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Aspirin (acetylsalicylic acid)

Key Concepts
Aspirin is widely used as an analgesic (pain reliever) and an antipyretic (for reducing
fever). It is also used to help prevent heart attacks, strokes, and blood clot formation in
people at risk of developing blood clots.
Aspirin (acetylsalicylic acid) is an aromatic compound containing both a carboxylic acid
functional group and an ester functional group.
Aspirin is a weak acid that is only slightly soluble in water.
Aspirin can be prepared by reacting salicylic acid and acetic anhydride in the presence of
an acid catalyst.

Structure of Aspirin (acetylsalicylic acid)


Aspirin (acetylsalicylic acid) contains three groups:

carboxylic acid functional group (R-COOH)


ester functional group (R-O-CO-R')
aromatic group (benzene ring)

Properties of Aspirin (acetylsalicylic acid)


Acidity

Aspirin is a monoprotic weak acid, Ka = 2.8 x 10-4 at 25oC, so very little of the molecular aspirin
(acetylsalicylic acid) dissociates to form acetylsalicylate ions.
For the equilibrium dissociation reaction:
aspirin (acetylsalicylic acid) acetylsalicylate ion + H+

+ H+

the equilibrium position lies well to the left, favouring molecular aspirin.

Solubility

Aspirin is only slightly soluble in water and acidic solutions such as is present in the stomach.
Aspirin contains polar functional groups which can form hydrogen bonds with polar water
molecules.
Aspirin is more soluble in basic (alkaline) solutions, so it readily dissolves in the duodenum which
is the first part of the intestine.

Ionic salts of aspirin, such as sodium acetylsalicylate, are more soluble in water since they form
stronger ion-dipole interactions with water.
These ionic salts of aspirin are sometimes marketed as "soluble aspirin". When you add water to
the soluble aspirin, eg, sodium acetylsalicylate, it dissociates to form sodium ions and
acetylsalicylate ions:

sodium acetylsalicylate acetylsalicylate ions + sodium ions

+ Na+

C9H7O4-Na+ C9H7O4- + Na+

In the acidic stomach, molecular aspirin crystallizes out:


acetylsalicylate ions + H+ aspirin

+ H+

C9H7O4- + H+ C9H8O4

Preparation of Aspirin (acetylsalicylic acid)


Salicylic acid will rapidly react with acetic anhydride in the presence of an acid catalyst to produce
aspirin (acetylsalicylic acid) and acetic acid (ethanoic acid).
Sulfuric acid or phosphoric acid are often used to catalyse the reaction.
acetic anhydride [H2SO4] aspirin acetic acid
salicylic acid + +
(ethanoic anhydride) (acetylsalicylic acid) (ethanoic acid)

[H2SO4]
+ + CH3COOH

[H2SO4]
C7H6O3(s) + C4H6O3(l) C9H8O4(s) + C2H4O2(aq)

Salicylic acid can react with acetic (ethanoic) acid in an esterification reaction, but the reaction is
very slow, taking days to reach equilibrium, and the yield is low:

acetic acid [H2SO4] aspirin


salicylic acid + + water
(ethanoic acid) (acetylsalicylic acid)

[H2SO4]
+ CH3COOH + H2 O

[H2SO4]
C7H6O3 + C2H4O2 C9H8O4(s) + H2 O

For this reason, the commercial preparation of aspirin relies on the faster reaction between
salicylic acid and the more reactive acetic anhydride which produces a greater yield of aspirin.

Reactions of Aspirin (acetylsalicylic acid)


1. Neutralization: acid + base salt + water

aspirin sodium a salt


+ + water
(acetylsalicylic acid) hydroxide (sodium acetylsalicylate)

+ NaOH(aq) + H2O(l)

C9H8O4(s) + NaOH(aq) C9H7O4(s)-Na+ + H2O(l)

2. The neutralization reaction can be used to determine the amount of aspirin (acetylsalicylic
acid) present in commercially available aspirin tablets using a back (indirect) titration
method.
3. Reaction with carbonate: acid + carbonate salt + carbon dioxide + water

sodium carbon
aspirin a salt
+ hydrogen + dioxide + water
(acetylsalicylic acid) (sodium acetylsalicylate)
carbonate gas
+ NaHCO3(aq) + CO2(g) + H2O(l)

C9H8O4(s) + NaHCO3(aq) C9H7O4(s)-Na+ + CO2(g) + H2O(l)

4. The reaction with bicarbonate (hydrogen carbonate ion) is commonly used to prepare the
salt of aspirin which is more soluble in water than the molecular form of aspirin.
5. Hydrolysis: cleavage of a covalent bond in a molecule by reaction with water

aspirin acetic acid


+ water salicylic acid +
(acetylsalicylic acid) (ethanoic acid)

+ H2O(l) + CH3COOH(aq)

C9H8O4(s) + H2O(l) C7H6O3(s) + C2H4O2(aq)

6. Old aspirin tablets may have a smell like vinegar as a result of the hydrolysis reaction
producing acetic acid (ethanoic acid).

Paracetamol (acetaminophen)
Key Concepts
Paracetamol (acetaminophen) was first synthesized by Joseph von Mering in 1893.
Paracetamol (acetaminophen) is widely used as an analgesic (pain reliever) and an
antipyretic (for reducing fever).
The systematic IUPAC name for paracetamol (acetaminophen) is N-(4-
hydroxyphenyl)ethanamide or N-(4-hydroxyphenyl)acetamide.
Paracetamol (acetominaphen) is also known as N-acetyl-p-aminophenol.
Paracetamol (acetaminophen) is sold under the names Panadol 1 in the UK, Australia and
New Zealnd and under the name Tylenol2 in the USA.
Paracetamol (acetaminophen) is an aromatic compound containing an OH (hydroxyl)
functional group and a HN-CO-R (amide) functional group.
Paracetamol (acetaminophen) is a weak acid.
Paracetamol (acetaminophen) is a white solid with a melting point of 170 oC which is
slightly soluble in water.
Paracetamol (acetaminophen) can be prepared from phenol (hydroxybenzene) in a three
step process involving:

(i) nitration

(ii) reduction

(iii) formation of the amide

Paracetamol (acetaminophen) undergoes hydrolysis in acidic conditions to produce an


amine and a carboxylic acid.

Structure of Paracetamol (acetaminophen)

Paracetamol (acetaminophen) contains three functional groups:

hydroxyl group (OH)


amide group (HN-CO-R)
aromatic group (benzene ring)

Properties of Paracetamol (acetaminophen)


Aciditity

Paracetamol (acetaminophen) is a weak acid.


+ H+

The equilibrium position lies very far to the left.


The vast majority of paracetamol molecules in an aqueous solution will be found as the
undissociated paracetamol molecules.

At 25oC, paracetamol (acetaminophen) has a 3Ka = 3.09 x 10-10

Solubility

cold hot
solvent ethanol The difference in the solubility of paracetamol
water water (acetaminophen) in water of different temperatures can be
solubility used to separate paracetamol (acetaminophen) from
1.43 5 14 commercially available panadol or tylenol.
(g/100 mL)

(AUS-e-TUTE Members should go the Members Tutorial for details of how to separate
paracetamol (acetaminophen) from commercially available tablets.)

It is possible to buy fizzy paracetamol tablets.


In these tablets the paracetamol has been mixed with citric acid (2-hydroxypropane-1,2,3-
tricarboxylic acid) and sodium hydrogencarbonate (sodium bicarbonate).
When placed in water, the citric acid and sodium hydrogencarbonate in the tablet react to produce
bubbles of carbon dioxide.
The bubbles of carbon dioxide gas help break the tablet up into smaller pieces that are easier to
swallow.

Synthesis of Paracetamol (acetaminophen)


Paracetamol (acetaminophen) can be synthesized from phenol in three steps:
Step 1:nitration of phenol

Phenol (hydroxybenzene) will react with sodium nitrate (an oxidizing agent) in the presence of
sulfuric acid to produce a mixture of structural isomers of nitrophenol.

H2SO4

+
NaNO3(aq)

4-nitrophenol 2-nitrophenol
phenol
(p-nitrophenol) (o-nitrophenol)
(hydroxybenzene)
25% yield 36% yield

When concentrated sulfuric acid (H2SO4) is added to sodium nitrate (NaNO3) the following
reaction occurs:

H2SO4 + 2NaNO3 Na2SO4 + 2HNO3

Then, in excess sulfuric acid, reactive nitronium ion, NO 2+, is produced:

HNO3 + H2SO4 NO2+ + HSO4- + H2O

The nitronium ion, NO2+, attacks the benzene ring of phenol to produce a mixture of various
structural isomers of nitrophenol.

The OH (hydroxyl) functional group of phenol (hydroxybenzene) is said to activate the benzene
ring at the 2- and 4- positions. This results in the formation of 2-nitrophenol and 4-nitrophenol.
The 3- and 5- positions of the benzene ring are not activated so 3-nitrophenol and 5-nitrophenol
are NOT produced.

4-nitrophenol can be separated from the mixture containing 2-nitrophenol:

by steam distillation: 2-nitrophenol forms fewer hydrogen bonds with water or other
nitrophenol molecules than 4-nitrophenol so it is more volatile in steam than 4-nitrophenol
or by column chromatography: 2-nitrophenol is less polar than 4-nitrophenol so it has less
affinity for silica than 4-nitrophenol.
Step 2: reduction of a nitro group to an amine

In carbon chemistry (organic chemistry) a reduction reaction has occurred if4:

a molecule loses oxygen

OR

a molecule gains hydrogen

In the reaction shown below, oxygen is lost from the nitro group of 4-nitrophenol and hydrogen is
added to form 4-aminophenol, so the reaction is a reduction reaction:

In the laboratory: Industrial preparation:

NaBH4 H2


Pd/1 M Pt
NaOH catalyst

4-
4- 4- 4-
aminophenol
nitrophenol nitrophenol aminophenol
74% yield

A catalyst such as palladium in the laboratory reaction, or platinum in the industrial reaction, is
required to provide a surface for the reaction to take place on.
The 4-nitrophenol molecules are held to the surface of the catalyst by weak forces of attraction,
which then weakens the strong covalent bonds in the nitro group making it vulnerable to attack by
hydrogen.

Step 3: formation of an amide

With the exception of tertiary amines, amines undergo reaction with anhydrides to produce
amides.

4-aminophenol, an amine, suspended in water at room temperature readily reacts with ethanoic
anhydride (acetic anhydride) to produce a precipitate of the amide paracetamol (acetaminophen) as
shown below:
amine acetic anhydride amide


room temperature water

paracetamol
4-aminophenol
(acetaminophen)

Reactions of Paracetamol (acetaminophen)


Acid Hydrolysis

Hydrolysis (reaction with water) of amides in acidic solution produces an amine and a carboxylic
acid.

Hydrolysis of paracetamol (acetaminophen) in acidic solution produces an amine (4-aminophenol)


and a carboxylic acid (acetic acid)

amide amine carboxylic acid

O H
H2O/H2SO4
|| |
+ HO- C - C -H
|
H
paracetamol ethanoic acid
4-aminophenol
(acetaminophen) (acetic acid)

Synthesis

The synthesis of aspirin is classified as an esterification reaction. Salicylic acid is treated with
acetic anhydride, an acid derivative, causing a chemical reaction that turns salicylic acid's
hydroxyl group into an ester group (R-OH R-OCOCH3). This process yields aspirin and
acetic acid, which is considered a byproduct of this reaction. Small amounts of sulfuric acid (and
occasionally phosphoric acid) are almost always used as a catalyst. This method is commonly
employed in undergraduate teaching labs.[126]

Reaction mechanism

Formulations containing high concentrations of aspirin often smell like vinegar[127] because
aspirin can decompose through hydrolysis in moist conditions, yielding salicylic and acetic
acids.[128]

Polymorphism

Polymorphism, or the ability of a substance to form more than one crystal structure, is important
in the development of pharmaceutical ingredients. Many drugs are receiving regulatory approval
for only a single crystal form or polymorph. For a long time, only one crystal structure for
aspirin was known. That aspirin might have a second crystalline form was suspected since the
1960s. The elusive second polymorph was first discovered by Vishweshwar and coworkers in
2005,[129] and fine structural details were given by Bond et al.[130] A new crystal type was found
after attempted cocrystallization of aspirin and levetiracetam from hot acetonitrile. The form II is
only stable at 100 K and reverts to form I at ambient temperature. In the (unambiguous) form I,
two salicylic molecules form centrosymmetric dimers through the acetyl groups with the (acidic)
methyl proton to carbonyl hydrogen bonds, and in the newly claimed form II, each salicylic
molecule forms the same hydrogen bonds with two neighboring molecules instead of one. With
respect to the hydrogen bonds formed by the carboxylic acid groups, both polymorphs form
identical dimer structures.[citation needed]

Mechanism of action
Main article: Mechanism of action of aspirin

Discovery of the mechanism

In 1971, British pharmacologist John Robert Vane, then employed by the Royal College of
Surgeons in London, showed aspirin suppressed the production of prostaglandins and
thromboxanes.[131][132] For this discovery he was awarded the 1982 Nobel Prize in Physiology or
Medicine, jointly with Sune K. Bergstrm and Bengt I. Samuelsson.[133] In 1984, he was made a
Knight Bachelor.

Suppression of prostaglandins and thromboxanes

Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its
irreversible inactivation of the cyclooxygenase (COX; officially known as prostaglandin-
endoperoxide synthase, PTGS) enzyme required for prostaglandin and thromboxane synthesis.
Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine
residue in the active site of the PTGS enzyme. This makes aspirin different from other NSAIDs
(such as diclofenac and ibuprofen), which are reversible inhibitors.

Low-dose aspirin use irreversibly blocks the formation of thromboxane A2 in platelets,


producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet
(89 days). This antithrombotic property makes aspirin useful for reducing the incidence of heart
attacks.[134] 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane
A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however,
higher doses of aspirin are required to attain further inhibition. [135]

Prostaglandins, local hormones produced in the body, have diverse effects, including the
transmission of pain information to the brain, modulation of the hypothalamic thermostat, and
inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood
clots. Heart attacks are caused primarily by blood clots, and low doses of aspirin are seen as an
effective medical intervention for acute myocardial infarction.

COX-1 and COX-2 inhibition

At least two different types of cyclooxygenase occur COX-1 and COX-2. Aspirin irreversibly
inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally produces
prostanoids, most of which are proinflammatory. Aspirin-modified PTGS2 produces lipoxins,
most of which are anti-inflammatory.[136] Newer NSAID drugs, COX-2 inhibitors (coxibs), have
been developed to inhibit only PTGS2, with the intent to reduce the incidence of gastrointestinal
side effects.[16]

However, several of the new COX-2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn
in the last decade, after evidence emerged that PTGS2 inhibitors increase the risk of heart attack
and stroke.[137][138] Endothelial cells lining the microvasculature in the body are proposed to
express PTGS2, and, by selectively inhibiting PTGS2, prostaglandin production (specifically,
PGI2; prostacyclin) is downregulated with respect to thromboxane levels, as PTGS1 in platelets
is unaffected. Thus, the protective anticoagulative effect of PGI2 is removed, increasing the risk
of thrombus and associated heart attacks and other circulatory problems. Since platelets have no
DNA, they are unable to synthesize new PTGS once aspirin has irreversibly inhibited the
enzyme, an important difference with reversible inhibitors.

Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products
such as the prostaglandins, converts this enzyme's activity form a prostaglandin-forming
cyclooxygenase to a lipoxygenase-like enzyme: aspirin-treated COX-2 metabolizes a variety
polyunsaturated fatty acids to hydroperoxy products which are then further metabolized to
specialized proresolving mediators such as the aspirin-triggered lipoxins, aspirin-triggered
resolvins, and aspirin-triggered maresins. These mediators possess potent anti-inflammatory
activity. It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to
lipoxygenase activity and the consequential formation of specialized proresolving mediators
contributes to the anti-inflammatory effects of aspirin.[139][140][141]

Additional mechanisms

Aspirin has been shown to have at least three additional modes of action. It uncouples oxidative
phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the inner
membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once
again to release protons.[142] In short, aspirin buffers and transports the protons. When high doses
of aspirin are given, it may actually cause fever, owing to the heat released from the electron
transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. In addition,
aspirin induces the formation of NO-radicals in the body, which have been shown in mice to
have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion,
which is an important step in immune response to infection; however, evidence is insufficient to
show aspirin helps to fight infection. [143] More recent data also suggest salicylic acid and its
derivatives modulate signaling through NF-B.[144] NF-B, a transcription factor complex, plays
a central role in many biological processes, including inflammation.

Aspirin is readily broken down in the body to salicylic acid, which itself has anti-inflammatory,
antipyretic, and analgesic effects. In 2012, salicylic acid was found to activate AMP-activated
protein kinase, which has been suggested as a possible explanation for some of the effects of
both salicylic acid and aspirin. [145][146] The acetyl portion of the aspirin molecule has its own
targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of
protein function at the post-translational level. Aspirin is able to acetylate several other targets in
addition to COX isoenzymes.[147][148] These acetylation reactions may explain many hitherto
unexplained effects of aspirin.

Pharmacokinetics
Acetylsalicylic acid is a weak acid, and very little of it is ionized in the stomach after oral
administration. Acetylsalicylic acid is quickly absorbed through cell membrane in the acidic
conditions of the stomach. The increased pH and larger surface area of the small intestine causes
aspirin to be absorbed more slowly there, as more of it is ionised. Owing to the formation of
concretions, aspirin is absorbed much more slowly during overdose, and plasma concentrations
can continue to rise for up to 24 hours after ingestion. [149][150][151]

About 5080% of salicylate in the blood is bound to albumin protein, while the rest remains in
the active, ionized state; protein binding is concentration-dependent. Saturation of binding sites
leads to more free salicylate and increased toxicity. The volume of distribution is 0.10.2 l/kg.
Acidosis increases the volume of distribution because of enhancement of tissue penetration of
salicylates.[151]

As much as 80% of therapeutic doses of salicylic acid is metabolized in the liver. Conjugation
with glycine forms salicyluric acid, and with glucuronic acid to form two different glucuronide
esters. The conjugate with the acetyl group intact is referred to as the acyl glucuronide; the
deacetylated conjugate is the phenolic glucuronide. These metabolic pathways have only a
limited capacity. Small amounts of salicylic acid are also hydroxylated to gentisic acid. With
large salicylate doses, the kinetics switch from first-order to zero-order, as metabolic pathways
become saturated and renal excretion becomes increasingly important. [151]

Salicylates are excreted mainly by the kidneys as salicyluric acid (75%), free salicylic acid
(10%), salicylic phenol (10%), and acyl glucuronides (5%), gentisic acid (< 1%), and 2,3-
dihydroxybenzoic acid.[152] When small doses (less than 250 mg in an adult) are ingested, all
pathways proceed by first-order kinetics, with an elimination half-life of about 2.0 to 4.5
hours.[153][154] When higher doses of salicylate are ingested (more than 4 g), the half-life becomes
much longer (1530 hours),[155] because the biotransformation pathways concerned with the
formation of salicyluric acid and salicyl phenolic glucuronide become saturated. [156] Renal
excretion of salicylic acid becomes increasingly important as the metabolic pathways become
saturated, because it is extremely sensitive to changes in urinary pH. A 10- to 20-fold increase in
renal clearance occurs when urine pH is increased from 5 to 8. The use of urinary alkalinization
exploits this particular aspect of salicylate elimination. [157]

Aspirin is Acetyl Salicylate. It is an ester. When made to react with aqueous acid, it hydrolyzes to an
organic acid and alcohol just like a normal ester. Aspirin (Acetyl Salicylate) will hydrolyze to Salicylic Acid
and Methanol.
C6H5COOH-COOCH3 + acidic H2O = C6H5(COOH)2 + CH3OH

When the same Acetyl Salicylate is made to react with dilute alkali like Na2CO3, it carries out the same
hydrolysis reaction. Difference is that end product formed will be Sodium Salicylate instead of Salicylic
Acid.

C6H5COOH-COOCH3 + (dil Na2CO3) H2O = C6H5(COOH)2 + CH3OH


C6H5(COOH)2 +dil. Na2CO3 = C6H5(COONa)2 + CO2 + H2O

The reaction that is used for the synthesis is shown below. In this reaction, an excess of acetic
anhydride (C4H6O3) is added to a measured mass of salicylic acid (C7H6O3) in the presence of a
catalyst, sulfuric acid (H2SO4). The mixture is heated to form the acetylsalicylic acid (C9H8O4)
and acetic acid (C2H4O2). After the reaction takes place, water is added to destroy the excess
acetic anhydride and cause the product to crystallize. The aspirin is then collected, purified by
recrystallization, and its melting temperature measured.

The reaction that is used for the synthesis is shown below. In this reaction, an excess of acetic
anhydride (C4H6O3) is added to a measured mass of salicylic acid (C7H6O3) in the presence of a
catalyst, sulfuric acid (H2SO4). The mixture is heated to form the acetylsalicylic acid (C9H8O4)
and acetic acid (C2H4O2). After the reaction takes place, water is added to destroy the excess
acetic anhydride and cause the product to crystallize. The aspirin is then collected, purified by
recrystallization, and its melting temperature measured.
Phenol react with FeCl3 (aq) to give a deep
purple complex.
Phenol is not present in the product but in
one of the reactant.
This test indicate the presence of unreacted
starting material (quantitative analysis
possible via visible spectroscopy).

The ferric chloride test is used to determine the presence or absence of phenols in a given sample (for
instance natural phenols in a plant extract). Enols, hydroxamic acids, oximes, and sulfinic acids give
positive results as well.[1] The bromine test is useful to confirm the result, although modern
spectroscopic techniques (e.g. NMR and IR spectroscopy) are far superior in determining the identity of
the unknown. The quantity of total phenols may be spectroscopically determined by the Folin-
Ciocalteau assay.

Aqueous titration works for those weak acids that have pKa in the 0-14 range. The pKa of p-
hydroxyacetanilide (acetaminophen) is about 9.5 (the phenolic proton being the acidic one), so this
should work fine:
C8H9NO2 (aq) + NaOH (aq) C8H8NO2Na (aq) + H2O.