Experiment 5. Benzilic Acid Rearrangement: Preparation of ...

[Pages:2]Chem 216 S11 Notes - Dr. Masato Koreeda Topic: _Experiment 5__ page 1 of 2.

Date: May 10, 2011

Experiment 5. Benzilic Acid Rearrangement: Preparation of Dilantin

Anticonvulsant drugs: Dilantin Sodium (phenytoin)* Tegretol (carbazepine) Phenobarbital

Epilepsy: one of the most common neurologic disorders, affecting ca. 1% of the population.

H N

O

O

N H

phenytoin (Dilantin)

N O NH2 carbamazapine

O HN ONO

H phenobarbital

*

Benzilic Acid Rearrangement

?Discovered in 1938 by Justus Liebig ? one of the first C-C bond migration reactions.

O

O benzil

migration!

NaOH

H2O/ethanol

O

H3O+-workup

O-Na+ HO

O OH

HO

benzilic acid

Reaction mechanism:

O -OH

O OH

O

O

bond migration, not bond breakage

O

OH

OH O

HO benzilic acid

O OH

H3O+ * R = H or C2H5

O

O

O

H OR *

O

HO

O

Chem 216 S11 Notes - Dr. Masato Koreeda Topic: _Experiment 5__ page 2 of 2.

Synthesis of Phenytoin (Dilantin)

O

O benzil

NH2 +O

NaOH

NH2 H2O/ethanol

urea

Reation Mechanism:

Date: May 10, 2011

H N

O ON

Na

H3O+ workup

H N

O

O

N H

phenytoin (Dilantin)

H

OH

NH

O

NH

H

pKa ~12

H

N

O

O

NH

H

NO N

OH H

* RO-H

H

O

ON O O

H2N

H O NO

H2N O

HO N O H2N

O

* R = H or C2H5

OR

H HO N O

H2N O

OR

NO

N

O

H

a Benzilic acid rearrangement step!

N O

N H O

H OR

N O

O

N H

H N

O ON

H

phenytoin (Dilantin)

H3O+-Workup

H N

O ON

O more acidic N-H

H

N O

N H

OR

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