Synthesis of Epoxides

– In this topic, we will talk about Synthesis of Epoxides by two methods: Peroxyacid epoxidation and Base-promoted cyclization of halohydrins.

Synthesis of Epoxides

– Epoxides are easily made from alkenes, and (unlike other ethers) they undergo a variety of useful synthetic reactions.

– For these reasons, epoxides are valuable synthetic intermediates.

– Here we review the epoxidation techniques already covered and consider in more detail the useful syntheses and reactions of epoxides.

(1) Peroxyacid Epoxidation

– Peroxyacids (sometimes called peracids) are used to convert alkenes to epoxides.

– If the reaction takes place in aqueous acid, the epoxide opens to a glycol. Therefore, to make an epoxide, we avoid strong acids.

– Because of its desirable solubility properties, metachloroperoxybenzoic acid (MCPBA) is often used for these epoxidations.

– MCPBA is a weakly acidic peroxyacid that is soluble in aprotic solvents such as CH₂Cl₂.

– The epoxidation takes place in a one-step, concerted reaction that maintains the stereochemistry of any substituents on the double bond.

– The peroxyacid epoxidation is quite general, with electron-rich double bonds reacting fastest.

– The following reactions are difficult transformations made possible by this selective, stereospecific epoxidation procedure.

– The second example uses magnesium monoperoxyphthalate (MMPP), a relatively stable water-soluble peroxyacid often used in large-scale epoxidations.

– These aqueous MMPP epoxidations, carried out at neutral pH to avoid opening the epoxide, avoid the large-scale use of hazardous chlorinated solvents.

(2) Base-Promoted Cyclization of Halohydrins

– A second synthesis of epoxides and other cyclic ethers involves a variation of the Williamson ether synthesis.

– If an alkoxide ion and a halogen atom are located in the same molecule, the alkoxide may displace a halide ion and form a ring.

– Treatment of a halohydrin with base leads to an epoxide through this internal SN2 attack.

– Halohydrins are easily generated by treating alkenes with aqueous solutions of halogens.

– Bromine water and chlorine water add across double bonds with Markovnikov orientation.

– The following reaction shows cyclopentene reacting with chlorine water to give the chlorohydrin.

– Treatment of the chlorohydrin with aqueous sodium hydroxide gives the epoxide.

– This reaction can be used to synthesize cyclic ethers with larger rings.

– The difficulty lies in preventing the base (added to deprotonate the alcohol) from attacking and displacing the halide.

– 2,6-Lutidine, a bulky base that cannot easily attack a carbon atom, can deprotonate the hydroxyl group to give a five-membered cyclic ether.

– Five-, six-, and seven-membered (and occasionally four-membered) cyclic ethers are formed this way.

Summary of Synthesis of Epoxides

1. Peroxyacid epoxidation

2. Base-promoted cyclization of halohydrins

References:

• Organic chemistry / L.G. Wade, Jr / 8th ed, 2013 / Pearson Education, Inc. USA.
• Fundamental of Organic Chemistry / John McMurry, Cornell University/ 8th ed, 2016 / Cengage Learningm, Inc. USA.
• Organic Chemistry / T.W. Graham Solomons, Craig B. Fryhle , Scott A. Snyder / 11 ed, 2014/ John Wiley & Sons, Inc. USA.