Historical Background

Historical Background

One of the earliest, and perhaps most significant-although accidental-examples of synthesis was reported by Friederich Wöhler in 1828. In an experiment designed to prepare ammonium cyanate from silver cyanate, he heated the latter with ammonium chloride expecting the outcome shown below.

The product Wöhler obtained did not correspond to the expected cyanate salt, but was identified as urea, NH₂CONH₂, an organic compound isolated from urine fifty years earlier. This result was revolutionary in two respects. First it provided another example of isomerism, in that ammonium cyanate, ammonium fulminate (NH₄O-N=C) and urea are all isomers, a novel concept for the time. Second it cast doubt on the widely held doctrine of vitalism, which maintained that all living organisms were endowed with a vital or life force that rendered them and their component parts uniquely different from ordinary "inorganic" matter. Thus, strongly heating organic substances such as carbohydrates and proteins yielded water, ammonia and carbonaceous solids (all inorganic), with loss of the vial essence. Wöhler's experiment was acclaimed as the first conversion of an inorganic substance into an organic compound.
Less than twenty years later, the German chemist Adolf Kolbe provided an even more convincing synthesis of organic from inorganic substances. The two equations written below outline his experiment. First, carbon disulfide, obtained by reaction of carbon with sulfur, was converted to carbon tetrachloride by heating with chlorine, and the simultaneous pyrolysis of CCl₄ yielded a mixture of products which included tetrachloroethene, presumably formed from dichlorocarbene (:CCl₂). Treatment of tetrachloroethene with aqueous chlorine (think HOCl) gave trichloroacetic acid, which Kolbe reduced electrolytically to acetic acid. This ended the reign of vitalism as a scientific theory.

During the 1850's, the French chemist Pierre Berthelot synthesized scores of simple organic compounds, ranging from ethanol to acetylene and benzene, setting the stage for more ambitious attempts. Just as the alchemists sought to transmute base metals into gold, early organic chemists were drawn to the isolation or preparation of rare dyes, exotic perfumes and unusual spices, often worth more than their weight in gold. A notable example of this interest is William Perkin's attempt to synthesize quinine.
Quinine, an important drug for the treatment of malaria, was available only from the bark of the South American tree Cinchona officinolis, and in the mid 1850's a decline in the native tree population had caused a large rise in the price of the drug. Very little was known about the compound, other than its molecular formula C₂₀H₂₄N₂O₂. Nevertheless, in the spring of 1856, William H. Perkin, a student (age 18) at the Royal College of Chemistry in London, attempted its synthesis in his home laboratory. Perkin reasoned that oxidation of a suitable 10-carbon amine, such as allyl toluidene, C₁₀H₁₃N, might generate quinine, as shown in the following equation.

This simple approach failed, and from our vantage point a century and a half later it is easy to see why. Many thousands of isomers having the molecular formula of quinine are possible, but only one unique configuration of these 48 atoms constitutes a molecule of quinine. That the atoms of allyltoluidine should, in the course of one reaction, selectively reorganize and combine in this specific fashion is beyond all reasonable probability.
Perkin's experiment was a failure only in the respect it did not yield quinine, and his subsequent study of aromatic amine oxidations demonstrates the value of persistence. From an impure sample of aniline he obtained a purple dye he called aniline purple (also called mauve), which became the cornerstone of the synthetic dyestuff industry in Europe and made a fortune for its discoverer.
A total synthesis of quinine was achieved in 1944 by R. B. Woodward and W. E. Doering (Harvard), and improved syntheses continue to be reported.