Ortho ester

Synthesis

Ortho esters are traditionally, but inefficiently prepared through the Pinner reaction of nitriles and alcohols in the presence of one equivalent of hydrogen chloride. The reaction requires anhydrous conditions, It begins with formation of imido ester hydrochloride: :RCN + OH + HCl → [RC(O)=NH2]+Cl− Upon standing in the presence of excess alcohol, this intermediate converts to the ortho ester: :[RC(O)=NH2]+Cl− + 2OH → RC(O)3 + NH4Cl A major side-reaction converts the alcohol to the corresponding alkyl chloride.

Acid chlorides can also drive the reaction from the corresponding amide, e.g.: :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: :RCCl3 + 3NaO → RC(O)3 + 3NaCl Compounds with an adjacent hydrogen atom on R tend to undergo elimination instead. Traditional esters can be converted to α,αdichloro ethers with phosphorus pentachloride. The resulting halogenated compounds undergo ether synthesis like the trichloroalkanes.

Carboxylic acids naturally form a trithio ortho ester when heated with a mercaptan of appropriate stoichiometry. The resulting compound undergoes transesterification to a traditional orthoester in the presence of zinc chloride.

Transesterification from a cheaper ortho ester is also possible; but performs best with unstabilized (electron-poorer) ortho esters. Stabilized ortho-esters tend to collapse to the corresponding non-ortho ester.

Reactions

Hydrolysis

Ortho esters are readily hydrolyzed in mild aqueous acid to form esters: : RC(O)3 + H2O → RCO2 + 2 OH

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

:[[File:OrthoesterHydrolysis.png|600px|Hydrolysis of methyl orthoformate to methyl formate]]

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 ester. :[[Image:Johnson-Claisen Rearrangement Scheme.png|450px|The Johnson–Claisen rearrangement]]

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. :[[Image:Bodroux-Chichibabin Aldehyde Synthesis Scheme.png|350px|Bodroux-Chichibabin aldehyde synthesis]]

Examples

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.

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.

:[[File:Hygromycin b.svg|thumb|center|[[Hygromycin B]], an [[antibiotic]], is one of several naturally occurring ortho esters.]]

References

References

1. Hünig, S.. (1964). "The modes of reaction of ambident cations". Angewandte Chemie.
2. DeWolfe, Robert H.. (1970). "Carboxylic Ortho Acid Derivatives". Academic Press.
3. DeWolfe, Robert H.. (March 1974). "Synthesis of carboxylic or carbonic ortho esters". Synthesis.
4. Houben, J.. "Über die Condensation von Mercaptanen mit Ameisensäure zu Orthotrithio-ameisensäureestern". Berichte der Deutschen Chemischen Gesellschaft.
5. {{Clayden
6. United States Patent Application 20070049501, Saini; Rajesh K.; and Savery; Karen, March 1, 2007
7. (February 1970). "Simple stereoselective version of the Claisen rearrangement leading to trans-trisubstituted olefinic bonds. Synthesis of squalene". Journal of the American Chemical Society.
8. (2005). "Protecting Groups". Thieme.
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