Honors Cup Synthetic Proposal
Section: 290-3
Group Members:
Kuei-Nin Tseng
Naomi Nemoto
Stephen Chiang
Kevin Brown
Title:
Introduction: (what makes your target interesting?)
Paracetamol (Tylenol) is an analgesic drug that is used widely throughout the world.
From pain relief to a simple cold, it is able to cure the human body of many ailments. Being able
to synthesize Tylenol would be an exciting task as it is done regularly in the pharmaceutical
field, and to create the molecule would be a step towards understanding how it aids the human
body. Additionally, despite extensive studies on the crystallization of the compound, it is only
very recently that the first of its solvates or adducts have been isolated and structurally
characterized. These include a monohydrate and a trihydrate.
Fabbiani, F.; Allan, D. R.; David, W.; Moggach, S. A.; Parsons, S.; Pulham, C. R.
CrystEngComm 2004. 6, 504-511.
Overall synthetic reaction scheme: (a Chemdraw or similar drawing of all three steps)
C
OH
H
O
N
N
OH
CH3
C
CH3
H
HO
HO
O
C
O
O
H3C
C
CH3
O
C
HO
O
O
H3C
C
N
O
CH3
S
OH
O
O
C
N
H
C
H3C
CH3
O
H
HO
CH3
Step 1
Synthetic transformation 1: (Chemdraw picture of first transformation)
O
OH
H
N
C
N
CH3
OH
C
CH3
H
O
HO
H2O
HO
NaO
Experimental 1 (notes if this transformation is not exactly the one reported in literature (e.g. on
a different scale) and how it was modified):
4-Hydroxyacetophenone (3g, 0.022 mol) was added to a solution of hydroxylamine
hydrochloride (5.13g, 0.074 mol) and sodium acetate (10.26g 0.125 mol) in water (26 ml). The
solution was stirred at reflux temperature for one hour. After this time, the aqueous solution was
extracted exhaustively with diethyl ether. The organic phase was dried with magnesium sulfate
and the solvent (aqueous sodium acetate) evaporated under vacuum. To the resulting crude,
hexane was added and the product starts to precipitate as a white solid.
Baleizao, C.; Corma, A.; Garcia, H.; Leyva, A. J. Org. Chem. 2004, 69, 439-446.
Corma, A.; Garcia, H.; Leyva, A. Tetrahedron 2004, 60, 8553-8560.
Expected yield: 78% 2.59 g
Safety, disposal and green issues 1:
The green issues for this first part of synthesizing acetaminophen are compliant with the interests
of the atmosphere. The solvent system used, sodium acetate along with water, are toxic to
humans. This includes carcinogenicity, reproductive and developmental toxicity, neurotoxicity,
and acute toxicity. Alternative solvent systems might be safer for the environment. Like sodium
acetate, magnesium sulfate has similar toxicity effects on humans. The short reflux time allows
for conservation of energy, in opposition to many reactions that require days and/or weeks of
reflux.
Step 2
Synthetic transformation 2: (Chemdraw picture of second transformation)
O
A
OH
C
N
O
O
B
O
C
H3C
CH3
C
C
N
O
CH3
CH3
O
H
C
C
HO
HO
H3C
O
CH3
Experimental 2 (notes if this transformation is not exactly the one reported in literature (e.g. on
a different scale) and how it was modified):
Compound A (2g, 0.013mol) add to acetic anhydride (1.53g 0.015mol) and then add 15ml of
80% acetic acid in a round bottom flask. Heat it under reflux for one hour. Cool to room
temperature. Quench the reaction. Extract and dry with MgSO4. Recrystallize.
Corma, A.; Garcia, H.; Leyva, A. Tetrahedron 2004, 60, 8553-8560.
Mori, T.; Takamoto, M.; Wada, T.; Inoue, Y. Photochem. Photobiol. Sci. 2003, 2(11), 11871199.
Expected yield:
70%
1.76 g
Safety, disposal and green issues 2:
For this second step, the green issues are typical of any lab substance. Both reagents are known
as being irritable to eyes and skin (especially moist skin), etc.
Step 3
Synthetic transformation 3: (Chemdraw picture of third transformation)
O
O
B
H3C
C
N
O
C
OH
O
O
C
N
H
C
H3C
CH3
S
O
CH3
H
HO
Experimental 3 (notes if this transformation is not exactly the one reported in literature (e.g. on
a different scale) and how it was modified):
Compound B (1.54g, 8mmol) added to 4 ml of sulfonic acid. Heat under reflux for one hour.
Cool to room temperature. Solvent evaporated and recrystallization of remaining solid.
Engqvist, R.; Javaid, A.; Bergman, J. Eur. J. Org. Chem. 2004, 12, 2589-2592.
Mori, T.; Takamoto, M.; Wada, T.; Inoue, Y. Photochem. Photobiol. Sci. 2003, 2(11), 11871199.
Expected yield:
60%
0.725 g
Safety, disposal and green issues 3:
No major safety and green issue. Follow normal lab disposal and safety conduct.
Overall budget:
Chemical
Ethanone
NH2OH
Ac2O
AcOH
MeSO3H
NaOAc
Supplier
MP Biomedical
NV/SA
Aldrich
Alfa Aesar
Chem-Impex
International Inc.
Acros Organics
Chem-Implex
International Inc.
Cost
Amt. Needed
Total
$0.50 per gram
3g
$1.50
$0.22 per mL
$0.02 per gram
5.13ml
1.53g
$1.13
$0.04
$0.03 per mL
15ml
$0.45
$0.03 per mL
4ml
$0.12
0.06 per gram
7.076ml
$0.43
Total costs per synthesis:
____$3.67_________
References (include at least two different sources for your experimentals):