RSC Advances View Article Online PAPER View Journal | View Issue Understanding the regioselectivity of Michael addition reactions to asymmetric divinylic Cite this: RSC Adv.,2017,7,56157 compounds† a bc d Rodrigo Navarro, * Cristina Monterde, Serena Molina, Monica´ Perez-´ Perrino,a Felipe Reviriego,a Anselmo del Prado, ‡a Alberto Gallardoa and Helmut Reineckea In the present paper, we describe the synthesis of novel monomers prepared by regioselective Michael addition to asymmetric divinylic compounds. This chemoselectivity was experimentally studied employing different reaction conditions and theoretically calculated using chemical globalandlocaldescriptors.Theglobal reactivity data show that incoming nucleophilic secondary amines preferentially attack the acrylic derived units acrylate and acrylamide, while deactivated methacrylate and N-vinyl-pyrrolidone require harder reaction conditions, which leads to the formation of by-products. Moreover, it is demonstrated that the presence of Received 6th October 2017 Creative Commons Attribution 3.0 Unported Licence. two vinyl units within a studied divinylic agent leads to a significant increase in its global reactivity parameters. Accepted 15th November 2017 Besides, the local reactivity parameters of asymmetric divinyl compounds show a preference for an attack at DOI: 10.1039/c7ra11005g the Cb of activated units compared to the Cb center of deactivated units. Based on these results, asymmetric rsc.li/rsc-advances divinyl compounds are very interesting starting materials for the preparation of new functionalized monomers. 1 Introduction methacrylates. Thus, this synthetic strategy has allowed for the easy preparation of polymethacrylates bearing pendant special The synthesis of monomers with tailored performance and groups such as phosphonate,2,3 hydroxyl,4 stearyl,5 or proden- 6 This article is licensed under a desirable properties, by simple and high yield procedures, is dronic amine moieties. The latest example, described by us, a challenging problem in modern materials science. A proce- reported the successful use of this strategy with an asymmetric dure that fulls the requirements of simplicity and high yields acrylamide/methacrylate divinylic compound. Some of these is the Michael addition reaction, which is one of the most useful monomers could be prepared in bulk. In addition, the formed Open Access Article. Published on 13 December 2017. Downloaded 9/25/2021 8:05:41 PM. and applied synthetic strategies and is oen an important icon b-aminoesters exhibit an enhanced sensitivity to hydrolysis, to provide a range of biologically active b-functionalized compared to standard aliphatic esters.6 Very recently, Armes systems. In particular, b-thioether esters or b-amino esters are et al. have described for the rst time the usefulness of this found in a large number of alkaloids and polyketides and are facile strategy using thiol-type nucleophiles to obtain cysteine- also versatile building blocks in organic synthesis. or glutathione-containing methacrylates7 in water and on Since the pioneering work of Mulhaupt¨ et al.1 on the selective a multi-gram scale. Besides, our group has also shown the Michael addition of diamines to the acrylate group of ethyl- effectiveness of this facile strategy using thiol-type nucleophiles eneglycol diacrylate methacrylate for the preparation of dime- to obtain cysteine- or glutathione-containing methacrylates7 in thacrylates, some other examples can be found in the recent water and on a multi-gram scale. Besides, our group has also literature that use this selectivity towards different acrylic shown the chemoselectivity of this reaction on polymerizable groups in asymmetric divinylic compounds to obtain novel vinylamide groups like vinylpyrrolidone,8 which did not inter- fere in the Michael addition of amines to acrylates. The selectivity of the Michael addition (carbonyl or Cb aInstitute of Polymer Science and Technology, Juan de la Cierva 3, 28006, Madrid, Spain. E-mail: [email protected]; Fax: +34 91 56 44 853; Tel: +34 91 56 22 900 carbon addition) towards Michael acceptors is strongly depen- bInstitute of Organic Chemistry, Juan de la Cierva 3, 28006, Madrid, Spain dent on the type and nature of the substituent linked to the cInstitute of Material Science, Sor Juana In´es de la Cruz 3, 28049, Cantoblanco, C]C double bond. In principle, the reaction can take two Madrid, Spain different reaction pathways, addition to a carbonyl carbon or d Imdea Water Institute, Av. Punto Com 2, 28805, Alcala´ de Henares, Madrid, Spain conjugated addition (addition to Cb). By varying the nature of † Electronic supplementary information (ESI) available: Reference Cartesian the substituent of the Michael acceptor, the ratio of Ccarbonyl/Cb coordinates for all the studied molecules and the relative energy of each that describes the preference of an addition to one carbon atom conformer. See DOI: 10.1039/c7ra11005g ‡ A. del Prado present address: Adolphe Merkle Institute, Chemin des Verdiers 4, or to the other can signi cantly be altered. Therefore, the a b Fribourg, Switzerland. electronic features of - unsaturated Michael acceptors play This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7,56157–56165 | 56157 View Article Online RSC Advances Paper a central role in determining the selectivity of the Michael addition. A number of global and local reactivity descriptors, namely, global electrophilicity, global hardness, global soness, local hardness, local soness, the Fukui function (f), and the nucleophilicity index (N) etc., have been proposed and derived Fig. 1 The chemical structure of asymmetric divinylic compounds from density functional theory (DFT). These descriptors have based on acrylic units. received great importance in order to determine the fate of a given reaction. Understanding the reactivity f of the total chemical process is quite important to study the changes in the this period, the solvent was removed by distillation and the global and local reactivity proles. In this context, Domingo’s9 obtained product was used without further purication steps. ’10,11 and Contreras groups have been involved for a long time in 1 d H-NMR (CDCl3, 300 MHz) : 6.12 (s, 1H), 5.50 (s, 1H), 4.18 (t, the study of a-b unsaturated compounds using these parame- 2H, J ¼ 5.8 Hz), 3.51 (m, 2H), 2.72–2.65 (m, 2H), 2.59–2.46 (m, ters to establish the polar character of chemical reactions. 4H), 2.35–2.32 (m, 2H), 1.93 (s, 3H), 1.00–0.96 (m, 6H). In the present paper, we explain the regioselectivity experi- mentally observed in the Michael addition reaction of nucleo- 2.3 Computational details philes to non-symmetric divinyl agents using different descriptors. Based on these results we present a versatile route Full geometry optimizations for the whole series of the vinyl and for the preparation of novel functionalized monomers with high divinyl compounds have been performed at the B3LYP/6- yields and it is applicable in some cases for the preparation of 31G(d,p) level of theory, which was implemented using hydrolysable conjugates. Gaussian 03W. All of the optimizations were implemented under vacuum. The local Fukui functions for the electrophilic À + (fk ) and nucleophilic (fk ) attacks were obtained from a single 2 Experimental point calculation at the optimized structures of the GS of the Creative Commons Attribution 3.0 Unported Licence. 2.1 Materials molecules using a method described elsewhere.14 Within this approach, the electrophilic and nucleophilic Fukui functions Unless otherwise noted, materials and solvents were obtained from that were condensed to groups of atoms are evaluated in terms commercially available sources and used without further purica- of the coefficients of the frontier molecular orbitals involved tion steps. N-Vinylpyrrolidone (VP), methacryloyl chloride, acryloyl and the overlap matrix. With the nucleophilic Fukui function at chloride, 2-hydroxyethyl methacrylate (HEMA) and 2-hydroxyethyl hand, the regional (site) electrophilicity power is readily ob- acrylamide were distilled and freshly used. The asymmetric À À tained by (u ¼ uf ). The values of the global and local crosslinkers 2-(acryloyloxy)ethyl methacrylate (AOEMA)and2- k k maximum charge transfer towards the electrophile are evalu- (acrylamidoethyl)methacrylate (AAEMA) were prepared following This article is licensed under a D ¼ Àm h D 6,12,13 ated using the following equations ( Nmax ( / ); ( Nmax- the synthetic protocols described elsewhere. + (k) ¼ DNmaxfk )). 2.2 Synthesis Open Access Article. Published on 13 December 2017. Downloaded 9/25/2021 8:05:41 PM. 3 Results and discussion 2.2.1 2-(Acrylamido)ethyl acrylate (AAEA). A solution of 20 mmol 2-hydroxyethyl acrylamide and 40 mmol triethylamine As mentioned above, asymmetric divinylic acrylate/ in 200 mL of chloroform was cooled to 0 C with an ice-bath. methacrylate compounds, such as AOEMA (structure shown in Under a stream of dry N2, a solution of 20 mmol acryloyl chlo- Fig. 1), have been used to obtain novel methacrylates by prof- ride in 50 mL of chloroform was added dropwise to the cooled iting from the different selectivities of both amine and mer- solution. The reaction mixture was then warmed up to room capto groups in Michael addition.1,3 Our group has recently temperature. The reaction was monitored by TLC layers. When extended this synthetic strategy to the molecular system the reaction nished, the organic phase was washed three times acrylamide/methacrylate (AAEMA, structure shown in Fig. 1).6 with water