reactions Article Hemiacetal Ester Exchanges, Study of Reaction Conditions and Mechanistic Pathway David Boucher 1,2, Jeppe Madsen 3, Nicolas Caussé 2, Nadine Pébère 2, Vincent Ladmiral 1,* and Claire Negrell 1,* 1 ICGM Univ. Montpellier, CNRS, ENSCM, Montpellier, France; [email protected] 2 CIRIMAT UMR 5085-CNRS, UT, INPT, UPS, ENSIACET, 4 allée Emile Monso, CS 44362, 31030 Toulouse, France; [email protected] (N.C.); [email protected] (N.P.) 3 Danish Polymer Centre, Department of Chemical and Biomedical Engineering, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark; [email protected] * Correspondence: [email protected] (V.L.); [email protected] (C.N.) Received: 6 October 2020; Accepted: 28 October 2020; Published: 30 October 2020 Abstract: A range of hemiacetal esters were synthesized by the reaction between carboxylic acids and butyl vinyl ether using n-dodecyl dihydrogen phosphate as catalyst. Specifically, nonanoic, propionic, acrylic, sebacic, and fumaric acids were used as substrates to prepare the corresponding hemiacetal esters. These compounds were used as model molecules to demonstrate the ability of hemiacetal ester functional groups to undergo the exchange reaction in the presence of weak carboxylic acids without any catalyst. Kinetics studies examined the effect of the carboxylic acid concentration on the exchange rate, and revealed that the exchange reaction proceeds through an associative mechanism. Keywords: hemiacetal ester; exchange reaction; associative; kinetics 1. Introduction Hemiacetal esters, also called acylated hemiacetals, (see Scheme1), possess a very interesting functional group, which has yet to be fully studied. It can be synthesized by a number of methods, such as through the addition of a carboxylic acid onto a vinyl ether [1], through Baeyer–Villiger oxidation of a cyclic ketone bearing a vicinal methoxy group [2], or through reaction of a ketone or acetaldehyde with β-hydroxy acids [3]. This function has mostly been used for its ability to dissociate under specific conditions. In particular, hemiacetal esters spontaneously dissociate into carboxylic acids and vinyl ethers upon heating. This thermal dissociation has been demonstrated to be structure-dependent by Otsuka et al. [4–6]. In a first publication [4], they showed that hemiacetals formed from carboxylic acids bearing unsaturated groups have a lower dissociation temperature than their saturated aliphatic analogs due to inductive and mesomeric electronic effects. These authors also showed that cyclic aliphatic acids led to even higher dissociation temperature. In a second publication [5], they demonstrated that vinyl ethers with higher inductive donor effects (such as tert-butyl vinyl ether compared to cyclohexyl vinyl ether) led to lower dissociation temperature. Finally, in a third publication [6], hemiacetal esters, prepared by the reaction between methacrylic acid and butyl or phenoxyethyl vinyl ether, were integrated into a copolymer with vinyl comonomers of varying polarity. This last study underlined that the dissociation temperature decreased with the increase in comonomer polarity. Reactions 2020, 1, 89–101; doi:10.3390/reactions1020008 www.mdpi.com/journal/reactions Reactions 2020, 3, x FOR PEER REVIEW 5 of 13 Reactionsin 6 h 2020(except, 1 in the case of fumaric acid, for which the conversion was measured after 24 h 90of reaction). The structures of the resulting hemiacetal esters are shown in Figure 1. SchemeScheme 1. 1.Acid-catalyzed Acid-catalyzed reaction reaction between between carboxylic carboxylic acids acids and and vinyl vinyl ether ether leading leading to hemiacetal to hemiacetal ester. ester. Thermal dissociation of the hemiacetal ester functional group that leads to the recovery of the carboxylic acid function [1] has been used for the preparation of recyclable [4] polymers. It has also been exploited to temporarily protect carboxylic acids [7–11]. This protecting strategy also proved useful to stabilize an epoxy-acid formulation by making the acid function available on demand [8]. Storage of epoxy-acid formulations at ambient temperature generally leads to a viscosity increase due to a slow reaction between the acids and the epoxides. However, Yamamoto and Ishidoya [8] demonstrated that when the acid group was protected with a hemiacetal ester function, the viscosity increase was significantly reduced during storage at 40 ◦C. In addition, the acid group could be regenerated and reacted with epoxides by heating the formulation at the dissociation temperature of the hemiacetal ester. Besides this stabilizing effect, the conversion of acid groups into hemiacetal ester has also been used to convert solid diacids into liquid dihemiacetal esters, which are easier to formulate [9] and better suited to trigger post-crosslinking reactions of thermoplastic polymers [10,11]. A similar protecting strategy has been notably used by Ruckenstein and Zang to produce amphiphilic copolymers [7]. They converted methacrylic acid into a hemiacetal ester, thus making copolymerization with highly hydrophobic styrene in toluene possible. The hydrophilic acidic group was then regenerated by hydrolysis in acidic medium (HCl 5 M) to yield an amphiphilic polymer otherwise difficult to prepare. Since then, this hydrolysis reactionFigure was 1. Struc usedtures in of other the synthesized studies to mono form and water-soluble dihemiacetal [ 12esters.] and alternative [13] copolymers, but also de-crosslinkable [14,15] or recyclable/degradable [16,17] polymers. Recently,Although hemiacetal 0.4 mol% estersof catalyst have was been enough used to induceto promote cationic quantitative polymerization conversion of vinyl of ethersthe monoacids [18–24]. In(Table the 1, presence BEN, BEP of, and Lewis BEA acids,) in 6 h, hemiacetal a five-fold estersproportion dissociate of n-dodecyl into a dihydrogen carboxylate phosphate and a vinyl was etherrequired carbocation to prepare able the to difunctional initiate the hemiacetal living cationic esters polymerization at a similar rate of (Table vinyl ethers.1, DBES According and DBEF to). This may be ascribed to the lower solubility of the diacids in butyl vinyl ether. In addition, the Ouchi et al. [18], this polymerization could be controlled by using a mild catalyst (SnBr4 or ZnCl2) and stoppedsurfactant with-like methanol. behavior of Furthermore, the catalyst Neitzelmay also et help al. [25 the,26 solubiliz] reportedation the of ability the diacids. of cyclic hemiacetal estersThe to homopolymerizecrude products were in the examined presence by ofNMR a Lewis spectroscopy base. This (Figure led to S5) the to formation determine of the either nature a polyesterand source or aof poly(esteracetal), the side products. depending Several on theside conditions products (Scheme were identified: S1). According acetaldehyde to the authors, with thischaracteristic polymerization signals required at 2.19 and the addition9.78 ppm, of 1 a-(1 primary-butoxyethoxy)butane alcohol as initiator. at 4.66 In theppm, presence and butan of a-1 small-ol at quantity3.66 ppm of (Figure diethyl S5 zinc for catalyst,the case of the DBEF). alcohol opens the ring by substitution of the acid group in the hemiacetalAs proposed ester function. by Galucci The and polyesteracetal Going [1], these is then side produced products by were ring-opening likely formed polymerization by a reaction of thebetween cyclic the hemiacetal hemiacetal ester ester by thewith carboxylate either water propagating or alcohol. end-group. The reaction This of w poly(esteracetal)ater (from moisture can be or thermallypresent as degraded. a trace impurity In contrast, in the in reagents) the presence with of hemiacetal a high amount ester of probably catalyst, led the to alcohol the formation opens the of ring the byconstitutive reaction with acid the and carbonyl. an uns Thistable leads 1-butoxyethan to the formation-1-ol ofhemiacetal an ester linkage (Scheme and 2 triggersa), which the releasereadily ofdissociates acetaldehyde into acetaldehyde by decomposition and butan of the-1 unstable-ol. Butan ethylacetal-1-ol can then end-group. react with The another polymerization hemiacetal thenester proceeds(Scheme by2b) ring-opening to form 1-(1- andbutoxyethoxy)butane. produces a polyester. However, These articles the reaction suggest of that vinyl diethyl ether zincwith catalyzes water to theform substitution acetaldehyde of acid and groups alcohol, in followed hemiacetal by reaction ester. of the alcohol with another vinyl ether, was also reportedFinally, [29] in and 1982, this Gallucci could be and another Going pathway [1] reported to the the side ability products. of hemiacetal esters to spontaneously undergo a substitution reactionwith stronger acid than the acid involved in the hemiacetal ester function. Specifically, they showed that when a hemiacetal ester derived from acetic acid was reacted, in the absence of any catalyst, with excess HCl or trifluoroacetic acid (TFA), the acetic acid was substituted by chlorine or TFA, respectively. This catalyst-free substitution reaction has not been further studied after the work of Galluci and Going, although it potentially opens the way to very interesting developments in the fields of re-processable, recyclable, or self-healing materials. These studies indeed suggest that hemiacetal esters may undergo an acid exchange reaction. Reactions 2020, 1 91 The aim of the present work is to further examine this substitution reaction in hemiacetal ester, find out if an equilibrium