hydroxymethylation

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{{cite journal |doi=10.15227/orgsyn.069.0120|title=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|journal=Organic Syntheses|year=1990|volume=69|page=120 |author=John Hooz |author2=Jorge Cabezas |author3=Sergio Musmanni |author4=Jose Calzada

|url=http://www.orgsyn.org/demo.aspx?prep=CV8P0226 |hdl=10669/87920|hdl-access=free}} or the alpha protons of an aldehyde.{{cite journal |doi=10.15227/orgsyn.092.0320|title=Organocatalyzed Direct Asymmetric α-Hydroxymethylation of Aldehydes|year=2015 |author=Robert K. Boeckman Jr |author2=Douglas J. Tusch |author3=Kyle F. Biegasiewicz |journal=Organic Syntheses |volume=92 |pages=320–327|doi-access=free }} In industry, hydroxymethylation of acetaldehyde with formaldehyde is used in the production of pentaerythritol:

File: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).{{Ullmann|doi=10.1002/14356007.a19_545.pub2|title=Phosphorus Compounds, Organic|year=2006|last1=Svara|first1=Jürgen|last2=Weferling|first2=Norbert|last3=Hofmann|first3=Thomas|isbn=3527306730}}

5-Methylcytosine is a common epigenetic marker. The methyl group is modified by oxidation of the methyl group in a process called hydroxymethylation:{{cite journal |doi=10.1038/ncomms12418|title=DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy|year=2016|last1=Greco|first1=Carolina M.|last2=Kunderfranco|first2=Paolo|last3=Rubino|first3=Marcello|last4=Larcher|first4=Veronica|last5=Carullo|first5=Pierluigi|last6=Anselmo|first6=Achille|last7=Kurz|first7=Kerstin|last8=Carell|first8=Thomas|last9=Angius|first9=Andrea|last10=Latronico|first10=Michael V. G.|last11=Papait|first11=Roberto|last12=Condorelli|first12=Gianluigi|journal=Nature Communications|volume=7|page=12418|pmid=27489048|pmc=4976219|bibcode=2016NatCo...712418G}}

:RCH₃ + O → RCH₂OH

This oxidation is thought to be a prelude to removal, regenerating cytosine.

A two-step hydroxymethylation of aldehydes involves methylenation followed by hydroboration-oxidation:{{cite journal |author=Eric J. Leopold|doi=10.15227/orgsyn.064.0164|title=Selective Hydroboration of a 1,3,7-Triene: Homogeraniol|journal=Organic Syntheses|year=1986|volume=64|page=164}}

: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:{{cite journal |author=Kohei Tamao |author2=Neyoshi Ishida |author3=Yoshihiko Ito |author4=Makoto Kumada

|doi=10.15227/orgsyn.069.0096|title=Nucleophilic Hydroxymethylation by the (Isopropoxydimethylsilyl)Methyl Grignard Reagent: 1-(Hydroxymethyl)Cyclohexanol from Cyclohexanone|journal=Organic Syntheses|year=1990|volume=69|page=96}}

:R₂C=O + ClMgCH₂SiR'₃ → R₂C(OMgCl)CH₂SiR'₃

:R₂C(OMgCl)CH₂SiR'₃ + H₂O + H₂O₂ → R₂C(OH)CH₂OH + "HOSiR'₃"

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:{{cite book|author=M. Caporali, L. Gonsalvi, F. Zanobini, M. Peruzzini |title=Synthesis of the Water-Soluble Bidentate (P,N) Ligand PTN(Me)|doi=10.1002/9780470651568.ch5|series=Inorganic Syntheses|year=2011|volume=35|pages=92–108}}

:[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{{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}}

Category:Carbon-carbon bond forming reactions