Organocatalysis

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 organocatalysis by illustrating the proper setup of a reaction that utilizes enamine catalysis. Organocatalysis is a form of catalysis that uses substoichiometric amounts of small organic molecules to accelerate reactions. This type of catalysis is complementary to other forms of catalysis such as transition metal or biocatalysis. Transition metal catalysis involves transition metals as catalysts and biocatalysis uses enzymes as catalysts. Some advantages of organocatalysis include the low toxicity and cost of the organocatalysts in comparison to many metal catalysts. In addition, most organocatalysts are not sensitive to air and moisture, unlike metal catalysts. In contrast to enzymes found in living organisms, the small molecules that act as organocatalysts are typically easy to access. Furthermore, organocatalysis offers complementary and new reactivity not observed with other forms of catalysis.

Cite this Video

JoVE Science Education Database. Organic Chemistry II. Organocatalysis. JoVE, Cambridge, MA, (2017).

Principles

Organocatalysts can be divided into four categories based on the type of catalyst. Most organocatalysts can be described as Lewis bases, Lewis acids, Bronsted bases, or Bronsted acids. These organocatalyst categories describe the mode of activation by which the catalyst acts to facilitate catalysis. In addition to these different modes of activation, organocatalysts can interact with substrates via covalent or non-covalent interactions; both of which have their advantages and disadvantages. Typically, covalent interactions are easier to control and thus predict. Oftentimes, catalysts that take advantage of non-covalent interactions require lower catalyst loadings in comparison to those that operate via covalent interactions.

Lewis bases, especially amines, are the most common type of organocatalyst. Several types of reactivity have been achieved by only using an amine catalyst. For example, the nucleophilicity of nucleophiles can be accentuated via enamine catalysis to perform selective alkylations or aldol reactions. Amine-based catalysts can also improve the electrophilicity of substrates via iminium catalysis to promote Michael additions or cycloadditions. Amine-based catalysts can even be used as phase-transfer catalysts to mediate reactions between two media phases.

In addition to substrate activation, these catalysts can also introduce chirality into the products they form, in a concept called asymmetric catalysis. One of the first examples of asymmetric organocatalysis used a chiral amino acid, proline, to catalyze an Aldol reaction (Figure 1). Proline condenses onto one of the ketones to generate a chiral enamine. In doing so, the organocatalyst generates a stronger nucleophile and introduces chirality such that the Aldol reaction can be stereoselective. The depicted example is of the Hajos-Parrish-Eder-Sauer-Wiechert reaction. The product of this reaction is an important precursor for the synthesis of steroid natural products and their derivatives.

Figure 1
Figure 1: One of the first examples of asymmetric organocatalysis used a chiral amino acid, proline, to catalyze an Aldol reaction.

Procedure

Figure 2

  1. Add (S)-proline (40 mg, 0.35 mmol, 0.35 equivalents), acetonitrile (MeCN, 5 mL), and the diketone (126 mg, 1 mmol, 1 equivalent) to a round-bottom flask (~ 20 mL) equipped with a magnetic stir bar.
  2. Stir the reaction mixture at 35 °C for 30 min.
  3. Add 3-buten-2-one (105 mg, 1.5 mmol, 1.5 equivalents) dropwise at 35 °C and stir at the same temperature for 1 week.
  4. Cool the reaction to room temperature and quench by adding ~ 5 mL of saturated aqueous ammonium chloride.
  5. Extract the aqueous layer with diethyl ether.
  6. Wash the combined organic layers with brine and dry with anhydrous magnesium sulfate.
  7. Filter the magnesium sulfate and concentrate via rotatory evaporation.
  8. Purify the crude residue via column chromatography.

Organocatalysts are low cost and low toxicity alternative to transition metals, and when compared to enzymes, they are more easily synthesized and obtained.

Organocatalysis involves small organic molecules that interact with chemical species to accelerate reactions without being consumed.

This video will illustrate the principles of organocatalysis, a procedure demonstrating an enamine catalyzed reaction, and some applications of organocatalysis.

Organocatalysts can be classified by their interactions with reactant molecules. In covalent interactions, catalysts form a reactive intermediate via a transient covalent bond in a step referred to as activation. These activated compounds then proceed to further react. The process completes with the recovery of the organocatalysis molecule.

Lewis bases, compounds that are typically electron donors, are the most common type of organocatalyst due to their versatility. For example, enamine catalysts enhance nucleophilicity, enabling selective alkylation and aldol reactions. Iminium, another amine-based catalyst, is used to improve the electrophilicity of reactants to promote Michael additions or cycloadditions.

These catalysts can also select for particular stereoisomer products in a process known as asymmetric catalysis. One of the first examples of this was an aldol reaction catalyzed by proline, a chiral amino acid.

Proline covalently bonds to a ketone, releasing water and generating a chiral enamine. This results in a stronger nucleophile that initiates a stereoselective aldol reaction. The reaction shown in this example is important for the production of precursor for the synthesis of steroids.

Now that we've covered the principles of organocatalysis let's take look at a procedure for an (S)-proline catalyzed aldol reaction.

First, bring the reactants and glassware to the fume hood. Add the reagents to a 20-mL round bottom flask with a magnetic stir bar. Then, stir the mixture at 35 °C for 30 minutes.

Then add 105 mg of 3-buten-2-one dropwise to the mixture, while maintaining the temperature. Leave the reaction to stir for one week at 35 °C.

After a week has a passed, cool the reaction to room temperature, and then quench it by adding approximately 5 mL of saturated aqueous ammonium chloride.

Next, extract the aqueous layer by adding 30 mL of diethyl ether. Separate the organic and aqueous layers by using a separatory funnel.

Then, wash the organic layers with a saturated sodium chloride solution, and dry with anhydrous magnesium sulfate. After, remove the magnesium sulfate from the solution via filtration.

Next, concentrate the product using rotary evaporation. Finally, purify the obtained residue via column chromatography.

The obtained product can now be analyzed using 1H NMR

The proton NMR of the product is used to analyze and identify the peaks of the Wieland-Miescher ketone. The compound has a total of 14 hydrogens. The downfield singlet at 5.85 ppm is characteristic for the alkene hydrogen a and integrates to 1. The alkane multiplets b, c, d, and e are found in their typical shifts ranging between 2.78 and 1.65 ppm, integrating to a total of 10 hydrogens. Lastly, the methyl group f is the most upfield singlet with a shift of 1.45 ppm with an integration of 3 hydrogens.

Now that we have looked at an organocatalysis procedure let's look at some applications

Asymmetric organocatalysis has become an indispensable process for the synthesis of pharmaceutical compounds. One example is the production of (S)-warfarin, an anticoagulant used to treat blood clots. In the past, its synthesis relied on chiral resolution, via crystallization or chromatography, from racemic mixtures. This process resulted in yields of about 19%. With the aid of an organic chiral catalyst, the wasteful chiral resolution process has been replaced with a synthesis that achieves yields of 99%.

Ionic liquids are salts that typically exist in the liquid state at room temperature. Ionic liquids are gaining attention in many research fields including organocatalysis. EMIMAc is an example of a compound that has organic cations and anions. In this application it is used as a catalyst in a stereoselective synthesis. The high stability, low volatility, and non-flammability of ionic liquids makes them a safe reaction media that is suitable for recycling.

You've just watched JoVE's video on organocatalysis. This video covered organocatalysis, a general procedure, and some applications. Thanks for watching!

Results

The purified product should have the following 1H NMR spectrum: 1H NMR δ 5.88 (1H, s), 2.6-2.7 (2H, m), 2.3-2.55 (4H, m), 2.0-2.2 (2H, m), 1.6-1.8 (2H, m), 1.4 (3H, s).

Applications and Summary

This experiment has demonstrated how to set up an enamine catalyzed reaction. Compared to other forms of catalysis, organocatalysis is a relatively young field of research, but in recent years the field of organocatalysis has experienced dramatic growth. The increased interest in organocatalysis has also given rise to research that makes use of more than one type of catalysis to achieve new types of reactivity. For example, there has been increased reports of using organocatalysis in conjunction with transition metal catalysis.

Asymmetric organocatalysis has been used to improve the synthesis of warfarin, a common anti-coagulant. The previous synthetic route relied upon chemical resolution (an inherently wasteful process) of the racemic mixture to afford the more active enantiomer (S)-warfarin in 19% yield. Now with the aid of asymmetric organocatalysis, (S)-warfarin can now be accessed without chemical resolution in 99% yield via iminium catalysis.

Figure 2
Figure 2: (S)-Warfarin.

The antiviral medication, Tamiflu, that is used to treat the flu has been synthesized using organocatalysis. This synthesis makes use of a common type of organocatalyst, a prolinol-derived catalyst. The organocatalyzed Michael addition sets two out of the three necessary stereocenters found in Tamiflu.

Figure 3
Figure 3: The antiviral medication, Tamiflu.

Figure 2

  1. Add (S)-proline (40 mg, 0.35 mmol, 0.35 equivalents), acetonitrile (MeCN, 5 mL), and the diketone (126 mg, 1 mmol, 1 equivalent) to a round-bottom flask (~ 20 mL) equipped with a magnetic stir bar.
  2. Stir the reaction mixture at 35 °C for 30 min.
  3. Add 3-buten-2-one (105 mg, 1.5 mmol, 1.5 equivalents) dropwise at 35 °C and stir at the same temperature for 1 week.
  4. Cool the reaction to room temperature and quench by adding ~ 5 mL of saturated aqueous ammonium chloride.
  5. Extract the aqueous layer with diethyl ether.
  6. Wash the combined organic layers with brine and dry with anhydrous magnesium sulfate.
  7. Filter the magnesium sulfate and concentrate via rotatory evaporation.
  8. Purify the crude residue via column chromatography.

Organocatalysts are low cost and low toxicity alternative to transition metals, and when compared to enzymes, they are more easily synthesized and obtained.

Organocatalysis involves small organic molecules that interact with chemical species to accelerate reactions without being consumed.

This video will illustrate the principles of organocatalysis, a procedure demonstrating an enamine catalyzed reaction, and some applications of organocatalysis.

Organocatalysts can be classified by their interactions with reactant molecules. In covalent interactions, catalysts form a reactive intermediate via a transient covalent bond in a step referred to as activation. These activated compounds then proceed to further react. The process completes with the recovery of the organocatalysis molecule.

Lewis bases, compounds that are typically electron donors, are the most common type of organocatalyst due to their versatility. For example, enamine catalysts enhance nucleophilicity, enabling selective alkylation and aldol reactions. Iminium, another amine-based catalyst, is used to improve the electrophilicity of reactants to promote Michael additions or cycloadditions.

These catalysts can also select for particular stereoisomer products in a process known as asymmetric catalysis. One of the first examples of this was an aldol reaction catalyzed by proline, a chiral amino acid.

Proline covalently bonds to a ketone, releasing water and generating a chiral enamine. This results in a stronger nucleophile that initiates a stereoselective aldol reaction. The reaction shown in this example is important for the production of precursor for the synthesis of steroids.

Now that we've covered the principles of organocatalysis let's take look at a procedure for an (S)-proline catalyzed aldol reaction.

First, bring the reactants and glassware to the fume hood. Add the reagents to a 20-mL round bottom flask with a magnetic stir bar. Then, stir the mixture at 35 °C for 30 minutes.

Then add 105 mg of 3-buten-2-one dropwise to the mixture, while maintaining the temperature. Leave the reaction to stir for one week at 35 °C.

After a week has a passed, cool the reaction to room temperature, and then quench it by adding approximately 5 mL of saturated aqueous ammonium chloride.

Next, extract the aqueous layer by adding 30 mL of diethyl ether. Separate the organic and aqueous layers by using a separatory funnel.

Then, wash the organic layers with a saturated sodium chloride solution, and dry with anhydrous magnesium sulfate. After, remove the magnesium sulfate from the solution via filtration.

Next, concentrate the product using rotary evaporation. Finally, purify the obtained residue via column chromatography.

The obtained product can now be analyzed using 1H NMR

The proton NMR of the product is used to analyze and identify the peaks of the Wieland-Miescher ketone. The compound has a total of 14 hydrogens. The downfield singlet at 5.85 ppm is characteristic for the alkene hydrogen a and integrates to 1. The alkane multiplets b, c, d, and e are found in their typical shifts ranging between 2.78 and 1.65 ppm, integrating to a total of 10 hydrogens. Lastly, the methyl group f is the most upfield singlet with a shift of 1.45 ppm with an integration of 3 hydrogens.

Now that we have looked at an organocatalysis procedure let's look at some applications

Asymmetric organocatalysis has become an indispensable process for the synthesis of pharmaceutical compounds. One example is the production of (S)-warfarin, an anticoagulant used to treat blood clots. In the past, its synthesis relied on chiral resolution, via crystallization or chromatography, from racemic mixtures. This process resulted in yields of about 19%. With the aid of an organic chiral catalyst, the wasteful chiral resolution process has been replaced with a synthesis that achieves yields of 99%.

Ionic liquids are salts that typically exist in the liquid state at room temperature. Ionic liquids are gaining attention in many research fields including organocatalysis. EMIMAc is an example of a compound that has organic cations and anions. In this application it is used as a catalyst in a stereoselective synthesis. The high stability, low volatility, and non-flammability of ionic liquids makes them a safe reaction media that is suitable for recycling.

You've just watched JoVE's video on organocatalysis. This video covered organocatalysis, a general procedure, and some applications. Thanks for watching!

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