Hydroxymethylation

Source: Wikipedia, the free encyclopedia.

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

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 thee Blanc chloromethylation
.

Related

References

  1. doi:10.15227/orgsyn.069.0120
    .
  2. doi:10.15227/orgsyn.092.0320
    .
  3. ISBN 978-3527306732
    .
  4. PMID 27489048
    .
  5. doi:10.15227/orgsyn.064.0164
    .
  6. doi:10.15227/orgsyn.069.0096
    .
  7. doi:10.1002/9780470651568.ch5.{{cite book}}: CS1 maint: multiple names: authors list (link
    )
  8. doi:10.15227/orgsyn.059.0153
    .
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