Hydration and alkoxylation of alkynes catalyzed by NHC-Au-OTf

Article abstract of DOI:10.1039/c8gc00508g

The NHC-Au-OTf [NHC = 1,3-bis(2,6-di-isopropylphenyl)-imidazol-2-ylidene] catalyst was tested in the alkoxylation and hydration of alkynes in a wide set of neoteric solvents for the first time. We found that most of these solvents (ethyl lactate, glycerol, propylene carbonate, d-limonene, γ-valerolactone, and p-cymene) are comparable or better solvents with respect to traditional VOSs. An important beneficial effect of γ-valerolactone was found in the hydration of inactive diphenylacetylene and one order of magnitude higher TOF was obtained with respect to the literature values. Kinetic experiments and DFT calculations seem to indicate that the polarity of the solvent and the presence of suitable proton acceptor/donor functionalities on the solvent itself could be taken into account.

Full text of DOI:10.1039/c8gc00508g

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DOI: 10.1039/C8GC00508G
Hydration and Alkoxylation of Alkynes Catalyzed
by NHCꢀAuꢀOTf
Mattia Gatto,[a] Walter Baratta, [a] Paola Belanzoni,[b][c][d]* Leonardo Belpassi,[c][d],
Alessandro Del Zotto,[a] Francesco Tarantelli,[b][c][d] Daniele Zuccaccia,[a][c]*
[a] Dipartimento di Scienze Agroalimentari, Ambientali e Animali, Sezione di Chimica,
Università di Udine, Via Cotonificio 108, Iꢀ33100 Udine, Italy;
[b] Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, Via
Elce di Sotto 8, Iꢀ06123, Perugia, Italy
[c] Istituto di Scienze e Tecnologie Molecolari del CNR (CNRꢀISTM), c/o Dipartimento di
Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, Via Elce di Sotto 8, Iꢀ
06123, Perugia, Italy;
[d] Consortium for Computational Molecular and Materials Sciences (CMS)2, Via Elce di
Sotto 8, Iꢀ06123, Perugia, Italy
Abstract
NHCꢀAuꢀOTf [NHC = (1,3ꢀbis(2,6ꢀdiꢀisopropylphenyl)ꢀimidazolꢀ2ꢀylidene] catalyst was
tested in the alkoxylation and hydration of alkynes in a wide set of neoteric solvents for the
first time. We found that most of these solvents (ethyl lactate, glycerol, propylene carbonate,
dꢀlimonene, γꢀvalerolactone, pꢀcymene) are comparable or better solvents with respect to
traditional VOS. An important beneficial effect of γꢀvalerolactone was found in the hydration
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of inactive diphenylacetylene and one order of magnitude higher TOF was obtained with
respect to the literature values. Kinetic experiments and DFT calculations seem to indicate
that the polarity of the solvent and the presence of suitable proton acceptor/donor
functionalities on the solvent itself could be taken into account.
Keywords:
Gold catalysis; hydration; neoteric solvent; γꢀvalerolactone; DFT
Introduction.
During the last 10 years, homogeneous gold(I) catalysis has become quite popular within the
organic chemistry community due to its activity and peculiar chemoꢀselectivity in
nucleophilic addition to a carbon−carbon unsaturated bond.1 On the other hand, most of the
protocols that employ gold(I) complexes as catalysts, are unsustainable from a green
chemistry point of view2: high catalyst loading, use of volatile organic solvent (VOS), silver
salts as halide scavenger, and nonꢀrecyclable catalysts are the major drawbacks.3 A great
effort was done in the area of neat and silverꢀfree gold catalysed reaction. In this context, for
example, Nolan and coꢀworkers gained good results in the regioꢀ and stereoselective
hydrocarboxylation of alkynes,4 the synthesis of homoallylic ketones,5 and the dehydrative
formation of ethers from benzylic alcohols and phenols.6
Recently, we investigated the activity of NHCꢀAuꢀX [NHC
=
(1,3ꢀbis(2,6ꢀdiꢀ
‒
‒
‒
‒
isopropylphenyl)ꢀimidazolꢀ2ꢀylidene, X‒ = BArF‒, BF4 , SbF6 , ClO4 , OTf‒, NTf2 , OTs‒,
TFA‒), BArF‒ = tetrakis(3,5ꢀbis(trifluoroꢀmethyl)phenyl)ꢀborate] as catalysts in solventꢀ,
acidꢀ and silverꢀfree hydration of alkynes at room/mild temperature and with suitable ionic
additives.7 The hydration (and related alkoxylation) of alkynes is an environmentally friendly
2

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method to form the carbonꢀoxygen bond that satisfies both carbon efficiency and atom
‒
economy rules.8 It was found that the catalysis occurred with OTf‒ and NTf2 as intermediate
coordinative and basic counterions only.9 The pivotal role of the counterion10 in all the steps
of the catalytic pathway (both nucleophilic attack11 and protodeauration step12) were
highlighted by kinetic experiments coupled with DFT calculations that allowed us to optimise
the experimental conditions, achieving high TON (104) and TOF (103 hꢀ1). Importantly, very
low Eꢀfactor (0.03ꢀ0.06) and high Effective Mass Yield, EMY, (94ꢀ97) values were reached
thanks to the green conditions employed.13
The neat conditions are not those suitable for promoting the reaction starting from solid
and/or viscous reagents. Besides, it was also observed that the addition of appropriate ionic
(such as NBut4OTf) or neutral additives (such as DMF and DMPU) could increase the rate of
the catalytic hydration and alkoxylation of alkynes reactions.14 For these reasons, a further
step towards new, efficient, and sustainable gold catalysed hydration and alkoxylation
reactions according to the 12 principles of Green Chemistry15 seems the use of green solvents
showing suitable functionalities.
Replacement of VOS with green solvents16 is a key topic in organic synthesis, and in many
transition metal catalysed organic process bioꢀbased solvents17 such as water18, γꢀ
valerolactone (GVL)19, glycerol20, lactic acid and its derivatives21, dꢀlimonene and pꢀ
24
cymene22 are employed instead of VOS. Other green solvents such as biodiesel23, scCO2
,
perfluorinated hydrocarbons25, polyethylene glycol (PEG)26, Deep Eutectic Solvent (DES)27
and ionic liquid (IL)28 also find frequent use in organic synthesis.
Use of neoteric solvents instead of VOS is rare in gold catalysis. Recently, the group of
GarcíaꢀÁlvarez reported the employment of DES in the cycloisomerisation and oneꢀpot
tandem cycloisomerisation/Diels–Alder reaction catalysed by Au(I) iminophosphorane
complexes.29 The same catalyst was also used in the cycloisomerization of alkynyl amides in
aqueous or eutecticꢀmixture solutions.30 Another example concerning gold catalysis in green
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media is the use of PPh3ꢀAuꢀCl for the direct oxidative amide synthesis starting from
aldehydes and amines in PEG.31
Here we present the results of the investigation on the activity of NHCꢀAuꢀOTf [NHC = (1,3ꢀ
bis(2,6ꢀdiꢀisopropylphenyl)ꢀimidazolꢀ2ꢀylidene] catalyst in the alkoxylation and hydration of
alkynes in a wide set of neuteric solvents. We found that most of these solvents (ethyl lactate,
glycerol, propylene carbonate, dꢀlimonene, γꢀvalerolactone, pꢀcymene) are comparable or
better solvents with respect to VOS. Kinetic experiments supported by DFT calculations
suggest the important role of the polarity of the solvent, which is related to free ions/ion pair
equilibrium of cationic gold catalyst (NHCꢀAuꢀOTf) and the presence of suitable proton
acceptor/donor functionalities on the solvent itself. Both factors (polarity and functionalities)
influence the three steps of the reaction pathway (preꢀequilibrium, nucleophilic attack and
protodeauration).
We were able to optimise the experimental conditions for the gold catalysed alkoxylation
(hydration) of alkynes in a wide range of green media. To the best of our knowledge, these
important goals have never been achieved before.
Results and Discussion
NHCꢀAuꢀOTf [NHC = (1,3ꢀbis(2,6ꢀdiꢀisopropylphenyl)ꢀimidazolꢀ2ꢀylidene] was synthesised
according to the procedure developed by Nolan and coꢀworkers32, by addition of HOTf to the
acetonyl complex NHCꢀAuꢀCH2ꢀ(C=O)CH3 (see Supporting Information for details) in order
to completely avoid the use of any silver additive, even in the generation of the gold catalyst.
NHCꢀAuꢀOTf has been evaluated as catalyst both in the methoxylation of 3ꢀhexyne (1) into
3,3ꢀdimethoxyhexane (1a) (Table 1) and the hydration of alkynes (Table 2, Table S1, and
Table S2) in different solvents.
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Table 1. NHCꢀAuꢀOTf catalysed methoxylation of 3ꢀ
hexynea
Timec TOFd
Conv.
εre
Entry
Solvent
(hꢀ1)
(%) b
(h)
VOS
1
2
chloroform
dichloromethane
acetone
99
96
98
98
63
27
9
2
6
288
220
280
180
80
4.81
8.93
21.0
22.2
37.3
37.3
37.3
3
4
4
3ꢀnitrotoluene
nitromethane
nitromethanef
nitromethaneh
Green
6.5
24
24
24
5
5a
5b
14g
9g
perfluoroꢀ
decalini
6
99
1
495
1.94
7
8
pꢀcymene
dꢀlimonene
propionic acid
ethyl palmitatei
anisole
99
96
77
99
96
1
4
2
2
2
495
205
350
340
315
2.24
2.4
9
3.35
3.07
4.3
10
11
isopropyl
acetate
12
96
2
285
6.3
13
14
15
16
17
18
PEGꢀ400
MIBK j
0
8
4
2
4
2
4
0
12.4
13.1
99
89
94
9
235
ethyl lactate
cyclohexanone
propionitrile
γꢀvalerolactone
223g 15.4
290
20
16.1
29.7
36.9
96
340
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18a γꢀvalerolactonef
18b γꢀvalerolactoneh
69
52
51
99
9
6
8
84g
36g
5
36.9
36.9
47.2
46.5
46.5
19
20
21
DMSO
glycerol
glycerolk
24
2
255
2
2
propylene
carbonate
22
98
11
145
66.1
23
24
cit.ac.ꢀDMU l
chOTfꢀDMU m
95
98
6.5
6
145
270
ꢀ
ꢀ
a
Catalysis conditions: NHCꢀAuꢀOTf (0.0022 mmol, 1.5
mg) 3ꢀhexyne (1.1 mmol, 125 µL), MeOH (2.2 mmol, 89
b
µL), solvent (200 µL). Determined by 1H NMR; average
value of three measurements. cTime necessary to reach the
d
reported conversion. TOF = (mol
/ mol catalyst) / t
product
calculated after 1 h of reaction. e εr = dielectric constant33.
g
f Amount of solvent increased to 500 µL. Calculated at
h
i
2h. Amount of solvent increased to 1250 µL. Two
phases were observed.34 j MIBK= methylꢀisobutyl ketone.
k
Conducted without MeOH, TOF and conversion are
related to the formation of acetal of glycerol. l Citric acid
m
(2 equiv)/dimethyl urea (3 equiv). Choline triflate (1
equiv)/ dimethyl urea (2 equiv).
A typical catalytic run was performed by mixing 3ꢀhexyne with 2.0 equiv of MeOH in the
presence of the catalyst (0.2 mol% with respect to the alkyne) and the proper solvent (0.2
mL) at 30 °C (Table 1). The progress of the reaction was monitored by NMR spectroscopy by
integrating the signal of 3ꢀhexanone formed by hydrolysis of the product 3,3ꢀ
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dimethoxyhexane (see Supporting Information). The complex NHCꢀAuꢀOTf was inefficient
in PEGꢀ400 only, as no formation of the product was detected after 8h (Table 1, entry 13).
Figure 1. TOF vs dielectric constant for VOS (red, in the order from left to right: chloroform,
dichloromethane, acetone, 3ꢀnitrotoluene, and nitromethane) and green solvents (green, in the
order form left to right: perfluoroꢀdecalin, pꢀcymene, dꢀlimonene, propionic acid, ethyl
palmitate, anisole, isopropyl acetate, MIBK, ethyl lactate, cyclohexanone, propionitrile, γꢀ
valerolactone, DMSO, glycerol, and propylene carbonate) employed in the methoxylation of
3ꢀhexyne catalysed by NHCꢀAuꢀOTf (selected values from Table 1).
Instead, high or even quantitative (>99%) formation of 3,3ꢀdimethoxyhexane was reached
within 1ꢀ24 h using other VOS and green solvents (Table 1).
In the case of VOS, quantitative (>96%) conversion of the substrate 1 into 1a was reached in
2, 6, 4, and 6.5 h in chloroform, dichloromethane, acetone, and 3ꢀnitrotoluene, respectively
(Table 1, entries 1ꢀ4). Much less efficiently, NHCꢀAuꢀOTf promoted the formation of the
reaction product in rather low yield (63% after 24 h) in nitromethane (Table 1, entry 5). As
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expected, a longer reaction time was observed upon increasing the volume of nitromethane
from 200 to 1250 µl (Table 1, entries 5a and 5b).
High conversions were generally attained within short reaction times using neoteric solvents.
Quantitative conversion was obtained after 1 h using pꢀcymene and perfluorodecalin, while a
twice time was necessary using ethyl palmitate, anisole, isopropyl acetate, ethyl lactate, and
glycerol. A longer reaction time (4 h) was necessary in the case of dꢀlimonene, MIBK,
cyclohexanone and γꢀvalerolactone and, finally, about 6 h were necessary using DES
solvents, formed by mixing 2 equiv of citric acid mixed with 3 equiv of dimethyl urea
(cit.ac.ꢀ DMU in Table 1, entry 23) or 1 equiv of choline triflate with 2 equiv of dimethyl
urea (chOTfꢀDMU in Table 1, entry 24). The reaction proceeded very slowly in propylene
carbonate (PC) and dimethyl sulfoxide (DMSO). Thus, about 11 h were necessary to obtain a
conversion of 98% in PC, (Table 1, entry 22), while only 51% of conversion was observed in
DMSO within 24 h (Table 1, entry 19). As observed for nitromethane, a longer reaction time
was observed upon increasing the volume of γꢀvalerolactone up to 1250 µl (Table 1, entries
18, 18a, 18b) and quantitative conversion was obtained in 24h.
The comparison of the catalytic activity of NHCꢀAuꢀOTf in different solvents was made by
examining the TOF value [TOF (hꢀ1) = moles of product/moles of catalyst/time (h), Table 1)].
The TOFs calculated for VOS ranged from 80 hꢀ1 (nitromethane) to 288 hꢀ1 (chloroform)
(Table 1, entries 1ꢀ5). A general trend can be observed: the TOF value decreases when the
polarity of the solvent increases. This finding suggests the importance of the equilibrium ion
pair/free ions of NHCꢀAuꢀ(3ꢀhexyne)OTf, due to the specific role of the anion during the
reaction (Figure 2).
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Figure 2. The equilibria of the precatalyst with alkyne and solvent and the free ions/ion pair.
We have previously investigated the level of aggregation between the counterion and cationic
linear gold complexes bearing different ligands, such as phosphines and carbenes, by
diffusion PGSE (Pulsed field Gradient Spin Echo) NMR spectroscopy as a function of
concentration and solvent.35 Different scenarios where obtained: from ion pair as the
predominant species in chloroform (εr = 4.80) to free ions in high polar solvents like
methanol (εr = 32.66), while the presence of both free ions and ion pairs was detected in
medium polarity solvents such as methylene chloride (εr = 8.93).
Previous experimental and theoretical observations in the methoxylation of alkynes indicate
that the counterion can promote both nucleophilic attack36,37,38 and proton shuttle.39 Thus, the
anion acts as a template during the nucleophilic attack through the formation of a hydrogen
bond and it can help the displacement of the proton during the protodeauration step.
By increasing the polarity of the solvent and decreasing the concentration of the catalyst, the
ion pair/free ions equilibrium is shifted towards the latter (Figure 2), thus during the
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nucleophilic attack and protodeauration, the anion is not involved. In these conditions, it has
been supposed that a second methanol molecule could be implied in the mechanism.9 In this
context, the higher TOF value calculated for the reaction run in acetone with respect to that
obtained for the reaction run in 3ꢀnitrotoluene (the dielectric constant values of these two
solvents are very similar, see Table 1 entry 3 vs entry 4) can be ascribed to a specific role of
the carbonyl functionality in the reaction mechanism.14
When green solvents are taken into account, it is most probable that, also in this case, the
polarity of the solvents can be crucial in determining the catalytic activity of NHCꢀAuꢀOTf.
Moreover, the presence of peculiar functional groups could i) help to promote nucleophilic
attack and/or protodeauration, ii) affect the catalytic performances of the catalyst upon
coordination of the solvent to the metal centre giving inactive NHCꢀAu(solvent)OTf species
(Figure 2).
For solvents showing the lowest dielectric constant values (< 2.4) we have obtained the
highest TOFs, this is the case of pꢀcymene and perfluorodecalin (TOF is 495 hꢀ1 for both
solvents, Table 1, entries 6 and 7), as expected. High TOF values (in the range 285ꢀ350 hꢀ1)
were obtained also using propionic acid, ethyl palmitate, anisole, and isopropyl acetate as the
solvent (Table 1, entries 9ꢀ12), whose dielectric constant values span the range 3.1ꢀ6.3. An
exception was found for dꢀlimonene for which, notwithstanding its low dielectric constant
(2.4), the much lower TOF value of 205 hꢀ1 was obtained (Table 1, entry 8). Such a result
should be ascribed to the greater affinity of the carbonꢀcarbon double bond toward gold
fragments.40 Stable LꢀAuꢀ(alkene/alkyne)X complexes have been synthesised and
characterised, and their behaviour in solution has been studied.41 The coordination of the
unsaturated hydrocarbon could reduce the amount of active catalyst in the cycle, and
consequently the TOF value is lowered (Figure 2).
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The TOF value of propionic acid is in line with that found for the other solvents showing
similar dielectric constant, thus confirming that the presence of a Brönsted acid does not
speed up the reaction, since the rate determinate step is the nucleophilic attack.11
For solvents with intermediate dielectric constant (between 12 and 20) the TOF value
decreases in comparison with those having lower polarity. The TOFs range from 223 hꢀ1 for
ethyl lactate (Table 1, entry 15) to 290 hꢀ1 for cyclohexanone (Table 1, entry 16). The high
value found for the latter could be related to the presence of carbonyl functionality as acetone
(see above). It is interesting to note that no reaction was observed in PEGꢀ400 after 8 hours.
We have previously studied the alkoxylation of 3ꢀhexyne by triethylene glycol monomethyl
ether catalysed by NHCꢀAuꢀX (X = OTs, BArF) complexes and we noted that the overall
reaction was strongly slowed down in the presence of the polyꢀether functionality.36
Furthermore, both catalysts promote full conversion in similar reaction time (note that when
methanol is employed as the nucleophile, the reaction promoted by NHCꢀAuꢀOTs is about
five fold faster than that catalysed by NHCꢀAuꢀBArF) because the OꢀH bond may be
polarized via specific intramolecular interactions, thus suppressing the anion effect.
Therefore, the reaction can be inhibited by the solvation ability of PEGꢀ400 towards both the
counterion and methanol.
For green solvents whose dielectric constant is higher than 27 (Table 1, entries 17ꢀ22)
contradictory results in terms of TOF/ɛ correlation have been found. In particular, very low
TOFs were obtained using propionitrile and DMSO (20 hꢀ1 and 5 hꢀ1, respectively, Table 1
entries 17 and 19). The poor catalytic activity of NHCꢀAuꢀOTf in these two solvents can be
correlated not only with their high dielectric constant value, but also with their remarkable
coordination ability towards gold (Figure 2).42 At this regard, it is worthy that in 2006, Nolan
and coworkers43 synthesised the stable NHCꢀAuꢀacetonitrile complex, frequently used as
precatalyst. The strong excess of propionitrile disadvantages the formation of the catalytic
active goldꢀalkyne complex, thus markedly reducing the TOF value (Figure 2). In a similar
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way, Zhdanko and Maier observed that DMSO is much more coordinating versus gold than
3ꢀhexyne44 (Figure 2) and therefore a marked reduction of catalytic activity in DMSO is
expected.
In the case of glycerol, notwithstanding its high dielectric constant value (46.5), a relative
high TOF value (255 hꢀ1) has been obtained (Table 1, entry 20). It was previously found,
from both experimental14b and theoretical37 point of view, that the nucleophilic attack of
MeOH can be helped by other surrounding molecules of MeOH. Thus, it is likely that in
glycerol the gold catalyst is prevalently present in solution as free ions, therefore, the high
catalytic activity could be ascribed to the active role of glycerol during the nucleophilic
attack. Besides, the coordination ability of glycerol towards the gold centre should be similar
to that of MeOH, namely, lower than that shown by 3ꢀhexyne.44 In should be noted that when
the catalysis was performed in pure glycerol without addition of MeOH, a negligible amount
of the diacetal was observed (Table 1, entry 21). This finding rules out the possibility that
glycerol can attack 3ꢀhexyne thus diminishing the alkyne amount during the nucleophilic
attack of MeOH.
Finally, a brief comment should be made about the higher values of TOF found in the case of
γꢀvalerolactone and propylene carbonate, 340 and 145 hꢀ1, respectively (Table 1, entries 18
and 22). As suggested for other high polarity solvents, the equilibrium free ions/ion pairs is
shifted towards free ions (Figure 2). Both solvents possess functionalities that resembles
those present in DMF and DMPU, that increase the reaction rate of the catalytic alkoxylation
of alkynes.14 We suggest that these solvents might play a fundamental role during the
reaction and in particular they i) do not interact with the NHCꢀAu+ fragment allowing the
coordination of 3ꢀhexyne, ii) can interact with the MeOH molecule during the nucleophilic
attack, and iii) can promote the protodeauration step.
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Even if for both DES solvents here employed no dielectric constant values were found in the
literature, it is however possible to rationalize their relatively high TOFs (Table 1, entries 23
and 24). In the case of cit. ac.ꢀDMU the urea functionality is able to promote the nucleophilic
attack of MeOH, as previously observed for γꢀvalerolactone and propylene carbonate. In the
case of the chOTfꢀDMU system, in addition to the role played by the urea functional group,
the huge amount of triflate ions can increase the catalytic performance due to their active role
in the alkoxylation reaction.36
For all solvents employed in this investigation, the plot of the TOF value vs the dielectric
constant is shown in Figure 1. It can be observed that, with the exclusion of those solvents
that possess functionalities able to promote the reaction (acetone, cyclohexanone, γꢀ
valerolactone and propylene carbonate) or, on the contrary, inhibit it (dꢀlimonene,
propionitrile and DMSO), the value of TOF is almost inversely correlated to the dielectric
constant. From Figure 1, it is evident that the major deviation is represented by γꢀ
valerolactone.
In order to deeply understand the high and unexpected activity of NHCꢀAuꢀOTf in γꢀ
valerolactone along with the possible active role of this solvent during the catalytic cycle,
DFT calculations have been performed (see Computational Details in the Supporting
Information). We have focused on the intriguing result that NHCꢀAuꢀOTf catalyzed
methoxylation of 3ꢀhexyne is much more efficient in γꢀvalerolactone (GVL) than in
nitromethane (NM), two solvents that show analogous dielectric constant (εr = 36.9 for GVL,
εr = 37.3 for NM, see Table 1). As mentioned above,11,12 it is wellꢀaccepted that the rate
determining step (RDS) in the mechanism of NHC gold(I)ꢀcatalyzed alkoxylation of alkynes
is the nucleophilic attack, where the anion plays a dual role, by acting both as a template,
holding the alcohol in the right position for the outerꢀsphere attack, and as a hydrogenꢀbond
acceptor, enhancing the nucleophilicity of the attacking alcohol. In the calculations, complex
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NHC’ꢀAuꢀOTf (NHC’ = 1,3 dimethylimidazolꢀ2ꢀylidene) and 2ꢀbutyne were considered as
models for the catalyst and substrate, respectively. The influence of the GVL and NM in the
methanol addition to 2ꢀbutyne reaction has been analyzed in detail by including an explicit
solvent molecule in the nucleophilic attack step. We should mention here that all implicit
solvent COSMO calculations have been performed with NM used as solvent (dielectric
constant εr = 35.87 in ADF2014.05 program). To understand the superior performance of
NHCꢀAuꢀOTf in GVL, the extreme scenario would be the solvent (GVL) replacing the anion
role in the nucleophile (methanol) activation and operating more effectively, eventually with
the solventꢀanion interaction also increasing the solvent (GVL) efficiency in this process. To
investigate this hypothesis, the activation energy barriers for the nucleophilic attack step
assisted by the anion and by the solvent (both GVL and NM) molecule were compared.
Results of this preliminary study are reported in the Supporting Information (Figures S2ꢀS7)
and show that the anion is indeed able to activate the nucleophile much more efficiently than
the solvent molecule. Much higher activation energy barriers have been calculated for both
NM and GVLꢀassisted nucleophilic attack than those obtained for the OTfꢀꢀassisted
nucleophilic attack. Thus, this extreme scenario that the better performance of the catalyst in
GVL could be ascribed to a solvent molecule replacing the OTfꢀ in the activation of methanol
can be ruled out. It is likely that the solventꢀanion interaction could influence the anion’s role
in the nucleophilic attack. Two distinct experimental conditions need to be addressed: i) ion
pairs as the predominant species, which could be differently affected by NM and GVL; and
ii) free ions as the predominant species, where methanol could be activated by the solvent in
the absence of the anion.
Firstly, we addressed experimental condition i) namely the solvent effect on the ion pairs. To
this aim, it is instructive to analyze the nucleophilic attack step under the following
conditions: with COSMO implicit solvent nitromethane (COSMO NM), with COSMO NM
plus an explicit NM solvent molecule, with COSMO NM plus an explicit NM solvent
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molecule interacting with the anion, and with COSMO NM plus an explicit GVL solvent
molecule interacting with the anion. These four reaction profiles are compared in Figure 3.
The optimized geometrical structures of all the species depicted in Figure 3 are collected in
the Supporting Information (Figures S2, S5, S8, and S9). The activation barrier
corresponding to the transition state structure involved in the nucleophilic attack with
inclusion of only implicit NM solvent is 10.2 kcal/mol (TS COSMO NM, Figure 3) and the
product is formed that lies 2.8 kcal/mol lower in energy with respect to the reference reactant
complex (Figure S10 in the Supporting Information). The OTfꢀ ion is located far from gold at
the substrate side, forming a hydrogen bond with the hydroxyl group of methanol. Inclusion
of an explicit NM solvent molecule slightly interacting with the nucleophile decreases the
activation energy barrier to 8.7 kcal/mol (TS_OTf(NM)’, Figure 3). The product is also
stabilized by hydrogen bonding between NM and methanol, lying 5.4 kcal/mol lower in
energy with respect to the corresponding reactant complex (Figure S11 in the Supporting
Information). When interaction between the explicit solvent molecule (NM or GVL) and
anion is introduced, a different structure for reactant complex should be considered.
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Figure 3. Energy profile for the nucleophilic attack step for the reaction between 2ꢀbutyne
and methanol catalyzed by NHC’ꢀAuꢀOTf. Energy profiles in different colours describe
different process conditions. Green: implicit solvent COSMO NM; red: COSMO NM plus
one explicit solvent NM molecule; blue: COSMO NM plus one explicit NM solvent molecule
interacting with OTfꢀ; grey: COSMO NM plus one explicit GVL solvent molecule interacting
with OTfꢀ . The structures of the most important involved species are also shown. Energy
values (kcal/mol) refer to corresponding RC_X(Y) complex taken as zero.
Among the numerous conformations arising from the position of the anion with respect to
gold, two conformations are of interest for our purposes, those where OTfꢀ is removed from
gold by interaction with a solvent molecule. We denote them as structure RC’_OTf(NM) and
RC’_OTf(GVL) for explicit NM and GVL molecule, respectively (Figure 3 and Figure S13
in the Supporting Information). Interestingly, compared to the corresponding RC_X(Y)
structure where OTfꢀ is located above gold, weakly interacting with it (Figures S1 and S4 in
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the Supporting Information), the NMꢀanion interaction destabilizes it by 5.4 kcal/mol,
whereas the GVLꢀanion interaction stabilizes it by 3.1 kcal/mol (Figure 3). This result
suggests that the anionꢀsolvent (ionꢀdipole) interaction favors the ion pair [NHC’ꢀAuꢀ2ꢀ
butyne]+/OTfꢀ separation in γꢀvalerolactone due to the higher polarity of this solvent with
respect to nitromethane (the dipole moment is 4.71 D for GVL and 3.46 D for NM), which is
responsible for the stabilization of RC’_OTf(GVL) compared to RC_OTf(GVL) structure.
From a kinetic point of view, however, the activation energy barrier for the nucleophilic
attack assisted by the anion interacting with the solvent molecule is much lower for
nitromethane than for γꢀvalerolactone (1.0 kcal/mol for NM vs. 6.7 kcal/mol for GVL, Figure
3), despite TS_OTf(GVL) is more stable than TS_OTf(NM) structure. The balancing of the
two effects (thermodynamic and kinetic), regulated by the different polarities of the solvents,
should determine the overall efficiency of the process. Within this picture, almost the entire
energy barrier to reach the transition state TS_OTf(NM) arises from the [NHC’ꢀAu]+/OTfꢀ
separation process, whereas that to get to the TS_OTf(GVL) one appears to mainly come
from the GVL/OTfꢀ interaction (i.e. from the larger GVL affinity for the anion due to its
higher dipole moment), which makes the anion less available for assisting the methanol
attack. In addition, it is important to note that the highest energy point for NM (blue) and
GVL (grey) reaction profiles is that for NM (6.4 kcal/mol for NM vs. 3.6 kcal/mol for GVL,
Figure 3), in perfect agreement with the experimental results. To explain the larger stability
of TS_OTf(GVL) with respect to TS_OTf(NM), the anion effect on the substrate activation,
which has been recognized by us in alkoxylation of alkynes promoted by LꢀAuꢀX
catalysts12b,45 should be considered. The ion pair [NHC’ꢀAuꢀ2ꢀbutyne]+/OTfꢀ separation and
the larger GVL affinity for OTfꢀ would make the 2ꢀbutyne slippage away from the
symmetrical η2 coordination to [NHC’ꢀAu]+ fragment slightly more easy. Upon η2 → η1
deformation, the electrophilicity of the substrate increases thus facilitating charge transfer
from the nucleophile to the carbon atom C1 farther away from gold in the transition state.
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Therefore the AuꢀC1 bond distance can be related to the nucleophilic attack activation
barrier.45 By simply comparing the AuꢀC1 distances in TS_OTf(NM) and TS_OTf(GVL)
(2.766 vs. 2.769 Å, respectively, Figure 3), the smaller η2 → η1 deformation induced by OTfꢀ
/NM environment in TS_OTf(NM) should be responsible for a decrease in the charge
subtracted from the substrate region consistent with the higher energy of TS_OTf(NM) with
respect to TS_OTf(GVL). This anion effect on the substrate activation is already evident in
RC_OTf(GVL) and RC_OTf(NM) complexes, by comparing their AuꢀC1 and AuꢀC2 bond
distances (AuꢀC1 = 2.220 Å, AuꢀC2 = 2.215 Å in RC_OTf(GVL); AuꢀC1 = AuꢀC2 = 2.218 Å
in RC_OTf(NM)). The lower OTfꢀ affinity towards the cationic [NHC’ꢀAu]+ fragment, due to
the more polar GVL, accounts for the 2ꢀbutyne slippage away from the symmetrical η2
coordination. Although the difference in the 2ꢀbutyne η1 deformation for TS_OTf(NM) and
TS_OTf(GVL) complexes is very small (ΔAuꢀC1 = 0.003 Å), it is significant in terms of
amount of the electronic charge subtracted from the region where the nucleophilic attack
occurs and, in turn, in terms of activation energy barriers. To get an estimate, a 2ꢀbutyne η1
deformation difference in the [NHCꢀAuꢀ2ꢀbutyne]OTs and [P(tBu)3ꢀAuꢀ2ꢀbutyne]OTs
transition states for the methanol nucleophilic attack step of 0.008 Å is responsible for a
difference in the amount of electronic charge subtracted from the triple bond of 0.016e, which
is consistent with differences in the activation energy barriers on the order of very few
kcal/mol.12b For interactions of similar nature, it is reasonable to assume that the ΔC1 value
we are dealing with can account for the stability difference between TS_OTf(NM) and
TS_OTf(GVL) we calculate, which is also on the order of very few kcal/mol. Thus, the
different solvent polarity, through a different degree of ion pair [NHC’ꢀAuꢀ2ꢀbutyne]+/OTfꢀ
separation due to the different solvent/OTfꢀ affinity, also affects the electrophilic character of
the alkyne at the transition state, with the more polar solvent inducing a more efficient
activation of the substrate by the [NHC’ꢀAu]+ fragment.
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Within experimental condition ii), i.e. free ions, the solvent polarity effect on the nucleophilic
attack step in the reaction between 2ꢀbutyne and methanol can be estimated by comparing
the energy profiles for chloroform (TCMA) (d = 1.01 D), NM (d = 3.46 D) and GVL (d =
4.71 D) solvent series, in the increasing polarity order, in the absence of the OTfꢀ anion (free
ions, Figure 2). Results are shown in Figure 4 and optimized geometrical structures are
reported in the Supporting Information (Figures S11ꢀS13). As expected, the transition state
structures (as well as the product complex structures) are stabilized by the more polar
solvents in the order GVL (8.3 kcal/mol) > NM (10.3 kcal/mol) > TCMA (15.1 kcal/mol).
Remarkably, the energy profile for GVL is qualitatively different from that for TCMA and
NM: a productꢀlike transition state is calculated for both TCMA and NM, whereas an earlier
transition state is obtained for GVL, thus indicating a more concerted mechanism for the
nucleophilic attack in γꢀvalerolactone. Looking at the transition state structures, the distance
between the oxygen atom of the hydroxyl group of methanol and the C1 carbon atom of the
substrate decreases from 2.027 Å in [TS_GVL]+ to 1.978 Å in [TS_NM]+ and 1.884 Å in
[TS_TCMA]+. Correspondingly, the 2ꢀbutyne slippage away from the symmetrical η2
coordination is now smaller in [TS_GVL]+ than in both [TS_NM]+ and [TS_TCMA]+, where
the η1 coordination of 2ꢀbutyne is due to the almost completely formed bond between C1 and
the oxygen atom of methanol (i.e. to their productꢀlike structure). In addition, the analysis
based on Voronoi Deformation Density (VDD)46 reveals that the charge on the oxygen atom
of the hydroxyl group of methanol amounts to ꢀ0.146 for GVL, ꢀ0.126 for NM, and ꢀ0.098 for
TCMA, thus suggesting that most of the electronic charge has been already transferred to C1
in [TS_TCMA]+ and [TS_NM]+, but not yet in [TS_GVL]+. We should mention here that
the calculated VDD charges on the oxygen atom of the hydroxyl group of methanol in
TS_OTf(GVL) and TS_OTf(NM) structures of Figure 3 are both ꢀ0.141. Overall, these
findings show that GVL polarity has an effect on the activation of the nucleophile through
polarization of the hydroxyl group.
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Figure 4. Energy profile for the nucleophilic attack step for the reaction between 2ꢀbutyne
and methanol catalyzed by [NHC’ꢀAu]+. Energy profiles in different colours describe
different solvents. Red: chloroform (TCMA); blue: nitromethane (NM); grey: γꢀvalerolactone
(GVL). The structures of the transition states are also shown. Energy values (kcal/mol) refer
to corresponding reactant complexes [RC_X]+ taken as zero.
In conclusion, the higher catalytic activity of NHCꢀAuꢀOTf for methoxylation of 3ꢀhexyne in
γꢀvalerolactone with respect to nitromethane can be ascribed to the different polarity of the
two solvents which affects the anion participation during the nucleophilic attack if ion pairs
are considered. For the more polar γꢀvalerolactone, the degree of ion pair separation is
superior, and thermodynamically more stable species, both reactant complex and transition
state, are formed. Transition state stability is additionally enhanced by the reduced
(increased) anion affinity for the cationic fragment (the solvent) in the more polar solvent,
which in turn increases the electrophilic character of the substrate. On the other hand, when
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free ions are taken into account, cationic transition states are stabilized by more polar γꢀ
valerolactone that also induces more polarization of the hydroxyl group of methanol.
Taking into account the beneficial role of GVL on the alkoxylation reactions, we decided to
use it in the hydration of diphenylacetylene (2), an inactivate solid alkyne, that cannot be
hydrated in neat conditions, previously optimized by us for liquid alkynes.7 GVL seemed to
be a good choice because not only it might play a helpful role in the mechanism of hydration
of alkyne but it also possess a good miscibility with water and a high boiling point. Main
results are reported in Table 2. Catalytic diphenylacetilene hydration performed with
phosphine gold complexes was initially studied by Tanaka and coworkers in 2002.47 Using
strongly acidic conditions at 70 °C the authors were able to obtain a TON of 53 in 5h in
methanol. An important breakthrough was achieved by Nolan and coworkers who used NHC
gold(I) complexes.48 Reaction conditions were optimized reducing the catalyst loading up to
0.1% using 1,4ꢀdioxane/water as the solvent and increasing the temperature (120°) in the
absence of any acid. A maximum TON of 770 and a TOF of 42 hꢀ1 were obtained.
Furthermore, respectable TON of 400 and TOF of 66 hꢀ1 values were attained by the same
group employing dimeric (NHCꢀAu)2SO4 complexes at 80 °C in the same solvent mixture.49
In our experiments, diphenylacetylene, 1.1 equiv of H2O and the gold catalyst (0.05 to 0.5
mol% with respect to diphenylacetylene) were mixed in 240 ꢀL of GVL at the desired
temperature (Table 2). The progress of the reaction was monitored by NMR spectroscopy
(see the Supporting Information). Almost quantitative conversion of (2) into 1,2ꢀ
diphenylethanone (2a) was obtained at 120°C at 0.1 mol% catalyst loading (Table 2, entry 1)
and at 80° C at 0.25 mol% catalyst loading (Table 2,entry 4). As expected, higher catalyst
loading (0.5 mol%) was necessary in order to have good conversion upon decreasing the
temperature to 50 °C. On the other hand, at 120° C the catalyst was inefficient or gave a poor
conversion when the catalytic loading was below 0.05 mol% (Table 2, entries 2 and 3).
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Similar conversion was observed (Table 2, entry 7) using ethyl lactate instead of GVL (Table
2, entry 6), while lower conversion is obtained using propylene carbonate (Table 2, entry 8)
as previously found in the alkoxylation of 3ꢀhexyne (Table 1, entry 22).
By examining in detail the conversion against the time (Table S1 in the Supporting
Information) for catalysis for the experiment conducted at 0.1 mol% at 120°C (Table 2, entry
1) it can be noted that a high conversion of 77 % is obtained already after only one hour
(TOF of 770 hꢀ1), see Figure S1 in the Supporting Information. This value is one order of
magnitude higher than those obtained in the literature48 and supports the beneficial effect of
GVL on the hydration of diphenylacetylene with respect to VOS, as observed in the
alkoxylation of 3ꢀhexyne.
Table 2. NHCꢀAuꢀOTf catalysed hydration of
diphenylacetylene in GVLa
Conv.
Loading
(mol%)b
Timed TOFe
Entry
t (°C)
(hꢀ1)
283
50
ꢀ
(%) c
99
15
ꢀ
(h)
3.5
6
1
2
0.1
0.05
0.02
0.25
0.5
120
120
120
80
3
30
7
4
86
90
70
65
34
49
20
31
28
6
5
50
9
6
0.25
0.25
0.25
50
9
7 f
50
9
8 g
50
24
a
Catalysis conditions: diphenylacetylene (0.5 mmol, 89
b
mg), water (0.55 mmol, 9.9 ꢀL) and GVL (240 ꢀL).
c
(mol of catalyst / mol of alkyne) x 100. Determined by
d
1H NMR; average value of three measurements. Time
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e
necessary to reach the reported conversion. TOF = (mol
f
product / mol catalyst)/t(h) at the reported conversion.
g
ethyl lactate instead of GVL.
instead of GVL.
propylene carbonate
We then screened other alkynes to verify the scope of this methodology (Table S2, in the
Supporting Information). Importantly, both internal and terminal alkynes bearing different
alkyl and aromatic groups reacted in GVL giving the corresponding ketone in high yield with
performances that are in line with those reported in literature when VOS were employed.
Conclusion
In this work, we have developed a green methodology for the alkoxylation and hydration of
alkynes run in neoteric solvents instead of traditional VOS promoted by cationic NHC gold
catalysts. As a primary and important goal, we found that the reaction proceeds very well in
most of the alternative solvents employed, such as ethyl lactate, glycerol, propylene
carbonate, dꢀlimonene, γꢀvalerolactone, and pꢀcymene. TOFs are comparable or even better
with respect to those obtained using VOS. On the other hand, when the reaction is performed
in DMSO or propionitrile the TOFs are much lower (Table 1).
Secondarily, we found that the activity of the catalyst (in terms of TOF) seems to be inversely
correlated to the polarity of the solvent (dielectric constant) as depicted in Figure 1. This
behaviour is consistent with the active role of the counterion in three steps of the reaction
pathway (preꢀequilibrium, nucleophilic attack and protodeauration). Increasing the dielectric
constant, the ion pair/free ions equilibrium (Figure 2) is shifted toward the latter and thus the
beneficial effect of OTfꢀ during the nucleophilic attack (RDS) of methanol (water) is reduced.
Another issue is the presence of suitable functional groups on the solvent itself. The presence
of proton acceptor/donor functionalities in cyclohexanone, glycerol and DES (cit.ac.ꢀDMU
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and chOTfꢀDMU) can speed up the reaction, even if these solvents possess mediumꢀhigh
dielectric constant.
On the contrary, the presence of a coordinating functional group in dꢀlimonene (C=C),
propionitrile (C≡N) and DMSO (S=O) slows down the reaction rate owing to the
coordination of the solvent to the metal centre that afford inactive NHCꢀAu(solvent)OTf
species. As a matter of fact, low polar nonꢀcoordinative pꢀcymene and perfluorodecalin
showed to be the best solvents (TOF = 495 hꢀ1). In addition, also the polar aprotic non
coordinating GVL gave a good TOF of 340 hꢀ1. DFT calculations corroborate these peculiar
experimental kinetic findings. For the polar γꢀvalerolactone, the degree of ion pair separation
is large, and thermodynamically more stable species, both reactant complex and transition
state, are formed (Figure 3). Transition state is also stabilised by the reduced (increased)
anion affinity for the cationic fragment (the solvent), which in turn increases the electrophilic
character of the substrate.
The beneficial effect of GVL was also found in the hydration of inactive diphenylacetylene,
frequently used as a benchmark. As a matter of fact, with respect to the literature values,
comparable TON and one order of magnitude higher TOF were obtained.
This study suggests that a sustainable production of chemicals with homogeneous gold
catalysts in neoteric solvents is reachable.50 Stimulated by these important results, we are
further exploring the use of gold catalysts in other nucleophilic addition reactions on
substrates with unsatured bonds (especially alkynes) in neoteric solvents.
ASSOCIATED CONTENT
Supporting Information
General procedures and materials, synthesis and characterization of compounds, catalysis
data and plot, and computational details and Cartesian coordinates for DFTꢀcalculated
structures. This material is available free of charge on the RSC Publications Website at
DOI:…
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AUTHOR INFORMATION
Corresponding Author
* D. Z. Eꢀmail: daniele.zuccaccia@uniud.it.
* P.B. Eꢀmail: paola.belanzoni@unipg.it
Funding Sources
This work was supported by grants from the MIUR (Rome, Italy) and the FIRBꢀFuturoꢀinꢀ
Ricerca project RBFR1022UQ:”Novel Au(I)ꢀbased molecular catalysts: from knowꢀhow to
knowꢀwhy (AuCat)”.
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