CHM 226 Suzuki Reaction

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1 INTRODUCTION Reactions that form carbon-carbon (C-C) bonds are very important because C-C bonds are the primary framework of all organic molecules. The Suzuki reaction is one of the most popular types of carbon-carbon bond forming reactions for research in organic synthesis, materials sciences, and pharmaceuticals. For instance, Johansson et al. use the Suzuki reaction to synthesis potential drugs that will act as an inhibitor for malarial aspartic proteases plasmepsin (Plm) I and II. 2 Dr. Suzuki won the 2010 Nobel Prize in Chemistry for his palladium catalyzed crosscoupling reaction between an organohalaide and an organoboron compound. While the original work, presented in 1979, involved coupling reactions of alkenyl boronates with alkenyl bromides, throughout the years the scope of this reaction has expanded to different substrates such as aryl chlorides or even more hindered substrates, as well as using lower catalyst loading conditions, and solvent-free and room temperature conditions. 1 Chalker et al utilize Suzuki cross couplings on protein surfaces under mild conditions. They found that using 2-amino-4,6-dihydroxypyrimidine as a ligand made the catalyst mild enough to sufficiently promote the cross coupling reaction on protein substrates. Performing cross coupling on peptides and proteins is an attractive method for modifying proteins which could then be used in biochemical and therapeutic contexts. 3 Scheme 2: Suzuki Cross-Coupling on Protein Surface 3

2 The Suzuki-Miyaura coupling reaction is done under many different reaction conditions but they all use palladium as a catalyst. Catalysts are often used in reactions to increase the rate of reaction but in this case, and for many other metal catalyzed reactions the catalyst causes the reaction. Many organic reactions utilize metal complexes as catalysts in sub-stoichiometric quantities, usually 0.1 to 10 mol%. Not only is it cost effective to use catalytic quantities of these expensive metal catalysts but it also makes the products easier to purify and decreases the amount of waste generated. Enhancements to metal catalysts are constantly being made by changing the ligands. The most commonly used ligands are phosphine based, however ligandless conditions are becoming more common due to the low cost. Another feature that makes this particular Suzuki reaction green is that water can often be used as the reaction solvent thereby generating less waste. Eliminating the use of an organic solvent in synthesis is extremely beneficial to the environment, especially for a reaction that is often done on large scales in industry. Catalytic mechanism are drawn as a cycle, the reagents and products enter and leave the cycle but the metal catalyst stays in the cycle. Palladium is generally found in the 0, II, and sometimes IV oxidation state. When drawing a mechanism the oxidation state of the metal should always be included as a superscript above the metal (see below). The mechanism of a standard Suzuki-Miyaura reaction is shown below and involves oxidative addition, transmetallation, and reductive elimination. Scheme 3: Standard Mechanism of Suzuki Coupling reaction Oxidative addition occurs when a metal inserts itself into an X Y bond, which is then broken when the metal inserts into it forming a Y M X species. This reaction is an oxidation reaction because the metal s oxidation state increases by 2. Transmetallation occurs when the organo boronic acid acting as nucleophile swaps the R group with the halide on Pd. Reductive elimination is the exact opposite of oxidative addition.

3 1. Barder, T.; Walker, S.D.; Martinelli, J.R.; Buchwald, S.L. J. Am. Chem. Soc., 2005, Johansson, P.; Lindberg, J.; Blackman, M.J.; Kvarnström I.; Vrang L.; Hamelink E.; Hallber A.; Rosenquist A.; Samuelsson B.. J. Med. Chem., 2005, Chalker, J. M.; Wood, C.S.C.; Davis, B.G., J. Am. Chem. Soc., 2009,

4 PRE-LAB QUESTIONS 1. Predict the product and draw the mechanism for the following Suzuki reaction.

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6 PROCEDURE Phenylboronic acid 4-iodophenol K 2 CO 3 Pd/C (10%) Equivalents MW (g/mole) mmole Amount (mg) 3.00 Before starting turn on the hot plate equipped with a sand bath, use a thermometer to monitor the temperature until it reaches 100 C. While waiting for the sand bath to heat up, take an NMR tube and rinse it with acetone and place it in the oven, you want your NMR tube to be clean and dry for when you prepare your NMR sample. Obtain a 50 ml round bottom flask equipped with a stir bar, add K 2 CO 3, 4-iodophenol, and 10mL of water, may not dissolve completely. Then take a separate round bottom flask, add Pd/C (10%) and water, swirl around to fully dissolve, and use a pipette to add solution to main reaction mixture. If there is still Pd left in the round bottom you can use a minimum amount of water to transfer it all. Attach the round bottom to the reflux condenser and heat it to reflux while stirring for 30 minutes. Do not start timing the 30 minutes until the reaction starts refluxing, a precipitate may form. After 30 minutes, detach the reflux condenser, turn off the hot plate, and remove the round bottom flask. Allow it to cool to room temperature. Once it has cooled to room temperature, add small amounts of aqueous HCl (2M). After each addition check the acidity with litmus paper until acidic. Isolate the solid by vacuum filtration and wash it with at least 10mL of water. In a 25mL Erlenmeyer flask dissolve the collected solid with 10mL of methanol and filter off the Pd/C and collect filtrate in 50-mL Erlenmeyer flask. Add 10 ml of distilled water to the Erlenmeyer flask, solid will precipitate. Heat the flask until all the solid has gone into solution. Once complete remove the flask from heat, cool to room temperature, and put on ice bath until crystals form. Weigh an empty, clean Hirsch funnel. Using the Hirsch funnel collect the recrystallized product by vacuum filtration and allow them to dry (if crystals still remain in flask add very small amount of water to transfer them into the funnel). Put your Hirsh funnel in a beaker and leave in drawer to ensure that it is completely dry for analysis on the next lab day. DAY 2 Take your Hirsch funnel from drawer and re-weigh it and calculate percent yield. Analyze the sample by the melting point and IR. Next take your dry NMR tube from oven. Add a small amount of product to test tube, using a CLEAN pipette take 1 ml of deuterated DMSO directly from the bottle, and add to test tube containing product. Make sure it is completely dissolved and then using pipette add the solution to the NMR tube. Cap the NMR tube, using sharpie write initials and section number on the cap of the NMR tube. Then give it to your TA.