1. 1 Chapter 9 Alcohols, Ethers and Epoxides

2. 2 Alcohols contain a hydroxy group (OH) bonded to an sp 3 hybridized carbon. Introduction—Structure and Bonding

3. 3 Alcohols, Ethers and Epoxides enols and phenols Compounds having a hydroxy group on a sp 2 hybridized carbon undergo different reactions than alcohols. Introduction—Structure and Bonding Will be discussed in chapter 11, 19

4. 4 Alcohols, Ethers and Epoxides Introduction—Structure and Bonding Ethers have two alkyl groups bonded to an oxygen atom.

5. 5 Alcohols, Ethers and Epoxides Epoxides are ethers having the oxygen atom in a three-membered ring. Epoxides are also called oxiranes. Introduction—Structure and Bonding The C—O—C bond angle for an epoxide must be 60°, a considerable deviation from the tetrahedral bond angle of 109.5°. Thus, epoxides have angle strain, making them much more reactive than other ethers.

6. 6 Alcohols, Ethers and Epoxides The oxygen atom in alcohols, ethers and epoxides is sp 3 hybridized. Alcohols and ethers have a bent shape like that in H 2 O. The bond angle around the O atom in an alcohol or ether is similar to the tetrahedral bond angle of 109.5°. Because the O atom is much more electronegative than carbon or hydrogen, the C—O and O—H bonds are all polar. Introduction—Structure and Bonding

7. 7 Alcohols, Ethers and Epoxides Nomenclature of Alcohols : -- ol

8. 8 Alcohols, Ethers and Epoxides When an OH group is bonded to a ring, the ring is numbered beginning with the OH group. Because the functional group is at C1, the 1 is usually omitted from the name. The ring is then numbered in a clockwise or counterclockwise fashion to give the next substituent the lowest number. For cyclic compounds

9. 9 Alcohols, Ethers and Epoxides Common names are often used for simple alcohols. Name all the carbon atoms of the molecule as a single alkyl group. Add the word alcohol, separating the words with a space. Nomenclature of Alcohols

10. 10 Alcohols, Ethers and Epoxides Compounds with two hydroxy groups : diols or glycols. Compounds with three hydroxy groups : triols and so forth. Nomenclature of Alcohols

11. 11 Alcohols, Ethers and Epoxides Simple ethers are usually assigned common names. To do so: Name both alkyl groups bonded to the oxygen, arrange these names alphabetically, and add the word ether. For symmetrical ethers, name the alkyl group and add the prefix “di-”. Nomenclature of Ethers

12. 12 Alcohols, Ethers and Epoxides More complex ethers are named using the IUPAC system. One alkyl group is named as a hydrocarbon chain, and the other is named as part of a substituent bonded to that chain: Name the simpler alkyl group as an alkoxy substituent by changing the –yl ending of the alkyl group to –oxy. Name the remaining alkyl group as an alkane, with the alkoxy group as a substituent bonded to this chain.

13. 13 Alcohols, Ethers and Epoxides Cyclic ethers have an O atom in the ring. A common example is tetrahydrofuran (THF). This name has a different origin

14. 14 Epoxides can be named in three different ways—As epoxyalkanes, oxiranes, or alkene oxides. To name an epoxide as an epoxyalkane, first name the alkane chain or ring to which the O atom is attached, and use the prefix “epoxy” to name the epoxide as a substituent. Use two numbers to designate the location of the atoms to which the O’s are bonded. Nomenclature of Epoxides

15. 15 Epoxides bonded to a chain of carbon atoms can also be named as derivatives of oxirane, the simplest epoxide having two carbons and one oxygen atom in a ring. The oxirane ring is numbered to put the O atom at position one, and the first substituent at position two. No number is used for a substituent in a monosubstituted oxirane. Epoxides can be named in three different ways—As epoxyalkanes, oxiranes, or alkene oxides.

16. 16 Epoxides are also named as alkene oxides, since they are often prepared by adding an O atom to an alkene. To name an epoxide in this way: Mentally replace the epoxide oxygen with a double bond. Name the alkene. Add the word oxide. Epoxides can be named in three different ways—As epoxyalkanes, oxiranes, or alkene oxides.

17. 17 Alcohols, Ethers and Epoxides Alcohols, ethers and epoxides exhibit dipole-dipole interactions because they have a bent structure with two polar bonds. Alcohols are capable of intermolecular hydrogen bonding. Thus, alcohols are more polar than ethers and epoxides. Physical Properties Steric factors affect hydrogen bonding.

18. 18 Alcohols, Ethers and Epoxides

19. 19 Alcohols, Ethers and Epoxides Interesting Alcohols glycerol Sugars, cellulose, starch etc.

20. 20 Alcohols, Ethers and Epoxides Interesting Ethers Diethyl ether is the best-known ether, first used as a general anesthetic in the 1830s. Because of its high flammability and side-effects on some patients, its place as an anesthetic has been taken by other substances. Cyclic polyether : crown ether

21. 21 Alcohols, Ethers and Epoxides Interesting Ethers The ability of crown ethers to complex cations can be exploited in nucleophilic substitution reactions, as shown in Figure 9.5.

22. 22 Alcohols, Ethers and Epoxides Interesting Ethers : nature’s crown ether Brevetoxin B is a naturally occurring polyether that interferes with Na + ion transport across cell membranes. “Red Tide”

23. 23 Interesting Epoxides : epoxides are reactive! Ethylene oxide : precursor of ethylene glycol, polyethylene glycol Natural epoxides

24. 24 Preparation of Alcohols, Ethers, and Epoxides Alcohols and ethers are both common products of nucleophilic substitution of alkyl halides. Williamson ether synthesis.

25. 25 Preparation of Alcohols, Ethers, and Epoxides

26. 26 S N 2 reaction Strong Nucleophile (An alkoxide salt) is needed to make an ether. Williamson ether synthesis. Cyclic ethers are formed through intramolecular reaction. When n= -2, epoxides

27. 27 Preparation of Epoxides Organic compounds that contain both a hydroxy group and a halogen atom on adjacent carbons are called halohydrins.

28. 28 Reactions of Alcohols Substitution, elimination, oxidation The OH group in alcohols is a very poor leaving group. For an alcohol to undergo nucleophilic substitution, OH must be converted into a better leaving group (activated). By using acid, ¯OH can be converted into H 2 O, a good leaving group. By converting to sulfonates, ¯ OH can be converted into ¯OSO 2 R, a good leaving group.

29. 29 Reactions of Alcohols

30. 30 Reactions of Ethers and Epoxides Ethers do not have a good leaving group and are difficult to activate. Epoxides are highly reactive due to high angle strain.

31. 31 Reactions of Alcohols—Dehydration Dehydration, like dehydrohalogenation, is a  elimination reaction in which the elements of OH and H are removed from the  and  carbon atoms respectively. Dehydration is typically carried out using H 2 SO 4 and other strong acids, or phosphorus oxychloride (POCl 3 ) in the presence of an amine base.

32. 32 Reactions of Alcohols—Dehydration Typical acids used for alcohol dehydration : H 2 SO 4 or p- toluenesulfonic acid (TsOH). More substituted alcohols dehydrate more easily, giving rise to the following order of reactivity. strong organic acid

33. 33 Alcohols, Ethers and Epoxides Reactions of Alcohols—Dehydration Dehydration follows the Zaitsev rule. The more substituted alkene is the major product when a mixture of constitutional isomers is possible.

34. 34 Alcohols, Ethers and Epoxides Reactions of Alcohols—Dehydration Secondary and 3 ° alcohols react by an E1 mechanism

35. 35 Alcohols, Ethers and Epoxides Reactions of Alcohols—Dehydration The E1 dehydration of 2 0 and 3 0 alcohols with acid gives clean elimination products without any by-products formed from an S N 1 reaction. Clean elimination takes place because the reaction mixture contains no good nucleophile to react with the intermediate carbocation, so no competing S N 1 reaction occurs. This makes the E1 dehydration of alcohols much more synthetically useful than the E1 dehydrohalogenation of alkyl halides.

36. 36 Alcohols, Ethers and Epoxides Reactions of Alcohols—Dehydration 1° alcohols undergo dehydration following an E2 mechanism. 1° carbocations are highly unstable, their dehydration cannot occur by an E1 mechanism involving a carbocation intermediate.

37. 37 Reactions of Alcohols—Dehydration While dehydrations have favorable entropy changes, the position of equilibrium favors reactants. Operation of the Principle of Le Châtelier in Alcohol Dehydrations removing a product from a reaction mixture as it is formed drives the equilibrium to the right, forming more product. Thus, the alkene, which usually has a lower boiling point than the starting alcohol, can be removed by distillation as it is formed, thus driving the equilibrium to the right to favor production of more product.

38. 38 Carbocation Rearrangements

39. 39 Alcohols, Ethers and Epoxides Carbocation Rearrangements Often, when carbocations are intermediates, a less stable carbocation will be converted into a more stable carbocation by a shift of a hydrogen or an alkyl group. This is called a rearrangement.

40. 40 Carbocation Rearrangements A 1,2-shift can convert a less stable carbocation into a more stable carbocation. Rearrangements can occur whenever a carbocation is formed as a reactive intermediate. 1,2-hydride shift

41. 41

42. 42 Dehydration of Alcohols Using POCl 3 and Pyridine Dehydration under basic condition A common method uses phosphorus oxychloride (POCl 3 ) and pyridine (an amine base) in place of H 2 SO 4 or TsOH. Dehydration proceeds by an E2 mechanism.

43. 43 Dehydration of Alcohols Using POCl 3 and Pyridine Mechanism : E2 mechanism

44. 44 Dehydration of Alcohols in the natural product synthesis

45. 45 Conversion of Alcohols to Alkyl Halides with HX Substitution reactions do not occur with alcohols unless ¯ OH is converted into a good leaving group. The reaction of alcohols with HX (X = Cl, Br, I) is a general method to prepare 1 °, 2 °, and 3 ° alkyl halides.

46. 46 Conversion of Alcohols to Alkyl Halides with HX More substituted alcohols usually react more rapidly with HX: The mechanism depends on the structure of the R group.

47. 47 Conversion of Alcohols to Alkyl Halides with HX 1 o alcohols and methanol react via an S N 2 mechanism

48. 48 2 o and 3 o alcohols react via an S N 1 mechanism

49. 49 Alcohols, Ethers and Epoxides Conversion of Alcohols to Alkyl Halides with HX The reactivity of hydrogen halides increases with increasing acidity.

50. 50 Conversion of Alcohols to Alkyl Halides with HX 2 o alcohols

51. 51 Conversion of Alcohols to Alkyl Halides

52. 52 Conversion of Alcohols to Alkyl Halides with SOCl 2 and PBr 3 For primary and 2° alcohols SOCl 2 (thionyl chloride) converts alcohols into alkyl chlorides. PBr 3 (phosphorus tribromide) converts alcohols into alkyl bromides. via an S N 2 reaction

53. 53

54. 54 Conversion of Alcohols to Alkyl Halides with SOCl 2 and PBr 3 For primary and 2° alcohols SOCl 2 (thionyl chloride) converts alcohols into alkyl chlorides. PBr 3 (phosphorus tribromide) converts alcohols into alkyl bromides. via an S N 2 reaction

55. 55 Alcohols, Ethers and Epoxides Conversion of Alcohols to Alkyl Halides with SOCl 2 and PBr 3

56. 56

57. 57 Alcohols, Ethers and Epoxides

58. 58 Tosylate—Another Good Leaving Group An alkyl tosylate is composed of two parts: the alkyl group R, derived from an alcohol; and the tosylate (short for p- toluenesulfonate), which is a good leaving group. A tosyl group, CH 3 C 6 H 4 SO 2 ¯, is abbreviated Ts, so an alkyl tosylate becomes ROTs.

59. 59 Tosylate—Another Good Leaving Group This process converts a poor leaving group (¯OH) into a good one (¯OTs). Tosylate is a good leaving group because its conjugate acid, p- toluenesulfonic acid (CH 3 C 6 H 4 SO 3 H, TsOH) is a strong acid (pK a = -7).

60. 60 Tosylate—Another Good Leaving Group Because alkyl tosylates have good leaving groups, they undergo both nucleophilic substitution and  elimination, exactly as alkyl halides do.

61. 61 Tosylate—Another Good Leaving Group Substitution occurs via an S N 2 mechanism. Tosylates are equivalent to halides.

62. 62 Example:

63. 63 Alcohols, Ethers and Epoxides Reaction of Ethers with Strong Acid cleavage occurs either side of the ether oxygen atom to give two alkyl halide products, so ethers are not generally as useful as alcohols in synthesis.

64. 64 Mechanism of

65. 65 Mechanism of

66. 66 Reactions of Epoxides Nucleophilic attack opens the strained three-membered ring, making it a favorable process even with a poor leaving group. Reactions occur with strong nucleophiles (such as OH -, CH 3 S -, CH 3 O - or CN - ), in the absence of acid and with weaker nucleophiles (such as Cl - ) in the presence of strong acid (such as HCl).

67. 67 Reactions of Epoxides Common nucleophiles that open the epoxide ring include ¯OH, ¯OR, ¯CN, ¯SR and NH 3. With these strong nucleophiles. The reaction occurs by an S N 2 mechanism.

68. 68 Reactions of Epoxides : stereochemical consequences Nucleophilic attack of ¯ OCH 3 occurs from the backside at either C—O bond, because both ends are similarly substituted. Since attack at either side occurs with equal probability, an equal amount of the two enantiomers (i.e., a racemic mixture) is formed.

69. 69 Alcohols, Ethers and Epoxides Reactions of Epoxides Optically inactive starting materials give optically inactive products!

70. 70 Alcohols, Ethers and Epoxides Reactions of Epoxides Acids HZ that contain a nucleophile Z also open epoxide rings by a two-step sequence. HCl, HBr and HI, as well as H 2 O and ROH in the presence of acid, all open an epoxide ring in this manner.

71. 71 Reactions of Epoxides

72. 72 Alcohols, Ethers and Epoxides Reactions of Epoxides

73. 73 Reactions of Epoxides

74. 74 Leukotriene Synthesis and Asthma Drugs Leukotriene C 4 Leukotriene A 4 CO 2 H C 5 H 11 Arachidonic acid C 5 H 11 CO 2 H OOH Lipoxygenase 5-HPETE CO 2 H O C 5 H 11 Sulfur nucleophile, RSH (glutathione) CO 2 H C 5 H 11 OH SR.... Zileuton blocks this step S NCONH 2 HO Zileuton

75. 75 Alcohols, Ethers and Epoxides Important Epoxide Ring Opening Reactions

76. 9.48, 9.49, 9.50, 9.52, 9.56, 9.58, 9.66, 9.67, 9.70, 9.71, 9.76 Homework Write mechanisms for following reactions.

77. Preview of Chapter 10 Alkenes Reactions of alkenes Addition reaction --- What is Markovnikov’s rule? -Which reactions follow markovnikov’s rule? Hydrohalogenation reaction, Hydration reaction Halogenation reaction, Halohydrin formation Hydroboration reaction