Insights into directing group ability in palladium-catalyzed C-H bond functionalization

Article abstract of DOI:10.1021/ja8045519

This paper describes a detailed investigation of factors controlling the dominance of a directing group in Pd-catalyzed ligand-directed arene acetoxylation. Mechanistic studies, involving reaction kinetics, Hammett analysis, kinetic isotope effect experiments, and the kinetic order in oxidant, have been conducted for a series of different substrates. Initial rates studies of substrates bearing different directing groups showed that these transformations are accelerated by the use of electron-withdrawing directing groups. However, in contrast, under conditions where two directing groups are in competition with one another in the same reaction flask, substrates with electron-donating directing groups react preferentially. These results are discussed in the context of the proposed mechanism for Pd-catalyzed arene acetoxylation.

Full text of DOI:10.1021/ja8045519

Published on Web 09/10/2008
Insights into Directing Group Ability in Palladium-Catalyzed
C-H Bond Functionalization
Lopa V. Desai, Kara J. Stowers, and Melanie S. Sanford*
Chemistry Department, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan 48109
Received April 5, 2008; E-mail: mssanfor@umich.edu
Abstract: This paper describes a detailed investigation of factors controlling the dominance of a directing
group in Pd-catalyzed ligand-directed arene acetoxylation. Mechanistic studies, involving reaction kinetics,
Hammett analysis, kinetic isotope effect experiments, and the kinetic order in oxidant, have been conducted
for a series of different substrates. Initial rates studies of substrates bearing different directing groups showed
that these transformations are accelerated by the use of electron-withdrawing directing groups. However,
in contrast, under conditions where two directing groups are in competition with one another in the same
reaction flask, substrates with electron-donating directing groups react preferentially. These results are
discussed in the context of the proposed mechanism for Pd-catalyzed arene acetoxylation.
Introduction
Palladium-catalyzed ligand-directed C-H bond functional-
ization has emerged as a powerful method for the direct
conversion of arenes and alkanes into new products.1-3 These
reactions allow for the highly site-selective transformation of a
C-H bond proximal to a coordinating functional group (L in
Scheme 1) into a new C-X bond (X ) O, Cl, Br, I, F, C, or
N). Importantly, most natural products, pharmaceuticals, and
agrochemicals contain suitable directing groups for this chem-
istry. As such, these transformations could be valuable for late-
stage derivatization and analogue generation in such important
classes of molecules.
Scheme 1. Palladium-Catalyzed Chelate-Directed C-H Bond
Functionalization
Figure 1. Examples of biologically active molecules containing multiple
potential directing groups.
The vast majority of Pd-catalyzed directed C-H function-
alization reactions in the literature involve simple organic
compounds containing a single directing group (Scheme 1).1-3
However, many molecules of interest have not just one but
multiple basic functional groups that could bind to a Pd center
and direct C-H bond functionalization (for three representative
examples, see Figure 1).4 As such, the development of selective,
efficient, and high-yielding transformations is predicated on a
clear understanding of the factors governing product distribu-
tions when multiple directing groups are present simultaneously.
This report describes a detailed investigation of Pd-catalyzed
directed arene acetoxylation as a function of directing group
electronics and structure. The implications of these results for
both the mechanism and the synthetic application of this
chemistry are discussed.
Pd-catalyzed C-H bond acetoxylation with PhI(OAc)2. As shown
in Scheme 2, we designed a series of experiments to compete two
directing groups against one another in the same reaction flask
(mimicking situations where two potential ligands are present
within the same molecule). In these systems, 1 equiv of substrate
I and 1 equiv of substrate II were subjected to Pd-catalyzed reaction
(1) (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904.
(b) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 14047. (c) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am.
Chem. Soc. 2006, 128, 7134. (d) Kalyani, D.; Dick, A. R.; Anani,
W. Q.; Sanford, M. S. Tetrahedron 2006, 62, 11483. (e) Kalyani, D.;
Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523.
(f) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8,
1141. (g) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149. (h)
Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (i) Desai, L. V.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 9542. (j) Dick, A. R.; Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300.
Results
Our first goal was to systematically study how the electronic
nature of a directing group affects the distribution of products in
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2008 American Chemical Society
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Desai et al.
Scheme 2. Competition Studies between Two Different Directing
Groups (L and L′)
at 100 °C), the monoacetoxylated products 1b-7b were
obtained in 70-93% isolated yield. Importantly, these trans-
formations exhibited extremely high (>100:1) selectivity for
ortho-functionalization of the aromatic ring; furthermore, the
less sterically congested ortho site (para to the methyl sub-
stituent) was acetoxylated with >25:1 selectivity in all cases.1g
We next carried out competition studies between electroni-
cally varied benzylpyridines in AcOH/Ac2O (Scheme 2). In
these experiments, a 1:1 molar ratio of 2-benzylpyridine 6a and
each substituted derivative (1a-5a and 7a) was subjected to 1
equiv of PhI(OAc)2 and 1 mol % of Pd(OAc)2. Upon completion
of the reaction, the yields and ratios of acetoxylated products
were determined by GC. In a representative experiment, the
reaction of an equimolar quantity of 6a and 2a afforded
Table 1. Acetoxylation of Substituted Benzylpyridine Derivatives
acetoxylated products 6b and 2b in a ratio of 1:0.77 (k6a/k2a
1/0.77) (Scheme 3).
)
entry
substrate
X
Y
product (yield, %)
Scheme 3. Competition between Benzylpyridines 2a and 6a
1
2
3
4
5
6
7
1a
2a
3a
4a
5a
6a
7a
H
H
H
H
CH3
H
CH3
OCH3
CF3
Cl
1b (70)
2b (75)
3b (91)
4b (74)
5b (74)
6b (75)
7b (93)
H
H
H
F
with 1 equiv of PhI(OAc)2. The ratio of acetoxylated products (I-
OAc/II-OAc) was then determined by gas chromatography (GC),
and this value represents the relative reaction rates of the two
directing groups (kI/kII) under a given set of conditions.
The data from these experiments were used to construct a
Hammett plot (Figure 2), which showed a nonlinear convex
relationship between σ and log(kX/kH). Such convex plots can be
indicative of a change in rate-determining step with electronic
Our initial studies focused on substituted benzylpyridine
derivatives 1a-7a as substrates for these transformations. These
substrates were designed with several criteria in mind. First,
pyridine derivatives are well-known to serve as highly effective
directing groups for Pd-catalyzed C-H bond functionaliza-
tion.1,2b,f,i,3a,c,i,l,n,s Second, substitution at the meta and para
positions of the pyridine ring allows for electronic modification
of the directing group. Third, these substrates contain a methyl
substituent at the meta position of the arene ring to limit
competing di-ortho-functionalization, which could complicate
product ratio analysis.1g Finally, and most importantly, these
substrates contain a methylene spacer between the directing
group and the arene, which is expected to limit electronic
communication between the pyridine substituent and the C-H
bond being functionalized.5 This should allow interpretation of
product ratios solely in terms of electronic perturbation of the
directing group.6
(3) For selected examples of palladium-catalyzed directed C-H activation/
C-C bond-forming reactions, see: (a) Yu, W.-Y.; Sit, W. N.; Lai,
K.-M.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2008, 130, 3304.
(b) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.
Chem. ReV. 2007, 107, 5318. (c) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. ReV. 2007, 107, 174. (d) Cai, G.; Fu, Y.; Li, Y.; Wan, X.;
Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666. (e) Giri, R.; Maugel, N. L.;
Li, J. J.; Wang, D. H.; Breazzano, S. P.; Saunders, L. B.; Yu, J. Q.
J. Am. Chem. Soc. 2007, 129, 3510. (f) Xia, J.-B.; You, S.-L.
Organometallics 2007, 26, 4869. (g) Chiong, H. A.; Daugulis, O. Org.
Lett. 2007, 9, 1449. (h) Shi, Z. J.; Li, B.; Wan, X.; Cheng, J.; Fang,
Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem., Int. Ed. 2007, 46, 5554.
(i) Chen, X.; Goodhue, C. E.; Yu, J. Q. J. Am. Chem. Soc. 2006, 128,
12634. (j) Chen, X.; Li, J. J.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q.
J. Am. Chem. Soc. 2006, 128, 78. (k) Orito, K.; Miyazawa, M.;
Nakamura, T.; Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.;
Yamashita, S.; Yamazaki, T.; Tokuda, M. J. Org. Chem. 2006, 71,
5951. (l) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 13154. (m) Zaitsev, V. G.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 4156. (n) Shabashov, D.; Daugulis, O. Org. Lett. 2005,
7, 3657. (o) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005,
44, 4046. (p) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.;
Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem.
Soc. 2004, 126, 14342. (q) Wakui, H.; Kawasaki, S.; Satoh, T.; Miura,
M.; Nomura, M. J. Am. Chem. Soc. 2004, 126, 8658. (r) Hennessy,
E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084. (s) Ritleng,
V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (t) Boele,
M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.;
de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002,
124, 1586. (u) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (v)
Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106, 5759.
(4) (a) Ali, A.; Hunt, J. A.; Kallashi, F.; Kowalchick, J. E.; Kim, D.; Smith,
C. J.; Sinclair, P. J.; Sweis, R. F.; Taylor, G. E.; Thompson, C. F.;
Chen, L.; Quraishi, N. PCT Int. Appl. WO 2007070173, 2007. (b)
Zhou, P.; Bernotas, R. C.; Li, Y.; Nowak, P. W.; Cole, D. C.; Manas,
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Denny, W. A. Bioorg. Med. Chem. 2002, 10, 2381.
As summarized in Table 1, all of the substituted pyridine
derivatives served as effective directing groups for Pd-catalyzed
C-H bond acetoxylation. Under optimized conditions (1 mol
% of Pd(OAc)2, 1.02–1.8 equiv of PhI(OAc)2 in AcOH/Ac2O
(2) For selected examples of palladium-catalyzed directed C-H activation/
C-heteroatom bond-forming reactions, see: (a) Inamoto, K.; Saito,
T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931.
(b) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem. Soc. 2006, 128,
9048. (c) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi,
Z. J. Am. Chem. Soc. 2006, 128, 7416. (d) Reddy, B. V. S.; Reddy,
L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391. (e) Wang, D.; Hao, X.;
Wu, D.; Yu, J. Q. Org. Lett. 2006, 8, 3387. (f) Yu, J. Q.; Giri, R.;
Chen, X. Org. Biomol. Chem. 2006, 4, 4041, and references therein.
(g) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560. (h) Giri, R.; Liang, J.; Lei, J. G.; Li, J. J.; Wang,
D. H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J. Q.
Angew. Chem., Int. Ed. 2005, 44, 7420. (i) Giri, R.; Chen, X.; Yu,
J. Q. Angew. Chem., Int. Ed. 2005, 44, 2112. (j) Dangel, B. D.;
Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001, 123, 8149.
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A R T I C L E S
Scheme 4. Individual Kinetic Studies
Figure 2. Hammett plot for competition experiments in AcOH/Ac2O.
Figure 4. Hammett plot for competition experiments in benzene.
Figure 3. Hammett plot for competition experiments in AcOH/Ac2O,
corrected for concentration of protonated benzylpyridine.
variation of the substituents.7 However, in this case, we reasoned
that the nonlinearity might instead be due to varying degrees of
pyridine protonation by the AcOH solvent. The Ka for this acid/
base reaction should vary substantially with substitution on the
pyridine, thereby changing the concentration of accessible ligand.
As such, we hypothesized that correcting for the concentration of
unprotonated benzylpyridine in AcOH/Ac2O might provide a linear
Hammett plot for these reactions.
The concentration of each unprotonated benzylpyridine was
estimated using standard acid/base equilibria8 based on the
approximation that Ka is equal to that of the analogous pyridine
derivative (eq 1).9 The experimental ratios of the acetoxylated
products (kX/kH) were then corrected on the basis of the
calculated concentrations of free benzylpyridine (see Supporting
Information, including Table S2, for full details). Gratifyingly,
the Hammett plot of this corrected data was linear (R2 ) 0.96)
and provided a F value of -5.46 (Figure 3).10
Figure 5. Hammett plot for individual kinetics in AcOH/Ac2O.
conducted in benzene. As anticipated, under optimal conditions
(5 mol % of Pd(OAc)2, 1.02 equiv of PhI(OAc)2, 80 °C), a linear
Hammett plot (R2 ) 0.94) with a F value of -2.01 was obtained
(Figure 4).10 While the slopes of the Hammett plots in AcOH/
Ac2O and benzene differ substantially, the negative F values
demonstrate that, in both solvents, substrates bearing more electron-
rich directing groups react preferentially under competition conditions.
We next sought to determine if the reaction rates of 1a-7a in
isolation were similar to the competition studies discussed above.
As such, the initial rate of Pd-catalyzed C-H activation/acetoxy-
lation for each benzylpyridine derivative was measured in AcOH/
Ac2O (Scheme 4). A Hammett plot was then constructed and
showed a nonlinear concave relationship between σ and log(kX/
kH) (Figure 5). A concave Hammett plot often reflects a change in
mechanism as the electronic nature of the aromatic ring is varied.7
However, on the basis of the results from the competition
experiments above, we hypothesized that the nonlinearity was more
likely due to competitive protonation of the pyridine. Indeed,
correction of the benzylpyridine concentrations based on pyridine
Ka values9 provided a linear Hammett plot (R2 ) 0.96) with a F
value of +4.74 (Figure 6).
To further confirm that equilibrium protonation was the source
of nonlinearity in AcOH/Ac2O, analogous competition studies were
Again, analogous kinetics experiments were performed in
benzene and provided a linear Hammett plot (R2 ) 0.96) with a F
(5) For previous examples of the stoichiometric cyclopalladation of
benzylpyridine, see: (a) Mawo, R. Y.; Johnson, D. M.; Wood, J. L.;
Smoliakova, I. P. J. Organomet. Chem. 2008, 693, 33, and references
therein. (b) Hiraki, K.; Fuchita, Y.; Takechi, K. Inorg. Chem. 1981,
20, 4316.
(8) See Supporting Information for full details of this calculation.
(9) All pKa values used are in solution phase. (a) http://research.chem.
psu.edu/brpgroup/pKa_compilation.pdf. (b) Borowiak-Resterna, A.;
Szymanowski, J.; Voelkel, A. J. Radioanal. Nucl. Chem. Art. 1996,
208, 75–86.
(6) Notably, a similar strategy for electronically isolating an aryl ring from
a directing group has been recently reported by Yu and co-workers in
mechanisticstudiesofPd-catalyzedoxazoline-directedareneoxygenation:Li,
J. J.; Giri, R.; Yu, J. Q. Tetrahedron 2008, 64, 6987.
(10) The Hammett data looked very similar (F )-5.20, R2 ) 0.94 in AcOH/
Ac2O and F )-1.58, R2 ) 0.80 in benzene) when these competition
experiments were analyzed at low conversion (5-15% combined yield
of the two products) as opposed to at the completion of the reaction.
(7) Anslyn, E. K.; Dougherty, D. A. Modern Physical Organic Chemistry;
University Science Books: Sausalito, CA, 2006; p 448.
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substrates containing eight different directing groups (L ) pyridine,
pyrimidine, pyrazine, pyrazole, isoxazoline, methyl oxime ether,
benzyl oxime ether, and amide) were synthesized.11 Importantly,
all contain a methylene spacer between L and the arene ring in
order to attenuate electronic communication between the two halves
of the molecule and a meta-methyl substituent to promote
monoacetoxylation.1g As shown in Table 2, each of these substrates
underwent clean and high-yielding Pd-catalyzed C-H acetoxyla-
tion with PhI(OAc)2 in AcOH/Ac2O.
Competition studies analogous to those described in
Scheme 2 were performed for substrates 6a and 8a-14a in
both AcOH/Ac2O and benzene. In a representative experi-
ment, benzylpyridine 6a and benzylpyrazole 10a reacted in
benzene to afford a 1:0.06 ratio of acetoxylated products 6b
and 10b. In AcOH/Ac2O, 6b was still the major product,
albeit with lower selectivity (1:0.4) (Scheme 5). On the basis
Figure 6. Hammett plot for individual kinetics in AcOH/Ac2O, corrected
for concentration of protonated benzylpyridine.
Scheme 5. Competition between Benzylpyridine 6a and
Benzylpyrazole 10a
Figure 7. Hammett plot for individual kinetics in benzene.
value of +1.40 (Figure 7). The positive F value in both solvents
shows that electron-withdrawing substituents on the pyridine ring
accelerate the rate of acetoxylation. Importantly, this is directly
opposite to the results of the competition experiments. As discussed
below, these data suggest that two different steps of the catalytic
cycle bearing opposite electronic requirements control the relatiVe
rates of functionalization in the presence and absence of other
directing groups.
of the data compiled from these experiments (Tables S2 and
S3), the relative reactivities of 6a and 8a-14a were ranked
(Figure 8). While the trends in the two solvent systems varied
slightly, the results were generally consistent with the more
basic directing groups dominating the reaction. For example,
competitions between the most basic heterocycles (pyridine,
We next investigated whether the electronic effects observed
with benzylpyridines 1a-7a were general across a wider range of
common directing groups. As shown in Table 2, a series of
Table 2. Isolated Yields for Substrates Containing Diverse Directing Groups
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Palladium-Catalyzed C-H Bond Functionalization
A R T I C L E S
Figure 8. Relative reactivity of directing groups from competition studies in AcOH/Ac2O and C6H6.
Table 3. Initial Rates for Substrates 6a and 8a-14a in AcOH/Ac2O and Benzene
pyrimidine, pyrazine, and pyrazole derivatives 6a, 8a, 10a,
and 14a) and substrates bearing less-basic directing groups
(isoxazoline, oxime ethers, and amide derivatives 9a, 11a,
12a, and 13a) generally afforded only acetoxylation of the
former with >50:1 selectivity. These results are consistent
with our prior observation1e of selective pyridine-directed
acetoxylation in molecules containing both a pyridine and
an oxime ether directing group.
The initial rate of Pd-catalyzed C-H bond acetoxylation for
each individual substrate was also determined. As summarized
in Table 3, the initial rates for acetoxylation of 6a and 8a-14a
in AcOH/Ac2O ranged over approximately 2 orders of magni-
tude from 0.1 × 10-1 to 6.4 × 10-1 mol L-1 min-1. Under
these conditions, the three substrates bearing six-membered
nitrogen-containing heterocyclesspyridine 6a, pyrimidine 8a,
and pyrazine 14asexhibited very different initial rates, with
the pyrimidine reacting 60 times faster than the pyrazine and 3
times faster than the pyridine (Table 3, entries, 1, 4, and 8).
Furthermore, in some cases, substrates bearing two very
electronically different directing groups, such as methyl oxime
ether 11a and pyridine 6a, reacted at nearly identical rates
(entries 4 and 5).
Solvent also had an effect on both the relative and absolute
rates of these transformations. In general, C-H activation/
acetoxylation was 2-4 times slower in benzene (with 5 mol %
of catalyst) versus AcOH/Ac2O (with 1 mol % of catalyst).
Furthermore, while isoxazoline 9a and pyrazole 10a reacted at
similar rates in AcOH/Ac2O, 9a reacted 2 times faster than 10a
in benzene (Table 3, entries 2 and 3). Additionally, oxime ether
11a and amide 13a showed high reactivity in AcOH/Ac2O;
however, these substrates formed only trace amounts of the
desired products under standard conditions in benzene.
Having explored the factors affecting the dominant direct-
ing group under carefully controlled conditions, we turned
our efforts to determining whether these insights could be
applied to more complex systems. As such, we synthesized
substrate 15a, which contains both an amide and an oxime
ether directing group. On the basis of the competition studies
discussed above, we predicted that the oxime ether would
direct C-H activation/acetoxylation selectively over the
amide. We were pleased to find that the reaction of 15a in
the presence of 3 mol % of Pd(OAc)2 and 2 equiv of
PhI(OAc)2 in AcOH/Ac2O afforded the diacetoxylated prod-
uct 15b in 72% yield, and none of the corresponding product
(11) Several oxazoline substrates were also examined, as these are widely
used as directing groups for Pd-catalyzed C-H functionalization;2,3,6
however, these afforded uncatalyzed acetoxylation of the starting
substrate. See ref 24 and the Supporting Information for full details.
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Scheme 6. Highly Selective Oxime Ether-Directed C-H Acetoxylation of Substrate 15a
Scheme 7. Amide-Directed C-H Functionalization of Product 15b
of amide-directed C-H acetoxylation was observed (Scheme
6). It is important to note that this reaction provided solely
product 15b, despite the fact that there are not methylene
spacers between the directing groups and the aromatic rings
being functionalized. Without these spacers, the amide is
expected to increase the electron density on the arene and
thereby increase its reactivity toward C-H activation,12 while
the electron-withdrawing oxime ether is expected to have
the opposite effect.12 Nonetheless, the trend predicted on the
basis of substrates 11a and 13a above held up well in this
system.
As shown in Scheme 7, the acetoxylated product 15b could be
further elaborated via Pd-catalyzed directed C-H activation
Figure 9. Proposed catalytic cycle for Pd-catalyzed C-H bond acetoxylation.
reactions. For example, the use of PhI(OAc)2 afforded triacetoxy-
lated product 15b-OAc, N-chlorosuccinimide provided chloro
product 15b-Cl,1d,e and the iodonium salt [(m-CF3C6H4)2I]BF4
generated the corresponding arylated product 15b-Ar.1h These
results demonstrate that the amide is a competent directing group
for Pd-catalyzed C-H functionalization reactions, thereby confirm-
ing that the high selectivity observed with 15b indeed reflects the
relative reactivity of the two directing groups.
intermediate C, (iv) C-O bond-forming reductive elimination to
generate PdII complex D, and (v) ligand exchange to release the
product and coordinate a new substrate to the metal center.
Literature precedent can be used to predict how electronic
modification of the directing group (L) will affect each step of
the catalytic cycle. Modification of L is expected to have a large
influence on the thermodynamics (and therefore Keq) associated
with steps i and v, which should be in rapid equilibria under
the reaction conditions. Prior work has shown that, with all else
being equal, more electron-donating ligands form stronger bonds
to PdII than their electron-deficient analogues.13,14
Discussion
With all these results in hand, we sought to determine which
mechanistic steps dictate the relative and absolute reactivity of a
directing group in Pd-catalyzed C-H bond acetoxylation. As
summarized in Figure 9, the catalytic cycle for these transformations
is proposed to involve five steps: (i) ligand coordination to the Pd
catalyst to generate complex A, (ii) cyclometalation to form
palladacycle B, (iii) oxidation of B by PhI(OAc)2 to afford PdIV
The cyclopalladation reaction (step ii) is believed to
proceed by an electrophilic12b,c,15 mechanism and/or by
formationofanagosticintermediatefollowedbydeprotonation.16,17
Both mechanisms involve the Pd acting as an electrophile;
(12) (a) Ackerman, L. J.; Sadighi, J. P.; Kurtz, D. M.; Labinger, J. A.;
Bercaw, J. E. Organometallics 2003, 22, 3884. (b) Ryabov, A. D.
Chem. ReV. 1990, 90, 403, and references therein. (c) Ryabov, A. D.;
Sakodinskaya, I. K.; Yatsimirsky, A. K. J. Chem. Soc., Dalton Trans.
1985, 2629. (d) Gutierrez, M. A.; Newkome, G. R.; Selbin, J. J.
Organomet. Chem. 1980, 202, 341.
(13) (a) Jeon, S. L.; Loveless, D. M.; Yount, W. C.; Craig, S. L. Inorg.
Chem. 2006, 45, 11060. (b) Manen, H.-J.; Nakashima, K.; Shinkai,
S.; Kooijman, H.; Spek, A. L.; Veggel, F. C. J. M.; Reinhoudt, D. N.
Eur. J. Inorg. Chem. 2000, 2533.
(14) Yagyu, T.; Iwatsuki, S.; Aizawa, S.; Funahashi, S. Bull. Chem. Soc.
Jpn. 1998, 71, 1857.
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Palladium-Catalyzed C-H Bond Functionalization
A R T I C L E S
as such, the rate of this step is expected to be accelerated by
electron-withdrawing ancillary ligands (L).12b,d Literature
precedent has shown that the oxidation of PdII complexes
(step iii of the catalytic cycle) is accelerated with more
electron-donating ligands, which render the metal center more
nucleophilic.18 Finally, the rate of C-O bond-forming
reductive elimination from PdIV (step iv) is expected to
increase with electron-withdrawing ancillary ligands (L).19
We can interpret our experimental data on the basis of this
analysis in order to gain insights into the selectivity-
determining step(s) under individual kinetics and competition
conditions.
Figure 10. Kinetic isotope effect experiment.
Individual Rate Studies: Benzylpyridine Derivatives. The
individual rate studies with substituted benzylpyridines (Scheme
4, Figures 6 and 7) afforded Hammett F values of +1.40 in benzene
and + 4.74 in AcOH, indicating that the reaction is accelerated
with less-basic benzylpyridines. On the basis of the analysis above,
these values suggest that either cyclopalladation (step ii in Figure
9) or C-O bond-forming reductive elimination (step iv in Figure
9) is rate determining.20 We propose that cyclopalladation is rate
limiting in these systems on the basis of several additional pieces
of data. First, literature precedent suggests that reductive elimination
will be fast under our reaction conditions (80 °C), since PdIV
complexes of general structure C are typically unstable at room
temperature.20-22 Second, comparison of the initial rates of
acetoxylation of substrate 16a versus its deuterated analogue 16a-
d5 provided a kH/kD of 3.54 in AcOH/Ac2O and 1.86 in C6H6
(Figure 10). This is consistent with a primary kinetic isotope effect
(KIE), where C-H(D) bond breaking is involved in the rate-
determining step of the reaction. Importantly, similar KIE values
(ranging from 1.8 to 4.4) have been observed in related Pd-
catalyzed C-H functionalization reactions that proceed by rate-
limiting C-H activation.2e,3d,f,h,l,m,t,23 Most relevant, Yu and co-
workers observed a KIE of 2.9 in Pd-catalyzed oxazoline-directed
Figure 11. Hammett plot for stoichiometric cyclopalladation of benzyl-
pyridines 1a-3a, 6a, 7a.
C-H acetoxylation reactions that also proceed via six-membered
palladacycles.6,24
Additional support for C-H activation as the rate-limiting
step came from stoichiometric studies of the reactions of 1a-7a
with Pd(OAc)2 (Figure 11). The rates of cyclopalladation were
monitored in benzene using UV-vis spectroscopy. As shown
in Figure 11, a Hammett plot was constructed and showed a F
value of +1.77 for stoichiometric C-H activation. This value
is similar in both sign and magnitude to that obtained in the
catalytic individual rate studies (F ) +1.4 in benzene), providing
further evidence to support turnover-limiting cyclopalladation.
We note that our catalytic experiments afforded significantly
different F values in AcOH/Ac2O (+4.74) versus C6H6 (+1.4).
Importantly, solvent has also been shown to have a significant
effect on the rates of stoichiometric cyclopalladation reactions.25
As such, we propose that the difference in magnitude between
the two solvents may be the result of a change in the nature/
(15) (a) Martin-Matute, B.; Mateo, C.; Cardenas, D. J.; Echavarren, A. M.
Chem. Eur. J. 2001, 7, 2341. (b) Marsella, A.; Agapakis, S.; Pinna,
F.; Strukul, G. Organometallics 1992, 11, 3578.
(16) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc.
2005, 127, 13754.
(17) (a) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 14570. (b) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.
(c) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(d) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 8754. (e) Garcia-Cuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066.
(f) Campeau, L. C.; Parisien; Jean, A.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 581. (g) Campeau, L. C.; Parisien, M.; Leblanc, M.; Fagnou,
K. J. Am. Chem. Soc. 2004, 126, 9186.
(18) (a) Valk, J. M.; Boersma, J.; van Koten, G. Organometallics 1996,
15, 4366. (b) Alsters, P. L.; Teunissen, H. T.; Boersma, J.; Spek, A. L.;
van Koten, G. Organometallics 1993, 12, 4691.
(22) We have reported that PdIV complexes containing two σ-aryl ligands
can be stable at room temperature: Dick, A. R.; Kampf, J. W.; Sanford,
M. S. J. Am. Chem. Soc. 2005, 127, 12790.
(19) For examples of analogous electronic effects in reductive elimination
from PdII, see: (a) Graham, D. C.; Cavell, K. J.; Yates, B. F. Dalton
Trans. 2006, 1768. (b) Nolan, S. P. In Palladium in Organic Synthesis;
Tsuji, J., Ed. Topics in Organometallic Chemistry 14; Springer-Verlag:
Berlin, Germany, 2005; pp 241-272.
(23) Chiong, H. A.; Pham, Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129,
9879.
(24) The oxazoline directing group from ref 6 could not be directly
compared to the current systems. Under our standard reaction
conditions, oxazoline 17a underwent a rapid, uncatalyzed reaction with
the oxidant to afford 17b (77% NMR yield) and 17c (19% NMR yield).
In the presence of Pd(OAc)2, 17b and 17c were still the major products,
and <5% of the expected aromatic C-H functionalization product
was formed. See Supporting Information for full details.
(20) Stability/reductive elimination from PdIV complexes with one alkyl/
aryl ligand and three other X-type ligands: Alsters, P. L.; Engel, P. F.;
Hogerheide, M. P.; Copijn, M.; Spek, A. L.; van Koten, G. Organo-
metallics 1993, 12, 1831.
(21) Some PdIV complexes containing multiple σ-akyl and/or σ-aryl ligands
have been isolated and shown to be stable at room temperature or
above. (a) Markies, B. A.; Canty, A. J.; Boersma, J.; van Koten, G.
Organometallics 1994, 13, 2053. (b) Byers, P. K.; Canty, A. J.;
Skelton, B. W.; White, A. H. Chem. Commun. 1986, 1722. However,
the proposed intermediate in the current transformations is a mono-
aryl PdIV species (B). Limited examples of such complexes have been
observed, and all undergo rapid reductive elimination at room
temperature (see ref 20).
(25) (a) Gomez, M.; Granell, J.; Martinez, M. Eur. J. Inorg. Chem. 2000,
217. (b) Ryabov, A. D. Inorg. Chem. 1987, 26, 1252.
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A R T I C L E S
Desai et al.
Scheme 8. Equilibrium for Substrate Binding under Competition Conditions
position of the transition state for C-H activation as a function
of reaction medium.
complexes that can form (A and A′) and that are expected to
be in equilibrium under the reaction conditions.30 According to
the Curtin-Hammett principle, the relative energies of these
two complexes (∆G°) in conjunction with ∆Gq for the turnover-
limiting C-H activation step from each will determine the
product distribution in these transformations.31
As discussed above, literature precedent has shown that coor-
dination of more electron-rich ligands to PdII is thermodynamically
favored. For example, Hammett F values ranging from -0.8 to
-1.3 were obtained from Keq measurements of the coordination
of substituted pyridines to PdII pincer complexes in CHCl3.13b
These values are similar to our results in benzene (F ) -2.01),
which is also a relatively nonpolar, noncoordinating solvent.
Notably, the literature F values for pyridine coordination were found
to increase to between -1.7 and -2.1 upon moving to the more
polar coordinating solvent DMSO.13a This may provide some
explanation for the substantially larger F of -5.46 that we observed
in the polar protic medium AcOH/Ac2O.
These data suggest that the ligand coordination equilibrium
(Scheme 8) dictates the selectivity of acetoxylation reactions
in the presence of multiple directing groups.31 However, it is
important to note that acidic solvents can significantly perturb
this equilibrium by competitively protonating more basic
directing groups (hence the convex Hammett plot for benzylpy-
ridine derivatives in Figure 2). Solvent also plays a significant
role in the trends observed for substrates 8a-14a (Figure 8).
For example, two similar oxime ether derivatives, 11a and 12a,
exhibited very different reactivity when the solvent was changed
from AcOH/Ac2O to benzene. Unlike benzyl oxime ether 12a,
the methyl oxime ether 11a did not afford any of the acetoxy-
lated product 11b in benzene. Similarly, benzylpyrimidine 8a
out-competed the benzylpyrazole 10a in AcOH/Ac2O; however,
a reversal of this selectivity was observed when the solvent was
changed to benzene. Additionally, in the competition experiment
between benzylpyridine 6a and benzylpyrazole 10a (Scheme
5), selectivity for the benzylpyridine product 6b increased
significantly (from 1:0.4 to 1:0.06) when the solvent was
changed from AcOH/Ac2O to benzene.
Individual Rate Studies: Other Directing Groups. In contrast
to the results with the benzylpyridine derivatives, the individual
rate studies with substrates 6a and 8a-14a did not show a strong
correlation between kobs and the basicity of the directing group.
For example, oxime 12a (pKa ≈ -2.90)26 reacted at a rate
similar to that of pyrazole 10a (pKa ≈ 2.18)27 in benzene, despite
a difference of 5 pKa units between the two directing groups.
This lack of correlation likely has both steric and electronic
origins. First, unlike benzylpyridines 1a-7a, which provide
essentially sterically identical coordination environments at the
Pd center, compounds 8a-14a differ substantially in terms of
both their steric parameters and their conformational flexibility.
Literature reports have shown that even relatively small steric
changes can have a significant influence on the relative and
absolute rates of cyclopalladation.12b,28 In addition, the pKa of
a directing group is not an ideal parameter for predicting the
subtle electronic influence of these ligands on C-H activation,
as it does not take into account the interplay of their σ-donor
and π-acceptor/donor abilities.29
Competition Experiments. When multiple potential chelating
functionalities are present in solution, substrates containing more
electron-rich/more basic directing groups react preferentially. This
can be concluded on the basis of three key results from the
competition studies: (i) the large negative F values obtained with
substituted benzylpyridines (Figures 3 and 4), (ii) the observation
that the most basic directing group (pyridine in substrate 6a) out-
competed all of the other directing groups among substrates
8a-14a (Figure 8), and (iii) the fact that heterocyclic ligands with
pKa values greater than zero (pyridine, pyrimidine, pyrazine,
pyrazole) outcompeted all substrates with pKa values less than zero
(oxime ether, amide, and isoxazoline). On the basis of the
considerations discussed above, these results suggest that either
ligand binding/exchange (steps i and v in Figure 9) or oxidation
(step iii in Figure 9) controls the relative reactivity of the two
substrates under these conditions. We were able to rule out the
latter on the basis of a study of the order of the reaction in
PhI(OAc)2. Under optimal conditions for acetoxylation with
substrate 6a, the reaction was found to be zero order in PhI(OAc)2,
both in the presence and in the absence of another substrate (3a)
(Figures S6-S7 and S9-S10).
While the origin of these solvent effects is still under investiga-
tion, these results have important implications for future applications
of this chemistry. In nonacidic solvents like benzene, the basicity
of a directing group appears to serve as a reasonable predictor of
its relative reactivity. However, an acidic solvent can be used to
attenuate inherent reactivity differences by effectively “protecting”
a potential ligand in its protonated form. We anticipate that this
and related strategies can be used to obtain, alter, or improve the
As a result, we propose that selectivity under the competition
conditions is controlled by the ligand coordination step. As
shown in Scheme 8, there are two possible coordination
(26) Sokolov, S. D.; Tikhomirova, G. B.; Turchin, K. F. Chem. Heterocycl.
Compd. 1985, 21, 507.
(27) Catalan, J.; Claramunt, R. M.; Elguero, J.; Laynez, J.; Menendez, M.;
Anvia, F.; Quian, J. H.; Taagepera, M.; Taft, R. W. J. Am. Chem.
Soc. 1988, 110, 4105.
(30) A similar F value of-1.7 to-2.1 in DMSO was observed by Craig in
studying substituted pyridine coordination to 1,4-phenylene bridged
bimetallic palladium complexes containing tridentate ligands.13a
(31) Importantly, the proposed effects of the equilibrium for ligand exchange
are consistent with the Curtin-Hammett principle as long as the
difference in the energy (∆G) between the two PdII pyridine coordina-
tion complexes is greater than the difference in the activation energies
(∆∆Gq) for the C-H activation step (the slow step of these
transformations). See Supporting Information for further details.
(28) (a) Mossi, W.; Klaus, A. J.; Rys, P. HelV. Chim. Acta 1992, 75, 2531.
(b) Thummel, R. P.; Jahng, Y. J. Org. Chem. 1987, 52, 73.
(29) (a) Crabtree, R. H. The Organometallic Chemistry of the Transition
Metals, 4th ed.; John Wiley and Sons, Inc.: Hoboken, NJ, 2005; 18-
26. (b) Slater, J. W.; Rourke, J. P. J. Organomet. Chem. 2003, 688,
112.
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Palladium-Catalyzed C-H Bond Functionalization
A R T I C L E S
oil was purified by chromatography on silica gel. Each substrate
was optimized for reaction time and equivalents of the oxidant as
described in the Supporting Information.
selectivity of directed C-H functionalization in the context of
complex molecules. Future studies will continue to explore how
these effects (and the effects of other solvents and additives)
translate into predicting and controlling the dominant directing
group in more complex systems.
Acetoxylation of Substrate 6a. The reaction was run for 6 h
with 1.02 equiv of PhI(OAc)2. The product 6b was obtained as a
yellow oil (86.9 mg, 75% yield, Rf ) 0.27 in 70% hexanes/30%
ethyl acetate). 1H NMR (CDCl3): δ 8.52 (dd, J ) 4.8, 1.6 Hz, 1H),
7.54 (dt, J ) 7.6, 1.6 Hz, 1H), 7.11-7.02 (multiple peaks, 4H),
6.94 (d, J ) 8.0 Hz, 1H), 4.06 (s, 2H), 2.30 (s, 3H), 2.16 (s, 3H).
13C{1H} NMR (CDCl3): δ 169.37, 159.88, 149.03, 146.79, 136.44,
135.78, 131.72, 130.83, 128.38, 122.85, 122.24, 121.24, 39.21,
20.78, 20.69. IR (thin film): 1759 cm-1. HRMS electrospray (m/
z): [M + H]+ calcd for C15H15NO2, 242.1181; found, 242.1177.
General Procedure for Kinetics Experiments. Kinetics experi-
ments were run in 2-dram vials sealed with Teflon-lined caps. Each
data point represents a reaction in an individual vial, with each
vial containing an identical concentration of oxidant, catalyst, and
substrate. The vials were charged with PhI(OAc)2 (0.0158 g, 0.049
mmol, 1.02 equiv, added as a solid), substrate (0.048 mmol, 1.0
equiv, added as a 0.96 M stock solution in AcOH), and Pd(OAc)2
(0.11 mg, 0.00048 mmol, 0.01 equiv, added as a 0.0096 M stock
solution in AcOH), and the resulting mixtures were diluted to a
total volume of 400 µL of a 1:1 mixture of AcOH and Ac2O. The
vials were then heated at 80 °C for various amounts of time.
Reactions were quenched by cooling the vial at 0 °C for 5 min,
followed by the addition of a 2% solution of pyridine in CH2Cl2 (2
mL). An internal standard (pyrene) was then added, and the
reactions were analyzed by gas chromatography. Each reaction was
monitored to ∼10% (8.6-11.0%) conversion, and rate constants
were calculated using the initial rates method. Each kinetics
experiment was run in triplicate, and the data shown in the Hammett
plots represent an average of these three runs.
Conclusions
In summary, we have conducted detailed studies to elucidate
the electronic requirements of a directing group in Pd-catalyzed
directed arene acetoxylation reactions. Under individual kinetics
conditions, the reactions are accelerated by electron-withdrawing
groups and a significant kinetic isotope effect is observed,
indicating that cyclopalladation is turnover limiting. However,
under competition conditions, substrates with electron-donating
directing groups react preferentially, suggesting that their relative
reactivities are dictated by Keq for substrate coordination under
these conditions. Importantly, the current studies have primarily
focused on one structural class of substrates where the directing
group and the C-H bond are separated by a methylene spacer.
As a result, ongoing investigations seek to probe whether the
observed effects are generalizable across a broader array of other
systems. We anticipate that the mechanistic insights gleaned
from this and related work will ultimately prove valuable in
future applications of this chemistry.
Experimental Section
General Procedures. NMR spectra were obtained on a Varian
Inova 400 (399.96 MHz for 1H; 100.57 MHz for 13C; 376.34 MHz
for 19F) unless otherwise noted. 1H NMR chemical shifts are
reported in parts per million (ppm) relative to TMS, with the
residual solvent peak used as an internal reference. Multiplicities
are reported as follows: singlet (s), doublet (d), doublet of doublets
(dd), doublet of doublets of doublets (ddd), doublet of triplets (dt),
triplet (t), quartet (q), quintet (quin), multiplet (m), and broad
resonance (br). IR spectra were obtained on a Perkin-Elmer
spectrum BX FT-IR spectrometer. Melting points were determined
with a Mel-Temp 3.0 (Laboratory Devices Inc.) instrument and are
uncorrected. HRMS data were obtained on a Micromass AutoSpec
Ultima Magnetic Sector mass spectrometer. Gas chromatography
was carried out on a Shimadzu 17A instrument using a Restek Rtx-5
(crossbond 5% diphenyl-95% dimethyl polysiloxane; 15 m, 0.25
mm i.d., 0.25 µm df) column.
General Procedure for Competition Experiments. A 2-dram
vial was sequentially charged with PhI(OAc)2 (0.0158 g, 0.049
mmol, 1.02 equiv, added as a solid), substrate I (0.048 mmol, 1.0
equiv, added as a 0.96 M stock solution in AcOH), substrate II
(0.048 mmol, 1.0 equiv, added as a 0.96 M stock solution in AcOH),
and Pd(OAc)2 (0.11 mg, 0.00048 mmol, 0.01 equiv, added as a
0.0096 M stock solution in AcOH), and the resulting mixtures were
diluted to a total volume of 400 µL of a 1:1 mixture of AcOH and
Ac2O. The reaction was heated at 80 °C for 12 h and then cooled
to room temperature. A GC standard (pyrene) was added, and the
reaction was analyzed by gas chromatography.
Materials and Methods. Pd(OAc)2 was obtained from Pressure
Chemical and used as received, and PhI(OAc)2 was obtained from
Merck Research Laboratories and used as received. Substrates
1a-15a were prepared as described in the Supporting Information.
Solvents were obtained from Fisher Chemical and used without
further purification unless otherwise noted. Flash chromatography
was performed on EM Science silica gel 60 (0.040-0.063 mm
particle size, 230-400 mesh), and thin-layer chromatography was
performed on Merck TLC plates precoated with silica gel 60 F254.
General Procedure for Directed C-H Bond Acetoxylation.
In a 20 mL scintillation vial, PhI(OAc)2 (0.49-0.86 mmol,
1.02-1.80 equiv) and Pd(OAc)2 (1.08 mg, 0.0048 mmol, 0.01
equiv) were combined in a mixture of AcOH (2 mL) and Ac2O (2
mL). Substrate (0.48 mmol, 1.0 equiv) was added, the vial was
sealed with a Teflon-lined cap, and the resulting solution was heated
at 100 °C for 3-24 h. The reaction was cooled to room temperature,
and the solvent was removed under vacuum. The resulting brown
Acknowledgment. This work was supported by NIH NIGMS
(RO1 GM073836). We also gratefully acknowledge the Arnold and
Mabel Beckman Foundation as well as Abbott, Amgen, AstraZen-
eca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Glaxo-
SmithKline, Merck Research Laboratories, and Roche for funding.
L.V.D. thanks Bristol Myers Squibb for a graduate fellowship. We
also acknowledge Dan Dawson (preliminary studies), Nick Deprez
(for m-[CF3Ph2I]BF4,) and Dipannita Kalyani (editorial assistance).
Supporting Information Available: Experimental details and
spectroscopic and analytical data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA8045519
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