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[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(CH2OH)4]Cl) is produced in this way from phosphine (PH3).[3]
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:[4]
- 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:[5]
- 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:[6]
- 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:[7]
- [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[8]
References
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