Importance• Phenols are very important antiseptic and germicidal agents

e.g. thymol, eugenol, …etc

• Most phenols & phenol ethers have powerful aromatic odour and flavour e.g. oil of clove & oil of anise

Isolation:

Phenols and Phenolic ethers

1. Fractional distillation

2. GCMS and HPLC

3. Fractional crystallization by cooling (for cryst. phenols)

4. Formation of phenolates (= phenates) with alkali which is water soluble.

• N.B.Phenolic ethers are neutral compounds and do not react with alkalis but generate phenols on heating with HI or HBr.

Separation of phenols based on their acidic property (Formation of phenolates)

• Phenols are weak acids.

• They are acidic enough to formwith dilute alkali watersoluble salts (phenolates)

• This property is used to separate phenols fromnon-phenolic constituents

Tests for identity• Phenolics give highly coloured compounds with FeCl3• Phenolics form a crystalline bromides with Br2 by substitution

reaction.• Phenols can be esterified with acid anhydrides, phenyl

isocyanate, benzoyl chloride or p-nitrobenzoyl chloride. (Like3ry alc., phenols are difficult to esterify so esterification requires3ry alc., phenols are difficult to esterify so esterification requires

the presence of an organic base such as pyridine.)

Estimation of Phenols•Phenol form water soluble salts with alkalies (using cassia flask).•Specific color reaction with specific reagents.•GC-MS and HPLC

Cassia flask method:Principle:Phenol formwater soluble salts with alkalis

Method: (using cassia flask).

• In a cassia flask, put known volume of oil.

• Add aq. KOHsolution and mix

• Phenol forms phenolate soluble salt in water and the nonphenolic part separatesas oily layer which can bephenolic part separatesas oily layer which can bemeasured in the graduated neck of cassia flask.

• N.B. KOH is preferred than NaOH because the

potassium salts of many phenols are more soluble thanthe corresponding sodium salts.

Monohydric phenol

• In oil of thyme family Labiatae• Colorless crystals• Aromatic thyme-like odor, pungent

taste

1-Thymol (3-hydroxy p-cymene)

• Isolated by: � By cooling the oil, thymol crystallizes.

� By fractional distillation.

� By 5% KOH → Phenolate→ acid treatment → phenol → steam distillation or extract with ether.

OH

Thymol

Synthesis1- From menthone:

O

Br2

Quinoline OH

2- From piperitone:

O

FeCl3

OH

3- From m-Cresol:

OH

+ CH3CHOHCH3

isopropyl alc OH

Identification & uses• Derivatization to phenylurethane and determination of

the melting points m.p. 106-107 ºC • Color reactions:

�Thymol/gl. Acetic acid + dps H2SO4 + one dp HNO3deep bluish green color

�Add few crystals of thymol to 3 ml NaOHand heat a pale red color is produced. Shake with 2 ml CHC13 to get reddish-color is produced. Shake with 2 ml CHC13 to get reddish-violet color in the organic layer

�Dissolving thymol in conc. H2SO4 gives violet color due toformation of thymol sulfonic acid.

Uses:– Local anesthetic, Antifungal, Anthelmentic– Mouthwashes, oral preparations, Antiseptic– Hepatoprotective, Antioxidant, free radical scavenger– Preparation of synthetic menthol, Immunostimulant

• obtained from the oil Thymus capitatusand other species of the family labiatae

2- Carvacrol:

OH

Carvacrol�Carvacrol preparation and chemicalproperties are similar to those of thymol with fewdifferences.�When carvacrol or thymol dissolved in conc. H2SO4,diluted and oxidized with KMnO , K CrO or Manganesediluted and oxidized with KMnO4, K2CrO4 or Manganesedioxide a yellow plates of thymoquine are produced .�Carvacrol and thymol give green color with FeCl3.�Thymoquine possesses hepatoprotctive activitycomparable with Silymarin and inhibits leucotrienes andthromboxane synthesis which could help in treatment ofcough.

Dihydric phenols and phenolic ethers

• Oil of clove, cinnamon Fam. Myrtaceae, Lauraceae

• Yellow oil, clove odor, burning spicy taste• Isolated by by shaking with 5% KOH,

separation of the non-phenolic part and

OH

OCH3

separation of the non-phenolic part and addition of dil. acid to the phenolic part and distillate eugenol.

• Identified by:– + % alc.FeCl3 blue color– Preparation of benzoate, phenylurethane

derivatives– + 3% aq. NaOH saturated with NaBr

rosettes of needles of sod. eugenateEugenol

Uses• Local anaethetic& antiseptic in toothache remedies• Spice & flavouring agent• Synthesis of vanillin (not practical)• Potential hypocholesterolemic agent

OH

OCH3

OH

OCH3

OAc

OCH3

CHO

OAc

OCH3

CHO

OH

OCH3

KOH HClAcetylation Oxid.

Heat

Eugenol Isoeugenol Vanillin

Monohydric phenolic ether

• Anise, fennel, star anise oils Fam. Umbelliferae

• Isolated by fractional distillation then crystallization at low temperature

OCH3

at low temperature• White crystalline• Sweet taste and odor • Uses:

– Flavoring mouthwashes, gargles– Flavoring in foods and beverages– Antioxidant

Anethole

Synthesis

OCH3OCH3

O

HCl Pyridine

OCH3

+ HHCl

H3PO4

Cl

Pyridine

AnetholeAnisole propionaldehyde

Anethole has to be stored in well-closed colored container away from light why??

OCH3

light/air/heat

OCH3

OCH3

CHO

OCH3

AnetholeAnethaldehyde

oxidation

P-p’- dimethoxystilbene(photoanethole)

Viscid consistencyyellow

Identification

OCH3

CHCHCH3

OCH3

CHO

OCH3

COOH

K2Cr2O7 [ O ]

m.p. 184°C

1-

CHCHCH3 CHO COOH

Aisaldehyde Anisic acid

2- Preparation of nitroso derivatives m.p. 126°C

Safrole• Safrole is colorless liquid, isolated fromthe oil of

sassafras and star anise by fractional distillationfollowed by crystallization after cooling.

• Safrole like eugenol isomerise to isosafrole on heatingwith KOH.

• Safrole and isosafrole gave red color with conc.H22SO4.

• Safrole and isosafrole are antiseptic and oxidized toheliotropin (piperonal) which is more fragrant.

• Safrole and heliotropine are used in flavoring andscenting and as insect repellant O

O

H2C CH CH2

Safrol use as a flavor is restricted and no longerused because its carcinogenicity to liver and itspresence in some medicinally used volatile oils, asnutmeg oil, became a problem

Tricyclic phenols and phenolic ethers•Myristicin:

Source: It is constituent of the oil of nutmeg and mace.

Isolation: Fractional distillation of the myristica oil.

OO

H2C CH CH2

H3CO

the myristica oil.

Uses: CNS stimulant

Hallucinogenic agent

• Identification:On oxidation with KMnO4 gives

myristinic acid

(definite m.p. 208-210 ºC)

• .

H2C CH CH2

OOH3CO

O

COOH

OH3CO

KMnO4

MyristicinMyristinic acid

Tetrahydrophenolic ethers

• In parsley seed oil

• Long colorless needles with faint parsley odor

• Isolated by fractional distillation OCH3

O

O

• Isolated by fractional distillation then cooling

• Identification:1- Preparation of apiole tribromide, m.p. 80C.2- On oxidation with KMnO4 gives apiolic acid (definite m.p. 173 ºC)

• Uses:Diuretic

H3CO

ApioleParsley camphor

Dillapiole

• Dillapiole is a colorless oil.

• obtained from dill oil by fractional distillation.

• Dillapiole possesses a chemical charaterstics similarto those of apiol and myristicin.

O

OH3CO

H3CO

to those of apiol and myristicin.

• It possesses hypolipidemic and insect repellantactivity and could be used as a lactagouge.

• Apiole and dillapiole possess mild CNS activity.

• Apiole prevent the calculi formation in kidney whiledillapiole protect from gall bladder stones formation

Terpene Oxides1,4-Cineol• It is isolated from oil of cubeb by fractional distillation.

• Quantification and qualification of 1,4-Cineol by GC-MS and HPLC

Cineole

O

EstimationUses:Antiseptic & expectorant

2- 1,8-Cineol (Eucalyptol)Eucalyptol is expectorant, diuretic, antiseptic,antispasmodic, stimulant.Prevent calculus formation in kidney or even help in dissolving the already formedcalculus either in kidney or gall bladder.

O

Eucalyptol

Terpene PeroxideAscaridoleOccurrence: In Chenopodiumoil

Preparation: by fractional distillation under reduced pressure

(to avoid explosion)

Characters: viscous yellowliquid with nasty disagreableodour&taste.

Test: Givebloodredcolorwith Fe+2 + ammoniumthiocyanate.

Ascaridole

O

O

Test: Givebloodredcolorwith Fe+2 + ammoniumthiocyanate.

Uses:Anthelmintic for round & hook worms

Estimation:(Iodometrically: based on the oxidizing action ofperoxides), the oil + acidified KI solution & the liberated I2 is

titrated against standard Na2S2O3 solution.N.B.• Blank experiment should be carried out• Temperature must be low to avoid addition of I2 to the double

bond and volatilization of I2

Esters in volatile oils

• Esters are widely distributed in many essential oils. The mostcommon is the acetate. However oil of winter green is composedmainly of methyl salicylate.

• Esterssaponify with alkalis to give the corresponding alcohol andtheacidsalt,andthis is thebasisfor theirquantization.theacidsalt,andthis is thebasisfor theirquantization.

• The best methods for detection and isolation of esters seems to bethe GC/MS and HPLC.

• Esters isolated fromthe volatile oil can be classified according tothe acyl radical into:

Methyl Esters Containing Nitrogen-Canthranilate

Occurrence: in leaf oil of sweet orange

Isolation: due to the basic nitrogen, methyl anthranilate

• can be isolated by shaking with dilHCl or dil H2SO4

• The formed sulfate is crystallized on cooling,recrystallized from alcohol and the ester isrecrystallized from alcohol and the ester isregenerated by treatment with NaOH or KOH.

Identification:

• By physical examination of the characteristicblue-violetfluorescence

• Uses:

• Antifungal

COOCH3

NH2

Acids• Some essential oils contain few free acids e.g.

citronellic acid (in citronella oil and geraniumoil) Salicylic acid, and p-anisic acid and manyfree acids are detected in water of cohobationof many oils, most likely due to hydrolysis ofsome esters. Some of these acids are aliphatic,some esters. Some of these acids are aliphatic,alicyclic or aromatic.