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Saurashtra University
Re – Accredited Grade ‘B’ by NAAC
(CGPA 2.93)
Vekariya, Nayan J., 2009, “Studies of some Bioactive Heterocyclic Entities”,
thesis PhD, Saurashtra University
http://etheses.saurashtrauniversity.edu/id/eprint/480
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STUDIES OF SOME BIOACTIVE
HETEROCYCLIC ENTITIES
A THESIS
SUBMITTED TO THE
SAURASHTRA UNIVERSITY
FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
IN
THE FACULTY OF SCIENCE (CHEMISTRY)
BY
NAYAN J. VEKARIYA
UNDER THE GUIDANCE
OF
Dr. SHIPRA BALUJA
Department of Chemistry
(DST-FIST funded & UGC-SAP sponsored)
Saurashtra University
Rajkot- 360 005
Gujarat - (INDIA)
December -2009
Gram: UNIVERSITY Phone: +91-281-2578512
Fax: +91-281-2576802
SAURASHTRA UNIVERSITY
University Road
Rajkot – 360 005.
Dr. Shipra Baluja Residence:
M.Sc., Ph.D. 20A/2, Saurashtra University
Associate Professor Karmachari society,
Department of Chemistry University Road,
Saurashtra University Rajkot - 360 005.
Rajkot – 360 005. GUJARAT (INDIA)
No.
Statement under O.Ph.D. 7 of Saurashtra University
The work included in the thesis is my own work under the supervision
of Dr. Shipra Baluja and leads to some contribution in chemistry subsidized
by a number of references.
Date: -12-2009
Place: Rajkot (Nayan J. Vekariya)
This is to certify that the present work submitted for the Ph.D. Degree
of Saurashtra University by Nayan J. Vekariya is his own work and leads to
advancement in the knowledge of chemistry.
The thesis has been prepared under my supervision.
Date: -12-2009
Place: Rajkot. Dr. Shipra Baluja
Associate Professor
Department of Chemistry
Saurashtra University
Rajkot – 360 005.
ACKNOWLEDGEMENT
I wish to make devote supplication to THE ALMIGHTY LORD
KRISHNA for his benediction, but for his inspiration this task would not have
been accomplished.
I feel great pleasure in expressing my deep and profound sense of gratitude to
my research guide Dr. Shipra Baluja Associate Professor, Department of Chemistry,
Saurashtra University for bringing me up to this stage of my career. It could hardly
have become possible for me to venture in the domain of research without her
continuous guidance, encouragement, motivative attitude, punctuality, and parental
care. I feel honored and consider my self very lucky to work under her tutelage. She
has been a guiding light to me during my research work will always remains so.
I wish to thanks to all the faculty members of this department. My sincere
thanks are due to Prof. P. H. Parsania Head of the Department for providing me
necessary facilities. I also thanks to all laboratory staff and administrative staff of
this department for their timely help.
I wish to express my gratitude to Dr. N. R. Sheth Professor & Head,
Department of Pharmaceutical science, Saurashtra University, Rajkot, for help in
conducting biological activities.
I owe my special thanks to Dr. K. P. Vaishnani, Dr. P. K. Kasundra, Dr. J.
C. Javiya, Dr. Nikunj Kachhadia, Dr.N. K. Godvani, Dr. A. A. Kulshreshtha for
their selfless help, moral support and guidance during hours of need. I would never
forget the company I had from my colleagues and friends Mehul, Jagdish, Ashish,
Rahul and Ravi.
I am very much thankful to Mepal Vivek for help me with instrumentation;
Zydus Research center, Ahmedabad, for NMR spectral analysis.
I am extremely thankful to my research colleagues and friends Gheta, Kapil
Dubal, Chirag, Rakesh, Savant, Dodo, Kaushik, and Dhol, for their support.
I wish to express my gratitude to my special Friends jignesh Gondaliya,
Vipul Radadiya, Mayur Radadiya, Mukesh Bhoghara, Nitin Vaghasiya,
Ghanshyam Vaghasiya.
I feel a deep sense of gratitude to my parents and beloved sister for their
untiring cooperation, which I received in the form of love, everlasting inspiration
and moral support during the period of my study, which was instrumental for the
successful completion of the work. I would like to share this moment of happiness
with my love “Geeta” .They rendered me enormous support during the whole tenure
of my research.
And finally, still there are many more Well Wishers, Friends, Relatives, who
directly and indirectly rendered me valuable help and moral strength to complete this
academic endeavor. I have deep reverence for all of them.
(Nayan J. Vekariya)
CONTENTS
Page. No.
SYNOPSIS i-viii
CHAPTER-1 GENERAL INTRODUCTION 1-4
CHAPTER-2 SYNTHESIS AND CHARACTERIZATION
SECTION-I SYNTHESIS OF CHALCONES 5-20
SECTION -II SYNTHESIS OF ACETYL PYRAZOLINE 22-34
SECTION -III SYNTHESIS OF DIHYDROPYRIMIDINTHIONS 35-51
SECTION – IV SYNTHESIS OF DIHYDROPYRIMIDINONES 52-66
SECTION –V SYNTHESIS OF 2-AMINO DIHYDROPYRIMIDINES 67-82
CHAPTER-3 PHYSICO CHEMICAL PROPERTIES
SECTION-I ACOUSTICAL PROPERTIES 83-111
SECTION -II DENSITY AND REFRACTIVE INDEX 112-126
SECTION -III CONDUCTANCE 127-141
SECTION -IV SOLUBILITY AND THERMODYNAMIC PARAMETERS 142-158
SECTION –V PARTION CO-EFFICIENT 159-170
SECTION -VI DISSOCIATION CONSTANTS 171-185
SECTION –VI THERMAL PROPERTIES 186-202
CHAPTER-4 BIOLOGICAL ACTIVITIES 203-209
A COMPREHENSIVE SUMMARY OF THE WORK 210-213
LIST OF PUBLISHED/ACCEPTED/COMMUNICATED PAPERS 249-250
SYNOPSIS
SYNOPSIS
STUDIES OF SOME BIO ACTIVE
HETEROCYCLIC ENTITIES
NAYAN J. VEKARIYA
SEPTEMBER- 2009
Department of Chemistry
Saurashtra University
Rajkot-360 005.
Gujarat (INDIA)
Synopsis…
Studies of some Bio Active heterocyclic… … …
2
SYNOPSIS of the thesis to be submitted to the Saurashtra University for the
degree of Doctor of Philosophy in Chemistry.
Faculty : Science
Subject : Chemistry
Title : “STUDIES OF SOME BIO ACTIVE
HETEROCYCLIC ENTITIES”
Name of the Candidate : NAYAN J. VEKARIYA
Registration number : 3675
Date of Registration : 17th SEPTEMBER 2007.
Name of the Guide : Dr. Shipra Baluja
Associate Professor
Department of Chemistry
Saurashtra University
Rajkot-360 005.
Submitted to : Saurashtra University
Place of work : Department of Chemistry
Saurashtra University
Rajkot-360 005.
Gujarat (INDIA).
Synopsis…
Studies of some Bio Active heterocyclic… … …
3
There are millions of organic compounds, some of them are heterocyclic
containing atoms other than carbon in the ring system. These compounds are
known to exhibit various biological activities such as antifungal, antibacterial,
antitubercular, antipyretic, antitumor etc. Thus, these compounds show vital role
in the field of pharmaceuticals because of their specific clinical reactivity.
Thus, in the present work, heterocyclic compounds were selected. Among
the various types of heterocyclic compounds, Acetyl pyrazolines and
Dihydropyrimidines containing nitrogen in the ring, were studied.
The present work is divided into four chapters.
Chapter-1 General Introduction
Chapter-2 Synthesis and characterization
Section-I Synthesis of Chalcones of vanillin derivatives
Section-II Synthesis of Acetyl pyrazolines
Section-III Synthesis of Dihydropyrimidinthions
Section-IV Synthesis of Dihydropyrimidinons
Section-V Synthesis of 2-Amino Dihydropyrimidines
Chapter-3 Physico-chemical properties
Section-I Acoustical Properties
Section-II Density and Refractive index
Section-III Conductance
Section-IV Solubility and Thermodynamic parameters
Section-V Partition Coefficient
Section-VI Dissociation Constants
Section-VII Thermal Properties
Chapter-4 Biological activities
CHAPTER – 1: GENERAL INTRODUCTION
This chapter describes literature survey of synthesis, characterization,
applications, physicochemical properties and antibacterial activities of
heterocyclic compounds.
Synopsis…
Studies of some Bio Active heterocyclic… … …
4
CHAPTER – 2: SYNTHESIS AND CHARACTERIZATION
This chapter deals with synthesis and characterization of some
Chalcones, Acetyl pyrazolines, and Dihydropyrimidines derivatives. there are five
sections in this chapter.
Section-I Synthesis of Chalcone derivatives
O
O
R
O
R=Aryl
Section-II Synthesis of Acetyl pyrazolines
O
O
N
R
N
O
R=Aryl
Section-III Synthesis of Dihydropyrimidenthaions
O
O
N
H
NH
NH
R
O
S
R=Aryl
Synopsis…
Studies of some Bio Active heterocyclic… … …
5
Section-IV Synthesis of Dihydropyrimidenons
O
O
N
H
NH
NH
R
O
O
R=Aryl
Section-V Synthesis of 2-Amino-Dihydropyrimidines
s O
O
N
H
N
NH
R
O
NH2
R=Aryl
CHAPTER – 3: PHYSICO-CHEMICAL PROPERTIES
Some physicochemical properties of Chalcones of vanillin derivatives have
also been studied in dimethylformamide and Chloroform. The various physico
chemical properties are discussed in the following seven sections:
Section-1 Acoustical Properties
Acoustical properties of solutions of different concentrations of Chalcones
in dimethylformamide and Chloroform were studied by measuring density,
viscosity and sound velocity (at 2 MHz) at 303.15 K. From these experimental
data, various acoustical parameters such as isentropic compressibility, Rao’s
Synopsis…
Studies of some Bio Active heterocyclic… … …
6
molar sound function, relaxation strength, molar compressibility, Vander Waals
constant, solvation number etc. were evaluated and the results are discussed in
the light of solvent – solute and solute – solute interactions.
Section-2 Density and Refractive index
Refractive index and molar refraction are useful properties of a material.
The molar refraction is of great importance for the calculation of dipole moment.
In this section, the density and refractive index of Chalcones were measured in
dimethylformamide and Chloroform solutions at 303.15 K.
From the refractive index measurements, the density and refractive index
of studied compounds were determined. The molar refraction of these
compounds have also been evaluated from the density and refractive index
values.
Section-3 Conductance
This section deals with the conductance measurement of solutions of
Chalcones in dimethylformamide and Chloroform solutions over a wide range of
concentration at 303.15 K. From these experimental values, specific conductance
and equivalent conductance were measured.
Section-4 Solubility and Thermodynamic parameters
In this section, solubility of Chalcones were determined at different
temperatures (293.15-313.15 K) in Chloroform and Dichloromethane. Further,
some thermodynamic parameters such as enthalpy, Gibb’s energy and entropy of
different solutions have been evaluated from the experimental data.
Section-5 Partition Coefficient
This section describes the partition coefficient of Chalcones in WaterOctanol system by UV spectrometer. From the spectral data, log P values were
evaluated.
Section-6 Dissociation Constants
This section deals with the dissociation constant of Chalcones in DMF Synopsis…
Studies of some Bio Active heterocyclic… … …
7
water system at 303.15 K.
Section-7 Thermal Properties
This section describes the thermal properties of Chalcones. Thermo
Gravimetric Analysis (TGA) and Differential Thermal Analysis (DSC)
measurements were made. From these thermograms, various kinetic
parameters, thermal stability and malting points of various compounds were
determined.
CHAPTER – 4: BIOLOGICAL ACTIVITIES
The antibacterial activity of synthesized compounds was studied against
some Gram positive and Gram negative bacteria in this chapter.
Signature of the Guide Signature of the Student
Dr. Shipra Baluja Nayan J. Vekariya
Associate Professor,
Department of Chemistry,
Saurashtra University,
Rajkot- 360 005.
CHAPTER - I
GENERAL
INTRODUCTION
INTRODUCTION
The study of heterocycles is an evergreen field in organic chemistry. It
always attracts the attention of scientists working not only in area of natural
compounds but also in synthetic organic chemistry.
Heterocyclic chemistry has been progressing owing to their natural
occurrence, specific chemical reactivity and broad spectrum utility. Heterocyclic
compounds are those which have a cyclic structure with two or more different
kinds of atoms in the ring.
The heterocyclic compounds are very widely distributed in nature and are
essential to living organisms. They play a vital role in the metabolism of all the
living cells. Among large number of heterocycles found in nature, nitrogen
heterocycles are the most abundant specially those containing oxygen or sulphur
due to their wide distribution in nucleic acid illustration and their involvement in
almost every physiological process of plants and animals.
The determination of structure of a biologically active molecule provides a
two fold benefit to pharmacy and medicine. It makes possible to pursue research,
leading to synthesis and modification of the structure. Various application of
heterocyclic compounds has been reported1-9. Some of these compounds are
also known to be used as a starting material for the synthesis of new drugs10-21.
Most of the alkaloids, pigments (such as indigo, haemoglobin, anthocyanin
etc.) and some well known drugs (like penicillin, streptomycin, sulphathiazole,
pyrenthrin, rotenmone, strychnine, reserpine, etc.) consist of heterocyclic ring
system.
Taking in view of the applicability of bio-active heterocyclic compounds,
the present work was undertaken to synthesize some new heterocycles bearing
pyrimidines and pyrazolines nucleus.
.
AIMS AND OBJECTIVES:
To synthesize several derivatives like chalcones, Acetyl pyrazoline,
dihydropyrimidine-2H-thiones,dihydropyrimidine-2H-imines, dihydropyrimidine-2H-ones bearing pyrimidines and pyrazoline nucleus.
To characterize these synthesized compounds for structure elucidation by
IR, 1H NMR and Mass spectral studies.
To study the physico chemical properties such as acoustical properties,
density, refractive index, conductance, heat of solutions, thermal properties,
dissociation constants and partition co-efficient of some synthesized
compounds in different solvents.
To evaluate antibacterial activity of some synthesized compounds against
different bacterial strains in DMSO.
REFERENCES
1. V. Polshettiwar and R. S. Varma,; “Greener and expeditious synthesis of bioactive
heterocycles using microwave irradiation” Pure Appl. Chem., 80, 4, 777–790, (2008).
2. T. Eicher, S. Hauptmann,; “ The Chemistry of Heterocycles:Structure, Reactions,
Syntheses, and Applications” 2nd ed., Wiley- VCH, Weinheim (2003).
3. M. Farouk,; “Bioactive Heterocyclic’s Based Nanotechnology” Synthesis and In-Vitro
Evaluation of New 3-Substituted Quinazolinediones, Part 1 Proc. Int. Conf. Nano
Technology Ind., King Saud University, Riyadh, Saudi Arabia, April 5-7, (2009).
4. G. Doleschall,; “Application of heterocyclic compounds in organic synthesis” Mag. Kemi.
Lapja., 35, 247-57, (1980).
5. T. Minami, T. Isonaka, Y. Okada, J. Ichikawa,; “Copper(I) salt-mediated arylation of
phosphinyl-stabilized carbanions and synthetic application to heterocyclic compounds”
J. Org. Chem., 58, 7009-15, (1993).
6. J. L. Díaz, D. Fernández-Forner, J. Bach and R.Lavilla,; “ A fast and efficient access to a
family of multifunctional 1,3,5-trisubstituted piperidines” Synth. Commun., 38(16), 2799–
13, (2008).
7. A. M. Delort, B. Combourieu,; “In situ 1H NMR study of the biodegradation of xenobiotics:
application to heterocyclic compounds” J. Ind. Micro. Biotech., 26, 2-8, (2001).
8. N. Isambert and R. Lavilla,; “ Heterocycles as key substrates in multicomponent
reactions: the fast lane towards molecular complexity” Chemistry, 14(28), 8444-54,
(2008).
9. G. M. Sreenivasa, E. Jayachandran, B. Shivakumar, K. J. Kumar, M. M. J.V. Kumar,;
“Synthesis of Bioactive Molecule Fluoro Benzothiazole Comprising Potent Heterocyclic
Moieties for Anthelmentic Activity” Arch. Pharm. Sci. Res. , 1 ,2 ,150 - 157 , (2009).
10. K. C. Majumdar and P. Biswas,; “Synthesis of bioactive heterocycles: One pot
regioselective synthesis of pyrano[3,2-f]benzo[b]thiophene derivatives” Tetrahedron, 55,
5, 29, 1449-1456,(1999).
11. F. Saczewski, J. Saczewski; Applications of 2-chloro-4,5-dihydroimidazole in
heterocyclic and medicinal chemistry, Trend. Hetero. Chem., 9, 19-31, (2003).
12. S. Y. Solodukhin, A. S. Peregudov, E. V. Vorontsov and N. D. Chkanikov,;
“Phenoxydifluoromethyl Substituted Nitrogen Heterocycles. Synthesis and
Heterocyclization Reactions of Ethyl 4,4-Difluoro- 4-phenoxyacetoacetate” Molecules , 9,
164-169, (2004).
13 W. J. Youngs, C. A. Tessier, J. C. Garrison, C. A. Quezada, A. Melaiye, S. Durmus, M.
Panzner; Medicinal applications of metal complexes of N- heterocyclic carbenes, ACS
Symposium Series, 903 (Med. Inorg. Chem.) 414-27, (2005).
14. J. Bastida, R. Lavilla and F. Viladomat,; “ Chemical and biological aspects of narcissus
alkaloids in the alkaloids. In” Chemistry and Biology” 61, Elsevier, Amsterdam,(2006).
15. Y. Kashman, A. Rudi, and D. Pappo,; “Recent heterocyclic compounds from marine
invertebrates: Structure and synthesis” Pure Appl.. Chem., 79, 4, 491–505, (2007).
16. M. Raposo, M. Manuela,; “ Recent developments in the chemistry of 2-thienylpyrroles:
synthesis, reactivity and applications” Targets in Hetero. Syst., 11, 122-54, (2007).
17. W. Su, W. Zhang, T. Wang, X. Yan, Cai, J. Duan,; “ Naphthane compound, derivative of
Andrographolide and its medicinal application” Fami. Zhu. Shen. Gong. Shu., 33pp
(2008).
18. M. A. Hassan, S. E. Zayed, M. Farouk, New 3-Substituted Quinazolinediones, Part 1.
One-pot Synthesis Of 3-Subsituted Quinazoline-2,4-dione Derivatives, under publication,
(2009).
19. H. Matsubara, Y. Obara, N. Kuba,; “Biological activity of heterocyclic compounds. II.
Blindness in baby chicks caused by administration of guanamines, guanides, and their
related compounds”, Nipp. Nog. Kag. Kaishi., 49, 505-11, (1975).
20. Y. Obara, Y. Umemoto, H. Matsubara,; “Studies on the biological activity of
heterocyclic compounds. Part IV. On the blinding activities and acute oral toxicities of
aminobenzenes, pyrimidines, purines, amino-s-triazines and their related compounds in
baby chicks” Nipp. Nog. Kag. Kaishi., 55, 1205-12, (1981).
21. N. I. Korotkikh, G. A. Losev, O. P. Shvaika, Synthesis and biological activity of
heterocyclic compounds with chalcogen-containing small cycles, 1st, Moskva, Russ.
Fed., 1, 350-355, (2001).
CHAPTER - 2
SYNTHESIS
AND
CHARACTERIZATION
SECTION – I
Synthesis of Chalcones
from Vanillin derivatives
Studies of some bio active hetero…….
Section-I: Synthesis of Chalcones
5
INTRODUCTION
The chemistry of chalcones has generated intensive scientific studies
throughout the world, due to their biological and industrial applications.
Chalcones are characterized by their possession of a structure in which two
aromatic rings are linked by an aliphatic three carbon chain.
Chalcones are prepared by condensation of aryl ketones with aromatic
aldehydes in presence of suitable condensing agents. They undergo a variety
of chemical reactions and are found to be useful in the synthesis of variety of
heterocyclic compounds. Chalcones have also been used as intermediate for
the preparations of compounds having therapeutic value1.
This class of compounds also serve as precursors for the synthesis of
different classes of various flavonoids, which are common substances in
plants that have an array of biological activities.2,3 Most of the phenolic natural
products are potentially useful intermediates for many industrial products and
agrochemical applications, including food sciences. The phenolic natural
products are closely related to free radicals, which play a major role in the
progression of many pathological disturbances.4
Literature survey reveals that chalcones derivatives exhibit diverse
pharmacological activities such as potential antimicrobial agents5, cytotoxic
agents6, Antimitotic7, antiinflammatory8,9, antiviral10 ,Fungicidal11 anesthetics,
etc. Dimmock et al. have reported quantitative structure-activity relationship
study of some chalcones.12 Rozmer et al. have also reported different effects
of two cyclic chalcone analogues on cell cycle of Jurkat T cells13. Wang et al.
have reported anticancer activity of 2-alkylaminomethyl-5diarylmethylenecyclopentanone hydrochlorides.14 Kirk et al. have reported
antiplasmodial chalcones inhibit sorbitol-induced hemolysis of Plasmodium
falciparum-infected erythrocytes.15 The anti-proliferative activities of some
chalcones have also been studied by Wu et al.16 Some other biological
activities of Chalcone derivatives have also been reported.17
Different methods are available in the literature for the synthesis of
chalcones.18-21 The most convenient method is the one, that involves the
Claisen- Schimidt condensation of equi molar quantities of an aryl methyl
ketones with aryl aldehyde in presence of alcoholic alkali22.
Studies of some bio active hetero…….
Section-I: Synthesis of Chalcones
6
Various workers have synthesized different types of Chalcones.23-26
Recently, interest has focused on the ferrocenyl chalcones which have been
reported by Noh et al.27 Zhou et al. have reported cyclodimerization of α, βunsaturated ketone by samarium iodide.28 Some new 1,5-benzodiazepines
have also been synthesized by Escobar et al. by microwave irradiation.29
The chalcones have been found to be useful for the synthesis of variety
of heterocyclic compounds such as cyanopyridone30, pyrrolobenzodiazepine
31, oxirane32, 1-carboxamidepyrazolines33, benzodioxane34 oxopyrimidines35,
benzodiazepine36, oxazapine 37 etc.
Thus, due to importance of this class of compounds, in the present
section, some new chalcones of vanillin derivatives have been synthesized.
Studies of some bio active hetero…….
Section-I: Synthesis of Chalcones
7
EXPERIMENTAL
Synthesis of (2E)-1-(4-ethoxy-3-methoxyphenyl)-3-phenylprop-2-en-1one: (NVA-01).
[A] Synthesis of 3,-methoxy4-ethoxy benzaldehyde:
An aqueous solution of vanillin (0.01M) was refluxed at 95-97 0C for
half an hour with stirring. To this solution, few drops of NaOH and diethyl
sulphate (0.012 M) were added slowly and again the reaction mixture was
refluxed for 5 to 7 hrs with stirring. After the completion of reaction, organic
layer was isolated and cooled at room temperature. The solid crude product
was isolated and crystallized from absolute ethanol. (Scheme-1)
[B] Synthesis of (2E)-1-(4-ethoxy-3-methoxyphenyl)-3-phenylprop2-en-1-one:
A mixture of 3,-methoxy4-ethoxy benzaldehyde (0.01 M) and
substituted acetophenone (0.012 M) in 40 ml MeOH was stirred for 24 hours
in presence of few drops of aqueous solution of NaOH. The product was
filtered and dried. The recrystalisation was done in ethanol. (Scheme-2)
Studies of some bio active hetero…….
Section-I: Synthesis of Chalcones
8
Scheme 1:
OH
O
O
CH3
DES
H2O, NaOH
Reflux O
O
O
CH3
CH3
Scheme 2:
O
CH3
R
MeOHNaOH
+
O
O
O
CH3
CH3
R
Sturring
O
O
O
CH3
CH3
24 hrs
Studies of some bio active hetero…….
Section-I: Synthesis of Chalcones
13
Table 1.1: Physical constants of chalcones.
Sr. No. Code R M.F. M. Wt. (g/mol)
Rf*
Value
M.P.
oC Yield
%
1 NVA -1 -4-Cl- C18H17ClO3 316 0.51 153 73
2 NVA -2 4-NO2- C18H17 NO5 327 0.58 153 59
3 NVA -3 -H C18H18O3 282 0.49 132 66
4 NVA -4 4-CH3 - C19H20O4 296 0.43 124 67
5 NVA -5 4-OCH3- C18H20O4 312 0.68 151 73
6 NVA -6 4-Br- C18H17BrO3 361 0.63 134 57
7 NVA -7 4-OH- C18H18O4 298 0.30 133 59
8 NVA -8 2,4-OCH3- C20H22O5 343 0.59 129 64
9 NVA -9 3-Cl- C18H17ClO3 316 0.57 170 75
* MeOH:Chloroform: 2:8
Studies of some bio active hetero…….
Section-I: Synthesis of Chalcones
10
The characterization was done by IR, 1H NMR and mass spectra.
Infrared spectra:
The IR spectra were recorded by SHIMADZU-FTIR-8400
Spectrophotometer in the frequency range of 4000-400 cm-1 by KBr powder
method. Figure 1.1 shows IR spectra of NVA-1. The IR spectral data for NVA1 is given in Table 1.2. The spectral data for all other compounds are reported
in Table 1.3.
1H NMR Spectra:
The NMR spectra were recorded by BRUKER Spectrometer (400 MHz)
using internal reference TMS and solvent CDCl3/DMSO. Figure 1.2 shows
NMR spectra of NVA-1. The spectral data for NVA-1 is given in Table 1.4.
Mass spectra:
The Mass spectra were recorded by GCMS-SHIMADZU-QP2010. Figure
1.3 shows mass spectra of NVA-1.The proposed mass fragmentation of the
same compound is also given in Scheme 1.1.
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
11
Figure 1.1: IR spectra of (2E)-1-(4-ethoxy-3-methoxyphenyl)-3phenylprop-2-en-1-one: (NVA-01).
Table 1.2: IR spectral data (2E)-1-(4-ethoxy-3-methoxyphenyl)-3phenylprop-2-en-1-one: (NVA-01).
Type Vibration mode
Frequency in cm-1
Observed Reported
Alkane
C-H str. (asym.) 2933.76 2975-2920
C-H str. (sym.) 2833.24 2880-2860
C-H def. (asym.) 1450.4 1470-1435
C-H def. (sym.) 1406.36 1395-1370
Aromatic
C-H str. 3006.71 3100-3000
C=C str. 1508.81 1585-1480
C-H i.p. def. 1074.3 1125-1090
C-H o.o.p. def. 824.4 860-810
Ketones C=O str. 1675 1685-1645 C=O str. (alip.) 1508.8 1585-1480
Ether C-O-C str. (asym.) 1255 1400-1000 C-O-C str. (sym.) 1074 1075-1020
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
12
Table 1.3: IR spectral data of synthesized chalcones.
Compounds C=C C=O C-O-C C-H (asym.) R
NVA-1 1512.32 1653.73 1232.54 2958 844
NVA-2 1495.52 1678.12 1248.34 2953 1318
NVA-3 1488.64 1682.32 1257.64 2955 --
NVA-4 1522.31 1642.47 1269.05 2922 2953
NVA-5 1512.32 1665.14 1273.05 2977 1276
NVA-6 1524.85 1654.84 1248.21 2967 778
NVA-7 1502.32 1662.14 1270.05 2973 3412
NVA-8 1518.12 1677.65 1272.42 2912 1231
NVA-9 1498.64 1679.12 1243.65 2970 776
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
13
Figure 1.2: 1H NMR spectra of (2E)-1-(4-ethoxy-3-methoxyphenyl)-3-phenylprop-2-en-1-one: (NVA-01).
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
14
Table 1.4: 1H NMR spectral data of (2E)-1-(4-ethoxy-3methoxyphenyl)-3-phenylprop-2-en-1-one: (NVA-01).
O
O
O
CH3
CH3
Cl a b c d e fg h i j j' i' Singal
No.
Signal
Position
(δ ppm)
Relative No.
of Protons Multiplicity Inference
1 3.34 3 singlet -OCH3
2 4.01-4.08 2 quartet -OCH2
3 1.30-135 3 triplet -CH3
4 6.96-6.99 1 doublet Ar-Hd
5 7.34-7.37 1 doublet Ar-H’e
6 7.53 1 singlet Ar-H’f
7 8.14-8.17 2 singlet -CH-CHg,h
8 7.60-7.63 2 doublet Ar-Hl+l”
9 7.72-7.83 2 doublet Ar-Hj+j’’
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
15
Figure 1.3: Mass spectra of (2E)-1-(4-ethoxy-3-methoxyphenyl)-3-phenylprop-2-en-1-one: (NVA-01).
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
16
[m/z=288] [m/z=282]
[m/z=254]
[m/z=180]
[m/z=152]
[m/z=155]
[m/z=77]
[m/z=316]
. .
.
.
.
.
.
.
O
O
O
CH3
CH3
Cl O
OH
O
CH3
Cl O
O
O
CH3
O
OH
O
CH3
O
O
O
CH3
O
OH
O
CH3
O
Cl OH
O
CH3
[m/z=124]
Scheme1.1:Proposed mass fragmentation (2E)-1-(4-ethoxy-3methoxyphenyl)-3-phenylprop-2-en-1-one: (NVA-01).
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
17
REFERENCES
1. R. Kalirajan, S. U. Sivakumar, S. Jubie, B. Gowramma and B. Sures,;
“Synthesis and Biological evaluation of some heterocyclic derivatives of
Chalcones” In. J. ChemTech Res., 1(1), 27-34, (2009).
2. S. Mukherjee, V. Kumar, A. K. Prasad, H. G. Raj, M. E. Bracke, C.
E. Olsen, S. C. Jain, V. S. Parmar,; “Synthetic and biological
activityevaluation studies on novel 1,3-diarylpropenones” Bioorg. Med.
Chem. ,9, 337–345, (2001).
3. D. Y. Kim, K. H. Kim, N. D. Kim, K. Y. Lee, C. K. Han, J. H. Yoon, S. K.
Moon, S. S. Lee, B. L. Seong,; “Design and biological evaluation of
novel tubulin inhibitors as antimitotic agents using a pharmacophore
binding model with tubulin” J. Med. Chem. 49, 5664–5670, (2006).
4. I. B. Afanas’ev,; “ Signaling functions of free radicals superoxide &
nitric oxide under physiological & pathological conditions” Mol.
Biotechnol., 37, 2–4, (2007).
5. Y. B. Vibhute and M. A.Basser,; “ Synthesis and activity of a new series
of Chalcones as antibacterial agents” Ind. J. Chem., 42B, 202-205,
(2003).
6. B. A. Bhat, K. L. Dhar, A. K.Saxena, M. Shanmugavel,; “ Synthesis and
biological evaluation of Chalcones and their derived Pyrazoles as
potential cytotoxic agents” Bio org. Med. Chem., 15 (3), 177-3180,
(2005).
7. M. L. Edwards, D. M. Stemerick, and P. S. Sunkara,; “ Synthesis of
Chalcones: A new class of Antimitotic agents” J. Med. Chem., 33,
1948-54, (1990).
8. R.Kalirajan, M.Palanivelu, V. Rajamanickam, G. Vinothapooshan and
K. Anandarajagopal,; “ Synthesis and biological evaluation of some
chalcone derivatives” Int. J. Chem. Sci., 5(1), 73-80, (2007).
9. U. Gupta, V. Sareen, V. Khatri, S. Chugh,; “ Synthesis and antifungal
activity of new Fluorine containing 4-(substituted Phenyl azo) Pyrazoles
and Isoxazoles” Ind. J. Hetero. Chem., 14, 265-266, (2005).
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
18
10. V. K. Pandey, V. D. Gupta and D. N.Tiwari,; “ Synthesis of Substituted
Benzoxazines as potential Antiviral agents” Ind. J. Hetero. Chem., 13,
399-400, (2004).
11. R. M. Mishra and A. Wahab,; “ Synthesis and Fungicidal activity of
some new 2, 3-Dihydro-4H-Benzimidazolo [3, 2-b] - [1, 3] - Thiazine-4ones” Ind. J. Hetero. Chem., 13, 29-32, (2003).
12. J. R., Dimmock N. M.Kandepu, A. J. Nazarali , T. P.Kowalchuk, N.
Motaganahalli, J.W.Quail, ; “ Conformational and quantitative structureactivity relationship study of cytotoxic 2-arylidenebenzocycloalkanones”
J. Med. Chem. ,42, 1358-1366, (1999).
13. Z. Rozmer, T. Berki, P. Perjési,; “ Different effects of two cyclic
chalcone analogues on cell cycle of Jurkat T cells” Toxicol. in Vitro, 20,
1354-1362, (2006).
14. J. Wang, L. Zhao, R. Wang, M. Lu, D. Chen, Y.Jing,; “Synthesis and
anticancer activity of 2-alkylaminomethyl-5-diarylmethylenecyclo
pentanone hydrochlorides and related compounds” Bioorg. Med.
Chem.,13, 1285–1291, (2005).
15. M. Go, M. Liu, P. Wilairat, P. J. Rosenthal, K. J. Saliba, K. Kirk,; “
Antiplasmodial chalcones inhibit sorbitol-induced hemolysis of
Plasmodium falciparum-infected erythrocytes” Antimicrob. Agents
Chemother., 48, 3241-3245, (2004).
16. J. Zhou, G. Geng, G. Batist, J. H. Wu,; “Syntheses and potential antiprostate cancer activities of ionone-based Chalcones” Bioorg. Med.l
Chem. Lett., 19, 1183–1186, (2009).
17. J. Wang, S. Wang, D. Song, D. Zhao, Y. Sha, Y. Jiang, Y. Jing and M.
Cheng,; “Chalcone Derivatives Inhibit Glutathione S-Transferase P1-1
Activity: Insights into the Interaction Mode of a, b-Unsaturated Carbonyl
Compounds” Chem. Bio. Drug. Des., 73, 511–514, (2009).
.18. W. Adam , J. Jekõ , A. Lévai ,C. Nemes, T. Patonay,; “Dimethyldi
oxirane epoxidation of chalcone and isoflavone glycoside acetates”
Eur.J. Org. Chem, 8,1547 – 1549, (1995).
19. M. S. Khanna, et al., “A novel approach to tetrahysrobenzothiazepines
from chalcones using o-aminothiophenol ” Ind. J. Chem. , 34B, 333335, (1995).
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
19
20. A. E-H. Attia, M. Michael,; “Azachalcones. IV+ Reactions of
Azachalcones with O-Phenylenediamine” Gazz. Chim. Ital. Wiley-VCH
Verlag GmbH , 112, 387-390, (1982).
21. G. Casiraghi, G. Casnati, E. Dradi, R. Messori and G. Satori; “A
general synthesis of 2'-hydroxychalcones from bromomagnesium
phenoxides and cinnamic aldehydes” Tetrahedron, 35, 2061, (1979).
22. L. Claisen, A. Claparède,; “Claisen-Schmidt Condensation” Ber. 14,
2460, (1881).
23. B. Malm,; “Substituted and branched poly chalcones. Syntheses and
characterization by spectrometric methods.” Makromol. Chem., 182 (5),
1307-17, (1981).
24. M. Ueda, T. Yokoo and M. Oda,; “Synthesis of poly (chalcone) by
poly condensation of aromatic dialdehydes with aromatic diacetyl
compounds.” Macromol. Chem. Phy., 195(7), 2569-77, (1994).
25. J. Rojas, J. N. Dominguez, J. E. Charris, G. Lobo, M. Paya and M. L.
Ferrandiz,; “Synthesis and inhibitory activity of dimethylamino-chalcone
derivatives on the induction of nitric oxide synthase.” Eur. J. Med.
Chem., 37(8), 699-705, (2002).
26. R. Perumal and S. Raja,; “Synthesis, optical and thermal studies of
dendritic architectures with chalcone surface groups.” Tetrahedron
Lett., 49(46), 6539-42, (2008).
27. K. Son, S. Kang, and D. Noh,; “Electrochemical and Fluorescent
Properties of Ferrocenyl Chalcone with N-Ethyl Carbazole Group” Bull.
Kor. Chem. Soc. 30, 2, 513, (2009).
28. L. H. Zhou, Y. M Zhang,; “Cyclodimerization of a,b-unsaturated
ketones promoted by samarium diiodide” Synth. Commun. 30, 597–60,
(2000).
29. C. A. Escobar, O. Donoso-Tauda, R. Araya-Maturana, D. Sicker,;
“Synthesis of 1,5- Benzodiazepines with Unusual Substitution
Pattern from Chalcones Under Solvent- Free Microwave Irradiation
Conditions “Synth. Comm., 39, 166 –174, (2009).
30. A. Kamal, N. Shankaraiah, S. Prabhakar, C. R. Reddy, N. Markandeya,
K. L. Reddy and V. Devaiah,; “Solid-phase synthesis of new
Synthesis and physicochemical…….
Section-I: Synthesis of Chalcones
20
pyrrolobenzodiazepine–chalcone conjugates: DNA-binding affinity and
anticancer activity” Bioorg. Med.Chem. Lett.18, 2434-2439, (2008).
31. V. Langer, S. Li and K. Lundquist,; “Chalcone epoxide intermediates in
the syntheses of lignin - related phenylcoumarans” Acta Cryst.
C62, 625-627, (2006).
32. A. Lévai and J. Jekő,; “ Synthesis of carboxylic acid derivatives of 2pyrazolines” Arkivoc, (i), 134-145, (2007).
33. A. Aitmambetov, A. V. Turov, A. M. Kornilov, D. Litkei and T. Patonai,
V. P. Khilya,; “Chemistry of isoflavone heteroanalogs. 11. Benzodioxane analogs of chalcone, flavone, and isoflavone” Chem. Het.
Comp., 2, 192–198, (1986).
34. R.N. Mistry And K. R. Desia,; “Studies on Synthesis of Some Novel
Heterocyclic Chalcone, Pyrazoline, Pyrimidine - 2 - One, Pyrimidine - 2
- Thione, para-Acetanilide Sulphonyl and Benzoyl Derivatives and their
Antimicrobial Activity” E. J. Chem., 2, 30-40, (2005).
35. M. Fodili et al.,; “An Efficient Synthesis of New 2-Pyronyl-1,5Benzodiazepine Derivatives,” Synthsis Thieme Stuttgart ,5, 811-814,
(1999).
36. Barot, V.M., et al., “New 7-(2'-Hydroxy-4' Methoxy-5'-Bromophenyl)-5Substituted Phenyl-2,3,6,7 Tetrahydro-1, 4-Oxazapine” J. Inst. Chem. ,
71, 70-71, (1999).
SECTION – II
Synthesis of
Acetyl pyrazoline
Studies of some bio-active hetero…….
Section-II: Synthesis of Acetyl pyrazoline
21
INTRODUCTION
Pyrazolines are well known important nitrogen-containing 5-membered
heterocyclic compounds having a wide spectrum of biological activities which
stimulated the research activity in this field.
Most of the pyrazoline derivatives are known to exhibit antimicrobial,2
anticonvulsant 3, anti-inflammatory4, antibacterial5 and anti-tumor6 properties.
Lévai et al. have reported synthesis of some hydroxylated 3,5-diaryl-2pyrazolines and studied their structure activity relationships.7 The
antidepressant activities of some 3,5-diphenyl-2-pyrazolines have also been
reported by Palaska et al8. Solankee et al studied the antibacterial activity by
using agar diffusion method9 of some acetyl pyrazolines. Recently,
Gowramma et al. have reported for anticancer activity of some pyrazolines.11
Various methods have been reported for the preparation of acetylpyrazoline derivatives1 ,12-15. Havrylyuk et al. have reported synthesis of novel
thiazolone based compound containing pyrazole moiety 16. Acetyl-pyrazolines
can also be constructed by the cyclo condensation of chalcones with
hydrazine hydrate17. A novel region selective synthesis of aryl-substituted
pyrazolines and pyrazoles has been developed by Alex et al.18. 1-Acetyl-3-(4chlorophenyl)-5-(4-methylphenyl)-2-pyrazoline has been synthesized and
characterized by elemental analysis, IR and X-ray single crystal diffraction by
Guo et al. 10
Spectrophotometric determination of pyrazolines and some acrylic
amides and esters have been reported by Mattocks et al.19 Le´vai et al. have
reported the synthesis of α,β-unsaturated ketones with hydrazines affords
3,5-disubstituted 2-pyrazolines.20 Kim et al. have reported the synthesis of
cyanopyrazoline derivatives21 whereas Koval et al. have reported synthesis
and structures of new copper complexes with the pyrazole-containing
ligands.22 Selvi et al. synthesized some of these derivatives by using
microwave.23 Jian et al. have also reported synthesis, characterization, crystal
structure studies of some pyrazoline derivatives.24
In the present section, some new acetyl pyrazolines have been
synthesized.
Studies of some bio-active hetero…….
Section-II: Synthesis of Acetyl pyrazoline
22
EXPERIMENTAL
Synthesis of 1-[3-(4-ethoxy-3-methoxyphenyl)-5-phenyl-1H-pyrazol-1yl]ethanone:
[A] Synthesis of 3,-methoxy4-ethoxy benzaldehyde:
An aqueous solution of vanillin (0.01M) was refluxed at 95-97 0C for
half an hour with stirring. To this solution, few drops of NaOH and diethyl
sulphate (0.012 M) were added slowly and again the reaction mixture was
refluxed for 5 to 7 hrs with stirring. The reaction was monitored by TLC. After
the completion of reaction, organic layer was isolated and cooled at room
temperature. The solid crude product was isolated and crystallized from
absolute ethanol. (Scheme-1)
[B] Synthesis of (2E)-1-(4-ethoxy-3-methoxyphenyl)-3-phenyl prop2-en-1-one:
A mixture of 3,-methoxy4-ethoxy benzaldehyde (0.01 M) and
substituted acetophenone (0.012 M) in 40 ml MeOH was stirred for 24 hours
in presence of few drops of aqueous solution of NaOH. Then, the product was
filtered and dried. The recrystalization was done in ethanol. (Scheme-2)
[C] Synthesis of 1-[3-(4-ethoxy-3-methoxyphenyl)-5-phenyl-1Hpyrazol -1-yl]ethanone:
A solution of Hydrazine hydrate (0.012 M), substituted (2E)-1-(4ethoxy-3-methoxyphenyl)-3-phenylprop-2-en-1-one (0.01M) in glacial acetic
acid was refluxed for 12 hours. The reaction mass was then poured in water
and filtered it. All the synthesized compounds were recrystallized from
hexane. (Scheme-3)
Studies of some bio-active hetero…….
Section-II: Synthesis of Acetyl pyrazoline
23
Scheme 1:
OH
O
O
CH3
DES
H2O, NaOH
O
O
O
CH3CH3
Reflux
Scheme 2:
O
CH3
R
MeOHNaOH
+
O
O
O
CH3
CH3
R
Sturring
O
O
O
CH3
CH3
24 hrs
Scheme 3:
R
+
O
O
CH3
O
CH3
NH2 NH2
H
+
Reflux
gl. A. A.
R = Functional group
O
O
O
CH3
CH3
N
O
O CH3
CH3
N
O
Studies of some bio-active hetero…….
Section-II: Synthesis of Acetyl pyrazoline
24
Table 1.1: Physical constants of Dihydropyrimidinones.
Sr. No. Code R M.F.
M. Wt.
(g/mol)
Rf*
Value
M.P.
oC Yield
%
1 NVB -1 4-CH3- C21H22 N2 O3 350 0.50 197 65
2 NVB -2 4-Cl- C20H19 N2 O3 370 0.51 223 59
3 NVB -3 4-OH- C20H20 N2 O4 352 0.45 254 61
4 NVB -4 4-OCH3- C21H22 N2 O4 366 0.49 221 58
5 NVB -5 2,4- OCH3- C20H20 N2 O5 368 0.54 224 59
6 NVB -6 4-Br- C20H19 BrO3 415 0.61 240 54
7 NVB -7 4-NO2- C20H19 N3O5 381 0.34 213 49
8 NVB -8 -H C20H20 N2 O3 336 0.55 270 61
9 NVB -9 3-Cl- C20H19 N2 O3 370 0.43 231 57
* Ethyl acetate:Hexane: 2:8
Studies of some bio-active hetero…….
Section-II: Synthesis of Acetyl pyrazoline
25
The characterization was done by IR, 1H NMR and mass spectra.
Infrared spectra:
The IR spectra were recorded by SHIMADZU-FTIR-8400
Spectrophotometer in the frequency range of 4000-400 cm-1 by KBr powder
method. Figure 1.1 shows IR spectra of NVB-1. The IR spectral data for NVB1 is given in Table 1.2. The spectral data for all other compounds are reported
in Table 1.3.
1H NMR Spectra:
The NMR spectra were recorded by BRUKER Spectrometer (400 MHz)
using internal reference TMS and solvent CDCl3/DMSO. Figure 1.2 shows
NMR spectra of NVB-1. The spectral data for NVB-1 is given in Table 1.4.
Mass spectra:
The Mass spectra were recorded by GCMS-SHIMADZU-QP2010.
Figure 1.3 shows mass spectra of NVB-1. The proposed mass fragmentation
of the same compound is also given in Scheme 1.1.
Studies of some bio active hetero…….
Section-I: Synthesis of Acetyl Pyrazolines
26
Figure 1.1: IR spectra of 1-[3-(4-ethoxy-3-methoxyphenyl)-5phenyl-1H-pyrazol-1-yl]ethanone: (NVB-01).
Table 1.2: IR spectral data of 1-[3-(4-ethoxy-3-methoxyphenyl)-5phenyl-1H-pyrazol-1-yl]ethanone:(NVB-01).
Type Vibration mode Frequency in cm
-1
Observed Reported
Alkane
C-H str. (asym.) 2956 2975-2920
C-H str. (sym.) 2865 2880-2860
C-H def. (asym.) 1429 1470-1435
C-H def. (sym.) 1387 1395-1370
Aromatic
C-H str. 3103 3100-3000
C=Cstr. 1581 1585-1480
C-H i.p. def. 1122 1125-1090
C-H o.o.p. def. 844 860-810
Ketones C=O str. (alip.) 1678 1740-1680
Nitrogen
C-N str. 1253 1350-1200
N-H str. 3145 3400-3200
N-H def. 1581 1650-1500
Ether C-O-C str. (asym.) 1182 1400-1000 C-O-C str. (sym.) 1072 1075-1020
Studies of some bio active hetero…….
Section-I: Synthesis of Acetyl Pyrazolines
27
Table 1.3: IR spectral data of synthesized Dihydropyrimidinones.
Compounds
C=O
(cyclic)
C=O
(alip.)
N-H C=C
C-H
(asym.) R
NVB-1 1678 1690 3145 1581 2958 3103
NVB-2 1721 1664 3343 1537 2953 698
NVB-3 1734 1672 3245 1531 2955 3324
NVB-4 1723 1665 3309 1521 2922 2853
NVB-5 1711 1667 3261 1519 2967 2976
NVB-6 1707 1678 3286 1534 2973 567
NVB-7 1720 1659 3311 1520 2912 1322
NVB-8 1734 1672 3245 1519 2970 776
NVB-9 1735 1677 3285 1501 2962 671
Studies of some bio active hetero…….
Section-I: Synthesis of Acetyl Pyrazolines
28
Figure 1.2:1H NMR spectra of 1-[3-(4-ethoxy-3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl] ethanone: (NVB-01).
Studies of some bio active hetero…….
Section-I: Synthesis of Acetyl Pyrazolines
29
Table 1.4: 1H NMR spectral data of 1-[3-(4-ethoxy-3methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl]ethanone:(NVB-01).
N
O
O CH3
CH3
N
O a
bcd
e f g h i i' j j' k Singal
No.
Signal
Position
(δ ppm)
Relative No.
of Protons Multiplicity Inference
1 1.31 3 triplet -CH3
2 4.02 2 quartet -OCH2
3 7.30-7.35 2 d-d Ar-Hc-Hd
4 7.37 1 singlet Ar-H’e
5 3.80 3 singlet -OCH3
6 6.97 1 singlet -CH
7 2.49 3 singlet -CO-CH3
8 7.78-7.83 2 doublet Ar-Hl+l”
9 7.64-7.69 2 doublet Ar-Hj+j’’
10 2.39 3 singlet Ar-CH3
Studies of some bio active hetero…….
Section-I: Synthesis of Acetyl Pyrazolines
30
Figure 1.3:Mass spectra of 1-[3-(4-ethoxy-3-methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl]ethanone: (NVB-01).
Studies of some bio active hetero…….
Section-I: Synthesis of Acetyl Pyrazolines
31
[m/z=336] [m/z=308]
[m/z=279]
[m/z=254]
[m/z=217]
[m/z=194][m/z=180]
[m/z=137]
[m/z=110]
[m/z=93]
[m/z=77]
[m/z=350]
. .
.
.
.
.
.
.
.
N
O
O
CH3
CH3
N
O
N
O
O
CH3
CH3
N
O
N
O
O CH3
CH3
NH
N
OH
O CH3
NH
OH
O CH3
N
O
O CH3
CH3
NH
N
O
O CH3
CH3
NH2
N
O
O
CH3
CH3
NH2
CH3 OH
O CH3
CH3
OH
OH
Scheme 1.1: Proposed mass fragmentation of 1-[3-(4-ethoxy-3methoxyphenyl)-5-phenyl-1H-pyrazol-1-yl]ethanone: (NVB-01).
Studies of some bio active hetero…….
Section-I: Synthesis of Acetyl Pyrazolines
32
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8. E. Palaska, M. Aytemir, I.T. Uzbay, D. Erol,; “ Synthesis and
Antidepressant Activities of Some 3,5-diphenyl-2-pyrazolines” Eur. J.
Med. Chem. 36, 539-543, (2001).
9. A. Solankee, Y. Prajapati,; “ An Efficient Synthesis Of Some New
Fluorine Containing Acetyl Pyrazoline And Isoxazole Derivatives And
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Studies of some bio active hetero…….
Section-I: Synthesis of Acetyl Pyrazolines
33
11. B. Gowramma, S. Jubie, R. Kalirajan, S. Gomathy and K. Elango,;
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12. D. E. Rivett, J. Rosevear, J. F. K. Wilshire,; “The Preparation and
Spectroscopic properties of some di- and tri-substituted 1, 3, 5Triphenyl-2-pyrazolines and related 2-pyrazolines” Aust. J. Chem. 36,
1649-1658, (1983).
13. K. Rurack, J. L. Bricks, B. Schulz, M. Maus, G. Reck, U. ReschGenger,; “Substituted 1,5- Diphenyl-3-benzothiazol-2-yl-2pyrazolines: Synthesis, X-ray Structure, Photophysics, and Cation
Complexation Properties.” J. Phys. Chem. A., 104, 6171-6188, (2000).
14. A. Wagner, C. W. Schellhammer, S. Petersen,; “ Aryl-∆2-pyrazolines
as Optical Brighteners” Angew. Chem., Int. Ed. Engl. 5, 699-704,
(1966).
15. P. Singh, J. S. Negi, G. J. Pant , M. S. M. Rawat and A. Budakoti,;
“Synthesis and Characterization of a Novel 2-Pyrazoline” Molbank
M614, (2009).
16. D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, L. Zaprutko, A. Gzella,
R. Lesyk,; “Synthesis of Novel Thiazolone-Based Compounds
Containing Pyrazoline Moiety and Evaluation of Their Anticancer
Activity” Eur. J. Med. Chem. 44 , 4, 1396-1404, (2009).
17. J. C. Jung, E. B. Watkins and M. A. Avery,; “ Synthesis and cyclization
reaction of pyrazoline-5-one derivatives” Heterocycles 65 , 77–94,
(2005).
18. K. Alex, A. Tillack, N. Schwarz, and M. Beller,; “Zinc-Catalyzed
Synthesis of Pyrazolines and Pyrazoles via Hydrohydrazination” Org.
Lett., 10, 12, (2008).
19. A. R. Mattocks,; “Spectrophotometric Determination of Pyrazolines and
Some Acrylic Amides and Esters” Eur. J. Med. Chem. 40, 8, 1347,
(1968).
20. A. Le´vai, A.M. S. Silva,D. C. G. A. Pinto,J. A. S. Cavaleiro,I. Alkorta,J.
Elguero,J. Jekö,; “Synthesis of Pyrazolyl-2-pyrazolines by Treatment of
Studies of some bio active hetero…….
Section-I: Synthesis of Acetyl Pyrazolines
34
3-(3-Aryl-3-oxopropenyl)- chromen-4-ones with Hydrazine and Their
Oxidation to Bis(pyrazoles)” Eur. J. Org. Chem. 4672_4679, (2004).
21. J. H. Ahn, H. M. Kim, S. H. Jung, S. K. Kang, K. R. Kim, S. D. Rhee, S.
D. Yong, H. G. Cheon and S. S. Kim,; “ Synthesis and DP-IV inhibition
of cyanopyrazoline derivatives as potent antidiabetic agents” Bioorg.
Med. Chem. Lett. ,14, 4461–4465, (2004).
22. I. A. Koval, A. M. Schuitema, W. L. Driessen J. Reedijk,; “
Unprecedented copper(II)-assisted acetal formation of a
formylsubstituted bispyrazole. The X-ray structures of copper[1,2-bis(3_-dimethoxymethylpyrazol-1_-yl)ethane] dichloride and dibromide “J.
Chem. Soc., Dalton Trans., 3663–3667, (2001).
23. Selvi, S.; Perumal, P. T. J. Heterocycl. Chem.,39, 1129, (2002).
24. F. F. Jian, P. S. Zhao, H. M. Guo, Y. F. Li,; “ Synthesis,
characterization, crystal structure and DFT studies on 1-acetyl-3-(2,4dichloro-5-fluoro-phenyl)-5-phenyl-pyrazoline” Spectrochim. Acta. Mol.
Biomol. Spectrosc., 69, 647-653, (2008).
SECTION – III
Synthesis of
Dihydropyrimidinthiones
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
35
INTRODUCTION
Dihydropyrimidines consists of a six membered heterocyclic ring
having two nitrogen atoms at one and three positions. In 1893, Pietro Biginelli
discovered a multicomponent reaction which leads to partly reduced
pyrimidinone derivatives1 Since that time, the Biginelli reaction has been
known as an efficient one-pot reaction protocol to prepare 3,4dihydropyrimidine-2(1H)- thion (DHPM) derivatives 2
These heterocyclic compounds exist in a variety of natural and
synthetic organic compounds and are known to possess wide spectrum of
biological and therapeutic properties such as antibacterial, anti viral, anti
tumor and anti inflammatory activities 3-5. Recently, some of dihydropyrimidine
2(1H)-thiones analogs have emerged as integral backbones of several
calcium channel blockers, antihypertensive agents and α-la-adrenergic
receptor antagonists 6-10. Moreover, several alkaloids, isolated from marine
sources also contain dihydropyrimidine core unit. These alkaloids also exhibit
interesting biological properties. 11-12 Various derivatives of dihydropyrimidines
have been synthesized (13-15), one of which is dihydropyrimidithiones.
Many researchers have attempted to determine the synthetic routes
and various biological activities of these compounds (16-18). The
antihypertensive agent of pure 4-aryl-3,4-dihydro-pyrimidin-2(1H)-ones and
thiones via enzymatic resolution have been reported by Kappe et al.19
Furthermore, Desai et al. 20 and Kumar et al. 21 have reported the anti
tubercular activity of some 1,4- dihydropyrimidines2(H)- thiones. Hattori et al.
designed some dihydropyrimidines-2(H)- thiones and studied their anticancer
activities.22 The use of these derivatives have also been used in oral adjuvant
chemotherapy. 23 Kumar et al. have also studied in vitro cytotoxicity against
Vero cell for some novel Biginelli Dihydropyrimidines. 24
These developments led to the preparation and pharmacological
evaluation of 3,4-dihydropyrimidines2(H)-thiones (DHPMs) of biological
interest. Sabitha et al.25 have synthesized dihydropyrimidinones by three
component condensation of an aldehyde, a keto ester and thiourea in the
presence of a catalytic amount of VCl3 in solution phase. Atwal et ai have also
reported synthesis of substituted 1,2,3,4-Tetrahydro-6-methyl-2-thioxo-5pyrimidinecarboxylic acid esters.26
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
36
In recent years, several methods for the synthesis of DHPMs have
been developed to improve and modify the Biginelli reaction by means of
microwave irradiation 27, ultrasound irradiation28, ionic liquids29, Lewis and
protic acid promoters such as lanthanide triflate30, H3BO331, silica chloride32,
HCOOH33 etc. Kappe et al. have reported direct microwave-assisted Pd(0)catalyzed/Cu(I)-mediated carbon-carbon cross-coupling of 3,4dihydropyrimidine-2-thiones.34 Wang et al. have also reported one-pot
Biginelli condensation reaction for the synthesis of some noval
dihydropyrimidithiones.35 However, in spite of their potential utility, many of
these reported one-pot protocols suffer from drawbacks such as the use of
expensive reagents, strong acidic conditions and long reaction times.
Further, Dihydropyrimidine2(H)-thiones, a variety of different
combinatorial protocols based on the classical Biginelli MCR have been
advanced36. Salehi et al. have reported synthesis of dihydrothiopyrimidine2(H)- thiones by using over silica sulfuric acid as a reusable catalyst under
solvent-free conditions37. Manjula et al. have reported that the cupric chloride–
lithium chloride combination catalyst as an efficient reagent system for the
single pot Biginelli reaction38. Photocatalytic oxidation of dihydropyrimidinone2(H)- thiones using titanium dioxide suspension has also been studied by
Nasr-Esfahani et al.39
In the present section, some new dihydropyrimidine2(H)-thiones have
been synthesized.
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
37
EXPERIMENTAL
Synthesis of 4-(3,-methoxy4-ethoxyphenyl)-6-methyl-2-Thio-N-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxamide.
[A] Synthesis of 3,-methoxy4-ethoxy benzaldehyde:
An aqueous solution of vanillin (0.01M) was refluxed at 95-97 0C for
half an hour with stirring. To this solution, few drops of NaOH and diethyl
sulphate (0.012 M) were added slowly and again the reaction mixture was
refluxed for 5 to 7 hrs with stirring. The reaction was monitored by TLC. After
the completion of reaction, organic layer was isolated and cooled at room
temperature. The solid crude product was isolated and crystallized from
absolute ethanol. (Scheme-1)
[B] Synthesis of 3-oxo-N-phenylbutanamide:
A mixture of substituted aniline (0.01 M) and ethyl acetoacetate (0.012
M) in 40 ml toluene was refluxed for 12 hours in presence of few drops of
slurry of NaOH in water. The reaction was monitoring with TLC. The excess of
toluene was distilled out and the reaction mixture was taken in hexane and
stirred with glass rod. The products were isolated in hexane and filtered. The
crude product was dried. This product was taken in aqueous NaOH solution
and neutralized with dilute HCl. The recrystalisation was done in ethanol.
(Scheme-2)
[C] Synthesis of 4-(4-ethoxy3-methoxyphenyl)-6-methyl-2-Thio-Nphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide:
A solution of 3-methoxy4-ethoxy aldehyde (0.01 M), substituted
diketones (0.012 M) and Thiourea (0.015 M) in methanol was refluxed for 12
hours in presence of few drops of con. HCl as catalyst. The product was
isolated and crystallized from ethanol. All the synthesized compounds were
recrystallized from ethanol. (Scheme-3)
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
38
Scheme 1:
OH
O
O
CH3
DES
H2O, NaOH
O
O
O
CH3CH3
Reflux
Scheme 2:
NH2
R
Toluene
NaOH
+ CH3 O
CH3
O O
120
0
C
NH CH3
O O
R
reflux
Scheme 3:
NH CH3
O O
R
+
O
O
CH3
O
CH3
+ NH2
NH2
S
H
+
Reflux
Methanol
NH
N
H
NH
O
CH3
O
O
CH3
S
CH3
R
R = Functional group
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
39
Table 1.1: Physical constants of Dihydropyrimidinones.
Sr. No. Code R M.F. M. Wt. (g/mol)
Rf*
Value
M.P.
oC Yield
%
1 NVT-1 4-Cl C21H22 ClN3O3 S 431 0.64 188 61
2 NVT -2 3,4-Cl- C21H21 Cl2N3O3 S 466 0.54 172 53
3 NVT -3 4-OCH3 C22H25 N3 O3 S 427 0.68 210 59
4 NVT -4 3-Cl,4-F- C21H21 ClFN3O3 S 449 0.46 203 57
5 NVT -5 3,4- CH3 C23H27 N3O3 S 425 0.68 219 57
6 NVT -6 3-Cl- C21H22 ClN3O3S 431 0.77 238 62
7 NVT -7 4-F- C21H22 ClN3O3 S 415 0.82 186 54
8 NVT -8 2-Cl,5-F- C21H21 ClFN3O3 S 449 0.59 232 62
9 NVT -9 C6H5- C21H23N3O3 S 397 0.63 154 58
10 NVT-10 2,4-Cl- C21H21 Cl2N3O3 S 466 0.70 184 67
* Ethyl acetate:Hexane: 2:8
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
40
The characterization was done by IR, 1H NMR and mass spectra.
Infrared spectra:
The IR spectra were recorded by SHIMADZU-FTIR-8400
Spectrophotometer in the frequency range of 4000-400 cm-1 by KBr powder
method. Figure 1.1 shows IR spectra of NVT-1. The IR spectral data for NVT1 is given in Table 1.2. The spectral data for all other compounds are reported
in Table 1.3.
1H NMR Spectra:
The NMR spectra were recorded by BRUKER Spectrometer (400 MHz)
using internal reference TMS and solvent CDCl3/DMSO. Figure 1.2 shows
NMR spectra of NVT-1. The spectral data for NVT-1 is given in Table 1.4.
Mass spectra:
The Mass spectra were recorded by GCMS-SHIMADZU-QP2010. Figure 1.3
shows mass spectra of NVT-1The proposed mass fragmentation of the same
compound is also given in Scheme 1.1.
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
41
Figure 1.1: IR spectra of 4-(3,methoxy4-ethoxyphenyl)-6-methyl- 2Thio -N-phenyl- 1,2,3,4-tetrahydropyrimidine-5-carboxamide: (NVT-01).
Table 1.2: IR spectral data of 4-(3,methoxy4-ethoxyphenyl)-6-methyl -2Thio-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide:(NVT-01).
Type Vibration mode Frequency in cm-1 Observed Reported
Alkane
C-H str. (asym.) 2943 2975-2900
C-H str. (sym.) 2871 2880-2810
C-H def. (asym.) 1455 1480-1435
C-H def. (sym.) 1361 1985-1350
Aromatic
C-H str. 3105 3100-3000
C=C 1510 1585-1480
C-H i.p. def. 1115 1125-1090
C-H o.o.p. def. 829 860-810
Ketones C=O str.(cyclic) 1735 1740-1680 C=O str. (aliphatic) 1656 1710-1650
Nitrogen
C-N str. 1259 1350-1200
N-H str. 3310 3400-3200
N-H def. 1656 1650-1500
Ether C-O-C str. (asym.) 1178 1400-1000 C-O-C str. (sym.) 1026 1075-1020
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
42
Table 1.3: IR spectral data of synthesized Dihydropyrimidinones.
Compounds
IR , (cm-1)
C=O
(cyclic)
C=O
(alip.) N-H
C=C
C=H
(asym.) R
NVT-1 1735 1656 3310 1510 2943 731
NVT-2 1739 1646 3317 1519 2944 765
NVT-3 1716 1679 3281 1529 2949 1132
NVT-4 1719 1684 3269 1528 2942 793
NVT-6 1722 1674 3274 1527 2941 812
NVT-7 1719 1663 3321 1527 2953 689
NVT-8 1727 1677 3267 1539 2952 749
NVT-9 1720 1658 3319 1510 2932 762
NVT-10 1722 1667 3267 1514 2967 758
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
43
Figure 1.2: 1H NMR spectra of 4-(3,methoxy4-ethoxyphenyl)-6-methyl-2-Thio-N-phenyl-1,2,3,4- tetrahydropyrimidine 5-carboxamide:(NVT-01).
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
44
Table 1.4: 1H NMR spectral data of 4-(3,methoxy4-ethoxyphenyl) -6methyl-2-Thio-N-phenyl-1,2,3,4-tetrahydropyrimidine-5carboxamide: (NVT-01).
NH
N
H
NH
O
CH3
O
O
CH3
S
CH3
Cl a b c d e
f g h ij k l l' m m' Singal
No.
Signal
Position
(δ ppm)
Relative No.
of Protons Multiplicity Inference
1a 1.15-1.29 3 Triplet -CH3
2b 3.81 2 quartets -OCH2
3c 6.88-6.90 1 doublet Ar-Hc
4d 6.80-6.83 1 doublet Ar-Hd
5e 7.01 1 singlet Ar-H’e
6f 3.56-3.66 3 singlet -OCH3
7g 5.35 1 singlet Ar-Hg
8h 9.81-9.95 1 singlet Ar-NHh
9i 10.03 1 singlet Ar-NHi
10j 2.28 3 singlet Ar- CH3
11k 9.46 1 singlet Ar-NH-CO
12l+l’ 7.34-7.31 2 doublet Ar-Hk+k’
13m+m’ 7.49-7.52 2 doublet Ar-Hl+l”
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
45
Figure 1.3: Mass spectra of 4-(3,methoxy4-ethoxyphenyl)-6-methyl-2-Thio-N-phenyl-1,2,3,4-tetrahydropyrimidine-5carboxamide: (NVT-01).
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
46
NH
N
H
NH
O
O
O
S
Cl CH3
NH
N
H
NH
O
O
OH
S
CH3
[m/z=383]
[m/z=353]
NH
N
H
NH
O
S
[m/z=291]
NH
N
H
NH2
O
OH
S
[m/z=263]
NH
N
H
O
OH
S
[m/z=248]
NH
N
H
O
S
[m/z=232]
NH
N
H
OH
S
[m/z=220]
NH
N
H
O
S
[m/z=182]
NH
N
H
S
O CH3
[m/z=154]
[m/z=108]
[m/z=77]
[m/z=431]
. .
.
.
.
..
.
.
.
. NH
N
H
NH
O
O
S
Scheme 1.1: Proposed mass fragmentation of 4-(3,methoxy4ethoxyphenyl)-6-methyl-2-oThio-N-phenyl-1,2,3,4- tetrahydropyrimidine5-arboxamide:(NVT-01).
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
47
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28. J.T. Li, J.F. Han, J.H. Yang, T.S. Li,; “ An Efficient Synthesis of 3,4dihydropyrimidin-2-ones catalyzed by NH2SO3H under ultrasound
irradiation.” Ultrason Sonochem. 10, 119-122, (2003).
29. J. J. Peng, Y. Q. Deng,; “ Ionic Liquids Catalyzed Biginelli Reaction
under solvent-free conditions.”Tetrahedron Lett. 42, 5917-5919, (2001).
30. Y. Ma, C. Qian, L. Wang, M. Yang,; “ Lanthanide triflate catalyzed
Biginelli reaction. one-pot synthesis of dihydropyrimidinones under
solvent-free conditions.” J. Org. Chem., 65, 3864-3868, (2000).
31. S. J. Tu, F. Fang, C. B. Miao, H. Jiang, Y. J. Feng, D. Q. Shi, X. S.
Wang,; “ One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Using
Boric Acid as Catalyst.” Tetrahedron Lett., 44, 6153-6155, (2003).
32. H. N. Karade, M. Sathe, M. P. Kaushik,; “ Synthesis of 4-Aryl
substituted 3,4-dihydropyrimidinones using silica-chloride under solvent
Free Conditions.” Molecules, 12, 1341- 1351, (2007).
33. J. Cheng, D.Y. Qi,; “ An efficient and solvent-free one-pot synthesis of
dihydropyrimidinones under microwave irradiation.” Chin. Chem. Lett..,
18, 647–650, (2007).
34. A. Lengar and C. O. Kappe,; “Tunable carbon-carbon and carbonsulfur cross-coupling of boronic acids with 3,4-dihydropyrimidine-2thiones” Org. Lett., Vol. 6, 5, (2004).
35. C. Liu and J. Wang ,; “Copper(II) Sulfamate: An Efficient catalyst for
the One-Pot synthesis of 3,4-dihydropyrimidine-2(1H)-ones and
thiones” Molecules, 14, 763-770, (2009).
36. R. W.Armstrong, A. P. Tempest, P. A. Brown, S. D. Keating,: “ MultipleComponent Condensation Strategies for Combinatorial Library
Synthesis.” Acc. Chem. Res., 29, 123-131, (1996).
Studies of some bio active hetero…….
Section-III: Synthesis of Dihydropyrimidin-Thiones
51
37. P. Salehi, M.Dabiri, M. A. Zolfigol, and M. A.Bodaghi Fard,; “Efficient
synthesis of 3,4-dihydropyrimidin-2(1h)-ones over silica sulfuric acid as
a reusable catalyst under solvent-free conditions” Heterocycles., 60,
2435 – 2440, (2003).
38. A. Manjula, B. Vittal Rao, and P. Neelakantan,; “An inexpensive
protocol for Biginelli reaction” Synth. Comm.,34, 14, 2665–2671,
(2004).
39. M. Nasr-Esfahani, M. Montazerozohori, and K. Abdi,; “Photocatalytic
oxidation of dihydropyrimidinones using titanium dioxide suspension
“Arkivoc (x), 255-264 (2009).
SECTION – VI
Synthesis of
Dihydropyrimidinones
Studies of some bio-active hetero…….
Section-I : Synthesis of 1,4 - Dihydropyrimidinones
52
INTRODUCTION
As mentioned in section-3, Biginelli disclosed a multicomponent
reactions to the synthesis dihydropyrimidinones (DHPM)1. These derivatives
are known to be interesting heterocyclic compounds for drug research2.
Different methods have been reported for the synthesis of
dihydropyrimidinones and its derivatives3-6 which have recently emerged as
important target molecules due to their therapeutic and pharmacological
properties7-8. Estrada has suggested computational approaches to design
pyrimidyl nucleosides with anti-HIV activity 9. Nucleoside derivatives are wellestablished today as effective antiviral agents in spite of the toxicity generally
associated with them.10-14 Recently, few workers have reported a number of
dihydropyridines to be adrenoceptor antagonists.15-18
Deng et al. have synthesized dihydropyrimidinones in high yields by onepot cyclocondensation of three components19. Various workers have used
ionic liquids as catalyst in Biginelli reaction for synthesized compounds.20-23
Recently, many researchers have been improved several procedures for
the preparation of DHPMs ( also known as Biginelli compounds). Kappe et al.
have synthesized dihydropyrimidine-2(1H)-one using polyphosphate ester .24
Hu et al. have used three component one pot condensation reaction for
efficient synthesis.25 One pot synthesis of dihydropyrimidines-2(1H)-one have
been reported by other workers.26,27 Bismuth and zeolite catalysized synthsis
have also been reported by Ramalinga et al.28 and Rani et al.29 respectively.
Lu et al.30 used lanthanum chloride as catalyst for one pot synthesis of 3,4dihydropyrimidin-2-ones. In some cases, methane sulfonic acid has been
widely used as a catalysis for the synthesis,31,32 to have good color in final
product, to increase the reaction rate, to avoid undesirable decomposition
byproducts etc. Jin et al. have reported an efficient synthesis of 3,4dihydropyrimidin-2-ones from the aldehydes, b-ketoesters, and urea in
ethanol using methanesulfonic acid as catalyst.33
In the present section, some new dihydropyrimidinones have been
synthesized.
Studies of some bio-active hetero…….
Section-I : Synthesis of 1,4 - Dihydropyrimidinones
53
EXPERIMENTAL
Synthesis of 4-(3,-methoxy4-ethoxyphenyl)-6-methyl-2-oxo-N-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxamide.
[A] Synthesis of 3,-methoxy4-ethoxy benzaldehyde:
An aqueous solution of vanillin (0.01M) was refluxed at 95-97 0C for
half an hour with stirring. To this solution, few drops of NaOH and diethyl
sulphate (0.012 M) were added slowly and again the reaction mixture was
refluxed for 5 to 7 hrs with stirring. The reaction was monitored by TLC. After
the completion of reaction, organic layer was isolated and cooled at room
temperature. The solid crude product was isolated and crystallized from
absolute ethanol. (Scheme-1)
[B] Synthesis of 3-oxo-N-phenylbutanamide:
A mixture of substituted aniline (0.01 M) and ethyl acetoacetate (0.012
M) in 40 ml toluene was refluxed for 12 hours in presence of few drops of
slurry of NaOH in water. The reaction was monitoring with TLC. The excess of
toluene was distilled out and the reaction mixture was taken in hexane and
stirred with glass rod. The products were isolated in hexane and filtered. The
crude product was dried. This product was taken in aqueous NaOH solution
and neutralized with dilute HCl. The recrystalisation was done in ethanol.
(Scheme-2)
[C] Synthesis of 4-(3,methoxy 4-ethoxyphenyl)-6-methyl-2-oxo-Nphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide:
A solution of 3-methoxy4-ethoxy aldehyde (0.01 M), substituted
diketones (0.012 M) and urea (0.015 M) in methanol was refluxed for 12 hours
in presence of few drops of concentrated HCl as catalyst. The product was
isolated and crystallized from ethanol. All the synthesized compounds were
recrystallized from ethanol.(Scheme-3)
Studies of some bio-active hetero…….
Section-I : Synthesis of 1,4 - Dihydropyrimidinones
54
Scheme 1:
OH
O
O
CH3
DES
H2O, NaOH
O
O
O
CH3CH3
Reflux
Scheme 2:
NH2
R
Toluene
NaOH
+ CH3 O
CH3
O O
120
0
C
NH CH3
O O
R
reflux
Scheme 3:
NH CH3
O O
R
+
O
O
CH3
O
CH3
+ NH2
NH2
O
H
+
Reflux
Methanol
NH
N
H
NH
O
CH3
O
O
CH3
O
CH3
R
R = Functional group
Studies of some bio-active hetero…….
Section-I : Synthesis of 1,4 - Dihydropyrimidinones
55
Table 1.1: Physical constants of Dihydropyrimidinones.
Sr. No. Code R M.F. M. Wt. (g/mol)
Rf*
Value
M.P.
oC Yield
%
1 NVU-1 4-Cl- C21H22 ClN3O4 415 0.59 198 60
2 NVU -2 3,4-Cl- C21H21 Cl2N3O4 450 0.54 182 52
3 NVU -3 4-OCH3- C22H25 N3 O4 411 0.62 210 58
4 NVU -4 3-Cl,4-F- C21H21 ClFN3O4 433 0.41 217 57
5 NVU -5 3,4- CH3 C23H27 N3O4 409 0.43 223 43
6 NVU -6 4-Cl- C21H22 ClN3O4 415 0.71 238 62
7 NVU -7 4-F- C21H22 ClN3O4 399 0.57 198 54
8 NVU -8 2-Cl,5-F - C21H21 ClFN3O4 433 0.59 232 62
9 NVU -9 -H- C21H23N3O4 381 0.63 174 58
10 NVU-10 2,4-Cl- C21H21 Cl2N3O4 450 0.49 189 45
* Ethyl acetate:Hexane: 2:8
Studies of some bio-active hetero…….
Section-I : Synthesis of 1,4 - Dihydropyrimidinones
56
The characterization was done by IR, 1H NMR and mass spectra.
Infrared spectra:
The IR spectra were recorded by SHIMADZU-FTIR-8400
Spectrophotometer in the frequency range of 4000-400 cm-1 by KBr powder
method. Figure 1.1 shows IR spectra of NVU-1. The IR spectral data for NVU1 is given in Table 1.2. The spectral data for all other compounds are reported
in Table 1.3.
1H NMR Spectra:
The NMR spectra were recorded by BRUKER Spectrometer (400 MHz)
using internal reference TMS and solvent CDCl3/DMSO. Figure 1.2 shows
NMR spectra of NVU-1. The spectral data for NVU-1 is given in Table 1.4.
Mass spectra:
The Mass spectra were recorded by GCMS-SHIMADZU-QP2010. Figure
1.3 shows mass spectra of NVU-1The proposed mass fragmentation of the
same compound is also given in Scheme 1.1.
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
57
Figure 1.1: IR spectra of 4-(3,methoxy4-ethoxyphenyl)-6-methyl2-oxo-N-phenyl- 1,2,3,4-tetrahydropyrimidine-5-carboxamide: (NVU01).
Table 1.2: IR spectral data of 4-(3,methoxy4-ethoxyphenyl)-6methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-arboxamide:
(NVU-01).
Type Vibration mode
Frequency in cm-1
Observed Reported
Alkane
C-H str. (asym.) 2933 2975-2900
C-H str. (sym.) 2833 2880-2810
C-H def. (asym.) 1450 1480-1435
C-H def. (sym.) 1450 1985-1350
Aromatic
C-H str. 3006 3100-3000
C=C str. 1508 1585-1480
C-H i.p. def. 1122 1125-1090
C-H o.o.p. def. 827 860-810
Ketones C=O str.(cyclic) 1720 1740-1680 C=O str. (alip.) 1675 1710-1650
Nitrogen
C-N str. 1255 1350-1200
N-H str. 3307 3400-3200
N-H def. 1568 1650-1500
Ether C-O-C str. (asym.) 1180 1400-1000 C-O-C str. (sym.) 1029 1075-1020
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
58
Table 1.3: IR spectral data of synthesized Dihydropyrimidinones.
Compounds
C=O
(cyclic)
C=O
(alip.)
N-H
C=C
C=H
(asym.)
R
NVU-1 1720 1675 3307 1508 2933 732
NVU-2 1715 1664 3321 1537 2953 687
NVU-3 1722 1673 3267 1529 2955 1123
NVU-4 1720 1659 3309 1520 2912 762
NVU-6 1711 1666 3261 1514 2967 758
NVU-7 1707 1678 3286 1502 2972 633
NVU-8 1720 1659 3309 1520 2912 762
NVU-9 1714 1669 3269 1519 2967 759
NVU-10 1709 1677 3285 1507 2962 671
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
59
Figure 1.2: 1H NMR spectra of 4-(3,methoxy4-ethoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine5-arboxamide: (NVU-01).
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
60
Table 1.4: 1H NMR spectral data of 4-(3,methoxy4-ethoxyphenyl) -6methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-arboxamide:
(NVU-01).
NH
N
H
NH
O
CH3
O
O
CH3
O
CH3
Cl a b c d e
f g h ij k l l' m m' Singal
No.
Signal
Position
(δ ppm)
Relative No.
of Protons Multiplicity Inference
1 1.33 3 singlet -CH3
2 3.98 2 quartet -OCH2
3 7.39 1 singlet Ar-Hc
4 7.31 1 singlet Ar-Hd
5 7.36 1 singlet Ar-H’e
6 3.36 3 singlet -OCH3
7 5.46 1 singlet Ar-Hg
8 9.44 1 singlet Ar-Hh
9 9.63 1 singlet Ar-HI
10 2.19 3 singlet Ar- CH3
11 8.10 1 singlet Ar-NH-CO
12 7.57-7.62 2 doublet Ar-Hk+k’
13 7.36-7.49 2 doublet Ar-Hl+l”
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
61
Figure 1.3: Mass spectra of 4-(3,methoxy4-ethoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5carboxamide: (NVU-01).
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
62
NH
N
H
NH
O
O
O
O
Cl CH3
NH
N
H
NH
O
O
OH
O
CH3
Cl [m/z=401]
NH
N
H
NH
O
O
O
O
CH3
[m/z=381]
NH
N
H
NH
O
O
[m/z=258]
NH
N
H
NH
O
O
[m/z=274]
NH
N
H
NH2
O
OH
O
OH
[m/z=263]
NH
N
H
O
OH
O
[m/z=232]
NH
N
H
O
O
[m/z=215]
NH
N
H
OH
O
[m/z=204]
NH
N
H
NH
CH3
[m/z=207]
NH
N
H
O
O
[m/z=165]
NH
N
H
O
NH2
[m/z=137]
[m/z=93]
[m/z=77]
[m/z=415]
. .
.
.
.
.
.
.
.
.
.
.
.
NH O
[m/z=125]
.
Scheme 1.1: Proposed mass fragmentation of 4-(3,methoxy4ethoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydro
pyrimidine-5-arboxamide:(NVU-01).
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
63
REFERENCES
1. P. Biginelli, ,; “The condensation reaction described by Biginelli” Gazz.
Chim. Ital. 23, 360-416,(1893).
2. For a review, see: (a) Kappe, C. O. Acc. Chem. Res. 33, 869-888,
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3. G. A. Gross, H. Wurziger, and A. Schober,; “Solid-Phase Synthesis of
4,6-Diaryl-3,4-dihydropyrimidine-2(1H)-one- 5-carboxylic Acid Amide
Derivatives: A Biginelli Three-Component Condensation Protocol
Based on Immobilized â-Ketoamides” J. Comb. Chem., 8, 153-155,
(2006).
4. C. O Kappe,.“ Examples and references for solution-phase, polymersupported, fluoros, and soluble polymer DHPM synthese is given
in:Kappe” QSAR Combi. Sci., 22, 630-645, (2003).
5. J. J. V. Eynde, O.Watte,; “Soluble vs insoluble polymer-assisted
synthesis is discussed in: Eynde” ArkiVoc 4, 93-101, (2003).
6. P. Shanmugam,; G.Annie,; P. T.Perumal,; “Solution-phase conditions
are given in: Shanmugam, J. Heterocycl. Chem., 40 (5), 879-884,
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7. C. O. Kappe,; “ For a review on dihydropyrimidones of this type”
Tetrahedron, 49, 6937-6963, (1993).
8. B. Schnell, U. T. Strauss, P. Verdino, K. Faber and C. O. Kappe,;
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agent (R)-SQ 32926y” Tetrahedron: Asym., 11 1449±1453,(2000).
9. E. Estrada, S. Vilar, E. Uriarte, and Y.Gutierrez,; “In silico studies
toward the discovery of new anti-HIV nucleoside compounds with the
use of TOPS-MODE and 2D/3D Connectivity Indices. 1. Pyrimidyl
Derivatives” J. Chem. Inf. Comput. Sci., 42, 1194-1203, (2002).
10. R. F. Schinazi.; “ Competitive inhibitors of human immunodeficiency
virus reverse transcriptase” Persp. Drug Discuss. Des.,1, 151- 180,
(1993).
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
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11. E. De Clercq,; “Toward improved anti-HIV chemotherapy: Therapeutic
strategies for intervention with HIV infections.” J. Med. Chem., 38,
2492-2517, (1995).
12. T. S. Mansour,; “ Storer, R. Antiviral nucleosides”. Curr. Pharm. Des.,
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13. M. H. el Kouni, ; “Trends in the design of nucleoside analogues as antiHIV drugs”. Curr. Pharm. Des., 8, 581-593, (2002).
14. P. C.Yates,; “ A molecular modeling study of nucleoside analogues as
potential anti-AIDS drugs” Struct. Chem., 2, 611-619, (1991).
15. J. M. Wetzel, S. W. Miao, C. Forray, L. A. Borden, Branchek, T. A. C.
Gluchowski,; “Discovery of R1a-adrenergic receptor antagonists based
on the L-type Ca2+ channel antagonist niguldipine.” J. Med. Chem., 38,
1579-1581, (1995).
16. W. C. Wong, G. Chiu, J. M. Wetzel, M. R.Marzabadi, D. Nagarathnam,
D.Wang, J. Fang, S. W. Miao, X. Hong , C. Forray, P. J.-J. Vaysse, T.
A. Branchek, C.Gluchowski, R.Tang, H. Lepor,; “ Identification of a
dihydropyridine as a potent α1a adrenoceptor-selective antagonist that
inhibits phenylephrine-Induced contraction of the human prostate” J.
Med. Chem., 41, 2643-2650, (1998).
17. D. Nagarathnam, J. M. Wetzel, S. W. Miao, M.R. Marzabadi, G.Chiu,
W. C. Wong, X..Hong, J. Fang, C.Forray, T. A. Branchek, W. E.
Heydorn, R. S. L. Chang, T. Broten, T. W. Schorn, C.Gluchowski,; “
Design and Synthesis of Novel α1a Adrenoceptor Selective
dihydropyridine antagonists for the treatment of Benign prostatic
hyperplasia.” J. Med. Chem., 41, 5320-5333, (1998).
18. D. Nagarathnam, S. W. Miao, G. Chiu, J. Fang, B.Lagu, T. G. Murali
Dhar, J. Zhang, S.Tyagarajan, M. R. Marzabadi, F. Zhang, W. C.
Wong, W. Sun, D. Tian, J. M. Wetzel, C. Forray, R. S. L. Chang, T. P.
Broten, T. W. Schorn, T. B. Chen, S. O’Malley, R. Ransom, K.
Schneck, R. Bendesky, C. M.. Harrell, C.Gluchowski,; “ Design and
Synthesis of novel α1a adrenoceptor-selective antagonists. 1.
structure-activity relationships of dihydropyrimidinones” J. Med. Chem.,
42, 4764-4777, (1999).
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
65
19. J. Peng and Y. Deng,; “Ionic liquids catalyzed Biginelli reaction under
solvent-free Conditions” Tetrahedron Lett. 42 5917–5919, (2001) .
20. Li, M., Guo, W., Wen, L., Li, Y., Yang, H. “One-pot synthesis of Biginelli
and Hantzsch products catalyzed by non-toxic ionic liquid (BMImSac)
and structural determination of two products.” J. Mol. Cata. A: Chem.,
2589 (1–2), 133–138, (2006),.
21. Fang, D., Luo, J., Zhou, X., Ye, Z., Liu, Z. “One-pot green procedure for
Biginelli reaction catalyzed by novel taskspecific room-temperature
ionic liquids.” J. Mol. Cata. A: Chem., 274, 208–211,(2007).
22. Zheng, R., Wang, X., Xu, H., Du, J. “Bronsted acidic ionic liquid: An
efficient and reusable catalyst for the synthesis of 3,4-dihydropyrimidin2(1H)-ones.” Synth. Commun., 36 (11), 1503–1513, (2006).
23. Liu, D., Gui, J., Zhu, X., Song, L., Sun, Z. “Synthesis and
characterization of task-specific ionic liquids possessing two Bronsted
acid sites.” Synth. Commun., 37, 759–765, (2007).
24. C.O. Kappe, S.F. Falsone,; “Polyphosphate ester-mediated synthesis
of dihydropyrimidines Improved conditions for the Biginelli reaction.”
Syn. lett ., 718, (1998).
25. E.H. Hu, D.R. Sidler, U.H. Dolling,; “ Unprecedented catalytic three
component one-pot condensation reaction: an efficient synthesis of 5alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones.” J. Org. Chem.,
63, 3454, (1998).
26. B.C. Ranu, A. Hajra, U. Jana,; “ Indium(III) Chloride-catalyzed one-pot
synthesis of dihydropyrimidinones by a three-component coupling of
1,3-dicarbonyl compounds, aldehydes, and urea: an improved
procedure for the Biginelli reaction.” J. Org. Chem., 65, 6270, (2000).
27. Y. Ma, C. Qian, L. Wang, M.Yang,; “ Lanthanide triflate catalyzed
Biginelli reaction. One-pot synthesis of dihydropyrimidinones under
solvent-free conditions.” J. Org. Chem., 65, 3864, (2000).
28. K. Ramalinga, P. Vijayalakshmi, T. N. B. Kaimal,; “ Bismuth(III)catalyzed synthesis of dihydropyrimidinones: improved protocol
conditions for the Biginelli reaction.” Synlett., 863, (2001).
29. V. Radha Rani, N. Srinivas, M. Radha Kishan, S. J. Kulkarni and K. V.
Raghavan,; “Zeolite-catalyzed cyclocondensation reaction for the
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
66
selective synthesis of 3,4-dihydropyrimidin-2(1H)-ones” Green Chem.,
3, 305–306, (2001).
30. J. Lu, Y. Bai, Z. Wang, B. Yang, H. Ma,; “ One-pot synthesis of 3,4dihydropyrimidin- 2 (1H)-ones using lanthanum chloride as a catalyst.”
Tetrahedron Lett. , 41, 9075, (2000).
31. A. Khodabocus, B. M. P. Beebeejaun,; “ Convenient acid catalysed
esterification of hydrooxyionone.” Sci. Technol. 5, 21, (2000).
32. D. R. Treadwell, D. M. Dabbs, I. A. Aksay,; “ Mullite (3Al2O3–2SiO2)
synthesis with aluminosiloxanes.” Chem. Mater., 8, 2056, (1996).
33. T. Jin, H. Wang, C.Xing, X. Li, and T. Li ,; “An Efficient One-Pot
Synthesis of 3,4-Dihydropyrimidin-2-ones Catalyzed by
Methanesulfonic Acid” Synth. Comm., 34, 16, 3009–3016, (2004).
SECTION – V
Synthesis of
2-Amino Dihydropyrimidines
Studies of some bio-active heterocyclic…
Section-I: Synthesis of 1,4 – Dihydropyrimidin-2H-imines
67
INTRODUCTION
Dihydropyrimidines, the synthetic potential of this new
heterocyclic synthesis remained unexplored for quite some time. In the 1970s
and 1980s interest slowly increased, and the scope of the original
cyclocondensation reaction was gradually extended by variation of all three
building blocks, allowing access to a large number of multifunctionalized
dihydropyrimidines1
In recent years interest has also focused on aza-analogs such as
dihydropyrimidines (DHPMs) which show a very similar pharmacological
profile to classical dihydropyridine calcium channel modulators 2,3. These
asymmetric DHPM derivatives have not only very potent calcium channel
modulators, but also have been studied extensively to expand the existing
structure-activity relationships and to get further insight into molecular
interactions at the receptor level 4-10.
Over the past decade, anti-bacterial activity of of 2-amino-5-cyano-6hydroxy-4-aryl pyrimidines has been developed by Deshmukh et al.11 Yarım et
al. have been reported structurel elucidation and pharmacological properties
of some dihdro-pyrimidine-2(1H)-imino derivatives.12 Toshio et al. have
reported antihypertensive properties of 5-acetyl-2-halo-4,6- disubstitutedpyrimidines as intermediates.13 The effect of tetrahydropyrimidine2(1H)-imino
derivatives on cardiovascular system has been studied by Vitolina et al.14
Gojkovic et al. have been reported a novel fungal catabolic pathway of
5,6-dihydropyrimidine2(1H)-imino15 which have also repoted model organism
for studying the catabolism of pyrimidines.16 Kautz et al. has also studied of
dihydropyrimidine amidohydrolase from calf liver.17 Matsuda et al reported
molecular cloning and sequencing of a cDNA encoding dihydropyrimidinase
from the rat liver.18 Vogels et al. reported pyrimidines bases, several anticancer drugs have been degraded via a reductive or an oxidative pathway 19.
and pharmacokinetics studies of pyrimidine based drugs, like 5-fluorouracil
have been achieved by Kubota et al.20
Potapov et al. have reported condensation of hetarylguanidines with
aldehydes (Ketones) and dicarbonyl compounds.21Shaabani et al. have
reported preparation 3,4-dihydropyrimidin- 2-(1H)-imino with NH4Cl as a
Studies of some bio-active heterocyclic…
Section-I: Synthesis of 1,4 – Dihydropyrimidin-2H-imines
68
catalyst under neutral and solvent-free Conditions.22 Dondoni et al. have been
studied synthesis of dihydropyrimidinyl and pyridyl R-amino Acids via threecomponent Biginelli and Hantzsch cyclocondensations.23 Nilsson et al
reported synthesis of Guanidine-containing heterocycles using the Biginelli
reaction.24 Deshmukh et al. have been reported A green, simple and
environmentally friendly approach towards one-step synthesis of 2,6-diamino4-phenyl pyrimidine-5-carbonitrile by three-component condensation by using
potassium carbonate and in presence of tetrabutyl ammonium bromide.25
In the present section, some new dihydro pyrimidine-imines have been
synthesized.
Studies of some bio-active heterocyclic…
Section-I: Synthesis of 1,4 – Dihydropyrimidin-2H-imines
69
EXPERIMENTAL
Synthesis of 4-(3,-methoxy4-ethoxyphenyl)-6-methyl-2-imino-N-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxamide.
[A] Synthesis of 3,-methoxy4-ethoxy benzaldehyde:
An aqueous solution of vanillin (0.01M) was refluxed at 95-97 0C for
half an hour with stirring. To this solution, few drops of NaOH and diethyl
sulphate (0.012 M) were added slowly and again the reaction mixture was
refluxed for 5 to 7 hrs with stirring. The reaction was monitored by TLC. After
the completion of reaction, organic layer was isolated and cooled at room
temperature. The solid crude product was isolated and crystallized from
absolute ethanol. (Scheme-1)
[B] Synthesis of 3-oxo-N-phenylbutanamide:
A mixture of substituted aniline (0.01 M) and ethylacetoacetate (0.012
M) in 40 ml toluene was refluxed for 12 hours in presence of few drops of
slurry of NaOH in water. The reaction was monitoring with TLC. The excess of
toluene was distilled out and the reaction mixture was taken in hexane and
stirred with glass rod. The products were isolated in hexane and filtered. The
crude product was dried. This product was taken in aqueous NaOH solution
and neutralized with dilute HCl. The recrystalisation was done in ethanol.
(Scheme-2)
[C] Synthesis of 4-(3,methoxy 4-ethoxyphenyl)-6-methyl-2- imino N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide:
A solution of 3-methoxy4-ethoxy aldehyde (0.01 M), substituted
diketones (0.012 M) and guanidine (0.015 M) in methanol was refluxed for 12
hours in presence of few drops of concentrated HCl as catalyst. The product
was isolated and crystallized from ethanol. All the synthesized compounds
were recrystallized from ethanol.(Scheme-3)
Studies of some bio-active heterocyclic…
Section-I: Synthesis of 1,4 – Dihydropyrimidin-2H-imines
70
Scheme 1:
OH
O
O
CH3
DES
H2O, NaOH
O
O
O
CH3CH3
Reflux
Scheme 2:
NH2
R
Toluene
NaOH
+ CH3 O
CH3
O O
120
0
C
NH CH3
O O
R
reflux
Scheme 3:
NH CH3
O O
R
+
O
O
CH3
O
CH3
+ NH2
NH2
NH
H
+
Reflux
Methanol
NH
N
H
NH
O
CH3
O
O
CH3
NH
CH3
R
R = Functional group
Studies of some bio-active heterocyclic…
Section-I: Synthesis of 1,4 – Dihydropyrimidin-2H-imines
71
Table 1.1: Physical constants of Dihydropyrimidinones.
Sr. No. Code R M.F.
M. Wt.
(g/mol)
Rf*
Value
M.P.
oC Yield
%
1 NVG-1 4-Cl- C21H23 ClN4O4 414 0.34 199 59
2 NVG-2 3,4-Cl- C21H22 Cl2N4O4 449 0.57 178 57
3 NVG -3 4-OCH3- C22H25 N4 O4 410 0.61 230 67
4 NVG -4 3-Cl,4-F- C21H22 ClFN4O4 432 0.43 223 57
5 NVG -5 3,4- CH3 C23H28 N4O4 408 0.35 249 55
6 NVG -6 4-Cl- C21H23ClN4O4 414 0.76 228 63
7 NVG -7 4-F- C21H23 ClN4O4 398 0.42 196 57
8 NVG -8 2-Cl,5-F C21H21 ClFN4O4 432 0.59 212 62
9 NVG -9 H C21H24N4O4 380 0.63 144 51
10 NVG-10 2,4-Cl- C21H22 Cl2N4O4 449 0.64 194 62
* Ethyl acetate:Hexane: 2:8
Studies of some bio-active heterocyclic…
Section-I: Synthesis of 1,4 – Dihydropyrimidin-2H-imines
72
The characterization was done by IR, 1H NMR and mass spectra.
Infrared spectra:
The IR spectra were recorded by SHIMADZU-FTIR-8400
Spectrophotometer in the frequency range of 4000-400 cm-1 by KBr powder
method. Figure 1.1 shows IR spectra of NVG-1. The IR spectral data for NVG1 is given in Table 1.2. The spectral data for all other compounds are reported
in Table 1.3.
1H NMR Spectra:
The NMR spectra were recorded by BRUKER Spectrometer (400 MHz)
using internal reference TMS and solvent CDCl3/DMSO. Figure 1.2 shows
NMR spectra of NVG-1. The spectral data for NVG-1 is given in Table 1.4.
Mass spectra:
The Mass spectra were recorded by GCMS-SHIMADZU-QP2010. Figure
1.3 shows mass spectra of NVG-1The proposed mass fragmentation of the
same compound is also given in Scheme 1.1.
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
73
Figure 1.1: IR spectra of 4-(3,methoxy4-ethoxyphenyl)-6-methyl2- imino -phenyl- 1,2,3,4-tetrahydropyrimidine-5-carboxamide:
(NVG-01).
Table 1.2: IR spectra of 4-(3,methoxy4-ethoxyphenyl)-6-methyl-2imino -phenyl- 1,2,3,4-tetrahydropyrimidine-5-carboxamide:
(NVG-01).
Type Vibration mode
Frequency in cm-1
Observed Reported
Alkane
C-H str. (asym.) 2939 2975-2900
C-H str. (sym.) 2842 2880-2810
C-H def. (asym.) 1447 1480-1435
C-H def. (sym.) 1427 1985-1350
Aromatic
C-H str. 3011 3100-3000
C=Cstr. 1580 1585-1480
C-H i.p. def. 1125 1125-1090
C-H o.o.p. def. 841 860-810
Ketones C=O str.(cyclic) 1710 1740-1680 C=O str. (alip.) 1684 1710-1650
Nitrogen
C-N str. 1258 1350-1200
N-H str. 3315 3400-3200
N-H def. 1583 1650-1500
Ether C-O-C str. (asym.) 1189 1400-1000 C-O-C str. (sym.) 1036 1075-1020
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
74
Table 1.3: IR spectral data of synthesized Dihydropyrimidinones.
Compounds
IR , (cm-1)
C=O
(cyclic)
C=O
(alip.)
N-H C=C
C=H
(asym.) R
NVG-1 1710 1684 3315 1580 2939 734
NVG-2 1707 1678 3286 1502 2972 633
NVG-3 1722 1673 3267 1529 2955 1129
NVG-4 1722 1669 3311 1529 2922 736
NVG-6 1711 1666 3261 1514 2967 758
NVG-7 1708 1679 3288 1522 2962 638
NVG-8 1720 1659 3309 1520 2912 762
NVG-9 1714 1670 3269 1519 2967 759
NVG-10 1709 1677 3285 1507 2962 671
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
75
Figure 1.2: 1H NMR spectra of 4-(3,methoxy4-ethoxyphenyl)-6-methyl-2-imino-N-phenyl-1,2,3,4 tetrahydropyrimidine
5-carboxamide: (NVG-01).
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
76
Table 1.4: 1H NMR spectral data of 4-(3,methoxy4-ethoxyphenyl)
-6-methyl-2-imino-N-phenyl-1,2,3,4-tetrahydropyrimidine-5carboxamide: (NVG-01).
NH
N
H
NH
O
CH3
O
O
CH3
NH
CH3
Cl a b c d e
f g h i j k l m m' n n' Singal
No.
Signal
Position
(δ ppm)
Relative No.
of Protons Multiplicity Inference
1a 1.26 3 singlet -CH3
2b 3.81 2 quvartret -OCH2
3c 7.39 1 doublet Ar-Hc
4d 7.31 1 doublet Ar-Hd
5e 7.36 1 singlet Ar-H’e
6f 3.35-3.52 3 singlet -OCH3
7g 5.46 1 singlet Ar-Hg
8h 8.10 1 singlet Ar- NH9i 9.66-9.82 1 singlet Ar NH10j 10.48-10.58 1 singlet Ar NH11k 3.36 3 singlet Ar-CH3
12l 8.72 1 singlet Ar-NH-CO
13m 7.57-7.62 2 doublet Ar-Hk+k’
14n 7.27-7.33 2 doublet Ar-Hl+l”
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
77
Figure 1.3: Mass spectra of 4-(3-methoxy4-ethoxyphenyl)-6-methyl-2-imino-N-phenyl-1,2,3,4-tetrahydropyrimidine-5carboxamide: (NVG-01).
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
78
NH
N
H
NH
O
O
O
NH
Cl CH3
NH
N
H
NH
O
O
OH
NH
CH3
Cl [m/z=401] [m/z=384]
[m/z=338]
NH
N
H
NH2
O
OH
NH
OH
[m/z=262]
NH
N
H
O
OH
NH
OH
[m/z=248]
NH
N
H
NH
OH
OH
[m/z=219]
NH
NH2 NH
[m/z=163]
[m/z=152]
NH
N
H
NH
O CH3
[m/z=112]
[m/z=108]
[m/z=77]
[m/z=415]
. .
.
.
.
..
.
.
.
.
NH
N
H
NH
O
OH
NH
O
Cl NH
N
H
NH
O
OH
NH
OH
Cl [m/z=372]
NH
N
H
NH
O
OH
NH
OH
O CH3
O
Scheme 1.1: Proposed mass fragmentation of 4-(3,methoxy4-ethoxy
phenyl)-6-methyl-2-imino-N-phenyl-1,2,3,4-tetrahydropyrimidine-5carboxamide:(NVG-01).
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
79
REFERENCES
1. P. A. Patil , R. P. Bhole, R. V. Chikhale, K. P. Bhusari,; “Synthesis of 3,4Dihydropyrimidine-2(1H)-one Derivatives using Microwave for their
Biological screening” Int. J. Chem. Tech. Res.,1, 2, 373-384, (2009).
2. B. Jauk, F. Belaj and C. O. Kappe,; “Synthesis and reactions of Biginellicompounds. Part 14.1 A rhodium-induced cyclization–cycloaddition
sequence for the construction of conformationally rigid calcium channel
modulators of the dihydropyrimidine type” J. Chem. Soc., Perkin Trans. 1,
307–314, (1999).
3. B. Jauk, T. Pernat and C. O. Kappe,; “Design and Synthesis of a
Conformationally Rigid Mimic of the Dihydropyrimidine Calcium Channel
Modulator SQ 32,926 “Molecules, 5, 227-239, (2000).
4. H. Cho,; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu, M.; Ohnaka, Y.;
Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda,
M.; Ishihara, T.; Funahashi, K.; Satah, F.; Morita, M.; Noguchi, T. J. Med.
Chem., 32, 2399, (1989).
5. K. Atwal, G. C. Rovnyak, J. Schwartz, S. Moreland, A. Hedberg, J. Z.
Gougoutas, M. F. Malley, D. M.Floyd,; “Dihydropyrimidine calcium
channel blockers: 2- heterosubstituted 4-aryl-1,4-dihydro-6-methyl-5pyrimidine carboxylic acid esters as potent mimics of dihydro pyridines” J. Med. Chem., 33, 1510, (1990).
6. K. S. Atwal, G. C. Rovnyak, S. D. Kimball, D. M. Floyd, S. Moreland, B. N.
Swanson, J. Z.Gougoutas, J. Schwartz, K. M. Smillie, M. F. Malley,;
“Dihydropyrimidine calcium channel blockers. II. 3-Substituted-4aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as
potent mimics of dihydropyridines” J. Med. Chem., 33, 2629, (1990).
7. K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S. Moreland, A.
Hedberg, B. C O´Reilly,; “Dihydropyrimidine calcium channel
blockers. 3. 3-Carbamoyl-4-aryl-1,2,3,4- tetrahydro-6-methyl-5-pyrimidine
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
80
carboxylic acid esters as orally effective antihypertensive agents” J. Med.
Chem., 34, 806, (1991).
8. G. C. Rovnyak, K. S. Atwal, A. Hedberg, S. D. Kimball, S. Moreland, J. Z.
Gougoutas, B. C. O´Reilly, , J. Schwartz, M. F. Malley,;
“Dihydropyrimidine calcium channel blockers. 4.Basic 3-substituted-4-aryl1,4- dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive
agents” J. Med. Chem., 35, 3254, (1992).
9. Grover, G.J.; Dzwonczyk, S.; McMullen, D. M.; Normadinam, C. S.; Sleph,
P. G.; Moreland, S. J. J. Cardiovasc. Pharmacol., 26, 289, (1995).
10. (a) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; DiMarco, J.
D.; Gougoutas, J.; Hedberg, A.; Malley, M.; McCarthy, J. P.; Zhang, R.;
Moreland, S. J. Med. Chem. 38, 119, (1995). (b) N. S. Begum and D. E.
Vasundhara,; “Ethyl 3-acetyl-4-(4-methoxyphenyl)-6-methyl--oxo-1,2,3,4tetrahydropyrimidine-5-carboxylate” Acta Cryst. E63, o3741-o3742,
(2007).
11. (a) Kappe, C. O.;’ “100 Years of the Biginelli Dihydropyrimidine Synthesis”
Tetrahedron 49, 6937, (1993) (b) Kappe, C. O. Acc. Chem. Res. 33, 879,
(2000).
12. A. Y.. Potapov, K. S. Shikhaliev, D. V. Krylsky, and M. Y. Krisin,; “Threecomponent condensation of hetarylguanidines with aldehydes (Ketones)
and dicarbonyl compounds” Chem. Hetero. Comp., 42, 10, (2006).
13. M. B. Deshmukh, S. M. Salunkhe, D. R. Patil ,P. V. Anbhule,; “A novel and
efficient one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl
pyrimidines and their anti- bacterial activity” Eur. J. Med. Chem.,
44, 2651-2654, (2009).
14. M. Yarım, S. Sarac, M. Ertan , O. (Sarnıc¸) Batu , K. Erol,; “Synthesis,
structural elucidation and pharmacological properties of some 5-acetyl3,4-dihydro-6-methyl-4-(substituted phenyl)-2(1H)-pyrimidinones” Il
Farmaco ,54, 359–363, (1999).
15. I. Toshio, N. Takashi, T. Yoshiho, M. Mitsuhiro, I. Shigeru, A. Hiroshi, I.
Masayaku,; “ Preparation of 5-acetyl-2-halo-4,6- disubstituted-pyrimidines
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
81
as intermediates for antihypertensives” Jpn. Kokai Tokkyo Koho JP, 114,
228948y, (1991).
16. R. Vitolina, A. Kimenis,; “Effects of tetrahydropyrimidine derivatives on the
cardiovascular system” Khim. Farm. Zh., 23 285, (1989).ref. CA 111
(1989) 188c.
17. A. Shaabani, A. Bazgir and F. Teimouri,; “Ammonium chloride-catalyzed
one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones under solvent-free
conditions” Tetrahedron Lett. ,44 , 857–859, (2003).
18. A. Dondoni, A. Massi, E. Minghini, S. Sabbatini, V.Bertolasi,; “ Model
studies toward the synthesis of dihydropyrimidinyl and pyridyl R-amino
acids via three-component Biginelli and Hantzsch cyclocondensations.” J.
Org. Chem., 68, 6172-6183, (2003).
19. Z.Gojkovic, , K. Jahnke, K. D. Schnackerz, and J. Piskur,; “ PYD2
encodes 5,6-dihydropyrimidine amidohydrolase, which participates in a
novel fungal catabolic pathway” J. Mol. Bio., 295, 1073-1087, (2000).
20. Z. Gojkovic, , S. Paracchini, and J. Piskur,; “A new model organism for
studying the catabolism of pyrimidines and purines.” Adv. Exp. Med. Biol.
431, 475-479, (1998).
21. J. Kautz, and K. D. Schnackerz,; “Purification and properties of 5,6dihydropyrimidine amidohydrolase from calf liver” Eur. J. Biochem. 181,
431-435, (1989).
22. K. Matsuda, S. Sakata, M. Kaneko, N. Hamajima, M. Nonaka, M. Sasaki,
N. Tamaki,; “Molecular cloning and sequencing of a cDNA encoding
dihydropyrimidinase from the rat liver” Biochim. Biophys. Acta ,1307, 140144, (1996).
23. G. D. Vogels, and C.van der Drift,; “Degradation of purines and
pyrimidines by microorganisms” Bacteriol. Rev. 40, 403-468, (1976).
24. T. Kubota,; “ 5-fluorouracil and dihydropyrimidine dehydrogenase” Int. J.
Clin. Oncol. ,8, 127-131, (2003).
Synthesis and physicochemical…….
Section-I: Synthesis of Dihydropyrimidinones
82
25. B. L. Nilsson and L. E. Overman,; “Concise synthesis of guanidinecontaining heterocycles using the Biginelli reaction” J Org Chem., 29;
71(20): 7706–7714, (2006).
26. M B Deshmukh, P. V. Anbhule, S. D. Jadhav, S. S. Jagtap, D. R. Patil, S
Salunkhe & S. A. Sankpal,; “A novel and environmental friendly, one step
synthesis of 2,6-diamino-4-phenyl pyrimidine-5-carbonitrile using
potassium carbonate in water” Ind. J. Chem.,47-B, (2008).
CHAPTER - 3
PHYSICO CHEMICAL
PROPERTIES
SECTION – I
ACOSTICAL PROPERTIES
Studies of some bio active hetero…….
Section-I: Acoustical property
  83
INTRODUCTION
“Ultrasound” refers to sound waves of such a high frequency that it cannot
be heard. These waves are also known as silent sound waves having
frequencies beyond the range of human hearing i.e. above 20 KHz (20,000
cycles per second). However, bats, dogs can hear these waves. Bats use
ultrasounds to move in darkness and also for searching food. Dolphins and some
other whales also use the ultrasounds as a hunting tool.
Now a day’s Ultrasonic technology is employed in a wide range of
applications in medicine, biology, industry, material science, agriculture, oceanography, sonochemistry research etc. due to its non-destructive nature 1-8.
High resolution ultrasound imaging has been used for determination of
melanoma invasion depth in vivo for preoperative staging purposes 9-10.
Ultrasonography provides a wide array of morphologic information without
invading or disturbing the tissues. The research potential of this technology and
its adaptability for computer-assisted assessment go far beyond simplistic
determination of ovulation, luteal formation, pregnancy diagnosis,
radioimmunoassay 11-13 etc. Further, these waves have applications in
angiography 14-16, echocardiography 17-19 and magnetic resonance imaging
techniques.20-21
Further, these ultrasound waves have been employed for the treatment of
several diseases, including thromboembolism, arteriosclerosis, cancer,
Cardiovascular, calcific tendinitis of the shoulder and gene delivery applications
22-27. Recently, ultrasound is used for making tablets from pharmaceutical
powders.
In the metallurgy, these ultrasonic waves are used for corrosion study,
electroplating 28, galvanizing 29, metal degreasing 30 ultrasonic welding for joining
of metals. 31 These waves also have applications in plastic and ceramic
industries. 32-35 Ultrasound wave’s applications in continuous culture have been
great potential for the biotechnological techniques 36-44. These waves have also
Studies of some bio active hetero…….
Section-I: Acoustical property
  84
been used to extract and release intracellular enzymes such as invertase, to
promote enzyme release, enhance productivity in biological processes 45 etc.
In field of agriculture, ultrasound waves have been utilized extensively in
chemical additives (fertilizers and plant protection preparations) for improving the
production yield of food produced. Further, it is used to study the substitution of
chemical fertilizers and soil additives with alternative treatment methods, such as
irradiation, measure composition traits in live cattle and the use of
electromagnetic energy. 46-49. It is also applied for inactivation of micro-organisms
in food and dairy industry 50-52. In materials chemistry, ultrasound waves have
been useful in the preparation of biomaterials, protein microspheres, in the
modification of polymers and polymer surfaces etc 53-58.
Recently, ultrasound radiations are used in synthetic organic chemistry,
which causes a decrease of reaction time, increase of yield, lower reaction
temperature, avoidance of phase transfer catalysis etc 59-64. Further, ultrasonic
velocity measurements have been used to study the nature of molecular
interactions in various binary 65-75 and ternary 76-81 liquid mixtures. Much work has
been done in solutions of polymers 82-87, pharma materials 88-91, amino acids 92-93
and other electrolytes 94-100 and non-electrolytes 101-105. However, little work has
been done for solutions of solid organic compounds 106-111.
Thus, in the present chapter, acoustical studies of some synthetic
chalcones of vanillin derivatives have been studied in DMF and Chloroform at
303.15 K over a wide range of concentrations. 
Studies of some bio active hetero…….
Section-I: Acoustical property
  85
EXPERIMENTAL
The selected solvents DMF and Chloroform for the present study are
distilled by the reported procedure112. The synthesized Chalcones were
recrystallized before use.
The densities and ultrasonic velocities of solvents and solutions of
Chalcones of different concentrations were measured at 303.15 K by using
pyknometer and single frequency ultrasonic interferometer operating at 2 MHz,
with the uncertainties of 0.0001 g/cm3 and 0.01% respectively.
Density measurements:
The weight of distilled water, pure solvents and solutions of Chalcone of
vanillin derivatives were measured by using pyknometer. The densities (ρ) were
evaluated by using following equation:
( ) ( )( )( )
3 wt. of solvent or solution density of waterρ g cm =
wt. of water
… (3.1.1)
Viscosity Measurements:
To determine the viscosity of solution, Ubbelohde viscometer (113) was
used, which obeys Stoke’s low. The measured quantity of the distilled water /
solvent / solution was placed in the viscometer, which was suspended in a
thermostat at 298.15 K. The digital stopwatch, with an accuracy of + 0.01 sec
was used to determine flow time of solutions. Using the flow times (t) and known
viscosity of standard water sample, the viscosity of solvent and solutions were
determined according to equation:
1 1 1
2 2 2
t t η ρ
η ρ
= ... (3 .1.2)
Sound velocity measurement:
Ultrasonic interferometer,(Mittal Enterprise, New Delhi, Model No. F-81)
working at frequency of 2 MHz was used to determine sound velocity.
Studies of some bio active hetero…….
Section-I: Acoustical property
  86
The solvent / solution were filled in the measuring cell with quartz crystal
and then micrometer was fixed. The circulation of water from the thermostat at
303.15 K was started and test solvent / solution in the cell is allowed to thermally
equilibrate. The micrometer was rotated very slowly so as to obtain a maximum
or minimum of anode current (n). A number of maximum reading of anode
current were counted. The total distance (d) travel by the micrometer for n=10,
was read. The wave length (λ) was determined according to the equation (3.1.3).
2d n λ = … (3.1.3)
The sound velocity (U) of solvent and solutions were calculated from the
wavelength and frequency (F) according to equation (3.1.4).
U Fλ= ... (3.1.4)
where, F= 2 × 106 Hertz.
Studies of some bio active hetero…….
Section-I: Acoustical property
  87
RESULTS AND DISCUSSION
Table 3.1.1 shows the experimental data of density (ρ), viscosity and sound
velocity (U) of pure solvents and solutions of synthesized Chalcones in DMF and
Chloroform at 303.15 K.
From these experimental data, various acoustical parameters were
evaluated using the following equations:
1. Isentropic compressibility:
Isentropic compressibility ( sκ ) was evaluated by Krishnamurty et al.
113
:
2
1
s U
κ
ρ
= … (3.1.5)
2. Intermolecular free path length:
The intermolecular free path length (Lf), was calculated by equation
114:
1 2f j sL K κ= … (3.1.6)
where KJ is Jacobson constant (=2.0965 X 10
-6)
3. Molar compressibility:
Molar compressibility (W) can be calculated by the following equation
115
:
1 7s
MW κ
ρ
−⎛ ⎞= ⎜ ⎟
⎝ ⎠
… (3.1.7)
The apparent molecular weight (M) of the solution can be calculated as:
1 1 2 2M M W M W= + … (3.1.8)
where W1 and W2 are weight fractions of solvent and solute, respectively. M1
and M2 are the molecular weights of the solvent and compounds respectively.
Studies of some bio active hetero…….
Section-I: Acoustical property
  88
4. Rao’s molar sound function:
Rao’s molar sound function (Rm) can be evaluated by an equation given
by Bagchi et al.
116
:
1 3m
MR U
ρ
⎛ ⎞
= ⎜ ⎟
⎝ ⎠
… (3.1.9)
5. Van der Waals Constant:
Van der Waals constant (b) can be calculated as follows 117:
2
21 1 13
M RT MUb
MU RTρ
⎧ ⎫⎡ ⎤⎪ ⎪⎛ ⎞= − + −⎢ ⎥⎨ ⎬⎜ ⎟
⎝ ⎠ ⎢ ⎥⎪ ⎪⎣ ⎦⎩ ⎭
... (3.1.10)
where R is the gas constant (=8.3143 JK-1 mol-1) and T is the absolute
temperature.
6. Relaxation Strength:
The relaxation strength (r) can be calculated as follows 118:
2
1r U
U
= −

⎡ ⎤
⎢ ⎥
⎣ ⎦
… (3.1.11)
where ∞U = 1.6 x 105 cm.s
-1
7. Solvation number:
2
1 1
1 100s
n s M XS
M X
κ
κ
⎡ ⎤− −⎡ ⎤= ⎢ ⎥ ⎢ ⎥⎣ ⎦⎣ ⎦
… (3.1.12)
where X is the number of grams of solute in 100 gm of the solution. M1 and M2
are the molecular weights and κS1 and κS are isentropic compressibility of solvent
and solute respectively.
Studies of some bio active hetero…….
Section-I: Acoustical property
  89
Table 3.1.1: The density (ρ), ultrasonic velocity (U) and viscosity (η) of
chalcone of vanillin derivatives in DMF and chloroform at 303.15 K.
Conc.
M
Density
ρ
g.cm-3
Velocity
U. 10-5
cm.s-1
Viscosity
η.103
poise
Density
ρ
g.cm-3
Velocity
U. 10-5
cm.s-1
Viscosity
η.103
poise
DMF Chloroform
NVA-1 NVA-1
0.00 0.9417 1.4388 5.7887 1.4748 0.9696 4.2657
0.01 0.9430 1.4444 6.7031 1.47481 0.9712 4.4573
0.02 0.9438 1.4448 6.7998 1.47492 0.9730 4.4754
0.04 0.946 1.4468 7.7111 1.47525 0.9744 4.5120
0.06 0.9482 1.4472 8.0514 1.47547 0.9760 4.5152
0.08 0.9493 1.4484 8.4512 1.47575 0.9784 4.5364
0.10 0.9512 1.4492 8.6957 1.47612 0.9831 4.5528
NVA-2 NVA-2
0.01 0.9424 1.4416 5.9300 1.4783 0.9694 4.4755
0.02 0.9427 1.4420 6.0617 1.4786 0.9708 4.4942
0.04 0.944 1.4424 6.1245 1.4753 0.9732 4.5198
0.06 0.9455 1.4440 6.1831 1.4757 0.9768 4.5235
0.08 0.9456 1.4456 6.2415 1.47608 0.9792 4.5450
0.10 0.9468 1.4464 6.3309 1.4763 0.9818 4.5609
NVA-3 NVA-3
0.01 0.9422 1.4424 5.8534 1.47496 0.9697 4.4895
0.02 0.9432 1.4432 5.9756 1.47548 0.9702 4.5089
0.04 0.9426 1.4436 6.1154 1.47596 0.9715 4.5459
0.06 0.9445 1.4444 6.2529 1.47648 0.9754 4.5501
0.08 0.9458 1.4448 6.3209 1.4769 0.9770 4.5717
0.10 0.9461 1.4460 6.3751 1.47722 0.9798 4.5879
NVA-4 NVA-4
0.01 0.9429 1.4396 6.0305 1.47638 0.9698 4.5104
0.02 0.9431 1.4404 6.4214 1.47666 0.9707 4.5290
0.04 0.9443 1.4412 6.7278 1.47713 0.9730 4.5660
0.06 0.9453 1.4420 6.8952 1.47753 0.9754 4.5698
0.08 0.9474 1.4432 7.1380 1.47792 0.9780 4.5914
0.10 0.9476 1.4456 7.2121 1.47814 0.9820 4.6073
NVA-5 NVA-5
0.01 0.9418 1.4396 5.8971 1.47531 0.9700 4.4639
0.02 0.9429 1.4400 5.9591 1.47559 0.9705 4.4826
0.04 0.9437 1.4412 6.0519 1.47606 0.9722 4.5196
0.06 0.9447 1.4424 6.1599 1.47646 0.9747 4.5233
0.08 0.9463 1.4436 6.2209 1.47682 0.9771 4.5448
0.10 0.9464 1.4448 6.2419 1.47704 0.9799 4.5607
Studies of some bio active hetero…….
Section-I: Acoustical property
  90
Conc.
M
Density
ρ
g.cm-3
Velocity
U. 10-5
cm.s-1
Viscosity
η.103
poise
Density
ρ
g.cm-3
Velocity
U. 10-5
cm.s-1
Viscosity
η.103
poise
DMF Chloroform
NVA-6 NVA-6
0.00 0.9417 1.4388 5.7887 1.47541 0.9735 4.5430
0.01 0.9422 1.4436 5.9417 1.47573 0.9740 4.5579
0.02 0.9433 1.4448 5.9982 1.4762 0.9753 4.5784
0.04 0.9445 1.4488 6.0790 1.47668 0.9755 4.6295
0.06 0.9458 1.4496 6.2086 1.4771 0.9771 4.6498
0.08 0.9473 1.4504 6.3114 1.47736 0.9785 4.6710
0.10 0.9476 1.4508 6.3477 1.47541 0.9735 4.5430
NVA-7 NVA-7
0.01 0.9445 1.4460 6.1651 1.47555 0.9684 4.4875
0.02 0.9449 1.4500 6.2710 1.47596 0.9686 4.5027
0.04 0.9479 1.4532 6.5356 1.47644 0.9701 4.5169
0.06 0.9489 1.4568 6.7900 1.47692 0.9734 4.5374
0.08 0.9503 1.4612 6.9038 1.47738 0.9743 4.5643
0.10 0.9543 1.4628 7.1169 1.47761 0.9796 4.6324
NVA-8 NVA-8
0.01 0.9461 1.4464 6.0469 1.47504 0.9678 4.5164
0.02 0.9461 1.4508 6.1976 1.47538 0.9688 4.5314
0.04 0.9471 1.4568 6.4258 1.47606 0.9715 4.5526
0.06 0.9491 1.4600 6.7800 1.47658 0.9754 4.6037
0.08 0.9507 1.4616 7.0589 1.4769 0.9770 4.6238
0.10 0.9516 1.4640 7.9042 1.47722 0.9798 4.6451
NVA-9 NVA-9
0.01 0.9434 1.4424 6.0086 1.47559 0.9690 4.5118
0.02 0.9441 1.4444 6.0496 1.47608 0.9700 4.5272
0.04 0.9447 1.4456 6.0827 1.47646 0.9727 4.5475
0.06 0.9454 1.4468 6.1336 1.47728 0.9766 4.5996
0.08 0.9462 1.4476 6.2243 1.4785 0.9782 4.6224
0.10 0.9474 1.4488 6.3912 1.47882 0.9810 4.6438
Studies of some bio active hetero…….
Section-I: Acoustical property
  91
Some of these calculated parameters are given in Table 3.1.2 for chalcones in
DMF and Chloroform respectively. Figure 3.1.1 shows the variation of ultrasound
velocity (U) with concentration in DMF and Chloroform. It is observed that overall
ultrasonic velocity (U) increases with concentration for all the compounds in both
the solvents. The velocity depends on intermolecular free length (Lf). The velocity
increases with decrease in Lf or vice versa. It is evident from Table 3.1.2 that Lf
decreases continuously, which suggests that there is strong interaction between
solvent (both DMF and Chloroform) and compound molecules.
This is further supported by isentropic compressibility (κs) and relaxation
strength (r) values. The variation of isentropic compressibility (κs) with
concentration of these compounds is also shown Figure 3.1.2 for all the solutions
in both the solvents. Both isentropic compressibility (κs) and relaxation strength
(r) (in Table 3.1.2) are observed to decrease with concentration for all the
compounds. The decrease of κs with increasing concentration might be due to
aggregation of solvent molecules around solute molecules indicating thereby the
presence of solute-solvent interactions.
Figure 3.1.3 shows the linear variation of molar compressibility (W) with
concentration whereas Table 3.1.2 shows the variation of molar sound function
(Rm) and Vander Waals constant (b) with concentration. The correlation
coefficients for these parameters are in the range of 0.9989- 0.9999. This linear
increase of these parameters suggests the absence of complex formation in
these systems.
Studies of some bio active hetero…….
Section-I: Acoustical property
  92
Table 3.1.2: Some acoustical parameters of chalcones in DMF and chloroform at
303.15 K.
Conc.
M
Lf Ao r
Rm.10-3
cm8/3
.s-1/3
b cm3.mol-1
Lf Ao r
Rm.10-3
cm8/3
.s-1/3
b cm3.mol-1
DMF Chloroform
NVA-1 NVA-1
0.00 0.1502 0.1913 4.0670 77.6131 0.1780 0.6328 3.7225 81.0257
0.01 0.1495 0.1850 4.1120 78.3705 0.1778 0.6316 3.7376 81.3111
0.02 0.1494 0.1846 4.1542 79.1661 0.1774 0.6302 3.7529 81.5909
0.04 0.1490 0.1823 4.2364 80.6957 0.1771 0.6291 3.7801 82.1439
0.06 0.1488 0.1819 4.3163 82.2103 0.1768 0.6279 3.8079 82.7028
0.08 0.1486 0.1805 4.4018 83.8148 0.1764 0.6260 3.8366 83.2579
0.10 0.1483 0.1796 4.4823 85.3328 0.1755 0.6225 3.8681 83.8072
NVA-2 NVA-2
0.01 0.1498 0.1882 4.1158 78.3607 0.1779 0.6329 3.7277 81.1451
0.02 0.1497 0.1877 4.1639 79.5521 0.1776 0.6319 3.7430 81.4397
0.04 0.1496 0.1873 4.2564 81.9877 0.1774 0.6300 3.7834 82.2482
0.06 0.1493 0.1855 4.3485 84.3850 0.1767 0.6273 3.8157 82.8502
0.08 0.1491 0.1837 4.4473 86.7819 0.1762 0.6255 3.8466 83.4527
0.10 0.1490 0.1828 4.5395 89.1708 0.1757 0.6235 3.8782 84.0640
NVA-3 NVA-3
0.01 0.1497 0.1873 4.1032 78.2372 0.1780 0.6327 3.7319 81.2282
0.02 0.1496 0.1864 4.1370 78.8685 0.1779 0.6323 3.7409 81.4106
0.04 0.1496 0.1859 4.2044 80.1451 0.1776 0.6313 3.7608 81.8059
0.06 0.1494 0.1850 4.2687 81.3553 0.1769 0.6284 3.7838 82.1984
0.08 0.1492 0.1846 4.3322 82.5585 0.1766 0.6271 3.8043 82.5961
0.10 0.1491 0.1832 4.4012 83.8502 0.1761 0.6250 3.8264 82.9991
NVA-4 NVA-4
0.01 0.1500 0.1904 4.1016 78.2582 0.1779 0.6326 3.7298 81.1793
0.02 0.1499 0.1895 4.1405 78.9851 0.1777 0.6319 3.7413 81.4041
0.04 0.1497 0.1886 4.2136 80.3662 0.1773 0.6302 3.7652 81.8583
0.06 0.1495 0.1877 4.2874 81.7583 0.1768 0.6283 3.7893 82.3158
0.08 0.1492 0.1864 4.3559 83.0409 0.1763 0.6264 3.8137 82.7733
0.10 0.1490 0.1837 4.4346 84.4952 0.1756 0.6233 3.8405 83.2403
NVA-5 NVA-5
0.01 0.1502 0.1904 4.1115 78.4477 0.1779 0.6324 3.7345 81.2746
0.02 0.1501 0.1900 4.1511 79.1961 0.1778 0.6321 3.7471 81.5359
0.04 0.1499 0.1886 4.2367 80.8065 0.1775 0.6308 3.7735 82.0629
0.06 0.1497 0.1873 4.3211 82.3927 0.1770 0.6289 3.8012 82.5932
0.08 0.1495 0.1859 4.4021 83.9147 0.1766 0.6270 3.8288 83.1253
0.10 0.1493 0.1846 4.4904 85.5744 0.1760 0.6249 3.8573 83.6651
Studies of some bio active hetero…….
Section-I: Acoustical property
  93
Conc.
M
Lf Ao r
Rm.10-3
cm8/3
.s-1/3
b cm3.mol-1
Lf Ao r
Rm.10-3
cm8/3
.s-1/3
b cm3.mol-1
DMF Chloroform
NVA-6 NVA-6
0.00 0.1502 0.1859 4.1239 78.6107 0.1780 0.6328 3.7225 81.0257
0.01 0.1496 0.1846 4.1745 79.5541 0.1773 0.6298 3.7421 81.3428
0.02 0.1494 0.1801 4.2815 81.5177 0.1772 0.6294 3.7580 81.6756
0.04 0.1489 0.1792 4.3844 83.4616 0.1769 0.6284 3.7907 82.3498
0.06 0.1487 0.1783 4.4858 85.3748 0.1769 0.6283 3.8220 83.0226
0.08 0.1485 0.1778 4.5925 87.3990 0.1765 0.6270 3.8552 83.6980
0.10 0.1484 0.1859 4.1239 78.6107 0.1763 0.6260 3.8885 84.3821
NVA-7 NVA-7
0.01 0.1502 0.1832 4.1230 78.5496 0.1782 0.6337 3.7375 81.3855
0.02 0.1492 0.1787 4.1862 79.6814 0.1782 0.6335 3.7551 81.7635
0.04 0.1487 0.1751 4.2974 81.7382 0.1779 0.6324 3.7926 82.5377
0.06 0.1482 0.1710 4.4178 83.9587 0.1772 0.6299 3.8325 83.3108
0.08 0.1477 0.1660 4.5366 86.1295 0.1770 0.6292 3.8692 84.0840
0.10 0.1472 0.1641 4.6376 88.0154 0.1761 0.6251 3.9125 84.8702
NVA-8 NVA-8
0.01 0.1492 0.1828 4.1040 78.1817 0.1784 0.6341 3.7340 81.3251
0.02 0.1487 0.1778 4.1570 79.1112 0.1782 0.6333 3.7487 81.6188
0.04 0.1482 0.1710 4.2559 80.8809 0.1776 0.6313 3.7792 82.2052
0.06 0.1477 0.1673 4.3469 82.5499 0.1769 0.6284 3.8115 82.7997
0.08 0.1472 0.1655 4.4376 84.2428 0.1766 0.6271 3.8416 83.4050
0.10 0.1467 0.1628 4.5324 85.9938 0.1761 0.6250 3.8730 84.0097
NVA-9 NVA-9
0.01 0.1502 0.1873 4.1027 78.2281 0.1781 0.6332 3.7310 81.2273
0.02 0.1496 0.1850 4.1411 78.9232 0.1779 0.6324 3.7423 81.4450
0.04 0.1494 0.1837 4.2185 80.3776 0.1774 0.6304 3.7673 81.9133
0.06 0.1492 0.1823 4.2954 81.8192 0.1766 0.6275 3.7926 82.3561
0.08 0.1490 0.1814 4.3711 83.2469 0.1763 0.6262 3.8141 82.7749
0.10 0.1489 0.1801 4.4450 84.6308 0.1757 0.6241 3.8393 83.2443
Studies of some bio active hetero…….
Section-I: Acoustical property
  94
Figure 3.1.1: Variation of ultrasonic velocity (U) of chalcones (NVA) with concentration in [A] DMF and [B]
chloroform at 303.15 K.
Studies of some bio active hetero…….
Section-I: Acoustical property
  95
Figure 3.1.2: Variation of Isentropic compressibility (κs) of chalcones (NVA) with concentration in [A] DMF
and [B] chloroform at 303.15 K.
Studies of some bio active hetero…….
Section-I: Acoustical property
  96
Figure 3.1.3: Variation of Molar compressibility (W) of chalcones (NVA) with concentration in [A] DMF and
[B] chloroform at 303.15 K.
Studies of some bio active hetero…….
Section-I: Acoustical property
  97
Figure 3.1.4: Variation of Solvation Number (Sn)of chalcones (NVA) with concentration in [A] DMF and [B]
chloroform at 303.15 K.
Studies of some bio active hetero…….
Section-I: Acoustical property
  98
The solvation number is a measure of structure forming or structure
breaking tendency of a solute in solutions. Figure 3.1.4 shows the variation of
solvation number (Sn) with concentration and Sn values are positive for both the
solvents. However, values are higher in DMF that those in Chloroform. As
evident from Fig.3.1.4 that in DMF, Sn values increases continuously with
concentration for all the studied compounds. Whereas in Chloroform are
observed to decreases with concentration except for NVA-6. This suggest that in
DMF, structure forming tendency continuously with concentration of compounds
but in Chloroform, as compound concentration increases structure forming
tendency decreases, although solute-solute interaction still exist.
Thus, it is concluded that in both DMF and Chloroform solutions of
Chalcones exhibit solute-solvent interactions exist.
Studies of some bio active hetero…….
Section-I: Acoustical property
  99
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SECTION – II
DENSITY
AND
REFRECTIVE INDEX
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Section –II: Density and Refractive Index
112
INTRODUCTION
The refractive index is a unitless number, between 1.3000 and 1.7000
for most compounds, and is normally determined to five digit precision 1.
Since the index of refraction depends on both the temperature of the sample
and the wavelength of light. The refractive index is commonly determined as
part of the characterization of liquid samples, in much the same way that
melting points are routinely obtained to characterize solid compounds. It is
also commonly used to help identify or confirm the identity of a sample by
comparing its refractive index to known values and assess the purity of a
sample by comparing its refractive index to the value for the pure substance.
It is one of the physical constants that can be used to describe a chemical
species. Further, it is useful for the identification of crystalline substance.
Refractive Index along with density, molecular mass and specific
volume is very useful in the evaluation of various thermodynamics properties
of chemical materials. The number of atoms, groups, radicals and bonds
present in the compound can also be calculated by refractive index
measurement.
A refractometer measures the extent to which light is bent (i.e.
refracted) when it moves from air into a sample and is typically used to
determine the index of refraction or refractive index of a liquid sample.
The most popular use of refractometer is to determine the percentage
of sugar 2-6, liquid mixture 7-9, liquid crystals 10-11, and determination of film
thickness 12-14 etc. The inter-dependence between refractive index and density
of inorganic solids has been investigated 15-19.
In the present section, the refractive index of solutions of Chalcones
has been measured in dimethyl formamide and Chloroform at 303.15 K.
From the experimental data, the density and refractive index of the
compounds have been evaluated.
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
113
EXPERIMENTAL
The solvents DMF and Chloroform were purified by fractionally
distillation by the reported method 20. For each compound, a series of
solutions of different concentrations were prepared in these solvents.
The density and refractive index of pure solvents and solutions were
measured by using pycnometer and Abbe Refractometre respectively at
303.15 K. The temperature was maintained by circulating water through jacket
around the prisms of Refractometre from an electronically controlled
thermostatic water bath (NOVA NV-8550 E). The uncertainty of temperature
was ± 0.1 oC and that of density and refractive index was ±0.0001 g/cm3 and
0.0005 respectively.
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
114
RESULTS AND DISCUSSION
Table 3.2.1 shows the experimental values of densities and refractive
index for all the studied solutions. From the experimental values of density of
solution, density of solid compound is evaluated by the following equation:
1 2
12 1 2
1 g g
ρ ρ ρ
= + … (3.2.1)
where ρ12 is the density of solution and ρ1 and ρ2 are the densities of solvent
and solute respectively. g1 and g2 are the weight fractions of solvent and
solute respectively.
Figure 3.2.1 shows the plot of 1 121 g ρ verses 2 1g g for NVA-1 in DMF
and Chloroform respectively. The inverse of slope of plot gives the density of
compound ( 2ρ ). The densities of all the compounds evaluated from such plots
are given in Table 3.2.2 for Chalcones respectively in DMF and Chloroform.
These density values of compounds can also be theoretically evaluated by
using the following equation (3.2.2),
A iKM N Vρ = Δ∑ … (3.2.2)
where ρ is the density of the compound, K is packing fraction (0.599), M is the
molecular weight of the compound, NA is the Avogadro’s number and ∆Vi is
the volume increment of the atoms and atomic groups present in the
compound. These theoretical values of density are reported in Table 3.2.2.
The calculated volume increment ∆Vi for different atomic groups are given in
Table 3.2.3.
Comparison of densities evaluated from graphs and those calculated
from eq. (3.2.2) showed that calculated values are different from those
evaluated graphically. Further, for the same compound, density in the two
solvents is different. This suggests that solvent plays an important role. In
solutions molecular interactions exist which differ in different solvents. These
interactions differ due to different substitutions in compounds. The presence
of these interactions has also observed in ultrasonic studies which are
discussed in section I of chapter 2. Due to these interactions there may be
some changes in volume which affects density.
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
115
Table 3.2.1: The density (ρ12) and refractive index (n) of chalcones in
DMF and chloroform at 303.15K.
DMF Chloroform
Conc.
M
ρ12
g.cm-3 n
ρ12
g.cm-3 n
NVA-1 NVA -1
0.00 0.9417 1.4271 1.4748 1.436
0.01 0.9430 1.4295 1.47481 1.4371
0.02 0.9438 1.4300 1.47492 1.4392
0.04 0.9460 1.4305 1.47525 1.4403
0.06 0.9482 1.4315 1.47547 1.4417
0.08 0.9493 1.4320 1.47575 1.4429
0.10 0.9512 1.4325 1.47612 1.4475
NVA -2 NVA -2
0.01 0.9424 1.4289 1.47484 1.4365
0.02 0.9427 1.4299 1.47486 1.4371
0.04 0.9440 1.4309 1.4753 1.4392
0.06 0.9455 1.4322 1.4757 1.4403
0.08 0.9456 1.4335 1.47608 1.4417
0.10 0.9468 1.4356 1.4763 1.4429
NVA -3 NVA -3
0.01 0.9422 1.4283 1.47496 1.4406
0.02 0.9426 1.4290 1.47548 1.4427
0.04 0.9432 1.4308 1.47596 1.4438
0.06 0.9445 1.4313 1.47648 1.4452
0.08 0.9458 1.4326 1.4769 1.4464
0.10 0.9461 1.4338 1.47722 1.451
NVA -4 NVA -4
0.01 0.9429 1.4276 1.47638 1.4446
0.02 0.9431 1.4282 1.47666 1.4457
0.04 0.9443 1.4287 1.47713 1.4471
0.06 0.9453 1.4305 1.47753 1.4483
0.08 0.9474 1.4311 1.47792 1.4529
0.10 0.9476 1.4319 1.47814 1.4531
NVA -5 NVA -5
0.01 0.9418 1.4292 1.47531 1.4386
0.02 0.9429 1.4299 1.47559 1.4392
0.04 0.9437 1.4311 1.47606 1.4413
0.06 0.9447 1.4323 1.47646 1.4424
0.08 0.9463 1.4334 1.47682 1.4438
0.10 0.9464 1.4345 1.47704 1.445
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
116
Conc.
M
ρ12
g.cm-3 n
ρ12
g.cm-3 n
NVA -6 NVA -6
0.00 0.9422 1.4280 1.4748 1.436
0.01 0.9433 1.4290 1.4754 1.4506
0.02 0.9445 1.4297 1.4757 1.4512
0.04 0.9458 1.4305 1.4762 1.4533
0.06 0.9473 1.4320 1.4766 1.4544
0.08 0.9476 1.4343 1.4771 1.4558
0.10 0.9422 1.4280 1.4773 1.457
NVA -7 NVA -7
0.01 0.9445 1.4276 1.4755 1.4400
0.02 0.9449 1.4278 1.4759 1.4421
0.04 0.9479 1.4281 1.4764 1.4432
0.06 0.9489 1.4288 1.4769 1.4446
0.08 0.9503 1.4303 1.4773 1.4458
0.10 0.9543 1.4308 1.4776 1.4504
NVA-8 NVA-8
0.01 0.9461 1.4284 1.4750 1.4382
0.02 0.9471 1.4296 1.4753 1.4403
0.04 0.9479 1.4308 1.4760 1.4414
0.06 0.9491 1.4320 1.4765 1.4428
0.08 0.9507 1.4334 1.4769 1.4440
0.10 0.9516 1.4348 1.4772 1.4486
NVA-9 NVA-9
0.01 0.9434 1.4285 1.4755 1.4385
0.02 0.9441 1.4296 1.4760 1.4406
0.04 0.9447 1.4312 1.4764 1.4417
0.06 0.9454 1.4324 1.4772 1.4431
0.08 0.9462 1.4338 1.4785 1.4443
0.10 0.9474 1.4349 1.4788 1.4489
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
117
Figure 3.2.1: The variation of 1/g1ρ12 with g2/g1 for NVA-1 in [A] DMF and
[B] chloroform at 303.15 K.
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
118
Table 3.2.2: Experimental and calculated densities of chalcones in
DMF and chloroform Solutions at 303.15 K.
Compounds
Density (g.cm-3) from Figure 3.2.1
Density (g.cm-3)
from Eqn. 3.2.2 DMF Chloroform
NVA-1 1.3441 1.5408 1.2478
NVA-2 1.1161 1.5552 1.3513
NVA-3 1.1287 1.6207 1.2501
NVA -4 1.1820 1.6287 1.1770
NVA -5 1.1287 1.6313 1.2510
NVA -6 1.1534 1.5898 1.2343
NVA -7 1.3587 1.5924 1.4364
NVA -8 1.2563 1.5974 1.3417
NVA -9 1.1274 1.7007 1.3018
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
119
Table 3.2.3: Volume increments of some atoms and groups of atoms.
Atoms or
Atomic group
Volume
Increments (Ao)3
Atoms or
Atomic group
Volume
Increments
(Ao)3
CH
C
C
1 4.
14.7
C Cl
1 77.
19.35
C
C
C
C
. 1 54.1 34
9.0
C O H
1 37.
5.36
C
C
C
N
1 37. 1 4.
10.2
C Br
11.20
C
C
C
O
11.65
BrC
14.29
C
C
C
H
1 08. 1 48.
1 28.
11.36
N
O
O
C 1 21.
1 57.
7.46
C
C
H
HH
1 541 54. .
23.5
C
O
H
HH
1 091 09. .
1 5.
26.3
C Cl
C
C
10.39
Car O Cal
1 37.1 5.
2.67
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
120
The molar refraction of a pure liquid (MRD)1 were calculated by the
following equation:
( )
2
21
1
1
n MMRD
n ρ
⎡ ⎤−
= ⎢ ⎥+⎣ ⎦
… (3.2.3)
where n, M and ρ are refractive index, molecular weight and density of pure
liquid respectively.
For solutions, the eq. (3.2.4) was used to determine molar refraction.
( )
2
12 1 1 2 2
212
12 12
1
1
n X M X MMRD
n ρ
⎡ ⎤ ⎡ ⎤− +
= ⎢ ⎥ ⎢ ⎥+⎣ ⎦ ⎣ ⎦
… (3.2.4)
where n12 and ρ12 are refractive index and density of solution respectively. X1
and X2 are the mole fractions and M1 and M2 are the molecular weight of the
solvent and solute respectively.
The plots of (MRD)12 verses concentration for Chalcones series in DMF
and Chloroform are given in Figures 3.2.2 and 3.2.3. It is evident from these
figures that (MRD)12 increase with the increase in concentration. The molar
refraction of solid compounds was determined by the equation:
( ) ( ) ( )1 212 1 2MRD X MRD X MRD= + … (3.2.5)
Using these (MRD)2 and density (ρ2) values, the refractive indexes of
all the compounds were calculated from eq. (3.2.3). The molar refraction
(MRD)2 and refractive index of all the compounds are reported in Table 3.2.4.
It is evident from Table 3.2.4 that both (MRD)2 and refractive index of
compounds are different in each solvent. This again proves that in different
solvents, intermolecular interactions are different, which affect these
parameters.
Further, for different compounds (MRD)2 are quite different whereas
refractive index differ only slightly. This suggest that although substitution
affect (MRD)2 largely, refractive index only slightly. However, the variation of
refractive index of all the compounds in a particular solvent is very less.
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
121
Figure 3.2.2: The plots of molar refraction (MRD)12 against concentration
of chalcones in DMF solutions at 303.15 K.
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
122
Figure 3.2.3: The plots of molar refraction (MRD)12 against concentration
of chalcones in chloroform solutions at 303.15 K.
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
123
Table 3.2.4: Molar refraction (MRD)2 and refractive index (n) of 0.1M
solution of chalcones in DMF and chloroform at 303.15 K.
Compounds
Solvents
DMF Chloroform
(MRD)2 n (MRD)2 n
NVA-1 89.1602 1.4325 113.69 1.4475
NVA-2 120.4816 1.4356 91.41 1.4429
NVA-3 100.6912 1.4238 123.88 1.4510
NVA -4 90.4335 1.4219 135.60 1.4531
NVA -5 111.7483 1.4245 98.38 1.4450
NVA -6 115.5976 1.4243 165.30 1.4470
NVA -7 84.0269 1.4208 134.06 1.4504
NVA -8 103.1638 1.4248 119.41 1.4486
NVA -9 107.2662 1.4249 112.98 1.4489
Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
124
REFERENCES
1. j. Hanson,; “ Chemistry lab. Techniques” copyright-(2003).
2. D. R. Smith and N. Kroll,; “Negative Refractive Index in Left-Handed
Materials” Phy. Rev. Lett., 85, 14, (2000).
3. K. Sangwal and W. Kucharczyk,; “ Relationship between density and
refractive index of inorganic solids” J. Phys. D: Appl. Phys., 20,
522-525 ,(1987).
4. D. Fulvio, B. Sivaraman, G. A. Baratta, , M. E. Palumboand N. J.
Mason,; “ Novel measurements of refractive index, density and midinfrared integrated band strengths for solid O2, N2O and NO2: N2O4
mixtures” Spectrochimica Acta Part A: Mol. Biomol. Spect., 72(5)
,1007–1013, (2009).
5. Y. Liu and P. H. Daum,; “Relationship between Refractive Index and
Density and Consistency of Mixing Rules” J. Aerosol Sci., 39, 974986, (2008).
6. M. I. Alonso, ; “Optical functions of chalcopyrite CuGaxIn1-xSe2
alloys” App. Phys. A-Mat. Sci. Proces., 74 (5) , 659-664, (2002).
7. L. Gentilin,i; “The determination of the refractive index in estimating the
sugar in musts of the Veneto region.” Annali. della Sperim.Agraria,
7, 983-1001, (1953).
8. S. Hill and W. J. H. Orchard; “Refractive index of sucrose solutions of
statistical appraisal.” Inter. Sugar J., 63, 42-44, (1961).
9. A. Emmerich,B. Prowe, and K. J. Rosenbruch; “Refractive index of
aqueous solutions of glucose, fructose and invert sugar as a function of
dry substance.” Zuckerindustrie, 109(6), 525-37, (1984).
10. J. H. Ko and W. J. Cheong,; “Simultaneous quantitative determination
of mono-,di-, tri-, tetra-, and penta-saccharides in yogurt
products by a simple HPLC system with a refractive index detector.”
Bull. Kor. Chem. Soc., 22(1), 123-26, (2001).
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Section –II: Density and Refractive Index
125
11. M. Barroso, M. Pineiro, M. E. Serra and M. J. Seixas,; “Refractometry
in determination of sugar and aspartame contents in commercial
beverages.” Quimica, 91, 61-65, (2003).
12. M. S. Ding,; “Electrolytic conductivity and glass transition temperatures
as functions of salt content, solvent composition, or temperature for
LiBF~4 in propylene carbonate + diethyl carbonate” J. Chem. Eng.
Data, 4, 1102-1109, (2004).
13. V. Campos, A. C. Gómez Marigliano, and H. N. Sólimo,; “Density,
viscosity, refractive index, excess molar volume, viscosity, and
refractive index deviations and their correlations for the (Formamide +
Water) system. isobaric (Vapor + Liquid) equilibrium at 2.5 kPa ” J.
Chem. Eng. Data , 53, 211–216, (2008).
14. N. Calvar, B. Gonza´lez, E. Go´mez, and J. Canosa,; “Density,
speed of Sound, and refractive index for binary mixtures containing
cycloalkanes and aromatic compounds at T ) 313.15 K” J. Chem. Eng.
Data, 54, 1334–1339, (2009).
15. F. M. Ezz-Eldin, N. A. Elalaily, W. M. Abd-Allah,; “Effect of irradiation,
corrosion or heat-treatment on the density and refractive index of some
bioglasses” Al-Azhar Bull. Sci., 11, 165-81, (2000).
16. V. A. Gunyakov, N. P. Shestakov, S. M. Shibli,; “Density and refractive
index measurements in hexaheptyloxytriphenylene, a discotic liquid
crystal” Liq. Cry., 30, 871-75, (2003).
17. S. Nair and M. Tsapatsis,; “Infrared reflectance measurements of
zeolite film thickness, refractive index and other characteristics”
Microporous Mesoporous Mat., 58(2), 81-89, (2003).
18. H. M. Shabana,; “Determination of film thickness and refractive index
by interferometry” Polym. Test., 23 (6), 695-702, (2004).
19. J. Diao and D. W. Hess,; ”Refractive index measurements of films with
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Studies of some bio-active heterocyclic…….
Section –II: Density and Refractive Index
126
20. J. A. Riddick, W. B. Bunger, T. Sakano, Organic Solvents: Physical
Properties and methods of purification, Fourth Edition., Techniques of
Chemistry, II, A Wiley-Interscience Publication, John Wiley, New York,
(1986).
SECTION – III
CONDUCTANCE
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
127
INTRODUCTION
Conductivity is the ability of a material to conduct electric current. The
conductance of such electrolytic solutions depends on the concentration of
the ions and also on the nature of the ions present (i.e., their charges and
mobilities).Thus the conductance behavior as a function of concentration has
been different for strong and weak electrolytes. Conductivity, the inverse of
resistivity is determined from the voltage and current values according to
Ohm's law 1.
Conductivity measurement has widespread use in industrial
applications that involve the detection of contaminants in water and
concentration measurements 2.
Literature survey shows that conductance of many inorganic and
organic compounds have been measured in aqueous and non-aqueous
solvents3-14. It is also used to determine the dissociation constant and
limiting equivalent conductance of weak electrolytes15, electro osmotic flow16,
for studying conformational changes in polyelectrolytes in aqueous solutions17
etc.
Further, conductometry method is useful to various biological
processes 18-21, to determine ascorbic acid in vitamin C tablet 22, carbon in
uranium carbide and its solution in nitric acid 23, enzymatic degradation of
microbial biofilm 24, dye-surfactant ion pair formation in aqueous solutions 25
etc. Morita et al reported ionic conductance of polymeric electrolytes and of
polymeric composite solid electrolytes 26. The antibiotic residues in bovin
kidneys have also been detected by conductometry 27.
Thus, in the present section conductance of all the synthesized
Chalcones was measured in DMF and Chloroform solutions at 303.15 K, over
a wide range of concentration.
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
128
EXPERIMENTAL
The solvents DMF and Chloroform were purified by fractionally
distillation by the method reported in the literature
28
.
The solutions of different concentrations were prepared for each
compound in DMF and Chloroform and the conductance of each solution was
measured by using Equip-tronics Conductivity Meter (Model No. 664) having
cell constant 0.86 cm-1 at 303.15 K. The measured conductance was
corrected by subtracting the conductance of pure solvent.
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
129
RESULTS AND DISCUSSION
The measured conductance (k) of each solution after correction was
used to determine the specific conductance (κ), which is then used for the
calculation of equivalent conductance (λc).
The equations used for calculating specific conductance (κ ) and
equivalent conductance (λc) are:
kκ θ= … (3.3.1)
1000c C
κλ = … (3.3.2)
where θ is the cell constant (= 0.86) and c is the concentration (g.equi./lit.) of
solution.
Tables 3.3.1 and 3.3.2 show the equivalent conductance of all the
studied compounds in DMF and Chloroform solutions at 303.15 K along with
measured conductance (k). The variation of conductance with concentration
for these compounds in both the solvents is given in Figures 3.3.1 and 3.3.2.
For studied compounds, conductivities are observed to be less in chloroform
than those in DMF. Further, for all the studied systems, conductance
increases with concentration. Up to 0.01 g.equi./lit. Conductance increases
linearly with concentration. However, for most of the compounds at higher
concentration, non-linearly increase is observed.
The equivalent conductance (λc) is plotted against √C for all studied
compounds and is shown in Figures 3.3.3 and 3.3.4. In both DMF and
Chloroform solutions, usually λc increases with dilution. But for certain
compounds in both the DMF (NVA-9), and Chloroform (NVA-2) solutions, λc
do not increase continuously but bend downward at low concentrations. This
typical behavior may be due to interactions within the molecule thereby
causing constriction within the molecule or due to association between solute
with solvent molecules. Further, It is evident from these figures that most of
the compounds behave as weak electrolytes whereas some of them exhibited
slightly strong electrolytic behavior. Further, the behavior is different in
different solvents.
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
130
So, for few compounds, λ0 values were evaluated by extrapolation.
These values are compared with those determined by an alternate procedure
using the following equation:
( )0 0 ck k c cλ φ= + + ….. (3.3.3)
where k and k0 are the electrolytic conductivity of the solutions and solvent
respectively. c is the equivalent concentration and the function Φ(c) denotes
the effect of interionic interactions. The limiting conductivity can be
determined accurately from the slope, dk/dc of plot of k verses c, provided
other derivatives (dk0/dc) and d[cΦ(c)]/dc in differential form of equation (3.3.3)
are neglected as compared to λ0, which can be determined from differential
form of equation (3.3.3) is
( )0 0
cd cdkdk
dc dc dc
φ
λ
⎡ ⎤
⎣ ⎦= + + ….. (3.3.4)
Table 3.3.3 shows the λ0 values for all studied compounds along with
those determined by extrapolation. For the system where λc decreases at low
concentrations, λ0 could not be evaluated. Comparison of λ0 values in Table
3.3.3 show that for most of the systems, values are in good agreement.
However, for some cases, deviations are significant suggesting thereby that
equations (3.3.3) and (3.3.4) are not valid for these systems. This is because
of the fact in these equations, interionic interactions are neglected which are
actually present in the studied solutions.
Table3.3.3 shows that only for some compounds, λ0 could not be
evaluated by extrapolation of plots λc against √C (Figures 3.3.3 and 3.3.4).
these values are much different than those calculated from eq. 3.3.4. The
reason may be due to the fact that in calculating λ0 by equation 3.3.4, the
terms for interionic interaction are ignored. As interaction exist in the studied
systems, this lead to series error as observed by large deviations in Table
3.3.3.
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
131
Table 3.3.1: The Conductance (k) and equivalent conductance (λC) of Chalcones in DMF at 303.15 K.
Conc.
(gm/lit)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
NVA-1 NVA-2 NVA-3 NVA-4 NVA-5
0 2.35 --- 2.35 --- 2.35 --- 2.35 --- 2.35 ---
0.001 6.38 34.6580 5.11 24.6820 3.52 10.0620 2.79 3.7840 3.02 5.7620
0.002 6.50 17.8450 5.86 15.5660 3.72 5.8910 3.10 3.2250 3.58 5.2890
0.004 6.66 9.2751 7.25 10.7715 4.12 3.8055 4.27 4.1280 4.24 4.0635
0.006 6.76 6.3210 8.34 8.7433 4.51 3.0960 5.19 4.0707 4.82 3.5403
0.008 6.93 4.9235 9.12 7.3960 4.92 2.7628 6.27 4.2140 5.23 3.0960
0.01 7.09 4.0764 10.10 6.7596 5.52 2.7262 7.57 4.4892 5.75 2.9240
0.02 8.64 2.7047 11.98 4.1882 6.98 1.9909 9.69 3.1562 8.03 2.4424
0.04 11.22 1.9071 14.03 2.5349 8.35 1.2900 12.38 2.1565 11.27 1.9178
0.06 13.57 1.6082 15.73 1.9336 9.99 1.0951 14.26 1.7071 13.91 1.6569
0.08 15.67 1.4319 17.27 1.6157 11.54 0.9879 16.07 1.4749 16.21 1.4900
0.1 18.07 1.3519 18.32 1.3829 13.34 0.9451 17.18 1.2754 18.31 1.3726
NVA-6 NVA-7 NVA-8 NVA-9
0.001 3.73 11.8680 2.78 3.6980 3.15 6.8800 2.61 2.2360
0.002 4.22 8.0410 3.00 2.7950 3.46 4.7730 2.92 2.4510
0.004 4.93 5.5470 3.54 2.5585 4.25 4.0850 3.78 3.0745
0.006 5.99 5.2173 4.10 2.5083 5.43 4.4147 4.75 3.4400
0.008 6.88 4.8698 4.71 2.5370 6.86 4.8483 5.84 3.7518
0.01 8.04 4.8934 5.57 2.7692 8.14 4.9794 7.34 4.2914
0.02 10.11 3.3368 7.80 2.3435 11.24 3.8227 9.69 3.1562
0.04 12.59 2.2016 9.37 1.5093 13.26 2.3457 11.55 1.9780
0.06 14.76 1.7788 10.38 1.1510 15.34 1.8619 13.27 1.5652
0.08 16.87 1.5609 11.79 1.0148 17.07 1.5824 14.55 1.3115
0.1 18.27 1.3691 13.57 0.9649 18.65 1.4018 15.62 1.1412
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
132
Table 3.3.2: The Conductance (k) and equivalent conductance (λC) of Chalcones in Chloroform at 303.15 K.
Conc.
(gm/lit)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
κ.105
(Ω)
C
(cm2/Ω.equiv.)
NVA-1 NVA-2 NVA-3 NVA-4 NVA-5
0 0.120 --- 0.120 --- 0.120 --- 0.120 --- 0.120 ---
0.001 0.140 0.1720 0.130 0.0860 0.320 1.7200 0.240 1.0320 0.270 1.2900
0.002 0.150 0.1290 0.140 0.0860 0.330 0.9030 0.250 0.5590 0.280 0.6880
0.004 0.180 0.1290 0.170 0.1075 0.360 0.5160 0.280 0.3440 0.310 0.4085
0.006 0.210 0.1290 0.200 0.1147 0.390 0.3870 0.310 0.2723 0.340 0.3153
0.008 0.240 0.1290 0.230 0.1183 0.420 0.3225 0.340 0.2365 0.370 0.2688
0.01 0.260 0.1204 0.280 0.1376 0.472 0.3027 0.390 0.2322 0.420 0.2580
0.02 0.310 0.0817 0.300 0.0774 0.490 0.1591 0.410 0.1247 0.440 0.1376
0.04 0.330 0.0452 0.320 0.0430 0.510 0.0839 0.430 0.0667 0.460 0.0731
0.06 0.370 0.0358 0.375 0.0366 0.550 0.0616 0.470 0.0502 0.547 0.0612
0.08 0.410 0.0312 0.460 0.0366 0.590 0.0505 0.510 0.0419 0.675 0.0597
0.1 0.470 0.0301 0.470 0.0301 0.640 0.0447 0.570 0.0387 0.761 0.0551
NVA-6 NVA-7 NVA-8 NVA-9
0.001 0.440 2.7520 0.360 2.0640 0.382 2.2532 0.434 2.7004
0.002 0.452 1.4276 0.520 1.7200 0.512 1.6856 0.611 2.1113
0.004 0.480 0.7740 0.800 1.4620 0.660 1.1610 0.853 1.5760
0.006 0.510 0.5590 1.080 1.3762 1.000 1.8920 1.312 1.7085
0.008 0.540 0.4515 1.411 1.3878 1.112 1.0664 1.643 1.6372
0.01 0.590 0.4042 1.790 1.4362 1.340 1.0492 1.900 1.5308
0.02 0.610 0.2107 2.750 1.1309 2.040 0.8256 3.150 1.3029
0.04 0.630 0.1097 3.710 0.7719 2.950 0.6085 4.340 0.9073
0.06 0.670 0.0788 4.890 0.6837 3.200 0.4415 5.040 0.7052
0.08 0.710 0.0634 6.250 0.6590 4.320 0.4515 5.690 0.5988
0.1 0.760 0.0550 7.280 0.6158 4.450 0.3724 5.830 0.4911
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
133
Figure 3.3.1: The variation of conductance with concentration for
chalcones in DMF at 303.15 K.
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
134
Figure 3.3.2: The variation of conductance with concentration for
chalcones in chloroform at 303.15 K.
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
135
Figure 3.3.3: The variation of equivalent conductance with √C for
chalcones in DMF at 303.15 K.
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
136
Figure 3.3.4: The variation of equivalent conductance with √C for
chalcones in chloroform at 303.15 K.
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
137
Table 3.3.3; The limiting equivalent conductance (λ0) of all the
compounds in DMF and Chloroform at 303.15 K.
Compound
Code
λ0
mho.cm2.equi.-1
from graph
λ0103
mho.cm2.equi.-1
from eq. (3.3.4)
λ0
mho.cm2.equi.-1
from graph
λ0103
mho.cm2.equi.-1
from eq. (3.3.4)
DMF Chloroform
NVA -1 -- 2.86 0.161 0.161
NVA -2 -- 6.77 -- 0.156
NVA -3 1.94 2.64 -- 0.258
NVA -4 -- 5.18 -- 0.214
NVA -5 7.12 3.23 -- 0.230
NVA -6 -- 5.16 -- 0.032
NVA -7 4.91 3.05 2.88 0.160
NVA -8 -- 5.61 -- 0.113
NVA -9 -- 4.92 -- 0.175
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
138
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Electrodiagnostic-Therapie, 14(1), 19-25, (1977).
20. I. I. Vybornova, A. N. Goltsov, S. Yu. Yepifanov, V. N. Kadantsev and
P. M. Krasilnikov,; “Modeling of mechanisms of influence of thermal
Studies of some bio active Hetero cyclic…….
Section –III: Conductance
140
and anthropogenic chemical factors on the functioning of biological
membranes.” Fiziologiya Cheloveka, 20(6), 124-36, (1994).
21. P. Canizares, A. Beteta, C. Saez, L. Rodriguez and M. A. Rodrigo,;
“Use of electrochemical technology to increase the quality of the
effluents of bio-oxidation processes. A case studied” Chemosphere,
72(7), 1080-85, (2008).
22. K. Grudpan, K. Kamfoo and J. Jakmunee,; “Flow injection
spectrophotometric orconductometric determination of ascorbic acid in
a vitamin C tablet using permanganate or ammonia” Talanta, 49(5),
1023-26, (1999).
23. M. K. Ahmed, R. Geetha, N. K. Pandey, S. Murugesan, S. B. Koganti,
B. Saha, P. Sahoo and M. K. Sundararajan,; “Conductometric
determination of carbon in uranium carbide and its solution in nitric
acid” Talanta, 52(5), 885-92, (2000).
24. C. Johansen, B. K. Bredtved and S. Moller,; “Use of conductance
measurements for determination of enzymatic degradation of microbial
biofilm” Methods in Enzymology, 310, 353-61, (1999).
25. S. Bracko and J. Span,; “Conductometric investigation of dyesurfactant ion pair formation in aqueous solution” Dyes and Pigments,
45(2), 97-102, (2000).
26. M. Morita, T. Fujisaki, N. Yoshimoto and M. Ishikawa,; “Ionic
conductance behavior of polymeric composite solid electrolytes
containing lithium aluminate.” Electrochimica Acta,46,1565-69, (2001).
27. A. L. Myllyniemi, H. Sipila, L. Nuotio, A. A. Niemi and B. T. Honkanen,;
“An indirect conductimetric screening method for the detection of
antibiotic residues in bovine kidneys.” Analyst, 127(9),1247-51, (2002).
28. J. A. Riddick, W. B. Bunger, T. Sakano,; “ Organic Solvents-Physical
Properties and methods of purification” Fourth Edition., Techniques of
Chemistry, II, A Wiley-Interscience Publication, John Wiley, New York
(1986).
SECTION – IV
SOLUBILITY
AND
THERMODYNAMIC
PARAMETERS
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
142
INTRODUCTION
The maximum amount of a substance that can dissolve in fixed
quantity of solvent at given temperature and pressure is called the solubility of
the substance.
The solubility data has been of fundamental importance in a large
number of scientific disciplines and practical applications such as in drug
discovery, drug formulation, transport of pollutants 1-4, crystallization-based
separation investigations etc.
Literature survey shows that a number of workers have studied
solubility of various compounds in various solvents 5-11. Domanska has
studied the solubility of n-paraffin hydrocarbons in binary solvents 12. Ma and
Xia have reported the solubility of aromatic acids in various solvents 13. The
solubilization behavior of a poorly soluble drug has also been studied in
presence of surfactants and cosolvents 14. The solubility of cinnamic acid
esters have also been studied in ionic liquids 15. Further, many researchers
have been worked on solubility of some fatty acid 16, ionic liquids 17, inorganic
salt 18-22, some trace elements 23-25,protein 26-27, drugs 28etc.
When a solute is dissolved in a solvent, heat is either absorbed or
evolved. Thus, dissolution of a solute in a solvent is accompanied by the heat
change i.e., enthalpy change (∆H) of the system. If the heat is absorbed i.e.,
the solution is cooler then ∆H is positive. If the heat is evolved i.e., the
solution is warmer then ∆H is negative. The heat of solution is defined as the
change in enthalpy when one mole of substance is dissolved in specified
quantity of solvent at a given temperature.
The molar heat of solution is one of the most basic of thermodynamic
properties and it has been useful for the advancement of theoretical
developments through an understanding of the intermolecular forces-solution
structure-property relationship 29.
The molar heat of solution and melting temperature of a substance can
be determined from the solubility measurements at different temperatures 30.
Using solubility data, various workers have reported various thermodynamic
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
143
parameters such as enthalpy, Gibb’s energy and entropy of different
substances in different pure and mixed solvents 31-37.
In the present work, the solubility for some chalcones was determined
in chloroform and dichloromethane at different temperatures (293.15 to
313.15) K. Further, some thermodynamic parameters such as enthalpy,
Gibb’s energy and entropy of different solutions have also been evaluated
from the solubility data.
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
144
EXPERIMENTAL
The solubility of Chalcones has been studied in chloroform and
dichloromethane (MDC). These solvents were purified by the method reported
in the literature 38.
The solubilities were measured by a gravimetric method 39. For each
measurement, an excess mass of chalcone was added to a known mass of
solvent. Then, the equilibrium cell was heated to a constant temperature with
continuous stirring. After, at least 3 h (the temperature of the water bath
approached constant value, then the actual value of the temperature was
recorded), the stirring was stopped and the solution was kept still for 2 h. A
portion of this solution was filtered and by a preheated injector, 2 ml of this
clear solution was taken in another weighted measuring vial (m0). The vial
was quickly and tightly closed and weighted (m1) to determine the mass of the
sample (m1- m0). Then, the vial was covered with a piece of filter paper to
prevent dust contamination. Then, the vial was placed in at room temperature
to evaporate the solvent. After the solvent in the vial had completely
evaporated, the vial was dried and reweighed (m2) to determine the mass of
the constant residue solid (m2- m0). All the weights were taken using an
electronic balance (Mettler Toledo AB204-S, Switzerland) with an accuracy of
± 0.0001 g. Thus, the solid concentration of the sample solution of mole
fraction, x, was then determined from the following equation:
2 0 1
2 0 1 1 2 2
( ) /
( ) / ( ) /
m m Mx
m m M m m M

=
− + −
.. (3.4.1)
where M1 is the molar mass of chalcones and M2 is the molar mass of the
solvent.
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
145
RESULTS AND DISCUSSION
The mole fraction solubility (x) of synthesized compounds in the
studied solvents is given in Table 3.4.1. It is evident from the Table that the
solubility increases with temperature in both the solvents. Figure 3.4.1 shows
the variation of mole fraction solubility (x) against temperature for NVA-1 in
chloroform and MDC.
It is observed that almost for all the compounds, solubility values
linearly with temperature. Further, overall solubility of studied compounds is
greater in MDC than that in chloroform.
The temperature dependence solubility in solvents is described by the
modified Apelblat equation 40,41
….. (3.4.2)
where x is the mass fraction solubility of compounds; T is the absolute
temperature and A, and B are the coefficients. The values of these
coefficients are given in Table 3.4.2. Using these values of A and B,
calculated solubilities xc were evaluated and are reported in Table 3.4.1.
The relative deviations (RD) between the experimental and calculated
values of solubilities are also calculated by equation 3.4.3 and are given in
Table 3.4.1.
Relative Deviation ⎛ ⎞⎜ ⎟
⎝ ⎠
cx - x=
x ….. (3.4.3)
Further, relative average deviations (ARD) and root-mean-square
deviations (rmsd) were calculated by equations 3.4.4 and 3.4.5 and are listed
in Table 3.4.2.
N
i c
i i
x x
x ⎛ ⎞−
⎜ ⎟
⎝ ⎠
∑1ARD = N ….. (3.4.4)
1/ 22
1
( )
1
N
ci i
i x xrmsd
N=
⎡ ⎤−
= ⎢ ⎥−⎣ ⎦
∑ ….. (3.4.5)
where N is the number of experimental points.
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
146
Table 3.4.1: The experimental solubility (x), calculated solubility
(xc) and relative deviation (RD) of NVA series in Chloroform and
Dichloromethane at different temperatures.
Chloroform Dichloromethane
Temp.
K x. 10
3 xc.103 100 RD x. 103 xc.103 100 RD
NVA-1 NVA-1
293.15 5.6660 5.1774 8.6230 8.9330 10.0937 -12.9851
298.15 6.5141 5.8374 10.3866 14.6171 13.2873 9.1010
303.15 7.3912 6.5815 10.9554 19.5442 17.4921 10.5013
308.15 8.2940 7.4204 10.5327 23.8635 23.0272 3.5010
313.15 9.2345 8.3663 9.4014 27.6761 30.3153 -9.5339
NVA-2 NVA-2
293.15 0.8125 0.7866 3.1948 3.5648 3.4788 2.4138
298.15 0.8699 0.8394 3.5077 6.1866 4.8386 21.7894
303.15 0.9286 0.8958 3.5378 8.7791 6.7299 23.3417
308.15 0.9936 0.9559 3.7940 11.350 9.3605 17.5256
313.15 1.0552 1.0201 3.3239 13.8922 13.019 6.2788
NVA-3 NVA-3
293.15 3.7360 3.1901 14.6139 1.0250 1.2626 -23.1777
298.15 4.0605 3.4730 14.4687 2.3081 1.9398 15.9599
303.15 4.3825 3.7811 13.7226 3.5770 2.9802 16.6842
308.15 4.7020 4.1165 12.4531 4.8318 4.5787 5.2377
313.15 5.0191 4.4816 10.7085 6.0726 7.0345 -15.8408
NVA-4 NVA-4
293.15 0.3365 0.5229 -55.4173 20.7421 23.3183 -12.4199
298.15 1.6490 1.0066 38.9531 26.7072 27.3631 -2.4564
303.15 2.9570 1.9377 34.4688 31.8882 32.1105 -0.6956
308.15 4.2650 3.7300 12.5439 38.8004 37.6811 2.8859
313.15 5.5685 7.1799 -28.9394 44.9301 44.2171 1.5863
NVA-5 NVA-5
293.15 6.2033 6.7354 -8.5778 0.7198 0.8754 -21.4893
298.15 6.6599 7.1340 -7.1192 1.4667 1.2860 12.2833
303.15 7.1025 7.5561 -6.3874 2.1875 1.8924 13.4899
308.15 7.5415 8.0033 -6.1236 2.8768 2.7837 3.2358
313.15 7.9670 8.4769 -6.3993 3.5398 4.0948 -15.6789
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
147
Chloroform Dichloromethane
Temp.
K x. 10
3 xc.103 100 RD x. 103 xc.103 100 RD
NVA-6 NVA-6
293.15 6.0741 6.6551 -9.5654 3.3644 3.916 -16.4136
298.15 9.7428 9.1095 6.5002 5.9615 5.4968 7.7959
303.15 13.5748 12.4692 8.1441 8.5123 7.7145 9.3724
308.15 17.5713 17.0681 2.8640 11.012 10.827 1.6766
313.15 21.7481 23.3630 -7.4255 13.467 15.195 -12.8318
NVA-7 NVA-7
293.15 6.5624 5.1287 21.8470 2.0630 1.7280 16.2401
298.15 7.4556 5.6964 23.5957 2.9055 2.1856 24.7747
303.15 8.3636 6.3269 24.3510 3.7936 2.7645 27.1277
308.15 9.2687 7.0273 24.1828 4.1240 3.4967 15.2110
313.15 10.180 7.8051 23.3281 5.7231 4.4228 22.7194
NVA-8 NVA-8
293.15 9.9591 8.6000 13.6468 4.5115 3.6677 18.7033
298.15 10.0359 8.6431 13.8781 5.4687 4.3040 21.2977
303.15 10.1120 8.6864 14.0980 6.4837 5.0506 22.1028
308.15 10.1880 8.7299 14.3110 7.5618 5.9268 21.6221
313.15 10.2632 8.7737 14.5131 8.7093 6.9549 20.1434
NVA-9 NVA-9
293.15 16.321 15.020 7.9679 9.2359 8.5974 6.9128
298.15 15.899 15.478 2.6482 11.891 10.448 12.1311
303.15 16.417 15.949 2.8497 14.639 12.697 13.2637
308.15 16.924 16.435 2.8911 17.500 15.431 11.8256
313.15 18.458 16.935 8.2489 20.380 18.752 7.9841
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
148
Table 3.4.2: Coefficient A and B of equation 3.4.1, Relative Average Deviation
(ARD), and root Mean Square Deviation (rmsd) of NVA series in
Chloroform and Dichloromethane.
Compounds A B 107 rmsd 100 ARD
Chloroform
NVA-1 -12.300 0.024 1.4345 9.9798
NVA-2 -10.960 0.013 0.0026 3.4716
NVA-3 -10.732 0.017 0.8183 13.1933
NVA-4 -45.960 0.131 2.1847 0.3218
NVA-5 -8.373 0.012 0.5934 -6.9214
NVA-6 -23.423 0.063 2.4110 0.1034
NVA-7 -11.430 0.021 9.9808 23.4609
NVA-8 -5.050 0.001 5.0819 14.0894
NVA-9 -5.958 0.006 2.3224 4.9211
Dichloromethane
NVA-1 -20.72 0.055 7.4939 0.1168
NVA-2 -25.01 0.066 5.3705 14.2698
NVA-3 -31.85 0.085 0.7688 -0.2273
NVA-4 -13.14 0.032 4.4389 -2.2199
NVA-5 -29.67 0.077 0.2300 -1.6318
NVA-6 -25.41 0.067 2.0889 -2.0800
NVA-7 -20.14 0.047 1.8868 21.2145
NVA-8 -14.99 0.032 4.9366 20.7738
NVA-9 -16.19 0.039 6.5944 10.4234
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
149
Using these solubility data, some thermodynamic parameters such as
enthalpy, entropy and Gibbs energy of dissolution have also been evaluated.
According to van’t Hoff analysis42, the standard enthalpy change of
solution is obtained from the slope the ln x versus 1/T plot.
ln x = [∆Hsol (T-Tm)]/RT.Tm ….. (3.4.6)
where T is temperature and Tm is the melting temperature of the studied
compounds.
However, in recent thermodynamic treatments, some modifications
have been introduced in the van’t Hoff equation to diminish the propagation of
errors and consequently to separate the chemical effects from those due to
statistical treatment used when enthalpy-entropy compensation plots are
developed 43. For this reason, the mean harmonic temperature (Thm) is used
in the van’t Hoff analysis, which is calculated by the following equation.
( )1
hm n
i nT T
=

….. (3.4.7)
where n is the number of temperatures studied and T is absolute temperature
of the experiment. In the present case, the Thm value obtained is 303.15 K.
So, the modified van’t Hoff equation is 44-45.
ln 1 1
sol
hm P
Hx R
T T
Δ∂
= −
⎛ ⎞∂ −⎜ ⎟
⎝ ⎠
….. (3.4.8)
where ∆Hsol is the heat of solution and R is the gas constant.
Figure 3.4.2 shows the van’t Hoff plots for NVA-1 in chloroform and
dichloromethane solutions. From the slope of these linear plots, the values of
∆Hsol were evaluated. Whereas Gibb’s energy of dissolution (∆Gsol) were
evaluated from the intercept using the following equation.45
∆Gsol = -RThm. intercept ….. (3.4.9)
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
150
Figure 3.4.1: The mole fraction solubility (x) against temperature (T/K) for
NVA-1 in Chloroform (A) and Dichloromethane (B).
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
151
Figure 3.4.2: van’t Hoff plots for for NVA-1 in [A] Chloroform and [B] MDC.
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
152
Table 3.4.3: The thermodynamic parameters of Chalcones in Chloroform
and MDC at 302.99 K (Thm).
Compound
code
∆Hsol ∆Gsol ∆Ssol ∆Hsol ∆Gsol ∆Ssol
kJ.mol-1 kJ.mol-1 J.mol
-
1.K-1 kJ.mol
-1 kJ.mol1
J.mol1.K-1
Chloroform Dichloromethane
NVA-1 0.0019 12.3893 -40.8846 0.0042 10.1776 -33.5771
NVA-2 19.1887 19.5098 -1.0597 50.9731 12.1971 127.9801
NVA-3 12.9948 14.0360 -3.4364 65.9051 14.6204 169.2648
NVA-4 100.8821 15.5675 281.5801 24.9370 8.7914 53.2886
NVA-5 9.5362 12.4742 -9.6969 59.1791 12.2903 154.7561
NVA-6 48.0799 11.0333 122.2719 51.9043 12.2903 130.7458
NVA-7 16.7361 12.0787 15.3717 36.5400 14.2324 73.6260
NVA-8 1.1473 11.5724 -34.4078 25.0501 12.7336 40.6504
NVA-9 5.1522 10.2801 -16.9247 29.8888 10.7260 63.2469
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
153
Using these evaluated ∆Hsol and ΔGsol values, the entropies of
solutions ΔS were obtained from the following equation 46
Δ ΔΔ sol solsol
hm H - GS =
T
….. (3.4.10)
It is evident from Table 3.4.3 that for all the compounds ∆Hsol and ΔGsol values
are positive whereas ∆Ssol values are both negative and positive for both the
solvents. When stronger bonds are broken and weaker bonds are formed,
energy is consumed and so ∆Hsol becomes positive 46. This indicates
endothermic dissolution of compounds where the enthalpy term contributes to
an unfavorable positive value of ΔGsol 46.
Thus, the positive values of ΔG indicates that the dissolution process is
not spontaneous. 46,47 whereas negative entropy suggests more ordered
structure in solutions 46.
Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
154
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molecular simulation results” J. Chem. Thermodyn., 37, 595–602,
(2005).
36. D. H. M. Belny, J. W. Mullin,; “ Solubilities of Higher Normal Alkanes in
m-Xylene” J. Chem. Eng. Data, 32, 9–10, (2006).
37. N. A. Manan, C. Hardacre, J. Jacquemin, D. W. Rooney and T. G. A.
Youngs,; “Evaluation of gas solubility prediction in ionic liquids using
COSMOthermX” J. Chem. Eng. Data, 54, 2005–2022, (2009).
38. J. A. Riddick, W. B. Bunger, and T. Sakano,; “Organic solventsphysical properties and methods of purification.” Fourth Ed., Techn.
Chem., II, A Wiley-Interscience public., John Wiley, New York (1986).
39. M. Zhu,; “Solubility and density of the disodium salt hemiheptahydrate
of ceftriaxone in water + ethanol mixtures.” J. Chem. Eng. Data, 46,
175-176, (2001).
40. A. Apelblat, and E. Manzurola,; “Solubilities of o-acetylsalicylic, 4aminosalic, 3,5-di nitrosalicylic, and p-toluic acid, and magnesium-DL Studies of some bio-active Heterocyclic…….
Section-IV: Solubility
158
aspartate in water from T= (278 to 348) K.” J. Chem. Thermodyn., 31,
85-91, (1999).
41. J. Gao, Z. W. Wang, D. M. Xu, and R. K. Zhang,; “Solubilities of
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(2001).
43. D. M. Aragon, M. A. Ruidiaz, E. F. Vargas, C. Bregni, D. A. Chiappetta,
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45. P. Bustamante, S. Romero, A. Pena, B. Escalera, and A. Reillo,;
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SECTION – V
PARTITION CO-EFFICIENT
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159
INTRODUCTION
The partition coefficient or distribution coefficient is the ratio of
concentrations of a substance in the two phases of a mixture of two
immiscible solvents at equilibrium.1 These coefficients have been a measure
of differential solubility of the substance between two solvents. The partition
coefficient is of great importance in various fields such as industry, pharmacy,
medicine, chemistry etc.
Partition coefficient is very useful in cosmetic formulations, since it is a
measure of the ability of a material to penetrate the hair and skin. Partition
coefficients have been also used in the liquid-liquid chromatographic
separations 2.
In pharmacokinetics, the distribution coefficient has a strong influence
on ADME properties (Absorption, Distribution, Metabolism, and Excretion) of
the drug 3. Whereas in Pharmacodynamics, the hydrophobic effect is the
major driving force for the binding of drugs to their receptor targets 4-5.
Moldovan et al. have suggested several physicochemical properties of
drug molecules, one of them is partition coefficient, which is used to
characterize the lipophilicity of drugs 6-7.
Lipophilicity of drug molecules plays an important role in their
absorption, permeation, and disposition by affecting the drug’s ability to be
absorbed through the gut wall and to cross the blood/brain barrier 8.
The distribution between water and an immiscible nonpolar solvent is
acknowledged as a useful descriptor for the hydrophobicity of a substance. nOctanol and water are widely accepted as the best two-phase system to
model the partitioning between biomass and water. Relationships between the
partition coefficient of this system and bioconcentration, 9-12 soil sorption, 13-15
and toxicity 16-18 for fish have also been found.
The common lipophilicity scale of molecules is defined by the
octanol/water partition coefficient; log P, which is a measure of the drug’s
preference for an organic compound for water versus a less polar organic
solvent 19.
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Section -V: Partition Co-efficient
160
Partition coefficients indicate drug transport characteristics – the ability
of drugs to reach the site of action from the site of application. Drugs are
distributed by the blood and must penetrate and traverse many cells to reach
the site of action. Hence, the partition coefficient indicates which tissues a
given compound can reach 20-21. The partition coefficient of a solute between
octanol and water has been widely used to predict drug pharmacokinetic
properties 22-24.
The partition coefficient or log P has been known to be one of the most
important quantitative parameters that correlate with the variation in biological
activities. In QSAR studies, log P is the most widely used hydrophobic
parameter. Liu et al have measured lipophilicity by reverse–phase high
performance liquid chromatography.25-26 The partition coefficient between
octanol-water phases of some organic compounds have also been studied by
some workers 27-29. Gasslander et al. have determined polymer-water partition
coefficient by using organic modifiers in the aqueous phase 30. Ming et al.
have reported that octanol-water partition coefficient of monobasic acidic
compounds 31.
In the present study, partition coefficients of synthesized chalcones
have been studied in n-Octanol-water system by UV spectroscopy at different
pH.
Studies of some bio-active heterocyclic…….
Section -V: Partition Co-efficient
161
EXPERIMENTAL
n-Octanol is of analytical grade. The purity of solvent was checked by
GC and found to be 99.9%. Distilled water was used throughout for all
experiments.
Preparation of standard solution:10 mg sample was dissolved in n-Octanol to give 100 ml solution of
100 ppm. This solution was known as standard solution. λmax values were
measured using UV spectrophotometer (Shimadzu, UV-1700, Pharmaspec)
from this solution. Suitable dilutions were made from this standard solution (8
μg to 20 μg) and absorbance (OD) was measured. The plot of OD verses
concentration gives the calibration curve.
Determination of Partition coefficient:A known amount of the compound under investigation was dissolved in
n-Octanol at a concentration not higher than 20 μg. Equal volumes of this
solution and water is mixed in oven dried stoppered flask and the mixture was
stirred for 24 hrs. at room temperature. After 24 hrs., the solution was
transferred into 250 ml of separating funnel and allow to stand to separate the
aqueous and organic layers. The organic layer will be upper one while lower
will be aqueous. The organic layer was then analyzed by UV
spectrophotometer. Using calibration curve, the concentration of compounds
in organic layer was then evaluated.
As, partition coefficient is highly influenced by pH, a wide range of pH
(0.84 to 8.0) is selected. For 0.84 pH, 0.1 N HCl was taken whereas for 6.0,
7.4 and 8.0, phosphate buffer was used.
Studies of some bio-active heterocyclic…….
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162
THEORY
Partition coefficient (P) is defined as the ratio of the compounds in
organic phase to that present in the aqueous phase. i.e., 32
org
aq C
P
C
= …(3.5.1)
where Corg and Caq are concentration of solute in organic and aqueous phases
respectively.
In the present case, concentrations were determined by UV
measurement so, equation (3.5.1) written as: 33
E
E E
BP
B A
=

…(3.5.2)
where, BE=Absorbance before separation and AE=Absorbance after
separation. From equation (3.5.2), log P were calculated for each set of
experiment.
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Section -V: Partition Co-efficient
163
RESULTS AND DISCUSSION
The values of log P for the studied compounds at different pH are
given in Table 3.5.1 and Figure 3.5.1. The log P values depend upon the
hydrophilic and hydrophobic character of compounds. These values are
higher for compounds having hydrophobic nature whereas lower log P is for
compounds of hydrophilic type.
Table 3.5.1 shows that log P depends on pH of solution. The selected
pH values for the present study were due to their existence in human body.
As HCl exists in gastric juice in stomach, 0.1 N HCl is taken. Blood has 7.4
pH, so the study is done at pH 7.4. Further, the middle and upper range of
body pH is 6.0 and 8.0 respectively, so study was done at this pH also.
In water, log P is maximum for NVA-07 suggesting thereby
hydrophobic nature of this compounds whereas NVA-01 is highly hydrophilic
as it’s log P value is minimum. NVA-07 contains -4-OH-C6H4 side chain
whereas NVA-01 contains -4-Cl-C6H4 side chain. Thus, the presence of -4OH-C6H4 side chain (in NVA-07) causes hydrophobic nature in neutral pH.
However, the hydrophilic or hydrophobic nature of studied compounds
varies with pH. In 0.1N-HCl, again NVA-07 is highly hydrophobic whereas
NVA-05 containing 4-OCH3-C6H4 group is found to be hydrophilic. Thus, in
gastric juice, NVA-07 will not be absorbed whereas NVA-05 can be easily
absorbed.
At 6.0 pH, log P is maximum in NVA-06 exhibiting maximum
hydrophobicity whereas NVA-7 becomes most hydrophilic. Thus, at 6.0 pH,
NVA-07 containing -4-OH-C6H4 substituent become hydrophilic whereas NVA06 containing 4-Br-C6H4 exibited hydrophobic nature. Thus, the result
suggests that NVA-07 can be easily absorbed by the blood. Overall the order
of hydrophobicity of compounds is:
NVA-06 > NVA-08 > NVA-03 > NVA-04 > NVA-09 > NVA-05 > NVA-01 >
NVA-02 > NVA-07.
In 7.4 pH range, among all these compounds NVA-02 containing 4NO2-C6H4 has minimum log P whereas maximum is observed for NVA-05
Studies of some bio-active heterocyclic…….
Section -V: Partition Co-efficient
164
Table : 3. 5.1. log P values of chalcones
Compounds
Code
Max absorption
Wavelength/nm
log P
Water 0.1N HCl
6.0
pH 7.4
pH 8.0
pH NVA-01 371 0.724 0.883 0.876 1.767 1.681
NVA -02 358 0.785 1.164 0.798 0.860 0.755
NVA -03 359 1.647 1.113 1.511 1.972 1.370
NVA -04 382 0.923 2.092 1.439 1.967 1.314
NVA -05 383 1.621 0.626 1.267 2.011 1.906
NVA -06 365 2.128 1.891 1.993 1.722 2.090
NVA -07 360 2.768 2.370 0.068 1.893 2.592
NVA -08 359 2.027 1.940 1.619 1.583 1.867
NVA -09 365 1.537 1.003 1.401 1.861 1.259
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Section -V: Partition Co-efficient
165
Figure: 3.5.1. log P for the studied compounds at different pH
Studies of some bio-active heterocyclic…….
Section -V: Partition Co-efficient
166
which can be considered more hydrophobic in nature. Thus, NVA-05 containing 4OCH3-C6H4 group will not be absorbed in blood, and is less likely to spread in the
body. However, it is more likely to accumulate in fatty tissues 34, 35. The order of
hydrophobicity of compounds is:
NVA-05 > NVA-03 > NVA-04 > NVA-07 > NVA-09 > NVA-01 > NVA-06 > NVA-08 >
NVA-02.
However, at pH 8.0, log P values maximum for NVA-07 and minimum for
NVA-02. Thus, at alkaline pH, NVA-07 will not be absorbed by the blood but can be
accumulated in fatty tissues as observed by Rowe et al. 34 and Fresta et al. 35. The
decreasing order of hydrophobicity of compounds is:
NVA-07 > NVA-06 > NVA-05 > NVA-08 > NVA-01 > NVA-03 > NVA-04 > NVA-09 >
NVA-02.
Thus, it is concluded that the studied compounds, NVA-07 shows hydrophobic
characteristic in neutral, acidic, and alkaline systems, although it contains -4-OHC6H4 side chain. At 6.0 and 7.4 pH, hydrophobicity decreases. The reason for
change in hydrophobic character at intermediate pH is not clear.
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167
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18. Hay et al.; “Modulation of the Partition Coefficient between Octanol and Buffer
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M. Ollivon,; “Partition coefficient of a surfactant between aggregates and
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phosphatidylcholine and octyl beta-D-glucopyranoside” Biophy. J., 69, 6,
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20. Darcy Shave and Pete Alden,; “ Determination of Partitioning Coefficient by
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21. M. Paternostre, O. Meyer, C. Grabielle-Madelmont, S. Lesieur, M. Ghanam,
M. Ollivon,; “Partition coefficient of a surfactant between aggregates and
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30. U. Gasslander, A. Arbin and A. C. Albertsson; “Polymer-water partition
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SECTION – VI
DISSOCIATION CONSTANTS
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Section VI: Dissociation constant
171
INTRODUCTION
The term dissociation constant is a specific type of equilibrium constant
that measures the tendency of a larger molecule to separate (dissociate)
reversibly into smaller components, as when a complex falls apart into its
component molecules, or when a salt splits up into its component ions. The
dissociation constant is usually denoted and is the inverse of the association
constant. In the special case of salts, the dissociation constant can also be
called an ionization constant or dissociation constant 1-4.
There are many applications of dissociation constants. The nature of
the functional groups can be determined by simple comparison of acidity or
dissociation constant of the unknown compound with those of known
compounds. The dissociation or formation constant also provide useful
informations about tautomeric equilibria 5-6, solvent-solute interactions 7 etc.
Now a day, various methods are available to determine dissociation
constant. Roy and Popelier have determined acidic dissociation constant of
substituted phenols in different solvent systems by the predictive QSPR
models 8. Manallack have measured the acid-base dissociation constant of a
drug 9 by measured for regulatory compliance. Hambor and Versteeg, have
studied the dissociation constant and thermodynamic properties of various
alkanolamines by measuring electromotive force 10-12. Casado et.al have
determined acid dissociation constant of ester and lactones 13 by measured
via kinetic study of its base-catalyzed hydrolysis.
Spectrophotometric determination of the dissociation constant of
different systems have been reported by various workers 14-17. Evagelou et al.
(18) have reported the dissociation constants of the cephalosporin’s, cefepime
and cefpirome by using UV spectrometry and pH potentiometry. Spectrometry
is an ideal method when a substance is not soluble enough for potentiometry
or when its pKa value is particularly low or high 19-22.
Literature survey shows that many workers studied the dissociation
constant of many complex substances 23-27 using different methods. The
dissociation constants of various other acids in pure and mixed solvents have
also been studied 28-33.
Studies of some bio-active heterocyclic…….
Section VI: Dissociation constant
172
Further, in last few years dissociation constant of many substances
have been studied such as carboxylic acid derivatives 34, vitamins 35, alcohols
36, Gas hydrate 37-39, Some organic compounds 40 by various workers.
Studies of some bio-active heterocyclic…….
Section VI: Dissociation constant
173
EXPERIMENTAL
The synthesized Chalcones of vanillin derivatives were recrystallized
from DMF, which was of LR grade and was distilled by the reported method
41.
100 ppm solution of sample was prepared in DMF. This solution known
as standard solution was used to determine λmax using UV spectrophotometer
(SHIMADZU PHARMA SPEC-1700 UV VISIBLE) equipped with 1 cm path
length cell, controlled by computer. The instrument was calibrated by usual
procedure.
The following set of mixtures were prepared.
(1) 2 ml HNO3 (0.01 M) + 4 ml NaNO3 (0.01 M) + 19 ml DMF
(2) 2 ml HNO3 (0.01 M) + 4 ml NaNO3 (0.01 M) + 2 ml ligand
solution (15 ppm) + 17 ml DMF
Thus, total volume of each set of solution was 25 ml and DMF:water ratio was
90:10(v/v).
To each set of solution, pH and absorbance (OD) were measured after
each addition of 0.1 ml NaOH till there was no change in OD.
A systronic pH meter (Model No. EQ 664) was used for the pH
determination. pH meter was calibrated by known buffer solutions. The glass
electrode and a saturated calomel electrode were used as indicator and
reference electrodes respectively.
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Section VI: Dissociation constant
174
THEORY:
The protonation of a weak B can be represented as:
BH+ B + H
+
….. (3.6.1)
So, the equilibrium constant (K) can be given as:
+
+
BH
BH
a .a
K =
a ….. (3.6.2)
where a represents the activity of each species. The activity a is related to
concentration c by the equation:
a=c.γ ….. (3.6.3)
where γ is the activity coefficient.
Substituting the values of a in eq. (3.6.2) gives,
[ ]
+H
K =a . B
BH
B
BH
γ
γ + +⎡ ⎤⎣ ⎦
….. (3.6.4)
where square brackets indicate the concentration of the species.
Combining the activity coefficient with K yields the mixed conditional
constant Ka (one that incorporates both activity and concentration) 42 gives:
[ ]
+a H
K =a .
B
BH +⎡ ⎤⎣ ⎦
….. (3.6.5)
Taking logarithm of above equation (3.6.5) gives:
[ ]
loga
BH
pK pH
B
+⎡ ⎤⎣ ⎦= + ….. (3.6.6)
Rearrangement of above equation gives:
[ ]log a
B
pH pK
BH +
= −
⎡ ⎤⎣ ⎦
….. (3.6.7)
Studies of some bio-active heterocyclic…….
Section VI: Dissociation constant
175
A plot of [ ]log B
BH +⎡ ⎤⎣ ⎦
versus pH will therefore yield a straight line and pH=pKa
when [ ]log B
BH +⎡ ⎤⎣ ⎦
=0, providing that the temperature and ionic strength are held
constant 42.
The concentrations of the individual species BH+ and B can be
determined spectrophotometrically by measuring the absorbance (OD) at
particular wavelength. However, if a series of solutions is prepared at various
pH and the total concentration of compound ct = [BH+]+[B] is constant, it can
be shown that the ratio of the conjugate forms is given by (42)
0
0
a b
b a
C A A I
C A A

= =

(Aa0 > Ab0) ….. (3.6.8 a)
or 0
0
a b
b a
C A A I
C A A

= =

(Ab0 > Aa0) ….. (3.6.8 b)
where Ca and Cb represent [BH+] and [B] respectively. A, Aa0 and Ab0
represent the measured absorbance, absorbance when [BH+]=ct and
absorbance when [B] =ct respectively. A plot of absorbance, obtained on the
series of solutions at a single wavelength, is plotted according to equation
(3.6.7) to determine pKa.
However, for some weak bases, it is reported that if slope m
of the plot (Fig.2) is not unity, pKa value should be calculated by the following
equation 42:
1/ 2.apK m H= ….. (3.6.9)
where H1/2 represents the pH at half protonation at log I=0.
Studies of some bio-active heterocyclic…….
Section VI: Dissociation constant
176
RESULTS AND DISCUSSIONS
Table 3.6.1 shows the experimental data of pH and OD for the studied
compounds. The plot of OD versus pH is shown in Figure 3.6.1 for NVA-01.
Using equation 3.6.8 (a or b), log I value were calculated and plotted against
pH. The plot is a straight line and pKa value is evaluated at log I=0. This value
of pKa is taken as half protonation (H1/2) by Ogretir et al. 43,44
Further, at each pH, from the absorbance data, pKa value was
evaluated from equation (3.6.7) and average of pKa is reported in Table 3.6.2
along with the value calculated from the graph.
In the studied compounds, the slope (m) of the plot (Figure 3.6.2) was
also calculated. It is reported 43,44 that if m values are between 0.85 and 1.05
then the bases are of Hammett type. In that case, m can be taken as unity.
Thus, in the present study, m values are found to be between 0.60 and 0.96,
so its observed that the studied compounds can be considered as other than
of Hammett type. In that case m cannot always unity 45. And so H1/2 is equal
to pKa, which is same as reported in Table 3.6.2.
Table 3.6.3 shows the compounds in their increasing order of acidity or
basicity. It is observed that the -Br groups at para position of the phenyl ring
makes NVA-06 the least acidic or most basic one, whereas NVA-07 is found
to be most acidic due to the -OH group at para position. This is an agreement
with the result of Berber and Ogretir who observed that the presence of OH
group increases the acidic character of compounds.43,44
Studies of some bio-active heterocyclic…….
Section VI: Dissociation constant
177
Table 3.6.1. Experimental data of pH and Absorbance (OD) of chalcones.
NVA-01
(λmax = 371)
NVA-02
(λmax = 358)
NVA-03
(λmax = 359)
NVA-04
(λmax = 382)
NVA-05
(λmax = 383)
pH OD pH OD pH OD pH OD pH OD
2.89 1.4803 2.87 1.8127 2.52 1.6027 2.4 1.4827 2.53 1.6043
2.98 1.4801 3.19 1.8103 2.84 1.6003 2.72 1.4803 3.07 1.6007
3.43 1.4795 3.45 1.807 3.1 1.597 2.98 1.477 3.73 1.6001
3.89 1.4783 3.9 1.8033 3.55 1.5933 3.43 1.4733 4.18 1.5997
4.25 1.4769 4.34 1.797 3.99 1.587 3.87 1.467 4.37 1.5976
4.77 1.4763 4.74 1.7893 4.39 1.5793 4.27 1.4593 4.54 1.5963
5.61 1.4759 5.05 1.7851 4.7 1.5751 4.58 1.4551 5.01 1.5952
5.82 1.4733 5.48 1.7793 5.13 1.5693 5.01 1.4493 5.35 1.5925
6.02 1.4677 6.1 1.763 5.75 1.553 5.63 1.433 5.65 1.583
6.15 1.4627 6.78 1.7527 6.43 1.5427 6.31 1.4227 5.93 1.5812
7.38 1.4563 7.6 1.7317 7.25 1.5217 7.13 1.4017 6.74 1.5766
8.02 1.423 8.48 1.6828 8.13 1.4728 8.01 1.3528 7.61 1.523
8.65 1.3859 9.34 1.6128 8.99 1.4028 8.87 1.2828 8.21 1.4729
9.65 1.2959 9.98 1.5267 9.63 1.3167 9.51 1.1967 8.85 1.4319
10.41 1.2263 10.5 1.5003 10.15 1.2903 10.03 1.1703 9.93 1.3309
11.18 1.1661 10.88 1.4731 10.53 1.2631 10.41 1.1431 10.45 1.2832
11.84 1.1527 11.54 1.4327 11.19 1.2227 11.07 1.1027 11.67 1.2507
12.38 1.1463 12.38 1.4225 12.03 1.2125 11.91 1.0925 12.07 1.2493
12.41 1.1334 12.41 1.4195 12.52 1.2095 12.4 1.0895 12.55 1.2476
12.53 1.1325 12.47 1.4195 13.05 1.2095 12.93 1.0895 12.81 1.2467
12.65 1.1323 12.58 1.4194 13.06 1.2094 12.94 1.0894 13.07 1.2466
Studies of some bio-active heterocyclic…….
Section VI: Dissociation constant
178
Continue….
NVA-06
(λmax = 365)
NVA-07
(λmax = 360)
NVA-08
(λmax = 359)
NVA-09
(λmax = 365)
pH OD pH OD pH OD pH OD
3.10 1.5903 2.68 1.8827 2.39 1.4943 2.6 1.5643
3.29 1.5901 3.22 1.8803 2.93 1.4907 3.14 1.5607
3.74 1.5895 3.88 1.877 3.59 1.4901 3.8 1.5601
4.20 1.5883 4.33 1.8733 4.04 1.4897 4.25 1.5597
4.56 1.5869 4.52 1.867 4.23 1.4876 4.44 1.5576
5.08 1.5863 4.89 1.8593 4.41 1.4863 4.61 1.5563
5.92 1.5859 5.16 1.8551 4.87 1.4852 5.08 1.5552
6.13 1.5833 5.51 1.8493 5.12 1.4825 5.42 1.5525
6.33 1.5777 5.82 1.833 5.51 1.473 5.72 1.543
6.76 1.5727 6.08 1.8227 5.79 1.4712 6.11 1.5412
7.69 1.5663 6.89 1.8017 6.60 1.4666 6.81 1.5366
8.33 1.533 7.76 1.7528 7.47 1.413 7.68 1.483
8.96 1.4959 8.36 1.6828 8.07 1.3629 8.28 1.4329
9.96 1.4059 9.01 1.5967 8.71 1.3219 8.92 1.3919
10.72 1.3363 9.87 1.5703 9.79 1.2209 10.11 1.2909
11.49 1.2761 10.6 1.5431 10.31 1.1732 10.52 1.2432
12.15 1.2627 11.82 1.5027 11.53 1.1407 11.74 1.2107
12.69 1.2563 12.22 1.4925 11.93 1.1393 12.14 1.2093
12.72 1.2434 12.47 1.4895 12.41 1.1376 12.62 1.2076
12.84 1.2425 12.59 1.4895 12.67 1.1367 12.88 1.2067
12.96 1.2423 12.77 1.4894 12.93 1.1366 13.14 1.2066
13.03 1.2422
Studies of some bio-active heterocyclic…….
Section VI: Dissociation constant
179
Table 3.6.2. pKa value from graph and Average pKa of chalcones
Compound
Code
pKa value from
graph (H1/2) Average pKa value
Correlation
coefficient
NVA-01 9.47 9.45 0.9775
NVA -02 9.53 9.59 0.9907
NVA -03 9.73 9.12 0.9928
NVA -04 9.10 9.22 0.9923
NVA -05 8.96 8.87 0.9930
NVA -06 9.85 9.69 0.9914
NVA -07
5.51
8.40
5.57
8.56
0.9981
0.9942
NVA -08 8.84 8.76 0.9772
NVA -09 9.01 8.96 0.9244
Table 3.6.3 Arrange chalcones in order of increasing acidity or
decreasing basicity strength by half protonation values as
follows:
Compound
Code
H1/2 Groups Acidity or basicity
NVA -06 9.85 4-Br
D
ec re as in g ba si ci ty o r i
nc re as in g ac id ity
in cr ea si ng b as ic ity
o r D
ec re as in g ac id ity
NVA -03 9.13 -H
NVA -02 9.53 4-NO2
NVA-01 9.47 4-Cl
NVA -04 9.10 4-CH3
NVA -09 9.01 3-Cl
NVA -05 8.96 4-OCH3
NVA -08 8.84 2,4-OCH3
NVA -07
5.51
8.40
4-OH
Studies of some bio-active heterocyclic…….
Section VI: Dissociation constant
180
Figure 3.6.1: The variation of OD with pH for NVA-01.
Figure 3.6.2 : The plot of log I versus pH for NVA-01.
Studies of some bio-active heterocyclic…….
Section VI: Dissociation constant
181
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SECTION – VII
THERMAL STUDY
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
186
INTRODUCTION
Studies on thermal properties of substances are of great importance
from both scientific and practical of view. Scientific and technological
achievements together with demands based on industrial requirement have
permitted the development of various types of materials that can with stand at
much higher temperatures and more corrosive environments.
Among the several instruments and technique, thermal analysis has
grown rapidly in recent years. This increasing importance is due to the
advancement of thermal analysis technology, relative cheapness of the
equipment and time required to achieve the desired results. These techniques
are able to characterize a wide range of materials and material properties. In
these techniques, the change in properties of material are followed as a
function of temperature when it is heated at constant predetermined rate
under specified ambient atmospheric conditions.
Some of the most commonly used techniques are Differential Scanning
Calorimetry (DSC), Differential Thermal Analysis (DTA), Thermo Gravimetric
Analysis (TGA), Evolved Gas Detection (EGD), Evolved Gas Analysis (EGA)
etc.
In the present study, thermal analysis is done by DSC and TGA
techniques. Thermogravimetric analysis (TGA) is a thermal analysis technique
which measures the weight change in a material as a function of temperature
and time, in a controlled environment. This can be very useful to investigate
the thermal stability of a material.
Differential scanning calorimetry (DSC) is a simple and rapid method of
estimating the purity of materials, which is used to provide quantitative and
qualitative information about physical and chemical changes involving
endothermic or exothermic processes or heat capacity changes.1,2 The
method is based on the van’t Hoff law of melting point depression.
Literature survey shows that thermal analysis of various types of
compounds such as drugs3,4, dyes5-7 , fertilizers8,9, polymers10-13, pharma
materials14-15, organic16-17 ,inorganic18-19 , vitamine20 , metal21 and compounds
have been reported. Recently, a number of investigators22-27have studied the
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
187
thermal properties of various materials. However, the little works have done
on the thermal properties of chalcones derivatives28-30.
In the present study, thermal properties of some new synthesized
chalcones have been studied by DSC and TGA techniques.
Using thermograms, various kinetic parameters have also been
evaluated.
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
188
THEORY:
From TGA curves, various kinetic parameters can be evaluated by
several methods. In all these methods, it is assumed that thermal and
diffusion barriers are negligible because small quantity of material is used.
The shape of any TGA curve depends on the nature of apparatus and the way
in which it is used. Further, Arrhenius equation is valid in all these methods.
The kinetic treatments are generally based on the relationship of the
type:
dC/dt = K f (C) ... (3.7.1)
where C is the degree of conversion, t is time and K is rate constant. f(C) is a
temperature independent function of C.
The constant K is assumed to have the Arrhenius form:
K = A e -E/RT ... (3.7.2)
C can also be defined as:
C = 1-(W/W0) ... (3.7.3)
where W0 and W are the initial weight at t=0 and weight at any time t of the
material.
Equation (3.7.3) can be written as:
(W/W0) = (1-C) ... (3.7.4)
W/ W0 is known as residual weight fraction.
Thus, the rate of conversion is,
dC/dt = - (1/W0) (dW/dt) ... (3.7.5)
For homogeneous kinetics, the conversion is assumed to be of the
form:
f (C) = (1-C)n ... (3.7.6)
where n is the order of the reaction.
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
189
Substituting the values from equation (3.7.2) and (3.7.6) in equation
(3.7.1) gives:
dC/ dt = A e -E/RT (1-C)n
or dC/dt = (A/β) e -E/RT (1-C)n ... (3.7.7)
where A is the frequency factor, β is the rate of heating and E is the energy of
activation.
Various methods for single and multiple heating rates have been
reported. The methods of single heating rate are as follows:
1. Freeman-Carroll 31 and Anderson-Freeman Method 32:
At a single heating rate, Freeman and Carroll gave the following
relation to analysis TGA data :
ln (dC/dt)/ln (1-C) = n-E/R [(1/T/(Δln(1-C)] ... (3.7.8)
A plot of left hand side against (1/T)/(Δln(1-C)) gives a straight line with
a slope equal to -E/R and the intercept is equal to n.
Anderson and Freeman then derived the following equation by using
equation (3.7.8):
(∆ln[dC/dt]) = n (∆ln(1-C)) - E/R ∆(1/T) ... (3.7.9)
The plot of (∆ln[dC/dt]) against (∆ln(1-C)) for equal intervals of ∆ (1/T)
gives a straight line with slope equal to n and intercept -E/R∆ (1/T).
2. Sharp-Wentworth method 33:
To analyse the TGA data for first order kinetics (n=1), Sharp and
Wentworth gave the relation:
log [(dC/dt)/(1-C)] = log (A/β) – (E /2.303R).(1/T) ... (3.7.10)
The plot of log [(dC/dt)/(1-C)] against 1/T would be a straight line with
slope equal to - (E/2.303R) and intercept equal to log (A/ β).
3. Chatterjee Method 34:
Based on the weight units, the following relation was developed by
Chatterjee:
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
190
n = [log(dW/dt)1-log(dW/dt)2] / (log W1-log W2) ... (3.7.11)
where W1 and W2 are the sample weights.
4. Horowitz and Metzger method 35 :
In this method, the value of energy of activation E can be determined
from a single TG curve by the relation:
ln [ln(1-C)-1] = (E/RTs
2
)θ ... (3.7.12)
where θ = T-Ts. Ts is the temperature at which the rate of decomposition is
maximum. The frequency factor A and entropy change ∆S can be determined
by the following equations:
ln E - ln (RTs
2
) = ln A - lnβ - E/RTs ... (3.7.13)
A = (kbT / h) e ∆S/R ... (3.7.14)
where kb is Boltzmann constant and h is Planck’s constant.
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
191
EXPERIMENTAL
Thermo gravimetric analysis (TGA) and Differential Scanning
Calorimetry (DSC) measurements were made on the instrument “Pyris-1,
Perkin Elmer Thermal Analysis” at the heating rate of 10 0C/min in nitrogen
atmosphere for all the chalcones derivatives.
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
192
RESULTS AND DISCUSSION
The TGA and DSC thermograms of NVA-1 and NVA-2 are given in
Figure 3.7.1 and 3.7.2. Various thermal properties such as initial
decomposition temperature, the decomposition temperature range, the
maximum degradation, the percentage weight loss, transitions along with
DSC temperature of all the synthesized chalcones derivatives are reported in
Table 3.7.1.
For all the compounds, degradation is single step process. Further, the
the decomposition temperature for all the studied compounds are not very
high. Looking to the value of maximum degradation temperature reported in
Table 3.7.1, it is evident that NVA-8 is most stable whereas NVA-2 is least
stable. This suggests that the presence of methoxy group increases stability
whereas p-nitro group decreases the stability to a greater extent. The thermal
decomposition may depend on different structural as well as electronic
intermolecular interactions. Further, maximum weight loss is observed for
NVA-5, followed by NVA-3, NVA-7 and NVA-9.
Further, from the thermograms, various kinetic parameters, such as
order of the degradation (n), energy of activation (E), frequency factor (A) and
entropy change (∆S) have also been calculated and are reported in Table
3.7.2.
It is evident from Table 3.7.2 that order of reaction varies from 1.06 to
6.17 for the studied compounds.
The energy of activation (E) is highest for NVA-4 and minimum for
NVA-5. The frequency factor (A) also varies in the same order i.e., maximum
for NVA-4 and minimum for NVA-5.
Further, change in entropy (∆S
0
) for all these degradations were also
calculated by equation (3.7.14) and are reported in Table 3.7.2. It is observed
that entropy (∆S
0
) values are positive for NVA-3, NVA-4, NVA-7, NVA-8 and
NVA-9 whereas for other compounds, ∆S0 values are negative.
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
193
The positive ∆S0 indicates that the transition state is less ordered than
the original compound whereas negative ∆S
0
corresponds to an increase in
the order of transition state than the reactants.
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
194
Figure 3.7.1: The TGA thermograms of NVA-1 and NVA-2.
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
195
Table 3.7.1: TGA/DSC data for synthesized NVA series.
Comp.
Code
Amt.
mg.
Initial
Decomp.
Temp.
oC Decomp.
range
oC % Wt.
loss
Residual Wt.
Loss
mg.
Transition
M. P. by
DSC 0C
M. P. by
Open capillary
0C
NVA-1 6.105 150 150-450 67.41 4.1150 Endo 151 153
NVA-2 6.642 80 80-450 55.51 3.8138 Endo 151.92 153
NVA-3 7.131 150 150-496 93.14 6.7245 Endo 130.86 132
NVA-4 8.398 125 125-497 75.62 6.4437 Endo 124.68 124
NVA-5 6.375 130 130-500 95.96 6.1512 Endo 151.21 151
NVA-6 6.115 160 160-496 65.27 4.1221 Endo 139.01 134
NVA-7 7.111 160 160-496 93.14 7.7383 Endo 130.20 133
NVA-8 6.742 175 175-498 87.41 5.8931 Endo 129.66 129
NVA-9 7.211 160 160-496 93.94 6.8186 Endo 168.86 170
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
196
Table 3.7.2: The kinetic parameters of chalcones derivatives.
Comp. code n
E
kJ.mol-1
A
s-1
∆S
J.mol-1.K-1
NVA-1 5.09 16.42 1.39E+00 -93.7675
NVA-2 6.17 16.43 1.43E+00 -93.5315
NVA-3 1.66 150.49 1.32E+14 173.7023
NVA-4 2.69 176.07 3.31E+16 219.5435
NVA-5 2.72 1.74 5.11E-03 -140.477
NVA-6 4.43 20.49 4.77E+00 -83.4241
NVA-7 1.65 152.27 2.30E+14 178.3199
NVA-8 1.06 138.51 1.72E+13 156.9048
NVA-9 1.71 125.23 1.12E+13 154.0233
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Section –V: Thermal Properties
197
Further, the melting points of studied compounds were evaluated from
DSC. Figure 3.7.2 shows DSC of NVA-1 and NVA-2 and melting points of all
the compounds are reported in Table 3.7.1 along with those observed by
open capillary method. Comparison of melting points, obtained by both
methods is found to be in good agreement.
Thus, the degradation in the studied compounds is single step process
with different order of reaction. Further, thermal stability depends upon the
type of substituent present.
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
198
Figure 3.7.2: The DSC graphs of NVA-1 and NVA-2.
Studies of some bio active heterocyclic…….
Section –V: Thermal Properties
199
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estimation of drug purity: various problems and their solutions in purity
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characterization and thermal study on allopurinol complexes” J. Mol.
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spectrometric investigation of buspirone drug in comparison with
thermal analyses and MO-calculations” Spectrochim. Acta, Part A:
Mole. Biomol. Spect., 67, 522-30, (2007).
5. M. E. M. Emam, I. M. M. Kenawy and M. A. H. Hafez,; “Study of the
thermal decomposition of some new cyanine dispersed dyes” J. Therm.
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6. K. Venkataraman,; “ The Chemistry of Synthetic Dyes” Academic
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spectroscopic studies of luminescent dye doped poly(methyl
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9. C. Muntean W. Brandl, A. Iovi and P. Negrea,; “Studies on the thermal
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“Thermochim. Acta, 439, 1-2, 21-26, (2005).
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10. J. Sickfeld, W. Mielke,; “Application of thermal analysis for the
investigation of epoxy resins” Prog. Org. Coatings., 12, 27-116,
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11. T. Kamon,; “ Application of thermal analysis to the curing of
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macroredox polymerization of styrene with hydroxy-terminated
polybutadiene” Euro. Poly. J., 39, 2077-89, (2003).
13. X. Weng,; “ Application of thermal analysis techniques in the study
of polymer materials” Guangzhou Huaxue., 33, 72-76, (2008).
14. L. Bond, S. Allen, M. C. Davies, C. J. Roberts, A. P. Shivji, S. J. B.
Tendler, P. M. Williams and J.Zhang,; “Differential scanning calorimetry
and scanning thermal microscopy analysis of pharmaceutical
materials” Int. J. Pharm., 243, 28, 71-82, (2002).
15. D. Faroongsarng, W. Kadejinda,and A. Sunthornpit,; “ Thermal
Behavior of a Pharmaceutical Solid Acetaminophen Doped with pAminophenol” AAPS Pharm. Sci. Tech. 1(3), 23, (2000).
16. M. A. Rashid, T. Hossain and M. A. Asgar,; “ The thermal behaviour of
simple aromatic organic compounds with AlCl3 as additives”
Thermochim. Acta, 259, 263-268, (1995).
17. A. Snyder, T. A. Peter; J. P. Dworzanski, W. M. Maswadeh, C. H.
Wick,; “Characterization of microorganisms by thermogravimetric
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18. L.W. Collins, E.K. Gibson and W.W. Wendlandt,; “The thermal
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19. Y. Xi, W. Martens, H. He, R. L. Frost,; “Thermogravimetric analysis
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20. T. F. Moura , D. Gaudy, M. Jacob, A. Terol , B. Pauvert ,A. Chauvet,;
“Vitamin C spray drying: study of the thermal constraint” Drug Develop.
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21. Y. Nie, Y. Xie, H. Peng, X. Li,; “ First-principles study of thermal
properties of metal Ti” Ziran Kexu., 38, 1072-77,(2007).
22. M. Rauma, G. Johanson,; “Comparison of the thermogravimetric
analysis (TGA) and Franz cell methods to assess dermal diffusion of
volatile chemicals” Toxicol. Vitro, 23, 5, 919-926, (2009).
23. K. Şerifaki, H. Böke, Ş. Yalçın and B. İpekoğlu,; “Characterization of
materials used in the execution of historic oil paintings by XRD,
SEM-EDS, TGA and LIBS analysis” Mat. Charact., 60, 4, 303-311,
(2009).
24. J. S. Torrecilla, E. Rojo, J.C. Domínguez and F. Rodríguez,; “Chaotic
parameters and their role in quantifying noise in the output signals from
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25. K. L. Manquais, C. Snape,I. McRobbie, J. Barker,and V. Pellegrini,;
“Comparison of the combustion reactivity of TGA and drop tube
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(2009).
26. Z. Ahmad, N. A. Al-Awadi, F. Al-Sagheer,; “Thermal degradation
studies in poly(vinyl chloride)/poly(methyl methacrylate) blends” Poly.
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27. R. M. Padmanabha, S. Alam,; “Synthesis and thermal behaviour of
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(2008).
28. T. Mihara, Y. Nakao and N. Koide,; “Synthesis and thermal properties
of main chain polyimides containing chalcone derivative” Polym. J., 36,
11, 899-908, (2004).
29. J. M. Devi K. S. Ali , V.R. Venkatraman, S.K. Ramakrishnan and K.
Ramachandran,; “A study on the thermal properties of cinnamoyl
chalcones” Thermochim. Acta., 438, 1-2, 29-34, (2005).
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202
30. X. T. Tao, T. Watanabe, K. Kono, T. Deguchi, M. Nakayama, and S.
Miyata,; “Synthesis and characterization of poly(aryl ether chalcone)s
for second harmonic generation” Chem. Mater., 8, 1326-1332, (1996).
31. E. S. Freeman, B. Carroll,; “The application of thermoanalytical
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traces” Ana. Chem., 35, 1464-68, (1963).
CHAPTER - 4
BIOLOGICAL ACTIVITIES
Studies of some bio-Active heterocyclic…….
Chapter –4: Biological Activities
203
INTRODUCTION
Biological activity is an expression describing the beneficial or adverse
effects of a drug on living matter. When the drug is a complex chemical
mixture, this activity is exerted by the substance's active ingredient or
pharmacophore but can be modified by the other constituents. The main kind
of biological activity is a substance's toxicity.
Biological activity spectrum of a compound represents the
pharmacological effects, physiological and biochemical mechanisms of action,
specific toxicity which can be revealed in compound’s interaction with
biological systems. Further, it describes the intrinsic properties of the
compound, which depends on its structure.
A literature survey shows that Chalcones have been reported to
demonstrate a wide rage of pharmacological activities.1This class of
compounds are known to possess a wide spectrum of biological activities
such as antiinflammatory2, antitumor3, antimalarial,4, antifungal5, antiulcer6,
analgesic7, anti-HIV8 properties.
Upadhyay et al. have studied antimicrobial activity of
chalcones.9 The antimicrobial activity of some novel benzimidazolyl chalcones
have also been reported by Baviskar et al. 10 Recently, Dawane et al. have
also been reported antimicrobial activities chalcones derivatives.11
Lee et al. have reported tris(methoxy)chalcone to be an antiinflammatory compound that reduces nitric oxide (NO) production by inhibiting
inducible nitric oxide (NO) synthase expression. The findings suggest that
some chalcones may be promising anti-inflammatory agents.12 The antiinflammatory activity of substituted chalcones derivatives have also been
reported by Zhang et al. 13
Chalcones are also key precursors in the synthesis of many biologically
important heterocycles such as benzothiazepine14, pyrazolines15, 1,4diketones16 and flavones.17 Hence, the synthesis of chalcones has generated
vast interest among organic as well as medicinal chemists.
In the present section, the antibacterial activity of some new Chalcones
has been studied against some Gram positive and Gram negative bacteria in
DMSO.
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Chapter –4: Biological Activities
204
EXPERIMENTAL
The solvent DMSO was also purified before use by standard method.18
All the synthesized compounds were re crystallized prior to use. For all the
compounds, agar well diffusion method was used.
Test Microorganisms:
The synthesized compounds were tested for its antibacterial activity
against Gram positive bacteria viz. Streptococcus pyogenes (NCIE 1925),
Bacillus subtilis (ATCC 2274) and Gram negative bacteria viz. proteus
mirabilis (NCIM 2241), salmonella typhimurium (ATCC 23564).
Microorganisms were obtained from National Chemical Laboratory
(NCL), Pune, India and were maintained at 4°C on nutrient agar slants.
Preparation of test compounds:
The solutions were prepared at a concentration of 1 mg/μl for all the
compounds.
Preparation of the plates and microbiological assay:
The antibacterial evaluation was done by agar well diffusion method2,3
using Mueller Hinton Agar No.2 as the nutrient medium. The agar well
diffusion method was preferred to be used in this study because it was found
to be better than the disc diffusion method as suggested by Parekh et al.3 The
bacterial strains were activated by inoculating a loop full of test strain in 25 ml
of N-broth and the same was incubated for 24 h in an incubator at 37o C. 0.2
ml of the activated strain was inoculated in Mueller Hinton Agar. Mueller
Hinton Agar kept at 45oC was then poured in the Petri dishes and allowed to
solidify. After solidification of the media, 0.85 cm ditch was made in the plates
using a sterile cork borer and these were completely filled with the test
solution. The plates were incubated for 24 h at 37oC. The mean value
obtained for the three wells was used to calculate the zone of growth inhibition
of each sample. The controls were maintained for each bacterial strain and
each solvent. The inhibition zone formed by these compounds against the
particular test bacterial strain determined the antibacterial activities of these
synthesized compounds.
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Chapter –4: Biological Activities
205
RESULTS AND DISCUSSION
Figure 4.1 shows inhibition against Gram positive bacteria in DMSO. It
is observed that against S. pyogenes, NVA-9 showed maximum inhibition
whereas NVA-2, NVA-3 showed minimum inhibition. NVA-1, NVA-4 and NVA5 showed no inhibition at all.
For B. subtilis, again NVA-9 exhibited maximum and NVA-1, NVA-3
and NVA-4 exhibited minimum inhibition.
Thus, in DMSO NVA-9 is the most effective compound for the studied
bacteria.
Figure 4.2 shows inhibition against Gram negative bacteria in DMSO.
Against P. mirabilis, NVA-5 showed maximum inhibition whereas NVA-4 had
no effect on the bacteria. For S. typhimurium, NVA-8 showed maximum
inhibition whereas NVA-2 shows minimum inhibition. There is no effect of
NVA-6, NVA-4.
The inhibition depends on the solvent, compound structure and
bacterial strain. NVA-9 contains m-chlorobenzene which is found to be
effective for both Gram positive bacteria. Whereas NVA-1, NVA-4 and NVA-5,
containing p-chloro benzene, p-methyl benzene and p-methoxy benzene
respectively could not affect these bacteria.
However, for Gram negative bacteria, p-methoxy benzene (as in NVA5) is most effective against P. mirabilis whereas for S. typhimurium, o,pdimethoxy benzene (as in NVA-8) is found to affect most. The presence of pmethyl benzene (in NVA-4) had no effect on both Gram negative bacteria. For
S. typhimurium, p-bromo benzene (in NVA-6) also had no affect. Thus, the
presence of p-methoxy benzene increases the inhibition in the studied
bacteria.
Thus, it can be concluded that for the studied chalcones derivatives,
the chloro group showed best antibacterial activity provided, it was at meta
position while the same chloro group at para position decreased the activity
for Gram positive bacteria. However, for Gram negative bacteria, methoxy
group showed best activity at para position. Whereas at meta and para
positions, the same methoxy group exhibited less activity. Thus, substitution
Studies of some bio-Active heterocyclic…….
Chapter –4: Biological Activities
206
affects the inhibition to a larger extent and studied compounds showed more
inhibition against Gram positive bacteria.
Studies of some bio-Active heterocyclic…….
Chapter –4: Biological Activities
207
Figure 4.1: Antibacterial activity of chalcones against Gram positive
bacteria in DMSO.
0
2
4
6
8
10
12
14
16
18
NVA 1 NVA 2 NVA 3 NVA 4 NVA 5 NVA 6 NVA 7 NVA 8 NVA 9
Bacterial Strain
Zo ne o f I
nh ib iti
on (m m )
S pyogenes B subtilis
Figure 4.2: Antibacterial activity of chalcones against Gram negative
bacteria in DMSO.
0
1
2
3
4
5
6
7
8
9
10
NVA 1 NVA 2 NVA 3 NVA 4 NVA 5 NVA 6 NVA 7 NVA 8 NVA 9
Bacterial Strain
Zo ne o f I
nh ib iti
on (m m )
p mirabilis s typhimurium
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208
REFERENCES
1. A. A. Bekhit, N. S. Habib, A. Din, A. Bekhit,; “Synthesis and
antimicrobial evaluation of chalcone and syndrome derivatives of
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2. H. K. Hiseh, T. H. Lee, J. P. Wang, J. J. Wang, C. N. Lin,; “ Synthesis
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9. R. K. Upadhyay, M. S. Upadhyay And S. Jain,; “Synthesis and
Antimicrobial Activity of 1[2-(10-p-Chlorobenzyl) phenothiazinyl]-3(substituted aryl)-2-propen-1-ones” E, J. Chem., 6, S254-S258, (2009).
Studies of some bio-Active heterocyclic…….
Chapter –4: Biological Activities
209
10. B. A. Baviskar, B. Baviskar, M. R. Shiradkar, U. A. Deokate And S. S.
Khadabadi,; “Synthesis and Antimicrobial Activity of Some Novel
Benzimidazolyl Chalcones” E. J. Chem., 6(1), 196-200, (2009).
11. K . S. Dawane , S. G. Konda , B. M. Shaikh , R. B. Bhosale,; “An
improved procedure for synthesis of some new 1,3-diaryl-2-propen-1ones using PEG-400 as a recyclable solvent and their antimicrobial
evaluation” Acta. Pharm., 59, 473–482, (2009).
12. S. H. Lee, G. S. Seo, J. Y. Kim, X.Y. Lin, H.D. Kim, D. H. Sohn,; “
Heme oxygenase 1 mediates antiinflammatory effects of 20,40,60tris(methoxymethoxy)chalcone” Eur. J. Pharm. , 532, 178–186, (2006).
13. X. Zhang, D. Zhao, Y. Quan,L. Sun, X. Yin,L. Guan,; “Synthesis and
evaluation of antiinflammatory activity of substituted chalcone
derivatives” Med. Chem. Res., DOI 10.1007/s00044-009-9202, (2009).
14. O. Prakash, A. Kumar, A. Sadana, R. Prakash, P. S. Singh, M. R.
Claramunt, D. Sanz, I. Alkortac and J. Elguero,; “ Study of the reaction
of chalcone analogs of dehydroacetic acid and o-aminothiophenol:
synthesis and structure of 1,5-benzothiazepines and 1,4benzothiazines” Tetrahedron ,61, 6642–6651, (2005).
15. R. Y. Prasad, L. A. Rao, L. Prasoona, K. Murali and R. P. Kumar,; “
Synthesis and antidepressant activity of some 1,3,5-triphenyl-2pyrazolines and 3-(2”-hydroxy naphthalen-1”-yl)-1,5-diphenyl- 2pyrazolines” Bioorg. Med. Chem. Lett., 15, 5030–5034, (2005).
16. S. Raghavan and K. Anuradha,; “ Solid-phase synthesis of 1,4diketones by thiazolium salt promoted addition of aldehydes to
chalcones” Tetrahedron Lett., 43, 5181–5183, (2002).
17. B. A. Bohn, Introduction to Flavonoids, Harward Acad.,
Amsterdam, (1998).
18. J. A. Riddick, W. B. Bunger, T. Sakano,; “ Organic Solvents: Physical
Properties and methods of purification, Fourth Edition” Techniques of
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(1986).
A
COMPREHENSIVE
SUMMARY
OF THE WORK
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210
A COMPREHENSIVE SUMMARY OF THE WORK
The present work is divided into following chapters:
CHAPTER - 1: This chapter describes the importance of heterocyclic
compounds with aims and objective of the present work.
CHAPTER - 2: The synthesis of Chalcones, Acetyl pyrazolines,
Dihydropyrimidinethiones, Dihydropyrimidinones, and Aminopyrimidines are
described in this chapter. . Further, the characterizations of all the synthesized
compounds are done by IR, NMR and mass spectral data. The chapter is
divided into five sections.
Section-I: In this section, synthesis of Chalcones are given along with their
physical constant data. The spectra and the characteristic peak positions of
IR and NMR spectra are reported. Further, mass spectra and possible
fragmentation scheme are given in this section.
Section-II: This section deals with the synthesis of Acetyl pyrazolines. The
physical constant data is also reported along with spectra and the
characteristic peak positions of IR and NMR spectra. The mass spectra and
possible fragmentation scheme are given.
Section-III: This section describes the synthesis of dihydropyrimidinthions.
The physical constant data, IR and NMR spectra and their spectral data and
mass spectra and possible fragmentation scheme are given.
Section-IV: In this section, synthesis of dihydropyrimidinones, their physical
constant data, IR and NMR spectra and their spectral data and mass spectra
and possible fragmentation scheme are given.
Section-V: The synthesis of 2-amino-dihydropyrimidines, their physical
constant data, IR and NMR spectra and their spectral data and mass spectra
and possible fragmentation scheme are given in this section.
Studies of some bio active heterocyclic…….
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211
CHAPTER - 3: The physicochemical properties of synthesized chalcones was
also studied. The different properties are given in different sections. For the
study of all physicochemical properties, DMF and Chloroform are used.
Section-I: This section describes the acoustical properties of chalcones in
DMF and chloroform solutions at 303.15 K. The density, ultrasonic velocity
and viscosity of a series of solutions of various concentrations were measured
in both the solvents for all the chalcones. From these experimental data,
various acoustical parameters were evaluated which helped to understand the
different types of interactions occurring in the solutions. It is observed that for
both the series, in the studied solvents, solute-solvent interactions dominate.
Section-II: In this section, the densities and refractive index of all the
chalcones were measured in DMF and Chloroform solutions at 303.15 K. The
experimental density values are found to be different than those calculated
theoretically for all the studied systems, which may be due to solvation of ions
in solutions. In solutions of different solvents, density is found to be different
due to different interactions. Further, molar refraction and refractive index of
chalcones were determined which are found to be different in each solvent.
Section-III: This section deals with the conductance of studied compounds
in solutions of DMF and Chloroform at 303.15 K. It is observed that for all the
studied compounds, conductivities are less in Chloroform than in DMF.
Further, all the studied compounds exhibited weak electrolytic nature in both
the solvents.
Section-IV: This section describes the solubility and thermodynamic
parameters of all the studied compounds in dichloromethane (MDC) and
Chloroform at different temperatures (293.15 -313.15 K). It is observed that
the solubility of all the compounds increases linearly with temperature in both
the solvents. Comparison of solubility of these compounds in MDC and
Chloroform shows that overall solubility is greater in Chloroform than in MDC.
Studies of some bio active heterocyclic…….
A Comprehensive Summary of the Work
212
The thermodynamic parameters such as Gibb’s energy (∆Gs), enthalpy (∆Hs)
and entropy (ΔSs) for the dissolution process in the two solvents were also
evaluated for all the compounds. It is observed that enthalpy and Gibb’s
energy are positive for all the compounds whereas entropy values are both
negative and positive. The positive ∆Hs indicates endothermic dissolution of
compounds whereas positive ΔG suggests that the dissolution process is not
spontaneous. Further, the negative values of entropy indicate less random
ness in solutions.
Section-V:. This section describes partition coefficient of chalcones, which
has been studied in n-Octanol-water system by UV spectroscopy at different
pH. It is concluded that out of all studied compounds, NVA-07 exhibits
maximum hydrophobic nature.
Section-VI: The dissociation constants of chalcones in DMF: water (90:10)
system is studied by UV spectroscopy in this chapter. It is observed that
acidity is maximum in NVA-07 having hydroxy group as expected whereas for
NVA-06 having halogen group, acidity is minimum. Thus, dissociation is
maximum for NVA-7 and minimum for NVA-6.
Section-VII: The thermal properties of synthesized chalcones are described
in this section. DSC and TGA thermo grams were scanned at the heating rate
of 100 C per minute. It is observed that thermal stability depends on the
presence of substituents in the compound. Out of all the studied compounds,
NVA-8 is most stable whereas NVA-2 is least stable. This suggests that the
presence of methoxy group increases stability whereas p-nitro group
decreases the stability to a greater extent. The thermal decomposition may
depend on different structural as well as electronic intermolecular interactions.
Further, maximum weight loss is observed for NVA-5, followed by NVA-3,
NVA-7 and NVA-9.
Further, the melting points determined by DSC and by open capillary
methods are found to be in good agreement.
Studies of some bio active heterocyclic…….
A Comprehensive Summary of the Work
213
Various kinetic parameters such as order of reaction, energy of
activation, frequency factor and entropy change were also calculated. Thus,
the degradation in the studied compounds is single step process with different
order of reaction.
CHAPTER - 4: The antibacterial activities of all the synthesized chalcones in
DMSO are explained in this chapter. Both Gram positive and Gram negative
bacterial were taken for the study. It is observed that different compounds
affect differently to different bacterial strains depending upon their substitution
group. 3-chloro benzene is most effective for Gram positive bacteria. Against
Gram negative bacteria, 4-methoxy benzene and 2,4-dimethoxy benzene are
found to be most effective.
List of Publication
Published Paper
1. “Acoustical studies of some derivatives of 4-amino benzoic acid in 1,4dioxane and dimethyl formamide at 308.15 K” Shipra Baluja, Nayan
Vekaria and Jagdish Movaliya, Iran. J. Chem. Chem. Eng. 27,129-135,
(2008).
2. “A Thermal study of some Schiff bases derivatives of α-naphthaamine”
S. Baluja, N. Pandya and N. Vekaria, Russ. J. Phys. Chem., 82, 16011604, (2008).
3. “Solubility of Enrofloxacin drug in different solvents at various
temperatures” Shipra Baluja, Rahul Bhalodia, Mehul Bhatt, Nayan
Vekariya and Ravi Gajera, J. Chem. Eng. Data, 53, 2897-2899, (2008).
4. “Solubility of Difloxacin in acetone, methanol and ethanol from
(293.15 to 313.15) K” Shipra Baluja, Rahul Bhalodia, Ravi Gajera,
Nayan Vekariya and Mehul Bhatt, J. Chem. Eng. Data, 54, 1091-1093
(2009).
5. “Physicochemical studies of some azomethines of 5-aminoisophthalic
acid in solutions of DMF and DMSO at 308.15 K” N. Vekaria, P.
Kasundara and Shipra Baluja, Int. J. Chem. Sci., 7, 533-538, (2009).
6. “Synthesis and acoustical studies of some chalcones of furaldehyde
in different solvents at 308.15K” Shipra Baluja, N. Vekaria, R. Gajera and
A. Kulshrestha, Int. J. Appl. Chem., 5, (2009).
7. “Theoretical comparison of viscosity in binary solution at 298.15 K.” Nayan
Vekariya, Mehul Bhatt and Shipra Baluja, Int. J. Appl. Chem,(Accepted)
(2009).
8. “Solubility of cholesterol in some alcohols from 298.15 to 318.15 K”.
Shipra Baluja, Ravi Gajera, Mehul Bhatt, Rahul Bhalodia and Nayan
Vekariya, SRL , Accepted (2009).
Communicated Paper
1. “Dissociation constant of some derivatives of α-napthylamine in mixed
sokvent by calvin bjerrum pH titration method.” russ. Journal of
physical chemistry,Shipra Baluja, Ashish, Nayan Vekariya
2. “Solubility study of pyrimidine derivatives” Mehul, Nayan, Shipra
Baluja, J. Chem. Eng. Data
3. “Solubility of a pharmacological intermidiate drug Isati in different
solvent at various temprerature” Ravi,Rahul,Nayan,Mehul,Shipra
Baluja, J. Chem. Eng. Data
4. Studies on physicochemical properties of some 1,2,4-Traizole
Schiffbase”Nayan, Asif, Shipra Baluja, Iran. J. Chem. Chem. Eng.
5. Physico chemical studies of some azomethines of α-napthylamine in
DMF and THF solution at 313.15K, Int. J. Appl. Physics.,Nayan,
Nirmal, Shipra Baluja
6. “Synthesis & Acoustical studies of some chalcones of vanillin
derivatives indifferent solvents at 303.15 K” Lattin American Applied
research, Nayan Vekariya, Mehul Bhatt, Shipra baluja.
7. “Solubility of a pharmacological intermediate drug Isatin in different
solvents at various temperatures” J. Chem. Eng. Data, Ravi Gajera,
Rahul Bhalodia, Mehul Bhatt, Nayan Vekariya and Shipra Baluja,

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