1. William H. Brown Christopher S. Foote Brent L. Iverson
Organic Chemistry
William H. Brown
Christopher S. Foote
Brent L. Iverson

2. Ethers & Epoxides
Chapter 11

3. Structure
The functional group of an ether is an oxygen atom bonded to two carbon atoms
in dialkyl ethers, oxygen is sp3 hybridized with bond angles of approximately 109.5°.
in dimethyl ether, the C-O-C bond angle is 110.3°

4. 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

5. Nomenclature: ethers IUPAC: the longest carbon chain is the parent
name the OR group as an alkoxy substituent
Common names: name the groups bonded to oxygen in alphabetical order followed by the word ether O H C H 3 C H 3 O C H 3 2 O O C H 2 3 C H 3
Ethoxyethane
(Diethyl ether)
trans-
2-Ethoxy-
cyclohexanol
2-Methoxy-2-
methylpropane (
tert-
Butyl methyl ether)

6. 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

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

8. Physical Properties Boiling points of ethers are
lower than alcohols of comparable MW
close to those of hydrocarbons of comparable MW
Ethers are hydrogen bond acceptors
they are more soluble in H2O than are hydrocarbons

9. Preparation of Ethers
Williamson ether synthesis: 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 on an industrial scale this way
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: proton transfer gives an oxonium ion
Step 2: nucleophilic displacement of H2O by the OH group of the alcohol gives a new oxonium ion

13. Preparation of Ethers
Step 3: 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: protonation of the alkene gives a carbocation
Step 2: reaction of the carbocation (an electrophile) with the alcohol (a nucleophile) gives an oxonium ion

16. Preparation of Ethers
Step 3: 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 dialkyl ether is cleaved to two moles of haloalkane

19. Cleavage of Ethers
Step 1: proton transfer to the oxygen atom of the ether gives an oxonium ion
Step 2: nucleophilic displacement on the 1° carbon gives a haloalkane and an alcohol
the alcohol is then converted to an 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
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
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

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 blocking groups are most commonly removed by treatment with fluoride ion, generally in the form of tetrabutylammonium fluoride

29. Silyl Ethers as Protecting Groups
we can use the TMS group as a 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 H H H 1 2 3 C H 3 H 3 C H 2 C C H 2 O C C O 1 O 2 H
Oxirane
(Ethylene oxide)
cis-
2,3-Dimethyloxirane (
2-Butene oxide)
1,2-Epoxycyclohexane
(Cyclohexene oxide)

31. Synthesis of Epoxides
Ethylene oxide, one of the few epoxides manufactured on an industrial scale, is prepared by air oxidation of ethylene A g 2 C H = + O 2 2 H 2 C C H 2 O
Oxirane
(Ethylene oxide)

32. Synthesis of Epoxides
The most common laboratory method is oxidation of an alkene using a peroxycarboxylic acid (a peracid) O O C O H C O H O M g 2 + C H 3 O C O -
Peroxyacetic acid
(Peracetic acid) C l O 2
meta-
chloroperoxy-
benzoic acid
(MCPBA)
Magnesium
monoperoxyphthalate
(MMPP)

33. Synthesis of Epoxides
Epoxidation of cyclohexene

34. Synthesis of Epoxides Epoxidation is stereospecific:
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 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 can also be 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 (Section 6.3F)
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 H H H 3 C C H 3 H H 1 . C l 2 , H O C C C C H 3 C C H 3 2 . N a O H , O
cis-
2-Butene
cis-
2,3-Dimethyloxirane

39. Synthesis of Epoxides Sharpless epoxidation
stereospecific and enantioselective

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

41. Reactions of Epoxides Acid-catalyzed ring opening
in the presence of an acid catalyst, such as sulfuric acid, epoxides are hydrolyzed to glycols H + O H + H 2 O O H O
Oxirane
(Ethylene oxide)
1,2-Ethanediol
(Ethylene glycol)

42. Reactions of Epoxides
Step 1: proton transfer to oxygen gives a bridged oxonium ion intermediate
Step 2: backside attack by water (a nucleophile) on the oxonium ion (an electrophile) opens the ring
Step 3:proton transfer to solvent completes the reaction

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

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

45. 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

46. 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:- 1 . L i A l H 4 C H C H 2 C H - 3 2 . H O O O H
Phenyloxirane
(Styrene oxide)
1-Phenylethanol

47. Ethylene Oxide
ethylene oxide is a valuable building block for organic synthesis because each of its carbons has a functional group

48. 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

49. 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

50. 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

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

52. 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

53. 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+

54. 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

55. Nomenclature Disulfide: contains 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

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

57. 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)

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

59. Ethers
&
Epoxides
End of Chapter 11