Article

Cite This: J. Am. Chem. Soc. 2017, 139, 15522-15529 pubs.acs.org/JACS

Factors Controlling the Reactivity and Chemoselectivity of

Resonance Destabilized Amides in Ni-Catalyzed Decarbonylative and
Nondecarbonylative Suzuki-Miyaura Coupling
Chong-Lei Ji and Xin Hong*
Department of Chemistry, Zhejiang University, Hangzhou, 310027, China
*
S Supporting Information
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ABSTRACT: N-Glutarimide amides have recently emerged as

an exceptional group of compounds with unusually high
reactivity in amide C−N bond activation. To understand the
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key factors that control the remarkable reactivity of these

resonance destabilized amides, we explored the Ni-catalyzed
decarbonylative and nondecarbonylative Suzuki-Miyaura cou-
pling with N-glutarimide amides through density functional
theory calculations. Two leading effects are responsible for the
C−N cleavage activity of N-glutarimide amides, the coordinat-
ing N-substituents and the geometric twisting. The carbonyl
substituent of the N-glutarimide amides provides crucial
nickel−oxygen interaction, which essentially acts as a directing
group to facilitate the formation of the reactive intermediate
for the amide C−N bond cleavage. The geometric twisting weakens the resonance stability by removing the acyl-nitrogen
conjugation, which lowers the energy penalty for the C−N bond stretch during oxidative addition. For the chemoselectivity of
decarbonylation versus carbonyl retention, we found that the C−C reductive elimination for ketone formation is kinetically faster
than that for biaryl formation, while ketone is thermodynamically less stable with respect to the decarbonylated biaryls. The
computations also suggest that the nickel catalyst is able to promote the decarbonylation of biaryl ketones via an unexpected C−
C bond activation.

■ INTRODUCTION
Ni-catalyzed C−N bond activation of amides has recently
emerged as a distinctive strategy to utilize amides in organic
synthesis.1 A number of exciting transformations, contributed
by Garg and co-workers,2 Szostak and co-workers,3,4 Shi and
co-workers,5 Zou and co-worker,6 Rueping and co-workers,7
Maiti and co-workers,8 Stanley and co-workers,9 and Molander
and co-workers,10 have been realized based on the Ni-mediated
C−N cleavage of amides. Compared to the common planar
amides, Szostak and co-workers discovered that N-glutarimide
amides exhibit significant geometric distortions and unusually
high reactivities in C−N bond activations,3,4 even in metal-free
conditions.11 The high reactivity of these N-glutarimide amides
are usually rationalized by the twisting geometric nature
(Scheme 1).3a,12
Despite the vast development of synthetic transformations
with N-glutarimide amides,3,4 the controlling factors that
differentiate the C−N bond activation reactivity of N-
glutarimide amides from those of other amides remain elusive.
In addition to this key question of reactivity, the Suzuki-
Miyaura coupling with N-glutarimide amides produced the
decarbonylated biaryl products,3a which is distinctive compared
with the nondecarbonylative Suzuki-Miyaura couplings involv-
ing other amides (Scheme 1).13 This chemoselectivity is
another general issue that exists in all transformations involving
C−N cleavage of amides. Understanding these two fundamen-
tal mechanistic questions with N-glutarimide amides is critical
toward the rational design of amide C−N bond activation and
functionalization.
Regarding the mechanistic studies of Ni-catalyzed amide C−
N bond activation, Houk and Garg elucidated the mechanism
of Ni/NHC-catalyzed esterification of anilides with DFT
calculations, and the three-centered oxidative addition model
successfully explains the reactivities of N-substituted aryl
amides.2a In addition, the group of Zhao and Zhu,14 as well
as the group of Fu and Yu,15 independently studied the
mechanism of the Ni/NHC-catalyzed Suzuki-Miyaura coupling
with Boc-activated amides, which elucidated the roles of K3PO4
and water in facilitating the transmetalation step.
To elucidate the origins of reactivity and chemoselectivity
with N-glutarimide amides, here we report the first computa-
tional study on the C−N bond activation of this special group
of amides, focusing on the Ni/PCy3-catalyzed Suzuki-Miyaura
coupling with aryl boronates. Two essential factors were found
to contribute to the exceptional reactivities of N-glutarimide
amides in the Ni-mediated C−N cleavage, the carbonyl
coordination, and the geometric twisting. The coordinating
Received: September 5, 2017
Published: October 10, 2017

© 2017 American Chemical Society 15522 DOI: 10.1021/jacs.7b09482

J. Am. Chem. Soc. 2017, 139, 15522−15529
Journal of the American Chemical Society
Scheme 1. Twisting Nature of N-Glutarimide Amides and
Comparisons between the N-Glutarimide Amides and the
Boc-Activated Amides in Ni-Catalyzed Suzuki-Miyaura
Coupling2b,3a
glutarimidyl moiety acts as a directing group which facilitates
the generation of the reactive intermediate for C−N bond
cleavage. In addition, the geometric twisting alleviates the
energy penalty for the C−N bond stretch, lowering the intrinsic
barrier for oxidative addition. These synergistic effects also
differentiate the target C−N bond from the adjacent C−N
bonds of the glutarimide substituent, preventing side reactions
involving undesired C−N bond cleavage. Thus, the inert nature
of the glutarimide group is an additional important factor that
contributes to the high reactivity of the N-glutarimide amides
toward the designed C−N bond activation. For the chemo-
selectivity between ketone and decarbonylated biaryl, the
formation of ketone product is kinetically favorable due to the
faster C−C reductive elimination, while ketone is thermody-
namically less stable than the decarbonylated biaryl products.
These mechanistic insights will shed light on the future design
of amide C−N bond activations and related synthetic
applications.
■
COMPUTATIONAL METHODS
All density functional theory (DFT) calculations were performed by
Gaussian 09 program.16 The geometry optimizations were conducted
using the B3LYP functional,17 with LANL2DZ basis set18 for nickel
and 6-31G(d) basis set for the other atoms. To confirm whether each
optimized stationary point is an energy minimum or a transition state,
as well as evaluate the zero-point vibrational energy and thermal
corrections at 298 K, the vibrational frequencies were computed at the
same level of theory as for the geometry optimizations. On the basis of
the gas-phase optimized structures, the single-point energies and
solvent effects were evaluated with the M06 functional,19 SDD basis
set20 for nickel, and 6-311+G(d,p) basis set for the other atoms. The
solvation energies were calculated using the self-consistent reaction
field with the CPCM implicit solvent model.21 Fragment distortion
and interaction energies were calculated with the M06 functional, SDD
basis set for nickel, and 6-311+G(d,p) basis set for the other atoms,
without the inclusion of solvation energy corrections. The details of
distortion/interaction analysis are provided in the Supporting
Information. The 3D diagrams of computed species were generated
using CYLView.22
■ RESULTS AND DISCUSSION
Proposed Catalytic Cycle. On the basis of previous
mechanistic studies on the nickel-catalyzed cross-coupling
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reactions with acyl derivatives,2a,14,15,23 the proposed catalytic
cycles of the Ni-catalyzed Suzuki-Miyaura coupling between
amides and arylboronic acids are shown in Scheme 2. Starting
Scheme 2. Proposed Catalytic Cycles of Ni-Catalyzed
Suzuki-Miyaura Coupling between Amides and Arylboronic
Acids
with the in situ generated Ni(0) active catalyst A, the oxidative
addition breaks the amide C−N bond and generates the
LnNi(acyl)(amino) intermediate B. B undergoes the trans-
metalation with boronic acid to form the LnNi(acyl)Ar2
intermediate C, and subsequent decarbonylation generates
the LnNiAr1Ar2 intermediate D. The C−C reductive elimi-
nation of D produces the biaryl product and regenerates the
nickel(0) active catalyst A. Alternatively, C can directly undergo
the C(acyl)−C(aryl) reductive elimination to produce the
ketone product.
We first studied the proposed catalytic cycle using the
experimental substrates, 1-benzoylpiperidine-2,6-dione and 2-
naphthaleneboronic acid. The free energy changes of the most
favorable pathway leading to the biaryl product are shown in
Figure 1. From the most stable nickel−amide complex 1, an
isomerization occurs to generate the preoxidative addition
intermediate 2. Subsequent oxidative addition via a five-
centered transition-state TS3 requires a barrier of 9.6 kcal·
mol−1 as compared to the intermediate 1, leading to the
PCy3Ni(acyl)(amino) intermediate 4. This exceptionally low
barrier for C−N cleavage corroborates the high reactivity of the
N-glutarimide amides. Notably, the N-glutarimide amides have
very low nN−π*(acyl) resonance, which correlates with the
amide reactivity in cross-coupling reactions according to
Szostak’s recent study12c and is one of the factors that
facilitates the oxidative addition via C−N cleavage (vide infra).
From 4, the coordination with sodium carbonate is quite
exergonic, and the signals responsible for the nickel−carbonate
complex without sodium cations are detected in the
stoichiometric electrospray ionization mass spectrometry
experiments by Szostak and co-worker.3a 5 further reacts with
2-naphthaleneboronic acid to generate the stable intermediate
6, and the sodium carbonate in 6 acts as an intramolecular base
to facilitate the transmetalation via TS7. The PCy3Ni(acyl)-
(naphthyl) intermediate 9 then undergoes the decarbonylation
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Figure 1. DFT-computed Gibbs free energy changes of the most favorable pathway of Ni/PCy3-catalyzed decarbonylative Suzuki-Miyaura coupling
between the N-glutarimide amide 14 and 2-naphthaleneboronic acid.
via TS10, and the subsequent C(sp2)−C(sp2) reductive
elimination via TS13 eventually produces the biaryl product
15 and regenerate intermediate 1 for the next catalytic cycle.
On the basis of the calculated free energy changes of the whole
catalytic cycle, the resting state is the pretransmetalation
intermediate 6, and the rate-limiting step is the C(sp2)−C(sp2)
reductive elimination with an overall barrier of 27.2 kcal·mol−1
(6 to TS13). This significant barrier explains the requirement
for high temperature in experiment.3a To further validate this
mechanistic model, we calculated the free energy barriers of a
number of substituted substrates and compared the computed
barriers with the competition experiments from Szostak’s
work3a (Figure S1). The satisfying consistency between the
computational and experimental results provides additional
support for the proposed mechanism. Our calculations also
showed that the aliphatic N-glutarimide amide has a higher
overall barrier for the same Suzuki-Miyaura coupling (Figure
S2).
Origins of the High Reactivity of N-Glutarimide
Amides in the Ni-Mediated C−N Bond Activation. To
understand the origins of the exceptional reactivity of N-
glutarimide amides in the Ni-mediated C−N bond cleavage, we
compared the N-glutarimide amide 14 to the N-Bn-N-Boc
benzamide 16 and the N-Me-N-Ph benzamide 21, which
represents three typical types of amides that are generally
employed in the Ni-catalyzed cross couplings.1 The free energy
changes of the Ni/PCy3-mediated C−N bond activation of the
three amides are included in Figure 2. The overall C−N bond
activation barrier of 14 is only 9.6 kcal·mol−1, while those of 16
and 21 are more than 6.0 kcal·mol−1 higher. In addition, the
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oxidative addition with 14 is significantly more exergonic than
the other two amides. Both the kinetics and thermodynamics
highlight the distinctive reactivities of the N-glutarimide amides.
We also compared the C−N bond activation of the N-
glutarimide amide 14 to that of the corresponding N-
succinimide amide, and this N-succinimide amide has a C−N
bond activation barrier of 13.0 kcal/mol (Figure S3). These
computed barriers of amide C−N bond activation agree well
with the observed reactivities of amides in Ni/PCy3-catalyzed
Suzuki-Miyaura coupling under the same conditions (Scheme
3).3a
The thermodynamics of the oxidative addition depends
highly on the coordinating N-substituents of amide. The
carbonyl group of 14 provides an additional strong Ni−O
interaction in the postoxidative addition intermediate 4, which
stabilizes this intermediate and makes the corresponding C−N
cleavages exergonic. For the Boc-activated amide 16, similar
Ni−O interaction exists in the intermediate 20, leading to the
exergonic oxidative addition. While for the anilide 21, no such
Ni−O interaction exists in tricoordinated nickel intermediate
20, and thus the oxidative addition is endergonic by 5.7 kcal·
mol−1.
To elucidate the effects on the kinetic barriers of C−N bond
activation, we decomposed the overall barrier to two parts: the
free energy of isomerization from the most stable nickel−amide
complex to the preoxidative addition intermediate (e.g., 1 to 2,
labeled in green, Figure 3), and the intrinsic barrier of oxidative
addition from the preoxidative addition intermediate to the C−
N cleavage transition state (e.g., 2 to TS3, labeled in yellow,
Figure 3). These comparisons reveal two crucial factors that
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Figure 2. DFT-computed free energy changes of Ni/PCy3-mediated C−N activation of three typical types of amides. Free energies are in kcal·mol−1.
Scheme 3. Comparisons of the Amide Reactivities in Ni/
PCy3-Catalyzed Suzuki-Miyaura Coupling3a
Figure 3. Components of the overall Ni/PCy3-mediated C−N bond
activation barriers of the three amides.
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contribute to the exceptional C−N bond activation reactivities
of N-glutarimide amides: the twisting C−N bond and the
coordinating N-substituents.
The comparisons between the N-glutarimide amide 14 and
the Boc-activated amide 16 suggest that the geometric twisting
can dramatically lower the intrinsic barrier of C−N cleavage.
Both 14 and 16 have a similar free energy of isomerization (1.9
and 3.8 kcal·mol−1, Figure 3) because both the corresponding
preoxidative addition intermediates (2 and 18) have similar
stabilizing nickel−oxygen (carbonyl) interactions. These
carbonyl substituents, glutarimidyl group of 14 and Boc
group of 16, essentially act as directing groups to facilitate
the generation of the reactive intermediates 2 and 18. While
both the amides 14 and 16 contain the directing carbonyl
groups, the cleaving C−N bond of N-glutarimide amide 14 is
intrinsically weaker than that of N-Boc amide 16. The
geometric twisting of 14 removes the nN−π*(acyl) resonance
of the amide C−N bond, making it a single C(acyl)−N bond.
This mitigates the energy penalty to distort the corresponding
C−N bond in TS19, leading to the significantly lower intrinsic
C−N cleavage barrier (7.7 kcal·mol−1 of 14 vs 13.1 kcal·mol−1
of 16). The results of distortion/interaction analysis24,25 on
TS3 and TS19 are included in the Supporting Information
(Figures S4 and S5).
In addition, the comparison between 14 and 21 highlights
the importance of coordinating leaving group for the formation
of preoxidative addition intermediates. The glutarimidyl group
of N-glutarimide amides provides the nickel−oxygen inter-
action that stabilizes the preoxidative addition intermediate 2.
In contrast, such directing effect is not present in the N-methyl-
N-phenylbenzamide 21, and the intermediate 23 has the amide
C−N bond coordinating to nickel. This weak coordination
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Figure 4. DFT-computed structures, free energies, and distortion/interaction analysis of the competing transition states of the Ni/PCy3-mediated
bond activations of the N-glutarimide amide 14. Energies are in kcal·mol−1.

Figure 5. DFT-computed free energy changes of the competing pathways for the ketone formation and biaryl formation from resting state 6.

destabilizes 23 and leads to the high isomerization energy from
22 to 23, eventually increasing the overall C−N bond activation
barrier.
Origins of Chemoselectivity of Bond Activations. We
next explored the origins of chemoselectivity of the Ni/PCy3-
mediated bond activations of N-glutarimide amide 14. The
optimized structures and free energies of the competing bond
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activation transition states are shown in Figure 4. The cleavage
of the twisted amide C−N bond via TS3 requires a barrier of
only 9.6 kcal·mol−1, while the C−N bond of the glutarimidyl
group requires a 17.2 kcal·mol−1 barrier for cleavage via TS26,
and the barrier of the C(aryl)−C(carbonyl) bond activation via
TS28 is 23.0 kcal·mol−1. Therefore, there is a strong
chemoselectivity toward the cleavage of the desired amide
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C−N bond, which is consistent with the experimental
observations that only this amide C−N bond was cleaved.3a
In addition, the high cleavage barriers for the C−C and C−N
bonds of the glutarimide group (via TS26 and TS28) highlight
the inert nature of this substituent, and the stability of N-
substituents is critical in achieving the high reactivity of the
desired C−N bond activation.
To understand the origins of this chemoselectivity, the
distortion/interaction analysis was applied on the competing
transition states (Figure 4). Comparing the two C−N bond
activation transition states, TS3 and TS26, the difference of
ΔEint is the leading cause for the chemoselectivity. ΔEint(TS3)
is −44.6 kcal·mol−1 while the ΔEint(TS26) is −18.6 kcal·mol−1.
This is due to the lack of nickel−oxygen interaction in TS26,
which again highlights the importance of the directing effect of
the glutarimidyl group. Comparing the C−N and C−C bond
activation transition states, TS3 and TS28, both the ΔEdist and
ΔEint disfavor the C−C bond activation transition-state TS28.
The ΔEint favors TS3 because of the favorable nickel−oxygen
interaction in this transition state. In addition, the C−N bond
of N-glutarimide amide 14 is essentially a single C(acyl)−N
bond due to the geometric twisting,26 which is much weaker as
compared to the C(aryl)−C(carbonyl) bond. The stretch of
the strong C−C bond leads to the large ΔEdist for TS28,
contributing to the high barrier of corresponding C−C bond
activation.
Origins of the Chemoselectivity of Decarbonylation
versus Carbonyl Retention. To understand the control of
the competition between decarbonylation and carbonyl
retention, we studied the free energy changes of the formations
of ketone and biaryl products from the resting state 6 (Figure
5). The formation of the biaryl product (blue pathway) has
been discussed above, and the reductive elimination via TS13 is
the rate-limiting step of this pathway. Alternatively, the
PCy3Ni(acyl)(aryl) intermediate 9 can undergo a direct
C(aryl)−C(acyl) reductive elimination via TS30 to generate
the ketone product 31 (red pathway). The formation of ketone
is kinetically favorable because of the faster reductive
elimination (TS30 vs TS13), while the ketone product is
thermodynamically less stable as compared to the biaryl
product (31 vs 15). In addition, it is noteworthy that the
ketone product 31 is less stable than the resting state of the
catalytic cycle 6. Therefore, lowering the reaction temperature
cannot allow the substantial formation of ketone product
because of the equilibrium between 31 and 6, which is
consistent with the experimental results.3a Only when the
reaction condition is sufficient enough to overcome the high
kinetic barrier for the biaryl formation (27.2 kcal·mol−1, 6 to
TS13), the irreversible C(aryl)−C(aryl) does reductive
elimination occur to produce the observed biaryl product.
This mechanistic rationale is supported by several related
experimental observations.3b,27 Since ketone is the kinetic
product, if a Ni-catalyzed cross coupling with N-glutarimide
amides can occur under mild conditions, the ketone formation
should be observed instead of the biaryl formation. Indeed,
Szostak and co-workers showed that the Ni-catalyzed Negishi
coupling with the same N-glutarimide amides can occur under
mild conditions, and this reaction produces the ketone
products3b (Scheme 4a). More importantly, our computations
essentially reveal a background reaction in which the nickel
catalyst promotes the decarbonylation of biaryl ketones to
generate biaryls (from 31 to 15) through an unexpected
C(aryl)−C(acyl) bond activation of ketone (via TS30). These
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Scheme 4. (a) Experimental Results That Support the
Formation of Ketone Product in Ni-Catalyzed Cross
Coupling with N-Glutarimide Amides;3b (b) Ni-Mediated
Decarbonylation of Aryl Ketone27
predictions are validated by Chatani’s recent breakthroughs on
the Ni-catalyzed decarbonylation of biaryl ketones27 (Scheme
4b). A Ni-mediated C(aryl)−C(acyl) bond activation
occurred,28 and subsequent decarbonylation and reductive
elimination produced the decarbonylated biaryl products. The
additional calculations with the experimental NHC ligand,
IMesMe, also showed a surmountable barrier for the decarbon-
ylation of phenyl naphthyl ketone (27.3 kcal/mol, Figure S6),
which provides direct comparisons to the reported exper-
imental results.27
In addition, Szostak’s experimental studies showed that the
Ni/PCy3-catalyzed decarbonylative Suzuki-Miyaura coupling
with N-glutarimide amides can tolerate acetyl group.3a These
results suggest that the alkyl aryl ketones are significantly less
reactive toward the proposed Ni-catalyzed decarbonylation as
compared to the biaryl ketones. To further validate the
hypothesized in situ decarbonylation, we studied the Ni/PCy3-
mediated decarbonylation of methyl naphthyl ketone, and
compared the results with those of phenyl naphthyl ketone
(Scheme 5). The overall barrier with phenyl naphthyl ketone is
5.8 kcal·mol−1 lower than that with methyl naphthyl ketone
(26.6 vs 32.4 kcal·mol−1), which is consistent with the fact that
acetyl group is tolerated in this reaction.3a
The increment of overall decarbonylation barrier with methyl
naphthyl ketone is mainly contributed by the substituent effects
on the C−C bond activation and reductive elimination. The
C−C bond activation is 13.8 kcal·mol−1 endergonic with phenyl
naphthyl ketone (31 to 9), while that with methyl naphthyl
ketone is endergonic by 17.1 kcal·mol−1 (32 to 34). This is due
to the change of dNi-π*acyl interaction in the LNi(acyl)(aryl)
intermediates (9 and 34); the benzoyl group of 9 is a stronger π
acceptor than the acetyl group of 34, which stabilizes the
intermediate 9 through the favorable dNi-π*acyl interaction.23c In
addition, the reaction with methyl naphthyl ketone requires the
C(sp3)−C(sp2) reductive elimination via TS37, which is
intrinsically more difficult compared with the C(sp2)−C(sp2)
reductive elimination via TS13.29 Therefore, the decarbon-
ylation reactivity of alkyl aryl ketones is significantly lower than
that of biaryl ketones.
■
CONCLUSIONS
In summary, the reactivities and selectivities of N-glutarimide
amides in Ni-catalyzed Suzuki-Miyaura coupling have been
elucidated with DFT calculations. Two critical factors lead to
the unusually high reactivity of N-glutarimide amides in Ni-
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Scheme 5. DFT-Computed Free Energy Changes of the Ni/
PCy3-Mediated Decarbonylation of Phenyl Naphthyl Ketone
(a) and Methyl Naphthyl Ketone (b)
mediated C−N bond activation, the coordinating N-substitu-
ents, and the geometric twisting. The coordinating glutarimidyl
substituent acts as a directing group, which facilitates the
formation of the reactive intermediate for the C−N bond
cleavage. This nickel−oxygen(carbonyl) interaction also allows
the formation of the tetra-coordinated nickel intermediate after
the oxidative addition, resulting in the exergonic C−N bond
cleavage. In addition, the geometric twisting removes the planar
acyl−nitrogen conjugation of amide, and the twisting C−N
bond of N-glutarimide amides is essentially a single N−C(acyl)
bond.26 This lowers the energy required for the C−N bond
stretch during the oxidative addition; thus, the intrinsic barrier
of C−N bond cleavage with N-glutarimide amides is low.
For the chemoselectivity of decarbonylation, a thermody-
namic versus kinetic control of product formation was
discovered. The biaryl ketones have a lower barrier of
formation than the decarbonylated biaryl products, while the
formation of biaryl ketones is thermodynamically less favorable.
The calculations suggest that the nickel catalyst is able to
promote the decarbonylation of biaryl ketones through a
unexpected C−C bond activation pathway. This proposed
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transformation was confirmed by Chatani’s recent experimental
studies.27
■
*
ASSOCIATED CONTENT
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b09482.
Additional computational results; coordinates and
energies of DFT-computed stationary points (PDF)
■ AUTHOR INFORMATION
Corresponding Author
*hxchem@zju.edu.cn (X.H.)
ORCID
Xin Hong: 0000-0003-4717-2814
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
Financial support from Zhejiang University, the Chinese
“Thousand Youth Talents Plan”, and the “Fundamental
Research Funds for the Central Universities” is gratefully
acknowledged. Calculations were performed on the National
Supercomputing Center in Shenzhen and the high-performance
computing system at the Department of Chemistry, Zhejiang
University.
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