Immobilized gold nanoparticles prepared from gold(III)-containing ionic liquids on silica: Application to the sustainable synthesis of propargylamines

Article abstract of DOI:10.3390/molecules23112975

A cycloaurated phosphinothioic amide gold(III) complex was supported on amorphous silica with the aid of an imidazolium ionic liquid (IL) physisorbed in the SiO₂ pores (SiO₂-IL) and covalently bonded to the SiO₂ (SiO₂@IL). Gold(0) nanoparticles (AuNPs) were formed in situ and subsequently immobilized on the SiO₂-IL/SiO₂@IL phase. The resulting catalytic systems Au-SiO₂-IL and Au-SiO₂@IL promoted the solvent-free A³ coupling reaction of alkynes, aldehydes, and amines in high yields under solvent-free conditions with very low catalyst loading and without the use of additives. The Au-SiO₂@IL catalyst showed good recyclability and could be reused at least five times with yields of propargylamines of ≥80%. This synthetic method provides a green and low cost way to effectively prepare propargylamines. Additionally, ³¹P high resolution magic angle spinning (HRMAS) NMR spectroscopy is introduced as a simple technique to establish the Au loading of the catalyst.

Full text of DOI:10.3390/molecules23112975

molecules
Article
Immobilized Gold Nanoparticles Prepared from
Gold(III)-Containing Ionic Liquids on Silica:
Application to the Sustainable Synthesis
of Propargylamines
Raquel Soengas * , Yolanda Navarro, María José Iglesias and Fernando López-Ortiz *
Área de Química Orgánica, Research Centre CIAIMBITAL, Universidad de Almería, Carretera de Sacramento
s/n, 04120 Almería, Spain; yng453@ual.es (Y.N.); mjigle@ual.es (M.J.I.)
*
Correspondence: rsoengas@ual.es (R.S.); flortiz@ual.es (F.L.-O.); Tel.: +34-950-015-478 (F.L.O.)
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Received: 16 October 2018; Accepted: 13 November 2018; Published: 14 November 2018
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: A cycloaurated phosphinothioic amide gold(III) complex was supported on amorphous
silica with the aid of an imidazolium ionic liquid (IL) physisorbed in the SiO pores (SiO –IL)
2
2
and covalently bonded to the SiO (SiO @IL). Gold(0) nanoparticles (AuNPs) were formed in situ
2
2
and subsequently immobilized on the SiO –IL/SiO @IL phase. The resulting catalytic systems
2
2
3
Au–SiO –IL and Au–SiO @IL promoted the solvent-free A coupling reaction of alkynes, aldehydes,
2
2
and amines in high yields under solvent-free conditions with very low catalyst loading and without
the use of additives. The Au–SiO @IL catalyst showed good recyclability and could be reused at
2
least five times with yields of propargylamines of
≥
80%. This synthetic method provides a green
31
and low cost way to effectively prepare propargylamines. Additionally, P high resolution magic
angle spinning (HRMAS) NMR spectroscopy is introduced as a simple technique to establish the Au
loading of the catalyst.
Keywords: gold; nanoparticles; multicomponent reaction; supported catalyst; propargylamine; HRMAS
1
. Introduction
Propargylamines are versatile synthetic intermediates and important structural elements of
numerous natural and synthetic products that show a wide range of biological activities [1–5].
Traditionally, these compounds have been synthesized by the nucleophilic attack of metal acetylides on
imines or their derivatives, but these reagents are used in stoichiometric amounts, are highly moisture
sensitive, and require strictly controlled reaction conditions [6]. An alternative atom-economical
procedure for the synthesis of propargylamines is the one-pot, three-component, metal-catalyzed
3
reaction of an alkyne, an aldehyde, and an amine, the so-called A coupling [
7
]. Homogeneous
3
catalysts based on a large number of transition metal ions have been used for the A coupling reaction,
including Cu [8–12], Ag [13–16], Cu/Ru bimetallic systems [17,18], Zn [19–21], Fe [22,23], In [24,25],
Ir [26
,
27], Hg [28], Ni [29], Rh [30], Mn [31], Co [32], Bi [33], and Cd [34]. Over the past few years,
3
increasing attention has been paid to the catalytic performance of Au in promoting the A coupling
reaction, including Au(I) and Au(III) salts and organic Au complexes [35
species showing very high catalytic activity, their rapid reduction under alkyne activation conditions
is an important drawback [39 41]. It should also be noted that homogeneous catalysts suffer from the
–38]. Despite cationic Au
–
difficulty of catalyst separation and reuse as well as the problem of product contamination with the
metal. The contamination of products with metals is a major problem in pharmaceutical development,
since trace amounts of metal contamination could have unwanted effects on biological systems.
In order to overcome these limitations, the use of heterogenizing homogeneous Au catalysts in organic
Molecules 2018, 23, 2975; doi:10.3390/molecules23112975
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Molecules 2018, 23, 2975
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synthesis has attracted a large amount of attention because the advantages of both homogeneous and
heterogeneous catalysis can be gathered in the system [42
and recyclable gold catalysts have been reported for A coupling reactions [45
–
44]. In this regard, a few heterogeneous
46]. During the last
3
,
decade, supported gold(0) nanoparticles (AuNPs) have been explored as sustainable and competitive
3
alternatives to gold complexes for A coupling reactions [47
–
49]. Despite AuNPs promoting the
3
A coupling in their pure form, they tend to agglomerate, which limits their efficiency in catalytic
processes [48]. On the contrary, supported AuNPs enhance the activity and selectivity of reactions and
could be easily heterogenized [48
have successfully been employed in A coupling reactions. Thus, clays [50
,
49]. Several nanocatalysts based on AuNPs and different supports
3
–
52], nanocomposites [53
59], resins [60], polymeric materials [61], magnetic
66] have been used in this reaction. However, there is still much
,54],
graphenes [55], metal-organic frameworks [56
supports [62 64], and biomaterials [65
–
–
,
room for improvement, as some of the reported procedures require the use of harmful organic solvents,
long reaction times, or a laborious and time-consuming support preparation process.
In recent years, ionic liquids [67,68] have attracted much recent interest in transition metal
catalysis, since they can act as co-catalysts and enhance the activity of metallic species present in
catalytic systems [69]. As a consequence of their pre-organized structure with hydrogen bonds
connecting cations and anions, the enhanced catalytic activity and stability of metal complexes and
nanoparticles in ionic liquids (ILs) is related to the surface electronic stabilization of imidazolium
aggregates forming protective layers. In recent years, the concept of supported ionic liquid phase
catalysis (SILPC) has gained much attention. In this regard, it has been proven that a thin film
of the ionic liquid supported on a porous material is suitable for the stabilization of catalytically
active complex or metal nanoparticles [70
only reduces the use of the relatively expensive ILs, but also immobilizes the metal complexes or
nanoparticles, facilitating their recovery and recycling [72 74]. SILP catalysts have been widely
,71]. Grafting ILs onto the surfaces of solid materials not
–
applied in palladium-catalyzed cross-coupling reactions, but only very limited study has been done
on SILP gold catalysis. A recent report described the immobilization of gold(III) on poly(ionic liquid)
coated on magnetic nanoparticles to produce a highly active, stable, and recoverable catalyst for
3
the synthesis of propargylamines via A coupling reactions carried out with water as a solvent [75].
Gold(III) nanoparticles supported on periodic mesoporous silica containing ionic liquid proved to be
3
an efficient catalyst for the A synthesis of propargylamines with chloroform as a solvent at a loading
of 0.2 mol% of gold [76]. Interestingly, under solvent free conditions, the reaction yield decreased to
50%. Furthermore, the performance of the analogous reaction using gold(0)-supported nanoparticles
showed a conversion of less than 15%. Despite the evident interest in performing the reaction under
solvent-free conditions from a sustainability point of view, there are very limited examples in the
−
literature [77
–
79]. AuCl4 dispersed over ionic liquids grafted on MCM-41 catalyst was used as a
3
catalyst to promote the solvent-less A coupling reaction [80]. However, the procedure suffered from a
significant decrease in the catalytic activity in successive reaction cycles. This result can be explained
on the basis of gold leaching. To sum up, the synthesis of propargylamines using eco-friendly and
reusable catalysts under solvent-free conditions is still a thrust area in the chemical field.
3
We have previously reported the solvent-less synthesis of propargylamines via A coupling
using a gold(III) cycloaurated phosphinothioic complex as the pre-catalyst [81]. The real catalysts
were identified as Au(I) nanoparticles. Attempts to isolate the Au(I)NPs produced their reduction to
Au(0)NPs and deactivation. We reason that the immobilization of gold nanoparticles in supported
3
ionic liquids would offer unique possibilities for the Au-catalyzed A coupling reaction. In the
work herein presented, we describe the stabilization of Au(0)NPs generated from a cycloaurated
phosphinothioic complex on an imidazolium ionic liquid supported on amorphous silica. The in situ
formed Au–SiO @IL maintains their catalytic activity in the solvent-free three-components synthesis of
2
propargylamines. Moreover, the AuNPs can be easily recovered from the catalytic mixture and reused
with almost unchanged activity for five cycles. In addition, the use of 31P HRMAS NMR spectroscopy
to study the pre-catalytic system is introduced for the first time.

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2
. Results and Discussion
Previous results from our group showed that the ortho-substituted phosphinothioic amide (dppta)
3
gold(III) complex 1 acts as a pre-catalyst in the highly efficient synthesis of propargylamine 5 via A
coupling reactions under very mild, solvent-free conditions [81]. During the course of the reaction,
the Au(III)-complex was transformed into the Sonogashira-type o-alkynylphosphinothioic amide
6
with generation of Au(I) nanoparticles, which are the real catalysts (Scheme 1). In order to reuse the
catalysts, the NPs were isolated through solvent washing in the air and centrifugation. This procedure
3
led to Au(0)NPs showing a large decrease in activity in the A coupling synthesis of
5
(yield < 20%).
To overcome this limitation, we proposed that the SILPC methodology could be applied to prepare
highly-active AuNPs stabilized by the immobilized ionic liquid. The resulting heterogeneous catalysts
would facilitate the recyclability. Immobilization of the ionic liquid was studied using two different
approaches: (i) physical adsorption of ionic liquids and (ii) covalent bonding via the attachment of
ionic liquid fragments to the support.
3
Scheme 1. A coupling reaction catalyzed by Au(III) complex 1.
2
.1. Physical Confinement of the Ionic Liquid and Complex 1 on the Silica Surface
We started our study by investigating a facile physical immobilization of the Au catalyst in an ionic
3
liquid in silica pores for use in sustainable A coupling reactions. The procedure of immobilization was
quite simple [82]; a suspension of spherical amorphous silica in a solution of (dppta)AuCl complex
2
1
in [bmim]PF and CH CN was evaporated to dryness and washed with diethyl ether to afford a
6 3
powdery and free-flowing immobilized catalyst. The system formed by pre-catalyst
1 and the SiO –IL
2
support [(dppta)AuCl –SILP] was characterized by IR spectroscopy and HRMAS NMR.
2
−
1
Infrared analysis (IR) showed the characteristic bands of the silica support at 3459 cm and
−
1
094 cm 1, belonging to the Si
−
OH stretch and the Si
−
O
−
Si stretch, respectively. In addition,
−
1
−1
−
the bands at 835 cm and 1642 cm , assigned to the stretching vibrations of PF and C=N
6
respectively, clearly indicated the presence of the ionic liquid [bmim]PF within the silica support
6
(
Figure S1). Blümel and co-workers demonstrated that HRMAS methods can be applied to the
1
13
14
acquisition of H, C, and N NMR spectra of ionic liquids immobilized on silica, including
two-dimensional H, H COSY and H, C HMQC correlations [83]. The H HRMAS NMR spectrum
1
1
1
13
1
of a DMSO-d suspension of the supported Au(III) complex (1% wt) showed reasonably well-resolved
6
signals for the IL protons and the isopropyl groups of complex
of silica (1 g) compared with the IL (100 mg) and complex (11 mg) used (Figure S2). Interestingly,
the presence of
could be also detected in the 13C HRMAS NMR spectrum despite the small amount
present (Figure S3). The analysis of these spectra in combination with the H, H COSY (Figure S4)
1 if one considers the large amount
1
1
1
1
1
13
1
13
and H, C HSQC-edited (Figure S5) correlations provided the assignment of the H and C signals
of IL and (see experimental). The phosphorus-containing complex and ionic liquid [bmim]PF6
allowed the use of P-NMR spectroscopy as a simple tool to determine the loading of gold into the
1
1
31

Molecules 2018, 23, 2975
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solid support. Figure 1a shows the 31P HRMAS NMR spectrum of (dppta)AuCl –SiO –[bmim]PF
6
2
2
measured in DMSO-d . The integrals of the singlet arising from
1 and the septuplet originated by the
6
PF6- moiety ( J = 706.2 Hz) provided a
1
1
:IL ratio of 1:19, which was in excellent agreement with the
PF
1
experimental mass balance used. Interestingly, and in sharp contrast to the H HRMAS NMR signals
(
Figure S2), relatively narrow signals were obtained for both pre-catalyst 1 and the counteranion of the
IL. These features can be attributed to differences in mobility between species. Broad signals in the
1
H HRMAS NMR spectrum arose from restricted mobility due to the grafting of the IL to the silica
−
(
short transverse relaxation times, T ), whereas the higher mobility of
1
and PF6 made it feasible to
2
31
1
obtain high resolution P HRMAS NMR signals [84]. Furthermore, it was possible to measure a H,
3
1
P HRMAS HMQC spectrum optimized for the detection of long-range scalar couplings. The expected
correlations of the 31P signal of
with aromatic protons and the methine protons of the isopropyl
groups were easily detected (Figure 1b). To the best of our knowledge, these are the first examples of
1
31
the application of P HRMAS NMR techniques to characterize dispersed substrates in ILs. Solid-state
3
1
P MAS NMR studies of a number of SILP catalysts have been reported [85,86].
(
a)
(b)
Figure 1.
(a
) 31P HRMAS NMR (202.46 MHz) and ( ) 1H, 31P HRMAS HMQC (500.13 MHz) spectra of
b
(
dppta)AuCl –SiO –[bmim]PF .
2 2 6
First, the synthesis of propargylamines under the supported catalyst was assessed in various
conditions, and the results are compiled in Table 1. Thus, 1 equiv of benzaldehyde 2a was allowed
to react with 1 equiv of piperidine 4a and 1.5 equiv of trimethylsilylacetylene 3a in the presence of
◦
variable amounts of the supported catalyst under solvent-free conditions at 60 C for 6 h under a
nitrogen atmosphere to afford propargylamine 5a. The reactions proceeded with excellent conversions
(Table 1, entries 1–2), similar to those reported for the unsupported phosphinothioic amide gold(III)
complex; these are included in Table 1 for comparison (entries 4 and 5). Using 1 mol% of supported
catalyst afforded a quantitative yield of 5a (Table 1, entry 1). Decreasing the catalyst loading to 0.5 mol%
gave an excellent yield of 98% of 5a (Table 1, entry 2). The catalyst loading could be further decreased
to 0.1 mol% as long as the reaction time was increased to 8 h. Under such conditions, propargylamine
5
a was formed with a 97% yield (Table 1, entry 3).
The work-up procedure was very simple: the supernatant liquid was separated and the remaining
solid was thoroughly washed with n-pentane. As expected, the 31P-NMR spectra of the crude
reaction mixtures showed only one signal at
δ
62.8 ppm, corresponding to the Sonogashira product 6a
was fully transformed in situ to
2
(
R = tetramethylsilane (TMS) in Scheme 1), indicating that complex
1
the catalytically active Au nanoparticles, which were efficiently immobilized by the supported ionic
liquid phase.

Molecules 2018, 23, 2975
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Table 1. Optimization of the A3 coupling reaction of benzaldehyde, trimethylsilylacetylene,
and piperidine.
Entry
Catalyst
(dppta)AuCl –SILP
n (mol%)
Time (h)
Conv. (%) a
1
2
3
4
5
1
6
6
8
6
8
99
98
97
97
99
2
(dppta)AuCl –SILP
0.5
0.1
1
2
(dppta)AuCl –SILP
2
(dppta)AuCl2
(dppta)AuCl2
0.1
a
1
Determined by H-NMR analysis of the reaction crude.
In order to prove this hypothesis, we achieved the characterization of the solid using the
scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray photoelectron
spectroscopy (XPS) methods.
Adsorption of the IL (bright spots) on the pores of the silica was readily observed in the SEM
images of Au–SiO –IL system (Figure 2a,b). The TEM image showed the AuNPs immobilized on
2
an amorphous matrix with a narrow size distribution with a diameter of about 7.6 nm (Figure 2c,d).
A similar pattern was observed in the Au(I)NPs formed in the absence of the SiO –IL support [81].
2
Figure 2. Scanning electron microscopy (SEM) (
a
,
b
) and transmission electron microscopy
3
(
(
TEM) (
c
,
d
) images of AuNPs formed in the A synthesis of 5a in the presence of 0.1 mol% of
dppta)AuCl –SiO –[bmim]PF under solvent-free conditions.
2
2
6
In the full XPS spectrum of AuNPs generated in the synthesis of 5a after one catalytic run,
the peaks corresponding to Au 4f, C 1s, Cl 2s, N 1s, O 1s, and Si 2p and 2s were clearly observed
(
Figure S6). The XPS spectrum of the N 1s core level region for the supported AuNPs showed a peak
at 401.9 eV, which corresponds to the bonding energy of the quaternary nitrogen of the ionic liquid
Figure 3a and Figure S7) [87]. In addition, the high-resolution Si 2p XPS spectrum displayed a peak
at 102.2 eV that was attributed to the Si–O–C bonds (Figure 3b and Figure S8) [88]. Finally, the XPS
(
spectrum in the Au 4f region showed two intense doublets at 82.7 and 86.4 eV for Au 4f7/2 and Au 4f5/2
,
respectively (Figure 3c and Figure S9), comprising the only Au species in the material and confirming

Molecules 2018, 23, 2975
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that, during the catalysis, the Au(III) complex was fully reduced, leading to the real catalysts, i.e.,
the Au(0)NPs, being dispersed on the supported ionic liquid phase of [bmim]PF encapsulated in
6
silica (Au–SILP). As mentioned previously, Au(I)NPs were identified as the active catalysts in the
3
unsupported A synthesis of 5a
[
81] (see Scheme 1), and the manipulation of the NPs in the air led
to deactivated Au(0)NPs. The results above indicate that the deactivation most probably arose from
agglomeration [48], a process inhibited when the Au(0)NPs were generated in the supported IL.
Figure 3. Core level regions X-ray photoelectron spectroscopy (XPS) spectra of the supported AuNPs
for (a) N 1s, (b) Si 2p, and (c) Au 4f.
With the optimized reaction conditions in hand, we extended our studies to different combinations
of aldehydes, amines, and alkynes (Table 2). The electron-withdrawing nature of the chlorine of
p-chlorobenzaldehyde did not have any effect on the reaction rate, so 94% conversion to 5b was
achieved in 8 h (entry 2). However, the electron-donating group of p-methoxybenzaldehyde slowed
the reaction significantly, as evidenced by the formation of 5c with 83% conversion in 14 h (entry
3). Phenylacetylene reacted slightly more slowly to give 5d with 94% conversion in 8 h (entry 4).
Electron-withdrawing groups in the alkyne also produced a decrease in the reaction rate. The use of
4
2
-fluorophenylacetylene as the alkyne provided 5e with a conversion of 86% in 14 h (entry 5), while
-methoxyphenylacetylene afforded 5f with a conversion of 90% in 14 h (entry 6). On the other hand,
the use of 3-methylphenylacetylene as the alkyne gave propargylamine 5g with a conversion of 93% in
8
h (entry 7). In the reaction of benzaldehyde, 1,3-diethynylbenzene, and piperidine in the presence
◦
of Au–SILP (0.1 mol% Au) at 60 C over 8 h, only the monopropargylamine 5h was formed (83%
conversion, entry 8). Morpholine proved to be as reactive as piperidine. The coupling of this amine
with benzaldehyde and trimethylsilylacetylene over 8 h furnished 5i with 97% conversion (entry 9),
whereas the analogous reaction using phenylacetylene as the alkyne formed propargylamine 5j with
a conversion of 98% (entry 10). Chiral propargylic amines 5k,l were synthesized with high levels
of conversion and excellent diastereoselectivity using (S)-2-(methoxymethyl)pyrrolidine as a chiral
reagent. Thus, 5k and 5l were obtained with conversions of 99% (de 97%, entry 11) and 87% (de 98%,
entry 12), respectively.
The catalyst was easily reused up to five times without taking any precautions after taking up the
supernatant layer and washing with n-pentane. As shown in Table 3, a steady decrease in catalytic
activity was observed after every cycle. This result might have arisen from the partial removal of the
gold-containing IL layer from the silica surface or the Au(0)NPs from the SiO –IL support.
2

Molecules 2018, 23, 2975
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3
Table 2. A coupling reaction catalyzed by Au–SILP.
Entry
R1
R2
R3
X
m
Time (h)
5
Conv. (%) a
1
2
3
4
5
6
7
8
9
Ph
TMS
TMS
H
H
H
H
H
H
H
H
H
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
1
1
1
1
1
1
1
1
1
1
0
0
8
8
14
8
14
14
8
8
8
8
8
a
b
c
d
e
f
g
h
i
97
94
83
94
86
90
93
83
97
4-ClC H4
6
4-OMeC H4 TMS
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-FC H4
6
2-OMeC H
6
4
3-MeC H
6
4
3(C
TMS
Ph
≡
C)C H
6
4
10
11
12
H
CH3
CH3
O
CH2
CH2
j
k
l
98
98(97) b
87(98) b
TMS
Ph
8
a
Conversion (conv.) determined by H-NMR analysis of the crude reaction. b Values in parentheses indicate
1
diastereomeric excesses, de. SILP: supported ionic liquid phase catalysis.
To check this hypothesis, the supernatant layer was filtered through a membrane filter (pore
diameter of 7 µm) after the reaction had been completed, and the mixture was analyzed with ICP-MS.
The analysis showed that a very small amount of Au (3.14 ppb) was released in the reaction medium.
This result is not consistent with the loss of activity of the catalyst due to gold leaching, but instead
supports the partial elimination of the IL from the solid support as being the major responsible of the
conversion decrease after every reaction cycle [82].
Table 3. Reusability of the Au–SILP catalyst.
Entry
Cycle
Conv. (%) a
1
2
3
4
5
1
2
3
4
5
97
90
81
75
62
a
1
Determined by H-NMR analysis of the reaction crude.
A tentative reaction mechanism for the synthesis of propargylamine
5 through the condensation
of an aldehyde, an acetylene, and an amine involving the immobilized AuNPs is shown in Scheme 2.
The nanoparticles may activate the alkyne to generate the corresponding supported alkynyl–gold
complex, which, upon addition to the iminium ion proceeding from the in situ reaction between the
aldehyde and the secondary amine, would provide propargylamine
new cycle.
5 and regenerate the catalyst for a

Molecules 2018, 23, 2975
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3
Scheme 2. Suggested mechanism for the A coupling synthesis of propargylamine
5 catalyzed
by Au–SILP.
2
.2. Covalent Bonding Via Ionic Liquid Fragments Attached to the Support
In order to avoid the detachment of the ionic liquid layer from the silica surface in the subsequent
reaction cycles, we next investigated the provision of strong attachment of the ionic liquid to the silica
surface via covalent bonds. According to the procedure described in the literature [89], the (EtO) Si
3
modified IL, either with chloride or with hexafluorophosphate anions, was immobilized on the silica
by the reaction of an alkoxy group bonded to the Si atom of the IL with an Si–OH group of the silica
material, forming covalent –Si–O–Si– bonding (Scheme 3). Then, a suspension of the silica with the
covalently attached IL (SiO @IL) in a solution of (dppta)AuCl complex
1 in CH CN was evaporated
3
2
2
to dryness and washed with diethyl ether to give a powdery immobilized catalyst. The supported
Au(III) complex on SiO @IL(PF ) [(dppta)AuCl -SiO @IL(PF )] was characterized by IR and HRMAS
2
6
2
2
6
NMR spectroscopy.
Scheme 3. Grafting of the ionic liquid (IL) onto the silica surface and preparation of the
immobilized catalyst.
The IR spectrum revealed the presence of bands at wavelengths of 3442 cm 1 and 1132 cm
assigned to the Si OH stretch and the Si Si stretch, respectively. The presence of the ionic liquid
is clearly indicated by the bands at 3117 cm and 3165 cm , attributed to the C
−
−1
−
− −
O
−
1
−1
−
H ring stretching

Molecules 2018, 23, 2975
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−
1
−1
vibration of the imidazolium, and also by the bands at 1632 cm and 846 cm , assigned to the C=N
−
1
stretching vibration and to the stretching vibration of PF6 , respectively (Figure S10). The H and
C HRMAS NMR spectra of (dppta)AuCl -SiO @IL(PF ) measured with DMSO-d as the solvent
showed the same features as the Au physisorbed catalyst (Figures S11 and S12). The H- and C-NMR
spectra could be assigned without difficulty (see experimental section). The very broad H and
13
2
2
6
6
1
13
1
13
C
signals observed for the CH SiO moiety reflect a decrease in mobility, which support the formation
2
of an Si–O bond with the solid support. More importantly, although the IL:
1 ratio (moles) of 85:1 in
31
(
dppta)AuCl –SiO @IL(PF ) was much bigger than that in the SILP system, the P HRMAS NMR
2
2
6
spectrum could be used to establish the loading of
dppta)AuCl indicated that complex was quantitatively dispersed into the IL (Figure S15). Due to
into the IL, 8192 scans were accumulated over a period of 5 h to achieve
1
into the IL. The integrals of the signals of PF - and
6
(
1
2
the high dilution of complex
1
an acceptable signal-to-noise ratio.
In order to compare the performance of the Au catalyst immobilized on the ionic liquid and
covalently grafted to the silica surface (Au–SiO @IL) vs. the physically adsorbed analogue (Au-SILP),
2
3
◦
we carried out the A coupling reaction of benzaldehyde, piperidine, and phenylacetylene at 60 C for
h with a catalyst loading of 0.1%. Under these conditions, the corresponding propargylamine was
8
obtained with 98% conversion, which is comparable to the results with the confined catalyst. In order
to check the reusability, the catalyst was repeatedly filtered out and subjected to a new reaction batch
without any further treatment. The recyclability of a catalyst is highly dependent on the counter
anion of the IL. Thus, for the chloride IL, a sharp decrease in catalytic activity was observed in the
second reaction cycle. In the third cycle, the chloride catalyst hardly showed any activity, whereas the
hexafluorophosphate catalysts showed only a very small decrease in the benzaldehyde conversion
(Table 4). The dependence of the physicochemical properties and activity of the imidazolium ILs on
the anion is not surprising and has been widely reported in the literature [90,91].
3
Table 4. A coupling reaction catalyzed by Au–SiO @IL and the recycling of the catalyst.
2
Conversion (%) a
Entry
Catalyst
Au–SiO @IL(Cl)
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
1
2
97
98
32
96
0
91
-
-
2
Au–SiO @IL(PF )
86
85
2
6
a
1
Determined through H-NMR analysis of the reaction crude.
The catalytic activity of the hexafluorophosphate catalyst was high over five reaction cycles, so the
recyclability of the covalently grafted supported phase catalyst was clearly superior to the physically
adsorbed support (Figure 4).
The Au–SiO @IL(PF ) catalyst was characterized using transmission electron microscopy and
2
6
X-ray photoelectron spectroscopy methods. The TEM image showed the AuNPs immobilized on the
IL-coated silica (Figure 5) with a narrow size distribution with a diameter of about 7.8 nm, comparable
to the physically adsorbed supported system (Figure 2).

Molecules 2018, 23, 2975
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Figure 4. Recyclability as a function of the catalyst. Blue: Au–SILP; green: Au–SiO @IL(Cl); yellow:
2
Au–SiO @IL(PF ).
2
6
Figure 5. Transmission electron microscopy (TEM) (
formed during the A synthesis of 5a in the presence of 0.1 mol% of (dppta)AuCl –SiO @IL(PF ) under
a
) and (
b
) (larger surface area) images of AuNPs
3
2
2
6
solvent-free conditions.
In the full XPS spectrum of the Au–SiO @IL(PF ) catalyst, the expected peaks corresponding to
2
6
Au 4f, C 1s, Cl 2s, N 1s, O 1s, and Si 2p and 2s were observed (Figure S16). The XPS spectrum of the N
s core level region for Au–SiO @IL(PF ) showed a peak at 400.0 eV, corresponding to the bonding
1
2
6
energy of the quaternary nitrogen of IL that was clearly observed (Figure 6a and Figure S17). The high
resolution Si 2p XPS spectrum of the Au–SiO @IL(PF ) could be split into two sublevels. The first one
2
6
at 101.6 eV was assigned to the Si–O–C bonds, while the other one at 102.9 eV corresponded to the
silicon participant from the siloxane network (Si–O–Si) (Figure 6b and Figure S18). Finally, the XPS
spectrum in the Au 4f region showed two intense doublets at 83.6 and 87.3 eV, comprising the only Au
species in the material and confirming that, during the catalysis, the ionic Au(III) species were reduced
(Figure 6c and Figure S19).
Figure 6. XPS spectra of the core level regions of Au–SiO @IL(PF ) for (a) N 1s, (b) Si 2p, and (c) Au 4f.
2
6

Molecules 2018, 23, 2975
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3
. Conclusions
In summary, we developed an environmentally benign, economically friendly, and sustainable A3
coupling reaction of alkynes, aldehydes, and amines by employing a cycloaurated phosphinothioic
amide gold(III) complex immobilized in a silica-supported ionic liquid. During the course of the
reaction, gold(0) nanoparticles were formed in situ and were subsequently confined to the SiO –IL
2
phase. The AuNPs immobilized in this way maintained good catalytic activity for 3–4 cycles, but
then a decrease in conversion was observed. This loss of activity can be attributed to the progressive
detachment of the ionic liquid from the silica surface. In order to overcome this limitation, the ILs
were grafted onto the silica surface by means of covalent bonds. Due to the more robust anchors that
prevented Au–IL leaching from the silica support, the reusability of the resulting Au–SiO @IL catalyst
2
3
1
was clearly enhanced, maintaining high activity for up to five reaction cycles. In addition, P HRMAS
NMR spectroscopy was used for the first time to establish the loading of Au into the ionic liquid phase.
4
. Materials and Methods
Benzaldehyde, piperidine, morpholine, phenylacetylene, and trimethylsilylacetylene were
obtained through commercial suppliers and purified by distillation before use. The rest of the reagents
were commercially purchased and used without further purification. Amorphous silica from Merck
was used as solid support (spherical for flash column chromatography; 40~50 mm diameter; 5~7 nm
2
pore size; 0.80~1.00 mL/g pore volume; 600~700 m /g surface area). Compounds 5a, [92
]
5b
[81],
5
c
[
81], 5d
[
93], 5e
[
94], 5f
[
95], 5
g
[
95], 5h
[
81], 5
i
[
9
], 5j
[
94], 5k
[
81], and 5l
[
81] have been described
1
13
previously. NMR spectra were obtained on a Bruker Avance III HD 300 ( H, 300.13 MHz; C,
5.47 MHz; 31P, 121.49 MHz) and Bruker Avance III HD 500 ( H, 500.13 MHz; C, 125.76 MHz; 31P,
1
13
7
2
8
02.46 MHz). Chemical shifts are given in ppm using tetramethylsilane (TMS) for H and 13C and
1
5% H PO for P as internal standards. Unless otherwise stated, H- and 31P-NMR spectra were
31
1
3
4
acquired from all crude reaction mixtures, in CDCl as solvent. Diastereoselectivities were determined
3
1
by integration of the H-NMR spectra of the crude reaction mixtures. The following abbreviations
are used to indicate the multiplicity of signals: bs, broad signal; h, heptuplet. Regarding HRMAS
1
13
31
NMR spectroscopy, the spectra were acquired using a 4 mm H/ C/ P HRMAS probehead on a
1
Bruker Avance III HD 500. The MAS rate used was 4600 Hz. A typical H HRMAS NMR spectrum
consisted of 32 transients using 52 K data points over a 11,000 Hz spectral width. For 13C HRMAS
NMR spectra, 16,000 transients were acquired using 64 K data points over 25,252 Hz spectral widths.
P HRMAS NMR spectra were acquired using 64 K data points over 59,524 Hz spectral widths
and an accumulation of 2–8 K. The H, P HMQC spectrum was acquired using the “hmqcgpqf”
pulse program. Selected spectral parameters were as follows: spectral width, 8711 Hz for H and
0,748 Hz for 31P; 128 increments recorded; cnst2 J = 8.3 Hz; and 1024 scans per increment in F1.
Two-dimensional double quantum-filtered H, H COSY45 spectra were recorded using the pulse
31
1
31
1
n
3
PH
1
1
◦
1
13
program “cosy45gpqf” with 128 increments and 64 scans. An edited two-dimensional H, C HSQC
spectrum was acquired using the “hsqcedetgpsp.3” pulse program including adiabatic pulses for
selection with 160 increments and 128 scans.
4
.1. TEM and XPS Measurements
The size and distribution of AuNPs formed in the reaction were studied by transmission electron
microscopy (TEM) using a JEOL-2100 TEM (Peabody, MA, USA) instrument operating at 200 kV fitted
with an Orius SC 200 Model 830 (Gatan Inc., Pleasanton, CA, USA) camera. Samples were prepared
by placing ca. 15
were allowed to dry and introduced in the instrument. For the statistical particle size analysis,
24 nanoparticles were analyzed using the measurement tools of the Digital Micrograph v2.31.734.0
Gatan Microscopy Suite, Gatan Inc., Pleasaton, CA, USA) software package. Data processing
and statistical studies were performed with Excel Office 2010 (Microsoft Corporation., Redmond,
µL of the solution onto a Formvar- and carbon-coated copper grid. The samples
5
(

Molecules 2018, 23, 2975
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WA, USA). X-ray photoelectron spectroscopy (XPS) was carried out on an ESCAPlus Omicron
spectrometer (Omicron Nanotechnology, Taunusstein, Germany) using a monochromated Mg X-ray
source (1253.6 eV). The binding energy scale was calibrated by setting the C 1s transition to 284.7 eV.
Data were analyzed using the Multipak XPS software package (Physical Electronics Inc., Chanhassen,
MN, USA).
4
.2. Scanning Electron Microscopy
Scanning electron microscopy (SEM) was done on a Hitachi S-3500N (Hitachi Ltd., Tokyo, Japan)
operated at 15 kV with a tungsten filament. Powder from each sample was placed on a stub and coated
with a 10 nm gold layer using a BAL-TEC SCD 005 Sputter Coater (BalTec Corporation, Canonsburg,
PA, USA) to obtain the images using a secondary electron detector.
4
.3. Representative Procedure for Catalyst Preparation
Method A: Silica powder (1 g) was added to a stirred solution of (dppta)AuCl complex
1
2
(
12 mg) in [bmim]PF (0.1 g) and CH CN (10 mL). After being stirred for 90 min at room temperature,
6 3
CH CN was evaporated to dryness to give a light yellow dry powder which was rinsed with diethyl
3
31
ether and dried in vacuo to afford the Au-supported catalyst (~1% wt based on weight gain and
P
HRMAS NMR). Spectroscopic data for the pre-catalyst (dppta)AuCl –SiO –[bmim]PF was as follows
2
2
6
(
molar ratio Au:IL 1:19, the (dppta)AuCl was assigned with the aid of 2D HRMAS NMR experiments):
2
1
H HRMAS NMR (500 MHz, DMSO-d6):
δ = 0.85 (bs, 3H, CH CH ), 1.14 (bs, 6H, CH(CH ) ), 1.19 (bs,
2 3 3 2
6
7
7
H, CH(CH ) ), 1.73 (bs, 2H, CH ), 3.65 (bs, 6H, CH(CH ) ), 3.80 (bs, 3H, NCH ), 4.1 (bs, 2H, CH N),
3 2 2 3 2 3 2
.39 (bs, 1H, NCHC) 7.43 (bs, 1H, NCHC), 7.43 (bs, 1H, ArH), 7.46 (bs, 1H, ArH), 7.62 (bs, 1H, ArH),
.70 (bs, 2H, ArH), 7.74 (bs, 1H, ArH), 8.13 (bs, 2H, ArH), 8.17 (bs, 1H, ArH), 8.43 (bs, 1H, NCHN) ppm;
1
3
C HRMAS NMR (125.8 MHz, DMSO-d6):
δ = 13.6 (CH ), 19.2 (CH ), 23.0 (CH(CH ) ), 31.7 (CH ),
3 2 3 2 2
3
6.1 (NCH ), 49.0 (NCH ), 50.7 (CH(CH ) ) 122.7 (CHN), 123.9 (NCH), 128.4 (CHAr), 129.9 (CHAr),
3
2
3 2
1
1
32.8 (CHAr), 129.9 (2
×
CHAr), 133.2 (CHAr), 133.3 (2
×
CHAr), 134.9 (CHAr), 135.1 (CHAr),
36.8 (NCN) ppm; 31P HRMAS NMR (202.5 MHz, DMSO-d ):
δ
=
−
144.1 (h, J 706.2 Hz), 68.9 ppm.
1
6
PF
Method B: 1-(Triethoxysilylpropyl)-3-methyl-imidazolium chloride and hexafluorophosphate
were prepared as reported in the literature [96]. Subsequently, the ILs were grafted over the silica
surface giving rise to SiO @IL(Cl) and SiO @IL(PF ), respectively. The procedure used was as follows:
2
2
6
1
g of the silica was placed into a round-bottom flask and firstly heated under reduced pressure with a
heat-gun; then, a solution containing 1.5 g of ionic liquid in 5 mL of dry toluene was added and the
◦
mixture was stirred at 90 C for 16 h. After cooling, the solid was filtered. Then, to a stirred solution
of (dppta)AuCl complex 1 (12 mg) in CH CN (10 mL), 1.1 g of either SiO @IL(Cl) or SiO @IL(PF ),
3 2 2 6
2
was added. After being stirred for 90 min at room temperature, CH CN was evaporated to dryness to
3
give a light yellow dry powder which was rinsed with diethyl ether and dried in vacuo to afford the
Au-supported catalysts Au–SiO @IL(Cl) and Au–SiO @IL(PF ), respectively (~1% wt based on weight
2
2
6
gain and 31P HRMAS NMR). The spectroscopic data for the pre-catalyst (dppta)AuCl –SiO @IL(PF )
2
2
6
was as follows (molar ratio Au:IL 1:85, not possible to assign the signals of the (dppta)AuCl complex
2
1
due to the very low relative proportion): H HRMAS NMR (500 MHz, DMSO-d ):
δ = 0.51 (bs, 2H,
6
SiCH ), 1.78 (bs, 2H, CH ), 3.88 (bs, 3H, NCH ), 4.16 (bs, 2H, CH N), 7.69 (bs, 1H, NCHC) 7.84 (bs,
2
2
3
2
13
1
2
H, NCHC), 9.36 (bs, 1H, NCHN) ppm; C HRMAS NMR (125.8 MHz, DMSO-d6):
δ = 8.8 (SiCH ),
2
31
3.9 (CH ), 36.1 (NCH ), 51.2 (NCH ), 122.5 (CHN), 123.8 (NCH), 136.9 (NCN) ppm; P HRMAS
2
3
2
1
NMR (202.5 MHz, DMSO-d ): δ = −144.1 (h, J 706.2 Hz), 68.8 ppm.
6
PF
4
.4. General Procedure for the Gold-Catalyzed, Three-Component Coupling
A mixture of aldehyde (1.97 mmol), amine (1.97 mmol), acetylene (2.95 mmol), and the
◦
corresponding supported Au catalyst (1% wt, 60 mg, 0.002 mmol) was heated at 60 C for 8 h,
after which time the solution was cooled and the catalyst was removed by filtration. The filtrate was
evaporated under reduced pressure to afford propargylamine 5. Yields were determined by integration

Molecules 2018, 23, 2975
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1
of the H-NMR spectra of the crude reaction mixtures. After separation and washing with n-pentane,
the catalyst was reused intact for the next reaction without any further pre-treatment. Representative
examples of the isolated products are as follows.
1-(1-Phenyl-3-(trimethylsilyl)prop-2-ynyl)piperidine (5a). Prepared according to the general procedure.
Purified by column chromatography on silica gel (3% EtOAc in hexanes). Colorless oil, 81% yield
1
(
4
0.432 g, 1.59 mmol). H-NMR (300.13 MHz, CDCl ):
δ
0.29 (s, 9H), 1.43
−
1.49 (m, 2H), 1.56 1.67 (m,
−
3
H), 2.48−2.52 (m, 4H), 4.63 (s, 1H), 7.29−7.40 (m, 2H, ArH), 7.61 (d, 2H, J = 7.5 Hz, ArH).
1-(3-(2-Methoxyphenyl)-1-phenylprop-2-yn-1-yl)piperidine (5f). Prepared according to the general
procedure. Purified by column chromatography on silica gel (5% EtOAc in hexanes). Colorless
1
oil, 82% yield (0.492 g, 1.61 mmol). H-NMR (300.13 MHz, CDCl ):
δ
1.48
−
1.53 (m, 2H), 1.62
−
1.68 (m,
3
4H), 2.63
−
2.66 (m, 4H), 3.94 (s, 3H), 4.91 (s, 1H), 6.92-6.99 (m, 2H, ArH), 7.31
.52−7.56 (m, 1H, ArH), 7.75 (d, 2H, J = 7.5 Hz, ArH).
−
7.43 (m, 4H, ArH),
7
1
-(3-(3-Ethynylphenyl)-1-phenylprop-2-ynyl)piperidine (5h). Prepared according to the general procedure.
Purified by column chromatography on silica gel (5% EtOAc in hexanes). Colorless oil, 80% yield
1
(
2
7
0.478 g, 1.58 mmol). H-NMR (300.13 MHz, CDCl3):
δ
1.46
−
1.49 (m, 2H), 1.60
−
1.65 (m, 4H),
.56
−
2.60 (m, 4H), 3.12 (s, 1H), 4.82 (s, 1H), 7.29
.64−7.68 (m, 3H, ArH).
−
7.42 (m, 4H, ArH), 7.46
−
7.53 (m, 2H, ArH),
(
S)-2-(Methoxymethyl)-1-(1-phenyl-3-(trimethylsilyl)prop-2-yn-2-yl)pyrrolidine (5k). Purified by column
chromatography on silica gel (5% EtOAc in hexanes). Colorless oil, 81% yield (0.486 g, 1.59 mmol).
1
H-NMR (300.13 MHz, CDCl3)
H), 2.63 2.71 (m, 1H), 3.20 3.28 (m, 1H), 3.39
H, ArH), 7.58−7.61 (m, 2H, ArH).
δ
: 0.26 (s, 9H), 1.59
−
1.75 (m, 3H), 1.89
−
1.98 (m, 1H), 2.49
−
2.53 (m,
7.38 (m,
1
3
−
−
−
3.54 (m, 2H), 3.43 (s, 3H), 5.11 (s, 1H), 7.25
−
Supplementary Materials: The Supplementary Materials are available online. Figure S1: IR spectrum
1
of the pre-catalyst (dppta)AuCl –SiO –[bmim]PF . Figure S2: H HRMAS NMR spectrum of the
2
2
6
1
3
pre-catalyst (dppta)AuCl -SiO -[bmim]PF . Figure S3: C HRMAS NMR spectrum of the precatalyst
dppta)AuCl -SiO –[bmim]PF . Figure S4: H, H COSY HRMAS NMR spectrum of the pre-catalyst
2
2
6
1
1
(
2 2 6
1
13
(
(
dppta)AuCl –SiO –[bmim]PF . Figure S5: H, C HSQC-Edited HRMAS NMR spectrum of the pre-catalyst
2 2 6
dppta)AuCl –SiO –[bmim]PF . Figure S6: Full XPS spectrum of the catalyst Au–SiO –[bmim]PF . Figure S7:
2
2
6
2
6
Core level region XPS spectra of N 1s of the catalyst Au–SiO –[bmim]PF . Figure S8: Core level region XPS
2
6
spectra of Si 2p of the catalyst Au–SiO –[bmim]PF , Figure S9: Core level region XPS spectra of Au 4f of the
2
6
catalyst Au–SiO –[bmim]PF , Figure S10: IR spectrum of the pre-catalyst (dppta)AuCl –SiO @IL(PF ), Figure
2
6
2
2
6
1
13
S11: H HRMAS NMR spectrum of the pre-catalyst (dppta)AuCl –SiO @IL(PF ), Figure S12: C HRMAS NMR
2
2
6
1
1
spectrum of the pre-catalyst (dppta)AuCl –SiO @IL(PF ), Figure S13: H, H gCOSY HRMAS NMR spectrum
2
2
6
1
13
of the pre-catalyst (dppta)AuCl –SiO @IL(PF ), Figure S14: H, C HSQC-edited HRMAS NMR spectrum
2
2
6
3
1
of the pre-catalyst (dppta)AuCl –SiO @IL(PF ), Figure S15: P HRMAS NMR spectrum of the pre-catalyst
2
2
6
(
dppta)AuCl –SiO @IL(PF ), Figure S16: Full XPS spectrum of the catalyst Au–SiO @IL(PF ), Figure S17: Core
2 2 6 2 6
level region XPS spectra of N 1s of the catalyst Au–SiO @IL(PF ), Figure S18: Core level region XPS spectra
2
6
of Si 2p of the catalyst Au–SiO @IL(PF ), Figure S19: Core level region XPS spectra of Au 4f of the catalyst
2
6
Au–SiO @IL(PF ).
2
6
Author Contributions: F.L.O. and R.S. conceived and designed the research. R.S. and Y.N. performed the
experiments. M.J.R. guide the experiments and supervised the data. F.L.O. and R.S. wrote the manuscript.
All authors revised the manuscript and approved the final version.
Funding: This research was funded by the Spanish Ministerio de Economía y Competitividad (MINECO) grant
number CTQ2014-57157-P and FEDER program.
Acknowledgments: We thank the MINECO and FEDER program for financial support. YNG thanks Ministerio
de Ciencia, Innovación y Universidades for a Ph.D. fellowship.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2018, 23, 2975
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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