FINALS

EX. 8 – SYNTHESIS OF METHYL SALICYLATE

REAGENTS
METHYL SALICYLATE
SALICYLIC ACID 20% SODIUM CARBONATE
-​ Also known as wintergreen oil or betula oil NATURAL SOURCES -​ Limiting reactant -​ Used to remove the unreacted salicylic acid
-​ An organic ester naturally produced from WINTERGREEN LEAVES -​ Reacts w/ methanol in the presence of -​ It reacts w/ salicylic acid to form sodium
many plant species Gaultheria procumbens L. sulfuric acid to form methyl salicylate salicylate w/ carbon dioxide as a by-product
Family Ericaceae -​ The ionic sodium salicylate would drawn into
-​ a volatile oil that has a characteristic flavor -​ The carboxylic acid group is replaced w/
aqueous layer and can be removed from the
and odor (minty) SWEET BIRCH TREE BARK ester group upon reaction extraction mixture
-​ Can be produced synthetically using Betula lenta L.
salicylic acid as precursor Family Betulaceae CONCENTRATED SULFURIC ACID ANHYDROUS MAGNESIUM SULFATE
-​ Can be produced naturally by maceration -​ Used as catalyst to accelerate the reaction -​ Used to remove the remaining water in the
and subsequent steam distillation MEADOWSWEET LEAVES of salicylic acid w/ methanol mixture of the organic solvent (petroleum
Filipendula ulmaria (L.) ether) and the desired product (methyl
Maxim. salicylate).
METHANOL
Family Rosaceae -​ It acts as a drying agent, dehydrating the
-​ The methyl group of the methanol attaches
mixture leaving the organic layer free from
to carboxylate ion forming an ester
water and other water-soluble impurities
-​ The hydroxyl group forms bond w/ h+
HISTORY USES
producing water
●​ Methyl salicylate was first isolated from In hgh conc:
the plant Gaultheria procumbens L. in -​ Rubefacient in deep heating liniments to
PETROLEUM ETHER
treat joint and muscular pain
1843 by French chemist Auguste Andre -​ Used to extract the methyl salicylate
-​ counter -irritant
Thomas Cahours (1813-1891) -​ Methyl salicylate is more soluble in organic solvent; other components in the mixture especially if
-​ Analgesic
●​ He identified it as an ester of salicylic very polar, will be drawn into water
In low conc:
acid and methanol -​ The aqueous layer is drained, leaving the organic solvent where the methyl salicylate is dissolved
-​ Flavoring agent in chewing gum and mints
-​ Removed from the mixture by steam bath
(0.04% and below)
-​ Provides fragrance in other products
-​ Odor-masking in some pesticides
SYNTHESIS
PREPARATIONS TOXICTY -​ Salicylic acid, methanol, sulfuric acid are mixed all together in an Erlenmeyer flask
●​ Efficascent Oil Liniment ●​ A single teaspoon (5 ml) of methyl -​ Boiling chips are added to prevent bumping of solution
salicylate contains 7g of salicylate, -​ Solution is refluxed for 1 hour
●​ Katinko Ointment
which is equivalent to more than
●​ Omega Pain Killer Liniment FISCHER ESTERIFICATION 1.​ EXTRACTION
twenty-three 300mg aspirin tablets
●​ Ben-gay Pain Relieving Cream -​ The carboxylic group of the salicylic acid is -​ After heating, solution is cooled in an ice bath
●​ Salicylism - N&V, hyperventilation and
●​ Salonpas Pain Relief Patch tinnitus deprotonated and the methyl group from the -​ Petroleum ether is used to extract the methyl
●​ White Flower Embrocation ●​ Methyl salicylate can also cause skin methanol reacts to form an ester, which is the salicylate
irritation and skin rashes methyl salicylate -​ Distilled water is added to wash off polar
-​ Reaction is catalyzed by sulfuric acid compounds
fischer esterification -​ 20% sodium carbonate is added to remove
unreacted salicylic acid
 2.​ DRYING & FILTRATION 3.​ MAXIMIZING THE YIELD SALICYLIC ACID
-​ Extract is dried using anhydrous magnesium -​ Adding the excess methanol. This shifts the
sulfate equilibrium to the right -​ a white crystalline compound isolated NATURAL SOURCES
-​ It is then filtered in a pre-weighed -​ Removing water formed by adding a drying from natural sources or synthetically WINTERGREEN LEAVES
evaporating dish agent like anhydrous magnesium sulfate to Gaultheria procumbens L.
produced from methyl salicylate
-​ Solvent is removed using steam bath the reaction mixtures. This shifts the Family Ericaceae
-​ natural salicylic acid is obtained from
-​ Methyl salicylate is weigh, and percentage equilibrium to the right.
yield is computed -​ Allowing the reaction mixture sufficient plants (wintergreen leaves and bark of SWEET BIRCH TREE BARK
time to reach equilibrium before stopping sweet birch tree) Betula lenta L.
the reaction. This will maximize the yield for -​ synthetic salicylic acid is chemically Family Betulaceae
the given conditions known as 2-hydroxybenzoic acid or
-​ Taking proper care during purification steps o-hydroxybenzoic acid MEADOWSWEET LEAVES
to minimize loss of any methyl salicylate Filipendula ulmaria (L.)
-​ this drug falls under the category
product Maxim.
analgesic, antipyretic and Family Rosaceae
anti-inflammatory agent
PHYSICAL TESTS FERRIC HYDROXAMATE TEST
-​ Color: clear colorless or -​ Esters when heated w/ hydroxylamine produce hydroxamic acids HISTORY USES
slightly yellowish that react w/ ferric ion to form intensely colored complexes, ●​ Raffaele Piria – an Italian chemist -​ Analgesic and antipyretic. Systemically,
-​ odor : minty (wintergreen commonly dark maroon in color ●​ he split salicin into a sugar and an salicylic acid produces these effects similar to
odor) -​ Related to the phenol test wherein compounds w/ high enolic those of aspirin.
aromatic component salicylaldehyde
-​ Appearance: oily, slightly character gives colored complexes w/ ferric ion -​ Anti-inflammatory. It possesses this activity
●​ converted the salicylaldehyde by due to its ability to inhibit cyclooxygenases.
viscous liquid -​ A preliminary test must be performed to check if compound
hydrolysis and oxidation, to an acid -​ Antibacterial. Salicylic acid salt (sodium
produces enough enol to form colored complexes with ferric ion
of crystallized colorless needles, salicylate) has known antibacterial activity,
which he named salicylic acid the reason why salicylic acid is found in
toothpastes and mouthwashes.
METHYL SALICYLATE
PREPARATIONS -​ Food preservative. Salicylic acid has mild
●​ official products in the market: antiseptic action which makes it a good food
●​ IUPAC name: Methyl-2-hydroxybenzoate ●​ Stability: sensitive to light and heat
preservative but only in small doses.
●​ Synonym: oil of wintergreen, betula oil, ●​ structure : a phenol w/ an attached ester group • Salicylic acid gel • Salicylic acid cream
-​ Keratolytic. It facilitates desquamation by
gaultheria oil on ortho position • Ap-ap solution • Whitfield’s ointment solubilizing the intercellular cement that binds
●​ Molecular formula: C8H8O3 • Salicylic acid plaster • Wart remover solution scales in the stratum corneum, thereby
●​ Physical description: clear colorless oily
• Medicated soap loosening the keratin.
liquid w/ minty odor
-​ Antifungal. The removal of the stratum
●​ Mol wt: 152.15 g/mol
SIDE EFFECTS corneum suppresses fungal growth. Also used
●​ Bp: 222 C
• internally: for treatment of dandruff, acne, psoriasis,
●​ Mp: -8.6 C
• GI irritation calluses, corns, keratosis pilaris, and warts.
●​ Solubility: 0.07 g per 100 ml water at 20C
-​ different cosmetic preparations contain
●​ Density:1.184 g/cm3 • salicylism toxicity
salicylic acid for various uses and treatments:
●​ Chemical safety: irritant • externally: -​ seborrheic dermatitis, mild to moderate acne
• skin irritation vulgaris, ichthyosis, psoriasis • warts, corns
• rashes and calluses, dandruff
EXPERIMENT 9 - SYNTHESIS OF SALICYLIC ACID • skin itching or swelling
 PHYSICAL TEST FERRIC CHLORIDE TEST
REAGENTS • color: white ●​ detect the presence of phenol
• odor: odorless ●​ principle: salicylic acid reacts with ferric
METHYL SALICYLATE CONCENTRATED SULFURIC ACID • appearance: crystalline powder chloride (FeCl3) to form ferric salicylate
-​ limiting reactant -​ source of H+ ions used to protonate the and hydrochloric acid
-​ precursor for the synthesis disodium salicylate (salt ion) ●​ positive result: purple color of solution
-​ the methyl group on its structure is -​ an excess of this strong acid was added to BROMINE WATER TEST (ferric salicylate)
replaced with a hydrogen upon fully convert the disodium salicylate into ●​ detects presence of multiple bonds ●​ 3 C7H6O3 (aq) + FeCl3 (aq) →
reaction salicylic acid and phenolic group Fe(C7H5O3)3 (aq) + 3 HCl (aq)
-​ this is achieved through hydrolysis ●​ principle: phenols undergo
substitution reaction with bromine REACTION WITH METHANOL
25% SODIUM HYDROXIDE SYNTHESIS water ●​ reaction w/ methanol principle: salicylic
-​ limiting reactant 1.​ methyl salicylate and sodium hydroxide ●​ positive result: decolorized solution acid will undergo esterification reaction
-​ precursor for the synthesis is mixed in an Erlenmeyer flask (HBr) with white precipitate forming methyl salicylate upon reaction
-​ the methyl group on its structure is 2.​ boiling chips are added to prevent boiling (2,4,6-tribromophenol) with methanol
replaced with a hydrogen upon over ●​ positive result: minty odor (methyl
reaction 3.​ the solution is refluxed and allowed to salicylate)
-​ this is achieved through hydrolysis cool
4.​ the solution is placed on an ice bath while
BASE HYDROLYSIS the sulfuric acid is added
●​ in methyl salicylate, the benzene ring 5.​ this process protonates the disodium
is substituted by a hydroxyl (–OH) salicylate salt
group and an ester (–COOCH3) group 6.​ the reaction is exothermic, thus releasing
●​ in salicylic acid, the ester group has heat
been replaced with a carboxyl 7.​ sulfuric acid is added dropwise while SALICYLIC ACID PRODUCT SAR
(–COOH) group swirling
●​ methyl salicylate is hydrolyzed using 8.​ addition of the acid is stopped after it IUPAC name: 2-hydroxybenzoic acid ●​ The ortho-position of the –OH group is
sodium hydroxide forming the saturates the solution converting the ●​ • synonym: o-hydroxybenzoic acid, essential for its activity.
disodium salicylate salt disodium salicylate salt into salicylic acid 2-carboxyphenol, acido salicilico ●​ If the position of the –OH group is changed
●​ the disodium salicylate salt is ●​ • molecular formula: C7H6O3 to meta- or para-positions with respect to
protonated using a strong acid FILTRATION AND DRYING ●​ • physical description: odorless –COOH, the activity is abolished.
1.​ the precipitate is filtered white crystalline powder ●​ Removing the –OH group reduces its activity
2.​ then it is washed using cold distilled ●​ • molecular weight: 138.12 g/mol ●​ Acetylation of salicylic acid will give aspirin,
3.​ water ●​ • boiling point: 211°C a potent analgesic.
4.​ the powder is dried and weighed ●​ • melting point: 158°C ●​ GIT side effects are associated with –COOH
5.​ the percentage yield is computed ●​ • solubility: 2.24 g per 1 L water at group.
25°C ●​ Substitutions on the aromatic ring will
●​ • density: 1.443 g/cm3 decrease its activity.
PHYSICOCHEMICAL TESTS ●​ • chemical safety: corrosive, irritant, ●​ Substitution of halogen atoms on aromatic
health hazard ring increases potency and toxicity.
●​ • stability: gradually discolors in
sunlight
●​ • structure: phenol with an attached
carboxyl group on ortho position
EXPERIMENT 10 - SYNTHESIS OF ASPIRIN
Common: Moderate to severe:
ASPIRIN ●​ Rashes ●​ Anaphylaxis
●​ GI ulcerations ●​ Tinnitus
●​ An odorless, white crystalline powder NATURAL AND SYNTHETIC PRODUCTION ●​ Abdominal pain ●​ Hallucinations
●​ Chemically known as 2-acetyloxybenzoic ●​ Natural production: from willow bark or ●​ Heartburn ●​ Severe nausea and vomiting
acid or acetylsalicylic acid (ASA) meadowsweet flowers ●​ Headache ●​ Bloody stools
●​ A weak acid that is only slightly soluble ●​ Synthetic production: salicylic acid + ●​ Nausea ●​ Fever lasting for 3 days
in water acetic anhydride in presence of acid ●​ Gastritis ●​ Swelling lasting more than 10 days
●​ An aromatic compound with carboxylic catalyst
acid and ester functional groups WILLOW BARK
●​ A known analgesic, antipyretic, ●​ Salix alba L.​
anti-inflammatory drug REAGENTS
●​ Family: Ericaceae​
HISTORY SALICYLIC ACID ACETIC ANHYDRIDE
●​ c3000–1500 BC: Willow used as MEADOWSWEET FLOWERS ●​ Limiting reactant= ●​ Irritant and lachrymator
medicine by Sumerians and Egyptians; ●​ Filipendula ulmaria (L.) Maxim.​ ●​ Precursor in synthesis ●​ Source of acetyl group
Ebers Papyrus refers to willow as ●​ Hydroxyl group reacts with acetyl group ●​ Involved in nucleophilic acyl substitution
anti-inflammatory/pain reliever ●​ Family: Rosaceae of acetic anhydride

●​ 400 BC: Hippocrates administers willow CONCENTRATED SULFURIC ACID DEIONIZED WATER
leaf tea to ease childbirth pain​ USES OF ASPIRIN ●​ Catalyst to accelerate the reaction ●​ Removes water-soluble impurities like
●​ Analgesic and anti-inflammatory: acetic acid and sulfuric acid
●​ 1763: Edward Stone submits report to ○​ Inhibits prostaglandin synthesis by
Royal Society on dried willow bark for irreversibly inactivating COX-1 and ETHYL ACETATE PETROLEUM ETHER
fever​ COX-2 ●​ Solvent for recrystallization of crude ●​ Solvent used to wash recrystallized
●​ Antipyretic: aspirin aspirin crystals
●​ 1828: Joseph Buchner extracts salicin ○​ Said to inhibit thermoregulatory ●​ Suitable since water may decompose ●​ Must be cooled before use
(bitter yellow crystals) from willow​ receptors in the hypothalamus aspirin
○​ Causes vasodilation and increased
●​ 1853: Charles Frédéric Gerhardt peripheral blood flow
determines structure of salicylic acid​ ○​ Exact mechanism remains unknown
○​ Intermediate doses (650 mg to 4 g/day) SYNTHESIS NUCLEOPHILIC ACYL SUBSTITUTION
●​ 1876: First clinical trial of salicin for provide analgesic and antipyretic ●​ Mix salicylic acid, acetic ●​ Salicylic acid reacts with acetic anhydride
fever and joint inflammation​ effects anhydride, and concentrated (with acid catalyst) to produce aspirin and
●​ Anti-thrombotic: sulfuric acid in Erlenmeyer flask acetic acid
●​ 1897: Felix Hoffmann at Bayer modifies ○​ Inhibits platelet aggregation by ●​ Heat solution until fully dissolved ●​ Salicylic acid can also react with acetic acid
salicylic acid to reduce irritation; Bayer irreversibly acetylating serine 350 of ●​ Add deionized water to remove in esterification, but the reaction is slow and
patents the process​ COX-1 water-soluble impurities yields are low
○​ Inhibits thromboxane A2 ●​ Cool solution to form crude
●​ 1899: Bayer names compound Aspirin ○​ Low doses (75–81 mg/day) sufficient for aspirin crystals VACUUM FILTRATION
(“A” for acetyl, “spir” from Spiraea anti-platelet effect RECRYSTALLIZATION ●​ Filter crystals through vacuum (Büchner)
ulmaria, “in” as common drug suffix) ●​ Removes unreacted salicylic acid, filtration
acetic anhydride, acetic acid, ●​ Dry crude crystals before recrystallization
SIDE EFFECTS and sulfuric acid
 ●​ Purifies aspirin
●​ Yields needle-like crystals with no
vinegar-like odor (vs. powdered
crude aspirin)

PHYSICOCHEMICAL TESTS

PHYSICAL TESTS MELTING POINT DETERMINATION

●​ Color: white ●​ MP: 135°C
●​ Odor: odorless ●​ Lower MP indicates presence of impurities
●​ Appearance: crystalline powder

FERRIC CHLORIDE TEST TITRIMETRIC ANALYSIS

●​ Detects phenol presence ●​ Determines amount of aspirin in sample
●​ Aspirin should yield negative ●​ Requires known volume and concentration of
result (no deep violet) NaOH
●​ Light purple may appear if ●​ Titrate aspirin with standardized NaOH to
salicylic acid impurities are find moles of acid
present​ ●​ Quantitatively assesses purity (assuming no
other acid contaminants)

ASPIRIN PRODUCT

●​ IUPAC name: 2-acetyloxybenzoic acid ●​ Solubility: 0.25 g per 100 mL water at

●​ Synonym: acetylsalicylic acid, ASA 15°C
●​ Molecular formula: C₉H₈O₄ ●​ Density: 1.40 g/cm³
●​ Physical description: odorless white ●​ Chemical safety: irritant
crystalline powder ●​ Stability: gradually hydrolyzes into
●​ Molecular weight: 180.16 g/mol salicylic acid and acetic acid when
●​ Boiling point: 284°C (decomposes) exposed to moisture
●​ Melting point: 135°C ●​ Structure: benzene ring with carboxyl
group and ester group on ortho position