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 ( (CH₂OH)₄l) 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:
: (CH₂OH)₄l + 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)₂NCH₂Tf{{cite journal , doi=10.15227/orgsyn.059.0153, title=Regioselective Mannich Condensation with Dimethyl(Methylene)Ammonium Trifluoroacetate: 1-(Dimethylamino)-4-Methyl-3-Pentanone, journal=Organic Syntheses, year=1979, volume=59, page=153, first1=Michel, last1=Gaudry, first2=Yves, last2=Jasor, first3=Trung Bui, last3=Khac

References

Carbon-carbon bond forming reactions