Multistep Synthesis of Phenytoin

The synthesis of phenytoin from benzil, benzoin, and benzaldehyde via reflux and vacuum filtration.

In this laboratory experiment a synthesis was performed through several separate steps. The purpose of the experiment was to synthesize Phenytoin from benzaldehyde through a series of three different synthesis. There was a total of three steps that led up to the synthesis of the final product, Phenytoin. The first step of the experiment yielded benzoin from an condensation of benzaldehyde resulting in a % yield and a melting point of 126-129 degrees celsius. Thiamine catalyst along with water and ethanol were added to the benzaldehyde, then NaOH was added until the solution turned yellow. After recrystallization, the product was benzoin. Step two was the oxidation of benzoin to benzil producing a yield at % and a melting point 83-85 degrees celsius. Nitric acid was added to the benzoin and heated, this was followed by recrystallization to yield the benzil. In step three the benzil from step two was used to synthesize Phenytoin. The benzil and 5,5Diphenylhydantoin were mixed with ethanol. After heating this, ethanoic KOH was added and the solution was left to reflux. The crystals were washed and collected. This ended the multistep synthesis. The final product was not successfully synthesized due to sources of error during procedures. Therefore, a low percent yield of 40.4% was found. The theoretical melting point for Phenytoin 298-305 degrees Celsius.

Introduction: This experiment was designed to synthesize phenytoin through a series of three steps. When synthesizing intricate organic molecules, multiple reaction steps are commonly required. Phenytoin is in the hydantoin class of anticonvulsants. This drug was approved by the FDA in 1953 for the treatment and prevention of seizures. The goal of this experiment is to synthesize phenytoin and providing enough product to perform the next step.

Results and Discussion: During this lab experiment, phenytoin was synthesized from benzil, which was later synthesized from benzoin. Benzoin was the product of a condensation of benzaldehyde. It was found after the condensation of benzaldehyde, the product had a melting point of 126-129 degrees celsius. The melting point of benzoin is stated to range from 132-137 degrees celsius, according to www.chemical1and21.com. The melting point is a little low, but good enough to use for the next step. The oxidation of benzil was extremely impure with a yield of 30%. During the second step, benzoin undergoes oxidation by nitric acid to form benzil. The melting point obtained was 83-85 degree celsius. The melting point of benzil is stated to range from 94-95 degrees celsius, according to www.chemical1and21.com. The melting point is a little low again, but good enough to use for the next step. The oxidation of benzoin was extremely pure with a yield of 123%. Benzoin was used in the final step with a melting point of 298-305 degrees celsius obtained and a yield of 40.4%. The melting point obtained indicated that the solution was pure, based off the true melting point of phenytoin of 295-298 degrees celsius according to www.chemical1and21.com. Some possible sources of error include loss of product while transferring from flask to flask causing some of the product to fall on lab desk and loss of product while vacuum filtration. Another source of error is not properly washing items used for lab. For example, I noticed that there may have been some soap residue left in my graduated cylinder causing the products to be impure.

Experimental: Benzoin Benzoin was synthesized through an condensation of benzaldehyde. Benzaldehyde (7.5 ml, 7.81125g, 0.074 mols), 95% ethanol (15.0 ml, 0.257 mols), sodium hydroxide (2.5 ml, 0.133 mols) were placed in a round bottom flask along with a dissolved thiamine (1.3 g, 0.004 mols) and water (4.0 ml).

The solution was placed in a ice cold bath until solid formed. Once solid formed, the mixture was filtrated via vacuum filtration and place to dry. Once dried, the weight and melting point were obtained.

Benzil In order to synthesize benzil, an oxidation reaction of benzoin occurs. In a round-bottom flask, concentrated nitric acid (14 ml) was added to benzoin (4.0g, 0.018 mols) and heated for thirty minutes. After five minutes, we began aspirating the nitrogen oxide from the flask using a vacuum tube. The resulting solution was poured into a beaker containing water (75 ml) and filtrated via vacuum filtration. The dried product was recrystallized using 95% ethanol and filtered again. Once dried, the weight and melting point were obtained.

Phenytoin Phenytoin was synthesized from a reaction of benzil. Flask #1 consisted of benzil (2.0g, 0.010 mols), urea (0.96g, 0.015 mols) , and ethanol (50 ml). Flask #2 consisted of sodium hydroxide pellets (1.8g) and water (6 ml). Once both solutions dissolved, flask #2 was added to flask #1. The new mixture was refluxed for an hour. After reflux, the mixture was cooled using a wet paper towel. Water (25 ml) was added after mixture was cool; slowly acidified the filtrate with concentrated hydrochloric acid. The mix was now ready to be filtrated via vacuum filtration. The dried product was recrystallized using 95% ethanol and filtered again. Once dried, the weight and melting point were obtained.

References: 1. www.chemicalbook.com 2. www.chemical1and21.com

The synthesis of phenytoin from benzil, benzoin, and benzaldehyde via reflux and vacuum filtration.

Linda Jean-Jacques Organic Chemistry II November 17, 2011