Hydroxymethylation

Hydroxymethylation is a chemical reaction that installs the CH₂OH group. The transformation can be implemented in many ways and applies to both industrial and biochemical processes.

Hydroxymethylation with formaldehyde

A common method for hydroxymethylation involves the reaction of formaldehyde with active C-H and N-H bonds:
A typical active C-H bond is provided by a terminal acetylene or the alpha protons of an aldehyde. In industry, hydroxymethylation of acetaldehyde with formaldehyde is used in the production of pentaerythritol:
P-H bonds are also prone to reaction with formaldehyde. Tetrakisphosphonium chloride is produced in this way from phosphine.

Hydroxymethylation in demethylation

is a common epigenetic marker. The methyl group is modified by oxidation of the methyl group in a process called hydroxymethylation:
This oxidation is thought to be a prelude to removal, regenerating cytosine.

Representative reactions

A two-step hydroxymethylation of aldehydes involves methylenation followed by hydroboration-oxidation:
Silylmethyl Grignard reagents are nucleophilic reagents for hydroxymethylation of ketones:

Reactions of hydroxymethylated compounds

A common reaction of hydroxymethylated compounds is further reaction with a second equivalent of an active X-H bond:
This pattern is illustrated by the use of formaldehyde in the production various polymers and resins from phenol-formaldehyde condensations. Similar crosslinking occurs in urea-formaldehyde resins.
The hydroxymethylation of N-H and P-H bonds can often be reversed by base. This reaction is illustrated by the preparation of trisphosphine:
When conducted in the presence of chlorinating agents, hydroxymethylation leads to chloromethylation as illustrated by the Blanc chloromethylation.

Related reactions

Hydroxymethylation is one of many hydroxyalkylations. It is more widely used because formaldehyde is more electrophilic than most aldehydes. Thus, hydroxyethylation involves the installation of the CH₂CH₂OH group, as practiced in ethoxylation.
Aminomethylation is yet another extension of hydroxymethylation. Commonly aminomethylations are the result of a Mannich reaction. Dimethylaminomethyl groups can be installed with Eschenmoser's salt, OTf