Honors Cup Synthetic Proposal
Section: 291
Group Members: Corina Mommaerts, Brittne Halford, Thomas Fai
Title: Preparation of Benzocaine (ethyl-p-aminobenzoate) from p-acetotoluidide
Introduction:
Benzocaine is one of many widely used anesthetics from a family of esters. These esters
are synthesized from the organic acid para-aminobenzoic acid (PABA) and ethanol, which are
also present in folic acid and vitamin B10. This essential drug is found in the liquid, gel, lozenge,
lotion, eardrop and aerosol spray forms. It used as a temporary topical anesthetic that numbs the
nerve endings near the surface of the skin where applied. Physicians throughout the world
prescribe benzocaine for people 4 months and older.
Benzocaine is frequently synthesized from p-nitrotoluene. This pathway involves many
reduction steps of the nitro group. However because of our small scale needs we have found a
procedure that involves the synthesis from p-acetotoluidide. P-acetotoluidide is oxidized by
magnesium sulfate to produce p-aminobenzoic acid, which is then heated with hydrochloric acid
to create an amino acid. Ethanol is added in the subsequent step to esterify the amino acid and
produce our desired product, benzocaine.
Reference:
"Benzocaine." Drugs.com. invisalign. 05 Feb. 2005
<http://www.drugs.com/cons/Benzocaine.html>.
Overall synthetic reaction scheme:
O
OH
KMnO4
HCl, NH3(aq)
MgSO4 7H2O / H2O
O
O
CH3COOH
NH
O
OH
O
NH
O
CH3CH2OH
conc. H2SO4
NH2
NH2
Step 1
Synthetic transformation 1:
O
OH
KMnO4
MgSO4 7H2O / H2O
O
NH
O
NH
Experimental 1 In a 1 L beaker or flask, add 7.6 g (.052 mol) p-acetotoluidide, 20 g (.08 mol)
magnesium sulfate hydrate (MgSO4 · 7H2O) and 500 mL H2O. Heat to about 85 degrees C.
Prepare a solution of 20.4 g KMnO4 (.128 mol) in 80 mL of boiling water. While stirring the pacetotoluidide solution vigorously, add the permanganate solution slowly over 30 minutes. After
all the permanganate has been added, swirl vigorously. Filter off the manganese dioxide
precipitate from the hot solution using a fluted filter, and wash with water. If the solution is still
purple from the permanganate, add 1 mL ethanol, boil until color has been discharged, and filter
again. Cool the solution and acidify to pH 3-4 with 20% aqueous sulfuric acid. Filter with
suction and dry.
*we scaled the reaction to 400%.
Expected yield:
50%
3.50 g
Safety, disposal and green issues 1:
P-acetotoluidide
Engineering Controls: Use adequate ventilation to keep airborne concentrations low.
Handling: Wash thoroughly after handling. Remove contaminated clothing and wash before
reuse. Use with adequate ventilation. Minimize dust generation and accumulation. Avoid contact
with eyes, skin, and clothing. Keep container tightly closed. Avoid ingestion and inhalation.
Storage: Store in a tightly closed container. Store in a cool, dry, well-ventilated area away from
incompatible substances.
Potassium Permanganate
Handling: Wash thoroughly after handling. Remove contaminated clothing and wash before
reuse. Use only in a well-ventilated area. Minimize dust generation and accumulation. Do not get
in eyes, on skin, or on clothing. Keep container tightly closed. Avoid contact with clothing and
other combustible materials. Do not ingest or inhale. Do not store near combustible materials.
Discard contaminated shoes.
Storage: Keep away from sources of ignition. Do not store near combustible materials. Keep
container closed when not in use. Store in a tightly closed container. Store in a cool, dry, wellventilated area away from incompatible substances.
Hazardous Decomposition Products: Irritating and toxic fumes and gases, oxygen, oxides of
potassium, oxides of manganese.
Other: Harmful to aquatic life in very low concentrations
P-acetamidobenzoic acid
Chemical Stability: Stable under normal temperatures and pressures.
Conditions to Avoid: Incompatible materials, dust generation, excess heat.
Incompatibilities with Other Materials: Oxidizing agents.
Hazardous Decomposition Products: Carbon monoxide, oxides of nitrogen, irritating and toxic
fumes and gases, carbon dioxide.
Ecotoxicity: Bacteria: Phytobacterium phosphoreum
Step 2
Synthetic transformation 2:
O
OH
O
OH
HCl, NH3(aq)
CH3COOH
O
NH
NH2
Experimental 2 Weigh 3.0 g (.0219 mol) p-acetaminobenzoic acid and add to 15 mL 18%
hydrochloric acid in a 50-mL round bottom flask. Attach a condenser and reflux for 25-30
minutes. Cool the mixture and add half its volume of cold water. Make the solution slightly
basic (pH 7-8 measured with wide-range pH paper) with 10% aqueous ammonia. For each 30
mL of solution, add 1 mL glacial acetic acid. Stir vigorously and cool solution in an ice bath.
Initiate crystallization with glass rod. Filter with suction and dry.
Expected yield:
40%
1.16 g
Safety, disposal and green issues 2:
P-aminobenzoic acid
Handling: Should be used in areas with adequate ventilation and away from fire.
Storage: Should be stored away from oxidizing agents and containers should remain closed.
Container may explode when heated and produce poisonous and corrosive gases.
Disposal: Pollutes waterways. Whatever cannot be saved for recovery or recycling should be
managed in an appropriate and approved waste disposal facility.
Step 3
Synthetic transformation 3:
O
OH
O
O
CH3CH2OH
conc. H2SO4
NH2
NH2
Experimental 3
In a 25-mL round-bottom flask, mix 1.0 g (.0075 mol) p-aminobenzoic acid, 7.5 mL of absolute
ethanol, and .75 mL (.0075 mol) of concentrated sulfuric acid. Attach a condenser and heat
under reflux for 1 hr. Cool to room temperature and neutralize with foaming sodium carbonate
(can check with litmus paper). Next, extract with dichloromethane (2 x 5-mL). Extract the
combined organic layers with two 15-mL portions of water and dry over anhydrous magnesium
sulfate. Remove the organic solvent and recrystallize from methanol-water.
*We scaled the reaction to 150%.
*Also, we figured we could use the Rotovap to remove the dichloromethane instead of
distillation, which required a steam bath.
Expected yield:
50%
.6 g
Safety, disposal and green issues 3:
Benzocaine
Handling: Remove contaminated clothing and wash before reuse. Use with adequate ventilation.
Minimize dust generation and accumulation. Avoid contact with eyes, skin, and clothing. Avoid
ingestion and inhalation.
Storage: Keep container closed when not in use. Store in a tightly closed container. Store away
from heat sources and ignition in a cool, dry, well-ventilated area away from incompatible
substances.
Safety: Do not inhale, taste, and prevent all contact with skin. Burning may produce carbon
monoxide, carbon dioxide, nitrogen oxides.
Disposal: Do not allow entry into drains or waterways. Whatever cannot be saved for recovery
or recycling should be managed in an appropriate and approved waste disposal facility
Overall budget:
Chemical
P-acetotoluidide
Sulfuric acid
Ethanol
KMnO4
MgSO4
Supplier
Lancaster
In Lab
In Lab
In Lab
In Lab
Cost
25 grams--10.70
Amt. Needed
7.6 grams
Total
$3.25
Total costs per synthesis: _____$3.25____
References (include at least two different sources for your experimentals):
Step 1:
Lee, C. K.; Ahn, Y. M. J. Org. Chem. 1989, 54, 3744-3747.
Kremer, C. B. J. Chem. Educ. 1956, 33, 71-72.
Step 2:
Wilcox, Charles F. Experimental Organic Chemistry – A Small Scale Approach. New York:
Macmillan Publishing Co., 1988; pp.437-439.
Kremer, C. B. J. Chem. Educ. 1956, 33, 71-72.
Step 3:
Vogel, A. I. Practical Organic Chemistry, 3rd Ed. New York: Longman Group Ltd., 1956;
pp.1000-1001.
Wilcox, Charles F. Experimental Organic Chemistry – A Small Scale Approach. New York:
Macmillan Publishing Co., 1988; pp.437-439.