Experimental and Computational Development of a Conformationally Flexible Template for the meta-C-H Functionalization of Benzoic Acids

Article abstract of DOI:10.1021/jacs.7b03296

A conformationally flexible template for the meta-C-H olefination of benzoic acids was designed through both experimental and computational efforts. The newly designed template favors a silver-palladium heterodimer low barrier transition state, and demonstrates that it is feasible to lengthen templates so as to achieve meta-selectivity when the distance between the functional handle of the native substrate and target C-H bond decreases. Analysis of the ortho-, meta-, and para-C-H cleavage transition states determined that the new template conformation optimizes the interaction between the nitrile and palladium-silver dimer in the meta-transition state, enabling palladium to cleave meta-C-H bonds with moderate-to-good yields and generally high regioselectivity. Regioselectivity is governed exclusively by the template, and kinetic experiments reveal that there is a 4-fold increase in rate in the presence of monoprotected amino acid ligands. Using a Boltzmann distribution of all accessible C-H activation transition states, it is possible to computationally predict meta-selectivity in a number of investigated templates with reasonable accuracy. Structural and distortion energies reported may be used for the further development of templates for meta-C-H activation of hitherto unexplored arene substrates.

Full text of DOI:10.1021/jacs.7b03296

Article
pubs.acs.org/JACS
Experimental and Computational Development of a
Conformationally Flexible Template for the meta-C−H
Functionalization of Benzoic Acids
Lizhen Fang,†,‡,∥ Tyler G. Saint-Denis,†,∥ Buck L. H. Taylor,§,∥ Seth Ahlquist,§ Kai Hong,† SaiSai Liu,‡
LiLi Han,‡ K. N. Houk,*,§ and Jin-Quan Yu*,†
†The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
‡School of Pharmacy, Xinxiang Medical University, Xinxiang Shi, Henan Province 453003, People’s Republic of China
§Department of Chemistry and Biochemistry, The University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: A conformationally flexible template for the meta-
C−H olefination of benzoic acids was designed through both
experimental and computational efforts. The newly designed
template favors a silver−palladium heterodimer low barrier
transition state, and demonstrates that it is feasible to lengthen
templates so as to achieve meta-selectivity when the distance
between the functional handle of the native substrate and target
C−H bond decreases. Analysis of the ortho-, meta-, and para-C−
H cleavage transition states determined that the new template
conformation optimizes the interaction between the nitrile and
palladium−silver dimer in the meta-transition state, enabling palladium to cleave meta-C−H bonds with moderate-to-good yields
and generally high regioselectivity. Regioselectivity is governed exclusively by the template, and kinetic experiments reveal that
there is a 4-fold increase in rate in the presence of monoprotected amino acid ligands. Using a Boltzmann distribution of all
accessible C−H activation transition states, it is possible to computationally predict meta-selectivity in a number of investigated
templates with reasonable accuracy. Structural and distortion energies reported may be used for the further development of
templates for meta-C−H activation of hitherto unexplored arene substrates.
context, we have recently developed several U-shaped end-on
nitrile templates that can direct palladation of remote meta-C−
H bonds5 by accommodating a highly strained cyclophane-like
transition states. Our group and others have also developed
various templates to extend to other substrate classes such as
hydrocinnamic acids, phenyl acetic acids, and benzyl alcohols/
amines (Figure 1a).6 In almost all previous reports of template-
mediated meta-C−H activation, the template is an inherently
rigid amide structure connecting to a coordinating nitrile or
pyridine,7 whereas the native substrate contains a conforma-
tionally flexible alkyl chain. Further, the distance from the target
C−H bond and the functional handle (e.g., an acid, amide) of
the substrate is typically 5−6 atoms (Figure 1a), and the
distance between the target C−H bond and the installed nitrile-
coordinating moiety is typically 10−11 atoms (Figure 1a).
Herein, we report the development of a simple template that
enables the meta-olefination of benzoic acids, typified by the
following: (A) a distance from target C−H bond and functional
handle of 4 atoms (Figure 1b); (B) a distance from target C−H
bond to template nitrile of 12 atoms (Figure 1b); and (C) a
template containing a conformationally flexible alkyl chain
1. INTRODUCTION
Transition-metal-catalyzed C−H activation has been exten-
sively studied due to its potential to directly convert C−H
bonds into C−C as well as C−heteroatom bonds, and in so
doing expedite synthetic endeavors and reduce waste and cost
traditionally associated with organic synthesis.1 The ubiquity of
C−H bonds in organic substrates offers a myriad of
opportunities to modify molecular structure through tran-
sition-metal-catalyzed C−H activation; however, such oppor-
tunities depend on the development of strategies to precisely
control site-selectivity during C−H activation. Because steric
and electronic properties of multiple C−H bonds in a given
molecule are similar, the recognition of distal and geometric
relationships of a target C−H bond with respect to a functional
group has afforded a powerful means of achieving site
selectivity.2 While the use of practical directing groups has
allowed synthetic chemists to achieve functionalization of C−H
bonds that are proximate and accessible in terms of geometry,3
those C−H bonds that are six bonds away from a directing
group or geometrically inaccessible are difficult to functionalize
in a controllable manner.
To fully exploit the power of this approach, it is necessary to
systematically design templates to match different classes of
substrates and C−H bonds located at various positions.4 In this
Received: April 20, 2017
© XXXX American Chemical Society
A
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transition state. Conversely, in the meta-C−H activation of
benzylic ethers study,10b a completely different mechanism was
observed so as to rationalize our observation that no ligand is
needed for high yields and high meta-selectivity: although the
C−H activation step also proceeds by a concerted CMD
pathway and this is both rate- and regioselectivity-determining,
the lowest accessible transition state contains a heterodimeric
Pd-(μ-OAc)3Ag species in which the nitrile group coordinates
the Ag, which bridges the Pd by two acetates, placing Pd
adjacent to the meta-C−H bond, explaining the high
regioselectivity. This previous study unveiled the importance
of distortional energy of the template on the C−H activation
step and has shed some light on the necessary requirements for
meta-selectivity. Specifically, it was determined that in the meta-
C−H activation of benzylic ethers, bulky i-Bu and t-Bu
substituents at specific locations on the template were critical
for reactivity as well as meta-selectivity by enabling predis-
tortion of the template into a transition state-like conformation.
Armed with the aforementioned experimental insights and
computational insights, we endeavored to use computational
methods for the rational design of a nitrile template for meta-
C−H olefination of benzoic acid substrates and evaluate the
scope of both benzoic acid derivatives as well as olefin coupling
partners using said template (Figure 1b). Compared to the
extensive development of ortho-functionalization of benzoic
acids,11 meta-C−H olefination of benzoic acids remains an
unsolved challenge, with scarce examples appearing in the
literature.12 We previously investigated a nondirected Pd(II)-
catalyzed olefination (Fujiwara−Moritani reaction) of electron-
deficient arenes including benzoic esters13 as well as a
nondirected rhodium(II) olefination of benzoic esters, although
the former reaction requires the arene substrate to be used as
solvent and the latter reaction gave poor regioselectivity and
poor yields.14 Several other reports exist for the meta-
olefination of benzoic esters in the absence of directing
groups,14,15 although these reactions suffer from either poor
regioselectivity or require blocking at the para-position. To
date, no efficient, practical, and directed regioselective method
exists for the meta-olefination of benzoic acids. From the
perspective of synthetic applications, said reaction would be
appealing given the dearth of methodology for the production
of cinnamic acid derivatives as well as vinylarenes with carboxyl
groups at the meta-position; this motif appears in several
compounds of pharmacological interest such as carboline
derivative 1a16 and octahydrophenanthrene derivative 1b,17
which are inhibitors of cGMP-specific phosphodiesterases and
modulators of gluticosteroid receptors, respectively (Figure 1c).
This study reports the logical design, experimental
investigation, and computational evaluation of a surprisingly
flexible 2-(2-(methylamino)ethoxy)benzonitrile template (Fig-
ure 1b), which lacks the steric bulk characteristic of our
previously reported templates for meta-C−H activation. This
template is capable of effecting generally good C−H activation
with yields up to 98% and meta-regioselectivity up to 92%.
Computationally, we propose that the nitrile on the designed
template coordinates Ag, rather than Pd, and that mechanis-
tically this meta-olefination occurs through a Pd-(μ-OAc)3-Ag
heterobimetallic intermediate in which Pd is precisely poised to
activate the target meta-C−H bond. This information builds
upon our previous works and will likely alter the future design
of templates for C−H activation by shedding light on the
possibility of metallic dimers involved in the key C−H cleavage
step of these reactions.
Figure 1. Palladium-catalyzed meta-C−H olefination. (A) Previously
disclosed techniques for meta-functionalization, (B) the herein detailed
method, and (C) pharmaceutical motifs containing the target scaffold
of interest.
wherein conformational flexibility is imparted by the template
rather than the substrate. That is to say, when the distance from
the functional handle and the target C−H bond is shortened
from 6 or 5 bonds (hydrocinnamic acid and phenylacetic acid
substrates, respectively) to 4 atoms (benzoic acids), we are able
to compensate by lengthening the net distance of the template
nitrile to the target C−H bond and in so doing achieve the
same cyclophane transition state (Figure 1b).8 Strain energies
of simple cyclophanes range from about 30 kcal/mol for [2.2]-
paracyclophane to about 2 kcal/mol for [4.4]-paracyclophane
and larger;9 the distortion/strain energy of successful templates
in this study is in the same range as those of large cyclophanes
(1−2 kcal/mol). Our experimental efforts and template design
were guided by computational studies, and the mechanism for
this novel template’s high regioselectivity was evaluated by both
computational as well as kinetic studies.
Several computational studies have been performed to
elucidate the mechanism of nitrile-enabled meta-C−H
activation, and two distinct pathways have been elucidated:
Houk and Wu10 have used density functional theory to
elucidate the mechanism and origins of meta-regioselectivity in
our Pd(II)-catalyzed C−H olefinations of benzylic ethers as
well as hydrocinnamic acids employing the aforementioned
nitrile templates (Figure 1a). In the meta-selective C−H
activation of hydrocinnamic acid derivatives,10a it was
determined that the monoprotected amino acid (MPAA)
ligands act as both a dianionic bidentate ligand and a proton
acceptor; in other words, the MPAA ligand serves dual roles in
the (A) stabilization of monomeric Pd complexes and (B) the
intramolecular deprotonation of the arene substrate in the
concerted metalation-deprotonation (CMD) C−H cleavage
B
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b
Table 1. Initial Templates Designed and Evaluated for Pd(II)-Catalyzed C−H Olefination
a
b
Only monomeric olefination adduct observed. Conditions: 0.1 mmol of T, 10 mol % Pd(OAc)2, 20 mol % Ac-Gly-OH, 0.25 mmol of ethyl
acrylate, 1 mL of HFIP, 70 °C, 24 h. Yields and selectivity determined by NMR with an internal standard of CH2Br2.
a b
,
Table 2. Screening Variables in the Reaction of a Simple Benzoic Acid Derivative
entry
ligand (20 mol %)
Ac-Gly-OH
Ooxidant
Pd(OAc)2
T (°C)
yield (%)
meta/others
mono/di
1
2
3
4
5
6
7
8
AgOAc
AgOAc
10%
10%
10%
5%
70
70
70
70
60
50
40
rt
82
12
44
70
98
68
54
21
95/5
93/7
90/10
90/10
91/9
91/9
93/7
96/4
8.2/1
7.0/1
10.0/1
5.3/1
11.3/1
7.6/1
2.6/1
2.6/1
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
AgOAc
AgOAc
AgOAc
AgOAc
AaOAc
10%
10%
10%
10%
a
Conditions: 0.1 mmol of substrate, 0.25 mmol of ethyl acrylate, 0.005 or 0.01 mmol of Pd(OAc)2, 0.02 mmol of Ag-Gly-OH, 0.3 mmol of AgOAc, 1
b
1
mL of HFIP, 70 °C for 24 h. Selectivity refers to the ratio of meta:others of monoolefinated products, as determined by crude H NMR
spectroscopy.
represent more flexible template structures. T1 provided the
corresponding olefination products in 76% yield with 88%
meta-selectivity and a mono olefination/diolefination (mono:-
di) ratio of 5:1, while T2 had a lower yield of 43%, but exhibited
improved meta-selectivity (95%) and an improved mono:di
ratio. Remarkably, T3 was olefinated in 98% yield, with 91%
meta-selectivity and a mono:di ratio of 10:1, while T4 exhibited
depreciated reactivity and selectivity. These findings are
2. RESULTS AND DISCUSSION
2.1. Reaction Optimization. We began our investigations
into the meta-olefination of benzoic acids by screening template
adducts T1−T4 (Table 1), all of which are typified by a target
meta-C−H bond being 12 atoms away from the nitrile moiety,
for olefination with ethyl acrylate in the presence of Ac-Gly-OH
in the presence of silver as a terminal oxidant. T1 and T2
represent more rigid template frameworks, whereas T3 and T4
C
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a b
,
Table 3. Optimization of Reaction for Substituted Benzoic Acids
entry
ligand (20 mol %)
additive (1 equiv)
yield (%)
meta/others
1
2
Ac-Gly-OH
42
24
4
60/40
61/39
33/67
33/67
45/55
31/69
31/69
60/40
40/60
10/90
50/50
Ac-Gly-OH
NaH2PO4
NaH2PO4
Na3PO4
KHCO3
K2CO3
3
Ac-Gly-OH
4
Ac-Gly-OH
9
5
Ac-Gly-OH
23
12
11
43
18
1
6
Ac-Gly-OH
7
Ac-Gly-OH
NaOAc
NaOTs
LiOAc
8
Ac-Gly-OH
9
Ac-Gly-OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Fmoc-Gly-OH
Fmoc-t-Bu-Gly-OH
Boc-Ph-Gly-OH
Boc-cyclohexyl-Gly-OH
N-chloroacetyl-Gly-OH
Trt-Gly-OH
15
0
trace
8
30/70
0
N,N-dimethyl-Gly-OH
Ac-Ala-OH
0
53
59
38
63
43
35
91
62/38
67/33
71/39
78/32
47/53
38/62
95/5
Ac-Leu-OH
Ac-t-Leu-OH
Ac-Val-OH
Ac-Val-OH
p-TsOH
CF3CO2H
NaOTs
Ac-Val-OH
Ac-Val-OH
a
Conditions: 0.1 mmol of substrate, 0.25 mmol of ethyl acrylate, 0.01 mmol of Pd(OAc)2, 0.02 mmol of ligand, 0.3 mmol of AgOAc, 0.1 mmol of
b
additive, 1 mL of HFIP, 70 °C for 24 h. Selectivity refers to the ratio of meta:others of monoolefinated products, as determined by crude 1H NMR
spectroscopy.
intriguing, given that from the outset it was expected that rigid
frameworks (T1, especially T2, which possesses geminal
dimethyl groups and by the Thorpe−Ingold effect should
favor cyclization) would encourage formation of the necessary
cyclophane for remote Pd-catalyzed C−H cleavage. Con-
sequently, several control templates were subsequently
designed to further attempt to highlight the remarkable
reactivity and regioselectivity of T3. First, T5 lacking the nitrile
template possessed little meta-selectivity and low reactivity,
underscoring the intrinsic electronic preferences for Pd-
catalyzed olefination. Second, T6 was designed and tested
under the pretense that the presence of the N-methyl was
paramount for cyclophane formation; the reduced yield and
selectivity obtained with substitution with isopropyl lends some
support to this hypothesis.
Two other templates, T7 and T8, were evaluated, both of
which contained geminal dimethyl groups α to the amide, and
the latter contained the N-methyl present in T3; these both
exhibited poorer yields and reduced selectivities. It is worth
noting that T7 exhibited meta-selectivity close to that of T5 (i.e.,
inverted selectivity), such that comparison in the regioselectiv-
ity preferences of T7 and T5 underscores the necessity of
methyl-substitution on the amide nitrogen. Finally, the
homologated template T9 was observed to have drastically
depreciated yield as compared to T3 (i.e., 16%) with only slight
preference for meta-olefination. Subsequently, we sought to
understand the influence of temperature, AgOAc, ligand, as well
as Pd(OAc)2 loadings on the reaction of 2a containing T3
(Table 2). It is evident that removal of Ac-Gly-OH (entry 2)
dramatically reduces yields; that said, it is worth noting that the
selectivity still favors meta-olefination. Removal of AgOAc and
only allowing air to serve as the terminal oxidant only cuts the
yield in slightly more than one-half (entry 3), and decreasing
Pd(OAc)2 loadings to 5 mol % only slightly reduces the yield
(entry 4). This outcome of the reaction is sensitively dependent
on temperature (entries 5−8), but selectivity is largely
unaffected.
We next sought to evaluate the scope of this template-
assisted meta-olefination in other substrate classes. Although
the initially disclosed conditions (e.g., use of Ac-Gly-OH) gave
high yields and selectivities in the simple benzoic acid
derivative, this method was not found to be broadly applicable
to other benzoic acid derivatives such as 2b (entry 1). We
believe that the steric repulsion imparted by ortho-substitution
clashes with the requisite amide bond of our benzoic acid
substrates, thus resulting in an initially lower-yielding reaction.
However, we endeavored to screen other monoprotected
amino acids and bases, and in so doing we believed we could
optimize conditions to afford a more reactive catalyst, therefore
resulting in superior yields and higher selectivities for ortho-
substituted substrates. Consequently, we pursued further
development of conditions that are potentially compatible
with a broad range of benzoic acids (Table 3). The addition of
various bases (entries 2−9) only hampered the reaction, and
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a b
,
Table 4. Substrate Scope of the meta-Olefination of Benzoic Acids
a
Conditions: 0.1 mmol of substrate, 0.25 mmol of ethyl acrylate, 0.01 mmol of Pd(OAc)2, 0.02 mmol of Ac-Val-OH, 0.3 mmol of AgOAc, 0.1 mmol
b
1
of NaOTS, 1 mL of HFIP, 70 °C for 24 h. Selectivity refers to the ratio of meta:others of monoolefinated products, as determined by crude H
NMR spectroscopy.
switching to bulkier ligands (entries 10−16) diminished
reactivity almost entirely. Screening simple acetyl-protected
amino acids led to improved reactivity (entries 17−23), while
acid (entries 21 and 22) decreased the yield (compare to entry
20), and addition of sodium tosylate (entry 23) slightly
increased the yield, improved meta-selectivity, and provided a
larger mono/di ratio. With improved conditions in hand, we
proceeded to investigate the breadth of this reaction on various
substituted benzoic acid substrates (Table 4).
selectivity still favors meta-substitution. Substitution at the
meta-position (m′) led to decreased yields when electron-
donating groups were present as well as diminished selectivity
(3e, 3f), which can be explained by electronic biases (e.g., the
methoxy group in 3f formally directs electron density to the
ortho-position). meta′-Substitution with fluorine (3g) decreased
yield and decreased selectivity, yet meta′-substitution with
chlorine decreased yield but still led to high meta-selectivity
(3h).
The parent benzoic acid (2a) provides both mono- and
disubstituted adducts. Benzoic acids with substitution at the
ortho position react in good yields when the ortho substitution
is electron-donating (3b, 3c), and when ortho-substitution is
electron-withdrawing (3d) the yield is diminished but
para-Substitution with electron-poor and electron-donating
groups (3i and 3j, respectively) generally gave good yields and
high selectivity. The moderate yield of 3i is likely due to the
steric bulk imparted by methoxy substitution. Finally,
disubstitution at the ortho- and ortho′-positions (3k) as well
E
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a b
,
Table 5. Olefin Scope of the meta-Olefination of Benzoic Acids
a
Conditions: 0.1 mmol of substrate, 0.25 mmol of olefin, 0.01 mmol of Pd(OAc)2, 0.02 mmol of Ag-Val-OH, 0.3 mmol of AgOAc, 0.1 mmol of
b
NaOTs, 1 mL of HFIP, 70 °C for 24 h. Selectivity refers to the ratio of meta:others of monoolefinated products, as determined by crude 1H NMR
spectroscopy; yields were calculated using an internal standard for CH2Br2.
a
Table 6. C−H Activation Transition States for Optimal Template T3
a
Note that artistic rendering of the template structure has been simplified.
as the ortho′- and meta′- (3l and 3m) and the meta′- and para-
positions (3n) all gave moderate-to-good yields as well as high
meta-selectivity. The scope of olefin coupling partners was also
briefly examined (Table 5). Olefins including α,β-unsaturated
ketones, aldehydes, alkyl and benzylic esters, amides, as well as
phosphonates were all competent olefins (4a−4f). Unfortu-
nately, and consistent with past findings, simple alkyl olefins are
unreactive. Further, although products 4e and 4f were
produced in lower yields, high meta-selectivity was still
observed. It is worth noting that the template is also easily
removable (see the Supporting Information).
flexibility, due to the presence of two contiguous methylene
carbons as well as a phenolic ether oxygen, would presumably
result in enhanced degrees of freedom of conformational states
through rotation, and thus diminish selectivity. Indeed,
increasing the number of methylene carbons in templates,
such as is the case of the homologous template T9, dramatically
decreases yield as well as meta-selectivity.
Perplexed by the reactivity and, more importantly, selectivity
of the simplest template investigated, T3, we investigated these
reactions computationally. We began by first identifying
possible transition states of the C−H cleavage of the simple
benzoic acid with T3 (Table 6) and determining their
preferences for ortho-, meta-, as well as para-selectivity. Initially,
we expected that the active catalyst would be monomeric
palladium ligated by a dianionic N-acetylglycine ligand (Pd−
2.2. Computational Elucidation of meta-Selectivity.
Given the lack of geminal disubstitution or rigidity in T3, it was
imagined from the outset that this template would be relatively
flexible as compared to other investigated templates. Such
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Figure 2. Comparison of the lowest energy conformation of template T3 with the favored transition state.
Table 7. Comparison of Computed and Experimental Regioselectivity of Template Derivatives
Gly), because reaction conditions are similar to our previous
studies10a and because removal of ligand dramatically decreases
the yield of the reaction, as stated earlier. That said, calculations
indicate that the para-olefination adduct should be favored
under this mechanism with a barrier of 24.7 kcal/mol for para-
C−H cleavage, while meta-C−H cleavage has a barrier of 26.1
kcal/mol. Consequently, we sought to evaluate other possible
transition states, including a palladium−silver heterodimer, a
palladium−palladium dimer in the absence of a ligated N-
acetyl−glycine (Pd−Ag and Pd−Pd, respectively), as well as a
transition state characterized by monomeric palladium in the
absence of N-acetyl−glycine (Pd). Intriguingly, meta-selective
C−H activation for the Pd−Ag transition state had the lowest
barrier (23.2 kcal/mol) as compared to all other transition
states evaluated. The meta-olefination product is also favored by
G
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Figure 3. Rate comparison of meta-C−H olefination with and without Ac-Gly-OH ligands. Data points represent the average of two independent
●
trials’ NMR yields, calculated using an internal standard of CH2Br2 (X,Y = time point, yield). Red represent reaction in the presence of Ac-Gly-
■
OH ligand, while represent reaction in the absence of any ligand. Rate comparison was made by dividing initial rate (i.e., slope of the plots).
Conditions: 0.1 mmol of substrate, 15 mol % Pd(OAc)2, 30 mol % Ac-Gly-OH, 0.3 equiv of AgOAc, 0.25 equiv of ethyl acrylate, 1 mL of HFIP, 70
°C, variable time.
the palladium homodimer mechanism, Pd−Pd, but this is
higher in energy as compared to the Pd−Ag mechanism.
Theoretical regioselectivities were next computed using a
Boltzmann distribution of all low-energy transition-state
conformations. Because of the flexible nature of the template,
a large number of conformations were located for each
transition state, many of which were within 3 kcal/mol of the
global minimum, thus contributing to product formation. When
the favored Pd−Ag mechanism is considered in isolation, it is
predicted that the transition state favors meta-selectivity by
98%, an overestimation as compared to the experimentally
observed meta-olefination of T3 (91%). However, because the
monomeric Pd−Gly mechanism is only 1.5 kcal/mol higher in
energy, some of the minor regioisomers could result from the
Pd−Gly mechanism. When low-energy conformations for both
mechanisms are factored into the Boltzmann distribution, the
computationally predicted regioselectivity drops to 94% meta-
selective C−H activation, which is in excellent agreement with
the experimental observations of 91%. It is important to note
that there will be significantly greater error in comparing the
free energies of monomeric, dimeric, and heterodimeric
transition states (perhaps 2−3 kcal/mol),18 than comparing
regioisomeric transition states of one type, such that the
agreement may be in part serendipitous. Nevertheless, the
calculations suggest a delicate balance between monomeric and
heterodimeric mechanisms.
gauche-type conformation (Figure 2). This geometry is
maintained in the meta-transition state, Pd−Ag, resulting in a
low template distortion energy (ΔE⧧template distortion) of 1.4 kcal/
mol. This is the energy required to distort the template into the
transition-state geometry without distorting the target C−H
bond. In contrast, greater conformational changes are necessary
in the ortho- and para-transition states, with distortion energies
of 3.3 and 4.8 kcal/mol, respectively. The interaction between
the catalyst and the template is also strongest in the meta-
transition state, because this template conformation allows the
optimal interaction between the nitrile and the silver atom.19
Because structural factors are clearly paramount in the
regioselectivity imparted by templates, several templates we
evaluated experimentally in Table 1 were subsequently studied
with computation to gain insight into the specific structural
features that favor meta-selectivity. In particular, we sought to
understand why the homologated template T9 and the ester
template T4 afforded product distributions with decreased
meta-selectivity. Adopting the analysis used in Table 6, both
Pd−Gly and Pd−Ag mechanisms were modeled for each
template of interest, and selectivities were computed using the
aforementioned Boltzmann distribution analysis. Interestingly,
our calculations show that the computed selectivity of the Pd−
Gly monomer pathway varies drastically depending on the
template structure (see entries 1−7, Table 7). The disagree-
ment of these computed selectivity with our experimental
observations suggests that the Pd−Gly monomer is unlikely to
be operative. Remarkably, when the Pd−Ag mechanism is
modeled for each template, meta-selectivity is consistently
We next sought to understand the meta-selectivity for the
Pd−Ag mechanism in greater detail. The lowest energy
conformation of T3 places the amide and aryloxy groups in a
H
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Figure 4. Kinetic isotope investigations in the presence of MPAA ligand Ac-Gly-OH. Data points represent the average of two independent trials’
■
●
NMR yields, calculated using an internal standard of CH2Br2 (X,Y = time point, yield). Red
represent protiated substrate, and
represent
deuterated substrate. Kinetic isotope effect (KIE = kH/kD) determined by dividing the slope of the initial rate of the reaction of 2e by the slope of the
initial rate of the reaction of 5. Conditions: 0.1 mmol of substrate, 15 mol % Pd(OAc)2, 30 mol % Ac-Gly-OH, 0.3 equiv of AgOAc, 0.25 equiv of
ethyl acrylate, 1 mL of HFIP, 70 °C, variable time.
favored, particularly for the most selective template (entries 1−
4), lending additional support for this mechanism.
low-energy conformations for both Pd−Ag and Pd−Gly
mechanisms are factored into the Boltzmann distribution to
compute combined selectivity, lower meta-selectivity is
predicted as compared to the Pd−Ag mechanism alone, in
accordance with experimental observation. This analysis
highlights the need to consider all feasible mechanisms when
attempting to predict or rationalize regioselectivities computa-
tionally.
Secondary amide template T7 (entry 7) also provides poor
selectivity experimentally. It was determined that for this
template the Pd−Gly mechanism is not favorable (ΔG⧧ = 27.9
kcal/mol favoring 99% ortho selectivity), but the Pd−Ag
mechanism (ΔG⧧ = 24.0 kcal/mol) is favored and predicts
meta-selectivity in 81%. This is inconsistent with the
experimental observation of 36% meta-selectivity; this incon-
sistency may be rationalized by the fact that computation
predicts that the secondary amide can act as a competing
directing group, leading to a higher level of ortho-product (see
the Supporting Information for a discussion of these transition
states).20 This competing directing group effect of the
secondary amide is further supported by the experimental
While the heterodimer mechanism Pd−Ag predicts the
correct regioisomer, the level of selectivity is typically
overestimated. This is especially problematic for poorer
templates, such as T4 and T9 (entries 5 and 6, respectively):
experimentally T4 gives a low meta:others regioselectivity of
47:53 (negligible regioselectivity), but the regioselectivity
predicted by the Pd−Ag mechanism is 85% meta-product; T9
gives a meta:others regioselectivity of 63:37, but the predicted
regioselectivity is 71% meta-product. Despite these seemingly
incongruent predictions, when the same Boltzmann distribution
analysis of all conformations of the two competing transition
states Pd−Gly and Pd−Ag is taken into account in computa-
tional prediction, it is possible to make fairly accurate
predictions on meta-selectivity.
This appears to be especially true for templates T4 and T9, in
which the barrier for the Pd−Gly monomer mechanism is
within 1 kcal/mol of the favored Pd−Ag mechanism. For
example, for T9, computation predicts 62% meta-selectivity, and
experimental observation affords 63% meta-selectivity. When all
I
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a
Scheme 1. Attempted meta-Olefination on a Deuterated Benzoic Acid Substrate
a
Conditions: 0.1 mmol of 5, 15 mol % Pd(OAc)2, 30 mol % Ac-Gly-OH, 0.3 equiv of AgOAc, 0.25 equiv of ethyl acrylate, 1 mL of HFIP, 70 °C,
variable time.
observation that T8, the N-methylated derivative of T7, affords
86% meta-selectivity (Table 1); in the absence of a competitive
coordinating group, the nitrile exclusively is responsible for
regioselectivity of the products.
of ligand or if it was equal to unity then ligand is not involved in
the turnover-limiting step, and (B) if the KIE in the absence of
ligand was dramatically greater than that in the presence of
ligand then ligand would necessarily be involved in the
turnover-limiting scenario. Upon attempting to carry out
further kinetic studies, we noticed that the deuterated substrate
5 did not react in the absence of ligand within 2 h, suggesting a
significant KIE, much greater than 1 (kH/kD ≫ 1), but one
whose magnitude could not be determined within the error of
the NMR measurement (Scheme 1). Overall, these two KIE
experiments in tandem suggest that the C−H activation step is
either turnover-limiting or at least contributes to the turnover
frequency. This information combined with the observed ligand
acceleration in Figure 3 suggests that ligand is therefore
involved in the turnover-limiting step or at least contributes to
turnover frequency.
2.4. Rationalization of Kinetic Data with Further
Computation: Development of a Proposed Reaction
Coordinate. Placed in a mechanistic quandary, in which
experimental and initial calculations seemed dissonant, we
continued computational studies to determine a mechanistic
model that accounts for the meta-selectivity and enhanced rate
in the presence of ligand. While the monomeric palladium
glycinate mechanism Pd−Gly would account for the ligand
acceleration, it predicts para-selectivity (ΔΔG⧧ = 1.4 kcal/mol)
(Table 6). Calculations show that a Pd−Ag heterodimer
mechanism is lower in energy and favors the observed meta-
product (ΔΔG⧧ = 2.3 kcal/mol). Again, this mechanism does
not account for the increased rate in the presence of ligand.
Therefore, we investigated the related mechanism Pd−Ag-2 in
which one of the acetates of the Pd−Ag heterodimer is replaced
by the carboxylate of the N-acetyl−glycine (Figure 5). As
expected, the barrier and selectivity for this mechanism are
unchanged (compare Pd−Ag-2 with Pd−Ag). While mecha-
nism Pd−Ag-2 is feasible, the C−H activation step alone does
not account for the kinetic data.
2.3. Kinetic Studies on the Influence of Ligand. As our
investigation into the mechanism of meta-selective C−H
activation of benzoic acids progressed, one major issue
emerged: while experimental studies absolutely required
MPAA ligand for the reaction to give high yields (Table 2,
entry 2), computation suggested MPAA ligand was not
involved in the C−H cleavage step as a predominant pathway
(instead Pd−Ag dimer is the major pathway).20 We were
curious to determine if the dramatic difference of yield in the
presence of ligand (compare 82% with 12%, entries 1 and 2 of
Table 2, respectively) was due to improved catalyst lifetime or
increased initial reaction rate.21 Monitoring the reaction by
NMR (Supporting Information) over 8 h showed that initial
rate could be measured in the first 2 h of the reaction. Using the
C−H olefination of the 3-methyl benzoic acid derivative, 2e, in
the presence and absence of N-acetyl−glycine, we ran parallel
reactions, quenching them at specified intervals, and
1
determined the conversion by H NMR spectroscopy of the
crude reaction product using a CH2Br2 internal standard
(Figure 3).
Our experiment deviated slightly from the standard
conditions in that 15 mol % Pd(OAc)2 and 30 mol % Ac-
Gly-OH ligand were used as it was anticipated that the reaction
would be low yielding due to poor turnovers in the ligandless
scenario (expected yield after 24 h = 12%). It is evident from
the plots in Figure 3 that ligand has a pronounced effect on the
initial rate of the reaction: under the present conditions, we
observed a 4.25-fold rate increase for reactions with Ac-Gly-OH
as compared to those without this ligand (from 3.6 × 10−3 to
1.53 × 10−2 M/min). This finding is in accordance with our
previously observed ligand acceleration in the meta-C−H
olefination of arenes.21
Because it was clear from initial rate studies that ligand
positively influences the initial rate of meta-C−H olefination
and this was inconsistent with the preferred computational
transition states and to gain more comprehensive mechanistic
data, we next sought to determine if C−H cleavage was in fact
rate-determining. Thus, the labeled m-toluic-d7 acid-derived
template 5 was prepared (see the Supporting Information), and
the initial rate of the unlabeled substrate 2e and the labeled
substrate 5 (Figure 4) was measured by performing parallel
reactions. The KIE (kH/kD) of 1.4 suggests that C−H activation
is not turnover limiting.22 On the other hand, the small but
measurable KIE is de facto greater than that of unity and eludes
some effect of C−H cleavage on the turnover-limiting step. We
next attempted to measure KIE in the ligandless scenario to
effectively determine if ligand is involved in the turnover-
limiting step. We hypothesized two different scenarios: (A) if
the KIE in the absence of ligand matched that in the presence
We next considered that the ligand could influence formation
of the active catalyst or substrate binding. In the absence of
Figure 5. Transition states Pd−Gly and Pd−Ag for meta-C−H
activation.
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ligand, the most stable heterodimeric catalyst is 7a (Figure 6),
which is 14 kcal/mol less stable than the precatalysts
of transition states 8a and 8b must be acknowledged,
stabilization of the active Pd−Ag catalyst and acceleration of
the substrate-binding step are consistent with the faster reaction
in the presence of MPAA ligand.
3. CONCLUSION
We have developed a method for the meta-olefination of
benzoic acid derivatives by the design and optimization of a
unique and curiously flexible template structure. This reaction
requires MPAA ligands and silver, which offer dramatic
improvements in yield. For simple substrates, yields are very
high (>90%) as is meta-selectivity (>90%) when Ac-Gly-OH is
used. Substitution on the benzoic acid arene ring necessitates
the use of different reaction conditions, which still favor meta-
selectivity but afford the corresponding adducts in moderate-
good yields. Computational investigations have elucidated the
(A) preferred transition state for C−H activation and (B)
conformational requirements of the ideal template structure,
one that does not significantly perturb the organization of a
Pd−Ag heterodimer. Kinetic studies demonstrated the depend-
ence of initial rate on Ac-Gly-OH, and studies on the KIE
coupled with this information undeniably show that C−H
activation is turnover-limiting and that Ac-Gly-OH is
demonstrably involved in the turnover-limiting step. Finally,
we have computed a free energy profile that shows that MPAA
stabilizes the Pd−Ag heterodimer prior to C−H activation and
lowers the barrier to coordination to the nitrile of the template.
Efforts are currently underway in our laboratory to devise
similarly flexible and easy-to-make templates analogous to T3
for meta-selective C−H activation of other arene classes, and
collaborative efforts between our groups are devoted to the
design and implementation of template-approaches for para-
C−H activation of arenes as well as other remote C−H
activation reactions. This study, especially the structural and
Figure 6. Heterodimer catalyst stabilization by N-acetyl−glycine.
Pd3(OAc)6 and Ag2(OAc)4 (the reference state in these
calculations). Ligand exchange of the κ2-acetate with N-
acetyl−glycine gives the more stable heterodimer 7b. Other
configurations of N-acetyl−glycine were studied, but the most
stable structure features bidentate coordination to palladium via
the imidic acid tautomer of N-acetylglycinate, which may act as
a hemilabile ligand leading to transition state Pd−Ag-2.
Substrate binding and C−H activation steps were next modeled
for both active catalysts 7a and 7b in a reaction coordinate
scheme (Figure 7). The substrate-binding step involves
coordination of the nitrile to silver via transition state 8a/8b.
Because ligand-binding transition states are notoriously difficult
to locate computationally, the barrier for this step was
approximated from scans of the potential energy surface. As
shown in Figure 7, the MPAA ligand stabilizes the Pd−Ag
complexes (7b and 9b) and also lowers the overall barrier for
formation of 10b, the critical intermediate in C−H activation.
In the absence of MPAA ligand, the rate-determining step is
formation of this intermediate, but the MPAA ligand facilitates
formation of 10b, and the rate-determining transition state
becomes C−H activation 11b. While uncertainty in the energy
Figure 7. Free energy profile for substrate binding and C−H activation.
K
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distortion analyses as well as the dialogue between synthetic
and computational chemistry groups, may be used to inspire
the development of novel templates for remote C−H
activation.
Kai Hong: 0000-0001-7341-4931
K. N. Houk: 0000-0002-8387-5261
Jin-Quan Yu: 0000-0003-3560-5774
Author Contributions
∥L.F., T.G.S.-D., and B.L.H.T. contributed equally.
4. METHODS
Notes
4.1. Computational Details. DFT calculations were performed
with Gaussian 09.23 Geometries were optimized with the ωB97X-D
functional24 in the gas phase. A mixed basis set of LANL2DZ(f) for Pd
and Ag with 6-31G(d) for all other atoms was used in geometry
optimizations. The LANL2DZ basis set was supplemented with an f-
type polarization function (exponent 1.472 for Pd, 1.611 for Ag).25
Thermal corrections were calculated from unscaled vibrational
frequencies at the same level of theory using a standard state26 of 1
mol/L and 343 K. Entropies were corrected for the breakdown of the
harmonic oscillator approximation at low frequencies by raising all
harmonic frequencies below 100 cm−1 to 100 cm−1.27 Electronic
energies were obtained from single-point energy calculations
performed with the M06 functional28 and a mixed basis set of SDD
for Pd and Ag with 6-311++G(d,p) for all other atoms. Although the
experiments are conducted in hexfluoroisopropanol, this solvent is not
available in Gaussian 09. Instead, the SMD29 solvation model for 2,2,2-
trifluoroethanol was used in M06 single-point energy calculations.
Computed structures are illustrated using CYLView.30
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Scripps Research Institute and
the U.S. NSF (CHE-1011898) as well as the NSF Center for
Selective C−H Activation (NSF CCHF) for financial support.
We thank the NSF and TSRI for financial support of T.G.S.-D.
B.L.H.T. gratefully acknowledges the National Institutes of
Health for a postdoctoral fellowship (F32GM106596).
Computational resources were provided by the UCLA Institute
for Digital Research and Education (IDRE) and the Extreme
Science and Engineering Discovery Environment (XSEDE),
which is supported by the NSF. L.F., S.S.L., and L.H. were
supported by the National Natural Science Foundation of
China (81172952).
4.2. Experimental Details: General Procedure. A 5 mL vial
equipped with a stir bar was charged with benzoic acid substrate (0.1
mmol), Pd(OAc)2 (0.01 mmol, 10 mol %), Ac-Val-OH (0.02 mmol,
20 mol %), AgOAc (0.3 mmol), and NaOTs (0.1 mmol), olefin of
interest (0.25 mmol), and HFIP (1 mL) at room temperature. The vial
was capped with a septum insert, stirred vigorously at 70 °C for 24 h,
then cooled to room temperature and diluted with EtOAc. The
resultant mixture was then filtered through a plug of Celite and further
washed with EtOAc. Purification was performed by silica gel-packed
flash column chromatography or by preparative TLC using eluents of
hexanes/EtOAc or DCM/EtOAc to afford products with the indicated
yield.
4.3. Rate and KIE Investigations. A 5 mL vial equipped with a
stir bar was charged with 2e or 5 (0.1 mmol), Pd(OAc)2 (0.015 mmol,
15 mol %), AgOAc (0.3 mmol), ethyl acrylate (0.25 mmol), and HFIP
(1 mL) in both the presence and the absence of ligand Ac-Gly-OH
(0.03 mmol, 30 mol %). The vial was capped with a septum insert,
stirred vigorously at 70 °C for variable time, then cooled to room
temperature, diluted with EtOAc, filtered through a plug of Celite,
evaporated, and NMR yields of products of the reaction of 2e or 5 (3e
and 6, respectively) were measured with an internal standard of
CH2Br2 (0.1 mmol). All points plotted represent the average of two
experiments performed separately. Rate constants were determined by
multiplication of the slope of the initial rate (occurring in the first 2 h)
by molar concentration. Kinetic isotope effect values, reported as kH/
kD, are reported as the division of the slope of the initial rate for
protiated substrate 2e divided by the slope of the initial rate for
deuterated substrate 5.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b03296.
■
S
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AUTHOR INFORMATION
■
Corresponding Authors
*houk@chem.ucla.edu
*yu200@scripps.edu
ORCID
Lizhen Fang: 0000-0001-8594-4710
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