Modified slides of William Tam & Phillis Chang Ch. 17 - 1 Chapter 17 Carboxylic Acids and Their...
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Modified slides of William Tam & Phillis Chang Ch. 17 Chapter 17 Chapter 17 Carboxylic Acids Carboxylic Acids and Their Derivatives and Their Derivatives Nucleophilic Nucleophilic Addition–Elimination Addition–Elimination at the Acyl Carbon at the Acyl Carbon
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Transcript of Modified slides of William Tam & Phillis Chang Ch. 17 - 1 Chapter 17 Carboxylic Acids and Their...
Modified slides of William Tam & Phillis ChangCh. 17 - 1
Chapter 17Chapter 17
Carboxylic AcidsCarboxylic Acidsand Their Derivativesand Their Derivatives
NucleophilicNucleophilicAddition–EliminationAddition–Eliminationat the Acyl Carbonat the Acyl Carbon
Ch. 17 - 2
Carboxylic Acid Derivatives
O
R Clacid chloride
O
R OHcarboxylic acid
O
R OR'ester
O
R NR'2amide
O
R O R'
O
acid anhydride
Introduction
Ch. 17 - 3
NomenclatureRules
Carboxylic acid as parent (suffix): ending with “–oic acid”
Carboxylate as parent (suffix): ending with “–oate”
Ch. 17 - 4
Anhydrides are named by dropping the acid and adding the word “anhydride”
Acid chloride suffix: “–oyl chloride”
Ester suffix: ending with “–oate”
Amide suffix: ending with “amide”
Nitrile suffix: ending with “nitrile”
Ch. 17 - 5
Examples
O
OHEthanoic acid(acetic acid)
O
OCH3
Methyl propanoate
O
NH'2Ethanamide
O
O
O
Ethanoic anhydride(acetic anhydride)
Ch. 17 - 6
Examples
Sodium benzoate
Ethanenitrile
O Na
O Cl
O
Benzoyl chloride
H3C C N
Ch. 17 - 7
Acidity of Carboxylic AcidsAcidity of Carboxylic Acids
pKa ~ 4-5
Compare
pKa of H2O ~ 16
pKa of H2CO3 ~ 7
pKa of HF ~ 3
Ch. 17 - 11
Acidity of Carboxylic Acids, Phenols & Alcohols
OH
O OH
OH
pKa = 4.20 pKa = ~ 10 pKa = ~ 17
Ch. 17 - 12
Acidity of Carboxylic Acids, Phenols and Alcohols
OHO
H2O+
OO
H3O++
O
O
Ch. 17 - 13
Acidity of Carboxylic Acids, Phenols and Alcohols
OH
H2O+
H3O++
O
O O
O
Ch. 17 - 14
Acidity of Carboxylic Acids, Phenols and Alcohols
(NO resonance stabilization)
OH H2O+
H3O++
O
Ch. 17 - 15
QuestionHow could you distinguish these 3 by
simple chemical tests?(acidity)
OH
O OH
OH
> >
Ch. 17 - 16
OH
+ NaOH
OH
+ NaOH
(immisciblewith H2O)
O Na
(soluble in water)
No Reaction
O
R OH + Na OH
O
R O Na+ H2O
(soluable )
Ch. 17 - 17
OH
+ NaHCO3 No Reaction
OH
+ NaHCO3 No Reaction
O
OH
+ NaHCO3
O
O Na + CO2(g) + H2O
(gas evolved)
Ch. 17 - 18
pKa 0.70 1.48
O
OH
ClCl
ClO
OH
HCl
ClO
OH
HH
ClO
OH
HH
H> > >
2.86 4.76
Stability of conjugate bases
O
O
ClCl
ClO
O
HCl
Cl>
O
O
HH
Cl>
O
O
HH
H>>
>> >> >
Ch. 17 - 19
4-Chlorobutanoic acid(pKa = 4.50)
O
OHCl
2-Chlorobutanoic acid(pKa = 2.85)
O
OH
Cl3-Chlorobutanoic acid
(pKa = 4.05)
O
OH
Cl
>
> > >>
> >>
>
Ch. 17 - 20
Dicarboxylic AcidsDicarboxylic Acids
HO2C CO2H
HO2CCH2CO2H
HO2C(CH2)4CO2H
CO2H
CO2H
StructureCommon
Name mp (oC) pK1
pKa
(at 25oC)
pK2
Oxalic acid
Malonic acid
Adipic acid
Phthalic acid
189 dec
136
153
206-208 dec
1.2
2.9
4.4
2.9
4.2
5.7
5.6
5.4
Ch. 17 - 29
Preparation of Carboxylic Acids
Oxidation cleavage of alkenesKMnO4
Ph
Ph O
O
OH
OH
1. KMnO4, OH−, heat
2. H3O+
+
ozonolysis
1. O3
2. H2O2
OHHOO O
Ch. 17 - 30
Oxidation of aldehydes & 1o alcohols
H
O
OH
O
1. Ag2O
2. H3O+
OH O
OH
1. KMnO4, OH−, heat
2. H3O+
H
O
OHorH2CrO4
OH
O
Ch. 17 - 31
Oxidation of alkyl benzene
1. KMnO4, OH−, heat
2. H3O+
ROH
O
(R = 1o or 2o alkyl groups)
Ch. 17 - 32
Oxidation of benzene ring
1. O3, CH3COOH
2. H2O2 OH
O
Ch. 17 - 33
Hydrolysis of cyanohydrins & nitriles
H+
H2OPh CH3
O
Ph CH3
NC OH
Ph CH3
C OH
O
HOHCN
H+
H2O, heat
HCNBr CN C
OH
O
Ch. 17 - 34
Carbonation of Grignard reagents
1. CO2
2. H3O+
Br
OH
O
Mg
Et2O
MgBr
Ch. 17 - 35
Nucleophilic Addition-Elimination at the Acyl Carbon
NuO
R Y+
Acyl substitution through nucleophilic addition-elimination
O
RY
Nu
Y
O
R Nu+
(Y = leaving group, e.g. OR, NR2, Cl)
Ch. 17 - 36
Acyl derivatives
O
R Clacid chloride
O
R OHcarboxylic acid
O
R OR'ester
O
R NR'2amide
O
R O R'
O
acid anhydride
Ch. 17 - 39
Usually the addition is the rate-determining step (r.d.s.). Elimination usually occurs spontaneously to regenerate the carbonyl group
Both steric and electronic factors that effect addition of a nucleophile
Ch. 17 - 40
Steric factor
O
Cl
O
Cl>reactivity of
e.g.
Electronic factorstrongly polarized acid derivatives
react more readily than less polar ones
Ch. 17 - 41
Thus, reactivity of
It is usually possible to convert a more reactive acid derivative to a less reactive one, but not vice versa
O
R Cl
O
R O R'
O O
R OR'
O
R NR'2
most reactive
>
least reactive
> >
Ch. 17 - 42
Acyl Chlorides
Synthesis of Acyl ChloridesSynthesis of Acyl Chlorides
From carboxylic acids
O
R Cl
O
R OH
reagentsSOCl2(COCl)2
PCl3 or PCl5
Ch. 17 - 43
OCl
O
O
R
O
Cl
OCl
O
O
R
O
Cl
O
R OH
ClCl
O
O
Mechanism
OCl
O
O
R
O
O
R Cl+ CO2 + CO + Cl
Cl
Ch. 17 - 44
Conversion of acid chlorides to carboxylic acids
O
R Cl
O
R OH+ H2O
base
Ch. 17 - 45
O
R OHB H +
O
R OH
H
OH
R OHCl
O
RCl
OH
H
Mechanism
B:
Ch. 17 - 46
Conversion to other carboxylic derivatives
O
R Cl
O
R OR'
O
R NR'2
O
R O R'
O
O
R' O Na
(ester)
(amide)
(acid anhydride)
R'OH
pyridine
R'2NH
Ch. 17 - 47
Carboxylic Acid Anhydrides
Synthesis of AnhydridesSynthesis of Anhydrides
O
R' Cl
O
R OH N
+
+ +
O
R O R'
O
N
H
Cl
Ch. 17 - 48
O
R' Cl
O
R O Na++
O
R O R'
ONa Cl
OH
OH
O
O
300oC+O
O
OSuccinicacid
Succinicanhydride
H2O
230oC
OH
OHO
O
O
O
O
H2O
Phthalicacid
Phthalic anhydride(~100%)
+
Ch. 17 - 49
Reactions of AnhydridesReactions of Anhydrides
Conversion to carboxylic acids
O
HO R'
O
R OH+
O
R O R'
O+ H2O
H+
Ch. 17 - 50
O
R OH
O
R O R'
OH
OH
R O R'
O
OHH
O
R O R'
O H+
Mechanism
H2O
OH
R O R'
O
OHH
R'COOH+
O
R OH
HH2O
Ch. 17 - 51
Conversion to other carboxylic derivatives
O
R O R'
O
O
R OR'
O
R OH
O
R NR'2
O
R O NR'2H2
R'OH
R2'NH
+
+
Ch. 17 - 52
Esters
EsterificationEsterification
O
R OR'
O
R OH+ R'OH
H++ H2O
Ch. 17 - 53
OH2
R OR'HO
O
R OH
H
"activated"
O
R O
H+
H
Mechanism
R'OH
H2O
OH
R OH
OHR'
O
R OR'
HO
R OR'
Ch. 17 - 54
Esters from acyl chlorides
O
OEt
+ EtOH
+
e.g.
N
+
N
H
Cl
O
Cl
Benzoylchloride
Ethyl benzoate(80%)
Ch. 17 - 55
Esters from anhydrides
OH
+
+
O
O
Benzoylalcohol
O
O
O
O
OH
Aceticanhydride
Benzoyl acetate
e.g.
Ch. 17 - 56
Base-Promoted Hydrolysis of EstersBase-Promoted Hydrolysis of Esters
Hydrolysis under basic conditions: saponification
O
R O+
O
R OR'
OH−
H2OR'OH
Ch. 17 - 57
Mechanism
O
R OR' OH
O
R OR'HO
O
R OH + OR'
O
R O+R'OH
H+O
R OH
Ch. 17 - 58
Hydrolysis of esters under acidic conditions
O
R OH+
O
R OR'
H+
H2OR'OH
Ch. 17 - 59
O
R OH
O
R OR'
HOH
R OR'O
HH
Mechanism
H2O
OH
R OR'
OHH
R'OH+
O
R OH
HH2O
Ch. 17 - 60
LactonesLactones
Carboxylic acids whose molecules have a hydroxyl group on a or carbon undergo intramolecular esterification
(cyclic esters) or - or -lactones
Ch. 17 - 61
O H
O H
O H
R
R OH
HO O
αβ
a -hydroxyacid
H AO
OHO H
R
H
O
O
R
+ O H
H
H
O
O
R
++A O H
H
H
a -lactone
Ch. 17 - 62
Lactones are hydrolyzed by aqueous base just as other esters are
H+/H2O
HA, slight excess
O
O
C6H5
C6H5O
O
OH
C6H5OH
O
OH
0oCHA, exactly1 equiv.
Ch. 17 - 63
AmidesAmides from Acyl ChloridesAmides from Acyl Chlorides
O
R Cl
:NHR'R"
O
R ClN
R'
R"H
O
R N R'
H
R":Cl:
R"R'HN:
Cl + R'R"NH2 +
O
R NR"
R'
Ch. 17 - 64
Amides from Carboxylic AnhydridesAmides from Carboxylic Anhydrides
R O R
O O+ N
R"
H R'2
N
R"
R'R
O O
R O
H
N R'H
R"
+
R', R" can be H, alkyl, or aryl.
Ch. 17 - 65
+ 2 NH3O
O
O
H2O
warm O NH4
NH2
O
O
OH
NH2
O
OPhthalamic acid
(81%)
Phthalamicanhydride
Ammoniumphthalamate
(94%)H3O
+
(- NH4+)
Ch. 17 - 66
+ H2O
OH
NH2
O
O
Phthalamic acid Phthalimide(~ 100%)
150-160oCN H
O
O
Ch. 17 - 67
Amides from EstersAmides from Esters
R' and/ or R" may be H.
R OR'"
O+ N
R"
H R'N
R"
R'R
O
+ R'"OH
OMe
O
+
MeNH2
heat
N
O
Me
HMeOH
e.g.
Ch. 17 - 68
Amides from Carboxylic Acids &Amides from Carboxylic Acids &Ammonium CarboxylatesAmmonium Carboxylates
R OH
O
+ NH3
NH2R
O
+H2O
R O NH4
O
heat
Ch. 17 - 69
DCC-Promoted amide synthesis
R OH
O
NR
O
+ DCU1. DCC
2. R'NH2R'
H
Ch. 17 - 70
Mechanism
R C
O
O
+
H
:
:
N
C
N
C6H11
C6H11
:C O C
N
NR
OH
C6H11
C6H11
::
C O C
N
NR
OH
C6H11
C6H11
:
Ch. 17 - 71
Mechanism (Cont’d)
C O C
N
NR
OH
C6H11
C6H11
:
:
:
::
:
O
CR O C
NHC6H11
N C6H11
:
:
::
::
proton
transfer
reactive intermediate
R' NH2
:
O C
NHC6H11
N C6H11
:
:
::
::
C
NH2
R
O
R'
:
R C
NHR'
O:
:
+ O C
NHC6H11
NHC6H11::
:
:
N,N'-Dicyclohexylurea(DCU)
an amide
Ch. 17 - 72
Hydrolysis of AmidesHydrolysis of Amides
O
R NH2
O
R OHNH4
H+
H2O, heat+
Acid hydrolysis of amides
Ch. 17 - 73
O
R NH2
HOH
R NH2O
HH
::O
R NH2
: H+
Mechanism
H2O
:
OH
R NH3HO
:
+ NH3
:O
R OH
H:O
R OH
:
Ch. 17 - 74
Basic hydrolysis of amides
O
R NH2
O
R ONH3
OH−
H2O, heat+
Ch. 17 - 75
O
R NH2HO
O
R OH NH2+
O
R NH2
OH
Mechanism
NH3 +
O
R O
Ch. 17 - 76
Nitriles Nitriles from the from the DehydrationDehydration of of AmidesAmides
useful preparing nitriles not available by SN2
:O
R NH2
:: P4O10 or (CH3CO)2O
heat(−H2O)
R C N: H3PO4(or CH3CO2H)(a nitrile)
+
Ch. 17 - 77
NH2
O
P4O10
dehydration
C N
Ch. 17 - 78
Synthesis
CNBrNaCN
DMSO
1o alkyl bromide SN2
Ch. 17 - 79
But synthesis ofCN
3o alkyl bromide
NaCN
DMSO
BrNo SN2 (only E2)
Ch. 17 - 80
Solution
dehydration
Br 1. Mg, Et2O
2. CO2
3. H3O+
OH
O
1. SOCl22. NH3
NH2
O
P4O10
CN
Ch. 17 - 81
Hydrolysis of NitrilesHydrolysis of Nitriles
base or acid
H2O, heatC NR
O
R OH
Catalyzed by both acid and base
Ch. 17 - 82
Examples
CNOH
O
H2SO4
H2O, Δ
(82%)
CNOH
O
2. H3O+
1. NaOH, H2O, Δ
(68%)
Ch. 17 - 83
R C N:H
OH H:
Mechanism
H2O
:
R C NH +R C NH
H
O H::
slow
O
CR NH
H
H
:
:
O
CR NH
H:
:
:H
OH H:
+O
CR NH2
H:
:
:
O
CR NH2
H: O
R OH
+ NH4several steps
(amide hydrolysis)
protonated nitrile
protonatedamide
amidetautomer
Ch. 17 - 84
O
R
O
NH2
:
HH OH OH
O
R
OH
NH2
:H
NH
R OH
:
+ O H:: :
O
R
O
NH2
:
R C N:
O H:: :
MechanismN
R OH
: :
H OH
OH
R
OH
NH::HHOHO
HOHHO
O
R O+ NH3 + OH
H OH
Ch. 17 - 85
LactamsLactams
NH
O
NHNH
OO
α
β
α
β
α
β
a β-lactam a -lactam a -lactam
Penicillin G
Ampicillin
Penicillin V
N
S CH3
CH3
CO2HO
N
H
R
O
R = C6H5CH2
R = C6H5CH
NH2
R = C6H5OCH2
Ch. 17 - 86
Derivatives of Carbonic AcidAlkyl Chloroformates & Carbamates (UrethanAlkyl Chloroformates & Carbamates (Urethanes)es)
Alkyl chloroformate
alkylchloroformate
ROH + + HCl
O
Cl Cl
O
RO Cl
Ch. 17 - 87
e.g.
+HCl
O
RO Cl
OH
O Cl
O
+
Benzylchloroformate
Ch. 17 - 88
Carbamates or urethanes
a carbamate(or urethane)
R'NH2+
O
RO Cl OH−
O
RO NHR'
Ch. 17 - 89
Protection
O Cl
O
+R NH2OH− ON
O
R
H
Deprotection+R NH2
ON
O
R
H
CO2 +
+R NH3 CO2 +Br
H2, Pd
HBr, CH2CO2H
protected amine
Ch. 17 - 90
Decarboxylation of Carboxylic Acids
decarboxylation+ CO2
O
R OHR H
100-150oC+ CO2
O
R OH
O O
R
A β-keto acid
−CO2
R
O
O
O O
R
: ::
: :
:
O
R
: :
HA
O
R
: ::acylacetate ion
resonance-stabilizedanion
Ch. 17 - 91
There are 2 reasons for decarboxylation
−CO2
R
O
O
OH
R
OH
O
R
β-keto acid enol ketone
Ch. 17 - 92
Chemical Tests for Acyl Compounds
OH
O OH
OH
> >
Recall: acidity of
Ch. 17 - 93
O
R OH Na OH+
O
R O Na+ H2O
(soluable in water)
OH
+ NaOH
OH
+ NaOH
(immisciblewith H2O)
O Na
(soluble in water)
No Reaction
Ch. 17 - 94
O
OH
+ NaHCO3
O
O Na
+ CO2(g) + H2O
(gas evolved)
OH
+ NaHCO3 No Reaction
OH
+ NaHCO3 No Reaction
Ch. 17 - 95
Polyesters, Polyamides,Step-Growth Polymers
HO OH
O
HO
O
OH
O
O
O
O
-H2O
+
(a polyester)
nm
mn
Polyesters
Ch. 17 - 96
H2N N
O
Cl
O
Cl
O
N
O
N
-HCl
H
H
H H
+
(a polyamide)
nm
mn
Polyamides
Ch. 17 - 97
HOOH
O
O
+ nn H2NNH2
heat
NN
O
O
H
Hn
+ 2n H2O
(Nylon 66)
Nylon 66
Ch. 17 - 98
+ nnOCH3
O
CH3O
O
HOOH
200oC
O
OO
O
n(Dacron)
+ 2n CH3OH
Dacron (Mylar)
Applications: film, recording tape
Ch. 17 - 99
Summary of the Reactions
R OH
O
Reactions of carboxylic acids
NaOH or NaHCO3 or other bases
O
CR O
R'OH, H+, Δ
O
CR OR'
SOCl2or PCl3or PCl5
O
CR Cl
O
R'base
Cl
O
CR O
CR'
O
1. LiAlH4
2. H2O, H+
RCH2OH
1. P, X22. H2O
O
COH
R
X
Ch. 17 - 100
R Cl
O
Reactions of acyl chlorides
R OH
O
H2O
R OR'
O
R'OH, base
R O
O
R'
O
R'COOHbase
R NR'
O
R'2NH
Ch. 17 - 101
R Cl
O
Reactions of acyl chlorides (Cont’d)
R OH
1. LiAlH4
2. H3O+
R H
O
1. LiAlH(OtBu)3, -78oC
2. H3O+
OH
R R'R'
1. R'MgX
2. H3O+
R
O
benzeneAlCl3
Ch. 17 - 102
R O R'
O O
Reactions of acid anhydrides
H2O
O
R'HO
O
R OH+
R"OH
O
R'HO
O
R OR"+
R"2NH
O
O NR"2H2R'
O
R NR"+
Ch. 17 - 103
Reactions of esters
O
R OH
H2O, H+, Δ
1. OH-
2. H2O, H+
O
R OH
R"OH, H+, ΔO
R OR"
NH3O
R NH2
OH
R R"R"
1. R"MgX
2. H3O+
1. LiAlH4
2. H3O+
R OH1. DIBAL, -78oC
2. H3O+
O
R H
Ch. 17 - 104
R C N
Reactions of nitriles
H+, H2O, Δ
O
R OH
OH−, H2O, Δ
O
R O
LiAlH(OtBu)3
or DIBAL, -78oC
1.
2. H3O+
O
R H
1. LiAlH4
2. H3O+
R NH2
End- 105
O
R NR'
R'
Reactions of amidesO
R OH
H2O, H+ or OH-
+ HNR'2
1. LiAlH4
2. H3O+
R NR'2
P4O10 (P2O5)
or Ac2O, D
(R' = H only)
C NR
