Chapter 17: Alcohols and Phenols

C O O H H

sp3

alcohol pKa~ 16-18

phenol (aromatic alcohol) pKa~ 10

Alcohols contain an OH group connected to a saturated carbon (sp3) Phenols contain an OH group connected to a carbon of a benzene ring

O H C C

H C C

O

chemistry dominated by the keto form
76

enol

keto

H

O

H

R

O

H

R

O

R

R

O

O

R'

water

alcohol
R S H

ether
R S R

peroxide
R S S R'

thiols

thioether

disulfides

Alcohols are classified as primary (1°), secondary (2°) or tertiary (3°), which refers to the carbon bearing the hydroxy group

methanol
H C O H H H

primary
R C O H H H

secondary
R C O R H H

tertiary
R C O R R H
77

1° carbon

2° carbon

3° carbon

39

For phenols. 78 OH OH OH NO2 NO2 2-methyl-2-pentanol 3-phenyl-2-butanol 3. 4.17. replace the -ane suffix for alkanes with an -ol for alcohols CH 3CH 2CH 2CH 3 CH 3CH 2CH 2CH 2OH OH butane 1-butanol 2-butanol 2.2-ethanediol) glycerol (1. The carbon bearing the -OH group gets number 1. follow benzene nomenclature and use phenol as the parent name. Number the carbon chain so that the hydroxyl group gets the lowest number 3.4-dinitrophenol Many alcohols are named using non-systematic nomenclature OH OH H3C C OH H3C H3C OH HO OH HO OH benzyl alcohol (phenylmethanol) allyl alcohol (2-propen-1-ol) tert-butyl alcohol (2-methyl-2-propanol) ethylene glycol (1. Number the substituents and write the name listing the substituents in alphabetical order.3-propanetriol) 79 40 .2. In general. alcohols are named in the same manner as alkanes.1: Nomenclature: 1.

2: Properties of alcohols and phenols: Hydrogen bonding: The structure around the oxygen atom of an alcohol or phenol is similar to that in water and is sp3 hybridized Alcohols and phenols have much higher boiling points than similar alkanes and alkyl halides H2 O MW=18 bp= 100° C C6H6 MW=78 bp= 80° C CH3CH2CH2CH3 MW=58 bp= -0° C C6H6OH MW=94 bp= 182° C CH3CH2CH2CH2Cl MW=92. which is also involved in a polar covalent bond (δ-) O H !. with the lone pair of a heteroatom (usually O or N). 81 which requires additional energy 41 .!+ N H C O !+ !C O C O H H O H O H O H H H O H H O H H H R O! ! ! H H O! R ! R O! H ! H O! R ! R O! ! H O! R H O H H H O H Hydrogen-bonds are broken when the alcohol reaches its bp.5 bp= 77° C C6H6CH3 MW=92 bp= 110° C CH3CH2CH2OH MW=74 bp= 116° C C6H6CH2OH MW=108 bp= 203° C 80 Alcohols and phenols. can form hydrogen bonds: non covalent interaction between a hydrogen atom (δ+) involved in a polar covalent bond.17.!+ O H H O H O H O H H O H H O H N H !. like water.

5 CH3CH2CH2CH2OH MW = 74 bp = 116° C pKa ~ 16 The steric environment around the oxygen atom can influence the physical properties of an alcohol 82 Solvation: upon acid dissociation the alkoxide ion is stabilized by solvation through hydrogen bonding between water and the negatively charge oxygen. The steric environment around the negatively charge oxygen influences the solvation effect R O H + H O H H R O + H O H H O H O H H H H O H O H H H H O H H C H C O H C C H H H H H H O H O H H H C O H H H O Acidity: methanol > 1° alcohol > 2° alcohol > 3° alcohol Reflects the ability water to stabilized the resulting alkoxide 83 though solvation 42 . alcohols are weak Brønsted bases and weak Brønsted acids. The nature of the R group can significantly influence the basicity or acidity H R O H + H X R O H + :X- oxonium ion R O H + H O H H R O + H O H alkoxide ion CH3CH2CH(OH)CH3 MW = 74 bp = 99° C pKa ~ 17 (CH3)C-OH MW = 74 bp = 82° C pKa ~ 18 CH3OH MW = 32 bp= 65° C pKa ~ 15.3: Properties of alcohols and phenols: acidity and basicity: Like water.17.

65 10.35 -NO2 7.15 10.16 84 Phenols are much more acidic than aliphatic alcohols: a benzene ring is generally considered electron withdrawing (inductive effect) the benzene ring stabilizes the negative charge of the phenoxide ion through resonance (Fig.85 8.28 9.4 F3C F3C F3C F2CHCH2OH 13.16 -OCH3 10.4 C !+ O Electron-withdrawing groups make an alcohol a stronger acid by stabilizing the conjugate base (alkoxide) -Br 9.38 X OH X OH ~ pKa X= -Cl -NO2 -OCH3 -CH3 9.3.21 10.17 8. 17.Electronic factors that influence acidity: inductive and resonance effect CH3CH2OH pKa ~ 16.9 -Cl 9. 595) 85 43 .46 X OH pKa ~ X= -H 9. p.15 -CH3 10.38 7.21 -NH2 10.3 F3CCH2OH 12.4 (F3C)3CCH2OH 5.0 FCH2 CH2 OH 14.

8) 87 44 .4: Preparation of alcohols: H3O+ OH Markovnikov addition H a) B2H6. 7.4) Hydroboration of alkenes (Ch.4) Oxymercuration of alkenes (Ch.5) Di-hydroxylation of alkenes (Ch. H2O2 BR2 H OH Anti-Markovnikov Overall syn addition of H–OH across the π-bond Markovnikov a) Hg(OAc)2. 7.Electron-withdrawing substituents make a phenol more acidic by stabilizing the phenoxide ion through delocalization of the negative charge and through inductive effects Electron-donating substituents make a phenol less acidic by destabilizing the phenoxide ion (resonance effect) The location of the substituent relative to the phenol is important 86 17. H2O b) NaBH4 OH OH HgOAc a) OsO4 b) NaHSO3 O O Os O O OH OH Syn addition of -OH groups Hydration of alkenes (Ch. 7. 7. THF b) NaOH.

M O H: C EtOH or ether O C H M H3O+ OH C H 89 45 . ether reduces aldehydes.17.5: Alcohols from reduction of carbonyl compounds Figure 10.5 (Chapter 10. carboxylic acids. ethanol reduces aldehydes to 1° alcohols and ketones to 2° alcohols lithium aluminum hydride (LAH): LiAlH4.5: Alcohols from reduction of carbonyl compounds add the equivalent of H2 across the π-bond of the carbonyl to give an alcohol O R C R' [H] R R' O C H H aldehyde (R or R´= H) → 1° alcohol ketone (R and R´≠ H) → 2° alcohol [H]: sodium borohydride: NaBH4.10) Increasing oxidation state C C C C C C O C OH C O C OR CO2 Cl Cl C Cl C Cl Cl C Cl Cl Cl C Cl Cl C NH2 C NH C N 88 17. and esters to 1° alcohols and ketones to 2° alcohols In general. NaBH4 and LiAlH4 will not reduce C=C.

organomagnesium R-X + Mg(0) ether or THF R-Mg(II)-X X= Cl. ether O Br Mg0.6: Alcohols from reaction of carbonyl compounds with Grignard reagents Alkyl halides will react with some metals (M0) in ether or THF to form organometallic reagents Grignard reagent. Br. carbonyl = H2C=O → 1° alcohol = aldehyde → 2° alcohol = ketone → 3° alcohol MgBr 1) H2C=O 2) H3O+ OH Br Mg0. 3°-alkyl. 2°-. aryl or vinyl !. ether MgBr 1) 2) H3O+ H OH Mg0.!+ _ C C MgX Carbanions: nucleophile reacts with electrophile R-MgX ≡ R: – 90 Grignard reagents react with aldehydes or ketones to give alcohols MgX O R: C ether O C R MgX H3O+ OH C R O C !!+ If. or I R can be a variety of groups: 1°-. ether CH3CH2Br CH3CH2MgBr 1) 2) H3O+ O OH 91 46 .17.

CONHR (amides) Reactive functional groups: aldehydes. -OH. -NO2. NH2. esters. nitriles 93 47 .Grignard reagents react with esters to give 3° alcohols O O H3C _ CH2CH3 1) 2 H3CMgBr 2) H3O+ HO CH3 CH3 H3CMgBr the H3O+ _ O CH3 OCH2CH3 O CH3 MgX Some functional groups are incompatible with Grignard reagents Grignard reagents are very strong bases as well as highly reactive nucleophiles O R O H _ H3C MgBr R O _ O MgX + CH4 H3O+ R O OH Carboxylic acids are simply deprotonated by Grignard reagents and do not give addition products 92 Grignard reagents will deprotonate alcohols Mg0 HO Br HO _ MgBr _ O BrMg H H3O+ HO H Other incompatible groups: -CO2H. -SO2R. ketones. halides. amides. -SH.

7 Some reactions of alcohols A.17. pyridine CH3 H 95 48 . THF H3C C C H3C H H3C CH3 H2C C CH2CH3 . pyridine H H CH3 CH3 H OH CH3 POCl3.H2O 94 Dehydration to alkenes with POCl3 E2 mechanism. requires a base (pyridine) H OH POCl3. Reactions involving the C-O bond Dehydration to alkenes: E1 mechanism (reactivity: 3° > 2° >> 1°) requires strong acid catalyst (H2SO4) water is a much better leaving group than HOusually follows Zaitzev’s rule OH H3C C CH2CH3 CH3 H2SO4 H2O.requires an anti-periplanar conformation between leaving group and the hydrogen that is being lost mild conditions.

Substitution reaction of alcohols with HX R-OH + HX R-X + H2 O Works better with more substituted alcohols H H Methyl H H R H C OH << R C OH H Primary (1°) < R C OH R < R C OH R Secondary (2°) Tertiary (3°) increasing reactivity SN1 mechanism involving a carbocation intermediate: rearrangements. Preparation of alkyl bromides by the treatment of alcohols with phosphorous tribromide (PBr3) R-OH + PBr3 R-Br + P(OH)3 SN2 mechanism: works best with 1° and 2° alcohols. stereochemistry: inversion 97 49 .7) 1. Prepartion of alkyl chlorides by the treatment of alcohols with thionyl chloride (SOCl2) R-OH + SOCl2 R-Cl + SO2 + HCl 3. but not with 3° alcohols.Conversion of an alcohol to an alkyl halide (R-OH → R-X) (Chapter 10. stereochemistry (racemization) 96 2.

p-TosCl) in pyridine gives a tosylates O Cl S O C OH + pyridine O C O S O CH3 tosylate CH3 98 Formation of the tosylate does not involve the C–O bond so the stereochemistry of the carbon attached to the alcohol is not affected Tosylates are good leaving groups and their reactivity is similar to alkyl halides PBr3 SN2 OH Br CN SN2 CN (R)-2-Bromohexane (S)-2-methylhexanenitrile (S)-2-hexanol TosCl OTos CN SN2 CN (S)-2-hexyl-p-toluene sulfonate (R)-2-methylhexanenitrile 99 50 .O SOCl2 Cl S O SN2 + Cl Cl OH (R)-2-Chlorohexane (S)-2-hexanol PBr3 O PBr2 SN2 + Br Br (R)-2-Bromohexane B. Reaction involving the O-H bond Conversion of an alcohol to a tosylate (ROTos) Reaction of an alcohol with with p-toluenesulfonyl chloride (tosyl chloride.

and 2° alcohols CrO3Cl to ketones. Solvent: CH2Cl2 N H chromic acid (Jones reagent): CrO3 (or Na2Cr2O7) + H2O + H2SO4 → H2 CrO4 2 H2CrO4 → H2Cr2 O7 + H2O oxidizes 1° alcohols to carboxylic acids.oxidizes 1° alcohols to aldehydes.17.8 Oxidation of Alcohols 100 Oxidation of primary alcohols with Cr(VI) exact structure of the chromium reagent depends on solvent and pH O R2CH-OH Cr(VI)O3 R R C H O Cr O O E2 R R O + Cr(IV) Cr(III) Base: chromate ester pyridinium chlorochromate (PCC). Solvent: H3O+ and acetone 101 51 . and 2° alcohols to ketones.

R O OH PCC CHO H2Cr2O7 OH CH2Cl2 H3O+. acetone R O H2O H hydration HO OH R H H2Cr2O7 acetone H3O+. acetone CO2H Aldehyde 1° alcohol Carboxylic Acid 102 17. The protecting group is then removed giving the original functional group (deprotection). which may prevent a desired reaction. Protecting group: Temporarily convert a functional group that is incompatible with a set of reaction conditions into a new functional group (with the protecting group) that is compatible with the reaction. 103 52 .RCH2-OH 1° alcohol H2Cr2O7 H3O+.9 Protection of Alcohols Hydroxyl groups are weak protic acids and can transfer a proton to a basic reagent.

7) phenols are highly activated toward electrophilic aromatic substitution and are o.p-directors 105 53 .10 Preparation of phenols alkali fusion reaction (Chapter 16.5-16. THF CHO OH H3C then H3O+ H3C O H3O+ OH HO H3C H3C Si O _ MgBr Si CH3 CH3 remove protecting group 104 17.2) Chapter 24.11 Reactions of Phenols: electrophilic aromatic substitution (Chapter 16.8: anilines (Ar-NH2) → phenols (Ar-OH) 17.Trimethylsilyl ethers as a protecting group for alcohols Mg0 HO Br HO _ MgBr _ O BrMg H H3O+ HO H (H3C)3SiCl (H3CH2C)3N protect alcohol H3C H3C Si O Br CH3 Mg0.

-H+ + e-.12 Spectroscopy of Alcohols and Phenols: Infrared (IR): Characteristic O–H stretching absorption at 3300 to 3600 cm−1 Sharp absorption near 3600 cm-1 except if H-bonded: then broad absorption 3300 to 3400 cm−1 range Strong C–O stretching absorption near 1050 cm−1 O H 107 54 .e-. -H+ 3 + e-. +H+ O H3C CH3 O H 3 106 17.e-. +H+ H3CO H3CO .e-. H2O (Fermy's salt) OH hydroquinone (reduced) . +H+ OH semiquinone .e-. +H+ O O quinone (oxidized) Ubiquinones (n= 1-10): Coenzyme Q OH H3CO H3CO OH CH3 H O O CH3 H OH . -H+ + e-.e-.Oxidation of phenols to quinones (please read) phenols can be oxidized by strong oxidants to give hydroquinones and quinones OH OH O (KSO3)2NO. -H+ + e-. +H+ H3CO H3CO O CH3 H n hydroquinone (reduced) n n semiquinone quinone (oxidized α−tocopherol (vitamin E) CH3 HO H3C CH3 O H CH3 . -H+ + e-.

1H NMR: protons attached to the carbon bearing the hydroxyl group are deshielded by the electron-withdrawing nature of the oxygen. δ 3.5 to 4.8. It is not uncommon for this proton not to be observed.0 . s. d. 6H != 3.5 ppm).0.5. 1H != 1. 109 55 .0 H H H H C C C OH H H H OH H H H C C C H H H H != 3. This proton usually appears as a broad singlet.64. 1H 108 Usually no spin-spin coupling between the O–H proton and neighboring protons on carbon due to exchange reaction C O H H H A C O H H + H A The chemical shift of the -OH proton occurs over a large range (2. br.

4 14.0 128.6 129.5 C8H10O 3H 2H 2H 1H 2H 13C: 153.8 32. The chemical shift range is 50-80 ppm OH H H H C C C H H H H != 63.2 DMSO-d6 (solvent) 110 C9H12O 3H 2H 5H 1H 1H 13C: 138.2 115.0 126.13C NMR: The oxygen of an alcohol will deshield the carbon it is attached to.8 7.7 132.6 111 56 .1 79.0 31.5 != 25 HO OH 145.1 129.

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