Ortho Esters

Introduction

Fig 1 Structure of ortho ester

In organic chemistry, ortho esters are a class of compounds with a functional group containing three alkoxy attached to one carbon atom, they have general formula RC(OR’)₃. Ortho esters may be considered as products of exhaustive alkylation of unstable ortho carboxylic acids which do not exist in a free state. An example is ethyl orthoacetate, with structural formula CH₃C(OCH₂CH₃)₃, more correctly known as 1,1,1-triethoxyethane, often used in organic synthesis as protecting groups for esters.

Properties

In general, physical properties of ortho esters present no analogous features. Most of the aliphatic ortho carboxylates are colorless liquids with characteristic odors, while a few ortho esters, particularly bicyclic and tricyclic compounds are colorless solids. Typically they are very slightly soluble in water (in which they are stable at neutral and alkaline PH), and are soluble in or miscible with organic solvents. because of their high chemical reactivity, ortho esters have be widely used in organic reactions.

Typical reactions

• Hydrolysis: Orthoesters are readily hydrolyzed in mild aqueous acid to form esters and alcohols. For example, trimethyl orthoformate CH(OCH₃)₃ can be hydrolyzed under acidic conditions to methyl formate and methanol, then may be further hydrolyzed (under alkaline conditions) to salts of formic acid and methanol (Fig 2).

Fig 2 Hydrolysis of trimethyl orthoformate

• 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 an unsaturated ester (Fig 3).

Fig 3 Johnson–Claisen rearrangement afford unsaturated ester

• Bodroux–Chichibabin aldehyde synthesis: In the Bodroux-Chichibabin aldehyde synthesis an orthoester reacts with a Grignard reagent to form an aldehyde, which is an example of formylation reaction (Fig 4).

Fig 4 Bodroux–Chichibabin aldehyde synthesis

Applications

• Protecting group: The application of ortho esters made it possible to develop extremely simple methods for the introduction of the formyl or acyl residue into an aromatic ring, at a double bond, and in the α -methyl and methylene groups of carbonyl and heterocyclic compounds. Acylation and also alkylation of oxygen, sulphur, nitrogen, phosphorus, and silicon atoms of a wide variety of organic and inorganic substances has been achieved with the aid of ortho esters.

• Polymer chemistry: Polyorthoesters are formed by transesterification of orthoesters with diols or by polyaddition between a diol and a diketene acetal. Polyorthoesters are used as hydrophobic implant materials for drug depots for continuous drug delivery by surface erosion. Four classes of polyorthoesters (polyorthoesters type I-IV) are well characterized as biodegradable polymers for drug implants.