Palladium-Catalyzed Cross Coupling
Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA
This experiment will demonstrate the concept of a pal…
- Add 4-iodoacetophenone (246 mg, 1 equivalent, 1 mmol), acrylic acid (100 μL, 1.5 equivalents, 1.5 mmol), sodium carbonate (Na2CO3, 318 mg, 3 equivalents, 3 mmol), PdCl2 (2 mg, 0.01 equivalents, 0.01 mmol), and water (5 mL, 0.2 M) to a round bottom flask (~ 20 mL) equipped with a magnetic stir bar.
- Heat the reaction to approximately 100 °C and stir until complete consumption of 4-iodoacetophenone (approximately 1 h).
- The reaction can be monitored by TLC.
- Cool the reaction mixture to room temperature after completion.
- Acidify the reaction mixture with 1 M aqueous HCl to ~ pH of 1.
- The pH of the reaction mixture can be checked with litmus paper.
- A solid should precipitate.
- Collect the solid via filtration.
- Purify the crude material by recrystallization using a 1:1 mixture of methanol/water.
Palladium-catalyzed cross-coupling reactions are a valuable tool for creating new carbon-carbon bonds.
Their development has enabled chemists to construct complex organic compounds from hydrocarbon fragments, and their use in the fine chemical and pharmaceutical industries has become wide-spread.
So profound is their impact on organic chemistry that they were the subject of the 2010 Nobel Prize in Chemistry.
This video will illustrate the principles of palladium-catalyzed cross coupling reactions, as well as a demonstration of the technique in the laboratory.
In these types of reactions, a palladium catalyst is used to facilitate the addition of a nucleophile, which is typically an organometallic compound, to a nucleophile, which is typically an organohalide
A Pd(0) species reacts with the organohalide via oxidative addition to form an organopalladium two species, which then reacts with the nucleophile to form a new carbon-carbon bond.
All of these reactions, with the exception of Heck coupling, follow the same mechanism: following the oxidative addition to form an organopalladium two species, a transmetallation step with the organometallic nucleophile occurs, forming a new species with two carbon-palladium bonds. Finally, reductive elimination occurs to create a new carbon-carbon bond and to regenerate palladium zero catalyst, which can continue to couple another nucleophile and electrophile.
In Heck coupling reactions, the organopalladium two species is formed similarly to the previous coupling reactions, but as opposed to a transmetallation step, a coordination step occurs in which the palladium two species forms a complex with an olefin. Following the coordination step, carbopalladation occurs to generate a new carbon-carbon and carbon-palladium bond. Next, beta-hydride elimination yields the desired substituted olefin and a palladium two hydride species, which undergoes reductive elimination to regenerate the palladium zero catalyst.
Now that we have discussed the principles of palladium-catalyzed cross-coupling reactions, let's look at a typical Heck coupling procedure.
To synthesize an ?,?-unsaturated carboxylic acid, we will react 4-iodoacetophenone and acrylic acid in the presence of a palladium catalyst. Begin by filling a 20-mL round-bottomed flask with acetophenone, acrylic acid, palladium two chloride, and dilute with 5 mL of water. Then add sodium carbonate to reduce the catalyst to palladium zero, and add a magnetic stir bar for mixing
After adding the reagents to the flask, stir the contents, and heat the reaction to reflux
Monitor the progress of the reaction by thin layer chromatography, or TLC, ensuring the complete consumption of acetophenone.
Once the reaction is complete, remove the flask from the heating source, and allow the mixture to cool to room temperature.
Once the mixture has cooled, acidify to pH 1 with 1 molar aqueous HCl, monitoring the pH with litmus paper, and the coupling product should precipitate from the solution.
After the mixture has been acidified, pour the contents onto a B?chner funnel covered with filter paper, and collect the solid by vacuum filtration.
To verify the structure of the coupling product, dissolve 2 mg of the dried material in 0.5 mL DMSO-d6 and analyze by NMR.
Now that we have seen an example laboratory procedure, let's see some useful applications of palladium-catalyzed cross-coupling reactions.
A major requirement in the manufacture of pharmaceutical compounds is minimal toxicity and flammability, and maximum stability in the process. Suzuki coupling reaction conditions are fairly safe, and this reaction is widely used in process chemistry, as in the synthesis of crizotinib, a lung cancer drug, from an aryl bromide and a boronic ester.
Taxol, a natural product also with anticancer properties, was discovered in the bark of the Pacific yew tree, Taxus brevifolia. Unfortunately, only 10 grams of pure compound can be collected per 1.2 tons of bark. The quantity of taxol needed in the clinic required the development of an efficient chemical synthesis, and an intramolecular Heck coupling reaction was instrumental in its large-scale production.
You've just watched JoVE's introduction to palladium-catalyzed cross-coupling reactions. You should now understand the principles behind them, how to perform an experiment, and some of their uses. Thanks for watching!
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Q1: What is the mechanism of palladium-catalyzed cross-coupling reactions?
Palladium-catalyzed cross-coupling uses a Pd(0) catalyst that undergoes oxidative addition with an organohalide to form an organopalladium(II) species. This intermediate then undergoes transmetallation with an organometallic nucleophile, followed by reductive elimination to generate a new carbon-carbon bond and regenerate the Pd(0) catalyst for continued coupling cycles.
Q2: How does Heck coupling differ from other palladium-catalyzed cross-coupling reactions?
Heck coupling differs in its intermediate steps. After forming the organopalladium(II) species, Heck coupling involves coordination with an olefin rather than transmetallation. Carbopalladation then generates new carbon-carbon and carbon-palladium bonds, followed by beta-hydride elimination to yield a substituted olefin and regenerate the Pd(0) catalyst.
Q3: What are the key steps in a typical Heck coupling laboratory procedure?
A Heck coupling procedure involves combining the organohalide, olefin, palladium catalyst, and base in a round-bottomed flask. The mixture is heated to reflux and monitored by thin layer chromatography for completion. After cooling, the product is acidified to precipitate, collected by vacuum filtration, and verified using NMR spectroscopy to confirm the coupling product structure.
Q4: Why are palladium-catalyzed cross-coupling reactions important in pharmaceutical synthesis?
Palladium-catalyzed cross-coupling reactions enable efficient construction of complex organic compounds with minimal toxicity and flammability. Suzuki coupling, for example, provides safe reaction conditions widely used in process chemistry for synthesizing pharmaceuticals like crizotinib, a lung cancer drug. These reactions allow chemists to create molecules in new and more efficient ways.
Q5: What role did palladium-catalyzed cross-coupling play in Taxol production?
Taxol, an anticancer natural product from Pacific yew tree bark, yields only 10 grams per 1.2 tons of bark. An intramolecular Heck coupling reaction was instrumental in developing an efficient chemical synthesis for large-scale production, enabling sufficient quantities for clinical use without depleting natural sources.
Q6: What reagents and conditions are used in a Heck coupling synthesis of unsaturated carboxylic acids?
A Heck coupling to synthesize an α,β-unsaturated carboxylic acid combines 4-iodoacetophenone and acrylic acid with palladium(II) chloride catalyst in water. Sodium carbonate reduces the catalyst to Pd(0). The mixture is heated to reflux, then acidified to pH 1 with hydrochloric acid to precipitate the coupling product for collection.
Q7: How is the product of a palladium-catalyzed cross-coupling reaction verified?
After isolating the coupling product by vacuum filtration and drying, the structure is verified by dissolving a small sample in deuterated solvent and analyzing by NMR spectroscopy. This technique confirms the successful formation of the new carbon-carbon bond and validates the coupling reaction outcome.