Suzuki Reaction
[Pd]
HO
Br +
HO2C
B
HO
HO2C
H2O, Na2CO3
NaO
N
The catalyst used in this lab:
NH2 • Pd(OAc)2
[Pd] =
N
NaO
2
Figure 1: The Suzuki cross-coupling reaction and catalyst used in this laboratory
Introduction: The Suzuki cross-coupling reaction is a palladium-catalyzed carbon-carbon bond
forming reaction that has been used in the synthesis of many valuable compounds such as
pharmaceuticals, polymers, and agrochemicals. A selection of these synthetic targets is shown
in Figure 2. The reaction is named after Prof. Akira Suzuki of Hokkaido University. In recognition
of the importance of this reaction, Suzuki received the Nobel Prize in Chemistry in 2010 (along
with Prof. Richard Heck of U. Delaware and Ei-ichi Negishi of Purdue University for their
eponymous palladium-catalyzed cross coupling reactions). The reaction is often referred to as
the Suzuki-Miyaura cross-coupling to acknowledge the contributions made by former Suzuki
group member Norio Miyaura, who later joined the faculty at HU himself.1
Suzuki coupling
H2N
NH
NH
HN
H
HN
HN N
N
O
Suzuki coupling
Suzuki coupling
Dragamacidin F (antiviral)
Stoltz et al, J. Am. Chem. Soc. 2004, 126, 9552
Valsartan (hypertension and heart failure treatment)
Novartis
Chem. Eng. News 2004, 82, Sept. 6, 49-58
R
Cl
Cl
N
O
Br
N
H
OH
N
N
HO
O
O
HN
O
Suzuki coupling
Boscalid (fungacide for food crops)
BASF (1000 t/yr)
Chem. Eng. News 2004, 82, Sept. 6, 49-58
Br
(HO)2B
N
n
Suzuki coupling
Polymer used in light emitting diode
Bryce et al. Adv. Mater. 2000, 12, 217
Figure 2: Selected examples of the Suzuki-Miyaura coupling in organic synthesis
The specific catalyst used in this lab (cf. Figure 1) was recently developed for cross-coupling
water-soluble biomolecules such as proteins.2 The catalyst is also useful to carry out aqueous
Suzuki reactions in general, as will be demonstrated in this laboratory.
Pd(0)
CO2H
Br
Reductive Elimination
CO2H
Oxidative Addition
(II)Pd
CO2H
Br Pd(II)
CO2H
OH
OH
HO B
OH
B
OH
OH
Br
HO Pd(II)
CO2H
Transmetallation
Figure 3: Mechanistic outline of the Suzuki-Miyaura cross-coupling reaction
The mechanism for this experiment’s Suzuki-Miyaura cross-coupling reaction is outlined in
Figure 3. The ligands that coordinate to palladium throughout the reaction are omitted for clarity.
In the first step, oxidative insertion of Pd(0)3 into the carbon-bromine bond of the aryl bromide,
providing an aryl Pd(II) intermediate. In the next step, the base (hydroxide in this case)
displaces the bromide from palladium. This hydroxyl group, now attached to the palladium
metal, can bind to the Lewis acidic aryl boronic acid to form an ate complex:
Ph B(OH) 2
Ph
Ar Pd O
Ar Pd OH
B
OH
OH
transmetallation
OH
HO Br
OH
H
ate complex
Ar Pd Ph
This pre-coordination of the palladium hydroxide to the boronic acid facilitates the subsequent
transfer of the phenyl group to palladium (transmetallation). In the final step, the final C-C bond
is formed by reductive elimination, which regenerates the Pd(0) catalyst.
The water-soluble palladium complex used in this lab is fairly cheap and easy to use. The
catalyst can be handled in open air and the reaction is run in an open flask. It is also very active:
in this reaction, the catalyst loading is only 0.01 mol%, meaning that for the reaction to go to
completion the palladium would need to go through 10,000 catalytic cycles.
The reaction in this experiment is run in water, and only a small amount of ethanol is used in the
recrystallization of the product. This minimizes the amount of organic solvent added to the
waste stream. Water is a desirable solvent in many respects: it is non-flammable, non-toxic, and
can enhance the rate of many reactions.4 The crude product can be isolated by filtration and
purified by recrystallization, with no need to perform extractions or column chromatography.
Only a small amount of the palladium catalyst is required for this cross-coupling. For these
reasons, this reaction is an example of the use of “Green Chemistry” principles. Green
Chemistry is the design of chemical products and processes that reduce or eliminate the use or
generation of hazardous substances. 5 It is important that chemists consider the hazardous
waste that is produced in reactions and the impact it has on the environment. Another way this
lab pertains to green chemistry is that it employs a catalyst rather than a stoichiometric reagent
to promote the formation of the key carbon-carbon bond.
Hazards
Safety glasses and nitrile gloves should be worn at all times. All aqueous waste should be
disposed of in the appropriate carboy. 4-Bromobenzoic acid, phenylboronic acid, sodium
carbonate, 2-amino-4,6-dihydroxyaminopyrimidine, and palladium acetate may be harmful if
inhaled, swallowed, or absorbed through skin. Palladium acetate and sodium carbonate are
irritants and may be harmful if swallowed or inhaled. The catalyst solution that has been
prepared for you should similarly be considered harmful. Hydrochloric acid is corrosive and can
cause burns to skin, eyes, and respiratory tract. Ethanol is highly flammable and can cause skin
and eye irritation. DMSO-d6 is absorbed readily through the skin and may transport harmful
substances into the body. The product of the coupling, 4-phenylbenzoic acid, is not considered
harmful, but care should be taken to avoid inhalation or contact with skin. Stirrer-hotplates
should be used with caution and kept away from flammable solvents. When the reaction is
quenched with HCl, the acid should be added slowly to ensure controlled evolution of carbon
dioxide upon reaction with sodium carbonate.
Procedure: Day One
Add 0.50 g of 4-bromobenzoic acid (2.5 mmol) and 0.37 g of phenylboronic acid (3.0 mmol)
(Note: Hygroscopic! Keep the bottle of phenylboronic acid closed when not in use) to a 125mL Erlenmeyer flask containing a large stirring bar. In a separate 50-mL beaker, add 0.80 g of
sodium carbonate (7.5 mmol) and 15 mL of deionized water and stir until dissolved. Add the
solution of sodium carbonate to the reaction flask containing the arylbromide and arylboronic
acid and stir the resulting mixture vigorously until all the reactants are dissolved. The process of
dissolution will take about 10 minutes. Meanwhile, measure 1.0 mL of the palladium catalyst
solution using a graduated cylinder. The concentration of palladium in this stock solution is 0.25
mM. Once the reactants are dissolved, begin heating the solution (the final reaction temperature
will be 70 ºC) and add the palladium catalyst solution to the flask by pipette. Record any
changes in the appearance of the reaction mixture throughout the procedure. The product of the
reaction should precipitate as a white solid after 20-60 minutes. The target temperature for this
reaction is 70 ºC, so after 5 minutes of reaction time, measure the temperature of the reaction
and keep checking the temperature every 5 minutes or so. To ensure the thermometer does not
break, stop the stirring when monitoring the temperature of the reaction mixture. Allow the
reaction to run for at least 30 minutes at 70 ºC.6 After this time, turn off the heat and let the
reaction cool to room temperature. Once the flask is at room temperature, place it in an ice bath.
Position the flask and ice bath so that the mixture is still stirred efficiently. While the mixture is
stirring, slowly pipette in 25 mL of 1M HCl directly into the flask. (Caution! The HCl must be
added dropwise! The HCl reacts with the excess carbonate to generate carbon dioxide. If the
HCl is added too quickly, the solution may foam over the reaction vessel.) The HCl solution
quenches the excess carbonate and also converts the sodium carboxylate product to a
carboxylic acid. Stir for 5 minutes once all of the HCl is added. Isolate the crude product by
vacuum filtration and use about 5 mL of water to rinse the product out of the flask. Let the
product dry on the filter for at least 2 minutes. Next, transfer the partially dried product to a 125mL Erlenmeyer and purify your product by recrystallization. First add 4 mL of 1M HCl and heat
the stirred solution to about 70 ºC. Slowly add enough ethanol to the solution so that all material
dissolves (approximately 30 mL EtOH). Let the solution cool to room temperature and then
place the flask into an ice bath for 15 minutes to complete the recrystallization. Isolate the
crystalline product by vacuum filtration. A few milliliters of cold ethanol can be used to wash
product out of the beaker if necessary. Leave the crystals to dry on the filter for at least 5
minutes. Finally, collect the product and store it until the next lab period.
Day Two
Weigh the recrystallized product and calculate the isolated yield. Measure the melting point and
obtain an IR spectrum of the product. Your TA will select one student’s product and obtain an
NMR spectrum (DMSO-d6 solvent) for you to analyze.
References
1) For an article on names in chemistry, including the naming of the Heck and Suzuki
reactions, see: http://blogs.scientificamerican.com/guest-blog/2011/08/02/whats-in-a-name-forchemists-their-fields-soul-2/
2) Chalker, J. M.; Wood, C. S. C.; Davis, B. G. A Convenient Catalyst for Aqueous and Protein
Suzuki-Miyaura Cross-Coupling. J. Am. Chem. Soc. 2009, 131, 16346-16347.
3) When a reaction is catalyzed by Pd(0), the mechanism for how it is produced from a Pd(II)
precursor is often not discussed, and in some cases may not even be known. In the Suzuki
reaction, one way that Pd(0) can be generated is by homocoupling the boronic acid precursor:
LnPd(II)
+ 2 PhB(OH) 2
transmetallation
LnPd
Ph
reductive
Ph
elimination
LnPd(0)
+
Ph-Ph
(homocoupling
product)
Because only a tiny amount of Pd(0) is required to catalyze the reaction, a negligible amount of
boronic acid is wasted, and only minor amounts of the homocoupling product are formed.
4) Organic Synthesis in Water. Grieco, P. A., Ed.; Blackie Academic & Professional: London,
1998.
5) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University
Press: New York, 1998.
6) Should any solids need to be rinsed down the flask or if the reaction becomes too
concentrated because of solvent evaporation, up to 20 mL of additional water can be added.
to the reaction mixture without detriment.