Organic Chemistry

1. Organic Chemistry

2. Ethers & Epoxides

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

4. Nomenclature: ethers IUPAC: the longest carbon chain is the parent. name the OR group as an alkoxy substituent Common names: name the groups attached to oxygen 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 Ethers are polar molecules oxygen bears a partial negative charge each carbon a partial positive charge

7. Physical Properties Ethers are polar molecules but, because of steric hindrance, only weak dipole-dipole attractive forces exist between their molecules in the pure liquid state Boiling points of ethers are lower than alcohols of comparable MW close to those of hydrocarbons of comparable MW Ethers hydrogen bond with H2O and are more soluble in H2O than are hydrocarbons

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

9. Preparation of Ethers Williamson ether synthesis: yields are highest with methyl and 1� halides, lower with 2� halides (competing ?-elimination) reaction fails with 3� halides (?-elimination only)

10. 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 is converted to a better one

11. 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

12. Preparation of Ethers Step 3: proton transfer to solvent completes the reaction

13. Preparation of Ethers Acid-catalyzed addition of alcohols to alkenes: yields are highest using an alkene that can form a stable carbocation methanol or a 1� alcohol

14. Preparation of Ethers Step 1: protonation of the alkene gives a carbocation Step 2: reaction of the alcohol (a Lewis base) with the carbocation (a Lewis acid)

15. Preparation of Ethers Step 3: proton transfer to solvent completes the reaction

16. Cleavage of Ethers Ethers are cleaved by HX to an alcohol and an alkyl halide 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-

17. Cleavage of Ethers A dialkyl ether is cleaved to two moles of alkyl halide

18. 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 the alcohol is then converted to the alkyl bromide or iodide by another SN2 reaction

19. Cleavage of Ethers 3� 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

20. Oxidation of Ethers Ethers react with O2 at a C-H bond adjacent to the ether oxygen to give hydroperoxides reaction is by a radical chain mechanism Hydroperoxide: a compound containing the OOH group

21. Ethers - Protecting Grps 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

22. Ethers - Protecting Grps the new C-C bond can be formed by alkylation of the acetylide 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 acetylide

23. Ethers - Protecting Grps A protecting group must be easily added to the sensitive group resistant to reagents used to transform the unprotected functional group easily removed to regenerate the original functional group In this chapter, we discuss two -OH protecting groups tert-butyl ether group trimethylsilyl (TMS) group

24. Ethers - Protecting Grps The tert-butyl protecting group formed by treatment of an alcohol with 2-methylpropene in the presence of an acid catalyst

25. Ethers - Protecting Grps the unprotected alkyne is alkylated

26. Ethers - Protecting Grps the tert-butyl protecting group is removed by treatment with aqueous acid

27. Ethers - Protecting Grps Trimethylsilyl (TMS) group treat the alcohol with chlorotrimethylsilane in the presence of a 3� amine, such as triethylamine the function of the 3� amine is to catalyze the reaction and to neutralize the HCl

28. Ethers - Protecting Grps the TMS group is removed by treatment with aqueous acid or with F- in the form of tetrabutylammonium fluoride

29. 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

30. Synthesis of Epoxides-1 Ethylene oxide, one of the few epoxides manufactured on an industrial scale, is prepared by air oxidation of ethylene

31. Synthesis of Epoxides-2 The most common laboratory method is oxidation of an alkene using a peroxycarboxylic acid (a peracid)

32. Synthesis of Epoxides-2 Epoxidation of cyclohexene

33. Synthesis of Epoxides-2 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

34. Synthesis of Epoxides-2 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

35. Synthesis of Epoxides-2 A mechanism for alkene epoxidation

36. Synthesis of Epoxides-3 A second general method involves 1. treatment of an alkene with Cl2 or Br2 in H2O to give a halohydrin; reaction is stereospecific 2. treatment of the halohydrin with base, causing an internal SN2

37. Synthesis of Epoxides-3 Problem: given the stereospecificity of this scheme, show that cis-2-butene gives cis-2,3-dimethyloxirane

38. Synthesis of Epoxides-4 Sharpless epoxidation stereospecific and enantioselective

39. Reactions of Epoxides Because of the strain associated with the three-membered ring, epoxides readily undergo a variety of ring-opening reactions

40. Reactions of Epoxides Acid-catalyzed ring opening in the presence of an acid catalyst, epoxides are hydrolyzed to glycols

41. Reactions of Epoxides Step 1: proton transfer to the epoxide gives a bridged oxonium ion intermediate Step 2: backside attack of H2O on the protonated epoxide opens the three-membered ring

42. Reactions of Epoxides Step 3: proton transfer to solvent completes the hydrolysis

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

46. Reactions of Epoxides Nucleophilic ring opening is stereospecific attach of the nucleophile is anti to the leaving group

47. Reactions of Epoxides

48. 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:-

49. 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

50. 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+

51. 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: list the groups bonded to sulfur followed by the word sulfide

52. 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

53. Preparation of Sulfides Symmetrical sulfides: treat one mole of Na2S with two moles of an alkyl halide

54. 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)

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

56. Prob 11.13 Account for the fact that tetrahydrofuran is considerably more soluble in water than diethyl ether.

57. Prob 11.15 Which ethers can be prepared by a Williamson synthesis? For those can can�t, explain why not.

58. Prob 11.16 Propose a mechanism for this reaction.

59. Prob 11.17 Draw structural formulas for the products when each compound is refluxed with concentrated HI.

60. Prob 11.18 Write a pair of chain propagation steps for this radical chain reaction. Assume initiation is by a radical R�. Account for the regioselectivity of the hydroperoxidation.

61. Prob 11.20 Propose a mechanism for each reaction.

62. Prob 11.21 Propose a mechanism for each step in this synthesis.

63. Prob 11.22 Propose a synthesis of each compound from ethylene oxide and any readily available alcohols.

64. Prob 11.25 How many stereoisomers are possible for 2-chloro-1,2-diphenylethanol? Which of the possible stereoisomers are formed in this reaction?

65. Prob 11.26 Propose a mechanism for this rearrangement.

66. Prob 11.27 Account for the stereospecificity of this epoxide ring opening reaction.

67. Prob 11.28 If the starting alkene is trans, what is the configuration of the epoxide formed in each sequence?

68. Prob 11.29 Show how this chiral epoxide can be prepared from an allylic alcohol precursor using the Sharpless epoxidation.

69. Prob 11.30 Assume reaction here is by HOCl, which behaves as if it were Cl+OH-. Account for the observed regiochemistry and stereochemistry.

70. Prob 11.31 Propose a mechanism for this rearrangement.

71. Prob 11.34 Show how to convert cyclohexene to these compounds.

72. Prob 11.34 (cont�d) Show how to convert cyclohexene to these compounds.

73. Prob 11.35 Show reagents for each reaction.

74. Prob 11.36 Given this retrosynthetic analysis, propose a synthesis for the target molecule.

75. Prob 11.38 Propose structural formulas for A, B, C, and D, and the type of mechanism by which each is formed.

76. Prob 11.39 Following are steps in the synthesis of gossyplure.

77. Prob 11.39 (cont�d) continuing from step 7 of the previous screen

78. Prob 11.39 (cont�d) continuing from step 4 of the previous screen

79. Prob 11.40 Propose a mechanism for each step and account for the regiospecificity of Steps 1 and 2.

80. Ethers & Epoxides