Ortho ester

In organic chemistry, an ortho ester is a functional group containing three alkoxy groups attached to one carbon atom, i.e. with the general formula RC(OR')₃. Orthoesters may be considered as products of exhaustive alkylation of unstable orthocarboxylic acids and it is from these that the name 'ortho ester' is derived. An example is ethyl orthoacetate, CH₃C(OCH₂CH₃)₃, more correctly known as 1,1,1-triethoxyethane.^[1]

The general formula of orthoesters.

Synthesis

Ortho esters can be prepared by the Pinner reaction, in which nitriles react with alcohols in the presence of one equivalent of hydrogen chloride. The reaction proceeds by formation of imido ester hydrochloride:

RCN + R′OH + HCl → [RC(OR′)=NH₂]⁺Cl⁻

Upon standing in the presence of excess alcohol, this intermediate converts to the ortho ester:

[RC(OR′)=NH₂]⁺Cl⁻ + 2 R′OH → RC(OR′)₃ + NH₄Cl

The reaction requires anhydrous conditions,^[1] and ideally a nonpolar solvent.^[2]: 6

Acid chlorides can also drive the reaction from the corresponding amide, e.g.:^[3]: 154

HCONH₂ + BzCl → HC(OBz)NH₂Cl

HC(OBz)NH₂Cl + ROH → HC(OR)₃ + NH₄Cl + BzOH.

Although a less common method, ortho esters were first produced by reaction of 1,1,1-trichloroalkanes with sodium alkoxide:^[1]

RCCl₃ + 3 NaOR′ → RC(OR′)₃ + 3 NaCl

Compounds with an adjacent hydrogen atom on R tend to undergo elimination instead.^[2]: 12 Traditional esters can be converted to α,α‑dichloro ethers with phosphorus pentachloride. The resulting halogenated compounds undergo ether synthesis like the trichloroalkanes.^[3]: 162

Carboxylic acids naturally form a trithio ortho ester when heated with a mercaptan of appropriate stoichiometry.^[4] The resulting compound undergoes transesterification to a traditional orthoester in the presence of zinc chloride.^[3]: 156 Traditional transesterification from a cheaper ortho ester is also possible.^[3]

Reactions

Hydrolysis

Ortho esters are readily hydrolyzed in mild aqueous acid to form esters:

RC(OR′)₃ + H₂O → RCO₂R′ + 2 R′OH

For example, trimethyl orthoformate CH(OCH₃)₃ may be hydrolyzed (under acidic conditions) to methyl formate and methanol;^[5] and may be further hydrolyzed (under alkaline conditions) to salts of formic acid and methanol.^[6]

Johnson–Claisen rearrangement

The Johnson–Claisen rearrangement is the reaction of an allylic alcohol with an ortho ester containing a deprotonatable alpha carbon (e.g. triethyl orthoacetate) to give a γ,δ-unsaturated ester.^[7]

Bodroux–Chichibabin aldehyde synthesis

In the Bodroux–Chichibabin aldehyde synthesis an ortho ester reacts with a Grignard reagent to form an aldehyde; this is an example of a formylation reaction.

Examples

Hygromycin B, an antibiotic, is one of several naturally occurring ortho esters.

OBO: 4-methyl-2,6,7-trioxa-bicyclo[2.2.2]octan-1-yl

Examples of orthoesters include the reagents trimethyl orthoformate and triethylorthoacetate. Another example is the bicyclic OBO protecting group (4-methyl-2,6,7-trioxa-bicyclo[2.2.2]octan-1-yl) which is formed by the action of (3-methyloxetan-3-yl)methanol on activated carboxylic acids in the presence of Lewis acids. The group is base stable and can be cleaved in two steps under mild conditions, mildly acidic hydrolysis yields the ester of tris(hydroxymethyl)ethane which is then cleaved using e.g. an aqueous carbonate solution.^[8]

The threefold symmetry of the cyclohexanehexol isomer scyllo-inositol (scyllitol) yields the triply-bridged orthoformate esters scyllitol orthoformate with an adamantane-like skeleton, and scyllitol bis-orthoformate with two fused adamantane-like skeletons. ^[9]

See also

• Acetal, C(OR)₂R₂
• Orthocarbonate, C(OR)₄.

References

1. E. H. Cordes (1969). "Ortho Esters". In Saul Patai (ed.). Carboxylic Acids and Esters. PATAI'S Chemistry of Functional Groups. pp. 623–667. doi:10.1002/9780470771099.ch13. ISBN 9780470771099.
2. DeWolfe, Robert H. (1970). Carboxylic Ortho Acid Derivatives. Organic Chemistry. Vol. 14. New York, NY: Academic Press. LCCN 70-84226.
3. DeWolfe, Robert H. (March 1974). "Synthesis of carboxylic or carbonic ortho esters". Synthesis (3): 153–172. doi:10.1055/s-1974-23268.
4. Houben, J. "Über die Condensation von Mercaptanen mit Ameisensäure zu Orthotrithio-ameisensäureestern" [On the condensation of mercaptans with formic acid unto formic acid trithio ortho esters]. Berichte der Deutschen Chemischen Gesellschaft (in German). 45: 2942–2946. doi:10.1002/cber.19120450319 – via the Internet Archive.
5. Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2001). Organic Chemistry (1st ed.). Oxford University Press. p. 345. ISBN 978-0-19-850346-0.
6. United States Patent Application 20070049501, Saini; Rajesh K.; and Savery; Karen, March 1, 2007
7. Johnson, William Summer.; Werthemann, Lucius.; Bartlett, William R.; Brocksom, Timothy J.; Li, Tsung-Tee.; Faulkner, D. John.; Petersen, Michael R. (February 1970). "Simple stereoselective version of the Claisen rearrangement leading to trans-trisubstituted olefinic bonds. Synthesis of squalene". Journal of the American Chemical Society. 92 (3): 741–743. doi:10.1021/ja00706a074.
8. Kocieński, Philip J. (2005). Protecting groups (3. ed.). Stuttgart: Thieme. ISBN 978-3-13-135603-1.
9. Hyo Won Lee and Yoshito Kishi (1985): "Synthesis of mono- and unsymmetrical bis-orthoesters of scyllo-inositol". Journal of Organic Chemistry, volume 50, issue 22, pages 4402–4404 doi:10.1021/jo00222a046