chap 18. carboxylic acids and their derivatives. nucleophilic substitution at the acyl carbon 18.1...
TRANSCRIPT
Chap 18. Carboxylic acids and their derivatives. Nucleophilic subst
itution at the acyl carbon
18.1 Introduction
The carboxyl group, -COOH, -CO2H, is one of the most widely occurring functional groups in chemistry and biochemistry. Not only are carboxylic acids themselves important, but the carboxyl group is the parent group of a large family
of related compounds.
All of these carboxylic acid derivatives contain the acyl group, RCO-. As a result, they are often called acyl compounds. They are called carboxylic acid derivat
ives.
R
O
Cl
R
O
O
O
R
R
O
O R
Acyl (or acid) chloride
Acid anhydride
Ester
R
O
NH2
R
O
NHR'
R
O
NR'R''
Amide
£¨õ£°·£©£¨õ£ÂÈ£©
£¨Ëáôû£©
£¨õ¥£©
£¨N-È¡´úõ£°·£©
£¨N,N-¶þÈ¡´úõ£°·£©
18.2 Nomenclature and physical properties
18.2A Carboxylic acids
CH3CH2CHCH2CH2COOH
CH3
4-Methylhexanoic acid
4 3 2 1
CH3CH=CHCH2CH2COOH6 5 4 3 2 1
4-Hexenoic acid
HCOOH CH3COOH
Methanoic acid Ethanoic acid(Formic acid) (Acetic acid)
£¨¼×Ëᣩ£¨ÒÏËᣩ £¨ÒÒËᣩ
£¨4-¼×»ù¼ºËᣩ
£¨4-¼ºÏ©Ëᣩ
ClCH2COOH
Chloroethanoic acid
£¨ÂÈ´úÒÒËᣩ
Cl3CCOOH
Trichloroethanoic acid
£¨ÈýÂÈ´úÒÒËᣩ
CH3(CH2)3CO2H
Pentanoic acid£¨ÎìËᣩ
£¨1-ÝÁËᣩ
COOH
COOH
COOH
Benzoic acid 1-Naphthoic acid 2-Naphthoic acid
£¨2-ÝÁËᣩ
18.2C Acidity of carboxylic acidsMost unsubtituted carboxylic acids have Ka values in the range of 10-4—10-5(pka = 4-5).
COOH
+ NaOH
COONa
+ H2O
Benzoic acid Sodium benzoate
(water insoluble) (water soluble)£¨±½¼×ËáÄÆ£©
CO2H + NaHCO3 CO2Na + CO2 + H2O
(pKa = 4.15)
If carboxylic acids have electron-withdrawing groups, they are stro
nger than unsubstituted acids.Cl
CCl
Cl
CO2H
Cl
CCl
H
CO2H
H
CCl
H
CO2H
H
CH
H
CO2H
pKa 0.7 1.48 2.85 4.75
由于氯原子电负性比碳大，氯原子表现出拉电子诱导效应 (Inductive effect) ，使羧酸容易电离出质子 (H+) 。羧酸的酸性增强。
pKa 2.85 4.05 4.50
CH3CH2CHC OH
O
Cl
CH3CHCH2C OH
O
CH2CH2CH2C OH
Cl Cl
O
2-Chlorobutanoic acid 3-Chlorobutanoic acid 4-Chlorobutanoic acid
氯原子的诱导效应随着距离的增长对羧基的影响减弱，因而羧酸的酸性变弱。
COOHCOOH COOHCOOH
NO2 Cl CH3
18.2E EstersThe names of esters are derived from the names of the alcohol (with the ending –yl) and the
acid (with the ending –ate or –oate).
CH3COCH2CH3
O
CH3CH2COC(CH3)3
O
CH3COCH=CH2
O
Ethyl acetate orethyl ethanoate
Vinyl acetate orethenyl ethanoate
tert-Butyl propanoate
ÒÒËáÒÒõ¥ ÒÒËáÒÒÏ©õ¥±ûËáÊ嶡õ¥
CH3COCH2CH2CH(CH3)2
O
CH3CH2CH2CH2C
O
OCH2CH2CHCH3
CH3Isopentyl acetate(used in synthetic banana flavor)
Isopentyl pentanoate(used in synthetic apple flavor)
ÒÒËáÒìÎìõ¥ ÎìËáÒìÎìõ¥
C
O
OCH3 C
O
OCH3Cl
Methyl benzoate Methyl p-chlorobenzoate
±½¼×Ëá¼×õ¥ ¶Ô-Âȱ½¼×Ëá¼×õ¥
HOOCCH2COOH CH3CH2OOCCH2COOCH2CH3
Malonic acid Diethyl malonate±û¶þËá ±û¶þËá¶þÒÒõ¥
18.2F Carboxylic anhydrides（酸酐）
Most anhydrides are named by dropping the word acid from the name of the carboxylic acid and then adding the word anhydride.
C
O
O
O
H3C
H3C C
O
O
O
H2C
H2C
O
O
O
C
O
O
O
HC
HC
Acetic anhydride Succinic anhydride Maleic anhydride Phthalic anhydride
ÒÒôû »·¶¡ôû »·¶¡Ï©ôûÂíÀ´ôû
ÁÚ±½¶þ¼×Ëáôû
18.2G Acyl chlorides ( 酰氯）Acyl chlorides are also called acid chlorides. They are named by dropping –ic acid from the
name of the acid and then adding –yl chloride. Examples are
CH3C
O
ClR C
O
Acyl group
CH3CH2C
O
Cl
O
Cl
Acetyl chloride Propanoyl chloride Benzoyl chloride
õ£»ù õ£ÂÈ ±ûõ£ÂÈ ±½¼×õ£ÂÈ
18.2H Amides ( 酰胺）
CH3C
O
NH2R C
O
Acyl group
CH3CH2C
O
NH2
O
NH2
Acetamide Propanamide Benzamideõ£»ù õ£°· ±ûõ£°· ±½¼×õ£°·
CH3C
O
NHCH3
N-Methylacetamide
N-¼×»ùÒÒõ£°·
CH3C
O
N(CH3)2
N,N-Dimethylacetamide
N,N-¶þ¼×»ùÒÒõ£°·
CH3C
O
N
C6H5
CH2CH2CH3
N-Phenyl-N-propylacetamide
N-±½»ù-N-±û»ùÒÒõ£°·
18.2I Nitriles ( 腈）CH3 C N CH3CH2CH2C N CH2=CHC N
Ethanenitrile(acetonitrile)
Butanenitrile Propenenitrile
ÒÒëæ ¶¡ëæ ±ûÏ©ëæ
C N C N
Benzenecarbonitrile(benzonitrile)
Cyclohexanecarbonitrile
±½¼×ëæ »·¼º»ù¼×ëæ
18.2J Spectroscopic properties of acyl compounds
IR;
Carboxylic acid; RCOOH 1700-1725cm-1
ArCOOH 1680-1700cm-1
C=O
Acid anhydride;
R
O
O
O
R
Ar
O
O
O
Ar
1800-1850cm-1
1780-1860cm-1
C=O
Acyl chloride;
R
O
Cl and Ar
O
Cl 1780-1850cm-1
Ester;
R
O
OR' 1735-1750cm-1
Ar
O
OR' 1715-1730cm-1
C=O
C=O
C=O
C=O
Amides;
R
O
NH2 1630-1690cm-1
C=O
1H NMR; RCOOH H 10-12
18.3 Preparation of carboxylic acids1. By oxidation of alkenes.
RCH=CHR'1) KMnO4, OH-
2) H3O+RCOOH + R'COOH
RCH CR'R"1) KMnO4, OH-
2) H3O+RCOOH + R'COR''
2. By oxidation of aldehydes
and primary alcohols.
RCHO1) Ag2O, or Ag(NH3)3OH-
2) H3O+RCOOH + Ag
1) KMnO4, OH-
2) H3O+
(Mirror reaction)
RCH2OH RCOOH
3. By oxidation of alkylbenzenes.
2) H3O+
1) KMnO4, OH-
2) H3O+
CH3 C6H5COOH
COOH
COOH
1) KMnO4, OH-
4. By oxidation of methyl ketones. （甲基酮的氧化）
2) H3O+C C6H5COOH
1) X2 / NaOH
O
CH3 + CHX3
(±·Â·´Ó¦£©
R C
O
CH32) H3O+
RCOOH1) X2 / NaOH
+ CHX3
(±·Â·´Ó¦£©
5. By hydrolysis of cyanohydrins and other nitriles.( 腈醇和腈的水
解）R
R'
O + HCN
R
C
R'
OH
CN
H+
H2O
R
C
R'
OH
COOH
RCH2X + NaCN RCH2COOHH+
H2O
BrCH2CH2CH2CH2Br NaCN NC(CH2)4CNH3O+
HOOC(CH2)4COOH
在合成上增加一个碳原子的羧酸。
6. By carbonation （羰基化） of Grignard reagents.
Grigard reagents react with carbon dioxide to yield magnesium carbon dioxide to yield magnesium carboxylates. Acidification produces carbox
ylic acids.
R X + Mgdiethyl ether
RMgXC OO
R C O
OMgX
H3O+ R C O
OH+ Mg
OH
X
Br + Mgdiethyl ether
PhMgXC OO
Ph C O
OMgX
H3O+ Ph C O
OH+ Mg
OH
X
Grignard reagents
Grignard reagents
CH3 + Mgdiethyl ether
C OO
(H3C)3C C O
OMgX
H3O+
(H3C)3C C O
OH
+ MgOH
X
Grignard reagents
C
CH3
CH3
Cl CH3 C
CH3
CH3
MgCl
CH2Br + Mgdiethyl ether
PhCH2MgXC OO
PhH2C C O
OMgX
H3O+ PhH2C C O
OH
+ MgOH
X
Grignard reagents
18.4 Nucleophilic substitutions at the acyl carbon
1. The reaction of an acyl group with water.
R
O
Cl + H2O RCOOH + HCl
R
O
O + H2O RCOOH + RCOH
R
O
OR' + H2O RCOOH + R'OH
O
R
R
O
NH2 + H2O RCOOH + NH3
2. The reaction of an acyl group with an alcohol.
R
O
Cl + ROH RCOOR + HCl
R
O
O + RCOOR + RCOOH
R
O
OR' + RCOOR' + ROH
O
R ROH
ROH õ¥½»»»·´Ó¦
The reaction mechanism is as follows
R
O
L +
ROHL= Cl, OCOR, OR,
NuH
HOH
R
O-
L
NuH
R
O
Nu
+ HLNucleophilic-Addition Elimination
18.4A Relative reactivity of acyl compounds ( 酰基化合物相对反应活性）
R
O
Cl R
O
O R
O
OR'
O
R R
O
NH2
Acyl chloride Acid anhydride Ester Amide
Ëáôûõ£ÂÈ õ¥ õ£°·
Acyl chlorides are the most reactive toward nucleophilic substitution and amides are the least reactive.
18.5 Acyl Chlorides18.5A Synthesis of acyl chlorides
R
O
OH
Acyl chloride
õ£ÂÈ
+ SOCl2 R
O
Cl + SO2 + HCl
Thionyl chlorideÑÇÁòõ£ÂÈ
R
O
OH
Acyl chloride
õ£ÂÈ
+ R
O
Cl +
Phosphorus trichloride
ÈýÂÈ»¯Á×
PCl3 H3PO3
R
O
OH
Acyl chloride
õ£ÂÈ
+ R
O
Cl +
Phosphorus pentachloride
ÎåÂÈ»¯Á×
PCl5 POCl3 + HCl
18.5B Reactions of acyl chlorides
R
O
OH
Acyl chloride
õ£ÂÈ
R
O
Cl
PCl3 or PCl5
SOCl2
R'COONa
(- NaCl)R'COOCRAnhydride
R'OH, Base
(-HCl)RCOOR'
Ester
NH3
(-NH4Cl)RCONH2
R'NH2
(-R'NH3Cl)RCONHR'
R'R''NHRCONR'R''
Amide
N-Substituted amide
N,N-Disubstituted amide
18.6 Carboxylic acid anhydrides18.6A Synthesis of carboxylic acid anhydri
des （酸酐的合成）
HO
O
R'
Acyl chloride
õ£ÂÈ
R
O
Cl +N R
O
O
O
R' +
N+H
Cl-
NaO
O
R'
Acyl chloride
õ£ÂÈ
R
O
Cl + R
O
O
O
R'
(- NaCl)
Cyclic anhydrides can somethimes be prepared by simply heating the appropriat
e dicarboxylic acid.O
O
OH
OH
300 oCO
O
O
+ H2O
Succinic acid Succinic anhydrideçúçêËá çúçêËáôû¶¡¶þËá »·¶¡¶þËáôû
O
O
OH
OH
230 oC
O
O
O
+ H2O
Phthalic acid Phthalic anhydride
ÁÚ±½¶þ¼×Ëá ÁÚ±½¶þ¼×Ëáôû
The reactions of acid anhydride
R
O
O
R'OHRCOOR' + RCOOH
Ester
RCONHR'R'NH2
RCONR'R''R'R''NH
Amide
N-Substituted amide
N,N-Disubstituted amide
O
R
NH3
õ£Ñõ¼ü¶ÏÁÑ
RCONH2
18.7A Synthesis of esters: Esterification ( 酯化反应）
Carboxylic acids react with alcohols to form esters through a condensation reaction known as
esterification:
General Reaction
R
O
OH + HOR'H+
R
O
OR' + H2O õ¥»¯·´Ó¦
Esterification Esterõ¥
Specific Examples;
+H+
O
OCH2CH3
Esterification Ethyl acetate
ÒÒËáÒÒõ¥
CH3
O
OH CH3 + H2O
Acetic acid
ÒÒËá
Ethanol
HOCH2CH3
+H+
O
OCH2CH3
Esterification Methyl benzoate
±½¼×ËáÒÒõ¥
C6H5
O
OH + H2O
Benzoic acid
±½¼×Ëá
Ethanol
HOCH2CH3 C6H5
用同位素 O18 标记法来研究酯化反应机理
+H+
O
OCH2CH3
Esterification Methyl benzoate
±½¼×ËáÒÒõ¥
C6H5
O
O18H + H2O18
Benzoic acid
±½¼×Ëá
Ethanol
HOCH2CH3 C6H51.
羧酸的酰氧键断裂
+H+
O
O18CH2CH3
Esterification Methyl benzoate
±½¼×ËáÒÒõ¥
C6H5
O
O18H + H2O
Benzoic acid
±½¼×Ëá
Ethanol
HOCH2CH3 C6H52.
醇的烷氧键断裂
实验证明，羧酸的酯化是按照羧酸的酰氧键断裂方式进行。即按 1 反应方式进行。
Acid-Catalyzed esterification mechanism
+H+
O
OCH2CH3
Esterification Methyl benzoate
±½¼×ËáÒÒõ¥
C6H5
O
O18H + H2O18
Benzoic acid
±½¼×Ëá
Ethanol
HOCH2CH3 C6H51.
H+
C6H5
O
O18H
H
-H+
+HOCH2CH3
C6H5
OH
O18H
OCH2CH3H+
- HOCH2CH3
C6H5
OH
O18H
OCH2CH3
H
+
- H+ H+
Acid-Catalyzed Ester Hydrolysis;
+
O
OCH2CH3
Methyl benzoate
±½¼×ËáÒÒõ¥
C6H5
O
OH+ H2O
Benzoic acid
±½¼×Ëá
Ethanol
HOCH2CH3C6H5
H+
Esters from Acyl chlorides （由酰氯制备酯）
O
Cl + HOCH2CH3N
O
OCH2CH3
Ethyl benzoate
(80%)
Benzoyl chloride
±½¼×õ£ÂÈ ±½¼×ËáÒÒõ¥
放出的氯化氢气体被吡啶吸收。N
H
+ Cl-
ßÁà¤ÑÎËáÑÎ
Esters from Carboxylic Acid Anhydrides ( 由酸酐制备酯）
H3C
O
O
O
H3C
+ HOCH2C6H5 CH3C
O
OCH2C6H5 + CH3COOH
Acetic anhydride
Benzyl
Alcohol
Benzyl acetate
£¨ÒÒôû£© £¨Üлù´¼£©
£¨ÒÒËáÜÐõ¥£©
O
O
O
+ CH3CHCH2CH3
OH
O
O
OH
OCHCH2CH3
CH3
Phthalic anhydride sec-Butyl alcohol sec-Butyl hydrogen phthalate
(97%)ÁÚ-±½¶þ¼×Ëáôû ÁÚ-±½¶þ¼×ËáµÚ¶þ¶¡õ¥
18.7B Base-promoted hydrolysis of esters: Saponification ( 皂化反应）
R
O
OR' + NaOHH2O
R
O
ONa + R'OH
Ester Sodium carboxylate Alcohol
R
O
OR'Ester
NaOH+ R
O-
OR'
OH
R
O
OH + -OR' R
O
ONa + HOR'
酯的碱性条件下的水解 ----- 称为皂化反应。
Evidence for this mechanism comes from studies done with isotopically labeled este
rs.( 同位素的标记来研究酯的水解机理）
R
O
O
Ester
NaOH+ R
O
ONa + HOR'18 18
R'
a b
a
õ£Ñõ¼üÍéÑõ¼ü
R
O
ONa + HOR'18
b
实验证明；酯的水解一般按照酰氧键断裂方式进行。
18.7C Lactones ( 内酯）
CH3CHCH2CH2C OH
O
OH
- hydroxy pentanoic acid
O
O
CH3
- ÎìÄÚõ¥ - ôÇ»ùÎìËá
CH2CH2CH2CH2C OH
O
- hydroxy pentanoic acid
- ÎìÄÚõ¥- ôÇ»ùÎìËá
OH
O
O
Erythromycin A 红霉素（抗生素的一种）
O
O
OHHO
H
O
OH
O
O
O
O
HO
N(CH3)2
CH3
CH3
OHCH3
OCH3
O
HO H
CH2OH
Vitamin C
H
HO
OH
άÉúËØ C
O
18.8 Amides ( 酰胺）
18.8A Synthesis of amides
Amides can be prepared in a variety of ways starting with acyl chlorides, acid anhydrides, esters, carboxylic acids, and carboxylic salts. All of these methods involve nucleophilic substitution reactions by ammonia or an amine at an acyl carbon. As we might expect, acid chlorides are the most reactive and carboxyla
te ions are the least.
18.8B Amides from acyl chloride
Primary amines, secondary amines, and ammonia all react rapidly with acid chlorides to from amides.
R
O
Cl + HNH2 R
O
NH2 + NH4Cl
An amide
R
O
Cl + HNHR R
O
NHR + RN+H3Cl-
An N-substituted amide
R
O
Cl + HNRR' R
O
NRR' + HN+RR'Cl-
An N,N-disubstituted amide
酰氯是非常活泼的，它很容易与氨，伯胺，仲胺反应生成酰胺
Reaction Mechanism
R
O
Cl + HNH2 R
O
NH2 + NH4Cl
An amide
R
O
Cl + NH3 R
O-
Cl
N H
H
H+
R
O
NH2
+ HCl
NH3
NH4Cl
18.8C Amides from carboxylic anhydrides
Acid anhydrides react with ammonia and with primary and secondary amines and form amides through ractions that are analogous to those
of acyl chlorides.
+ HNH2 R
O
NH2 + RCO2NH4
R
O
O
An amide
O
R
+ HNHR R
O
NHR + RCO2N+H3
An N-substituted amide
R
O
O
O
R
+ HNRR' R
O
NRR' + RCO2RR'H2N+
An N,N-disubstituted amide
R
O
O
O
R
+ HNH2O
O
O
Phthalic anhydride
O
O
NH2
OH
150-160oC
NH
O
OPhthalimide
ÁÚ±½¶þ¼×õ£ÑÇ°·ÁÚ±½¶þ¼×Ëáôû
- H2O
18.8G Nitriles from the dehydration of amides
( 由酰胺制腈）Amides react with P2O5 or with boiling
acetic anhydride to form nitriles.
R
O
NH2P2O5 or (CH3CO)2O
R C N
A nitrile
+ H3PO4 or CH3CO2H
ëæ
heat, - H2O
18.8H Hydrolysis of nitriles （腈的水解）
R C N
A nitrileëæ
H+, H2O
OH- , H2O
heat
heat
RCOOH
RCOO-
CH2Cl CH2COOH
NaCN
CH2CN
H+, H2O, heat
±½ÒÒëæ
18.8I Lactams ( 内酰胺 )Cyclic amides are called lactams.
NH
NH
NHO
R
O
R
O
R
A
- Lactam
A - Lactam - LactamA
N
S
NH
O
R
O
CH3
CH3
COOH
R = C6H5CH2 -
R = C6H5CH -
NH2
R = C6H5OCH2 -
( penicillin G)
(ampicillin)
(penicillin V)
(ÇàùËØ G)
( penicillin)
Polyamides （聚酰胺）NH
O
H2O-OC(CH2)5NH2
O
¾ÛºÏ *
O
(CH2)5NH
O
(CH2)5NH *
nNylon-6
ÄáÁú-6
¼ºÄÚõ£°·
- Caprolactam
¾ÛºÏO
(CH2)5
O
NH
nNylon-6,6
ÄáÁú-6,6
n HOC(CH2)4COH + n H2N (CH2)6NH2
O O
Adipic acid Hexamethylenediamine(CH2)6 NH
¾Û¼º¶þõ£¾Û¶þ°·
1£¬6-¼º¶þ°·¼º¶þËá
Nylon 6 or Nylon 6,6 can also be converted into fibers by melt spinning. ( 熔融纺丝 )
18.9 α- Halo Acids (α- 卤代酸）Aliphatic carboxylic acids react with bromine or chlorine in the presence of phosphorus (or a
phosphorus halide) to give α- halo acids.O
OH1) X2 , P
2) H2ORCH2
RCHCO2H
X
- halo acidO
OH1) Br2 , P
2) H2O
- Bromobutanoic acid
CH3CH2CH2
Butanoic acid
CH3CH2CHCOOH
Br
- ä嶡ËᶡËá
α- Halo acids are important synthetic intermediates because they are capable of reacting with a
variety of nucleophiles;
1 ） Conversion to α- hydroxy acids
(α- 卤代酸可以转换成 α- 羟基酸）
- Bromobutanoic acid
CH3CH2CHCOOH
Br
- ä嶡Ëá
1) K2CO3, H2O
100 oC2) H2O
CH3CH2CHCOOH
OH
2-Hydroxybutanoic acid 2-ôÇ»ù¶¡Ëá (69%)
2 ） Conversion to α- amino acids
(α- 卤代酸可以转换成 α- 氨基酸）
- Bromobutanoic acid
CH3CH2CHCOOH
Br
- ä嶡Ëá
CH3CH2CHCOOH
NH2-Aminobutanoic acid 2-°±»ù¶¡Ëá
NH3
18.10 Derivatives of carbonic acid（碳酸的衍生物）
Carboic acid H2CO3 is an unstable compound that decomposes spontaneously (to produce carbon dioxide and water) and, therefore, can not be isolated. However, many acyl chlorides, esters, and amides that are derived from carbonic acid are stable compounds that have im
portant applications.
Carbonyl dichloride (ClCOCl), a highly toxic compound that is also called phosgene, can be thought of as the diac
yl chloride of carbonic acid.
Cl
O
Cl
Carbonyl dichloride
+ 2 HOCH2CH3 CH3CH2OCOCH2CH3
O
Diethyl carbonatePhosgene
+ 2 HCl
£¨¹âÆø£©2 H2O
HO
O
OH + 2 HCl
air
Cl
O
Cl
Carbonyl dichloridePhosgene£¨¹âÆø£©
+ 4 NH3 H2N
O
NH2 + 2 NH4Cl
Urea
ÄòËØ
18.11 Decarboxylation of carboxylic acids
（羧酸的脱羧基 -COOH ）The reaction whereby a carboxylic acid loses CO2 is called a decarboxylation.
R
O
Odecarboxylation
H R H + O C O
ÍÑôÈ Carbon dioxide
decarboxylation+ O C O
ÍÑôÈ Carbon dioxide
CH3CH2CCH2C CH3CH2C
O O
O H
O
CH3
- ÎìͪËá 2-¶¡Íª2- Butanone
P 807 Additional problems
18.19, 18.20, 18.21, 18.24, 18.27, 18.35, 18.44