Chem 216 S11 Notes - Dr.

Masato Koreeda Date: May 10, 2011

Topic: _Experiment 3__ page 1 of 3.

Experiment 3. Ester Formation: Preparation of Benzocaine.

Esterification [see Ege’s: Sections 15.6 B-D, pp 622-626]

O O
H+
+ H3C-CH2-O-H CH2CH3 + H2O
H3C OH Δ H3C O
acetic acid ethanol ethyl acetate

The experimental equilibrium constant for the reaction above is:

[ethyl acetate] x [H2O]

Keq = = 3.38
[acetic acid] x [ethanol]

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
H+
CH3COOH + 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 O
H+
+ H3C-CH2-18O-H 18O CH2CH3 + H2O
H3C OH H3C
Δ
Suggesting H3C- CH2 ---18OH not cleaved in this reaction.
Also,
this bond
this bond
not cleaved
O not cleaved
O HO H H+ H3C
+ O H + H2O
H3C OH CH3 Δ
CH3
optically active
optically active
Chem 216 S11 Notes - Dr. Masato Koreeda Date: May 10, 2011
Topic: _Experiment 3__ page 2 of 3.

Mechanism:
resonance stabilized
alcohol
H O H H
O O S O O O
H C2H5OH
H3C O H O H3C O H H3C O H
H2SO4
acid [acetic acid]
catalyst
C2H5-OH
ester hydrate
tetrahedral, sp3
note: H H
O O O intermediate
H O H3C C O H H3C C O H
H3C O C2H5
O S O pKa -9 O O
H ester [ethyl acetate] H5C2 H H5C2 H
O
C2H5-OH C2H5-O-H
H pKa -6
O

H3C O H HO-C2H5
H H
H O O H
C2H5-O-H pKa - 2.4 + H2O H3C C O H
H3C O C2H5
O
H5C2
----------------------------------------------------------------------------------------------------------------------------
Direct SN2-like substitution not possible at an sp2 center

H δ+
O O
C2H5-OH C2H5-O
H3C O H H3C Not feasible
δ+O H
H H

III. Synthesis of Benzocaine

O note: O
+N
O O Novocain (local anesthetic)
Benzocaine (local anesthetic) H
Cl-
H2N = ethyl p-aminobenzoate H2N

Dissociation of p-aminobenzoic acid (see: van der Graaf, et al. J. Org. Chem. 1981, 46, 653).
O
H3N+ Zwitter ion
O K1 O- K2 O
H3N+ + H2N
OH O O-
H2N neutral
cation pK1 = 2.42 pK2 = 4.88 anion
OH
O
H3N+ pK = 2.5
OC2H5
Chem 216 S11 Notes - Dr. Masato Koreeda Date: May 10, 2011
Topic: _Experiment 3__ page 3 of 3.

Dissociation of p-aminobenzoic acid (see: van der Graaf, et al. J. Org. Chem. 1981, 46, 653) (cont’d)

O
H3N+ + H+
KA O- KC
Zwitter ion
O O
H3N+ H2N + H+
KZ
OH O-
cation O anion
KB H2N + H+
KD
OH
pKA = 3.40
neutral
pKB = 2.47
pKC = 3.90
pKD = 4.83
10.5 = [Zwitter ion] pKZ = 0.93
89.5 [neutral]

Synthesis of Benzocaine
O pKa = 2.52
H3N+ This is what you will
O- have right after the rx.
Zwitter ion H2SO4
H2SO4 O (catalytic) O
+ + C2H5OH H3N+ H3N+
O (large excess) OH Δ (reflux) OC2H5
H2N HSO4-
OH + H2O
cation (salt)
neutral
Then, add Na2CO3 (aq) to
O adjust pH slightly above 8.
H2N
OC2H5
Benzocaine
drying tube glass wool
“Refluxing”

To heat the solution (with a reflux condenser on) CaCl2

water-jacketed (drying agent)
so that the vapors formed condense to a liquid reflux condenser OUT
and the liquid flows back to the reaction vessel
and is to be heated again. Consequently, the cooling water
reaction temperature can be maintained at the IN
boiling point of the solvent used. reaction
solution vaporized solvent

magnetic
stirring bar or sand
spin vane
heater/stirrer
For the description of reflux, Reflux set-up
See pp 31-32 of the textbook.