Download Chapter 19 Carboxylic Acid Derivatives Nucleophilic Acyl

Chapter 19 Carboxylic Acid Derivatives
Nucleophilic Acyl Substitution
Nomenclature:
In carboxylic acid chlorides, anhydrides, esters and amides, the parent is the carboxylic
acid. In each case be sure to include the carbonyl carbon when numbering the chain. This
always gets the lowest number.
Carboxylic acid chloride (usually abbreviated to acid chloride) acyl chloride: Name acyl
group by replacing the parent carboxylic acid ending “-ic acid” with “-yl chloride” (or
other halide).
O
CH3CH2
O
C Cl parent carboxylic acid: propanoic acid
propanoyl chloride
O
O
CH3
CH2
4
CHCH2
3 2
C Cl
1
3-butenoyl chloride
C Br
C Cl
p-fluorobenzoyl bromide
acetyl chloride
F
Carboxylic acid anhydride: replace “acid” with “anhydride”.
O
CH3
O
O
C O C CH3
acetic anhydride
O
O
CH3CH2CH2
C O C
benzoic anhydride
O
C O C CH2CH2CH3
propanoic anhydride
When the two acyl groups are different, list them in alphabetical order.
O
O
C O C CH2CH2CH2CH3
benzoic pentanoic anhydride
Esters:
Name the alkyl portion first and then name the acyl portion by substituting “-ic acid” of the
parent carboxylic acid with “-ate”.
1
O
CH3
Br
O
C OCH2CH3
CH3CH2CH2
CH3
2
CH
CH3 5
CH3
3
1 O
4
6
OH
C OCH3
methyl butanoate
ethyl acetate
O
isopropyl 5-bromo-2-hydroxy-3-hexenoate
Amides:
Unsubstituted: Change “-oic acid” of the parent carboxylic acid to “-amide”.
O
O
CH3
C
C
NH2
acetamide
O
4
NH2
CH3
6
benzamide
3
5
2
1 NH2
CH3
3-methyl-2-hexenamide
Substituted amides: Name as N-alkyl and N,N-dialkyl derivatives of a parent amide. List
the N-alkyl substituents in alphabetical order. If the same N-alkyl substituent reappears as
a substituent on the parent chain, the substituent is combined with the N-alkyl substituent
as a di-, tri-, etc and its position on the parent indicated by number.
O
C
O
CH3
CH2CH3
N CH2CH3
N
CH3
CH2CH3
N-ethyl-N-methylbenzamide
N,N-diethylbutanamide
6
5
O
CH3
1 N
3
4
2
CH3
N,N-3-trimethylhexanamide
Nitriles: Add the suffix “-nitrile” to the name of the parent hydrocarbon chain that
includes the carbon of the nitrile group itself. Nitriles can also be named by replacing the
“-ic acid” or “-oic acid” with “-onitrile”.
CH3CH2CH2
4 3 2
C N
1
butanenitrile or butanonitrile
CH3
CH
CH3
CH3
C
N
ethane nitrile
C
N
benzonitrile
acetonitrile
2-methylpropanenitrile
(or common name; isopropyl cyanide)
CN
Reactivity Order:
2
The order of reactivity for the carboxylic acid derivatives is extremely important in
organizing the large amount of information and the large number of reactions in this
chapter. The reactivity order is as follows:
Acid chloride > anhydride > thioester > ester > amide
Most reactive
least reactive
O
Most Reactive
General Rule:
R C Cl
least stabilized carbonyl
O
O
R C O C
R'
O
R C
S
Conversion of one class of compound to another is feasible
only in the direction that goes from a more reactive carbonyl
(higher in the reactivity order) to a less reactive carbonyl (lower
in the reactivity order) or in the driection that converts a less
stabilized carbonyl to a more stabilized one.
R'
O
R C O R'
So, a carboxylic acid chloride can be used to synthesize
anhydrides, thioesters, ester and amides but amides can
not be used to synthesize any other derivatives.
O
R C
Least Reactive
Most stabilized carbonyl
N R'
R''
There is a very large range of reactivity between the most reactive (acid chlorides) and the
least reactive (amides). In general, acid chlorides react about 1013 times faster in
nucleophilic acyl substitution reactions than amides.
In order to understand the reactivity order, we need to look at the general reaction –
nucleophilic acyl substitution - that all of these derivatives undergo. It is shown below for
basic conditions in which the nucleophile is an anion. The slow step is the initial attack of
the nucleophile on the carbonyl carbon to form the tetrahedral intermediate. Loss of the
leaving group - with its electrons – is fast.
Basic conditions
O
Nu
+
R C X
slow
O
fast
R C X
O
R C
Nu
+
X
Nu
tetrahedral intermediate
A generalized mechanism in acidic conditions is given below. In acidic conditions there
are additional proton transfer steps but these are very fast. All species are already
hydrogen-bonded to protons and the proton transfer steps are essentially instantaneous.
The slow step is still the attack of the nucleophile on the carbonyl. As we will see, there
3
are minor variations depending on the individual reaction and in writing mechanisms it is
common practice to combine the proton transfer steps so as to save writing.
Acidic Conditions
O
Nu
H +
O
fast
R C X
+
H
R C X
H Y
+ Y
H
O
slow
R C X
Nu
Nu
O
H Y
+
R C
H
Nu
R C
H
Y
Nu
H
tetrahederal
intermediate
O
H
R C X
Since the slow step is the attack of the nucleophiles on the carbonyl carbon, what
determines the rate of this reaction is the degree of electron deficiency at the carbonyl
carbon. As we know, the carbonyl carbon has a partial positive charge so we can also say,
that the greater the positive charge on the carbonyl carbon, the more reactive it will be to
nucleophiles, which by definition, has to have a partial negative charge and a lone pair.
As we will see, there are two opposing trends: the X-group in each of our carboxylic acid
derivatives has a lone pair that can donate electrons to the carbonyl carbon and make the
carbonyl carbon LESS electron rich and all of the X-groups have an atom that is MORE
electronegative than the carbonyl carbon and so there is an opposing inductive effect that
works to decrease the electron density at the carbonyl carbon, making it more positive, and
more reactive.
For acid chlorides: The chlorine is a relatively strong electron withdrawing group and the
carbonyl carbon – chlorine bond is relatively long because chlorine is in the second row of
the periodic table and larger than carbon. This makes the chlorine lone pair 3p orbital too
far away to overlap effectively with the π-orbital of the carbonyl and so the net effect is
that the carbonyl carbon of acid chlorides is relatively electron deficient and therefore very
reactive.
R
C
Cl
In acid chlorides, the inductive effect of electron withdrawal is
stronger than the resonance effect of electron donation.
4
H Y
Nu
Nu
O
H
R C X
Y
O
O
fast
H
For Acid Anhydrides: oxygen is more electronegative than chlorine (3.44 v. 3.16) and so
withdraws electrons from the carbonyl carbon inductively (i.e. through the bond) but
oxygen is a first row element and the C-O bond is considerably shorter than the C-Cl bond.
Consequently there is much better overlap of the oxygen lone pair with the π-orbital of the
carbonyl. But since there are two carbonyl carbons competing for the oxygen lone pair,
the lone pair donation (resonance effect) is diluted.
O
R
C
O-
O
O
R'
C
R
C
O
O-
O
O
R
R'
C
C
O
C
R'
For thioesters: Sulfur is a third row element, like chlorine, and so it is considerably larger
than oxygen. The C-S bond is relatively long and this makes for poor overlap of the lone
pair 3p orbital and the π-orbital of the carbonyl. But thioesters are less reactive than acid
chlorides and anhydrides due to the fact that the sulfur is considerably less electronegative
than oxygen and chlorine. The inductive electron withdrawing effect of the sulfur is less
than that of oxygen or chlorine due to the decreased electronegativity of sulfur versus
oxygen (2.58 v. 3.44).
For esters: The oxygen substituent of esters is an overall electron-donating group. There is
the electron withdrawing effect due to the greater electronegativity of oxygen as compared
to carbon but this is outweighed by the electron donating effect of the oxygen lone pair due
to resonance.
resonance effect donates
O
R
C
R'
O
OR
C
O
R'
In esters, the electron donation of the oxygen
lone pair is stronger than the eelctron
withdrawal due to the greater electronegativity
of oxygen as compared to carbon.
inductive effect withdraws electrons
For amides: Nitrogen is less electronegative than oxygen (3.04 v. 3.44) but is still more
electronegative than carbon (2.55) so in amides there is still an electron withdrawing
inductive effect through the C-N bond but there is a much larger electron donating effect
due to resonance donation of the nitrogen lone pair into the carbonyl π-orbital.
O
R
C
strong resonance effect donates
electrons
ON
R'
R
N
C
R''
R''
inductive effect withdraws electrons slightly
5
R'
The strong resonance donation gives the carbon-nitrogen bond in amides lots of double
bond character. The C-N bond in amides is much shorter than a normal C-N bond.
1.47 A°
H
R C
N R'
1.35 A°
O
R C
N R'
H R''
R''
There is a considerable barrier to rotation around the C-N bond since there is a lot of sp2
character for the amide nitrogen. All of the three bonds of the amide lie in the same plane.
O
R'
C N
R''
R
R'
R
C N
O
Eact = 75 - 85 Kj/mol (18-20 Kcal/mol)
R''
Carboxylate anion: This is also stabilized by resonance. The negatively charged oxygen is
a powerful electron donor and so a Carboxylate anion behaves very differently from the
other carboxylic acid derivatives under discussion. The carbonyl carbon is not
electrophilic and is not attacked by nucleophiles.
O
O-
R C O-
R C O
Again, to convert one carboxylic acid derivative into another one, the reaction is feasible
only if the new derivative lies BELOW it in reactivity or, in other words, only if the
conversion is from a less stable carbonyl to a more stable one.
A very useful way to remember the reactivity order is to consider the leaving group ability
of the X group. As we discussed above, the slow step (rate determining step) of the
reaction is the attack on the carbonyl and loss of the leaving group is fast but the leaving
group ability of X does correlate with the overall rate of the reaction. And so we can
remember the reactivity order by considering which is the better leaving group. As we
know, the more stable the anion – i.e. the weaker the base – the better the leaving group.
6
O
O
>
R C Cl
R C O C
R'
>
R C
S
O
> R C O R'
R'
O
O
>
R C
N R'
-O
Cl-
C
Conjugate Acid
-S
R'
-O
R'
HO C
HS
R'
HO R'
R'
16
10
5
-6
R'
-N
R C O-
O-2
R'
R''
O
HCl
>>
R''
O
Leaving Group
pKa
O
O
(does not exist)
HN R'
R''
36
weakest acid, Strongest base
worst leaving group
least reactive derivative
strongest acid, weakest base
best leaving group
most reactive derivative
This is simply a mnemonic, a useful way to remember the reactivity order but you can see
that there is good correlation between the reactivity and leaving group ability.
Acid chlorides
Preparation
Acid chlorides are extremely reactive and are generally prepared in situ from carboxylic
acids by heating in a solution of thionyl chloride. The thionyl chloride is generally used in
excess as the solvent and when the reaction is finished the excess is removed by
distillation, leaving behind the moisture sensitive and highly reactive acid chloride.
Aqueous workups are to be avoided since the acid chlorides react rapidly with water to
reform the carboxylic acid.
O
Cl
Cl
S Cl
O
CH3
O
C OH
+ Cl
S Cl
CH3
O-
O
S Cl
S Cl
O
O
C O H
strong Lewis acid
HCl
+ CH3
C Cl
C O H
ClO
Cl-
O
SO2 +
CH3
CH3
S Cl
C O H
Cl
O
CH3
C O H
Cl
Reactions of Acid chlorides
Acid chlorides are the most reactive of the carboxylic acid derivatives and can therefore be
used to prepare all of the other derivatives: (1) anhydrides (2) thioesters (3) esters (4)
amides (5) carboxylic acids.
7
(1) Anhydride preparation:
(a) Anhydrides can be prepared from an acid chloride using a neutral carboxylic acid as the
nucleophile. Usually a mild, non-nucleophilic base such as pyridine is added to the
reaction mixture so as to neutralize the HCl that is produced.
O
CH3
C Cl
+
HO C
HN
O-
O
N
CH3
H
N
O H
C Cl
O
CH3
C
C Cl
O
O
CH3
C
O
neutral tetrahedral
intermediate
proton transfer occurs to give the neutral
tetrahedral intermediate
O
N
H
O
+
C O C
N
Cl-
(b) We can also use the carboxylate salt in which case we do not need to add pyridine. The
by-product is NaCl, rather than HCl.
O
CH3
C Cl +
O
Na+ -O
C
OCH3
C Cl
O
O
CH3
O
C O C
+ NaCl
C
O
tetrahedral intermediate
(2) Ester Preparation
As with the preparation of anhydrides, we can use neutral conditions (alcohol with a mild
base) or basic conditions (alkoxides).
(a) From neutral alcohols with pyridine as the base:
8
O-
O
CH3
C Cl
+
HO CH2CH3
N
CH3
O H
C Cl
O
H
N
HN
CH3
C Cl
CH2CH3
O
CH2CH3
neutral tetrahedral
intermediate
proton transfer occurs to give the neutral
tetrahedral intermediate
CH3
N
O
H
C O CH2CH3 +
N
Cl-
(b) From basic alkoxides: No pyridine is needed.
O
CH3
C Cl +
O-
O
Na+ -O
C CH2CH3
CH3
O
C Cl
O
CH3
C O CH2CH3 + NaCl
C CH2CH3
O
tetrahedral intermediate
(3) Preparation of amides
We prepare amides from ammonia and primary and secondary amines. Tertiary amines
give unstable products that cannot be isolated. Since amines are fairly strong bases and
good nucleophiles we (1) don not need to add a second base such as pyridine and we
simply use an excess of the amine to neutralize the HCl that is produced (provided that our
amine is relatively inexpensive). And (2) we do not need to use an amine anion since the
neutral amine is an excellent nucleophile.
H
O
CH3
C Cl +
O-
H
H N CH2CH3
CH3
H
C Cl
H N H
CH3CH2NH2
H
H N CHCH3
CH2CH3
CH3
O H
H N CH2CH3
O
C Cl
N H
CH2CH3
tetrahedral intermediate
CH3
C
+
H
ClH N CHCH3
H
9
NHCH2CH3
(4) Hydrolysis of Acid Chlorides
Acid chlorides are easily hydrolyzed by water to give the carboxylic acid. This is not a
useful reaction synthetically since acid chlorides are produced from carboxylic acids but it
is a reaction that we must be aware of and usually try to avoid.
H
O
CH3
+
C Cl
H O H
O-
H
CH3
O H
H O
C Cl
O
H
H
O H
CH3
H
H
O
C Cl
O
H
O H
CH3
C O H + H O H
Cl-
H
neutral tetrahedral intermediate
proton transfer occurs to
give the neutral
tetrahedral intermediate
Anhydrides
After acid chlorides, the next most reactive derivatives are the anhydrides. They can be
used to form the esters and amides and are also subject to hydrolysis.
It is best to think of acid chlorides and anhydrides as reagents used for the preparation of
the more stable end products, the esters and the amides.
Preparation
In the laboratory anhydrides are usually prepared from acid chlorides, as we have just seen.
O
CH3
C Cl
O
+
O
HO C
CH3
N
H
O
+
C O C
N
Cl-
Other common derivatives are prepared by special methods on an industrial scale. These
include
O
CH3
O
C O C CH3
O
O
O
phthalic anhydride
acetic anhydride
O
O
O
10
maleic anhydride
Reactions of Anhydrides
Since a nucleophile can attack either carbonyl, symmetrical anhydrides are usually used so
as to give one product.
(1) Preparation of Esters
(a) We can use neutral alcohols. With the neutral alcohols we usually use acid catalysis to
activate the carbonyl carbon of the anhydride to nucleophilic attack since the neutral
alcohol is a relatively weak nucleophile. Acid catalysis increases the rate of formation of
the tetrahedral intermediate.
O
O
R C O C
R
+
HOR'
O
cat. H+
O
R C O R' +
HO C
R
For example:
H
O
CH3
O
O
H O CH2CH2CH3
C O C CH3
CH3
O
H
O
CH3
C O C CH3
CH3CH2CH2 O H
CH3CH2CH2 O H
O
H
C O C CH3
CH3CH2CH2OH H
O
CH2CH2CH3
H
CH3CH2CH2 O H
O
CH3
C OH
CH3
O
O
C O + CH3CH2CH2O C CH3
O
CH3
O
H
HOCH2CH2CH3
C O C CH3
O
CH2CH2CH3
(b) Ester can also be formed from anhydrides in basic conditions using alkoxides.
O
CH3
O
C O C CH3 + O
O
CH3
O
C O C CH3
O
O C CH3 + CH3
O
C O
O
(2) Amide formation from anhydrides
Primary and secondary amines react with anhydrides to give amides. No catalysis is
needed, since amines are basic and good nucleophiles. Use of acid would protonate the
amine rather than the carbonyl carbon, making the amine non-nucleophilic.
11
O
CH3
O
O
H
C O C CH3 +
CH3
N
H3+NPh
O
C O C CH3
O H
O
CH3
C O C CH3
H N H
H
H2NPh
N H
PhNH2
CH3
O
O
C O H3+NPh + CH3
C
N
H
(3) Hydrolysis
Anhydrides are not stable in water and are converted back to the parent carboxylic acids.
The reaction is generally slow at room temperature and is accelerated by heat.
O
O
O
H
O +
O
O H
H
O
O
H O
C O
O
H
H
O
OH2
H2O
H
C O
H O
C
H
C
O
Esters
Preparation:
(1) As we saw, esters can be prepared directly from carboxylic acids and alcohols under
conditions of acid catalysis.
C OH
+ HOCH3
O
C OCH3 +
(2) From acid chlorides
12
OH
O
C
H2SO4
H O
O-
O
C
O
H
H2O
OH
OH
H
O
CH3CH2
O
N
C Cl +
CH3CH2
HOCH2CH3
C OCH2CH3
+
O
O
CH3CH2
ClN H
C Cl +
Na+ -OCH
2CH3
CH3CH2
C OCH2CH3
+
NaCl
(3) From anhydrides:
Acidic conditions:
O
CH3
O
+
C O C CH3
O
H2SO4
HOCH2
CH3
O
+ CH3
C O CH2
C OH
Basic conditions:
O
CH3
O
O
C O C CH3 +
Na+ -OCH
CH3
2
O
+ CH3
C O CH2
C O-
(4) Baeyer-Villiger oxidation of ketones with peroxy acids. An alkyl or aryl group
migrates from carbon to oxygen.
O
R C
O
R'
+
ketone
R''
C OOH
peroxy acid
O
O
+
R C OR'
R''
C OH
ester
Generally the more electron rich group migrates (3° > 2° > cyclohexyl > benzyl > phenyl >
1° > methyl). This reaction is very useful for cyclic symmetric ketones. The product is a
lactone (cyclic ester) that contains one more atom, so it is a ring-expansion reaction. For
example:
H
O
-O
O
H
O O C
O
+
O
O
O O C
HO O C
H
O
HO C CH3 +
13
O
O
O
O
O
+
-O
C CH3
Physical Properties of Esters
Esters are moderately polar compounds that have higher boiling points than hydrocarbons
but lower than alcohols and much lower than carboxylic acids. Esters cannot donate
hydrogen-bonds but they can accept them, so they have some solubility in water.
CH3
OH
O
CH3
C CH2CH3
H
2-methylbutane
CH3
CH3
C CH2CH3
H
2-butanol
b.p. 99°C
C OCH3
methyl acetate
b.p. 57°C
b.p. 28°C
33 g/100mL
solubility in H2O
H
H O
O
CH3
C OCH3
Reactions of Esters
(1) (Review) Reduction with lithium aluminum hydride to a primary alcohol.
O
CH3
OH
LiAlH4
C OCH3
CH3
C
H
H
Et2O
(2) Conversion of esters to amides with primary and secondary amines. Amides are below
esters in the reactivity scale and so can be converted to amides.
O
CH3
O-
H
C OCH3 + N
heat
H
Ph
NH2
CH3
C OCH3
H N H
+
14
O H
H3+N Ph
CH3
H2NPh
C OCH3
N H
O
CH3
C
N H
(3) Hydrolysis of esters to carboxylic acids in acidic or basic conditions.
O
O
R C OR'
Aqueous acid
R C OH
+
R'OH
or aqueous base
(a) Ester hydrolysis in acidic conditions is fully reversible and is the exact reverse of ester
formation. We drive the reaction to the right in favor of hydrolysis by using an excess of
water.
O
O
CH3
C OCH3 +
H O H
H2O
H
CH3
H
H
O
CH3
C OCH3
H O
H2O
H
H O H
H
C OCH3
O
CH3
H2O
H
O
H
C OCH3
O
H
H
H
O
CH3
C OH
+
HOCH3
(b) Ester hydrolysis can also take place in basic conditions using aqueous sodium
hydroxide. This reaction is called saponification (from the Latin sapon for soap because
the basic hydrolysis of animal fat was a traditional way of making soap). One advantage of
the basic hydrolysis is the reaction is irreversible. The initial carboxylic acid formed is
irreversibly deprotonated by the basic hydroxide solution. To isolate the neutral carboxylic
a final protonation step is required. The pH is made acidic by the addition of aqueous HCl.
O
CH3
C OCH3 +
Na+ -OH
H2O
OCH3
O
C OCH3
heat
CH3
OH
Final step is irreversible and this
drives the equilibrium to the right in
favor of hydrolysis.
CH3
O
H3O+
C OH
H2O
C O H + -OCH3
pKa 5
stronger acid
O
CH3
C O-
+
HOCH3
pKa 16 weaker acid
Note that cleavage always occurs between the carbonyl carbon and the oxygen, not
between the alcohol carbon and the oxygen.
15
O
R
C
R'
O
Cleavage is always of this bond
Therefore cleavage of esters with optically active alcohols results in retention of
configuration of the alcohol moiety.
O
C
O
-OH
CH3
C H
Na+ -OH
CH2CH3 H2O
OC
O
O
C
O
CH2CH3
H
S-configuration
O
CH3
C H
H
+
O
C
O
HO
-O
CH3
C H
CH2CH3
CH3
C H
CH2CH3
+
S-configuration
(4) Reaction of Esters with Grignard and organolithium reagents.
Grignard and organolithium reagents react twice with esters to give tertiary alcohols in
which two of the substituents are the same.
O
C
OCH3
THF
O
O
C
C
OCH3
CH2CH3
2 BrMgCH2CH3
hemi-acetal, unstable
HO
C CH2CH3
CH2CH3
Thioesters
16
CH2CH3
2 BrMgCH2CH3
H3
O+
+
O MgBr
C CH2CH3
CH2CH3
Preparation: Thioesters can be prepared from acid chlorides or anhydrides using the same
conditions as discussed above for esters.
From acid chlorides:
O
O
R
C Cl
+
pyridine
HSR'
R
+
SR'
NH Cl
O
O
R
C
C Cl
Na+ -SR'
+
R
C
+
SR'
O
C
Cl
+ Na+ -SCH2CH3
NaCl
O-
O
C Cl
C
SCH2CH3
SCH2CH3
From anhydrides
O
R
O
C O C R
+
HSR'
O
heat
R
C
O
SR'
+
HO C R
Reactions
Thioesters will react with alcohols, alkoxides and amides. They see limited use in
laboratory synthesis but are very important in biological systems.
O
R
C
O
SR'
+
Nu
H
R
C Nu
HSR'
O
O
C
+
SCH2CH3
+
HOCH3
C
HCl
OCH3 + HSCH2CH3
Thioesters are about as reactive as esters even though the ΔG for hydrolysis is more
negative. The rates for hydrolysis are about the same as for esters.
But thioesters are much more reactive toward amine nucleophiles than esters. This helps
to account for the importance of thioesters in biochemistry. Many biochemical reactions
involve acyl transfer. The thioester, acetyl coenzyme A transfers acyl groups to alcohols,
amines and other nucleophiles.
17
NH2
N
O
CH3
S
H
H
N
N
OH
N
O
O P O P O
CH
O 3
O
O
CH3
O-
N
O
OH
Acetyl Coenzyme A
N
H
H
O
H
OH
O P OO-
Acetyl coenzyme A has many functions. One of them is in the biosynthesis of melatonin.
Melatonin is a hormone secreted by the pineal gland. It regulates circadian rhythms,
including the wake-sleep cycle.
O
NH2
HO
NH C CH3
HO
serotonin
N
H
O
NH C CH3
CH3O
N-acetyltransferase
N
H
Acetyl Coenzyme A
N
H
Amides
Amides are a very important functional group, especially in biochemistry since the bond in
all proteins (the “peptide” bond) is an amide linkage.
Amides have strong dipole moments due to the considerable electron donation of the
nitrogen lone pair. This gives the C-N bond considerable double bond characters, as we
have discussed.
O
H
C
O
O
N
H
H
H
C
N
H
H
C
N
H
Dipole: 3.7 D
H
H
formamide
Delocalization of the nitrogen lone pair decreases the amount of positive charge at the
carbonyl carbon, making it less electrophilic toward nucleophilic attack.
18
Amides are capable of strong intermolecular hydrogen-bonding, giving very high boiling
points, much higher even than carboxylic acids.
H
H
O
C
N
H
H
H
O C
H
O
C
N
O
H
H
H
H
O
C
N
H
H
O
CH3
C
N
H
H
C
N H
O
N
H
CH3
C
CH3
H
acetamide
acetone
b.p. 221°C
b.p. 56°C
The boiling point decreases as the number of hydrogen-bonds decreases.
CH3
C
O
O
O
N
H
CH3
C
N
H
H
b.p. 221°C
b.p. 206°C
CH3
CH3
C
N
CH3
CH3
b.p. 165°C
Acidity of Amides
Since nitrogen is less electronegative than oxygen the N-H bond is stronger than the O-H
bond or a carboxylic acid and amides are much weaker acids. They are comparable in
acidity to alcohols, with pKa’s of ~16.
O
O
CH3CH2
pKa 36
NH2
CH3
C
pKa 16
N
H
H
CH3
O
C
N
pKa 10
H
C
O
H
CH3
CH3CH2
pKa 16
O
CH3
C
O
H
pKa 4.78
Synthesis of Amides
As we have seen, amides are at the bottom of the reactivity scale and can be synthesized by
all of the other derivatives we have talked about: from (1) acid chlorides, (2) anhydrides,
19
(3) thioesters, (4) from esters. Since an acid is produced when acid chlorides or anhydrides
are used, an extra equivalent of the amine is often added so as to neutralize this acid. If the
amine is expensive, another base may be added.
O
R
O
C Cl
O
R
+
H N R'
R C N R' +
R'
R'
O
O
O
C O C R
+
C N R' +
R
H N R'
R
C OH
R'
R'
O
O
R
R' = H, alkyl or aryl
HCl
C OR''
+
H N R'
R C N R' +
R'
R'
HOR"
Cyclic amides or lactams can be formed.
O
α
O
α
NH
β
δ
β
α
γ
γ-lactam
δ-lactam
NH
NH
β
γ
O
β-lactam
The β-lactams are very important in medicinal chemistry since they are the key reactive
functional group in the penicillin antibiotics.
H
N
CH2
O
S
N
O
CH3
CH3
H
N
CH
H2N
O
S
N
O
CO2H
CH3
CO2H
cephalosporin
penicilin G
The 4-membered ring lactam is much more reactive than normal lactams due to angle
strain. It undergoes a ring opening reaction when attacked by a sulfhydryl group of one of
the bacterial enzymes involved in cell wall synthesis. Humans do not have this enzyme
and therefore are not harmed by the drug. The penicillin is a “suicide inhibitor” because it
20
forms an irreversible covalent bond with the target bacterial enzyme, shutting down its
function and eventually leading to death of the bacterial cell.
Ph
H
N
Ph
S
O
CH3
N
+
HS
CH3
O
H
N
Enzyme
O
CO2H
S
O
Enzyme
S
C
S
O
Ph
-O
O
Covalent adduct of enyme and penicilin
CH3
CH3
CO2H
Enzyme
H
N
CO2H
N
H
HN
Ph
N
-O
H
CH3
CH3
S
S
CH3
N
CH3
H
S
CO2H
Enzyme
Reactions of Amides
Because amides are the least reactive of the carboxylic acid derivatives, the only
significant reactions they undergo are hydrolysis. This occurs under acidic or basic
conditions.
O
R
O
Acid or base
C N R'
R
C O H
+
H N R'
heat
R'
R'
Acidic Conditions
H
H
O
O
CH3CH2
O
H 2O
C N H + H O H
H
H
CH3CH2
C N H
H 2O
H
CH3CH2
H2O
C N H
O H
H
H
H O H
H
H
H
O H
O
H N H
H N H
H
H
+ CH3CH2
C OH
CH3CH2
H
21
H O H
C N H
O H
H
Note that in the first step, protonation of the amide occurs on the carbonyl oxygen, not on
the nitrogen. Protonation on the carbonyl allows for resonance stabilization of the
resulting cation by the nitrogen lone pair. If protonation were to occur on the nitrogen, no
such resonance stabilization by oxygen lone pair would be possible.
H
H
O
CH3CH2
O
C N H
CH3CH2
H
C N H
resonance stabilization from the nitrogen lone pair
H
O H
CH3CH2
C N H
H
No resonance stabilization possible from the
oxygen lone pair since the carbon would then
have five bonds.
Basic conditions
The final step is irreversible deprotonation of the carboxylic acid in the basic conditions.
To isolate the neutral carboxylic acid,
H
O
CH3CH2
C N H +
Na+ -OH
H2O
OCH3CH2
H
C N H
OH
CH3CH2
C O H
H
O
CH3CH2
O
H O
C O H
Na+ -OH
Add H3O+
O
CH3CH2
C O-
Nitriles
Preparation
(1) Nitriles can be prepared by means of an SN2 reaction of cyanide anion with alkyl
halides.
R
CH2 X
+
M+ -:CN
R
CH2 CN
(2) By reaction of cyanide anion with an aldehyde or ketone to form the cyanohydrin.
22
+
NH3
O
R
C R'
+
M+ -:CN
HCN
H
OR
CN
OH
R
C R'
C R'
CN
CN
(3) Dehydration of Amides
Amides can be dehydrated using a strong dehydrating agent such as phosphorus pentoxide,
which is the anhydride of phosphoric acid.
O
R
C NH2
P4O10
R
C N
Reactions of Nitriles
(1) Hydrolysis: Nitriles can be hydrolyzed in either acidic or basic conditions. Nitriles are
quite stable and need fairly high temperatures for the hydrolysis.
(a) Basic hydrolysis:
Hydroxide attacks the nitrile carbon and the nitrogen gets a negative charge. The nitrogen
anion then is protonated by water. This initial intermediate rearranges to the amide. The
amide can be isolated but it is usually hydrolyzed to the carboxylic acid.
H
H O
H
H
CH3CH2
C
N + Na+ -OH
H O
CH3CH2
C
CH3CH2
N
C
O
OH
N
H
HOCH3CH2
C
H
N
H
O
-OH
amide
H
H O
H
CH3CH2
C O-
CH3CH2
O
C O
O
(2) Acidic Hydrolysis:
23
H
CH3CH2
-OH
O H
C
O-
N
H
CH3CH2
N + H O H
C
H2O
CH3CH2
H
H2O
H
O H
H
CH3CH2
CH3CH2
C
CH3CH2
N
H
N H
H
O
H
H2O
CH3CH2
C
C
O
H O H
H
O
N H
H
CH3CH2
N
C
O
H
N H H O H
H
H
OH2
H
H O H
H
O H
C
H
H
H
H2O
H
O
H
O
H2O
H2O
N
C
CH3CH2
N H
C
H
H
O
CH3CH2
C
O
(3) Reaction of Nitriles with Grignard and organolithium reagents:
Nitriles are electrophilic and are attacked by Grignards and organolithium reagents to give
ketones after the work up. Unlike esters, they react only once since the initial intermediate
is an anion that is no longer electrophilic. Hydrolysis of the imine occurs during the acidic
workup.
CH3CH2
C
N +
CH3MgBr
THF
CH3CH2
C
N
CH3
O
CH3CH2
C CH3
MgBr+
Add
H3O+
iminium anion,
initial reaction product
until work up
H
H2O
H2O H
H
O H
O H
CH3CH2 C N H
CH3CH2 C N H
CH3 H3O+
CH3 H
H3O+
24
CH3CH2
C
N H
CH3
H3O+
H2O
CH3CH2
H
C
N H
CH3