Practical Experiment 5: Phenytoin
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Phenytoin is synthesized from benzil in a multi-step reaction involving a pinacol rearrangement. Benzil and urea are condensed in the presence of base to form an intermediate 1,2-diol, which is then protonated to form an oxonium ion. Dehydration leads to a carbonium ion that undergoes a 1,2 shift of the phenyl ring to form a phenonium ion. Rearrangement of this ion generates the final product, phenytoin, which is isolated by acidification and recrystallization with a 91.4% yield.
![Procedure: [Ref: B. S. Furniss, A. J. Hannaford, P. W. G. Smith, Vogel’s textbook of practical
organic chemistry, 5th edition, Copublished in the United States with John Wiley & Sons, Inc., New
York Page No. 1153
Sachin Kumar Ghosh, Advanced General Organic Chemistry A Modern Approach, Published by
New Central Book Agency (P) Ltd., Kolkata, 2nd edition, Page No. 604-605]
Place 5.3 g (0.0125 mol) of benzil (Expt 6.143), 1.5 g (0.05 mol) of urea, 7.5 ml of 30 per cent
aqueous sodium hydroxide solution and 35 ml of ethanol in a 100- ml round-bottomed flask. Attach
a reflux condenser and boil under reflux using an electric heating mantle for at least 2 hours. Cool
to room temperature, pour the reaction product into 62.5 ml of water and mix thoroughly. Allow to
stand for 15 minutes and then filter under suction to remove an insoluble by-product. Render the
filtrate strongly acidic with concentrated hydrochloric acid, cool in ice-water and immediately filter
off the precipitated product under suction.
Recrystallise at least once from industrial spirit to obtain about 2.8 g (44%) of pure 5,5-
diphenylhydantoin, m.p. 297-298 °C.](https://image.slidesharecdn.com/exp5phenytoin1-210626113119/85/Practical-Experiment-5-Phenytoin-2-320.jpg)
![Principle:
Synthesis of 5,5-diphenylimidazolidine-2,4-dione (1) involves Pinacol-pinacolone
rearrangement reaction. The base catalysed reaction proceeds via an intermediate
heterocyclic pinacol (1,2 diol), which on acidification yields phenytoin.
Step Ι] Condensation of urea and benzil to form glycol (1,2-diol)
Benzil Urea Glycol (1, 2-diol)](https://image.slidesharecdn.com/exp5phenytoin1-210626113119/85/Practical-Experiment-5-Phenytoin-4-320.jpg)
![Step ΙΙ] Protonation of glycol to form oxonium ion
Glycol (1,2-diol) Oxonium ion
Step ΙΙΙ] Dehydration to form corbonium ion.
Carbonium ion](https://image.slidesharecdn.com/exp5phenytoin1-210626113119/85/Practical-Experiment-5-Phenytoin-5-320.jpg)
![Step ΙV] 1,2 shift of phenyl ring to form phenonium ion
Phenonium ion
Step V] Rearrangement of carbonium ion
Rearranged carbonium ion
Step VΙ] Loss of proton to give 5,5-diphenylimidazolidine-2,4-dione (1) (pinacolone)](https://image.slidesharecdn.com/exp5phenytoin1-210626113119/85/Practical-Experiment-5-Phenytoin-6-320.jpg)
Practical Experiment 5: Phenytoin
- 1. Title: Synthesis of Phenytoin from Benzyl Presented by… Prof. Sonali R. Pawar Phenytoin is used to control seizures. It does not treat all types of seizures, and your doctor will determine if it is the right medicine for you.
- 2. Procedure: [Ref: B. S. Furniss, A. J. Hannaford, P. W. G. Smith, Vogel’s textbook of practical organic chemistry, 5th edition, Copublished in the United States with John Wiley & Sons, Inc., New York Page No. 1153 Sachin Kumar Ghosh, Advanced General Organic Chemistry A Modern Approach, Published by New Central Book Agency (P) Ltd., Kolkata, 2nd edition, Page No. 604-605] Place 5.3 g (0.0125 mol) of benzil (Expt 6.143), 1.5 g (0.05 mol) of urea, 7.5 ml of 30 per cent aqueous sodium hydroxide solution and 35 ml of ethanol in a 100- ml round-bottomed flask. Attach a reflux condenser and boil under reflux using an electric heating mantle for at least 2 hours. Cool to room temperature, pour the reaction product into 62.5 ml of water and mix thoroughly. Allow to stand for 15 minutes and then filter under suction to remove an insoluble by-product. Render the filtrate strongly acidic with concentrated hydrochloric acid, cool in ice-water and immediately filter off the precipitated product under suction. Recrystallise at least once from industrial spirit to obtain about 2.8 g (44%) of pure 5,5- diphenylhydantoin, m.p. 297-298 °C.
- 3. O O + H2N O H2N NaOH, EtOH H3O N H H N OH OH O N H H N O O Benzil Urea 1,2-diol Phenytoin Aim: To synthesize and characterized Phenytoin from Benzil.
- 4. Principle: Synthesis of 5,5-diphenylimidazolidine-2,4-dione (1) involves Pinacol-pinacolone rearrangement reaction. The base catalysed reaction proceeds via an intermediate heterocyclic pinacol (1,2 diol), which on acidification yields phenytoin. Step Ι] Condensation of urea and benzil to form glycol (1,2-diol) Benzil Urea Glycol (1, 2-diol)
- 5. Step ΙΙ] Protonation of glycol to form oxonium ion Glycol (1,2-diol) Oxonium ion Step ΙΙΙ] Dehydration to form corbonium ion. Carbonium ion
- 6. Step ΙV] 1,2 shift of phenyl ring to form phenonium ion Phenonium ion Step V] Rearrangement of carbonium ion Rearranged carbonium ion Step VΙ] Loss of proton to give 5,5-diphenylimidazolidine-2,4-dione (1) (pinacolone)
- 7. CALCULATIONS :- Molecular weight of benzil = 210.23gm/M Molecular weight of phenytoin= 252.26gm/M Weight taken of benzil =2.65gm/M Practical yield = 2.9gm X(theoretical yield )=molecular weight phenytoin x weight of benzil taken molecular weight of benzil =252.26g/M x 2.65g/210.23g/M = 3.17gm Percentage yield = practical yield /theoretical yieldx100% Percentage yield =2.9/3.17x100% Percentage yield = 91.4%
- 8. Calculation: TLC: Structure: Formula: C15H12N2O2 Theorotical Yield: 3.17gm Practical Yield: 2.9gm % Yield: 91.4% Melting/Boiling Point: 2930c / 4640c Rf Value: 0.64