Doctrine of Signatures - a principle that assigns healing properties to plants on the basis ofthe association between their physical characteristics and those of the disease or the affectedpart 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 theseeds of skullcap, for example, resemble small skulls and, it transpires, are effective atcuring headache. Similarly, the hollow stalk of garlic resembles the windpipe and is used forthroat and bronchial problems. By the same token, willow grows in damp places and willheal rheumatic conditions, caused by a build-up of fluid on the joints.

Doctrine of Signatures

Auroleus Phillipus Theostratus Bombastus von Hohenheim "Paracelsus"

Salicylic Acid and Derivatives400 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 tonibble 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, hesurmised that the willow might also have therapeutic properties by the "Doctrine ofSignatures" - whereby the cause of a disease offers a clue to its treatment.

"As this tree delights in a moist or wet soil, where agues chiefly abound, the general maximthat many natural maladies carry their cures along with them or that their remedies lie not farfrom 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 weightwith me".

"An Account of the Success of the Bark of the Willow in the Cure of Agues. In a Letter to the Right Honourable GeorgeEarl of Macclesfield, President of R. S. from the Rev. Mr. Edmund Stone, of Chipping-Norton in Oxfordshire" publishedin the Philosophical Transactions Volume 53 by the Royal Society of London 1763

O

H

HO

OH

H

H

HOH

HO

OHOH

Salicin (analgesic f rom willow bark)

AspirinSalicin (willow bark) can be hydrolyzed/oxidized to glucose and salicylaldehyde (meadosweetplant, Spirea species). Salicylic acid was named spirsaure (Spirea + saure) by Germandiscoverers but called salicylic acid by the English who traced its chemical history back to thewillow tree.

C

OH

OH

O

H2C

O

OH

C

OH

H

O

O

OH

OH

HO

HO

Salicylic AcidSalicin Salicylaldehyde

C

O

CCH3O

OH

O

Aspirin

(Acetylsalicylic Acid)

Dissociation of Carboxylic AcidsAspirin (acetylsalicylic acid) – member of compound called salicylates used inmedicine for its analgesic (pain-relieving), anti-pyretic (fever-reducing) and anti-inflammatory effects.

After ingestion, aspirin first travels into the stomach and then the intestines. In theacidic environment of the stomach, aspirin remains in its neutral form, but in thebasic environment of the small intestine, aspirin is deprotonated to form itsconjugate base, an ion. To be active, aspirin must cross a cell membrane, and todo so, it must be neutral, not ionic.

benzoic acid

CO

O

H CO

O

H

O

CCH3O

aspirin

(acetylsalicylic acid)

Base

CO

O

O

CCH3O

conjugate base

neutral form ionic form

This f orm exis ts in the stomach This f orm exis ts in the intestines

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Two different cyclooxygenase isozymes (COX-1 and COX-2) are responsible forprostaglandin synthesis. COX-1 is involved with the usual production of prostaglandins andplays a role as a ‘housekeeping enzyme’ in maintaining the lining of the stomach and inendothelial cells contributing to the normal function of the cardiovascular system via releaseof prostacyclin (PGI2). In contrast, COX-2 is induced by specific stimuli and is thought to beinvolved in inflammation and mitogenesis responses. NSAIDs like aspirin and ibuprofen(Advil, Motrin, Nuprin) and naproxen (Aleve) inactivate both the COX-1 and COX-2enzymes. This activity also results in an increase in gastric secretions, making an individualmore susceptible to ulcer formation.

CO2H

H3CO

CO2HCO2H

O

O

Aspirin Ibuprofen Naproxen

COO-

OC

CH3

O

H2CHO

enzyme

(active)

+transesterification

COO-

OH

acetylsalicylateaspirin

salicylate

H2CO

acetylated enzyme

(inactive)

+

CH3C

O

A transesterification reaction that blocks prostaglandin synthesis is responsible for aspirin’sactivity as an anti-inflammatory agent. Prostaglandins have several functions, one of which isinflammation. The enzyme prostaglandin synthase catalyzes the conversion of arachiodonicacid into PGH2 a precursor of prostaglandins and thromboxanes.

Aspirin

Arachiodonic acid Prostaglandin synthasePGH2

Prostaglandins

Thromboxanes

Prostaglandin synthase is composed of two enzymes, one of which (cyclooxygenase) has aserine –CH2OH which reacts with aspirin to inactivates the enzyme. Prostaglandins cannot besynthesized 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 heartattacks that result from blood clot formation (anticoagulant)

Acetylation

O

CCH3 O

C

O

CH3

OH

+

O

CCH3 O

C

O

CH3

NH2

+

OCCH3

O

HNCCH3

O

Acetic anhydride forms acetate esters from alcohols and N-substituted acetamidesfrom amines

O

CCH3 O

C

O

CH3

Acetic Anhydride (Ac2O)

+ HO CH2CH3

O

CCH3 OCH2CH3

Ethyl Acetate

Acetylation

O

CCH3 O

C

O

CH3

Acetic Anhydride

OH

CO2H

HO

NH2

O

CO2H

HO

HN

CCH3

O

CCH3

O

Acetaminophen (Tylenol)

Acetylsalicylic Acid (Aspirin)

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 foryears, but aspirin slowly decompose over time; b) Children’s Tylenol can be sold as a liquid (acetaminophen dissolved in water), but aspirin cannot.

Acetaminophen reduces pain and fever, but it is not anti-inflammatory, so it is ineffective intreating conditions like arthritis, which has a significant inflammatory component. In largerdoses, acetaminophen causes liver damage, so dosage recommendations must be carefullyfollowed.

Scheme:

Acetic anhydride forms acetate esters from alcohols

CO

O

H

O

CCH3O

COH

O

OH

H3CCO

O

CCH3

O

acetic anhydridesalicylic acid acetic acidO-acetylsalicylic acid

Aspirin

+H2SO4 (cat)

+

O

COHH3C

Preparation of Aspirin and IR Spectroscopy

O

CCH3 O

C

O

CH3

Acetic Anhydride (Ac2O)

+ HO CH2CH3

O

CCH3 OCH2CH3

Ethyl Acetate

• 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-OHdimer

Single broad absorption whichoften 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 peakExact region depends on typeof C=O

~1600 cm-1 and ~1500 cm-1 Aromatic C=C stretch Peak at ~1600 cm-1 usuallysplit 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

• 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

CO

O

H

O

CCH3O

CO

O

O

CCH3O

NaHCO3

CO

O

H

O

CCH3O

H+

• Identification of the product

• 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.

Preparation of Aspirin and IR Spectroscopy

carbonyl of a carboxylic acid

carbonyl of an ester

CO

O

H

O

CCH3O

H

O C

H

H

H

aromatic

C-H

aliphatic (sp3)

C-H

aromatic

C=C