1. Chapter 15 Alcohols, Diols, and Thiols

2. 15.1 Sources of Alcohols

3. Methanol is an industrial chemical: solvent, antifreeze, fuel. Principal use: preparation of formaldehyde. Prepared by hydrogenation of carbon monoxide. CO + 2H 2  CH 3 OH Methanol

4. Ethanol is an industrial chemical. Most ethanol comes from fermentation. Synthetic ethanol is produced by hydration of ethylene. Synthetic ethanol is denatured by adding: methanol, benzene, pyridine, castor oil, gasoline, etc. Ethanol

5. Isopropyl alcohol is prepared by hydration of propene. All alcohols with four carbons or fewer are readily available. Most alcohols with five or six carbons are readily available. Other alcohols

6. Natural Product Alcohols Natural product - Any organic substance isolated from living organisms or material derived from living organisms.

7. Review - Preparation of Alcohols Hydroboration-oxidation of alkenes Nucleophilic 1,2-addition of organometallic reagents to carbonyl compounds Hydration of alkenes

8. Reduction of aldehydes and ketones. Reduction of carboxylic acids. Reduction of esters. Reaction of Grignard reagents with epoxides. 1,2-Diols by dihydroxylation of alkenes. New Ways to Prepare Alcohols

9. 15.2 Preparation of Alcohols by Reduction of Aldehydes and Ketones

10. CRH OHOHOHOH H CRH O Reduction of Aldehydes Gives Primary Alcohols

11. Pt, ethanol (92%) Example: Catalytic Hydrogenation CH 3 O CH 2 OH O CH 3 O CH + H2H2H2H2

12. CRH OHOHOHOH R' C R R' O Reduction of Ketones Gives Secondary Alcohols

13. (93-95%) Example: Catalytic Hydrogenation + H2H2H2H2OPt ethanol HOH

14. H:–H:–H:–H:– CRH OHOHOHOH H CRH O H:–H:–H:–H:– CRH OHOHOHOH R' C R R' O Retrosynthetic Analysis

15. Sodium borohydride Na+ – B HHHH Lithium aluminum hydride Li + – Al HHHH Metal Hydride Reducing Agents Both act as hydride (H: – ) donors.

16. Sodium Borohydride O CH O2NO2NO2NO2N O NaBH 4 methanol (82%) CH 2 OH O2NO2NO2NO2NHOH (84%) NaBH 4 ethanol Aldehyde Ketone

17. More reactive than sodium borohydride. Cannot use water, ethanol, methanol, etc. as solvents. Diethyl ether is most commonly used solvent. Lithium Aluminum Hydride

18. Aldehyde KetoneO CH 3 (CH 2 ) 5 CH 1.LiAlH 4, diethyl ether 2. H 2 O O (C 6 H 5 ) 2 CHCCH 3 1.LiAlH 4, diethyl ether 2. H 2 O (84%) CH 3 (CH 2 ) 5 CH 2 OH (86%) OH (C 6 H 5 ) 2 CHCHCH 3

19. Neither NaBH 4 or LiAlH 4 reduces carbon-carbon double bonds. O HOH 1.LiAlH 4, diethyl ether 2. H 2 O (90%) Selectivity

20. 15.3 Preparation of Alcohols By Reduction of Carboxylic Acids and Esters

21. Lithium aluminum hydride is only effective reducing agent. Reduction of Carboxylic Acids Gives Primary Alcohols CRH OHOHOHOH H C R HO O

22. Reduction of a Carboxylic Acid 1.LiAlH 4, diethyl ether 2. H 2 O COH O CH 2 OH (78%)

23. Lithium aluminum hydride preferred for laboratory reductions. Catalytic hydrogenation used in industry but conditions difficult or dangerous to duplicate in the laboratory (special catalyst, high temperature, high pressure). Reduction of Esters Gives Primary Alcohols

24. Reduction of an Ester 1.LiAlH 4, diethyl ether 2. H 2 O (90%)O COCH 2 CH 3 CH 3 CH 2 OH CH 2 OH +

25. 15.4 Preparation of Alcohols From Epoxides

26. CH 3 (CH 2 ) 4 CH 2 MgBr H2CH2CH2CH2C CH 2 O + 1. diethyl ether 2. H 3 O + CH 3 (CH 2 ) 4 CH 2 CH 2 CH 2 OH (71%) Reaction of Grignard Reagents with Epoxides

27. Epoxide rings are strained (~29 kcal mol -1 ) and prone to nucleophilic attack at the carbon centers.

28. 15.5 Preparation of Diols

29. OO HCCH 2 CHCH 2 CH CH 3 H 2 (100 atm) Ni, 125°C HOCH 2 CH 2 CHCH 2 CH 2 OH CH 3 3-Methyl-1,5-pentanediol (81-83%) Example: Reduction of a Dialdehyde

30. Vicinal diols have hydroxyl groups on adjacent carbons. Ethylene glycol (HOCH 2 CH 2 OH), an antifreeze, is a familiar example. Hydroxylation of Alkenes Gives Vicinal Diols

31. Osmium Tetraoxide is Key Reagent C C HOHOHOHO OHOHOHOH C C OsO 4 O O Os OO C C Cyclic osmate ester

32. Example CH 2 CH 3 (CH 2 ) 7 CH (CH 3 ) 3 COOH, OsO 4 (cat), tert-Butyl alcohol, HO – (73%) CH 3 (CH 2 ) 7 CHCH 2 OH OHOHOHOH

33. Dihydroxylation with OsO 4 Is a Sterespecific Reaction Only the cis-1,2-diol obtained because of the mechanism of initial cycloaddition step: both oxygen atoms on OsO 4 attack same face of the alkene.

34. 15.6 Reactions of Alcohols: A Review and a Preview

35. Review of Reactions of Alcohols Reaction with hydrogen halides (alkyl halides). Reaction with thionyl chloride (alkyl chlorides). Reaction with phosphorous tribromide (alkyl bromides). Acid-catalyzed dehydration (alkenes). Conversion to p-toluenesulfonate esters (tosylates).

36. New Reactions of Alcohols Conversion to ethers Esterification Esters of inorganic acids Oxidation Cleavage of vicinal diols

37. 15.7 Conversion of Alcohols to Ethers

38. Conversion of Alcohols to Ethers Acid-catalyzed condensation of alcohols is an equilibrium reaction; most favorable for primary alcohols and works best if water is removed.

39. Example

40. Step 1: CH 3 CH 2 O H H OSO 2 OH CH 3 CH 2 O H OSO 2 OH H + – + Mechanism of Formation of Diethyl Ether

41. Step 2: CH 3 CH 2 HH+ O CH 3 CH 2 O H + + CH 3 CH 2 CH 3 CH 2 O H HHO Unlike hydroxide (HO - ), H 2 O is an excellent leaving group, so acid catalysis is the key.

42. Mechanism of Formation of Diethyl Ether Step 3: + CH 3 CH 2 CH 3 CH 2 O H OCH 2 CH 3 H + CH 3 CH 2 CH 3 CH 2 O OCH 2 CH 3 H H +

43. Intramolecular Etherification

44. 15.8 Esterification

45. Esterification: A Reversible Process 1) Fischer esterification (a classical transformation). 2) Condensation process (H 2 O produced). 3) Acid-catalyzed (H 2 SO 4 is source of H + and dehydrating agent). 4) Reversible - aqueous acid hydrolyzes esters to carboxylic acids. Acidic Dehydration Acidic Hydrolysis Acid + Alcohol Ester + Water

46. Example of Fischer Esterification

47. Reaction of Alcohols with Acyl Chlorides Advantages over Fischer Esterification? Fast, high yields, mild conditions and not reversible.

48. Example

49. Reaction of Alcohols with Acid Anhydrides Note similar behavior of acid anhydrides to acyl chlorides.

50. Example

51. 15.10 Oxidation of Alcohols

52. Primary alcohols from H 2 O Oxidation of Alcohols RCH 2 OH ORCHORCOH Secondary alcohols O RCR'RCHR' OH

53. Aqueous solution Mn(VII) Cr(VI) KMnO 4 H 2 CrO 4 KMnO 4 H 2 CrO 4 Na 2 Cr 2 O 7 K 2 Cr 2 O 7 Typical Oxidizing Agents

54. Aqueous Cr(VI) FCH 2 CH 2 CH 2 CH 2 OH K 2 Cr 2 O 7 H 2 SO 4, H2OH2OH2OH2O FCH 2 CH 2 CH 2 COH (74%)O Na 2 Cr 2 O 7 H 2 SO 4, H2OH2OH2OH2O (85%) H OH O

55. Mechanism Involves formation and elimination of a chromate ester. C OHOHOHOH HOCrOH OO H C OHO O CrOH CO O HH

56. All are used in CH 2 Cl 2. Pyridinium dichromate (PDC) (C 5 H 5 NH + ) 2 Cr 2 O 7 2– Pyridinium chlorochromate (PCC) C 5 H 5 NH + ClCrO 3 – Nonaqueous Sources of Cr(VI)

57. PDC CH 2 Cl 2 O(94%) CH 2 OH (CH 3 ) 3 C CH Oxidation of a Primary Alcohol with PDC

58. Oxidation of a Primary Alcohol with PCC CH 3 (CH 2 ) 5 CH 2 OH PCC CH 2 Cl 2 O CH 3 (CH 2 ) 5 CH (78%) ClCrO 3 – N H +

59. 15.11 Biological Oxidation of Alcohols

60. alcoholdehydrogenase Enzyme-Catalyzed CH 3 CH 2 OH + NAD++ + + H NAD H CH 3 CH O

61. Nicotinamide adenine dinucleotide (oxidized form) HO HO O O N N NH 2 P O P O O HO OH H C O N O O OO + __ Structure of NAD +

62. Enzyme-Catalyzed CH 3 CH 2 OH + N H CNH 2 O+ R N H OR CH 3 CH OH +H ++

63. 15.12 Oxidative Cleavage of Vicinal Diols

64. Cleavage of Vicinal Diols by Periodic Acid CC HO OH HIO 4 C O O C +

65. Cleavage of Vicinal Diols by Periodic Acid

66. Cyclic Diols Are Cleaved

67. 15.13 Thiols

68. Nomenclature of Thiols 1) Analogous to alcohols, but suffix is -thiol rather than -ol 2) Final -e of alkane name is retained, not dropped as with alcohols CH 3 CHCH 2 CH 2 SH CH 3 3-Methyl-1-butanethiol

69. 1) Hydrogen bonding is much weaker in thiols than in alcohols (S—H bond is less polar than O—H). 2) Low molecular weight thiols have foul odors. 3) Thiols are stronger acids than alcohols. 4) Thiols are more easily oxidized than alcohols; oxidation takes place at sulfur. Properties of Thiols

70. Thiols Are Less Polar than Alcohols MethanolMethanethiol bp: 65°C bp: 6°C

71. Have pK a s of about 10-11; can be deprotonated in aqueous base... Thiols Are Stronger Acids than Alcohols Stronger acid (pK a = 10-11) Weaker acid (pK a = 15.7) H RS OHOHOHOH – RS H OHOHOHOH –++

72. RS – and HS – Are Weakly Basic and Good Nucleophiles HClH C6H5SC6H5SC6H5SC6H5S C 6 H 5 SNa SN2SN2SN2SN2 (75%) KSH SN2SN2SN2SN2 (67%) BrSH

73. Oxidation of Thiols Takes Place at Sulfur ThiolDisulfide RS H RS SR Thiol-disulfide redox pair is important in biochemistry. Other oxidative processes place 1, 2 or 3 oxygen atoms on sulfur.

74. Oxidation of Thiols Takes Place at Sulfur ThiolDisulfide RS H RS SR Sulfenic acid RS OH Sulfinic acid RS OH O –+ Sulfonic acid RS OH O –2+ O –

75. HSCH 2 CH 2 CH(CH 2 ) 4 COH SHSHSHSH O 2, FeCl 3 Sulfide-Disulfide Redox Pair O (CH 2 ) 4 COH  -Lipoic acid (78%) OS S 6,8-Dimercaptooctanoicacid

76. 15.14 Spectroscopic Analysis of Alcohols

77. O—H stretching: 3200-3650 cm –1 (broad) C—O stretching: 1025-1200 cm –1 Infrared Spectroscopy

78. Infrared Spectrum of Cyclohexanol

79. S—H stretching: 2550-2700 cm –1 (weak) Infrared Spectroscopy Example: 2-Mercaptoethanol HOCH 2 CH 2 SH HOCH 2 CH 2 SH

80. Chemical shift of O—H proton is variable; depends on temperature and concentration. O—H proton can be identified by adding D 2 O; signal for O—H disappears (converted to O—D). H—C—O signal is less shielded than H—C—H. 1 H NMR C O HH  3.3-4 ppm  0.5-5 ppm

81. 01.02.03.04.05.06.07.08.09.010.0 Chemical shift ( , ppm) 2-Phenylethanol CH2CH2OHCH2CH2OHCH2CH2OHCH2CH2OH

82. Sulfur is less electronegative than oxygen, so it is less deshielding. 1 H NMR CH 3 CH 2 CH 2 CH 2 OH CH 3 CH 2 CH 2 CH 2 SH  3.6  2.5

83. Chemical shift of C—OH is  60-75 ppm. Deshielding effect of O is much larger than that of S. 13 C NMR CH 3 — CH 2 — CH 2 — CH 2 — OH  14  19  35  62 CH 3 — CH 2 — CH 2 — CH 2 — SH  13  21  36  24