5.8: Organocatalysis

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!