The formose reaction, discovered by Aleksandr Butlerov in 1861, is also called the Butlerov reaction. This process creates sugars from formaldehyde. The word "formose" combines the words "formaldehyde" and "-ose," which is a suffix that means "sugar."

Reaction and mechanism

The reaction is helped by a base and a divalent metal like calcium. The steps in the process include aldol reactions, reverse aldol reactions, and aldose-ketose isomerizations. Some substances formed during the reaction are glycolaldehyde, glyceraldehyde, dihydroxyacetone, and tetrose sugars. In 1959, Breslow suggested a mechanism for the reaction with these steps:

At the start, the reaction has an induction period where only a nonproductive process called Cannizzaro disproportionation happens, turning formaldehyde into methanol and formate. The first step, forming glycolaldehyde from formaldehyde, occurs very slowly and may be caused by light or free radicals, but the exact process is unknown. However, the reaction is autocatalytic: glycolaldehyde helps speed up the reaction by combining two formaldehyde molecules to create more glycolaldehyde. Even a tiny amount (as little as 3 ppm) of glycolaldehyde can start the reaction. The autocatalytic cycle begins when glycolaldehyde reacts with formaldehyde to form glyceraldehyde. Glyceraldehyde then changes into dihydroxyacetone through an aldose-ketose isomerization. Dihydroxyacetone combines with formaldehyde in another aldol reaction to form tetrulose, which changes into aldotetrose (either threose or erythrose) through another isomerization. A retro-aldol reaction of aldotetrose produces two glycolaldehyde molecules, creating a net gain of one glycolaldehyde molecule from two formaldehyde molecules, with glycolaldehyde itself acting as a catalyst. During this process, dihydroxyacetone can also combine with glycolaldehyde to form ribulose, which changes into ribose, an important part of ribonucleic acid. Careful control of reaction conditions is needed, or the alkaline environment may cause aldoses to undergo the Cannizzaro reaction.

The aldose-ketose isomerization steps are supported by calcium binding. However, studies using isotope labeling show these steps happen through a hydride shift mechanism, not via an intermediate enediolate, as previously thought.

Significance

The formose reaction was once considered important in understanding how life began because it can create complex sugars, such as ribose, from simple formaldehyde. However, scientists no longer believe this reaction plays a key role in the origin of life. In an experiment that mimicked early Earth conditions, pentoses formed from mixtures of formaldehyde, glyceraldehyde, and borate minerals like colemanite (Ca₂B₆O₁₁·5H₂O) or kernite (Na₂B₄O₇·H₂O). Challenges remain, though, including how easily pre-made sugars can bind to pre-made nucleobases and how to select ribose from a mixture of sugars. Formaldehyde and glycolaldehyde have been detected in space through spectroscopy, which has made the formose reaction a topic of interest in astrobiology.