Download Chapter 19 - U of L Class Index

Carboxylic Acids and Their Derivatives
Carboxylic Acid Derivatives can be prepared from, and converted into carboxylic acids.
Preparation from a Carboxylic Acid
O
R
C
O
OH
SOCl2
C
R
O
C
2 R
OH
- H2O
C
C
R
O
R
Cl
O
O
O
C
Anhydrides
R
R
H
+ R'OH
Cl
O
O
C
C
O
C
R
O
+ H2O
R
C
OR'
R
+ H2O
R
O
O
Cl
+ HNR'2
R
C
R
NR'2
+ HCl
O
C
H
OR' + H2O
R
O
R
C
C
OR'
+ HO -
H2O
R
C
R
C
N
+ H2O
OH
+ R'OH
C
O-
+ R'OH
H+
NR'2 + H2O
C
O
NR'2
+ HO -
H2O
R
Nitriles
NH2
C
O
O
R
H3PO4, ∆
OH
O
Amides
C
C
2 R
R
O
R
+ HCl
OH
+
+
OH
H2O
O
Esters
O
O
Hydrolysis to O
carboxylic
C
acids
R
Acid
Halides
R
C
N + H2O
C
O-
+ HNR'2
O
∆, H+
R
C
OH
+ NH4+
Nucleophilic Addition to Aldehydes and Ketones vs. Nucleophilic Substitution of Carboxylic Acid Derivatives
For example, with a strong nucleophile, "H -", a hydride:
Addition
Substitution
O
O
C
C
OH
-
H
R
H
H
R
+
R
H
C
H
C
R
H
Aldehydes and ketones have no substituents that are leaving
groups. Remember, H - and H3C - are absolutely terrible leaving
groups.
Just as in SN2 reactions, you cannot displace a leaving
group by a species that is itself a better leaving group.
For example:
-
C
Cl
R
The reverse reactions
Cl -
CH2 OH
R
Cl -
HO - +
R
Cl
CH2 OH
R
+ - OH
+ Cl -
O
C
Cl
C
R
Cl - +
R
C
OH
+ Cl -
O
O
CH2
H
Nucleophiles add to carboxylic
acid derivatives to form a
tetrahedral intermediate. This
intermediate can reform the
carbonyl by displacing the
attached leaving group. The net
result is the substitution of the
leaving group by the nucleophile.
O
CH2 Cl
C
R
"Tetrahedral
Intermediate"
HO -
R
R
Cl
O
H
H
H
-
O-
O
OH
The order of reactivity of carboxylic acid derivatives is simply from best leaving group to worst:
Acid chloride > anhydride > carboxylic acid = ester > amide
Cl > R-CO2 >
HO =
RO - > R2N Any derivative on the right can be prepared from one to its left, but not the other way around
(except for carboxylic acids that can be prepared from all these derivatives).
R
C
Cl
+ - OH
Nucleophilic Addition-elimination Reactions of Carboxylic Acid derivatives and
their relative reactivity
Nucleophilic Acyl
Substitution
SN2
Nu:
H2
C
R
X
R
H2
C
R
R C Cl
O
R C Cl
O
X
R
C
Nu
+ X
"Tetrahedral
Intermediate"
Nu:
O
O
R C O C R
O
X
C
R
O
Nu
R C O C R
O
C
Nu
+ X
O
O
O
O
R C OR'
O
R C OR'
O
R C OH
O
R C OH
O
R C NH2
O
R C NH2
O
R C O C R
Leaving
Group
(X)
Just as in SN2, you cannot displace a leaving group by a better leaving group.
O
R C O
O
R C O
Preparation of Carboxylic Acids
Carboxylic Acids can be prepared from the hydrolysis of their derivatives.
Other methods
O
CH2CH3
C
Aq. KMnO4, heat
CO2H
Aq. KMnO4, heat
Jone's Reagent
C
CH2OH
C
Pentanal
(or other strong
oxidizing agents)
H
Benzoic Acid
Hexanedioic Acid
(Adipic Acid)
CO2H
1-Pentanol
or
OH
Pentanoic O
Acid
(Valeric Acid)
O
O
Br
Mg, Et2O
Bromocyclohexane
OH
MgBr
C
1.) CO2
2.) H +
Cyclohexylmagnesium Bromide
OH
Cyclohexanoic Acid
Hydrolysis of Nitriles
O
CH2 C N
H2O, H2SO4
100°C, 3 h
Phenylacetonitrile
C
1-Cyanocyclohexene
N
1.) KOH (aq.),
reflux, 17 h
2.) H +
CH2 C OH
78%
2-Phenylethanoic acid
(Phenylacetic acid)
CO2H
79%
1- Cyclohexenoic Acid
Acid Halides (u su a lly ch lor id es or b r om id es)
O
O
C
C
CH3
Br
Eth a n oyl Ch lor id e
(Acetyl Ch lor id e)
Cl
Ben zoyl Br om id e
Prepared by heating a carboxylic acid in Thionyl Chloride
CH3
O
O
C
C
OH
CH3
+ SOCl 2
O
O
O
S
+ Cl
-
+H
O
C
CH3
Cl
-
O
S
Cl
Cl
+
Th ion yl Br om id e gives a cyl b r om id es
O
SO2 + Cl
-
O
-
C
CH3
Cl
Prepared by heating a carboxylic acid with PBr3 .
Ph
O
O
C
C
OH
Ph
+ PBr 3
OCOPh
O
P
Ph
OCOPh
+ Br
-
+
+H
OCOPh
C
O
P
OCOPh
Br
PCl 3 gives a cid ch lor id es.
O
H3 PO3
Oxalyl Chloride is a kin d er , gen tler m eth od of for m in g
a cid ch lor id es.
O
H
C
O
OH
Cl
C
H
C
H
CH3 CO2
OCH3
Br
Cl
H
CH3 CO2
C
O
O
C
Ph
OCH3
Cl
Reactions of Acid Halides
Anhydrides
upon reaction with carboxylate salts. This is one of the best ways to prepare
"mixed anhydrides" (anhydrides derived from two different carboxylic acid parents).
O
O
CH3
C
+
ONa+
Cl
Sodium Acetate
O
C
CH3
O
C
O
C
Acetic Benzoic
Anhydride
Benzoyl Chloride
Carboxylic Acids upon reaction with HO - or water
O
O
C Cl
C OH
aq. NaOH
+ NaCl
Benzoic Acid
Esters upon reaction with alcohols.
O
HO
O
C
HO
O
CH3
PhCOCl,
Ph
Pyridine, CH2Cl2
O
C
O
O
O
C
O
HO
CH3
Phenyl esters can be prepared this way. (Difficult otherwise)
O
OH
Cl
C CH
3
Pyridine
Useful way to tie up the acidic proton. As in aspirin.
O
C
O
CH3
CH3
CH3
Amides upon reaction with amines
O
O
C
Br
CH3CH2
Propanoyl
Bromide
O
CH3
C
C
NH2
CH3CH2
Propanamide
(A 1° amide)
+ NH3
Ammonia
Cl +
CH3
C
+
N
H
N-Phenylethanamide
(A 2° amide)
O
CH CH
Aniline
O
C
ClH4N
O
H2N
Ethanoyl
Chloride
+ NH4Br
2
CH2CH3
Cl
C
3
N
H N
CH2CH3
CH2CH3
ClH2N
CH2CH3
CH2CH3
Benzoyl
Chloride
N,N-Diethylbenzamide
(A 3° amide)
Diethylamine
Aldehydes
upon reaction with Lithium tri-t-butoxyaluminumhydride, LiHAl(t-BuO)3
O
H
C
H
Cl
C
O
H Al O
C
O
C
O
H
C
H
CH3CO2
CH3CO2
OCH3
OCH3
Aryl Ketones upon Friedel-Crafts reaction with aromatic compounds
O
O
Cl
C CH
3
C
AlCl3
CH3
CH3O
OCH3
Methoxybenzene (Anisole)
p-Methoxyacetophenone
H
Reactions of Anhydrides
Carboxylic Acids with water or hydroxide as the nucleophile
O
O
H2O +
2 CH3CO2H
C
C
H3C
O
CH3
Esters from alcohols
Another good method of making phenyl esters (esters of phenol).
COOH
COOH
O
OH
+
Salicylic Acid
H3C
C
O
O
C
CH3
CH3
Acetic anhydride
Acetyl salicylic
Acid
Cyclic Anhydrides give "half esters":
+ CH3COOH
O
O
CH2CH3
C
O HO CH CH2CH2CH3
C
2-Ethylhexanol
O
Phthalic Anhydride
O
O
O
CH2CH3
C O CH CH2CH2CH3
C OH
O
H+
CH2CH3
C O CH CH2CH2CH3
CH2CH3
HO CH CH2CH2CH3
C O CH CH2CH2CH3
CH2CH3
O
"Dioctyl Phthalate", a plasticizer (used principally in PVC)
[Di-(2-ethylhexyl)phthalate]
Amides with amines.
O
H3C
C
O
O
C
O
H2N
CH3
H3C
C
N
H
N-Phenylacetamide
(Acetanilide)
O
Esters
R = H, Alkyl or Aryl
R' = Alkyl or Aryl
C
R'
R
O
Nomenclature - Esters are chemically derived from two portions - an alcohol and a
carboxylic acid - and are named as such.
O
CH3CH2
O H HO
C
CH3
H
O
+
C
CH3 + H2O
Ethanol
Water
Ethanoic acid
Ethyl
Ethanoate
(or Acetic Acid)
(or Ethyl Acetate)
The reaction described above is often referred to as a "condensation reaction".
CH3CH2
O
If the alcohol and acid are located on the same molecule, then a cyclic ester is
the product. Such molecules are called "lactones" and are in all respects, esters.
O
O
C
H+
HO
C
O + H2O
OH
3-Hydroxybutanoic Acid
Butyrolactone
Esters are prepared from the reaction of :
Acid halides + alcohols
Anhydrides + alcohols
These are the best methods for the preparation of phenyl esters (esters of phenol)
and esters of sterically hindered alcohols.
O
O
CH3
CH3
NEt3 (Triethylamine)
C
C
CH3
O C CH3
Cl + HO C CH3
Ph
t-Butyl Benzoate CH3
CH3
Benzoyl
Chloride
t-Butanol
O
O
Pyridine,
OH
CH2CH3
O
CH2Cl2
C
C
Pr
Pr C O
O
Propanoic Anhydride
Phenyl Propanoate
Phenol
Occasionally, esters are prepared by Sn2 reactions where the nucleophile is a carboxylate.
O
O
C
O - Na+ + CH3I
Sodium
Methyl
Acrylate
Iodide
C
OCH3 Methyl Acrylate
Acid Catalyzed Esterification
O:
:
C
H
OH
CH3
Acet ic acid
C
CH3 + H O
2
O
Meth yl Aceta te
CH3
HO CH3
Meth an ol
:
CH3
+
+
H
O:
O
OH
C
C
OH
CH3
OH
+
CH3 C
OH
+
H O
CH3
OH
HO CH3
OH
C
CH3
O
OH
OH2 +
CH3
CH3
CH3
OH
C+
O
CH3
C
H
OH
+
CH3
OH
O
H
CH3
OH2
CH3
OH
C
O+
CH3
C
OH
O
+
CH3
+ H
O
CH3
O
C
O
CH3
CH3
Th is r ea ction is called a con d en sat ion r ea ction b ecau se
wat er is p r od u ced .
C
H
+
O
CH3
Transesterification
One thing to keep in mind with handling esters is the possiblity of transesterification.
For example, let's say you wanted to convert the following aldehyde into its dimethyl
acetal. The alkyl group on the ester is also liable to be exchanged. We call this
transesterifcation. It can be a nuisance. Of course, it works the other way too. Attempts
to prepare esters from carboxylic acids that also incorporate an acetal can also be
complicated by transacetalation.
O
C
O
OCH3
CH3O
H
C
CH3OH, H +
C
C
O
OCH2CH3
C
H
O
OCH3
H
OCH3
CH3O
OCH2CH3
CH3CH2O
C
CH3OH, H +
C
O
H
C
OCH3
OH
Transacetalation in the preparation of an
ester.
Transesterification during the preparation
of an acetal.
There is a very important example of a useful transesterification reaction between a
diester and a diol.
O
CH3O
O
C
C
OCH3
HO
Dimethyl Terephthalate
H+
OH
CH3O
O
O
C
C
Ethylene glycol
HO
CH3O
CH3O
O
O
C
C
O
O
C
C
O
O
O
O
+ CH3OH
OH
HO
O
OH
O
O
O
C
C
O
OH
+ CH3OH
OCH3
O
O
C
C
O
O
C
C
O
n
Poly(ethylene terephthalate), a polyester.
OH
+ CH3OH
Terylene, Dacron
(mylar film, magnetic
recording tape, frozen
food packaging, yarn)
Reactions of Esters
Base Induced Hydrolysis - "Saponification"
O
O
C
OCH3
+ NaOH
C
H2O
O - Na +
+ CH3OH
Na+ O
O
C
C
OCH3
+
OH
O
C
OCH3
OH
O H
-
OCH3
Na+
Na
Methyl Benzoate
O
O
C
Subsequent
Addn of HCl
OH
C
O- +
Na
+ CH3OH
+ NaCl
Note that an SN2 mechanism is also plausible, but does not in fact compete. How do we
know?
O
O
C
OCH3
-
C
OH
O - + CH3OH
A very important example of a saponification reaction.
O
H2C
HC
H2C
O
C
O
(CH2)16CH3
(CH2)18CH3 NaOH
O C
O
O
C
(CH2)20CH3
O
A triacylglycerol or triglyceride.
H2C
HC
H2C
OH
Na+ - O
C
(CH2)16CH3
OH
Na+ - O C
(CH2)18CH3
OH
Glycerol
Na+ - O
O
C
(CH2)20CH3
O
Sodium salts of Palmitic,
Stearic, and Arachidic acids resp.
Lipids - Fats and Oils
The only difference between fats and oils? Both are triglycerides.
Fats (butter, lard)
Oils (corn, olive, peanut, coconut, canola, sesame etc.)
As we have seen, fats and oils are triglycerides - triesters of glycerol and three
fatty acids (long straight-chain carboxylic acids). The acid components of these
esters are usually different.
Saturated Fatty Acids
Lauric
CH3(CH2)10COOH
Myristic CH3(CH2)12COOH
Palmitic
CH3(CH2)14COOH
Stearic
CH3(CH2)16COOH
Arachidic CH3(CH2)18COOH
Unsaturated Fatty Acids
Palmitoleic Acid
Oleic Acid
CH3(CH2)4CH2
CH2(CH2)6COOH
CH3(CH2)6CH2
CH2(CH2)6COOH
Linoleic Acid
CH3(CH2)3
Linolenic Acid
CH3 CH2
Arachidonic Acid
CH3(CH2)3
CH2
O2C
Fat
O2C
O2C
O2C
Oil
O2C
O2C
CH2
CH2(CH2)6COOH
CH2(CH2)6COOH
CH2(CH2)2COOH
Still More Reactions of Esters
Ammonolysis
Reaction with Amines (or ammonia) gives Amides via Nucleophilic Substitution
O
O
C OR + H-N(CH3)2
CH3
CH3
C N(CH )
3 2
Reduction - Esters can be reduced to alcohols by LAH but not by NaBH4. Note that
both portions of the ester (alcohol and acid) are liberated as alcohols. Since this is
the case mixtures may result. If one of the alcoholic products is easily removed, this
is an excellent way to prepare alcohols.
O
CH2OH
C
1.) LAH, Et2O
OCH2CH3
2.) H +
_
O
C
H
O
OCH2CH3
C
-
H
_
+ CH3CH2O
O
C
OCH2CH3
H
H_
O
OH
C
CH3CH2OH
H
H
H
C
+
H
H
Grignard Reactions
OH
O
C
OCH3
Et2O
+ 2 CH3CH2MgBr
2.) H +
C
CH2CH3
CH2CH3
This is a great way to make 3° alcohols in which two of the alkyl substituents are
the same (both derived from the Grignard reagent). The mechanism for this process
is completely analogous to that of hydride reaction above. Just replace "H - " with
"Et-" and you have it.
O
Amides
R
C NR'
2
A word about the electronic nature of amides in comparison to other functional groups. In amides and esters, the
lone pair electrons of the heteroatom next to the carbonyl can be delocalized into the C=O bond. Nitrogen can do
this much more effectively than oxygen (because N is less electronegative). As a result, the delocalized resonance
structure contributes more to the nature of amides than the corresponding structure for esters. This helps explain
why amides are less basic than amines and less reactive than esters (which are, in turn less reactive than
aldehydes/ketones). There are other manifestations of this property.
Aldehydes/
Ketones
O
IR
C=O
R
C H
1715 cm-1
Amides
O
R
O
Esters
O
-
+ R'
C
N
R
R'
1695-1650 cm-1
C NR'
2
Because of the delocalization of electrons,
there is substantial single-bond character in
the carbonyl. This lowers the force constant
and consequently the position of the C=O
band.
R
C OR'
O-
O-
+
R C OR'
R
C
+
OR'
1750-1735 cm-1
In esters, an inductive effect is said to be
operating (left-most structure). This increases
the polarization of the C=O bond increasing the
attraction of the two atoms and therefore
increasing the force constant.
This also implies that there is a substantial
amount of double-bond character in the C-N
O
bond. This in turn implies that there may not
CH3
C
be free rotation about the C-N bond. There is
H
N
clear evidence of this in the NMR spectra of
CH3
3° amides (as shown for N,N-Dimethylformamide).
The two methyl groups resonate at different positions.
O-
+ CH 31.1 ppm
3
C
N
H
CH3 36.2 ppm
Nomenclature and Classification
Like esters, amides can be thought to consist of two parts: a carboxylic acid portion
and an amine portion.
O
OH
NH3
- H2O
C
:
:
C
O
A primary
amide.
NH2
Benzamide
Ammonia
Benzoic Acid
O
H2N
- H2O
C
H
OH
Methanoic Acid
(Formic Acid)
H
C
A secondary
amide.
:
:
O
N
H N-Phenylmethanamide
(N-Phenylformamide)
Aniline
O
CH3
OH
Ethanoic Acid
(Acetic Acid)
N
CH3
- H2O
CH3
CH3
C
:
H
C
:
O
N
CH3 A tertiary
amide.
CH3
N,N-Dimethylethanamide
(Dimethyl acetamide, DMA
a teratogen)
Dimethylamine
O
N
:
C
+ H2N-OH
- H2O
C
OH
O
H+
Beckman
Rearrangement
C
:
:
Cyclic Amides are called "Lactams"
N
H
Caprolactam
As we have already noted, amides can be prepared from the reaction of amines with
Acid halides
Anhydrides
Esters
Carboxylic acids
i.e. from all of the other carboxylic acid derivatives.
Reactions of Amides
Hydrolysis with Aqueous Acid or Base
CH3CH2
C
CH
:
O
NH2
O
H2O, H2SO4
CH3CH2
Heat
CH
C
_
+
+ NH4 HSO4
OH
88%
H3C
NH2
KOH, heat
ethanol/water
:
C
:
2-Phenylbutanamide
O
_ +
CH3CO2 K
N
95%
H
Reduction (with strong hydride reducing agents)
O
H
H
:
N CH2CH3 1.) LAH, Ether
2.) H +
CH2CH3
N,N-Diethylbenzamide
C
N CH2CH3
:
C
CH2CH3
Benzyldiethylamine
Polymerization
C
Cat. Nu-
N
C
C
H
:
Nu
O
O
Nu
N
_
H
N
:
N
H
O:
C
:
O
C
Nu
O
C
N
_
H
N
H O
C
O H
A polyamide.
C N
n
_
:
N
HO
: :
C
:
O
:
Nu
N
H
H
Another polyamide
HO
O
C
C
H2N
OH
1,6-Hexanediamine
(Hexamethylene Diamine)
O Hexanedioic Acid
(Adipic Acid)
_
O
NH2
O
+
H3N
C
_
O
C
+
NH3
n
Heat to drive off H2O
O
C
O
O
H
C
N
N
n
H
Polyhexamethyleneadipamide
Nylon 6,6
Developed during the war to replace silk.
Nylon first debuted in toothbrushes. It is one of the strongest of all synthetic fibres.
Now used mainly in tires where its strength is important. Nylon was developed by
W. H. Carothers of DuPont. Believing himself to be a failure as a scientist, he
committed suicide three weeks before the patent was filed. Nylon stockings were
first sold in New York on May 15, 1940. In two hours, 4 million pair were sold.
Yet another polyamide
HO2C
CO2H H2N
NH2
- H2O
C
Kevlar
C N
N
O
O H
H
n
Still yet another polyamide
R1
H2N
CH
R
CO2H
H2N
C
O
H
O
N
C
R2
R3
N
C
H
O
H
O
N
C
R4
R5
N
C
H
O
OH
R = H, CH3, CH2OH, CH2SH, CH2CO2H, (CH2)4NH2, iPr, iBu, PhCH2 and many more !