Chapter 15 Alcohols, Diols, and Thiols Dr. Wolf's CHM 201 & 202 15-1 2

Sources of Alcohols Dr. Wolf's CHM 201 & 202 15-2 2

Methanol is an industrial chemical end uses: solvent, antifreeze, fuel principal use: preparation of formaldehyde Dr. Wolf's CHM 201 & 202 15-3 3

Methanol is an industrial chemical end uses: solvent, antifreeze, fuel principal use: preparation of formaldehyde prepared by hydrogenation of carbon monoxide CO + 2H2 ® CH3OH Dr. Wolf's CHM 201 & 202 15-4 3

Ethanol is an industrial chemical Most ethanol comes from fermentation Synthetic ethanol is produced by hydration of ethylene Synthetic ethanol is denatured (made unfit for drinking) by adding methanol, benzene, pyridine, castor oil, gasoline, etc. Dr. Wolf's CHM 201 & 202 15-5 4

Isopropyl alcohol is prepared by hydration of propene. Other alcohols 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. Dr. Wolf's CHM 201 & 202 15-6 5

Reactions discussed in earlier chapters (Table 15.1) Sources of alcohols Reactions discussed in earlier chapters (Table 15.1) Hydration of alkenes Hydroboration-oxidation of alkenes Hydrolysis of alkyl halides Syntheses using Grignard reagents organolithium reagents Dr. Wolf's CHM 201 & 202 15-7 6

Reduction of aldehydes and ketones Reduction of carboxylic acids Sources of alcohols New methods in Chapter 15 Reduction of aldehydes and ketones Reduction of carboxylic acids Reduction of esters Reaction of Grignard reagents with epoxides Diols by hydroxylation of alkenes Dr. Wolf's CHM 201 & 202 15-8 6

Preparation of Alcohols by Reduction of Aldehydes and Ketones Dr. Wolf's CHM 201 & 202 15-9 8

Reduction of Aldehydes Gives Primary Alcohols Dr. Wolf's CHM 201 & 202 15-10 9

Example: Catalytic Hydrogenation CH3O CH + H2 Pt, ethanol CH3O CH2OH (92%) Dr. Wolf's CHM 201 & 202 15-11 10

Reduction of Ketones Gives Secondary Alcohols Dr. Wolf's CHM 201 & 202 15-12 9

Example: Catalytic Hydrogenation OH O Pt + H2 ethanol (93-95%) Dr. Wolf's CHM 201 & 202 15-13 10

Retrosynthetic Analysis OH C R H O H:– C R H OH R' C R R' O H:– Dr. Wolf's CHM 201 & 202 15-14 13

Metal Hydride Reducing Agents – B H – Al H Na + Li + Sodium borohydride Lithium aluminum hydride act as hydride donors Dr. Wolf's CHM 201 & 202 15-15 14

Examples: Sodium Borohydride Aldehyde O CH O2N O2N NaBH4 CH2OH methanol (82%) Ketone H OH O NaBH4 ethanol (84%) Dr. Wolf's CHM 201 & 202 15-16 10

Lithium aluminum hydride more reactive than sodium borohydride cannot use water, ethanol, methanol etc. as solvents diethyl ether is most commonly used solvent Dr. Wolf's CHM 201 & 202 15-17 20

Examples: Lithium Aluminum Hydride Aldehyde 1. LiAlH4 diethyl ether O CH3(CH2)5CH CH3(CH2)5CH2OH 2. H2O (86%) Ketone O 1. LiAlH4 diethyl ether OH (C6H5)2CHCHCH3 (C6H5)2CHCCH3 2. H2O (84%) Dr. Wolf's CHM 201 & 202 15-18 10

neither NaBH4 or LiAlH4 reduces isolated double bonds Selectivity O neither NaBH4 or LiAlH4 reduces isolated double bonds 1. LiAlH4 diethyl ether 2. H2O H OH (90%) Dr. Wolf's CHM 201 & 202 15-19 20

Preparation of Alcohols By Reduction of Carboxylic Acids and Esters Dr. Wolf's CHM 201 & 202 15-20 22

Reduction of Carboxylic Acids Gives Primary Alcohols lithium aluminum hydride is only effective reducing agent Dr. Wolf's CHM 201 & 202 15-21 9

Example: Reduction of a Carboxylic Acid 1. LiAlH4 diethyl ether O COH CH2OH 2. H2O (78%) Dr. Wolf's CHM 201 & 202 15-22 10

Reduction of Esters Gives Primary Alcohols (Also Chapter 19) Lithium aluminum hydride preferred for laboratory reductions Sodium borohydride reduction is too slow to be useful Catalytic hydrogenolysis used in industry but conditions difficult or dangerous to duplicate in the laboratory (special catalyst, high temperature, high pressure Dr. Wolf's CHM 201 & 202 15-23 25

Example: Reduction of an Ester 1. LiAlH4 diethyl ether 2. H2O (90%) O COCH2CH3 CH3CH2OH CH2OH + Dr. Wolf's CHM 201 & 202 15-24 10

Preparation of Alcohols From Epoxides Dr. Wolf's CHM 201 & 202 15-25 22

Reaction of Grignard Reagents with Epoxides MgX R H2C CH2 O CH2 CH2 OMgX H3O+ RCH2CH2OH Dr. Wolf's CHM 201 & 202 15-26 9

Example CH2 H2C CH3(CH2)4CH2MgBr + O 1. diethyl ether 2. H3O+ CH3(CH2)4CH2CH2CH2OH (71%) Dr. Wolf's CHM 201 & 202 15-27 29

Preparation of Diols Dr. Wolf's CHM 201 & 202 15-28 22

reactions used to prepare alcohols hydroxylation of alkenes Diols are prepared by... reactions used to prepare alcohols hydroxylation of alkenes Dr. Wolf's CHM 201 & 202 15-29 20

Example: reduction of a dialdehyde HCCH2CHCH2CH CH3 H2 (100 atm) Ni, 125°C HOCH2CH2CHCH2CH2OH CH3 3-Methyl-1,5-pentanediol (81-83%) Dr. Wolf's CHM 201 & 202 15-30 33

Hydroxylation of Alkenes Gives Vicinal Diols vicinal diols have hydroxyl groups on adjacent carbons ethylene glycol (HOCH2CH2OH) is most familiar example Dr. Wolf's CHM 201 & 202 15-31 35

Osmium Tetraoxide is Key Reagent syn addition of —OH groups to each carbon of double bond HO OH C C O Os C Dr. Wolf's CHM 201 & 202 15-32 36

tert-Butyl alcohol HO– Example CH2 CH3(CH2)7CH (CH3)3COOH OsO4 (cat) tert-Butyl alcohol HO– CH3(CH2)7CHCH2OH OH (73%) Dr. Wolf's CHM 201 & 202 15-33 37

tert-Butyl alcohol HO– Example (CH3)3COOH OsO4 (cat) H OH HO H tert-Butyl alcohol HO– (62%) Dr. Wolf's CHM 201 & 202 15-34 37

Reactions of Alcohols: A Review and a Preview Dr. Wolf's CHM 201 & 202 15-35 1

Table 15.2 Review of Reactions of Alcohols reaction with hydrogen halides reaction with thionyl chloride reaction with phosphorous tribromide acid-catalyzed dehydration conversion to p-toluenesulfonate esters Dr. Wolf's CHM 201 & 202 15-36 2

New Reactions of Alcohols in This Chapter conversion to ethers esterification esters of inorganic acids oxidation cleavage of vicinal diols Dr. Wolf's CHM 201 & 202 15-37 2

Conversion of Alcohols to Ethers Dr. Wolf's CHM 201 & 202 15-38 4

Conversion of Alcohols to Ethers RCH2O H CH2R OH H+ RCH2O CH2R + H OH acid-catalyzed referred to as a "condensation" equilibrium; most favorable for primary alcohols Dr. Wolf's CHM 201 & 202 15-39 5

Example H2SO4, 130°C 2CH3CH2CH2CH2OH CH3CH2CH2CH2OCH2CH2CH2CH3 (60%) Dr. Wolf's CHM 201 & 202 15-40 10

Mechanism of Formation of Diethyl Ether Step 1: CH3CH2O •• • • H OSO2OH H H + – + CH3CH2O OSO2OH • • H Dr. Wolf's CHM 201 & 202 15-41 7

Mechanism of Formation of Diethyl Ether Step 2: CH3CH2 • • H + O • • H O + CH3CH2 CH3CH2O • • H + CH3CH2O •• • • H Dr. Wolf's CHM 201 & 202 15-42 7

Mechanism of Formation of Diethyl Ether Step 3: + CH3CH2 CH3CH2O • • H CH3CH2 CH3CH2O • • •• + OSO2OH – •• • • H OSO2OH •• Dr. Wolf's CHM 201 & 202 15-43 7

Intramolecular Analog HOCH2CH2CH2CH2CH2OH H2SO4 130° O reaction normally works well only for 5- and 6-membered rings (76%) Dr. Wolf's CHM 201 & 202 15-44 9

Intramolecular Analog HOCH2CH2CH2CH2CH2OH via: H2SO4 130° O H + • • •• O (76%) Dr. Wolf's CHM 201 & 202 15-45 9

Esterification (more on esters and other acid derivatives in later chapters) Dr. Wolf's CHM 201 & 202 15-46 10

Esterification a condensation reaction called Fischer esterification R'COH O R'COR O H+ ROH + + H2O a condensation reaction called Fischer esterification acid catalyzed reversible Dr. Wolf's CHM 201 & 202 15-47 11

Example of Fischer Esterification CH3OH + COH O 0.1 mol 0.6 mol (i.e. excess) H2SO4 COCH3 O + H2O 70% yield based on benzoic acid Dr. Wolf's CHM 201 & 202 15-48 11

Reaction of Alcohols with Acyl Chlorides R'CCl O R'COR O ROH + + HCl high yields not reversible when carried out in presence of pyridine Dr. Wolf's CHM 201 & 202 15-49 11

Example CH3CH2 O + OH O2N CCl CH3 pyridine CH3CH2 O OC NO2 CH3 (63%) Dr. Wolf's CHM 201 & 202 15-50 14

Reaction of Alcohols with Acid Anhydrides R'COCR' R'COR O R'COH O ROH + + analogous to reaction with acyl chlorides Dr. Wolf's CHM 201 & 202 15-51 11

Example O + C6H5CH2CH2OH F3CCOCCF3 pyridine O C6H5CH2CH2OCCF3 (83%) Dr. Wolf's CHM 201 & 202 15-52 14

Esters of Inorganic Acids Dr. Wolf's CHM 201 & 202 15-53 17

Esters of Inorganic Acids ROH + HOEWG ROEWG + H2O EWG is an electron-withdrawing group (HO)3P O + – HONO2 (HO)2SO2 Dr. Wolf's CHM 201 & 202 15-54 18

Esters of Inorganic Acids ROH + HOEWG ROEWG + H2O EWG is an electron-withdrawing group (HO)3P O + – HONO2 (HO)2SO2 CH3OH + HONO2 CH3ONO2 + H2O (66-80%) Dr. Wolf's CHM 201 & 202 15-55 18

Oxidation of Alcohols Dr. Wolf's CHM 201 & 202 15-56 24

Oxidation of Alcohols Primary alcohols O O RCH2OH RCH RCOH Secondary alcohols O from H2O RCHR' OH RCR' Dr. Wolf's CHM 201 & 202 15-57 25

Typical Oxidizing Agents Aqueous solution Mn(VII) Cr(VI) KMnO4 H2CrO4 H2Cr2O7 Dr. Wolf's CHM 201 & 202 15-58 26

Aqueous Cr(VI) FCH2CH2CH2CH2OH H2SO4 K2Cr2O7 H2O O FCH2CH2CH2COH (74%) Dr. Wolf's CHM 201 & 202 15-59 27

Aqueous Cr(VI) H OH FCH2CH2CH2CH2OH H2SO4 K2Cr2O7 H2SO4 H2O Na2Cr2O7 FCH2CH2CH2COH (74%) (85%) Dr. Wolf's CHM 201 & 202 15-60 27

Nonaqueous Sources of Cr(VI) All are used in CH2Cl2 Pyridinium dichromate (PDC) (C5H5NH+)2 Cr2O72– Pyridinium chlorochromate (PCC) C5H5NH+ ClCrO3– Dr. Wolf's CHM 201 & 202 15-61 28

Example: Oxidation of a primary alcohol with PCC (pyridinium chlorochromate) + ClCrO3– O CH3(CH2)5CH PCC CH3(CH2)5CH2OH CH2Cl2 (78%) Dr. Wolf's CHM 201 & 202 15-62 29

Example: Oxidation of a primary alcohol with PDC (pryidinium dichromate) CH2OH (CH3)3C PDC CH2Cl2 O CH (CH3)3C (94%) Dr. Wolf's CHM 201 & 202 15-63 29

Mechanism O H H O C HOCrOH C OH O CrOH involves formation and elimination of a chromate ester Dr. Wolf's CHM 201 & 202 15-64 31

Mechanism H O H O H H O C HOCrOH C OH O CrOH •• H Mechanism O H H O C HOCrOH C OH O CrOH involves formation and elimination of a chromate ester C O Dr. Wolf's CHM 201 & 202 15-65 31

Biological Oxidation of Alcohols Dr. Wolf's CHM 201 & 202 15-66 33

Enzyme-catalyzed NAD (a coenzyme) + CH3CH2OH + alcohol dehydrogenase + Dr. Wolf's CHM 201 & 202 15-67 34

Figure 15.3 Structure of NAD+ HO O N NH2 P OH H C + _ nicotinamide adenine dinucleotide (oxidized form) Dr. Wolf's CHM 201 & 202 15-68 35

Enzyme-catalyzed N H CNH2 O + R + H CH3CH2OH + + 15-69 34 Dr. Wolf's CHM 201 & 202 15-69 34

Enzyme-catalyzed CNH2 O H H CH3CH O N R •• 15-70 34 Dr. Wolf's CHM 201 & 202 15-70 34

Oxidative Cleavage of Vicinal Diols Dr. Wolf's CHM 201 & 202 15-71 37

Cleavage of Vicinal Diols by Periodic Acid HO OH O O C HIO4 C + Dr. Wolf's CHM 201 & 202 15-72 38

Cleavage of Vicinal Diols by Periodic Acid CH CCH3 CH3 OH HO HIO4 CH O CH3CCH3 O + (83%) Dr. Wolf's CHM 201 & 202 15-73 38

Cyclic Diols are Cleaved OH O HCCH2CH2CH2CH HIO4 Dr. Wolf's CHM 201 & 202 15-74 38

Preparation of Thiols Dr. Wolf's CHM 201 & 202 15-75 1

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 Dr. Wolf's CHM 201 & 202 15-76 6

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 CH3CHCH2CH2SH CH3 3-Methyl-1-butanethiol Dr. Wolf's CHM 201 & 202 15-77 6

Properties of Thiols 1. low molecular weight thiols have foul odors 2. hydrogen bonding is much weaker in thiols than in alcohols 3. thiols are stronger acids than alcohols 4. thiols are more easily oxidized than alcohols; oxidation takes place at sulfur Dr. Wolf's CHM 201 & 202 15-82 6

Thiols are less polar than alcohols Methanol Methanethiol bp: 65°C bp: 6°C 6

Thiols are stronger acids than alcohols have pKas of about 10; can be deprotonated in aqueous base – •• OH • • – H RS •• •• H •• OH + RS + • • stronger acid (pKa = 10) weaker acid (pKa = 15.7) Dr. Wolf's CHM 201 & 202 15-83 7

RS– and HS – are weakly basic and good nucleophiles C6H5S C6H5SNa SN2 (75%) KSH SN2 (67%) Br SH 2

Oxidation of thiols take place at sulfur RS •• H RS •• SR thiol (reduced) disulfide (oxidized) thiol-disulfide redox pair is important in biochemistry other oxidative processes place 1, 2, or 3 oxygen atoms on sulfur Dr. Wolf's CHM 201 & 202 15-84 8

Oxidation of thiols take place at sulfur RS •• H RS •• SR thiol disulfide RS •• OH O • • – + •• – O • • • • RS •• OH 2+ RS OH O • • • • •• – sulfenic acid sulfinic acid sulfonic acid Dr. Wolf's CHM 201 & 202 15-85 8

Example: sulfide-disulfide redox pair SH O HSCH2CH2CH(CH2)4COH O2, FeCl3 S O S a-Lipoic acid (78%) (CH2)4COH Dr. Wolf's CHM 201 & 202 15-86 9

Spectroscopic Analysis of Alcohols Dr. Wolf's CHM 201 & 202 15-87 1

Infrared Spectroscopy O—H stretching: 3200-3650 cm–1 (broad) C—O stretching: 1025-1200 cm–1 (broad) Dr. Wolf's CHM 201 & 202 15-88 6

Figure 15.4: Infrared Spectrum of Cyclohexanol C—H O—H C—O 2000 3500 3000 2500 1000 1500 500 Wave number, cm-1 Dr. Wolf's CHM 201 & 202 15-89 8

1H NMR chemical shift of O—H proton is variable; depends on temperature and concentration O—H proton can be identified by adding D2O; signal for O—H disappears (converted to O—D) H C O H d 3.3-4 ppm d 0.5-5 ppm Dr. Wolf's CHM 201 & 202 15-90 6

Figure 15.5 (page 607) CH2CH2OH Chemical shift (d, ppm) 1 15-91 1.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 Chemical shift (d, ppm) Dr. Wolf's CHM 201 & 202 15-91 1

13C NMR chemical shift of C—OH is d 60-75 ppm C—O is about 35-50 ppm less shielded than C—H CH3CH2CH2CH3 CH3CH2CH2CH2OH d 13 ppm d 61.4 ppm Dr. Wolf's CHM 201 & 202 15-92 6

UV-VIS Unless there are other chromophores in the molecule, alcohols are transparent above about 200 nm; lmax for methanol, for example, is 177 nm. Dr. Wolf's CHM 201 & 202 15-93 6

Mass Spectrometry of Alcohols molecular ion peak is usually small a peak corresponding to loss of H2O from the molecular ion (M - 18) is usually present peak corresponding to loss of an alkyl group to give an oxygen- stabilized carbocation is usually prominent Dr. Wolf's CHM 201 & 202 15-94 6

Mass Spectrometry of Alcohols molecular ion peak is usually small a peak corresponding to loss of H2O from the molecular ion (M - 18) is usually present peak corresponding to loss of an alkyl group to give an oxygen- stabilized carbocation is usually prominent CH2 R OH •• CH2 R OH •+ •• + R • CH2 OH •• Dr. Wolf's CHM 201 & 202 15-95 6

End of Chapter 15