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:
 * R3C-H +  CH2O  →  R3C-CH2OH
 * R2N-H +  CH2O  →  R2N-CH2OH

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. Tetrakis(hydroxymethyl)phosphonium chloride ([P(CH2OH)4]Cl) is produced in this way from phosphine (PH3).

Hydroxymethylation in demethylation
5-Methylcytosine is a common epigenetic marker. The methyl group is modified by oxidation of the methyl group in a process called hydroxymethylation:
 * RCH3 +  O  →  RCH2OH

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:
 * RCHO +  Ph3P=CH2 →  RCH=CH2  +  Ph3PO
 * RCH=CH2  +  R2BH  →  RCH2-CH2BR2
 * RCH2-CH2BR2 +  H2O2  →  RCH2-CH2OH  +  "HOBR2"

Silylmethyl Grignard reagents are nucleophilic reagents for hydroxymethylation of ketones:
 * R2C=O +  ClMgCH2SiR'3 →  R2C(OMgCl)CH2SiR'3
 * R2C(OMgCl)CH2SiR'3 +  H2O  +  H2O2  → R2C(OH)CH2OH  +  "HOSiR'3"

Reactions of hydroxymethylated compounds
A common reaction of hydroxymethylated compounds is further reaction with a second equivalent of an active X-H bond:
 * hydroxymethylation: X-H +  CH2O  →  X-CH2OH
 * crosslinking: X-H +  X-CH2OH  →  X-CH2-X  +  H2O

This pattern is illustrated by the use of formaldehyde in the production various polymers and resins from phenol-formaldehyde condensations (Bakelite, Novolak, and calixarenes). 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 tris(hydroxymethyl)phosphine:
 * [P(CH2OH)4]Cl + NaOH → P(CH2OH)3 + H2O + H2C=O + NaCl

When conducted in the presence of chlorinating agents, hydroxymethylation leads to chloromethylation as illustrated by the Blanc chloromethylation.

Related

 * Hydroxyethylation involves the installation of the CH2CH2OH group, as practiced in ethoxylation.
 * Aminomethylation is often effected with Eschenmoser's salt, [(CH3)2NCH2]OTf