title: Hydroxymethylation
text: # Hydroxymethylation
  
  Hydroxymethylation is a chemical reaction that installs the $CH_2OH$ 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:
  
      $R_3C-H$ + $CH_2O$ → $R_3C-CH_2OH$
      $R_2N-H$ + $CH_2O$ → $R_2N-CH_2OH$
  
  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 $([P(CH_2OH)_4]Cl)$ is produced in this way from phosphine $(PH_3).$
  
  ## 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:
  
      $RCH_3$ + O → $RCH_2OH$
  
  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 + $Ph_3P=CH_2$ → $RCH=CH_2$ + $Ph_3PO$
      $RCH=CH_2$ + $R_2BH$ → $RCH_2-CH_2BR_2$
      $RCH_2-CH_2BR_2$ + $H_2O_2$ → $RCH2-CH_2OH$ + $"HOBR_2"$
  
  Silylmethyl Grignard reagents are nucleophilic reagents for hydroxymethylation of ketones:
  
      $R_2C=O$ + $ClMgCH_2SiR'_3$ → $R_2C(OMgCl)CH_2SiR'_3$
      $R_2C(OMgCl)CH_2SiR'_3$ + $H_2O$ + $H_2O_2$ → $R_2C(OH)CH_2OH$ + $"HOSiR'_3"$
  
  ## 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 + $CH_2O$ → $X-CH_2OH$
      crosslinking: X-H + $X-CH_2OH$ → $X-CH_2-X$ + $H_2O$
  
  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:
  
      $[P(CH_2OH)_4]Cl$ + NaOH → $P(CH_2OH)_3$ + $H_2O$ + $H_2C=O$ + NaCl
  
  When conducted in the presence of chlorinating agents, hydroxymethylation leads to chloromethylation as illustrated by thee Blanc chloromethylation.
  
  ## Related
  
  * Hydroxyethylation involves the installation of the $CH_2CH_2OH$ group, as practiced in ethoxylation.
  * Aminomethylation is often effected with Eschenmoser's salt, $[(CH_3)_2NCH_2]OTf$
  