Chemistry 391 10/30/02

Carbonyl Chemistry VCarbonyl Chemistry V

++CCOO--

CCOO

KetoKeto--enol enol Tautomerism Tautomerism

CH 3C CH 3

OCH 3C

OH

CH 2

E nolK etone

OO••••

CR'CR'

••••

RR22CC

HHOOHH

HH

••••••••

OO

HH

HH ••••••••

Chemistry 391 10/30/02

Acid CatalyzedAcid Catalyzed αα HalogenationHalogenationOO

RR22CCR'CCR'

OO

RR22CCR'CCR'

• X2 can be Cl2, Br2, or I2.

• Substitution is specific for replacement of α hydrogen.

• Not a free-radical reaction.

HH

++ XX22HH++

++ HHXX

XX

Chemistry 391 10/30/02

Mechanism of Mechanism of αα HalogenationHalogenation

Two steps:Two steps:

• first step is slow conversion of aldehyde or ketone to the corresponding enol; is rate-determining

• second step is the fast reaction of the enolwith halogen; far faster than the first stage

Mechanism of Mechanism of αα HalogenationHalogenation

RCHRCH22CR'CR'

OO

slowslow RCHRCH CR'CR'

OHOH

enolenol

HH++ XX22

fastfast RCHCR'RCHCR'

OO

XX

• Enol is the key intermediate

Chemistry 391 10/30/02

Acid catalyzed aAcid catalyzed a--HalogenationHalogenation

OH

vs.

OH

CH3

OI

CH3

OI2

HI, H2O

Chemistry 391 10/30/02

BaseBase catalyzedcatalyzed αα--HalogenationHalogenation• Base-promoted α-halogenation

Step 1: formation of an enolate anion

C

OH

HH

-OH CH2

O

CH2

O

+ H2O

Chemistry 391 10/30/02

Base catalyzedBase catalyzed αα--HalogenationHalogenation

• Base-promoted α-halogenationStep 2: nucleophilic attack of the enolate anion on halogen

CH2

O

Br Br CH2 Br

O

Br-

Chemistry 391 10/30/02

αα--HalogenationHalogenation•• So…there are So…there are majormajor differences between aciddifferences between acid--

catalyzed and basecatalyzed and base--promoted promoted αα--halogenationhalogenation

1. Acid catalysis gives the most substituted product2. The rate of acid-catalyzed introduction of a second

halogen is slower than the first– introduction of the electronegative halogen on the α-carbon

decreases the basicity of the carbonyl oxygen toward protonation

Chemistry 391 10/30/02

αα--HalogenationHalogenation• In base catalyzed α-halogenation, each each

successivesuccessive halogenationhalogenation is more rapid than is more rapid than the previous one the previous one – the introduction of the electronegative halogen

on the α-carbon increases the acidity of the remaining α-hydrogens and, thus, each successive α-hydrogen is removed more rapidly than the previous one

Chemistry 391 10/30/02

Relative Rates RuleRelative Rates Rule

CH3

O

1 + 1 Cl2CH2Cl

O

OH -

SLOW

FASTER

CHCl2

O

FASTER STILL

CCl3

O

??

Chemistry 391 10/30/02

TheThe HaloformHaloform ReactionReaction

• Under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon bond cleavage.

• This is called the haloform reaction because chloroform, bromoform, or iodoform is one of the products.

Chemistry 391 10/30/02

HaloformHaloform ReactionReaction

• Iodoform Reaction• A qualitative test for methyl ketones• A decent way to synthesize carboxylic acids

R C

O

CH3

3I2

NaOHR C

O

CII

I

HO-

R C

O

O- + HCI3

Iodoform

First stage is substitution of all available First stage is substitution of all available ααhydrogens hydrogens by halogenby halogen

RCCHRCCH33

OO

RCCRCCXX33

OO

XX22, HO, HO– XX22, HO, HO–– –

RCCHRCCH22XX

OO

RCCHRCCHXX22

OOXX22, HO, HO––

Formation of theFormation of the trihalomethyltrihalomethyl ketone is ketone is followed by its hydroxidefollowed by its hydroxide--induced cleavageinduced cleavage

HOHO ••••––

••••••••

RCRC

OO ••••••••

CCXX33++

•••• ––

RCRC

OO ••••

HOHO ••••••••

••••

CCXX33

––•••• CCXX33

••••

RCRC

OO ••••

OHOH••••

••••++– +–

••••

••••

RCRC

OO ••••

OO••••

••••+ HCHCXX33

ExampleExample

(CH(CH33))33CCCCCCHH33

OO

BrBr22,, NaOHNaOH, H, H22OO

CCHBrHBr33++(CH(CH33))33CCONaCCONa

OO

HH++

(CH(CH33))33CCOHCCOH

OO

Chemistry 391 10/30/02

HaloformHaloform ReactionReaction• Summary of Iodoform Reaction

• A qualitative test for methyl ketones• A decent way to synthesize carboxylic acids

R C

O

CH3

3I2

NaOHR C

O

CII

I

HO-

R C

O

O- + HCI3

Iodoform

Chemistry 391 10/30/02

Carboxylic AcidsCarboxylic Acids

R CO

OHC

O

O-R + H+

R CO-

OChapter 17

Chemistry 391 10/30/02

Nomenclature Nomenclature -- IUPACIUPAC• IUPAC names: drop the -e from the parent

alkane and add the suffix -oic acid• If the compound contains a carbon-carbon

double bond, change the infix -an- to -en-

Propenoic acid (Acrylic acid)

trans-3-Phenylpropenoic acid

(Cinnamic acid)

trans-2-Butenoic acid

(Crotonic acid)

CCO2 H

CH

H3 C H

CH2 =CHCO 2 H CCO2 H

CH

C6 H5 H

Chemistry 391 10/30/02

NomenclatureNomenclature--CommonCommon

• When common names are used, the letters α, β, γ, δ, etc. are often used to locate substituents

Alanine)(α-Aminopropionic acid;(γ-Hydroxybutyric acid)2-Aminopropanoic acid4-Hydroxybutanoic acid

4 3 2 15

δ γ β αO

HOCH2 CH2 CH2 CO2 H

C-C-C-C-C-OH

CH3 CHCO2 HNH2

Chemistry 391 10/30/02

Naming the SaltsNaming the Salts

• To name the salt of the carboxylic acid, name the cation followed by the name of the anion (two words).

• The anion is named by removing -oic acid and adding ate

Benzoic acid Benzoic acid Sodium benzoateSodium benzoate

Butyric acidButyric acid Ammonium butyrateAmmonium butyrate

Boiling PointsBoiling Points

• Intermolecular forces, especially hydrogen bonding, are stronger in carboxylic acids than in other compounds of similar shape and molecular weight

bpbp (1(1 atmatm)) 31°C31°C 80°C80°C 99°C99°C

OH OO

OH141°C141°C

Chemistry 391 10/30/02

Physical PropertiesPhysical Properties• In the liquid and solid states, carboxylic

acids are associated by hydrogen bonding into dimeric structures

δ- δ+

δ-δ+

CO H O

COHO

CH3H3C

Chemistry 391 10/30/02

Acidity Acidity •• Carboxylic acids are weak acidsCarboxylic acids are weak acids

– The pKa of typical aliphatic and aromatic carboxylic acids falls within the range 4 to 5

R CO

OHC

O

O-R + H+

R CO-

O

•The greater acidity of carboxylic acids relative to alcohols, both of which have oxyanions conjugate bases is because:

•the carboxylate anion is stabilized by resonance

Chemistry 391 10/30/02

Infrared Spectrum of 4Infrared Spectrum of 4--PhenylbutanoicPhenylbutanoic acidacid

2000200035003500 30003000 25002500 1000100015001500 500500Wave number, cmWave number, cm--11

C=O

O—H and C—H stretch

monosubstitutedbenzene

C6H5CH2CH2CH2CO2H

11H NMR of Carboxylic acidsH NMR of Carboxylic acids

The acidic proton in the HOThe acidic proton in the HO-- croup of a croup of a carboxylic acid is normally the least carboxylic acid is normally the least shielded of all protons in ashielded of all protons in a 11HH nmr nmr spectrum: (d 10spectrum: (d 10--12 12 ppmppm; broad)…it ; broad)…it moves and it is subject to exchangemoves and it is subject to exchange

Chemistry 391 10/30/02

CCHH22CCHH22CCHH22COCOHH

OO

12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

Chemical shift (Chemical shift (δδ,, ppmppm))

1313C NMR of Carboxylic acidsC NMR of Carboxylic acids

The Carbonyl carbon on the carboxylic acid The Carbonyl carbon on the carboxylic acid group is at low field (group is at low field (δδ 160160--185185 ppmppm), but not ), but not quite as quite as deshieldeddeshielded as the carbonyl carbon of as the carbonyl carbon of anan aldehydealdehyde or ketone (or ketone (δδ 190190--215215 ppmppm). ).

Chemistry 391 10/30/02

Mass SpectrometryMass Spectrometry– The McLafferty rearrangement gives a

characteristic peak at m/z = 60

•+

•+

+

McLafferty rearrangement

m/z 60

HH2 C

H2 CCH2

C

O

COH

O

CH2

HOHH2 C

H2 C

Chemistry 391 10/30/02

Chemistry 391 10/30/02

AcidityAcidity• Electron-withdrawing substituents near the

carboxyl group increase acidity through their inductive effect

2.903.184.76 2.86 2.59

CH2 CO2 HCH2 CO2 H CH2 CO2 HCH2 CO2 HCH2 CO2 HFClBrH I

Acid Strength

Chemistry 391 10/30/02

AcidityAcidity• Substitution by multiple electron-

withdrawing groups further increases acidity

Chloroacetic Trichloroacetic Dichloroacetic Acetic

pKa: 2.86 0.701.484.7 6

H3CCO2H H2ClCCO2H HCl2CCO2H Cl3CO2H

Acid Strength

Chemistry 391 10/30/02

AcidityAcidity• The inductive effect of an electron-

withdrawing substituent falls off rapidly with its distance from the carboxyl group

pKa: 4.52 3.98 2.83

4-Chlorobutanoic 3-Chlorobutanoic 2-Chlorobutanoic

Cl Cl Cl

CH2 CH2 CH2 CO2 H CH3 CH2 CHCO2 HCH3 CHCH2 CO2 H

Acid Strength

Chemistry 391 10/30/02

Reactions of AcidsReactions of Acids

• Reduction• Decarboxylation• Esterification• Formation of Acid Halides

Chemistry 391 10/30/02

ReductionReduction• The carboxyl groups is one of the organic

functional groups most resistant to reduction– it is not affected by catalytic hydrogenation

under conditions that easily reduce aldehydesand ketones to alcohols, and reduce alkenes and alkynes to alkanes

– it is not reduced by NaBH4

Chemistry 391 10/30/02

Reduction by LiAlHReduction by LiAlH44

• Lithium aluminum hydride reduces a carboxyl group to a 1° alcohol– reduction is carried out in diethyl ether, THF, or

other nonreactive, aprotic solvent

1 . LiAlH 4 , ether2 . H 2 O

COH

O

+ +LiOH Al(OH) 3CH2 OH

Chemistry 391 10/30/02

Selective ReductionSelective Reduction

• Using the less reactive NaBH4, it is possible to reduce the carbonyl group of an aldehyde or ketone without affecting a carboxyl group

OOH

CHCH2 CH2 CH2 COHCCH2 CH2 CH2 COH

O O1 . NaBH4

2 . H 2 O

Chemistry 391 10/30/02

FischerFischer EsterificationEsterification• The key intermediate in Fischer esterification is

the tetrahedral addition intermediate formed by addition of ROH to the C=O group

••

••

••••

••••

C OCH3

OH

O

R

H

••

••

•• ••

C OH

O

R ••

••

•• ••

C OCH3

O

R••

••HOCH3+ ••

••HOH+

H+ H+

tetrahedral carbonyl addition intermediate