Dimethylcuprate-catalyzed decarboxylative coupling of allyl acetate

Article abstract of DOI:10.1021/om300717g

Allylic alkylation of organocuprates represents an important class of C-C bond forming reactions. A drawback of these reactions is their stoichiometric nature. Although metal-catalyzed decarboxylative coupling reactions offer new opportunities for formation of C-C bonds, catalytic allylic alkylation reactions of organocuprates have not been previously reported. Here, multistage mass spectrometry experiments performed on ion trap mass spectrometers in conjunction with electronic structure calculations are used to demonstrate that the dimethylcuprate anion, [CH₃CuCH₃]^-, can catalyze decarboxylative coupling of allyl acetate in the gas phase via a simple two-step catalytic cycle. In step 1, [CH₃CuCH₃] ^- undergoes a cross-coupling reaction with allyl acetate to yield [CH₃CuO₂CCH₃]^- as the major product ion. Step 2 involves subjecting the product ion to collision-induced decarboxylation to re-form [CH₃CuCH₃]^-, thereby closing the catalytic cycle. Since the details of step 2 have been previously described (Rijs, N.; Khairallah, G. N.; Waters, T.; O'Hair, R. A. J.J. Am. Chem. Soc. 2008, 130, 1069-1079), here the focus is on step 1. Comparison of the reactivity of dimethylcuprate toward allylic susbtrates reveals that while allyl acetate reacts around 70 times more slowly than allyl iodide, it is more selective for cross-coupling. This is rationalized by DFT calculations, which reveal that an increase in kinetic barrier is responsible for both reactivity trends. The lowest energy path was found to involve a stepwise π-oxidative addition proceeding via an η²-C₃H₅O ₂CCH₃ intermediate and extrusion of a leaving group (LG) anion, followed by a reductive elimination where this LG is recomplexed to the copper center. Finally, DFT calculations were used to shed light on the role of leaving groups LG = CH₃CO₂^-, I^-, Br^-, Cl^- in the allylic alkylation. While selectivity is indeed achieved at the cost of reactivity, the LG effects were more complex than can be accounted for by a simple consideration of the anion proton affinity (APA) of the LG.

Full text of DOI:10.1021/om300717g

Article
pubs.acs.org/Organometallics
Dimethylcuprate-Catalyzed Decarboxylative Coupling of Allyl
Acetate
Nicole J. Rijs and Richard A. J. O’Hair*
School of Chemistry, Bio21 Institute of Molecular Science and Biotechnology, and ARC Centre of Excellence for Free Radical
Chemistry and Biotechnology, The University of Melbourne, Victoria 3010, Australia
S
* Supporting Information
ABSTRACT: Allylic alkylation of organocuprates represents an important class
of C−C bond forming reactions. A drawback of these reactions is their
stoichiometric nature. Although metal-catalyzed decarboxylative coupling
reactions offer new opportunities for formation of C−C bonds, catalytic allylic
alkylation reactions of organocuprates have not been previously reported. Here,
multistage mass spectrometry experiments performed on ion trap mass
spectrometers in conjunction with electronic structure calculations are used
to demonstrate that the dimethylcuprate anion, [CH3CuCH3]−, can catalyze decarboxylative coupling of allyl acetate in the gas
phase via a simple two-step catalytic cycle. In step 1, [CH3CuCH3]− undergoes a cross-coupling reaction with allyl acetate to
yield [CH3CuO2CCH3]− as the major product ion. Step 2 involves subjecting the product ion to collision-induced
decarboxylation to re-form [CH3CuCH3]−, thereby closing the catalytic cycle. Since the details of step 2 have been previously
described (Rijs, N.; Khairallah, G. N.; Waters, T.; O’Hair, R. A. J. J. Am. Chem. Soc. 2008, 130, 1069−1079), here the focus is on
step 1. Comparison of the reactivity of dimethylcuprate toward allylic susbtrates reveals that while allyl acetate reacts around 70
times more slowly than allyl iodide, it is more selective for cross-coupling. This is rationalized by DFT calculations, which reveal
that an increase in kinetic barrier is responsible for both reactivity trends. The lowest energy path was found to involve a stepwise
π-oxidative addition proceeding via an η2-C3H5O2CCH3 intermediate and extrusion of a leaving group (LG) anion, followed by a
reductive elimination where this LG is recomplexed to the copper center. Finally, DFT calculations were used to shed light on
the role of leaving groups LG = CH3CO2 , I−, Br−, Cl− in the allylic alkylation. While selectivity is indeed achieved at the cost of
−
reactivity, the LG effects were more complex than can be accounted for by a simple consideration of the anion proton affinity
(APA) of the LG.
cross-coupling catalyzed by palladium(II) acetate in the final
step of the biomimetic synthesis of the marine alkoloid lamellarin
G trimethyl ether.5a More recently, decarboxylative coupling of
biaryls has led to an array of biologically active compounds.5b
As highlighted previously,6 allylic alkylations are an
important class of copper-mediated reaction, useful in
constructing many commercially and biologically important
molecules.7 We recently examined the gas-phase reactions of
group 11 dimethylmetalates with allyl iodide and found that
dimethylcuprate promoted a cross-coupling reaction, with
concurrent formation of a methylcopper iodide anion by-
product, [CH3CuI]− (eq 3, LG = I−). These reactions were
INTRODUCTION
■
From a green chemistry perspective, decarboxylative coupling is
a highly desirable process in terms of atom economy, since
neutral extrusion of carbon dioxide from an ester enables C−C
bond formation (eq 1).1 Unfortunately, direct thermolysis of
RCO2R′ → R−R′ + CO2
(1)
esters typically yields a mixture of products.2 Decarboxylative
cross-coupling is the process of neutral extrusion of carbon
dioxide from a carboxylate feedstock (for example, a carboxylic
acid or salt) to form an active organometallic species which can
participate in cross-coupling (eq 2).3 Metals used to catalyze
[CH3CuCH3]− + C3H5LG → [CH3CuLG]− + CH3C3H5
cat.
(3)
RCO2H + R′X ⎯⎯→ R−R′ + CO2 + HX
(2)
carried out in an ion trap mass spectrometer, where
[CH3CuCH3]− was formed via double decarboxylation of
[CH3CO2CuO2CCH3]− using collision-induced dissociation
(CID).8
decarboxylative cross-coupling reactions commonly include the
group 11 metals, palladium and rhodium.3b A wide range of
functionality on the carboxylate (R) is tolerated, making this a
versatile method for C−C coupling. Allylic and benzylic esters
are readily employed as substrates in such catalytic decarbox-
ylative reactions (eq 2, R′ = allyl, benzyl; X = carboxylate
group).4 In one of the earliest examples of such a reaction,
Steglich and co-workers used intramolecular decarboxylative
Special Issue: Copper Organometallic Chemistry
Received: July 27, 2012
Published: September 20, 2012
© 2012 American Chemical Society
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It occurred to us that the allylic alkylation process could be
made catalytic by changing the leaving group (LG) from iodide
to acetate, thereby closing the catalytic cycle by re-forming the
active species 1 (Scheme 1.).
predict the most likely reaction mechanism for allylic alkylation,
and (iv) compare the effects of acetate versus halide leaving
groups in allylic alkylation reactions.
EXPERIMENTAL SECTION
■
Scheme 1. Proposed Two-Step Catalytic Cycle for the
Dimethylcuprate Catalyzed Decarboxylative Coupling of
Allyl Acetate
Reagents. Copper(II) acetate and allyl acetate were obtained from
Aldrich. Acetic acid-d4 was obtained from Cambridge Isotope
Laboratories. All chemicals were used without further purification.
Mass Spectrometry. Ion−molecule reactions (IMR) were
performed on a modified Finnigan LCQ quadrupole ion trap mass
spectrometer equipped with a Finnigan ESI (electrospray ionization)
source, as previously described.14 Additional IMR were performed in a
Thermo Finnigan LTQ linear ion trap mass spectrometer.15 Gronert
has shown that the temperature of ions trapped in an ion trap mass
spectrometer without ion activation are at near-thermal conditions
(i.e., room temperature).14c
Accurate mass measurements were conducted using the FT-MS to
establish the stoichiometry of product ions derived from the ion−
molecule reactions, as previously described.15 Methanolic solutions of
copper(II) acetate with concentrations of 0.5−1.0 mM were injected
into the ESI source at a flow rate of 5 μL/min. Typical electrospray
source conditions involved needle potentials of 3.5−4.5 kV and a
heated capillary temperature of 180 °C. Mass selection, collisional
activation, and ion−molecule reactions were carried out using the
“advanced scan” function of the LCQ software, which allows the Q
value and the reaction time to be varied. The neutral substrate allyl
acetate was introduced at various concentrations into the ion trap via
the helium inlet line. Rates were measured by varying the time delay
between isolation of the [CH3CuCH3]− reactant ion and its mass analysis
(“Reaction Delay”, RD). The decay of [CH3CuCH3]− was monitored
over at least six values of RD. The intensity of the reactant ion was
calculated by integration of its ion count within the mass-selected window.
Pseudo-first-order rates were estimated by extrapolation of plots of
−ln(([CH3CuCH3]− intensity)/(total ion intensity)) vs RD. Rate
constants were calculated by dividing the pseudo-first-order rate
coefficient by the calculated concentration of allyl acetate in the ion
trap. The rate constants and branching ratios reported are the average of
at least five independent measurements conducted on at least four
separate days.16 Standard deviations in rate constants were typically
around 30%. A conservative estimate of error is 25%, but relative rates
are expected to be more accurate due to cancellation of errors.
Collision rates were calculated via the average dipole orientation
(ADO) theory of Su and Bowers using the COLRATE program.17
Theoretical Calculations. Theoretical calculations were carried
out to provide insights into the bimolecular and catalytic reactivity of
the dimethylcuprate. Gaussian 09,18 utilizing the B3LYP hybrid
functional,19 was used for all geometry optimizations and vibrational
frequency calculations. The Stuttgart Dresden (SDD) basis set and
effective core potential (ECP) were used for the copper atoms, while
the 6-31+G(d) all-electron basis set was used for carbon, hydrogen,
and oxygen.20 Optimized B3LYP geometries of organocuprate
complexes were previously compared with those determined from
X-ray crystallography.8 There was excellent structural agreement
between the calculated geometries and those determined exper-
imentally. Thus, this combination of method and basis set was chosen,
as it predicts structures well. All transition-state (TS) geometries were
characterized by the presence of a single imaginary frequency, and
intrinsic reaction coordinates (IRC) were examined to ensure smooth
connection of reactants and products. The energetics presented were
calculated with B3LYP utilizing the larger Def2-QZVP basis set (C, H, O,
all electron; Cu, including ECP),21 defined as B3LYP/Def2-QZVP//
B3LYP/SDD6-31+G(d). All quoted relative energies (E0) include zero
point vibrational energy (unscaled) calculated at the optimization level
and are not corrected for basis set superposition error.
Thus, an extension to organocuprate-catalyzed decarbox-
ylative allylic alkylations would combine the power of copper in
(i) mediating nucleophilic substitution reactions with con-
venient substrates bearing carboxylate leaving groups and (ii)
catalyzing decarboxylation reactions to form organocopper
complexes.3,5b With regard to the first point, reactions between
allylic esters and cuprates have been known for more than 40
years.9 The stereoselectivity of these reactions was noted early
on,10 along with the potential intermediacy of π-allyl
intermediates.11 The mechanism of reaction between allyl
acetate and dimethylcuprate has been examined computation-
ally by Nakamura and co-workers.12 While a detailed analysis of
the bimetallic cuprate/lithium species was undertaken, only a
limited study of the intrinsic reactivity of the bare dimethyl-
cuprate anion toward allyl acetate was considered. In this
reaction, the kinetic barrier was found to be significantly
above the level of the separated reactants, and thus no reaction
would be expected to take place. However, the assistance or
possible transfer of the carboxylate leaving group was not
reported. These coupling reactions are stoichiometric, and the
organocuprate-catalyzed decarboxylative coupling of allyl esters
has hitherto not been reported. With regard to the second
point, copper-catalyzed protodecarboxylation reactions have
been extensively used in organic synthesis since they were first
reported by Shepard et al. in 1930,5c and using a combination
of mass spectrometry experiments and DFT calculations, we
have examined the gas-phase decarboxylation reactions of a
range of copper(I) carboxylate complexes, including the
mechanism and energetics for the formation of [CH3CuCH3]−
from [CH3CuO2CCH3]− (step 2 of Scheme 1).8
Previous studies have highlighted that catalytic cycles can be
studied in in the gas phase.13 Using multistage mass spectro-
metry experiments, catalytic intermediates or byproducts may
be isolated, and their unimolecular or bimolecular reactivity
can be probed.13 In conjunction with theoretical modeling this
approach can illuminate the mechanisms of the various steps
involved in catalysis.
Given the fact that the bare dimethylcuprate anion has been
shown to react with allyl iodide (described above, eq 3) and the
iodide anion has been shown to assist allylic alkylation by
lowering reaction barriers,6 the aim of the work described here
is to (i) establish whether bare dimethylcuprate anion reacts
with allyl acetate in an allylic alkylation reaction in the gas
To assess the robustness of B3LYP energetic trends, key stationary
points were calculated with the M06 functional22 and the B2PLYPD
double hybrid functional23 (Supporting Information, Table S1). For
the allyl acetate system, the predicted energetic trends are entirely
consistent among all three methods. Thus, as these trends were also
−
phase, (ii) determine whether the leaving group (CH3CO2 ) is
transferred to the copper center for subsequent regeneration of
the catalytically active species, (iii) use DFT calculations to
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Scheme 2. Generation and Potential Gas-Phase Ion−Molecule Reactions of Dimethylcuprate with Allyl Acetate
consistent between these methods for allyl iodide, the subsequent
leaving group comparisons are made with B3LYP derived energies.
Visualizations of the molecules appearing in this report were created
using MacMolPlt.24
RESULTS AND DISCUSSION
■
Experimental Results. Dimethylcuprate precursor ions were
generated via multistage mass spectrometry methods using a
double-decarboxylation strategy. Decarboxylation of copper
carboxylate was promoted by CID (Scheme 2). As this process
has been described in detail in previous reports,8 here the focus is
on establishing how dimethylcuprate reacts with allyl acetate, and
whether the catalytic cycle shown in Scheme 1 operates.
The IMR were conducted in an MS4 experiment in a fashion
analogous to that previously described6 by allowing the mass-
selected 63Cu dimethylcuprate anion (m/z 93) to react with
allyl acetate (Scheme 2). These reactions were also undertaken
with the isotopologues d3-dimethylcuprate and d6-dimethylcup-
rate (m/z 96 and 99, respectively). Since the neutral products of
ion−molecule reactions are not detected in our experiments, they
are inferred from the detected ionic products.6 The resultant
IMR spectra are shown in Figure 1. Figure 1a reveals that a
substitution reaction takes place with allyl acetate, according to
eq 4, forming the product [CH3CuO2CCH3]− (m/z 137).
[CH3CuCH3]− + C3H5O2CCH3
→ [CH3CuO2CCH3]− + C3H5CH3
(4)
The results of deuterium labeling experiments (Figure 1b,c)
confirm the assignment that substitution involves the acetate
group from the allyl acetate neutral, according to eqs 5 and 6.
[CD3CuCH3]− + C3H5O2CCH3
→ [CH3CuO2CCH3]− + C3H5CD3
(5a)
→[CD3CuO2CCH3]− + C3H5CH3
Figure 1. MS4 mass spectra showing ion−molecule reactions among
allyl acetate (C3H5O2CCH3) and (a) dimethylcuprate anion
[CH363CuCH3]− (m/z 93), (b) d3-dimethylcuprate anion
[CD363CuCH3]− (m/z 96), and (c) d6-dimethylcuprate anion
[CD363CuCD3]− (m/z 99). The mass-selected ion is marked with
an asterisk in each spectrum. The peaks I−VI correspond to primary
and secondary products, while # denotes [CH363CuCl]−.
(5b)
[CD3CuCD3]− + C3H5O2CCH3
→ [CD3CuO2CCH3]− + C3H5CD3
(6)
The results for the 65Cu isotope (shown in the Supporting
Information, Figure S1) also confirm this reactivity. Thus,
[CH3CuO2CCH3]− is the product ion arising from C−C bond
formation via cross-coupling of a cuprate methyl group with the
allylic substrate (Scheme 1). A comparison of integrated ion
abundances of the product ions [CH3CuO2CCH3]− (m/z 137)
and [CD3CuO2CCH3]− (m/z 140) formed in the competing
cross-coupling reactions of [CD3CuCH3]− (eqs 5a and 5b)
allows the determination of a secondary deuterium kinetic
isotope (kH/kD) effect of 1.2 0.1, which is essentially identical
with that determined for the allylic alkylation reaction with allyl
iodide.6,25
The peaks denoted with roman numerals (I−VI) in Figure 1
are other primary or secondary products, and their masses were
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confirmed via accurate mass FT-MS (Supporting Information,
Table S2). Suggested assignments based on the isotopic masses,
where X = H, D, are as follows: (I) [CX3CuH]−, (II)
[CH3CuCX3]−, (III) [CX3CuO2CH]−, copper formate, (IV)
[CX3Cu(C3H3O2)]− (where C3H3O2 is an empirical formula),
(V) [CH3CO2CuO2CCH3]−, (VI) [CX3CuCX2(C3HO4)]− or
[CX3CuCX2(C4H5O3)]−, where C3HO4 and C4H5O3 are
empirical formulas. Another minor peak (see Table S2), was
found to be (VII) [CH3Cu(C7H11O2)]−. The origin of # is
most likely due to a minor chloride contamination in the IMR
line (i.e., # = [CX3CuCl]−). Two secondary products were
established as [CH3CO2CuO2CCH3]− (m/z 181, V) and
[CH3CuCX3]− (II), the former due to a second coupling reaction
and the latter resulting from decarboxylation of the product ion
[CX3CuO2CCH3]− (X = H, D) (eq 7 and Figure 2).
reacts via homocoupling to produce [C3H5CuI]−,6 the related
homocoupling product ion, [C3H5CuO2CCH3]−, is not observed
at m/z 163. Thus, the allyl acetate substrate appears to be selective
for cross-coupling. The other conspicuously absent product ion is
the leaving group anion, which would otherwise be visible at m/z
59 (CH3CO2−). The iodide anion (m/z 127) is a prominent
feature of the IMR spectra of dimethylcuprate reacting with allyl
iodide.6 DFT calculations suggested that I− can be formed via
multiple mechanistic pathways. However, the absence of CH3CO2−
in the spectra in Figure 1 suggests that the acetate leaving group is
sequestered by the copper center in the allylic alkylation reaction.
This is a promising feature, as the potential precursor to the
catalytic species (Scheme 1), the acetate ligand, is not lost.
The kinetics for the IMR of [CH3CuCH3]− with allyl acetate
were measured. The rate of reaction (kmeasured) was determined
to be (11 4) × 10−13 cm3 molecule−1 s−1 (the error corresponds
to 1 standard deviation), which translates to a modest reaction
efficiency of 0.032% (the collision rate, kADO, is estimated to be
3.44 × 10−9 cm3 molecule−1 s−1). Indeed, the reaction with allyl
acetate is more that 70 times slower than that for allyl iodide.
Thus, changing the LG to acetate slows the allylic alkylation
reaction.
[CX3CuO2CCH3]− → [CX3CuCH3]− + CO2
(7)
These experimental results show that, while allyl acetate is
significantly slower to react than allyl iodide, the reaction is more
selective. Conservation of the leaving group is of prime importance
for setting up the catalytic precursor, [CH3CuO2CCH3]−, to
dimethylcuprate. Indeed, [CH3CuO2CCH3]− is readily decar-
boxylated, as shown both by small amounts of secondary products
being formed in the exothermic ion−molecule reaction (Figure 1)
and by CID of the mass selected product ion (Figure 2). Thus, the
gas-phase catalytic cycle for the dimethylcuprate-catalyzed
decarboxylative coupling of allyl acetate has been experimentally
established (Scheme 1). In the next section the most likely
reaction mechanism and the effect of the leaving groups on the
allylic alkylation reaction (step 1 of Scheme 1) are determined via
the use of DFT calculations.
Computational Results. The results of the gas-phase IMR
of dimethylcuprate with allyl acetate revealed the re-formation of
the copper carboxylate species, suggesting that cross-coupling
occurs. In addition, the reaction was more than 70 times slower for
allyl acetate than for allyl iodide. Electronic structure calculations
were undertaken to gain insight into the most viable reaction
mechanisms and the origin of these differences in reactivity.
The pathways analyzed here were informed by our previous
work on allyl iodide:6 concerted nucleophilic substitution at the
SN2′ (Scheme 3, path A, γ-carbon) or SN2 (Scheme 3, path B,
α-carbon) position; stepwise σ-type oxidative addition (α-
carbon) followed by reductive elimination (Scheme 3, path C)
and stepwise π-type oxidative addition followed by reductive
elimination (Scheme 3, path D, γ-carbon) resulting in cross-
coupling. The potential for homocoupling via the M(III)
intermediate formed in path D was also examined. The leaving
group (LG) was found to alter the mechanism of π-type oxi-
dative addition, and this will be discussed in more detail. A key
criterion for establishing the likely mechanism(s) of the reaction
is the recognition that the near-thermal conditions of ion−
molecule reactions in an ion trap mass spectrometer14c dictates
that the barrier(s) should be below the level of the energy of the
separated reactants. As chemical accuracy is not expected to
be met with the B3LYP computational method, the pathways
which are close to or below the energy of the separated reactants
will be considered viable under the experimental conditions used.
As noted in the Experimental Section, additional calculations were
Figure 2. MS5 spectra, IMR of [CD3CuCD3]− with allyl acetate
(Figure 1c) resulting in [CD3CuO2CCH3]− (m/z 140). CID on this
ion at m/z 140 results in decarboxylation (the mass difference of 44
corresponds to loss of CO2 (eq 7)).
A careful analysis of the temporal evolution of the product
ions allowed the branching ratios of the primary product ions
for the reaction of allyl acetate and dimethylcuprate (m/z 93)
to be established (Table 1). While the mechanistic origins of
Table 1. Branching Ratios of Product Ions for the Gas-Phase
Ion−Molecule Reaction of Allyl Acetate with
Dimethylcuprate (m/z 93)
a
assignment
mass (m/z)
branching ratio (%)
[CH3CuO2CH]− (III)
[CH3CuO2CCH3]−
[CH3Cu(C3H3O2)]− (IV)
123
137
149
4
81
15
a
Only the identifiable primary products were included in these
branching ratio measurements.
the ions [CH3CuO2CH]− (III) and [CH3Cu(C3H3O2)]− (IV)
have unfortunately not been established, two key points are
that (i) the product ion at m/z 137, methylcopper acetate
[CH3CuO2CCH3]−, is the most abundant ionic product (81%)
and (ii) CID on the product ion at m/z 140 formed via IMR in
Figure 1c results in decarboxylation according to eq 7, where
X = D (Figure 2), confirming that the reactive dimethylcuprate
species [CH3CuCH3]− may be re-formed thermally and thus
closes the catalytic cycle (Scheme 1, step 2).
An interesting aspect of the allyl acetate substrate reactivity
with dimethylcuprate is the absence of two classes of product
observed for the related allyl iodide system. While allyl iodide
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a
Scheme 3. Potential Mechanistic Pathways A−D
a
LG = leaving group (acetate).
Figure 3. Calculated B3LYP/Def2-QZVP//B3LYP/SDD6-31+G(d): (a) relative energies (kJ mol−1) for minima and transition states relevant to
bimolecular reactions of [CH3CuCH3]− + C3H5O2CCH3 via paths A and B; (b) structures of minima and transition states relevant to the
bimolecular reactions of [CH3CuCH3]− + C3H5O2CCH3 via paths A and B of Scheme 3.
carried out using other computational methods in order to
evaluate the predicted trends in the relative energetics for the
different mechanisms shown in Scheme 3. These show that
pathway D has the lowest energy barriers for all methods used
(see the Supporting Information, Table S1). In the next sections,
each of the mechanistic pathways are discussed in detail.
Paths A and B. Both concerted nucleophilic substitution
paths A and B (SN2′ and SN2; Scheme 3, eqs 8 and 9) have high
kinetic barriers (Figure 3, 93.4 and 85.2 kJ mol−1). Despite
being exothermic overall, these reactions are not expected to
occur under the experimental conditions of the ion trap.
The TS geometries for paths A and B (Figure 3, TS2-3) are
structurally similar to those found for LG = iodide. The TS
vibration shows inversion of the hydrogen atoms on the methyl
group of the cuprate undergoing C−C bond formation, plus
simultaneous elimination of the acetate leaving group. These TS
geometries do not give a direct transfer of LG− (CH3CO2−) to
the copper center. The opportunity to form [CH3CuO2CCH3]−
is available via IMC 3; however, free LG− is expected to be ob-
served in the mass spectrum should these SN2 or SN2′ mech-
anisms be occurring. This is not the case, since CH3CO2− is not
observed in Figure 1. Thus, the combination of experiment and
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Figure 4. Calculated B3LYP/Def2-QZVP//B3LYP/SDD6-31+G(d): (a) relative energies (kJ mol−1) for minima and transition states relevant to
bimolecular reactions of [CH3CuCH3]− + C3H5O2CCH3 via path C (σ oxidative addition); (b) structures of minima and transition states relevant
bimolecular reactions of [CH3CuCH3]− + C3H5O2CCH3 via path C of Scheme 3.
theory suggest that paths A and B are not the preferred cross-
coupling mechanisms to yield [CH3CuO2CCH3]−.
Path C. The stepwise σ-oxidative addition/reductive elimi-
nation cross-coupling pathway, path C (Scheme 3), also has a
substantial kinetic barrier (TS2-4; Figure 4, 72.5 kJ mol−1). Thus,
oxidative addition via this pathway (Scheme 3, eq 10) is not
expected to occur experimentally.
The structure of the TS of OAσ for LG = acetate is analogous
to that of LG = iodide, involving very little bend from linearity
of the cuprate and an SN2-like TS vibration of the M−C bond
forming groups, though the kinetic barrier is significantly higher
in energy than that of the latter (−37.5 versus 72.5 kJ mol−1,
respectively). The TS for REσ follows a similar trend, where the
geometries are similar to those previously analyzed (the typical
RE geometry found for methyl iodide26 and REσ allyl iodide).6
Figure 5. Comparison of cross-coupling pathways via π-oxidative
addition and reductive elimination. Energies of limiting kinetic barrier
(TS REπ) are annotated, while others are omitted for simplicity.
However, the energy is increased for the acetate leaving group
(compare C3H5LG TS REσ, LG = I−, −37.5 kJ mol−1 to LG =
CH3CO2 , 28.7 kJ mol−1).
−
The cross-coupling reaction via path C is dependent on (1)
the LG anion being an effective leaving group (i.e., the stability
of the anion) and (2) the Lewis basicity of the anion being
appropriate for assisting the REσ process. The gas-phase anion
mechanisms to cross-coupling (Scheme 4), dependent on the
role of the LG.
A π-oxidative addition (TS2-6) results in an η2-(C3H5O2CCH3)
intermediate, 6. Subsequently, there is a LG elimination
(TS6-7); thus, the η3-(C3H5) intermediate is formed in a step-
wise manner. This is unlike π-oxidative addition with LG = iodide,
where the η3-(C3H5) intermediate is formed in a process that is
concerted with respect to the loss of the LG (Figure 6a in ref 6).
Thus, the Cu(III) IMC 7 is formed in a stepwise OAπ fashion.
Three alternatives to cross-coupling are then possible via 7
(Scheme 4): path D′, where the LG interacts with metal leading
to RE, path D″, where the LG forms an ion−molecule complex
resulting in RE and the same products as for D′, and path D′′′,
where LG dissociates and neutral product completes RE without.
The latter neutral pathways have been previously explored12 and,
since they are energetically demanding, are unlikely to occur.
This is clearly shown in Figure 5, where TS RE from a
neutral pathway has a kinetic barrier of 103.2 kJ mol−1 and is
the kinetically least favorable of all the cross-coupling paths
examined thus far. The other two REπ options are lower in
energy and are thus more viable. The ion−molecule pathway,
TS REπ D″, has a kinetic barrier of 35.1 kJ mol−1 and also has
−
proton affinity (APA, eq 13) of CH3CO2 is 1456 versus
1315.24 kJ mol−1 for I−,27 indicating the latter is a weaker base
and a better leaving group. This appears to correlate with the
energetic trend to OAσ. In terms of (2), I− is a soft base and
CH3CO2− is a hard base.28 It is less clear what role this plays in
assisting or stabilizing the RE TS at the copper center. A
combination of anion size (and hence bond length), basicity,
and polarization effects are likely to play a role. It is observed
that iodide is superior in reactivity to acetate via this cross-
coupling mechanism, due to possessing lower kinetic barriers;
however, acetate is more likely to be transferred to the copper
center as a ligand.
LG− + H+ → H−LG ΔHrxn = APA
(13)
Path D. The lowest energy pathway for a cross-coupling
reaction between allyl acetate and dimethylcuprate is path D
(Scheme 3). An examination of path D reveals three potential
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Scheme 4. Mechanistic Pathways to Cross-Coupling via π-Oxidative Addition and Reductive Elimination (Path D)
the opportunity to form a coordinating LG ligand. The ligand-
coordinated mechanism, D′, has the lowest energy with a
barrier of 26.0 kJ mol−1 and will be discussed in more detail.
Figure 6 shows the energy of all the consecutive steps
involved in π-OA/RE via path D, along with the reaction
structures. The TS barriers to OAπ, LG dissociation, and REπ
are 19.2, 23.4, and 26.0 kJ mol−1, respectively, followed by a
low-lying TS for olefin elimination (−169.8 kJ mol−1). These
are far lower barriers (by 50−70 kJ mol−1) than for any of the
other cross-coupling paths A−C (Scheme 3) and thus represent
the most likely reaction mechanism for allylic substitution
involving allyl acetate. The TS geometries for REπ are similar to
those examined for LG = iodide; however, the acetate group is
interacting with the copper center to a greater extent than the
iodide (compare ref 6 TS9-10, Figure 4, with this work, TS8-9,
Figure 6). This is very clearly shown by the Cu−LG distances
in the TS REπ (Cu−I = 5.25 Å versus Cu−O = 2.26 Å).
Thus, the LG is stabilizing the RE TS in the two viable
pathways of Scheme 4 and is transferred to the copper center.
There is no opportunity for LG loss, which is consistent with
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Figure 6. Calculated B3LYP/Def2-QZVP//B3LYP/SDD6-31+G(d): (a) relative energies (kJ mol−1) for minima and transition states relevant to
bimolecular reactions of [CH3CuCH3]− + C3H5O2CCH3 via path D (π-addition) of Scheme 3; (b) structures of minima and transition states
relevant to bimolecular reactions of [CH3CuCH3]− + C3H5O2CCH3 via path D (π-addition) of Scheme 3.
−
the absence of CH3CO2 in the IMR spectra (Figure 1).
Though the carboxylate anion assists in stabilizing the TS RE, it
does not lower the reaction barrier by the same magnitude as a
participating iodide anion does (26.0 versus −45.4 kJ mol−1,
respectively). Though this pathway is the lowest energy and
thus the most viable pathway for cross-coupling, it resides
above the energy of the separated reactants. However, the DFT
method used is not expected to attain absolute chemical accuracy
when considering TS barriers. Indeed, the barriers drop on
moving to the M06 and B2PLYPD methods, with the latter
below the energy of the separated reactants (see the Supporting
Information Table S1). Thus, in the absence of lower energy
pathways, path D is the most likely mechanism for the cross-
coupling reaction inferred from the experiments.
expected to occur in competition with the cross-coupling
reaction (TS8-9, 26.0 kJ mol−1). Thus, the origin of the cross-
coupling selectivity is a noncompetitive barrier height (TS7-11,
REhomo) preventing reductive elimination to give the homo-
coupling product.
Re-Formation of the Organocuprate via Decarboxylation
and Mechanistic Summary. As the kinetic barrier of
decarboxylation is beneath the energy of the separated reactants
(Figure 8), it is predicted that enough energy will be available
in the system for a decarboxylation reaction to occur from the
cross-coupling product ion (eq 7). As Figure 1b,c reveals, a
small amount of decarboxylation occurs spontaneously, to form
the active species dimethylcuprate at m/z 93 and 96, respectively.
However, the barrier to decarboxylation (145.2 kJ mol−1 above the
energy of the carboxylate29), together with collisional cooling of
[CH3CuO2CCH3]− by the helium bath gas, will limit the extent of
this reaction under the reaction conditions used.
In summary, in the case of the allylic substrate allyl acetate, it
was found experimentally that changing the LG from iodide to
acetate the selectivity for cross-coupling is improved at the cost
of slowing the reaction. These results are rationalized by DFT
predictions, which show the reaction barriers to cross-coupling
are increased in all cases in comparison with allyl iodide. These
higher barriers would slow the reaction. The origin of selectivity
was also found to be due to the raising of the kinetic barriers,
Homocoupling via Path D. In the IMR experiments with
allyl acetate, the ionic product, [C3H5CuO2CCH3]−, from the
homocoupling pathway was not observed (Figure 1). Given
that the homocoupling product was observed during IMR
between dimethylcuprate and allyl iodide,6 calculations were
carried out to find the origin of this difference in reactivity.
Figure 7 reveals that the kinetic barrier to this reaction via eq 12
(Scheme 3) and subsequent REhomo (TS7-11) is 58.2 kJ mol−1.
Indeed, this barrier height is substantially above the energy of
separated reactants for all computational methods used (see the
Supporting Information, Table S1) and thus it would not be
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Figure 7. Calculated B3LYP/Def2-QZVP//B3LYP/SDD6-31+G(d): (a) relative energies (kJ mol−1) for minima and transition states, relevant to
bimolecular reactions of [CH3CuCH3]− + C3H5O2CCH3 via path D (π-addition) and homocoupling; (b) structures of minima and transition states
relevant to bimolecular reactions of [CH3CuCH3]− + C3H5O2CCH3 via path D (π-addition) and homocoupling.
act as a leaving group can be assessed via the gas-phase anion
proton affinity (APA, eq 13), which is a measure of the intrinsic
gas-phase basicity of the anion. The experimental values for APA
for this series of leaving groups are given in Table 2 and highlight
that the LG ability follows the order CH3CO2− < Cl− < Br− < I−
(preferred).27 It was of interest to determine whether the reactivity
is a direct consequence of this ordering or if other factors (e.g.,
anion size, softness) were involved. Thus, key TS barriers to allylic
alkylation for LG = Cl−, Br−, along with LG = CH3CO2−,
I− (Scheme 3), were calculated to assess if the predicted
trend matched that of the LG APAs, and the data are also given
in Table 2).
The calculated TS values show that kinetic barriers of SN2
and SN2′ type reactions increase with the APA of the leaving
group in the order CH3CO2− > Cl− > Br− > I− (lowest kinetic
barrier). This seems reasonable, given that the process of
breaking the C−LG bond is concurrent with C−C bond
formation. This trend has been noted previously for the
reaction of a range of electrophiles in SN2 reactions: for
example, alkyl substrates with both halide and trifluoroacetate
(TFA) leaving groups.30 However, paths A and B are not the
preferred mechanisms of reaction for cross-coupling for any of
the electrophiles analyzed here.
Figure 8. Calculated B3LYP/Def2-QZVP//B3LYP/SDD6-31+G(d)
decarboxylation energies relative to the energies of the products
formed from allylic alkylation.
with the homocoupling kinetic barrier being too high to be
competitive with cross-coupling. The most viable pathway for
the formation of a cross-coupled product was found to be path
D, where the LG interacts with the metal center, thereby
stabilizing the RE TS. The lack of LG loss in the IMR mass
spectrum was also rationalized, as it becomes complexed to the
The energetic trend for OAσ is qualitatively similar to the
APA order. Indeed, the trend in charge distribution (Table 3) is
consistent with the APA trend and accounts for the decrease in
OA. On the basis of calculated values, the ordering of dipole
moment magnitude is LG = CH3CO2 < I− < Cl− ≤ Br−
−
−
(Table 3). In addition, while the molecular dipole moment for
the halogenated molecules is oriented along the C−LG bond,
the allyl acetate dipole is oriented perpendicular to the C−LG
bond axis, due to the orientation of the oxygen atoms of the
acetate group. Therefore, the halogenated molecules will
favorably react due to both a larger dipole moment and
direction of the dipole vector. Allyl iodide is the most reactive
of these substrates, which falls outside the trend in dipole
moments. It is more reactive than the other halides due to both
its higher polarizabilty (Table 3) and its being a more effective
leaving group (Table 2). Steric crowding by the LG may also
hinder the TS OAσ for acetate more than for the halides.
metal center via path D. Thus, no free CH3CO2 is generated.
This is an important step for a catalytic decarboxylative allylic
alkylation. Given the observed consequences of leaving group
on mechanism (for e.g. the change in OAπ), the next section
focuses in more detail on the effects of changing the LG.
Comparison of Leaving Group Effects. The work so far has
shown that switching the leaving group on the allylic substrate
results in changes to both reactivity and selectivity (when LG = I−,
−
CH3CO2 ) for the allylic alkylation reaction with dimethylcup-
rate. A better understanding of the leaving group effects on
this reaction may be gained from a systematic comparison of
C3H5LG (LG = Cl−, Br−, I−, CH3CO2−). The ability of an ion to
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Table 2. Gas-Phase Experimental Anion Proton Affinities (APAs, eq 13, in kJ mol−1) of Different LGs and Key TS Barriers
a
(Scheme 3) for Cross-Coupling Calculated with B3LYP/SDDDef2-QZVP//B3LYP/SDD6-31+G(d)
rel energy (kJ mol−1) of TS barriers for allylic alkylation
path C
path D (D′)
path A
SN2
path B
LG
APA (eq 13) (kJ mol−1
)
SN2′
OAσ
REσ
OAπ
LGelim
REπ
−
CH3CO2
Cl−
Br−
1456
85.2
36.5
17.4
2.2
93.4
46.4
27.2
11.4
72.5
7.2
28.7
−12.5
−27.0
−37.5
19.2
7.3
23.4
−32.3
n/a
26.0
−16.2
−29.9
−45.4
1394.9
1353.9
1315.24
−13.5
−27.3
−6.6
−26.0
I−
n/a
a
Energies are relative to separated reactants [CH3CuCH3]− and C3H5LG (kJ mol−1). APA values are from ref 27. n/a = not applicable.
Table 3. B3LYP Calculated Properties Molecular Dipole Moment, Average Polarizability, and Charge Distribution for C3H5LG
−
(LG = CH3CO2 , Cl−, Br−, I−)
calcd charge distribution (APT, H summed into heavy atoms)
a
LG
dipole moment, μ (D)
av polarizability, αav (au)
α-carbon
β-carbon
γ-carbon
LG
−
CH3CO2
Cl−
2.04
2.49
2.51
67.8
47.0
57.8
66.1
0.49
0.44
0.42
0.36
0.02
−0.04
−0.06
−0.06
−0.02
0.00
−0.49
−0.40
−0.37
−0.31
Br−
0.01
I−
2.24
−0.00
Average polarizabilty αav = /3(αxx + αyy + αzz).31
a
1
The trend in REσ is less affected by the LG anion. The anions
are likely to alter the orbital symmetry and energies of the
copper(III) TS complex via the vacant coordination site. The
Lewis basicity, polarizability, and size of the LG anion are likely
to be taking part in this process; however, the extent of
involvement of each is not clear from the predictions here
alone. Pathway C is a competitive reaction mechanism for LG =
Cl−, Br−, I− but not for LG = CH3CO2 , which is a
−
consequence of a combination of LG attributes.
For OAπ, the effect of the leaving group is quite apparent by the
change in mechanism upon moving down Cl− to Br− (Table 3).
The two better LGs (Br− and I−) dissociate directly in a concerted
TS when forming the copper(III) intermediate. The two poorer
LGs (CH3CO2− and Cl−) react via a mechanism where inter-
mediates are formed, which may subsequently dissociate via
another TS. For LG = Cl−, this is the rate-limiting step, and the
loss of LG is facile. However, this is not the case for LG = acetate.
This indicates Cl− is an intermediate LG. The change in
mechanism is also apparent in the TS OAπ geometries (Figure 9).
While LG = Br−, I− (Figure 9c,d) have similar TS geometries
−
and imaginary vibrations, LG = CH3CO2 is considerably
different, where the addition is more symmetrical and akin to
olefin addition, without concurrent loss of the LG. LG = Cl−
shares characteristics of both TS types mentioned above,
−
being most like the TS for LG = CH3CO2 , forming an
Figure 9. Comparison of TS OAπ for [CH3CuCH3]− + C3H5LG,
with LG = (a) CH3CO2, (b) Cl, (c) Br, and (d) I. The energy (ΔE) is
in kJ mol−1.
intermediate where the LG has not dissociated. In solution-
phase NMR experiments, differences in reactivity between
allyl chloride and allyl acetate with dimethylcuprate that
were ascribed to the reaction mechanism have also been
observed.32
The TS REπ species for all four LGs are similar in energy to
those of the TS REσ. It also unclear here what role the LG
anion plays on lowering the TS REπ. It is again likely that anion
size and polarizabilty contribute to the metal orbital symmetry
and energies in the TS, although to what extent is not yet clear.
The reaction via path D is thus dependent on leaving group
ability and, to a lesser extent, the ability to assist in RE. The
nature of this TS will also determine whether the LG is
transferred to the metal center.
To assess how the selectivity changes with LG, the TS for
REhomo was also calculated (Table 4). These results show that
selectivity is indeed improved at the cost of reactivity, LG =
Cl−, CH3CO2 are less reactive, and REhomo is not competitive
−
with cross-coupling, while the more reactive LG = I−, Br− are
predicted to yield some homocoupling side product.
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frequencies for reactants, intermediates, products, and tran-
sition states, an M06 and B2PLYPD energy comparison, high-
resolution MS data, and the full citation for ref 18. This material
is available free of charge via the Internet at http://pubs.acs.org.
Table 4. Predicted Homocoupling Kinetic Barriers with
−
LG = CH3CO2 , Cl−, Br−, I− Calculated with B3LYP/
a
SDDDef2-QZVP//B3LYP/SDD6-31+G(d)
LG
TS to homocoupling rel energy (kJ mol−1) REhomo
−
CH3CO2
Cl−
58.2
b
AUTHOR INFORMATION
Corresponding Author
*Tel: +61 3 8344-2452. Fax: +61 3 9347-5180. E-mail: rohair@
unimelb.edu.au.
■
Br−
−10.0
−30.0
I−
a
Energies are relative to separated reactants [CH3CuCH3]− and
b
C3H5LG (kJ mol−1). No TS to REhomo located.
Notes
The authors declare no competing financial interest.
In summary, iodide is more reactive as a leaving group, while
CH3CO2− is more selective but less reactive. A previous mech-
anistic study has compared the reactivity of cuprates with the alkyl
halide electrophiles CH3I and CH3Br and found an analogous
trend.33 However, the allylic alkylation reaction is not as simple as
this example, with the net effect on the Cu(III) intermediate likely
to be important where this is the rate-limiting step, rather than the
LG ability on the OA step alone. This is highlighted by the change
in the OAπ TS (Figure 9), where clear differences in mechanism
due to the LG substituent are observed.
ACKNOWLEDGMENTS
■
We thank the ARC for financial support via grant DP110103844
(to R.A.J.O.). N.J.R. thanks the Faculty of Science for both (1) a
Science Faculty Scholarship and (2) an Albert Shimmins
Postgraduate Writing-Up Award. The VICS is acknowledged for
the Chemical Sciences High Performance Computing Facility
(Gomberg).
REFERENCES
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CONCLUSIONS
■
The first gas-phase catalytic cycle for decarboxylative allylic
alkylation has been demonstrated using a combination of mass
spectrometry experiments and DFT calculations. Dimethylcup-
rate, [CH3CuCH3]−, was shown to undergo a cross-coupling
−
reaction with allyl acetate and LG (CH3CO2 ) was selectively
transferred to the metal center to generate [CH3CuO2CCH3]−
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alkylation reactions previously observed between allylic esters
and cuprates in the condensed phase.9−11 Decarboxylation of
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−
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■
S
* Supporting Information
Text, figures, and tables giving IMR mass spectra with copper
isotope 65Cu, Cartesian coordinates, energies, and vibrational
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