Synthesis and antibacterial activity of carvacryl ethers

Article abstract of DOI:10.1080/10286020903455907

Structural modifications of phenolic monoterpenoid obtained by reacting carvacrol with various substituted α-chloro acetanilides, to improve biological activities which give the product with better yield and higher purity under mild reaction conditions wi

Full text of DOI:10.1080/10286020903455907

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Synthesis and antibacterial activity of
carvacryl ethers
Jagdish U. Patil a , Kamalakar C. Suryawanshi b , Prakash B. Patil c
, Sanjay R. Chaudhary d & Nilesh S. Pawar e
a U.P. College , Dahivel, Sakri, 424 314, India
b Smt. P.K. Kotecha Mahila Mahavidyalaya , Bhusawal, 425 202,
India
c R.L. College , Parola, 425 111, India
d Sri. V.S. Naik A.C.S. College , Raver, 425 508, India
e Synthetic Organic Research Laboratory, Department of
Chemistry , Pratap College , Amalner, Jalgaon, 425 401,
Maharashtra, India
Published online: 04 Feb 2010.
To cite this article: Jagdish U. Patil , Kamalakar C. Suryawanshi , Prakash B. Patil , Sanjay R.
Chaudhary & Nilesh S. Pawar (2010) Synthesis and antibacterial activity of carvacryl ethers, Journal
of Asian Natural Products Research, 12:2, 129-133, DOI: 10.1080/10286020903455907
To link to this article: http://dx.doi.org/10.1080/10286020903455907
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Journal of Asian Natural Products Research
Vol. 12, No. 2, February 2010, 129–133
ORIGINAL ARTICLE
Synthesis and antibacterial activity of carvacryl ethers
Jagdish U. Patila, Kamalakar C. Suryawanshib, Prakash B. Patilc,
Sanjay R. Chaudharyd and Nilesh S. Paware*
aU.P. College, Dahivel, Sakri 424 314, India; bSmt. P.K. Kotecha Mahila Mahavidyalaya, Bhusawal
425 202, India; cR.L. College, Parola 425 111, India; dSri. V.S. Naik A.C.S. College, Raver 425 508,
India; Synthetic Organic Research Laboratory, Department of Chemistry, Pratap College,
e
Amalner, Jalgaon 425 401, Maharashtra, India
(Received 17 August 2009; final version received 1 November 2009)
Structural modifications of phenolic monoterpenoid obtained by reacting carvacrol
with various substituted a-chloro acetanilides, to improve biological activities which
give the product with better yield and higher purity under mild reaction conditions with
the help of microwave irradiation techniques.
Keywords: carvacrol; monoterpenoids; microwave irradiation; antibacterial activity;
structure–activity relationships
1. Introduction
various substituted a-chloro acetanilides,
to improve biological activities which give
the product with better yield and higher
purity under mild reaction conditions with
the help of microwave (MW) irradiation
techniques [5,6].
Carvacrol is an important phenolic mono-
terpenoid obtained from the essential oils. It
resembles phenols in their chemical proper-
ties, but their hydroxyl groups are more
reactive [1,2]. Carvacrol is an antiseptic,
carminative, disinfectant, and escharotic;
combined, it forms an efficient gargle in
inflammatory conditions. It is not employed
internally. In dental practice, carvacrol has
been used as a substitute for creasote,
carbolic acid, and glycerole of thymol in the
treatment of odontalgia, sensitive dentine,
alveolar abscess, and as an antiseptic in the
pulp canals of teeth [3,4].
We report herein a rapid, simple, and
efficient method for the synthesis of car-
vacryl ethers needed for the study of
structure–activity relationships.
2. Results and discussion
Considering that MW irradiation using
commercial domestic oven has been used to
accelerate organic reactions, the high heating
efficiency gives remarkable rate enhance-
ment and dramatic reduction in reaction
times and better yields. It appears interesting
to introduce a substituted acetanilide moiety
into carvacrol under MW irradiation. The
synthesis of ether compounds by conden-
The pesticidal efficiency of substituted
acetanilides and carvacrol promoted us to
undertake the synthesis of the derivatives
of natural monoterpenoids. The structural
modifications of phenolic monoterpenoids
were obtained by reacting carvacrol with
*Corresponding author. Email: nileshpawar1329@rediffmail.com
ISSN 1028-6020 print/ISSN 1477-2213 online
q 2010 Taylor & Francis
DOI: 10.1080/10286020903455907
http://www.informaworld.com

130
J.U. Patil et al.
Scheme 1. Synthesis of carvacryl ethers.
sation of carvacrol (2) with various sub-
stituted a-chloro acetanilides (1a–f) (Scheme
1) under MW irradiation technique in short
time is reported (Table 1). The investigations
showed that carvacrol reacts very smoothly
with different types of substituted acetani-
lides. The yield of carvacryl ethers was found
to be moderate. In order to determine the
optimum conditions for the synthesis of ether
derivatives of carvacrol in faster and efficient
ways, the effect of variation in the molar
ratios of reagent and the irradiation time and
power level of MW setup was investigated.
After some experimentation, it was found
that setup conditions generally provide
carvacryl ethers in moderate yields. The
optimum conditions employed are as follows
: the molar ratio of a-chloro acetanilides and
carvacrol is 1:1.1 and the irradiation time (2–
3 min and 300 W power level) of MW setup
is for 30 s time intervals. The compounds
were obtained in optimum yield by MW
irradiation technique with the aim to increase
the yield. The synthesized compounds were
identified on the basis of IR, 1H NMR, MS,
and CHNS analyzer. The data of all the
synthesized compounds are given in
Section 3.
In the present work, all the synthesized
compounds are tested for their bacterial
potency against four bacterial species, viz.
Proteus vulgaris, Staphylococcus aureus,
Escherichia coli, and Bacillus subtilis
species.
3. Experimental
3.1 General experimental procedures
Various aromatic amines (aniline, p-
toluidine, m-nitro aniline, m-chloro ani-
line, m,p-dichloro aniline, and a-naphthyl
amine), chloro acetyl chloride, carvacrol,
sodium hydroxide, pyridine, and solvents
were synthetic grade commercial products
(SD Fine Chemicals, Mumbai, India and
Qualigens Ltd, Mumbai, India) and were
distilled before use.
Melting points were determined using
the open capillary method in the paraffin
liquid and are uncorrected. IR spectra
(cm21) were recorded on a Perkin-Elmer
1
RX1 FT-IR spectrophotometer. H NMR
spectra were recorded on a Bruker DRX-
300 MHzFT-NMRspectrometer(chemical
shifts in ppm). FAB-MS were recorded on
a Jeol SX 102/Da-600 mass spectrometer

Journal of Asian Natural Products Research
Table 1. MW synthesis of carvacryl ethers.
131
Reaction time
Yieldb
Conventional MW
Molecular
formula
MP
(8C)
Conventional MW
(h)
Entrya Ar
(min)
(%)
(%)
3a
3b
3c
3d
3e
3f
ZC6H5
C18H21NO2
Zp-CH3C6H4 C19H23NO2
Zm-NO2C6H4 C18H20N2O4
55–60
75
60–62
4.0
4.5
5.0
4.5
5.0
4.5
1.5
3.0
3.0
2.5
2.5
1.0
50
48
47
55
62
60
91
92
90
92
94
93
Zm-ClC6H4
Zm,p-Cl2C6H3 C18H19NO2Cl2 105
ZC10H7 C22H23NO2 107–110
C18H20NO2Cl Semi-solid
a
Notes: All products were identified using comparison of their physical and spectral data (IR, NMR, MS, and
CHNS analyzer).
bIsolated yields.
and elemental analyses were performed on
a Perkin-Elmer Series II CHNS Analyzer
2400. A Samsung (Model No. OM 9925 E)
microwave oven (2450 MHz, 800 W) was
used for all experiments. The purity of
compounds was checked by TLC.
techniques considerably reduced the reac-
tion time and improved the yield and
purity of products [9–13].
3.4 General procedure
A mixture of carvacrol (2.9 g, 0.013), 1–
2 ml of 1% solution of NaOH and
0.013 moles of a-chloro acetanilide 1a–f
solution in acetone (2 ml) was placed in an
Erlenmeyer flask. This was subjected to
MW irradiation for sufficient interval of
time using resting intervals of 1 min, and
after every 30 s of irradiation, the progress
of the reaction was monitored by TLC
(9:1). The product was extracted with
ether (2£ 20 ml) and the extract was
washed with water and dried over sodium
sulfate. Removal of the solvent afforded
carvacryl ethers, needle-shaped crystals,
which were dried and recrystallized in
ethanol to obtain a pure form of products
listed in Table 1.
3.2 Synthesis of N-chloro acetyl aryl
amines (a-chloro acetanilides)
The N-chloro acetyl aryl amines 1a–f were
synthesized and identified by comparing
their spectral data with reported values in
the literature [7,8] or their melting points.
3.3 Synthesis of carvacryl ethers using
MW method
For the synthesis of carvacryl ethers by the
conventional method, i.e. compounds 3a–f
,
practical yield was less, more time was
required, isolation procedure became diffi-
cult, and also the product obtained required
purification either by column chromatog-
raphy or by preparative TLC. Due to these
problems, we synthesized the same com-
pounds using MW irradiation technique.
MW irradiation technique has opened
new prospects in synthetic organic chem-
istry not only from the view point of high
reaction rates and ease of experimental
procedures but also due to high yields of
products, their purity and reaction selec-
tivity, and cleanliness. The use of MW
3.4.1 Compound 3a
IR nmax (cm21): 3268 (ZNH stretching),
2956–2854 (Ar-H stretching), 1598 (
sCvO stretching of amides), 1464
(ZCZO stretching), 1253–1378 (Ar-
OZCH2 stretching); 1H NMR spectral
data (CDCl3, 300 MHz): d 8.28 (1H, s,
NZH), 6.67–7.47 (8H, m, Ar-H), 4.60
(2H, s, ZOZCH2), 3.31–3.37 (1H, m,
ZCHr), 2.33 (3H, s, Ar-CH3), 1.29–1.31

132
J.U. Patil et al.
(6H, d, J ¼ 6.6 Hz, 2-CH3 gem). Elemen-
tal analysis: C, 76.29%, H, 7.47%, N,
4.94%; calcd for C18H21NO2: C, 75.99%,
H, 7.41%, N, 4.91%.
J ¼ 6.9 Hz, 2-CH3 gem); ESI-MS: m/z
317.5 [M]þ, 318, 289, 177, 149, 136, 121,
105, 95. Elemental analysis: C, 68.03%, H,
6.34%, N, 4.41%; calcd for C18H20NO2Cl:
C, 67.94%, H, 6.25%, N, 4.19%.
3.4.2 Compound 3b
IR nmax (cm-1): 3400 (NH stretching),
2854 (Ar-H stretching), 1708 (sCvO
stretching of amides), 1463 (ZCZO
stretching), 1255–1378 (Ar-OZCH2
stretching); 1H NMR spectral data
(CDCl3, 300 MHz): d 8.30 (1H, s, NZH),
6.66–7.47 (7H, m, Ar-H), 4.61 (2H, s,
ZOZCH2), 2.85–2.91 (1H, m, ZCHr),
2.32–2.33 (3H, s, Ar-CH3), 1.22–1.24
(6H, d, J ¼ 6.6 Hz, 2-CH3 gem). ESI-MS:
m/z 297 [M]þ, 298, 297, 284, 283, 256,
253, 179, 163, 149, 133. Elemental
analysis: C, 76.73%, H, 7.80%, N,
4.71%; calcd for C19H23NO2: C, 76.62%,
H, 7.71%, N, 4.67%.
3.4.5 Compound 3e
IR nmax (cm21): 3264 (ZNH stretching),
2854 (Ar-H stretching), 1748 (sCvO
stretching of amides), 1462 (ZCZO
stretching), 1291–1378 (Ar-OZCH2
stretching), 868–812 (ZCl group); 1H
NMR spectral data (CDCl3, 300 MHz): d
8.34 (1H, s, NZH), 6.49–7.84 (6H, m, Ar-
H), 4.65 (2H, s, ZOZCH2), 3.28–3.71
(1H, m, ZCHr), 2.33 (3H, s, Ar-CH3),
1.29–1.31 (6H, d, J ¼ 6.9 Hz, 2-CH3
gem); ESI-MS: m/z 352 [M2H]2, 351,
336, 310, 298, 289, 273, 190, 174, 163,
149, 133. Elemental analysis: C, 61.37%,
H, 5.44%, N, 3.98%; calcd for C18H19
NO2Cl2: C, 62.21%, H, 5.35%, N, 3.77%.
3.4.3 Compound 3c
3.4.6 Compound 3f
IR nmax (cm-1): 3366 (ZNH stretching),
2854 (Ar-H stretching), 1594 (sCvO
stretching of amides), 1464 (ZCZO
stretching), 1253–1378 (Ar-OZCH2
stretching), 1523 (ZNO2 group); 1H
NMR spectral data (CDCl3, 300 MHz): d
8.00 (1H, s, NZH), 6.66–7.98 (7H, m, Ar-
H), 4.66 (2H, s, ZOZCH2), 2.79–2.92
(1H, m, ZCHr), 2.34 (3H, s, Ar-CH3),
1.22–1.25 (6H, d, J ¼ 6.9 Hz, 2-CH3 gem).
Elemental analysis: C, 65.84%, H, 6.14%,
N, 8.53%; calcd for C18H20N2O4: C,
65.72%, H, 5.95%, N, 8.24%.
IR nmax (cm21): 3420 (ZNH stretching),
2854 (Ar-H stretching), 1696 (sCvO
stretchingofamides), 1463(ZCZO stretch-
ing), 1377–1246 (Ar-OZCH2 stretching);
1H NMR spectral data (CDCl3, 300 MHz): d
8.87 (1H, s, NZH), 6.77–8.18 (10H, m, Ar-
H), 4.77 (2H, s, ZOZCH2), 3.46–3.52 (1H,
m, ZCHr), 2.35 (3H, s, Ar-CH3), 1.25–
1.35 (6H, d, J ¼ 6.6 Hz, 2-CH3 gem).
Elemental analysis: C, 79.25%, H, 6.95%,
N, 4.20%; calcd for C22H23NO2: C, 78.98%,
H, 6.77%, N, 4.03%.
Thus, neat reactants subjected to MW
irradiation gave the required products
more quickly and with better yield in
comparison to the traditional method-
ologies [14].
3.4.4 Compound 3d
IR nmax (cm-1): 3411 (ZNH stretching),
2854 (Ar-H stretching), 1595 (sCvO
stretching of amides), 1254–1378 (Ar-
OZCH2 stretching), 1459–1523 (multiple
1
3.5 Antibacterial activity
bond ZCH stretching); H NMR spectral
data (CDCl3, 300 MHz): d 8.12 (1H, s,
NZH), 6.68–7.88 (7H, m, Ar-H), 4.62 (2H,
s, ZOZCH2), 2.78–2.90 (1H, m, ZCHr),
2.33 (3H, s, Ar-CH3), 1.22–1.25 (6H, d,
In the present work, all the synthesized
compounds are tested for their bacterial
potency against different bacteria species
(B. subtilis, E. coli, P. vulgaris, and

Journal of Asian Natural Products Research
Table 2. Antibacterial activities of compounds 1a–f and 3a–f
133
.
Zone of inhibition in mm at a concentration of 20 mg ml21
Compounds
P. vulgaris
S. aureus
E. coli
B. subtilis
Aniline
1a
1b
1c
1d
1e
–
25
25
28
–
20
34
23
–
–
–
–
17
20
–
–
10
–
07
–
–
–
–
–
–
05
–
–
–
25
18
12
13
25
20
20
13
08
–
07
09
14
18
14
–
07
–
–
1f
Carvacrol
3a
3b
3c
3d
3e
3f
–
–
16
10
07
21
18
06
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S. aureus). The results are summarized in
Table 2. It was assumed to synthesize
various derivatives of the natural mono-
terpenoid and compare the respective
bioactivities with their parent compound;
carvacrol, to initiate structure–activity
relationships; to consider the mode of action
of these compounds. Such a structural
bioactivity relationship data will be ben-
eficial in the field of pest management for
designing the active molecules.
[8] S.R. Pattan, M.S. Ali, J.S. Pattan, S.S.
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Acknowledgements
This paper is dedicated to Prof. P.P. Mahulikar,
Head, Department of Industrial Chemistry,
School of Chemical Sciences, North Mahar-
ashtra University, Jalgaon, Maharashtra, India.
Also, we are very thankful to SAIF, CDRI,
Lucknow, India, for providing necessary
valuable data of all the synthesized compounds.
[11] R.S. Varma, Green Chem. 1, 43 (1999).
[12] R.S. Varma, Tetrahedron 58, 1235
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