Hydroxymethylation

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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.

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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:

Pentaerythritol Synthesis.svg

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.

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]

References

  1. ↑ John Hooz; Jorge Cabezas; Sergio Musmanni; Jose Calzada (1990). "Propargylation of Alkyl Halides: (E)-6,10-Dimethyl-5,9-Undecadien-1-Yne and (E)-7,11-Dimethyl-6,10-Dodecadien-2-yn-1-ol". Organic Syntheses. 69: 120. doi:10.15227/orgsyn.069.0120. hdl: 10669/87920 .
  2. ↑ Robert K. Boeckman Jr; Douglas J. Tusch; Kyle F. Biegasiewicz (2015). "Organocatalyzed Direct Asymmetric α-Hydroxymethylation of Aldehydes". Organic Syntheses. 92: 320–327. doi: 10.15227/orgsyn.092.0320 .
  3. ↑ Svara, Jürgen; Weferling, Norbert; Hofmann, Thomas (2006). "Phosphorus Compounds, Organic". Ullmann's Encyclopedia of Industrial Chemistry . Weinheim: Wiley-VCH. doi:10.1002/14356007.a19_545.pub2. ISBN   3527306730.
  4. ↑ Greco, Carolina M.; Kunderfranco, Paolo; Rubino, Marcello; Larcher, Veronica; Carullo, Pierluigi; Anselmo, Achille; Kurz, Kerstin; Carell, Thomas; Angius, Andrea; Latronico, Michael V. G.; Papait, Roberto; Condorelli, Gianluigi (2016). "DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy". Nature Communications. 7 12418. Bibcode:2016NatCo...712418G. doi:10.1038/ncomms12418. PMC   4976219 . PMID   27489048.
  5. ↑ Eric J. Leopold (1986). "Selective Hydroboration of a 1,3,7-Triene: Homogeraniol". Organic Syntheses. 64: 164. doi:10.15227/orgsyn.064.0164.
  6. ↑ Kohei Tamao; Neyoshi Ishida; Yoshihiko Ito; Makoto Kumada (1990). "Nucleophilic Hydroxymethylation by the (Isopropoxydimethylsilyl)Methyl Grignard Reagent: 1-(Hydroxymethyl)Cyclohexanol from Cyclohexanone". Organic Syntheses. 69: 96. doi:10.15227/orgsyn.069.0096.
  7. ↑ M. Caporali, L. Gonsalvi, F. Zanobini, M. Peruzzini (2011). Synthesis of the Water-Soluble Bidentate (P,N) Ligand PTN(Me). Inorganic Syntheses. Vol. 35. pp. 92–108. doi:10.1002/9780470651568.ch5.{{cite book}}: CS1 maint: multiple names: authors list (link)
  8. ↑ Gaudry, Michel; Jasor, Yves; Khac, Trung Bui (1979). "Regioselective Mannich Condensation with Dimethyl(Methylene)Ammonium Trifluoroacetate: 1-(Dimethylamino)-4-Methyl-3-Pentanone". Organic Syntheses. 59: 153. doi:10.15227/orgsyn.059.0153.
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