Gold-gold cooperation in the addition of methanol to alkynes

Article abstract of DOI:10.1002/anie.201204003

The gold(I)-mediated reaction between an internal alkyne and methanol proceeds by a dual activation mechanism, which directly results in formation of gem-diaurated intermediates. Reaction intermediates were investigated by IR multiphoton dissociation spectroscopy, kinetics by NMR spectroscopy, and the mechanism by DFT calculations. Copyright

Full text of DOI:10.1002/anie.201204003

Angewandte
Chemie
DOI: 10.1002/anie.201204003
Gold Catalysis
Gold–Gold Cooperation in the Addition of Methanol to Alkynes**
ˇ
ˇ
ˇ
ˇ
ˇ
Jana Roithovꢀ,* Stepꢀnka Jankovꢀ, Lucie Jasꢁkovꢀ, Jirꢁ Vꢀna, and Simona Hybelbauerovꢀ
Gold catalysis is one of the hot topics in
current organic synthesis. The “gold-rush”
started with the discovery that seemingly
inert gold can efficiently catalyze the addition
of nucleophiles, such as water or methanol, to
alkynes.[1,2] Nowadays is gold efficiently used
for the construction of complex structures
through reaction cascades based on p activa-
tions of multiply unsaturated molecules.[3–11]
The key steps are often based on couplings
À
À
between a C C triple bond and a C C double
À
bond. Couplings between two C C triple
bonds are usually initiated by the addition of
an alcohol to one of the triple bonds.[12–14]
The generally accepted reaction mecha-
nism for the gold(I)-mediated addition of
either water or methanol to an alkyne
involves coordination of cationic gold to the
À
C C triple bond, which promotes the addi-
tion of the nucleophile.[15–18] The addition is
completed by the migration of a proton
bound to the oxygen atom of the incoming
nucleophile to the second carbon atom of the
multiple bond. The proton migration is
assisted by solvent molecules.[15]
Figure 1. a) ESI-MS source spectrum of a MeOH solution of 1-phenylpropyne with catalyst
(2.5 mol% [AuCl(PMe3)]/3 mol% AgSbF6). b) Time dependence of the relative abundances
of [D3]-X and X upon adding CH3OH to a solution of 1-phenylpropyne in CD3OD and the
catalyst (CH3OH/CD3OD 1:1 (v/v)) after 1 hour reaction time. The solid lines correspond
to fitted exponential functions (see also the Supporting Information, Figure S5). The
sections of the MS spectra (c) show the averaged spectra in the beginning (1–5 min) and
Herein, we report an investigation of the in the end (26–30 min) of the experiment.
gold(I)-mediated addition of methanol to an
alkyne by means of electrospray ionization
mass spectrometry (ESI-MS),[19] NMR experiments, and
theoretical calculations. Furthermore, the key reaction inter-
mediate is characterized by IR multiphoton dissociation
(IRMPD) spectroscopy. The reaction was investigated for 1-
phenylpropyne, Ph C C Me, with [AuCl(PMe3)] as the
catalyst.[20]
À ꢀ À
Electrospray ionization of a methanolic solution of 1-
phenylpropyne and [AuCl(PMe3)] leads to the [Au(PMe3)2]+
cation and its cluster bound by the chlorine counterion,
[Au2Cl(PMe3)2]+ (Figure 1a; for an assignment of minor
peaks, see the Supporting Information). Furthermore, two
complexes containing the alkyne can be detected: [Au-
(PhCCMe)(PMe3)]+ and a complex X with m/z 693. Colli-
sion-induced dissociation experiments with mass-selected X
(Supporting Information, Figure S1) as well as analogous
experiments in [D4]methanol (Supporting Information, Fig-
ure S4) show that X contains 1-phenylpropyne, two gold
atoms with two trimethylphosphine groups, and a methoxy
group. If this ion were a simple cluster of two [Au(PhCCMe)-
(PMe3)]+ cations bound by a methanolate counterion, a clus-
ter bound by chloride would also be expected, which is
however not present in the spectrum. Therefore, the complex
X may correspond to a possible intermediate. In minor
abundance, a complex between the (trimethylphosphino)gold
cation and the product of the addition of methanol to 1-
phenylpropyne is detected, which is denoted as Y (m/z 421;
addition of methanol to 1-phenylpropyne can lead to (E)/(Z)-
2-methoxy-1-phenylpropene or (E)/(Z)-1-methoxy-1-phenyl-
[+]
ˇ
ˇ
ˇ
[*] Prof. J. Roithovꢀ, Dr. S. Jankovꢀ, L. Jasꢁkovꢀ, Dr. J. Vꢀna,
Dr. S. Hybelbauerovꢀ
Department of Organic Chemistry, Faculty of Science, Charles
University in Prague
Hlavova 2030/8, 12843 Prague 2 (Czech Republic)
E-mail: roithova@natur.cuni.cz
Homepage: http://www.orgchem.cz/roithova
[+] Present address: Institute of Organic Chemistry and Technology,
Faculty of Chemical Technology, University of Pardubice (Czech
Republic)
[**] The authors gratefully acknowledge financial support from the
Grant agency of the Czech Republic (207/11/0338), the European
Research Council (StG ISORI) and the Ministry of Education of the
Czech Republic (MSM0021620857). The results from CLIO were
obtained thanks to the funding from the European Union’s Seventh
Framework Programme (FP7/2007-2013) under grant agreement
no. 226716. The CLIO staff, particularly Vincent Steinmetz, are
gratefully acknowledged for their help and assistance. We thank
ˇ
ˇ
Zdenek Tosner for helping with the NMR spectra acquisition.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204003.
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propene). X is formally related to Y by replacement of H by
AuPMe3. Thus, we can consider two possible pathways for the
formation of X: 1) addition of [Au(OMe)(PMe3)] instead of
methanol to the initially formed mononuclear gold complex
[Au(PhCCMe)(PMe3)]+, or 2) addition of methanol followed
by deprotonation and subsequent complexation with Au-
(PMe3)+ (Supporting Information, Scheme S1).
To check whether X represents a possible intermediate in
the condensed phase or is formed during the electrospray
process, the reaction mixture in CD3OD was kept for one
hour, then diluted to a double volume by CH3OH and
immediately monitored by ESI-MS. The spectra recorded
right after the mixing the solvents show dominant abundance
of the [D3]-X complex (m/z 696), whereas after about 20 min,
the statistically expected 1:1 ratio of the unlabeled X and the
labeled [D3]-X complex is established (Figure 1b,c). First, this
result demonstrates that X represents a species formed in the
solution and thus it is not a gas-phase artifact. Second, the
experiment allows us to determine the half-life of X as about
3.7 minutes at 258C in the reaction solution (Supporting
Information, Figure S5). The same experiment also confirms
that species Y corresponds to a (trimethylphosphino)gold
complex with the product of the methanol addition, because
only the [D4]-labeled complex is observed in the beginning.
At longer reaction times, we also observe the product of the
complexes of the products owing to addition of CH3OH,
CH3OD, and CD3OH (m/z 421, 422, and 424 respectively),
but the statistical ratio is still not achieved after 20 min (cf.
Figure 1c). This finding implies that X is formed substantially
faster than Y. Thus, X is not a secondary product formed from
Y by deprotonation and subsequent complexation with
[Au(PMe3)]+. On contrary, Y can be formed from X by
hydrolysis, and this step is a subject to a substantial kinetic
isotope effect, as shown by the ratio of signals at m/z 421 and
422 (exchange of [Au(PMe3)]+ by H+ and D+, respectively).
The structure of intermediate X was characterized by
IRMPD spectroscopy. This method provides IR spectra for
mass-selected ions in the gas phase,[21,22] which are usually
assigned based on comparison with the theoretical spectra.
Out of many considered isomers of X, the most stable
structures correspond to complexes with the methoxy group
Figure 2. a) IRMPD spectrum of X (m/z 693) and theoretical IR spectra
of possible reaction intermediates (b–d).
modes of the addition product are missing (for more
examples, see the Supporting Information, Figure S6).
The reaction was further investigated using NMR spec-
troscopy (Figure 3). For the C2 addition, we mainly observe
the addition of two molecules of methanol (2,2-dimethoxy-1-
phenylpropane along with small amounts of 1-phenyl-2-
propanone formed by hydrolysis of the ketal with traces of
water), which suggests that the second addition is much faster
than the first addition of methanol. On the other hand, for the
C1 addition, we see clearly products of both the single and the
double addition of methanol. This observation can be
attributed to the different steric demands of the intermediates
and also provides an explanation as to why the intermediate
for the less-stable product is preferentially sampled with the
IRMPD experiments. Kinetic modeling of the NMR data
(Figure 3) predicts that the second addition of the methanol
molecule to the C2 carbon atom proceeds about 100 times
faster than the first addition, whereas the second step is only
six times faster than the first for the C1 addition.
Inspired by these experiments, we have investigated the
reaction mechanism for the first addition of methanol using
density functional theory.[24] The classically considered reac-
tion pathway, in which the [Au(PhCCMe)(PMe3)]+ ion is
proposed to react with methanol, proceeds with high energy
barriers, and the initial methanol addition is endothermic by
more than 50 kJmolÀ1 (Supporting Information, Figure S10,
Table S1). However, it has been shown by Lein et al. for the
AuCl3-mediated addition of water to alkynes that the reaction
is assisted by another molecule of water, which accepts
a proton from the incoming H2O molecule and thereby
stabilizes the initial addition product.[15] In the reaction
investigated herein (Figure 4a), such a scenario leads from
À
attached to the carbon atom of the C C double bond in that
the second carbon atom of this double bond carries both
(trimethylphosphino)gold units.[23] The more stable inter-
mediate is formed by the addition of the methoxy group to the
C2 carbon; however, the theoretical IR spectrum of the
product of the C1 addition agrees better with the experimen-
tal spectrum (Figure 2); most likely, a mixture of both
intermediates is sampled by IRMPD. By comparison of the
experimental and theoretical spectra, the band at 1490 cmÀ1
À
can be assigned to a stretching mode of the C C double bond
formed upon addition of gold methanolate to 1-phenyl-
propyne. The bands at 1275 cmÀ1 and 1125 cmÀ1 agree well
À
with the stretching vibrations of the C O bonds between the
oxygen atom and the carbon atoms of the vinyl and the
methyl groups, respectively. The band at 955 cmÀ1 corre-
sponds to the deformation vibration of the phosphine ligands.
Clearly, the spectrum of a simple adduct (Figure 2d) does not
explain the experimental spectrum as the characteristic
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The theoretical results thus show that the mechanism
involving two (trimethylphosphino)gold cations proceeds
with smaller energy barriers and the formations of the
intermediates are highly exothermic. The results are consis-
tent with all experimental observations and also with the fact
that we observe this intermediate readily and in large
abundance. On the other hand, if the mechanistic scenario
involving catalysis with just one gold cation should account
for the experimental observations, then the endothermic
intermediates 2 and 4 would have to be deprotonated and the
formation of the complex with another (trimethylphosphi-
no)gold cation would have to be faster than the reprotonation
step to form 3 and 5, respectively.[25–28] This would require that
the second gold cation is already involved in the process of the
deprotonation, and from the mechanistical point of view it
would lead again to the conclusion that two gold cations are
À
involved in the addition of methanol to a triple C C bond. An
À
=
alternative route via neutral [Ph C(AuPMe3) C(CH3)-
(OMe)] as an intermediate[29,30] appears less likely, because
we do not observe such a protonated species by ESI-MS (that
is, protonation by H+ and D+ should immediately lead to a 1:1
ratio of [D3]-Y and [D4]-Y in the experiment shown in
Figure 1c).
Figure 3. Relative ratios of 1-phenylpropyne and the products of C1
and C2 additions as a function of the reaction time as monitored by
NMR spectroscopy. The yield of 1-phenyl-1-methoxypropene is shown
in red. Products of the addition of two molecules of methanol (sum of
the corresponding ketals and ketones formed upon hydrolysis with
a residual moisture) are shown in blue for the C1 addition and in
green for the C2 addition. The solid lines correspond to the results of
the kinetic modeling according to the equations displayed on top.
The results presented herein demonstrate that the addi-
À
tion of methanol to a triple C C bond proceeds with a dual
activation mechanism in that the triple bond is activated by
the coordination with the gold catalyst and methanol is added
in the form of gold methanolate. The dual activation
mechanism results in direct formation of gem-diaurated
intermediates. A similar scenario was recently suggested for
cycloisomerization reactions of polyunsaturated hydrocar-
bons catalyzed by gold(I) complexes.[31–35] Thus, widening of
this concept to the additions of O-nucleophiles can have
a substantial effect on the mechanistic understanding of the
gold-catalyzed reactions. Furthermore, as the addition of
alcohol represents an initial step of many cascade reactions
involving alkynes, the understanding of the mechanistic
aspects may guide in designing new synthetic methods.[36]
the initial structure 1 to transition structures TS1/2 or TS1/4
stabilized by hydrogen bonding. Nevertheless, formation of
the respective primary products of C2 addition (2) and C1
addition (4) remains endothermic (23 and 32 kJmolÀ1,
respectively). The subsequent hydrogen atom migration
mediated by the second molecule of methanol is a subject
to a higher energy barrier than the initial methanol addition,
but it can be expected that involvement of additional solvent
molecules lowers this barrier.
The reaction pathway involving two gold atoms starts with
adduct 6, in which the [Au(PhCCMe)(PMe3)]+ ion is bound to
[Au(MeO)(PMe3)] by the oxygen atom (Figure 4b). The
favored reaction pathway corresponds to an anti-periplanar
addition of [Au(MeO)(PMe3)] to the triple bond coordinated
to the gold cation. The coupling reaction at C2 (TS6/7)
proceeds with an energy barrier of 27 kJmolÀ1 and at C1
(TS6/9) with an energy barrier of 23 kJmolÀ1. The addition is
highly exothermic, and it is expected that the (trimethylphos-
phino)gold cation, which is loosely bound in the less stable
isomers 7 and 9, will easily migrate from the oxygen atom to
the carbon to yield the more stable complexes 8 and 10
(formed directly by syn-periplanar addition). These product
complexes correspond to the intermediates observed with the
ESI-MS experiments. The addition to the C1 carbon proceeds
with a lower energy barrier, but it leads to a thermodynami-
cally disfavored product, similar to the mechanism involving
just one gold cation. We note in passing that possible routes to
the formation of 1, 6, and [Au(MeO)(PMe3)] are discussed in
the Supporting Information.
Experimental Section
The reaction mixture was prepared by mixing a supernatant solution
of AgSbF6 and [AuCl(PMe3)] in methanol (either CH3OH or
CD3OD) with 1-phenylpropyne so that a 0.24m solution of 1-
phenylpropyne with 2.5 mol% of the (trimethylphosphino)gold
catalyst was prepared (for details, see the Supporting Information).
For the mass spectrometry experiments, the reaction mixture was
diluted 10-fold.
Mass spectrometry experiments were performed with a TSQ 7000
mass spectrometer[37,38] with
a quadrupole–octopole–quadrupole
configuration. The ions were generated by electrospray ionization
(ESI) from the reaction mixtures described above at soft ionization
conditions, and the mass spectra were recorded by scanning the first
quadrupole. The IR multiphoton dissociation spectrum of the mass-
selected ions (generated as above) with m/z 693 was recorded with
a Bruker Esquire 3000 ion trap mounted to a free electron laser
(FEL) at CLIO (Center Laser Infrarouge d’Orsay, Orsay, France).[39]
The FEL was operated in the 43 MeV electron-energy range. Each
point in the spectrum is an average of 20 measurements. The ions
were mass-selected and stored in an ion trap. The fragmentation was
induced by four laser macropulses admitted to the ion trap. The
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Figure 4. Potential energy surfaces (mPW1PW91/cc-pVDZ:LANL2DZ(Au)) for the [AuPMe3]+ catalyzed reaction of 1-phenylpropyne with
a) methanol assisted by another molecule of methanol and b) with [Au(OMe)(PMe3)]. The relative energies are given in kJmolÀ1 at 298 K in
methanol (red numbers) and at 0 K in the gas phase (black numbers in brackets).
reported IRMPD spectrum is not corrected for the power of the free-
electron laser, which slightly changes in dependence of the wave-
numbers (Supporting Information, Figure S7).
optimized structures and their energies are listed in the Supporting
Information, Table S1.
The NMR experiments were recorded using Bruker AVAN-
CE III (600 MHz) and the d scale was referenced to a solvent residual
peak at d = 3.31 ppm. The solutions of the catalyst and the reactant
were mixed and immediately introduced to the NMR instrument. The
instrument was tuned for 20 min and then acquisition was started. The
representative spectrum together with the assignments of peaks is
shown in the Supporting Information, Figure S8.
Calculations were performed using the density functional theory
method mPW1PW91[40,41] as implemented in the Gaussian09 pack-
age.[42] As a basis set, the combination of the cc-pVDZ basis set for C,
H, O and P and the LanL2DZ basis set for Au was used. The IR
spectra were calculated using a larger basis set (cc-pVTZ for C, H, O,
and P and LanL2DZ for Au). All of the reported structures represent
genuine minima or transition states on the respective potential-
energy surfaces, as confirmed by analysis of the corresponding
Hessian matrices. All minima and transition states were further
reoptimized using the polarized continuum model for modeling the
effect of solvent[43] and frequency calculations were again performed
to control the identity of the stationary points as well as to obtain
thermochemical corrections for energies at 0 K and Gibbs energies at
298 K. The scaling factor for the calculated IR spectra is 0.96.[44] All
Received: May 23, 2012
Revised: June 14, 2012
Published online: && &&, &&&&
Keywords: density functional calculations · gold catalysis ·
.
ion spectroscopy · kinetics · reaction intermediates
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Communications
Gold Catalysis
ˇ
ˇ
J. Roithovꢁ,* S. Jankovꢁ, L. Jasꢂkovꢁ,
ˇ
J. Vꢁna, S. Hybelbauerovꢁ
&&&& — &&&&
Gold–Gold Cooperation in the Addition of
Methanol to Alkynes
The gold(I)-mediated reaction between an
internal alkyne and methanol proceeds by
a dual activation mechanism, which
directly results in formation of gem-
diaurated intermediates. Reaction inter-
mediates were investigated by IR multi-
photon dissociation spectroscopy, kinet-
ics by NMR spectroscopy, and the mech-
anism by DFT calculations.
6
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These are not the final page numbers!