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]

H3C OH

O

acetic acid

H3C-CH2-O-H

ethanol

H+

Δ H3C OCH2CH3

O

H2O++

ethyl acetate The experimental equilibrium constant for the reaction above is:

[ethyl acetate] x [H2O] [acetic acid] x [ethanol]Keq = = 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 + C2H5OH CH3C(=O)OC2H5 + H2OH+

____________________________________________________________________________________________________________________ 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].

H3C

OH3C-CH2-18O-H

H+

Δ H3C 18O CH2CH3

OH2O++

Suggesting H3C- CH2 ---18OH not cleaved in this reaction.

H3C

O

CH3

HO H

optically activeCH3

O H

optically active

H+

Δ

H3CO

+ H2O+

this bond not cleavedthis bond

not cleaved

Also,

OH

OH

Chem 216 S11 Notes - Dr. Masato Koreeda Date: May 10, 2011 Topic: _Experiment 3__ page 2 of 3. Mechanism:

H3C O

O

HSO

OO O

HH

H3C O

O

H

SO

OO O

HH

H

H3C O

O

H

H

resonance stabilized

C2H5-OH

CH3C OO

O H

H5C2

H

C2H5-OH

CH3C OO

O H

H5C2

H

tetrahedral, sp3 intermediate

H

ester hydrate

CH3C OO

O H

H5C2

HH

H3C O

O

C2H5+ H2O

HO-C2H5

H3C O

O

C2H5

ester [ethyl acetate]C2H5-O-H

acid [acetic acid]

H

alcohol

H2SO4

C2H5OH

catalyst

pKa -9

C2H5-O-HH

pKa - 2.4

H

H3C O

O

H

H pKa -6

note:

----------------------------------------------------------------------------------------------------------------------------

H3C O

O

HH

C2H5-OHH3C O

O

HH

C2H5-OHδ+

δ+

Direct SN2-like substitution not possible at an sp2 center

Not feasible

III. Synthesis of Benzocaine

O

O

H2NBenzocaine (local anesthetic)= ethyl p-aminobenzoate

note:

O

O

H2N

+N

Cl-H

Novocain (local anesthetic)

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

OH

OH3N+ O-

OH3N+

OH

OH2Ncation neutral

Zwitter ion

+K1 K2

O-

OH2N

anionpK1 = 2.42 pK2 = 4.88

OC2H5

OH3N+ pK = 2.5

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)

OH

OH3N+

O-

OH3N+

OH

OH2N

cation

neutral

Zwitter ionKC

O-

OH2N

anion

pKA = 3.40pKB = 2.47pKC = 3.90pKD = 4.83pKZ = 0.93

+ H+

+ H+

+ H+

KA

KB KD

KZ

10.589.5 = [Zwitter ion]

[neutral]

Synthesis of Benzocaine

OC2H5

OH3N+

O-

OH3N+

OH

OH2N

neutral

Zwitter ion+ + C2H5OH

(large excess)

H2SO4

OH

OH3N+

cation (salt)

HSO4-

H2SO4(catalytic)

+ H2O

OC2H5

OH2N

Benzocaine

Δ (reflux)

This is what you willhave right after the rx.

Then, add Na2CO3 (aq) toadjust pH slightly above 8.

pKa = 2.52

heater/stirrer

drying tube glass wool

CaCl2(drying agent)

cooling water

IN

OUTwater-jacketed

reflux condenser

sandmagnetic

stirring bar orspin vane

vaporized solventreaction solution

“Refluxing”

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 vesseland is to be heated again. Consequently, the reaction temperature can be maintained at the boiling point of the solvent used.

For the description of reflux, Reflux set-up See pp 31-32 of the textbook.