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Antioxidants - A way of life
ANTIOXIDANTS Directory www.b5srl.com JANUARY/FEBRUARY 2004 58 NutraCos
Sudarshan Chemical
Industries Ltd.
162, Wellesley Road,
Pune 411001, India,
MAHENDRA P. SINGH
BHANU R. HIRANI
VEERINDER K. KOUL
ANTIOXIDANTS USED IN INDUSTRY
Antioxidants are used to retard the reaction of organic materials with atmospheric oxygen. Such reactions can cause degradation of
mechanical, aesthetic and electrical properties of polymers, loss of flavor and development of rancidity in foods, increase in viscosity,
acidity and formation of insolubles in lubricants.
Hydrogen donating antioxidants such as sterically
hindered phenols and secondary aromatic amines are
excellent free radical scavengers. Mechanism of action of
sterically hindered phenol as free radical scavengers is
given in Figure 1.
Lots of work have been carried out in the past to study
the effect of substitution on the phenolic ring. Hindered
phenolic ring with at least one bulky alkyl group in the
ortho position appears necessary for high antioxidant
activity (1-3). Steric hindrance decreases the ability of a
phenoxy radical (A
.
) to abstract a hydrogen atom from the
substrate and thus produces an alkyl radical (4) which is
capable of initiating oxidation.
A

+ RH !AH + R

Strong -ve inductive effect such as cyano or carboxy on

aromatic ring decreases the ability of phenol to donate its
hydrogen atom to a peroxy radical of the substrate and
therefore, reduces its antioxidant properties.
Some of the major commercially important phenolic
antioxidants used in the industry are shown in Figure 2.
Sterically hindered amines are extremely effective for
protection of polyolefins and other polymeric materials
against photodegradation. They are derived from
2,2,6,6-tetramethylpiperidine (XII). These
stabilizers act as light-stable antioxidants
through the mechanism shown in
Scheme 1 to protect polymers from air
oxidation in presence of sun light (5).
Antioxidants derived from
p-phenylenediamine and diphenylamine
are highly effective peroxy radical scavengers. As a matter
of fact, they are more effective than phenolic antioxidants
for unsaturated polymers. They act as an antioxidant as
well as antiozonants. Some of the important commercial
antioxidants based on such aromatic amines are shown in Figure 3.
Trivalent phosphorus compounds, as antioxidants, are used most frequently in combination with sterically hindered phenols for
broad range of applications in rubbers and plastics (6). They have added advantage over phenolic and secondary aromatic amine
antioxidants as they do not develop color oxidation products and are able to suppress color development caused by oxidation of
substrate and phenolic antioxidants. Some of the important commercial antioxidants of this class are shown in Figure 4.
Food additives which are covered under FDA have stringent parameters and hence only few known antioxidants are being
used such as citric acid, vitamin E, butylated hydroxyl toluene (BHT, XVIII), n-propyl gallate (XIX) and butylated hydroxyl
anisole (XX) (Figure 5).
Gasoline and jet engine fuels contain unsaturated molecules, which get oxidized on storage to form undesired products over a
period of time. 2,4-dimethyl-6-tert-butylphenol, 2,6-di-tert-butyl-p-cresol (I) and related substituted hindered phenols are, therefore,
used as antioxidants in fuel and lubricants in the concentration of about 5-10 ppm.
Polyolefin polymers are subjected to high temperature conditions about 300C during injection molding. Therefore, antioxidants are
being used to protect such materials against degradation during processing and, thereby, maintaining desired viscosity of the material.
A phosphite such as tris (2,4-di-tert-butylphenyl) phosphite (XV) or bis (2,4-di-tertbutylphenyl) pentaerythritol diphosphite in
combination with a phenolic antioxidant such as octadecyl 3,5-di-tert-butyl-4-hydroxy-
hydrocinnamate (IX) are, therefore, used as antioxidants for polyolefin polymers in the
concentration range of 0.01 to 0.5% depending upon type of polymers used and the severity of
the processing conditions.
Nonstaining antioxidants such as butylated hydroxy toluene (XVIII), 2,4-bis
(octylthiomethyl)-6-methylphenol, 4,4'-bis(","-dimethylbenzyl) diphenylamine or phosphite
such as tris (nonylphenyl) phosphite may be used in the concentration of 0.01% to 0.5% to protect
oxidation of polyunsaturated elastomers. Similarly, staining antioxidant such as N-isopropyl-
N-phenyl-p-phenylenediamine is preferred antioxidant for tyres. Amine antioxidants having
antiozonant activities are also being used up to 3% prior to vulcanization of rubbers.
Figure 1 Chemical reaction of 2,6-di-tert-butyl-p-cresol in an oxidizing medium
Scheme 1
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59 NutraCos www.b5srl.com ANTIOXIDANTS Directory JANUARY/FEBRUARY 2004
ANTIOXIDANTS USED IN LIVING BEINGS
Antioxidant defuses free radicals which are
highly reactive intermediates generated from
various oxidation reactions. Free radicals damage
our cells resulting in premature aging, reduced
immune function, inflammation and ultimately
degenerative diseases set in. Over 85 diseases such
as heart diseases, cancer, arthritis, cataracts and
emphysema etc. have been linked to the formation
of free radicals in the body.
Our body has powerful antioxidants such as
superoxide dismutase, catalase and glutathione
peroxidase which protect our body from hazardous
oxidation reactions. There are various naturally
occurring antioxidants available such as Vitamin E,
Vitamin C, #-Carotene, Folic acid etc., which help
body to protect from various diseases caused by the
formation of free radicals in the system. The most
important free radicals present in the body are radical
derivatives of oxygen. These include oxygen in its triplet state
(3O
2
) or singlet state (1O
2
), superoxide radical anion (O
2
$
),
hydroxyl radical (HO

), Nitric oxide peroxynitrite (ONOO

).
Oligomeric proamtocyanidins (OPC), occurring in most
living beings, are highly active antioxidants and free radical
scavengers. OPCs are chemically classified as flavanols and are
present in red wine, flowers, leaves, fruits, berries, nuts,
sorghum, beans, etc. Seeds of grapes are most feasible
commercial source of OPC. OPCs are 50 times more potent
than vitamin E and 20 times more than vitamin C. OPCs are
major protectors of collagen, the basic foundation of our blood
vessels and all connective tissues such as skin ligaments
around joints and tendons.
Melatonin (XXI), a naturally occurring antioxidant present
in our body, was found to be a potent free radical scavenger in
the year 1993. Melatonin scavenges a variety of reactive
oxygen and nitrogen species including hydroxyl radicals,
hydrogen peroxide, and singlet oxygen nitric oxide and peroxynitrite ion
(7). Melatonin participates in several immunological functions.
It promotes sleep, inhibits cancer cell growth and acts as anti-aging
chemical. Melatonin may prolong the animal life span upto 27% (8)
and protects neurons against damage which is induced by variety
of oxidative stresses (9). Based on QSAR study, the indole moiety
of the melatonin molecule (XXI) is the reactive centre of interaction with
oxidants due to its high resonance stability and very low activities
on energy barrier towards the free radical reactions. It is shown that
ethoxy and amide side chains of the molecule also contribute significantly to melatonins antioxidant property.
Lots of work have been carried out on Melatonin and its derivatives. Recent studies showed that methoxy group substituted at 6
position of indole ring of Melatonin (XXII) acts as better free
radical scavenger than Melatonin (XXI) (Figure 6) because of
increase in intensity of electron cloud on the indole ring.
Substitution on 6 position also helps in blocking of metabolic
action of sterol specific enzyme in the liver and thus degradation
rate of the compound (XXII) is decreased. Hence, biological half-
life of compound (XXII) is increased significantly as compared to
Melatonin (XXI) molecule. It also reduces binding affinity to the
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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ANTIOXIDANTS Directory JANUARY/FEBRUARY 2004 60 NutraCos
membrane Melatonin receptors and, thereby,
reducing side effect of the molecule (XXII) (10).
Similarly, Thiazolidinecarboxylic acid (TCA)
(XXIII) and N-Acetyl Thiazolidine carboxylic acid
(ATCA) (XXIV) have also been commercially
exploited as good antioxidants and plant growth
regulators. It has also been shown that they also act
as anti cancer due to their free radical scavenging
properties.
SYNTHESIS OF ANTIOXIDANTS
Various well known commercial synthetic methods
are available in literature to synthesize Vitamin E,
Vitamin C, #-Carotene, Folic acid and other
antioxidants mentioned in the article. However,
special emphasis is made on the synthesis of
Melatonin, TCA and ATCA which are being recently
used as antioxidants worldover.
Melatonin
Melatonin is synthesized by reacting
potassiumphthalimide, dibromopropane and ethyl
acetoacetate to form ethyl-2-acetyl-phthalimido-
pentanoate which, in turn, is further reacted with
diazo-p-anisidine to form 2-carboxyethyl-
3-(2-phtalimidoethyl)-5-methoxyindole.
Product thus formed, on hydrolysis gives 5-methoxy-
tryptamine (11). Acetylation of 5-methoxytryptamine produces
Melatonin (XXI) (Scheme 2).
Similarly, Melatonin derivative (XXII) has been recently
synthesized (Scheme 3) by using Mannich reaction with
5,6-dimethoxy indole followed by reaction with DMF/NaCl
and methyl iodide to form 5,6-dimethoxy-3-indoleacetonitrile
which is further reacted with aluminium hydride to form
5,6-dimethoxytryptamine (11). Acetylation of 5,6-dimethoxy-
tryptamine produces melatonin derivative (XXII).
Thiazolidine Carboxylic Acid (TCA) is being synthesized by
reacting formaldehyde with L-Cysteine. TCA thus obtained, is
further acetylated with acetic anhydride to form N-Acetyl
Thiazolidinecarboxylic acid. (N-ATCA) (Scheme 4).
CONCLUSION
Antioxidants are gaining importance in our daily life day by
day due to free radical generation in abundance. Therefore,
organic chemists and biologists are being faced lot of
challenges to safe guard global interest by developing
relatively new cheap commercial antioxidants having better
activity with longer retention time.
Table I Classification of major antioxidants
Scheme 2
Scheme 3 Synthesis of melatonin derivative
Scheme 4 Synthesis of TCA and N-ATCA
REFERENCES
1) Development in Polymer Stabilization; Pospisilin, J.P.; Scott, E. Eds.;
Applied Science Publishers Ltd.: London, 1979, Vol.1, p.6
2) NIXON, A.C.; MINOR, H.B.; CALHOUM, G.M. Ind. Eng. Chem. 1956, 48,1874
3) ROSENWALD, R.H.; et al. Ind. Eng. Chem. 1950, 41, 162
4) SCOTT, G. Atmospheric Oxidation and Oxidants; Elsevier:
Amsterdam,The Netherlands, 1965, p.109
5) KLEMCHUK, P.P.; GANDE, M.E. Makromol. Chem. Macromol. Symp. 1989,
28, 117-144
6) DEXTER, SPIVACK AND STEINBERG; USP 3,644,482 (1969)
7) TAN, D.-X.; REITER, R.J.; et al.; Current Topics in Medicinal Chemistry
2002, 2 (2), 181-197
8) PIERPAOLI, W.; REGELSON, W. Proc. Natl. Acad.Sci. USA 1994, 91, 787
9) REITER, R.J. Prog. Neurobiol. 1998, 56, 359 (1998)
10) TAN et al.; USP 6,114,373 (2000)
11) FRASCHINI et al.; USP 5,122,535 (1992)