Two metals are better than one in the gold catalyzed oxidative heteroarylation of alkenes

Article abstract of DOI:10.1021/ja2012627

We present a detailed study of the mechanism for oxidative heteroarylation, based on DFT calculations and experimental observations. We propose binuclear Au(II)-Au(II) complexes to be key intermediates in the mechanism for gold catalyzed oxidative heteroarylation. The reaction is thought to proceed via a gold redox cycle involving initial oxidation of Au(I) to binuclear Au(II)-Au(II) complexes by Selectfluor, followed by heteroauration and reductive elimination. While it is tempting to invoke a transmetalation/reductive elimination mechanism similar to that proposed for other transition metal complexes, experimental and DFT studies suggest that the key C-C bond forming reaction occurs via a bimolecular reductive elimination process (devoid of transmetalation). In addition, the stereochemistry of the elimination step was determined experimentally to proceed with complete retention. Ligand and halide effects played an important role in the development and optimization of the catalyst; our data provides an explanation for the ligand effects observed experimentally, useful for future catalyst development. Cyclic voltammetry data is presented that supports redox synergy of the Au...Au aurophilic interaction. The monometallic reductive elimination from mononuclear Au(III) complexes is also studied from which we can predict a ～15 kcal/mol advantage for bimetallic reductive elimination.

Full text of DOI:10.1021/ja2012627

ARTICLE
pubs.acs.org/JACS
Two Metals Are Better Than One in the Gold Catalyzed Oxidative
Heteroarylation of Alkenes
Ekaterina Tkatchouk,‡ Neal P. Mankad,† Diego Benitez,‡ William A. Goddard, III,*,‡ and
F. Dean Toste*,†
‡Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, United States
†Department of Chemistry, University of California, Berkeley, California 94720, United States
S Supporting Information
b
ABSTRACT: We present a detailed study of the mechanism for oxidative heteroarylation,
based on DFT calculations and experimental observations. We propose binuclear
Au(II)ꢀAu(II) complexes to be key intermediates in the mechanism for gold catalyzed
oxidative heteroarylation. The reaction is thought to proceed via a gold redox cycle
involving initial oxidation of Au(I) to binuclear Au(II)ꢀAu(II) complexes by Selectfluor,
followed by heteroauration and reductive elimination. While it is tempting to invoke a
transmetalation/reductive elimination mechanism similar to that proposed for other
transition metal complexes, experimental and DFT studies suggest that the key CꢀC
bond forming reaction occurs via a bimolecular reductive elimination process (devoid of
transmetalation). In addition, the stereochemistry of the elimination step was determined
experimentally to proceed with complete retention. Ligand and halide effects played an important role in the development and
optimization of the catalyst; our data provides an explanation for the ligand effects observed experimentally, useful for future catalyst
development. Cyclic voltammetry data is presented that supports redox synergy of the Au Au aurophilic interaction. The
3 3 3
monometallic reductive elimination from mononuclear Au(III) complexes is also studied from which we can predict a ∼15 kcal/mol
advantage for bimetallic reductive elimination.
’ INTRODUCTION
proposed as the first steps in the mechanism either oxidation of
Au(I) to Au(III) by Selectfluor followed by arylboronic acid
transmetalation, or transmetalation followed by oxidation to
form an aryl Au(III) complex. Both pathways produce a high
oxidation state arylgold(III) intermediate that coordinates and
activates the alkene substrate toward heteroauration. This pro-
posed intermediate undergoes nucleophilic alkene addition,
followed by traditional reductive elimination to regenerate the
Au(I) catalyst. On the basis of Zhang’s proposed transmetala-
tion/reductive elimination mechanism, a similar mechanism
could be envisioned (Scheme 1b) for the gold-catalyzed hetero-
arylation reaction. However, on the basis of experimental ob-
servations and preliminary computational evidence, we proposed
a bimolecular reductive elimination step that does not involve
transmetalation of the arylboronic acid coupling partner
(Scheme 1a). To help resolve this and other discrepancies, we
report herein a detailed computational and experimental investigation
on the three main mechanistic stages of oxidative heteroarylation:
oxidation, heteroauration, and reductive elimination.
During the past few decades, group 10 transition metal
catalyzed cross couplings have become indispensable in organic
synthesis.1 This has been enabled by the rich redox reactivity of
Pd, Pt, and Ni with organic molecules. In contrast, while
homogeneous gold catalysis has emerged as one of the most
active fields of organometallic chemistry,2 reports of transfor-
mations based on overall redox neutral gold(I) activation of
π-bonds toward nucleophilic attack have almost exclusively
dominated the recent literature.3 Developments by Hashmi,4
Zhang,5 Toste,6 and others7 have increased the scope of the
already rich chemistry of Au(I) by developing oxidative trans-
formations proposed to involve Au(I)/Au(III) cycles. In this
regard, the gold-catalyzed oxidative heteroarylation of alkenes
has attracted attention as a versatile transformation that may
resemble traditional cross-coupling reactions. The original
reactivity paradigm has been expanded to include various
nucleophiles (oxy and aminoarylations), coupling partners
(arylboronic acids and arylsilanes), and π-bonds (alkenes and
alkynes). Moreover, both intra- and intermolecular variants
have been described. Despite the significant progress recently
achieved in the development of gold-catalyzed oxidative cou-
pling reactions, there remain considerable uncertainties about
the mechanism.
’ RESULTS AND DISCUSSION
Oxidation. DFT Analysis. During our ongoing mechanistic
studies on reactions using LAuX as catalyst and Selectfluor as
The few experimental reports on the oxidative heteroarylation
of alkenes propose two distinct conflicting mechanisms. Zhang
Received: February 10, 2011
Published: August 23, 2011
r
2011 American Chemical Society
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Scheme 1. Proposed Pathways for the Oxidative Heteroarylation of Alkenesa
a (a) Proposed bimolecular reductive elimination pathway, and (b) transmetalation/unimolecular reductive elimination pathway.
We studied three potential oxidation pathways depending on
the molecularity of the reaction (Figure 1, Scheme 2), all leading
to a common intermediate presumed to lead to nucleophilic
aminoauration. We envisioned initial 2-electron 1-center oxida-
tion of LAu(I)X to LAu(III)XF(Solv)+ by Selectfluor followed
by either coordination of the normally more abundant substrate
(Scheme 2a) or interaction with LAu(I)X (Scheme 2b). We
deem these two pathways as monometallic oxidations that lead to
a binuclear complex. We also considered a possible bimetallic
oxidation (2-electron 2-center) pathway characterized by
a concerted oxidation of a weakly bound Au(I) dimer.10
Au(I)ꢀAu(I) interactions or “aurophilic bonding”,11 especially
in complexes with bidentate ligands10,12 (e.g., dppm) may favor
the bimetallic oxidation pathway (Scheme 2c). We were able to
find transition structures leading to the formation of a binuclear
gold complex with a goldꢀgold bond for processes where
substrate is bound to Au (Figure 1a, Scheme 2a), and without
bound substrate (Figure 1b, Scheme 2b). Our calculations using
the M06 functional and LACV3P**++(2f) basis set suggest that
monometallic oxidation with binuclear substrate coordination
(Scheme 2b) pathway is competitive with the bimetallic path-
way (Scheme 2c). Given the challenge of computing accurate
entropies,13 especially in cases with a change in the number
of particles, we propose that, for the case of a monodentate
phosphine ligand, the monometallic binuclear pathway could
be operative. On the other hand, the use of a bidentate
phosphine, especially one that brings the gold atoms in close
proximity (such as dppm), should favor the bimetallic oxida-
tion pathway due to the minimal entropic cost. Notably, the
binuclear complex is the lowest point in the enthalpy surface,
and thus the pathway to its formation could be determined by
the concentration of species.
oxidant, our group identified several key mechanistic clues
(eqs 1ꢀ7). The failure to produce pyrrolidine B (eq 1) from
alkylgold(I) complex A with phenylboronic acid and Selectfluor
is consistent with oxidation preceding aminoauration. Further-
more, during catalyst optimization, we found binuclear catalyst
dppm(AuBr)2 [dppm = bis(diphenylphosphanyl)methane] to
exhibit superior performance compared to the mononuclear
PPh3AuBr (81% vs 47% yield). We speculated that a bimetallic
catalytic process8 might be operative especially considering the
significant literature reports on binuclear Au(II) and Au(III)
complexes9 and the recent reports by Ritter on the advantages
of bimetallic reductive elimination in Pd catalyzed aromatic
CꢀH oxidation. To investigate this, we performed calculations
on the oxidative aminoarylation reaction using the binuclear
catalyst.
Cyclic Voltammetry. The superior performance of digold
catalysts over monogold catalysts for so-called Au(I)/Au(III)
catalysis6 is particularly interesting given recent proposals
by Ritter and co-workers that cooperative “redox synergy” of
Ag Ag and Pd Pd interactions qualitatively modulates
3 3 3
3 3 3
redox potentials and thereby facilitates oxidative catalysis.8 We
therefore sought to measure quantitatively how Au Au inter-
3 3 3
actions modulate redox potentials in catalytically relevant Au
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Figure 1. Transition structures 3, 5, and 9, including selected interatomic distances (Å) for the oxidative formation of binuclear Au species.
complexes. To accomplish this, we obtained cyclic voltammo-
grams of complexes 15ꢀ20.
In this context, we sought to determine whether this weak
aurophilic bonding measurably affects redox potentials. The
cyclic voltammogram of 18 featured two irreversible, 1-electron
oxidations that were shifted cathodically from complexes 15 and
17 by approximately 140 mV (Figure 2a). A corresponding
rereduction peak (that was absent during reductive scans) was
observed at ꢀ0.45 V, approximately where reduction of 17
occurred (Figure 2a). The 140 mV cathodic shift in oxidation
potential of 18 relative to 15 and 17, as well as the 160 mV anodic
shift in reduction potential of 17 relative to 16, are to our
knowledge the first quantitative measurements evaluating the
extent that aurophilic interactions modulate redox potentials.
The observed trend in redox potentials is fully consistent
with early observations by Fackler and others that aurophilic
Au(I)/Au(I) complexes are able to activate organohalide sub-
strates that are inert toward mononuclear Au(I) complexes,
through a bimetallic oxidative addition driven by Au(II)/Au(II)
bond formation.18 This concept has catalytic relevance given that
the first step in the proposed heteroarylation catalytic cycle
represents a 2-electron oxidation of the catalyst, and that the
turnover step represents a 2-electron reduction of the catalyst.
We next determined that this concept holds for carbene-
ligated gold complexes as well as for phosphine-ligated gold
complexes. The digold(I) complex DIMes(AuCl)2 (20, DIMes = 1,
10-di(mesityl)-3,30-methylenediimidazol-2,20-diylidene) was synthe-
sized by acidolysis of DIMes(AuMe)2 with HCl. The crystal
structures of both DIMes(AuMe)2 and 20 are provided in the
Supporting Information; neither complex provided evidence of
The monogold complexes 15 and 16 provided benchmark
redox potentials in the absence of Au Au interactions. An
3 3 3
oxidative scan of 15 revealed two irreversible, 1-electron oxida-
tions at approximately 1.48 and 1.98 V,14 corresponding to
Au(II)/Au(I) and Au(III)/Au(II) redox events, respectively
(see Supporting Information). These oxidative peaks were
absent for the fully oxidized 16, which instead exhibited an
irreversible, 2-electron Au(III)/Au(I) reduction at ꢀ0.69 V with
a corresponding reoxidation at 0.72 V (Figure 2b).
The known mixed-valent digold complex 17 has been shown
to lack any significant Au Au interaction in solution (based on
short Au Au contacts in the solid state. Nonetheless, both 20
3 3 3
3 3 3
UVꢀvis) or in the solid state (based on X-ray crystallography).15
Indeed, an oxidative scan for 17 revealed two irreversible,
1-electron oxidation events with potentials similar to those for
complex 15 (1.48 and 1.96 V for Au(II)Au(III)/Au(I)Au(III)
and Au(III)Au(III)/Au(II)Au(III), respectively), confirming
that the distant presence of a coordinatively saturated Au(III)
center has negligible effect on the oxidation potential of the
Au(I) center in 17 (see Supporting Information for overlay).
Interestingly, the irreversible, 2-electron reduction for 17 was
observed at a less negative potential relative to that of 16 by
and its monogold analogue 19 exhibited irreversible, 2-electron
oxidation events by cyclic voltammetry, with the 2-electron
oxidation of 19 occurring at a higher potential (1.96 V) than
that of 20 (1.64 V).19 Thus, though the aurophilic interaction
proved unobservable by X-ray crystallography in the case of 20,
our results suggest the existence of a weak and fluxional interac-
tion in solution with a measurable impact on redox potential.
This causes digold(I) complex 20 to be oxidized at a milder
potential than monogold complex 19. The compiled electro-
chemistry results presented herein are summarized in Table 1.
Lastly, we note that DFT calculations using the M06 functional
and LACV3P**++(2f) basis set correctly reproduce the observed
trend in redox potentials and predict a difference of 0.26 V in the
oxidation potentials of complexes 19 and 20 (see Supporting
Information), which can be viewed as a validation of this DFT
method for analyzing bimetallic gold complexes.
approximately 160 mV (Figure 2b), suggesting that Au Au
3 3 3
interactions become important upon reduction of the Au(III)
center in 17.
Though complexes similar to the digold(I) complex 18 exhibit
aurophilic Au(I) Au(I) interactions in solution (based on
3 3 3
EXAFS),16 18 itself has been characterized both with and without
a short Au Au contact in the solid state depending on the
Aminoauration. Binuclear intermediates also appear to be
key to aminoauration. For example, our calculations showed that
using [Ph3PAu]+, aminoauration does not lead to a stable cyclized
3 3 3
crystallization method.17 Thus, the Au(I) Au(I) interaction
3 3 3
may be of the same order of magnitude as crystal packing forces.
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Scheme 2. Mechanistic Hypotheses for Oxidation Leading to a Substrate Coordinated Binuclear Complex
intermediate. Relaxed coordinate scans of the cyclization reaction
using [Ph3PAu]+, exhibited an uphill process with no minimum
for the cyclized intermediate (see Supporting Information). This
may seem counterintuitive since aminoauration has been de-
scribed before;20 however, the substrates that cyclize successfully
involve stronger nucleophiles than amides. Because ionization by
solvation (heterolysis) of the gold halide LAuCl is unfavorable
(predicted to be endothermic by ∼30 kcal/mol in acetonitrile),21
we envision that a mononuclear mechanism would involve oxida-
tion of LAuX, followed by exothermic (by 12.9 kcal/mol) coor-
dination of the resulting gold(III) complex with the alkene.
Subsequent intramolecular base-assisted (amine originating from
the reduction byproduct of Selectfluor) addition of the amide
nucleophile then would lead to a cyclized phosphinegold(III)
intermediate.
On the other hand, bimetallic aminoauration was indeed
found to be a downhill process according to DFT (Scheme 3).
A transition state for the aminoauration pathway was located
using the binuclear catalysts with PPh3 and dppm ligands. We
find the aminoauration barrier using both PPh3 and dppm
ligands to be ∼8 kcal/mol (8.8 kcal/mol for PPh3 and 7.7 kcal/mol
for dppm).
arylboronic acids, arylsilanols, and aryltrimethylsilanes with LAuX
under relevant noncatalytic reaction conditions (eqs 2 and 3).6
However, these tests do not rule out a reversible process with a Keq
that greatly favors reactants. Thus, transmetalation was tested under
catalytic conditions by subjecting substrate and active catalyst
PPh3AuPh to Selectfluor in acetonitrile (eq 4). The lack of reactivity
in the absence of an exogenous arylboronic acid, together with
the recovered reactivity upon addition of PhB(OH)2 (eq 5) argues
against a pathway involving direct transmetalation. Notably, it
was observed that the transferred aryl group originates from the
arylboronic acid and not from the phenylgold species (eq 6),
conclusively establishing the absence of transmetalation under the
present reaction conditions. We investigated these observations
computationally; relaxed coordinate scans for transmetalation to
Au(III) fluoride species were not able to locate a viable pathway and
exhibited high energies (>80 kcal) without formation of a Au-Ph
bond. These data suggest that transmetalation to Au(I) and Au(III)
species within the catalytic cycle of oxidative heteroarylation is not
operative.
Given the absence of direct transmetalation, we posited that
C-aryl bond formation resulting from traditional reductive
elimination should also be inoperative.23 We therefore focused
on investigating likely CꢀC bond formation steps. Considering
the exothermicity provided by the formation of a BꢀF (or SiꢀF)
bond, we examined the minimum energy pathway by decreasing
the distance between arylboronic acid and Au(III) fluoride
species. Relaxed coordinate scans exhibited concerted reductive
elimination with formation of both CꢀC and BꢀF bonds,
Reductive Elimination. DFT Study. Probably, the largest dis-
crepancy between the proposed mechanisms is transmetalation.
Zhang initially proposed a mechanism involving arylboronic acid
transmetalation (before or after oxidation) based on the reactivity
that boronates display in analogous to d10 metal-catalyzed cross
coupling reactions.22 We were unable to observe transmetalation of
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Scheme 3. Mechanistic Hypothesis for Aminoauration and Bimetallic Reductive Eliminationa
a Free energies at 298 K (ΔG298K) at M06/LACV3P**++(2f) level of theory.
Figure 2. Cyclic voltammetry data: (a) oxidative scans for complexes 17 (solid) and 18 (dashed); (b) reductive scans for complexes 16 (solid) and 17
(dashed). Conditions: CH2Cl2 solvent, 0.1 M Bu4NPF6, 100 mV/s scan rate.
effectively achieving regeneration of the catalyst and product
demetalation in one step. We found a concerted but asynchro-
nous five-membered cyclic transition structure (Figure 3a), in
which the BꢀF bond is formed prior to the CꢀC bond. The
polarized AuꢀF bond and the BꢀF interaction are key for
reductive elimination.
Stereochemical Analysis. To further characterize the nature of
CꢀC reductive elimination, we sought to determine the stereo-
chemical course of this reaction. Stereochemical analyses of the
overall catalytic aminoarylation reaction have been performed
both by Zhang5b and by Toste,6b but different conclusions
regarding the stereochemical course of CꢀC bond formation
were reached depending on whether syn- or anti-aminoauration
was assumed. To gain further insight, herein we focus now on
exploiting our previously reported ability to isolate6c alkylgold(III)
fluoride complexes [(IPr)Au(R)F2] (IPr = 1,3-bis(2,6-di-iso-
propylphenyl)imidazol-2-ylidene) and thus study CꢀC reductive
elimination as a stoichiometric transformation. In particular, we
chose to examine the coupling of PhB(OH)2 with [(IPr)Au-
(R)F2] bearing the neo-hexyl-d2 substituent (i.e., R = syn- or anti-
CHDCHDtBu), whose relative stereochemistry can be easily
3
monitored by measuring the vicinal JHH coupling in routine
1H NMR experiments (Scheme 4).24
Reaction of syn-tBuCHDCHDB(OH)2 (3JHH = 4.2 Hz) with
(IPr)AuOH25 resulted in clean transmetalation with inversion of
stereochemistry, producing anti-tBuCHDCHDAu(IPr) (3JHH
=
11.2 Hz) in good yield. Because alkyl transfer from boron to
gold is unprecedented,26 connectivity of the unlabeled analogue
tBuCH2CH2Au(IPr) was established by X-ray crystallography
(see Supporting Information). To our knowledge, the stereochemistry
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of B-to-Au transmetalation has not been studied previously.
The stereochemistry of B-to-Pd transmetalation has been
studied previously by analysis of catalytic reaction products,
with inversion of stereochemistry27 during transmetala-
tion being postulated less commonly than retention of
stereochemistry.28
Subsequent reaction with PhB(OH)2 proceeded with retention of
stereochemistry, producing anti-tBuCHDCHDPh (3JHH = 12.4
Hz) as the sole CꢀC coupling product (Scheme 4). Analogous
results were obtained by performing the CꢀC coupling with syn-
tBuCHDCHDAu(IPr) (3JHH = 5.4 Hz) to yield syn-tBuCHD-
CHDPh (3JHH = 5.0 Hz).
In order to test the validity of our experimental design, we
chose to examine the stereochemical course of CꢀI reductive
elimination from Au(III). Scott et al. have shown29 that reaction
of (IPr)AuMe with I2 results in oxidative addition to form
trans-(IPr)AuMeI2 as a transient intermediate, followed by
reductive elimination of MeI. A detailed kinetics analysis in that
report indicated inner-sphere CꢀI reductive elimination rather
than SN2-like attack of outer-sphere Iꢀ on a cationic methylgold(III)
intermediate. Thus, CꢀI reductive elimination is expected to
proceed with retention of stereochemistry. Indeed, we found that
reaction of anti-tBuCHDCHDAu(IPr) with I2 resulted in quanti-
tative conversion to anti-tBuCHDCHDI (3JHH = 12.8 Hz).
We have previously shown that oxidation of (IPr)AuMe with XeF2
produces cis-(IPr)AuMeF2, which reacts with PhB(OH)2 to pro-
duce toluene (eq 7).6c In order to test the stereochemical course
of this CꢀC reductive elimination process, we oxidized anti-
tBuCHDCHDAu(IPr) with XeF2 to generate cis-[anti-tBuCHD-
CHDAuF2(IPr)]. 19F NMR properties of this oxidized intermediate
were consistent with those previously reported for cis-(IPr)AuMeF2.
Electronic Structure and Halide Effect. Given the importance
of the concerted formation of the BꢀF (or SiꢀF) bond in the
cross coupling step, we expect that the more polarized the AuꢀF
will lower the barrier for the reductive carbonꢀcarbon bond
formation. We observe this structurally with calculated bond
distances and electronically with NBO analyses (Table 2).30 The
AuꢀF bond distance for the intermediate that precedes reductive
elimination increases from 2.02 Å for the PPh3 mononuclear
complex, to 2.07 Å for the PPh3 binuclear complex. Electro-
nically, the natural charge on F atom is ꢀ0.70 e for the mono-
nuclear complex and ꢀ0.81 e for the binuclear complex. This
effect has been observed before as a structural trans effect and
trans influence that is amplified by the AuꢀAu bonding system.31
In addition, it is expected that a bromide ligand further polarizes
the trans AuꢀF bond relative to a chloride. Indeed, we find that
the AuꢀF bond is elongated by ∼0.01 Å with respect to the Cl
complex (Table 2). Moreover, the charge on fluorine is 0.01e
more negative in natural charge in the FꢀAuꢀAuꢀBr complex
compared to the FꢀAuꢀAuꢀCl tetrad. The natural atomic
orbital bond orders follow this trend; the AuꢀF natural bond
order decreases from 0.233 for FꢀAuꢀCl to 0.218 for FꢀAuꢀBr
to 0.169 for FꢀAuꢀAuꢀCl to 0.160 for FꢀAuꢀAuꢀBr. Taken
together, these observations suggest that the bromide ligand
increases the polarization of the AuꢀF bond, which is key for the
reductive elimination to occur; this hypothesis is in agreement with
the higher activity of the dppm/bromide catalyst. The molecular
orbitals for the intermediate that undergoes reductive elimination
support this view (Figure 4). The HOMO is bonding for CꢀAuꢀAu
and antibonding for FꢀAu and AuꢀCl. Using NBO analyses, we
also characterized the AuꢀAu bond as a polarized interaction
that involves the 5dz2 orbital with partial 6s (∼7%) character on
the donor Aub atom to an empty orbital on Aua that is mostly 6s
Table 1. Summary of Electrochemistry Data
complex
Eox for Au(I) (V)a
Ered for Au(III) (V)a
15
16
17
18
19
20
1.48b
/
1.48b
1.34b
1.96c
/
ꢀ0.69
ꢀ0.53
/
/
/
1.64c
+
a Referenced to FeCp2 /FeCp2. b Potential of first 1-electron oxidation.
c Potential of 2-electron oxidation.
Figure 3. Transition structures for the bimolecular reductive elimination from (a) mononuclear PPh3Au, (b) binuclear [PPh3Au]2, and (c) binuclear
(dppm)Au2 complexes.
Scheme 4. Stereochemistry of CꢀC Reductive Elimination
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Table 2. Selected Bond Distances, Natural Bond Orders and
Natural Atomic Charges of Mononuclear
[(PPh3)(AuX)F(Cyclized Substrate)]and Binuclear Au
access to binuclear Au(II)ꢀAu(II) intermediates lowers the
barriers for all three of these steps, supported by our cyclic
voltammetry data. In accord with our experimental findings, our
computational studies indicate that the AuꢀF bond plays a key
role in the bimolecular reductive elimination. Thus, we conclude
that the spectator halide (Br vs Cl) in the gold catalysts impacts
reactivity by changing the nature of the AuꢀF bond.
Intermediates [(PPh3)2(AuX)2F(Cyclized Substrate)]
FꢀAuꢀCl FꢀAuꢀBr FꢀAuaꢀAubꢀCl FꢀAuaꢀAubꢀBr
Bond Distances and Natural Bond Orders
An overall proposed catalytic cycle based on all experimental
and computational data presented herein is shown in Scheme 5
for the catalyst dppm(AuBr)2. Facile oxidation of the aurophilic
Au(I)Au(I) catalyst with Selectfluor is partially driven by Au-
(II)ꢀAu(II) σ-bond formation, yielding cationic [dppm(AuBr2)-
(AuF)]+. Heteroauration then occurs in an anti sense to give a
neutral alkylgold species. Concerted bimolecular reductive elim-
ination with an arylboronic acid coupling partner then occurs with
retention of stereochemistry to give a catalytic process with overall
inversion of stereochemistry as has been noted before.5b,c,6b
AuꢀF
AuꢀX
AuꢀAu
1.98 Å
(0.233)
2.30 Å
(0.418)
ꢀ
1.99 Å
(0.218)
2.48 Å
(0.394)
ꢀ
2.06 Å
(0.175)
2.49 Å
2.07 Å
(0.160)
2.67 Å
(0.260)
2.64 Å
(0.228)
2.66 Å
(0.232)
(0.236)
Natural Atomic Charges
Aua
Aub
X
+0.905
+0.850
/
+0.819
+0.615
ꢀ0.545
ꢀ0.732
+0.806
/
+0.510
ꢀ0.561
ꢀ0.729
’ ASSOCIATED CONTENT
ꢀ0.446
ꢀ0.667
ꢀ0.354
ꢀ0.675
S
Supporting Information. Synthetic details, computational
b
F
details, crystallographic data, and XYZ coordinates. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
wag@wag.caltech.edu; fdtoste@berkeley.edu
’ ACKNOWLEDGMENT
Figure 4. Selected molecular orbitals for key intermediate 12-dppm
[(dppm)(AuCl)2F(Cyclized Substrate)].
This material is based upon work supported as part of the Center
for Catalytic Hydrocarbon Functionalization, an Energy Frontier
Research Center funded by the U.S. Department of Energy, Office
of Science, Office of Basic Energy Sciences under Award Number
DE-SC0001298. Computational facilities were funded by grants
from AROꢀDURIP and ONR-DURIP. N.P.M. was supported
by an NIH Kirchstein-NRSA postdoctoral fellowship. Prof. Chris
Chang provided access to a potentiostat for cyclic voltammetry
measurements.
Scheme 5. Revised Mechanism for Heteroarylation of Al-
kenes Catalyzed by dppm(AuBr)2
’ REFERENCES
(1) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.-Int. Ed.
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character (∼87%) with partial 5dz2 character (∼11%). This
molecular orbital (HOMO-54) is shown in Figure 4.
’ CONCLUSIONS
In summary, based on combining both experimental observa-
tions and computational investigations, we propose a mechanism
for gold-catalyzed heteroarylation reactions that is composed
of three main steps: (1) oxidation of Au(I) by Selectfluor, (2) activa-
tion of the alkene followed by nucleophilic addition, and (3) bi-
molecular reductive elimination. Our calculations show that
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Journal of the American Chemical Society
ARTICLE
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+
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