Palladium-Catalyzed Cross Coupling

Organic Chemistry II

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Overview

Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA

This experiment will demonstrate the concept of a palladium-catalyzed cross coupling. The set-up of a typical Pd-catalyzed cross coupling reaction will be illustrated. Pd-catalyzed cross coupling reactions have had a profound effect on how synthetic chemists create molecules. These reactions have enabled chemists to construct bonds in new and more efficient ways. Such reactions have found widespread applications in the fine chemical and pharmaceutical industries. Pd-catalyzed cross coupling reactions add another tool to the chemist's toolbox for constructing carbon-carbon bonds, which are central to organic chemistry. The combination of the importance of making carbon-carbon bonds and the impact of Pd-catalyzed cross coupling have resulted in these reactions being the subject of the 2010 Nobel Prize in Chemistry. Ei-ichi Negishi, one of the recipients of the 2010 Nobel Prize in chemistry, explained in his Nobel lecture that one of his motivations for developing this chemistry was to develop "widely applicable straightforward Lego-like methods for hooking up two different organic groups".

Cite this Video

JoVE Science Education Database. Organic Chemistry II. Palladium-Catalyzed Cross Coupling. JoVE, Cambridge, MA, (2017).

Principles

Pd-catalyzed cross coupling reactions consist of an electrophile (typically an organohalide), a nucleophile (typically an organometallic compound or an alkene), and a palladium catalyst. Regardless of the electrophile or nucleophile used, all Pd-catalyzed cross couplings rely on the Pd-catalyst to activate and combine both partners. Generally speaking, a Pd(0) species reacts with the organohalide via an oxidative addition to form an organopalladium species (RPdX). This organopalladium species then reacts with the nucleophilic partner to generate a new organopalladium species and ultimately construct a new carbon-carbon bond. Depending of the nucleophilic partner, the Pd-catalyzed cross coupling is given a specific name (see Table 1 below).

Nucleophile Reaction name
Organoboron Suzuki
Organostannane Stille
Organozinc Negishi
Organomagnesium (Grignard reagent) Kumada
Organosilane Hiyama
Olefin/alkene Heck
Alkyne Sonogashira

Table 1: List of Pd-catalyzed cross coupling reaction names and their nucleophilic partners.

There are two general mechanisms associated with these Pd-catalyst cross couplings. One for the Heck reaction, and one for the other cross coupling reactions. Overall, the Heck reaction couples an alkene with an organohalide to generate a now more substituted olefin (Figure 1). The first step of a Heck reaction is the same as all other Pd-catalyzed cross couplings. To begin, oxidative addition occurs between the Pd(0)-catalyst and the organohalide to generate an organopalladium(II) species. Next, the olefin coordinates to this newly formed organopalladium(II) species. After olefin coordination, carbopalladation occurs to generate a new carbon-carbon and carbon-palladium bond. Next, beta-hydride elimination occurs to generate a Pd(II)-hydride species and the olefin product. Finally, reductive elimination of HX regenerates the Pd(0)-catalyst, which can continue coupling to another molecule of organohalide and olefin.

Figure 1
Figure 1: The Heck reaction couples an alkene with an organohalide to generate a now more substituted olefin.

For the remaining cross coupling reactions, the mechanism is as follows (Figure 2). Oxidative addition between the organohalide and Pd(0) catalyst results in the formation of an organopalladium(II) species. This organopalladium(II) species reacts with the nucleophilic organometallic compound in a step called transmetalation to generate an organopalladium(II) species with two carbon-palladium bonds. Finally, reductive elimination occurs to create a new carbon-carbon bond and regenerate the Pd(0) catalyst.

Figure 2
Figure 2: Mechanism for the remaining cross coupling reactions.

Procedure

Image 1

  1. 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.
  2. Heat the reaction to approximately 100 °C and stir until complete consumption of 4-iodoacetophenone (approximately 1 h).
    1. The reaction can be monitored by TLC.
  3. Cool the reaction mixture to room temperature after completion.
  4. Acidify the reaction mixture with 1 M aqueous HCl to ~ pH of 1.
    1. The pH of the reaction mixture can be checked with litmus paper.
    2. A solid should precipitate.
  5. Collect the solid via filtration.
  6. 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 α,β-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 Büchner 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!

Results

The product should be a solid with the follow 1H NMR spectrum: 1H NMR (400 MHz, DMSO-d6): δ (ppm) 2.60 (s, 3H), 6.67 (d, J = 16.0 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H). 7.83 (d, J = 8.4 Hz, 2H). 7.97 (d, J = 8.4 Hz, 2H).

Applications and Summary

These Pd-catalyzed cross coupling reactions have changed the way molecules are synthesized in academic and industrial settings. The impact of this technology can be seen in how chemists construct complex structures for pharmaceuticals, agriculture chemicals, and materials. Beyond Pd-catalyzed cross couplings, transition metal catalysis has changed (and is continuing to change) the way synthetic chemists prepare molecules that can have an impact on society through their potential therapeutic use.

Many molecules of interest for treating diseases have linkages connecting aromatic or heteroaromatic rings. Palladium cross coupling reactions, like the Suzuki reaction, have found widespread use in the pharmaceutical industry for making these types of structures. For example, Crizotinib (Xalkori), an anti-cancer drug for the treatment of non-small cell lung carcinoma, is synthesized on a several kilo-scale using a Suzuki coupling.

Figure 3
Figure 3: Crizotinib (Xalkori), an anti-cancer drug.

Palladium cross couplings have also been applied towards the synthesis of Taxol (an anticancer drug), Varenicline (an anti-smoking drug), and precursors for high performance electronic resins.

Figure 2
Figure 4: Taxol (an anticancer drug), Varenicline (an anti-smoking drug), and precursors for high performance electronic resins.

Image 1

  1. 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.
  2. Heat the reaction to approximately 100 °C and stir until complete consumption of 4-iodoacetophenone (approximately 1 h).
    1. The reaction can be monitored by TLC.
  3. Cool the reaction mixture to room temperature after completion.
  4. Acidify the reaction mixture with 1 M aqueous HCl to ~ pH of 1.
    1. The pH of the reaction mixture can be checked with litmus paper.
    2. A solid should precipitate.
  5. Collect the solid via filtration.
  6. 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 α,β-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 Büchner 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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