Transcript Chapter 10 Carboxylic Acids and their Derivatives

Chapter 10 Carboxylic Acids and their
Derivatives
O
sp
2
RCOOH
C
R
RCO2H
OH
Carboxyl group
Nomenclature: - oic acid
OH
Br
CH3-CH-CO2H
CH2=CH-CO2H
2-bromopropanoic acid
propenoic acid
CH3-CH-CH2-C-OH
3-hydroxybutanoic acid
CO2H
HO2CCH2CH2CO2H
Benzoic acid
Butanedioic acid
O
Commonly occuring acids:
HCOOH
CH3CO2H
Formic acid (methanoic)
Acetic acid (ethanoic)
O
Acyl group R-C-
O
e.g.
H-CFormyl group
O
CH3-CAcetyl group
i.e. Names derived from common name of the carboxylic acid
O
P h-CBenzoyl group
10.2 Physical Properties
Short chain derivatives- liquids with sharp odours
e.g. Acetic acid (vinegar 4-5%); butyric acid (rancid butter)
Polar compounds: Form hydrogen bonds-high boiling points for their molecular weights
- even higher than alcohols
e.g.
O
OH
H3C
CH3-C-OH
Same M.W.
118 oC
97 oC
Carboxylic acids form hydrogen bonded dimers- held together by 2 H bonds
H
O
O
C
C
R
Shorter chain acids- H2O soluble due to H bonding
O
H
O
R
10.3 Acidity
Carboxylic acids - relatively weak acids; dissociate in water to a carboxylate anion
and a hydronium ion
O
O
R-C-O-H
+ H2O
R-C-O
+ H3O
acidic site
Ka = [RCO-2] [H3O+]
pKa = -log10Ka = 4.74 (CH3CO2H)
[RCO2H]
Much more acidic than alcohols
CH3CH2OH + H2O
O
CH3C-OH + H2O
e.g. CH3CO2H is 1011 times stronger acid than CH3CH2OH
CH3CH2O + H3O
Ka 10-16
O
CH3CO
Why is this ?
+ H3O
Ka 10-5
Resonance stabilisation in the carboxylate anion
O
O
C
C
H3C
H3C
O
O
O
H3C
C
O
Negative charge equally shared over the 2 oxygen atoms
- stabilises the carboxylate anion considerably
- no resonance stabilisation in ethoxide anion CH3CH2O-
10.6 Carboxylate salts
Carboxylic acid + base
salt
e.g.
CH3-CO2H + Na+ -OH
CH3CO2- Na+ + H2O
Sodium ethanoate (sodium acetate)
Other bases: Na2CO3, NH3
CH3CO2H + NH3
CH3CO2- NH4+
ammonium ethanoate
2 CH3CO2H + Na2CO3
2 CH3CO2- Na+ + CO2 + H2O
Therefore carboxylic acids dissolve in aqueous base
10.7 Preparation of acids
(a) Oxidation of 1o alcohols
[CH3CHO]
CH3CH2OH
Oxidants: KMnO4, CrO3
CH3CO2H
Proceeds via aldehyde
Can also oxidise aldehydes to acids:
CH3CH2CHO
Ag2O
CH3CH2CO2-
+
Ag
H2O
+
H
CH3CH2CO2H
(b) Nitrile/cyanide hydrolysis
R
C
Nitrile
or
Cyanide
N + 2 H2O
HCl
R-CO2H +
NH4+ Cl-
O
O
R
C
N
+ 2 H2O
NaOH
R-C-O Na
H3O+
R-C-OH
+ NH3
Nitrile hydrolysis- can be conducted under either acidic or basic conditions
When conducted under basic conditions the product is the salt (sodium carboxylate).
Neutralisation provides the carboxylic acid
e.g.
N
CO2H
C
hydrolysis
Recall alkyl cyanides can be prepared from the corresponding alkyl halide
by a nucleophilic substitution
CH3-CH2-CH2-Br
Na+ -CN
CH3CH2CH2-C
N
+ Na+ Br-
hydrolysis
O
CH3CH2CH2-C-OH
2 step route to carboxylic acids
O
R-Br
(i) NaCN
R-C-OH
(ii) H3O+
Note: 1 carbon extra in product
10.8 Carboxylic Acid Derivatives
O
R-C-OH
- OH replaced by other groups
e.g.
O
R-C-OR1
Esters
O
O
O
R-C-Cl
R-C-Br
Acyl halide (chloride)
O
R-C-O-C-R
Acid anhydride
Acyl bromide
O
R-C-NH2
Amide
Esters and amides occur widely in nature
10.9 Esters
O
O
CH3-C-OCH3
O
CH3-C-OCH2CH3
methyl acetate (methyl ethanoate)
CH3CH2CH2C-OCH3
methyl butanoate
ethyl acetate
O
Nomenclature:
OCH2CH3
Alkanoic acid
ethyl benzoate
Alkyl Alkanoate
OR group
Pleasant odours- flavour/fragrance of fruits and flowers, e.g. ethyl butanoate
10.10 Preparation of esters: Fischer esterification
O
O
R-C-OH
carboxylic acid
+
1
+ R OH
alcohol
H
R-C-OR1
ester
+ H2O
Acid catalyst e.g. HCl, H2SO4
If remove water as it forms can push the reaction to completion.
Alternative: Distill out the ester as it forms
Mechanism:
O
OH
+
Protonation activates the C towards
attack by nucleophiles
H
R-C-OH
+
R-C-OH
H
OH
OH
O
H
R
R-C-OH
C
R
OH
transfer
R1
O
C
O
H
OR1
O
R1
H
+
H
- H2O
H
Nucleophile
H
O
O
+
R
C
1
OR
-H
R
C
OR1
Good leaving group
O
O
H+
CH3-C-OH
CH3-C-OCH2CH3 + H2O
+ HOCH2CH3
O from the alcohol component
OH
O
R-C-OH
sp2
R
C
O
OH
1
OR
sp3
Tetrahedral intermediate
Nucleophilic acyl substitution
(i) Nucleophilic addition
(ii) Elimination
R
C
sp2
OR1
10.13 Ester Hydrolysis
O
O
R-C-OR1
H+
+ H2O
R-C-OH
+ R1OH
or
OH-
Can be hydrolysed under acidic or basic conditions- usually conducted in aqueous base (saponification)
O
O
1
R-C-OR
+-

+ Na OH
H2O
1
R-C-O-Na+ + R OH
sodium carboxylate
H3O+
O
R-C-OH
Another example of nucleophilic acyl substitution
O
O
R-C-OR1
R
OR1
C
Hydroxide anion- powerful nucleophile
OH
OH
Tetrahedral intermediate
Nucleophile
O
R
C
O
O
OR1
R
C
OH
+
OR1
R
C
O
+ HOR1
OH
Last step is essentially irreversible as alkoxide anion is a strong enough base to completely deprotonate
the carboxylic acid
At the end of reaction addition of aqueous acid protonates the carboxylate anion to form the carboxylic acid
O
R
C
O
+ H3O+
O
R
C
OH
+ H2O
Saponification: Used in preparation of soaps
e.g.
CO2H
CO2 Na
CO2CH3
NaOH
H3O+
H2O
+ CH3OH
O
O
CH3CH2CH2C-OCH2CH3
NaOH
CH3CH2CH2C-O- Na+
H2O
ethyl butanoate
O
CH3CH2CH2C-OH
butanoic acid
H3O+
+ CH3CH2OH
Benzoic acid
10.14 Ammonolysis of esters
O
O
CH3-C-OCH2CH3
+
NH3
CH3-C-NH2
+ CH3CH2OH
1o amide
Ethoxy group replaced by amino group- similar reaction mechanism to saponification using
NH3 as nucleophile in place of -OH
10.16 Ester reduction/carboxylic acid reduction
O
R-C-OH
(i) LiAlH4
(ii) H2O
R-CH2OH
1o alcohol
e.g. CH3CO2H
aectic acid
CH2-OH
CO2H
LiAlH4
Benzyl alcohol
LiAlH4
CH3CH2OH
ethanol
O
R-C-OR1
LiAlH4
R-CH2OH + HOR1
2 moles of alcohol formed
O
e.g.
CH3-C-OCH2CH3
LiAlH4
Note: For reduction of carboxylic acids and esters
must use LiAlH4. NaBH4- not strong enough
CH3CH2OH + HOCH2CH3
2 moles of ethanol
O
CH3CH2C-OCH3
LiAlH4
CH3CH2CH2OH + HOCH3
i.e.
O
OR1
R-C
Molecule broken across C-O bond to form 2 moles of alcohols
Mechanism

O
O

CH3-C-OCH3
H3C
H
H
Al
H
H
H
C
O
OCH3
CH3-C-H + OCH3
Aldehyde formed is then rapidly reduced to 1o alcohol- can't easily stop the reduction
at the aldehyde stage
O
CH3-C-H
CH3-CH2-O
H2O
(as complex with aluminium)
H
2 alcohols isolated after aqueous work-up
Al
H
CH3CH2OH
H
H2O
CH3O
H
CH3OH
O
CH3CH2CH2CH2C-OCH2CH3
LiAlH4
CH3CH2CH2CH2CH2OH + HOCH2CH3
O
CH2OH
C-OCH3
LiAlH4
+ HOCH3
O
LiAlH4
OCH2CH3
OH
+ HOCH2CH3
10.18 Acyl Halides
- Sometimes known as acid halides
- Usually chloride or bromide
O
O
R-C-Cl
R-C-Br
RCOCl/RCOBr
sp2 hybridised at carbon
Cl/Br strong electronegative substituents

O

R-C-X

Carbon more electrophilic than in other carbonyl derivatives
Preparation- from carboxylic acids
O
O
R-C-OH
+ SOCl2
R-C-Cl
+ HCl
+ SO2
gaseous byproducts
O
O
R-C-OH
+ PCl5
R-C-Cl
+ HCl
+ POCl3
Reactivity
Due to the highly electrophilic carbon they react rapidly with nucleophiles
O
O
+ Nu
R-C-Cl
R-C-Nu + Cl
Chloride displaced by the incoming nucleophile via an addition-elimination mechanism

O
R
O

C
Cl
R
O
C
R-C-Nu + Cl
Cl
Nu
Nu
Tetrahedral Intermediate
sp2
sp3
sp2
Examples
O
CH3-C-Cl
O
+ H2O
CH3-C-OH + H2O
Water as a nucleophile results in hydrolysis
of the acyl chloride to the carboxylic acid
O
O
CH3-C-Cl
Alcohol as nucleophile forms
the ester
CH3-C-OCH3 + HCl
+ HOCH3
O
O
CH3-C-Cl
+ 2 NH3
CH3-C-NH2
+ NH4+ Cl-
Ammonia as nucleophile produces
primary amide
Note: 2 moles of NH3 required as 1 mole reacts with the HCl released
Further examples
O
O
C
Et OH
Cl
C
OEt
+ HCl
H2O
2 NH3
O
C
O
OH
+ HCl
C
NH2
+ NH4+ Cl-
O
O
CH3OH
Cl
OCH3
+ HCl
2 NH3
H2O
O
NH2
O
+ NH4+ ClOH
+ HCl
Acyl halides are strong acylating agents- transfer acyl groups to a range of nucleophilic species
O
R-C-X
O
+ Nu
R-C-Nu + X
acyl group
Nomenclature Acyl Halides
O
O
O
e.g.
P h-C-Cl
CH3CH2CH2-C-Br
Benzoyl chloride
Butanoyl bromide
CH3-C-Cl
Acetyl chloride
(ethanoyl chloride)
10.19 Acid Anhydrides
O
O
R-C-O-C-R
O
e.g.
O
CH3-C-O-C-CH3
Acetic Anhydride ~ 1 million tons annually
O
O
CH3-C-OH
H-O-C-CH3
O
- H2O
O
CH3-C-O-C-CH3
Use name of acid e.g. acetic acid and replace "acid" with "anhydride"
Acetic anhydride or ethanoic anhydride
Preparation
(i) Dehydration of carboxylic acids
(ii) Reaction of acyl halide with carboxylate salt
O
O
CH3-C-Cl
acetyl chloride
+
O
O
CH3C-O-C-CH3 + Na+ Cl-
Na O-CCH3
sodium acetate
Acetate anion as nucleophile
from acyl halide
from acetate anion
Acid anyhdrides react in similar fashion to acyl halides but are less reactive
O
O
CH3C-O-C-CH3
O
OCCH3
acetate ion leaving group
O
CH3-C-Cl
Cl
chloride ion leaving group
O
O
CH3C-O-C-CH3
H2O
O
O
CH3-C-OH
+ HOC-CH3
Acids
Use of water as nucleophile results in hydrolysis to 2 carboxylic acids
O
O
CH3C-O-C-CH3
O
CH3CH2OH
O
CH3-C-OCH2CH3
+ HOC-CH3
ester
Use of alcohol as nucleophile forms the ester
O
O
CH3C-O-C-CH3
NH3
O
O
CH3-C-NH2
+ HOC-CH3
amide
Use of ammonia as nucleophile forms the amide
Note: 1 mole of carboxylic acid formed in each reaction
Synthesis of Aspirin
O
OH
O
O-C-CH3
O
+ CH3-C-O-C-CH3
+ HOCCH3
CO2H
CO2H
Acetylsalicyclic Acid (Aspirin)
Salicylic Acid
-OH of salicyclic acid as nucleophile
O
ester
10.20 Amides
- Occur widely in nature e.g. proteins
O
O
Primary amides
Secondary amides
R-C-NH2
O
O
R-C-NH-R1
R1
Tertiary amides R
C
R2
O
O
O
CH3
H
C
NH2
Methanamide
(Formamide)
H3C
N
C
NH2
Ethanamide
(Acetamide)
H3CH2CH2C
Butanamide
NH2
H
C
N
CH3
N,N-Dimethylformamide
(DMF)
Preparation of Amides
(i) Acylation of Amines
O
CH3-C-Cl
O
+ NH3
CH3-C-NH2
+ HCl
NH3
NH4Cl
Overall reaction
O
CH3-C-Cl
O
+ 2 NH3
CH3-C-NH2
+ NH4 Cl
Can also use acetic anhydride
(ii) Heating ammonium carboxylates
O
R-C-OH
- not as efficient as (i)
O
+ NH3
R-C-O
O
NH4
Heat
R-C-NH2
+ H2O
Alkaloids
- pg 332
- Basic, N containing compounds of plant or animal origin
- Potent pharmacological properties e.g. morphine, nicotine
Dart poison frogs- Ecuador
Potent compounds in skin secretions
In 1992 a compound was isolated which is a much stronger painkiller than morphine- Epibatidine
Cl
H
N
N
Amides: Very polar
- Form strong hydrogen bonds
O
H
R
C
N
H
H

O
N
H
C

R
Reactions:
(a) Hydrolysis
O
O
H
R
C
+ H2O
N
H
H+ or
R
OH
Reaction slower than esters, acid chlorides or anhydrides
C
OH
+ NH3
(b) Reduction to amines
O
R
C
NH2
LiAlH4
R-CH2NH2
Must use strong reducing agent, not NaBH4 which is not reactive enough to reduce an amide
N.B. Compared to esters the reduction pathway is different- there is no cleavage of the
C-N bond
O
R
C
OCH2CH3
LiAlH4
CH3CH2OH + HOCH2CH3
O
R
C
NH2
Bond not
broken
LiAlH4
CH3CH2NH2
10.21 Summary
O
R
C
Cl
Decreasing reactivity
towards reaction with nucleophiles
O
R
O
C
O
C
CH3
O
R
OR1
C
O
R
C
NH2
Same products formed in many reactions, e.g. Hydrolysis of any of the 4 derivatives forms the carboxylic acid
O
H2O
H
OH
R
C
OH
+ HX
or
Depends on which derivative is used