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This is an open access article published under an ACS AuthorChoice License, which permits
copying and redistribution of the article or any adaptations for non-commercial purposes.
Laboratory Experiment
pubs.acs.org/jchemeduc
Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling in a Green Alcohol
Solvent for an Undergraduate Organic Chemistry Laboratory
Liana Hie, Jonah J. Chang, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S Supporting Information
*
ABSTRACT: A modern undergraduate organic chemistry laboratory
experiment involving the Suzuki-Miyaura coupling is reported.
Although Suzuki-Miyaura couplings typically employ palladium
catalysts in environmentally harmful solvents, this experiment features
the use of inexpensive nickel catalysis, in addition to a “green” alcohol
solvent. The experiment employs heterocyclic substrates, which are
important pharmaceutical building blocks. Thus, this laboratory
procedure exposes students to a variety of contemporary topics in
organic chemistry, including transition metal-catalyzed cross-couplings,
green chemistry, and the importance of heterocycles in drug discovery,
none of which are well represented in typical undergraduate organic chemistry curricula. The experimental protocol uses
commercially available reagents and is useful in both organic and inorganic instructional laboratories.
KEYWORDS: Second-Year Undergraduate, Upper-Division Undergraduate, Organic Chemistry, Laboratory Instruction,
Hands-On Learning/Manipulatives, Organometallics, Green Chemistry, Heterocycles
M
Scheme 1. Typical Suzuki-Miyaura Cross-Coupling and a
Modern Variant Featuring the Use of a Green Solvent,
Heterocyclic Substrates, and a Nickel Catalyst
ethods for the assembly of carbon-carbon (C-C)
bonds are a cornerstone of any undergraduate organic
chemistry course. Most commonly, textbooks and curricula
prominently feature classical reactions such as Grignard
additions1 and Friedel-Crafts acylations,2 which serve as
excellent pedagogical tools. The incorporation of more modern
C-C bond forming reactions into the undergraduate
curriculum has been a topic of interest, such that many new
textbooks at least brie?y mention new tactics for C-C bond
construction that are commonly used in research laboratories.3
One particularly attractive class of transformations that has
seen increased attention in undergraduate organic chemistry
curricula is transition metal-catalyzed cross-coupling reactions.4
Reactions such as the Suzuki-Miyaura, Negishi, and Heck
couplings provide indispensable tools in academia and industry
for C-C bond formation. The importance of these transformations is underscored by the awarding of the 2010 Nobel
Prize in Chemistry to Suzuki, Negishi, and Heck for their
pioneering studies of these key reactions.5 In an e?ort to expose
undergraduate students to these couplings, new experimental
procedures have been put forth with much success.6 For
example, Deveau and co-workers recently reported a palladiumcatalyzed Suzuki-Miyaura coupling suitable for undergraduate
laboratories,6a which also features important lessons involving
medicinal chemistry and green chemistry.6a-c,7
An operationally simple variant of the Suzuki-Miyaura crosscoupling (Scheme 1) is described.8 Analogous to a typical
Suzuki-Miyaura coupling, an aryl electrophile is joined to an
aryl boronic acid fragment using a transition metal catalyst to
give a biaryl product. In the protocol described herein, several
features are highlighted: (A) The substrate and the boronic
© 2014 American Chemical Society and
Division of Chemical Education, Inc.
acids used are commercially available heterocycles.9 Oxygenand nitrogen-containing heterocycles are common building
Published: September 5, 2014
571
dx.doi.org/10.1021/ed500158p | J. Chem. Educ. 2015, 92, 571-574
Journal of Chemical Education
Laboratory Experiment
product is then analyzed via 1H and 13C NMR spectroscopy
using a postlaboratory worksheet. A detailed description of the
experiment is described in the Supporting Information.
blocks used in pharmaceutical research for the preparation of
new medicines.10 (B) The solvent utilized is tert-amyl
alcohol,11,12 which is considered a “green” alternative to typical
organic solvents.13,14 It is estimated that 20-85 kg of organic
solvent waste is produced per kilogram of drug produced in a
six- to eight-step drug manufacturing process, so the use of
green solvents is especially desirable.15 (C) The catalyst
employed is a commercially available and air-stable nickel
complex,16-19 which compares well to more commonly used
palladium catalysts. Furthermore, nickel is a nonprecious metal
and is, therefore, more abundant and less expensive compared
to its precious metal counterpart palladium.20
This laboratory experiment exposes students to a variety of
contemporary topics in organic chemistry, including crosscoupling reactions, catalysis, and the importance of heterocycles
in drug discovery. Moreover, this experiment introduces the
critical concepts of green chemistry,13 which are often
overlooked in traditional undergraduate organic chemistry
curricula.
¦
¦
¦
HAZARDS
Closed-toed shoes, long pants, safety glasses, gloves, and ?ameresistant laboratory coats should be worn at all times. All
hazardous materials should be handled and disposed of in
accordance with the recommendation of the materials’ safety
data sheet and EH&S. Bis(tricyclohexylphosphine)nickel(II)
dichloride (NiCl2(PCy3)2) and heterocyclic boronic acids may
be harmful if inhaled, swallowed, or absorbed through skin. 5Bromopyrimidine and potassium phosphate are irritants and
may be harmful if inhaled, swallowed, or absorbed through skin.
Tert-amyl alcohol is an irritant and may, therefore, cause skin
and eye irritation; it is also ?ammable and may be harmful if
inhaled, swallowed, or absorbed through skin. Hydrochloric
acid and sodium hydroxide are corrosive and can cause burns to
the skin, eyes, and respiratory tract. Ethyl acetate and hexanes
are ?ammable and volatile organic solvents. The n-hexane in
hexanes is a neurotoxin. CDCl3 is toxic and a cancer suspect
agent. The products of the coupling are not considered
harmful, but care should be taken to avoid inhalation or contact
with skin.
PEDAGOGICAL GOALS
• To develop a contemporary undergraduate instructional
laboratory experiment involving the Suzuki-Miyaura
cross-coupling reaction as a means to expose students to
typical reaction sequences encountered by academic and
industrial researchers.
• To bring attention to current and important topics in
organic chemistry, including cross-couplings, transition
metal catalysis, green chemistry, and heterocycles in
pharmaceutical research.
• To provide students with training in standard organic
chemistry laboratory techniques, including reaction
setup, reaction monitoring, compound puri?cation, and
structure elucidation by 1H and 13C NMR analysis.
¦
RESULTS AND DISCUSSION
The nickel-catalyzed Suzuki-Miyaura coupling using green
solvents was recently described.21 Despite the promise of this
protocol, some e?orts were necessary to render this transformation suitable for an undergraduate instructional experiment (see the Instructors’ Notes in the Supporting Information
for further details). We ?rst examined several heterocyclic
substrates and heterocyclic boronic acids.9 The substrates
shown in Scheme 1 were found to be optimal based on their
commercial availability and ability to react using low loadings of
the nickel catalyst in tert-amyl alcohol as the solvent. A brief
selection of our optimization e?orts using conventional heating
or microwave heating is highlighted in Table 1. The conditions
shown in entries 3 and 7 (conventional heating) were identi?ed
as optimal conditions. It should be noted that the experiment
could be performed in a microwave reactor with comparable
yields (see entries 4 and 8).
OVERVIEW OF LABORATORY EXPERIMENT
This experiment is designed for an upper-division undergraduate organic chemistry laboratory but is also appropriate
for second-year undergraduate organic and advanced inorganic
chemistry laboratories. The experiment requires 4-5 h to
complete and can be performed over two laboratory periods, if
necessary. Students complete a prelaboratory worksheet before
conducting the experiment to ensure they understand the
experiment and any safety concerns. A postlaboratory worksheet further promotes student understanding and helps
students perform a critical analysis of their results.
Table 1. Survey of Reaction Conditions
¦
EXPERIMENT
Students work individually and complete a prelaboratory
worksheet. Each student is assigned an unknown heterocyclic
boronic acid as a coupling partner whose identity is determined
after the coupling reaction using NMR spectroscopy. Students
weigh the substrate (5-bromopyrimidine), boronic acid, base
(K3PO4), and catalyst (1 mol %) and combine them in a 1
dram (~4 mL) vial. After adding a stir bar and tert-amyl
alcohol, the reaction is stirred at room temperature for 30 min,
and then heated to 80 °C using a preheated heating block or an
oil bath. After heating for 1 h, students use thin-layer
chromatography (TLC) to determine if the reaction is
complete and gauge the purity of the product. The mixture is
subjected to aqueous workup and the crude product is puri?ed
via ?ash column chromatography on silica gel. The isolated
a
Conditions: 5-bromopyrimidine (1.0 equiv), heterocyclic boronic
acid (2.5 equiv), tert-amyl alcohol (0.3 M). bYield was determined by
1
H NMR analysis of the crude reaction mixtures using hexamethylbenzene as an internal standard. cThe reaction was conducted in a
microwave reactor.
572
dx.doi.org/10.1021/ed500158p | J. Chem. Educ. 2015, 92, 571-574
Journal of Chemical Education
Laboratory Experiment
heterocycles in drug discovery, and green chemistry. This
experiment will allow educators to introduce a variety of topics
e?ciently into their undergraduate organic chemistry curricula,
which are otherwise often neglected in conventional undergraduate organic chemistry laboratories.
The optimized experimental protocol was implemented
during one term of an advanced undergraduate organic
chemistry lecture and laboratory course, which mainly consisted
of students majoring in Chemistry or Biochemistry. Students
were brie?y introduced to cross-coupling reactions, including
the Suzuki-Miyaura coupling,8 and green chemistry during the
course lecture meeting. They then read the laboratory handout,
which covered experimental details and various background
information on cross-couplings, green chemistry, and heterocycles. Students completed a prelaboratory worksheet, which
was designed to make sure students understood the chemistry,
the experimental protocol, and safety considerations. Completion of the prelaboratory worksheet satisfactorily was
required for students to carry out the experiment.
Each student was given one of the two unknown boronic
acids and carried out the Suzuki-Miyaura coupling experiment.
The main aspects of this experiment included reaction setup,
monitoring, puri?cation, and spectroscopic analysis. Of the 30
students who carried out the experiment, 29 of them were able
to isolate their desired product after chromatography. Students
used 1H NMR and 13C NMR analysis (student spectra are
given in the Supporting Information) to determine the identity
of their unknown boronic acids and their cross-coupled
products. Yields ranged from 28-95% for those who used
the furanyl boronic acid, whereas yields were in the 39-100%
range for those who employed the pyridyl boronic acid.
Average yields were 61% and 76%, respectively. Lower yields
were likely caused by the loss of product during workup or
puri?cation. Residual solvent was seen in several cases during
1
H NMR analysis of products. However, other notable
impurities, such as unreacted boronic acid, were rarely seen.
A required postlaboratory worksheet was used to facilitate data
analysis and further expand on the key chemical concepts from
this experiment.
¦
ASSOCIATED CONTENT
S Supporting Information
*
Detailed student handout; prelaboratory worksheet; postlaboratory worksheet; notes for instructors; NMR spectra of
products, including spectra from students. This material is
available via the Internet at http:/pubs.acs.org.
¦
AUTHOR INFORMATION
Corresponding Author
*E-mail: neilgarg@chem.ucla.edu.
Notes
The authors declare no competing ?nancial interest.
¦
ACKNOWLEDGMENTS
We thank the students and teaching assistants (Byron Boon,
Tioga Martin, Robert Jordan, Brice Curtin, Gerhard Kummerow, and Tyler Allred) of the Chem 144 organic chemistry
laboratory course (Fall 2013) for their feedback on this
experiment, in addition to Daniel Richter and Julie Manley for
helpful discussions. The authors are grateful to the ACS Green
Chemistry Institute Pharmaceutical Roundtable and the
University of California, Los Angeles for ?nancial support.
These studies were supported by shared instrumentation grants
from the NSF (CHE-1048804) and the National Center for
Research Resources (S10RR025631).
¦
Discussion Topics
This experiment provided the opportunity to discuss a range of
important topics relevant to undergraduate organic chemistry
lecture material and modern laboratory practices. With regard
to organic chemistry, discussion topics included, but were not
limited to, transition metal-catalyzed cross-couplings,4 the
mechanism of the Suzuki-Miyaura coupling,8 and heterocycles.10 Moreover, this experiment provided an opportunity to
address modern, big picture topics, such as pharmaceutical
research and the growing importance of green chemistry. In the
laboratory, students were exposed to a contemporary
experimental protocol and gained experience in a variety of
methods and techniques. This included reaction setup on a
small scale (e.g., 100 mg of substrate and only 4.4 mg of the
nickel catalyst), reaction analysis using thin layer chromatography (TLC), aqueous workup, ?ash column chromatography,
and NMR analysis. An anonymous student evaluation of the
experiment indicated that students recognized the concepts
emphasized in the experiment (see Supporting Information).
REFERENCES
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Mechanism of Reaction. Q. Rev. Chem. Soc. 1967, 21 (2), 259-285.
(b) Ashby, E. C.; Laemmle, J.; Neumann, H. M. Mechanisms of
Grignard Reagent Addition to Ketones. Acc. Chem. Res. 1974, 7 (8),
272-280.
(2) (a) Gore, P. H. The Friedel-Crafts Acylation Reaction and its
Application to Polycyclic Aromatic Hydrocarbons. Chem. Rev. 1955,
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Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Aryl-Aryl Bond
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Development: An Industrial Perspective; John Wiley & Sons, Inc.:
Hoboken, 2012.
¦
CONCLUSIONS
A modern protocol was developed for the Suzuki-Miyaura
coupling that is suitable for use in undergraduate instructional
laboratories. The experimental procedure was straightforward
and provided student training in modern laboratory methods
and techniques. In addition, the laboratory exposed students to
a variety of contemporary topics in organic chemistry, including
transition metal-catalyzed cross-couplings, the importance of
573
dx.doi.org/10.1021/ed500158p | J. Chem. Educ. 2015, 92, 571-574
Journal of Chemical Education
Laboratory Experiment
(5) Nobleprize.org: The O?cial Web Site of the Nobel Prize. The
Nobel Prize in Chemistry 2010. http://www.nobelprize.org/nobel_
prizes/chemistry/laureates/2010/ (accessed Aug 2014).
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Deveau, A. M. Discovering Green, Aqueous Suzuki Coupling
Reactions: Synthesis of Ethyl (4-Phenylphenyl)acetate, a Biaryl with
Anti-Arthritic Potential. J. Chem. Educ. 2012, 89 (8), 1064-1067.
(b) Aktoudianakis, E.; Chan, E.; Edward, A. R.; Jarosz, I.; Lee, V.; Mui,
L.; Thatipamala, S. S.; Dicks, A. P. “Greening Up” the Suzuki Reaction.
J. Chem. Educ. 2008, 85 (4), 555-557. (c) Hamilton, A. E.; Buxton, A.
M.; Peeples, C. J.; Chalker, J. M. An Operationally Simple Aqueous
Suzuki-Miyaura Cross-Coupling Reaction for an Undergraduate
Organic Chemistry Laboratory. J. Chem. Educ. 2013, 90 (11), 1509-
1513. (d) Callam, C. S.; Lowary, T. L. Suzuki Cross-Coupling
Reactions: Synthesis of Unsymmetrical Biaryls in the Organic
Laboratory. J. Chem. Educ. 2001, 78 (7), 947-948. (e) Hoogenboom,
R.; Meier, M. A. R.; Schubert, U. S. The Introduction of HighThroughput Experimentation Methods for Suzuki-Miyaura Coupling
Reactions in University Education. J. Chem. Educ. 2005, 82 (11),
1693-1696. (f) Herrmann, W. A.; Bo¨hm, V. P. W.; Reisinger, C.-P.
Introduction to Homogenous Catalysis: Carbon-Carbon Bond
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(7) Dicks, A. P. Green Organic Laboratory in Lecture and Laboratory;
CRC Press: Taylor & Franciss Group: Boca Raton, 2012.
(8) (a) Martin, R.; Buchwald, S. L. Palladium-Catalyzed Suzuki-
Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands. Acc. Chem. Res. 2008, 41 (11), 1461-1473. (b) Shan,
F.-S. Transition-Metal-Catalyzed Suzuki-Miyaura Cross-Coupling
Reactions: a Remarkable Advance from Palladium to Nickel Catalysts.
Chem. Soc. Rev. 2013, 42 (12), 5270-5298. (c) Miyaura, N.; Suzuki, A.
Palladium-Catalyzed Cross-Coupling Reactions of Organoboron
Compounds. Chem. Rev. 1995, 95 (7), 2457-2483. (d) Suzuki, A.
Recent Advances in the Cross-Coupling Reactions of Organoboron
Derivatives with Organic Electrophiles, 1995-1998. J. Organomet.
Chem. 1999, 576 (1-2), 147-168.
(9) 5-Bromopyrimidine is commercially available from CombiBlocks, Inc. (CAS #4595-59-9) at an approximate cost of $ 0.75
USD/gram. Furan-3-boronic acid is commercially available from
Combi-Blocks, Inc. (CAS #55552-70-0) at an approximate cost of $
10 USD/gram. 2-Methoxypyridine-3-boronic acid is commercially
available from Combi-Blocks, Inc. (CAS #163105-90-6) at an
approximate cost of $10 USD/gram. Simpler and less expensive
boronic acids can be substituted: see ref 21.
(10) (a) Dinges, J.; Lamberth, C., Eds. Bioactive Heterocyclic
Compounds Classes: Pharmaceuticals; Wiley-VCH: Weinheim, 2012.
(b) Quin, L. D.; Tyrell, J. Fundamentals of Heterocyclic Chemistry:
Importance in Nature and in the Synthesis of Pharmaceuticals; WileyInterscience: Hoboken, 2010.
(11) For green solvent selection guides, see: (a) Alfonsi, K.; Colberg,
J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, …
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