Trimethyl orthoformate

Trimethyl orthoformate (TMOF) is the organic compound with the formula HC(OCH₃)₃. A colorless liquid, it is the simplest orthoester. It is a reagent used in organic synthesis for the formation of methyl ethers.^[3] The product of reaction of an aldehyde with trimethyl orthoformate is an acetal. In general cases, these acetals can be deprotected back to the aldehyde by using hydrochloric acid.

Trimethyl orthoformate^[1]

Names
Preferred IUPAC name Trimethoxymethane
Other names 2-Methoxyacetaldehyde dimethyl acetal Methoxymethylal Methyl orthoformate
Identifiers
CAS Number	149-73-5 Y
3D model (JSmol)	Interactive image
ChemSpider	8655
ECHA InfoCard	100.005.224
EC Number	205-745-7
PubChem CID	9005
UNII	XAM28819YJ Y
CompTox Dashboard (EPA)	DTXSID7027122
InChI InChI=1S/C4H10O3/c1-5-4(6-2)7-3/h4H,1-3H3
SMILES O(C)C(OC)OC
Properties
Chemical formula	C4H10O3
Molar mass	106.121 g·mol−1
Appearance	Colorless liquid
Odor	pungent
Density	0.9676 g/cm3
Melting point	−53 °C (−63 °F; 220 K)
Boiling point	100.6 °C (213.1 °F; 373.8 K)
Solubility	soluble in ethanol, diethyl ether
Vapor pressure	1 kPa at 7 °C[2]
Refractive index (nD)	1.3773
Hazards
GHS labelling:
Pictograms
Signal word	Danger
Hazard statements	H225, H315, H319, H335
Precautionary statements	P210, P233, P240, P241, P242, P243, P261, P264, P271, P280, P302+P352, P303+P361+P353, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P370+P378, P403+P233, P403+P235, P405, P501
Flash point	13 °C (55 °F; 286 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Synthesis

Trimethyl orthoformate is prepared on an industrial scale by the methanolysis of hydrogen cyanide:^[4]

HCN + 3 HOCH₃ → HC(OCH₃)₃ + NH₃

Trimethyl orthoformate can also be prepared from the reaction between chloroform and sodium methoxide, an example of the Williamson ether synthesis.

Use

Trimethyl orthoformate is a useful building block for creating methoxymethylene groups and heterocyclic ring systems. It introduces a formyl group to a nucleophilic substrate, e.g. RNH₂ to form R-NH-CHO, which can undergo further reactions. It is used in the production of some fungicides (for example: azoxystrobin 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.^[4]

Trimethyl orthoformate is also an effective reagent for converting compatible carboxylic acids to their corresponding methyl esters.^[5] Alternatively, acid-catalyzed esterifications with methanol can be driven closer to completion by employing trimethyl orthoformate to convert water byproduct to methanol and methyl formate.

See also

• Triethyl orthoformate (triethoxymethane), another trialkyl orthoformate
• Other methoxymethanes
  • Methoxymethane (dimethyl ether)
  • Dimethoxymethane (methylal)
  • Tetramethoxymethane (tetramethyl orthocarbonate)
• Pinner reaction
• Trimethoxysilane, heavier analog, isoelectronic compound

References

1. Trimethyl orthoformate at Sigma-Aldrich
2. Alfa Aesar SDS
3. Liu, Hui; Tomooka, Craig S.; Xu, Simon L.; Yerxa, Benjamin R.; Sullivan, Robert W.; Xiong, Yifeng; Moore, Harold W. (1999). "Dimethyl Squarate and ITS Conversion to 3-Ethenyl-4-Methoxycyclobutene-1,2-Dione and 2-Butyl-6-Ethenyl-5-Methoxy-1,4-Benzoquinone". Organic Syntheses. 76: 189. doi:10.15227/orgsyn.076.0189.
4. Ashford's Dictionary of Industrial Chemicals, Third edition, 2011, ISBN 978-0-9522674-3-0, page 9388
5. Paine, John B. (1 July 2008). "Esters of Pyromellitic Acid. Part I. Esters of Achiral Alcohols: Regioselective Synthesis of Partial and Mixed Pyromellitate Esters, Mechanism of Transesterification in the Quantitative Esterification of the Pyromellitate System Using Orthoformate Esters, and a Facile Synthesis of the Ortho Pyromellitate Diester Substitution Pattern". The Journal of Organic Chemistry. 73 (13): 4929–4938. doi:10.1021/jo800543w. PMID 18522420.