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Research Project entitled
“Microwave-Assisted Synthesis of Heterocyclic
compounds (especially Coumarin and Quinazolines
Derivatives) and their theoretical studies”
Submitted To
University Grants Commission
Western Regional Office
Ganeshkhind, Pune - 411007
By
PawarThansingBhavsing
L.V.H.College, Panchavati, Nashik
And
ArunBalkeshSawant
M.S. G. College Malegaon camp, Nashik
(2012-2013)& (2013-2014)
Chapter-1
Introduction
Carbonyl group is a part of several biologically important molecules such
as proteins, lipids andhormones. Carbonyl carbon is joined to other three
atoms by sigma bonds, since these bonds utilize sp2 orbitals they lie in plane,
and are 120oapart. The remaining p orbital of oxygen to form a Pi bond, carbon
and oxygen are thus joined by double bond. The electrons of the carbonyl
double bond hold together atoms of quite different electronegativity, and hence
the electrons are not equally shared, in particular the pi electron cloud is pulled
strongly toward the more electronegative atom, oxygen.
The carbonyl carbon becomes more reactive towards the electron deficient
center. This group can interact with basic group like –OH/NH2 to form a
complex and influence the properties of such compounds.
The microwave assisted organic synthesis is becoming very popular in
recent years owing to its merits over conventional synthesis. There are several
methods available for heterocyclic compound synthesis such as coumarin
derivatives, quinazolines derivatives etc. which are known to possess diverse
biological activity.
A Goal of organic synthesis is the discovery environmentally friendly
reactions, where a minimum of waste is produced and reactions have high atom
economy. The applications of microwave (MW) irradiation in organic synthesis
have been the force of considerable attention in recent years and are becoming
increasingly popular technology. Therefore, the present work has been
undertaken.
Computational Details:
The modern method of computational chemistry can provide valuable
insight to experimentalists to explain the results, suggest novel interpretations
and support or disprove hypothesis.
In recent years, experimental results have been frequently supported with
theoretical calculations which have proved quite helpful in explaining the
comparative reactivities and many other properties of the organic
molecules/complexes. Extensive calculations are carried out to determine the
optimized geometries, electronic structure and thermochemical data.PM6 being
the more refined and expected to give the molecular parameters to a level of
better accuracy.
The advent of density functional theory (DFT) has providedan alternative
means of including electron correlation in the study of the vibrational
frequencies of moderately large molecules of DFT functionals that are
available today, perhaps the most prominent are B-LYP andB3-LYP. B-LYP
uses a combination of the Becke exchange functional) coupled with the
correlational functional of Lee,Yang, and Parr (LYP), while the hybrid B3-
LYP procedureuses Becke’s three-parameter exchange functional (B3),
asslightly modified by Stephens et al., in combination with theLYP correlation
functional.
Chapter-2
Experimental
Experimental Section
The experiments were started with the study of one-pot, two-component
Pechmann condensation using FeF3 as a catalyst under solvent-free microwave
irradiation.
OH
+O
CH3
O
O RR
O O
MW -irraddiationR
Fig. 1
Coumarins were synthesized by usingequimoles of phenols and ethyl
acetoacetate in the presence of FeF3 as a catalyst to create the corresponding
products, as illustrated above in the model reaction Fig.2.Thephenolslike m-cresol
and resorcinol with ethyl acetoacetate were used for further coumarin derivatives.
FeF3 acts as an effective catalyst, significantly increasing the reaction
rate. A mixture of phenols (2mmol), ethyl acetoacetate (2mmol), and FeF3 (0.10 g)
was ground and the homogenized mixture was heated by microwave irradiation for
about7 to 10 minutes. The progress of the reaction was monitored by using TLC
(ethylacetate:n-hexane as 1:0.5). After complete conversion as indicated by TLC,
the mixture was extracted withpetroleum ether and washed with water. The
products were purified byrecrystallization from ethanol (95%).
The Azocoumarin dyes were synthesized in two-step procedure, formation
ofdiazonium salt, then coupling reaction with coumarin , as shown in Fig .3
whereAr = substituted phenyl ring, to synthesize dyes type I, or substituted.
SYNTHESIS OF SUB. THIAZOLE DERIVATIVES :
C
R
OBr
C
S
NH2H2N
Et-OH, 1hr
NaOH(2pill.)S
N
NH2
R
1
23(a-e)
Fig. 2
SYNTHESIS OF SUB. CAUMARIN DERIVATIVES
Fig. 3
Table- Physico-chemical data synthesized derivatives 3(a-d)
Sr No. Product R
Moluculer
formula
Yield(%) M.P(0c)
1 6a 4-OH C21H14O4N2S 80 135
2 6b 4-Cl C21H13O3N2ClS 86 154
3 6c 2-OH C21H14O4N2S 84 143
4 6d 2-Cl C21H13O3N2ClS 83 158
5
6e 4-OH-
3-OCH3
C22H16O4N2S 81 162
Spectrum of synthesized compound :
IR:
4-[2-(5-Mercapto-[1,3,4]thiadiazol-3-yl)-4-methyl-6-phenyl-2,3,3a,6-tetrahydro-pyrazolo[3,4-c]pyrazol-3-yl]-phenol
Fig. 4
Microwave Synthesis of Some Chlcone Derivatives
Dihydropyrimidones are important class of organic compounds due to therapeautic
and pharmocoligicalproperties , such as anti-inflamatory, antihypertension,
anticancer and antimicrobial activities. They also act as inhibitors for the
propogation of the malerialparasite .they also act as acalcium channel blocker.
NH
NH
OR
R
R
Fig. 5
Strucure of Dihydropyrimidone
O
O O
EtH2N
O
NH2
CHO
Cl+ +
LEMON JUICE MW 15 MIN
NH
NH
O
ClO
FIG. A ) SYNTHESIS OF DIHYDROPYRIMIDONE DERIVATIVE
NH
NH
O
ClO
ArCHO+
NH
NH
O
ClO
Ar
FIG. B) SYNTHESIS OF CHALCONE DERIVATIVES
PIPERIDINE DMF
MW-10-20MIN
Table-:Synthesis of chalcone derivatives under microwave irradiation
PRODUCT R TIME(min) YEILD(%) M.P(0C)
4a 2-OH,3-NO2 12 88 232
4b 2,3(OCH3)2
6 NO2
15 65 248
4c 4-Cl 13 90 238
4d 4-OCH3 14 83 252
4e 3-NO2 16 86 180
Fig. 6 : Spectrum of synthesized compound :
IR:
4-(2-Chloro-phenyl)-5-[3-(2-hydroxy-3-nitro-phenyl)-acryloyl]-6-methyl-3,4-dihydro-1H-pyrimidin-2-one
The unique advantages of this method include a one-pot synthesis
strategy,experimental simplicity under solvent-free microwave irradiation, high
yields obtained under shortreaction times, easy and quick isolation of the products.
The majority of the compounds exhibitedsignificant activity against selected
bacteria and fungi with inhibition zones almost comparable tothose of the standard
drugs.
Chapter-3
Biological Activity
Introduction
Treatment of diseases with chemical substances has been known since the
fifteenth century. Chemical agents not only provide the structure basis and energy
supply of living organism but also regulate their functional activities. The
interaction between potent chemical and living system contribute to the
understanding of the life process and provide effective method for the treatment,
prevention and diagnosis of many diseases. Fighting against diseases with drugs is
the endless struggle. The field and scope of medicine is too vast.
In this chapter, the synthesized thiazole derivatives were evaluated for
antibacterial activity against bacterial strains.
Antibacterial Activity
The information regarding the various species of bacteria used to carry out
screening is given below:
The plates were thin incubated at 37oC for 24 hours. The strength is reported by
measuring the diameter of zone of inhibition in mm and the results were
standardized against tetracycline. The solution without compound (only 10%
DMSO) was used control. The diameters of zone of inhibition are given in Table 1.
Table-: Antibacterial activity of synthesized thiazolederivatives 4(a-d)
(Zone of inhibition was measured in mm)
Product Bacteria
Ec Pv Bs Sa
6a 18 10 19 --
6b 13 14 10 12
6c 16 13 16 18
6d 20 -- 20 18
6e 22 12 16 20
Penicillin 24 22 26 24
Ec- Escherichia coli, Pv- Proteus vulgaris
Bs- Bacillus subtillis, Sa- Staphylococcus aureus
-- No activity, NA-Not Applicable
Fig. 7
Conclusion:
In this project, I report the synthesis of some new heterocyclic derivatives
(Caumarin derivatives) under conventional method. The short reaction time, good
yields are the advantages of this method. Hense compounds further screened for
antibacterial activity. The antibacterial data revealed that Caumarin derivatives
showed moderate to good active.
Table-: Antibacterial activities of synthesized compounds
Sample Bacteria Fungi
E.coli B.sub. Fm Af
1 12 8 7 4
2 14 12 11 12
3 18 15 8 5
4 12 18 11 9
5 9 12 16 12
6 16 10 14 10
7 12 8 12 16
8 8 12 16 11
Control -- -- -- --
Penicillin 14 19 16 14
Zone of inhibition was measured in mm
Fig-8 In vitro Antibacterial and antifungal activity of synthesizes chalcone
derivatives.
Results and Discussion:
The unique advantages of this method include a one-pot synthesis strategy,
experimental simplicity under solvent-free microwave irradiation, high yields
obtained under short reaction times, easy and quick isolation of the products. The
majority of the compounds exhibitedsignificant activity against selected bacteria
and fungi with inhibition zones almost comparable to those of the standard drugs.
Chapter-4
DFT Studies
Computational Details
DFT Studies of 2-[(2-substitutedphenyl)carbamoyl]benzoic acids.
All the synthesized and non synthesized molecules are optimized and
submitted to DFT calculations at B3LYP levels with 6-311+G(d, P) basis set
by the use of G03 W series of program.
For the synthesized compounds the density functional theory (DFT) at
the B3LYP levels were performed using Gaussian 03(W)[5-9]. The frontier
molecular energies, electronic chemical potential, chemical hardness, chemical
softness and global electrophilicity indices have been calculated at
DFT/B3LYP/6-31G(d,p) level of theory. In our present study the theoretical
FT-IR spectra and GIAO/SCF 1H NMR calculations of the title molecules were
carried out and compared with the experimental data.
Results and Discussion
The values of dipole moment and energies for molecule were calculated
as shown in Table 1. According to DFT (B3LYP) calculations, the compound
(b) has large dipole and large energy was observed.
Table : Total Energy, Dipole Moment (D), Thermal Energy (E), Heat Capacity
(CV) and Entropy (S) of 2-[(2-substitutedphenyl)carbamoyl]benzoic
acids.
Compounds D
(Debye)
E
( kcal mol-1
)
CV
(cal mol-1
K-
1)
S
(cal mol-1
K-
1)
(a) 3.0039 153.133 61.674 132.141
(b) 3.2288 171.946 66.319 138.915
(c) 1.0774 144.405 61.035 133.469
TheHOMO-LUMO energy gap of 2-[(2-
substitutedphenyl)carbamoyl]benzoic acids given in Table.4.2. reflects the
chemical activity of the molecule. LUMO as an electron accepter represents the
ability to obtain an electron, and HOMO represents the ability to donate an
electron.
(a) HOMO LUMO
Fig.4.3: 2-[(2-hydroxyphenyl)carbamoyl]benzoic acid(a); and the shapes of HOMO and LUMO of (a)
(b) HOMO LUMO
Fig.4.4: 2-[(2-methoxyphenyl)carbamoyl]benzoic acid (b); and the shapes of HOMO and LUMO of (b)
(c) HOMO LUMO
Fig.4.5: 2-[(2-chlorophenyl)carbamoyl]benzoic acid (c); and the shapes of HOMO and LUMO of (c)
The shapes of HOMO and LUMO of all the compounds obtained by the
population analysis were shown in figure 3, 4 and 5 for compound (a), (b) and
(c) respectively. Focus on benzoic acid ,carbamoyl (-NH-C=O) groups and
substituents A (- OH,- OCH3 and –Cl). There was no HOMO coefficient and
middle LUMO coefficient on benzoic acid group. While on carbamoyl group
middle HOMO and LUMO coefficient, and on substituent A middle HOMO
and no LUMO coefficient
Table-: The DFT/B3LYP/6-31G(d,p) compound optimized energies, electronic
chemical potential (µ), chemical hardness (η) and global electrophilicity indices
(ω) of 2-[(2-substituted phenyl)carbamoyl]benzoic acids.
Compound Optimized
energy
(au)
HOMO
energy
(eV)
LUMO
energy
(eV)
µ
(eV)
η (eV) ω
(eV)
(a) -895.81 -0.20998 -0.05731 -0.134
0.076
0.117
(b) -935.12 -0.20704 -0.05696 -0.132
0.075
0.116
(c) -1280.18 -0.22864 -0.06326 -0.146
0.083
0.129
Table-Vibrational assignments of 2-[(2-substitutedphenyl)carbamoyl]benzoic
acids.
Compou
nd
-OH stretch N-H stretch C=O stretch
(Acid)
C=O stretch
(Amide)
Exp. Theo. Exp. Theo. Exp. Theo. Exp. Theo.
(a) 3637,
3474
3620 3179 3471 1719 1728 1642 1685
(b) 3405 3614 3121 3483 1713 1743 1640 1697
(c) 3302 3613 3471 1707 1745 1674 1704
Table-4.4 GIAO nuclear magnetic shielding tensor of phthalamic acids.
Molecule δ in ppm Protons
2-[(2-hydroxyphenyl)carbamoyl]benzoic acid (a)
3.43 Phenolic -
proton
6.13 Acidic proton
7.43 N-H proton
2-[(2-methoxyphenyl)carbamoyl]benzoic acid (b)
3.74&4.05 -OCH3 protons
6.11 Acidic proton
7.62 N-H proton
2-[(2-chlorophenyl)carbamoyl]benzoic acid (c) 6.15 Acidic proton
7.37 N-H proton
Conclusion
2-[(2-substitutedphenyl)carbamoyl]benzoic acids were synthesized and
characterized by spectral analysis. The same compounds were used for
computational study the theoretical FT-IR spectra and GIAO/SCF 1H NMR
calculations of the title molecules were carried out and compared with the
experimental data. Small difference between experimental and calculated
vibrational modes were observed it may be due to the fact that hydrogen bond
vibrations present in the crystal, the experimental result reported here are for the
solid phase while theoretical calculations pertain to the isolated molecule in gas
phase. The frontier molecular energies, HOMO and LUMO energies electronic
chemical potential, chemical hardness, chemical softness and global
electrophilicity indices have been calculated at DFT/B3LYP/6-31G(d,p) level of
theory and concludes that (b) and (a) are more reactive and (c) is the less reactive.
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