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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

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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

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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

__________________________________________

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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–

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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

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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

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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

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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)

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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

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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)

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Examples

Penicillins: Penicillin G, Amoxicillin, Ampicillin, Oxacillin

Cephalosporins: Cephalexin (Keflex), Cefadroxil (Duricef), Loracarbef

(Lorabid), Ceftriaxone (Rocephin)

Carbapenems & Monobactams: Aztreonam (Azactam), Ertapenem (Invanz)

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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: