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.