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 thee Blanc chloromethylation.

Related Research Articles

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In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and no other functional groups form a homologous series with the general chemical formula CnH2n−2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature. Like other hydrocarbons, alkynes are generally hydrophobic.

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

In organic chemistry, a ketone is a functional group 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.

In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms are commonly used in chemistry, biochemistry, soil science, and the biological sciences.

A diol is a chemical compound containing two hydroxyl groups. An aliphatic diol is also called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified.

<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">Acyl halide</span> Oxoacid compound with an –OH group replaced by a halogen

In organic chemistry, an acyl halide is a chemical compound derived from an oxoacid by replacing a hydroxyl group with a halide group.

In organic chemistry, ozonolysis is an organic reaction where the unsaturated bonds of alkenes, alkynes, or azo compounds are cleaved with ozone. Alkenes and alkynes form organic compounds in which the multiple carbon–carbon bond has been replaced by a carbonyl group while azo compounds form nitrosamines. The outcome of the reaction depends on the type of multiple bond being oxidized and the work-up conditions.

The Bouveault–Blanc reduction is a chemical reaction in which an ester is reduced to primary alcohols using absolute ethanol and sodium metal. It was first reported by Louis Bouveault and Gustave Louis Blanc in 1903. Bouveault and Blanc demonstrated the reduction of ethyl oleate and n-butyl oleate to oleyl alcohol. Modified versions of which were subsequently refined and published in Organic Syntheses.

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<span class="mw-page-title-main">Chloromethyl methyl ether</span> Chemical compound

Chloromethyl methyl ether (CMME) is a compound with formula CH3OCH2Cl. A colorless liquid, it is a chloroalkyl ether. It is used as an alkylating agent. In organic synthesis, it is used for introducing the methoxymethyl ether (MOM) protecting group, and is thus often called MOM-Cl or MOM chloride. It also finds application as a chloromethylating agent in some variants of the Blanc chloromethylation.

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In nitrile reduction a nitrile is reduced to either an amine or an aldehyde with a suitable chemical reagent.

<span class="mw-page-title-main">Jones oxidation</span> Oxidation of alcohol

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<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 slightly 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. It can be produced commercially and is used as a reagent for the production of pharmaceuticals and pesticides.

In organic chemistry, alkynylation is an addition reaction in which a terminal alkyne is added to a carbonyl group to form an α-alkynyl alcohol.

<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">Diethylphosphite</span> Chemical compound

Diethylphosphite 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. Diethylphosphite 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:

References

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