Suzuki-Miyaura Coupling

Fall 2016

Introduction Ø The procedure introduces the

concept of metal-catalyzed cross-coupling reactions between carbon species.

Ø This experiment will require you to refine your synthetic skills in the area of conduction air-sensitive reactions.

Ø Final report will be in the format

of Tetrahedron Letters. As with all experiments you are not permitted to cut and paste structures from this handout.

Ø Skill grade is based on the

quality of the data and the methods employed.

Guidelines From the Nobel.org website: The Suzuki reaction: In 1979 Akira Suzuki started to use boron in palladium-catalyzed cross coupling. This element is the mildest activator, and it is even less toxic than zinc, which is an advantage in large-scale applications. The Suzuki reaction is for example used in the industrial synthesis (thousands of tons) of a substance that protects crops from fungi. The reaction is also used in research and development; a few examples are shown below.

German scientists are using the Suzuki reaction to create organic polymers that emit light when a current runs through them. The goal is to improve super-thin OLED (organic light-emitting diode) displays.

Swedish scientists are using the Suzuki reaction to develop new light-capturing molecules. These can be spray-painted onto a surface and could become a part of future flat solar cells.

The Suzuki reaction has been used to develop variants of the antibiotic vancomycin. These variants are effective against strains of bacteria that are otherwise resistant (MRSA).

2 CHEM 431 W Fall 2015

Overview

You will synthesize the boronic ester, 1, portion for the Suzuki cross-coupling using a Grignard technique.

The boronic ester will then be coupled with 4-iodoanisole, 2, in the Suzuki reaction to afford 4-methoxybiphenyl, 3.

Part 1: Preparation of the Grignard reagent and its boronic ester

Into a round bottom flask equipped with a reflux condenser add 0.26 g (10.8 mmol) of

magnesium shavings, which were previously dried in an oven and free from oxide and a small crystal

of I2. Pump/purge under N2. Now add a degassed solution of 10 mL of dry THF containing 1.05 mL of

bromobenzene (10 mmol). Begin heating gently to induce the reaction. Discontinue heating when

bubbling begins. Note: Keep a beaker with 250 mL of cold water nearby in case the reaction

becomes turbulent.

When the reaction is complete (the majority of Mg is consumed), prepare another N2-

pump/purged flask with a magnetic stirring bar to which is added 1.3 mL (10 mmol) of

trimethylborate, and 10 mL of dry THF under nitrogen. Place the system in a dry ice and ethanol bath,

and add the Grignard reagent solution prepared above dropwise via a syringe. After the addition,

allow the reaction to reach room temperature and stir for 12 h.

Part 2: Acidification and isolation of phenylboronic acid

Transfer the contents of the reaction flask into a 100 mL flask equipped with a magnetic stir bar

and measure the pH (universal indicator paper). With constant stirring, add 10% H2SO4 dropwise until

the pH is between 1 and 3. Remove the THF using a rotary evaporator (remove ~20 mL). Measure the

pH, and add 10% KOH dropwise until at a pH between 12 and 13, thus precipitating Mg(OH)2.

Remove the methanol formed in this stage using a rotary evaporator, and then vacuum filter to

remove the formed hydroxide. Add 10% H2SO4 to the filtrate to a pH of 2 to 3. Add 20 mL of distilled

water, and heat to boiling. Wait for 12 h for the crystallization of phenylboronic acid to be

completed.

3 CHEM 431 W Fall 2015

Part 2: Acidification and isolation of phenylboronic acid (cont.)

After complete crystallization of phenylboronic acid, filter the crystals by vacuum filtration, and dry

them in a pre-heated oven for 30 minutes (60-80 °C). Cool the crystals, and weigh them to calculate

the reaction yield. Determine the IR spectrum, and melting range to verify its purity (mp 214-216 °C).

Part 3: Synthesis of 4-methoxybiphenyl by Suzuki-Miyaura cross-coupling

With pure phenylboronic acid in hand, the reaction to form 4-methoxybiphenyl can be performed

in a round-bottom flask under a nitrogen atmosphere. Add 0.183 g of phenylboronic acid (1.5 mmol),

0.276 g of K2CO3 (2 mmol), and the palladium catalyst provided (0.2 mol%) along with a magnetic

stir-bar, then pump-purge the flask with nitrogen. Then, add 2 mL of DMF solvent containing 0.234 g of

4-iodoanisole (1 mmol) and 10 µL of undecane (internal standard L of undecane (internal standard for GC-MS analysis). Allow the

reagents to react at 100 °C (oil bath) with stirring for 3 to 4 hours. Check the reaction at this point

with GC-MS to ensure reaction is complete.

Part 4: Work-up of the Suzuki-Miyaura cross-coupling reaction

Open the reaction flask at room temperature, and transfer the contents to a centrifuge tube.

Dilute the reaction mixture with 10 mL of water. Extract the aqueous phase with 2 mL of DCM x 5.

Each extract (lower layer) will be removed via a syringe pump pipette (use first 2 mL DCM to wash

out reaction flask). Concentrate the combined extracts on the rotary evaporator to remove

dichloromethane. Re-dilute this concentrate with hexanes (10 mL) and transfer back to the

centrifuge tube. Wash the upper organic layer with water (5 x 2 mL), and with each wash remove

the lower aqueous layer (bottom) with a syringe pump pipette. This removes DMF. Dry the upper

hexane layer over anhydrous sodium sulfate and concentrate on the rotary evaporator in a clean,

dry pre-weighed flask. Obtain the mass of the crude product. Obtain an 1H NMR spectrum to

ascertain purity. If impure, purify the 4-methoxybiphenyl by column chromatography on silica using a

gradient of hexanes and ethyl acetate.

Analysis:

Final product to be analyzed by 1H NMR, 13C NMR, COSY and HSQC. Assign as many peaks as

possible on both the 1H and 13C NMR. Obtain an FT-IR as well as a GC-MS trace of the purified

material in dichloromethane.

4 CHEM 431 W Fall 2015

HAZARDS

Magnesium, trimethylborate, THF, methanol and DMF are flammable. H2SO4 and KOH are corrosive. Pd(PPh3)4 and 4-iodoanisole are harmful if inhaled. 4-Methoxybiphenyl, and biphenyl (by-product) are irritant. Dupont's catalyst must be handled with care because its hazards are not known, however, it is thermal and air stable. The use of low quantities of catalyst (0.2 mol%) and small amount of by-product generated show that the proposed catalytic system (for Suzuki-Miyaura cross-coupling) is of low toxicity to the students. All experiments were conducted with students wearing eye protection, nitrile gloves, and fume hood (for harmful reagents).

Report

Final write-up should be in the style of the Elsevier journal Tetrahedron Letters.

http://ees.elsevier.com/tetl/default.asp?acw=&utt=4a71b8c5e8db0513129db478676884ff911bbe3-oaHt

Topics that should be covered in your write-up:

• Introduction includes background on synthesis of organoboronic acids and cross-coupling reactions.

• Mechanism and mechanistic discussion of the Suzuki-Miyaura reaction, including an illustration of the catalytic cycle.

• Discussion of the catalyst you used and its advantages for this type of coupling reaction. • Discuss the formation of any by-products or side reactions noted • Discuss reaction conditions for each step • Discuss spectral assignments for IR and NMR data. • Reference thoroughly • Experimental data to be in the proper supporting information format