Chapter 18

1. Chapter 18 Ethers and Epoxides; Thiols and Sulfides

2. Introduction • Ethers are compounds with two organic groups (alkyl, aryl, or vinyl) bonded to the same oxygen atom, R–O–R’, in a ring or in an open chain industrial solvent anesthetic perfume solvent

3. Thiols (R–S–H) and sulfides (R–S–R’) are sulfur analogs of alcohols and ethers, respectively • Sulfur replaces oxygen

4. 1.Naming Ethers • Ethers are named according to IUPAC rules: • Simple ethers with no other functional groups are named by identifying the two organic substituents and adding the word ether • If other functional groups are present, the ether part is considered an alkoxy substituent

5. Simple ethers with no other functional groups are named by identifying the two organic substituents and adding the word ether

6. If other functional groups are present, the ether part is considered an alkoxy substituent

7. Practice Problem: Name the following ethers according to IUPAC rules • Diisopropyl ether • Cyclopentyl propyl ether • p-Bromoanisole or • 4-Bromo-1-methoxybenzene • 1-Methoxycyclohexene • Ethyl isobutyl ether • Allyl vinyl ether

8. 2.Structure and Properties of Ethers • The geometry around the O atom of an ether (ROR) is similar to that of water (HOH) • R-O-R has an ~ tetrahedral bond angle (112° in dimethyl ether) • The O atom is sp3-hybridized

9. The oxygen atom gives ethers a slight dipole moment

10. Ethers have higher boiling points than alkanes with similar MW

11. 3.Synthesis of Ethers • Ethers can be synthesized by: • Acid-catalyzed dehydration of alcohols • Williamson ether synthesis • Alkoxymercuration of alkenes

12. i. Acid-catalyzed dehydration of alcohols • Symmetrical etherscan be prepared by acid-catalyzed dehydration of primary alcohols(SN2) • Example: Diethyl ether is prepared industrially by sulfuric acid–catalyzed dehydration of ethanol • Acid-catalyzed dehydration of secondary and tertiary alcohols yield alkenes(E1)

13. Practice Problem: Why do you suppose only symmetrical ethers are prepared by the sulfuric acid-catalyzed dehydration procedure? What product(s) would you expect if ethanol and 1-propanol were allowed to react together? In what ratio would the products be formed if the two alcohols were of equal reactivity?

14. ii. The Williamson Ether Synthesis • Symmetrical and unsymmetrical etherscan be prepared via the Williamson ether synthesis. • It is a process in which metal alkoxides react with primary alkyl halides and/or tosylates via SN2 • It is the best method for the preparation of ethers

15. Alkoxides are prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH Acid Base Sodium salt of the alcohol

16. Silver Oxide-Catalyzed Ether Formation is a variation of the Williamson ether synthesis • Direct reaction of alcohols in Ag2O with alkyl halide forms ether in one step • Example: Glucose reacts with excess iodomethane in the presence of Ag2O to generate a pentaether in 85% yield

17. Mechanism of the Williamson Ether Synthesis • The Williamson ether synthesis involves SN2 reaction of an alkoxide ion with a primary alkyl halide • An alkoxide nucleophile (RO-) displaces a halide ion (X-) via SN2 • Primary halides and tosylates work best for SN2 because more hindered substrates undergo competitive E2 elimination of HX

18. Unsymmetrical ethers should be synthesized by reaction between the more hindered alkoxide ion and less hindered alkyl halide rather than vice versa Example: Synthesis of tert-butyl methyl ether

19. Practice Problem: How would you prepare the following ethers using Williamson synthesis? • Methyl propyl ether • Anisole (methyl phenyl ether) • Benzyl isopropyl ether • Ethyl 2,2-dimethylpropyl ether

20. iii. Alkoxymercuration of Alkenes • Ethers can be prepared via Alkoxymercuration of Alkenes followed by demercuration • Alkoxymercuration occurs when an alkene reacts with an alcohol in mercuric acetate or trifluoroacetate • Demercurationinvolves reduction of C-Hg by NaBH4

21. Mechanism of Alkoxymercuration/Demercuration • The mechanism involves: • Electrophilic addition of Hg2+ to an alkene, followed by reaction of intermediate cation with alcohol: Overall Markovnikov addition of alcohol to alkene • Reduction of C-Hg by NaBH4

22. Practice Problem: How would you prepare the ethyl phenyl ether? Use whichever method you think is more appropriate, the Williamson synthesis or the alkoxymercuration reaction.

23. Practice Problem: Write the mechanism of the alkoxymercuration reaction of 1-methylcyclopentene with ethanol. Use curved arrows to show the electron flow in each step.

24. Practice Problem: How would you prepare the following ethers? Use whichever method you think is more appropriate, the Williamson synthesis or the alkoxymercuration reaction. • Butyl cyclohexyl ether • Benzyl ethyl ether (C6H5CH2OCH2CH3) • sec-Butyl tert-butyl ether • Tetrahydrofuran

25. 3.Reactions of Ethers • Ethers undergo: • Acidic Cleavage • Claisen Rearrangement

26. i. Acidic Cleavage • Ethers are generally unreactive to most reagents but react with strong acids (HIandHBr)at high temperature • HI, HBr produce an alkyl halide from less hindered component by SN2 (tertiary ethers undergo SN1)

27. Mechanism of the Acidic Cleavage • The acidic cleavage reaction takes place: • via SN2 mechanism at the less highly substituted site if only primary and secondaryalkyl are bonded to the ether O • via SN1 or E1 mechanism if one of the alkyl groups bonded to the ether O is tertiary

28. Ethers with primary and secondaryalkyl groups react with HI or HBr via SN2 mechanism • I- or Br- attacks the protonated ether at the less hindered site

29. Ethers with a tertiary, benzylic, or allylic group react with HI or HBr via SN1 or E1 mechanism • These can produce stable intermediate carbocations • Example: tert-Butyl cyclohexyl ether reacts via E1

30. Practice Problem: Predict the products of the following reaction: • Ethers with primary and secondaryalkyl groups – via SN2 • Ethers with a tertiary, benzylic, or allylic group– via SN1 or E1

31. Practice Problem: Predict the products of each of the following reactions:

32. Practice Problem: Write the mechanism of the acid-catalyzed cleavage of tert-butyl cyclohexyl ether to yield cyclohexanol and 2-methylpropene

33. Practice Problem: Why are HI and HBr more effective than HCl in cleaving ethers? Nucleophilicity usually increases going down a column of the periodic table The halide reactivity order is I- > Br- > Cl-

34. ii. Claisen Rearrangement • Claisen rearrangementis specific to allyl aryl ethers, ArOCH2CH=CH2 • Heating the allyl aryl ether to 200–250°C leads to ano-allylphenol • Result is alkylation of the phenol in an ortho position

35. Mechanism of the Claisen Rearrangement • The reaction proceeds via a pericyclic mechanism: • a concerted reorganization of bonding electrons involving a 6-electron, 6-membered ring transition state leading to 6-allyl-2,4-cyclohexadienone intermediate • The mechanism is consistent with 14C labelling

36. Practice Problem: What product would you expect from Claisen rearrangement of 2-butenyl phenyl ether?

37. 4.Cyclic Ethers: Epoxides • Cyclic ether behaves like an acyclic ether, except if the ring is 3-membered • Dioxane and tetrahydrofuran are used as solvents

38. Epoxides (Oxiranes) • An epoxide is a three-membered ring ether • It is also called an oxirane (root “ir” from “tri” for 3-membered; prefix “ox” for oxygen; “ane” for saturated) • It has a unique chemical reactivity (behaves differently from other open-chain ethers) due to the strain of the 3-membered ring

39. Ethylene oxide (1,2-epoxyethane) is industrially important as an intermediate • It is the simplest epoxide (oxirane) • It is prepared by reaction of ethylene with oxygen at 300°C and silver oxide catalyst

40. In the laboratory, epoxides can be prepared by: • Treatment of an alkene with a peroxyacid • Treatment of a halohydrin with base

41. i. Preparation of Epoxides Using a Peroxyacid • An epoxide is prepared by treatment of an alkene with a peroxyacid (RCO3H) • m-chloroperoxybenzoic acid is a common peroxyacid used

42. The mechanism of epoxidation by treatment of an alkene with a peroxyacid (RCO3H): • is a one-step process in which peroxyacids transfer oxygen to the alkene with syn stereochemistry (no intermediates)

43. ii. Preparation of Epoxides from Halohydrins • An epoxide is prepared by treatment of a halohydrin with base • Addition of HO-X to an alkene gives a halohydrin • Treatment of a halohydrin with base eliminates HX and gives an epoxide

44. The mechanism of epoxidation by treatment of a halohydrin with a base is an intramolecular Williamson ether synthesis: • The nucleophilic alkoxide ion and the electrophilic alkyl halide are in the same molecule

45. Practice Problem: What product would you expect from reaction of cis-2-butene with m-chloroperoxybenzoic acid? Show the stereochemistry

46. Practice Problem: Reaction of trans-2-butene with m-chloropero -xybenzoic acid yields an epoxide different from that obtained by reaction of the cis isomer. Explain.

47. 5.Ring-Opening Reactions of Epoxides • There are two types of ring-opening reactions of epoxides: • Acid-Catalyzed Epoxide Opening • Base-Catalyzed Epoxide Opening

48. i. Acid-Catalyzed Epoxide Opening • Water adds to epoxides with dilute acid at room temperature • The product is a 1,2-diol, also called vicinal glycol (on adjacent C’s: vicinal) • Epoxides react under milder conditions because of ring strain

49. Ethylene Glycol • 1,2-ethanediol is synthesized from acid catalyzed hydration of ethylene oxide • Widely used as automobile antifreeze (lowers freezing point of water solutions)

50. The mechanism of acid-catalyzed epoxide cleavage involves: • Protonation: Acid protonates oxygen • Backside attack of a nucleophile: water adds to opposite side (trans addition)