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Carboxylic Acid Derivatives
Ch.21 Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution
Carboxylicacid
CR OHO
Ester
CR OO
R'
Acid anhydride
CR OO
CO
R'
Nitrile
CR N
Thioester
CR SR'O
Acyl phosphate
CR OO
PO
O-
O-
Carboxylicacid chloride
CR ClO
Amide
CR NH2
O
R Y
O Nu-
R Nu
O+ Y-
Nucleophilic Acyl Substitution
21.1 Nomenclature
Acid Halides: RCOX
Cl
Acetyl chloride
OCl
Benzoyl chloride
O
Cl
Cyclohexanecarbonyl chloride
O
-oic acid → -yl-carboxylic acid → -carbonyl
Acid Anhydrides: RCO2COR'
O
Acetic anhydride
OO
Benzoic anhydride
OO
O
OO O
Succinic anhydride
acid → anhydride
O
Bis(chloroacetic) anhydride
O O
Acetic benzoic anhydride
OO
O
Cl Cl
- anhydride from substituted monocarboxylic acid: bis-- unsymmetrical anhydride: cite two carboxylic groups alphabetically
Amides: RCONH2 -(o)ic acid → amide-carboxylic acid → -carboxamide
NH2
Acetamide
ONH2
Cyclohexanecarboxamide
O
NH2
Hexanamide
O
NH
N-Methylacetamide
ON
N,N-Diethylcyclohexanecarboxamide
O
CH3
- substututed amide: N-alkyl----amide
Esters: RCO2R'
OEthyl acetate
O
EtO OEt
O O
Diethyl malonate
O
O
tert-Butyl cyclohexanecarboxylate
- name alkyl group attached to oxygenthen -ic acid → -ate
21.2 Nucleophilic Acyl Substitution Reactions
R Y
O O-
YNu
RNu-
R Nu
O+ Y-
tetrahedral intermediate(alkoxide anion)
Nucleophilic acyl substitution: Y = OR', Cl, OCOR', NR'2
- addition-elimination mechanism: different from SN2 mechanism
Relative Reactivity of Carboxylic Acid Derivatives
C
O
< < <
more reactive
RRR
C
O
HRR
C
O
HHR
C
O
HHH
Steric effect:
R NH2
O
R OR'
O
R Cl
O
R O
O O
R< < <
more reactive
Electronical effect:
- strongly polarized derivatives are more reactive- leaving group ability
Conversion of a more reactive derivatives to less a reactive derivatives; but reverse direction is not possible
R NH2
OR OR'
O
R Cl
O
R O
O O
R
- only ester and amides are commonly found in nature- acid chloride and acid anhydride undergo nucleophilic attack by water
R NH2
O
R OR'
O
R H
O
R R'
O
R OH
OH2O
R'OH
NH3
[H-]
R'MgX further
reaction
further
reaction
Hydrolysis
Alcoholysis
Aminolysis
Reduction
Grignardreaction
R Y
O
Kinds of Nucleophilic Acyl Substitutions
21.3 Nucleophilic Acyl Substitution Reactions of Carboxylic Acids
R NH2
O
R OR'
O
R O
O
R Cl
O O
R'R OH
O
Conversion to acid chloride
R OH
O SOCl2
CHCl3 R Cl
O
R OH
OR O
OCl
SCl
O
SCl
O
HR O
OS
Cl
O
Cl
Cl-
+ HCl
base
R O
OS
Cl
O
ClR Cl
OCl-SO2 ++
mechanism:
Conversion to acid anhydride:- acyclic anhydrides are difficult to prepare- acetic anhydride is commonly used H3C O
O O
CH3
Acetic anhydride
COOH
COOH 200oCO
O
O
+ H2O
- 5, 6-membered cyclic anhydrides are obtained by high temperature dehydration
Fisher esterification: acid-catalyzed, HCl, H2SO4
R OH
O cat. H2SO4
R'OH R OR'
O+ H2O
Alkylation of carboxylates with 1o alkyl halides
Conversion to esters:
R ONa
O R'-X
R OR'
O+ NaX
mechanism
R OH
O cat. H2SO4
H3O+
R OH
OH
HO-R'
OH
OHROR
H
O
OROR H
H
H
R OR'
O+
H2O
- reversible process: use excess of alcohol for complete esterification
- substitution of OH by OR'
R OH
O cat. H2SO4
R O*CH3
O+ H2OCH3O*H+
Conversion to amide
R OH
O
R O-
O
NH4+
NH3
- amines are base: direct conversion to an amide is not possible
21.4 Chemistry of Acid Halides
R OH
O SOCl2
CHCl3 R Cl
O
R Cl
O Ar-H
AlCl3 R Ar
O
Preparation
Reactions
acid bromide, acid iodide: unstable
Friedel-Craft acylation:
Reactions
R NH2
O
R OR'
O
R H
O
R R'
O
R OH
OH2O
R'OHNH3
[H-]
R'MgX further
reaction
further
reaction
Acid
Ester
Amide
Aldehyde
Ketone
R
OH
R R'
OH
R'
10 Alcohol
30 Alcohol
R Cl
O
Hydrolysis:
R Cl
O
H2O
O-
ClHOR
HR O
O
H
HR OH
OBase
+ HCl
- use base (pyridine, NaOH) to neutralize HCl
Alcoholysis: Ester formation
R Cl
O
R OR'
OR'OH
pyridine NH
Cl-+
(or Et3N)
- use base (pyridine, Et3N) to neutralize HCl formed- reactivity: 1o > 2o > 3o alcohol
H3C Cl
O
pyridineHO
OH
HO
O CH3
O
- selective esterification of unhindered alcohol
Aminolysis
R Cl
O
R NHR'
O2 R'NH2+ R'NH3
+ Cl-
- use 2 equiv. of amine
Cl
O
HN(CH3)2
2 eq.
N(CH3)2
O
+ Me2NH2+ Cl-
CO
ClMeO
MeO
MeO
HN O
aq. NaOHCO
NMeO
MeO
MeO
O + NaCl
- for valuable amines; use external bases
Reduction:
R Cl
O 1. LiAlH4
2. H3O+R CH2 OH
- little practical value: acid is more readily available and reduced to alcohol
R Cl
O
H-
O-
ClHR R H
O
R O-
H-
H HH3O+
R OH
H H
Reaction of acid chloride with organometallic reagents
R Cl
O 1. 2 R'MgX
2. H3O+ RC
OH
R' R'
R Cl
O
R'MgX
O-
ClR'R R R'
O
R'MgX
R OH
R' R'
Diorganocopper reagent: Gilman reagent
R Cl
O R'2CuLiR R'
O
R CuR'2
O
Cl
OEt2CuLi
ether, -78oC
O
92%
- diorganocopper reaction occurs only with acid chlorides- carboxylic acid, ester, anhydride, amide do not react with diorganocopper reagents
21.5 Chemistry of Acid Anhydride
R ONa
O
R' Cl
O+
R O R'
O O
ether+ NaCl
Preparation
Reactions
R NH2
O
R OR'
O
R H
O
R O
OR OH
OH2O
R'OH NH3
[H-] further
reactionAcid
Ester Amide
Aldehyde
R
OH
10 AlcoholR'
O
H3C O CH3
O OOH
O
OH
Ac2O
Pyridine OH
O
O
CH3O
+ AcOH
Aspirin
- Acetic anhydride is commonly used- selective reaction is possible if two functional groups have different reactivity
H3C O CH3
O O
NH2 Pyridine+ AcOH
HO HO
HN
O
Acetaminophen
- AcCl: highly reactive, HCl (NaCl) as by-product- Ac2O/pyr: moderate reactivity, AcOH (AcONa) as by-product
21.6 Chemistry of Esters
O
O
O
O OCOROCOROCOR
from pineapples from bananna A fat(R = C11-17 chains)
OO
O
O
Dibutyl phthalate (a plasticizer)
- fragrant odors of fruits and flowers
industrial use- Ethyl acetate (solvent)- dialkyl phthalate (plasticizer: keep polymers from becoming brittle)
R Cl
O
R OR'
OR OH
O
R'OH
H+
R'OH
pyrR ONa
OR'-X
SN2
1o alkyl halides
Preparation of esters
Reactions of esters
R NH2
O
R OH
R''
R H
O
R OR'
O
R OH
OH2O
NH3
[H-] further
reactionAcid
30 AlcoholAmide
Aldehyde
R
OH
10 Alcohol
R''
R''MgX
Hydrolysis:
R OR'
O
NaOH
O-
OR'HOR
R O
O
H
R O-
O
R'O-+
R'OH+
Na+
Na+
Na+
acid salt
H3O+
R OH
O
Saponification: basic hydrolysis
R OR'
O
R OH
O+
or H3O+
H2O
NaOHR'OH
Acid-catalyzed hydrolysis: reversible
R OR'
O H+
H3O+
R OR'
OH OH
OR'HOR
H
O
OHOR R'
H
H
R OH
O+
H2O
H2O
R'OH +
Aminolysis: not often used, acid chloride method is commonly used
R OCH3
O
R NH2
O+
NH3 CH3OH
not so reactive to amine
- NaBH4 cannot reduce ester under normal condition
Reduction: LiAlH4
R OCH3
O
R OH+ CH3OH
LiAlH4
ether
R OR'
O
H-
O-
OR'HR R H
O
R O-
H-
H HH3O+
R OH
H H
LiAlH4
etherO
O
OH
OH
- intermediate aldehyde is more reactive than ester
O
O
O
OHDIBAL
-78oC
- intermediate aldehyde can be isolated by DIBAH (i-Bu2AlH)
R OCH3
O
R H1. DIBAL toluene O
2. H3O+
Grignard addition: add 2 equivalent of RMgX, yield 3o alcohol product
- intermediate ketone is more reactive than ester
2 eq. MeMgBr
etherOMe
O
Me
OH
Me
2 eq.MeMgBr
etherO
O
H3C OHH3C OH
21.7 Chemistry of Amides
R NR'2
O
R NHR'
O
R Cl
O
NH3 R'2NH
R NH2
OR'NH2
Preparation
- amide bonds are stable, used for protein building
H2N
R
O
OHN
R
ON
R'
ON
R"
O
Amino acids A protein (polyamide)
HHH
Reactions
Hydrolysis: require severe conditions, synthetically not useful
R NHR'
O
R OH
O+
or H3O+
H2O
NaOH
heat
RNH2
slow(inefficient)
- NaBH4 cannot reduce amides
Reduction: LiAlH4
R NH2
O
R NH2
1. LiAlH4
2. H3O+
R NH2
O
H-
O
NH2HR R NH2
H HAl
R NH2H-
H
mechanism
- oxygen atom leaves as an aluminate anion
NH
O
NH1. LiAlH4
2. H3O+
R NHR'
O
R NHR'1. LiAlH4
2. H3O+
21.8 Thiol Esters and Acyl Phosphate: Biological Carboxylic Acid Derivatives
Acetyl CoA(a thiol ester)
N
NN
NNH2
O
OHOPOO-
O
O-
OPOO-
OPOO-
NH
NH
SH3C
OH
OO
O
Thioester
CR SR'O
Acyl phosphate
CR OO
PO
O-
O-
H3C SCoA
O Nu-
H3C Nu
O+ -SCoA
H3C SCoA
OOHO
HO
OHNH2
OH
+ OHO
HO
OHNH
OH
CH3
O
+ HSCoA
Glucosamine
C2-O3POCH2CH OO
PO
O-
O-HO
3-Phosphoglyceroyl phosphate
C2-O3POCH2CH HO
HO
Glyceraldehyde 3-phosphate
NADH
"H-"+ PO4
3-
Mg2+
21.9 Polymers and Polyesters: Step-Growth Polymers
Chain-growth polymers: chain-reaction process of one type of monomer
RIn +R
n
Step-growth polymers: polymerization between two difunctional molecules
A B A B n
Step-growth polymers:
H2N(CH2)nNH2 + CO
Cl (CH2)n CO
Cl CO
HN(CH2)nNH (CH2)n CO
A diamine A diacid chloride A polyamide(Nylon)
HO(CH2)nOH + CO
HO (CH2)n CO
OH CO
O(CH2)nO (CH2)n CO
A diol A diacid A polyester
Nylons: polyamide = diamine + diacid
HOOH
O
OAdipic acid
+ H2NNH2
Hexamethylenediamine
HN
NH
O
O n
+ 2n H2O
Nylon 66
heat
N
OH
Caprolactam
HN
O
n
Nylon 6, Perlon
Fibers,large cast articles
Fibers,clothing, tire cord, bearings
Polyesters: dialcohol + diacid
MeO2C CO2Me + HOOH
Dimethyl terephthalate Ethylene glycol
200oC
C COO
OO
n+ 2n CH3OH
Polyester, Dacron, Mylar
Fibers,clothing, tire cord, film
Polycarbonate: dialcohol + carbonate
O O
O CCH3
CH3
HO OH+
Diphenylcarbonate Bisphenol A
300oC
CCH3
CH3
O O CO
n
+ 2n PhOH
Lexan
- high impact strength; machinery housing, telephone, safety helmet
Polyurethane: dialcohol + diisocyanate
+
Toluene-2,6-diisocyanate Poly(2-buteno-1,4-diol)
HO(CH2CH=CHCH2)nOHNN C OCO
CH3
HN
HN
CH3
O
O
O
O(CH2CH=CHCH2)nO
n
Spandex
- foams, fibers, coatings
21.10 Spectroscopy of Carboxylic Acid Derivatives
IR Spectroscopy
1735 cm-1RCOOR'1800 cm-1RCOCl
1650-1850 cm-1CO
NMR Spectroscopy
200 ppmaldehyde, ketone160-180 ppm~ 2 ppm,
acid derivatives13C NMRCHCOY1H NMR
1H NMR Spectrum
β-Lactam AntibioticsChemistry @ Work
β-lactam antibiotics: four membered lactam ring; block bacterial cell wall synthesis
N
SN
OO
CH3
CH3
H H
CO2Na
H
Penicillin G
N
N
OO
H HH
Cephalexin(a cephalosporin)
NH2S
CH3COOH
Chapter 21
Problem Sets
32, 36, 37, 42, 53, 62
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