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.

Related Research Articles

<span class="mw-page-title-main">Ketone</span> Organic compounds of the form >C=O

In organic chemistry, a ketone is an organic compound with the structure R−C(=O)−R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group −C(=O)−. The simplest ketone is acetone, with the formula (CH3)2CO. Many ketones are of great importance in biology and in industry. Examples include many sugars (ketoses), many steroids, and the solvent acetone.

<span class="mw-page-title-main">Hydrazone</span> Organic compounds - Hydrazones

Hydrazones are a class of organic compounds with the structure R1R2C=N−NH2. They are related to ketones and aldehydes by the replacement of the oxygen =O with the =N−NH2 functional group. They are formed usually by the action of hydrazine on ketones or aldehydes.

A diol is a chemical compound containing two hydroxyl groups. An aliphatic diol may also be called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. They are used as protecting groups of carbonyl groups, making them essential in synthesis of organic chemistry.

<span class="mw-page-title-main">Imine</span> Organic compound or functional group containing a C=N bond

In organic chemistry, an imine is a functional group or organic compound containing a carbon–nitrogen double bond. The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bonds. Imines are common in synthetic and naturally occurring compounds and they participate in many reactions.

<span class="mw-page-title-main">Phosphonium</span> Family of polyatomic cations containing phosphorus

In chemistry, the term phosphonium describes polyatomic cations with the chemical formula PR+
4. These cations have tetrahedral structures. The salts are generally colorless or take the color of the anions.

<span class="mw-page-title-main">Hemiaminal</span> Organic compound or group with a hydroxyl and amine attached to the same carbon

In organic chemistry, a hemiaminal is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: −C(OH)(NR2)−. R can be hydrogen or an alkyl group. Hemiaminals are intermediates in imine formation from an amine and a carbonyl by alkylimino-de-oxo-bisubstitution. Hemiaminals can be viewed as a blend of aminals and geminal diol. They are a special case of amino alcohols.

<span class="mw-page-title-main">Tebbe's reagent</span> Chemical compound

Tebbe's reagent is the organometallic compound with the formula (C5H5)2TiCH2ClAl(CH3)2. It is used in the methylidenation of carbonyl compounds, that is it converts organic compounds containing the R2C=O group into the related R2C=CH2 derivative. It is a red solid that is pyrophoric in the air, and thus is typically handled with air-free techniques. It was originally synthesized by Fred Tebbe at DuPont Central Research.

<span class="mw-page-title-main">Methyl vinyl ketone</span> Chemical compound

Methyl vinyl ketone (MVK, IUPAC name: butenone) is the organic compound with the formula CH3C(O)CH=CH2. It is a reactive compound classified as an enone, in fact the simplest example thereof. It is a colorless, flammable, highly toxic liquid with a pungent odor. It is soluble in water and polar organic solvents. It is a useful intermediate in the synthesis of other compounds.

The Blanc chloromethylation is the chemical reaction of aromatic rings with formaldehyde and hydrogen chloride to form chloromethyl arenes. The reaction is catalyzed by Lewis acids such as zinc chloride. The reaction was discovered by Gustave Louis Blanc (1872-1927) in 1923.

<span class="mw-page-title-main">Trimethylsilyl azide</span> Chemical compound

Trimethylsilyl azide is the organosilicon compound with the formula (CH3)3SiN3. A colorless liquid, it is a reagent in organic chemistry, serving as the equivalent of hydrazoic acid.

<span class="mw-page-title-main">Tetrakis(hydroxymethyl)phosphonium chloride</span> Chemical compound

Tetrakis(hydroxymethyl)phosphonium chloride (THPC) is an organophosphorus compound with the chemical formula [P(CH2OH)4]Cl. The cation P(CH2OH)4+ is four-coordinate, as is typical for phosphonium salts. THPC has applications as a precursor to fire-retardant materials, as well as a microbiocide in commercial and industrial water systems.

<span class="mw-page-title-main">Trimethylsilyl trifluoromethanesulfonate</span> Chemical compound

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) is an organosilicon compound with the formula (CH3)3SiO3SCF3. It is a colorless moisture-sensitive liquid. It is the trifluoromethanesulfonate derivative of trimethylsilyl. It is mainly used to activate ketones and aldehydes in organic synthesis.

<span class="mw-page-title-main">Trimethyloxonium tetrafluoroborate</span> Chemical compound

Trimethyloxonium tetrafluoroborate is the organic compound with the formula [(CH3)3O]+[BF4]−. This salt is a strong methylating agent, being a synthetic equivalent of CH+3. It is a white solid that rapidly decomposes upon exposure to atmospheric moisture, although it is robust enough to be weighed quickly without inert atmosphere protection. Triethyloxonium tetrafluoroborate is a closely related compound.

<span class="mw-page-title-main">Propionaldehyde</span> Chemical compound

Propionaldehyde or propanal is the organic compound with the formula CH3CH2CHO. It is the 3-carbon aldehyde. It is a colourless, flammable liquid with a pungent and fruity odour. It is produced on a large scale industrially.

<span class="mw-page-title-main">Isovaleraldehyde</span> Chemical compound

Isovaleraldehyde organic compound, also known as 3-methylbutanal, with the formula (CH3)2CHCH2CHO. It is an aldehyde, a colorless liquid at STP, and found in low concentrations in many types of food. Commercially it is used as a reagent for the production of pharmaceuticals, perfumes and pesticides.

<span class="mw-page-title-main">Ureas</span>

In chemistry, ureas are a class of organic compounds with the formula (R2N)2CO where R = H, alkyl, aryl, etc. Thus, in addition to describing the specific chemical compound urea ((H2N)2CO), urea is the name of a functional group that is found in many compounds and materials of both practical and theoretical interest. Generally ureas are colorless crystalline solids, which, owing to the presence of fewer hydrogen bonds, exhibit melting points lower than that of urea itself.

<span class="mw-page-title-main">Dimethylphosphine oxide</span> Chemical compound

Dimethylphosphine oxide is an organophosphorus compound with the formula (CH3)2P(O)H. It is a colorless liquid that soluble in polar organic solvents. It exists as the phosphine oxide, not the hydroxy tautomer. A related compound is diphenylphosphine oxide. Both are sometimes called secondary phosphine oxides.

<span class="mw-page-title-main">Diethylphosphite</span> Chemical compound

Diethyl phosphite is the organophosphorus compound with the formula (C2H5O)2P(O)H. It is a popular reagent for generating other organophosphorus compounds, exploiting the high reactivity of the P-H bond. Diethyl phosphite is a colorless liquid. The molecule is tetrahedral.

In organic chemistry, methylenation is a chemical reaction that inserts a methylene group into a chemical compound:

<span class="mw-page-title-main">Bis(dimethylamino)methane</span> Chemical compound

Bis(dimethylamino)methane is the organic compound with the formula [(CH3)2N]2CH2. It is classified as an aminal as well as a ditertiary amine, in fact the simplest. It is a colorless liquid that is widely available. It is prepared by the reaction of dimethylamine and formaldehyde:

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.
  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   978-3527306732.
  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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