Chem 216 S11 Notes - Dr. Masato Koreeda
Topic: _Experiment 3__ page 1 of 3.
Date: May 10, 2011
Experiment 3. Ester Formation: Preparation of Benzocaine.
Esterification [see Ege’s: Sections 15.6 B-D, pp 622-626]
O
H3C
OH
O
H+
+
H3C-CH2-O-H
acetic acid
H3C
Δ
O
ethanol
CH2CH3
+
H2O
ethyl acetate
The experimental equilibrium constant for the reaction above is:
Keq =
[ethyl acetate] x [H2O]
[acetic acid] x [ethanol]
= 3.38
As in any equilibrium processes, the reaction may be driven in one direction by adjusting the
concentration of one of the either the reactants or products (Le Châtelier’s principle).
I. Esterification (see Ege’s: Sections 15.6 B – D, pp 622 – 626)
Equilibrium compositions
CH3COOH
+
H+
C2H5OH
CH3C(=O)OC2H5
+
H2O
____________________________________________________________________________________________________________________
i) at start:
1.0
1.0
0
0
at equilibrium
0.35
0.35
0.65
0.65_
ii) at start
1.0
10.0
0
0
at equilibrium
0.03
9.03
0.97
0.97_
iii) at start
1.0
100.0
0
0
at equilibrium
0.007
99.007
0.993
0.993
_____________________________________________________________________________
Taken from “ Introduction to Organic Chemistry”; 4th Ed.; Streitweiser, A. et al.; Macmillan Publ.: New York, 1992.
II. The Mechanism for the Acid-catalyzed Esterification [Commonly referred to as the
Fischer esterification: see pp 622-623, Ege’s book].
O
OH
H3C
+
O
H+
H3C-CH2-18O-H
Δ
H3C
Suggesting H3C- CH2 ---18OH
18O
CH2CH3 +
H2O
not cleaved in this reaction.
Also,
this bond
not cleaved
O
H3C
+
OH
this bond
not cleaved
O
HO H
CH3
optically active
H+
Δ
H3C
O
H
CH3
optically active
+
H2O
Chem 216 S11 Notes - Dr. Masato Koreeda
Topic: _Experiment 3__ page 2 of 3.
Date: May 10, 2011
Mechanism:
H
O
H3C
O H
resonance stabilized
alcohol
O
O S O
H
O
O
C2H5OH
H3C
H2SO4
acid [acetic acid]
catalyst
H
O
O H
H3C
H
O H
C2H5-OH
ester hydrate
note:
O
O
H
pKa -9
O S O
H
O
O
H3C
H3C
H
H
O
H3C C O H
O
H5C2
O
H3C C O H
O
H5C2
H
O C2H5
ester [ethyl acetate]
HO-C2H5
O H
O
H
C2H5-O-H pKa - 2.4
H3C
H
C2H5-O-H
C2H5-OH
H pKa -6
tetrahedral, sp3
intermediate
H
O C2H5
H
O
H
H3C C O H
O
H5C2
+ H2O
---------------------------------------------------------------------------------------------------------------------------Direct SN2-like substitution not possible at an sp2 center
H δ+
O
C2H5-O
H3C
O
C2H5-OH
H3C
O H
H
Not feasible
δ+O H
H
III. Synthesis of Benzocaine
note:
O
O
O
O
Benzocaine (local anesthetic)
= ethyl p-aminobenzoate
H2N
+N
H
H2N
Novocain (local anesthetic)
Cl-
Dissociation of p-aminobenzoic acid (see: van der Graaf, et al. J. Org. Chem. 1981, 46, 653).
O
O
K1
H3N+
H3N+
+
K2
O
OH
cation
Zwitter ion
O-
pK1 = 2.42
OH
O
H3N+
OC2H5
neutral
H2N
pK = 2.5
pK2 = 4.88
O
H2N
Oanion
Chem 216 S11 Notes - Dr. Masato Koreeda
Topic: _Experiment 3__ page 3 of 3.
Date: May 10, 2011
Dissociation of p-aminobenzoic acid (see: van der Graaf, et al. J. Org. Chem. 1981, 46, 653) (cont’d)
O
H3N+
KA
O-
+ H+
KC
Zwitter ion
O
H3N+
O
KZ
OH
+ H+
H2N
O-
O
cation
anion
+ H+
H2N
KB
KD
OH
pKA = 3.40
pKB = 2.47
pKC = 3.90
pKD = 4.83
pKZ = 0.93
neutral
10.5
89.5
= [Zwitter ion]
[neutral]
Synthesis of Benzocaine
O
H3N+
pKa = 2.52
OZwitter ion
+
+
O
H2N
C2H5OH
H2SO4
(large excess)
H2SO4
(catalytic)
O
H3N+
OH Δ (reflux)
HSO4-
OH
OC2H5
+ H2O
Then, add Na2CO3 (aq) to
adjust pH slightly above 8.
O
H2N
Benzocaine
OC2H5
drying tube
“Refluxing”
glass wool
CaCl2
(drying agent)
OUT
water-jacketed
reflux condenser
cooling water
reaction
solution
magnetic
stirring bar or
spin vane
For the description of reflux,
See pp 31-32 of the textbook.
O
H3N+
cation (salt)
neutral
To heat the solution (with a reflux condenser on)
so that the vapors formed condense to a liquid
and the liquid flows back to the reaction vessel
and is to be heated again. Consequently, the
reaction temperature can be maintained at the
boiling point of the solvent used.
This is what you will
have right after the rx.
IN
vaporized solvent
sand
heater/stirrer
Reflux set-up