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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