Download Ex 3 Aspirin

Doctrine of Signatures
Auroleus Phillipus Theostratus Bombastus von Hohenheim
"Paracelsus"
Doctrine of Signatures - a principle that assigns healing properties to plants on the basis of
the association between their physical characteristics and those of the disease or the affected
part of the body.
‘Nature marks each growth… according to its curative benefit.’
Paracelsus noticed how the qualities of plants so often reflect their appearance – that the
seeds of skullcap, for example, resemble small skulls and, it transpires, are effective at
curing headache. Similarly, the hollow stalk of garlic resembles the windpipe and is used for
throat and bronchial problems. By the same token, willow grows in damp places and will
heal rheumatic conditions, caused by a build-up of fluid on the joints.
Salicylic Acid and Derivatives
400 BC Hippocrates prescribed bark and leaves of the willow tree to reduce pain and fever.
1763 AD Revered Edward Stone - while suffering from various ‘agues’, was prompted to
nibble a piece of bark from a willow tree and was struck by its extremely bitter taste.
Knowing the bark of the Peruvian cinchona tree (quinine ) has a similarly bitter taste, he
surmised that the willow might also have therapeutic properties by the "Doctrine of
Signatures" - whereby the cause of a disease offers a clue to its treatment.
H OH
HO
OH
HO
H
H
OH
O
OH
H
Salicin (analgesic f rom willo w bark)
"As this tree delights in a moist or wet soil, where agues chiefly abound, the general maxim
that many natural maladies carry their cures along with them or that their remedies lie not far
from their causes was so very apposite to this particular case that I could not help applying it;
and that this might be the intention of Providence here, I must own, had some little weight
with me".
"An Account of the Success of the Bark of the Willow in the Cure of Agues. In a Letter to the Right Honourable George
Earl of Macclesfield, President of R. S. from the Rev. Mr. Edmund Stone, of Chipping-Norton in Oxfordshire" published
in the Philosophical Transactions Volume 53 by the Royal Society of London 1763
Aspirin
Salicin (willow bark) can be hydrolyzed/oxidized to glucose and salicylaldehyde (meadosweet
plant, Spirea species). Salicylic acid was named spirsaure (Spirea + saure) by German
discoverers but called salicylic acid by the English who traced its chemical history back to the
willow tree.
H2
C
OH
O
C
O
HO
O
O
H
OH
C
O
OH
OH
HO
Salicylaldehyd e
Salicy lic Acid
OH
O
O
OH
Salicin
C
OH
C
C H3
Aspirin
(Acety lsalicylic Acid)
Dissociation of Carboxylic Acids
Aspirin (acetylsalicylic acid) – member of compound called salicylates used in
medicine for its analgesic (pain-relieving), anti-pyretic (fever-reducing) and antiinflammatory effects.
O
C
O
CH 3
C
O
benzoic acid
H
C
CH 3
O
O
O
C
O
Base
H
C
O
O
O
aspirin
(acetylsalicylic acid)
conjug ate base
n eu tral fo rm
This f orm exis ts in th e stomach
ionic fo rm
This f orm exis ts in th e intestines
After ingestion, aspirin first travels into the stomach and then the intestines. In the
acidic environment of the stomach, aspirin remains in its neutral form, but in the
basic environment of the small intestine, aspirin is deprotonated to form its
conjugate base, an ion. To be active, aspirin must cross a cell membrane, and to
do so, it must be neutral, not ionic.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Two different cyclooxygenase isozymes (COX-1 and COX-2) are responsible for
prostaglandin synthesis. COX-1 is involved with the usual production of prostaglandins and
plays a role as a ‘housekeeping enzyme’ in maintaining the lining of the stomach and in
endothelial cells contributing to the normal function of the cardiovascular system via release
of prostacyclin (PGI2). In contrast, COX-2 is induced by specific stimuli and is thought to be
involved in inflammation and mitogenesis responses. NSAIDs like aspirin and ibuprofen
(Advil, Motrin, Nuprin) and naproxen (Aleve) inactivate both the COX-1 and COX-2
enzymes. This activity also results in an increase in gastric secretions, making an individual
more susceptible to ulcer formation.
O
O
C O2H
CO2H
CO 2H
H3C O
Aspirin
Ibup ro fen
Naprox en
Aspirin
A transesterification reaction that blocks prostaglandin synthesis is responsible for aspirin’s
activity as an anti-inflammatory agent. Prostaglandins have several functions, one of which is
inflammation. The enzyme prostaglandin synthase catalyzes the conversion of arachiodonic
acid into PGH2 a precursor of prostaglandins and thromboxanes.
Prostaglandins
Arachiodonic acid
Prostaglandin synthase
PGH2
Thromboxanes
Prostaglandin synthase is composed of two enzymes, one of which (cyclooxygenase) has a
serine –CH2OH which reacts with aspirin to inactivates the enzyme. Prostaglandins cannot be
synthesized and inflammation is suppressed. Thromboxanes stimulate platelet aggregation,
and this is why low levels of aspirin is believed to reduce the incidence of strokes and heart
attacks that result from blood clot formation (anticoagulant)
-
COO
O
C
CH3
O
acetylsalicylate
aspirin
H2
+ HO C
enzyme
(active)
transesterification
COO
O
-
OH
salicylate
H3C C
+
H2
O C
acetylated enzyme
(inactive)
Acetylation
Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides
from amines
O
CH3
C
O
O
O
C
HO CH2CH3
+
CH3
Acetic Anhydride (Ac2O)
+
CH3
+
CH3
OCH2CH3
C
C
O
O
O
O
NH2
C
Ethyl Acetate
O
OH
CH3
C
CH3
O
C
CH3
CH3
O
H
N
O
C
C
O
CH3
Acetylation
With reference to the structures of acetylsalicylic acid (aspirin) and acetaminophen (Tylenol)
explain each statement: a) Acetaminophen tablets can be stored in the medicine cabinet for
years, but aspirin slowly decompose over time; b) Children’s Tylenol can be sold as a liquid
(acetaminophen dissolved in water), but aspirin cannot.
OH
Acetylsalicylic Acid (Aspirin)
CO2H
O
CH3
C
O
O
O
C
C
CH3
O
CO2H
CH3
H
N
Acetic Anhydride
NH2
HO
HO
C
CH3
O
Acetaminophen (Tylenol)
Acetaminophen reduces pain and fever, but it is not anti-inflammatory, so it is ineffective in
treating conditions like arthritis, which has a significant inflammatory component. In larger
doses, acetaminophen causes liver damage, so dosage recommendations must be carefully
followed.
Preparation of Aspirin and IR Spectroscopy
Scheme:
O
OH
C
+
OH
H3C
O
O
C
C
O
C
CH 3
O
H2SO 4 (cat)
CH 3
C
O
O
O
H
+
H 3C
C
O
salicylic acid
acetic anhydride
O-acetylsalicylic acid
Aspirin
acetic acid
Acetic anhydride forms acetate esters from alcohols
O
CH 3
OH
C
O
O
O
C
CH 3
Acetic Anhy dride (Ac2O)
+
HO
CH2C H3
CH 3
C
OCH 2CH3
Ethyl Acetate
Preparation of Aspirin and IR Spectroscopy
• Infrared Spectroscopy
– To determine the presence or absence of functional groups
or bonds in a molecule
– Covalent bonds behave as springs
– Springs bend and stretch
– Bending and stretching vibrations within covalent bonds
cause them to absorb infrared radiation.
• Typical IR spectrum
• Plot of percent transmittance vs. frequency of
vibration
• Frequency is an energy given in wavenumbers (cm-1)
where wavelength is expressed in cm.
Preparation of Aspirin and IR Spectroscopy
Common IR absorptions
Regions
Bond or Functional Groups
Comments
~3350 cm-1
O-H stretch
Broad, intense
~3200 – 2800 cm-1
O-H stretch from CO-OH
dimer
Single broad absorption which
often swallows other peaks
~3150 – 3050 cm-1
Aromatic C-H stretch
Usually several
~2950 – 2850 cm-1
Aliphatic C-H stretch
Usually several
~1700 cm-1
C=O stretch
One single strong peak
Exact region depends on type
of C=O
~1600 cm-1 and ~1500 cm-1
Aromatic C=C stretch
Peak at ~1600 cm-1 usually
split into a doublet
~600 – 850 cm-1
Aromatic C-H bending
Usually several peaks, intense
Preparation of Aspirin and IR Spectroscopy
•
•
Procedure, in “Catalyst”, pg 146 - 147
Do not use water baths
Purification
• 1) Disperse sample in sodium bicarbonate
O
C
O
CH 3
O
•
•
CH 3
O
O
C
C
O
NaHCO 3
H
C
O
O
+
O
C
CH 3
O
H
C
O
H
O
2) Filter by vacuum
– Waste disposal: DO NOT POUR FILTRATE DOWN THE
DRAIN. This filtrate is what must be acidified in the next step.
The book is wrong.
3) Ferric Chloride test – a test for phenols
– A positive test is violet color with FeCl3
– A negative test is not more than a light violet color
Preparation of Aspirin and IR Spectroscopy
•
Identification of the product
O
C
CH3
carbo nyl of an ester
O
C
O
•
•
•
O
H
arom atic
C=C
carbon yl of a carbox ylic acid
H
H
O C H
H
aro matic
C-H
aliph atic (sp 3)
C-H
For preparing samples:
~ 1 mg of sample per 100 mg KBr
In your reports, don’t characterize by melting point. Report procedure, no
comparison to literature melting point.