ch.21 carboxylic acid derivatives and nucleophilic...
TRANSCRIPT
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