Mechanism, reactivity, and selectivity in palladium-catalyzed redox-relay heck arylations of alkenyl alcohols

Article abstract of DOI:10.1021/ja4109616

The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of β-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict a ΔΔG^a of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C-O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.

Full text of DOI:10.1021/ja4109616

Article
pubs.acs.org/JACS
Open Access on 01/11/2015
Mechanism, Reactivity, and Selectivity in Palladium-Catalyzed
Redox-Relay Heck Arylations of Alkenyl Alcohols
Liping Xu,† Margaret J. Hilton,‡ Xinhao Zhang,† Per-Ola Norrby,*,§,∥ Yun-Dong Wu,*,†
Matthew S. Sigman,*,‡ and Olaf Wiest*,†,⊥
†Lab of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate
School, Shenzhen 518055, China
‡Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
§Department of Chemistry and Molecular Biology, University of Gothenburg, Kemigarden 4, SE 412 96 Goteborg, Sweden
̊
̈
∥Pharmaceutical Development, Global Medicines Development, AstraZeneca, Pepparedsleden 1, SE-431 83 Molndal, Sweden
̈
⊥Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556-5670, United States
S
* Supporting Information
ABSTRACT: The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various
useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of
β-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck
product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final
carbonyl group transformation. M06 calculations predict a ΔΔG⧧ of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the
enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic
effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C−O dipole
of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-
bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers,
where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product.
Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.
Scheme 1. Heck Arylation of Acyclic Alkenol Alcohols and
Aryl Diazonium Salts
INTRODUCTION
■
The Heck reaction is an excellent method to introduce an
aromatic group to one end of a double bond using palladium-
catalysis.1,2 The asymmetric variant of the Heck reaction has
received great attention as it generates chiral centers when
forming new carbon−carbon bonds, of vast importance in
natural product and pharmaceutical syntheses.3−5 One of the
most significant limitations is the requirement of a biased
alkene, such as a styrene or an α,β-unsaturated carbonyl, in
order to achieve high regiocontrol of the initial migratory
insertion and the resultant β-hydride elimination of the formed
Pd-alkyl intermediate. Another strategy for achieving selectivity
in Heck reactions is to use alkenes with adjacent coordinating
or directing groups.6−13 which has been applied in decarbox-
ylative14 and oxidative15−20 Heck reactions to achieve high site
selectivity. Sigman and others reported a highly regioselective
Heck reaction of electronically nonbiased alkenes without
chelating groups.18,21−23 Very recently, Sigman and co-workers
reported a highly enantioselective redox-relay Heck arylation of
acyclic alkenol alcohols (Scheme 1). They reported the use of
aryl diazonium salts24 and, more recently, an oxidative variant
employing aryl boronic acid derivatives25 as the coupling
partners. Both deliver remotely functionalized carbonyl
products in high enantioselectivity and with fair to excellent
site selectivity, depending on the reactant combinations. The
newly formed carbonyl group is remote from the site of
carbon−carbon bond formation, which suggests a chain-
walking process of the Pd-catalyst species to ultimately
transform the unsaturation of the alkene to the alcohol.26−31
This type of reaction is very attractive for two reasons: first, it
occurs with generally high site selectivity and enantioselectivity
with unbiased achiral substrates; and second is the simulta-
neous functionalization of multiple carbons through a
presumably iterative β-hydride elimination/migratory insertion
process.
The Heck reaction has been well-studied theoretically, most
frequently using the B3LYP functional.22,23,32−41 Many studies
have focused on the main selectivity-determining step, the
migratory insertion.19,20,42−44 In addition, the β-hydride
elimination step that is an important feature of the current
reaction has also been investigated.30,31 For asymmetric Heck
reactions, previous studies have focused on cyclic sub-
Received: October 27, 2013
Published: January 11, 2014
© 2014 American Chemical Society
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strates.32,45 However, to our knowledge, the more complex
situation, where asymmetry is induced in an open-chain alkene,
has not been studied theoretically. To this end, we have carried
out a mechanistic study on the title reaction using density
functional theory methods. These calculations provide a
complete picture of the mechanism and a rationalization of
the observed site-selectivity and enantioselectivity for this
unique variant of the Heck reaction.
positioned either trans or cis to the chiral oxazoline on the
ligand. The perpendicular coordination of homoallylic alcohols
to the Pd(II) species may occur from two different prochiral
faces. On each face, the substituted methyl group can be
positioned either below the “square plane”, proximal to the tert-
butyl group, or above the “square plane”, distal from the tert-
butyl group. As a result, a total number of eight conceivable
isomeric Pd(II)−π-alkene species needs to be considered. The
next steps are alkene insertion into the Pd−aryl bond to deliver
the Pd(II)−alkyl species and β-hydride elimination to form a
hydrido−palladium alkene species. Subsequent repetition of the
reinsertion and β-hydride elimination sequence gives a
hydroxyalkyl−palladium species, which after deprotonation
regenerates the Pd(0) species ligated to the carbonyl. This
complex can either dissociate to give the final product and
regenerate the catalyst or possibly react first with another
equivalent of the aryl diazonium salt before liberating the
product and closing the catalytic cycle.
Isomerization of the Initial Intermediates. The starting
aryl−palladium(II) alkene intermediate (structure INtrans‑1 in
Scheme 2) has two possible configurations, with the aryl group
positioned either trans or cis to the chiral oxazoline on the
ligand. Holder et al studied the trans−cis isomerization of the
tricoordinated arylpalladium(II) and showed that the isomer-
ization via a dissociative mechanism has a high activation free
energy.48 However, it is well-known that cis−trans-isomer-
ization can be strongly accelerated by basic ligands like
chloride49,50 or phosphines.51 We therefore tested the
hypothesis that the same type of process could be initiated
by the coordination of the solvent, DMF. Our calculations
show a feasible, low-energy path through an associative
mechanism (INDMF‑iso, Scheme 3) by the coordination of an
COMPUTATIONAL DETAILS
■
As a model system to elucidate the mechanism, we studied the
reaction shown in Scheme 1. The computational methodology was
benchmarked using a series of hybrid and dispersion corrected density
functionals (Table S1 in the Supporting Information [SI]). It was
found that the results for the six dispersion corrected functionals tested
are very similar. Throughout the manuscript, the results from
unconstrained geometry optimizations using the M06 functional46
implemented in Gaussian0947 are reported. This functional includes
corrections for dispersion interactions and was found to be reliable for
studies of Heck43 and related reactions.45,48 The Lanl2DZ and 6-
31+G(d) basis sets were used for Pd and all other atoms, respectively.
Single point calculations using the SDD basis set for Pd and the 6-
311++G(d, p) basis set for all other atoms and the SMD solvent
model with the parameters for DMF were used to account for solvent
effects. Frequency calculations at the same level of theory at the
optimized geometries confirmed the stationary points as minima (zero
imaginary frequencies) or transition state (one imaginary frequency)
and provided the thermal corrections to the single point energies.
Several conformations for each of the species have been investigated
but only the results for the lowest energy conformer are presented.
The final free energies from the single point calculations with solvent-
and thermal corrections are reported in kcal/mol. For clarity, the
charge state of this cationic reaction is not shown in some Figures.
Partial charges with hydrogens summed into the carbons they are
attached to were calculated using the NBO Charge Analysis.
Scheme 3. Isomerization of Starting Intermediates with
Associated Mechanism
RESULTS AND DISCUSSION
■
The Catalytic Cycle. The proposed catalytic cycle of the
asymmetric Heck redox-relay arylation is shown in Scheme 2. It
begins with oxidative addition of an aryl diazonium salt to a
Pd(0) species to form an aryl−Pd(II) complex in situ. This
complex may have two possible structures, with the aryl group
Scheme 2. Catalytic Cycle of the Asymmetric Heck Redox-
Relay Reaction
additional DMF molecule. Analogous to earlier studies (e.g., ref
52), we were unable to locate the TS for this isomerization,
presumably due to the complex coordinate of the Berry
pseudorotation. However, the relatively low free energy of the
trigonal biyramidal intermediate (5.4 kcal/mol), together with
the results from the earlier studies discussed above, indicates a
potential isomerization pathway. With a rapidly isomerizing
starting complex, the migratory insertion should be under
Curtin-Hammett control and, thus, be solely dictated by the
relative energies of the competing insertion transition states.
We note that under conditions where a similar aryl-Pd species
is configurationally stable, Holder et al.48 noted a significant
decrease in enantioselectivity, indicating that under catalytic
conditions, the intermediate can isomerize rapidly. As in our
case, they also failed to locate the TS of the transformation,
attesting to the complexity of the isomerization path.
Free Energy Profiles and the Relay Strategy. The
computed Gibbs free energy surface for the Pd-catalyzed redox
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Figure 1. Potential energy surface of the reaction pathway, the alternative conventional Heck reaction pathway (via TS7, shown in red), and the
direct alkene dissociation pathway (shown in blue).
relay Heck reaction of (E)-pent-3-en-1-ol with p-carboxyme-
thoxyphenyl diazonium salt is shown in Figure 1 with the low
energy pathway depicted in black. Previous electrospray and
tandem mass spectrometry studies53,54 of the Heck reaction
have shown that the oxidative addition of aryl diazonium salts
to palladium is very fast. Recent computational studies on the
Pd-catalyzed conjugated addition of aryl boronic acids to β-
substituted cyclic enones also showed this step as well as the
coordination of the olefin to be facile.48 Finally, the reaction can
also be performed using aryl boronic acids as the source of the
aryl group.25 Therefore, we started our investigation from the
Pd(II)-aryl alkene alcohol species INtrans‑2, which leads to the
lower energy pathway (compare Figure S2 in the SI for the
alternative pathway). The rotation of the alkene in the
perpendicular orientation relative to the square plane of Pd(II)
into the plane leads to the alkene insertion transition state for
the formation of the new carbon−carbon bond. This step
requires an activation free energy of 10.7 kcal/mol and
establishes the site- and enantioselectivity of the reaction, and
will be discussed in detail below. The product of this step,
complex 1, undergoes a series of rapid isomerizations to form
the less stable complex 2. The transformation of 1 to 2 requires
another cis−trans isomerization because the subsequent
reaction pathway with the alkyl chain in the trans position to
the pyridyl group requires higher free energies of activation
(Figure S2 in SI). The cis−trans isomerization again proceeds
through a solvent-assisted pathway in analogy to the one
discussed above and is likely to involve several steps. To
confirm that these steps are fast for the reasons discussed
above, we have calculated intermediate 16 along this isomer-
ization pathway and have found that it is low in energy,
(Scheme S1 in SI), indicating that this isomerization is indeed
facile.
It is noteworthy that 1 could in principle form the typical
Heck product 13 via TS7 (red pathway in Figure 1). However,
this step is predicted to have a free energy of activation of 6.9
kcal/mol for the formation of 11. Ultimately, the formation of
the Heck product is 13 kcal/mol higher in energy than 1. The
formation of the less stable intermediate 11 is reversible.
Therefore, the formation of the typical Heck product should
occur only to a very small extent, and even this will revert to 1,
reentering the main catalytic sequence.
Intermediate 2 undergoes the first β-hydride elimination via
TS3 to form complex 3. This step requires an activation free
energy of 6 kcal/mol. After formation of 3, the displacement of
the alkene from the cationic palladium is calculated to be
endothermic by 14.9 kcal/mol and is therefore unlikely to
occur. This is presumably due to the electrophilic nature of the
electrophilic palladium cation, which is further enhanced by the
electron withdrawing CF3 group on the ligand, diminishing the
Lewis basic properties of the pyridine. The precise electronic
structure of the ligand is therefore crucial for the control of the
relay versus the dissociation step and, ultimately, the products
formed. These computational results demonstrate the im-
portance of careful ligand design to control the outcome of the
reaction. We note that in a more classical Heck reaction, this
intermediate would be likely to undergo deprotonation,
terminating the cycle and yielding Pd(0). The lack of strong
base in the current reaction allows reinsertion and further chain
walking.
Intermediate 3 proceeds through a series of repetitive alkene
insertion and β-hydride elimination steps. Intermediate 3
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Table 1. Structures and Activation Free Energies of Alkene Insertion Step
γ,S
β,R
γ,R
β,S
TS
TS1
TS2
TS1
TS2
TS1
TS2
TS1
TS2
ΔG⧧ (kcal/mol)
10.7
11.7
13.2
15.0
γ,S
β,R
γ,R
β,S
TS
ΔG⧧ (kcal/mol)
11.8
12.8
13.0
13.4
undergoes alkene reinsertion (TS4) to form complex 4 with an
activation free energy of 4.3 kcal/mol. Complex 4 isomerizes to
a less stable complex 5, followed by a second β-hydride
elimination (TS5) to form the enol palladium hydride complex
6. This step requires an activation free energy of 5.0 kcal/mol.
It is noteworthy that this sequence of alkene insertion and β-
hydride eliminations, positioning the Pd-carbon bond closer to
the oxygen, is energetically downhill as indicated by the
comparison of the related species of 2 and 4 or 3 and 6. As will
be discussed in more detail later, this is due to the favorable
interaction of the negative partial charge on the palladium-
bound carbon with the positive partial charge of the carbon
bound to the oxygen, providing a thermodynamic driving force
for the experimentally observed migration of the double bond.
The final step in this sequence is the formation of the
hydroxyalkyl-palladium species 7 where palladium is in the α-
position to the electronegative oxygen. This structure has a
relative free energy of −9.9 kcal/mol, which provides a
thermodynamic sink to the chain-walking sequence effectively
terminating the reaction. The presence of the palladium in the
α-position also increases the acidity of the hydroxyl proton,
leading to the final step of oxidative deprotonation by DMF
with formation of the final carbonyl product bound to Pd(0). It
should be noted that this is likely to be a multistep process and
that the reported energies should be considered as upper limits
because implicit solvent models will underestimate the
solvation stabilization of the protonated DMF. The corre-
sponding deprotonation with DMF could also occur from any
other species in the catalytic cycle (Pd−H or β−C-H), but it is
equally unfavorable in all cases, and will therefore only occur to
a significant extent from 7, which is both the most abundant
intermediate and has the kinetically most labile proton. This
species can either dissociate to regenerate the catalyst or react
directly with another equivalent of the aryl source to close the
catalytic cycle. The direct reaction with another substrate will
be highly exergonic for the case of release of the very stable
molecular nitrogen and still significantly exergonic for the case
of the aryl boronic acid substrate. It is therefore the more likely
process.
is selectivity-determining. There are eight possible isomeric
alkene insertion transition states, which adopt a square-planar
geometry. In TS1 and TS2, the aryl group is positioned trans
and cis to chiral oxazoline on the ligand, respectively, which can
lead to either of the two constitutional isomers and
enantiomers (β/γ and (R)/(S), respectively). We have studied
the relative free energies of these eight transition states to
elucidate the origin of the experimentally observed site
selectively and enantioselectivity.
Our calculations show that the two low energy structures
TS1γ,S and TS1β,R are about 1 kcal/mol more stable than the
corresponding TS2s. This is due to the aryl group being
positioned perpendicular to the pyridine group on the ligand.
This allows a C−H-π interaction between the hydrogen and the
aryl center (shown in blue dashed lines in Table 1 and Figure
t
2) with a distance of ∼2.0 Å. In TS2γ,S and TS2β,R, the Bu
Selectivity-determining Transition States. The results
depicted in Figure 1 demonstrate that the alkene insertion step
Figure 2. Optimized geometries of the isomers of TS1 and TS2. Bond
distances (in Å) and activation free energies are shown.
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group on the ligand is pointing toward the aryl (shown in red in
Table 1), causing steric repulsion and destabilizing TS2.55
Because the isomerization between INtrans‑1 and INcis‑1 is fast as
discussed earlier, the lowest energy pathway proceeds through
TS1γ,S with a free energy of activation of 10.7 kcal/mol to form
the experimentally observed major product.24,25
β-position.56 The resulting charge on one alkene terminus
interacts with the C−O dipole of the pendant alcohol moiety.
The effect will thus disfavor substitution (i.e., formation of a
less negative charge) at the alkene terminus closest to the
alcohol. We note that this electrostatic interaction will diminish
with distance but will give the same expected major
constitutional isomer also for homologues of the substrate.
This is consistent with the experimentally observed decrease in
site selectivity as a function of the chain length and also the
correlation presented by one of us using differential 13C NMR
shifts of the alkene carbons.24,25 Similar trends are obtained for
the higher energy TS2s, suggesting that the analysis is general.
The results in Table 2 also show a correlation of the
geometry with the experimentally observed site selectivity. The
ideal dihedral angle CAr−Pd−Cβ−Cγ (Table 2) is near zero for
the square-planar geometry required in the migratory insertion
transition state. However, the results show that they are
distorted from the ideal geometry as a result of steric repulsion.
Table 2 shows that the dihedral angle CAr−Pd−Cβ−Cγ in
TS1γ,S is 11.1°, while it increases to 15.5° in TS1β,R. In the less
favored transition structures, TS1γ,R and TS1β,S, it is even more
distorted from the square-planar geometry. This indicates that
steric repulsion also plays a role on site selectivity.
Conversely, the free energies of the two higher energy
transition states leading to the other two constitutional- and
stereoisomers are lower for TS2γ,R and TS2β,S than the
corresponding TS1s because, in TS2, the phenyl group is
t
oriented toward the butyl group with its short axis, making it
sterically more favorable than the sp3 carbon oriented toward
t
the butyl group.
We will start the discussion of these results with an analysis
of the factors controlling the site selectivity of the reaction. The
second most stable TS, TS1β,R, leads to the experimentally
observed minor product with different site selectivity and is 1
kcal/mol higher in energy than TS1γ,S. The calculated ratio of
regioisomers is 5.4:1, which is in good agreement with the
experimental value (2.5:1). Although TS2s are less favorable
than TS1s, it is worth noting that the same preference for the
Cγ site selectivity is obtained for TS2γ,S (11.8 kcal/mol) and
TS2β,R (12.8 kcal/mol) for similar reasons. In contrast, the
TS2s are favored for the higher energy pathways that lead to
minor isomers. We will therefore focus most of the following
discussion on TS1, with brief mention of TS2, leading to minor
isomers where appropriate. Figure 2 presents the geometries of
the four lowest energy transition structures, and Table 2
summarizes key structural and electronic parameters for each.
The previously reported results25 for a series of substituted
alkenyl alcohols also demonstrated that steric effects influence
the site selectivity, with bulkier groups leading to greater
amounts of the γ-insertion product. This is because in the β-
insertion transition structure (e.g., TS1β,S), increasing the size
of the substituent from methyl, which is pointing toward the
oxazoline group in TS1β,S(Table 2), increases steric repulsion,
making this pathway less favorable. This interaction does not
occur in TS1 γ,S, leading to increased site selectivity.
Table 2. NBO Charges and Key Dihedral Angles in TS1 and
TS2
The steric effects for transition structure isomers TS1 are
even more significant for the enantioselectivity of the reaction.
The origin of this steric effect becomes clear upon analysis of
the geometries shown in Figure 2. In the lowest energy
transition structure leading to the minor (R)-enantiomer,
t
TS2γ,R, the bulkier aryl substituent is pointing toward the Bu
group. This suggests that there is significant steric repulsion
compared to that for the transition structure leading to the
major (S)-enantiomer TS1γ,S where the hydroxyl ethyl group is
γ,S
TS1
TS1β,R
TS2γ,R
TS2β,S
t
charge CHβ
0.00
0.12
11.1°
0.11
0.01
15.5°
−0.02
0.13
0.12
pointing away from the Bu group. The dihedral angle CAr−
charge CHγ
−0.01
−17.8°
Pd−C−C is −16.3°, significantly larger than that in
TS1γ,S(11.1°), indicating a steric repulsion in this transition
structure. Therefore, the activation free energy is 2.3 kcal/mol
higher than that of TS1γ,S. This corresponds to an er in
quantitative good agreement with the experimental observation
of 97:3. It should be noted that an analysis of the essentially
isoenergetic transition structure TS1γ,R where the hydroxy-
methyl group occupies the position of the aryl group leads to
the same result.
CAr−Pd−Cβ−Cγ
−16.3°
These results show that the site selectivity is determined by
the difference in electronic structure between the two sp2
carbons. The site selectivity can be understood in terms of an
electrophilic interaction of the palladium, leading to a
polarization of the alkene in the transition state. The electrons
of the alkene form the new Pd−C bond, resulting in almost no
net charge change on the Pd-bound alkene carbon, but a
buildup of positive charge on the alkene terminus that will
become bound to the transferring aryl moiety. An NBO charge
analysis indicates that, in the isomers of TS1, the alkene carbon
forming a bond to Pd is substantially more negative than the
carbon forming the bond to the aryl moiety. This negative
charge can interact favorably with the positive charge of the
oxygen-bound carbon (i.e., with the C−O bond dipole) in the
γ-isomers of the TS, but not in the β-isomers. This is in good
agreement with an earlier Hammett study of the cationic Heck
reaction with styrene substrates, where substituents mostly
affected the rate of substitution at the α-position rather than the
This steric effect also explains the enantioselectivity in the
other pair of enantioselectivity-determining transition states,
TS1β,R and TS2β,S,, due to the steric repulsion between the
methyl and tbutyl group discussed earlier. Although the
enantioselectivity of the minor regioisomer has not been
determined for this substrate, related minor isomeric products
have been reported to have high enantioselectivity,25 consistent
with our prediction.
Reactivity and Selectivity of E- and Z-alkenes. To
analyze the dependence of the reaction on substrate geometry,
we studied the relative reactivity and selectivity of the (E)- and
(Z)-isomers of hept-4-en-2-ol. It should be noted that the
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Figure 3. Selectivity-determining transition states for the ethyl-substituted homoallylic secondary alcohols.57
coordination of the alkene substrate in IN, the intermediate
before the aryl addition transition states, is in rapid equilibrium
(Scheme S2 in SI). When (E)- and (Z)-hept-4-en-2-ol are in a
mixture, DE-IN-a, DE-IN-b, DZ-IN-a, and DZ-IN-b in Figure
3 are in equilibrium. This allows the application of the Curtin−
Hammett principle, and the reactivity and selectivity of the
reaction will be determined by the relative stabilities of the
relevant transition structures.
It can be seen from the results in Figure 3 that DZ-IN-a
derived from the (Z)-isomer, is 2.4 kcal/mol less stable than the
lowest energy complex DE-IN-b. This is due to the steric
repulsion of the (Z)-alkene with the tBu group in DZ-IN-a that
cannot be alleviated without inducing a repulsive interaction
with the aryl group. As a result, the (E)-isomer is predicted to
dominate in the equilibrium and react faster than the (Z)-
Figure 4. Competition experiment between (Z)- and (E)-hept-4-en-2-
ol.
isomer through the lowest energy transition state DE-TS1γ,S.
However, the site selectivity of the (Z)-isomer is with an energy
difference of 0.8 kcal/mol predicted to be higher than the site
selectivity of the (E)-isomer. The enantioselectivity of the (Z)-
substrate is predicted to be lower than that of the (E)-isomer,
although both isomers are predicted to give very high
enantioselectivity.
The data shown in Figure 3 lead to a series of experimentally
verifiable predictions. It is experimentally known that the (E)-
and the (Z)-isomers of hept-4-en-2-ol react in 58% and 79%
yield with enantiomeric ratios of 90:10 and 96:4, respectively.24
Thus, the computational results overestimate the experimen-
tally observed enantioselectivities even though the qualitative
prediction of high enantioselectivity is correct.
selectivity for the product derived from the (Z)-isomer to be
∼20:1, while the one derived from the (E)-isomer is 5:1. This is
in good agreement with the computational prediction that the
(Z)-isomer should give high site selectivity.
Finally, we determined the relative reactivity of the two
isomers of hept-4-en-2-ol under standard reaction conditions
(for experimental details, see SI) in the competition experiment
shown in Figure 4. Consistent with the computational
predictions, but somewhat counterintuitive based on the
inherently higher energy of (Z)-alkenes, the (E)-alkene is
found to react faster than the corresponding (Z)-alkene.
Although the products of the reaction shown in Figure 3
have been reported previously,24 the site selectivity for the two
substrates has not been disclosed. We have determined the site
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Science Foundation (NSF CHE 1058075), the Swedish
Research Council (Grant No. 2010-4856), and by the FP7-
funded SYNFLOW program, (www.synflow.eu). M.S.S.
acknowledges support from the National Institutes of Health
(NIGMS RO1 GM063540). We also acknowledge the
allocation of computational resources the TeraGrid
(TGCHE090124 and TG-CHE120050) and the Notre Dame
Center for Research Computing.
CONCLUSIONS
■
The mechanism, reactivity, and selectivity of the redox relay,
palladium-catalyzed Heck arylation of alkenyl alcohols has been
studied by computational and experimental methods. The
results for the site selectivity and enantioselectivity for the
model substrate (E)-pent-3-en-1-ol are in quantitative agree-
ment with the available experimental data and show that
migratory insertion is the selectivity-determining step of the
reaction. The site selectivity is determined by subtle differences
in the electronic structure of the reacting olefin as well as by
steric effects that distort the transition structure away from the
ideal square planar geometry. The enantioselectivity of the
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ASSOCIATED CONTENT
* Supporting Information
Experimental details, optimized Cartesian coordinates and
complete reference 47 for Gaussian 09. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
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AUTHOR INFORMATION
Corresponding Authors
pon@chem.gu.se
chydwu@ust.hk
sigman@chem.utah.edu
owiest@nd.edu
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Notes
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ACKNOWLEDGMENTS
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We gratefully acknowledge support of this work by the
National Science Foundation of China (21133002, 2123201,
and 21302006), , the MOST of China (2013CB911501), the
Shenzhen Peacock Program (KQTD201103), the U.S. National
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NOTE ADDED IN PROOF
■
An alternative study of the same reaction was recently
published: Dang, Y.; Qu, S.; Wang, Z.-X.; Wang, X. J. Am.
Chem. Soc. 2014, 136 (3), 986−998.
NOTE ADDED AFTER ASAP PUBLICATION
■
Scheme 2 was incorrect in the version published ASAP January
22, 2014; the correct version reposted January 23, 2104. NOTE
ADDED IN PROOF was added January 24, 2014.
1967
dx.doi.org/10.1021/ja4109616 | J. Am. Chem. Soc. 2014, 136, 1960−1967