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^[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 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, [(CH₃)₂NCH₂]OTf^[8]