1. Chapter 10 Copyright © 2010 Pearson Education, Inc. Organic Chemistry, 7 th Edition L. G. Wade, Jr. Structure and Synthesis of Alcohols

2. Chapter 102 Structure of Water and Methanol Oxygen is sp 3 hybridized and tetrahedral. The H—O—H angle in water is 104.5°. The C—O—H angle in methyl alcohol is 108.9°.

3. Chapter 103 Examples of Classifications CH 3 C CH 3 CH 3 OH * CH 3 CH OH CH 2 CH 3 * CH 3 CH CH 3 CH 2 OH * Primary alcoholSecondary alcohol Tertiary alcohol

4. Chapter 104 IUPAC Nomenclature Find the longest carbon chain containing the carbon with the —OH group. Drop the -e from the alkane name, add -ol. Number the chain giving the —OH group the lowest number possible. Number and name all substituents and write them in alphabetical order.

5. Chapter 105 Examples of Nomenclature 2-methyl-1-propanol 2-methylpropan-1-ol 2-methyl-2-propanol 2-methylpropan-2-ol 2-butanol butan-2-ol CH 3 C CH 3 CH 3 OH CH 3 CH CH 3 CH 2 OH CH 3 CH OH CH 2 CH 3 3 2 1 1 2 3 4 2 1

6. Chapter 106 Alkenols (Enols) Hydroxyl group takes precedence. Assign the carbon with the —OH the lowest number. End the name in –ol, but also specify that there is a double bond by using the ending –ene before -ol 4-penten-2-ol pent-4-ene-2-ol CH 2 CHCH 2 CHCH 3 OH 5 4 3 2 1

7. Chapter 107 Naming Priority 1.Acids 2.Esters 3.Aldehydes 4.Ketones 5.Alcohols 6.Amines 7.Alkenes 8.Alkynes 9.Alkanes 10. Ethers 11. Halides Highest ranking Lowest ranking

8. Chapter 108 Hydroxy Substituent When —OH is part of a higher priority class of compound, it is named as hydroxy. 4-hydroxybutanoic acid also known as  -hydroxybutyric acid (GHB) CH 2 CH 2 CH 2 COOH OH carboxylic acid 4 3 2 1

9. Chapter 109 Common Names Alcohol can be named as alkyl alcohol. Useful only for small alkyl groups. isobutyl alcohol sec-butyl alcohol CH 3 CH CH 3 CH 2 OH CH 3 CH OH CH 2 CH 3

10. Chapter 1010 Naming Diols Two numbers are needed to locate the two —OH groups. Use -diol as suffix instead of -ol. hexane-1,6- diol 1 2 3 4 5 6

11. Chapter 1011 Glycols 1, 2-diols (vicinal diols) are called glycols. Common names for glycols use the name of the alkene from which they were made. ethane-1,2- diol ethylene glycol propane-1,2- diol propylene glycol

12. Chapter 1012 Phenol Nomenclature —OH group is assumed to be on carbon 1. For common names of disubstituted phenols, use ortho- for 1,2; meta- for 1,3; and para- for 1,4. Methyl phenols are cresols. 3-chlorophenol (meta-chlorophenol) 4-methylphenol (para-cresol)

13. Chapter 1013 Give the systematic (IUPAC) name for the following alcohol. The longest chain contains six carbon atoms, but it does not contain the carbon bonded to the hydroxyl group. The longest chain containing the carbon bonded to the —OH group is the one outlined by the green box, containing five carbon atoms. This chain is numbered from right to left in order to give the hydroxyl-bearing carbon atom the lowest possible number. The correct name for this compound is 3-(iodomethyl)-2-isopropylpentan-1-ol. Solved Problem 1 Solution

14. Chapter 1014 Boiling Points of alcohols Alcohols have higher boiling points than ethers and alkanes because alcohols can form hydrogen bonds. The stronger interaction between alcohol molecules will require more energy to break them resulting in a higher boiling point.

15. Chapter 1015 Solubility in Water Small alcohols are miscible in water, but solubility decreases as the size of the alkyl group increases.

16. Chapter 1016 Table of K a Values

17. Chapter 1017 Formation of Alkoxide Ions Ethanol reacts with sodium metal to form sodium ethoxide (NaOCH 2 CH 3 ), a strong base commonly used for elimination reactions. More hindered alcohols like 2-propanol or tert-butanol react faster with potassium than with sodium.

18. Chapter 1018 Formation of Phenoxide Ion The aromatic alcohol phenol is more acidic than aliphatic alcohols due to the ability of aromatic rings to delocalize the negative charge of the oxygen within the carbons of the ring.

19. Chapter 1019 Charge Delocalization on the Phenoxide Ion The negative charge of the oxygen can be delocalized over four atoms of the phenoxide ion. There are three other resonance structures that can localize the charge in three different carbons of the ring. The true structure is a hybrid between the four resonance forms.

20. Chapter 1020 Grignard Reagents Formula R—Mg—X (reacts like R: - + MgX). Ethers are used as solvents to stabilize the complex. Iodides are most reactive. May be formed from any halide.

21. Chapter 1021 Reactions with Grignards

22. Chapter 1022 Organolithium Reagents Formula R—Li (reacts like R: - + Li) Can be produced from alkyl, vinyl, or aryl halides, just like Grignard reagents. Ether not necessary, wide variety of solvents can be used.

23. Chapter 1023 Reaction with Carbonyl

24. Chapter 1024 Formation of Primary Alcohols Using Grignard Reagents Reaction of a Grignard with formaldehyde will produce a primary alcohol after protonation.

25. Chapter 1025 Synthesis of 2º Alcohols Addition of a Grignard reagent to an aldehyde followed by protonation will produce a secondary alcohol.

26. Chapter 1026 Synthesis of 3º Alcohols Tertiary alcohols can be easily obtained by addition of a Grignard to a ketone followed by protonation with dilute acid.

27. Chapter 1027 Show how you would synthesize the following alcohol from compounds containing no more than five carbon atoms. This is a tertiary alcohol; any one of the three alkyl groups might be added in the form of a Grignard reagent. We can propose three combinations of Grignard reagents with ketones: Solved Problem 2 Solution

28. Chapter 1028 Any of these three syntheses would probably work, but only the third begins with fragments containing no more than five carbon atoms. The other two syntheses would require further steps to generate the ketones from compounds containing no more than five carbon atoms. Solved Problem 2 (Continued) Solution (Continued)

29. Chapter 1029 Reaction of Grignards with Carboxylic Acid Derivatives

30. Chapter 1030 Mechanism CO Cl H 3 C MgBr RMgBr C CH 3 Cl OR Step 1: Grignard attacks the carbonyl forming the tetrahedral intermediate. Step 2: The tetrahedral intermediate will reform the carbonyl and form a ketone intermediate.

31. Chapter 1031 Mechanism continued HOH C CH 3 R OHR C CH 3 R OR MgBr C CH 3 R O RMgBr + C CH 3 R OR MgBr Step 3: A second molecule of Grignard attacks the carbonyl of the ketone. Step 4: Protonation of the alkoxide to form the alcohol as the product.

32. Chapter 1032 Addition to Ethylene Oxide Grignard and lithium reagents will attack epoxides (also called oxiranes) and open them to form alcohols. This reaction is favored because the ring strain present in the epoxide is relieved by the opening. The reaction is commonly used to extend the length of the carbon chain by two carbons.

33. Chapter 1033 Limitations of Grignard Grignards are good nucleophiles but in the presence of acidic protons it will acts as a strong base. No water or other acidic protons like O—H, N—H, S—H, or terminal alkynes. No other electrophilic multiple bonds, like C═N, C  N, S═O, or N═O.

34. Chapter 1034 Reduction of Carbonyl Reduction of aldehyde yields 1º alcohol. Reduction of ketone yields 2º alcohol. Reagents:  Sodium borohydride, NaBH 4  Lithium aluminum hydride, LiAlH 4  Raney nickel

35. Chapter 1035 Sodium Borohydride NaBH 4 is a source of hydrides (H - ) Hydride attacks the carbonyl carbon, forming an alkoxide ion. Then the alkoxide ion is protonated by dilute acid. Only reacts with carbonyl of aldehyde or ketone, not with carbonyls of esters or carboxylic acids.

36. Chapter 1036 Mechanism of Hydride Reduction The hydride attacks the carbonyl of the aldehyde or the ketone. A tetrahedral intermediate forms. Protonation of the intermediate forms the alcohols.

37. Chapter 1037 Lithium Aluminum Hydride LiAlH 4 is source of hydrides (H - ) Stronger reducing agent than sodium borohydride, but dangerous to work with. Reduces ketones and aldehydes into the corresponding alcohol. Converts esters and carboxylic acids to 1º alcohols.

38. Chapter 1038 Reduction with LiAlH 4 The LiAlH 4 (or LAH) will add two hydrides to the ester to form the primary alkyl halide. The mechanism is similar to the attack of Grignards on esters.

39. Chapter 1039 Reducing Agents NaBH 4 can reduce aldehydes and ketones but not esters and carboxylic acids. LiAlH 4 is a stronger reducing agent and will reduce all carbonyls.

40. Chapter 1040 Catalytic Hydrogenation Raney nickel is a hydrogen rich nickel powder that is more reactive than Pd or Pt catalysts. This reaction is not commonly used because it will also reduce double and triple bonds that may be present in the molecule. Hydride reagents are more selective so they are used more frequently for carbonyl reductions.

41. Chapter 1041 Thiols (Mercaptans) Sulfur analogues of alcohols are called thiols. The —SH group is called a mercapto group. Named by adding the suffix -thiol to the alkane name. They are commonly made by an S N 2 reaction so primary alkyl halides work better.

42. Chapter 1042 Synthesis of Thiols The thiolate will attack the carbon displacing the halide. This is an S N 2 reaction so methyl halides will react faster than primary alkyl halides. To prevent dialylation use a large excess of sodium hydrosulfide with the alkyl halide.

43. A better way into thiols

44. Chapter 1044 Thiol Oxidation Thiols can be oxidized to form disulfides. The disulfide bond can be reduced back to the thiols with a reducing agent.

45. Reactions

47. Chapter 1147 Oxidation States of Carbons

48. Chapter 1148 Oxidation States of Carbons

49. Chapter 1149 Oxidation of 2° Alcohols 2° alcohol becomes a ketone. Oxidizing agent is Na 2 Cr 2 O 7 /H 2 SO 4. Active reagent probably is H 2 CrO 4. Color change is orange to greenish- blue.

50. Chapter 1150 Oxidation Mechanism

51. Chapter 1151 Oxidation of 1° Alcohols to Carboxylic Acids Chromic acid reagent oxidizes primary alcohols to carboxylic acids. The oxidizing agent is too strong to stop at the aldehyde.

52. Chapter 1152 Pyridinium Chlorochromate (PCC) PCC is a complex of chromium trioxide, pyridine, and HCl. Oxidizes primary alcohols to aldehydes. Oxidizes secondary alcohols to ketones.

53. Chapter 1153 3° Alcohols Cannot Be Oxidized Carbon does not have hydrogen, so oxidation is difficult and involves the breakage of a C—C bond. Chromic acid test is for primary and secondary alcohols because tertiary alcohols do not react.

54. Chapter 1154 Example of the Swern Oxidation

55. Chapter 1155 Swern Oxidation

56. Chapter 1156 Suggest the most appropriate method for each of the following laboratory syntheses. (a) cyclopentanol ––––––> cyclopentanone Many reagents are available to oxidize a simple secondary alcohol to a ketone. For a laboratory synthesis, however, dehydrogenation is not practical, and cost is not as large a factor as it would be in industry. Most labs would have chromium trioxide or sodium dichromate available, and the chromic acid oxidation would be simple. PCC and the Swern oxidation would also work, although these reagents are more complicated to prepare and use. Solved Problem 1 Solution

57. Chapter 1157 Suggest the most appropriate method for each of the following laboratory syntheses. (b) 2-octen-l-ol ––––––> 2-octenal (structure below) This synthesis requires more finesse. The aldehyde is easily over-oxidized to a carboxylic acid, and the double bond reacts with oxidants such as KMnO 4. Our choices are limited to PCC or the Swern oxidation. Solved Problem 1 (Continued) Solution

58. Chapter 1158 Enzymatic Oxidation Alcohol dehydrogenase catalyzes an oxidation: the removal of two hydrogen atoms from an alcohol molecule. The oxidizing agent is called nicotinamide adenine dinucleotide (NAD + ).

59. Chapter 1159 Alcohol as a Nucleophile ROH is a weak nucleophile. RO - is a strong nucleophile. New O—C bond forms; O—H bond breaks. RX C O H

60. Chapter 1160 Alkoxide Ions: Williamson Ether Synthesis Ethers can be synthesized by the reaction of alkoxide ions with primary alkyl halides in what is known as the Williamson ether synthesis. This is an S N 2 displacement reaction and as such, works better with primary alkyl halides to facilitate back-side attack. If a secondary or tertiary alkyl halide is used, the alkoxide will act as a base and an elimination will take place.

61. Chapter 1161 Substitution and Elimination Reactions Using Tosylates

62. Chapter 1162 S N 2 Reactions with Tosylates The reaction shows the S N 2 displacement of the tosylate ion ( - OTs) from (S)-2-butyl tosylate with inversion of configuration. The tosylate ion is a particularly stable anion, with its negative charge delocalized over three oxygen atoms.

63. Chapter 1163 Summary of Tosylate Reactions

64. Chapter 1164 Reduction of Alcohols Dehydrate with concentrated H 2 SO 4, then add H 2. Make a tosylate, then reduce it with LiAlH 4. CH 3 CHCH 3 OH H 2 SO 4 CH 2 CHCH 3 H 2 Pt CH 3 CH 2 CH 3 alcohol alkene alkane alcohol CH 3 CHCH 3 OH TsCl CH 3 CHCH 3 OTs LiAlH 4 alkane CH 3 CH 2 CH 3 tosylate

65. Chapter 1165 Reaction of Alcohols with Acids The hydroxyl group is protonated by an acid to convert it into a good leaving group (H 2 O). Once the alcohol is protonated a substitution or elimination reaction can take place.

66. Chapter 1166 Reaction with HBr –OH of alcohol is protonated. –OH 2 + is good leaving group. 3° and 2° alcohols react with Br - via S N 1. 1° alcohols react via S N 2. H 3 O + Br - ROH ROH H RBr

67. Chapter 1167 Reaction with HCl Chloride is a weaker nucleophile than bromide. Add ZnCl 2, which bonds strongly with –OH, to promote the reaction. The chloride product is insoluble. Lucas test: ZnCl 2 in concentrated HCl:  1° alcohols react slowly or not at all.  2  alcohols react in 1-5 minutes.  3  alcohols react in less than 1 minute.

68. Chapter 1168 S N 2 Reaction with the Lucas Reagent Primary alcohols react with the Lucas reagent (HCl and ZnCl 2 ) by the S N 2 mechanism. Reaction is very slow. The reaction can take from several minutes to several days.

69. Chapter 1169 S N 1 Reaction with the Lucas Reagent Secondary and tertiary alcohols react with the Lucas reagent (HCl and ZnCl 2 ) by the S N 1 mechanism.

70. Chapter 1170 When 3-methyl-2-butanol is treated with concentrated HBr, the major product is 2-bromo-2- methylbutane. Propose a mechanism for the formation of this product. The alcohol is protonated by the strong acid. This protonated secondary alcohol loses water to form a secondary carbocation. Solved Problem 2 Solution

71. Chapter 1171 A hydride shift transforms the secondary carbocation into a more stable tertiary cation. Attack by bromide leads to the observed product. Solved Problem 2 (Continued) Solution (Continued)

72. Chapter 1172 Reactions with Phosphorus Halides Good yields with 1° and 2° alcohols. PCl 3 for alkyl chlorides (but SOCl 2 better). PBr 3 for alkyl bromides. P and I 2 for alkyl iodides (PI 3 not stable).

73. Chapter 1173 Mechanism with PBr 3 Oxygen attacks the phosphorus, displacing one of the halides. Br - attacks back-side (S N 2).

74. Chapter 1174 Reaction of Alcohols with Thionyl Chloride Thionyl chloride (SOCl 2 ) can be used to convert alcohols into the corresponding alkyl chloride in a simple reaction that produces gaseous HCl and SO 2.

75. Chapter 1175 Mechanism of Thionyl Chloride Reaction

76. Appel reaction Also CBr 4, or Br 2

77. Appel reaction Mechanism

78. Chapter 1178 Dehydration of Cyclohexanol The dehydration of cyclohexanol with H 2 SO 4 has three steps: Protonation of the hydroxide, loss of water, and deprotonation. Alcohol dehydration generally takes place through the E1 mechanism. Rearrangements are possible. The rate of the reaction follows the same rate as the ease of formation of carbocations: 3 o > 2 o > 1 o.

79. Chapter 1179 Energy Diagram, E1

80. Chapter 1180 Pinacol Rearrangement In the pinacol rearrangement, a vicinal diol converts to the ketone (pinacolone) under acidic conditions and heat. The reaction is classified as a dehydration since a water molecule is eliminated from the starting material.

81. Chapter 1181 Mechanism of the Pinacol Rearrangement The first step of the rearrangement is the protonation and loss of a water molecule to produce a carbocation.

82. Chapter 1182 Mechanism of the Pinacol Rearrangement (Continued) There is a methyl shift to form a resonance- stabilized carbocation, which upon deprotonation by water, yields the pinacolone product.

83. Chapter 1183 Periodic Cleavage of Glycols Glycols can be oxidatively cleaved by periodic acid (HIO 4 ) to form the corresponding ketones and aldehydes. This cleavage can be combined with the hydroxylation of alkenes by osmium tetroxide or cold potassium permanganate to form the glycol and the cleavage of the glycol with periodic acid. Same products formed as from ozonolysis of the corresponding alkene.

84. Chapter 2384 Periodic Acid Cleavage Periodic acid cleaves vicinal diols to give two carbonyl compounds. Separation and identification of the products determine the size of the ring. =>

85. Chapter 1185 Fischer Esterification Reaction of an alcohol and a carboxylic acid produces an ester. Sulfuric acid is a catalyst. The reaction is an equilibrium between starting materials and products, and for this reason, the Fischer esterification is seldom used to prepare esters.

86. Chapter 1186 Reaction of Alcohols with Acyl Chlorides The esterification reaction achieves better results by reacting the alcohol with an acyl chloride. The reaction is exothermic and produces the corresponding ester in high yields with only HCl as a by-product.

87. Chapter 1187 Nitrate Esters The best known nitrate ester is nitroglycerine, whose systematic name is glyceryl trinitrate. Glyceryl nitrate results from the reaction of glycerol (1,2,3-propanetriol) with three molecules of nitric acid.

88. Chapter 1188 Phosphate Esters

89. Chapter 1189 Phosphate Esters in DNA