Wöhler’s 1828 Synthesis of Urea

From the alchemists of the middle ages to the modern synthesis of numerous targeted medicines, chemistry has taken drastic transformations. Arguably, the most pivotal of all changes in the discipline was Frederich Wöhler’s 1828 synthesis of urea that challenged the long-held belief of vitalism—the theory that living organisms were governed by a set of “vital” forces distinct from the forces of physics and chemistry.

Friedrich Wöhler was one of the most prolific German scientists of his time. He received the best chemical training available at the time under the renowned Swedish chemist Jöns Berzelius. Among Wöhler’s other accomplishments were the first-ever isolation of aluminum, an accidental but unelaborated proof of the concept of isomerism, and a paper on free radicals published in collaboration with Justus Liebig.

Wöhler’s synthesis of urea was simple compared to most modern organic chemistry syntheses. He first attempted to synthesize ammonium cyanate (NH₄OCN) as part of his study on cyanate salts. He reacted silver cyanate (AgOCN) with ammonium chloride (NH₄Cl). A white, crystalline solid was produced, which had very different properties than all other cyanates. He then attempted treating lead cyanate (Pb(OCN)₂) with ammonium hydroxide (NH₄OH), creating a white crystal solid with organic properties. When this compound was tested against urea isolated from urine using potash, chalk, acids, and bases, the two compounds turned out to be identical with exact matching chemical and physical properties. Hence, Wöhler had synthesized urea from lead cyanate and ammonium hydroxide.

At the time, Wöhler did not understand the exact chemical reaction and mechanisms of his experiment. His synthesis was very much serendipitous as urea was a by-product of the reactions that Wöhler used to synthesize ammonium cyanate. He had noted the formation of an unexpected white, crystalline substance void of the properties of the cyanate salt he had predicted.

The synthesis itself is a double displacement reaction followed by a reversible rearrangement of the atoms to form urea, a more stable product:

The implications for Wöhler’s urea synthesis is still very much a heated debate. Wöhler had synthesized urea, an organic molecule, using inorganic substances and laboratory equipment. At the time, the prevalent paradigm of vitalism believed that life resulted from a set of “vital forces” inherent to living organisms and physically distinct from any non-living physical or chemical force.

Wöhler’s experiment was the first widely-recognized in-vitro synthesis of an organic compound, instead of the conventionally believed limit of in-vivo synthesis for organic compounds. Thus, for the purposes of simplicity, people praised Wöhler for sounding the death knell of vitalism. In fact, a 2000 survey by a historian showed that 90 percent of published organic chemistry at the time textbooks referenced this belief. Wöhler famously wrote to his teacher Berzelius, a vitalist, on the account of the synthesis:

“ I cannot, so to say, hold my chemical water and must tell you that I can make urea without the help of a kidney or even an animal, neither man nor dog. Ammonium cyanate is urea.”

However, modern research has ignited skepticism over this mythifying praise for Wöhler. What Wöhler had achieved was exaggerated and amplified throughout the ages. Historian of Chemistry Peter J. Rambert calls this phenomenon the “Wöhler Myth.” In the aforementioned letter to Berzelius, Wöhler seemed to be concerned with the implications of what was to be known as isomerism—that two compounds can have the same chemical formula but different structures, than …. He wrote:

“[The formation of urea] would thus be an indisputable example that two entirely different bodies could contain the same proportions of the same elements, and only a dissimilar kind of union brings out the peculiarities in the properties.”

Rambert had summarized the Wöhler Myth in three arguments arranged in a syllogism:

(1) Wöhler synthesized urea, an organic compound, “from the elements”;

(2) vitalism holds that only vital forces can create organic compounds;

(3) therefore, Wöhler proved vitalism is wrong and dealt a serious blow to vitalism. Rambert addressed critical faults for each of these arguments.

(1): Wöhler’s synthesis relied on materials derived from organic sources, only that he synthesized in vitro. Strictly, his synthesis could never be called “from the elements.”

(2): Already, the chemical world at the time, including most vitalists and Berzelius, was in consensus that organic and inorganic matters abide the same laws. Given that, it was a modest leap to conclude that organic compounds could be synthesized from inorganic sources.

(3): Vitalism persisted strongly through the 19th century and only ended in the 1930s. Decades after the synthesis, the most prestigious chemists still regarded vital forces in equal validity as gravity or electricity.

Nevertheless, Wöhler’s legacy is worth celebrating. He did not single-handedly terminate a millennial-old belief, as people tend to romanticize due to a love for simplistic stories, yet his work was still a milestone in organic chemistry. Wöhler demonstrated the power of in vitro synthesis and the capability for a lab to produce just about any chemical compound. Wöhler’s speculations about multiple structures having the same chemical formula also eventually proved to be fruitful when Berzelius discovered and named isomerism in 1830.

Organic chemistry has developed rapidly since Wöhler. Almost a century after Wöhler’s first in vitro synthesis of urea, Fritz Haber and Carl Bosch engineered the Haber-Bosch process for urea synthesis, which produces enough urea to fertilize crops and sustain global population growth. Without it, we would only be able to produce two thirds of the food we do today. Wöhler was a precursor to all these accomplishments of organic chemistry.