Thiol-yne click reaction: an interesting way to derive thiol-provided catechols

Article abstract of DOI:10.1039/d0ra09687c

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, 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 tested as ligands in the preparation of coordination polymer nanoparticles (CNPs), by taking the advantage of their different coordination sites with metals such as iron and cobalt.

Full text of DOI:10.1039/d0ra09687c

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Thiol-yne click reaction: an interesting way to
derive thiol-provided catechols†
Cite this: RSC Adv., 2021, 11, 2074
a
Juan Mancebo-Aracil,a Duham Zanotto,a Daniel Ruiz-Molinab
*
Fabiana Nador,
a
and Gabriel Radivoy
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,
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
tested as ligands in the preparation of coordination polymer nanoparticles (CNPs), by taking the
advantage of their different coordination sites with metals such as iron and cobalt.
Received 14th November 2020
Accepted 8th December 2020
DOI: 10.1039/d0ra09687c
rsc.li/rsc-advances
Regardless of the method used to promote the reaction, it is
important to bear in mind that both alkyne and thiol groups are
Introduction
inherently nucleophilic, hence the activation of one or both
groups is necessary for the construction of vinyl suldes.5 In
this sense, the use of activated alkynes, meaning alkynes
bearing an adjacent electron-withdrawing group (such as
carboxylic acid, ester or amide group), resulted in a reduction of
the electronic density on the alkyne, thus enhancing the
nucleophilic attack of the thiol. The reaction of thiols, especially
aliphatic ones, with propiolic acid esters is very slow in the
absence of catalysts, but is remarkably accelerated by bases12
due to the increased concentration of thiolate ions in an alka-
line solution.13 Because of its click characteristics, which
include a fast, quantitative and selective reaction under mild
conditions, the hydrothiolation of activated alkynes has been
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
Vinyl suldes are of great interest because they can be used as
versatile building blocks in organic synthesis1 and as interme-
diates for the synthesis of biologically active compounds2 and
new materials,3 among others.
The thiol-yne click (TYC) reaction, also known as alkyne
hydrothiolation, is one of the simplest and most atom-
economical approach to produce alkenyl suldes from thiols
and alkynes.4,5 The TYC reaction commonly occurs in the
presence of free radicals,6 strong acids,7 bases8 or transition
metals9 and, as shown in Scheme 1, in principle can lead to one
of the regio- and stereoisomeric vinyl suldes: A (branched)
through a Markovnikov orientation, B (E linear) and C (Z linear),
or produce mixtures of them through an anti-Markovnikov
orientation (Scheme 1).10,11
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
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,
despite the extraordinary characteristics of catechol-derived
structures, their preparation is challenging mainly due to the
vulnerability of catechol to oxidation. As a result, only a few
synthetic methodologies have been described and even among
these, relatively lengthy synthetic routes, comprising
Scheme 1 Schematic representation of alkyne hydrothiolation.
a
´
Instituto de Quımica del Sur (INQUISUR-CONICET), Universidad Nacional del Sur,
´
Av. Alem 1253, 8000 Bahıa Blanca, Argentina. E-mail: fabiana.nador@uns.edu.ar
b
`
`
Insitut Catala de Nanociencia i Nanotecnologia (ICN2), Edici ICN2, UAB Campus,
Bellaterra, 08193 Barcelona, Spain
† Electronic supplementary information (ESI) available: TEM and STEM images,
EDX analysis and NMR spectra. See DOI: 10.1039/d0ra09687c
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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
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
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
with the vinyl sulde intermediate than with the starting alkyne.
Results and discussion
The catalysts were prepared by the addition of the support to
a suspension of freshly prepared copper nanoparticles (CuNPs).
The CuNPs were generated by the fast reduction of anhydrous
copper(II) chloride, using lithium sand and a catalytic amount
of DTBB (4,40-di-tert-butylbiphenyl, 10 mol%) as the reducing
system, in THF at room temperature (see Scheme S1†). The
catalysts were ready for use as prepared, aer ltration and
drying, and without any pre-treatment. Different inorganic
Thus, no vinyl sulde could be obtained through the TYC
reaction in the presence of catechols.
On this basis, we attempted to apply TYC reaction to the
modication of catechol structures bearing a thiol functionality
as end-group. As already mentioned, in most cases the addition
of a base to promote the hydrothiolation reaction of activated
alkynes, is mandatory. However, the catechol moiety is not
Table 1 Optimization of reaction conditionsa
Selectivity
Z : E
Entry
Catalyst (Cu mg)
Solvent
Temp. (ꢀC)
Conv. A + Bb (%)
Conv. Cb (%)
1
2
3
CuNPs/C (10)
CuNPs/TiO2 (10)
CuNPs/ZnO (10)
CuNPs/TiO2 (30)
CuNPs/TiO2 (30)
CuNPs/ZnO (15)
CuCI2 (100)
CuNPs/TiO2 (30)
CuNPs/TiO2 (30)
CuNPs/TiO2 (30)
CuNPs/TiO2 (30)
TiO2 (0)
THF
THF
THF
THF
THF
THF
THF
Dioxane
DMSO
DCM
DCE
25
25
25
25
66
66
66
90
70
40
80
40
23
44
31
65
77
44
77
15
30
14
23
10
100
—
100
22
18
60
40 : 60
32 : 68
31 : 69
43 : 57
49 : 51
70 : 30
—
37 : 63
—
85 : 15
86 : 14
—
4
5c
6
7
8
9
10
11
12
—
d
—
75
82
—
DCM
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.
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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
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 presꢀence 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-
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-
decanethiol remaining unreacted. In contrast, the reaction
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
by CuNPs/TiO2, an increase in the catalyst loading signicantly
improved the conversion to products A and B, but with
a marked drop in the stereꢀoselectivity (entry 4). In addition,
a rise in temperature to 66 C led to a 77% conversion to the
desired products, leaving no unreacted thiol (entry 5). However,
the very good conversion towards A and B was accompanied by
an increase in the amount of disulde formed, even working
under a nitrogen atmosphere.
A similar behaviour was observed with the CuNPs/ZnO
catalyst, as the conversion also improved at a higher reaction
temperature and catalyst loading, but in this case the stereo-
selectivity markedly favoured the Z-vinyl sulde (entry 6). The
use of CuCl2 as the catalyst gave a complete conversion to
disulde C (entry 7). With regard to the reaction solvent,
previous reports have shown that the use of THF in the presence
of Cu(I) and O2 favours the formation of the disulde product.30
In view of this, we tested other solvents, such as dioxane, DMSO,
DCM and 1,2-DCE. As shown in Table 1 (entries 8–11), when the
reaction was carried out in DCM, almost the same conversion as
in THF was observed but with a notably improved stereo-
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
Fig. 1 Recycling of the CuNPs/TiO2 catalyst in the synthesis of 3-
(heptadecylthio)acrylamide.
300 nm (see Fig. S1 and S2†). Energy-dispersive X-ray (EDX)
analysis on various regions showed the presence of copper on
the small spherical aggregates located on the surface, whereas
titanium was detected mainly in the seed particles (Fig. S3†).
Electron energy loss spectroscopy (EELS) was performed on
those small spherical aggregates, conrming the presence of
copper.
The heterogeneous nature of the CuNPs/TiO2 catalyst led us
to test its recyclability. Thus, the hydrothiolation of propiola-
mide with 1-octadecanothiol was carried out and the catalyst
could be recovered by ltration, washed with DCM and reused
at least three times without a signicant loss of its regio- or
stereoselectivity. As shown in Fig. 1, the conversion value
showed a drop of about 10% in the activity of the rst cycle, but
remained constant along the last two cycles.
With the optimized conditions in hand, the scope of the TYC
reaction was studied for a series of alkynes (2), mainly terminal
ones, with several thiols bearing catechol pendant groups. The
starting catechols were synthesized according to the procedure
previously reported by our group, which was based on the
attachment of dithiolated chains to pyrocatechol in two stages
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
average size of 30 ꢁ 15 nm, homogeneously distributed over
Scheme 2 (a) Thiol conjugate addition and hydrothiolation of alkynes.
(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.
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(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
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%.
Table 2 Scope of the TYC reaction between Michael adducts (1) and activated alkynes (2)a
Entry
1
Michael adduct
Alkyne
Time (h)
41
Product
% Conv.b,c
86 (40)
Selectivity Z : Ed
83 : 17 (83 : 17)
2
3
22
24
48
48
48
72
24
24
24
46
87 (53)
97 (69)
78 (39)
90 (46)
78 (36)
45 (23)
67 (50)
69 (37)
60
86 : 14 (87 : 13)
85 : 15 (99 : 1)
82 : 18 (81 : 19)
86 : 14 (86 : 14)
79 : 21 (80 : 20)
90 : 10 (90 : 10)
81 : 19 (77 : 23)
58 : 44 (56 : 44)
52 : 48
4
5
6
7
8
9
10e
11
53 (21)
64 : 36 (67 : 33)
12
13
96
24
47 (14)
92 (31)
99 : 1 (99 : 1)
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
e
isolated products are shown in brackets are shown in brackets. Conditions: alkyne (0.4 mmol), Michael adduct (0.5 mmol), catalyst (120 mg,
30.2 mol%), DCE (4 mL) and heating at ꢂ80 ꢀC.
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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
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
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).
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-
transition metal (Cu) and the acid–base character of the support
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.
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formation of oval-shaped nanoparticles grouped in chains and
clusters, with an average size of 100 ꢁ 50 nm. Meanwhile, EDX
analysis showed the presence of S, C, O and Co elements on the
entire analyzed surface. This result was particularly interesting
since the traditional methodology in our group for preparing
CNPs has been one whereby the metallic salt is mixed with two
types of ligands: corresponding to a catechol derivative and to
Application of compound 3 as a ligand in the synthesis of
CNPs
As a preliminary test and taking into account the experiences of
our group in the preparation of CNPs for different purposes,
such as contrast agents,37 carriers in HIV/AIDS therapy38 or
platforms for drug delivery,39 we decided to carry out the prep-
aration of CNPs with some of the synthesized ligands and
different metallic salts, such as FeCl3$6H2O and CoCl2$6H2O.
The synthesis of CNPs is very straightforward and consisted of
mixing the organic ligand in EtOH under magnetic stirring, and
adding, drop by drop, the metallic salt dissolved in water, over
the alcoholic phase. Following this methodology, several of the
ligands synthesized were tested with Fe(III), showing the
formation of an iron–catecholate complex in all cases as the
solution instantaneously turned to blue-violet, followed by the
formation of a precipitate. Then, the solution was centrifuged
and washed several times with water and EtOH, and nally
analyzed by SEM and EDX (Fig. 2). Among the cases evaluated,
only some of them presented characteristics of a regularly
structured material. For example, Fig. 2a and b show the SEM
micrographs of the nanoparticles generated by the combination
of ligands 3ca and 3ab with the FeCl3$6H2O salt, respectively.
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
the presence of S, C, O and Fe elements in the entire analyzed
surface.
a
ditopic N,N0-ligand (1,4-bis(imidazole-1-ylmethyl)benzene
(bix) or 4,40-bipyridyl). In this way, it is estimated that the
general structure achieved is that represented in Fig. S4.†40
However, more recently, it has been determined that, depend-
ing on the metallic salt used, there could be a higher proportion
of coordinated catechol than bix, or quite the reverse, affecting
both the structure of the polymer obtained as well as the correct
elucidation of its repeating unit. The synthetic approach pre-
sented here, would allow us to have in the same ligand either
the catechol group and the pyridine ring, which are both able to
coordinate with the metal. It is important to mention that those
ligands 3 without a pyridine ring in their structure were not able
to form a precipitate with Co(II). Moreover, those ligands, such
as 3cc bearing a pyridinic ring but with a longer spacer chain,
were less prone to forming a precipitate, producing a slight
turbidity, even aer 24 h.
Conclusions
In summary, we have reported an interesting approach for the
synthesis of vinyl suldes bearing catechol pendant groups, via
a thiol-yne click reaction, promoted by a heterogeneous catalyst
based on CuNPs supported on TiO2, in 1,2-DCE and under
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.
Fig. 2c shows the results obtained by analysis of the precip-
itate formed by mixing compound 3bc, with a pyridinic ring,
and a Co(II) salt. Thus, the SEM micrograph revealed the
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
preparation of CNPs by using selected vinyl suldes and
metallic salts, such as Fe(III) and Co(II). Analysis of the resulting
CNPs by SEM and TEM demonstrated the formation of oval-
Fig. 2 SEM micrographs, histograms and EDX spectra for CNPs
prepared by mixing: (a) 3ca ligand with Fe(III), (b) 3ab ligand with Fe(III)
and (c) 3bc ligand with Co(II). Scale bars are 500 nm.
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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
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-
biphenyl (DTBB, 80 mg, 0.3 mmol) in THF (10 mL) at room
temperature under a nitrogen atmosphere. The reaction
mixture, which was initially dark blue, rapidly changed to black,
indicating that the suspension of copper nanoparticles was
formed. This suspension was diluted with THF (10 mL) followed
by the addition of the TiO2 (2.4 g). The resulting mixture was
stirred for 1 h at room temperature, quenched with water and
then ltered. The solid was successively washed with EtOH (15
mL) and dried under vacuum.
Experimental
General
All moisture-sensitive reactions were carried out under
a nitrogen atmosphere. Anhydrous tetrahydrofuran was freshly
distilled from sodium/benzophenone ketyl. All the starting
materials were of the best available grade (Aldrich, Merck, Alfa
Aesar) and were used without further purication. Nitric acid
69% and hydrochloric acid 30% used for analysis of the metal
traces were purchased from Scharlab SL. The standard solution
of Cu was obtained from Perkin Elmer. Commercially available
copper(II) chloride dihydrate was dehydrated upon heating in an
oven (150 ꢀC, 45 min) prior to use for the preparation of the
CuNPs. Column chromatography was performed with Merck
silica gel 60 (0.040–0.063 mm, 240–400 mesh) and hexane/EtOAc
as the eluent. The reactions were monitored by thin-layer
chromatography on silica gel plates (60F-254) visualized under
UV light and/or using FeCl3 in water for staining. Nuclear
magnetic resonance (NMR) spectra were recorded on a Bruker
ARX-300 spectrometer using CDCl3 or CD3OD as solvents. Nitric
acid 69% and metal traces and chlorhydric acid 30% used for
analysis of the metal traces by ICP-MS were purchased from
Scharlab SL. The standard solution of Cu was obtained from
Perkin Elmer.
For CuNPs/TiO2 characterization, TEM and STEM images,
together with EDX and EELS spectra, were obtained with an FEI
Tecnai G2 F20 instrument coupled to an EDAX detector and
a Quantum SE 963 Gatan Imaging Filter (GIF). The samples
were prepared by casting a drop of the corresponding sample
dispersion on a holey carbon copper grid, and then by evapo-
rating off the solvent at room temperature. The copper content
in the supported catalyst was determined by using an ICP-MS
NexION 300X instrument from Perkin Elmer. Before its use,
all glass material was washed with HNO3 40% for 72 h and
Preparation of Michael adducts 1
For the preparation of 1a–d, 2 mmol of the corresponding
dithiol was dissolved in 3 mL of CH2Cl2 in a Schlenk ask under
nitrogen. For more polar dithiols, 3 mL of a 1 : 2 mixture
MeOH : CH2Cl2 was used. To this solution, 460 mL of triuoro-
acetic acid (TFA, 2 mmol) was added with stirring. In a separate
ask, a solution of 468 mg of NaIO4 (2.2 mmol) in 80 mL of H2O
was prepared and cooled in an ice bath. Next, 220 mg of pyro-
catechol (2 mmol) dissolved in 1 mL of Et2O was added to the
aqueous solution and le stirring vigorously for 15 min. The
orange-reddish o-benzoquinone was extracted with 4 ꢃ 15 mL
of CH2Cl2, and the organic phase was dried over anhydrous
Na2SO4, ltered and immediately added to the dithiol solution.
The reaction mixture was stirred in the dark at room tempera-
ture under nitrogen for 6 h. Aer this, the solvent and the TFA
were evaporated under reduced pressure and the crude was
puried by ash column chromatography (hexane–EtOAc) to
give the corresponding Michael adducts. Compounds 1a–d were
characterized by comparison of their physical and spectroscopic
data with those described in the literature (see ESI S3†).26
Preparation of the alkynes
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 ꢂ78 ꢀ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
1
in 3 mL of concentrated ultrapure HNO3/HCl (1 : 1) in a Mile- compound 2a as white needles. H 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
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and le under nitrogen and at room temperature for 1 day. The
solution was extracted with diethyl ether (5 ꢃ 5 mL). The ether
extracts were combined and washed successively with 5 mL of
cold water, 5 mL of saturated sodium bicarbonate solution and
5 mL of cold water and then dried over anhydrous calcium
chloride. A further purication was not necessary, yielding
625 mg (88%) of compound 2f as a colourless oil. 1H NMR (300
MHz, CDCl3) d: 3.78 (s, 6H). 13C NMR (75 MHz, CDCl3) d: 151.9
(C), 74.3 (C), 53.2 (CH3).
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The Michael adduct 1 (0.4 mmol) and alkyne 2 (0.4 mmol) were
added to a reaction tube containing CuNPs/TiO2 (120 mg,
30.2 mol% Cu) in 1,2-DCE (4 mL) under air. The reaction
mixture was warmed to 80 ꢀC and monitored by TLC until total
conversion of the starting material. The catalyst was removed by
ltration and washing with hexane–AcOEt. Finally, the ltrate
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sulde, 3. Full data for all the compounds are provided below
(see ESI S3†).
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Authors' contributions
FN carried out the funding acquisition, conceptualization,
investigation, methodology and writing. JMA participated in the
conceptualization, investigation, methodology and writing. DZ
participated in the methodology. DRM participated in the
investigation. GR carried out the funding acquisition, investi-
gation and writing. All authors read and approved the nal
manuscript.
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Conflicts of interest
There are no conicts to declare.
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Acknowledgements
This work was supported by the ANPCyT (Project PICT 2016-
0385), SGCyT-UNS (Project PGI 24/Q106) and CONICET (Project
PIP 11220130100498CO). We thank Belen Ballesteros and
´
`
Marcos Rosado from Electron Microscopy Unit of Institut Catala
`
de Nanociencia i Nanotecnologia (ICN2) in Barcelona, Spain;
˜
and Maria Julia Yanez from Electron Microscopy Unit in Centro
´
´
´
Cientıco Tecnologico – CONICET, Bahıa Blanca, Argentina for
´
their measurements and assistance. We thank Miguel Angel
´
Moreno-Villaecija for carrying out the ICP/MS analysis.
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2082 | RSC Adv., 2021, 11, 2074–2082
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