2. Structure
The functional group of an ether is an oxygen atom bonded to two carbon atoms.
In dialkylethers, oxygen is sp3 hybridized with bond angles of approximately 109.5°.
Figure 11.1 In dimethyl ether, the simplest ether, the C-O-C bond angle is 110.3°.

3. Structure
In other ethers, the ether oxygen is bonded to an sp2 hybridized carbon.
In ethyl vinyl ether, for example, the ether oxygen is bonded to one sp3 hybridized carbon and one sp2 hybridized carbon.

4. Nomenclature: ethers IUPAC: the longest carbon chain is the parent.
Name the OR group as a substituent.
Common names: name the groups bonded to oxygen in alphabetical order followed by the word ether.

5. Nomenclature: ethers
Although cyclic ethers have IUPAC names, their common names are more widely used.
IUPAC: prefix ox- shows oxygen in the ring.
The suffixes -irane, -etane, -olane, and -ane show three, four, five, and six atoms in a saturated ring.

6. Physical Properties
Figure 11.2 Although ethers are polar compounds, only weak dipole-dipole attractive forces exist between their molecules in the pure liquid state.

7. Physical Properties Boiling points of ethers are
lower than alcohols of comparable MW.
close to those of hydrocarbons of comparable MW.
Figure 11.3 Ethers are hydrogen bond acceptors.

8. Physical Properties

9. Preparation of Ethers
Williamson ether synthesis: Ether synthesis by the SN2 displacement of halide, tosylate, or mesylate by alkoxide ion.

10. Preparation of Ethers Yields are highest with methyl and 1° halides,
lower with 2° halides (competing -elimination).
Reaction fails with 3° halides (-elimination only).

11. Preparation of Ethers Acid-catalyzed dehydration of alcohols
Diethyl ether and several other ethers are made this way on an industrial scale.
A specific example of an SN2 reaction in which a poor leaving group (OH-) is converted to a better one (H2O).

12. Preparation of Ethers
Step 1: Add a proton. Proton transfer gives an oxonium ion.
Step 2: Make a bond between a nucleophile and an electrophile and simultaneously break a bond to give stable molecules or ions. Nucleophilic displacement of H2O by the -OH group of the alcohol gives a new oxonium ion.

13. Preparation of Ethers
Step 3: Take a proton away. Proton transfer to solvent completes the reaction.

14. Preparation of Ethers Acid-catalyzed addition of alcohols to alkenes
Yields are highest using an alkene that can form a stable carbocation and
using methanol or a 1° alcohol that is not prone to undergo acid-catalyzed dehydration.

15. Preparation of Ethers
Step 1: Make a bond between a  bond and an electrophile—add a proton. Protonation of the alkene gives a carbocation intermediate.
Step 2: Make a bond between a nucleophile and an electrophile. Reaction of the carbocation (an electrophile) with the alcohol (a nucleophile) gives an oxonium ion.

16. Preparation of Ethers
Step 3: Take a proton away. Proton transfer to solvent completes the reaction.

17. Cleavage of Ethers
Ethers are cleaved by HX to an alcohol and a haloalkane.
Cleavage requires both a strong acid and a good nucleophile; therefore, the use of concentrated HI (57%) and HBr (48%).
Cleavage by concentrated HCl (38%) is less effective, primarily because Cl- is a weaker nucleophile in water than either I- or Br-.

18. Cleavage of Ethers
A dialkylether is cleaved to two moles of haloalkane.

19. Cleavage of Ethers
Step 1: Add a proton. Proton transfer to the oxygen atom of the ether gives an oxonium ion.
Step 2: Make a bond between a nucleophile and an electrophile and simultaneously break a bond to give stable molecules or ions. Nucleophilic displacement on the 1° carbon gives a haloalkane and an alcohol.
The alcohol is then converted to a haloalkane by another SN2 reaction.

20. Cleavage of Ethers
3°, allylic, and benzylic ethers are particularly sensitive to cleavage by HX.
tert-Butyl ethers are cleaved by HCl at room temp.
In this case, protonation of the ether oxygen is followed by C-O cleavage to give the tert-butyl cation.

21. Oxidation of Ethers
Ethers react with O2 at a C-H bond adjacent to the ether oxygen to give hydroperoxides.
Reaction occurs by a radical chain mechanism.
Caution: Hydroperoxides are explosive!
Hydroperoxide: A compound containing the -OOH group.

22. Silyl Ethers as Protecting Groups
When dealing with compounds containing two or more functional groups, it is often necessary to protect one of them (to prevent its reaction) while reacting at the other.
Suppose you wish to carry out this transformation.

23. Silyl Ethers as Protecting Groups
The new C-C bond can be formed by alkylation of an alkyne anion (Section 7.5).
The -OH group, however, is more acidic (pKa 16-18) than the terminal alkyne (pKa 25).
Treating the compound with one mole of NaNH2 will give the alkoxide anion rather than the alkyne anion.

24. Silyl Ethers as Protecting Groups
A protecting group must
add easily to the sensitive group.
be resistant to the reagents used to transform the unprotected functional group(s).
be removed easily to regenerate the original functional group.
In this chapter, we discuss trimethylsilyl (TMS) and other trialkylsilyl ethers as -OH protecting groups.

25. Silyl Ethers as Protecting Groups
Silicon is in Group 4A of the Periodic Table, immediately below carbon.
Like carbon, it also forms tetravalent compounds such as the following.

26. Silyl Ethers as Protecting Groups
An -OH group can be converted to a silyl ether by treating it with a trialkylsilyl chloride in the presence of a 3° amine (to neutralize the HCl byproduct).

27. Silyl Ethers as Protecting Groups
Replacement of one of the methyl groups of the TMS group by tert-butyl gives a tert-butyldimethylsilyl (TBDMS) group, which is considerably more stable than the TMS group.
Other common silyl protecting groups include the TES and TIPS groups.

28. Silyl Ethers as Protecting Groups
Silyl ethers are unaffected by most oxidizing and reducing agents, and are stable to most nonaqueous acids and bases.
The TBDMS group is stable in aqueous solution within the pH range 2 to 12, which makes it one of the most widely used -OH protecting groups.
Silyl protecting groups are most commonly removed by treatment with fluoride ion, generally in the form of tetrabutylammonium fluoride in THF.
Si-O (BDE 368kJ/mol) Si-F (BDE 582kJ/mol)

29. Silyl Ethers as Protecting Groups
We can use the TMS protecting group in the conversion of 4-pentyn-1-ol to 4-heptyn-1-ol.

30. Epoxides
Epoxide: A cyclic ether in which oxygen is one atom of a three-membered ring.
Simple epoxides are named as derivatives of oxirane.
Where the epoxide is part of another ring system, it is shown by the prefix epoxy-.
Common names are derived from the name of the alkene from which the epoxide is formally derived.

31. Synthesis of Epoxides
Ethylene oxide, one of the few epoxides manufactured on an industrial scale, is prepared by air oxidation of ethylene.

32. Synthesis of Epoxides
The most common laboratory method is oxidation of an alkene using a peroxycarboxylic acid (a peracid).

33. Synthesis of Epoxides
Epoxidation of cyclohexene

34. Synthesis of Epoxides
Epoxidation is stereospecific (the stereochemistry of the products depends on the stereochemistry of the reactants):
Epoxidation of cis-2-butene gives only cis-2,3-dimethyloxirane.
Epoxidation of trans-2-butene gives only trans-2,3-dimethyloxirane.

35. Synthesis of Epoxides
A mechanism for alkene epoxidation must take into account the facts that the reaction
takes place in nonpolar solvents, which means that no ions are involved.
is stereospecific with retention of the alkene configuration, which means that even though the pi bond is broken, at no time is there free rotation about the remaining sigma bond.

36. Synthesis of Epoxides
A mechanism for alkene epoxidation.

37. Synthesis of Epoxides Epoxides are also synthesized via halohydrins.
The second step is an internal SN2 reaction.

38. Synthesis of Epoxides
Halohydrin formation is both regioselective and stereoselective; for alkenes that show cis,trans isomerism, it is also stereospecific.
Conversion of a halohydrin to an epoxide is stereoselective.
Problem: Account for the fact that conversion of cis-2-butene to an epoxide by the halohydrin method gives only cis-2,3-dimethyloxirane.

39. Synthesis of Epoxides Sharpless epoxidation
stereospecific and enantioselective

40. Sharpless Asymmetric Epoxidation
When predicting the stereochemistry of a Sharpless epoxidation, it is helpful to draw the allylic alcohol as shown below. When drawn in this manner the stereochemistry can be predicted.

41. Reactions of Epoxides
Ethers are not normally susceptible to attack by nucleophiles.
However, because of the strain associated with the three-membered ring, epoxides readily undergo a variety of ring-opening reactions.

42. Reactions of Epoxides Acid-catalyzed ring opening
In the presence of an acid catalyst, such as sulfuric acid, epoxides are hydrolyzed to glycols.

43. Reactions of Epoxides
Step 1: Add a proton. Proton transfer to oxygen gives a bridged oxonium ion intermediate.

44. Reactions of Epoxides
Step 2: Make a bond between a nucleophile and an electrophile and simultaneously break a bond to give stable molecules or ions. Backside attack by water (a nucleophile) on the oxonium ion (an electrophile) opens the ring.

45. Reactions of Epoxides
Step 3:Take a proton away. Proton transfer to solvent completes the reaction.

46. Reactions of Epoxides
Attack of the nucleophile on the protonated epoxide shows anti stereoselectivity.
Hydrolysis of an epoxycycloalkane gives a trans-1,2-diol.

47. Reactions of Epoxides
Compare the stereochemistry of the glycols formed by these two methods.

48. Epoxides
The value of epoxides is the variety of nucleophiles that will open the ring and the combinations of functional groups that can be prepared from them.

49. Reactions of Epoxides
Treatment of an epoxide with lithium aluminum hydride, LiAlH4, reduces the epoxide to an alcohol.
The nucleophile attacking the epoxide ring is hydride ion, H:-

50. Ethylene Oxide
Ethylene oxide is a valuable building block for organic synthesis because each of its carbons may be converted to a functional group.

51. Ethylene Oxide
Part of the local anesthetic procaine is derived from ethylene oxide.
The hydrochloride salt of procaine is marketed under the trade name Novocaine.

52. Epichlorohydrin
The epoxide epichlorohydrin is also a valuable building block because each of its three carbons contains a reactive functional group.
Epichlorohydrin is synthesized from propene.

53. Epichlorohydrin
The characteristic structural feature of a product derived from epichlorohydrin is a three-carbon unit with -OH on the middle carbon, and a carbon, nitrogen, oxygen or sulfur nucleophile on the two end carbons.

54. Epichlorohydrin
An example of a compound containing the three-carbon skeleton of epichlorohydrin is nadolol, a b-adrenergic blocker with vasodilating activity.

55. Crown Ethers
Crown ether: A cyclic polyether derived from ethylene glycol or a substituted ethylene glycol.
The parent name is crown, preceded by a number describing the size of the ring and followed by the number of oxygen atoms in the ring.

56. Crown Ethers
The diameter of the cavity created by the repeating oxygen atoms is comparable to the diameter of alkali metal cations.
18-crown-6 provides very effective solvation for K+

57. Thioethers The sulfur analog of an ether
IUPAC name: select the longest carbon chain as the parent and name the sulfur-containing substituent as an alkylsulfanyl group.
Common name: list the groups bonded to sulfur followed by the word sulfide.

58. Nomenclature Disulfide: A compound containing an -S-S- group.
IUPAC name: select the longest carbon chain as the parent and name the disulfide-containing substituent as an alkyldisulfanyl group.
Common name: list the groups bonded to sulfur and add the word disulfide.

59. Preparation of Sulfides
Symmetrical sulfides: treat one mole of Na2S with two moles of a haloalkane.

60. Preparation of Sulfides
Unsymmetrical sulfides: convert a thiol to its sodium salt and then treat this salt with an alkyl halide (a variation on the Williamson ether synthesis).

61. Oxidation Sulfides
Sulfides can be oxidized to sulfoxides and sulfones by the proper choice of experimental conditions.

62. Problem 11.26
Acid-catalyzed hydrolysis of the following epoxide gives a trans diol. Of the two possible trans diols, only one is formed. How do you account for this stereoselectivity?

63. Problem 11.26
The key to this problem is that the incoming nucleophile and the leaving protonated epoxide must be anti coplanar. In a cyclohexane ring, anti coplanar corresponds to trans and diaxial.