catalytic catalytic behavior, behavior, the Hammettthe Hammett acidity acidity functions functions (H0) for(H the0) for di ﬀtheerent different catalysts werecatalysts compared were compared (see Table (see2). Table H 0 was 2). H chosen0 was chosen as it is as one it isof one the of mostthe most eﬀective effective ways ways to to express express the Brønstedthe Brønsted acidity acidity in an in organican organic medium medium [39 [39,40].,40]. It It is is readily readily apparent apparent thatthat stronger acidity acidity (H (H0 0< <0, 0, entriesentry 7–12) 7–12) prompts prompts faster faster reactions reactions but but also also higher higher formation formation of of side side products. products. On On the the other other hand, hand, when using weaker acids (H0 = 1–3, entries 17–22) the reactions are more selective towards the when using weaker acids (H0 = 1–3, entries 17–22) the reactions are more selective towards the formationformation of of the the desireddesired productproduct 33..

Table 2. Catalyzed reaction between HC(OMe)3 and Gly Table 2. Catalyzed reaction between HC(OMe)3 and Gly.

a a b Entry Catalyst Time (h) Conversiona (%) Selectivity (%)a H0 b Entry Catalyst Time (h) Conversion (%) Selectivity (%) H0 1 2 3 Others 1 2 3 Others 1 --- 1 96 19 1 80 - 1 — 1 96 19 1 80 - 22 —--- 24 24 >99 >99 33 00 97 97 - - 33 PPTSPPTS 1 1 >99 >99 00 33 97 97 - - 44 PPTSPPTS 24 24 >99 >99 00 33 97 97 - - 55 DBUHBr DBUHBr 1 1 96 96 25 25 00 75 75 - - 6 DBUHBr 24 >99 7 0 93 - 67 DBUHBr H SO 1 24 >99 >99 9 7 20 93 84 - 5 12.3 [41] 2 4 − 78 HH2SO2SO4 4 24 1 >99 >99 429 12 84 16 5 41 −12.3 [41] 9 A-15 1 >99 12 3 79 6 2.2 [42,43] 8 H2SO4 24 >99 42 1 16 41 − 10 A-15 24 >99 17 1 70 12 911 A-36 A-15 1 1 >99 >99 7 12 13 79 87 6 5 −2.22.65 [42,43] [42,43 ] − 1012 A-36 A-15 24 24 >99 >99 13 17 11 70 75 12 11 1113 FeClA-363 1 1 >99 >99 27 01 87 91 5 7 −2.65 [42,43] 1214 FeCl A-363 24 24 >99 >99 10 13 11 75 78 11 11 15 AlF3 1 >99 9 1 87 3 3 1316 AlFFeCl3 24 1 >99 >99 32 10 91 92 7 4 1417 BSMImHSOFeCl3 4 1 24 >99 >99 0 102 1 78 98 11 - 1.02 [44] 18 BSMImHSO 24 >99 0 1 99 - 15 AlF3 4 1 >99 9 1 87 3 19 BSMImBr 1 >99 0 2 98 - 2.91 c [45] 1620 BSMImBrAlF3 24 24 >99 >99 03 11 92 99 4 - d 1721 BSMImHSOBSMImHSO4 4 1 1 >99 >99 17 0 22 98 81 - - 1.02 [44] d 1822 BSMImHSOBSMImBr 4 1 24 >99 >99 11 0 21 99 87 - - 1923 BSMImBr K2CO3 1 1 0 >99 0 0 02 98 0 - - 2.91 c [45] 24 [P1888]CH3OCO2− 1 0 0 0 0 - 20 BSMImBr 24 >99 0 1 99 - a Reaction conditions: Gly (5.43 mmol) and HC(OMe)3 with Q = 10, 10%w/w Gly of catalyst, 90 ◦C, 1–24 h. Conversion 21 BSMImHSO4 d 1 >99 17 2 81 - of Gly and products selectivity determined by GC. b Hammett acidity function according to literature data. c the value22 reportedBSMImBr was calculated d for butylsulfonylmethylimidazolium 1 >99 chloride. 11 2 d 87The reaction - was carried out at T23= 25 ◦C. K2CO3 1 0 0 0 0 - 24 [P1888]CH3OCO2− 1 0 0 0 0 -

3. MaterialsReaction and conditions: Methods Gly (5.43 mmol) and HC(OMe)3 with Q = 10, 10%w/w Gly of catalyst, 90 °C, 1–24 h. a Conversion of Gly and products selectivity determined by GC. b Hammett acidity function 3.1. Generalaccording Information to literature data. c the value reported was calculated for butylsulfonylmethylimidazolium d Allchloride. the chemicals The reaction were was purchased carried out from at T Aldrich = 25 °C. and used as received. Trioctylmethylphosphonium methylcarbonate ([P ]CH OCO ) was synthesized according to a literature procedure [38]. 3. Materials and Methods1888 3 2− GC analyses were run using a Perkin Elmer Elite-624 capillary column (L = 30 m, Ø = 0.32 mm, 1 film thickness = 1.8 µm). The following conditions were used. Carrier gas: N2; flow rate: 3.5 mL min− ; 1 split ratio: 1:1; initial T: 50 ◦C (4 min), ramp rate: 10 ◦C min− ; final T: 180 ◦C; ramp rate: 20 ◦C min, final T: 240 ◦C (10 min). GC-MS (EI, 70 eV) analyses were run using a Grace AT-624 capillary column (L = 30 m, Ø = 0.32 mm, film thickness = 1.8 µm). The following conditions were used. Carrier Catalysts 2019, 9, 534 8 of 13

1 1 gas: He; ﬂow rate: 1.2 mL min− ; split ratio: 10:1; initial T: 50 ◦C (4 min), ramp rate: 10 ◦C min− to 1 13 1 180 ◦C; ramp rate: 20 ◦C min, ﬁnal T: 240 ◦C (10 min). H, C{ H}, DEPT-135, DEPT-90, APT, NOESY, HSQC, HMBC, COSY NMR spectra were recorded on a Bruker 400 MHz (1H: 400 MHz; 13C: 100 MHz) spectrometer. For 1H and 13C{1H} NMR the chemical shifts (δ) have been reported in parts per million (ppm) relative to the residual undeuterated solvent as an internal reference.

3.2. Synthesis/Isolation of Reaction Products

3.2.1. Synthesis of (2-methoxy-1,3-dioxolan-4-yl) Methanol (1) Glycerol (5.12 g, 55.6 mmol) was added in a two-neck round bottom flask equipped with a dripping funnel and a heating condenser held at 70 ◦C. The flask was heated at 90 ◦C and HC(OMe)3 (6.1 mL, 55.6 mmol) was added dropwise under stirring and kept for 1 h. In Figure5, the gaschromatographic trace of the reaction crude is reported, highlighting the presence of diastereomers. The reaction mixture was then distilled over potassium carbonate three times to isolate one pure distereoisomer of 1 in 10% yield, hereafter identified as 1a (the peaks with retention time 15.0 min in Figure4). The characterization of the other diastereoisomer 1b (retention time 15.8 min) is inferred from the spectra of the mixture. 1H NMR (400 MHz, Acetone)1a: δ = 5.72 (s, 1H), 4.23–4.18 (m, 1H), 4.11–4.04 (m, 1H), 3.84–3.78 (m, 1H), 3.66 (ddd, J = 6.0, 5.2, 2.7, 2H), 3.26 (s, 3H). 13C NMR (101 MHz, Acetone) δ = 115.93, 77.03, 65.47, 62.86, 50.22. GC-MS: 134 (M+,0);133 (1); 103 (100); 61 (31); 57 (46); 47 (15); 45 (32); 44 (31); 43 (65). 1b: 5.73 (s, 1H), 4.32 (ddt, J = 6.9, 5.6, 5.0, 1H), 4.11–4.04 (m, 1H), 3.84–3.78 (m, 1H), 3.57 (dd, J = 6.0, 5.0, 2H), 3.23 (s, 3H). 13C NMR (101 MHz, Acetone) δ = 115.82, 76.09, 65.42, 62.22, 50.00. GC-MS: 134 (M+,0);133 (1); 103 (100); 74 (8); 61 (18); 57 (47); 47 (15); 45 (28); 44 (14); 43 (46). All the 1H, 13C, COSY, HMBC, HSQC, COSY NMR and the GC-MS spectra are reported in Figures S1–S12.

3.2.2. Synthesis of 2,6,7-Trioxabyciclo [2.2.1] Heptane (2) Any attempt to isolate 2 from the crude reaction mixture proved unsuccessful and it was identiﬁed only by GC-MS (Figure S13). GC-MS: 102 (M+,8);101 (4); 45 (15); 44 (100); 43 (62); 42 (6).

3.2.3. Synthesis of 4-(Dimethoxymethoxy)Methyl)-2-Methoxy-1,3-Dioxolane (3)

Glycerol (0.526 g, 5.71 mmol) and HC(OMe)3 (6.3 mL, 57.2 mmol) were added in a round-bottomed ﬂask and the mixture was stirred at 90 ◦C. During the reaction the methanol was distilled out the mixture by heating the condenser at 70 ◦C. After 24 h the mixture was cooled down and then concentrated under vacuum (60 ◦C, 35 mbar). 3 was obtained a mixture of two diastereomers in 95% yield without any further puriﬁcation (purity 98% by GC). The diastereoisomeric ratio of 3 was 1:1 according to GC and 1H NMR analyses (Figure S16). Any attempts to separate the two isomers (hereafter called 3a or 3b) failed. 1H NMR (400 MHz, Acetone) 3a + 3b: δ = 5.76 (s, 1H), 5.73 (s, 1H), 5.11 (s, 1H), 5.10 (s, 1H), 4.44 (dq, J = 6.9, 5.3, 1H), 4.34–4.27 (m, 1H), 4.11 (ddd, J = 7.9, 6.8, 5.6, 2H), 3.81–3.77 (m, 2H), 3.71 (dd, J = 10.6, 6.1, 1H), 3.65–3.61 (m, 1H), 3.57 (dd, J = 6.2, 5.3, 2H), 3.31–3.29 (m, 12H), 3.26 (s, 3H), 3.25 (s, 3H). 13C NMR (101 MHz, Acetone) δ = 116.13, 115.86, 113.99, 113.95, 74.80, 74.11, 66.00, 65.68, 64.82, 63.80 (d, J = 2.1), 50.72, 50.71, 50.21, 50.04. GC-MS: 3a: 208 (M+,0);131 (1); 117 (8); 103 (12); 75 (100); 61 (13); 57 (25); 47 (11); 43(9). 3b: 208 (M+,0);131 (2); 117 (8); 103 (12); 75 (100); 61 (13); 57 (25); 47 (11); 45(6); 43 (9). Further discussion on the structural characterization and the 1H, 13C{1H}, DEPT-135, DEPT-90, APT, NOESY, HSQC, HMBC and COSY NMR and GC-MS spectra (Figure S14–S24) are reported in Supporting Information. Catalysts 2019, 9, 534 9 of 13

3.3. Synthesis of the Acidic Catalysts

3.3.1. Synthesis of Pyridinium Para-Toluensulfonate (PPTS) The synthesis was carried out following a literature procedure [46]. 1H NMR (400 MHz, MeOD) δ = 8.89 (dt, J = 5.2, 1.6, 2H), 8.68 (tt, J = 7.9, 1.6, 1H), 8.16–8.09 (m, 2H), 7.75–7.69 (m, 2H), 7.27–7.22 (m, 2H), 2.38 (s, 3H). The spectrum is in agreement with the literature (Figure S25).

3.3.2. Synthesis of Diazobicycloundecenium Bromide (DBUHBr) An aqueous solution of hydrobromic acid (40% v/v, 13.2 mmol) was dripped into a vessel containing an equimolar amount of DBU under continuous stirring. After 24 h, the aqueous solution was concentrated by rotary evaporation (60 ◦C, 40 mbar) and any trace of water was removed under 1 reduced pressure (60 ◦C, 1 mbar) until a white solid was obtained (yield = 99%). H NMR (400 MHz, D2O) δ = 3.50 (dt, J = 18.0, 5.6, 4H), 3.28 (t, J = 5.9, 2H), 2.62–2.55 (m, 2H), 1.97 (tt, J = 7.2, 5.2, 2H), 13 1.74–1.60 (m, 6H). C NMR (101 MHz, D2O) δ = 165.95, 54.19, 48.26, 38.01, 32.87, 28.47, 25.90, 23.34, 18.96. (Figures S26 and S27).

3.3.3. Synthesis of Butylsulfonylmethylimidazolium Hydrogensulfate (BSMImHSO4) 1-methylimidazole and 1,4-butane-sultone were charged into a 100 mol round-bottom ﬂask in an equimolar amount (0.1 mol) and stirred at 80 ◦C for 16 h. The white solid zwitterionic product was washed with ethyl ether (10 5 mL) to remove any unreacted starting materials and the solid was × dried in vacuum. Then, a stoichiometric amount of sulfuric acid (95% v/v H2O) was added and the mixture stirred at 60 ◦C for 10 h, to obtain the ionic liquid BSMImHSO4. The IL was washed again with dichloromethane and ether and dried under vacuum. BSMImHSO4 was obtained in 95% of yield 1 and it was used without any further puriﬁcation. H NMR (400 MHz, D2O) δ = 8.61 (s, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 4.11 (s, 2H), 3.77 (s, 3H), 2.82 (s, 2H), 1.88 (s, 2H), 1.62 (s, 2H). 13C NMR (101 MHz, D2O) δ = 135.90, 123.60, 122.11, 50.01, 48.86, 35.61, 28.04, 20.87. All spectra (Figures S28 and S29) are in agreement with those reported in literature [40].

3.3.4. Synthesis of Butylsulfonylmethylimidazolium Bromide (BSMImBr) 1-methylimidazole and 1,4-butane-sultone were charged into a 100 mol round-bottom ﬂask in an equimolar amount (0.1 mol) and stirred at 80 ◦C for 16 h. The white solid zwitterionic product was washed with ethyl ether (10 5 mL) and dried in vacuum (yield = 90%). Then a stoichiometric amount × of hydrobromic acid (40% v/v H2O) was added and the mixture stirred at 60 ◦C for 10 h to yield to the ionic liquid BSMImBr. The ionic liquid (IL) was washed again with dichloromethane and ether to remove non-ionic residues and dried under vacuum. The IL was obtained with a 90% yield and 1 used without any further puriﬁcation. H NMR (400 MHz, D2O) δ = 8.66–8.61 (m, 1H), 7.40 (t, J = 1.8, 1H), 7.34 (t, J = 1.8, 1H), 4.15 (t, J = 7.0, 2H), 3.79 (d, J = 0.6, 3H), 2.87–2.81 (m, 2H), 1.97–1.87 (m, 2H), 13 1.68–1.58 (m, 2H). C NMR (101 MHz, D2O) δ = 135.92, 123.63, 122.14, 50.04, 48.90, 35.68, 28.08, 20.90. (Figures S30 and S31)

3.4. General Procedures for the Gly-HC(OMe)3 Reactions

3.4.1. Catalyst-Free Conditions Glycerol (0.5 g, 5.43 mmol) and cyclopentyl methyl ether (100 µL) as an internal standard were added in a two-neck round-bottomed ﬂask equipped with a dripping funnel and a condenser. The mixture was stirred at the selected temperature (T = 25 or 90 ◦C) and HC(OMe)3 was added dropwise by varying the molar ratio Q from 1 to 10. The reaction was allowed to proceed for 24 h under stirring and samples were collected and analyzed by GC at regular intervals. For reactions run at 90 ◦C, the condenser was heated at 70 ◦C in order to continuously distill methanol. Catalysts 2019, 9, 534 10 of 13

3.4.2. Catalyzed Reaction The above reported procedure was followed with the exception that the selected catalyst (10% w/wGly) was added with glycerol and cyclopentyl methyl ether, before the addition of HC(OMe)3.

3.4.3. Catalytic Procedure for the Synthesis of 3

Glycerol (0.5 g, 5.43 mmol), HC(OMe)3 (5.9 mL, 54.3 mmol) and a catalytic amount of the selected catalyst (BSMImHSO4, BSMImBr, 3% mol/molgly) were added in a round-bottomed flask and the mixture was stirred at 90 ◦C. During the reaction the methanol was distilled out the mixture by heating the condenser at 70 ◦C. After 1h, the mixture was cooled down and the solution was passed through a short plug of alumina. The filtered solution was concentrated under vacuum (60 ◦C, 35 mbar). 3 was obtained as a mixture of two diastereomers in 96% yield without any further purification (purity 98% by GC).

4. Conclusions The thermal and catalytic reactivity of glycerol with trimethyl orthoformate was fully explored here for the first time. Under catalyst-free conditions, with an equimolar mixture of Gly and HC(OMe)3 (Q = 1), the reaction leads to the unselective formation of a dynamic equilibrium mixture of products 1, 2, and 3 (Scheme1 and Table1). The products were isolated and fully characterized by GC-MS, 1H, 13C, and 2D-NMR spectroscopy revealing the formation exclusively of the five-membered ring isomers of 1 and 3, obtained as mixtures of two diastereoisomers. The equilibrium of this reaction is remarkably shifted towards the formation of 3 as evinced for longer reaction times, higher temperature and/or using a large excess of orthoformate (Q = 10). 3 could thus be obtained selectively in high yields at 90 ◦C with 10 equivalents of trimethyl orthoformate after 24 h. Both the reaction time and temperature can be reduced by using Brønsted and Lewis-acid catalysts. The strongest acidic catalysts (H2SO4, A-15, A-36, iron chloride, and aluminium fluoride) accelerate attainment of the dynamic equilibrium of the reaction to yield preferentially 3, but also promote ill-defined degradation products. Less acidic catalysts such as the ionic liquids BSMImHSO4 and BSMImBr also accelerate attainment of the thermodynamically favored product 3 (98–99%) without however further degradations as indicated by the stability of 3 over time. Overall, the present results shed light on the reaction pathway and on the equilibria that govern conversion of glycerol into its orthoesters 1 and 3 and it allows to selectively synthesize 3 by a proper choice of reaction conditions. The glycerol-based orthoesters represent new building blocks en route to the development of more complex glycerol-OEs architectures.

Supplementary Materials: The following are available online at http://www.mdpi.com/2073-4344/9/6/534/s1, GC-MS chromatograms, NMR spectra and reaction profiles. Figure S1: MS spectra of 1a. Figure S2: 1H NMR of 1a. Figure S3: 13C{1H} NMR of 1a. Figure S4: HSQC spectra 1a. Figure S5: HMBC spectra of 1a. Figure S6: COSY spectra of 1a. Figure S7: MS spectra 1b. Figure S8: 1H NMR of 1a,b. Figure S9: 13C{1H} NMR of 1a,b. Figure S10: HSQC of 1a,b. Figure S11: HMQC of 1a,b. Figure S12: COSY of 1a,b. Figure S13: GC-MS spectra of 2. Figure S14: MS spectra of 3a. Figure S15: MS spectra of 3b. Figure S16: 1H NMR of 3a,b. Figure S17: 13C{1H} NMR of 3a,b. Figure S18: DEPT-135 of 3a,b. Figure S19: DEPT-90 of 3a,b. Figure S20: ATP of 3a,b. Figure S21: COSY of 3a,b. Figure S22: HMBC of 3a,b. Figure S23: HSQC of 3a,b. Figure S24: NOESY of 3a,b. Figure S25: 1H NMR of PPTS. 1 13 1 1 Figure S26: H NMR of DBUHBr. Figure S27: C{ H} NMR of DBUHBr. Figure S28: H NMR of BSMImHSO4. 13 1 1 13 1 Figure S29: C{ H} NMR of BSMImHSO4. Figure S30: H NMR of BSMImBr. Figure S31: C{ H} NMR of BSMImBr. Figure S32: Conversion of Gly and products selectivity for the catalyst-free reaction between Gly and HC(OMe)3 in function of the reaction time at room temperature and Q = 1. Figure S33: Conversion of Gly and products selectivity for the catalyst-free reaction between Gly and HC(OMe)3 in function of the reaction time at room temperature and Q = 10. Figure S34: Conversion of Gly and and products selectivity for the reaction between HC(OMe)3 and Gly in presence of Pyr-PTSA (10% w/wGly) in function of the reaction time at room temperature and Q = 10. Figure S35: GC-MS chromatograph of the reaction between HC(OMe)3 and Gly (Q = 10, 90 ◦C, 24 h) in presence of sulfuric acid. Figure S36: MS spectra of the undefined compounds with retention time: 16.43 min. Figure S37: MS spectra of the undefined compounds with retention time: 16.59 min. Figure S38: MS Catalysts 2019, 9, 534 11 of 13 spectra of the undefined compounds with retention time: 16.43 min. Figure S39: MS spectra of the undefined compounds with retention time: 21.72 min. Author Contributions: Conceptualization, A.P. and M.S.; Methodology, R.C.; Investigation, R.C. and E.A.; Data curation, E.A.; Writing—original draft preparation, R.C. and E.A.; Writing—review and editing, A.P. and M.S.; Supervision, A.P. and M.S.; Funding acquisition, M.S. Funding: This research received no external funding. Acknowledgments: E.A. acknowledges the European Social Fund for a post-doc scholarship. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

Glyc glycerol OEs orthoesters Q molar ratio HC(OMe)3:glycerol PPTS pyridinium paratoluensulfonate DBUHBr diazabicycloundeconium bromide A-15 Amberlyst 15 A-36 Amberlyst 36 BSMIMHSO4 butylsulfonylmethylimidazolium hydrogensulfate BSMIMBr butylsulfonylmethylimidazolium bromide ([P1888]CH3OCO2−) trioctylmethylphosphonium methylcarbonate

References

1. Bozell, J.J.; Petersen, G.R. Technology development for the production of biobased products from biorefinery carbohydrates—The US Department of Energy’s “Top 10” revisited. Green Chem. 2010, 12, 539–554. [CrossRef] 2. Mota, C.J.; Pinto, B.P.; de Lima, A.L. Glycerol, 1st ed.; Springer: Berlin/Heidelberg, Germany, 2017; pp. 21–103. 3. Hu, J.; Gu, Y.; Guan, Z.; Li, J.; Mo, W.; Li, T.; Li, G. An efficient palladium catalyst system for the oxidative carbonylation of glycerol to glycerol carbonate. ChemSusChem 2011, 4, 1767–1772. [CrossRef][PubMed] 4. Pearson, D.M.; Conley, N.R.; Waymouth, R.M. Palladium-catalyzed carbonylation of diols to cyclic carbonates. Adv. Synth. Catal. 2011, 353, 3007–3013. [CrossRef] 5. Gabriele, B.; Mancuso, R.; Salerno, G. Oxidative carbonylation as a powerful tool for the direct synthesis of carbonylated heterocycles. Eur. J. Org. Chem. 2012, 2012, 6825–6839. [CrossRef] 6. Casiello, M.; Monopoli, A.; Cotugno, P.; Milella, A.; Dell’Anna, M.M.; Ciminale, F.; Nacci, A. Copper (II) chloride-catalyzed oxidative carbonylation of glycerol to glycerol carbonate. J. Mol. Catal. A Chem. 2014, 381, 99–106. [CrossRef] 7. Chavan, S.P.; Bhanage, B.M. Pd/C: An efficient and heterogeneous protocol for oxidative carbonylation of diols to cyclic carbonate. Tetrahedron Lett. 2014, 55, 1199–1202. [CrossRef] 8. Guidi, S.; Calmanti, R.; Noè, M.; Perosa, A.; Selva, M. Thermal (catalyst-free) transesterification of diols and glycerol with dimethyl carbonate: A flexible reaction for batch and continuous-flow applications. ACS Sustain. Chem. Eng. 2016, 4, 6144–6151. [CrossRef] 9. Calmanti, R.; Galvan, M.; Amadio, E.; Perosa, A.; Selva, M. High-temperature batch and continuous-flow transesterification of alkyl and enol esters with glycerol and its acetal derivatives. ACS Sustain. Chem. Eng. 2018, 6, 3964–3973. [CrossRef] 10. Cattelan, L.; Perosa, A.; Riello, P.; Maschmeyer, T.; Selva, M. Continuous-flow o-alkylation of biobased derivatives with dialkyl carbonates in the presence of magnesium–aluminium hydrotalcites as catalyst precursors. ChemSusChem 2017, 10, 1571–1583. [CrossRef] 11. Perosa, A.; Moraschini, A.; Selva, M.; Noè, M. Synthesis of the fatty esters of Solketal and glycerol-formal: Biobased specialty chemicals. Molecules 2016, 21, 170. [CrossRef] 12. Guidi, S.; Noè, M.; Riello, P.; Perosa, A.; Selva, M. Towards a rational design of a continuous-flow method for the acetalization of crude glycerol: Scope and limitations of commercial amberlyst 36 and AlF3 3H O as · 2 model catalysts. Molecules 2016, 21, 657. [CrossRef][PubMed] 13. Selva, M.; Guidi, S.; Noè, M. Upgrading of glycerol acetals by thermal catalyst-free transesterification of dialkyl carbonates under continuous-flow conditions. Green Chem. 2015, 17, 1008–1023. [CrossRef] Catalysts 2019, 9, 534 12 of 13

14. Cordes, E.; Bull, H. Mechanism and catalysis for hydrolysis of acetals, ketals, and ortho esters. Chem. Rev. 1974, 74, 581–603. [CrossRef] 15. Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 4th ed.; Wiley: New York, NY, USA, 2014. 16. Kociensky, P.J. Protecting Groups, 3rd ed.; Thieme-Verlag: New York, NY, USA, 2005. 17. Gabriele, B.; Mancuso, R.; Salerno, G.; Veltri, L.; Costa, M.; Dibenedetto, A. A general and expedient synthesis of 5- and 6-membered cyclic carbonates by palladium-catalyzed oxidative carbonylation of 1, 2- and 1, 3- diols. ChemSusChem 2011, 4, 1778–1786. [CrossRef][PubMed] 18. Zhou, X.; Luo, S.; Tang, R.; Wang, R.; Wang, J. Diblock copolymers of polyethylene glycol and a polymethacrylamide with side-chains containing twin ortho ester rings: Synthesis, characterization, and evaluation as potential pH-responsive micelles. Macromol. Biosci. 2015, 15, 385–394. [CrossRef][PubMed] 19. Heller, J.; Barr, J. Poly(ortho esters) from concept to reality. Biomacromolecules 2004, 5, 1625–1632. [CrossRef] [PubMed] 20. Brachvogel, R.-C.; Hampel, F.; Von Delius, M. Self-assembly of dynamic orthoester cryptates. Nat. Commun. 2015, 6, 7129. [CrossRef][PubMed] 21. Löw, H.; Mena-Osteritz, E.; von Delius, M. Self-assembled orthoester cryptands: Orthoester scope, post-functionalization, kinetic locking and tunable degradation kinetics. Chem. Sci. 2018, 9, 4785–4793. [CrossRef][PubMed] 22. Crank, G.; Eastwod, F. Derivatives of orthoacids. I. Bicyclic orthoesters. Aust. J. Chem. 1964, 17, 1385–1391. [CrossRef] 23. Crank, G.; Eastwood, F. Derivatives of orthoacids. II. The preparation of oleﬁns from 1, 2-diols. Aust. J. Chem. 1964, 17, 1392–1398. [CrossRef] 24. Tshibalonza, N.N.; Monbaliu, J.-C.M. Revisiting the deoxydehydration of glycerol towards allyl alcohol under continuous-ﬂow conditions. Green Chem. 2017, 19, 3006–3013. [CrossRef] 25. Hall, H., Jr.; DeBlauwe, F.; Pyriadi, T. 2,6,7-Trioxabicyclo[2.2.1]heptane. J. Am. Chem. Soc. 1975, 97, 3854. [CrossRef] 26. Yokoyama, Y.; Padias, A.B.; De Blauwe, F.; Hall, H., Jr. Synthesis and polymerization of 2, 6, 7-trioxabicyclo[2.2.1]heptane and 1-Methyl-2, 6, 7-trioxabicyclo [2.2.1]heptane. Macromolecules 1980, 13, 252–261. [CrossRef] 27. Heller, J.; Barr, J.; Ng, S.Y.; Abdellauoi, K.S.; Gurny, R. Poly (ortho esters): Synthesis, characterization, properties and uses. Adv. Drug Del. Rev. 2002, 54, 1015–1039. [CrossRef] 28. Padias, A.B.; Szymanski, R.; Hall, H.K. Synthesis and polymerization of atom-bridged bicyclic acetals and ortho esters. In Ring-Opening Polymerization; American Chemical Society: Washington, DC, USA, 1985; Volume 286, pp. 313–333. 29. Yokoyama, Y.; Hall, H. Ring-opening polymerization of atom-bridged and bond-bridged bicyclic ethers, acetals and orthoesters. In New Polymerization Reactions; Springer: Berlin/Heidelberg, Germany, 1982; pp. 107–138. 30. Zhang, L.; Yu, M.; Wang, J.; Tang, R.; Yan, G.; Yao, W.; Wang, X. Low molecular weight PEI-based vectors via acid-labile ortho ester linkage for improved gene delivery. Macromol. Biosci. 2016, 16, 1175–1187. [CrossRef] [PubMed] 31. Amarasekara, A.S. Acidic ionic liquids. Chem. Rev. 2016, 116, 6133–6183. [CrossRef] 32. Cox, J. A bond energy scheme—II: Strain and conjugation energies in cyclic compounds. Tetrahedron 1963, 19, 1175–1184. [CrossRef] 33. Fletcher, S.E.; Mortimer, C.T.; Springall, H.D. 118. Heats of combustion and molecular structure. Part VII. 1:3-Dioxane and 1:3:5-trioxa-cycloalkenes. J. Chem. Soc. 1959, 580–584. [CrossRef] 34. Brachvogel, R.-C.; von Delius, M. Orthoester exchange: A tripodal tool for dynamic covalent and systems chemistry. Chem. Sci. 2015, 6, 1399–1403. [CrossRef] 35. Kaupmees, K.; Trummal, A.; Leito, I. Basicities of strong bases in water: A computational study. Croat. Chem. Acta 2014, 87, 385–395. [CrossRef] 36. Mezheritskii, V.V.; Olekhnovich, E.P.; Dorofeenko, G.N. The properties of orthoesters and their applications in organic synthesis. Russ. Chem. Rev. 1973, 42, 392. [CrossRef] 37. Cordes, H. Ortho esters. In Carboxylic Acids and Esters; Patai, S., Ed.; Wiley: Hoboken, NJ, USA, 1969. Catalysts 2019, 9, 534 13 of 13

38. Fabris, M.; Lucchini, V.; Noè, M.; Perosa, A.; Selva, M. Ionic liquids made with dimethyl carbonate: solvents as well as boosted basic catalysts for the Michael reaction. Chem. Eur. J. 2009, 15, 12273–12282. [CrossRef] [PubMed] 39. Thomazeau, C.; Olivier-Bourbigou, H.; Magna, L.; Luts, S.; Gilbert, B. Determination of an acidic scale in room temperature ionic liquids. J. Chem. Soc. 2003, 125, 5264–5265. [CrossRef][PubMed]

40. Tao, D.-J.; Wu, J.; Wang, Z.-Z.; Lu, Z.-H.; Yang, Z.; Chen, X.-S. SO3H-functionalized Brønsted acidic ionic liquids as eﬃcient catalysts for the synthesis of isoamyl salicylate. RSC Adv. 2014, 4, 1–7. [CrossRef] 41. Olah, A.; Prakash, G.K.S.; Sommer, J. Superacids; Wiley: Chichester, UK, 1985. 42. Bringué, R.; Iborra, M.; Tejero, J.; Izquierdo, J.F.; Cunill, F.; Fité, C.; Cruz, V.J. Thermally stable ion-exchange resins as catalysts for the liquid-phase dehydration of 1-pentanol to di-n-pentyl ether (DNPE). J. Catal. 2006, 244, 33–42. [CrossRef] 43. Harmer, M.A.; Sun, Q. Solid acid catalysis using ion-exchange resins. Appl. Catal. Gen. 2001, 221, 45–62. [CrossRef] 44. Ni, L.; Xin, J.; Jiang, K.; Chen, L.; Yan, D.; Lu, X.; Zhang, S. One-step conversion of biomass-derived furanics into aromatics by Brønsted acid ionic liquids at room temperature. ACS Sustain. Chem. Eng. 2018, 6, 2541–2551. [CrossRef] 45. Yao, L.; Liu, S.; Li, L.; Yu, S.; Liu, F.; Song, Z. Synthesis of hydroxymethylfurfural from sucrose using brönsted-lewis acidic ionic liquid. Bull. Chem. Soc. Ethiop. 2016, 30, 283–286. [CrossRef] 46. Miyashita, M.; Yoshikoshi, A.; Grieco, P.A. Pyridinium p-toluenesulfonate. A mild and eﬃcient catalyst for the tetrahydropyranylation of alcohols. J. Org. Chem. 1977, 42, 3772–3774. [CrossRef]

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).