Hydration of Alkynes Catalyzed by L-Au-X under Solvent- and Acid-Free Conditions: New Insights into an Efficient, General, and Green Methodology

Article abstract of DOI:10.1021/acs.organomet.8b00689

L-Au-X [L = 1,3-bis(2,6-di-isopropylphenyl)-imidazol-2-ylidene {NHC^iPr}, tris(3,5-bis(trifluoromethyl)phenyl)phosphine {PArF}, bis(imino)acenaphtene-1,3-bis(2,6-di-isopropylphenyl)dihydroimidazol-2-ylidene {BIAN}, 1,3-bis(2,6-di-isopropyl-phenyl)dihydroimidazol-2-ylidene {NHC^CH₂}, bis(tert-butylamino)methylidene {NAC}, 2-(di-tert-butylphosphino)biphenyl {JohnPhos}, tricyclohexylphosphine {PCy₃}, triphenylphosphine {PPh₃}, tris(2,4-di-tert-butylphenyl)phosphite {POR₃}; X^- = Cl^-, OTf^-, OTs^-] catalysts were tested in the hydration of alkynes in neat and acid-free conditions. The overall catalytic evidence confirms that not only the counterion as previously observed by us but also the ligand play a crucial role. As a matter of fact, only complexes bearing NHC ligands showed appreciable catalytic activity. A complete rationalization of the ligand and counterion effects enabled us to develop a highly efficient methodology for the hydration of inactive diphenylacetylene in solvent-, silver-, and acid-free conditions. Thus, it was possible to reduce the catalyst loading to 0.01 mol % (with respect to diphenylacetylene) leading, to the best of our knowledge, to the highest TON (3400) and TOF (435 h^-1) values found at 120 °C. The favorable catalytic conditions allowed us to reach for the first time very low E-factor (0.03) and high EMY (77) values for this substrate.

Full text of DOI:10.1021/acs.organomet.8b00689

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Hydration of Alkynes Catalyzed by L−Au−X under Solvent- and
Acid-Free Conditions: New Insights into an Efficient, General, and
Green Methodology
Mattia Gatto, Alessandro Del Zotto, Jacopo Segato, and Daniele Zuccaccia*
̀
Dipartimento di Scienze Agroalimentari, Ambientali e Animali, Sezione di Chimica, Universita di Udine, Via Cotonificio 108,
I-33100 Udine, Italy
S
* Supporting Information
ABSTRACT: L−Au−X [L = 1,3-bis(2,6-di-isopropylphenyl)-imida-
zol-2-ylidene {NHCiPr}, tris(3,5-bis(trifluoromethyl)phenyl)-
phosphine {PArF}, bis(imino)acenaphtene-1,3-bis(2,6-di-
isopropylphenyl)dihydroimidazol-2-ylidene {BIAN}, 1,3-bis(2,6-di-
isopropyl-phenyl)dihydroimidazol-2-ylidene {NHCCH }, bis(tert-
2
butylamino)methylidene {NAC}, 2-(di-tert-butylphosphino)biphenyl
{JohnPhos}, tricyclohexylphosphine {PCy3}, triphenylphosphine
{PPh3}, tris(2,4-di-tert-butylphenyl)phosphite {POR3}; X− = Cl−,
OTf−, OTs−] catalysts were tested in the hydration of alkynes in neat
and acid-free conditions. The overall catalytic evidence confirms that
not only the counterion as previously observed by us but also the
ligand play a crucial role. As a matter of fact, only complexes bearing
NHC ligands showed appreciable catalytic activity. A complete rationalization of the ligand and counterion effects enabled us to
develop a highly efficient methodology for the hydration of inactive diphenylacetylene in solvent-, silver-, and acid-free
conditions. Thus, it was possible to reduce the catalyst loading to 0.01 mol % (with respect to diphenylacetylene) leading, to the
best of our knowledge, to the highest TON (3400) and TOF (435 h−1) values found at 120 °C. The favorable catalytic
conditions allowed us to reach for the first time very low E-factor (0.03) and high EMY (77) values for this substrate.
reaction conditions reducing the catalyst loading up to 10 ppm
using NHC ligands instead of phosphanes.10
Recently, several other papers appeared dealing with the use
of Au(I) catalysts for the hydration of alkynes aimed at
rationalizing ligand11,12 and counterion effects4,5,13 and, to a
minor extent, at developing green conditions for this
reaction.14,15
As regards the ligand effect in the related methoxylation of
alkynes, Meyer and Zhdanko suggested that both steric and
electronic factors must be taken into account, because the
nature of the ligand is connected with the formation and
stability of the off-cycle intermediate of the type [(L−Au)(L−
Au)(vinylether)]+.11 More recently, Hammond, Xu, and others
instead suggested that the steric factor is much more important
in the methoxylation of alkynes followed by hydration.12
In contrast, the correct choice of the counterion in the
methoxylation of alkynes promoted by L−Au−X depends on
the ligand, although X− ions with intermediate co-ordinative
and basicity characteristic, such as OTs− and OTf−, are
frequently the best choice.4,5,13
INTRODUCTION
■
During the last 10 years, gold has become a powerful tool in
the hands of organic chemists.1 Nucleophilic additions to a
carbon−carbon unsaturated bond are typical reactions
catalyzed by L−Au−X compounds (L = ancillary ligand and
X− = counterion). The gold metal precatalyst L−Au−X acts as
a Lewis acid coordinating unsaturated hydrocarbons (UHC) in
the pre-equilibrium step affording the [L−Au−UHC]X
intermediate, which subsequently undergoes nucleophilic
attack by a nucleophile (Nu−H), with formation of an
organogold species. The gold−carbon bond in these
intermediates is typically cleaved by a proton (protodeauration
step) to give the desired product and regenerate the catalyst.
The impact of the ligand L2 and counterion X−3 on the steps of
the mechanism of gold catalysis has already been compre-
hensively addressed. Our contribution in the field of
counterion effects in gold catalysis is prevalently focused on
the hydration of alkynes and related alkoxylation.4,5
The hydration of alkynes is an important environmentally
friendly reaction in organic chemistry that satisfies both the
atom economy rule and carbon efficiency.6 Teles and co-
workers first introduced the use of gold(I) catalysts.7,8 TON
and TOF values of 1000 and 1000 h−1, respectively, were
obtained under optimized conditions using PPh3-Au+ as the
catalyst.9 Later on, Nolan was able to further optimize the
We put a first brick in developing green conditions by
performing the hydration of alkynes using as catalysts NHC−
Au−X complexes [NHC = (1,3-bis(2,6-di-isopropylphenyl)-
Received: September 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00689
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
imidazol-2-ylidene, X− = BArF−, BF4 , SbF6 , ClO4 , OTf−,
−
−
−
RESULTS AND DISCUSSION
■
NTf2 , OTs−, TFA−, BArF− = tetrakis(3,5-bis(trifluoro-
−
The compounds L−Au−X [L = 1,3-bis(2,6-di-isopropylphen-
yl)-imidazol-2-ylidene {NHCiPr}, tris(3,5-bis(trifluoromethyl)-
phenyl)phosphine {PArF}, bis(imino)acenaphtene-1,3-bis(2,6-
di-isopropylphenyl)dihydroimidazol-2-ylidene {BIAN}, 1,3-
bis(2,6-di-isopropyl-phenyl)dihydroimidazol-2-ylidene
methyl)phenyl)borate] in solvent- and silver-free conditions
at room/mild temperature with suitable ionic additives.16
Kinetic experiments coupled with DFT calculations17 have
−
allowed us to conclude that only with OTf− and NTf2
counterions the catalysis is achieved. We were able to reduce
the catalyst loading up to 0.01 mol % with respect to the
substrate, achieving high TON (104) and TOF (103 h−1), very
low E-factor18 (0.03−0.06) and high EMY19 (94−97) values.
More recently, we applied the NHC−Au−OTf catalyst to the
alkoxylation and hydration of alkynes in a wide set of neuteric
solvents.20 We found that ethyl lactate, glycerol, propylene
carbonate, D-limonene, γ-valerolactone, and p-cymene are
comparable or better solvents with respect to VOS.
{NHCCH }, bis(tert-butylamino)methylidene {NAC}, 2-(di-
2
tert-butylphosphino)biphenyl {JohnPhos}, tricyclohexylphos-
phine {PCy3}, triphenylphosphine {PPh3}, tris(2,4-di-tert-
butylphenyl)phosphite {POR3}; X− = Cl−, OTf−, OTs−]
were synthesized according to literature procedures (see the
Supporting Information for details) or generated in situ during
the catalytic tests (Table 1).
Table 1. L−Au−X (0.1 mol %) Catalyzed Hydration of 3-
Hexyne at 30 °C in the Presence of NBu4OTf
Here, we extend our previous works, studying L−Au−X [L
= 1,3-bis(2,6-di-isopropylphenyl)-imidazol-2-ylidene
{NHCiPr}, tris(3,5-bis(trifluoromethyl)phenyl)phosphine
{PArF}, bis(imino)acenaphtene-supported-1,3-bis(2,6-di-
isopropylphenyl)dihydroimidazol-2-ylidene {BIAN}, 1,3-bis-
(2,6-di-isopropyl-phenyl)dihydroimidazol-2-ylidene
a b
,
AgOTf
(mol %)
conv.
d
time (h)
e f
c
,
entry
L
X−
(%)
(TOF)
g
1
NHCiPr
NHCiPr
BIAN
NHCCH
NAC
JohnPhos
PCy3
PArF
OTf−
Cl−
>99
70
76
76
0
75
0
0
2 (495)
2 (350)
2 (380)
2 (380)
24
4 (188)
24
24
24
24
3.5 (285)
4 (248)
8 (122)
24 (4)
5 (148)
24 (3)
24
24 (1)
24 (7)
2 (495)
4 (248)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
{NHCCH }, bis(tert-butylamino)methylidene {NAC}, 2-di-tert-
Cl−
2
Cl−
2
butyl(o-diphenyl)phosphine {JohnPhos}, tricyclohexylphos-
phine {PCy3}, triphenylphosphine {PPh3}, tris(2,4-di-tert-
butylphenyl)phosphite {POR3} (Figure 1), X− = Cl−, OTf−,
Cl−
Cl−
Cl−
Cl−
PPh3
Cl−
0
0
POR3
NHCiPr
BIAN
NHCCH
NAC
JohnPhos
PCy3
PArF
Cl−
OTs−
OTs−
OTs−
OTs−
OTs−
OTs−
OTs−
OTs−
OTs−
OTf−
OTf−
>99
>99
98
9
74
6
0
3
17
>99
>99
2
PPh3
POR3
BIAN
NHCCH
2
a
Catalytic conditions: 3-hexyne (1.75 mmol, 200 μL), 5 mol %
NBu4OTf (0.087 mmol, 34.3 mg), H2O (1.92 mmol, 35 μL), L−Au−
X (0.00175 mmol) and AgOTf (0.00175 mmol, 0,45 mg) when
b
c
indicated. mol % = (moles of catalyst/mol of alkyne) × 100. See
d
1
text. Determined by H NMR; averaged value of three measure-
ments. Time necessary to reach the reported conversion. TOF =
(nproduct/ncatalyst)/t (time in h) at the reported conversion. From ref
e
f
g
16.
Figure 1. Ligands employed in this work.
In-depth kinetic and mechanistic studies on gold(I)-
catalyzed nucleophilic addition to a carbon−carbon unsatu-
rated bond allowed us to understand the ligand effects in the
different steps of the catalytic cycle.2 The stereoelectronic
structure of the ligand modulates the acidic character of the
metal fragment in the catalytic cycle and affects the stability of
the postulated intermediates.21,22
The complexes L−Au−X here reported were chosen with
the deliberate purpose of varying considerably the stereo-
electronic character of L, and they have been tested as catalysts
in the hydration of 3-hexyne (1) to form 3-hexanone (1a) and
diphenylacetylene (2) to form 1,2-diphenylethanone (2a)
(Tables 1 and 2) in solvent- and acid-free conditions, in order
to extend and complete our previous investigation.16 Also, the
OTs−] catalysts for the hydration of alkynes in solvent- and
acid-free conditions. In particular, we investigated the effect of
the ligand employed, the ionic additive, the silver salt, and the
temperature. Finally, a highly efficient methodology for the
hydration of unreactive diphenylacetylene in solvent-, silver-,
and acid-free conditions has been developed. The results
obtained are remarkable, as it is possible to reduce the catalyst
loading to 0.01 mol %, reaching the highest TON (3400),
TOF (435 h−1), and EMY (77) values, as well as the lowest E-
factor (0.03) value.
B
DOI: 10.1021/acs.organomet.8b00689
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 2. NHCiPr−Au−OTf Catalyzed Hydration of
a
Diphenylacetylene
loading
(mol %)
anion
(X)
conv.
c
time (h)
de
b
,
entry
T (°C)
(%)
(TOF)
1
2
3
4
5
0.1
65
80
OTf−
OTf−
OTf−
OTf−
OTf−
OTf−
OTs−
82
42
94
85
27
88
7
8 (102)
8 (105)
4 (470)
8 (435)
5 (560)
8 (220)
8 (17)
0.05
0.05
0.025
0.01
0.05
0.05
120
120
120
120
120
f
6
7
a
Catalysis conditions: diphenylacetylene (1.75 mmol, 312 mg), 5 mol
% NBu4OTf (0.087 mmol, 34.3 mg) and H2O (1.92 mmol, 35 μL).
b
c
(moles of catalyst/mol of alkyne) × 100. Determined by 1H NMR;
d
average value of three measurements. Time necessary to reach the
e
reported conversion. TOF = (nproduct/ncatalyst)/t (time in h) at the
reported conversion. With D2O instead of H2O.
f
Figure 2. Hydration of 3-hexyne with 0.1 mol % of L−Au−X in the
role played by silver salts (Table 1) and ionic additives other
than NBu4OTf (Table S2) on the catalytic performances has
been evaluated. In fact, it is well-known that NBu4OTf can
increase the catalytic performances of gold in the cyclo-
isomerization of N-(prop-2-ynyl)benzamide to 2-phenyl-5-
vinylidene-2-oxazoline, in the methoxylation of 3-hexyne, in
the intermolecular hydroamination of alkynes, in the cyclo-
isomerization of allenone, in the cyclization of 4-pentynoic acid
and finally in the synthesis of α-pyrone.23
presence of 5 mol % NBu4OTf.
This finding clearly indicates that a decomposition of the
catalyst takes place in the neat conditions employed (also
confirmed by the formation of a film of gold on the walls of the
reaction vessel). Decomposition of phosphine-based gold
catalyst is frequently documented in the literature.26
Even for the more stable complex bearing the NHCiPr ligand,
a decomposition process seems to be present and promoted by
the silver salt in neat- and acid-free conditions. Thus, no
quantitative conversion of 1 into 1a (Table 1, entry 1 vs entry
2) was observed even prolonging the reaction time to 24 h
(Table S1). The role of silver additives in gold catalysis is
frequently debated27 and both beneficial and detrimental
effects have been highlighted.28
A typical catalytic run was performed by mixing the alkyne
and 1.1 equiv of H2O in the presence of the catalyst (from 0.1
to 0.01 mol % with respect to the alkyne), AgOTf (when L−
Au−Cl precursors were used), and a proper additive (up to 5
mol % with respect to the alkyne) in the temperature range of
30−120 °C (Tables 1 and 2). In order to easily compare the
catalytic results with those previously obtained by us,16
complex NHCiPr−Au−OTf has been included in Table 1.
The progress of the reaction was monitored by NMR
spectroscopy (see the Supporting Information). To evaluate
the catalytic activity in different conditions, the TOF value
[TOF (h−1) = (number of mole of product)/mol of catalyst)/
elapsed time, (Tables 1 and 2)] was calculated for each run.
Initially, complexes of the type L−Au−Cl were tested in the
presence of one equiv of AgOTf (Table 1, entries 2−10). Gold
catalysts bearing PArF, NAC, PCy3, PPh3, and POR3 ligands
proved inefficient, as no conversion was observed after 24 h
(Table 1, entries 5 and 7−10). On the contrary, good but not
quantitative conversion (around 75%) of 1 into 1a was reached
In order to compare the different ligands and to overcome
silver-induced decomposition of the gold catalyst, we decided
to explore L−Au−OTs catalysts, as L−Au−OTf complexes are
not stable and isolable with all the ligands here employed.29
Unfortunately, even in silver-free conditions, decomposition or
deactivation of phosphine-based catalysts was observed during
the catalysis (Table 1, entries 16−19) with the exception of
JohnPhos−Au−OTs that gave a conversion of 74% after 5 h
with a TOF of 148 h−1 (Table 1, entry 15). This value is
similar to that obtained with the JohnPhos−Au−Cl/AgOTf
system (Table 1, entry 6).30 The comparison between the
catalytic activity of NHCiPr−Au−OTs and NHCiPr−Au−OTf
evidences the better performance of the latter (Table 1, entry 1
vs entry 11). A quantitative conversion of 1 into 1a was
observed with both species, but it was reached after 2 and 3.5 h
using NHCiPr−Au−OTf and NHCiPr−Au−OTs, respectively
(see also Figure 2). A possible explanation of such a neat
difference could be found in the higher coordinating ability of
OTs− with respect to OTf− toward the gold fragment. We have
previously found that OTs− inhibited the hydration of 3-
hexyne in neat conditions.16 It is likely that the nonactive form
NHC−Au−OTs is slowly converted into the more active
NHC−Au−OTf during the course of the reaction, owing to
the presence of an excess of NBu4OTf.
within 2 h using NHCiPr, BIAN, and NHCCH ligands (Table 1,
2
entries 2−4, Figure 2) or 4 h using JohnPhos (Table 1, entry
6). These values did not increase upon prolonging the reaction
time to 24 h.
Notably, the TOF obtained using the NHCiPr−Au−Cl/
AgOTf system is 350 h−1, a lower value with respect to that
reported in the literature16 under silver-free condition (495
h−1, see Table 1, entry 1 vs entry 2).
As mentioned above, for the L−Au−Cl/AgOTf systems
where L is PCy3, PArF, POR3, PPh3, and NAC (Table 1,
entries 5 and 7−10), no formation of any product was
observed within 24 h. In trying to understand this, we studied
the hydration reaction promoted by PPh3−Au−Cl/AgOTf
(Table 1, entry 9) by 31P NMR spectroscopy. The spectra were
recorded at the end of the reaction (see the Supporting
Information for details), and the expected signal at δ 41.9 ppm
due to the formation of [(PPh3)2Au]OTf11,24,25 was observed.
Taking into account that (a) phosphine-based gold catalysts
are poorly active, (b) silver salts induce deactivation of the
catalyst, and (c) L−Au−OTs species are less active than L−
Au−OTf, we decided to extend the investigation to other gold
catalyst bearing NHC ligands and OTf− as the counterion.
C
DOI: 10.1021/acs.organomet.8b00689
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Therefore, BIAN−Au−OTf and NHCCH −Au−OTf were
examined as catalysts and compared with NHCiPr−Au−OTf.
Quantitative conversion of 1 into 1a was reached in 2 h using
BIAN−Au−OTf (Table 1, entry 20), whose activity was the
same shown by NHCiPr−Au−OTf (Table 1, entry 1). Much
Diphenylacetylene, 1.1 equiv of H2O, and NHCiPr−Au−OTf
(from 0.01 to 0.1 mol % with respect to diphenylacetylene)
were mixed with NBu4OTf (5 mol %) at the desired
temperature. Using 0.1 mol % of catalyst, a high conversion
of 2 into 2a was obtained in 8 h working at 65 °C. (Table 2,
entry 1). Then, we tried to optimize the reaction conditions by
varying both temperature and catalyst loading (Figure 2). An
almost quantitative yield (94%) of 2a was achieved by
increasing the temperature to 120 °C and reducing the catalyst
amount to 0.05 mol % (Table 2, entry 3). Unfortunately, a
further decrease of NHCiPr−Au−OTf concentration to 0.025
and 0.01 mol % resulted in a progressive decline in conversion
(Table 2, entries 4 and 5). The highest TOF of 560 h−1 was
reached at 120 °C with a catalyst loading of 0.01 mol % (Table
3, entry 5), while the highest TON of 3400 was obtained at the
same temperature with 0.025 mol % of NHCiPr−Au−OTf. In
these catalytic conditions, a very high EMY value (77) as well
as an excellent E-factor value (0.03) were achieved.
2
less efficiently, NHCCH −Au−OTf promoted the quantitative
2
formation of 1a after a twice reaction time (Table 1, entry 21).
The results so far demonstrate that the best performances in
the hydration of 3-hexyne in neat conditions are obtained
when L in L−Au−X complexes is a NHC type ligand, while
the use of silver salts must be avoided.
As regards the use of ionic additives, we have previously
found that NBu4OTf improves the rate of the reaction,
NH4OTf does not show any appreciable effect, and [BMIM]-
OTf even stops the reaction.16 NBu4OTf acts as PTC (phase
transfer catalysts).31 The n-butyl chains in the cationic
fragment NBu4 increase the solubility of the salt in 3-hexyne,
while at the same time the amount of water in the organic
phase is enhanced.
+
To highlight the excellent results obtained by applying our
protocol, it seems useful to compare the present catalytic
parameters with the best ones reported to date in the literature
(see Table 3). In 2002, Tanaka and co-workers studied the
catalytic hydration of 2 promoted by phosphine gold
complexes.7 Under strongly acidic conditions at 70 °C in
methanol, a TON of 53 in 5 h was obtained, and the E-factor
and EMY values were 6 and 10, respectively. Nolan and co-
workers in 2009 introduced NHC gold(I) complexes.10 The
catalyst loading was reduced to 0.1 mol %, a 1,4-dioxane/water
2:1 mixture was used as the solvent, the temperature was
increased to 120 °C, while no acid was added. A maximum
TON of 770 and a TOF of 42 h−1 were achieved. Despite the
sharp increase of the TON, the EMY value obtained (13) was
still low. Furthermore, TON of 400 and TOF of 67 h−1 were
attained by the same group employing as catalysts dimeric
(NHC-Au)2SO4 complexes at 80 °C.33 However, under these
conditions, E-factor and EMY values did not improve. Very
recently, this reaction was studied also by us using γ-
valerolactone (GVL) as the solvent.20 An appreciable
maximum TOF of 283 h−1 was reached with a catalyst loading
of 0.1 mol %. Although there has been a marked improvement
of E-factor (2.6) and EMY (28) values, both are still very far
from being acceptable in terms of effective green catalysis.
In order to shed some light on the reaction mechanism, we
conducted some experiments using D2O instead of H2O to
quantify the KIE value in these aprotic and apolar conditions at
high temperature (Table 2, entry 6). Previously, we have found
that the addition of 5 mol % mol of NBut4OTf resulted in a
neat change of the KIE value from 3.8 to 2.5 in the solvent-
and silver-free hydration of 3-hexyne.16 These KIE values point
out that the turnover-limiting step is the proton transfer. Using
D2O instead of H2O, we observed a small reduction of TOF,
which shifted from 470 to 433 h−1 (see the Supporting
Information, compare entries 3 and 6 in Table S3), and the
calculated KIE was 1.2. Therefore, it is very plausible that in
the hydration of diphenylacetylene the RDS can be the
nucleophilic attack because this substrate is much less reactive
with respect to internal aliphatic alkynes.
In order to understand the effectiveness of different
ammonium triflate salts, in terms of different number and
length of alkyl chains, we deeply investigated the effect of
addition of 5 mol % of Bn3NHOTf, Bu2NH2OTf, Me2(Et)-
(Dec)NOTf, (Cy)NH3OTf, and Aliquat-OTf in the catalytic
performances of NHCiPr−Au−OTf (see the Supporting
Information for details). Summarizing, we found that
NBu4OTf continues to be the most effective additive (Table
S2), as previously observed.16,23
Kept in mind that the NHCiPr−Au−OTf/NBu4OTf (5 mol
%) system is the best combination for solvent-, silver-, and
acid-free hydration of alkynes, we decided to apply it in the
hydration of diphenylacetylene (2), an inactive solid alkyne
that can be hydrated in neat conditions by increasing the
temperature above its melting point (62 °C) to afford 1,2-
diphenylethanone (2a). The most salient results are
summarized in Table 2 and shown in Figure 3. Hydration of
diphenylacetylene is a benchmark reaction frequently studied
in the literature in the presence of solvent and additives such as
silver salts and acids.32 However, its optimization is far from
being achieved, especially from a green point of view.
Regarding the role of the counterion in the pre-equilibrium
step, we have previously observed that when OTs− is employed
instead of OTf−, the catalyst in the pre-equilibrium step is
shifted toward the nonactive inner sphere ion pair (Table 1)
owing to the higher co-ordinating ability of OTs− with respect
to OTf− toward cationic gold fragments.16 This difference is
Figure 3. Hydration of diphenylacetylene with different loadings of
NHCiPr−Au−OTf, in the presence of 5 mol % NBu4OTf, at different
temperatures.
D
DOI: 10.1021/acs.organomet.8b00689
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 3. Main Parameters for Hydration of Diphenylacetylene in 1,2-Diphenylethanone
Tanaka7
Nolan10
Nolan33
Zuccaccia20
This work
3400
435
120
NO
YES (NBu4OTf)
0.3
77
solvent
TON
MeOH/H2O (2:1)
dioxane/H2O (2:1)
MeOH/H2O (2:1)
γ-valerolactone
80
80
70
NO
770
43
120
YES
NO
4.8
400
67
80
NO
NO
5
990
283
120
NO
NO
2.6
TOF (h−1
T (°C)
)
Ag+ additives
other additives
E-factor
YES (H2SO4)
6
10
a
EMY
13
10
28
a
EMY= Effective mass yield.
Funding
This work was supported by grants from the MIUR (Rome,
confirmed in the present work, as the conversion of 94% (4 h)
shown by NHCiPr−Au−OTf (Table 2, entry 3) drops to 7% (8
h) when NHCiPr−Au−OTs is employed as the catalyst (Table
2, entry 7). We can conclude that notwithstanding the
temperature has been raised to 120 °C the counterion effect
is the same observed for the hydration of 3-hexyne. Thus, the
equilibrium is strongly shifted toward the precatalyst when
OTs− is involved.
̀
Italy): Finanziamento annuale individuale delle attivita base di
ricerca (faabr2017) and the FIRB-Futuro-in-Ricerca project
RBFR1022UQ: “Novel Au(I)-based molecular catalysts: from
know-how to know-why (AuCat)”.
Notes
The authors declare no competing financial interest.
REFERENCES
CONCLUSION
■
■
(1) (a) Garayalde, D.; Nevado, C. Gold-Containing and Gold-
Generated 1,n-Dipoles as Useful Platforms toward Cycloadditions and
Cyclizations. ACS Catal. 2012, 2, 1462−1479. (b) Obradors, C.;
Echavarren, A. M. Intriguing mechanistic labyrinths in gold(I)
catalysis. Chem. Commun. 2014, 50, 16−28. (c) Wang, Y.-M.;
Lackner, A. D.; Toste, F. D. Development of Catalysts and Ligands for
Enantioselective Gold Catalysis. Acc. Chem. Res. 2014, 47, 889−901.
(d) Hashmi, A. S. K. Dual Gold Catalysis. Acc. Chem. Res. 2014, 47,
864−876. (e) Yeom, H.-S.; Shin, S. Catalytic Access to α-Oxo Gold
Carbenes by N−O Bond Oxidants. Acc. Chem. Res. 2014, 47, 966−
977. (f) Zhang, L. A Non-Diazo Approach to α-Oxo Gold Carbenes
via Gold-Catalyzed Alkyne Oxidation. Acc. Chem. Res. 2014, 47, 877−
888. (g) Qian, D.; Zhang, J. Gold-catalyzed cyclopropanation
reactions using a carbenoid precursor toolbox. Chem. Soc. Rev.
2015, 44, 677−698. (h) Dorel, R.; Echavarren, A. M. Gold(I)-
Catalyzed Activation of Alkynes for the Construction of Molecular
In this work, we extended our previous works studying the
hydration of 3-hexyne and diphenylacetylene promoted by L−
Au−X complexes in solvent- and acid-free conditions, in the
presence of NBut4OTf as additive. At first, we investigated the
effect of the neutral ligand L employed. Decomposition of
phosphane-based catalysts was observed by 31P NMR spec-
troscopy during the catalysis with the exception of JohnPhos.
In contrast, NHC ligands showed superior performances due
to their enhanced stability with respect to phosphanes in our
conditions. We also observed that the use of silver salts in
combination with L−Au−Cl complexes resulted in a
decomposition of the in situ formed catalyst even when
NHC ligands were employed.
Finally, a highly efficient and green methodology for the
hydration of diphenylacetylene in solvent-, silver-, and acid-free
conditions has been developed. It was possible to reduce, for
the first time, the catalyst loading to 0.01 mol %, reaching the
highest TON (3400), TOF (435 h−1), and EMY (77) values as
well as the lowest E-factor value (0.03). These results are
remarkable and suggest that a sustainable production of 1,2-
diphenylethanone with gold catalysts can be pursued if both
the ligand and counterion effects are taken into account.34
̈
Complexity. Chem. Rev. 2015, 115, 9028−9072. (i) Pflasterer, D.;
Hashmi, A. S. K. Gold catalysis in total synthesis - recent
achievements. Chem. Soc. Rev. 2016, 45, 1331−1367.
(2) Wang, W.; Hammond, G. B.; Xu, B. Ligand Effects and Ligand
Design in Homogeneous Gold(I) Catalysis. J. Am. Chem. Soc. 2012,
134, 5697−5705.
(3) (a) Zuccaccia, D.; Belpassi, L.; Tarantelli, F.; Macchioni, A.
Ligand Effects on Bonding and Ion Pairing in Cationic Gold(I)
Catalysts Bearing Unsaturated Hydrocarbons. Eur. J. Inorg. Chem.
2013, 2013, 4121−4135. and reference cited therein. (b) Jia, M.;
Bandini, M. Counterion Effects in Homogeneous Gold Catalysis. ACS
Catal. 2015, 5, 1638−1652. and reference cited therein.
ASSOCIATED CONTENT
■
S
* Supporting Information
(4) (a) Biasiolo, L.; Ciancaleoni, G.; Belpassi, L.; Bistoni, G.;
Macchioni, A.; Tarantelli, F.; Zuccaccia, D. Relationship between the
anion/cation relative orientation and the catalytic activity of nitrogen
acyclic carbene−gold catalysts. Catal. Sci. Technol. 2015, 5, 1558−
1567. (b) Biasiolo, L.; Trinchillo, M.; Belanzoni, P.; Belpassi, L.;
Busico, V.; Ciancaleoni, G.; D’Amora, A.; Macchioni, A.; Tarantelli,
F.; Zuccaccia, D. Unexpected Anion Effect in the Alkoxylation of
Alkynes Catalyzed by N-Heterocyclic Carbene (NHC) Cationic Gold
Complexes. Chem. - Eur. J. 2014, 20, 14594−14598. (c) Trinchillo,
M.; Belanzoni, P.; Belpassi, L.; Biasiolo, L.; Busico, V.; D’Amora, A.;
D’Amore, L.; Del Zotto, A.; Tarantelli, F.; Tuzi, A.; Zuccaccia, D.
Extensive Experimental and Computational Study of Counterion
Effect in the Reaction Mechanism of NHC-Gold(I)-Catalyzed
Alkoxylation of Alkynes. Organometallics 2016, 35, 641−654.
(5) Biasiolo, L.; Del Zotto, A.; Zuccaccia, D. Toward Optimizing the
Performance of Homogeneous L−Au−X Catalysts through Appro-
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00689.
General procedures and materials, synthesis and
characterization of compounds, catalysis data and plot
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: daniele.zuccaccia@uniud.it.
ORCID
Daniele Zuccaccia: 0000-0001-7765-1715
E
DOI: 10.1021/acs.organomet.8b00689
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
priate Matching of the Ligand (L) and Counterion (X−). Organo-
metallics 2015, 34, 1759−1765.
(6) (a) Hintermann, L.; Labonne, A. Catalytic hydration of Alkynes
and its application in synthesis. Synthesis 2007, 2007, 1121−1150.
(b) Alonso, F.; Beletskaya, I. P.; Yus, M. Transition-Metal-Catalyzed
Addition of Heteroatom-Hydrogen Bonds to Alkynes. Chem. Rev.
2004, 104, 3079−3160.
(7) Teles, J. H.; Brode, S.; Chabanas, M. Cationic Gold(I)
Complexes: Highly Efficient Catalysts for the Addition of Alcohols
to Alkynes. Angew. Chem., Int. Ed. 1998, 37, 1415−1418.
(8) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Highly
Efficient AuI-Catalyzed Hydration of Alkynes. Angew. Chem., Int. Ed.
2002, 41, 4563−4565.
(9) Hayashi, Tanaka, and co-workers (see ref 8) reported low
catalyst loadings (100 ppm) and low amounts of acid promoter (4
mol %) only for the hydration of 1-octyne. For all other alkynes, the
catalyst loading typically ranged from 0.2 to 1 mol %, while the acid
(21) (a) Hashmi, A. S. K. Homogeneous Gold Catalysis Beyond
Assumptions and Proposals-Characterized Intermediates. Angew.
Chem., Int. Ed. 2010, 49, 5232−5241. (b) Obradors, C.;
Echavarren, A. M. Intriguing mechanistic labyrinths in gold(I)
catalysis. Chem. Commun. 2014, 50, 16−28.
(22) (a) Schmidbaur, H.; Schier, A. Gold η2-Coordination to
Unsaturated and Aromatic Hydrocarbons: The Key Step in Gold-
Catalyzed Organic Transformations. Organometallics 2010, 29, 2−23.
and reference therein. (b) Brooner, R. E. M.; Widenhoefer, R.
Cationic, Two-Coordinate Gold π Complexes. Angew. Chem., Int. Ed.
2013, 52, 11714−11724. (c) Liu, L.; Hammond, G. B. Recent
advances in the isolation and reactivity of organogold complexes.
Chem. Soc. Rev. 2012, 41, 3129−3139.
(23) Wang, W.; Kumar, M.; Hammond, G. B.; Xu, B. Enhanced
Reactivity in Homogeneous Gold Catalysis through Hydrogen
Bonding. Org. Lett. 2014, 16, 636−639.
(24) Attar, S.; Bearden, W. H.; Alcock, N. W.; Alyea, E. C.; Nelson,
J. H. Phosphole complexes of gold(I) halides: comparison of solution
and solid-state structures by a combination of solution and CP/MAS
phosphorus-31 NMR spectroscopy and x-ray crystallography. Inorg.
Chem. 1990, 29, 425−433.
loading varied from 25 to 50 mol %.
I
́
(10) Marion, N.; Ramon, R. S.; Nolan, S. P. [(NHC)Au ]-Catalyzed
Acid-Free Alkyne Hydration at Part-per-Million Catalyst Loadings. J.
Am. Chem. Soc. 2009, 131, 448−449.
(11) Zhdanko, A.; Maier, M. M. The Mechanism of Gold(I)-
Catalyzed Hydroalkoxylation of Alkynes: An Extensive Experimental
Study. Chem. - Eur. J. 2014, 20, 1918−1930.
(25) (a) Zuccaccia, D.; Belpassi, L.; Rocchigiani, L.; Tarantelli, F.;
Macchioni, A. A Phosphine Gold(I) π-Alkyne Complex: Tuning the
Metal−Alkyne Bond Character and Counterion Position by the
Choice of the Ancillary Ligand. Inorg. Chem. 2010, 49, 3080−3082.
(b) Zuccaccia, D.; Belpassi, L.; Tarantelli, F.; Macchioni, A. Ion
Pairing in Cationic Olefin−Gold(I) Complexes. J. Am. Chem. Soc.
2009, 131, 3170−3171.
(12) Ebule, R. E.; Malhotra, D.; Hammond, G. B.; Xu, B. Ligand
Effects in the Gold Catalyzed Hydration of Alkynes. Adv. Synth. Catal.
2016, 358, 1478−1481.
(13) Zhdanko, A.; Maier, M. E. Explanation of Counterion Effects in
Gold(I)-Catalyzed Hydroalkoxylation of Alkynes. ACS Catal. 2014, 4,
2770−2775.
́
́
(26) (a) Cordon, J.; Lopez-de-Luzuriaga, J.; Monge, M.
Experimental and Theoretical Study of the Effectiveness and Stability
of Gold(I) Catalysts Used in the Synthesis of Cyclic Acetals.
Organometallics 2016, 35, 732−740. (b) Kumar, M.; Jasinski, J.;
Hammond, G. B.; Xu, B. Alkyne/Alkene/Allene-Induced Dispropor-
tionation of Cationic Gold(I) Catalyst. Chem. - Eur. J. 2014, 20,
3113−3119.
(14) (a) Romero, N. A.; Klepser, B. M.; Anderson, C. E. Au(III)-
Catalyzed Tandem Amination-Hydration of Alkynes: Synthesis of α-
(N-2-Pyridonyl)ketones. Org. Lett. 2012, 14, 874−877. (b) Fernandez,
G. A.; Picco, A. S.; Ceolin, M. R.; Chopa, A. B.; Silbestri, G. F.
Synthesis and Structural Characterization of Water-Soluble Gold(I)
N-Heterocyclic Carbene Complexes. An X-ray Absorption Fine
Structure Spectroscopy (XAFS) Study. Organometallics 2013, 32,
6315−6323. (c) Xu, X. Y.; Kim, S. H.; Zhang, X.; Das, A. K.; Hirao,
H.; Hong, S. H. Abnormal N-Heterocyclic Carbene Gold(I)
Complexes: Synthesis, Structure, and Catalysis in Hydration of
Alkynes. Organometallics 2013, 32, 164−171. (d) Czegeni, C. E.;
Papp, G.; Katho, A.; Joo, F. Water-soluble gold(I)−NHC complexes
of sulfonated IMes and SIMes and their catalytic activity in hydration
of alkynes. J. Mol. Catal. A: Chem. 2011, 340, 1−8. (e) Almassy, A.;
Nagy, C. E.; Benyei, A. C.; Joo, F. Novel Sulfonated N-Heterocyclic
Carbene Gold(I) Complexes: Homogeneous Gold Catalysis for the
Hydration of Terminal Alkynes in Aqueous Media. Organometallics
2010, 29, 2484−2490.
(15) Xu, Y.; Hu, X.; Shao, J. J.; Yang, G.; Wu, Y.; Zhang, Z.
Hydration of alkynes at room temperature catalyzed by gold(I)
isocyanide compounds. Green Chem. 2015, 17, 532−537.
(16) Gatto, M.; Belanzoni, P.; Belpassi, L.; Biasiolo, L.; Del Zotto,
A.; Tarantelli, F.; Zuccaccia, D. Solvent-, Silver-, and Acid-Free
NHC−Au−X Catalyzed Hydration of Alkynes. The Pivotal Role of
the Counterion. ACS Catal. 2016, 6, 7363−7376.
(17) (a) Ciancaleoni, G.; Belpassi, L.; Zuccaccia, D.; Tarantelli, F.;
Belanzoni, P. Counterion Effect in the Reaction Mechanism of NHC
Gold(I)-Catalyzed Alkoxylation of Alkynes: Computational Insight
into Experiment. ACS Catal. 2015, 5, 803−814. (b) D’Amore, L.;
Ciancaleoni, G.; Belpassi, L.; Tarantelli, F.; Zuccaccia, D.; Belanzoni,
P. Unraveling the Anion/Ligand Interplay in the Reaction Mechanism
of Gold(I)-Catalyzed Alkoxylation of Alkynes. Organometallics 2017,
36, 2364−2376.
(27) (a) Wang, D.; Cai, R.; Sharma, S.; Jirak, J.; Thummanapelli, S.
K.; Akhmedov, N. G.; Zhang, H.; Liu, X.; Petersen, J. L.; Shi, X. Silver
Effect” in Gold(I) Catalysis: An Overlooked Important Factor. J. Am.
Chem. Soc. 2012, 134, 9012−9019. (b) Zhdanko, A.; Maier, M. E.
Explanation of “Silver Effects” in Gold(I)-Catalyzed Hydroalkox-
ylation of Alkynes. ACS Catal. 2015, 5, 5994−6004. (c) Homs, A.;
Escofet, I.; Echavarren, A. M. On the Silver Effect and the Formation
of Chloride-Bridged Digold Complexes. Org. Lett. 2013, 15, 5782−
5785.
(28) Lu, Z.; Han, J.; Hammond, G. B.; Xu, B. Revisiting the
Influence of Silver in Cationic Gold Catalysis: A Practical Guide. Org.
Lett. 2015, 17, 4534−4537.
(29) (a) Preisenberger, M.; Schier, A.; Schmidbaur, H. (Phosphine)-
gold(I) trifluoromethanesulfonates, trifluoroacetates and trichloro-
thioacetates. J. Chem. Soc., Dalton Trans. 1999, 0, 1645−1650.
̈
(b) Zhdanko, A.; Strobele, M.; Maier, M. E. Coordination Chemistry
of Gold Catalysts in Solution: A Detailed NMR Study. Chem. - Eur. J.
2012, 18, 14732−14744.
(30) We studied the JohnPhos−Au−Cl/AgOTf system (Table 1,
entry 6) by means of 31P NMR spectra recorded at the end of the
reaction (see the Supporting Information for details). A main signal at
δ 63.9 ppm was observed, indicating that a [JohnPhos−Au−(3-
hexyne)]OTf is prevalently present during the reaction. Ciancaleoni,
G.; Belpassi, L.; Tarantelli, F.; Zuccaccia, D.; Macchioni, A. A
combined NMR/DFT study on the ion pair structure of [(PR1 R2)-
2
Au(η2-3-hexyne)]BF4 complexes. Dalton Trans 2013, 42, 4122−4131.
(31) Makosza, M. Phase-transfer catalysis. A general green
methodology in organic synthesis. Pure Appl. Chem. 2000, 72,
1399−1403.
(18) E-factor = mass of waste/mass of desired product.
(19) Effective mass yield, EMY = (mass of desired product/total
mass of material used) × 100.
(20) Gatto, M.; Baratta, W.; Belanzoni, P.; Belpassi, L.; Del Zotto,
A.; Tarantelli, F.; Zuccaccia, D. Hydration and alkoxylation of alkynes
catalyzed by NHC−Au−OTf. Green Chem. 2018, 20, 2125−2134.
(32) (a) Leyva, A.; Corma, A. Corma, Isolable Gold(I) Complexes
Having One Low-Coordinating Ligand as Catalysts for the Selective
Hydration of Substituted Alkynes at Room Temperature without
Acidic Promoters A. J. Org. Chem. 2009, 74, 2067−2074. (b) Gaillard,
́
S.; Bosson, J.; Ramon, R. S.; Nun, P.; Slawin, A. M. Z.; Nolan, S. P.
F
DOI: 10.1021/acs.organomet.8b00689
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Development of Versatile and Silver-Free Protocols for Gold(I)
Catalysis. Chem. - Eur. J. 2010, 16, 13729−13740. (c) Nun, P.;
́
Ramon, R. S.; Gaillard, S.; Nolan, S. P. Efficient silver-free gold(I)-
catalyzed hydration of alkynes at low catalyst loading. J. Organomet.
Chem. 2011, 696, 7−11. (d) Weerasiri, K. C.; Chen, D.; Wozniak, D.
I.; Dobereiner, G. E. Internal Alkyne Regio- and Chemoselectivity
using a Zwitterionic N-Heterocyclic Carbene Gold Catalyst in a
Silver-Free Alkyne Hydration Reaction. Adv. Synth. Catal. 2016, 358,
4106−4113. (e) Collado, A.; Patrick, S. R.; Gasperini, D.; Meiries, S.;
Nolan, S. P. Influence of bulky yet flexible N-heterocyclic carbene
ligands in gold catalysis. Beilstein J. Org. Chem. 2015, 11, 1809−1814.
́
(33) Brill, M.; Nahra, F.; Gomez-Herrera, A.; Zinser, C.; Cordes, D.
B.; Slawin, A. M. Z.; Nolan, S. P. Gold-N-Heterocyclic Carbene
Complexes of Mineral Acids. ChemCatChem 2017, 9, 117−120.
̈
(34) (a) Schießl, J.; Schulmeister, J.; Doppiu, A.; Worner, E.;
Rudolph, M.; Karch, R.; Hashmi, A. S. K. An Industrial Perspective on
Counter Anions in Gold Catalysis: Underestimated with Respect to
“Ligand Effects. Adv. Synth. Catal. 2018, 360, 2493−2502. (b) Schießl,
̈
J.; Schulmeister, J.; Doppiu, A.; Worner, E.; Rudolph, M.; Karch, R.;
Hashmi, A. S. K. An Industrial Perspective on Counter Anions in
Gold Catalysis: On Alternative Counter Anions. Adv. Synth. Catal.
2018, 360, 3949−3959.
G
DOI: 10.1021/acs.organomet.8b00689
Organometallics XXXX, XXX, XXX−XXX