Trimethyl orthoformate (TMOF) is the

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with the formula HC(OCH₃)₃. A colorless liquid, it is the simplest orthoester. It is a

reagent In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...

used in

organic synthesis Organic synthesis is a branch of chemical synthesis concerned with the construction of organic compounds. Organic compounds are molecules consisting of combinations of covalently-linked hydrogen, carbon, oxygen, and nitrogen atoms. Within the gen ...

for the formation of

methyl ether Methyl ether may refer to: * Any chemical compound of the ether class that includes a methyl group * Dimethyl ether, often simply called methyl ether See also *Methoxy group In organic chemistry, a methoxy group is the functional group consisti ...

s. The product of reaction of an

aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

with trimethyl orthoformate is an

acetal In organic chemistry, an acetal is a functional group with the connectivity . Here, the R groups can be organic fragments (a carbon atom, with arbitrary other atoms attached to that) or hydrogen, while the R' groups must be organic fragments n ...

. In general cases, these acetals can be deprotected back to the aldehyde by using

hydrochloric acid Hydrochloric acid, also known as muriatic acid or spirits of salt, is an aqueous solution of hydrogen chloride (HCl). It is a colorless solution with a distinctive pungency, pungent smell. It is classified as a acid strength, strong acid. It is ...

Synthesis

Trimethyl orthoformate is prepared on an industrial scale by the methanolysis of

hydrogen cyanide Hydrogen cyanide (formerly known as prussic acid) is a chemical compound with the chemical formula, formula HCN and structural formula . It is a highly toxic and flammable liquid that boiling, boils slightly above room temperature, at . HCN is ...

:Ashford's Dictionary of Industrial Chemicals, Third edition, 2011, , page 10744 :HCN + 3 HOCH₃ → HC(OCH₃)₃ + NH₃ Trimethyl orthoformate can also be prepared from the reaction between

chloroform Chloroform, or trichloromethane (often abbreviated as TCM), is an organochloride with the formula and a common solvent. It is a volatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor to refrigerants and po ...

and

sodium methoxide Sodium methoxide is the simplest sodium alkoxide. With the formula , it is a white solid, which is formed by the deprotonation of methanol. It is a widely used reagent in industry and the laboratory. It is also a dangerously caustic base. ...

, an example of the

Williamson ether synthesis The Williamson ether synthesis is an organic reaction, forming an ether from an organohalide and a deprotonated alcohol (alkoxide). This reaction was developed by Alexander Williamson in 1850. Typically it involves the reaction of an alkoxide ...

Use

Trimethyl orthoformate is a useful building block for creating methoxymethylene groups and heterocyclic ring systems. It introduces a

formyl group In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

to a

nucleophilic In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they a ...

substrate, e.g. RNH₂ to form R-NH-CHO, which can undergo further reactions. It is used in the production of some

fungicide Fungicides are pesticides used to kill parasitic fungi or their spores. Fungi can cause serious damage in agriculture, resulting in losses of yield and quality. Fungicides are used both in agriculture and to fight fungal infections in animals, ...

s (for example:

azoxystrobin Azoxystrobin is a broad spectrum systemic fungicide widely used in agriculture to protect crops from fungal diseases. It was first marketed in 1996 using the brand name Amistar and by 1999 it had been registered in 48 countries on more than 50 cr ...

and picoxystrobin), as well as for some members of the floxacin family of antibacterial drugs. A number of pharmaceutical intermediates are also made from trimethyl orthoformate. Trimethyl orthoformate is also an effective reagent for converting compatible

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

s to their corresponding methyl esters. Alternatively, acid-catalyzed esterifications with

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

can be driven closer to completion by employing trimethyl orthoformate to convert water byproduct to methanol and

methyl formate Methyl formate, also called methyl methanoate, is the methyl ester of formic acid. The simplest example of a carboxylate ester, it is a colourless liquid with an ethereal odour, high vapor pressure, and low surface tension. The gas form is odourl ...

References

{{reflist Reagents for organic chemistry Orthoesters Methyl esters