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Carboxylic Acid Derivativesand
Nucleophilic AcylSubstitution Reactions
McMurray TextMcMurray TextChapter 21Chapter 21
Carboxylic Acid Derivatives
R X
O
R OR'
O
R NH2
O
R O
O
R'
O
R OH
O
Ester
Acid Halide
Acid AnhydrideAmide (1°)
NomenclatureNomenclatureAcid Halides (Acyl Halides)
Cl
Cl
O
O
H3CH2CHC Cl
O
CH3
Change Change “–“–icic acid acid”” in the parent carboxylic in the parent carboxylicacid to acid to “–yl” followed by the followed by the halide.
hexanedioyl chloride(from hexanedioic acid)
H3C Cl
O
acetyl chloride(from acetic acid)
2-methylbutanoyl chloride(from 2-methylbutanoic acid)
NomenclatureNomenclatureSymmetrical Acid Anhydrides
O
O O
Change Change ““acidacid”” in the parent carboxylic acid in the parent carboxylic acidto to “anhydride.”
butanoic anhydride(from 2 butanoic acids)
O
O O
acetic anhydride(from 2 acetic acids)
NomenclatureNomenclatureUnsymmetrical Acid Anhydrides
O H
O O
Name the two acids alphabetically andName the two acids alphabetically andchange change ““acidacid”” to to “anhydride.”
ethanoic methanoic anhydride
O
O O
acetic benzoic anhydride
NomenclatureNomenclatureEsters
O
O
EtO OEt
O O
O
O
Name R group bonded to O, followed by bonded to O, followed byreplacing replacing “–“–icic acid acid”” in the parent acid with in the parent acid with “–ate.”
ethyl acetate diethyl propanedioate
O
O
methyl butanoate isopentyl acetate
NomenclatureNomenclatureAmides
NH2
O
N
O
H
1° amides: Change Change “–“–oicoic acid acid”” (IUPAC) or (IUPAC) or ““--icic acid acid””(common) in the parent acid(common) in the parent acid to to “–amide.”
2° and 3° amides: First identify the First identify the substituentsubstituent groups groups(preceded by (preceded by ““NN--””)and then the parent amide.)and then the parent amide.
H N
O
acetamide
N-Methylacetamide N,N-Dimethylformamide
NucleophilicNucleophilic AcylAcyl Substitution Substitution
R Lv
O
Nu+
Nu
O
Lv
R
R Nu
O
Lv+
tetrahedralintermediate
Reactivity of Acid Derivatives:Reactivity of Acid Derivatives:StericSteric Effects Effects
C
O
R
R
R
C
O
H
R
R
C
O
H
R
H
C
O
H
H
H
< < <
Reactivity toward nucleophilic substitution
Most Hindered Least Hindered
Reactivity of Acid Derivatives:Reactivity of Acid Derivatives:Electronic EffectsElectronic Effects
R NH2
O
R OR'
O
R O
O
R'
O
R X
O
< < <
Ester AcidHalide
Acid AnhydrideAmide
Reactivity toward nucleophilic substitutionCarbonyl carbonleast electrophilic
Carbonyl carbonmost electrophilic
NucleophilicNucleophilic AcylAcyl Substitution Substitution RxnsRxns
R
O
Y
Reduction
H-R
O
H
H-
GrignardReagent
R1MgX R
O
R1R1MgX
Hydrolysis
H2OR
O
OH
Alcoholysis
R1OHR
O
OR1
Aminolysis
NH3R
O
NH2
Preparation of Preparation of AcylAcyl Halides Halides
R OH
O
SOCl2
PBr3
R Cl
O
R Br
O
Note: Acid fluorides are extremely reactive andrequire different preparation methods.
Preparation of AnhydridesPreparation of Anhydrides
R
O
OH
Carboxylic acid
2 R
O
O
O
R
Carboxylic acidAnhydride
+ H2O
COOH
COOH
Heat
O
O
O
Succinic acid Succinic anhydride
Cyclic Anhydride+ H2OHeat
R
O
OHNaOH
R
O
O-Na+
R1
O
Cl
R
O
O
O
R1Mixed Anhydride
Preparation of EstersPreparation of Esters
R1OHR
O
OR1R
O
OHH+
Fischer Esterification
+ H2O
R
O
OH
H+
R
O
OH
H
R1OH
R
OH
O
HO
R1
H
R
O
O
HO
R1
H H
-H2OR
O
OR1
H O
H
H
R
O
OR1
Note: If one uses labeled alcohol, the label is retained in the product.
Preparation of AmidesPreparation of Amides
No simple method for the preparation ofNo simple method for the preparation ofamides from carboxylic acids!amides from carboxylic acids!
Amides from acids discussed in 26.10Amides from acids discussed in 26.10
InterconversionInterconversion of Derivatives of Derivatives All acid derivatives can be converted toAll acid derivatives can be converted to
carboxylic acids.carboxylic acids. A derivative A derivative can be converted to a less be converted to a less
reactive derivative.reactive derivative. A derivative A derivative cannot be converted to a be converted to a
more reactive derivative.more reactive derivative. Anhydrides can be converted to estersAnhydrides can be converted to esters
and amides, but not into acid halides.and amides, but not into acid halides.
InterconversionInterconversion
Lecture 2 (with review)Lecture 2 (with review)
Reactivity of Acid Derivatives:Reactivity of Acid Derivatives:Electronic EffectsElectronic Effects
R NH2
O
R OR'
O
R O
O
R'
O
R X
O
< < <
Ester AcidHalide
Acid AnhydrideAmide
Reactivity toward nucleophilic substitutionCarbonyl carbonleast electrophilic
Carbonyl carbonmost electrophilic
NomenclatureNomenclature Acid chloride: Acid chloride: ““--ylyl chloride chloride””
Anhydride: Anhydride: ““anhydrideanhydride””
Ester: Ester: ““-ate-ate””
Amide: Amide: ““amideamide””O
O
isopentyl acetateH3C Cl
O
acetyl chloride(from acetic acid)
NucleophilicNucleophilic AcylAcyl Substitution Substitution
R Lv
O
Nu+
Nu
O
Lv
R
R Nu
O
Lv+
tetrahedralintermediate
InterconversionInterconversion
Acid Halide HydrolysisAcid Halide Hydrolysis
R Cl
O
OH2
O
R
Cl
OH2
O
R O
H
H
OH
O
R OH
A base such as pyridine, triethylamine, or NaOHis used to remove the HCl that is formed.
Acid
Acid Halides into AnhydridesAcid Halides into Anhydrides
O
OH NaOH
O
O-Na+ H3C
O
Cl
O
O
O
CH3
Mixed Anhydride
Acid chloride/carboxylate reaction useful for preparingeither symmetrical or unsymmetrical anhydrides.
Acid Halide Acid Halide AlcoholysisAlcoholysis
Cl
O OH
O
O
N
NH
Cl
++
+
Ester
Acid Halide Acid Halide AminolysisAminolysis
+ NH4ClC
O
Cl2 NH3
C
O
NH2
Benzoyl Chloride Benzamide
Formation of a primary amide
C
O
Cl2 H N
H
CH3C
O
NH
CH3
+ CH3NH3Cl Formation of a secondary amide
C
O
Cl
2 H N
CH3C
O
N
CH3
HN
CH3H
Cl-+ Formation of a tertiary amide
O Cl NH
O N
Cl
H
O N
H
Cl
O N
N,N-diethyl-m-toluamide(DEET)
3° amide!
m-toluyl chloride
Acid Halide ReductionAcid Halide Reduction
RC
O
ClGrignardReagent
R1MgXR
C
O
R1R1MgX
RC
OH
R1 R1
Ketone Tertiary alcohol
1. LAHR
C
O
H RC
OH
H HLAH
Aldehyde Primary alcohol
RC
O
OR1
Ester2. H3O+Cl
Acid Halides into Acid Halides into KetonesKetonesGilman reagent: R2CuLi
(lithium diorganocopper)
C
O
Cl (CH3)2CuLiC
O
CH3
No overoxidation as opposed to Grignard reactions!
Note: Carboxylic acids, esters, acid anhydrides, and amidesdo not react with Gilman reagents.
Acid Anhydride ReactionsAcid Anhydride Reactions Less reactive than acid chlorides, but react
in a similar fashion… HydrolysisHydrolysis
React with water to form carboxylic acidsReact with water to form carboxylic acids AlcoholysisAlcoholysis
React with alcohols to form estersReact with alcohols to form esters AminolysisAminolysis
React with amines to form amidesReact with amines to form amides ReductionReduction
React with LiAlH4 to form 1React with LiAlH4 to form 1° alcohols° alcohols
Acid AnhydrideAcid AnhydrideAlcoholysis:
Aminolysis:
Ester
Amide
Ester HydrolysisEster Hydrolysisbase-catalyzed hydrolysis
(saponification)
RC
O
OR1
CH2O
CHO
CH2O
C
O
(CH2)16CH3
C
O
(CH2)16CH3
C
O
(CH2)16CH3
NaOH
H2O
CH2OH
CHOH
CH2OH
+ H3C(CH2)16 C
O
ONa3
Sodium Stearate SoapGlycerolTriglyceride
OH
RC
O
OR1
OHR
C
O
OH + R1OR
C
O
O+ R1OH-
Ester HydrolysisEster Hydrolysis
RC
O
OR1
RC
O
OR1
RC
O
OR1
H
H
OH
H
OHH
RC
O
O
H
OH H
R1
RC
O
OH
H
+ R1OH
RC
O
OH
H
RC
O
OH+ H3O
+
HO
H
acid-catalyzed hydrolysis(reverse Fischer Esterification)
Acid
Ester Ester AminolysisAminolysisEsters react with ammonia and
with 1° and 2° amines to form amides.
Ph
OEt
O
NH3
Ph
NH2
O
EtOH
+
+
Ester ReductionEster Reduction
1. LAHR
C
O
H RC
OH
H HLAH
Aldehyde Primary alcohol
RC
O
OR1
Ester2. H3O+
RC
O
ClGrignardReagent
R1MgXR
C
O
R1R1MgX
RC
OH
R1 R1
Ketone Tertiary alcohol
OR
Amide HydrolysisAmide Hydrolysis
RC
O
OHRC
O
NH2
1. HO
2. H3O+
Acid
Amide ReductionAmide Reduction Amides into Amines using LiAlHAmides into Amines using LiAlH44
Product of reduction is an amine, not anProduct of reduction is an amine, not analcohol as with the other acid derivativesalcohol as with the other acid derivatives
RC
NH2RC
O
NH2
1. LAH
2. H3O+
H H
Primary amine
RC
O
NH2
H
RC
OAlH3
NH2H
RC
H
NH H
H
RC
NH2
H H
Primary amine
NucleophilicNucleophilic Substitution Substitution RxnsRxns Summary Summary
-0Rxn00Amide
Rxn-Rxn00Ester
RxnRxn-RxnRxnCarboxylic Acid
RxnRxnRxn-0Acid Anhydride
RxnRxnRxnRxn-Acid Chloride
AmideEsterCarboxylicAcid
AcidAnhydride
AcidChloride
StartingMaterial
Product
0 = No reaction