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Chemistry 131
Lecture 12: Carboxylic Acid Derivatives
Chapter 17 in McMurry, Ballantine, et. al. 7th edition
HW #6: 17.32, 17.38, 17.40, 17.42, 17.44, 17.46, 17.48, 17.50, 17.54, 17.56,
17.58, 17.60, 17.62, 17.64, 17.66, 17.68
Esters
Esters can be made in reasonable yields from the corresponding acid and
alcohol using an acid catalyst, but the reaction is reversible (alcohols as
analogs of water) so some measure must be taken to drive the reaction to
completion using LeChâtelier’s Principle:
By adding excess alcohol or acid, depending on which is more precious
Removal of water or ester
5-hydroxypentanoic acid can be heated up in mildly acidic conditions
to form a cyclic ester or lactone, which occurs faster and gives higher
yields than other esterification reactions (particularly at higher
temperatures).
o The fact that the alcohol and acid are tethered together in 5-
hydroxypentanoic acid and react faster gives us insight into life
at the scale of organic chemistry
2
Ester Nomenclature
To name esters, treat as a carboxylic acid salt: where the cation would go in the
name, put whatever substituent is there. This is consistent with our usual
system of naming compounds with substituents. No indication of placement at
the oxygen is necessary (since substituents in other areas have “locants”)
Please name the following compounds
O O Na+
______________________________________________
O O
______________________________________________
O O
__________________________________________
O O
__________________________________________
Amides
May be synthesized from acids and amines, but only at high temperatures;
much better to use an acid chloride, acid anhydride or following the body’s
lead, trade an ester for an amide.
An acid chloride? What the heck is that and why do they work so well
in making amides from amines
3
Amide Nomenclature
To name amides, drop the –ic acid (common naming) or –oic acid (formal
naming) portion and add amide. Note in this case we need to indicate any
substituents attached to the N (formerly part of the amine) by using N as a
locant and not a number. As an example, consider 2,2-dimethylpropanamide
vs. N,N-dimethylpropanamide
Please name the following compounds
O NH
2
______________________________________________
O NH
______________________________________________
O NH
__________________________________________
O N
__________________________________________
4
Physical Properties of Esters & Amides
Question: Are esters relatively insoluble in water?
O
OH
OH O
O+ + H2O
H+
Acetic acid & ethanol are both freely soluble, but for ethyl acetate 1 ml
dissolves in 10 mL H2O @ 25 oC
Answer: Yes, when compared to the acid and alcohol from which they came!
Question: Why?
Answer: What are you asking me for? Perhaps it is due to the fact the
electron density drawn from the carbonyl carbon is replaced to a slight
extent by the adjacent oxygen, as shown by the electrostatic potential map
for methyl ethanoate
We can show the higher electron density on the carbonyl by the following
resonance form – notice you are placing a positive charge on the O which
makes this a poor contributor (compare to the analogous amide below)
CH3
O
O CH3
O+
O–
5
On the other hand, if counting carbons, there are 4 C in ethyl acetate
1-butanol solubility in water = 8 g/100 mL
Solubility of 1 mL in 10 mL of water for ethyl acetate is equivalent to
9 g/100 mL since d20 = .904 g/mL
This makes our life a little more complex in that we can no longer
simply count oxygens, we have to consider solubility as a function of
functional group
An ester functional group has about the same solubilizing capacity as the
corresponding alcohol, ether, aldehyde, or ketone
Overall, the rule of thumb for borderline solubility is:
4 C for alcohol, ether, aldehyde, ketone, & esters
5 C for unionized carboxylic acids
5-6 C for amines1
6 C for amides
20-25 C for ionized carboxylic acids and amines
6 C for amides?! Indeed! Having a nitrogen next to the carbonyl compared
to an oxygen makes for a profound difference. Let’s compare N-
ethylacetamide to ethyl acetate. N-ethyl acetamide can be made by reacting
acetic acid and ethyl amine at high temperatures
HeatH2O
High
1Pentanamine is freely soluble in water, hexanamine has a solubility of 1.2 g/100 mL
6
Recall ethyl acetate has limited H2O solubilty (10 mL/100 mL H2O) and has a
boiling point of 77 oC. N-ethylacetamide is completely soluble in water and
has BP = 205 oC!
In the case of amides, the charge separated resonance form plays a much
greater role, since [as we know] N more willingly accepts a positive charge.
The resulting polarity of amides causes many of them to be solid at room
temperature
Acetamide mp = 81 oC, bp = 222 oC
CH3
O
NH2 CH
3NH
2
+
O
Below is an electrostatic potential map for ethanamide (acetamide), clearly
showing the influence of the nitrogen adjacent to the carbonyl
Note the resonance depiction that explains the high degree of polarity of
the amide also helps explain why amides are not basic:
The contribution of the charge separated resonance form is significant
enough that amides are planer at both the carbonyl and nitrogen. This has a
major influence on the allowed secondary and tertiary structures of proteins
7
Characteristic reactions of Esters and Amides
In a word, HYDROLYSIS!
Question: What is the common product generated when esters and amides
are formed from carboxylic acids?
Question: What is the common functional group generated when esters and
amides are hydrolyzed?
Ester Hydrolysis and Transesterification
Esters can by hydrolysed (this is why old aspirin smells like vinegar) to the
corresponding acid and alcohol:
Problem: Esterification reactions in acidic conditions are reversible. Put
another way
Forming an ester will not go to completion in acidic conditions
Hydrolyzing an ester will not go to completion in acidic conditions
8
Solution – hydrolyze in base. In this case the reaction is catalyzed by the
presence of the much stronger nucleophile hydroxide:
The presence of hydroxide also drives the reaction by undergoing an acid-
base reaction with the liberated carboxylic acid:
Transesterification
Given an acidic catalytic environment, we can trade 1 alcohol in an ester for
another. This process is called transesterification and may be controlled by
the relative amounts of alcohol present. It is important biologically; as an
example
The synthesis of the neurotransmitter acetylcholine from acetyl-CoA and
choline
O
SCoA
OH
N+
O
O
N+
+ + CoASH
Recall thiols are analogs of alcohols; acetyl-CoA is a thioester
Instead of losing water when the alcohol attacks, we lose another
alcohol (or thiol in this case)
9
Amide Hydrolysis
As with esters hydrolysis can be carried out in both acidic and basic
conditions
In strong acid conditions, the ammonia (unsubstituted amide) or amine
formed reacts with the acid catalyst to form the corresponding salt:
In strong base conditions, the carboxylic acid formed reacts with the
base catalyst to form the corresponding salt, just like for base
catalysed ester hydrolysis:
Below are the structures of the local anesthetics procaine (Novocain) and
lidocaine (Xylocaine), Procaine is an ester and short acting, lidocaine is an amide
and longer acting. Hydrolysis of the ester or amide terminates the anesthetic
effect. As a general rule2 the amides are longer acting than the corresponding
esters, due to the fact that amides in effect have “greater than single bond
character” between the N and the carbonyl C, making them harder to hydrolyze
R1
O
NH
R2
R1 NH+
O
R2
NH2
O
ON
Procaine
NH
O
N
Lidocaine
2 Bear in mind these compounds must also fit into an esterase or amidase enzyme to
catalyze their hydrolysis. How well they fit also impacts their duration of action
10
Since the amide N forms a stronger bond to the carbonyl carbon than does
the ester O, one can displace the ester alcohol with an amine to form an
amide. This is precisely the strategy the body uses to get around the
complication of an acid-base reaction when amino acids are condensed
together to form amides
Cyclic esters are known as lactones, cyclic amides are referred to as
lactams. The most important examples of lactams are the penicillins and the
cephalosporins (see following page), which are susceptible to hydrolysis of
the cyclic amide
N
S
OCO
2H
NH H
O
Benzylpenicillin(Penicillin G)
11
Examples
Penicillins: Penicillin G, Amoxicillin, Ampicillin, Oxacillin
Cephalosporins: Cephalexin (Keflex), Cefadroxil (Duricef), Loracarbef
(Lorabid), Ceftriaxone (Rocephin)
Carbapenems & Monobactams: Aztreonam (Azactam), Ertapenem (Invanz)
12
Phosphoric Anhydrides and Esters
3 important points here:
Phosphates can form esters and anhydrides, which are stable enough
to persist in aqueous solution; as a result they are found extensively in
biochemistry
o Phosphoesters may be hydrolysed by water (under the right
catalytic conditions). As an example protein kinases vs.
phosphatases as molecular switches:
Phosphoric anhydrides, like other anhydrides, are in a high energy
state; the hydrolysis of these species liberates considerable energy
o ATP
o Consider the metabolic implications of not being able to store
our cellular “energy currency” ATP for long periods of time
Our cells require a constant supply of ATP
Food we can store (obviously!) but to make ATP we must
ultimately deliver the electrons stripped out of food to
oxygen
No oxygen, no ATP =
Phosphates can form “double esters” and as such may be thought of as “linkers”
o Conversion of triglycerides to phosphoglycerides: