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.
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-CH2OHA typical active C-H bond is provided by a terminal acetylene[1] or the alpha protons of an aldehyde.[2] 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(CH<sub>2</sub>OH)<sub>4</sub>]Cl) is produced in this way from phosphine (PH3).
5-Methylcytosine is a common epigenetic marker. The methyl group is modified by oxidation of the methyl group in a process called hydroxymethylation:[3]
RCH3 + O → RCH2OHThis oxidation is thought to be a prelude to removal, regenerating cytosine.
A two-step hydroxymethylation of aldehydes involves methylenation followed by hydroboration-oxidation:[4]
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:[5]
R2C=O + ClMgCH2SiR'3 → R2C(OMgCl)CH2SiR'3
R2C(OMgCl)CH2SiR'3 + H2O + H2O2 → R2C(OH)CH2OH + "HOSiR'3"
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:[6]
[P(CH<sub>2</sub>OH)<sub>4</sub>]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.