1

Chapter 17

Alcohols and Phenols

Alcohols and Phenols

- alcohols

- compounds that have hydroxyl groups bonded to saturated, sp3-hybridized carbon atoms

- phenols

- compounds that have hydroxyl groups bonded to aromatic rings

- enols

- compounds that have a hydroxyl group bonded to a vinylic carbon

OH

OH

C COH

Naming Alcohols and Phenols

- classified as primary (1o), secondary (2o), or tertiary (3o)

- named as derivatives of the parent alkane

C

H

OHR

H

C

H

OHR

R

C

R

OHR

R

primary (1o) secondary (2o) tertiary (2o)

2

Rules for Alcohols1) Select longest carbon chain containing the hydroxyl group; derive the parent name -e with -ol

2) Number the alkane chain beginning at the end nearer the hydroxyl group

3) Number substituents according to position on the chain and list substituents in alphabetical order

Examples:

C

OH

CH3

CH2CH2CH3H3C

HO H

HO H

CH

CH3

CHCH3

OH

2-methyl-2-pentanol cis-1,4-cyclohexanediol 3-phenyl-2-butanol

Common Alcohols

CH2OHH2C CHCH2OH C

CH3

CH3

OHH3C

HOCH2 CH2OH HOCH2 CHCH2OH

OH

benzyl alcoholallyl alcohol

tert-butyl alcohol

ethylene glycolglycerol

Naming Phenols

- “phenol” is both the name of the hydroxy compound and family name for hydroxy-substituted aromatic compounds

OHH3C OH

O2N NO2

m-methylphenol 2,4-dinitrophenol

3

Properties of Alcohols and Phenols

- alcohols and phenols have geometry nearly the same as water

- R-O-H angle ~ 109o

- oxygen atom is sp3 hybridized

Physical Properties of Alcohols

- alcohols have much higher boiling points than hydrocarbons and alkyl halides

Compound Molecular Mass Boiling Point

1-propanol

butane

chloroethane

60 g/mol

58 g/mol

65 g/mol

97 oC

-0.5 oC

12.5 oC

Comparison of Boiling Points

4

- phenols have elevated boiling points relative to hydrocarbons

phenol: bp = 181.7oC toluene: bp = 110.6oC

OH CH3

Physical Properties of Phenols

Hydrogen Bonding by Alcohols and Phenols

Basicity and Acidity

- alcohols and phenols are both weakly basic and weakly acidic

- reversibly protonated by strong acids to yield oxonium ions, ROH2+

- dissociate slightly in dilute aqueous solution by donating a proton to water, generating H3O+ and alkoxide ion RO-, or a phenoxide ion, ArO-:

OHH

H X+ O

H

H HX

ORH O

HH+ R O O

H

H H+

5

Factors Affecting Basicity and AcidityAlcohols1) solvation and steric effects

- smaller substituents promote solvation of the alkoxide ion that results from dissociation

- the more easily the alkoxide ion is solvated, the more stable it is

- the more stable the alkoxide ion, the more acidic the parent alcohol

methoxide ion, CH3O-

(pKa = 15.5) t-butoxide ion, (CH3)3CO-

(pKa = 18.0)

OH3C OC

CH3

H3C

CH3

2) inductive effects

- electron-withdrawing substitutents stabilize an alkoxide ion by spreading the charge over a large volume, making the alcohol more acidic

(pKa = 5.4) (pKa = 18.0)

OC

CH3

H3C

CH3

OC

CF3

F3C

CF3

Generation of Alkoxides

- alcohols react with alkali metals and with strong bases to form alkoxides

C

CH3

CH3

OHH3C + 2 K C

CH3

CH3

OH3C K+ + H2

tert-butyl alcohol potassium tert-butoxide

6

CH3OH + NaH CH3O- Na+ + H2

methanol sodium methoxide

CH3CH2OH + NaNH2 CH3CH2O- Na+ + H2

sodium ethoxideethanol

OH + CH3MgBr O +MgBr + H2O

cyclohexanol bromomagnesiumcyclohexoxide

Examples

Phenols

- phenols are a million times more acidic than alcohols

- greater acidity is because the phenoxide ion is resonance-stabilized

- delocalization of the negative charge over the ortho and para positions of the aromatic ring results in increased stability of the phenoxide anion

- phenols with an electron-withdrawing substituent are generally more acidic since the substitutents delocalize the negative charge

- phenols with an electron-donating substituent are generally less acidic since the substitutents destabilize the phenoxide ion

O O

EWG EDG

Resonance Stabilization of thePhenoxide Ion

7

Preparation of AlcoholsReview

1) hydration of alkenes by way of hydroboration/oxidation and oxymercuration/reduction

CH3

H

BH2

H3C

H

H

OH

H3C

H

OH

H

H3C

HgOAc

OH

H3C

H2O2

-OH

BH3

THF

Hg(OAc)2

H2O

NaBH4

trans-2-methylcyclohexanol

1-methylcyclohexanol

1-methyl-cyclohexene

2) hydroxylation of an alkene with OsO4 followed by reduction with NaHSO3

CH3

O

O

H3C

H

OsO

O

OH

OH

H3C

H

CH3

H

O

CH3

OH

HO

H

OsO4

pyridine

Hg(OAc)2

H2O

NaHSO3

H3O+1-methyl-cyclohexene

1-methyl-trans-1,2-cyclohexanediol

1-methyl-1,2-epoxy-cyclohexane

1-methyl-cis-1,2-cyclohexanediol

8

Reduction of Carbonyl Compounds

C

OC

OH[H]

Reduction of Aldehydes and Ketones

- aldehydes are reduced to primary alcohols and ketones are reduced to secondary alcohols

CR H

O

CR R'

O

CR H

OH

H

CR H

OH

R'

aldehyde primary alcohol

ketone secondary alcohol

[H]

[H]

Reagents for Aldehyde and Ketone Reduction

- sodium borohydride NaBH4 is usually chosen because of its safety and ease of handling

C H

O

CH3CH2CH2 C H

OH

H3CH2CH2C

H

1. NaBH4, EtOH

2. H3O+

butanal1-butanol (85%)

COHH

C

O1. NaBH4, EtOH

2. H3O+

dicyclohexyl ketone dicyclohexylmethanol (88%)

O

COHH

1. LiAlH4, ether

2. H3O+

2-cyclohexanone 2-cyclohexenol

9

Reduction of Carboxylic Acids and Esters

- carboxylic acids and esters are reduced to give primary alcohols

CR OH

O

CR OR'

OC

R H

OH

H

primary alcohol

[H]or

- NaBH4 reduces esters slowly and does not reduce carboxylic acids; LiAlH4 reduces all carbonyl groups

CH3(CH2)7CH CH(CH2)7 COH

O1. LiAlH4, ether

2. H3O+CH3(CH2)7CH CH(CH2)7CH2OH

9-octadecenoic acid 9-octadecen-1-ol (87%)

CH3CH2CH CH COCH3

OCH3CH2CH CHCH2OH

1. LiAlH4, ether

2. H3O+

methyl-2-pentenoate 2-penten-1-ol (91%)

Examples

Mechanism

- can be regarded to involve attack of a hydride ion to the positively polarized, electrophilic carbon atom of the carbonyl group

- protonation by acid gives the alcohol

C

O HC

H

O

CH

OH

alcoholalkoxide

intermediate

carbonylcompound

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Reactions with Grignard Reagents

R X R MgX

C

OC

R

OH1. RMgX, ether

2. H3O+

Grignard reagent

R = 1o, 2o, or 3o alkyl, aryl, vinylic

X = Cl, Br, or I

HOMgX+

Formaldehyde Reaction

Aldehyde Reaction

MgBrC

H H

O CH2OH1. Mix

2. H3O++

cyclohexylmagnesiumbromide

formaldehyde cyclohexylmethanol(65%)

H3C C

CH3

CH2 CH

O

H

MgBrH3C C

CH3

CH2 C

OH

H H

+1. ether solvent

2. H3O+

3-methylbutanalphenylmagnesium

bromide3-methyl-1-phenyl-1-

butanol (73%)

Ester Reaction

Ketone Reaction

O OH

CH2CH31. CH3CH2MgBr, ether

2. H3O+

cyclohexanone 1-ethylcyclohexanol(89%)

C

O

OCH2CH3CH3CH2CH2CH21. CH3CH2MgBr, ether

2. H3O+C

OH

CH3CH3CH2CH2CH2

CH3

+ CH3CH2OH

ethylpentanoate2-methyl-2-hexanol (85%)

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Carboxylic Acid Reaction

CR' OH

O

CR' O

ORMgBr + RH +

+MgBr

carboxylic acid carboxylic acid salt

- carboxylic acids do not give addition products with Grignard reagents because the acidic carboxyl hydrogen reacts with the basic Grignard reagent to yield a hydrogen carbon (RH) and magnesium salt of the acid

Limitations of Grignard Reagents

- Grignard reagent cannot be prepared from an organohalide if there are other reactive functional groups in the same molecule

- this limits the structures of the products

- Grignard cannot be made where FG =

moleculeBr FG

= -OH, -NH, -SH, -COOH

=CH

OCR

O

CNR2

O

C N NO2 SO2R

, ,

, ,

protonateGrignard

adds toGrignard

Mechanism

C

O RC

R

O

CR

OHH3O+

carbonylcompound alkoxide

intermediatealcohol

- Grignard reagent acts as a nucleophilic carbon anion, or carbanion; the addition of the Grignard is analogous to the addition of a hydride

12

Reactions of Alcohols

C

OH

O-H reactionsC-O reactions

Dehydration of Alcohols (C-O bond)

- a number of methods have been developed:

1) acid-catalyzed dehydration (mild)

2) acid-catalyzed dehydration (harsh)

3) phosphorus oxychloride

C COHH

C C + H2O

Acid-catalyzed dehydration

- E1 mechanism that involves three steps

OHH3CCH3

H3O+, THF

50oC

1-methylcyclohexanol 1-methylcyclohexene (91%)

C

CH3

OH

CH2CH3H3C CHCH3CH3

CH3

CH2CH3CH3

CH3H3O+, THF

25oC

2-methyl-2-butanol

2-methyl-2-butene(trisubstituted)

2-methyl-1-butene(disubstituted)

+

- acid-catalyzed reaction follows Zaitsev’s rule, giving the more highly substituted alkene as major product

13

Reactivity

C

OH

H

HRC

OH

RHRC

OH

RRR > >

reactivity

- tertiary substrates always react fastest in E1 reactions because they lead to highly stabilize tertiary carbocation intermediates

Mechanism

Phosphorus Oxychloride

- E2 mechanism, -OPOCl2 is excellent leaving group

- pyridine serves as both solvent and base

OH

CH3

H

CH3POCl3

pyridine, OoC

1-methylcyclohexanol 1-methylcyclohexene (96%)

14

Mechanism

Conversion of Alcohols into Alkyl Halides(C-O Bond)

- tertiary alcohols are converted using HCl or HBr at OoC through an SN1 mechanism

- secondary and primary alcohols are resistant to acid and are converted using either SOCl2 or PBr3 through an SN2 mechanism

RCH2OHSOCl2

RCH2Cl + SO2 + HCl

RCH2OHPBr3

RCH2Br + HOPBr2

Mechanism

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Conversion of Alcohols into Tosylates (O-H Bond)

- reaction produces alkyl tosylates which are synthetically useful since they behave like alkyl halides

- in contrast to alkyl halides, the products undergo only one Walden inversion to form a product

- the product is therefore of opposite stereochemistry relative to the reactants

OR H

CH3

SOO

Clpyridine+

CH3

SOO

OR

alcoholp-toluenesulfonyl

chloride

tosylate

+ pyridine·HCl

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Oxidation of Alcohols

CH

OH

C

Ooxidize

reduce

Primary Alcohol

Secondary Alcohol

Tertiary Alcohol

CR H

OH

H

CR H

OC

R O

O

H[O] [O]

CR H

OH

R'C

R R'

O[O]

CR R''

OH

R'

[O]NO REACTION

ketone

aldehyde carboxylic acid

Reagents

- large number of reagents can be used:

KMnO4, CrO3, Na2CrO7

- depends on factors such as cost, convenience, reaction yield, and alcohol sensitivity

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Preparation of an Aldehyde from a Primary Alcoholon Laboratory Scale

- use of pyridinium chlorochromate (PCC)

- most other oxidizing agents oxidize primary alcohols to carboxylic acids

CH2OH C

O

H

PCC

CH2Cl2

N H CrO3Cl-PCC =

CH3(CH2)8CH2OHCrO3

H3O+, acetoneC OH

O

CH3(CH2)8

citronellol citronellal (82%)

1-decanol decanoic acid(93%)

Secondary Alcohols to Give Ketones

- large scale and inexpensive, use Na2Cr2O7:

- for sensitive alcohols, use PCC:

C OH

CH3

CH3

H3C C O

CH3

CH3

H3CNa2Cr2O7

H2O, CH3CO2H,heat

4-tert-butylcyclo-hexanol

4-tert-butylcyclo-hexanone (91%)

OHCH3

CH3

O

OCH3

CH3

O

PCC

CH2Cl2,25oC

testosterone 4-androstene-3,17-dione (82%)

Mechanism

- pathway closely related to E2 reaction

- reaction produces a C-O bond (compare to C-C bond)

CH

OH

Cr

O

O O

CH

OH Cr

O

O

OBase

CH

OH Cr

O

O

O

Base

E2 C

O

carbonylcompound

chromateintermediate

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Protection of Alcohols

- it is often necessary to circumvent synthetic incompatibilities using protecting groups

1) introduce the protecting group

2) carry out the desired reaction

3) remove the protecting group

HO CH2CH2CH2 Br HO CH2CH2CH2 MgBrMg

Etherx

- common protecting group for alcohols is trimethylsilyl (TMS) ether

Trimethylsilyl (TMS) ether

Si

CH3

CH3

ClH3CROH + SiCH3

CH3

CH3OR + (CH3CH2)3NH+ Cl-(CH3CH2)3N

alcoholchlorotrimethylsilane a trimethylsilyl ether

OH OSi(CH3)3+ (CH3)3SiCl

(CH3CH2)3N

Example

cyclohexanol cyclohexyl trimethylsilylether (94%)

19

Removal of the Protecting Group

OSi

CH3

CH3CH3

OH

cyclohexanolcyclohexyl TMS ether

H3O+

+ (CH3)3SiOH

- protecting group can be removed using acid or with fluoride ion

Preparation of Phenols

Cl OH1. NaOH, H2O, 340oC, 2500 psi

2. H3O+

Dow Process

Alternative Synthesis

C

H

CH3H3C C

OOH

CH3H3C OHO2 H3O+

heat C CH3H3C

O

+

cumene cumene hydroperoxidephenol

acetone

Mechanism

20

Hemiacetal

Acetal

COR'

OH

COR'

OR'

C

O+ 2R’OH

Acid

catalyst

Laboratory Preparation

- owing to the harsh reaction conditions, the reaction is limited to alkyl-substituted phenols

SO3H

CH3CH3

OH

CH3

SO3

H2SO4

1. NaOH, 300oC

2. H3O+

toluene p-toluenesulfonicacid

p-methylphenol(72%)

Uses of PhenolsOH

Cl

Cl

ClCl

Cl

OH

Cl

Cl

ClCl

Cl

Cl

Cl

OH3

CH3

OH

C(CH3)3(H3C)3C

pentachlorophenol(wood preservative)

hexachlorophene(antiseptic)

butylated hydroxytoluene(food preservative)

Cl

Cl

OCH2COOH

2,4-dichlorophenoxyacetic acid(herbicide)

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Reactions of Phenols

1) Electrophilic Aromatic Substitution

- -OH group is strongly activating, ortho- and para-directing

- phenol is therefore highly reactive for electrophilic halogenation, nitration, sulfonation, Friedel-Crafts reactions

ortho- para-

HO

Y

HO Y

2) Oxidation of Phenols

- oxidation yields 2,5-cyclohexadiene-1,4-dione or quinone

- reactions can be accomplished with Na2Cr2O7 and (KSO3)2NO

(KSO3)2NO

H2O

O

O

OH

phenol

benzoquinone (70%)

Reversible Oxidation

- oxidation-reduction (redox) properties of quinones makes quinones a valuable class of compounds

O

O

OH

OH

SnCl2, H2O

Fremy’s salt

benzoquinone hydroquinone

22

- redox behavior is found in biology, where compounds known as ubiquinones act as biochemical oxidizing agents to mediate electron-transfer processes in the mitochondria

O

O

CH3H3CO

H3CO (CH2 CH CCH2)nH

CH3

Ubiquinones

O

O

CH3H3CO

H3CO R

OH

OH

CH3H3CO

H3CO R

O

O

CH3H3CO

H3CO R

OH

OH

CH3H3CO

H3CO R

+ NAD+NADH + H+ +

+ H2O+ ½O2

NADH + ½O2 + H+ NAD+ + H2O

Energy Production in the Mitochondria

Spectroscopy of Alcohols and Phenols

Infrared Spectroscopy

- alcohols characteristic O-H stretching absorption at 3300 - 3600 cm-1

- depends upon the extent of hydrogen bonding

- unassociated: sharp absorption at 3600 cm-1

- hydrogen bonds: broad absorption at 3300 - 3400 cm-1

- strong C-O stretching band near 1050 cm-1

- phenols broad absorption at 3500 cm-1 plus aromatic bands at 1500 and 1600 cm-1

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Infrared Spectrum of Cyclohexanol

Infrared Spectrum of Phenol

NMR Spectroscopy

- 13C NMR spectra:

- 1H NMR spectra:

- hydrogens on oxygen-bearing carbons are deshielded (3.5. - 4.5 δ)

- hydrogen atom of -OH undergoes exchange:

(can exchange hydrogenfor deuterium)

OH 69.5 δδδδ

35.5 δδδδ24.4 δδδδ

25.9 δδδδ

C O

H

H C O

H

H'H’A

C O H C O DD2O

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1H NMR Spectrum of 1-Propanol

Mass Spectrometry

- alcohols fragment by two pathways: alpha cleavage and dehydration

- both fragments are apparent in mass spectra

C CH2R

OH

R

R

C

OH

R

R

+

+ CH2R.

+ .

C COHH

C C

+ . + .

H2O +

Mass Spectrum of 1-Butanol