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What is the Formose Reaction?

The formose reaction (also known as Butlerov reaction) was first discovered by the Russian chemist Alexander Butlerov in 1861 (1). Butlerov boiled a mixture of formaldehyde, a 1-carbon sugar, and lime solution (Ca(OH)2) and noticed the mixture turned yellow with a brown tint and noticed the smell of burnt sugar. The products were separated from the mixture and tasted sweet. Unbeknownst to Butlerov, the products did indeed contain sugars, and not just one or two, but a large variety!


How did these sugars form?

The mechanisms of the formose reaction revolve around the formation of an enol, which consists of an alkene with a hydroxyl (OH) group attached. A ketone or aldehyde can undergo a two-way conversion (interconversion) into their corresponding enol in a process called keto-enol tautomerism (Figure 1). In basic conditions, the proton (H+) attached to the α-carbon* can be easily removed by the OH–. The resulting negative charge is transferred to the oxygen which removes a proton from the environment, forming an enol.


*α-carbon (n): the carbon next to the carbonyl (C=O) group.

Figure 1. Keto-enol tautomerism of glycolaldehyde

A pair of electrons from the double bond of the enol can attack the carbonyl of another aldehyde or ketone, linking the two molecules. This condensation is called an aldol addition (Figure 2) and is the mechanism by which short-chained carbohydrates become longer. In the formose reaction, aldol addition tends to occur with formaldehyde due to its excess, although addition with other sugars is also possible.

Figure 2. Aldol addition between glycolaldehyde and formaldehyde

You might also be wondering, once the enol is formed, can the carbonyl bond reform on a different pair of C-O? And indeed it can. The interconversion between an aldehyde sugar (aldose) and ketone sugar (ketose) is technically called the Lobry de Bruyn-van Ekenstein transformation. Having said that, I don't think you would be off the mark to call it keto-enol tautomerism either.


Once the sugars reach above 3 carbons, some of them undergo retroaldol fragmentation (Figure 3) into smaller sugars formed earlier in the reaction. In basic conditions, one of the OH groups can be deprotonated, giving the oxygen a negative charge. A series of electron transfers break the bond between the carbon connected to the oxygen and an α-carbon. The final step is the protonation of the α-carbon to remove the negative charge.

Figure 3. Retroaldol fragmentation of erythrose into 2 glycolaldehyde molecules

The focus on ribose

Historically, prebiotic chemists have focused on the formose reaction for its ability to make ribose. Ribose is the sugar component found in RNA which, according to the RNA World hypothesis, was the first genetic molecule to evolve on the early Earth. This hypothesis was the result of a few key observations. RNA can both store and transfer genetic information, like DNA, and catalyse reactions, like enzymes. On top of that, ribonucleotides (the monomers that make up RNA) are integrated throughout the metabolic network, most notably in adenosine triphosphate (ATP), which is often referred to as the energy currency of the cell.


However, if nothing else, more than 50 years of research has shown that making ribonucleotides is far from trivial, which is especially true under the constraints of early Earth geochemistry. While there are many facets to this obstacle, this post will focus on the parts relevant to the formose reaction.


As mentioned earlier, the formose reaction doesn't contain just ribose, but a plethora of sugars. The yield of ribose when isolated is abysmally tiny (<1%) and ribose is not particularly stable. Once all the formaldehyde is consumed, the formose reaction turns yellow due to caramelisation and the sugars reacts with one another forming tar. In addition, the reaction between ribose and the nucleobases (A, T, G, C, and U) is not thermodynamically favourable in water.


A different perspective

Let's take another look at the formose reaction. As the reaction progresses, short-chained sugars lengthen via aldol additions with formaldehyde. Sugars with four or more carbons split into multiple short-chained sugars, starting even more cycles (Figure 4). As the population of formose sugars increases, so does the rate of the reaction. This phenomenon is known as autocatalysis.

Figure 4. Mechanism of autocatalysis in the formose reaction proposed by Breslow (2)

Autocatalysis is ubiquitous in biology. A parent cell splitting into two daughter cells or chemical signals that trigger pathways leading to their own productions are both examples of autocatalysis. Under the right conditions, autocatalytic reactions can exhibit exciting behaviours such as oscillating concentrations and chemical waves, the most well-known example of which is the Belousov-Zhabotinsky reaction.


Conclusion

Due to its ability to form interesting products and its autocatalytic behaviour, the formose reaction is regarded as one of the pillars of prebiotic chemistry. To this day, scientists are still unravelling the complexity of the formose reaction. Many seek to improve the yield and selectivity of ribose using minerals, while others search for the necessary conditions to observe life-like behaviours. As the field of astrobiology grows and the necessary technology develops, it is exciting to think about the findings yet to be made about this deceptively simple reaction.


References

(1) A. Butlerow, C. R. Acad. Sci., 1861, 53, 145–147.

(2) R. Breslow, Tetrahedron Lett., 1959, 1, 22–26.

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