Aerobic C-H acetoxylation of 8-methylquinoline in PdII- pyridinecarboxylic acid systems: Some structure-reactivity relationships

Article abstract of DOI:10.1021/om400618n

Catalytic oxidative C-H acetoxylation of 8-methylquinoline as a model substrate with O₂ as oxidant was performed using palladium(II) carboxylate catalysts derived from four different pyridinecarboxylic acids able to form palladium(II) chelates of different size. A comparison of the rates of the substrate C-H activation and the O₂ activation steps shows that the C-H activation step is rate-limiting, whereas the O₂ activation occurs at a much faster rate already at 20 C. The chelate ring size and the chelate ring strain of the catalytically active species are proposed to be the key factors affecting the rate of the C-H activation.

Full text of DOI:10.1021/om400618n

Article
pubs.acs.org/Organometallics
Aerobic C−H Acetoxylation of 8‑Methylquinoline in PdII−
Pyridinecarboxylic Acid Systems: Some Structure−Reactivity
Relationships
Daoyong Wang, Peter Y. Zavalij, and Andrei N. Vedernikov*
S
* Supporting Information
ABSTRACT: Catalytic oxidative C−H acetoxylation of 8-
methylquinoline as a model substrate with O2 as oxidant was
performed using palladium(II) carboxylate catalysts derived
from four different pyridinecarboxylic acids able to form
palladium(II) chelates of different size. A comparison of the
rates of the substrate C−H activation and the O2 activation
steps shows that the C−H activation step is rate-limiting,
whereas the O2 activation occurs at a much faster rate already
at 20 °C. The chelate ring size and the chelate ring strain of the
catalytically active species are proposed to be the key factors affecting the rate of the C−H activation.
organopalladium(II) complexes 8, 9, and 11 toward O2 in
acetic acid solutions. Considering 1 as a reference compound,
we chose acids 3 and 4 to probe the effect of the length of the
arms bearing the carboxylate groups on the catalytic activity of
the derived palladium(II) complexes, whereas 2, a sulfonate
analogue of 3, was chosen to probe the impact of a labile
sulfonate donor. A labile sulfonate group was found to be very
efficient in enabling the PtII−C(sp3) functionalization with O2,
as was demonstrated by using a facially chelating bis(2-
pyridyl)methanesulfonate ligand (dpms; Chart 1).8,10,11
In turn, longer chelate arms in the anions derived from 2−4
may allow these ligands to adapt different modes of
coordination to the metal, e.g. facial vs meridional, observed
in palladium(II) complexes derived from 1.5
INTRODUCTION
■
Palladium-catalyzed heteroatom-directed oxidative C−H func-
tionalization reactions recently attracted significant attention as
convenient and versatile synthetic tools for organic chemists.1
These reactions rely on the use of specific strong oxidants such
as PhIX2 (X = OOCR, Cl), N-halosuccinimides (halogen = Cl,
Br, I),1a N-fluoropyridinium and N-fluoroammonium salts,
peroxosulfates,2 alkylperoxides, and their derivatives.3 These
oxidants are not environmentally benign and are often costly.
Very few methods employ inexpensive “green” oxidizing agents
such as hydrogen peroxide4 and dioxygen.5−8 Previously we
reported the use of O2 as the terminal oxidant in the catalytic
oxidative C−H acetoxylation of various 5-substituted 8-
methylquinolines in PdII−4-R-2,6-pyridinedicarboxylic acid
(H2pdaR, R = H, OH, t-Bu)−AcOH−Ac2O systems.5 This
catalytic reaction can be viewed as a sequence of the substrate
C−H activation by the (pdaR)PdII fragment followed by
dioxygen activation by the resulting organopalladium com-
pound and a product release step (Scheme 1). The key steps,
(a) the ligand exchange between 8-methylquinoline and a
precatalyst (pdatBu)PdII(DMF), (b) the C−H activation of the
coordinated substrate, and (c) the functionalization of the
resulting palladacycle with O2, have been demonstrated.
Bearing in mind the importance of methods suitable for the
C−H functionalization utilizing O2 as the only oxidant,9 we
engaged in a more detailed study of the reaction above. In this
work we report the relationship between the structure and the
reactivity of palladium catalysts in the aerobic acetoxylation of
8-methylquinoline used as a model substrate. More specifically,
we explore the reactivity toward this substrate of the PdII
carboxylates 5−7 derived from the pyridinecarboxylic acids 1,
3, and 4 (Chart 1), the kinetics of C−H activation of 8-
methylquinoline by complexes 5−7, and the performance of
the acid 1−4/Pd(OAc)2 systems in catalytic C−H acetox-
ylation. We also compare the reactivity of the related
RESULTS AND DISCUSSION
■
Synthesis of Ligands 2 and 3. The lithium salt of 6-
sulfonatomethyl-2-pyridinecarboxylic acid, 2, was prepared
from ethyl 6-methylpicolinate (13)12 using bromination with
NBS, nucleophilic substitution of bromine in the resulting 6-
bromomethyl derivative 14 with K2SO3 in a strongly alkaline
aqueous solution, hydrolysis of the resulting ester, and reaction
of 6-sulfomethyl-2-pyridinecarboxylic acid with lithium carbo-
nate (Scheme 2). Compound 2 was fully characterized by
means of 1H and 13C NMR spectroscopy, ESI mass
spectrometry, and elemental analysis.
The 6-carboxymethyl-2-pyridinecarboxylic acid 3 was pre-
pared from 6-bromomethylpicolinate 14 (Scheme 2) by
treating it with potassium cyanide followed by hydrolysis of
the resulting nitrile 15 in hydrochloric acid. The target acid 3
was isolated as a hydrate and was fully characterized by means
Received: June 26, 2013
Published: August 22, 2013
© 2013 American Chemical Society
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Scheme 1. Aerobic (pdaR)PdII-Catalyzed C−H Acetoxylation of Substituted 8-Methylquinolines
Chart 1
of 1H and 13C NMR spectroscopy, ESI mass spectrometry, and
elemental analysis.
The product was characterized by means of 1H NMR
spectroscopy, ESI mass spectrometry, and elemental analysis.
According to 1H NMR spectroscopy, two compounds in about
a 62:38 ratio are present in DMSO-d6 solutions of 5. The major
species shows a symmetric pattern, which is consistent with the
structure 5. The minor species shows two nonequivalent
pyridine proton signals, which is consistent with a dimeric
structure found earlier for various phosphine complexes
[Pd(pda)(PR3)] (R = Me, Cy, Ph).14
The 1,4-pyridinediacetic acid 4 is a known compound that
was prepared using the published procedure.13
Preparation of Palladium(II) Pyridinecarboxylates.
Attempts to prepare 4-tert-butyl-2,6-pyridinedicarboxylato
dimethyl sulfoxide palladium(II) (5) from 1 and Pd(OAc)2
following a procedure reported for the similar DMF complex
(pdatBu)PdII(DMF)5 using DMSO as a solvent resulted in the
reduction of Pd(OAc)2 to Pd0. More successful was the use of
reaction of 1 and Pd(OAc)2 in MeCN to form an acetonitrile
analogue of 5 with subsequent DMSO-for-MeCN ligand
exchange, similar to the method used for Pd(pda)(DMSO).14
The dimethyl sulfoxide complex 6, (L3)PdII(DMSO), where
L3 is 6-carboxylatomethyl-2-pyridinecarboxylate, was isolated in
high yield by reacting palladium(II) acetate and the dicarboxylic
acid 3 in DMSO solution at 80 °C (Scheme 3). The product
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Scheme 2
was fully characterized. The ESI-MS (m/z) data support its
formulation as a mononuclear palladium(II) complex, con-
sistent with the assigned structure 6.
Scheme 4
Scheme 3
contained no acetate ligand and no free carboxylic groups,
consistent with the chelate structure 9.
In contrast to the reaction of 16 and 2, the reaction between
16 and pyridinecarboxylic acid 3 in dimethylformamide
resulted in the formation of a poorly soluble white solid,
presumably of a polymeric structure. The poor solubility of the
product in most common solvents such as CHCl3, CH2Cl2,
AcOH, MeOH, H2O, and DMSO precluded its characterization
by means of NMR spectroscopy and purification by
recrystallization. Characterization of the solid by means of
elemental analysis was not satisfactory.
Dimethyl sulfoxide complex 7 of the formula (L4)-
PdII(DMSO), where L4 is 2,6-pyridinediacetate, was prepared
from palladium(II) acetate and an equimolar amount of 2,6-
pyridinediacetic acid (4) in DMSO (Scheme 3) and fully
characterized. The ESI-MS data for 7 dissolved in methanol
1
show the presence of mononuclear species, and its H NMR
The reaction of 16 and 2,6-pyridinediacetic acid 4 in acetic
acid solution resulted in the formation of complex 11. The
appearance of the 1H NMR spectra of 11 dissolved in
chloroform-d was consistent with a fast exchange in the metal
coordination sphere of the coordinated carboxylate and the free
carboxylic group of the singly deprotonated 4 (HL4). In
particular, two broad doublets at 4.55 and 4.75 ppm integrating
as 2H each were assigned to two diastereotopic hydrogen
atoms of the methylene groups of two acetic acid residues
involved in a fast exchange in the ligand HL4. The coordinated
HL4 produced a doublet and a triplet in the aromatic region of
the spectrum with an integral intensity ratio of 2:1 and a broad
signal at 12.67 ppm assigned to the hydrogen atom of the
carboxylic group of HL4. An additional complication to this
picture was the presence of a singlet at 2.10 ppm integrating as
3H, which was assigned to an acetic acid molecule of
crystallization. To confirm the structural assignment, attempts
at growing X-ray-quality crystals of 11 were made, but they
were not successful because of the limited solubility of this
compound in a number of solvents. Hence, a decision was
made to prepare a more lipophilic analogue of 11, complex 12
spectra are consistent with the assigned Cs-symmetric structure.
Attempts to prepare a palladium(II) complex derived from 6-
sulfonatomethyl-2-pyridine carboxylic acid (2) and Pd(OAc)2
in DMSO solution resulted in a complex mixture of products,
according to 1H NMR spectroscopy. The target compound was
detected in the reaction mixtures by means of ESI mass
spectrometry but was not isolated in pure form.
Preparation of 8-Methylquinoline-Derived Pallada-
cycles 9, 11, and 12 Supported by Pyridinecarboxylate
Ligands. Cyclopalladated 8-methylquinoline complexes 9, 11,
and 12 derived from acids 1, 2, and 4, respectively, were
prepared from the dinuclear acetato-bridged palladacycle 16 or
its more lipophilic isopropyl analogue 17 and the correspond-
ing carboxylic acids 1, 2, and 4 in acetic acid or
dimethylformamide solution (Scheme 4).
The reaction between 16 and monocarboxylic acid 2 in
dimethylformamide resulted in the formation of complex 9,
which was isolated in analytically pure form. The ESI-MS
showed the presence of the anion with the m/z ratio expected
for (9-Li)−. According to NMR spectroscopy, the product
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bearing an isopropyl group in the fifth position of the quinoline
residue.
DMSO complex 5 (entry 2), which are virtually undistinguish-
able, with regard to their performance. The next two best-
performing systems are based (i) on Pd(OAc)2 + pyridineacetic
acid 3, having one long carboxylate-bearing arm (entry 3), and
(ii) the derived palladium(II) complex 6 (entry 4). The 2,6-
pyridinediacetic acid 4 having two long carboxylate-bearing
arms (entry 5) and the derived complex 7 (entry 6) were
substantially less efficient. Finally, even less efficient was the
system including the 6-(sulfomethyl)pyridine-2-carboxylic acid
2 (entry 7). The low efficiency of the latter may result, in part,
from the poor solubility of the derived palladium complex in
the reaction mixtures. With this system excluded from
comparison, the acid 4/Pd(OAc)2 combination allows for the
least efficient catalysis, whereas 1/Pd(OAc)2 and 5 were the
best.
Complex 12 was synthesized in a similar fashion using the
palladacyclic derivative of 5-isopropyl-8-methylquinoline 1715
(Scheme 4). Its dichloromethane solutions showed the
presence of two species in about 10:1 ratio with an identical
1
pattern of H NMR signals. The second species was presumed
to be the isomer of the major complex, featuring a trans
arrangement of the carboxylate oxygen and the quinoline
1
nitrogen atoms. Similar to the case for 11, H NMR spectra of
12 show signs of a fast exchange between the coordinated
carboxylate group and the noncoordinated acetic acid residue of
HL4. For instance, at 20 °C the signals of two methylene
groups of the pyridineacetate ligand HL4 appear as two broad
doublets at 4.44 and 4.69 ppm (2J = 15 Hz) but at −50 °C
these methylene groups exhibit four broad signals at 3.69, 3.91,
5.10, and 5.54 ppm with an intensity ratio of 1:1:1:1, thus
confirming their involvement in a fast exchange at higher
temperatures. Similarly, at −50 °C the coordinated HL4
produces a triplet at 7.82 ppm and two unresolved broad
signals at 7.3−7.5 ppm with an integral intensity ratio of 1:1:1.
The isopropyl group attached to the quinoline core of 12
produced two broad signals of the diastereotopic methyls at
1.15 and 1.45 ppm of equal intensity. Finally, the identity of 12
was confirmed using single-crystal X-ray diffraction (Figure 1).
Combined with our previous results (Scheme 1),5 the
observed similar catalytic activity of systems in entries 1 and 2
suggests that the same 8-methylquinoline complex derived from
5 by substitution of the DMSO ligand may be the catalytically
active species involved in both reactions. Similarly, we presume
that 8-methylquinoline complexes derived from 6 and 7 are the
active species involved in catalysis in reactions in entries 3−4
and 5−6, respectively.
C−H Activation of 8-Methylquinoline by (L)-
PdII(DMSO) Complexes 5−7. To get some insight into the
origin of the different catalytic activity of complexes 5−7, we
analyzed the C−H activation step by these complexes with 8-
methylquinoline as the substrate.
a. C−H Activation Kinetics. The C−H activation step was
probed using the reaction of 8-methylquinoline and 1 equiv of
complex 5, 6, or 7 at 60 °C in the solvent CD3COOD. Though
5−7 have relatively poor solubility in acetic acid, they dissolved
in 2−5 min at 20 °C in the presence of 1 equiv of 8-
methylquinoline, which was attributed to the formation of 8-
methylquinoline adducts A and palladacyclic complexes
designated as B and C in Scheme 5. In particular, in the case
of 5 its dissolution led to an about 1:1 mixture of 5 and its 8-
methylquinoline derivative A plus some small (∼5%) amount
of palladacycles B + C. Similarly, upon the dissolution of 6 or 7
at 20 °C about 1:1 mixtures of 6 or 7 and their corresponding
8-methylquinoline adducts A were produced, though no
metallacycles B + C were detected. At 60 °C, the C−H
activation becomes faster for all three complexes 5−7. In
combination with the H/D exchange, the C−H activation leads
to a gradual decrease of the total intensity of the three signals,
one originating from the methyl group of free 8-methylquino-
line, one from the methyl group of the palladium-coordinated
substrate, and one from the cyclometalated substrate methylene
group. The progress of the C−H activation and H/D exchange
Figure 1. ORTEP drawing with 50% probability ellipsoids for 12,
showing the conformer with a facial arrangement of the ligand donor
atoms. The acetic acid of crystallization is not shown.
X-ray-quality crystals of 12 containing one molecule of acetic
acid of crystallization were produced by layering the acetic acid
solution of 12 with ether. The unit cell of 12 contains two
independent molecules with a different conformation of the
free acetic acid residue, one with a facial arrangement of the
ligand donor atoms (Figure 1) and another with the carboxylic
group pointing away from the metal.
Pd(OAc)2−L (L = 1−4) Systems in the Catalytic
Aerobic C−H Acetoxylation of 8-Methylquinoline. With
the three new pyridinecarboxylic acids 2−4 in hand, we
examined the efficiency of the derived palladium(II) complexes
in the catalytic aerobic oxidation of 8-methylquinoline. The
previously reported precatalyst 1 + Pd(OAc)2, was used as a
reference.5 All reactions were run for 24 h in AcOH at 80 °C
with stirring under 1 atm of O2 in the presence of 5 mol % of 5,
6, or 7 or 5 mol % of catalyst prepared in situ from Pd(OAc)2
and the corresponding acids 1−4. The results are summarized
in Table 1.
1
was monitored by the H NMR integration of these signals.
The experimental results were analyzed using numerical
integration and the kinetics model given in Scheme 5 (see the
Supporting Information for details). In this analysis we assumed
that (i) the equilibrium among the solvent and protio (B) and
deuterio (C) compounds is very fast in comparison to the rate
of C−H/C−D cleavage/formation reactions, (ii) the position
of the equilibrium between B and C is dependent only on the
ratio of [CD3COOD] and [CD3COOH], which is a constant
for a given batch of the NMR solvent, (iii) the ligand exchange
between free and coordinated 8-methylquinoline is much faster
than the C−H/C−D cleavage/formation (Scheme 5, top) and
K ≈ 1 for all the substrates, consistent with our observations,
and (iv) all of the C−H activation, Pd−C bond cleavage, and
The nature of the ligand has a significant impact on the
performance of the catalytic reaction. The most efficient
catalytic systems are based on the combination of Pd(OAc)2
and 2,6-pyridinedicarboxylic acid 1 (entry 1) or the derived
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Table 1. PdII-Catalyzed Oxidation of 8-Methylquinoline with O2 in AcOH−Ac2O System
a
entry
catalyst
conversion (%)
yield (%)
1
2
3
4
5
6
7
1 + Pd(OAc)2
69
69
59
53
20
15
7
64
62
54
45
13
11
7
5
3 + Pd(OAc)2
6
4 + Pd(OAc)2
7
2 + Pd(OAc)2
a
The reactions were performed with 0.5 mmol of substrate in 2 mL of AcOH under 1 atm of O2. The yields were determined as averages for two to
1
three runs using H NMR integration with 1,4-dioxane as the internal standard.
Scheme 5. The C−H Activation Kinetics Model
H/D exchange reactions considered were assumed to follow
(pseudo) first-order kinetics. The experimental data and their
best least-squares fits are shown in Figure 2.
The calculated first order rate constants kH for the C−H
activation of 8-methylquinoline with complexes 5, 6 and 7 are
given in Table 2. According to the values in Table 2, the 2,6-
pyridinedicarboxylate ligand in complex 5 is the most effective
at promoting faster C−H activation of 8-methylquinoline at the
palladium(II) center and the 2,6-pyridinediacetate ligand in
complex 7 is the least effective. The dicarboxylate ligand
present in 6 allows for intermediate activity.
b. DFT Calculations. To rationalize the results in Table 2,
we performed the theoretical analysis of the C−H activation
step in the most and least active systems in Table 2. The
theoretical analysis was carried out using DFT calculations and
included modeling of acetic acid as a solvent.16 The reaction
Gibbs energy profile for the 8-methylquinoline complex 19
derived from 5 was analyzed first (Figure 3a). C−H bond
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Figure 2. Relative integral intensity of the 8-methylquinoline methyl group in the reaction of 8-methylquinoline with 5 (solid circles), 6 (solid
triangles), and 7 (solid squares) in CD3COOD solution. Conditions: [LPd(DMSO)] (0.05 mmol), 8-methylquinoline (0.05 mmol), CD3COOD
(0.6 mL), 60 °C. Empty symbols represent results of the best least-squares fit of the experimental data.
Pd···H and Pd···C distances are 1.94 and 2.26 Å, respectively.
Importantly, the Pd−carboxylate oxygen separation is 3.02 Å,
thus suggesting that one of the chelate rings in the complex 19
must open completely on the way from the reactant to the
transition state. The presence in 19 of three fused rings, one
pyridine ring and two five-membered palladium carboxylate
rings, causes some ring strain, as can be seen from the small
value of the OPdO angle of 161.5°. The chelate ring strain may
be responsible for diminishing the energy necessary for one
ring opening and formation of TS1.
Table 2. Calculated First-Order Rate Constants kH and the
Gibbs Activation Energies for the C−H Activation of 8-
Methylquinoline with Complexes 5−7 in CD3COOD
Solution at 60 °C
complex
kH (s−1
)
ΔG⧧ (kcal/mol)
5
6
7
(2.8 0.1) × 10−3
(1.23 0.1) × 10−4
(4.7 0.1) × 10−5
23.5
25.6
26.2
A similar DFT analysis was performed for the 2,6-
pyridinedicarboxylate complex 20 derived from 7 featuring a
pyridine ring fused with two six-membered chelate rings
(Figure 4a). The chelate rings are not strained as can be seen
from the almost normal OPdO angle value of 178.7°.
Accordingly, a greater energy is needed to open one of the
chelate rings on the way to the reaction transition state TS2.
The DFT-calculated Gibbs activation energy for the C−H
activation of 20 is 30.5 kcal/mol in the gas phase and 28.5 kcal/
mol in acetic acid solution, which agree reasonably well with
the experimental value of 26.2 kcal/mol (Table 2). The
transition state TS2 can also be viewed as being typical for
cyclometalation−deprotonation reactions.17 The shortest car-
cleavage leading to 8 is slightly unfavorable thermodynamically;
its calculated Gibbs activation energy is 24.2 kcal/mol in the gas
phase and 21.6 kcal/mol in acetic acid solution. These
activation parameters agree reasonably well with the exper-
imental value of 23.5 kcal/mol (Table 2). Our analysis of the
reaction path using the intrinsic reaction coordinate (IRC)
shows that no intermediates such as agostic complexes are
involved. The transition state TS1 (Figure 3b) is typical for
cyclometalation−deprotonation reactions involving palladium-
(II) carboxylates.17 One of the carboxylate oxygen atoms is in
close proximity to the Pd-coordinated methyl group C−H
bond with an O···H distance of 1.44 Å. The agostic C−H bond
is elongated with a C−H distance of 1.34 Å. The corresponding
Figure 3. (a) Reaction Gibbs energy profile for the cyclopalladation of 8-methylquinoline complex 19. The OPdO angle in the reactant is 161.5°. (b)
Reaction transition state TS1 (in acetic acid). Selected distances (Å): O···H, 1.44; C···H, 1.34; Pd···H, 1.94; Pd···C, 2.26; Pd···O, 3.02.
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Figure 4. (a) Reaction Gibbs energy profile for the cyclopalladation of 8-methylquinoline complex 20. The OPdO angle in the reactant is 178.7°. (b)
Reaction transition state TS2 (in acetic acid). Selected distances (Å): O···H, 1.58; C···H, 1.24; Pd···H, 1.98; Pd···C, 2.32; Pd···O, 2.86.
a
boxylate oxygen atom−methyl group hydrogen distance is 1.58
Å, which is noticeably longer in comparison to TS1. The
agostic C−H bond is 1.24 Å, shorter than in TS1. The shortest
Pd···H and Pd···C contacts are 1.98 and 2.32 Å, respectively.
Overall, TS2 looks like an “earlier” transition state in
comparison to TS1, which may be related to the expected
greater basicity of the acetate oxygen in TS2 in comparison to
the pyridinecarboxylate oxygen in TS1. In spite of the expected
difference in basicity of the carboxylate oxygen atoms, the
Gibbs activation energy for C−H activation is noticeably higher
for 20 vs 19, which may be a consequence of the greater energy
cost needed for opening of the palladium(II) carboxylate
chelate ring in 20.
No DFT analysis of the reactivity of 8-methylquinoline
complex derived from 6 was performed. One can expect that, in
comparison to 19, the anticipated diminished chelate ring strain
in this palladium(II) carboxylate containing two six-membered
and one five-membered fused ring will place its reactivity
somewhere between those of 19 and 20, as is observed
experimentally (Table 2).
Oxidation of Palladacycles with O2. Aerobic oxidation of
pyridinecarboxylate-supported cyclopalladated complexes 8−11
was performed by stirring mixtures containing 0.025 mmol of
the substrate and 0.6 mL of AcOH under 1 atm of O2 at 20 °C.
Most of the systems were heterogeneous at this temperature
because of the poor solubility of palladacycles in acetic acid. In
spite of that fact, in all of the cases the solids disappeared in less
than 1 h. The combined yields of 8-quinolylmethanol and 8-
quinolylmethylacetate produced after 1 h of reaction are
comparable, ranging from 32 to 62%. Hence, the half-life for
the oxidation of 8−11 is about 1 h at 22 °C, which translates to
a Gibbs activation energy of 17.2 kcal/mol. Hence, the
oxidation rates are relatively fast in comparison to the C−H
activation step, which is slower even at 60 °C (Table 3). The
radical chain mechanism of oxidation of the PdII−CH3 bond
proposed earlier by Goldberg et al.18 for a dimethylpalladium-
(II) bipyridyl complex may be operational here. At this point
we can conclude that the reaction rate-limiting step is the C−H
activation.
Table 3. Oxidation of Palladacycles 8−11 with O2
yield of 8-
yield of 8-
quinolylmethanol quinolylmethyl acetate combined
entry substrate
(%)
(%)
yield (%)
1
2
3
4
8
32
26
40
10
13
12
22
22
45
38
62
32
9
10
11
a
The reactions were performed with 0.025 mmol of the palladacycle in
1 mL of AcOH under 1 atm of O2. The yields were determined by 1H
NMR spectroscopy using 1,4-dioxane as internal standard.
CONCLUSIONS
■
The new catalytic systems for the oxidative C−H acetoxylation
of 8-methylquinoline with O2 as the only oxidant and catalysts
comprised of Pd(OAc)2/pyridinecarboxylic acids 2−4 and/or
the derived palladium(II) complexes 5−7 were studied. The
pyridinecarboxylic acids 2−4 have the substituents in positions
2 and 6 of the pyridine ring that include the carboxylic group,
acetic acid, and methanesulfonic acid residues. The last two
may allow for the formation of more flexible palladium(II)
chelates in comparison to the reference compound containing
the 2,6-pyridinedicarboxylic acid core 1. These new catalytic
systems showed a slightly lower (Pd(OAc)2 + 3) or noticeably
lower activity in comparison to the reference system Pd(OAc)2
+ 1. Analysis of the rates of the C−H activation and O2
activation steps shows that the C−H activation is the rate-
limiting step determining the catalytic activity of the systems. In
turn, the size of the chelate rings and the chelate ring strain in
palladium(II) pyridinecarboxylates 5−7 were proposed to be
important factors governing the reactivity of these complexes
toward C−H bonds of the substrate. The combination of a
fused six-membered pyridine ring and two five-membered
chelate rings present in complex 19 makes it more reactive.
These results may be useful for development of novel
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hexane/EtOAc/Et3N 100/10/2) to afford pure 6-cyanomethylpyr-
idine-2-carboxylic acid ethyl ester 15 (0.85 g, 75%).
palladium(II) carboxylate based systems for C−H functional-
ization.
6-Cyanomethylpyridine-2-carboxylic acid ethyl ester 15 (0.85 g, 4.5
mmol) was mixed with 10 mL of 37% HCl. The mixture was heated at
100 °C for 15 h. After treatment of the mixture with charcoal and
filtration, the solvent was removed. The resulting solid was
recrystallized from hot water (60 °C) to give 6-(carboxymethyl)-
pyridine-2-carboxylic acid 3 as colorless needles (0.37 g, 45%).
1H NMR (500 MHz, 22 °C, DMSO-d6): δ 3.86 (s, 2H), 7.59 (m,
1H), 7.95 (m, 2H), 12.86 (br, 2H). 13C NMR (125 MHz, 22 °C,
DMSO-d6): δ 43.6, 123.3, 128.0, 138.2, 148.2, 155.7, 166.5, 172.0. ESI-
MS (m/z) of a solution of 3 in methanol: [M + 1]+ 182.052, calcd for
3-H+, C8H8NO4, 182.045. Anal. Found (calcd for C8H7NO4; with 0.1
H2O of crystallization): C, 52.46 (52.52); H, 3.89 (3.97); N, 7.62
(7.66).
Preparation of Dimethyl Sulfoxide 4-tert-Butyl-2,6-
dicarboxylatopalladium(II) 5. A solution of Pd(OAc)2 (44.8 mg,
0.2 mmol) in acetonitrile (2 mL) was mixed with a solution of 1 (49.1
mg, 0.22 mmol) in hot water (2 mL). The mixture was stirred for 5 h
at 20 °C and then reduced in volume to 1.5 mL. The resulting light
yellow precipitate was collected by filtration and dried under vacuum.
The obtained solid was dissolved in hot DMSO. When the solution
was clear, the solvent was removed under vacuum. The resulting
residue was triturated with a mixture of dichloromethane and hexanes
to give a solid which was collected by filtration and dried under
vacuum. Yield: 49 mg, 60%.
EXPERIMENTAL SECTION
■
General Procedures. All manipulations were carried out under
purified argon using standard Schlenk and glovebox techniques.
Solvents were dried and distilled following standard protocols and
stored in Teflon-sealed flasks in an argon-filled glovebox. All reagents
for which a synthesis is not given are commercially available from
Aldrich, Acros, Alfa Aesar, or Pressure Chemicals and were used as
received without further purification. Deuterated solvents from
Cambridge Isotope Laboratories were dried, vacuum-transferred, and
stored in an argon-filled glovebox. 4-tert-Butyl-2,6-pyridinecarboxylic
acid 1,5 2,6-pyridinediacetic acid 4,13 and complex 8,5 (H-t-Bu-
pda)Pd(CH2-8-quinolyl), derived from 4-tert-butyl-pyridine-2,6-dicar-
boxylic acid, are known compounds that were prepared following
1
published procedures. H (400 or 500 MHz) and 13C NMR (100 or
125 MHz) spectra were recorded on Bruker AVANCE 400 and Bruker
DRX-500 spectrometers. Chemical shifts are reported in ppm and
referenced to residual solvent resonance peaks. ESI-MS experiments
were performed using a JEOL AccuTOF-CS instrument. Elemental
analyses were carried out by Columbia Analytical Services, Tucson,
AZ.
Preparation of 6-(Sulfomethyl)pyridine-2-carboxylic Acid,
Lithium Salt 2. Ethyl 6-methylpicolinate 13 (1.65 g, 10 mmol) and
N-bromosuccinimide (1.96 g, 11 mmol) were mixed in dry chloroform
(30 mL) in a 50 mL Schlenk flask. The mixture was refluxed for 2 days.
The resulting red solution was cooled, washed with 5% sodium
carbonate solution (3 × 30 mL), and dried with anhydrous sodium
sulfate. The solvent was removed on a rotavap, and the reddish oil was
dried under vacuum. 6-Bromomethylpyridine-2-carboxylic acid ethyl
ester 14 was obtained in 40% yield according to 1H NMR. This crude
product was used in the next step without purification.
1H NMR (400 MHz, 22 °C, DMSO-d6): δ 1.35 (s, 9H), 7.80 (s,
2H); dimer 1.30 (s, 9H), 7.45 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz,
1H) (coordinated DMSO cannot be observed due to exchange with
DMSO-d6). ESI-MS (m/z) of a solution of 5 in methanol: [M+H]+
405.958, calcd for 5·H+, C13H18NO5PdS, 405.994. Anal. Found (calcd
for C13H17NO5PdS): C, 38.35 (38.48); H, 4.50 (4.22); N, 3.40 (3.45).
Preparation of palladium(II) Pyridinecarboxylates 6 and 7.
Pd(OAc)2 (44.8 mg, 0.2 mmol) and the corresponding acid 3 or 4 (0.2
mmol) were mixed in 2 mL of DMSO, and the mixture was heated at
80 °C for 1 h. The solvent was removed under vacuum, and the
residue was triturated with ether, filtered off, washed with ether, and
dried to give a powder.
Potassium sulfite (2.0 g, 12.6 mmol) and 90% potassium hydroxide
(0.4 g, 6.4 mmol) were dissolved in 25 mL of water. The resulting
solution was added to 6-bromomethylpyridine- 2-carboxylic acid ethyl
ester placed in a 100 mL flask. The reaction mixture was stirred for 24
h at room temperature. Nonionic organic impurities were extracted
with dichloromethane (3 × 30 mL). The yellow aqueous phase was
brought to pH 3 with concentrated HCl and then boiled for 5 min
with charcoal and filtered. Water was removed, and the resulting solid
was dried under vacuum. The solid was extracted with boiling benzene
(3 × 20 mL) to separate 6-methylpicolinic acid. The residue was
washed with cold 6 M HCl (20 mL) to remove most of the inorganic
impurities. Further purification of the crude 6-(sulfomethyl)pyridine-
2-carboxylic acid was performed by recrystallization from hot water to
give colorless crystals (0.30 g, 35%). The monolithium salt of 6-
(sulfomethyl)pyridine-2-carboxylic acid, 2, can be obtained in
quantitative yield by treating the acid with 0.5 equiv of lithium
carbonate.
[(L3)Pd(dmso)] 6 was obtained as a light brown powder in 95%
yield. 1H NMR (500 MHz, 22 °C, DMSO-d6): δ 2.55 (s, 6H), 4.14 (s,
2H), 7.70 (m, 2H), 8.22 (t, J = 7.5 Hz, 1H). 13C NMR (125 MHz, 22
°C, DMSO-d6): δ 41.0, 45.6, 125.0, 128.8, 142.4, 158.3, 169.5, 171.2.
ESI-MS (m/z) of a solution of 6 in methanol: [M + 1]+ 363.961, calcd
for 6-H+, C10H12NO5PdS, 363.947. Anal. Found (calcd for
C10H11NO5PdS): C, 33.32 (33.03); H, 3.41 (3.05); N, 3.65 (3.85).
[(L4)Pd(dmso)] 7 was obtained as a yellow powder in 92% yield.
1H NMR (500 MHz, 22 °C, DMSO-d6): δ 2.55 (s, 6H), 4.26 (s, 4H),
7.55 (d, J = 7.5 Hz, 2H), 8.04 (t, J = 7.5 Hz, 1H). 13C NMR (125
MHz, 22 °C, DMSO-d6): δ 40.9, 49.0, 123.6, 142.4, 157.0, 170.3. ESI-
MS (m/z) of a solution of 7 in methanol: [M + 1]+ 377.993, calcd for
7-H+, C11H14NO5PdS, 377.963. Anal. Found (calcd for
1
1
C10H11NO5PdS with /3 DMSO based on H NMR spectrum): C,
1H NMR (500 MHz, 22 °C, D2O): δ 4.66 (s, 2H), 8.06 (d, 1H, JHH
34.60 (34.71); H, 4.33 (3.74); N, 3.56 (3.47).
= 7.5 Hz), 8.30 (d, 1H, JHH = 8.0 Hz), 8.49 (t, 1H, JHH = 8.0 Hz). 13
C
Palladacycle Supported by 6-(sulfonatomethyl)pyridine-2-
carboxylate 9. To a solution of [Pd(CH2-8-quinolyl)(OAc)]2 16
(30.7 mg, 0.1 mmol) in dimethylformamide (1 mL) was added the 6-
(sulfonatomethyl)pyridine-2-carboxylic acid lithium salt 2 (22.3 mg,
0.1 mmol) in dimethylformamide (1 mL) dropwise under an argon
atmosphere at room temperature. A light yellow precipitate formed in
10 min. The mixture was stirred for a further 0.5 h. Diethyl ether (8
mL) was added slowly to the mixture to allow for more solid to
precipitate. The mixture was left standing at −32 °C overnight. The
yellow solid was filtered off, washed with diethyl ether (2 × 1 mL), and
dried under vacuum overnight to give the product. Yield 89%.
1H NMR (500 MHz, 22 °C, DMSO-d6): δ 3.83 (s, 2H), 4.14 (s,
2H), 7.63 (t, J = 7.5 Hz, 1H), 7.68 (dd, J = 7.0, 1.0 Hz, 1H), 7.74 (dd,
J = 8.0, 5.0 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.88 (br, 1H), 7.95 (br,
1H), 8.05 (m, 1H), 8.66 (dd, J = 8.0, 1.0 Hz, 1H), 9.01 (d, J = 5.0 Hz,
1H). 13C NMR (125 MHz, 22 °C, DMSO-d6): δ 60.0, 123.6, 125.1,
129.8, 129.9, 140.0, 151.3, 153.2, 169.9. ESI-MS (m/z) of a solution of
NMR (125 MHz, 22 °C, D2O): δ 54.7, 125.2, 130.0, 145.4, 146.8,
148.2, 164.7. ESI-MS (m/z) of a solution of 2 in methanol: [M + 1]+
224.023, calcd for 2-H+, C7H7LiNO5S, 224.021. Anal. Found (calcd for
3
C7H6LiNO5S with
/
H2O based on 1H NMR spectrum using
2
DMSO-d6 as solvent): C, 33.87 (33.61); H, 3.33 (3.63); N, 5.54
(5.60).
Preparation of 6-(Carboxymethyl)pyridine-2-carboxylic
1
Acid 3. A crude bromination product containing, according to H
NMR spectroscopy, 6-bromomethylpyridine-2-carboxylic acid ethyl
ester 14 (6 mmol) and ethyl 6-methylpicolinate 13 (12 mmol) was
dissolved in 50 mL of tetrahydrofuran, and then a solution of KCN
(0.58 g, 9 mmol) in 10 mL of water was added. The mixture was
stirred at 50 °C for 15 h. Most of the THF was removed on a rotavap.
The residue was extracted with dichloromethane. The organic layer
was washed with water, dried, and evaporated to give a brown oil. This
crude product was purified by flash column chromatography (SiO2,
4889
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Organometallics
Article
9 in methanol: [M − Li]− 462.978, calcd for [9-Li]−, C17H13N2O5PdS,
in a 25 mL Schlenk tube. The mixture became turbid when heated at
80 °C for 30 min. A clear solution was obtained after 8-
methylquinoline (0.5 mmol) and acetic anhydride (2.5 mmol) were
added. The Schlenk tube was purged with O2 for 10 min and then
heated to 80 °C. Some light yellow precipitate was observed after 1 h,
except when 2 was used. More solid formed after 24 h, except for the
case when 2 was used. Upon cooling to room temperature, a sample of
462.958. Anal. Found (calcd for C17H13LiN2O5PdS with 2 DMF based
1
on H NMR spectrum): C, 44.76 (44.78); H, 4.71 (4.41); N, 8.80
(9.08).
Palladacycle Supported by 6-Carboxymethyl-2-pyridinecar-
boxylate 10. To a solution of [Pd(CH2-8-quinolyl)(OAc)]2 16 (30.7
mg, 0.1 mmol) in dimethylformamide (1 mL) was added 6-
(carboxymethyl)pyridine-2-carboxylic acid 3 (18.1 mg, 0.1 mmol) in
dimethylformamide (1 mL) dropwise under an argon atmosphere at
room temperature. A yellow precipitate formed in 5 min. The mixture
was stirred for a further 0.5 h. Diethyl ether (8 mL) was added slowly
to the mixture to allow for more solid to precipitate. The mixture was
left at −32 °C overnight. The yellow solid was filtered off, washed with
diethyl ether (2 × 1 mL), and dried under vacuum overnight. Yield
99%.
1
the mixture was diluted with CD3COOD and the H NMR spectrum
was recorded. Yields of the organic products, 8-quinolylmethanol and
1
8-quinolylmethyl acetate, given in Table 3 were determined by H
NMR integration using 1,4-dioxane as an internal standard.
General Procedure for the C−H Activation Kinetics Experi-
ments between 8-Methylquinoline and CD3COOD by Com-
plexes 5−7. 8-Methylquinoline (7.2 mg, 0.05 mmol), complex 5, 6,
or 7 (0.05 mmol), and dioxane (5.0 μL, internal standard) were mixed
with CD3COOD (0.6 mL) in an NMR tube fitted with a J. Young
Teflon valve under argon. The NMR tube was shaken until the solid
dissolved completely. A 1H NMR spectrum was recorded at this point.
Then the NMR tube was submerged in a preheated oil bath (60 °C).
Attempts to characterize complex 10 by NMR were unsuccessful
because of its poor solubility in most solvents (e.g., CHCl3, CH2Cl2,
AcOH, MeOH, H2O, DMSO). Anal. Found (calcd for
C18H14N2O4Pd): C, 50.91 (50.43); H, 4.05 (3.29); N, 6.78 (6.53).
Palladacycle Supported by 6-Carboxymethyl-2-pyridylace-
tate 11. To a solution of [Pd(CH2-8-quinolyl)(OAc)]2 16 (30.7 mg,
0.1 mmol) in acetic acid (2 mL) was added 2,6-pyridinediacetic acid 4
(19.5 mg, 0.1 mmol) in acetic acid (2 mL) dropwise under an argon
atmosphere at room temperature. The mixture was stirred for a further
0.5 h. Diethyl ether (8 mL) was added slowly to the mixture to allow
for product to precipitate. The mixture was left standing at −32 °C
overnight. The yellow solid was filtered off, washed with diethyl ether
(2 × 1 mL), and dried under vacuum overnight to give the product.
Yield 86%.
1
The percent deuterium incorporation was determined by H NMR
integration with respect to the internal standard.
General Procedure for Aerobic Oxidation of Cyclopalla-
dated Complexes 8, 9, and 11. The cyclopalladated complex 8, 9,
or 11 (0.025 mmol) and 2 μL of dioxane (internal standard) were
mixed with CD3COOD (1 mL) in a NMR tube fitted with a J. Young
1
Teflon valve under argon. A H NMR spectrum (zero point) was
recorded before O2 was introduced into the NMR tube. The tube was
maintained at 20 °C and was shaken periodically. The yields of the
oxidation products, 8-quinolylmethanol and 8-quinolylmethyl acetate,
1
were determined by H NMR integration after 1 h. In all cases, the
1H NMR (500 MHz, 22 °C, CDCl3): δ 3.55 (s, 2H), 4.55 (br d, 2H,
J = 12.4 Hz), 4.75 (br d, 2H, J = 12.5 Hz), 6.88 (dd, J = 8.0, 5.0 Hz,
1H), 7.37−7.43 (m, 5H), 7.77−7.82 (m, 2H), 8.70 (d, J = 4.0 Hz,
1H), 12.31 (br, 1H). 13C NMR (150 MHz, 22 °C, CDCl3): δ 48.4,
120.7, 122.9, 124.2, 127.7, 127.8, 136.7, 138.4, 147.3, 148.7, 151.5,
157.3, 172.0. Anal. Found (calcd for C19H16N2O4Pd with 1 AcOH
1
signals of starting materials disappeared in the H NMR spectra after
that time.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
based on H NMR spectrum): C, 49.84 (50.16); H, 4.38 (4.01); N,
Text, figures, tables, and a CIF file giving details of the DFT
calculations, kinetics data analysis, X-ray characterization for 12,
and NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
5.74 (5.57).
Palladacyclic 5-Isopropyl-8-methylquinoline Derivative
Supported by 6-Carboxylmethyl-2-pyridylacetate (12). To a
solution of [Pd(5-iPr-8-quinolylmethyl)(OAc)]2 (34.9 mg, 0.1 mmol)
in acetic acid (2 mL) was added 2,6-pyridinediacetic acid 4 (19.5 mg,
0.1 mmol) in acetic acid (2 mL) dropwise under an argon atmosphere
at room temperature. The mixture was stirred for a further 0.5 h.
Diethyl ether (8 mL) was added slowly to the mixture to allow for the
product to precipitate. The mixture was left standing at −32 °C
overnight. The yellow solid was filtered off, washed with diethyl ether
(2 × 1 mL), and dried under vacuum overnight. Yield 91%. Two
isomeric species in about a 10:1 ratio were detected in chloroform
AUTHOR INFORMATION
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
This material is based upon work supported as part of the
Center for Catalytic Hydrocarbon Functionalization, an Energy
Frontier Research Center funded by the U.S. Department of
Energy, Office of Science, Office of Basic Energy Sciences,
under Award Number DE-SC0001298.
solutions of 12 by means of H NMR spectroscopy.
Anal. Found (calcd for C22H22N2O4Pd with 1 AcOH): C, 53.10
(52.90); H, 5.82 (4.81); N, 5.28 (5.14).
1
Data for the major isomer are as follows. H NMR (500 MHz, 22
°C, CDCl3): δ 1.35 (d, J = 7.0 Hz, 6H), 3.49 (hept, J = 7.0 Hz, 1H),
3.53 (s, 2H), 4.45 (d, J = 14.0 Hz, 2H), 4.76 (d, J = 15.0 Hz, 2H), 7.01
(dd, J = 8.0, 5.0 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 8.0 Hz,
2H), 7.44 (d, J = 7.0 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 8.19 (d, J = 8.5
Hz, 1H), 8.72 (d, J = 4.5 Hz, 1H), 12.67 (br s, 1H). 13C NMR (125
MHz, 22 °C, CDCl3): δ 24.4, 28.8, 49.5, 66.6, 121.5, 124.8, 125.3,
127.5, 128.8, 134.1, 139.5, 142.3, 146.2, 149.6, 153.5, 158.5, 173.7.
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