Carboxylic Acids and Their Derivatives Nucleophilic ...
Transcript of Carboxylic Acids and Their Derivatives Nucleophilic ...
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Chapter 17
Carboxylic Acids and Their DerivativesNucleophilic Addition–Elimination
at the Acyl Carbon
Ch. 17 - 1
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Ch. 17 - 2
1. Introduction 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
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Ch. 17 - 3
2. Nomenclature and PhysicalProperties
Nomenclature of Carboxylic Acids and Derivatives● Rules Carboxylic acid as parent
(suffix): ending with “–oic acid” Carboxylate as parent (suffix):
ending with “–oate”
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Ch. 17 - 4
Most anhydrides are named by dropping the word acid from the name of the carboxylic acid and then adding the word “anhydride”
Acid chloride as parent (suffix): ending with “–oyl chloride”
Ester as parent (suffix): ending with “–oate”
Amide as parent (suffix): ending with “amide”
Nitrile as parent (suffix): ending with “nitrile”
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Ch. 17 - 5
Examples
O
OHEthanoic acid(acetic acid)
O
OCH3
Methyl propanoate
O
NH'2Ethanamide
O
O
O
Ethanoic anhydride(acetic anhydride)
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Ch. 17 - 6
Examples
Sodium benzoate
Ethanenitrile
O Na
O Cl
O
Benzoyl chloride
H3C C N
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Ch. 17 - 7
2C. Acidity of Carboxylic Acids
O
R OH
pKa ~ 4-5
Compare
● pKa of H2O ~ 16
● pKa of H2CO3 ~ 7
● pKa of HF ~ 3
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Ch. 17 - 8
When comparing acidity of organic compounds, we compare the stability of their conjugate bases. The more stable the conjugate base, the stronger the acid
pKa
CH3COOH CH3CH2OH
4.75 16
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Ch. 17 - 9
+ H2O
O
CH3 O H
A1
+ H3O+
O
CH3 O
B1
A2
+ H2OCH3CH2 O H
B2
+ H3O+CH3CH2 O
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Ch. 17 - 10
The conjugate base B1 is more stable (the anion is more delocalized) than B2due to resonance stabilization
O
CH3 O
O
CH3 O
O
CH3 O
● Thus, A1 is a stronger acid than A2
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Ch. 17 - 11
Acidity of Carboxylic Acids, Phenols and Alcohols
OH
O OH
OH
pKa = 4.20 pKa = ~ 10 pKa = ~ 17
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Ch. 17 - 12
OH
O
H2O+
Acidity of Carboxylic Acids, Phenols and Alcohols
O
O
H3O++
O
O
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Ch. 17 - 13
Acidity of Carboxylic Acids, Phenols and Alcohols
OH
H2O+
H3O++
O
O O O
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Ch. 17 - 14
Acidity of Carboxylic Acids, Phenols and Alcohols
OH
H2O+ H3O++
O
(NO resonance stabilization)
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Ch. 17 - 15
Question If you are given three unknown
samples: one is benzoic acid; one is phenol; and one is cyclohexyl alcohol; how would you distinguish them by simple chemical tests?● Recall: acidity of
OH
O OH
OH
> >
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Ch. 17 - 16
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
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Ch. 17 - 17
O
OH
+ NaHCO3
O
O Na
+ CO2(g) + H2O
(gas evolved)
OH
+ NaHCO3 No Reaction
OH
+ NaHCO3 No Reaction
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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>>
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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
>
>
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Ch. 17 - 20
2D. Dicarboxylic 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
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Ch. 17 - 21
2J. Spectroscopic Properties ofAcyl Compounds
IR Spectra● The C=O stretching band occurs at
different frequencies for acids, esters, and amides, and its precise location is often helpful in structure determination
● Conjugation and electron-donating groups bonded to the carbonyl shift the location of the C=O absorption to lower frequencies
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Ch. 17 - 22
IR Spectra● Electron-withdrawing groups bonded to
the carbonyl shift the C=O absorption to higher frequencies
● The hydroxyl groups of carboxylic acids also give rise to a broad peak in the 2500-3100-cm-1 region arising from O–H stretching vibrations
● The N–H stretching vibrations of amides absorb between 3140 and 3500 cm-1
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Ch. 17 - 23
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Ch. 17 - 24
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Ch. 17 - 25
1H NMR Spectra● The acidic protons of carboxylic
acids are highly deshielded and absorb far downfield in the δ 10-12 region
● The protons of the a carbon of carboxylic acids absorb in the δ2.0-2.5 region
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Ch. 17 - 26
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Ch. 17 - 27
13C NMR Spectra● The carbonyl carbon of carboxylic
acids and their derivatives occurs downfield in the δ 160-180 region (see the following examples), but not as far downfield as for aldehydes and ketones (δ 180-220)
● The nitrile carbon is not shifted so far downfield and absorbs in the δ115-120 region
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Ch. 17 - 28
13C NMR chemical shifts for the carbonyl or nitrile carbon atom
δ 177.2
O
CH3C OH
O
CH3C OEt
O
CH3C Cl
O
CH3C NH2
H3C C N
δ 170.7 δ 170.3
δ 172.6 δ 117.4
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Ch. 17 - 29
3. Preparation of Carboxylic Acids
By oxidation cleavage of alkenes● Using KMnO4
Ph
Ph O
O
OH
OH
1. KMnO4, OH−, heat
2. H3O+
+
● Using ozonolysis
1. O3
2. H2O2
OHHOO O
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Ch. 17 - 30
By oxidation of aldehydes & 1o alcohols● e.g.
H
O
OH
O
1. Ag2O
2. H3O+
OH O
OH1. KMnO4, OH−, heat
2. H3O+
H
O
OHorH2CrO4
OH
O
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Ch. 17 - 31
By oxidation of alkyl benzene
1. KMnO4, OH−, heat
2. H3O+
ROH
O
(R = 1o or 2o alkyl groups)
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Ch. 17 - 32
By oxidation of benzene ring● e.g.
1. O3, CH3COOH
2. H2O2 OH
O
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Ch. 17 - 33
By hydrolysis of cyanohydrins and other nitriles● e.g.
H+
H2OPh CH3
O
Ph CH3
NC OH
Ph CH3
C OH
O
HOHCN
H+
H2O, heat
HCNBr CN C
OH
O
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Ch. 17 - 34
By carbonation of Grignard reagents● e.g.
1. CO2
2. H3O+
Br
OH
O
Mg
Et2O
MgBr
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Ch. 17 - 35
4. Acyl Substitution: Nucleophilic Addition-Elimination at the Acyl Carbon
NuO
R Y+
This nucleophilic acyl substitution occurs through a nucleophilic addition-elimination mechanism
O
RY
Nu
YO
R Nu+
(Y = leaving group, e.g. OR, NR2, Cl)
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Ch. 17 - 36
This type of nucleophilic acyl substitution reaction is common for carboxylic acids and their derivatives
O
R Clacid chloride
O
R OHcarboxylic acid
O
R OR'ester
O
R NR'2amide
O
R O R'
O
acid anhydride
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Ch. 17 - 37
Unlike carboxylic acids and their derivatives, aldehydes & ketones usually do not undergo this type of nucleophilic acyl substitution, due to the lack of an acyl leaving group
O
R Ya carboxylic acid
derivative
O
R H
O
R R'
A good leaving group
Not a good leaving group
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Ch. 17 - 38
Relative reactivity of carboxylic acid derivatives towards nucleophilic acyl substitution reactions● There are 2 steps in a nucleophilic
acyl substitution The addition of the nucleophile
to the carbonyl group The elimination of the leaving
group in the tetrahedral intermediate
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Ch. 17 - 39
● Usually the addition step (the first step) is the rate-determining step (r.d.s.). As soon as the tetrahedral intermediate is formed, elimination usually occurs spontaneously to regenerate the carbonyl group
● Thus, both steric and electronic factors that affect the rate of the addition of a nucleophile control the reactivity of the carboxylic acid derivative
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Ch. 17 - 40
● Steric factor
O
Cl
O
Cl>reactivity of
e.g.
● Electronic factor The strongly polarized acid
derivatives react more readily than less polar ones
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Ch. 17 - 41
● Thus, reactivity of
● An important consequence of this reactivity 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'2most
reactive
>
least reactive
> >
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Ch. 17 - 42
5. Acyl Chlorides
5A. Synthesis of Acyl Chlorides
Conversion of carboxylic acids to acid chlorides O
R Cl
O
R OH
● Common reagents SOCl2 (COCl)2 PCl3 or PCl5
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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
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Ch. 17 - 44
Nucleophilic acyl substitution reactions of acid chlorides● Conversion of acid chlorides to
carboxylic acids
O
R Cl
O
R OH+ H2O
base
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Ch. 17 - 45
O
R OHB H +
O
R OH
H
OH
R OHCl
O
RCl
OH
H
O
R Cl H2O
● Mechanism
B:
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Ch. 17 - 46
● Conversion of acid chlorides 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
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Ch. 17 - 47
6. Carboxylic Acid Anhydrides
6A. Synthesis of Carboxylic AcidAnhydrides
O
R' Cl
O
R OH N
+
+ +
O
R O R'
O
N
H
Cl
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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%)
+
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Ch. 17 - 49
6B. Reactions of Carboxylic AcidAnhydrides
Conversion of acid anhydrides to carboxylic acids
O
HO R'
O
R OH+
O
R O R'
O+ H2O
H+
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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
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Ch. 17 - 51
Conversion of acid anhydrides 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
+
+
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Ch. 17 - 52
7. Esters
7A. Synthesis of Esters: Esterification
O
R OR'
O
R OH+ R'OH
H++ H2O
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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'
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Ch. 17 - 54
Esters from acyl chlorides
O
OEt
+ EtOH
+
e.g.
N
+
N
H
Cl
O
Cl
Benzoylchloride
Ethyl benzoate(80%)
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Ch. 17 - 55
Esters from carboxylic acid anhydrides
OH
+
+O
OBenzoylalcohol
O
O
O
O
OH
Aceticanhydride
Benzoyl acetate
e.g.
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Ch. 17 - 56
7B. Base-Promoted Hydrolysis ofEsters: Saponification
Hydrolysis of esters under basic conditions: saponification
O
R O+
O
R OR'
OH−
H2OR'OH
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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
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Ch. 17 - 58
Hydrolysis of esters under acidic conditions
O
R OH+
O
R OR'
H+
H2OR'OH
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Ch. 17 - 59
O
R OH
O
R OR'
HOH
R OR'O
HH
O
R OR'
H+
Mechanism
H2O
OH
R OR'
OHH
R'OH+O
R OH
HH2O
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Ch. 17 - 60
7C. Lactones
Carboxylic acids whose molecules have a hydroxyl group on a γ or δcarbon undergo an intramolecular esterification to give cyclic esters known as γ- or δ-lactones
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Ch. 17 - 61
O H
O H
O H
R
R OH
HO O
αβ
γδ
a δ-hydroxyacid
H AO
OHO H
R
H
O
O
R
+ O H
H
H
O
O
R
++A O H
H
H
a δ-lactone
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Ch. 17 - 62
Lactones are hydrolyzed by aqueous base just as other esters are
H+/H2O
HA, slight excessO
O
C6H5
C6H5O
O
OH
C6H5OH
O
OH
0oCHA, exactly1 equiv.
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Ch. 17 - 63
8. Amides8B. Amides 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'
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Ch. 17 - 64
8C. Amides from CarboxylicAnhydrides
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.
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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+)
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Ch. 17 - 66
+ H2O
OH
NH2
O
O
Phthalamic acid Phthalimide(~ 100%)
150-160oCN H
O
O
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Ch. 17 - 67
8D. Amides 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.
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Ch. 17 - 68
8E. Amides from Carboxylic Acids andAmmonium Carboxylates
R OH
O+ NH3
NH2R
O+H2O
R O NH4
O
heat
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Ch. 17 - 69
DCC-Promoted amide synthesis
R OH
O
NR
O
+ DCU1. DCC
2. R'NH2R'
H
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Ch. 17 - 70
C O C
N
NR
OH
C6H11
C6H11
:
::
::
:R C
O
O+
H
:
:
::
N
C
N
C6H11
C6H11
:
:
Dicyclohexyl-carbodiimide
(DCC)
Mechanism
C O C
N
NR
OH
C6H11
C6H11
:
::
:
::
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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
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Ch. 17 - 72
8F. Hydrolysis of Amides
O
R NH2
O
R OHNH4
H+
H2O, heat+
Acid hydrolysis of amides
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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
:
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Ch. 17 - 74
Basic hydrolysis of amides
O
R NH2
O
R ONH3
OH−
H2O, heat+
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Ch. 17 - 75
O
R NH2HO
O
R OH NH2+
O
R NH2
OH
Mechanism
NH3 +O
R O
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Ch. 17 - 76
8G. Nitriles from the Dehydration ofAmides
This is a useful synthetic method for preparing nitriles that are not available by nucleophilic substitution reactions between alkyl halides and cyanide ions
:O
R NH2
:
:
P4O10 or (CH3CO)2O
heat(−H2O)
R C N: H3PO4(or CH3CO2H)(a nitrile)
+
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Ch. 17 - 77
e.g.
NH2
O
P4O10
dehydration
C N
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Ch. 17 - 78
Example● Synthesis of C N
CNBrNaCN
DMSO
1o alkyl bromide⇒ SN2 reaction with ⊖CN works fine
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Ch. 17 - 79
But synthesis ofCN
NaCN
DMSO
BrNo Reaction!
3o alkyl bromide⇒ No SN2 reaction
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Ch. 17 - 80
Solution
dehydration
Br 1. Mg, Et2O
2. CO2
3. H3O+
OH
O
1. SOCl22. NH3
NH2
O
P4O10
CN
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Ch. 17 - 81
8H. Hydrolysis of Nitriles
base or acid
H2O, heatC NR
O
R OH
Catalyzed by both acid and base
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Ch. 17 - 82
Examples
CNOH
O
H2SO4
H2O, ∆
(82%)
CNOH
O2. H3O
+1. NaOH, H2O, ∆
(68%)
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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
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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
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Ch. 17 - 85
8I. Lactams
NH
ONH
NH
OO
α
β
α
βγ
δα
β γ
a β-lactam a γ-lactam a δ-lactam
Penicillin G
Ampicillin
Penicillin V
N
S CH3
CH3
CO2HO
N
H
R
O
R = C6H5CH2
R = C6H5CH
NH2
R = C6H5OCH2
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Ch. 17 - 86
9. Derivatives of Carbonic Acid9A. Alkyl Chloroformates and
Carbamates (Urethanes)
Alkyl chloroformate
alkylchloroformate
ROH + + HClO
Cl Cl
O
RO Cl
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Ch. 17 - 87
e.g.
+HCl
O
RO Cl
OH
O Cl
O
+
Benzylchloroformate
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Ch. 17 - 88
Carbamates or urethanes
a carbamate(or urethane)
R'NH2+O
RO Cl OH−
O
RO NHR'
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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
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Ch. 17 - 90
10. Decarboxylation of CarboxylicAcids
decarboxylation+ CO2
O
R OHR H
100-150oC+ CO2
O
R OH
O O
R
A β-keto acid
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Ch. 17 - 91
There are two reasons for this ease of decarboxylation
−CO2
R
O
O
OH
R
OH
O
Rβ-keto acid enol ketone
−CO2
R
O
O
O O
R
: : :
: :
:
O
R
: :
HA
O
R
: ::
acylacetate ion
resonance-stabilizedanion
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Ch. 17 - 92
11. Chemical Tests for AcylCompounds
OH
O OH
OH
> >
Recall: acidity of
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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
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Ch. 17 - 94
O
OH
+ NaHCO3
O
O Na
+ CO2(g) + H2O
(gas evolved)
OH
+ NaHCO3 No Reaction
OH
+ NaHCO3 No Reaction
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Ch. 17 - 95
12. Polyesters and Polyamides:Step-Growth Polymers
HO OH
O
HO
O
OH
O
O
O
O
-H2O
+
(a polyester)
nm
mn
Polyesters
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Ch. 17 - 96
H2N N
O
Cl
O
Cl
O
N
O
N
-HCl
H
H
H H
+
(a polyamide)
nm
mn
Polyamides
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Ch. 17 - 97
HOOH
O
O
+ nn H2NNH2
heat
NN
O
O
H
Hn
+ 2n H2O
(Nylon 66)
Example: Nylon 66
● Applications: clothing, fibers, bearings
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Ch. 17 - 98
+ nnOCH3
O
CH3O
O
HOOH
200oC
O
OO
O
n(Dacron)
+ 2n CH3OH
Example: Dacron (Mylar)
● Applications: film, recording tape
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Ch. 17 - 99
13. Summary of the Reactions of Carboxylic Acids and Their Derivatives
R OH
O
Reactions of carboxylic acids
NaOH or NaHCO3 or other bases
O
CR O
R'OH, H+, ∆
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
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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
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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
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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"+
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Ch. 17 - 103
O
R OR'
Reactions of esters
O
R OH
H2O, H+, ∆
1. OH-
2. H2O, H+
O
R OH
R"OH, H+, ∆O
R OR"
NH3O
R NH2
OH
R R"R"
1. R"MgX2. H3O
+
1. LiAlH4
2. H3O+
R OH1. DIBAL, -78oC2. H3O
+
O
R H
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Ch. 17 - 104
R C N
Reactions of nitriles
H+, H2O, ∆
O
R OH
OH−, H2O, ∆
O
R O
LiAlH(OtBu)3or DIBAL, -78oC
1.
2. H3O+
O
R H
1. LiAlH4
2. H3O+
R NH2
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Ch. 17 - 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
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Ch. 17 - 106
END OF CHAPTER 17