The mechanism of gold(I)-catalyzed hydroalkoxylation of alkynes: An extensive experimental study

Article abstract of DOI:10.1002/chem.201303795

An extensive experimental study of the mechanism of gold(I)-catalyzed hydroalkoxylation of internal alkynes has been conducted by using NMR spectroscopy. This study was focused on the organogold intermediates, observations of actual catalytic intermediates in situ, and the reaction kinetics that are involved in this reaction. Based on the experimental results, a complete mechanistic picture was established, including on- and off-cycle processes that explain the role of diaurated species. We have shown that gold-catalyzed hydroalkoxylation of internal alkynes is a reaction that requires only one gold atom for the catalytic cycle, disproving a recent hypothesis regarding the involvement of cooperative gold catalysis.

Full text of DOI:10.1002/chem.201303795

DOI: 10.1002/chem.201303795
Full Paper
&
Reaction Mechanisms
The Mechanism of Gold(I)-Catalyzed Hydroalkoxylation of
Alkynes: An Extensive Experimental Study
Alexander Zhdanko* and Martin E. Maier*[a]
Abstract: An extensive experimental study of the mecha-
nism of gold(I)-catalyzed hydroalkoxylation of internal al-
kynes has been conducted by using NMR spectroscopy. This
study was focused on the organogold intermediates, obser-
vations of actual catalytic intermediates in situ, and the reac-
tion kinetics that are involved in this reaction. Based on the
experimental results, a complete mechanistic picture was es-
tablished, including on- and off-cycle processes that explain
the role of diaurated species. We have shown that gold-cata-
lyzed hydroalkoxylation of internal alkynes is a reaction that
requires only one gold atom for the catalytic cycle, disprov-
ing a recent hypothesis regarding the involvement of coop-
erative gold catalysis.
Introduction
of a proton. Following this, protodeauration occurs to give
enol ether C. Further transformation of C into acetal F is con-
sidered to be a classical proton-catalyzed process. A number of
p complexes (A) have already been described;[3] however, the
properties of vinyl gold species B have never been investigat-
ed experimentally. The closest analogue to this structure was
described by Hashmi and co-workers in 2009.[4] Further infor-
mation was provided by experimental model studies on vinyl
gold species not bearing a heteroatom at the double bond. In
particular, protodeauration was found to be a highly stereose-
lective process, occurring with retention of the configuration
at the double bond.[5] In addition to this experimental evi-
dence, there have been a number of theoretical studies on the
mechanism of this reaction.[6] However, no experimental re-
search focusing on the actual catalytic intermediates has been
carried out; only the catalytic process as a whole has been re-
ported so far.[7] Some theoretical studies continue to support
syn-alcohol addition, introducing even more ambiguity into
the mechanistic picture.
The hydroalkoxylation of alkynes catalyzed by cationic gold(I)
complexes was first described 15 years ago,[1,2] and has long
been considered to occur through four key steps (Scheme 1).
In 2010 it was reported, by Fꢀrstner et al., that enol-ether
derived vinyl gold species B is very aurophilic and can readily
form gem-diaurated species D by attracting a second LAu+
unit.[8,9] In a previous study, we provided a convenient route to
enol-ether derived diaurated species D and confirmed the hy-
pothesis of Fꢀrstner et al.[10] Our previous study provided
access to the relevant catalytic intermediates, allowing in-
depth research on the role of D within the catalytic cycle.
Herein, we provide a detailed NMR investigation into the
mechanism of gold-catalyzed hydroalkoxylation. The aim of
this investigation was to gain insight into each of the elemen-
tary steps in the catalytic cycle.
Scheme 1. Gold-catalyzed hydroalkoxylation and concurrent formation of
gem-diaurated species D.
The first step is complexation of the gold catalyst to the sub-
strate to form p complex A. Upon complexation, the substrate
becomes activated towards nucleophilic attack by an alcohol
(either inter- or intramolecularly). Nucleophilic attack leads to
the formation of the vinyl gold complex, B, with the liberation
[a] A. Zhdanko, Prof. Dr. M. E. Maier
Institut fꢀr Organische Chemie, Universitꢁt Tꢀbingen
Auf der Morgenstelle 18, 72076 Tꢀbingen (Germany)
Fax: (+49)7071-295137
E-mail: vinceeero@gmail.com
martin.e.maier@uni-tuebingen.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303795.
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Results and Discussion
The mechanism of protonolysis of diaurated species
Originally, diaurated species D was proposed as an off-cycle in-
termediate.[8] However, to fully understand the mechanism of
hydroalkoxylation, it is necessary to understand whether D
continues to contribute to the overall process, or if the gold
center gets trapped as species D. Therefore, we have studied
the possibility that D can undergo protodeauration.
There are two possibilities that have to be considered
(Scheme 2). Firstly, a nucleophile-assisted dissociative pathway,
in which D first forms vinyl gold species B, which undergoes
Scheme 3. Kinetics of the nucleophile-assisted protodeauration of D3.
tored by NMR spectroscopy (the CH2O signal was used for
quantitative determination of D3). As expected, the reaction
followed pseudo-first-order kinetics. The rate of the reaction is
independent of the concentration of the acid, indicating that
the reaction does not occur as a direct SE2 process, but rather
as a stepwise process through initial formation of the vinyl
gold species B3 as the rate-limiting step (Scheme 3). Impor-
tantly, fast protodeauration ensures that an equilibrium be-
tween D3 and B3 is never established. Therefore, in this case,
the conversion of diaurated species D3 into vinyl gold species
B3 can be considered as an irreversible rate-limiting step.
These findings unambiguously indicate that protodeauration
of the diaurated species cannot occur through the direct reac-
tion with an acid as a SE2 process, but must occur by means of
a nucleophile-assisted dissociative process that involves the
formation of free vinyl gold species B. This finding is in accord-
ance with conclusions by Gagne et al.[9f]
Scheme 2. Preliminary consideration of the possible protonolysis pathways
of the diaurated species.
subsequent protodeauration to finally liberate the product and
the catalyst. Secondly, one might also envision the reaction to
occur as a direct SE2 process. However, in a different example,
Gagne and Wiedenhoefer have already reported that an SE2
process does not operate.[9f] Because the SE2 process for the
gold exchange at diaurated species cannot be completely
ruled out,[11] we have investigated the possibility of protodeau-
ration to resolve any ambiguities.
To establish the correct mechanism, we studied the reaction
of D2 and D1 (Figure 1) with acids (tBu2PyH+, TfOH·(Me2N)2CO)
under several conditions. We found that protonolysis is greatly
Protonolysis of enol-ether derived vinyl gold
Our attention was then turned to the reactivity of vinyl gold
species B towards acids. During this study we realized that this
type of vinyl gold species is more susceptible to protodeaura-
tion than any other vinyl gold species described in the litera-
ture.[12] Most of the vinyl gold species encountered in this
study undergo protodeauration immediately even by using
PrSpH+ (1,8-bis(dimethylamino)naphthalene salt) in CDCl3 or
MeOD. More interestingly, these species also undergo proto-
deauration immediately in methanol. However, strong elec-
tron-withdrawing groups slow down this process significantly.
Conjugation with the p system of an alkene or phenyl ring
also slows down protodeauration.
Figure 1. The diaurated species used in protonolysis studies.
enhanced in the presence of a suitable nucleophile, unambigu-
ously suggesting that the nucleophile-assisted dissociative
mechanism is operating (see the Supporting Information). To
confirm this mechanism, we conducted a series of kinetic ex-
periments. Species D3 was reacted with tBu2PyH+ OTfÀ in
CD2Cl2, in the presence of various amounts of Me2S (8–
29 equivalents), as shown in Scheme 3. The reaction was moni-
To quantitatively describe the structural effects of the sub-
strate and ligand on the protodeauration, we studied the reac-
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Scheme 4. Stereo- and regiospecific protodeauration of vinyl gold species B
as opposed to B’.
sponding enol-ether products. This result is in accordance with
another model study.[14]
Figure 2. Protonolysis of vinyl gold species B1–6 by 4-tert-butylphenol.
Competitive experiments on protodeauration or auration of
the vinyl gold species
tions of vinyl gold species B1–B6 (generated in situ) with 4-
tert-butylphenol, which is a suitably strong acid (Figure 2). Un-
fortunately, rigorous quantitative comparison of the rate of
protodeauration was not possible because none of the reac-
tions displayed general second-order kinetics. This is explained
by the formation of molecular aggregates between free
phenol and its phenoxide product, accounting for the autore-
tardation of the reaction.[13] Nevertheless, some quantitative in-
formation could be obtained; we estimated the relative initial
rates and vinyl gold species half-life periods (measured from
0–50% conversion) and found that the rate of protodeauration
increases in the presence of electron-donating ligands. Also, it
is likely that steric interactions play no (or an insignificant) role
in this reaction. Thus, protodeauration of vinyl gold species B3,
bearing bulky ligand L2, reaches 50% conversion almost four
times faster than B1 (bearing a PPh3 ligand), and 37 times
faster than B4 (bearing electron-deficient ligand L5; see
Scheme 5 for structure). Furthermore, because the reaction
was insensitive to an excess of Et4N+ ClÀ, it can be concluded
that protodeauration does not require any precoordination to
the gold center and starts upon interaction of the double
bond with the proton source.
Diaurated species are reluctant to undergo protonolysis, there-
fore, it can be concluded that fast product formation in gold-
catalyzed hydroalkoxylation can only occur by protodeauration
from the vinyl gold intermediate. However, this protodeaura-
tion process is in competition with the formation of a diaurated
species. Therefore, it is important to understand the depend-
ence of this competition on the structural parameters of the
vinyl gold species.
To address this issue, we conducted competitive studies on
the protodeauration or auration of vinyl gold intermediates.
For this purpose, diaurated species D1, D3, D4, and D5 were
treated with Et4N+ ClÀ (1 equivalent) to quantitatively generate
the corresponding vinyl gold species in situ. These species
were then treated with a solution of tBu2PyH+ and the LAuNC-
Me+ SbF6À. The results strongly depend on the ligand attached
to the gold center (Scheme 5). When the bulky L2-containing
species was used protodeauration was favored, whereas when
PPh3 and L5 ligands were used the formation of a diaurated
species was favored. These results directly correlate with the
stability of diaurated species and the trends in the protodeau-
ration of vinyl gold species.[15] Based on this result, it can be
An important aspect of protodeauration, established by
these experiments, is the stereo- and regioselectivity of the
process. The protodeauration can be concluded to be a one-
way reaction, towards product C, because the alkyne substrate,
S, cannot be reformed during the protodeauration reaction
(Scheme 4). This behavior is opposite to that of vinyl gold spe-
cies B’, an intermediate in the gold-catalyzed hydroalkoxylation
of allenes.[9f] This difference in behavior is due to the strong
mesomeric effect of oxygen, making the carbon atom the only
possible site for protonation in B, but not in B’. Also, the proto-
deauration of B5 and B6 occurred with complete retention of
configuration, as revealed by the NOESY spectra of the corre-
Scheme 5. Competitive protodeauration/auration of vinyl gold species.
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concluded that sterically hindered electron-rich ligands (L2)
will favor protodeauration over the formation of D. For other li-
gands (PPh3, L5), formation of D is favored.
However, E is a cationic complex that could be susceptible
to deprotonation, resulting in the formation of vinyl gold spe-
cies B. Therefore, it is important to determine whether the for-
mation of E from B is reversible under catalytic conditions. For
this purpose, we attempted the auration of enol ether C2
under basic conditions. Treatment of C2 with catalyst 2 and
a proton sponge, in CDCl3, did afford diaurated species D2 as
the only product, but in low yield (8%, in situ) after 19 h at
room temperature (Scheme 7). On the one hand, this result
p-enol-ether gold complexes as intermediates
Enol-ether product C is a component in the system even if it is
eventually transformed into an acetal, therefore, it is necessary
to consider its complexation to the gold catalyst. The corre-
sponding complexes E have been independently reported by
A. Jones et al.[16] During our investigation, we discovered that if
catalytic hydroalkoxylation is performed under buffered condi-
tions (using 2,6-di-tert-butylpyridine, tBu2Py, as an additive),
the targeted synthesis of enol ethers becomes possible. Under
these conditions, we were able to observe p complexes of
enol ethers with gold centers.
Scheme 7. Direct auration of enol ether C2.
Thus, when 3-heptynol, S2, was treated with catalyst 2
(L2AuNCMe+ SbF6À, 5%) in the presence of tBu2Py (34%), in
CDCl3, cyclization occurred immediately (within 5 min), provid-
ing enol ether C2 in quantitative yield (in situ). At the end of
this reaction, the gold catalyst was predominantly present as
a new p-enol-ether complex E2 which was characterized in
situ and exhibited typical spectroscopic values for a complex
of this type, analogous to the literature data (Scheme 6).[16] The
proved that the direct auration of enol ethers, a hitherto un-
precedented process, is possible.[17] However, because this pro-
cess occurred so slowly, even under basic conditions, it would
be virtually impossible under the weakly acidic conditions of
catalytic hydroalkoxylation. Therefore, proton addition to the
vinyl gold species to provide E can be considered as an irrever-
sible process within the catalytic cycle, whereas release of C
from E is an ordinary reversible ligand-exchange process at the
gold center.
Catalytic performance of diaurated species in the hydroal-
koxylation reaction
Diaurated species are unable to undergo direct protonolysis,
therefore, it is important to ascertain whether there are other
ways in which they might contribute to the catalytic process.
To investigate this subject, we performed four experiments by
using two substrates and two diaurated species (10mol% Au;
see Scheme 8). We found that in both cross-experiments no
circulation of gold was observed through the diaurated spe-
cies. The fact that the diaurated species remained completely
unreacted indicated that the catalytic activity was due to the
turnover of traces of free LAu+ species, and that these species
performed so many catalytic cycles that the substrate had
completely reacted before the diaurated species could be re-
newed. Furthermore, this observation suggests that tricoordi-
nate gold complexes, LAu(B)(Alkyne)+ (T), do not trigger hy-
droalkoxylation, but are only transition states in the SN2 ligand-
exchange processes, otherwise the diaurated species would be
renewed (see below for further corroboration). Hence, we have
demonstrated that the diaurated species themselves are not
active catalysts and are only able to communicate with the cat-
alytic cycle through the ligand-exchange pathway. This finding
implies that in processes that have used diaurated species as
catalysts, these species were not acting as direct catalysts, but
instead through dissociation.[18] Accordingly, the less stable D2
was more active because it can dissociate more easily than D3.
In addition, we observed circulation through diaurated spe-
cies in other experiments. Thus, partial circulation was ob-
Scheme 6. p-enol-ether complex E2 and its stability. PrSp=proton sponge
(1,8-bis(dimethylamino)naphthalene).
uncomplexed and complexed enol ether showed two clear
separate signal sets, indicating slow mode of LAu(C2)+/C2
ligand exchange in CDCl3. However, in methanol this exchange
becomes a fast equilibrium [Eq. (1)], as evidenced by a single
doublet for the tBu groups. Ligand-exchange reactions charac-
terize the enol ether as a weak ligand for gold(I) centers,
taking an intermediate position between MeCN and Me2S, in
accordance with the literature data.[16]
Since E exists as an individual compound, it is reasonable to
postulate that the addition of a proton to the vinyl gold spe-
cies is a necessary step in the mechanism of catalytic hydroal-
koxylation (Scheme 6).
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place smoothly). This observation demonstrates nucleophilic
catalysis by the solvent, consisting of speeding up the circula-
tion of the gold species through establishing additional fast-
working ligand-exchange equilibria that do not affect the
global equilibrium. This kind of nucleophilic catalysis, by
a weakly nucleophilic solvent or indifferent third nucleophile,
is frequently observed in ligand exchange at gold centers.
Direct observation of catalytic intermediates in situ
To get a complete understanding of the mechanism of gold-
catalyzed hydroalkoxylation, we conducted kinetic studies by
using NMR spectroscopy. In each experiment we monitored
the disappearance of the substrate with time, the presence of
organic intermediate products, and the development of the
final products. Besides this, particular attention was given to
the observation of catalytic organogold intermediates (resting
states) in situ. Complete tables, diagrams, explanations, and
spectra are given in the Supporting Information.
Initially, catalytic hydroalkoxylation of 3-pentyn-1-ol (S1), in
À
CD3OD, in the presence of catalyst 1 (Ph3PAuNCMe+ SbF6
)
was investigated (Scheme 10).[19] This reaction is characterized
Scheme 8. Absence of gold circulation in catalysis by diaurated species D.
Scheme 10. Cyclization of S1 catalyzed by 1.
by immediate and complete formation of diaurated species
D1, as observed by NMR spectroscopy. According to the reac-
tion stoichiometry, formation of D1 is accompanied by the for-
mation of the same amount of a strong acid (HSbF6). This acid
further catalyzed the transformation of the enol ether so that
only a negligible amount (<0.4%) of the enol ether is detecta-
ble. The overall reaction was found to be half-order in sub-
strate and first-order in gold (see below).
Scheme 9. Observation of gold circulation in catalysis by diaurated species.
served when a less-reactive alcohol S4 was used (Scheme 9).
Formation of D7 is possible owing to preferential protodeaura-
tion of electron-rich B2 compared with that of the vinyl gold
species bearing an electron-withdrawing group (EWG). This re-
action liberates L2Au(Sol)+, which eventually ends up in the
new diaurated species D7. Fast circulation (leading to com-
plete and immediate renewal of the diaurated species) was ob-
served in the cyclization of S2, catalyzed by D1/TfOH in MeOD
(Scheme 9). Again, no circulation was observed for the same
reaction in CDCl3 (despite the overall catalytic reaction taking
In contrast, when using the more bulky catalyst 2, we found
that diaurated species D3 does not form as quickly as when
catalyst 1 was used.[20] Rather, D3 accumulates relatively slowly
(within few minutes) and eventually becomes predominant, re-
sulting in the appearance of a characteristic “rush” period and
the L-shape curve of the kinetic plot shown in Scheme 11. The
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Scheme 11. Observation of the ’’rush’’ period.
shape of this curve is readily explained; the reaction starts very
fast, but the gold species inevitably starts to form the diaurat-
ed species, resulting in significant slowing of the reaction.
Indeed, an experiment with 0.15% catalyst loading allowed us
to observe accumulation of D3, during an extended period of
time, and to register the signals of L2Au(Sol)+ and B3 disap-
pearing at the end of the rush period. Therefore, it can be sug-
gested that formation of the diaurated species accounts for
catalyst deactivation. This problem is not encountered at
higher loadings of 2. When more gold catalyst is present, it is
possible that the reaction can reach completion during the
very fast rush period, before any D3 can accumulate.[21] Howev-
er, after the rush period (when formation of diaurated species
is complete) the system establishes half-order kinetics for the
rest of conversion (see below).
Scheme 13. Hydroalkoxylation of hexyne S8.
presence of various catalysts in CDCl3 (Scheme 13). This study
indicated that bulky electron-rich catalysts 2 and 3 did not
form diaurated species at all, whereas more electron-deficient
and less-crowded catalysts (1, 4, and 5) readily formed the cor-
responding diaurated species. Therefore, in this case, the reac-
tion is much more efficiently catalyzed by electron-deficient
catalysts, even though the catalysis might be accompanied by
the formation of the corresponding diaurated species.
Catalyst 2 (less likely to form the diaurated species) is more
active than 1 for the cyclization of S1. Therefore, we investigat-
ed whether the pure vinyl gold species could be observed if
the formation of the diaurated species is completely sup-
pressed. Recalling that sterically hindered alcohol S7 forms ex-
tremely unstable diaurated species with catalyst 2,[15] we used
this substrate for the reactions with catalyst 2. We performed
catalytic runs at different catalyst loadings (0.04–0.13 mol%)
and in all cases the gold catalyst rested as a single compound,
which was unambiguously proven to be vinyl gold species B8
by comparison with an authentic sample prepared in situ
under noncatalytic conditions (Scheme 12). This finding is the
The above experiments demonstrated that the formation of
a diaurated species is, generally, not obligatory for gold cataly-
sis and the formation of this species can vary broadly (from 0
to 100%). Secondly, and very importantly, thorough monitor-
ing of resting states should be performed to allow unambigu-
ous conclusions to be made.
Probing the early stages of the catalytic cycle
Our experimental data has provided a clear understanding of
the mechanism of gold-catalyzed hydroalkoxylation, starting
from the formation of the vinyl gold species. All that remained
was to define what happens before the formation of this spe-
cies, at the early stages of the catalytic cycle. It is well known
that alkynes form a p complex A which is a reasonable propos-
al for the first step of the catalytic process.[22] However, exactly
how A transforms into the vinyl gold species continues to be
a subject of debate. According to one model, p complex A
reacts directly with an alcohol to give cationic addition prod-
uct BH, which immediately expels a proton to give vinyl gold
species B (Scheme 14, route a).[6] The only experimental study
that investigated the viability of this hypothesis was conducted
in the gas phase under strictly bimolecular collisions. Under
these conditions, formation of the CÀO bond was found to be
impossible.[23] A number of theoretical studies have been pub-
Scheme 12. Direct observation of vinyl gold species.
first direct evidence of the intermediacy of a vinyl gold species
in a catalytic alkyne hydroalkoxylation process. Next, we estab-
lished that the reaction is drastically accelerated by acid, prov-
ing protodeauration to be the rate-limiting step of this pro-
cess.
Similarly, we investigated an intermolecular hydroalkoxyla-
tion of hex-3-yne S8, a more challenging reaction type, in the
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IPrAu(Sol)+ (Sol=solvent, MeCN, H2O, etc.). This result is signifi-
cant because it demonstrates that, A3 is the necessary inter-
mediate. Also, because A3 is formed quantitatively, the first-
order dependence with respect to the gold center also means
that the reaction is first-order in A3. Finally, quantitative forma-
tion of A3 indicates that the ligand-exchange equilibrium
(Scheme 15) remains strongly to the right during most of the
conversion. This finding explains why the reaction is zero-order
in substrate; on reaching saturation the change in concentra-
tion of the substrate does not lead to a substantial change in
the concentration of A3. However, closer to the end of reac-
tion the concentration of A3 will not be equal to the concen-
tration of Au and the reaction will deviate from the zero-order
law. Interestingly, the reaction exhibited 1.3-order kinetics in
MeOH, the reason for which will be discussed below.
Scheme 14. Current viewpoints to account for the CÀO bond-forming event.
lished, concluding that alcohol addition to p complex A must
be thermodynamically disfavored and that the subsequent
proton transfer can only occur in the presence of neighboring
molecules in the condensed phase.[6] Recently, a new hypothe-
sis based on theoretical calculations was proposed.[24] This hy-
pothesis suggested that diaurated species could form by the
direct reaction of two gold-containing species, cationic p com-
plex A and a neutral molecule of gold methoxide LAuOMe (co-
operative catalysis, Scheme 14, route b). However, LAuOMe
must arise from a reversible reaction of the gold catalyst with
methanol (Scheme 14, [Eq. (2)]). This reaction is highly disfa-
vored because LAuOMe is a highly basic compound that may
not exist under the weakly acidic conditions that are typical for
gold-catalyzed hydroalkoxylation.[25]
The role of the ligand-exchange equilibrium
In order to confirm that A (the necessary starting point of hy-
droalkoxylation) arises as the result of the ligand-exchange
equilibrium with a LAuX species and S, we studied the chemi-
cal kinetics of a number of reactions (Scheme 16). The resting
state of the catalysts was monitored in each case by NMR
In order to resolve the above ambiguities, we relied on ki-
netic experiments. We hypothesized that information about
the early stages of the catalytic cycle may only be obtained if
formation of the vinyl gold species becomes the rate-limiting
step and the formation of any diaurated species is suppressed.
These two conditions were applied in a series of experiments
described below.
+
spectroscopy. Thus, the reaction catalyzed by a L2AuSMe2 /
À
Catalysis by IPrAuNCMe+ SbF6
The reaction of hex-3-yne with MeOH, catalyzed by
À
IPrAuNCMe+ SbF6 (IPr=1,3-bis(2,6-diisopropylphenyl)-1,3-di-
hydro-2H-imidazol-2-ylidene), in CDCl3 or CD2Cl2, exhibited
zero-order dependence in substrate, but first-order in gold
(Scheme 15). The examination of the reaction mixtures by NMR
spectroscopy revealed complete formation of IPrAu(hex)+
(hex=hex-3-yne) A3, the concentration of which remains con-
stant during the conversion and eventually converts into
Scheme 15. Addition of methanol to 3-hexyne.
Scheme 16. Reaction kinetics and resting states.
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Me2S system (see Scheme 16 a), exhibited first-order kinetics in
tradicted by our experimental study.[29] The cooperative cataly-
sis mechanism is contradictory to all of our kinetic observa-
tions (it would require second-order kinetics with respect to
the gold species, which was never observed). Also, the cooper-
ative catalysis mechanism is contradictory to the direct obser-
vation of vinyl gold species in situ (Scheme 12). Furthermore,
the presence of an acid promoter would diminish the equilibri-
um shown in [Eq. (2)] (Scheme 14), and negatively affect the re-
action. For the reactions carried out in this section no acid de-
pendence was observed. However, in many cases, the reaction
can be greatly accelerated in the presence of additional acid in
comparison with the use of a gold catalyst alone.
S1, first-order kinetics in gold species, minus first-order kinetics
+
in Me2S, and had L2AuSMe2 as a resting state. The reaction
catalyzed by L2AuCl (see Scheme 16 b), exhibited first-order ki-
netics in S1, half-order kinetics in gold species, and had L2AuCl
as a resting state. In these cases, the ligand-exchange equili-
bria (Scheme 16, [Eq. (4 and 5)]) are strongly on the side of the
resting states.
The intermolecular reaction catalyzed by 2 (see Scheme 16 c)
exhibited pseudo-half-order kinetics in substrate and first-order
1
kinetics in gold.[26] In each experiment, the H NMR spectrum
of catalyst 2 exhibited a single doublet, the chemical shift of
which gradually changed from 1.46 to 1.43 ppm (correspond-
ing to the pure catalyst in methanol). This observation indi-
cates that the catalyst existed as a L2Au(hex)+/L2Au(Sol)+ mix-
ture undergoing fast ligand exchange. As the reaction pro-
gresses to completion, only L2Au(Sol)+ remains and the spec-
troscopic values of the free catalyst are restored.[27] In this case,
the ligand-exchange equilibrium (Scheme 16, [Eq. (6)]) does
not favor any side strongly.
The transformation of gold–alkyne complex A into vinyl
gold species B: the role of hydrogen bonding
Although the results of the above experiments excluded the
possibility of a cooperative catalysis pathway, these experi-
ments did not reveal exactly how A was transformed into vinyl
gold species B. However, we have shown that the catalytic re-
action occurs because of the availability of A and that the reac-
tion must proceed via B (and not D). Therefore, we propose
the involvement of BH, resulting from pure anti-addition
(Scheme 17). This elusive intermediate cannot be observed di-
rectly and remains hypothetical. However, based on the cur-
rent knowledge of related species, we are able to predict the
All reactions were independent from acid, to establish that
protodeauration is not the rate-limiting step in these cases.
The kinetics laws were theoretically derived based on the as-
sumption that the necessary intermediate A must arise as
a result of the corresponding ligand-exchange equilibrium.
Also, the material balance of the system was taken into ac-
count. The theoretically derived rate laws (Figure 3) were in ac-
cordance with experimentally observed laws, confirming the
following: 1) The hydroalkoxylation is only possible from A;
2) The reaction will follow first-order kinetics with respect to A,
but the order of the reaction with respect to the catalyst and
substrate S may vary, depending on the functional depend-
ence [A]=f(S, c(Au)) being operative; 3) Hypothetical tricoordi-
nate complexes LAu(N)(Alkyne)+ are only intermediates (or
transition states) of SN2 ligand-exchange processes and pro-
ductive hydroalkoxylation is not triggered in this state;
4) Simple ligand-exchange equilibria (known to be very fast
processes for the coordination of gold)[28] are established.
This result fully supports the original model (Scheme 14a),
and the cooperative catalysis mechanism (Scheme 14b) is con-
Scheme 17. The transformation of A into B.
Figure 3. The first-order dependence in [A] is the common root of the kinetics laws shown.
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properties of BH. Thus, it is well known, that any species of the
type LAuÀC=CÀX and LAuÀCÀCÀX are prone to elimination,
resulting in the parent alkyne or alkene (depending on the
quality of X as a leaving group).[30] Also, the inability of hydro-
alkoxylation to proceed in the gas phase, under conditions of
bimolecular collisions,[23] is in agreement with proton transfer
from BH only being possible in solution phase, as was suggest-
ed by earlier computational studies.[6] It can be concluded that
the formation of BH (the CÀO bond forming event) must be
philicity of the oxygen atom, activating methanol for addition
(at the same time enhancing deprotonation of BH), whereas
association with a strong hydrogen-bond donor (PhOH) has
the opposite effect. THF did not exhibit any substantial effect,
despite having the ability to form hydrogen bonds. This indi-
cates that the strength of the hydrogen-bond effect depends
on the “quality” of an associated molecule as hydrogen-bond
donor or acceptor. Together with the average 1.3-order kinetics
in methanol that was previously established for this reaction,
this fact suggests that hydrogen bonding with ether or alcohol
has a weak influence on the reaction kinetics.
a highly reversible endothermic process (always k1 !k ). Fur-
À1
thermore, we are able to conclude that proton loss by BH is ir-
reversible. This follows from the experimental observations
and considerations discussed above and in Scheme 4.
The hydrogen-bond effect can be interpreted, with regards
to chemical kinetics, as shown in Scheme 19. Thus, considering
the formation of homo- and heteromolecular species that are
However, two important aspects remain unclear with regard
to the A into B transformation: 1) The importance of the hy-
drogen bonding involving ROH, as suggested by the computa-
tional study; 2) The elimination of H+ is considered to be
a very fast step (k2 is large), therefore, it becomes unclear
whether the whole sequence, from A to B, should be consid-
ered as a combination of one reversible step and a second irre-
versible step (if kÀ1 ꢀk2), or as a sequence of two irreversible
steps (if kÀ1 !k2). Remarkably, all of the experiments described
above do not provide an answer. Regardless of the real situa-
tion, both considerations result in the same kinetics, that is,
first-order kinetics with respect to A (Scheme 17).
To begin to answer these questions, we studied the effect of
various hydrogen-bond donors (PhOH) and acceptors (THF,
DMF) in the reaction of hexyne S8 in CDCl3 (Scheme 18). A dra-
Scheme 19. An interpretation of hydrogen-bond effects by chemical kinet-
ics.
in equilibrium with each other (K2, K3…, Kz), each of them is re-
active towards A (k1, k2…, kz) and the rate law appears as
a polynomial equation. According to this treatment, if the for-
mation of these associated species was really necessary for
a simple reaction with MeOH, very strong dependence on the
concentration of MeOH would be observed because the molar
fraction of the associated species depends on the concentra-
tion of MeOH in the order ꢁ2, which at low concentrations of
MeOH will lead to at least second-order kinetics in methanol.
The chemical shift of the OH proton in solvents such as
CDCl3 or CD2Cl2 strongly depends on the concentration of the
alcohol, a direct consequence of the formation of molecular as-
sociates. That effect is the same as that observed in our earlier
experiments: d(OH) changes from 1.37 to 3.25 ppm as the
amount of MeOH increases from 2.3 to 20 equivalents
(Scheme 15). Evidently, the molar fraction of the molecular as-
sociates increased significantly, whereas the average order in
MeOH was 1.3, which is close to 1. This indicates that the over-
all effect of hydrogen bonding between MeOH molecules is
not strong and the reaction system still behaves as if it was
simply a bimolecular reaction with a free molecule of MeOH in
the solvent. This experimental finding is in contrast with the
earlier computational study, which suggested that the associa-
tion of the alcohol is crucial. Our experiments have established
that hydrogen bonding is not obligatory for simple MeOH ad-
dition to take place. However, the reactivity of MeOH can be
Scheme 18. Effect of hydrogen-bond donors and acceptors.
matic increase in the reaction rate was seen in the presence of
DMF (10 equivalents), whereas phenol slowed down the reac-
tion. Given the fact that DMF and PhOH behave as chemically
inert additives, not influencing the formation and reactivity of
gold–acetylene complex A3 and not giving rise to any new
products, the changes in the reaction rate are, presumably,
due to their influence on the reactivity of MeOH through hy-
drogen bonding.[31] This influence can be explained by the for-
mation of molecular aggregates with variable reactivity to-
wards A3. It can be concluded that the association of MeOH to
a strong hydrogen-bond acceptor (DMF) increases the nucleo-
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changed significantly in the presence of a third additive (or
a co-solvent), which forms strong molecular associates with dif-
ferent reactivity (and also changes the d(OH) chemical shift).
From a practical point of view it is worth noting the strong
positive effect of DMF, which can be used as a solvent or co-
solvent. However, this advantage can be invalidated by DMF’s
basicity, which can negatively affect an acid-dependent reac-
tion (see below).
diaurated species are derived from v=Àk[A], in which [A]=
f(S, c(Au)) by using the ligand-exchange equilibrium and mate-
rial balance that is shown in Figure 3.
The kinetics of the reaction accompanied by formation of
a diaurated species requires a more sophisticated treatment
because three key steps need to be considered; the formation
of vinyl gold species B (k1), the formation of diaurated species
D (k2/k ), and protodeauration (k3) (Scheme 21). The (k2/k
)
À2
À2
equilibrium is part of global ligand-exchange equilibrium.
However, in contrast with the other equilibria discussed, this
equilibrium is dependent on the concentration of vinyl gold
species B, which itself depends on the rate of protodeauration
(k3) and, hence, from the acidity of the system. In turn, because
the formation of D is accompanied by the formation of an
equal amount of acid, the acidity of the system actually de-
pends on D. It is clear that all parts of the system become
highly interrelated. Still, the behavior of a catalytic system that
results in immediate and complete formation of D is amenable
to easy analysis. Thus, by using the steady-state approximation
shown in [Eq. (8)] (Scheme 21), for B (always present in unde-
tectable amounts) and the steady-state approximation shown
in [Eq. (9)] (Scheme 21), for D (always present, contains all of
the gold in the system), the expression for A shown in
[Eq. (10)] (Scheme 21), can be calculated.[32] Putting this expres-
sion into the overall reaction rate ([Eq. (7)], Scheme 21), results
in the rate law shown in [Eq. (11)] (Scheme 21).[33] According to
this law the reaction kinetics are characterized as being half-
order in substrate, half-order in D and half-order in acid. The
following important consequences are drawn from this work-
ing law: 1) If the formation of D is complete, the reaction will
always depend on acidity, regardless of whether protodeaura-
tion is the rate-limiting step of the catalytic cycle or not;
2) The reaction does not depend on the presence of any indif-
ferent nucleophile (N), unless it causes significant deviations
from the necessary condition for the material balance c(Au)=
2[D], which would become c(Au)=2[D]+[LAu(N)+];3) The reac-
tion follows this law regardless of how the catalytic system is
created, either from the catalyst alone (giving rise to 0.5 equiv-
Generalized mechanistic picture
Based on the experimental evidence, a complete mechanistic
picture of the catalytic process can be assembled (Scheme 20).
From this mechanism all experimentally observed kinetics laws
are derived. The kinetics of the reactions characterized by rate-
limiting formation of vinyl gold species B and no formation of
Scheme 20. The mechanism of the gold-catalyzed hydroalkoxylation of al-
kynes.
Scheme 21. Reaction kinetics at immediate and complete formation of the diaurated species.
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alents of H+ and 0.5 equivalents of D per 1 equivalent of gold
catalyst), or from the catalyst and acid or from D and acid.
4) Proton delivery, from BH to E, does not occur intramolecu-
larly through a chain of alcohol molecules clustered around BH
by hydrogen bonding (as suggested by an earlier computa-
tional study[6]). Rather, the proton from BH is removed, becom-
ing free in solution, and then proton addition to B occurs to
give E as an independent intermolecular event.
These principles were demonstrated by the reaction of penty-
nol S1 in methanol using various catalytic systems. We experi-
mentally determined that this reaction can be described by the
rate laws shown in Scheme 21, originating from the general rate
law [Eq. (11)] containing keff =0.27Æ0.02 L1/2 mmolÀ1/2 minÀ1,
irrespective of the catalytic system. In particular, first-order ki-
netics with respect to the gold species is established by cata-
lyst 1 alone, leading to the rate law shown in Scheme 10. Ac-
cording to the tolerance of the system to an indifferent nucle-
ophile, the kinetic profile is insensitive to small amounts of
Me2S.
substrate for 1,2-elimination, the reverse process. However, BH
is also a highly acidic species that can partake in rapid proton
transfer to a nearby molecule. Therefore, some of the extreme-
ly elusive short-lived BH molecules will succeed in the transfor-
mation into vinyl gold species B. The difficulty of the alcohol
addition to A, which will eventually form B, is the reason for
the reaction rate order: intermolecular<6-exo-dig !5-endo-
dig. Intermolecular hydroalkoxylation is, therefore, the most
challenging, typically requiring excess alcohol. Neutral hydro-
gen-bond acceptors facilitate, whereas hydrogen-bond donors
inhibit, the transformation of A into B. Electron-poor ligands
increase the electrophilicity of A, greatly enhancing the trans-
formation of A into B. The formation of B is irreversible, provid-
ing a fundamental basis for the reaction to proceed until no
alkyne is left in the mixture. Vinyl gold species B is also
a highly reactive species; it can competitively undergo proto-
nolysis or auration to give p complex E or diaurated species D,
respectively. Formation of E is a necessary step in the process,
whereas formation of D is a drawback for the whole catalytic
cycle. Although formation of D is reversible, it is strongly fa-
vored thermodynamically; B binds the catalytic LAu+ species
more strongly than an alkyne (the substrate) by a factor of
106–109.[15] Furthermore, D is completely unable to undergo
direct protodeauration. Therefore, any gold centers that are
trapped in this species are simply unable to take part in the
catalytic cycle. Hence, D is viewed as an off-cycle inert com-
plex, participating in the global ligand-exchange equilibrium in
the same way as any other LAu(N)+ complex. Destruction of D
by using an indifferent nucleophile (N) will further inhibit the
overall catalytic reaction. The application of very bulky ligands
at the gold center, branched substrates, and acidic promoters
can totally eliminate the formation of D. To complete the cata-
lytic cycle, the resulting enol ether gold complex E will quickly
undergo ligand exchange with any nucleophile (including the
substrate) to finally liberate enol ether product C. The latter
will stay as such or will be transformed into the corresponding
acetal by means of a classical acid-catalyzed process, depend-
ing on the acidity of the reaction mixture. It is important to
highlight that the formation of D is accompanied by the libera-
tion of an equal amount of a super acid, which can drastically
change the outcome of the initial gold-catalyzed process by
speeding up additional acid-catalyzed processes (desired or
undesired). Catalytic systems that are not accompanied by the
formation of D will be less acidic than the systems with a high
concentration of D (B quickly undergoes protodeauration so
there will be no significant accumulation of H+, unless D is
formed). As a consequence, the outcome of a gold-catalyzed
reaction in the presence of various ligands (for example, PPh3
or L2) can differ because of the level of acidity developed in
the mixture, a reason that is not directly related to the gold
catalysis itself.
If a reaction is characterized by the partial formation of D,
the reaction kinetics cannot easily be analyzed because the
steady-state approximation cannot be applied to either of the
resting states of the catalyst. This situation takes place in reac-
tions with a rush period (a kinetic effect caused by accumula-
tion of diaurated species with time, Scheme 11) or for a reac-
tion, in which partial formation of D is caused by a relatively
low KD value, with the result that the actual concentrations of
the equilibrium participants do not allow the equilibrium
system to stay entirely on the side of species D, whereas the
equilibrium KD is established at any time. In the latter case the
catalyst will rest in at least two resting states and will follow
a kinetic profile that fits between the kinetic profile at com-
plete formation of D and the kinetic profile at complete forma-
tion of the other resting states. These principles are exempli-
fied by the following experimental observations. The reaction
of pentynol S1 in MeCN follows first-order kinetics with respect
to the substrate, despite being accompanied by the formation
of D3 (14% maximum). This means that the catalytic system
has resting states (major: L2AuNCMe+ and minor: D3) that are
close in ratio to that of L2AuNCMe+/MeCN(sol), which is an auro
buffer (see above, Figure 2). For example, the reaction of S4 in
MeOD follows the order in substrate between half- and first-
order because of significant, but not complete, formation of
D7. These cases are considered in more detail in the Support-
ing Information.
Conclusion
Based on experimental observations, a complete mechanism
for gold-catalyzed hydroalkoxylation was constructed
(Scheme 20). The reaction starts with reversible coordination of
the alkyne at the gold center, forming p complex A (within the
global ligand-exchange equilibrium among all possible
LAu(N)+ complexes).[34] The binding affinity of alkynes is gener-
ally low and is weaker than MeCN. The p complex A then un-
dergoes reversible anti-addition of an alcohol to form BH. This
equilibrium is strongly shifted to the left because BH is a good
With regard to the problem of the formation of diaurated
species, we have shown that gold catalysis would be even
more powerful if there was not an intrinsic property of gold
centers to form this idle species. In perspective, new catalysts
could be designed to result in increased reaction rates, produc-
tivity, and scope for gold catalysis. For example, the inability to
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354, 555; f) T. J. Brown, D. Weber, M. R. Gagnꢂ, R. A. Widenhoefer, J. Am.
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ally high efficiency of the catalyst recently reported by Hashmi
et al.[35]
Acknowledgements
Financial support by the state of Baden-Wꢀrttemberg is grate-
fully acknowledged. We thank Dr. K. Eichele and the Institut fꢀr
Anorganische Chemie for allowing us to use their NMR spec-
trometer.
[11] A. Zhdanko, M. E. Maier, unpublished results.
[12] K. E. Roth, S. A. Blum, Organometallics 2010, 29, 1712.
[13] The influence of phenoxide on the reactivity of the parent phenol is
a well-known phenomenon, see: a) M. F. Nielsen, O. Hammerich, Acta
Chem. Scand. 1989, 43, 269; b) S. E. Denmark, R. C. Weintraub, N. D.
Gould, J. Am. Chem. Soc. 2012, 134, 13415.
Keywords: catalysis
mechanisms
· gold · hydroalkoxylation · reaction
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[15] The stability of diaurated species, depending on the enol-ether core
and the ligand at the gold center, has been quantitatively evaluated,
see: A. Zhdanko, M. E. Maier, Organometallics 2013, 32, 2000.
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[17] See the Supporting Information for more details and explanation of
this result. We suppose that deprotonation of an enol-ether p complex
by a strong base to give a vinyl gold species should be successful, but
only under strictly water-free and nucleophile-free conditions excluding
any ligand exchange.
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2,3-pentadien-1-ol as an impurity was responsible for formation of
extra species and influenced the whole kinetics. This finding is de-
scribed in the Supporting Information. In this case, the substrate has to
be essentially free of any allene.
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lics 2011, 30, 6328; c) A. S. K. Hashmi, W. Yang, Y. Yu, M. M. Hansmann,
M. Rudolph, F. Rominger, Angew. Chem. 2013, 125, 1368; Angew. Chem.
Int. Ed. 2013, 52, 1329; d) see reference [3f]; e) see reference. [9f].
[31] The Supporting Information contains more subtle details about what
exactly is observed. Control experiments to prove that DMF behaved as
a hydrogen-bond acceptor and not as a nucleophile reactive with A3
were also performed.
[34] All ligand-exchange steps at gold appear to be fast and the corre-
sponding equilibria are established throughout the entire process. The
high reactivity of LAu+ resembles that of H+, so LAu+ can be called the
“magic proton”, in accordance with the isolobal principle: H. G. Rauben-
heimer, H. Schmidbaur, Organometallics 2012, 31, 2507.
[35] M. C. Blanco Jaimes, C. R. N. Bçhling, J. M. Serrano-Becerra, A. S. K.
Hashmi, Angew. Chem. 2013, 125, 8121; Angew. Chem. Int. Ed. 2013, 52,
7963.
[32] Steady-state approximation for D, in this case, is equivalent to the equi-
librium approximation for the process.
[33] The same law is derived if the concentration of B is expressed through
A, D, and S and H+ is put into expression for the rate of protodeaura-
tion.
Received: September 27, 2013
Revised: November 25, 2013
Published online on January 8, 2014
Chem. Eur. J. 2014, 20, 1918 – 1930
www.chemeurj.org
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