Cation-π Interactions in the Benzylic Arylation of Toluenes with Bimetallic Catalysts

Article abstract of DOI:10.1021/jacs.8b05143

A method to directly arylate toluene derivatives with aryl bromides to generate diarylmethanes, which are important building blocks in drug discovery, is described. In this method, KN(SiMe₃)₂ in combination with a (NIXANTPHOS)Pd catalyst accomplished the deprotonative activation of toluene derivatives to permit cross-coupling with aryl bromides. Good to excellent yields are obtained with a range of electron-rich to neutral aryl bromides. Both electron-rich and electron-poor toluene derivatives are well tolerated, and even 2-chlorotoluene performs well, providing a platform for introduction of additional functionalization. This discovery hinges on the use of a main group metal to activate toluene for deprotonation by means of a cation-π interaction, which is secured by a bimetallic K(NIXANTPHOS)Pd assembly. Mechanistic and computational studies support acidification of toluene derivatives by the K⁺-cation- π interaction, which may prove pertinent in the development of other, new reaction systems.

Full text of DOI:10.1021/jacs.8b05143

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Article
Cation-# Interactions in the Benzylic Arylation
of Toluenes with Bi-metallic Catalysts
Sheng-Chun Sha, Sergei Tcyrulnikov, Minyan Li, Yue Fu, Marisa C Kozlowski, Patrick J Walsh, and Bowen Hu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05143 • Publication Date (Web): 05 Sep 2018
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Cation-π Interactions in the Benzylic Arylation of Toluenes with Bi-
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Sheng-Chun Sha, Sergei Tcyrulnikov, Minyan Li, Bowen Hu, Yue Fu, Marisa C. Kozlowski* and Pat-
rick J. Walsh*.
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania
19104, United States.
ABSTRACT A method to directly arylate toluene derivatives with aryl bromides to generate diarylmethanes, which are important
building blocks in drug discovery, is described. In this method, KN(SiMe3)2 in combination with a (NIXANTPHOS)Pd catalyst
accomplished the deprotonative activation of toluene derivatives to permit cross-coupling with aryl bromides. Good to excellent
yields are obtained with a range of electron-rich to neutral aryl bromides. Both electron-rich and electron-poor toluene derivatives
are well tolerated, and even 2-chlorotoluene performs well, providing a platform for introduction of additional functionalization.
This discovery hinges on the use of a main group metal to activate toluene for deprotonation by means of a cation-π interaction,
which is secured by a bimetallic K(NIXANTPHOS)Pd assembly. Mechanistic and computational studies support acidification of
toluene derivatives by the K+–cation- π interaction, which may prove pertinent in the development of other, new reaction systems.
INTRODUCTION
functionalized at the benzylic position via catalytic dehydro-
genative cross-coupling methods.7,8
A. Stahl and co-workers
Aromatic hydrocarbons are inexpensive and abundant com-
ponents of petroleum distillates and have been employed as
solvents and reagents on laboratory and industrial scales.
They are common starting materials for the preparation of
more functionalized and higher value small molecules with
applications in synthesis, materials science, and pharmaceuti-
cal chemistry.1,2 Inspired by the challenge of conversion of
simple aromatic hydrocarbons into valuable synthetic building
blocks, chemists have focused on transition metal promoted
C–H functionalizations of aromatic hydrocarbons.
Ar'
cat. [Cu]
tBuOOtBu
R'
Ar' BX2
+
R
B. Liu and co-workers
Ar''
cat. [Cu]
NFSI
+
R''
Ar'' B(OH)2
R''
Scheme 1. Copper catalyzed activation of toluenes.
Among catalysts that activate C–H bonds, several differ-
ent modes of C–H bond cleavage have been documented.3
Most common are direct oxidative addition of C–H bonds and
concerted metallation deprotonation processes.4-10 These cata-
lysts can be difficult to optimize, because the demands on the
catalyst are quite stringent. Furthermore, the arene substrates
usually possess multiple types of C–H bonds, giving rise to
selectivity problems. Both reactivity and selectivity issues can
be addressed by outfitting substrates with directing groups that
bear Lewis basic centers to bind to the catalyst and position it
in the proximity of the C–H bond of interest.11-14
We are interested in alternative strategies to selectively ary-
late weakly acidic (pKa 25–35) benzylic C–H bonds of arenes
and heteroarenes.17-23 Our strategy relies on reversible depro-
tonation of the C–H bonds of the benzylic pronucleophile in
the presence of the catalyst, which then arylates the substrate.
A limitation of this approach is that some benzylic C–H bonds,
such as those in toluene, have such high pKa values (~43 for
toluene in DMSO24) that appreciable deprotonation in the
presence of a transition metal catalyst is difficult. To circum-
vent this drawback, we sought to increase the acidity of the
benzylic C–H, thus facilitating deprotonation. Coordination of
arenes to transition metals in an η6-fashion renders the ben-
zylic C–H bonds more acidic.3 Based on this idea, we devel-
oped the palladium catalyzed arylation of activated toluene
derivatives (η6-C6H5–CH2Z)Cr(CO)3 [Z = H, Ph, OR, NR2,
Scheme 1, M’ = Cr(CO3)],25 including an enantioselective
version (Z = NR2).26 This strategy was also successful in al-
lylic substitution reactions with toluene derivatives activated
Alternatively, several groups have taken advantage of the
decreased bond strength of benzylic C–H bonds over aromatic
C–H bonds to achieve selective activation of toluene deriva-
tives via benzylic radical intermediates. Most relevant to this
investigation, the groups of Stahl15 and Liu16 have developed
mild methods for the copper catalyzed arylation of toluene
derivatives with arylboronic acids to prepare diarylmethanes
(Scheme 1). Toluene derivatives have also been successfully
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with Cr(CO3).27,28 While these reactions were successful, they
Ln
M
Ln
M
Ln
M
A
Ph2P
PPh2
Ph2P
PPh2
1
2
3
4
5
6
Ph2P
PPh2
required generation of a stoichiometric, stable metal arene
adduct. The ultimate goal, however, is to develop a dual cata-
lytic cycle wherein the arene activating metal, M’ (Scheme 2),
functions catalytically by exchanging from the product to a
new starting arene. Reactions incorporating this concept have
proven challenging,29-32 despite the great potential impact of
this strategy.
O
O
O
M’–base
– H–base
N
H
N
pKa ~ 21
M’
NIXANTPHOS
Xantphos
Ar'
7
8
9
K~Pd bimetallic cat.
B
O
Scheme 2. Ideal Dual Catalytic Cycle for Toluene Activa-
tion
Ar
C-3 Arylation
H
H
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+
Ar’–Br
1 equiv
O
Ar
K~Pd bimetallic cat.
18-Crown-6
1.2 equiv
Ar'
Z
O
Ar
Li~Pd bimetallic cat.
12-Crown-4
M
Br
Benzylic Arylation
HN(SIMe3)2
MN(SIMe3)2
M'Ln
L2Pd
Ar
C
C-3
Arylation
Benzylic
arylation
Z
PPh2
Z
Arene
activation-
exchange
Coupling
cycle
M = K, K~Pd
0
:
:
100
0
93% y.
L2Pd
M
N
O
Pd
M'Ln
M = K, K•(18-C-6)~Pd
M = Li, Li•(12-C-4)~Pd
100
51% AY*
91% y.
Ar
M'Ln
Z
Ar–Br
100
:
0
PPh2
* Unoptimized assay yield (AY)
L2Pd
Ar
Z
Z
Ar
M'Ln
D
In studies with bimetallic catalysts based on van Leeuwen’s
NIXANTPHOS33,34 (Figure 1A) some clues toward achieving
this goal were discovered. Namely, we observed under basic
conditions the ligand’s N–H (pKa ~22)24 is deprotonated and
there is a main group metal (Li, Na, K) associated with the
ligand backbone.18 Furthermore, based on experimental and
computational studies, cooperativity between the main group
element and transition metal leads to unprecedented reactivi-
ty.18,21,35 Specifically, C3 arylation was observed with 2-
benzylfurans using KN(SiMe3)2, and (NIXANTPHOS)Pd-
based catalyst exclusively furnishing the C-3 arylated product
with excellent yield (93%, Figure 1B and 1C). Addition of
18-crown-6, which entrains the cation, resulted in a dramatic
switch in the selectivity favoring benzylic arylation with ex-
clusion of the C-3 product. Finally changing to LiN(SiMe3)2
in the presence of 12-crown-4 resulted in selective formation
of the benzylic arylation product (91% isolated yield) and
none of the C-3 arylation product detected. Thus, near perfect
selectivity could be obtained simply by changing the base and
additive. The preponderance of the C-3 arylation product was
proposed to arise from a cation-π adduct between K+ and the
phenyl of the 2-benzylfuran (Figure 1D).
Pd
K
C3
Cation-π
interaction
!
Figure 1. A) Structures of neutral and deprotonated
NIXANTPHOS and Xantphos, B–C) Arylation of 2-benzylfuran,
cation and crown ether dependent selectivity and D) Calculated
cation-π interaction.
Juxtaposing these two projects, we were motivated to inves-
tigate cation-π interactions36-38 of the type in Figure 1 for the
deprotonation of toluene derivatives.39 Herein, we present our
findings in the catalytic and selective monoarylation of toluene
derivatives using KN(SiMe3)2, aryl bromides, and
a
K(NIXANTPHOS)Pd catalyst (eq 1). A computational study
points to cation-π interactions facilitating the deprotona-
tion/arylation of toluene.
H
H
NIXANTPHOS Pd G3
(2.5 mol %)
CH3
(1)
Ar
+
Ar Br
R
R
1.5 equiv KN(SiMe3)2
110 oC, 12 h
up to 99% yield
OMs
Ph2
Pd
P
NIXANTPHOS Pd G3 =
NH2
O
NH
Ph2P
RESULTS AND DISCUSSION
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Initial Studies in Toluene Arylation. At the outset of our
study, we performed a ligand screen to examine a range of
phosphines in the arylation of toluene. Thus, 43 well-known
mono- and bidentate phosphines (2 µmol for monodentate
ligands and 1 µmol for bidentate ligands) and the Buchwald
3rd-generation palladium precatalyst dimer (0.5 µmol) were
combined with 4-tert-butylbromobenzene (10 µmol) and
KN(SiMe3)2 (15 µmol) in 100 µL of toluene (eq 2). The reac-
tion mixtures were heated to 110 oC for 12 h before cooling to
rt, quenching, addition of biphenyl internal standard, and anal-
ysis by HPLC. Of the ligands screened, NIXANTPHOS gave
the highest assay yield (AY) of the diphenylmethane deriva-
tive by a factor of 2 (see Supporting Information for tabulated
ligands and results). Interestingly, XANTPHOS,34 which is
similar in its ligand framework but does not possess the depro-
tonatable N–H (Figure 1A), and thus cannot form a bimetallic
catalyst, did not generate any diphenylmethane product.
resulted in conversion to the diarylmethane in 80 and 58%
assay yields (AY, determined by H NMR of the unpurified
1
1
2
3
4
5
6
7
8
reaction mixtures), respectively (eq 3–4). In contrast, use of
LiN(SiMe3)2 led to Buchwald-Hartwig reaction to furnish 4-
tert-butyl aniline after workup in 67% assay yield (eq 5). No
product was observed in control experiments lacking either
Pd(OAc)2 or NIXANTPHOS.
5 mol % Pd(OAc)2
7.5 mol % NIXANTPHOS
Br
(3)
1.5 eq KN(SiMe3)2,
110 oC, 12 h
tBu
tBu
9
Toluene, 0.05 M
80% yield
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5 mol % Pd(OAc)2
7.5 mol % NIXANTPHOS
Br
(4)
(5)
1.5 eq NaN(SiMe3)2,
110 oC, 12 h
Toluene, 0.05 M
tBu
tBu
58% yield
H
H
43 phosphines
Buchwald 3rd gen. precat
Br
TMS
N
(2)
5 mol % Pd(OAc)2
7.5 mol % NIXANTPHOS
Br
3 equiv KN(SiMe3)2
tBu
tBu
TMS
Toluene, 110 oC, 12 h
1.5 eq LiN(SiMe3)2,
110 oC, 12 h
Toluene, 0.05 M
tBu
tBu
Top ligand:
NIXANTPHOS
67% yield
Ms
O
Buchwald 3rd gen. precat.
Pd
Further optimization revealed that decreasing the amount of
KN(SiMe3)2 from 3 to 1.5 equiv did not significantly impact
the AY (Table 1, entries 1–2). Increasing the concentration
from 0.05 M to 0.1 M caused a drop in the yield to 68% (entry
3), decreasing the concentration to 0.033 or 0.025 M resulted
in slightly higher AY (entries 4–5). Changing from Pd(OAc)2
to the Buchwald NIXANTPHOS precatalyst had the largest
impact, increasing the AY to 95%. Lowering the temperature
from 110 to 80 °C under the same conditions was not benefi-
cial (71%, entry 7) and no product was seen at ambient tem-
perature (entry 8). With the precatalyst, further lowering the
amount of base to 1.2 equiv resulted in only 65% AY (entry 9).
Finally, reducing the loading of the precatalyst to 2.5 and 1.0
mol % resulted in 93 and 75% yield, respectively (entries 10–
11).
2
NH2
There are several features about this reaction that are re-
markable. First, conventional protocols for deprotonation of
toluene require much stronger bases than KN(SiMe3)2, such as
super bases.40-42 The pKa of the MN(SiMe3)2 conjugate acid
[HN(SiMe3)2, pKa 26 in THF]43 is much lower than the gener-
ally accepted pKa value of toluene (43 in DMSO).24 Second,
the selectivity of the catalyst for the conversion of toluene and
aryl bromide to diphenylmethane with little or no generation
of the triarylmethane is especially notable since the diarylme-
thane is considerably more acidic (pKa ~33 in DMSO) than
toluene.24 In addition, a similar Pd(NIXANTPHOS)-derived
catalyst is amongst the most efficient for the arylation of di-
phenylmethane derivatives with aryl bromides or chlorides to
give triarylmethanes. Unlike the reaction in eq 2 in toluene
solvent, ethereal solvents, like cyclopentyl methyl ether, were
employed in the synthesis of triarylmethanes.17,18,23 Of course,
etheral solvents will coordinate to the potassium of the
K(NIXANTPHOS)Pd-based catalyst and will impact the abil-
ity of the potassium to participate in cooperative interactions
with palladium and the substrate.
Table 1. Optimization of Pd-Catalyzed Arylation of Tolu-
enea
Pd source
NIXANTPHOS
Br
H3C
+
tBu
2a (1 equiv)
KN(SiMe3)2, T
12 h, conc.
tBu
entry
base
T
Pd source Pd (mol %)/ conc
ligand (mol %) (M)
AY
(%)b
80
81
68
84
83
95
7
Our previous findings, discussed in the introduction, led us
to attribute the observed unusual reactivity to the effect of the
base counterion that is coordinated to the deprotonated
NIXANTPHOS ligand. This hypothesis is supported by the
acidity of the N–H of the NIXANTPHOS (pKa ~22, DMSO),24
which will be deprotonated during the reaction causing the
counterion to be associated with the reactive complex. The
deprotonated ligand has been characterized crystallographical-
ly.18 To probe this premise, we examined different counteri-
ons of M[N(SiMe3)2] (M = K, Na, Li) in the present reaction.
Arylation of toluene with KN(SiMe3)2 and NaN(SiMe3)2 bases
(equiv)
3
(°C)
1
2
3
4
5
6
7
8
110 Pd(OAc)2
110 Pd(OAc)2
110 Pd(OAc)2
110 Pd(OAc)2
110 Pd(OAc)2
110 Pd precatc
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
5
0.05
0.05
0.10
0.033
0.025
033
1.5
1.5
1.5
1.5
1.5
1.5
1.5
80
24
Pd precatc
Pd precatc
5
033
5
033
0
3
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9
1.2
1.5
1.5
110 Pd precatc
110 Pd precatc
110 Pd precatc
5
2.5
1
033
033
033
65
93
75
1
2
3
4
NIXANTPHOS Pd G3
2.5 mol%
Ar
10
11
Ar Br
a
b
Reaction conducted on a 0.1 mmol scale Assay yields
1.5 equiv KN(SiMe3)2, Toluene
0.033 M, 110 oC, 12 h
1
(AY) determined by H NMR spectroscopy of the reaction
mixture c NIXANTPHOS Pd G3 used.
1a–1i
3aa–3ai
5
6
7
8
9
MeO
Me2N
Substrate Scope. Diarylmethanes are core structures in a
number of bioactive compounds, and their synthesis has at-
tracted significant attention.44,45 In general, they are prepared
by cross-coupling with either aryl46-57 or benzylic58-63 organo-
metallic reagents, although cross electrophile coupling reac-
tions are growing in importance.64 Preparation of diarylme-
thanes from inexpensive feed stocks, such as toluene deriva-
tives, is potentially the most economical. With these consider-
ations in mind, we set out to explore the scope of the arylation
of toluene with aryl bromides (Scheme 3). Aryl bromides
bearing electron donating groups, such as 4-tert-Bu (2.5 mol%
Pd), 4-OMe (5 mol% Pd) and 4-N,N-dimethyl (5 mol% Pd)
were excellent substrates (3aa–3ac, 80–95% isolated yield).
Sterically hindered 2-bromotoluene and 1-bromonaphathalene
reacted efficiently at 2.5 mol% catalyst loading, providing
product 3ad and 3ae in 90–92% yield. The TIPS protected 4-
bromophenol underwent arylation at 5 mol% catalyst loading
to provide the coupled product 3af in 80% yield. Indoles are
amongst the most common substructures in natural products
chemistry. Thus, 5-bromo-1-methyl-1H-indole was found to
be a good coupling partner, affording the product 3ag with 5
mol% Pd in 95% yield. Other heterocycle containing sub-
strates, such as 1-(4-bromophenyl)pyrrolidine and 3-bromo-9-
phenyl-9H-carbazole also furnished monoarylation products in
≥ 95% yield. Unfortunately, aryl bromides bearing electron-
withdrawing substituents proved recalcitrant, decomposing
under the reaction conditions [including aryl bromides with 2-
Cl, 4-F, 4-CN, 3-CF3, 4-CF3, 3,5-(CF3)2]. Furthermore, we did
not observe product formation with aryl iodides or triflates
bearing electron withdrawing groups. Overall, the protocol
proved to be robust with various aryl bromides bearing elec-
tronically neutral or electron donating groups undergoing ary-
lation with Pd loadings as low as 2.5%.
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3ab, 80%b
3ac, 95%b
3aa, 93%
(iPr)3SiO
CH3
3af, 80%b
3ad, 92%
3ae, 90%
MeN
N
N
3ag, 95%b
3ah, 95%
3ai, 96%
Reactions conducted on a 0.1 mmol scale b 5 mol % Cata-
a
lyst was used.
Scheme 3. Arylation of Toluene with Aryl Bromidesa
We next set out to examine toluene derivatives as substrates
(Scheme 4). The isomeric xylenes exhibited surprisingly dif-
ferent reactivity under the arylation conditions. For example,
ortho-xylene reacted with 4-tert-butyl bromobenzene to form
desired product 4ba in 99% yield. The yield dropped with
meta-xylene and para-xylene (4ca, 4da) to 80 and 64%, re-
spectively. Mesitylene was also subjected to the reaction con-
ditions and formed the arylation product 4ea in 63% yield.
Toluene derivatives with electron donating and electron with-
drawing groups at the ortho-position gave high yields of 90%
(2-OMe, 4fa), 85% (2-F, 4ga) and 81% (2-Cl, 4ha). Interest-
ingly, no byproduct derived from the oxidative addition of 2-
chlorotoluene was found, despite the known ability of
K(NIXANTPHOS)Pd catalyst to oxidatively add aryl chlo-
rides (in cyclopentyl methyl ether solvent).18 Ethyl benzene
underwent arylation at the benzylic position to give the
branched product 4ka in 75% yield. Interestingly, alkyl substi-
tuted benzene derivatives with longer alkyl chains were unre-
active, suggesting that there may be a restrictive pocket size in
4
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palladium and potassium centers. In the present case, the ary-
the deprotonation step that is responsible for the high selectivi-
1
2
3
4
5
6
7
8
ty in the formation of diarylmethanes over triarylmethanes (as
discussed later). The coupling between 2-methylnaphthalene, a
solid at room temperature (melting range 32–35 C), and 4-
bromo-N,N-dimethylaniline provided the product in 49% yield.
Overall, common toluene derivatives were well tolerated un-
der the reaction conditions.
lation of toluene with aryl bromide 1a, suffered a decrease in
yield from 93% without crown ether to 64 and 20% upon addi-
tion of 1.5 and 3.0 equiv of 18-crown-6, respectively (Table 2,
entries 1–3). Likewise, use of 1.5 and 3.0 equiv of 15-crown-
5 caused a decrease in yield from 93% without crown ether to
35 and 10%, respectively (entries 4–5). These results can be
interpreted as indirect evidence that the arylation of toluene
requires the K(NIXANTPHOS)Pd catalyst to have a potassi-
um that is not exhaustively coordinated.
o
Scheme 4. Arylation of Toluene Derivativesa
9
10
11
12
13
14
15
16
17
18
19
20
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22
23
24
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43
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46
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58
59
60
NIXANTPHOS Pd G3
Table 2. Impact of Additives on the Arylation of Toluenea
R
R
2.5 mol %
Ar CH3
2b–2k
+
NIXANTPHOS Pd G3
1.5 equiv KN(SiMe3)2,
0.033 M, 110 oC, 12 h
Br
Br
H3C
2.5 mol %
Ar
1a
4ba–4ka
+
1.5 equiv base, 110 oC,
12 h, 0.033 M, additives
tBu
tBu
1a (1 equiv)
tBu
tBu
tBu
tBu
tBu
entry
base
additives
–
equiv yield (%)b
CH3
1
2
3
4
5
KN(SiMe3)2
–
93
64
20
35
10
KN(SiMe3)2 18-crown-6
KN(SiMe3)2 18-crown-6
KN(SiMe3)2 15-crown-5
KN(SiMe3)2 15-crown-5
1.5
3.0
1.5
3.0
H3C
CH3
4da, 64%
4ba, 99%
4ca, 80%
tBu
tBu
a
b
Reaction conducted on a 0.1 mmol scale Yield deter-
OMe
F
mined by 1H NMR spectroscopy of the crude reaction mixture.
H3C
CH3
To gain insight into the catalyst substrate interactions that
enable this unusual reactivity of toluene derivatives, we initi-
ated computational studies. In particular, we searched for in-
teractions mediated by NIXANTPHOS that would be absent in
unreactive catalyst analogs (i.e. the XANTPHOS derivative).
Knowing that π-activation of toluene, as seen with chromium
activated toluene derivatives,25,26 is an important potential
modality, computational methods were needed that could cap-
ture such interactions. CCSD(T) calculations in combination
with large basis set are among the most accurate ab-initio
methods available today, but were not tractable for the larger
system in hand. Thus, B3LYP/6-31G(d) and M06/6-
311+G(d,p)65 methods were benchmarked against CCSD(T)/6-
311++G(2d,2p), which has been reported to reproduce cation-
π interaction energies and geometries (Table 3).37 For lithium,
the M06 method was found to be closest to the experimental
and CCSD values of the interaction energy, while both B3LYP
and M06 gave reasonable agreement for potassium. For ge-
ometries, good agreement between the calculated B3LYP and
CCSD distance was observed. As such, B3LYP was used for
geometry optimization whereas energies were generated with
M06 single point calculations on the B3LYP geometries.
4ea, 63%
4fa, 90%
4ga, 85%
tBu
tBu
Cl
F
Cl
4ha, 81%
4ia, 78%
4ja, 74%
tBu
H3C
CH3
N
4ka, 75%
4la, 49%b
a Reactions conducted on a 0.1 mmol scale
b Reactions conducted with 1:1 mixture of Buchwald Pd G3
dimer and NIXANTPHOS.
Mechanism. With the optimized reaction conditions in Ta-
ble 1 (entry 10), we investigated the cation effect with
KN(SiMe3)2 in the presence of crown ether additives. As not-
ed in the Introduction, addition of crown ethers to the arylation
of 2-benzyl furans (Figure 1C) with the bimetallic
K(NIXANTPHOS)Pd catalyst changed the regioselectivity
from C-3 arylation to benzylic arylation (Figure 1B–C). We
hypothesized that sequestration of the potassium, as was ob-
served in the solid state structure of K-18-Crown-
6•(NIXANTPHOS),18 inhibited cooperativity between the
Table 3. Benchmarking Computational Methods
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Both deprotonations are endothermic. However, the corre-
1
2
3
4
5
6
7
8
sponding Keq value for deprotonation of toluene via TS 1 is
~1010 times more favorable than that for deprotonation of tolu-
ene via TS C. Overall, the deprotonation via TS 1 is faster,
and it results in the formation of higher concentration of the
tolyl anion. Moreover, the formed tolyl anion is in proximity
to the Pd center, allowing immediate transmetallation to occur.
These three factors combined, are proposed to substantially
accelerate the overall coupling process compared to the case
of a noninteracting, “innocent” ligand (e.g. Xantphos).
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a
A: B3LYP/6-31G(d); B: M06/6-311+G(d,p)//B3LYP/6-31G(d);
C: CCSD(T)/6-311++G(2d,2p).
Using these methods, we analyzed the energetics of depro-
tonation of toluene with KN(SiMe3)2 base where H3Si served
as a model for Me3Si (Figure 2). Several possible reaction
pathways with different deprotonation modes and a dimeric
aggregation state of the base were considered. The latter is
essential since KN(SiMe3)2 exists primarily in the oligomeric
form in low polarity solvents.66 Our findings indicate that co-
ordination of potassium to the π-system of toluene significant-
ly lowers the activation energy for deprotonation. Thus, TS B
is about 10 kcal/mol lower in energy than TS A. In TS B, π-
activation of toluene is provided internally, where the activat-
ing potassium atom is a part of the deprotonating base dimer.
External π-coordination by a second base dimer provides simi-
lar activation for deprotonation of the toluene (TS C). Using
the non-simplified base structure (with Me3Si fragments) and
additional coordinated solvent molecules in calculations did
not have a significant effect on the relative energies of the
transition states (See Supporting Information for details).
Figure 3. Relative Gibbs free energies and enthalpies (in
parenthesis) of ligand-assisted deprotonation of toluene,
kcal/mol. Values calculated with SMD-toluene-M06/6-
311+G(d,p)/ Pd:LANL2DZ //B3LYP/6-31G(d)/Pd:LANL2DZ
relative to the isolated dimeric base units, toluene and depro-
tonated ligand.
Since the system exists in some highly aggregated state, it is
also important to consider the activation energies calculated
relative to oligomeric species. Such analysis suggests that
while deprotonation with assistance by ligand is facile, the
unassisted deprotonation is still possible, albeit slower. This
important result suggests that under harsh reaction conditions,
silylamide bases are capable of establishing acid-base
equilibirum for deprotonation of low-acidic benzylic positions.
Figure 2. Relative Gibbs free energies and enthalpies (in brack-
ets) for deprotonation of toluene relative to corresponding oligo-
meric intermediates, kcal/mol. Values calculated with SMD-
toluene-M06/6-311+G(d,p)//B3LYP/6-31G(d).
Figure 4. Relative Gibbs free energies and enthalpies (in
brackets) of ligand-assisted deprotonation of toluene, kcal/mol.
Values calculated with SMD-toluene-M06/6-311+G(d,p)/
Pd,Br: LANL2DZ //B3LYP/6-31G(d)/Pd,Br: LANL2DZ rela-
tive to corresponding oligomeric intermediates
Using the structure of TS C as a reference, the energy of the
corresponding transition state where toluene is deprotonated
by K[NIXANTPHOS] rather than K[N(SiMe3)2] was analyzed
(Figure 3). Comparison of the energies of transition states TS
1 and TS C indicates substantial stabilization of TS 1 due to
the interaction of ligand with the outer-sphere potassium atom.
This prediction was confirmed experimentally. Under the
reaction conditions, tolyl anion can be trapped with
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benzylbromides, furnishing corresponding product in low
yields (Scheme 5, eq 6 and 7, unoptimized conditions).
1
2
3
Scheme 5. Deprotonation Study - Benzylation
4
5
6
1.5 eq KN(SiMe3)2
Br
(6)
110 ºC, 12 h
Toluene, 0.05 M
16% AY
7
8
9
tBu
1.5 eq KN(SiMe3)2
Br
(7)
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11
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60
tBu
110 ºC, 12 h
Toluene, 0.05 M
22% AY
Another interesting aspect of this coupling is that aryl chlo-
rides are inert in this transformation (see Scheme 4), which is
unexpected as oxidative addition to aryl chlorides occurs with
M(NIXANTPHOS)Pd catalysts at room temperature.18 Since
potassium–halogen interactions were identified as mediating
the deprotonation of toluene (TS 1, Figure 3), the low reactivi-
ty of aryl chlorides was hypothesized to arise from a weaker
K–Cl interaction in the deprotonation transition state. Exami-
nation at the corresponding transition states revealed that acti-
vation energies for deprotonation step in both cases are very
similar (~32 kcal/mol, Figure 5). However, further analysis
revealed a cumulative impact of both the oxidative addition
and the deprotonation on the reactivity (Figure 5). Namely,
oxidative addition of the chloride is uphill such that the depro-
tonation transition state moves to an inaccessibly high level on
the overall reaction coordinate diagram.
Figure 6. PM6-optimized transition states of deprotonation of
toluene derivatives. The relative values of rate constants are pro-
vided.
We applied our model to rationalize the observed low reac-
tivity of diphenylmethane. Based on the optimized geometry
of TS 1, we constructed the corresponding non-truncated tran-
sition state and used semi-empirical calculations to optimize it,
leaving the deprotonation 6-membered transition state core
intact (Figure 6). The calculations indicated that one of the
phenyl groups undergoes steric interactions with the
NIXANTPHOS ligand raising the energy for deprotonation.
This destabilization manifests in a much higher activation
energy and correspondingly slower reaction rate (Figure 6).
As a further test of the validity of this model, we decided to
analyze its predictive ability. Using the semi-empirical model-
ing approach described above, we examined the reactivity of
the 4-tert-butyltoluene in the coupling reaction. Our calcula-
tions revealed steric interactions between the tert-butyl group
and the silyamide groups of the potassium that undergoes π-
interaction with the arene of 4-tert-butyltoluene. These inter-
actions should significantly lower the rate of the correspond-
ing couplings as indicated by the values of relative rate con-
stants (Figure 6). Subsequent experiments confirmed this pre-
diction. Coupling of 4-tert-butyltoluene with 4-bromo N,N-
dimethylaniline (used to facilitate isolation) resulted in very
low conversion under the standard conditions (15% yield,
Scheme 6, eq 8). Likewise, 3,5-di-tert-butyltoluene exhibited
similar reactivity (Scheme 6, eq 9). In a competition experi-
ment, equimolar amounts of toluene and 3,5-di-tert-
butyltoluene were subjected to the standard coupling condi-
tions with 4-bromo N,N-dimethylaniline. The product derived
from toluene arylation formed in 95% AY, while the arylation
of 3,5-di-tert-butyltoluene furnished <5% AY (Scheme 6, eq
10). These results support the computational model that the
size of the group(s) positioned far from the reacting methyl
Figure 5. Relative Gibbs free energies and enthalpies (in paren-
thesis) of deprotonation of toluene in Br and Cl systems, kcal/mol.
Values
calculated
with
SMD-toluene-M06/6-
311+G(d,p),Pd:LANLl2DZ//B3LYP/6-31G(d),Pd:LANL2DZ
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group have a significant impact on the deprotonation transition for construction of systems to allow deprotonation and selec-
1
2
3
4
5
6
7
state. Without the proposed model, such results would be sur-
prising given that the tert-butyl groups are located distal rela-
tive to the methyl substituent undergoing deprotonation.
tive reaction in other contexts.
We are currently applying cation-π interactions to activate
benzylic C–H’s to other reactions and working to reduce the
equivalents of toluene derivatives by examining other reaction
solvents.
Based on these models, we hypothesize that the ligand and
the oligomeric base fragments create a cavity that allows only
certain toluene derivatives to successfully ‘dock’ and take
advantage of the π-activation that facilitates deprotonation.
ASSOCIATED CONTENT
Supporting Information. Experimental and computational
procedures and data. This material is available free of charge
via the Internet at http://pubs.acs.org.
8
9
Scheme 6. Reactivity of the 4-tert-butyltoluene
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NIXANTPHOS Pd G3
AUTHOR INFORMATION
Corresponding Author
(2.5 mol%)
1.5 eq KHMDS
Br
(8)
Me
Me
tBu
N
N
110 ºC, 12 h
0.033 M in
Me
Me
Patrick J. Walsh, pwalsh@sas.upenn.edu
Marisa C. Kozlowski, marisa@sas.upenn.edu
1mc
1c
15% yield
tBu
NIXANTPHOS Pd G3
(2.5 mol%)
ACKNOWLEDGMENT
tBu
Br
1.5 eq KHMDS
(9)
Financial support for this work was provided by NIH/NIGMS
(GM087605 to M. C. K.) and the National Science Foundation
(CHE-1464744 to P. J. W. and CHE1464778 to M. C. K.).
M.C.K. acknowledge XSEDE (TG-CHEM120052) for computa-
tional resources.
Me
Me
N
N
110 ºC, 12 h
tBu
Me
tBu
Me
1c
0.033 M in
1nc
14% yield
tBu
REFERENCES
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(2.5 mol%)
Me
(1)
Nandiwale, K. Y.; Thakur, P.; Bokade, V. V.
Br
N
1.5 eq KHMDS
Appl. Petrochem. Res. 2015, 5, 113.
Me
(10)
Me
1ac
N
(2)
Bai, H.; Yi, W.; Liu, J.; Lv, Q.; Zhang, Q.;
110 ºC, 12 h
95% yield
Me
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Hartwig, J. F. Organotransition Metal
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4% yield
CONCLUDING REMARKS
In summary, we have developed a method to directly arylate
toluene derivatives with aryl bromides to generate diarylme-
thanes, which are important building blocks in drug discovery.
Entry to these adducts in good to excellent yields from toluene
derivatives, many of which are readily available solvents, has
the potential to be more efficient overall since steps to add
halide or organometal functionalities are not required. Mecha-
nistic and computational studies point to activation of the tolu-
ene by means of η6-coordination with a main group element.
The resultant adduct is more acidic than the parent, such that a
base normally ineffective in the deprotonation of toluene de-
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tion is facilitated by the use of alkane rather than ethereal sol-
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deprotonation. The concepts described herein provide a basis
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W. A.; Duarte, F.; Paton, R. S. Chem. Sci. 2018, 9, 2655.
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calculations also point to the stability of TS C (see Supporting
Information for details).
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Journal of the American Chemical Society
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TOC GRAPHIC
Ar
Me
R
2.5 mol % PdNiXantPhos
63-99% Yield
16 Examples
1.5 equiv KHMDS, 12h
ArBr, 0.03M, 110oC
R
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K
(H3Si)2N
PMe2
O
N
K
P
Me2
Pd
Me
increasing
acidity of
toluene
X
K
H
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N(SiH3)2
(H3Si)2N
K
increasing
basisity of
KHMDS
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