Mechanistic Investigations of the Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Benzyl Acrylates

Article abstract of DOI:10.1021/jacs.7b06917

A mechanistic study of the Pd-catalyzed enantioselective 1,1-diarylation of benzyl acrylates that is facilitated by a chiral anion phase transfer (CAPT) process is presented. Kinetic analysis, labeling, competition, and nonlinear effect experiments confirm the hypothesized general mechanism and reveal the role of the phosphate counterion in the CAPT catalysis. The phosphate was found to be involved in the phase transfer step and in the stereoinduction process, as expected, but also in the unproductive reaction that provides the traditional Heck byproduct. Multivariate correlations revealed the CAPT catalyst's structural features, affecting the production of this undesired byproduct, as well as weak interactions responsible for enantioselectivity. Such putative interactions include π-stacking and a CH···O electrostatic attraction between the substrate benzyl moiety and the phosphate. Analysis of the computed density functional theory transition structures for the stereodetermining step of the reaction supports the multivariate model obtained. The presented work provides the first comprehensive study of the combined use of CAPT and transition metal catalysis, setting the foundation for future applications.

Full text of DOI:10.1021/jacs.7b06917

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Article
Mechanistic Investigations of the Pd(0)-Catalyzed
Enantioselective 1,1-Diarylation of Benzyl Acrylates
Manuel Orlandi, Margaret J Hilton, Eiji Yamamoto, F. Dean Toste, and Matthew S Sigman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06917 • Publication Date (Web): 11 Aug 2017
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Mechanistic Investigations of the Pd(0)-Catalyzed Enantioselective
1,1-Diarylation of Benzyl Acrylates
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Manuel Orlandi,† Margaret J. Hilton,†, Eiji Yamamoto,†,§ F. Dean Toste,‡ Matthew S. Sigman†,*
†Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, USA.
‡Department of Chemistry, University of California, Berkeley, California 94720, United States.
ABSTRACT: A mechanistic study of the Pd-catalyzed enantioselective 1,1-diarylation of benzyl acrylates that is facilitated
by a Chiral Anion Phase Transfer (CAPT) process is presented. Kinetic analysis, labeling, competition and non-linear ef-
fect experiments confirm the hypothesized general mechanism and reveal the role of the phosphate counterion in the
CAPT catalysis. The phosphate was found to be involved in the phase transfer step and in the stereoinduction process as
expected, but also in the unproductive reaction that provides the traditional Heck byproduct. Multivariate correlations
revealed the CAPT catalyst’s structural features, affecting the production of this undesired byproduct, as well as weak in-
teractions responsible for enantioselectivity. Such putative interactions include π-stacking and a CH···O electrostatic at-
traction between the substrate benzyl moiety and the phosphate. Analysis of the computed DFT transition structures for
the stereodetermining step of the reaction supports the multivariate model obtained. The presented work provides the
first comprehensive study of the combined use of CAPT and transition metal catalysis setting the foundation for future
applications.
(CAPT) catalysis7 with palladium catalysis could be ap-
INTRODUCTION
plied to our system. In this process, an insoluble aryldia-
zonium salt 1 undergoes salt metathesis with a chiral
phosphate anion (PA, 2) to form a soluble chiral ion pair
(Scheme 1B).
As asymmetric catalysis has evolved as a significant re-
source in stereoselective synthesis,1 so has the mechanis-
tic underpinnings of such catalytic processes, on the basis
of which this field continues to mature. Consequently,
Scheme 1. A) 1,1-diarylation of benzyl acrylates using
CAPT and Pd catalysis. B) Hypothesized reaction
mechanism involving a CAPT strategy for the 1,1-
difuntionalization of olefins.
current organic, organometallic, and enzymatic catalytic
methodologies efficiently provide valuable chiral products
in optically pure form. Furthermore, stereoselective, mul-
ticomponent catalytic reactions have also been developed,
accessing complex products from the union of simple
starting materials.2 However, multicomponent reactions
are intrinsically prone to the formation of undesired by-
products and are challenging to render enantioselective.
Thus, the selective combination of multiple building
blocks into a single chiral product remains an emerging
technology for synthetic chemists.
In this context, several groups have developed Pd-
catalyzed three-component coupling reactions for the 1,1-
difunctionalization of olefins.3 From our first demonstra-
tion of the reaction class3e to our recently reported enan-
tioselective variant (Scheme 1A),4 a significant quantity of
time has elapsed, substantiating the challenges associated
with identifying a suitable enantioselective catalyst. In-
deed, classical ligands did not promote the desired alkene
difunctionalization process as undesired pathways were
accessed, resulting in mainly Heck and Suzuki products.5
Accordingly, an alternative approach was required.
Inspired by Toste and coworkers and their approach to
an enantioselective 1,1-arylborylation reaction of alkenes,6
we envisioned that coupling chiral anion phase transfer
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General mechanism and Heck byproduct
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In order to understand the role of the Pd-catalyst and
provide support for the proposed catalytic cycle in
Scheme 1B, labeled substrate (Z)-5a-d was submitted to
the standard reaction conditions in the presence of 2c,
PhN2BF4 (1a) and 4-OH-PhB(OH)2 (3a). Consistent with
the hypothesized reaction sequence and similar previous-
ly reported experiments,3h a selective transfer of the deu-
terium atom from the (Z)-β-position of (Z)-5a-d to the α-
position of the final product 6-d was observed (Scheme
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2A). This experiment also excludes the possibility that β-
HE to give C (Scheme 1B) influences the stereochemical
outcome. Indeed, reinsertion of the alkene into the Pd-H
on the same face of the trans and cis olefins would lead to
different enantiomers of the final product (Scheme 2B).
However, the trans diastereomer of the Heck byproduct is
almost exclusively formed (< 3% of cis isomer was ob-
served in some cases) by selective elimination of D.
Additionally, the crossover experiments in Scheme 2C
were performed in order to assess whether the Heck by-
product dissociation is reversible. Specifically, benzyl
acrylate 5a was reacted with boronic acid 3a and either
diazonium salts 1b or 1c in the presence of benzyl cin-
namate 4a, the Heck byproduct, and PA 2a. Under these
conditions, only products 6b or 6c were observed from 1b
or 1c, respectively (Scheme 2C). The recovery of 97% of 4a
and the absence of product 6a, which would result from
the participation of 4a in the reaction sequence with 3a,
suggests that dissociation of the Heck product 4 from
complex C (DIS, Scheme 1B) is irreversible. Therefore, H-
MI (Scheme 1B) is not stereodetermining as the catalyst
remains bound to the same alkene face in order to access
the 1,1-diarylation product. Overall, both sets of experi-
ments suggest that initial migratory insertion from inter-
mediates A to B is stereodefining.
Next, the palladium catalyst can perform an oxidative ad-
dition (OA) with the chiral ion pair to give intermediate
A. Olefin coordination and migratory insertion (MI) re-
sults in intermediate B. Subsequent β-hydride elimination
(β-HE) provides C and reinsertion (H-MI) of the hydride
delivers the stabilized π-benzyl complex D. Finally,
transmetallation (TM) with B2pin2 (in the Toste example)
or arylboronic acid 3, followed by reductive elimination
(RE), restores the catalyst and releases the desired prod-
uct (Scheme 1B).4,6
The key strategy of cooperative CAPT and Pd catalysis,
examples of which are rare,4,6,8 allowed for the successful
development of these two enantioselective 1,1-
difunctionalization reactions, especially as previous at-
tempts under homogeneous conditions failed. Despite the
high levels of enantioselectivity that are observed in the
1,1-diarylation4 (up to 98% ee) and 1,1-arylborylation6 (up
to 96% ee) of acrylates, an unresolved issue involves lower
reaction yields due to competing formation of the tradi-
tional Heck product 4 by dissociation (DIS, Scheme 1B).
To assess if any reaction improvements could be designed
or implemented, we initiated mechanistic investigations,
focusing on understanding each elementary step and any
intermolecular interactions that may influence the reac-
tion outcome(s). We predicted that the insight garnered
through these detailed studies could lead to increased re-
action efficiency and to the extension of this reactivity
pattern to other systems. As a result of these studies, we
clarify the role of each component in the Pd-catalyzed
enantioselective 1,1-diarylation of benzyl acrylates using a
chiral phosphate anion and identified interactions occur-
ring in the TS between the chiral phosphate and the sub-
strate through a combination of experimental and com-
putational analyses.
Scheme 2. A) Deuterium-labeling experiment. B) Ef-
fect of
β-HE selectivity on stereoselectivity. C) Cross-
over experiments.
RESULTS AND DISCUSSION
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Standard reaction conditions: Pd2(dba)3·CHCl3 (2 mol%), 2a
ling the P:H ratio. In other words, the formation of 4 is
1
2
3
4
(4 mol%), acrylate (0.1 mmol, 1 equiv), PhN2BF4 1a (0.1 mmol,
1 equiv), 4-OH-PhB(OH)2 3a (0.12 mmol, 1.2 equiv), NaHCO3
(0.12 mmol, 1.2 equiv), diethyl ether (2 ml, 0.05 M). The reac-
tions were stirred (> 1000 rpm) at 20 °C for 20 h.
not due to a simple thermodynamic dissociation, but ra-
ther to a kinetic event that is in competition with the TM
step leading to the desired product.
Additional insights into the nature of this process were
gained through non-linear effect (NLE) experiments,
which were performed under standard conditions with
acrylate 5b, 1a, 3a, and mixtures of (R)- and (S)-2b (Figure
1A). Substrate 5b was selected since it provided the high-
est enantioselectivity when used in combination with cat-
alyst 2b. A linear correlation (R2=0.99) between the prod-
uct and the catalyst ee was found, which suggests the
presence of a single PA ligand during the stereodetermin-
ing MI event (Figure 1B). However, an unexpected NLE on
the P:H ratio outcome was observed (Figure 1C).11 As the
enantiomeric ratio of 2b decreases, the P:H ratio erodes.
This NLE could be explained with two reasonable possible
scenarios (Figure 1D):
5
6
7
8
In order to understand the role of each component in
the reaction, a kinetic analysis was performed using H
1
NMR spectroscopy with benzyl acrylate 5a, 1a, and 3a as
benchmark reagents. A zeroth order reaction was found
when Et2O was employed as a solvent (Figure S1). Since
the first reagent involved in the reaction sequence (the
diazonium salt 1a) is insoluble in this solvent, the phase
transfer event is likely rate limiting. However, a similar
scenario could be expected in the case of a rate limiting
RE or MI wherein the olefin has high affinity for the Pd
catalyst.9 Thus, in order to gain additional information
about the steps that follow the CAPT sequence, the same
kinetic analysis was performed in THF (see SI for details),
in which the base (NaHCO3) is the only insoluble compo-
nent. Even with a soluble aryldiazonium salt, the 1,1-
diarylproduct is formed in 50% ee,4 suggesting that the
proximity of or coordination between the metal and PA
2c also occurs in THF to an appreciable extent. Thus, the
reaction likely proceeds through a similar mechanism in
the two solvents, excluding the phase transfer event, and
the information acquired can be translated between the
two solvents.
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•
Path A) the chiral PA acts as a base and depro-
tonates the chiral intermediate C leading to
the Heck byproduct and to Pd(0) by irreversi-
ble reductive elimination.
•
Path B) The chiral PA acts as a nucleophile and
activates the boronic acid towards TM through
the formation of a chiral borate E.
In both proposed pathways, the presence of
matched/mismatched interactions between two different
species containing a PA molecule would lead to a NLE on
the P:H ratio.12 In order to determine which one of the
two possible pathways is likely responsible for the ob-
served NLE, the model reaction in Figure 1A was per-
formed with different relative amounts of Pd catalyst and
PA (Pd:2b ratio). If a PA molecule acts as a base according
to Path A, a directly proportional relationship would be
observed between P:H and Pd:2b ratios. Indeed, in that
case, having a higher concentration of 2b (lower Pd:2b
ratio) would kinetically favor the production of the Heck
byproduct (lower P:H ratio). Conversely, an inverse rela-
tionship between these two ratios would be consistent
with Path B, because the presence of increasing amount
of 2b (lower Pd:2b ratio) would favor the production of
the desired product (higher P:H ratio, Figure 1D). As
shown in Figure 2, an increased Pd:2b ratio corresponds
to an increased P:H ratio, which is consistent with Path A
as well as the irreversible nature of the Heck product dis-
sociation.
Sampling the reaction in THF revealed a much faster
rate than in Et2O and a non-zero reaction order. Both the-
se observations suggest that the phase transfer process is
rate limiting in Et2O (see SI for details). Exploring the de-
pendence of the reaction rate on the concentration of the
three reaction components provided the rate law in equa-
tion 1 (see SI for details, rate=d([4a]+[6a])/dt):
ꢅ
ꢈꢅ ꢈꢅ ꢈ
ꢄ ꢆꢇ ꢉꢇ ꢊꢇꢋ
ꢌꢍꢌ
ꢏ ꢐ ꢉꢇ ꢏ ꢑꢅꢆꢇꢈꢅꢉꢇꢈ
ꢀꢁꢂꢃ = ꢎ ꢆꢇ
(1)
ꢅ
ꢈ
ꢅ
ꢈ
According to previous studies on a similar Heck reac-
tion,9,10 these kinetic experiments suggest that MI is rate
determining for the reaction in THF. Indeed, varying [5a]
resulted in the most significant variation in the reaction
rate, while changing either [1a] or [3a] resulted in insig-
nificant changes in rate. However, since diazonium salt 1a
is insoluble in Et2O, its concentration [1a] in this solvent
is constant and small. Thus, equation 1 can be reduced to
equation 2 based on the assumption that in Et2O b[1a]
and d[1a][5a] are negligible with respect to c[5a].
ꢅ
ꢈꢅ ꢈ
ꢀꢁꢂꢃ = ꢒꢓꢎꢔ ꢆꢇ ꢊꢇꢋ
ꢕꢓꢕ
≈ ꢖꢗꢘꢙꢂꢁꢘꢂ
(2)
Consistent with these equations, the reaction was
found to be zeroth order in the boronic acid 3a. Nonethe-
less, even if the boronic acid is not involved in the rate
determining step of the reaction, its concentration [3a]
was found to be correlated with the desired product yield.
Indeed, higher [3a] leads to improved Product:Heck (P:H)
ratios (Figure S4). As the Heck product 4 does not reenter
the catalytic cycle after dissociation, these data suggest
the presence of two competing kinetic processes control-
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Figure 2. Dependence of the P:H ratio on the Pd:2b ratio. P:H
1
1
ratios were determined via H NMR analysis of the crude re-
2
action mixture.
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0
20 40 60 80 100
catalyst ee (%)
0
20 40 60 80 100
catalyst ee (%)
Figure 3. Catalytic cycle
Twelve PA catalysts (2a-2l) with differing an aryl group
at R2 were evaluated under standard conditions (Figure
4A). The resulting P:H ratios spanned a range of 1.5
kcal/mol and were related to molecular descriptors calcu-
lated from the PA molecular model (Figure 4B) using lin-
ear regression modeling. As a result, two Sterimol param-
eters14 (B56, maximum width of the 6-substituent of the
PA aryl group, and L4, length of the 4-substituent of the
same arenes) provided a good correlation as shown in
Figure 1. A) Reaction conditions for NLE experiments. B) No
NLE in the product ee. C) NLE in the P:H ratio. P:H ratios
were determined via H NMR analysis of the crude reaction
mixture. D) Two possible scenarios explaining the observed
NLE in the P:H ratio.
1
The experiments reported above provide a mechanistic
picture, summarized in Figure 3. Under CAPT conditions
in Et2O, phase transfer was found to be rate limiting, yet
under homogenous conditions, migratory insertion (MI)
was determined to be rate limiting and also stereodefin-
ing. Dissociation of the Heck product is irreversible, and a
NLE of the PA catalyst ee was observed on the P:H ratio.
Deprotonation of the [Pd]‒H by the PA catalyst is pro-
posed to control the ratio of the desired product to Heck
byproduct. Thus, the identity of the PA likely influences
the relative rates of hydride reinsertion versus deprotona-
tion. For example, bulkier PAs should provide higher P:H
ratios since larger aryl substituents at the BINOL 3,3’-
positions would shield the phosphate group, thus lower-
ing its effectiveness as a kinetic base. To test this hypoth-
esis, we applied multidimensional analysis tools13 to quan-
titatively interrogate the PA substituent effects on this
bifurcating step of the reaction sequence.
Figure
4B
(R2=0.96,
L1O[Leave-1-Out
cross-
validation]=0.94, intercept=0.01). The magnitude of each
term’s coefficient emphasizes the importance of B56 over
L4 in describing the effects on the P:H ratios. According to
this model, PAs bearing bulky groups (larger B56 values)
in the 6,6’-positions provided better P:H ratios (2b, 2c
and 2e; blue rectangle in Figure 4B). By reducing the size
of such substituents, the P:H selectivity decreased to ca.
1:1 (2a and 2d; red rectangle), and for PAs bearing no 2,6-
substituents, cinnamate 4a became the major product
(purple rectangle). Thus, with bulkier aryl substituents on
the PA, deprotonation of the [Pd]‒H is inhibited, promot-
ing a higher P:H ratio. Finally, the term -0.23 L4 describes
the subtle effect that catalysts with long substituents in
the 4-position of the aryl group typically performed worse
than the 4-unsubstituted ones (for instance, compare 2b
with 2c and 2e, and 2j with 2i, 2k and 2l).
5.0
4.0
3.0
2.0
1.0
0.0 0.5 1.0 1.5 2.0 2.5
Pd:2b ratio
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Figure 5. Dependence of the ee on the benzyl substituent.
Enantiomeric excesses determined by SFC analysis as an av-
erage of two experiments.
1.0
0.5
Twelve PAs (2a-2l) and 18 acrylates (5a-5r) were com-
bined to provide a library of 145 datapoints (see SI for the
full list). A selected subset was analyzed graphically to
identify any trends between catalysts and acrylates (Fig-
ure 6).16 From this visual analysis, catalyst 2a (green line)
demonstrates a unique response as a function of the ben-
zyl acrylate compared to other PAs. Specifically, a strong
dependence of the ee on the benzyl substituent(s) was ob-
served, resulting in a ꢀꢀG‡ range of ca. 1.9 kcal/mol when
catalyst 2a was used. In contrast, the reaction was mainly
under catalyst control with all other PAs as there was a
much less significant effect of the acrylate’s substitution
patterns on the enantioselectivity (ꢀꢀG‡ range < 0.7
kcal/mol). Additionally, 2,6-disubstituted catalysts 2b-2e
provide enhanced selectivity than 2g and 2j, which do not
contain any substituents at the aryl 2,6-positions.
0.0
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
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ꢀ0.5
ꢀ1.0
ꢀ1.0
ꢀ0.5
0.0
0.5
1.0
Measured ꢀꢀG‡ (kcal/mol)
Figure 4. A) CAPT catalysts used in the present study. B)
Multivariate model for the P:H ratios obtained with PAs 2a-
2l in the 1,1-diarylation of benzyl acrylate 5a. The P:H ratios
expressed in kcal/mol are reported in parentheses.
Through these sets of detailed experiments and anal-
yses, each step of the mechanism was investigated, which
provided elucidation of the role of each reaction compo-
nent (Figure 3). In particular, the reaction efficiency was
found to be highly dependent on the CAPT catalyst’s na-
ture. The PA was found to be directly involved in the for-
mation of the main byproduct 4 through decomposition
of the Pd‒H complex C.8 Moreover, multivariate correla-
tion techniques allowed us to identify the specific PA fea-
tures that most affect the reaction’s product distribution
and could be tuned for future reaction optimization.
The unique behavior of 2a is diagnostic of and con-
sistent with the presence of different stereocontrolling
interactions with respect to the other PAs, which suggests
that the origin of enantioselectivity is distinct for this cat-
alyst and the remaining catalysts evaluated. Therefore, for
the purposes of this investigation, we selected to sepa-
rately investigate 2a and 2b-2l when interrogating the ste-
reodefining step and the potential types of NCIs at play.
Preliminary insight was previously reported on the effects
of the benzyl acrylate’s substitutions on the enantioselec-
tivity when 2a was employed. In particular, the NBO
atomic charge of the benzyl group’s 2,6-substituents
(NBOH26) and the substrate’s polarizability were found to
be descriptive parameters in an initial multivariate mod-
el.4 Thus, a π-stacking interaction between the anthra-
cenyl group on the PA and the benzyl acrylate was pro-
posed as an influential element during the TS.
Enantioselectivity
In our preliminary report detailing the development of
this reaction, a profound structural effect of the acrylate
substrate’s benzyl group on enantioselectivity was ob-
served (Figure 5).4 A range of 35-96% ee was measured
depending on the benzyl substituents. As this group is
remote from the reaction site, the initial hypothesis was
that noncovalent interactions (NCIs) between this group
and the catalyst are at the core of these disparate ob-
served effects. In contrast to the simplistic “sterically”
driven models of enantioselection often suggested tradi-
tionally, it is clear that a wide swath of NCIs play an es-
sential role in most enantioselective reactions.15 With this
in mind, we turned to a data intensive approach to inves-
tigate the substituent effects on the likely NCIs in this
system.16
In order to further investigate this putative interaction,
we applied a strategy recently defined by our groups to
use simulated π-interactions with an appropriate model
system to describe the substituent effects on a potential π
stacking interaction.17 Specifically, parameters derived
from stacked complexes of benzene, the probe represent-
ing the PA’s anthracenyl group, and the requisite arenes,
representing the substrate’s benzyl moiety, were comput-
ed (Figure 7A).18 A trend was identified between the inter-
action energy of such stacked complexes (SEπ) and the
observed enantioselectivity from 17 benzyl acrylates (R2 =
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ence of two NCIs that affect the stereoselectivity: 1) π-
stacking between the catalyst’s anthracenyl group and the
benzyl substituent of the substrate; 2) C‒H∙∙∙X interaction
involving the 2,6-hydrogens of the substrate’s aryl group.
0.58, see Figure S11), supporting the hypothesis that a π
stacking interaction could be influencing the stereodefin-
ing step.
1
2
3
4
5
6
7
8
As additional interactions are presumably required in
describing the substituent effects on enantioselectivity,
other molecular descriptors were considered. As a result,
ꢀꢀG‡ and the NBO charge of the benzyl carbon C1
(NBOC1, Figure 7A) were found to be modestly correlated
(R2 = 0.57, Figure S11).19 In comparison to the previously
reported model,4 NBOC1 can be interpreted as a surrogate
of NBOH26. Indeed, the charges of C1 and H2/H6 are rea-
sonably correlated due to anisotropic effects, yet NBOC1
addresses the issues associated with comparing halogens
and hydrogens’ charges (substrates 2c and 2d contain
halogens at the 2,6-positions). These electronic de-
scriptors may indicate that H2/H6 may be engaging in a
C‒H∙∙∙X interaction.
Additional information about the identity of C–H bond
interacting group X can be garnered from a multivariate
model previously reported that describes the enantiose-
lectivity obtained with a set of 12 PAs (2a-2l) and acrylate
5a. (Figure 7B).4 This model includes three parameters for
the catalysts: α (arene torsional angle), B13 (minimum
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width of the arene meta-substituents) and νPOsy (phos-
phate symmetrical stretching). While the former de-
scriptors account for geometrical and steric effects, νPOsy
may describe the ability of the phosphate moiety to en-
gage with the substrate in an electrostatic interaction or
to ligate to Pd. Thus, on the basis of the models in Figure
7A-7B, we hypothesized that 2a could be involved in the
coordination of the substrate via π-stacking with the an-
thracenyl group and an electrostatic interaction with the
phosphate (C‒H∙∙∙O=P). With the hypothesis that these
two NCIs contribute to the origin of the stereodiscrimina-
tion, we turned to computational analysis of the TS to
Through multivariate linear regression modeling, the
combination of parameters SEπ and NBOC1 resulted in the
model depicted in Figure 7A (R2 = 0.87), which utilizes
S
two parameters in three terms: Eπ, NBOC1 and the cross
term NBOC1 SEπ. The presence of this cross term may sug-
gest a synergistic effect between the two potential inter-
actions. Overall, the obtained model supports the pres-
provide
further
evidence
for
these
hypothe-
ses.15b,15c,15e,15f,15h,17,21
2.5
2.0
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1.0
0.5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
0.0
ꢀ0.5
Figure 6. Graphical trend analysis of the stereoselectivities obtained from the combination of 7 PAs and 13 benzyl acrylates.
The mechanistic studies presented above are consistent
with a stereodetermining initial migratory insertion and
that only one PA molecule is involved in this step (vide
infra). Thus, TS structures for the insertion of benzyl
acrylate 5a into the Pd‒Ph bond in the presence of 2a
were calculated. The geometries were optimized at the
M06-2X/LanL2DZ:6-31G(d) level of theory22 and subse-
quent single point energy (SPE) calculations were per-
formed with M06-2X/SDD:6-311++G(d,p) within the
PCM23 solvation model for Et2O (SPE for the two most
stable TSs were also calculated at the ωB97XD/SDD:6-
311++G(d,p) level24). Thermal corrections were calculated
from the vibrational analysis at the M06-2X/LanL2DZ:6-
31G(d) level of theory on the optimized geometries, and
an additional correction to the entropy was also included
using Truhlar’s quasi-harmonic approximation.25 The
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Having revealed the mode of action of CAPT catalyst
most stable TSs leading to the (R)- and (S)-product are
1
2
3
4
5
6
7
8
depicted in Figure 7C (TS-R and TS-S, respectively). In-
terestingly, both TSs show the substrate’s benzyl group
folded into the catalyst’s chiral pocket and engaged into
NCIs, such as π-stacking. Other conformers in which such
interactions are not present typically display higher ener-
gy (>4 kcal/mol, see SI). This observation confirms the
importance of the benzyl group for molecular recogni-
tion. Despite both TS-R and TS-S geometries demonstrat-
ing NCIs between the substrate’s benzyl ring and the
catalyst’s anthracenyl/phosphate groups, only TS-R (TS
leading to the experimentally observed enantiomer) pre-
sents a parallel orientation between the two arenes for
optimal π-stacking (interaction distance: ca. 3.3 Å). More-
over, TS-R also exhibits a shorter distance between the
2,6-hydrogen of the substrate’s benzyl group and the
phosphate (C‒H∙∙∙O=P electrostatic interaction) with re-
spect to TS-S (2.33 vs. 2.53 Å, respectively), suggesting a
more stabilizing interaction. These differences between
the two TSs account for the computed ꢀꢀG‡ values that
match with the experimental value (Figure 7C). Thus, the
presented computations agree with the information pre-
viously obtained through multivariate correlations and
validate the rationalization for the observed stereoselec-
tivity when catalyst 2a was used.
2a, we sought to gain mechanistic insight about the other
catalysts evaluated (2b-2l) and to understand more clearly
why these catalysts are unique compared to 2a. To this
end, a multivariate correlation analysis of a set of 119 data
points from different combinations of PAs 2b-2l and acry-
lates 5a-5r were performed (see SI for details). Overall,
only six terms were required in order to provide a good
description of the catalytic system with the model in Fig-
ure 8 (R2 for the training set = 0.89, intercept = 0.06).
Moreover, external and cross validations demonstrate the
model’s robustness (R2 for the validation set = 0.89, L26O
= 0.86). The equation is composed of three parameters for
the catalysts, all of which appeared in the model in Fig-
ure7B, and three for the substrates: NBOC1 (see model in
Figure 7A), νCH2 (benzyl CH2 scissoring frequency) and
νRing (aryl ring compression frequency). Both νCH2 and
νRing were previously reported to be descriptive for this
system and likely account for electronic perturbations
due to the varying substituents. Analyzing each term’s co-
efficient confirms that the reaction is mainly under cata-
lyst control since parameters α and νPOsy dominate the
model with the largest coefficients. Additionally, the con-
textual presence of νPOsy and
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ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
ꢀ ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
ꢀ ꢀ
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Measured ꢀꢀG‡ (kcal/mol)
Measured ꢀꢀG‡ (kcal/mol)
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Figure 7. A) Model and parameters for 17 benzyl acrylates (5a-5c, 5e-5r) and PA 2a. 5d is an outlier for this model. B) Model and
parameters for 12 PAs (2a-2l) and benzyl acrylate 5a. C) Low-lying energy TSs TS-R and TS-S. Substrate 5a is highlighted in
green. All the energy values are reported in kcal/mol. Method A: M06-2X/SDD:6-311++G(d,p)[PCM-Et2O]. Method B: M06-
2X/SDD:6-311++G(d,p). Method C: ωB97XD/SDD:6-311++G(d,p). Exp: experimental values obtained from equation ꢀꢀG‡ = -
RTln(e.r.).
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4
5
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NBOC1 may suggest the presence of a C‒H∙∙∙O=P interac-
tion, similar to what was previously described for catalyst
2a (vide infra). Thus, the main difference between catalyst
2a and the set of catalysts 2b-2l is likely due to the ability
1.50
1.25
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of the anthracenyl group to engage the substrate in a π-
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1.00
interaction. Even though NCIs are typically weak, the en-
ergy associated with such π-stacking interactions provides
a substantial enough boost to enable a highly enantiose-
lective migratory insertion event.
0.75
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ꢀ
ꢀ
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ꢀ
ꢀ
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0.00
CONCLUSIONS
Herein, mechanistic studies of the enantioselective Pd-
catalyzed 1,1-diarylation of benzyl acrylates that is enabled
by chiral anion phase transfer are reported. A deuterium-
labeling experiment supported the previously hypothe-
sized general mechanism, and crossover-experiments es-
tablished the irreversibility of the Heck byproduct disso-
ciation. In particular, NLE experiments showed that the
CAPT catalyst, which is responsible for the observed en-
antioselectivity, was also found to act as a base, deproto-
nating the Pd‒H intermediate C (Figure 3) and leading to
the formation of byproduct 4. Multidimensional analysis
supports this hypothesis, as bulkier PAs slow the for-
mation of 4. More importantly, these experiments provide
experimental support for the hypothesis that this class of
catalysts can be tuned to control reaction outcomes be-
yond enantioselectivity.
ꢀ0.25
ꢀ0.50
ꢀ0.50 ꢀ0.25 0.00 0.25 0.50 0.75 1.00 1.25 1.50
Measured ꢀꢀG‡ (kcal/mol)
Figure 8. Multivariate model for 11 PAs (2b-2l) and 18 acry-
lates (5a-5r). The model includes 119 datapoints divided in a
training set (78 points, black circles) and a validation set (41
points, red squares). The validation set presented one outlier
(blue triangle).
The origin of the enantioselectivity was also studied.
Combining insight from multivariate correlations and
computational TS analysis provided a clear mode of ac-
tion for catalyst 2a that involves several influential, puta-
tive NCIs. High ee is likely achieved through the ability of
the PA’s anthracenyl substituent to engage the substrate
in a specific π-stacking interaction. An electrostatic inter-
action between the phosphate group and the substrate
benzyl’s 2,6-hydrogens also contributes to substrate
recognition during the stereodefining step.26 Multivariate
correlations demonstrated that this particular NCI is pre-
served among
all the tested catalyst/substrate combinations. As we fore-
see an increase in the use of the CAPT strategy within the
transition metal catalysis domain, we envision that the
present study will provide mechanistic support for the ex-
tension of this valuable approach to other chemical sys-
tems and our efforts in this context will be reported in
due course.
ASSOCIATED CONTENT
Supporting Information.
Experimental and modeling details, table of parameters, DFT
energies and geometries. This material is available free of
charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
*sigman@chem.utah.edu
Present Addresses
M.J.H.: Department of Chemistry, Yale University, 225 Pro-
spect Street, New Haven, Connecticut 06520, United States.
§E.Y.: Department of Chemistry, Kyushu University, 744 Mo-
tooka, Nishi-ku, Fukuoka 819-0395, Japan.
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tive kinetic resolution would be required to observe a NLE on
ACKNOWLEDGMENT
1
2
3
4
5
6
the product ee. Hence, we posit that the consequences of the
NLE in the P:H ratio cannot be observed in the product ee due to
the small magnitude.
13) Sigman, M. S.; Harper, K. C.; Bess, E. N.; Milo, A. Acc. Chem.
Res. 2016, 49, 1292.
We thank the NIH (1 R01 GM121383) for support of this work.
M.O. thanks the Ermenegildo Zegna Group for a postdoctor-
al fellowship. Computations were conducted at the Center
for High Performance Computing (CHPC) of the University
of Utah.
14) Harper, K. C.; Bess, E. N.; Sigman, M. S. Nat. Chem. 2012, 4,
366.
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12) In both cases, one could expect to observe a NLE on the
product ee due to kinetic resolution of C or D by a PA molecule
or E, respectively (Figure 1D). However, the erosion of P:H ratio
as a function of the PA ee is modest (from 66:33 for enantiopure
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