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Carboxylic Acid
Derivatives: Nucleophilic Acyl
Substitution Reactions
羧酸衍生物 : 親核醯基取代反應
酸酐 酯
醯鹵
醯胺 硫酯 醯磷酸 2
General Reaction Pattern
Nucleophilic acyl substitution
Carboxylic acids are among the most widespread of molecules.
A study of them and their primary reaction “nucleophilic acyl substitution” is fundamental to understanding organic chemistry
3
21.1 Naming Carboxylic Acid Derivatives
Acid Halides, RCOX
Derived from the carboxylic acid name by replacing the -ic acid ending
O
HO
OH
O
Succinic acid
5
Naming Esters, RCO2R’
Esters, RCO2R’
Identifying alkyl group R’ attached to oxygen and the
carboxylic acid, replacing –ic acid with “-ate”
RCO2 R’
Common names
IUPAC
Ethyl ethanoate
(from ethanoic 6
Naming Amides, RCONH2
With unsubstituted NH2 group. replace -oic acid or
-ic acid with “-amide”, or by replacing the -carboxylic
acid ending with –carboxamide
If the N is further substituted, identify the substituent
groups (preceded by “N”) and then the parent amide
O
HCN(CH3 ) 2
N,N-Dimethylformamide
(DMF)
7
Naming Thioester, RCOSR’
IUPAC name, the ester, with the “-oate” or 'carboxylate"
ending replaced by “-thioate” or "carbothioate"
Common name, thio+(carboxylate common name)
Common names
IUPAC
Methyl ethanethioate
8
Naming Acyl Phosphates, RCO2PO3-
9
10
21.2 Nucleophilic Acyl Substitution
Carboxylic acid derivatives have an acyl carbon
bonded to a group Y that can leave
A tetrahedral intermediate is formed and the leaving
group is expelled to generate a new carbonyl
compound, leading to nucleophilic acyl substitution
addition
addition
elimination
12
*
Characteristic Reactions
Nucleophilic acyl substitution 親核醯基取代反應 : an
addition-elimination 加成-脫去 sequence
resulting in substitution of one nucleophile for
another
O :O- O
addition elimination
C + :N u- C C + :Y-
R Y R Nu R Nu
Y
Tetrahedral carbonyl Substitution
addition intermediate product
13
Mechanism of Nucleophilic Acyl Substitution
addition
tetrahedral addition
intermediate
elimination
14
Relative reactivity of carboxylic acid derivatives
羧酸衍生物相對反應活性
Steric factor
Relative reactivity of carboxylic acid derivatives
• Electrophilic carbonyl groups are more reactive to
addition
• acyl halides are most reactive, amides are least
離去基能力 : -
Cl >- OCOR >- OR >- NH2
Basicity: -
Cl < -
OCOR < -
OR < -
NH2
Electronic factor
從共振效應看, L 上的孤電子對與 C = O 共振,使羰
基碳正電性降低而穩定。共振效應愈大,碳正電性愈穩
定,反應活性愈低,而四種衍生物共振效應的強弱為:
O O O
R C R C R C
L L L
17
Reactivity 羧酸衍生物相對反應活性
Reactivity decreases as leaving group becomes more basic.
The weaker the base , the better the leaving group
離去基能力 : -
Cl >- OCOR >- OR’ >- NH2 18
Interconversion of Acid Derivatives
A more reactive acid derivative can be converted into a less
reactive one
Acid halides and acid anhydrides react rapidly with water
Interconversion of Derivatives
More reactive derivatives can be
converted to less reactive
derivatives.
20
General Reactions of Carboxylic Acid Derivatives
Hydrolysis 水解 - Water is used as a reagent to
make carboxylic acids
Alcoholysis 醇解– Alcohol is used as reagent
to make esters
Aminolysis 胺解 - Ammonia or an amine is used
to make an amide
Reduction - Hydride source is used to make an
aldehyde or an alcohol
Grignard reaction - Organometallic reagent is
used to make a ketone or an alcohol
Some General Reactions of Carboxylic Acid
Derivatives
21.3 Reactions of Carboxylic Acids
–OH is a poor leaving group
Direct nucleophilic acyl substitution of a
carboxylic acid is difficult
Reactivity of the acid can be increased by:
Using a strong acid catalyst to protonate the
carboxyl
Converting –OH into a better leaving group
Specific reagents such as acid chlorides,
anhydrides, esters, and amides can be
prepared from carboxylic acids
O - O
Y
C C
R OH R Y
Acid Derivatives
Conversion of Carboxylic Acids into Acid Chlorides
Conversion of carboxylic acids into acid chlorides
Reaction with thionyl chloride 亞硫醯氯 , SOCl
2
24
Mechanism of Thionyl Chloride Reaction
Nucleophilic acyl substitution pathway
Carboxylic acid is converted into a chlorosulfite intermediate which replaces
the –OH of the acid with a much better leaving group, then reacts with chloride
addition elimination
25
Conversion of Carboxylic Acids into Acid
Anhydrides
Conversion of carboxylic acids into acid anhydrides
Acid anhydrides can be derived from two molecules
of carboxylic acid by heating to remove water
26
Conversion of Carboxylic Acids into Esters
Conversion of carboxylic acids into esters
Through reaction of a carboxylate anion with a primary alkyl halide
27
Fischer Esterification
Fischer esterification reaction: Synthesis of esters by an acid-catalyzed nucleophilic acyl
substitution reaction of a carboxylic acid with an alcohol
Acid + alcohol yields ester + water.
Acid catalyzed for weak nucleophile alcohol.
All steps are reversible.
28
Mechanism of the Fischer Esterification
Evidence of Mechanism:
18O-label CH O*H react with benzoic acid
3
When 18O-labeled methanol reacts with benzoic acid,
the methyl benzoate produced is 18O-labeled but the
water produced is unlabeled
29
Key mechanism: Fischer Esterification
Nucleophilic acyl substitution
addition
elimination
*
30
(CH 2) Protonation of Carboxylic acid:
protonated carbonyl or protonated hydroxyl?
For acetic acid, protonation cccurs on the doubly bonded
oxygen bause that product is stabilized by two resonance
forms
31
Fischer Mechanism (1)
Addition:
Acid-catalized protonation of carbonyl and attack of
alcohol, a weak nucleophile.
+ +
O H OH OH
CH2CH3 CH2CH3
ester hydrate
羧酸衍生物的親核醯基取代反應實際上是經歷
(1) 親核加成 (2) 脫去兩步反應
32
Fischer Mechanism (2)
Elimination:
Acid-catalized protonation of -OH and loss of water.
+
H +
H OH OH H
+
C OH O C O
COH C OH R
O O
O O
CH2CH3 CH2CH3
CH2CH3 CH2CH3
ester
Key mechanism:
• addition-elimination mechanicm of nucleophilic acyl substitution
memorize it!
33
Fischer Esterification
a key intermediate in Fischer esterification is the
tetrahedral carbonyl addition intermediate (TCAI)
or tetrahedral intermediate formed by addition of
ROH to the C=O group
H TCAI
O
R C OCH3
O
H
H + H+
O O
R C OH + HOCH3 R C OCH3 + HOH
34
Fischer Esterification
Fischer esterification is an equilibrium reaction
by careful control of experimental conditions, it
is possible to prepare esters in high yield
if the alcohol is inexpensive relative to the
carboxylic acid, it can be used in excess to
drive the equilibrium to the right
alternatively, water can be removed by
azeotropic distillation
+ H2O
35
Conversion of Carboxylic Acids into Amides
•
Conversion of carboxylic acids into amides
• difficult to prepare by direct reaction of carboxylic
Dicyclohexylcarbodiimide (DCC )
coupling reagent 偶合試劑
N C N
36
Mechanism of
amide formation
by reaction of a
carboxylic acid
and an amine with
dicyclohexylcarbo
addition
diimide (DCC).
elimination
38
Conversion of Carboxylic Acids into Alcohols
Reduction is a nucleophilic acyl substitution reaction in
which –H replaces –OH to give an aldehyde
addition elimination
39
*
Conversion of Carboxylic Acids into Alcohols
Borane 硼烷 reacts with carboxylic acids faster than any
other functional groups.
Borane, BH3 in THF, reduces carboxylic acid to
alcohol, but does not reduce nitro group.
40
21.4 Chemistry of Acid Halides
Preparation of acid halides 醯鹵
Acid chlorides 醯氯 are prepared from carboxylic acids by
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Reactions of Acid Halides
Nucleophilic acyl substitution mechanisms
Halogen replaced by OH, by OR, or by NH2
Reduction yields a primary alcohol
Grignard reagent yields a tertiary alcohol
42
Interconversion of Derivatives
43
Hydrolysis: Conversion of Acid Halides into Acids
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Conversion of Acid Halides into Anhydrides
Conversion of acid halides into anhydrides
Nucleophilic acyl substitution reaction of acid chloride
with a carboxylate anion gives acid anhydride
45
Conversion of Acid Halides to Esters
Alcoholysis 醇解 : Esters are produced in the
reaction of acid chlorides with alcohols in the
presence of pyridine or NaOH.
The reaction is strongly affected by steric hindrance
46
Aminolysis: Conversion of Acid Halides into Amides
47
Conversion of Acid Halides into Amides
鎮靜劑 48
Reduction: Conversion of Acid Chlorides into Alcohols
Conversion of acid chlorides into alcohols: Reduction and Grignard reaction
LiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols
Reduction occurs via nucleophilic acyl substitution mechanism
49
Reaction of Acid Chlorides with Grignard Reagents
Grignard reagents react with acid chlorides to yield tertiary
alcohols with two identical substituent
Reduction occurs via nucleophilic acyl substitution mechanism
50
Formation of Ketones from Acid Chlorides
Conversion of acid chlorides into ketones: Diorganocopper reaction
Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li+ R2Cu
Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and
formation of the ketone
RCOOH, RCOR', RCO2COR' ,RCONH2 do not react
oxidative reductive
addition elimination
51
21.5 Chemistry of Acid Anhydrides
52
Reactions of Acid Anhydrides
Similar to acid chlorides in reactivity
53
Interconversion of Derivatives
54
Conversion of Acid Anhydrides to Esters
Conversion of acid anhydrides into esters
Acetic anhydride forms acetate esters
(Acetylation) from alcohols
阿斯匹林 55
Conversion of Acid Anhydrides to Amides
Conversion of acid anhydrides into amides
Acetic anhydride forms N-substituted acetamides from
amines
乙醯胺酚
Panadol (普拿疼) 56
21.6 Chemistry of Esters
Many esters are pleasant-smelling liquids: fragrant odors
of fruits and flowers
Also present in fats and vegetable oils
57
Preparation of esters
Preparation of Esters
Esters are usually prepared from carboxylic acids
Acid chlorides are converted into esters by treatment with an alcohol in the presence of base
58
Reactions of Esters
Reactions of Esters
Less reactive toward nucleophiles than are
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Hydrolysis: Conversion of Esters into
Carboxylic Acids
Hydrolysis 水解 : An ester is hydrolyzed by aqueous base or
aqueous acid to yield a carboxylic acid plus an alcohol
Saponification 皂化 : Ester hydrolysis in basic solution
60
Mechanism of Base-induced Ester Hydrolysis
nucleophilic acyl substitution
Hydroxide catalysis
via an addition
intermediate addition
tetrahedral addition
intermediate
elimination
61
Mechanism of
acid-catalyzed
ester hydrolysis
addition
tetrahedral addition
intermediate
elimination
62
Ester hydrolysis in biological chemistry
63
Conversion of Esters into Aamides : Aminolysis
64
Leaving Groups in Nucleophilic Acyl 補充
Substitution
-
OCH3 leave in an
exothermic step.
SN2
Endothermic:
the reaction rate
is sensitive to
leaving group
Acyl
substitution
Exothermic:
the reaction rate is
not sensitive to
leaving group
66
67
Mechanism of Reduction of Esters
68
Reduction Of Esters With Reducing Agent DIBAL
Partial reduction of ester with 1 equivalent of
weaker reducing agent diisobutylaluminum
hydride (DIBAL or DIBAH) to yield an aldehyde
69
Reaction of Esters with Grignard Reagents
Conversion of esters into alcohols: Grignard reaction
Esters react with 2 equivalents of a Grignard reagent to yield a tertiary alcohol
70
21.7 Chemistry of Amides
Amides are abundant in living organisms
Proteins, nucleic acids, and other pharmaceuticals
have amide functional groups
Amides are the least reactive of the common acid
derivative
a cyclic amide,
lactam 內醯胺 Uracil
71
Preparation of Amides
72
Reactions of Amides
Conversion of Amides into Carboxylic Acids: Hydrolysis
Heating in either aqueous acid or aqueous base produces a carboxylic acid
and amine
Acidic hydrolysis by nucleophilic addition of water to the protonated amide,
addition
elimination
73
Basic Hydrolysis of Amides
• Basic hydrolysis is difficult in comparison to
analogous acid-catalyzed reaction because amide
ion is a very poor leaving group
• Addition of hydroxide and loss of amide ion
addition elimination
74
Amide hydrolysis In biological chemistry
75
Conversion of Amides into Amines : Reduction
Conversion of amides into amines: Reduction
Reduced by LiAlH
4 to an amine rather than an alcohol
Converts C=O CH2
76
Mechanism of Reduction
Addition of hydride to carbonyl group
Loss of the oxygen as an aluminate anion to give
an iminium ion intermediate which is reduced to
the amine
77
Uses of Reduction of Amides
The reaction is effective with both acyclic and cyclic amides, or
lactams 內醯胺
Good route for preparing cyclic amines
78
21.8 Chemistry of Thioesters and Acyl Phosphates:
Biological Carboxylic Acid Derivatives
Nucleophilic carboxyl substitution in nature often
involves a thioester 硫酯 or acyl phosphate 醯磷酸
Acetyl CoA’s are most common thioesters in nature
79
.
•
Acetyl CoA whose thioesters serve as a biochemical acyl
transfer reagents. Acetyl CoA transfers an acetyl group to a
nucleophile, with coenzyme A serving as the leaving group.
葡萄糖胺
乙醯葡萄糖胺
‘ 維骨力’
結締組織成分
關節滑液囊的潤滑液
80
Resonance Overlap in Ester and Thioesters
Thioesters are more reactive than esters because:
- S-R is a better leaving group than -O-R
The resonance overlap in a thioester is not as
effective as that in an ester.
2p 3p
2p 2p
21.9 Polyamides and Polyesters: Step-
Growth Polymers
Reactions occur in distinct linear steps, not as chain
reactions
Reaction of a diamine and a diacid chloride gives an
ongoing cycle that produces a polyamide (nylon)
A diol with a diacid leads to a polyester
82
Polyamides (Nylons)
Polyamides (Nylons)
Heating a diamine with a diacid produces a polyamide called nylon
Example - Nylon 66 尼龍 66 is prepared from adipic acid 己二酸 and
hexamethylene-diamine 己二胺 at 280°C
84
Polyesters
The polyester from diphenyl carbonate 碳酸二苯酯 and
bisphenol 雙酚 is called Lexan® ( 聚碳酸酯 Polycarbonate PC, 熱塑
性材料 )
85
Biodegradable Polymers
• Sutures and biodegradable polymers
• Common biodegradable polymers include:
• Poly(glycolic acid) (PGA)
• Poly(hydroxybutyrate) (PHB)
aldehydes or ketones
Amides absorb near the low end of the
87
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Nuclear Magnetic Resonance Spectroscopy
Hydrogens on the carbon next to a C=O are near 2~3
in the 1H NMR spectrum.
All acid derivatives absorb in the same range so NMR
does not distinguish them from each other
89
13
C NMR
90
Summary
Carboxylic acid derivatives are compounds in which
the –OH group of a carboxylic acid has been
replaced by another substituent
Acid halides, acid anhydrides, esters, and amides
are the most common
Thioesters and acyl phosphates are common in
biological molecules
Nucleophilic acyl substitution reaction dominates the
chemistry of carboxylic acid derivatives
Step-growth polymers are prepared by reactions
between difunctional molecules