An efficient method on nitration of eugenol using NH4NO3 and KHSO4

Article abstract of DOI:10.14233/ajchem.2014.15367

The main objective of this research was to find new method for the synthesis of nitro-eugenol. Nitro-eugenol is of considerable importance in the production of other fine chemicals such as amino-eugenol for further chemical synthesis and has also been reported to possess antibacterial, antioxidant and anticancer properties. In an attempt to synthesize nitro-eugenol in high yield, some different nitration methods of eugenol have been applied. An efficient method using NH₄NO3 in the presence of KHSO₄ as a catalyst has been found to give nitro-eugenol in good yield.

Full text of DOI:10.14233/ajchem.2014.15367

Asian Journal of Chemistry; Vol. 26, No. 1 (2014), 173-175
http://dx.doi.org/10.14233/ajchem.2014.15367
An Efficient Method on Nitration of Eugenol Using NH4NO3 and KHSO4
1,*
1
1
1
2
I.M. SUDARMA , N. WAZNI , N. WILDAWATY , E. YUANITA and I.W. SUANA
1Department of Chemistry, University of Mataram, Jl. Majapahit 62 Mataram 83125, Indonesia
2Department of Biology, University of Mataram, Jl. Majapahit 62 Mataram 83125, Indonesia
*Corresponding author: Tel/Fax: +62 370 646506; E-mail: sud_arma@yahoo.co.id
Received: 26 February 2013;
Accepted: 20 June 2013;
Published online: 26 December 2013;
AJC-14497
The main objective of this research was to find new method for the synthesis of nitro-eugenol. Nitro-eugenol is of considerable importance
in the production of other fine chemicals such as amino-eugenol for further chemical synthesis and has also been reported to possess
antibacterial, antioxidant and anticancer properties. In an attempt to synthesize nitro-eugenol in high yield, some different nitration
methods of eugenol have been applied. An efficient method using NH4NO3 in the presence of KHSO4 as a catalyst has been found to give
nitro-eugenol in good yield.
Keywords: Nitration, Eugenol, Nitro-eugenol, NH4NO3, KHSO4.
of nitro-eugenol synthesis. Thus, a convenient method for the
regioselective synthesis of nitro-eugenol is desirable. Eugenol
has been investigated and reported for further chemical trans-
formation8 -11 and chemical transformation methods of this
compound to nitro-eugenol (2) derivative was investigated.
Herein, we report our results on the regiospecific nitration of
eugenol using several reagents and solvents (Scheme-I).
INTRODUCTION
Eugenol (4-allyl-2-methoxyphenol) (1), a main constituent
of the essential oil obtained from commonly consumed spices
such as Syzygium aromaticum (clove). has been used for anti-
bacterial1, acaricidal2, antihelicobacter3 and antiproliferative4.
It is used in the form of a paste or mixture as dental cement,
filler and restorative material. Plant oils, including clove, may
be used in livestock to inhibit microbial fermentation in waste
products. Clove oil may be found in high concentration licorice
(glycyrrhizin) products to prevent gel formation in an aqueous
solution5.
2 (55.4%)
NO2
HO
b
MeO
2 (35.0%)
HO
d
a
2 (86%)
Eugenol is considered as a phenolic compound which
undergo electrophilic aromatic substitution reactions through
nitration. Nitration of organic compounds has long been a very
active and rewarding area of research and is the subject of a
large body of literature or methods. Nitration is the most
important method for introduction of nitrogen functionality
on aromatic ring. The nitration of aromatic compounds may
be achieved with many nitrating reagents and is a very useful
method in organic synthesis and also, nitro compounds find
use in many industrial applications6. Nitro compounds can be
reduced easily to the corresponding amino derivatives.
Eugenol is an aromatic compound similar to benzene with
three substituents (hydroxy, methoxy and allyl). These substi-
tuents lead the regioselectivity for further reaction of eugenol.
The regioselectivity is governed by steric hindrance, interaction
between the substituent and the reagent, electronic effects and
solvent effects7. Those effects will give low to moderate yields
+
MeO
O
CH3
1
O
c
MeO
NO2
3 (48.2%)
HO
HO
2 (63.2%)
+
4 (2.9%)
Scheme-I: Synthesis methods of nitro-eugenol (2). Conditions: (a) HNO3/
CH3COOH, rt. 1 h, refluxed 20 min, (b) HNO3/dilute H2SO4,
heated 55 ºC, 20 min, (c) NaNO3/KHSO4SiO2/H2O (1:1)
CH2Cl2 rt. 5.5 h, (d) NH4NO3/KHSO4, CH3CN, rt. 0.5 h,
refluxed 5 h
Our objective in undertaking this work was to overcome
the limitation and draw-back of the reported methods, to reach
good or high yielding one pot synthesis of nitro-eugenol using

174 Sudarma et al.
Asian J. Chem.
a combination of reagents and solvents, to consider the rules
of green chemistry to implement nitration in ecofriendly
conditions.
131, 119, 103, 91 (base peak). IR (KBr, νmax, cm-1, film): 3232
(O-H), 3084 (C=CH-Ar), 3014 (CH=CH2), 2936, 2829, 1634
(C=C), 1547 (NO2), 1399, 1327, 1260 (C-O), 1127 (C-O),
1
1066, 999, 912, 764. H NMR (400.1 MHz, CDCl3): δ 3.35
EXPERIMENTAL
(2H, d, J = 6.6 Hz, H1'); 3.93 (3H, s, OCH3); 5.13 (2H, m,
H3'); 5.91 (1H, m, H2'); 6.96 (1H, s, H3); 7.50 (1H, d, J = 0.9
Hz, H5); 10.67 (1H, s, OH). 13C NMR (100.6 MHz, CDCl3): δ
39.4 (C1’); 56.7 (OCH3); 115.1 (C5); 117.1 (C3’); 118.6 (C3);
131.2 (C4); 133.6 (C6); 135.9 (C2’); 144.9 (C1); 149.8 (C2).
Compound (3) (oil): M+. 206, calcd. (%) for C12H14O3. Major
fragments: 164 (M+. -COCH3) (base peak), 149, 147, 131, 119,
103, 91. 1H NMR (400.1 MHz, CDCl3): δ 2.31 (3H, s, CH3CO2-
); 3.38 (2H, d, J = 6.7 Hz, H1’); 3.82 (3H, s, OCH3); 5.10 (2H,
m, H3’); 5.97 (1H, m, H2’); 6.77 (2H, m, H3 and H5); 6.95
(1H, d, J = 7.9 Hz, H6).
Unless otherwise stated, all chemical reagents were pur-
chased with the highest commercially available purity (Merck
and Sigma) and were used without previous purification. The
material used included: clove, dichloromethane, hexane,
nitric acid, glacial acetic acid, sulfuric acid, sodium nitrite,
potassium sulphate, silica gel, ammonium nitrite, acetonitrile,
sodium hydroxide, methanol, anhydrous sodium carbonate
analytical thin layer chromatography.
GC-MS were recorded on GC-MS QP-5050A, BC-17A
and MS 5050A Merk Shimadzu. GC Parameters were setup
as follows, oven temp (ºC) = 60.0, oven equil. time (min) =
0.50; injection temp. (ºC) = 280.0; interface temp (ºC) = 300.0;
column length (m) = 30; column diameter (mm) = 0.25; column
pressure (kPa) = 100; column flow (mL/min) = 1.6; linear
velocity = 46.4; split ratio = 22; total flow (mL/min) = 40.2;
program time (min) = 27.00. MS parameter, start M/Z = 33.00
end M/Z = 550.00; scan interval (s) = 0.50; scan speed (amu/s)
= 1000.
Method (b): Nitration of eugenol using HNO3/dilute
H2SO4: A 50 mL round bottomed flask with magnetic stirrer
was charged with H2SO4 0.01 M (5 mL) and eugenol 0.5 g
(3.05 mmol) then stirred for 5 min (solution A). 70 % HNO3
(10 mL) was mixed with H2SO4 0.01 M (10 mL) (solution B).
(solution B) was added slowly to the (solution A) and stirred
at room temperature for 1 h then refluxed for 20 min. Worked
up as method b to afford yellowish oil (0.72 g). Purified by
chromatography column gave the desired compound (2) (0.353
g, 55.4 %).
The original H NMR, 13C NMR and DEPT spectra are
1
directly reproduced throughout. The were generally recorded
in CDCl3 on a Bruker spectrometer at 400 MHz.
Method (c): Nitration of eugenol using NaNO3/KHSO4:
Eugenol (1.0 g, 6.10 mmol) was dissolved in dichloromethane
(25 mL) and was added to a mixture which contained 4.5 g
(33 mmol) of potassium hydrogen sulphate, 3 g (35.3 mmol)
of sodium nitrate and 3.5 g of wet silica to 50 % P/P; the
mixture was left with constant stirring at room temperature
for 4 h. The complete disappearance of the starting product
was confirmed by thin layer chromatography (TLC)
(dichloromethane: n-hexane 1:3). The reacted mixture was
filtered through silica and the solid was washed with dichloro-
methane and the solvent evaporated in vacuum to give a reddish
oil. Pure product was obtained after chromatographic column
(5:1-3:1 dichloromethane in hexane), which gave of the desired
compound (2) (956 mg, 75 % yield). Carrasco et al., reported
(Scheme-I), their method produced compund (2) (63.2 %)
and compound (4) (2.9 %).
Procedure
Extraction and GC-MS analysis: Dried leaves of
Syzygium aromaticum (250 g) was grounded to fine particles
and percolated with dichloromethane (500 mL) and kept for
24 h and then the liquid extract was filtered and evaporated to
afford yellowish oil (20.02 g, 8 %). This oil was analyzed by
GC-MS and 1H NMR to confirm the presence of eugenol.
Isolation of eugenol: Eugenol was obtained from the
clove oil leaves, according to standard procedure12 and identi-
fied by GC-MS and NMR analyses. M+. 164, calcd. (%) for
C10H12O2 major fragments: 49 (M+. -CH3), 131, 121, 103, 91,
77 (C6H6, base peak). 1H NMR (400.1 MHz, CDCl3): δ 3.35
(2H, d, J = 6.6 Hz, H1'); 3.93 (3H, s, OCH3); 5.13 (2H, m,
H3'); 5.50 (1H, s, OH); 5.91 (1H, m, H2'); 6.5 - 6.96 (3H,
aromatic protons).
Method (d): Nitration of eugenol using NH4NO3/
KHSO4:A round bottomed flask (50 mL) with magnetic stirrer
was charged 1.00 g eugenol (6.10 mmol) and acetonitrile (20
mL) then stirred for 5 min. Potassium hydrogen sulphate (0.64
g) and ammonium nitrate (1.4 g) were added and stirred at
room temperature for 0.5 h then refluxed for 5 h. Worked up
as method Bita Baghernejad et al.13 to afford yellowish to redish
oil (1.1 g, pure by tlc analysis).
Method (a): Nitration of eugenol using HNO3/
CH3COOH: A 50 mL round bottomed flask with magnetic
stirrer was charged with 70 % nitric acid (10 mL) and glacial
acetic acid (10 mL) then stirred for 5 min. Eugenol 0.5 g (3.05
mmol) was dissolved in glacial acetic acid (5 mL) and added
slowly to the solution of nitric acid and acetic acid and stirred
at room temperature for 1 h and then refluxed for 20 min.
Water (50 mL) was added and the mixture stirred strongly
until all organic material had precipitated. The mixture was
then filtered to afford a yellow residue. The residue dissolved
with dichloromethane and water (50 mL) was added then the
organic layer filtered and dried with anhydrous sodium
carbonate. Dichloromethane was evaporated to give 0.65 g
yellowish oil. After chromatography column gave the desired
compound (2) (0.22 g, 35.0 %) and compound (3) (0,30 g,
48.2 %). Compound (2) (oil): M+. 209, calcd. (%) for
C10H11NO4 major fragments: 195 (M+. -CH2), 178, 163, 147,
RESULTS AND DISCUSSION
Eugenol is an aromatic compound which has similar prop-
erties to benzene. Nitration of benzene derivatives with electron
donating substituent such as phenol leads to substitution at
the o- and p-positions according to a statistical distribution.
Simple phenol undergo electrophilic aromatic substitution
reactions by nitration and an ortho nitro group onto phenols is
desirable (Scheme-II)12.

Vol. 26, No. 1 (2014)
An Efficient Method on Nitration of Eugenol Using NH4NO3 and KHSO4 175
TABLE-1
NITRATION OF EUGENOL WITH DIFFERENT METHODS
Conditions
No.
1
Method
Nitro-eugenol yield (%)
a
b
c
d
HNO3/CH3COOH, rt. 1 h, refluxed 20 min
HNO3/dilute H2SO4, heated 55 ºC, 20 min
NaNO3/KHSO4 SiO2/H2O (1:1) CH2Cl2 rt. 5.5 h
NH4NO3/KHSO4, CH3CN, rt. 0.5 h, refluxed 5 h
35.0
55.4
2
3
63.5 -75.0
86.0
4
OH
OH
acidic salt can act as a solid HNO3 equivalent and wet SiO2
acts as a reaction medium providing a heterogeneous effective
surface area for in situ generation of HNO3 in low concentrations6.
Among the solvents used such as acetic acid (method a),
CH2Cl2 (method c) and CH3CN (method d), the latter gave the
best yields of the nitro-eugenol at reflux temperature. The
replacement of NaNO3 in method (c) with NH4NO3 in method
(d) also gave significance yield. The low cost and the avail-
ability of the reagents, easy and clean work-up and high yield
make method d attractive for nitro-eugenol synthesis.
OH
OH
NO2
NO2
NH4NO3/KHSO4
CH3CN, rt
+
+
75%
NO2
NO2
5%
20%
Scheme-II: Nitration of simple phenol
Structurally eugenol is similar to phenol but its has two
more substituents (methoxy and allyl) will give effect for
further substitution reaction. Preliminary studied showed that
nitration of eugenol with method (a) gave very low yield.
Competitive reaction occurred when CH3COOH used as a
catalyst due to the formation of ester by CH3COOH with
phenolic group of eugenol. Based on this reason, new diffe-
rent methods have to be develop to afford high yields of nitro-
eugenol (Table-1).
Conclusion
Method (d) using green, available, inexpensive and easy
to handle NH4NO3/KHSO4 reagent was believed to be a suitable
method for the synthesis of nitro eugenol.
ACKNOWLEDGEMENTS
Concentrated nitric acid can effect nitration but it is not
as reactive as a mixture of nitric acid with sulfuric acid. Method
(b) used dilute sulfuric acid as catalyst is desirable to over-
come the competitive reaction of CH3COOH in method (a)
but it was still to give low yield.
The authors thank Directorate General Higher Education
(DIKTI), Indonesian Education and Culture Department
through Hibah Unggulan Perguruan Tinggi for financial support.
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high yielding nitration with a more reasonable mechanism for
generation of NO2+. Nitration can also be carried out in organic
solvents. In these solvents the formation of NO2+ is often the
rate controlling step.
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