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.

Hydroxyethylation involves the installation of the CH₂CH₂OH group, as practiced in ethoxylation.
Aminomethylation is often effected with Eschenmoser's salt, [(CH₃)₂NCH₂]OTf^[8]

References

^ 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.
^ 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.
^ 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.
^ 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.
^ Eric J. Leopold (1986). "Selective Hydroboration of a 1,3,7-Triene: Homogeraniol". Organic Syntheses. 64: 164. doi:10.15227/orgsyn.064.0164.
^ 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.
^ 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)
^ 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.

[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.

[Ullmann-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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