phenols, phenolic ethers, Thymol, Carvacrol, Thymol derivatives, anethole or Anise camphor, Anethole derivatives, Guaiacol, Eugenol, Safrole, Myristicin, Isomyristicin, Parsley Apiole ( Parsley camphor) and Dill Apiole

1. Phytochemistry
Volatile oils
Phenols and Phenolic ethers
By
Dr. Mostafa Mahmoud Hegazy ( PH.D.)
Pharmacognosy Dept.

2.  Most of these compounds possess powerful aromatic odors and flavors,
which make oils such as, clove, anise and sassafras etc … very popular.
 They are responsible for the antiseptic and germicidal properties of
certain oils.
 They constitute the largest group of phenyl propanoid constituents
detected in volatile oils.
Phenols and Phenolic ethers
Isolation
1- Formation of water-soluble salts… acidification … free phenol extracted
with ether or steam distillation.
OH
3-5% KOH
O- K+
Water soluble saltsPhenol
(Weak acid)
acid
2- Cooling the oil to allow the phenols to crystallize.

3. Phenols
Weakly acidic
Phenolic ethers
Very stable, neutral compounds
React with Br2 (electrophilic substitution) forming bromides used for identification
+ FeCl3 highly colored compounds + HBr or HI Phenol
React with alkali forming water soluble salts Not react with alkali
Determination
Phenates are soluble in water, the potassium salts are
more soluble than the corresponding sodium salts.
The non-phenolic portion separates as an upper layer,
its volume is determined (cassia flask) and the amount
of phenol is calculated by difference (% v / v).
Disadvantages:
1- Alkali-soluble compounds (e.g. acids) or water-
soluble adulterants (e.g. alcohols) are calculated as
phenols.
2- The phenolate solution can dissolve a part of the
non-phenolic portion of the oil.
3- The method is unsuitable for determination of
small amounts.
Zeisel’s method: The released
alkyl (methyl or ethyl) iodide is
received in a solution of silver
nitrate in ethanol upon which an
equivalent amount of silver
iodide(ppt) , separated and
weighed.The amount of silver
iodide that precipitates is equivalent
to the phenolic ether present.
OH
OR
OR OH
HI
Phenol
+ + RI
Phenolic ether
R = OCH3 or OCH2CH3

4. OCH3
OH
OH
Thymol Carvacrol Anisole
OCH3
OH O CH2
O
O CH2
O
O CH2
OH3CO H3CO
OCH3
Eugenol Safrole Myristicin Apiole
OCH3
Estragole
(Methyl chavicole)
Allyl isomers
OCH3
OCH3
OH O CH2
O
O CH2
O
O CH2
OH3CO H3CO
OCH3
Anethole Isoeugenol Isosafrole Isomyristicin Isoapiole
Propenyl isomers
Classification:
according to the number of phenolic and/or
ether groups into:
Mono-, di-, tri- and tetrahydric compounds.

5. Monohydric phenol
Thymol
Source:
In oil of Thyme family Labiatae
properties
Colorless crystals, Aromatic thyme-like odor and pungent taste
Isolated by:
1- Fractional distillation
2- Cooling to crystallize thymol
3- Extraction with 5% KOH then acidification to obtain thymol
OH
Thymol

6. OH
CH3
OH
OHH3C
CH3
CATALYST
O
Thymol
m-Cresol
Menthone
Br 2
/quinoline
reduction
O
Piperitone
FeCl3
Synthesis of Thymol

7. Color reactions:
Thymol in gl. Acetic acid + dps H2SO4 + one dp HNO31) Deep bluish green color
alc.Thymol + alc. FeCl32) No color
(because in water, 2 molecules of thymol
unite together to form non-phenol compound)
OH
Thymol
HO
- H2O
O
Thymol + NaOH4) Colorless or Pale red
on water bath
CHCl3
Violet color
in CHCl3 layer
colorimetric assay of phenols
(c.f. carvacrol which gives a green color)
Thymol in conc H2SO4 + FeCl33) Violet color
5- with phthalic anhydride yield thymol phthalein (violet red or red in color that
turns to intense blue in dilute alkali) used as indicator.

8. Identification:
Derivatization to phenylurethane and determination of the melting points
•Uses:
1- Disinfectant, antibacterial used in antiseptic mixtures applied to mucous
cavities such as gargles. Local anaesthetic in tooth ache (dental analgesic).
2- Gastro intestinal disinfectant in fermentative gastritis, enteritis etc …
•Anthelmintic in case of infestation with nematodes.
3- Preservative in food and drug industries (destroying molds).
OIIO
COOH
OH O
C
NHCH2CH
CH3
CH3
O
Dithymol diiodide Thymol-N-isoamyl-carbamateThymotic acid
Thymol iodide [Aristol®
, Iodothymol®
, Thymiode®
] for dental antisepsis as potent
anti-infective and antifungal.
Thymotic acid: Similar to salycilates, this derivative acts as potent analgesic.
Thymol- N-isoamyl-carbamate [Egressin®
]: It is used as effective anthelmintic in
case of nematode infestation.

9. Monohydric phenolic ether
Anethole ( Anise camphor )
Source: Anise, fennel, star anise oils Fam. Umbelliferae.
Isolation: by fractional distillation then crystallization at low temperature.
properties: White crystalline, Sweet taste and odor.
Anethole has to be stored in well-closed colored container away from
light why??
OCH3
light/air/heat
OCH3
CHO
OCH3
OCH3
oxidation
Anethole
Anethaldehyde
P-p’- dimethoxystilbene
(photoanethole)
yellow color
Photoanethole
Viscous , yellow liquid,
bitter taste, immiscible
with alcohol 70%
colorless, crystalline
solid,
sweet taste, soluble
in alcohol 70%

10. OCH3OCH3
+
O
H
HCl
H3PO4
Cl
Pyridine
OCH3
Anethole
Anisole propionaldehyde
Synthesis
Identification
1- Oxidation with KMNO4 to p-anisaldehyde then anisic acid that is identified by its
m.p. (184ºC).
2- Formation of a condensation product with maleic anhydride that has a specific
m.p. (310ºC).
Uses
Anise-flavored oils (anise, fennel and star anise), anethole, and semi-synthetic
products with anise-like odor are extensively used as flavoring agents in
pharmaceutical technology and beverages manufacture for example:
All kinds of food products especially confectionery, as well as alcoholic and non-
alcoholic beverages.
Pharmaceuticals and cosmetics such as dentifrices, mouth washes and gargles.

11. Anethole derivatives of pharmaceutical importance
Anethole trithione
OCH3
p-Anol
OH
o-(p-Anisoyl)benzoic
acid sodium salt
C
OCH3
S
S
S
O
COONa
1- Anethole trithione (3 p-Anisyl trithione, Heporal®
, Mucimol®
, Sulfarlem®
, Tiotrifar®
):
this compound has a very bitter taste; it occurs as orange-colored prisms and is used
as choleretic.
2- o-(p-Anisoyl) benzoic acid sodium salt: this is characterized by being soluble in
water and 150 times as sweet as cane sugar, proposed as sweetening agent.
3- p-Anol (p-propenyl phenol): this is a solid with weak clove-like odor, and is an
intermediate in synthesis of estrogens.

12. OH
OCH3
Guaiacol
H3CO O O OCH3
C
O
Guaiacol carbonate
Guaiacol
Source
Guaiacol is isolated from Guaiacum resin.
Uses
Guaiacol, together with its carbonate and phosphate
derivatives, is used as expectorant.

13. Dihydric phenols and phenolic ethers
Eugenol
• Source: Oil of clove, cinnamon.
• Properties: Yellow oil, clove odor, burning
spicy taste and Heavier than water.
• Isolation: by aq. 3-5% KOH.
• Identification:
1) Eugenol + alc. FeCl3 blue color
2) Eugenol + 3% aq. NaOH saturated with NaBr
rosettes of needles of sod. eugenate
OH
OCH3
Eugenol

14. Uses:
1- It inhibits nerve conduction and is used as a local anesthetic in toothache
remedies (dental analgesic).
2- It acts as anti-inflammatory by inhibition of prostaglandin synthesis.
3- It has also bactericidal activity.
4- As flavoring agent in pharmaceutical preparations as well as perfume,
cosmetic and soap industries.
5- As insect attractant.
6- As starting material for preparation of high-grade vanillin (by oxidation).
OH
OCH3
OH
OCH3
OAc
OCH3
CHO
OAc
OCH3
CHO
OH
OCH3
KOH HClAcetylation Oxid.
Heat
Eugenol Isoeugenol
Vanillin

15. O CH2
O
SafroleSource:

oil of sassafras (Sassafras albidum, over 80%).
Uses:
The use in foods has been banned Safrole is carcinogenic and
hepatotoxic risks.
formerly used as a pediculicide.
The use of safrole in toilet preparations is also controlled.

16. O CH2
OH3CO
O CH2
OH3CO
Myristicin
(6-methoxy safrole)
Isomyristicin
(6-methoxy isosafrole)
Trihydric phenolic ethers
Myristicin and Isomyristicin
Source: Myristicin is obtained from oils of nutmeg (Myristica fragrans, 5-12%),
mace, French parsley and dill. Isomyristicin occurs in oils of dill herb and
mace.
Isolation: Myristicin is isolated by fractional distillation from the
corresponding oils.
Properties:
Myristicin is a liquid while isomyristicin is a solid.

Myristicin is converted to isomyristicin by boiling with alcoholic KOH.

17. Identification:
Myristicin and isomyristicin can be identified by:

Preparation of bromoderivatives.

Oxidation to the corresponding acids that have specific m.p.
Uses: Nutmeg is used as a spice.

Ingestion of large quantities causes drowsiness, stupor and
death.

These psychotropic properties ?? are attributed to myristicin
that is transformed in the human body into an amphetamine
derivative.

10 mg Myristicin = 1 gm nutmeg

One grated nutmeg = one tablespoon = 6 – 7 g

typical neuropsychological doses ranging from 5 – 30 g.

moderate toxicity caused two whole nutmegs (14 gm) or 18 gm
powder

lethal dose caused by 3 whole nutmegs (21 gm) or 25-30 gm
powder or 300 mg Myristicin

18. • Source: In parsley seed oil
• Properties: Long colorless needles
with faint parsley odor
• Isolation: by cooling at low temperature
then recrystallization from alcohol
Source
oil of Indian dill fruits (Anethum
sowa up to 30 %).
Uses
Apiole was formerly official and has been used as emmenagogue but was deleted due
to its toxicity.
Both Parsley and Dill Apioles exert a synergistic effect with insecticides.
O CH2
OH3CO
OCH3
Parsley Apiole
3, methoxy myristicin
3, 6 dimethoxy safrole
O CH2
OH3CO
H3CO
Dill Apiole
5, methoxy myristicin
5, 6 dimethoxy safrole
Tetrahydric phenolic ethers

19. Properties
OCH3
O
O
H3CO
alc. KOH
BOIL
OCH3
O
O
H3CO
Apiole
Isoapiole
KMNO4
CHO
OCH3
O
O
H3CO
COOH
OCH3
O
O
H3CO
Apiolaldehyde Apiolic acid
oxidation

20. For more educational lectures
cognosy4all.blogspot.com

21. cognosy4all.blogspot.com
Pharmacognosy and Herbal Medicine Dr. Mostafa