III.1 Title: Application of the Palladium on Graphene/Graphene Oxide Catalyst System to CrossCoupling and C–H Activation Reactions
Participants: B. Frank Gupton, Keith C. Ellis, M. Samy El-Shall and Christopher T. Williams
Motivation
Since its discovery in 2004, graphene has been one of the most widely studied materials in all of
science. Its unique structural and electronic properties have motivated the development of new
composite materials for nanoelectronics and related Figure 1: Palladium-Catalyzed Reactions
devices. However, it’s high thermal, chemical and
mechanical stability as well as its large surface area
represents desirable attributes as support layers for
metallic nanoparticles in catalysis. One of the catalytic
applications for which graphene support systems have
been shown to demonstrate significant advantages is in
the area of cross-coupling chemistry.
Palladium(0)-catalyzed cross-coupling reactions
have been of strategic importance in organic synthesis
since their discovery in the 1970s.1-5 Carbon-carbon crosscoupling reactions, such as the Suzuki and Heck couplings
(Figure 1A), are currently the most widely used chemical
transformations. These reactions have been widely used for
the assembly of complex organic molecules in a broad
range of applications in the chemical and pharmaceutical
industries. They remain the method of choice for carboncarbon bond formation.
Cross-coupling reactions have been most frequently
practiced under homogeneous conditions employing a
ligand to enhance the catalytic activity and selectivity for
specific reactions. However, the issues associated with
homogeneous catalysis remain a challenge to
pharmaceutical applications due to the lack of recyclability
and potential contamination from residual metals in the
reaction product. Product contamination is of particular
importance in pharmaceutical applications where this
chemistry is practiced extensively.12-13 Ligand-free
heterogeneous palladium(0) catalysis presents a
promising option to address this problem as evidenced by
the significant increase in research efforts in this area.
Therefore,
the
development
of
highly
active
heterogeneous Pd(0) nanocatalysts that can be easily
separated from the reaction medium and recycled is an
important goal of nanomaterials research that is likely to
have considerable impact on cross-coupling applications in
the future.
An important emerging complimentary technology is the selective conversion of unactivated
C–H bonds to C–O, C–N, C–C, C–Cl/Br/I, C–F or C–CF3 (C-H activation chemistry, Figure 1B) using
oxidative, chelation-directed palladium-catalyzed methods. A series of oxidative, chelation-directed
methods that catalyze each of these six C–H activation reactions (Figure 1B) using a novel
Pd(II)/Pd(IV) catalytic cycle (Figure 1C) have been reported.6-11 The use of an additional ligand, such
as phosphines or diamines, is not required in any of these six catalytic C–H activation reactions.
Preliminary Data
Figure 2: Pd0/graphene catalyzed Suzuki
Recently, we reported on cross-coupling catalytic cross-coupling
activity of Pd(0) and Pd(II) nanoparticles deposited onto
graphene14-15 and carbon nanotubes (CNT).16 These
catalysts demonstrated extremely high turnover frequencies
(108,000 h-1) for Suzuki cross-coupling (Figure 2) with less
than 200 ppb Pd in the reaction product. 14 These catalysts
were effective with a wide range of substrates and could
also be used in Heck and Sonogashira applications. The
processes used to produce these catalysts are simple,
scalable and very reproducible. Furthermore, the catalysts
were easily recovered and recycled under batch reaction
conditions. The Pd nanoparticles associated with both the
graphene and the CNT’s are uniformly dispersed across the
substrate surfaces (Figure 3A and 3B). However, the
fundamental nature of the remarkable catalytic activity and
stability/recyclability of these materials, as
3: TEM images of:
well as the scope of these catalysts for Figure
A) Pd/graphene
B) Pd/MWCNT
other C-C cross-coupling reactions and CH activation reactions, has yet to be
determined.
As Preliminary Data for this
application, we have demonstrated that
Pd(II)/CNT catalyzes C-H to C-Halogen
activation reactions (Figure 4A and 4B).
Treatment of benzo[h]quinoline with the
Pd(II)/CNT
catalyst
and
Nchlorosuccinimide (NCS, Figure 4A) or Nbromosuccinimide (NBS, Figure 4B) at
100 °C in acetonitrile rapidly gave the
desired product from the chelationcontrolled
reaction
in
moderate
yield
(unoptimized) and high turnover frequency. The Figure 4: Preliminary Data for C-H to C-Halogen Reaction
turnover
frequencies
observed
in
these
preliminary, unoptimized reactions with the
heterogeneous catalyst are an order of magnitude
greater than those observed with the known
Yield
Turnover Freq.
Catalyst
Time
homogeneous catalyst system. This increase in
7.03 mol product/
Heterogeneous
5 hours
71%
mol catalyst hr
Pd(II)/CNT
turnover frequency and reduction in the reaction
(unoptimized)
(2 mol %)
time are significant improvements that make this
0.13 mol product/
Homogengeous
3 days
95%
mol catalyst hr
Pd(OAc)2
C-H activation reaction feasible for use in
1
(1 mol %)
pharmaceutical and industrial applications.
Hypothesis
The increased activity and stability of Pd(0)
and Pd(II) in the heterogeneous catalyst systems
are related to the unique surface properties of
graphene and CNTs, which if understood, can be
further optimized and used to expand the scope of
the method.
Catalyst
Heterogeneous
Pd(II)/CNT
(2 mol %)
Homogengeous
Pd(OAc)2
(1 mol %)1
Time
Yield
5 hours
60%
(unoptimized)
1.5 days
93%
Turnover Freq.
55.03 mol product/
mol catalyst hr
2.60 mol product/
mol catalyst hr
Objectives
1. Use in-situ and ex-situ spectroscopy to explore the surface properties of novel Pd/graphene and
Pd/CNT catalysts before, during, and after use in Suzuki cross-coupling.
2. Expand the scope of the catalysts to include Pd(II)-catalyzed C–H activation reactions.
Research Plan
Objective 1: Catalyst Characterization.
Prior to reaction, metal dispersion, particle size and distribution of each catalyst will be
determined, along with surface oxidation states and the nature of exposed metal sites via CO
adsorption. The same characterization will be employed post-reaction, in order to determine the final
state of the material. The support and catalyst surfaces will then be examined in-situ in the liquidphase Suzuki cross-coupling reaction mixture using attenuated total reflection infrared (ATR-IR)
spectroscopy17-23 to explore adsorption of reactants, intermediates, and products as a function of
adsorption and reaction time at various temperatures. HRTEM, AFM, Resonance Raman
spectroscopy will provide information on the nature of defects, defect structures, defect density and
extent of disorder and disorder in the graphene and Pd-graphene nanosheets.24-28 Together with flow
reactor kinetic measurements, the high performance (particularly stability) of these catalysts over
extended time periods, will be elucidated.
Objective 2: Expand Scope to C-H Activation Chemistry.
We will first explore the feasibility of Pd(II)/graphene oxide [Pd(II)/GO] 14, 29 and Pd(II)/CNT as
catalysts for each of the six C–H activation reactions using the model substrate benzo[h]quinoline
(See Figure 1A, Figure 4A, and Figure 4B).6 We will evaluate the nanoparticles in parallel against
catalysis by homogeneous Pd(OAc)2 using the reported reaction conditions.6-11 Once we have
determined which of the six transformation can be catalyzed by Pd(II)/GO and/or Pd(II)/CNT, we will
choose two transformation and fully optimize the reaction parameters, which will include time,
temperature, solvent, additives, heating methods, and alternative oxidants. We will also explore the
scope, evaluating additional substrates and directing groups. Once optimized, we will fully
characterize the active catalyst for these two transformations using SEM, TEM, XPS, AFT, ART-IF,
Resonance Raman spectroscopy, and all other appropriate methods. We will also test the
recyclability of the catalyst and evaluate palladium contamination of the reaction products by ICP-MS.
First Year Deliverable:
 Analysis of graphene/CNT-supported Pd by HRTEM-AFM-Raman methods.
 Identification of surface species on Pd/graphene during a Suzuki reaction.
 Demonstrate that Pd(II)/graphene oxide and/or Pd(II)/CNT catalyzes C–H activation reactions.
 Optimized conditions and scope for two C–H activation reactions.
First Year Milestone(s)
Months 1-6:
 Pre- and post-reaction analysis of Pd/graphene by HRTEM-AFM-Raman.
 Explore Pd(II)/graphene oxide catalyst for C–H activation reactions.
Months 7-12:
 In-situ ATR-IR measurements of Pd/graphene during Suzuki cross coupling.
 Optimization of two of the most promising C–H activation reactions.
Cost: $60,000 for one year. Possible successive years for further studies, $60,000.
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