RSC Advances This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online PAPER View Journal | View Issue Thiol-yne click reaction: an interesting way to Cite this: RSC Adv., 2021, 11, 2074 derive thiol-provided catechols† Open Access Article. Published on 07 January 2021. Downloaded on 2/9/2021 7:57:05 AM. Fabiana Nador, *a Juan Mancebo-Aracil,a Duham Zanotto,a Daniel Ruiz-Molinab and Gabriel Radivoy a The hydrothiolation of activated alkynes is presented as an attractive and powerful way to functionalize thiols bearing catechols. The reaction was promoted by a heterogeneous catalyst composed of copper nanoparticles supported on TiO2 (CuNPs/TiO2) in 1,2-dichloroethane (1,2-DCE) under heating at 80  C. The catalyst could be recovered and reused in three consecutive cycles, showing a slight decrease in its catalytic activity. Thiol derivatives bearing catechol moieties, obtained through a versatile Michael addition, were reacted with different activated alkynes, such as methyl propiolate, propiolic acid, Received 14th November 2020 Accepted 8th December 2020 propiolamide or 2-ethynylpyridine. The reaction was shown to be regio- and stereoselective towards anti-Markovnikov Z-vinyl sulfide in most cases studied. Finally, some catechol derivatives obtained were DOI: 10.1039/d0ra09687c tested as ligands in the preparation of coordination polymer nanoparticles (CNPs), by taking the rsc.li/rsc-advances advantage of their different coordination sites with metals such as iron and cobalt. Regardless of the method used to promote the reaction, it is Introduction important to bear in mind that both alkyne and thiol groups are Vinyl suldes are of great interest because they can be used as inherently nucleophilic, hence the activation of one or both versatile building blocks in organic synthesis1 and as interme- groups is necessary for the construction of vinyl suldes.5 In diates for the synthesis of biologically active compounds2 and this sense, the use of activated alkynes, meaning alkynes new materials,3 among others. bearing an adjacent electron-withdrawing group (such as The thiol-yne click (TYC) reaction, also known as alkyne carboxylic acid, ester or amide group), resulted in a reduction of hydrothiolation, is one of the simplest and most atom- the electronic density on the alkyne, thus enhancing the economical approach to produce alkenyl suldes from thiols nucleophilic attack of the thiol. The reaction of thiols, especially and alkynes.4,5 The TYC reaction commonly occurs in the aliphatic ones, with propiolic acid esters is very slow in the presence of free radicals,6 strong acids,7 bases8 or transition absence of catalysts, but is remarkably accelerated by bases12 metals9 and, as shown in Scheme 1, in principle can lead to one due to the increased concentration of thiolate ions in an alka- of the regio- and stereoisomeric vinyl suldes: A (branched) line solution.13 Because of its click characteristics, which through a Markovnikov orientation, B (E linear) and C (Z linear), include a fast, quantitative and selective reaction under mild or produce mixtures of them through an anti-Markovnikov conditions, the hydrothiolation of activated alkynes has been orientation (Scheme 1).10,11 used in many interesting applications, such as polymer syntheses14 or post-polymerization modications,15,16 the design of covalent adaptable networks (CANs)17 and the chemoselective modication of amino acids side chains in unprotected peptides.13,18 On the other hand, in recent years, an increasing number of works have focused on the synthesis of new bioinspired catechol-based molecules, which have shown to be useful in the Scheme 1 Schematic representation of alkyne hydrothiolation. fabrication of novel functional materials,19 including adhe- sives,20 capsules,21 coatings,22 hydrogels23 and in the formation of coordination polymer nanoparticles (CNPs).24 However, a Instituto de Quı́mica del Sur (INQUISUR-CONICET), Universidad Nacional del Sur, despite the extraordinary characteristics of catechol-derived Av. Alem 1253, 8000 Bahı́a Blanca, Argentina. E-mail: fabiana.nador@uns.edu.ar structures, their preparation is challenging mainly due to the b Insitut Català de Nanociència i Nanotecnologia (ICN2), Edici ICN2, UAB Campus, vulnerability of catechol to oxidation. As a result, only a few Bellaterra, 08193 Barcelona, Spain synthetic methodologies have been described and even among † Electronic supplementary information (ESI) available: TEM and STEM images, these, relatively lengthy synthetic routes, comprising EDX analysis and NMR spectra. See DOI: 10.1039/d0ra09687c 2074 | RSC Adv., 2021, 11, 2074–2082 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online Paper RSC Advances protection/deprotection of the catechol ring, harsh reaction compatible with even moderately basic media, due to its conditions and overall poor atom economy have been re- oxidation to o-quinone by atmospheric oxygen or another mild ported.25 Accordingly, some members of our group recently re- oxidant. An alternative is to carry out the hydrothiolation of ported a systematic and straightforward methodology for the alkynes substituted with electron-withdrawing groups and This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. synthesis of functional catechols with thiol pendant groups, promoted by transition metals, thus taking advantage of the obtained by oxidation of the simplest catechol (pyrocatechol) to benecial effect of an increase in the nucleophilicity of the thiol the corresponding o-quinone, followed by the conjugated caused by the presence of metal species. In this context, copper- nucleophilic addition of different dithiol molecules.26,27 based catalytic systems are of particular interest since the acti- Although there are several examples of methodologies with vation of both the alkyne and the thiol is thought to be the key catechol derivatives where the thiol–ene reaction has been step in this reaction.5 Open Access Article. Published on 07 January 2021. Downloaded on 2/9/2021 7:57:05 AM. exploited, the thiol-yne reaction in the presence of catechol Here we report our results on the thiol-yne click reaction moiety has been less explored. To the best of our knowledge, between activated alkynes, substituted with electron- only two very interesting examples related to this issue have withdrawing groups, and different thiol derivatives bearing been published. A functional copolymer polyPDP, containing catechol pendant moieties. The reaction was regio- and ster- blocks with alkyne and catechol pendant groups respectively, eoselective towards the anti-Markovnikov Z-vinyl sulde in the easily reacted with 4-arm thiol PEG via a TYC reaction under UV vast majority of cases studied. The heterogeneous and low cost exposure, to produce self-adhesive hydrogels,28 while another CuNPs/TiO2 catalyst also showed a high activity and good study described the reduction of graphene oxide to graphene by recyclability. Additionally, some of the vinyl suldes obtained alkynyl-terminated dopamine, and post-functionalization with were used in the preparation of CNPs, taking advantage of their thiols by photochemical click reaction between the alkyne and chelating properties. thiols.29 As described in both articles, the TYC reaction was activated by UV irradiation, but resulted in a double addition of thiol molecules on account of the fact that radicals react faster Results and discussion with the vinyl sulde intermediate than with the starting alkyne. Thus, no vinyl sulde could be obtained through the TYC The catalysts were prepared by the addition of the support to reaction in the presence of catechols. a suspension of freshly prepared copper nanoparticles (CuNPs). On this basis, we attempted to apply TYC reaction to the The CuNPs were generated by the fast reduction of anhydrous modication of catechol structures bearing a thiol functionality copper(II) chloride, using lithium sand and a catalytic amount as end-group. As already mentioned, in most cases the addition of DTBB (4,40 -di-tert-butylbiphenyl, 10 mol%) as the reducing of a base to promote the hydrothiolation reaction of activated system, in THF at room temperature (see Scheme S1†). The alkynes, is mandatory. However, the catechol moiety is not catalysts were ready for use as prepared, aer ltration and drying, and without any pre-treatment. Different inorganic Table 1 Optimization of reaction conditionsa Selectivity Entry Catalyst (Cu mg) Solvent Temp. ( C) Conv. A + Bb (%) Conv. Cb (%) Z:E 1 CuNPs/C (10) THF 25 23 77 40 : 60 2 CuNPs/TiO2 (10) THF 25 44 15 32 : 68 3 CuNPs/ZnO (10) THF 25 31 30 31 : 69 4 CuNPs/TiO2 (30) THF 25 65 14 43 : 57 5c CuNPs/TiO2 (30) THF 66 77 23 49 : 51 6 CuNPs/ZnO (15) THF 66 44 10 70 : 30 7 CuCI2 (100) THF 66 — 100 — 8 CuNPs/TiO2 (30) Dioxane 90 d — 37 : 63 9 CuNPs/TiO2 (30) DMSO 70 — 100 — 10 CuNPs/TiO2 (30) DCM 40 75 22 85 : 15 11 CuNPs/TiO2 (30) DCE 80 82 18 86 : 14 12 TiO2 (0) DCM 40 — 60 — a Conditions: alkyne (0.1 mmol), thiol (0.1 mmol), catalyst, solvent (2 mL) and a reaction time of 20 h. b Conversion determined by 1H-NMR analysis of the mixture. c Reaction carried out under a N2 atmosphere. d Conversion could be not calculated due to the presence of many by-products. © 2021 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2021, 11, 2074–2082 | 2075 View Article Online RSC Advances Paper materials, such as activated carbon, nanosized silica coated maghemite (MagSilica®), TiO2, zeolite Y (ZY), MgO, Al-MCM-41, ZnO and CeO2, were tested as supports for the CuNPs. As listed in Table 1, 2-ethynylpyridine and 1-octadecanethiol This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. were used as model substrates in order to test the activity of different catalysts in the TYC reaction. The reaction of 2-ethy- nylpyridine (0.1 mmol) with 1-octadecanethiol (0.1 mmol) was conducted in the presence of different CuNPs/support catalysts (10 mg) in THF at 25  C for 20 h. The most promising systems are shown in Table 1, entries 1–3. In these cases, the regiose- Open Access Article. Published on 07 January 2021. Downloaded on 2/9/2021 7:57:05 AM. lectivity was excellent, providing only the anti-Markovnikov adduct, but the stereoselectivity was moderate, giving an average Z : E isomers ratio of near 35 : 65. The observed conversion was low for both the CuNPs/TiO2- and CuNPs/ZnO- catalyzed TYC reactions (entries 2 and 3), with 40% of 1-octa- Fig. 1 Recycling of the CuNPs/TiO2 catalyst in the synthesis of 3- decanethiol remaining unreacted. In contrast, the reaction (heptadecylthio)acrylamide. promoted by the CuNPs/C catalyst gave a full conversion to disulde C as the main product, together with vinyl suldes A and B in a lower proportion (entry 1). For the reaction catalyzed 300 nm (see Fig. S1 and S2†). Energy-dispersive X-ray (EDX) by CuNPs/TiO2, an increase in the catalyst loading signicantly analysis on various regions showed the presence of copper on improved the conversion to products A and B, but with the small spherical aggregates located on the surface, whereas a marked drop in the stereoselectivity (entry 4). In addition, titanium was detected mainly in the seed particles (Fig. S3†). a rise in temperature to 66  C led to a 77% conversion to the Electron energy loss spectroscopy (EELS) was performed on desired products, leaving no unreacted thiol (entry 5). However, those small spherical aggregates, conrming the presence of the very good conversion towards A and B was accompanied by copper. an increase in the amount of disulde formed, even working The heterogeneous nature of the CuNPs/TiO2 catalyst led us under a nitrogen atmosphere. to test its recyclability. Thus, the hydrothiolation of propiola- A similar behaviour was observed with the CuNPs/ZnO mide with 1-octadecanothiol was carried out and the catalyst catalyst, as the conversion also improved at a higher reaction could be recovered by ltration, washed with DCM and reused temperature and catalyst loading, but in this case the stereo- at least three times without a signicant loss of its regio- or selectivity markedly favoured the Z-vinyl sulde (entry 6). The stereoselectivity. As shown in Fig. 1, the conversion value use of CuCl2 as the catalyst gave a complete conversion to showed a drop of about 10% in the activity of the rst cycle, but disulde C (entry 7). With regard to the reaction solvent, remained constant along the last two cycles. previous reports have shown that the use of THF in the presence With the optimized conditions in hand, the scope of the TYC of Cu(I) and O2 favours the formation of the disulde product.30 reaction was studied for a series of alkynes (2), mainly terminal In view of this, we tested other solvents, such as dioxane, DMSO, ones, with several thiols bearing catechol pendant groups. The DCM and 1,2-DCE. As shown in Table 1 (entries 8–11), when the starting catechols were synthesized according to the procedure reaction was carried out in DCM, almost the same conversion as previously reported by our group, which was based on the in THF was observed but with a notably improved stereo- attachment of dithiolated chains to pyrocatechol in two stages selectivity to Z-vinyl sulde (Z/E ratio ¼ 85/15) (entry 10). Moreover, the use of 1,2-DCE as the solvent and the possibility that higher temperatures could be reached, substantially improved the conversion to the desired product and reduced the amount of disulde formed (entry 11). The use of 1,2-DCE in the hydrothiolation reaction has been previously reported by other authors as leading to excellent results.31,32 Finally, no conversion to products A and B was observed in the presence of the support alone (entry 12). In view of these experimental observations, the best conditions found were those corresponding to entry 11 in Table 1. The copper-on-titanium oxide catalyst was characterized by different techniques. The copper content in the catalysts, ca. 6.4–7.0 wt%, was determined by inductively coupled plasma optical emission spectroscopy (ICP-MS). Analysis by TEM revealed the presence of small spherical aggregates with an Scheme 2 (a) Thiol conjugate addition and hydrothiolation of alkynes. average size of 30  15 nm, homogeneously distributed over (b) Synthesized Michael adducts with their respective conversion seed-like particles of the support with a length between of 100– values. Isolated product yields are indicated in brackets. 2076 | RSC Adv., 2021, 11, 2074–2082 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online Paper RSC Advances (see Scheme 2a).26 Here, pyrocatechol is rst oxidized to o- Applying this previously reported procedure, four Michael benzoquinone with NaIO4 in an aqueous solution. Then, the adducts were obtained with conversions in the range of 37–52% solution is extracted with DCM, and the dry organic extracts are (Scheme 2b). Although the conversion values to the Michael added over a solution of a dithiol and an excess of triuoracetic adduct may seem to be rather low, it should be noted that the This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. acid (TFA) in DCM. At this point, the thiol produces a nucleo- oxidation step from pyrocatechol to quinone occurs at around philic attack on the quinoid ring, giving a keto–enol interme- 75% conversion, thus leaving at least 25% of the starting dithiol diate that spontaneously tautomerizes into the substituted unreacted. Considering this, and referencing the values of catecholic form, yielding the Michael adduct 1. mono-adduct obtained for that initial 75% of quinone, the conversion values would be around 52–75%. Open Access Article. Published on 07 January 2021. Downloaded on 2/9/2021 7:57:05 AM. Table 2 Scope of the TYC reaction between Michael adducts (1) and activated alkynes (2)a Entry Michael adduct Alkyne Time (h) Product % Conv.b,c Selectivity Z : Ed 1 41 86 (40) 83 : 17 (83 : 17) 2 22 87 (53) 86 : 14 (87 : 13) 3 24 97 (69) 85 : 15 (99 : 1) 4 48 78 (39) 82 : 18 (81 : 19) 5 48 90 (46) 86 : 14 (86 : 14) 6 48 78 (36) 79 : 21 (80 : 20) 7 72 45 (23) 90 : 10 (90 : 10) 8 24 67 (50) 81 : 19 (77 : 23) 9 24 69 (37) 58 : 44 (56 : 44) 10e 24 60 52 : 48 11 46 53 (21) 64 : 36 (67 : 33) 12 96 47 (14) 99 : 1 (99 : 1) 13 24 92 (31) 52 : 48 (55 : 45) 14 24 90 (63) 40 : 60 (39 : 61) a Conditions: alkyne (0.4 mmol), Michael adduct (0.4 mmol), catalyst (120 mg, 30.2 mol%), DCE (120 mg, 30.2 mol%), DCE (4 ml) and heating at 80  C. b Conversion determined by 1H-NMR analysis of the crude mixture. c The yields of products are shown in brackets. d The selectivities Z : E of isolated products are shown in brackets are shown in brackets. e Conditions: alkyne (0.4 mmol), Michael adduct (0.5 mmol), catalyst (120 mg, 30.2 mol%), DCE (4 mL) and heating at 80  C. © 2021 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2021, 11, 2074–2082 | 2077 View Article Online RSC Advances Paper We then studied the conjugation of dithiols molecules hydrothiolation product was relatively good. However, bearing an apolar alkyl chain (1,6-hexanedithiol and 1,4-buta- a considerable amount of decarboxylated product was observed. nedithiol, 1a and 1b, respectively), a polar moiety (2,2-(ethyl- With regard to the reaction time, it is important to note that enedioxy)diethanethiol, 1c), and pendant hydroxyl groups (DL- all the thiols used (Michael adducts) were aliphatic and had This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. dithiothreitol, 1d). The carbon chain between both thiol groups different carbon-chain lengths. As has already been repor- should function as a spacer in the catechol derivative, providing ted,10,12a,31 in many cases, aliphatic thiols require both longer a degree of exibility, as well as enough spatial separation when reaction times and higher temperatures, to achieve satisfactory needed. Moreover, changes in the polarity of the spacer could conversions compared to aromatic ones. modify the solubility of these adducts in aqueous or polar While the conversions observed in Table 2 ranged from good media. Additionally, the procedure for obtaining the Michael to excellent, a signicant decrease in the isolated product yields Open Access Article. Published on 07 January 2021. Downloaded on 2/9/2021 7:57:05 AM. adduct 1 could be successfully scaled up to a 9 mmol scale, was observed when the crude reaction products were puried. keeping the same conversion value as that of the reaction This fact was mainly attributed to catechol's numerous inter- carried out at the 1 mmol scale. actions,34 such as non-covalent forces and chemical bonding, The results of the TYC reaction between the prepared with both the TiO2 and silica present in the catalyst and the Michael adducts 1a–d and different activated alkynes with stationary phase in the chromatographic column, respectively. adjacent electron-withdrawing groups are presented in Table 2. A strategy that worked very effectively in some cases was to wash The starting alkynes were readily synthesized from methyl the crude reaction mixture with different mixtures of solvents propiolate and acetylenedicarboxylic acid, respectively (see (see Experimental section). For example, the products 3ca and Experimental section). Under the optimized conditions shown 3bc could be recovered with only a loss of about 25% compared in Table 1, the alkyne (0.4 mmol) and the thiol (0.4 mmol) were to the conversion values determined by NMR. On the other then reacted upon heating in 1,2-DCE at 80  C in the presence of hand, it is important to note that practically in all cases, the the CuNPs/TiO2 catalyst (120 mg, 30.2 mol%). Fortunately, the relationship between the Z and E isomers was maintained even hydrothiolation of propiolamide (2a) with 1a produced an aer column chromatography purication (see Table 2). excellent conversion to 3aa with a very good stereoselectivity (Z/ Although the exact mechanism involved is difficult to ascertain E ratio ¼ 83/17) aer 41 h (Table 2, entry 1). Similar promising at this stage, based on our results and previous reports by other results were obtained with the Michael adducts 1b and 1c groups in the same area,5,35 a plausible mechanistic pathway could (entries 2 and 3). When other activated alkynes, such as methyl be proposed that proceeds via an external nucleophilic anti- propiolate 2b, were tested, the products of the TYC reaction Markovnikov attack from activated thiol species to the corre- followed a similar trend as that observed for 2a, that is, good to sponding activated alkyne. In this context, it is worth mentioning excellent conversions into the anti-Markovnikov vinyl sulde that in our CuNPs/TiO2 catalyst, the Lewis acid character of the and very good Z stereoselectivity (entries 4–7). transition metal (Cu) and the acid–base character of the support Interestingly, the corresponding s-cis and s-trans rotamers (TiO2) could lead to activation of the alkyne, thiol or both. were detected for both products in entries 3 and 6. It is known On the one hand, the catalyst could be increasing the nucle- that these types of conformers are usually observed in acyclic ophilicity of the thiol by deprononation of the SH group by the a,b-unsaturated esters, amides or carboxylic acids.33 In our case, Lewis basic sites present at the “non-innocent” support (TiO2). both the cis isomer and s-cis rotamer were the major products, This necessity for free basic sites on the catalyst surface to acti- with a 1 : 1 ratio between them. vate the thiol could also serve as an explanation for the low When 2-ethinyl pyridine (2c) was used as the starting alkyne, reactivity observed when propiolic acid was used as a starting the conversions were signicantly lower than those observed alkyne (see entry 12, Table 2). Alternatively, the activation of the with propiolamide (2a) and methyl propiolate (2b). In all cases, S–H bond by the very active CuNPs should not be disregarded. At it was observed that much of the starting thiol was quickly this point, it should be noted that the TiO2 support could be oxidized to the corresponding disulde, with a considerable playing another important role, that is, as a xer of the catechol amount of 2c remaining unreacted (entries 8–11). The use of an moiety to the surface of the catalyst by coordination between the excess of the thiol (1.25 equivalents) produced practically no Lewis acid sites on titanium and one or both of the oxygen atoms change in conversion to 3cc (entry 10, footnote c). of the hydroxyl groups at the catechol aromatic ring.34 On the Among the terminal alkynes tested, the lowest conversion other hand, based on our experience working with CuNPs as was obtained with propiolic acid (entry 12, 47%), even aer 96 h catalysts for various alkyne transformations,36 one could assume of reaction. However, in this case, the stereoselectivity to the Z- that the activation of the carbon–carbon triple bond on the isomer was excellent with a Z : E ratio of 99 : 1. On the other alkyne could proceed via p-coordination with copper. Another hand, the internal alkyne dimethyl acetylenedicarboxylate 2f classical mode of activation for terminal alkynes, that cannot be gave the best conversion values when reacted with the Michael disregarded involves the formation of metal–vinylidene spe- adducts 1b and 1c (entries 13–14). It is well known that the cies.35b If this were the case, the thiol would attack the electro- higher reactivity of 2f is due to the low electron density on the philic a-carbon of the cumulene to selectively provide the anti- triple carbon–carbon bond which is connected to two carbonyl Markovnikov products. Work in this area remains ongoing and groups, and following this trend, when we tried to carry out the we are actively carrying out some additional experiments and reaction using acetylenedicarboxylic acid, the conversion to the DFT calculations in order to disclose the precise mechanism for this CuNPs/TiO2-catalyzed thiol-yne reaction. 2078 | RSC Adv., 2021, 11, 2074–2082 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online Paper RSC Advances Application of compound 3 as a ligand in the synthesis of formation of oval-shaped nanoparticles grouped in chains and CNPs clusters, with an average size of 100  50 nm. Meanwhile, EDX analysis showed the presence of S, C, O and Co elements on the As a preliminary test and taking into account the experiences of entire analyzed surface. This result was particularly interesting our group in the preparation of CNPs for different purposes, This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. since the traditional methodology in our group for preparing such as contrast agents,37 carriers in HIV/AIDS therapy38 or CNPs has been one whereby the metallic salt is mixed with two platforms for drug delivery,39 we decided to carry out the prep- types of ligands: corresponding to a catechol derivative and to aration of CNPs with some of the synthesized ligands and different metallic salts, such as FeCl3$6H2O and CoCl2$6H2O. a ditopic N,N0 -ligand (1,4-bis(imidazole-1-ylmethyl)benzene The synthesis of CNPs is very straightforward and consisted of (bix) or 4,40 -bipyridyl). In this way, it is estimated that the general structure achieved is that represented in Fig. S4.†40 mixing the organic ligand in EtOH under magnetic stirring, and Open Access Article. Published on 07 January 2021. Downloaded on 2/9/2021 7:57:05 AM. However, more recently, it has been determined that, depend- adding, drop by drop, the metallic salt dissolved in water, over ing on the metallic salt used, there could be a higher proportion the alcoholic phase. Following this methodology, several of the of coordinated catechol than bix, or quite the reverse, affecting ligands synthesized were tested with Fe(III), showing the both the structure of the polymer obtained as well as the correct formation of an iron–catecholate complex in all cases as the elucidation of its repeating unit. The synthetic approach pre- solution instantaneously turned to blue-violet, followed by the formation of a precipitate. Then, the solution was centrifuged sented here, would allow us to have in the same ligand either and washed several times with water and EtOH, and nally the catechol group and the pyridine ring, which are both able to coordinate with the metal. It is important to mention that those analyzed by SEM and EDX (Fig. 2). Among the cases evaluated, ligands 3 without a pyridine ring in their structure were not able only some of them presented characteristics of a regularly to form a precipitate with Co(II). Moreover, those ligands, such structured material. For example, Fig. 2a and b show the SEM as 3cc bearing a pyridinic ring but with a longer spacer chain, micrographs of the nanoparticles generated by the combination were less prone to forming a precipitate, producing a slight of ligands 3ca and 3ab with the FeCl3$6H2O salt, respectively. turbidity, even aer 24 h. The images revealed the formation of oval-shaped nano- particles, arranged in chains and clusters, with average diam- eters between 100–300 nm. Moreover, EDX analysis evidenced Conclusions the presence of S, C, O and Fe elements in the entire analyzed surface. In summary, we have reported an interesting approach for the Fig. 2c shows the results obtained by analysis of the precip- synthesis of vinyl suldes bearing catechol pendant groups, via itate formed by mixing compound 3bc, with a pyridinic ring, a thiol-yne click reaction, promoted by a heterogeneous catalyst based on CuNPs supported on TiO2, in 1,2-DCE and under and a Co(II) salt. Thus, the SEM micrograph revealed the heating at 80  C. The results showed that the alkynes activated with electron-withdrawing groups adjacent to the triple bond were the most efficient in obtaining the desired products. Under these conditions, the reaction was regio- and stereoselective towards the formation of anti-Markovnikov Z-vinyl suldes in the vast majority of cases, with good to excellent conversions (47–97%). The heterogeneous and low cost CuNPs/TiO2 catalyst also showed a high activity and good recyclability. While there are numerous reports in which the alkyne hydrothiolation is carried out by employing activated alkynes, this reaction remains poorly explored and even rarer in the presence of a catechol moiety. Regarding the mechanism of the reaction, although it is difficult to ascertain at this stage, we believe that, based on the experimental evidence, there may be a nucleophilic attack through activated thiol species, mainly by deprotonation of the SH group by the basic sites of TiO2. This necessity of free basic sites on the catalyst surface to activate the thiol could also serve as an explanation for the low reactivity observed when propiolic acid was tested as a starting alkyne. On the other hand, we assume that the activation of the carbon–carbon triple bond on the alkyne could proceed via p-coordination with copper. Finally, as a preliminary test to demonstrate the potential of these types of new compounds as ligands, we carried out the Fig. 2 SEM micrographs, histograms and EDX spectra for CNPs preparation of CNPs by using selected vinyl suldes and prepared by mixing: (a) 3ca ligand with Fe(III), (b) 3ab ligand with Fe(III) metallic salts, such as Fe(III) and Co(II). Analysis of the resulting and (c) 3bc ligand with Co(II). Scale bars are 500 nm. CNPs by SEM and TEM demonstrated the formation of oval- © 2021 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2021, 11, 2074–2082 | 2079 View Article Online RSC Advances Paper shaped nanoparticles with average diameters between 100– For CNPs characterization, SEM images were performed in 300 nm with some of the ligands tested. This approach, in a LEO EVO 40XVP system operated at 10 kV coupled to an EDX which several coordinating groups can coexist in the same detector Oxford X-Max 50. Samples were prepared by drop ligand, would allow improvements in monitoring and charac- casting of the corresponding dispersion on an aluminium tape This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. terizing these CNPs. followed by evaporation of the solvent under room conditions, Overall, through this methodology, new products with then metallized with gold in a sputter coater. potential application in the eld of materials chemistry were obtained. Preparation of the CuNPs/TiO2 catalyst Anhydrous copper(II) chloride (404 mg, 3 mmol) was added to a suspension of lithium (63 mg, 9 mmol) and 4,40 -di-tert-butyl- Open Access Article. Published on 07 January 2021. Downloaded on 2/9/2021 7:57:05 AM. Experimental biphenyl (DTBB, 80 mg, 0.3 mmol) in THF (10 mL) at room General temperature under a nitrogen atmosphere. The reaction mixture, which was initially dark blue, rapidly changed to black, All moisture-sensitive reactions were carried out under indicating that the suspension of copper nanoparticles was a nitrogen atmosphere. Anhydrous tetrahydrofuran was freshly formed. This suspension was diluted with THF (10 mL) followed distilled from sodium/benzophenone ketyl. All the starting by the addition of the TiO2 (2.4 g). The resulting mixture was materials were of the best available grade (Aldrich, Merck, Alfa stirred for 1 h at room temperature, quenched with water and Aesar) and were used without further purication. Nitric acid then ltered. The solid was successively washed with EtOH (15 69% and hydrochloric acid 30% used for analysis of the metal mL) and dried under vacuum. traces were purchased from Scharlab SL. The standard solution of Cu was obtained from Perkin Elmer. Commercially available Preparation of Michael adducts 1 copper(II) chloride dihydrate was dehydrated upon heating in an oven (150  C, 45 min) prior to use for the preparation of the For the preparation of 1a–d, 2 mmol of the corresponding CuNPs. Column chromatography was performed with Merck dithiol was dissolved in 3 mL of CH2Cl2 in a Schlenk ask under silica gel 60 (0.040–0.063 mm, 240–400 mesh) and hexane/EtOAc nitrogen. For more polar dithiols, 3 mL of a 1 : 2 mixture as the eluent. The reactions were monitored by thin-layer MeOH : CH2Cl2 was used. To this solution, 460 mL of triuoro- chromatography on silica gel plates (60F-254) visualized under acetic acid (TFA, 2 mmol) was added with stirring. In a separate UV light and/or using FeCl3 in water for staining. Nuclear ask, a solution of 468 mg of NaIO4 (2.2 mmol) in 80 mL of H2O magnetic resonance (NMR) spectra were recorded on a Bruker was prepared and cooled in an ice bath. Next, 220 mg of pyro- ARX-300 spectrometer using CDCl3 or CD3OD as solvents. Nitric catechol (2 mmol) dissolved in 1 mL of Et2O was added to the acid 69% and metal traces and chlorhydric acid 30% used for aqueous solution and le stirring vigorously for 15 min. The analysis of the metal traces by ICP-MS were purchased from orange-reddish o-benzoquinone was extracted with 4  15 mL Scharlab SL. The standard solution of Cu was obtained from of CH2Cl2, and the organic phase was dried over anhydrous Perkin Elmer. Na2SO4, ltered and immediately added to the dithiol solution. For CuNPs/TiO2 characterization, TEM and STEM images, The reaction mixture was stirred in the dark at room tempera- together with EDX and EELS spectra, were obtained with an FEI ture under nitrogen for 6 h. Aer this, the solvent and the TFA Tecnai G2 F20 instrument coupled to an EDAX detector and were evaporated under reduced pressure and the crude was a Quantum SE 963 Gatan Imaging Filter (GIF). The samples puried by ash column chromatography (hexane–EtOAc) to were prepared by casting a drop of the corresponding sample give the corresponding Michael adducts. Compounds 1a–d were dispersion on a holey carbon copper grid, and then by evapo- characterized by comparison of their physical and spectroscopic rating off the solvent at room temperature. The copper content data with those described in the literature (see ESI S3†).26 in the supported catalyst was determined by using an ICP-MS NexION 300X instrument from Perkin Elmer. Before its use, Preparation of the alkynes all glass material was washed with HNO3 40% for 72 h and Synthesis of propiolamide, 2a.41 Methyl propiolate (2 mmol) rinsed with MilliQ water. Plastic material was washed with was dissolved in 4 equivalents of 25% NH3/H2O (8 mmol) and HNO3 0.5% and rinsed with MilliQ water before use. The stirred at 78  C for 1 h. Then, all the volatile compounds were standard solution of 1000 ppm Cu in 5% HNO3 was diluted up removed under reduced pressure. While solvent removal was to 1 ppm and used to prepare the calibration curves (20, 40, 80, occurring, the corresponding amide precipitated easily. A 120 and 240 ppb Cu). Digestion of the samples was carried out further purication was not necessary, yielding 126 mg (91%) of in 3 mL of concentrated ultrapure HNO3/HCl (1 : 1) in a Mile- compound 2a as white needles. 1H NMR (300 MHz, CDCl3) d: stone ETHOS EASY microwave digester. The microwave system 6.17 and 5.90 (broad s, 2H, NH2), 2.86 (s, 1H). 13C NMR (75 MHz, was set at 1800 W with a temperature ramp of 25 min up to CDCl3) d: 153.6 (C), 77.2 (C), 74.4 (CH). 230  C, then being kept for 15 min more at this temperature. Synthesis of dimethyl acetylenedicarboxylate, 2f.42 To 4 mL Digested samples were diluted with HNO3 0.5% to a nal (97 mmol) of methanol in a round-bottomed ask, 0.84 mL of dilution of 1/100, 1/400 and 1/1000 for later analysis. Elemental concentrated sulfuric acid was added in small portions with analysis was carried out using a Flash EA 2000 CHNS, Thermo cooling. To this cooled solution was added 570 mg (5 mmol) of Fisher Scientic system. acetylenedicarboxylic acid. The ask was tted with an adapter 2080 | RSC Adv., 2021, 11, 2074–2082 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online Paper RSC Advances and le under nitrogen and at room temperature for 1 day. The 2 (a) M. S. Kabir, M. Lorenz, M. L. Van Linn, O. A. Namjoshi, solution was extracted with diethyl ether (5  5 mL). The ether S. Ara and J. M. Cook, J. Org. Chem., 2010, 75, 3626–3643; extracts were combined and washed successively with 5 mL of (b) Q. Li, Ti. Dong, X. Liu and X. Lei, J. Am. Chem. Soc., cold water, 5 mL of saturated sodium bicarbonate solution and 2013, 135, 4996–4999. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 5 mL of cold water and then dried over anhydrous calcium 3 (a) A. B. Lowe, C. E. Hoyleb and C. N. Bowman, J. Mater. chloride. A further purication was not necessary, yielding Chem., 2010, 20, 4745–4750; (b) M. M. Bassaco, 625 mg (88%) of compound 2f as a colourless oil. 1H NMR (300 M. Monçalves, F. Rinaldi, T. S. Kaufman and C. C. Silveira, MHz, CDCl3) d: 3.78 (s, 6H). 13C NMR (75 MHz, CDCl3) d: 151.9 J. Photochem. Photobiol., A, 2014, 290, 1–10. (C), 74.3 (C), 53.2 (CH3). 4 K. Choudhuri, M. Pramanik, A. Mandal and P. Mal, Asian J. Org. Chem., 2018, 7, 1849–1855. Open Access Article. Published on 07 January 2021. Downloaded on 2/9/2021 7:57:05 AM. General procedure for the synthesis of vinyl sulde, 3, 5 R. Castarlenas, A. Di Giuseppe, J. J. Pérez-Torrente and catalyzed by CuNPs/TiO2 L. A. Oro, Angew. Chem., Int. Ed., 2013, 52, 211–222. 6 (a) M. Lo Conte, S. Pacico, A. Chambery, A. Marra and The Michael adduct 1 (0.4 mmol) and alkyne 2 (0.4 mmol) were A. Dondoni, J. Org. Chem., 2010, 75, 4644–4647; (b) added to a reaction tube containing CuNPs/TiO2 (120 mg, L. Benati, L. Capella, P. C. Montevecchi and P. Spagnolo, J. 30.2 mol% Cu) in 1,2-DCE (4 mL) under air. The reaction Chem. Soc., Perkin Trans. 1, 1995, 1035–1038. mixture was warmed to 80  C and monitored by TLC until total 7 (a) S. Kanagasabapathy, A. Sudalai and B. C. Benicewicz, conversion of the starting material. The catalyst was removed by Tetrahedron Lett., 2001, 42, 3791–3794; (b) C. G. Screttas ltration and washing with hexane–AcOEt. Finally, the ltrate and M. Micha-Screttas, J. Org. Chem., 1979, 44, 713–719. was concentrated under vacuum and the product was puried 8 (a) A. Kondoh, K. Takami, H. Yorimitsu and K. Oshima, J. by column chromatography to give the corresponding vinyl Org. Chem., 2005, 70, 6468–6473; (b) Z.-L. Wang, sulde, 3. Full data for all the compounds are provided below R.-Y. Tang, P.-S. Luo, C.-L. Deng, P. Zhong and J.-H. Li, (see ESI S3†). Tetrahedron, 2008, 64, 10670–10675; (c) N. Zhao, C. Lin, L. Wen and Z. Li, Tetrahedron, 2019, 75, 3432–3440. Authors' contributions 9 (a) S. N. Riduan, J. Y. Ying and Y. Zhang, Org. Lett., 2012, 14, 1780–1783; (b) H. Ma, X. Ren, X. Zhou, C. Ma, Y. He and FN carried out the funding acquisition, conceptualization, G. Huang, Tetrahedron Lett., 2015, 56, 6022–6029. investigation, methodology and writing. JMA participated in the 10 Y. Yang and R. M. Rioux, Chem. Commun., 2011, 47, 6557– conceptualization, investigation, methodology and writing. DZ 6559. participated in the methodology. DRM participated in the 11 A. Dondoni and A. Marra, Eur. J. Org. Chem., 2014, 3955– investigation. GR carried out the funding acquisition, investi- 3969. gation and writing. All authors read and approved the nal 12 (a) M. Kodomari, G. Saitoh and S. Yoshitomi, Bull. Chem. manuscript. Soc. Jpn., 1991, 64, 2485–2487; (b) P. D. Halphen and T. C. Owen, J. Org. Chem., 1973, 38, 3507–3510; (c) Conflicts of interest Y. Sarra, M. Sadatshahabi, K. Alimohammadi and M. Tajbakhsh, Green Chem., 2011, 13, 2851–2858. There are no conicts to declare. 13 H.-Y. Shiu, T.-C. Chan, C.-M. Ho, Y. Liu, M.-K. Wong and C.-M. Che, Chem.–Eur. J., 2009, 15, 3839–3850. Acknowledgements 14 (a) O. Daglar, U. S. Gunay, G. Hizal, U. Tunca and H. Durmaz, Macromolecules, 2019, 52, 3558–3572; (b) C. K. W. Jim, A. Qin, This work was supported by the ANPCyT (Project PICT 2016- J. W. Y. Lam, F. Mahtab, Y. Yu and B. Z. Tang, Adv. Funct. 0385), SGCyT-UNS (Project PGI 24/Q106) and CONICET (Project Mater., 2010, 20, 1319–1328; (c) A. B. Lowe, Polymer, 2014, PIP 11220130100498CO). We thank Belén Ballesteros and 55, 5517–5549; (d) O. Daglar, E. Cakmakci, U. S. Gunay, Marcos Rosado from Electron Microscopy Unit of Institut Català G. Hizal, U. Tunca and H. Durmaz, Macromolecules, 2020, de Nanociència i Nanotecnologia (ICN2) in Barcelona, Spain; 53(8), 2965–2975. and Maria Julia Yañez from Electron Microscopy Unit in Centro 15 U. S. Gunay, M. Cetin, O. Daglar, G. Hizal, U. Tunca and Cientı́co Tecnológico – CONICET, Bahı́a Blanca, Argentina for H. Durmaz, Polym. Chem., 2018, 9, 3037–3054. their measurements and assistance. We thank Miguel Ángel 16 (a) V. X. Truong and A. P. Dove, Angew. Chem., Int. Ed., 2013, Moreno-Villaécija for carrying out the ICP/MS analysis. 52, 4132–4136; (b) O. Daglar, S. Luleburgaz, E. Baysak, U. S. Gunay, G. Hizal, U. Tunca and H. Dumaz, Eur. Polym. Notes and references J., 2020, 137, 109926. 17 N. Van Herck, D. Maes, K. Unal, M. Guerre, J. M. Winne and 1 (a) J. Doroszuk, M. Musiejuk, Ł. Ponikiewski and D. Witt, F. E. Du Prez, Angew. 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