chapter 14 carboxylic acid derivatives: nucleophilic acyl substitution 14.1 carboxylic acid...
TRANSCRIPT
Chapter 14 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
14.1 Carboxylic Acid Derivatives and Nomenclature14.2 Structure of carboxylic acid derivatives14.3 Preparation of carboxylic acid derivatives14.4 Nucleophilic substitution at the acyl carbon14.4.1 Hydrolysis14.4.2 Reactions with alcohols 14.4.3 Reactions with amines
14. 5 Reduction 14.5.1 Reduction by LiAlH4 (LAH) and its derivatives14.5.2 Reduction by Na14.5.3 Reaction with Grignard reagents14.6 Reactions of amides14.6.1 Dehydration of amides14.6.2 The Hofmann Rearrangement14.7 Spectroscopic analysis of carboxylic acid derivatives
RC
O
LCH3CH2C
O
ClCH3CH2C
O
Cl
Propanoyl chloride丙酰氯
Acyl halides酰卤
CH3C O CCH3
O OCH3C O CCH3
O O
Acetic anhydride乙酸酐
Carboxylic acid anhydrides
酸 酐
Propanoic acid
CO
OC2H5CH3CO
OC2H5CH3
Esters酯
Acetic acid
Ethyl acetate乙酸乙酯
Acetic acid
Propanoyl chloride
Acetic anhydride
Ethyl acetate
P309,10.1P309,10.1
C
O
OCH2CH3C
O
OCH2CH3
Benzoic acidEthyl benzoate（苯甲酸乙酯）
14.1 Carboxylic Acid Derivatives and Nomenclatures
CH3C
O
NH2
C6H5C
O
NHCH3
HC
O
NCH3
CH3
Acetamide乙 酰胺
N-MethylbenzamideN- 甲基苯甲 酰胺
N,N-Dimethylform-amide (DMF)
N, N- 二甲基甲 酰胺
Amides酰胺
Acetic acidAcetamide
PhC N
Nitrile腈
Benzonitrile苄腈
Phenyl cyanide苯基氰
Benzoic acidBenzonitrile
CH3CHCH2CH2CN
CH3
4-Methylpentanenitrile4- 甲基戊腈
R
O L
A common feature of carboxylic acid derivatives:
CH3C
O
L + H2O CH3C
O
OH + HL
Hydrolysis to carboxylic acids
PhC N + H2O PhCOOHH+
+ NH4+
14.2 Structure of carboxylic acid derivatives
R CO
LR C
O
LR C
O
L
p - π Conjugation
L: X < OCR' < OR' < NHR'O
+C Effect:
14.3 Preparation of Carboxylic Acid Derivatives14.3.1 Preparation of Acyl Halides
RC
O
OH
SOCl2
PBr3
RC
O
Cl
EtherRC
O
Br
SOCl2(Thionyl chloride)PBr3(Phosphorous tribromide)14.3.2 Preparation of Acid Anhydride
RC
O
Cl R'C
O
OH+N
RC
O
O CR'
O
+ + N
H
Cl
RC
O
Cl R'C
O
ONa+ RC
O
O CR'
O
14.3.3 Preparation of Esters
RC
O
OH + R'OHH+
RC
O
O R'
RC
O
Cl R'OH+Pyridine
RC
O
O R'
14.3.4 Preparation of Amides
RC
O
Cl +
NH3
R'NH2
R'2NH
RC
O
NH2
RC
ONHR'
RC
ONR'2
14.4 Nucleophilic substitution at the acyl carbon
14.4.1 Hydrolysis
(C6H5)2CHCH2CCl
O
+ H2ONa2CO3
0¡æ, 65%(C6H5)2CHCH2COH
O
CH3 CH
CH
C
C
O
OO
H2O, ¡÷
94%
CH3 CH
CH
C
C
O
O
OH
OH
O O
H2O, NaOH
90% OH
CO
OH
P318,10.5P318,10.5
Ch.P390Ch.P390
RC
O
L + Nu:RC
O
L R C
O
Nu
L RC
O
NuAddition Elimination + L
CH3C
O
NH Br C2H5OH-H2O, KOH95%
CH3C
O
O-K+
+ NH2 Br ¡÷£¬Mechanism:
Saponification( 皂 化 反应 )
Step 1 Nucleophilic addition of hydroxide ion to carbonyl group.
R CO
O R'+ O H R C
O R'
O H
O
Base-promoted hydrolysis of ester
Hydrolysis of Acyl halides is catalyzed by a base.
Hydrolysis of Acid anhydridesEstersAmides
Catalyzed by a acid or a base.
P331P331
R C
O R'
O H
OR C
O
O H+ R' O
Step 2 Elimination of leaving group to restore carbonyl group:
Step 3 Proton transfer to yield alcohol and carboxylate ion:
CO
O H+ R' OR C
O
OR + R' O H
RCO
X>RC
ORC
O
OR'RC
O
NH2> >
RCO
O
14.4.2 Reactions with alcoholsAcyl halides
Acid anhydridesEstersNitriles
Alcohols orphenols
Esters
Hydrolysis of Nitriles: P320P320
R C N
H3O+,heat R COOH
R COOHO, H2O
heat
Reactivity of carboxylic acid derivatives:
CO
Cl+ C
O
OCH2CH3CH3CH2OH
N+ N
H
Cl
Benzoyl chloride Ethyl benzoate(80%)
2 (CH3CO)2O
O
+ HO OHH2SO4 CH3C
O
O O CCH3
O
+ 2 CH3COOH93%
Esters Alcohols Esters (Exchange of esters)
O
OHOH
+ CH3COCCH3
O OPyridine
O
OHOCCH3
O
+ CH3COO
Salicylic acid( 水杨酸 )
Asprin( 阿司匹林 )
CH2 CH C
O
OC2H5 + CH3CH2CH2CH2OHH+, 94%
Methyl acrylate（丙烯酸甲酯）
Butyl alcohol（丁醇）
CH2 CH C
O
OCH2CH2CH2CH3 + C2H5OH
Butyl acrylate ( 丙烯酸丁酯 )
(94%)
CH3CH2CH2COOCH3
CH3C
O
OCH2CH2CH(CH3)2
CH3CN + C2H5OHHCl,H2O
CH3COOC2H5
Alcoholysis of Nitriles: Ch.P391Ch.P391
C6H5CO
Cl + HNNaOH
H2O C6H5CO
N
Benzoylchloride
Piperidine （哌啶）
N-Benzoyl-Piperidine
（ N- 苯甲酰哌啶）（ 87-91% ）
FCH2C
OOCH2CH3 + NH3
H2O FCH2C
ONH2 + CH3CH2OH
Ethyl Floroacetate
（氟乙酸乙酯）Floroacetamide（氟乙酸酰胺）
(90%)
14.4.3 Reactions with aminesAcyl halides
Carboxylic acid anhydridesEsters
Ammoniaor amines Amides
14. 5 Reduction14.5.1 Reduction by LiAlH4 (LAH) and its derivatives
C16H15CCl
O¢ÙLiAlH4, Et2O
¢Ú H2O,98%C16H15CH2OH
C
C
O
O
O¢ÙLiAlH4, Et2O
¢Ú H2O,87%
CH2OH
CH2OH
CH3CH CHCH2COOCH3¢ÙLiAlH4, Et2O
¢Ú H2O,75%CH3CH CHCH2CH2OH
+ CH3OH
CN(CH3)2
O¢ÙLiAlH4, Et2O
¢Ú Reflux,88%CH2N(CH3)2
F3C CH2CN¢ÙLiAlH4, Et2O
¢Ú H2O,53%F3C CH2CH2NH2
1) LiAlH(OR)3Acyl halidesAmides 2) H2O
Aldehydes
AmidesNitriles
AminesLiAlH4
Acryl halidesCarboxylic acidAcid anhydrides
Esters
Primaryalcohols
LiAlH4
14.4.2 Reduction by NaBouveault - Blanc reduction
Esters NaEthanolButanolPentanol
reflux Primary alcohols
CH3(CH2)7CH CH(CH2)7COOC2H5Na,C2H5OH
50%
CH3(CH2)7CH CH(CH2)7CH2OHEthyl oleate油酸乙酯 Oleic alcohol
油醇 The unique method for the preparation of unsaturated primary alcohols in industry
Ch. P393Ch. P393
14.5.3 Reaction with Grignard reagents
C6H5 C
O
OC2H5 + C6H5:MgBr 醚或苯Reflux
C6H5 C
O
OC2H5
C6H5
C6H5 C
O
C6H5
MgBr
MgBrOC2H5
C6H5:MgBr C6H5 C
O
C6H5
C6H5
MgBrH2O
NH4ClC6H5 C
OH
C6H5
C6H5
CH3C
O
Cl + CH3CH2CH2CH2MgCl醚£¬FeCl3-70¡æ,72%
CH3C
O
CH2CH2CH2CH3
1 mol RMgX Low temperature
RMgX Ketones Tertiaryalcohols
Carboxylic acidderivatives
RMgX
CH3CH2C N + C6H5MgBr CH3CH2C NMgBr
C6H5H3+O
¡÷ , 91%CH3CH2C O
C6H5
Et2O
Reactions of nitriles with Grignard reagents
Addition
1. RMgX Imine亚胺
Nitriles2. H2O
HydrolysisKetones
RLi reacts in the same way and are often used instead of RMgX
14.6 Reactions of amides14.6.1 The dehydration of amides
AmidesDehydrating agents: P4O10 (P2O5), （脱水剂） (CH3CO)2O Heating To form nitrils
(CH3)2CHC
O
NH2P4O10
200¡æ(CH3)2CHC N
2-Methylpropanamide2- 甲基丙酰胺
2-Methylpropanenitrile2- 甲基丙腈
（ 69-86% ）
Br2 / OH －
Carbonyl group had been plucked out
CH2CNH2
O
+ Br2 + 4NaOH94%
CH2NH2 + 2NaBr
+ Na2CO3 + 2H2O
14.6.2 The Hofmann Rearrangement （ Hofmann 降解反应） N-unsubstituted amides
to form primary amines having one less carbon atom than amide
Mechanism:Step 1 Formation of an N-bromo amide intermediate:
R C
O
N H
H
OHR C
O
N
H
Br Br R C
O
N Br + Br
H
Deprotonation of amideAmide nitrogen anionas a nucleophile
Ch.P396,( 丙 )
Ch.P396,( 丙 )
Step 2 Rearrangement of the N-bromo amide to an isocyanate （异氰酸酯）
R C
O
N Br
H
OHR C
O
N Br £ Br
O C N R
Deprotonation of N-bromo amide, the group R migrates from C atom to N atom to form an isocyanate.Step 3 Hydrolysis of isocyanate by base-catalyzed
N C OR N C OHROH
NH2 + CO3 + H2O
H2O
ROH
Carbamic acid ( 异氰酸 )dissociates to an amine and CO2
The features of Hofmann rearrangement:1. N-unsubstituted amides as substrates2. Rearrangement proceeds with retention of configuration at migrating group
C
HPhCH2
H3CC
ONH2
Br2, NaOHH2O
C
HPhCH2
H3CNH2
(S)-2-Methyl-3-Phenylpropanamide
(S)-1-Phenyl-2-propanamine
14. 7 Spectroscopic analysis of carboxylic acid derivatives
Table 1. The stretching frequency of C=OIR:
RC N : The stretching frequency of C N:2210~2260 cm-1
CompoundsStretching frequency of C=O
(cm-1)
RCOCl(RCO)2ORCO2RRCONH2
1815~17851850~1800 and 1780~1740
17351680~1630
EstersCarboxylic acid
anhydrides
Stretching frequency of C － O:1310 ~1050 cm-1
Amides: Stretching frequency of N – H bond: 3500 ~3200 cm-1
CH3C
O
L RCH2C N
α - H δ: 2 ~ 3 ppm
1H NMR:
13C NMR:C N
δ: 120 ppmAmide: N - H δ: 5 ~8 ppm
Problems to chapter 14P 346 10.31 (a),(d),(e) 10.32(c)~(g) 10.33(b),(d),(g) 10.37 10.39 10.41 10.42 (a),(c) 10.45 10.46(a), (c) 10.47 10.55 10.56(b)
P 346 10.31 (a),(d),(e) 10.32(c)~(g) 10.33(b),(d),(g) 10.37 10.39 10.41 10.42 (a),(c) 10.45 10.46(a), (c) 10.47 10.55 10.56(b)
10.5710.5810.5910.6010.6110.62
10.5710.5810.5910.6010.6110.62