Ligand-Enabled Meta-C-H Alkylation and Arylation Using a Modified Norbornene

Article abstract of DOI:10.1021/jacs.5b08914

2-Carbomethoxynorbornene is identified as a more effective transient mediator to promote a Pd(II)-catalyzed meta-C(sp²)-H alkylation of amides with various alkyl iodides as well as arylation with previously incompatible aryl iodides. The use of a tailor-made quinoline ligand is also crucial for this reaction to proceed.

Full text of DOI:10.1021/jacs.5b08914

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Communication
Ligand-Enabled Meta-C–H Alkylation and
Arylation Using A Modified Norbornene
Peng-Xiang Shen, Xiao-chen Wang, Peng Wang, Ru-Yi Zhu, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08914 • Publication Date (Web): 27 Aug 2015
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Ligand-Enabled Meta-C–H Alkylation and Arylation Using A Modified Norbornene
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Peng-Xiang Shen, Xiao-Chen Wang, Peng Wang, Ru-Yi Zhu and Jin-Quan Yu*
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037
RECEIVED DATE (automatically inserted by publisher); yu200@scripps.edu
stage of development.2d,2e Analysis of the catalytic cycle of our
Abstract: 2-Carbomethoxynorbornene is identified as a
more effective transient mediator to promote a Pd(II)-
catalyzed meta-C(sp2)–H alkylation of amides with various
alkyl iodides as well as arylation with previously
incompatible aryl iodides. The use of a tailor-made quinoline
ligand is also crucial for this reaction to proceed.
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norbornene-mediated meta-C–H arylation and methylation
reactions (Fig. 1) led us to focus on tuning the reactivity of
intermediates III and IV which can potentially participate in
multiple reaction pathways, some of which are non-productive.
Our preliminary experimental result with ethyl iodide also
suggests that the formation of the cyclobutane adduct as the major
side product largely outcompetes the ethylation pathway.
Reductive elimination from either III or IV could be responsible
for this observation. Considering that norbornene is intimately
involved in these competing steps, we envisioned that it is
possible to favor the desired oxidative addition of ethyl iodide
with III or aryl-ethyl reductive elimination from IV by
systematically modifying the structure of norbornene. Notably,
Catellani previously observed that bicyclo[2.1.1]hex-2-ene and
bicyclo[2.2.2]oct-2-ene other than norbornene can also react with
aryl halides to give benzocyclobutene,14 albeit without forming
the Catellani reaction product.
Directed-C–H activation has been largely associated with the
functionalizations of ortho-C–H bonds.1 The development of a U-
shaped template to direct meta-C–H activation has provided a
promising solution to this problem.2 To further improve the
efficiency and scope of meta-C–H activation reactions, we have
established a ligand-enabled catalytic system that combines
Pd(II)-catalyzed ortho-C–H activation with norbornene-mediated
Pd(II)/Pd(IV) catalysis developed by Catellani and Lautens (eq
1)3,4 to achieve meta-selective C–H alkylation and arylation.5 A
related meta-C–H arylation adopting similar strategy has also
recently appeared in literature.6 Prior to these developments, an
elegant C-2 alkylation of indole using norbornene as the mediator
has also been reported by Bach (eq 2).7 In our amide-directed
meta-C–H activation reactions,5 there exist significant limitations.
First, alkylation with alkyl iodides containing β-hydrogen is
problematic (the use of 6 equiv ethyl iodide is required to give
only 21% yield). Second, aryl iodide coupling partners without
ortho-coordinating groups are not compatible except for a single
example with highly reactive 3,5-bis(trifluoromethyl)-
iodobenzene.5 Herein we report the development of a more
efficient norbornene-type mediator that can promote efficient
meta-C–H alkylation with a wide range of alkyl iodides as well as
arylation with common aryl iodides in the presence of a
quinoline-based ligand. This approach is fundamentally different
from other meta-selective C–H activation/carbon-carbon bond
forming reactions.8,9,10
NHArF
NHArF
O
O
H
H
R
H
Pd(II)Ln
H+
step 7
step 1
O
O
(II)
(II)
N
N
ArF
Pd
ArF
Pd
Ln
R
Ln
H
I
VI
step 6
step 2
ArFHNOC
ArFHNOC
(II)
H
(II)
R
Pd Ln
Pd Ln
V
II
step 3
step 5
ArFHNOC
ArFHNOC
(IV)
(II)
step 4
Pd Ln
Pd
Ln
I
R
IV
III
RI
O
Challenges associated with C–H alkylation reactions are
anticipated from the extensive studies on transition metal-
catalyzed C–C coupling involving alkyl coupling partners.11
Although a few ortho-C–H alkylation reactions have been
developed,12,13 directed meta-C–H alkylation with simple alkyl
iodides have not been reported to date despite significant synthetic
importance. For example, our U-shaped template-directed meta-
C–H coupling is not compatible with alkyl boron reagents at this
Pd(II)Ln
Pd(0)Ln
NHArF
side-product
Figure 1. Plausible Catalytic Cycle for Norbornene-Mediated
Meta-C–H Alkylation
Prior to the extensive tuning of the norbornene structure, we
needed to identify a pyridine- or quinoline-based ligand that will
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give the optimum reactivity for C–H activation and norbornene
Since the preliminary screening of various readily available
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insertion steps leading to the formation of intermediate III.
Guided by our previous extensive studies of these ligands in the
meta-C–H arylation reaction,5 a brief survey of a few superior
ligands rapidly identified L1 as the most effective ligand as
indicated by the formation of the benzocyclobutene adduct in 85%
yield (Table 1). Hence we began to prepare various norbornenes
and test them in the meta-C–H alkylation reaction with EtI in the
presence of ligand L1 (Table 1).
norbornenes did not afford significant improvement, we decided
to synthesize new norbornenes to accelerate the migratory
insertion (step 2) of the arylpalladium species with norbornene.
Considering the superior reactivity of styrenes and acrylates in
Heck coupling and C–H olefination reactions due to the
polarization of the double bond,15 we introduced phenyl, acetyl,
sulfonyl, nitrile, and ester groups to the 2-position in conjugation
with the double bond (N11-N15). Among these modified
norbornenes, N15 was identified to be the most effective mediator
affording the meta-C–H alkylation product in 97% yield. The use
of catalytic amount of N15 (0.5 equiv) is feasible, albeit affording
lower yield (72%, see supporting information). The low reactivity
with N12-N14 indicates that the desired reaction pathway is
highly sensitive to the electronic and steric effects of the double
bond. For example, the carbon-palladium bond α to keto and
nitrile group formed from N12 and N14 seems to retard the meta-
C–H activation (step 3). In the presence of DOAc, the fully
recovered starting material containing high ortho-D-incorporation
and no meta-D-incorporation supports this hypothesis (see
supporting information). It is also important to note that the
cyclobutane adduct is not formed with norbornenes N12-N15
even in the absence of EtI, presumably the substitution of
electron-withdrawing groups at the 2-position prevents the
reductive elimination through both steric hindrance and electronic
effect. In addition to being dependent on the structure of
norbornene, this reaction is also significantly influenced by the
ligands. Replacement of L1 by other phosphine and carbene
ligands also decreases yield of the alkylated product to 10 and
45% respectively (see supporting information).
Since the high reactivity of the norbornene insertion is largely
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a number of
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norbornenes fused with an aryl group at the 5,6-positions (N2-N4).
These structural modifications significantly reduced the formation
of the cyclobutane adducts 4. However, the yield of the meta-
alkylation product is only moderately improved when the
trifluoromethyl group-bearing norbornene derivative N4 is used.
Further tuning the ring strain by replacing the carbon at the 6
position with an oxygen significantly reduced the overall
reactivity (N5). We then introduced various electron-withdrawing
functional groups at the 5, 6 and 7 positions to study the electronic
effects (N6-N10). A noticeable increase in yield was observed
with N7 containing two ester groups. The comparison of the
results with N6 and N7 is revealing. While the steric hindrance at
the 5 and 6 positions of N7 seems to hamper the undesired
reductive elimination pathway leading cyclobutane adduct 4g, the
norbornene insertion step (step 2) is presumably also drastically
inhibited compared to N6 affording lower reactivity.
Table 1. Modified Norbornenes for Meta-Alkylationa,b
Me
Pd(OAc)2 (10 mol%)
NHArF
Norbornene derivative
Me
With these high-yielding conditions in hand, we examined the
scope of alkyl iodides (Table 2). Alkyl iodides with long carbon
(1.5 equiv)
AgOAc (3.0 equiv)
DCE, 75 °C, 16 h
O
NHArF
+
3a
Et
I
Et
O
H
+
Table 2. Meta-Alkylation with A Variety of Alkyl Iodidesa,b
2.5 equiv
2a
Me
Me
H
1
ArF = 4-(CF3)C6F4
NHArF
t-Bu
(L1)
Me
O
N
O
(10 mol%)
4a-l
R
OCH3
3a: 12%
4a: 75%
3a: 6%
4b: 61%
3a: 11%
4c: 27%
H3CO
N1
N2
N3
O
3a: 18%
3a: <5%
4e: <5%
3a: 10%
4f: 88%
CF
3 4d: 26%
CO2Me
N4
N5
BnO
N6
3a: 20%
4g: 20%
3a: <5%
4h: 9%
CO2Me
CO2Me
OH
OH
N.R.
N7
N8
N9
O
3a: 12%
4i: <5%
3a: 15%
4j: 0%c
Me
N
N.R.
Ph
Boc
O
N10
N11
N14
N12
3a: 29%
4k: 0%c
3a: 97%
(72%)d
4l: 0%c
N.R.
MeO2C
N15
PhO2S
NC
N13
a
Conditions: 1 (0.1 mmol), 2a (2.5 equiv), Pd(OAc)2 (10 mol%), L1 (10 mol%),
Norbornene derivative (1.5 equiv), AgOAc (3.0 equiv), DCE (1.5 mL), 75 oC, air, 16
a Conditions: 1 (0.1 mmol), 2 (2.5 equiv), Pd(OAc)2 (10 mol%), L1 (10 mol%), N15
b
c
h. 1H NMR yields, using CH2Br2 as internal standard. Possible side-product was
not observed with or without the addition of 2a. d Using 0.5 equiv of N15 instead of
1.5 equiv.
o
b
c
(1.5 equiv), AgOAc (3.0 equiv), DCE (1.5 mL), 75 C, air, 16 h.. Isolated yields.
Using 3.0 equiv of N15 instead of 1.5 equiv. d 1 (1 mmol scale) e Ethyl bromide (2.5
equiv), 48 h; 1H NMR yield measured using CH2Br2 as internal standard.
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chain afford the meta-alkylated products in good yields (3a-3c). A
conditions give a mixture of di and mono-butylation products in
1
2
3
4
5
6
7
8
similar result is obtained with more sterically hindered i-butyl
iodide (3d). Alkyl iodides containing trifluoromethyl, aryl, benzyl
and silyl protected hydroxyl, protected amino group, chloro,
nitrile and ketal functionalities are all excellent coupling partners
rendering this meta-alkylation method broadly useful (3e-3l).
Surprisingly, alkyl iodide containing an ester group gives the
product in low yield (40%) under standard conditions, which is
improved to 74% by using 3.0 equiv of N15 (3m). Meta-
ethylation of 1 is also performed in 1 mmol scale to give 3a in
91% yield (Table 2). Ethyl bromide is also compatible affording
3a in 40% yield after extending reaction time to 48 h (Table 2).
Under current conditions, secondary alkyl iodides or bromides
decomposed without giving the desired alkylation product.
This newly established meta-alkylation protocol is also
extended to other amide substrates derived from phenyl acetic
acids using butyl iodide as the coupling partner (Table 3).
Substrates containing ortho-methoxy, fluoro and chloro groups
give the desired meta-butylated products in good yields (6a-c).
Meta-methoxy, methyl, fluoro, chloro and trifluoromethyl are also
well-tolerated (6d-6h). The butylation of the para-fluoro and non-
substituted phenylacetamides (5i, 5j) under the standard
the ratio of 1:1. However, the di-butylated phenylacetamides 6i-di
and 6j-di are obtained as the major products in 77 and 65% yields
respectively by using 20 mol% Pd catalyst and 5 equiv of butyl
iodide. Reducing the butyl iodide to 2 equiv gives the mono-
butylated phenylacetamide 6j-mono as the main product in 44%
yield. Naphthalene substrate 5k is selectively butylated at the 3-
position in excellent yield (92%). Meta-alkylation of tetralone,
dihydrobenzofuran and indoline substrates also proceeds in
moderate yields (6l-n), even though the amide directing group is
out of plane with the ortho and meta-C–H bonds. However,
extending this method to other heterocycles such as pyridines and
thiophenes are unsuccessful. Our meta-alkylation protocol is also
compatible with mandelic acid and phenylglycine substrates
affording the desired products 6o and 6p in good yields.
Unfortunately, substantial racemization occurred during the
installation of our amide directing group using previously
reported conditions (5o is obtained in 67% ee). However, no
racemization was observed in this meta-alkylation reaction when
using mandelic acid derived amide 5o with 67% ee as the
substrate (See supporting information).
The ability of this modified norbornene to enable meta-C–H
alkylation encouraged us to revisit our previously reported meta-
arylation reaction (Table 4).4 This previous protocol is only
compatible with aryl iodides bearing an ortho-coordinating group
or multiple electron-withdrawing substituents. Using norbornene
N15, meta-arylation with broad range of aryl iodides proceeded
smoothly, overcoming previous limitation. Phenyl iodide and
other aryl iodides containing chloride, trifluoromethyl and ester,
as well as methyl, amino and methoxy groups all give good to
excellent yields. Notably, 5-iodoindole is also compatible
affording the desired product in 57%.
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Table 3. Meta-Alkylation of Substituted Phenylacetamidea,b
R2
H
R2
CONHArF
Pd(OAc)2 (10 mol%)
L1 (10 mol%)
CONHArF
R1
R1
nBu
I
+
N15 (1.5 equiv)
AgOAc (3.0 equiv)
DCE, 75 oC, 16 h
2.5 equiv
2b
H
nBu
Cl
5a-n
6a-n
ArF = 4-(CF3)C6F4
OMe
F
CONHArF
CONHArF
CONHArF
Table 4. Meta-Arylation with A Variety of Aryl Iodidesa,b
nBu
nBu
nBu
nBu
6c, 85%c
6a, 65%c
6b, 85%
Me
Me
Ar
Pd(OAc)2 (10 mol%)
L1 (20 mol%)
MeO
Me
F
CONHArF
CONHArF
CONHArF
CONHArF
CONHArF
Ar
I
+
N15 (3.0 equiv)
AgOAc (3.0 equiv)
PhCF3, 90 oC, 24 h
H
3.0 equiv
nBu
nBu
H
1
6d, 73%c
6e 73%
6f, 75%
8a-h
7a-h
ArF = 4-(CF3)C6F4
nBu
Cl
F3C
CONHArF
CONHArF
CONHArF
Me
Me
Me
Me
F
CONHArF
nBu
CONHArF
CONHArF
nBu
6g, 85%
nBu
CONHArF
6h, 66%c
6i-di, 77%d
nBu
CONHArF
CONHArF
CONHArF
N
nBu
Bn
Boc
Me
8c, 87%
Me
CF3
nBu
nBu
6j-di, 65%d
6j-mono, 15%d
6j-mono, 44%e
6j-di, 8%e
8a, 73%
Me
8b, 86%
8d, 84%
Me
6k, 92%
Me
CONHArF
CONHArF
CONHArF
nBu
nBu
CONHArF
nBu
CONHArF
CONHArF
CONHArF
N
Ts
O
O
6l, 61%
6m, 52%c
6n, 52%c
OMe
Cl
CO2Me
N
OAc
NPhth
Ts
nBu
nBu
CONHArF
CONHArF
8e, 87%
8f, 80%
8g, 78%
8h, 57%
nBu
6o-di, 80%d
nBu
a Conditions: 1 (0.1 mmol), 7 (3.0 equiv), Pd(OAc)2 (10 mol%), L1 (20 mol%), N15
(3.0 equiv), AgOAc (3.0 equiv), PhCF3 (1.5 mL), 90 oC, air, 24 h. b Isolated yields.
6p-di, 69%d
The multiple elementary steps involved in this catalytic cycle
add complexity to the investigation of the origin of the beneficial
effect of this modified norbornene (Figure 1). A number of
mechanistic aspects, however, are worth commenting based on
our preliminary studies. First, the stereochemistry of the
carbopalladation step (step 2) is mostly likely to be exo as
a
Conditions: 5 (0.1 mmol), 2b (2.5 equiv), Pd(OAc)2 (10 mol%), L1 (10 mol%),
b
N15 (1.5 equiv), AgOAc (3.0 equiv), DCE (1.5 mL), 75 oC, air, 16 h. Isolated
c
d
yields. Using 3.0 equiv of N15 instead of 1.5 equiv. Using 2b (5.0 equiv),
Pd(OAc)2 (20 mol%), L1 (20 mol%), N15 (3.0 equiv), AgOAc (6 equiv), DCE (3.0
ml). e Using 2b (2.0 equiv), L1 (20 mol%), 95 oC.
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H.; Tan, K. L. J. Am. Chem. Soc. 2013, 135, 18778. (d) Wan,
established in the stoichiometric reaction of Ph-Pd-I with
norbornene.16 Second, the protonolysis of the arylpalladium bond
is crucial for regenerating the Pd(II) catalyst and closing the
catalytic cycle. To support our hypothesis, reaction of 1 is
performed in the presence of 10 equiv deuterated acetic acid (eq
3). The observed 70% D-incorporation at the ortho-position is
consistent with the protonolysis pathway. The proton source from
the amide substrate and the HOAc generated from the C–H
activation step could account for the 30% H-incorporation at the
ortho-position. Trifluoromethylated amide 5h was also subjected
to the same deuterium labeling experiment to get better separation
of aromatic protons on NMR spectrum, which gave similar D-
labeling pattern (see supporting information). Finally, the impact
of this modified norbornene N15 is also illustrated in the Catellani
arylation reaction. It is well-known that the Catellani ortho-
arylation using norbornene is limited to aryl iodides bearing
ortho-substituents.3c,17 Other aryl iodides only give a series of
side-products containing bicyclic structure (eq 4).18 In contrast,
the Catellani ortho-arylation followed by Heck reaction proceeds
with N15 to give the standard product 9a-b in good yield (eq 5).
L.; Dastbaravardeh, N.; Li, G.; Yu, J.-Q. J. Am. Chem. Soc. 2013,
135, 18056. (e) Yang, G.; Lindovska, P.; Zhu, D.; Kim, J.; Wang, P.; Tang,
R.-Y.; Movassaghi, M.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 10807. (f)
Bera, M.; Modak, A.; Patra, T.; Maji, A.; Maiti, D. Org. Lett. 2014, 16,
5760. (g) Deng, Y.; Yu, J.-Q. Angew. Chem., Int. Ed. 2015, 54, 888.
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Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem. Int. Ed. Engl. 1997,
36, 119. (b) Lautens, M.; Piguel, S. Angew. Chem. Int. Ed. 2000, 39, 1045.
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(f) Wilhelm, T.; Lautens, M. Org. Lett. 2005, 7, 4053. (g) Catellani, M.
Top. Organomet. Chem. 2005, 14, 21. (h) Mariampillai, B.; Alliot, J.; Li,
M.; Lautens, M. J. Am. Chem. Soc. 2007, 129, 15372. (i) Rudolph, A.;
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Martins, A., Mariampillai, B.; Lautens, M. Top. Curr. Chem. 2010, 292, 1.
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J.-Q. Nature 2015, 519, 334.
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Marafie, J.; Ledger, A. E. W.; Liu, P. M.; Mahon, M. F.; Kociok-Kohn, G.;
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J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., III
Science 2002, 295, 305. (b) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura,
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Cheng, C.; Hartwig, J. F. Science 2014, 343, 853.
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Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099. (b) Zhou, J.; Fu, G. C. J.
Am. Chem. Soc. 2003, 125, 12527. (c) Hills, I. D.; Netherton, M. R.; Fu, G.
C. Angew. Chem., Int. Ed. 2003, 42, 5749.
(12) For selected examples of ortho-alkylation with alkylborons: (a) Chen, X.;
Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634. (b) Giri, R.;
Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-
Q. J. Am. Chem. Soc. 2007, 129, 3510. (c) Wang, D.-H.; Wasa, M.; Giri, R.;
Yu, J.-Q. J. Am.Chem.Soc.2008,130,7190.(d)Shi,B.-F.;Maugel,N.;Zhang,
Y.-H.;Yu,J.-Q. Angew. Chem., Int. Ed.2008,47,4882.(e)Thuy-Boun, P. S.;
Villa, G.; Dang, D.; Richardson, P.; Su, S.; Yu, J.-Q. J. Am. Chem. Soc.
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(13) For selected examples of ortho-alkylation with alkyl halides. Pd: (a)
Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106, 5759. (b)
Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 6097.
(c) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965. (d)
Zhao, Y.-S.; Chen, G. Org. Lett. 2011, 13, 4850. Ni: (e) Aihara, Y.;
Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308. (f) Song, W.-F.; Lackner,
S.; Ackermann, L. Angew. Chem., Int. Ed. 2014, 53, 2477. Ru: (g)
Ackermann, L.; Novák, P.; Vicente, R.; Hofmann, N. Angew. Chem., Int.
Ed. 2009, 48, 6045. Co: (h) Chen, Q.; Ilies, L.; Nakamura, E. J. Am. Chem.
Soc. 2011, 133, 428. (i) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013,
135, 9279. Fe: (j) Ilies, L.; Matsubara, T.; Ichikawa, S.; Asako, S.;
Nakamura, E. J. Am. Chem. Soc. 2014, 136, 13126. (k) Fruchey, E. R.;
Monks, B. M.; Cook, S. P. J. Am. Chem. Soc. 2014, 136, 13130. (l) Monks,
B. M.; Fruchey, E. R.; Cook, S. P. Angew. Chem., Int. Ed. 2014, 53, 11065.
(14) Catellani, M.; Ferioli, L. Synthesis 1996, 769.
(15) Deeth, R. J.; Smith, A.; Brown, J. M. J. Am. Chem. Soc. 2004, 126, 7144.
(16) For mechanistic studies of reaction involving norbornene-containing Pd-
complexes: (a) Bocelli, G.; Catellani, M.; Chiusoli, G. P. J. Organomet.
Chem. 1985, 278, 225. (b) Catellani, M.; Chiusoli, G. P. J. Organomet.
Chem. 1988, 346, C27. (c) Catellani, M.; Mann, B. E. J. Organomet.
Chem. 1990, 390, 251. (d) Li, C.-S.; Jou, D.-C.; Cheng, C.-H. J. Chem.
Soc. Chem. Commun. 1991, 710. (e) Bocelli, G.; Catellani, M.; Ghelli, S. J.
Organomet. Chem. 1993, 458, C12. (f) Catellani, M.; Fagnola, M. C.
Angew. Chem. Int. Ed. Engl. 1995, 33, 2421. (g) Chai, D. I.; Thansandote,
P.; Lautens, M. Chem. Eur. J. 2011, 17, 8175.
In summary, we have developed a meta-alkylation reaction and
significantly improved the scope of meta-arylation reaction of
phenyl acetamides. The design of a more reactive norbornene
analogue and appropriate choice of a quinoline-type ligand are
crucial for the success of this development. The acquired insight
from this study will guide further development of this emerging
meta-C–H functionalization strategy.
Acknowledgements. We gratefully acknowledge The Scripps
Research Institute and NIH (NIGMS, 1R01 GM102265) for
financial support.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org
.
References
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