Exploring the mechanism of Stille C-C coupling via peptide-capped Pd nanoparticles results in low temperature reagent selectivity

Article abstract of DOI:10.1039/c2cy20636f

Herein we systematically probed the atom-leaching mechanism of Pd nanoparticle-driven Stille coupling to further elucidate the fate of the highly active Pd⁰ atoms released in solution. In this regard, initial oxidative addition at the particle surface results in Pd atom abstraction for reactivity in solution. As a result, two reaction sites are present, the particle surface and pre-leached Pd atoms, thus different degrees of reactivity are possible. This effect was probed via aryl halide combinations that varied the halogen identity allowing for oxidative addition of two substrates simultaneously. The results demonstrate that the system was highly reactive for iodo-based compounds in the mixture at room temperature; however, reactivity at bromo-based substrates was only observed at slightly elevated temperatures of 40.0 °C. As such, substrate selectivity was evident from the catalytic materials that can be controlled based upon the aryl halide composition and reaction temperature. Furthermore, both intermolecular and intramolecular selectivity is possible, thus raising the degree of reaction complexity that can be achieved.

Full text of DOI:10.1039/c2cy20636f

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Exploring the mechanism of Stille C–C coupling via
peptide-capped Pd nanoparticles results in low
temperature reagent selectivity
Cite this: DOI: 10.1039/c2cy20636f
Dennis B. Pacardo and Marc R. Knecht*
Herein we systematically probed the atom-leaching mechanism of Pd nanoparticle-driven Stille coupling
to further elucidate the fate of the highly active Pd0 atoms released in solution. In this regard, initial
oxidative addition at the particle surface results in Pd atom abstraction for reactivity in solution. As a
result, two reaction sites are present, the particle surface and pre-leached Pd atoms, thus different
degrees of reactivity are possible. This effect was probed via aryl halide combinations that varied the
halogen identity allowing for oxidative addition of two substrates simultaneously. The results
demonstrate that the system was highly reactive for iodo-based compounds in the mixture at room
temperature; however, reactivity at bromo-based substrates was only observed at slightly elevated
temperatures of 40.0 1C. As such, substrate selectivity was evident from the catalytic materials that can
be controlled based upon the aryl halide composition and reaction temperature. Furthermore, both
intermolecular and intramolecular selectivity is possible, thus raising the degree of reaction complexity
that can be achieved.
Received 11th September 2012,
Accepted 15th November 2012
DOI: 10.1039/c2cy20636f
www.rsc.org/catalysis
the carbon efficiency of the reaction. To achieve these capabilities, it
is important to fully understand and exploit the mechanism
Introduction
Recent advances in nanotechnology have enabled the design
and fabrication of new materials with unique properties for a
wide range of applications. An emerging important application
for nanomaterials focuses on their use in catalytic technologies.1
For instance, a variety of different materials have been realized
for reactivity in C–C coupling,2–11 olefin hydrogenation,12–15
nitro-group reduction,16–18 and remediation of trichloro-
ethene.19–21 This reactivity typically arises from the inorganic core;
however, catalytic activity can also be achieved via the ligands bound
to the particle surface.22,23 While the basic catalytic properties of
these materials have been demonstrated, enhancing and/or
expanding their functionality is highly desirable. Typically, this
can be achieved in two ways: by optimizing for reactivity under
ambient/green conditions or by increasing the degree of catalytic
selectivity based upon the reagents.24–27 Together, such approaches
are important as they lower the environmental impact of catalysis,
minimize energy consumption required to drive the reaction, as well
as limit the number of separation steps required to purify the final
product. The latter point of separation is critically linked to catalyst
selectivity that minimizes byproduct formation, thus also enhancing
employed by the catalytic nanomaterials, which can be challenging
to study due to the complexity of the system and the limited
analytical techniques available. Through this understanding,
individual steps of the catalytic cycle could be exploited to enhance
the system and/or realize reagent selectivity.
We have previously reported the biomimetic synthesis of
nanocatalysts designed using Pd-specific peptides that bind
directly to the nanoparticle surface.3,28 In this regard, the Pd4
peptide (TSNAVHPTLRHL) caps growing Pd nanoparticles upon
recognition of the face centered cubic (fcc) metallic structure
through the strong interactions of the histidine residues.3,28–32
Using this approach, B2 nm Pd nanoparticles can be generated
that are highly reactive for the Stille C–C coupling reaction.3 As
such, the reaction can be employed to elucidate important
surface structural effects of the biotic/abiotic interface of the
materials that would be difficult to study. Using the Pd4-capped
Pd nanoparticles for Stille coupling under non-traditional con-
ditions of an aqueous solvent at room temperature, quantita-
tive product yields were observed at low catalyst loadings
(>0.001 mol% Pd).3,28 Furthermore, both the particle size and
catalytic reactivity can be tuned as a function of the peptide
sequence, where minor structural changes can result in signifi-
cant alterations in the catalytic functionality.29–31 Taken together,
Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables,
Florida 33146, USA. E-mail: knecht@miami.edu; Tel: +1 305 284-9351
c
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Scheme 1 Representative scheme for reagent selectivity of the peptide-capped Pd nanoparticles for two aryl halide substrates at different reaction temperatures
based upon the catalytic mechanism.
these materials represent a model system for studying ligand- different aryl halide substrates, Stille coupling with an
capped catalysts that could address environmental and energy organostannane reagent can be achieved, where selectivity is
concerns.3,28
observed as a function of the reaction temperature, aryl halide
Given the advantages of generating efficient catalytic composition, and the catalytic mechanism. As summarized in
systems, it is important to understand the underlying princi- Scheme 1, the Pd nanoparticles selectively couple aryl iodide
ples driving the reaction. Recent studies of the Stille coupling substrates over bromo- or chloro-derivatives in the same reac-
reaction using the Pd4-capped Pd nanoparticles suggest that an tion mixture at room temperature generating the anticipated
atom-leaching mechanism is possible (Scheme 1).28 In this product; however, a mild increase in system temperature to
mechanism, the particles act as catalytic reservoirs containing 40.0 1C enables reactivity at the bromo substrate. These results
the active metal species, which has been similarly proposed for indicate functional group catalytic selectivity that is inversely
other C–C coupling reactions.1,4,28,33,34 During the initial related to the strength of the carbon–halogen bond. By increasing
oxidative addition step, Pd atoms are abstracted from the the reaction temperature to 60.0 1C, catalytic selectivity is lost
nanoparticles, from which the catalytic cycle can then occur wherein reactivity at both iodo and bromo substituents is
in solution to produce the final product and regenerate the Pd0 observed. Furthermore both intermolecular (separate reagents)
species. These free Pd0 atoms can then be recycled through the and intramolecular (two reactive sites in a single reagent)
catalytic process until reaction completion, upon which the selectivity is observed, raising the level of reaction complexity
atoms are quenched by the remaining particles.1,28,31 These Pd possible under low-temperature conditions using the peptide-
nanoparticles also demonstrated varying degrees of reactivity capped materials. This selectivity is achieved based upon the
with aryl halides as a function of the halogen group. To that catalytic leaching mechanism, where an apparent energy barrier
end, iodo-derivatives are typically reactive for Stille coupling at is present that prevents bromo-based reactivity at room tempera-
room temperature, while bromo-based species require a slight ture. This suggests that oxidative insertion of the Pd0 materials
increase in temperature to 40.0 1C for reactivity.28 This across the C–Br bond is prevented, regardless of whether the
temperature effect could be directly related to the bond dis- metallic component is constrained within the zerovalent particle
sociation energies of the carbon–halogen bond wherein C–Br or pre-leached into solution. These results are important for
(285 kJ molÀ1) > C–I (232 kJ molÀ1).35 While it is clear that aryl advancing catalytic nanotechnologies to achieve energy- and
bromides are unable to abstract Pd0 atoms from the nano- carbon-efficient systems.
particle surface at room temperature,28 it is unclear if the
abstracted Pd0 atoms can insert across the C–Br bond to drive
the reaction under such conditions. As such, to more fully
Experimental
Chemicals
understand and elucidate the fundamental catalytic properties
of the system and the overall mechanism, additional studies
are required that could be used to enhance the reactivity of the KOH, N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA),
materials.
and dichloromethane were purchased from Acros Organics.
Here we report the reactivity and substrate selectivity of 4-Bromobenzoic acid (2) was acquired from Alfa Aesar. 4-Chloro-
4-Iodobenzoic acid (1), NaBH4, CDCl3, NaCl, 4-tert-butylphenol,
peptide-capped Pd nanoparticles in a mixture of reagents. This
study provides important information concerning the catalytic
reaction mechanism and degree of reactivity. By employing
benzoic acid (4) and 3-bromo-5-iodobenzoic acid (5) were
purchased from TCI America. 3-Chloro-5-iodobenzoic acid (8),
3-bromo-5-chlorobenzoic acid (10), and 2-chloro-5-iodobenzoic
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acid (19) were obtained from Oakwood Products, while
This same system was also studied at 60.0 1C throughout the
3,5-diiodobenzoic acid (11) was acquired from Spectra Group reaction to determine the effect of higher temperature. In this
Limited. PhSnCl3, K2PdCl4, 3,5-dibromobenzoic acid (13), setup, the reaction mixture was prepared and mixed, from
2-bromo-5-iodobenzoic acid (17), and 2-chloro-4-iodobenzoic which aliquots were transferred to separate vials and immediately
acid (21) were obtained from Sigma-Aldrich. Finally, 2,5- placed in an oil bath heated to 60.0 1C. At selected time points,
diiodobenzoic acid (14) was purchased from MP Biomedicals. the reactions were quenched and the products were extracted and
Diethyl ether was obtained from VWR and 18 mO cm water quantitated using the standard approach.
(Millipore) was employed throughout. All reagents were used as
Aryl dihalide reactivity
received without additional purification.
The effects of multiple halogen functional groups within a
single molecule on both the catalytic mechanism and the
reaction selectivity were initially studied using 5. In a reaction
vial, 0.25 mmol of 5 and 0.6 mmol of PhSnCl3 were dissolved in
6.00 mL of 1.5 M KOH. To this mixture, 0.25 mL of the freshly
prepared Pd nanoparticles (0.05 mol% Pd) was added and the
reaction was stirred at room temperature for 24.0 h. Once
complete, the reaction was quenched using 50.0 mL of 5%
HCl. The products of the reaction were extracted and quanti-
tated as described above. Additional variations to this basic
procedure were also studied by changing the Pd catalyst
concentration and/or reaction temperature while holding all
other conditions constant. The same procedure was employed
for the following aryl dihalides: 8, 10, 14, 17, 19, and 21. For 11
and 13, identical procedures were also used; however, the
starting materials were dissolved using 15.0 mL of 1.0 M
KOH and 7.0 mL of 1.5 M KOH, respectively, due to reagent
solubility.
The time-resolved formation of the coupling products
between 5 and PhSnCl3 was monitored by scaling up the
reaction and extracting aliquots at selected time intervals.
Specifically, 3.75 mmol of 5 and 9.0 mmol of PhSnCl3 were
co-dissolved in 90.0 mL of 1.50 M KOH. When the reagents
were dissolved, 5.00 mL of the freshly prepared Pd nano-
particles (0.05 mol% Pd) was added. 6.00 mL aliquots were
then taken and quenched every 30.0 min for 5.0 h followed by
product extraction and quantitation. A similar procedure was
Characterization
The reaction products were characterized using GC-MS and
1H NMR. For GC-MS analysis, B1 mg of the product was
dissolved in 200 mL of MSTFA, which was allowed to react for
2.00 h.3 The sample was then diluted with 2.00 mL of dichloro-
methane before analysis using an Agilent 5975C GC-MS system.
All products, including those generated using both the mono-
and di-substituted aryl halides, were processed using this
approach. For 1H NMR analysis, a Bruker 400 MHz spectro-
meter with an autotuning multinuclear probe was employed.
The percent yields of the products were determined by comparing
the peaks of the internal standard (t-butyl phenol) with the product
peak.3 For the reactions using 1 and 2, the peak at 8.17 ppm
corresponds to the biphenylcarboxylic acid (3) product while the
peak at 6.7 ppm corresponds to the internal standard. The ratio of
the integration of these two peaks was used to calculate the
percent yield of the reaction as previously demonstrated.3 Further-
more, the amount of unreacted starting materials was determined
by comparing the ratio of the peaks at 7.8 ppm (1), 7.93 ppm (2),
and 8.0 ppm (4) with that of t-butyl phenol. For the di-substituted
aryl halides, identical methods were employed where peaks
associated with the mono- and di-substituted products were used
to determine the product yield.
Catalytic reactions with multiple aryl halides
For all reactions, Pd nanoparticles capped with the Pd4 peptide used for 11; however, product formation was monitored every
were prepared at a Pd : peptide ratio of 3.3 using previously 10.0 min for 1.00 h, followed by 30.0 min intervals over an
described methods.3 For the catalytic reactions involving two additional 2.00 h.
separate aryl halide substrates, a system composed of 1 and 2 is
described; however, identical procedures and conditions were
employed for reactions with two reagents. In a reaction flask at
Results and discussion
room temperature, 5.00 mmol of 1 and 5.00 mmol of 2 were Based upon the proposed Pd leaching mechanism, aryl halide
co-dissolved in 160 mL of 2.25 M KOH. To this solution, oxidative addition occurs at two specific locations: at the
12.0 mmol of PhSnCl3 was added, followed by the direct nanoparticle surface and at free Pd0 atoms in solution.1,4,28,33,34
injection of 10.0 mL of the freshly prepared Pd4-capped Pd Initially, oxidative addition at the nanoparticle surface occurs
nanoparticles. Under these conditions,
a reaction with to leach the Pd atoms into solution, from which subsequent
0.05 mol% Pd was generated with respect to the total aryl oxidative addition processes can occur with additional aryl
halide concentration in solution. Immediately upon nano- halide reagents.28 Intrinsically, the reactivity for these two steps
particle addition, 8.00 mL aliquots were extracted, separated could be significantly different based upon the aryl halide
into vials, reacted while stirring, and subsequently quenched substrate. For instance, from previous studies using the
with 50.0 mL of 5% HCl at specified time intervals. After 2.0 h peptide-capped materials, it is known that aryl iodides can
at room temperature, the remaining reaction vials were placed oxidatively add to the Pd metal at the nanoparticle surface at
in an oil bath at 40.0 1C and then quenched at selected time room temperature, while aryl bromides cannot;3,28 however,
points. For all of the quenched reactions, the product was different reactivity for the leached Pd0 atoms could be observed
extracted, characterized, and quantitated.
as a function of the halogen group. In this regard, while no
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reaction is observed for aryl bromides at room temperature concomitant with an increase in the product quantity. Interest-
with the Pd nanoparticles, Stille coupling could be noted from ingly, the rate of consumption of 2 at 40.0 1C was slower than
such reagents using the leached Pd0 atoms. Such mechanistic the consumption of 1 at room temperature, suggesting a
information could be quite useful in the design of selective change in the reaction rate as a function of halogen identity.
catalytic materials. As such, equal amounts of aryl halides that
These results indicate that the peptide-capped Pd nano-
varied the halogen only were co-reacted with the peptide- particles preferentially drive coupling at the iodo-derivative
capped Pd nanoparticles to monitor product formation. over the bromo-species at room temperature, regardless of
Initially, 1, 2, and 4 were used since the substrates exhibited whether Pd0 atoms are pre-leached into solution. Pd0 atoms
different levels of reactivity: 1 is known to readily react for Stille are abstracted from the nanoparticle surface by aryl iodide
coupling at room temperature, slightly higher temperatures of oxidative addition, thus they would be available for reactivity
40.0 1C are required to drive the same reaction with 2, while 4 with the aryl bromide compound upon completion of the first
does not typically react.3,28
Stille coupling cycle. As such, this suggests that an energy
Fig. 1a schematically presents the process employed for barrier exists for aryl bromide oxidative addition at both the
using two different aryl halide substrates in the reaction. For nanoparticle surface and the highly reactive Pd0 atoms in
this, 1 and 2 are commixed in the reaction medium with solution.
PhSnCl3 and sufficient Pd nanoparticles to reach a concen-
To probe this mechanistic observation, additional studies of
tration of 0.05 mol% Pd. The reaction is initially monitored at different aryl halide combinations and selected reaction
room temperature (B25.0 1C), followed by heating to 40.0 1C temperatures were employed. Initially, an identical coupling
after 2.00 h. The progress of the reaction, monitored at selected system was studied with 1 and 2; however, the reaction was
time points, is shown in Fig. 1b. The plot represents the processed at 60.0 1C throughout the experiment. At this temperature,
amount, in mmol, of 1 (blue triangles), 2 (red circles), and both substrates should readily undergo coupling to generate
the product, 3 (green squares), present in the reaction at the common product 3, as shown in Fig. 1c. In this study, rapid
given time. Immediately after catalyst addition at room consumption of 1 is observed, faster than at room temperature,
temperature, rapid consumption of 1 was observed as shown resulting in complete reagent consumption within 40.0 min.
by the exponential decrease in the amount of reagent in the Additionally, immediate coupling is observed for 2; however,
reaction. After 1.0 h, only trace amounts of this reagent were the rate of the reaction for the bromo-derivative is slower
present in the mixture, which reached complete consumption compared to the iodo-derivative. Complete exhaustion of 2 is
at 2.0 h. Consequently, the quantity of product 3 rapidly not observed, resulting in B70% of the substrate generating
increased over the initial 1.0 h time frame to eventually product, consistent with previous studies.28 Further co-reactivity
saturate. Conversely, the amount of 2 remained constant for studies were also conducted using a mixture of 1 and 4, as
the first 2.0 h of the reaction at room temperature. A minor presented in Fig. 2. Fig. 2a specifically presents the study of the
decrease may be present; however, this is within the statistical reaction at room temperature, while Fig. 2b presents the analysis
noise of the study. After 2.0 h at room temperature, the reaction of the reaction at 60.0 1C. As anticipated, when the reaction was
mixture was mildly heated to 40.0 1C, where previous results processed at room temperature, rapid formation of product 3
demonstrated maximal reactivity for 2.28 At the elevated (green squares) was observed from 1 (blue triangles), with
temperature, the bromo-based substrate is consumed, complete reagent consumption at 2.00 h, while no coupling
was noted from 4 (black diamonds) throughout the process.
When the reaction was studied at the elevated temperature of
60.0 1C (Fig. 2b), rapid consumption of 1 was noted over a
40.0 min time frame with no product formation arising from the
chloro-derivative. Additional Stille coupling studies of mixtures
of 2 and 4 were performed using the peptide-capped Pd nano-
particle catalysts. Fig. 2c presents the catalytic analysis for the
Stille coupling reaction using these two reagents at room
temperature with a 0.05 mol% Pd catalyst concentration. Under
these conditions, no coupling product is observed after 5.00 h.
When the reaction was studied at a temperature of 60.0 1C,
Fig. 2d, consumption of 2 is noted (red circles) along with an
increase in the formation of 3 (green squares). Again, no
reactivity of 4 is observed even at the higher temperature with
leached Pd0 present in the medium. Fig. 2e presents the scheme
for the competition reaction between 2 and 4 at different
Fig. 1 Effects of aryl halide mixtures for the Stille coupling reaction using peptide-
capped Pd nanoparticle catalysts. Part (a) presents the reaction between 1 and 2
temperatures.
at the indicated temperatures. Part (b) displays the time based analysis of the
Taken together, these studies demonstrate important results
reactions using 1 and 2 at 25.0 1C (blue region) for 2.0 h, followed by heating the
concerning the reactivity of Pd nanoparticles for C–C coupling
reactions based upon the catalytic mechanism. In the proposed
reaction mixture to 40.0 1C (red region), while part (c) presents the Stille coupling
analysis over time using 1 and 2 at 60.0 1C throughout the study.
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affect the oxidative addition processes and could potentially be
applied to different C–C coupling reactions. Furthermore, these
capabilities could also be exploited to engender the biomimetic
system with catalytic selectivity. In that regard, these studies
suggest selectivity for iodo-based substrates over bromo- and
chloro-based reagents as a function of temperature. This selective
reactivity is based upon the mechanism of the reaction and the
thermodynamics of the system. While this was observed for
intermolecular reaction systems, intramolecular reactivity and
selectivity may also be possible; however, the electronics of the
system may change the degree of reactivity.
The reactivity of aryl dihalide substrates was initially studied
using a benzoic acid derivative containing two different halide
groups, 5 (Table 1, entry 1). In this reaction, the effect of having
two reaction centers on the aryl ring was investigated through
the formation of two likely products, 3-bromo-5-phenylbenzoic
acid (6) and 3,5-diphenylbenzoic acid (7); the former is
generated from the reaction of the iodo-component of the
substrate, while the latter from the reaction of both the
iodo- and bromo-components. A third product is possible,
3-iodo-5-phenylbenzoic acid; however, this product is unlikely
Fig. 2 Parts (a and b) present the time resolved analysis of the Stille coupling
process employing mixtures of 1 and 4 at room temperature and at 60.0 1C,
respectively, while parts (c and d) display the same temperature analysis for
mixtures of 2 and 4 at the same temperatures. The scheme for the reaction of 2
and 4 at different temperatures is shown in part (e).
Table 1 Analysis of Stille coupling reactions using aryl dihalide substrates and the
peptide-capped Pd nanoparticle catalyst
Possible products
Aryl
Entry dihalides
Mono-
substituted yield
Percent
Di-
Percent
substituted yield
leaching mechanism (Scheme 1), aryl halide oxidative addition
occurs at the nanoparticle surface, which abstracts reactive Pd
species. After completion of the catalytic cycle, highly reactive
Pd0 components are released in the reaction medium, from
which secondary oxidative addition with additional substrates
can occur to recycle through the process. Eventually, these
reactive Pd0 species are quenched by the remaining particles
in the mixture; however, two different oxidative addition steps
are present that are likely to be both thermodynamically and
kinetically different. These results indicate that while the two
oxidative additions are indeed different, the reactivity for the
separate processes remains similar. To that end, aryl iodides
are reactive for oxidative addition at room temperature at both
the nanoparticle surface and the leached Pd0 atoms, while
elevated temperatures are required for reactivity in both processes
for aryl bromides. Regardless of the oxidative addition step, aryl
chlorides remain unreactive. Such results are likely to be related to
the relative values of the C–X bond dissociation energies asso-
ciated wherein C–I (232 kJ molÀ1) o C–Br (285 kJ molÀ1) o
C–Cl (338 kJ molÀ1).35 As such, in the Stille coupling reaction, the
aryl iodide substrate reacts rapidly at room temperature, indicating
that both oxidative addition steps readily occur without the need
for thermal activation. On the other hand, the bromo-species
require mild heating to 40.0 1C for the coupling reaction to occur
due to the stronger C–Br bond. The aryl chloride, however, does
not undergo coupling even at 60.0 1C due to the greater energy
required for activation of the C–Cl bond. Mechanistically, these
results provide a greater understanding of the different factors that
70.8 Æ 0.9a
22.1 Æ 2.5a
33.6 Æ 1.9b
19.3 Æ 6.0c
12.9 Æ 11.2d
60.9 Æ 1.3b
80.6 Æ 6.4c
69.8 Æ 11.5d
1
2
3
4
5
88.2 Æ 4.6a
89.2 Æ 9.0b
97.2 Æ 3.5c
95.5 Æ 7.6d
0.0a
0.0b
0.0c
0.0d
0.0a
0.0b
0.0c
0.0d
0.0a
0.0b
0.0c
0.0d
0.0a
0.0b
0.0c
0.0d
88.6 Æ 9.0a
87.5 Æ 7.4b
96.6 Æ 3.8c
82.4 Æ 13.9d
0.0a
0.0a
0.0b
0.0b
32.5 Æ 3.0c
30.9 Æ 3.2d
24.6 Æ 3.7c
39.5 Æ 1.4d
a
b
Reaction conditions: 0.05 mol% Pd, 25 1C, 24 h. 0.10 mol% Pd,
c
d
25 1C, 24 h. 0.10 mol% Pd, 40 1C 24 h. 0.05 mol% Pd, 60 1C 24 h.
c
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When the same reaction was performed at a higher catalyst
loading of 0.10 mol% Pd, the amount of di-substituted product
7 generated increased to 60.9 Æ 1.3%, while that of mono-
substituted product 6 decreased to 33.6 Æ 1.9% (Table 1, entry 1).
Such changes are likely due to more rapid product formation
rates based upon the higher catalyst loading. Further shifting of
the reaction towards the di-substituted product (7) was observed
by heating the reaction system. When studying the process at
40.0 1C using 0.10 mol% Pd, the yields of 7 reached 80.6 Æ 6.4%,
while the yields for 6 were 19.3 Æ 6.0%. When the reaction
mixture was heated to 60.0 1C, the yields of the two products
were statistically similar to the results at 40.0 1C, indicating a
potential saturation point for product formation at higher
temperatures. These results suggest that at elevated tempera-
tures, the formation of di-substituted product 7 increases due to
the additional thermal energy where both the C–I and C–Br
bonds can now undergo oxidative addition with both the particle
surface and leached Pd0 atoms. This process, however, could still
occur in a step-wise fashion due to the more rapid reaction event
at the iodo group over the bromo group, giving rise to the
formation of intermediate 6. Furthermore, no evidence of the
3-iodo-5-phenylbenzoic acid intermediate was ever observed.
These results demonstrate that intramolecular selectivity is
Fig. 3 Part (a) presents the likely reaction scheme for the Stille coupling process
using the peptide-capped Pd nanoparticles employing 5 as the aryl dihalide
reagent, while part (b) displays the time-based results for the reaction at room
temperature.
based upon the observed reactivity of iodo over bromo groups. possible for the peptide-capped Pd nanocatalyst under ambi-
Using 0.05 mol% Pd at 25.0 1C, 70.8 Æ 0.9% of 6 and 22.1 Æ ent/low temperature conditions using low catalyst concentra-
2.5% of 7 were produced after 24.0 h. These results suggest that tions based upon the reaction mechanism and system
the iodo-component of the aryl dihalide preferentially undergoes thermodynamics.
Stille coupling at room temperature, leading to the formation of
Expanding the scope of the intramolecular selectivity of the
the mono-substituted product. Interestingly, the generation nanocatalyst was explored using different derivatives of benzoic
of the di-substituted product at room temperature indicates that acid dihalides (Table 1). For the reaction using 8, only the
the C–Br bond in the mono-substituted product is potentially mono-substituted product, 3-chloro-5-phenylbenzoic acid (9),
activated to undergo oxidative addition and eventual Stille was generated at an 88.2 Æ 4.6% yield after 24.0 h at room
coupling (discussed below).
temperature using 0.05 mol% Pd (Table 1, entry 2). Increasing
To further understand the dynamics of the system, time-based the catalyst loading and/or raising the reaction temperature
analysis of the reaction was employed to monitor product generated increasing amounts of mono-substituted product 9
formation (Fig. 3). Over the first 5.00 h of the reaction at room to nearly quantitative yields. As expected, the chloro-compo-
temperature, formation of mono-substituted product 6 (blue nent of the reagent was not reactive, thereby the formation of
circles) is observed from coupling at the iodo-group of 5 (green di-substituted product 7 was not observed; the formation of
squares). Minor formation of the di-substituted product, 7 (red intermediate 9 did not significantly activate the C–Cl bond to
triangles), is observed 1.50 h after reaction initiation. Note that the facilitate coupling. Interestingly, when employing 10 as the
formation of the mono-substituted product is noted first, followed substrate, no coupling was observed for either the bromo or
by production of the di-substituted species. Furthermore, the chloro groups under any reaction conditions (Table 1, entry 3).
rates of C–C coupling are also quite slower as compared to 1 Such results may arise from inductive effects of the electro-
and 2 above. As such, these results suggest that coupling at aryl negative chloro-component, which could cause deactivation of
dihalides provides changes to the electronics of the system that the bromo-component, even at higher temperatures. In general,
impact the coupling reactions; however, the general selectivity of the different halide groups of the aryl dihalide systems follow a
the catalyst remains. This results in slower coupling reactions, as similar trend observed above with the mono-substituted
well as activation of the second halogen group within the ring reagents. In this regard, the Pd nanoparticles generally react
system. To that end, the electron-donating phenyl ring in 6 at the iodo-component first, followed by the bromo-component,
possibly activates the bromo-component at room temperature. with no reactivity for the chloro-component under the selected
As a result, weakening of the C–Br bond could occur, thus making conditions. Activation of the second functional group is also
it more susceptible to oxidative addition. The C–Br species from 6 possible, but the low coupling rates at these positions still allow
could then participate in the atom abstraction process or react for selective coupling at the initial reactive site (i.e. iodo over
with the free Pd0 atoms available in solution after the initial bromo).
catalytic cycle at the iodo-component; however, only minimal
di-substituted product yields are observed.
Reactions of aryl dihalide substrates with the same halogen
group at the 3 and 5 positions were also studied. Initially, 11
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regard, the coupling at the first iodo-group is likely to be the
rate-limiting step, otherwise mono-substituted product 12
should have been observed. This step-wise reactivity is more
probable due to the kinetic consideration of the atom-leaching
mechanism wherein there is a higher probability of a single
halogen site reacting with a Pd atom, rather than the two
halogens simultaneously coupling with separate catalysts.
Changing the halogen groups to bromides such as in 13
demonstrated an additional change in reactivity. For this
system, the two possible products, 6 and 7, from coupling at
either one or both of the halogens, respectively, were not
obtained at room temperature using either 0.05 or 0.10 mol%
Pd (Table 1, entry 5). Such results were expected based upon the
energy required for oxidative addition using bromo-based
reagents. When the reaction mixture was heated to 40.0 1C
with 0.10 mol% Pd, however, the reactivity of the di-bromo
substrate was increased, generating both the mono-substituted
intermediate 6 and the di-substituted final product 7 with
yields of 32.5 Æ 3.0% and 24.6 Æ 3.7%, respectively, after
24.0 h. When the reaction was performed at 60.0 1C with
0.05 mol% Pd, the yield of the di-substituted product increased
to 39.5 Æ 1.4%, with a mono-substituted product yield of 30.9 Æ
3.2%. The increase in the amount of 7 at 60.0 1C was attributed
to the activating effect of the biphenyl moiety in the mono-
substituted intermediate on the C–Br bond and the increased
thermal energy, driving the catalytic reaction to produce more
of the di-substituted product.
Fig. 4 Part (a) presents the likely reaction scheme for the Stille coupling reaction
using the peptide-capped Pd nanoparticles employing 11 as the aryl dihalide
reagent, while part (b) displays the time-based results for the reaction at room
temperature.
was employed for Stille coupling using 0.05 mol% Pd at room
temperature (Table 1, entry 4). The two highly reactive iodo-
components generated di-substituted product 7 in 88.6 Æ 9.0%
yield, after 24.0 h. A general increase in the formation of the
di-phenyl product was observed proportional to the catalyst
loading and reaction temperature, as anticipated. Interestingly,
the mono-substituted intermediate, 3-iodo-5-phenylbenzoic
The reactivity of the Pd nanoparticles towards aryl dihalides
was further explored using substrates containing halogen
groups at different positions in the benzoic acid ring. Initially,
the 2,5-orientation of halide groups was studied using the Stille
coupling reaction of 14 with PhSnCl3; however, no reactivity
was observed at either iodo group (Table 2, entry 1). This is
likely due to irreversible binding of the carboxylic acid moiety
acid (12), was never observed under any conditions. To probe to the nanoparticle surface during the oxidative addition of the
the reaction mechanism for 11, a time-based analysis of the iodide in the 2-position.3,4 This binding event allows for the
reaction at room temperature with a catalyst loading of
0.05 mol% Pd was studied, as shown in Fig. 4. The results
indicate that after 10.0 min, the di-substituted product, 7
(blue squares), was the only isolated product of the coupling
reaction; an increase in formation of 7 over the time frame of
the study was observed with a complementary consumption of
additional interaction of the acid group with the Pd surface
leading to catalyst deactivation. When the halide at the 2-position
was changed to bromide in 17, no reactivity was observed for
coupling at either position after 24.0 h at room temperature
using 0.05 mol% Pd (Table 2, entry 2). Interestingly, when the
catalyst loading was increased to 0.10 mol% Pd, a 6.8 Æ 0.9%
the starting material (11, red circles). Throughout the study, yield of the mono-substituted product, 2-bromo-5-phenyl-
mono-substituted intermediate 12 from coupling at a single benzoic acid (18), was obtained. Increasing the temperature of
iodo group was never observed. To produce such results two
likely reaction mechanisms are possible: (1) simultaneous
coupling at both iodo groups using separate catalytic Pd
materials or (2) coupling at a single group to produce inter-
mediate 12 that activates the second iodo-group to substantially
increase the second-step reaction rate. Based upon the results
the reaction to 40.0 1C with a Pd loading of 0.10 mol% resulted
in a substantial increase in the formation of 18, generating a 23.3 Æ
1.6% yield after 24.0 h. When the reaction was performed at
60.0 1C with a catalyst loading of 0.05 mol% Pd, a further
increase in the yield of 18 (41.3 Æ 1.4%) was obtained after
24.0 h. No indication of reactivity towards the bromo-substituent
of the coupling reaction for 5, the latter mechanism for the was noted under any of the reaction conditions. Catalytic
di-iodo reagent is more likely. In this regard, the initial attach- poisoning of the nanoparticle surface was not observed due to
ment of the phenyl group from the coupling reaction of one of
the iodo-species produces the bi-aryl ring system that activates
the second C–I bond. This then results in exceedingly rapid
coupling, generating the di-substituted product (7). In this
the required thermal activation of the C–Br bond for reactivity
and due to the more reactive C–I bond driving oxidative
addition. As a result, the interaction between the carboxylic acid
functional group and the Pd surface was minimized. When 19
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Catalysis Science & Technology
Table 2 Effects of the halogen group position in the aryl ring for the Stille
The results of the aryl dihalide reactions demonstrate the
degree of intramolecular selectivity of the peptide-capped Pd
nanocatalysts given two different halide groups in the same
substrate. Similar to the results of the intermolecular reactivity,
the observed trend for the catalyst selectivity towards aryl
dihalides is directly related to the increasing bond strength
of the C–X species; however, the orientation of the two halogens
within the ring structure can lead to activating and/or
deactivating effects. The reactivity of the aryl dihalide
coupling reaction employing peptide-capped Pd nanoparticles
Possible products
Aryl
Mono-
substituted
Percent
yield
Di-
substituted
Percent
yield
Entry dihalides
0.0a
0.0b
0.0c
0.0d
0.0a
0.0b
0.0c
0.0d
1
2
3
substrates likely follows
a
step-wise process wherein
the mono-substituted intermediate was generated first by the
reaction of the more active C–I component. To this end, the
orientation of the halide groups in the aryl dihalide substrate
affects the reactivity of the halide components, but not the
selectivity of the nanocatalyst. The 1,4-position of the halogens
tends to deactivate the carbon–halogen bond such that higher
Pd loadings are required to drive the reaction at room
temperature; however, the 1,3-orientation likely activates the
bond for the coupling reaction using less Pd. The presence of
activating or deactivating groups in the aryl ring did not alter
the selectivity of the Pd nanocatalyst with respect to halide
identity.
0.0a
0.0a
0.0b
0.0c
0.0d
6.8 Æ 0.9b
23.3 Æ 1.6c
41.3 Æ 1.4d
0.0a
0.0a
0.0b
0.0c
0.0d
70.1 Æ 15.8b
83.1 Æ 6.0c
88.0 Æ 8.3d
73.9 Æ 4.0a
92.8 Æ 4.3b
97.9 Æ 2.4c
95.5 Æ 5.5d
0.0a
0.0b
0.0c
0.0d
4
Conclusions
a
b
We have studied the reactivity of different aryl halide substrates
in a single reaction system to probe the reactivity, catalytic
mechanism, and selectivity of peptide-capped Pd nano-
particles. While a variety of catalytic nanoparticles have been
studied for C–C coupling reactions,4,9–11 the peptide-based
materials are interesting as they react in an aqueous-based
solvent, with very low Pd concentrations and reaction tempera-
tures. To further such materials for enhanced reactivity, a
fundamental understanding of the reaction mechanism is
required. In this sense, the release of free Pd0 atoms into the
solution after the initial catalytic cycle of highly active iodo-
components does not allow for coupling at less active bromo-
groups. The results indicate that the oxidative addition of the
C–Br bond requires thermal activation at 40.0 1C, suggesting
that an energy barrier must be overcome to enable coupling,
thereby allowing for a degree of thermal-control for reaction
selectivity at low temperatures. In both intermolecular and
intramolecular systems, the selectivity trend for the Pd
nanoparticles directly correlates with the strength of the
C-halide bond dissociation energy wherein the weakest C–I
bond readily reacts at room temperature, while the C–Br bond
requires mild heating and the C–Cl bond does not react.
Consequently, in aryl dihalide systems, the presence of activating/
deactivating groups in the ring alters the electronics and reactivity of
the halide components, but the selectivity of the catalyst is generally
retained with regards to the halide identity. These results present a
deeper understanding of the catalytic mechanism for nanoparticle-
driven C–C coupling reactions, which could be useful for the design
of optimized systems.
Reaction conditions: 0.05 mol% Pd, 25 1C, 24 h. 0.10 mol% Pd,
c
d
25 1C, 24 h. 0.10 mol% Pd, 40 1C 24 h. 0.05 mol% Pd, 60 1C 24 h.
was used in the reaction (Table 2, entry 3), no detectable product
was generated at room temperature with 0.05 mol% Pd; however,
when the catalyst loading was increased to 0.10 mol% Pd, the
mono-substituted product, 2-chloro-5-phenylbenzoic acid (20),
was generated with a yield of 70.1 Æ 15.8% over 24.0 h. Increas-
ing the temperature of the reaction generated an increasing
amount of 20 with 83.1 Æ 6.0% (0.10 mol% Pd) and 88.0 Æ 8.3%
(0.05 mol% Pd) yields at 40.0 1C and 60.0 1C, respectively. Since the
chloro-component was not reactive under the given conditions,
catalyst surface poisoning was not observed. The reactivity
differences between the iodo-component in these two compounds
likely arise from changes in the electronics of the rings structure.
The 2,4-position of the halide groups in benzoic acid was
also examined using 21 (Table 2, entry 4). The initial reaction
was performed at room temperature using 0.05 mol% Pd,
generating 2-chloro-4-phenylbenzoic acid (22) with 73.9 Æ
4.0% yield after 24.0 h. When the catalyst loading was increased
to 0.10 mol% Pd, the yield increased to 92.8 Æ 4.3% after 24.0 h,
while at elevated temperatures, almost quantitative yields were
obtained for mono-substituted product 22 at the selected
catalyst loadings. The increase in the product yield for the
reaction of iodo-component 21 compared with 19 suggests
that the coupling reaction was accelerated by the combined
effect of the chloro-component in the 2-position and electron-
withdrawing carboxylic acid moiety, which is para to the
iodo group.
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16 R. Bhandari and M. R. Knecht, ACS Catal., 2011, 1, 89–98.
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This material is based upon work supported by the National
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