The use of herbal remedies to treat illness and disease goes back thousands of years, but the medical use of chemicals prepared in the laboratory has a much shorter history.

Barbiturates, a large class of drugs with a wide variety of uses, constitute one of the earliest successes of medicinal chemistry. The synthesis and medical use of barbiturates goes back to 1904 when Bayer, a German chemical company, first marketed a compound called barbital, trade named Veronal, as a treatment for insomnia. Since that time, more than 2500 different barbiturate analogs have been synthesized by drug companies, more than 50 have been used medicinally, and about a dozen are still in use as anesthetics, anticonvulsants, sedatives, and anxiolytics.

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Figure 22.8 Different barbiturates come in a multitude of colors, giving rise to similarly colorful street names when the drugs are abused. (credit: “Medications” by freestocks.org/Flickr, Public Domain)

The synthesis of barbiturates is relatively simple and relies on reactions that are now familiar: enolate alkylations and nucleophilic acyl substitutions. Starting with diethylmalonate, alkylation of the corresponding enolate ion with simple alkyl halides provides a wealth of different disubstituted malonic esters. Reaction with urea, (H2N)2C═O, then gives the product barbiturates by a twofold nucleophilic acyl substitution reaction of the ester groups with the –NH2 groups of urea (Figure 22.9). Amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal) are typical examples.

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Figure 22.9 The synthesis of barbiturates relies on malonic ester alkylations and nucleophilic acyl substitution reactions. More than 2500 different barbiturates have been synthesized over the past 100 years.

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In addition to their prescribed medical uses, many barbiturates have also found widespread illegal use as street drugs. Each barbiturate often comes as a tablet of regulated size, shape, and color. Although still used today, most barbiturates have been replaced by safer, more potent alternatives with markedly different structures.

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