Chem 263
Nov 26, 2009
Carboxylic acids continued
More Reactive
O
SOCl2
R
Cl
O
O
R
O
R
O
R'
HCl
OH
O
R
OR'
H+
NaOH
O
R
NR'2
O
R
O-M+
Less Reactive
Penicillin was discovered by Alexander Fleming in 1928. It is a lactam (a cyclic amide),
and more specifically, it is a β lactam. The first patient was treated in 1941. The 1945
Nobel Prize was awarded to Fleming, along with Howard Florey and Ernest Chain for the
use of penicillin as an antibiotic.
H
N
O
H
H
S
N
O
COOH
benzyl penicillin
John Sheehan determined how to produce 6-aminopenicillanic acid (6-AMA) which is
used to make various derivatives of penicillin, including ampicillin. Ampicillin is orally
active, while the oral activity of benzyl penicillin is low.
H
N
H
H
H
H
H 2N
S
S
H2O, HCl
O
N
N
O
O
COOH
COOH
6-APA
benzyl penicillin
NH2
H
N
H
H
S
O
N
O
COOH
Ampicillin
The actual synthesis is slightly complicated and required protections and deprotections,
which you are not responsible for knowing.
Example for review of concepts and ester reactions – Reserpine
N
H3CO
H
N
H
O
H
OCH3
O
H
H3COOC
OCH3
OCH3
OCH3
The molecule above is reserpine. It is isolated from Indian snake root (Rauwolfia
serpentina) and was found to reduce blood pressure. It is also used to treat schizophrenia.
However, it causes depression.
Although it is a big molecule, you should be able to calculate its formula and molecular
weight, as well as identify all of its functional groups.
amine
indole
ester
N
H3CO
H
O
N
H
H
OCH3
ether
O
H
amine
H3COOC
OCH3
OCH3
ether
OCH3
ether
ester
How many stereogenic centers does it have?
Answer: 6. they are numbered below.
N
H3CO
1
N
H
H
O
3
H
2
6
OCH3
O
H
4
5
H3COOC
OCH3
OCH3
OCH3
Is the stereogenic carbon #1 in R or S configuration?
Answer: It is R configuration. First we assign priority of each substituents. N gets the first
priority and H is the last. The other two substituents are just carbons. However, if we look
further, we see that one of the carbons is actually an alkene carbon and has a bond to
nitrogen, whereas the other carbon is a methylene group with a bond to carbon and two
bonds to hydrogen. The carbon bearing the nitrogen gets higher priority than the
methylene carbon (which has one carbon substituent), so the configuration is
counterclockwise with the hydrogen toward you. When hydrogen is put to the back, the
configuration is clockwise, therefore, an “R.” configuration.
A similar method can be used to examine carbon #6, which as an R configuration.
H3CO
1
N
2
H
O
4
H
N
H
3
OCH3
O
H
H3COOC
OCH3
OCH3
OCH3
When it is allowed to react with ammonia, the esters are converted to amides. Since there
are two ester functional group in this molecule, there would be two amides formed as
products. The groups that react are highlighted in the starting material.
N
H3CO
H
O
N
H
H
OCH3
O
H
H3COOC
OCH3
OCH3
OCH3
NH3
N
H3CO
O
H
N
H
OCH3
H
H 2N
OH
H
+
H 3C
OH
+
OCH3
H 2N
OCH3
O
OCH3
Hydrolysis of Esters
O
O
NaOH
H3C
H2O
O
+
CH3CH2OH
O Na
H3C
sodium acetate
ethyl acetate
Mechanism:
O
O
H3C
O
H3C
OCH2CH3
OH
OH
O
O
H
H3C
O Na
H3C
O
OCH2CH3
The hydroxide anion attacks the carbonyl carbon in the first step, and a tetrahedral
intermediate is formed. This process is reversible (so if the negative charge on oxygen
comes down and kicks out the OH group instead of ethoxide anion in the second step, we
get the starting material again).
In the second step, The ethoxide anion is ejected and carboxylic acid is formed. However,
under the basic conditions, the proton on carbonxylic acid is abstracted by the ethoxide
anion to form carboxylate anion and ethanol.
The pKa for acetic acid is 4.5, whereas the pKa of ethanol is 17. Ethoxide is a stronger
base, therefore it will deprotonate the acetic acid to give acetate.
The process of hydrolyzing esters with base is called saponification. Saponification
means process of making soap. When you accidentally pour NaOH in your hand, you feel
your hand has a soapy feeling. What occurs is that the fat (triglyceride) in your hand is
getting hydrolyzed.
O
O
O
O
R
O
O
R
glycerol triester = triglyceride
O
O
R
O
OH
O
NaOH
H2O
O
R
OH
R
OH
+
Na
O
O
R
soap
O
glycerol
Crude soap curds contain glycerol and excess alkali as well, but the soap can be purified
by boiling with water and adding NaCl to precipitate the pure sodium carboxylate salts.
The salts are collected, perfume is added and the substance is pressed into bars for
household use.
Soaps act as cleansers because the two ends of the molecule are very different. The
sodium carboxylate end of the long chain fatty acid is ionic and therefore hydrophilic
(water-loving). As a result, it tries to dissolve in water. The long chain hydrocarbon on
the other hand, is non-polar and hydrophobic (water-fearing). It therefore tries to avoid
water and dissolve in grease. The net effect is that soaps are attracted to both water and
greases are therefore valuable cleansers.
O
O- K+
non-polar
polar
When soaps are dispensed into water, the long hydrocarbon chain clusters together in a
tangled hydrophobic ball, while the ionic heads on the surface of the cluster stick out into
the water layer. These spherical clusters are known as micelles and are shown below. The
ball depicts the ionic head (polar end) of the fatty acid (carboxylate salt) whereas the
chain represents the hydrocarbon chain (non-polar end).
Soap works because it has a polar ‘head’ which interacts with water, and an alkyl nonpolar ‘tail’ which can interact with compounds that are non-polar such as grease. Many
of these molecules come together to form a micelle, where the polar heads face outward
to the water, while the tails point inward. This allows the grease to be dispersed and
washed away.
Micelle with some greasy material. The circles represent the polar heads (the –COO-),
while the lines represent the non-polar tails (the alkyl chain)
Carbon dioxide and derivates
Demo- Oscillating Reaction
The following occurs in the demo that was shown in class:
H
H
O
O
O
HO
O
O
C
HO
O
malonic acid
O
HO
β-keto (carbonyl) acids decarboxylate readily as shown upon gently heating or catalysis
O
C
O
Carbon dioxide is produced via combustion reactions, such as burning and
respiration (breathing).
It can be used to synthesize carboxylic acids:
O
C
RMgX
O
O
H+
O-
C
C
O
OH
+MgX
R
R
Carbon dioxide dissolves in water to form carbonic acid. This can be deprotonated to
form bicarbonate, which can be used as a buffer. This is a buffer in blood.
O
O-
H
C
O
C
O
H
O
H+
OH
OH
O-
Na+
C
OH
Na+ -Base
C
OH
O
Carbonic acid
O
Sodium Bicarbonate
(NaHCO3)
Carbon Dioxide Derivatives:
O
Cl
Cl
Phosgene
A war gas that was used in WWI, it’s a bis-acid chloride.
Carbonates:
O
RO
OR
O
O
eg.
O
diethyl carbonate
You need to know this structure:
O
H2N
NH2
Urea
Urea hydrolysis can be used as an indicator for ulcers. The bacteria (Helicobacter) that
causes ulcers are capable of hydrolyzing urea. If 13C labeled urea is used, and the bacteria
is present the person will exhale 13C labeled carbon dioxide.