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1. INTRODUCTION

Computational chemistry is a branch of chemistry that

generates data which complements experimental data on the

structures, properties and reactions of the substances. Computational

chemistry is concerned with the numerical computation of molecular

electronic structures and molecular interactions. It is a well developed

mathematical model that can be programmed for implementation on a

computer. It is an application of chemical, mathematical and

computing skills to the solution of chemical problems. Computational

chemistry has become a useful way to investigate materials that are

too difficult to find or too expensive to purchase. It also helps

chemists to make predictions before running the actual experiments

so that they can be better prepared for making observations.

The basis for many computational chemistry theorems and

programs are the quantum mechanics, classical mechanics, statistical

physics and statistical thermodynamics. Computational chemistry is

used to determine the electronic structure of the molecules; to

optimize the molecular geometry; to calculate the vibrational

frequencies; to identify the transition state and the reaction path of a

chemical reaction; to calculate charge distributions, potential energy

surface, heat of reactions, reaction rate constants and many more

physical and chemical properties of a molecule that cannot be

assessed by experiments.

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The most important numerical techniques are semi – empirical,

ab – initio and molecular mechanics.

Quantum physics is used in semi – empirical methods. These

methods use many approximations from empirical data to provide the

input to the mathematical models. It can be used only for organic

molecules of moderate size with a few elements. The semi – empirical

calculations are much faster than ab – initio calculations but the

results obtained from these calculations are mostly erratic.

In molecular mechanics method, all the constants used in the

equations to be solved are obtained either from experimental data or

from ab – initio calculations. It allows the modelling of too big

molecules such as proteins, enzymes and DNA segments. The

molecular property is studied in this molecular mechanics approach.

The potential energy is computed as a function of all atomic positions.

This is done by constructing a simple expression for molecular force

field.

The word ‗ab – initio‘ is from Latin meaning ‗from scratch‘. This

is a group of methods in which molecular systems can be studied by

calculating the Schrödinger equation, the fundamental constant

values and the atomic numbers of the atoms present. The most

common type of this approach is the Hartree – Fock calculation (HF)

which includes the average effect of the coloumbic electron – electron

repulsion. The approximate energies calculated by this method are

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always equal to or greater than the exact energy value. The basis

functions used can provide the best or worst approximation to the

exact numerical single electron solution of the HF equation. The

energies from HF calculations tend to increase with the increasing

basis size to a limiting value called the Hartree – Fock limit. To avoid

making HF mistakes in the first place there is a method called

Quantum Monte Carlo (QMC) which works with a correlated wave

function that evaluates the integrals using Monte Carlo integration.

These calculations are time consuming, but give accurate results.

In Density Functional Theory (DFT) method total energy is

expressed in terms of total electron density. The ab – initio methods

are computationally expensive, they take enormous amounts of

computer CPU time, memory and disk space. Correlated calculations

are even more time consuming process. The ab – initio calculations

yield very good qualitative results and to give more accurate

quantitative results the molecule considered must be small (tens of

atoms).

In this work, DFT method is used for computational studies.

Hence, the theoretical background of DFT has been discussed briefly.

1.1. Density Functional Theory (DFT):

The electron density (ρ) at each point determines the properties

of atomic and molecular systems. This is the fundamental conception

in density functional theory. The domineering method for the

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quantum mechanical simulation of periodic systems is the DFT. DFT

is broadly used for simulation of energy surfaces in molecules1.

In ab initio calculation of molecular properties DFT is

progressively more used. DFT codes have snowballing adaptability,

efficiency and availability. The ratio of accuracy to computational cost

is an appealing property of DFT calculations. Numerically accurate

DFT calculations are made possible by the introduction of analytical

gradient techniques2 and its efficiency has been significantly upgraded

by the introduction of analytical second derivative techniques3. The

accuracy of DFT calculations based on the density functional adopted.

The available density functionals are classified on the basis of

erudition and accuracy. They are classified into three classes namely

local functional, non - local functional and hybrid functional.

Local functional is used for the exchange and correlation

functional in the commencement of the DFT calculations. Non – local

functionals are then added. They are gradient functional added to

local functional. Recently hybrid functionals are used. They are

functionals with some percentage of HF exchange fused together with

DFT. Among the hybrid functionals based on adiabatic connection

method, the functional of Becke4 in which the values of three weighing

factors are estimated by optimizing the fit of predicted properties to

experiment.

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The ground state energy is calculated in quantum mechanical

calculations by solving Schrödinger equation and determining the 3N

dimensional wave function. The charge density is the diagonal

elements of the first order density matrix. The two theorems that steer

to the fundamental statement of DFT are Hohenburg – Kohn theorem

and Kohn – Sham theorem.

According to Hohenburg – Kohn theorem5 the electron density

determines the external potential and for any positive definite trial

density ρt,

then E[ρt] E0 (1)

where,

ρt(r) – spin dependent probability of finding an electron in volume

element ‗dr‘.

E[ρt] – energy of functional of density

E0 – ground state energy

Substituting the electronic wave function ρt(r) in the Schrödinger

equation

(2)

The system‘s energy E = E (ρ). The energy functional E[ρ(r)] contains

three terms viz., the kinetic energy, T(ρ), the interaction with the

external potential,Vext(ρ) and the electron – electron interaction, Vee(ρ).

(3)

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where,

Exchange Correlation energy which contains

everything which is unknown.

Becke introduced an approach of including a component of the

exact exchange energy calculated from Hartree – Fock theory. This

type of functional are called hybrid functional and are represented as

(4)

where a,b are coefficients determined by reference to a system for

which the exact result is known. Becke determined the coefficients by

a fit to the observed atomisation energies, ionisation potentials, proton

affinities and total atomic energies for a number of small molecules.

The mixture of exact HF exchange and approximate DFT

exchange is commonly employed to increase performance. Several

different mixing ratios have been promoted. Becke Half and Half LYP

use a 1:1 ratio of HF and DFT exchange energies.

(5)

The most common hybrid method is the Becke – 3 – parameter (B3)

method. The representation of the method is given by

(6)

When B3 is paired with LYP correction coefficients, the method

is referred to B3LYP method. Becke has also used a single parameter

with LYP correction and it is represented as BLYP method.

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The extended basis sets considers the higher orbitals of the

molecule and account for size and shape of molecular charge

distributions. There are several types of extended basis sets like

Double – Zeta, Triple – Zeta, Quadruple – Zeta, Split valence, polarized

sets, Diffuse sets. The simplified method of calculating double zeta for

the valence orbitals is called a Split – Valence set. It is done only for

valence orbital because the inner shell electrons are not as vital to the

calculation and it is described with a single slater orbital. 3 – 21G, 4 –

31G, 6 – 31G6 are some examples of commonly used split valence

basis sets. The first number indicates the number of Gaussian

functions summed to describe the inner shell orbital, the second

number indicates the number of Gaussian functions that comprise

the first slater type orbital(STO) of the double zeta and the third

number indicates the number of Gaussian functions summed in the

second STO.

To include the higher angular momentum functions known as

polarization functions. The effects of polarization are explained by

polarization functions. These polarization functions are indicated after

G in the notation for basis sets with a separate designation for heavy

atoms and hydrogen. ‗6 – 31G* or 6 – 31G (d) basis set‘ has d –

functions on heavy atoms and p – functions on hydrogen.

When an atom is an anion or an excited atom, the loosely bound

electrons are responsible for the energy in the tail of the wave

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function. This makes the inclusion of diffuse functions necessary for

the prediction of anions accurately. Diffuse functions explain some

non – bonding interactions too. It is represented by ‗+‘ or ‗++‘ after the

numbers of Gaussian function for the second STO. Differences

between diffuse basis sets are due to difference in their core. ‗+‘

represents diffusion in which ‗p‘orbitals are involved and ‗++‘

represents diffusion in which ‗p‘ and‗s‘ orbitals are concerned.

For example, 6 – 31G++(d,p) or 6 – 31++G** - This represents

six summing Gaussian functions for the inner shell orbital, three

Gaussian functions for the first STO of the valence orbital and one

Gaussian for the second STO. The sign ‗++‘ is included as the diffusion

is concerned with ‗p‘ and‗s‘ orbitals. (d,p) includes the polarization

effect concerned with both d – functions on heavy atoms and p –

functions on hydrogen atoms present in the molecule.

1.1.1. Geometry optimization:

Geometry optimization is done to find the configuration of

minimum energy of the molecule. The procedure calculates the wave

function and the energy at a starting geometry. This is followed by the

search for a new geometry of a lower energy. The quest for a new

geometry continues till the lowest energy geometry is found.

Algorithms like Benry algorithms are used at each step to select new

geometry. The algorithms used aims for the rapid convergence to the

geometry of the lowest energy. The geometry at minimal energy will

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have zero force on all atoms. The calculation yields information on the

atomic coordinates of optimized molecules, optimized parameters like

atomic distances and angles, Highest occupied molecular orbitals

(HOMO)/ Lowest occupied molecular orbitals(LUMO) eigen values in

Hatrees, dipole moments and mulliken atomic charges.

Casadesus et al7 used density functional theory along with the

time dependent formalism (TD - DFT) to directly localise the stationary

points in the A-1B2 first singlet excited state of tropolone (1). The

equilibrium geometry of tropolone (Fig 1) in the excited state is found

to be planar. The optimization is performed with restriction to the C2V

symmetry. An active space of 10 electrons and 10 orbitals (10,10) has

been used inorder to include all the orbitals involved in electronic

excitation.

Chrzastek et al8 used DFT B3 - LYP/ 3 - 21G method for

optimising the geometry of four azodiazaphenanthrenes (2a – 2d) and

three diazaphenanthrenes (3a – 3c). The geometry of the

diazaphenanthrenes are optimized by AM1 method too. The geometric

parameters of the diazaphenanthrenes and the effective charges

computed by DFT and AM1 calculations are compared. The DFT

computed effective charges for diazaphenenthrenes at ring nitrogen is

found to be lower and higher for the carbonyl carbon atoms than the

AM1 computed values.

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Ciesielski et al9 investigated structural parameters of a

complex formed betweem Co(II) and a terpyridine ligand(4).

Unrestricted Becke three parameter hybrid exchange functional

combined with the Lee - Yang - Parr correlation functional (B3LYP)

with the LANL2DZ, 6 - 31G(d, p) and 6 - 31G++(d,p) basis sets are

applied for geometry optimizations. The new terpyridine ligand and its

Co(II) complex is synthesized and its geometry is investigated using

DFT methods. This study showed that DFT calculations can be used

as an additional tool to investigate the molecular geometries of

transition metal complexes with good accuracy. The real structure of

metal ligand complex molecule is found to be in agreement with the

results of calculation using B3LYP/6 - 31G (d,p) method with the

polarizable continuum model of theory. These calculations are used to

determine the multiplicity of the complexated metal ion which predicts

its magnetic properties.

Ghani et al10 have synthesized and studied the structural

properties of 2 - [ ( 1H - benzimidazol - 2 - ylmethyl) - amino] – benzoic

methyl ester (5). DFT calculations using B3LYP functional combined

with 6 - 31G (d) basis set showed good agreement between theoretical

and experimental values of structural parameters, vibrational and

NMR spectroscopy. The relative errors in the calculated structural

parameters are less than 2%. The optimized bond lengths are slightly

longer than the experimental values agreeing within 0.007 - 0.026 Ǻ

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and the bond angles are slightly different by 0.2o - 2.2o. This is

because the calculations are performed in gaseous state where as

packing molecules with inter - and intra molecular interactions are

treated in experimental measurements.

Noaimi et al11 have performed the geometry optimization of

eight neutral mixed phosphine azoimine complexes of ruthenium (6a –

6h). It has been performed using the GAUSSIAN 03 protocol at DFT/

B3LYP level with 6 - 31G*/LANL2DZ mixed basis. One of the eight

complexes cis - [RUII(Ph2P(CH2)2PPh2) (4 - tolyl)3Cl2] has been

characterized by X - ray diffraction analysis and the structural

parameters are found to be in large agreement with the optimized

structure obtained by DFT calculations.

Machura et al12 have examined the reaction of [ReO2(Py)4]Cl

with imidazo[1,2] pyridine and a novel dioxorhenium (V) complex -

[ReO2(impy)4]Cl. MeCN. 2H2O (7) with trans - [O = Re = O]+ core has

been obtained. The X - ray crystal structure of the complex has been

determined and the electronic structure has been examined using the

density functional theory (DFT) method. The gas phase geometry of

cation [ReO2(impy)4]+ has been fully optimized without any symmetry

restrictions in singlet ground states with the DFT method using the

B3LYP hybrid exchange correlation functional. The calculations are

performed using LANL2DZECP basis set with additional d and f

functions for the rhenium and the standard 6 - 31G basis set for the

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other atoms. The diffuse and polarization functions are added for

oxygen and nitrogen atoms. The optimized geometric parameters of

the cation [ReO2(impy)4]+ has given a very good estimation of Re - O

and Re - N bond lengths. The bond angles and general trends

observed in the experimental data are also well reproduced in the

calculations.

Tokutome et al13 have studied two diacetylene molecu;es with

ynamine moiety, 5 - (diphenyl amino) - 2,4 - pentadiyne - 1 - ol (8a)

and 6 - (diphenylamino) - 2 - methylhexa - 3,5 - diyne - 2 - ol (8b) and

have characterized it by single crystal diffraction. The molecular

structures of the compounds are optimized using DFT calculations.

Using B3LYP functional with 6 - 311G(d,p) basis set. The optimized

structural parameters calculated for the molecules are compared with

the experimental data. The DFT calculations reproduced the crystal

structures except for the parts which are easily affected by the crystal

packing.

Dani et al14 have synthesized three new compounds, 5 -

benzyl - N - phenyl - 1, 3, 4 - thiadiazol - 2 – amine (9a); 2 - (5 -

phenyl - 1, 3, 4 - thiadazol - 2 - yl)pyridine (9b) and 2 - ( 5 - methyl -

1, 3, 4 - thiadiazole - 2 - ylthio) - 5 - methyl - 1, 3, 4 - thiadiazole (9c)

by Mn(II) catalyzed reactions. The new compounds have been

characterized using elemental analysis, spectral methods and single

crystal X - ray data. The geometry optimization has been performed

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with GAUSSIAN 03 and GaussView 4.1 program packages using DFT

method at B3LYP level with 6 - 31+G(d,p) basis set. The computed

structural parameters have been compared with the single crystal X -

ray data. The slight disagreement in the bond lengths and angles are

due to the fact that the experimental results are for the solid phase

and the theoretical calculations are for gas phase.

Kumar et al15 have synthesized phenoxyalkyl esters (10) of

bis(indolyl) methanes from indole and formyl phenoxyalkyl esters by

an efficient solvent - free synthesis method using Potassium titanyl

oxalate. Structure optimization of the esters have been carried out

using DFT method with B3LYP/3 - 21G(d) basis set without any

geometric constraints. The conformational analysis have been

performed at the MM - UFF, PM3, HF/ 3 - 21G(d) levels too and

compared with that of DFT method. Among all levels of calculations

DFT method represented good correlation between the calculated

geometrical parameters and the single crystal XRD data

Piro et al16 have determined the molecular structure of two

mixed and closely related conformers of 4 - hydroxy - 3 (3 - methyl - 2

- butenyl) acetophenone (11) by X - ray diffraction methods. The

conformational structures of the compound in the gas phase have

been calculated by the DFT method and the geometrical parameters

have been compared with the X - ray data. The difference between the

experimental and theoretical results could be attributed to the effect of

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crystal packing forces acting on 4 - hydroxy - 3 (3 - methyl - 2 -

butenyl) acetophenone molecules in the lattice.

Dani et al17 have generated Ni(II), Cu(II) and Zn(II) complexes of

Z - N' (1, 3, 4 - thiadiazol - 2 - yl) acetimidate (12a – 12c) by

synthesizing the new ligands. The complexes have been characterized

using elemental analysis, spectral methods, magnetic susceptibility

measurements and single crystal X - ray data analysis. The geometry

optimization has been performed with B3LYP functional and basis set

6 - 31+G(d.p) for the conformers of 2 - amino - 1, 3, 4 - thiadiazole

and Z - N' (1, 3, 4 - thiadiazol - 2 - yl) acetimidate. The geometry

optimization for the metal complexes have been made using DFT

method with B3LYP functional and basis sets 6 - 31+G(d,p) {C, H, N,

O, S}/ LANL2DZ{M = Ni(II), Cu(II) and Zn(II)}. The basis set LANL2DZ

serves the purpose of including the pseudo potential of the core

electrons in the metal atoms. The computed structural parameters

and geometrical parameters obtained by X - ray crystallography are

found to be in good agreement with each other.

Sovic et al18 have reported the synthesis of four 2 - substituted

perimidine derivatives (13) and its characterization by spectral

methods and single crystal X - ray structure analysis. Density

functional theory (DFT) full geometry optimizations of the compounds

and the H - bonding of the compound have been carried out using

GAUSSIAN 03W program. The hybrid method applied is B3LYP/ 6 -

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311++G(d,p). Geometry optimization computations on the structures

of Ethyl - 1H - perimidine - 2 - carboxylate, perimidine - 2- carboxylic

acid and 2 - cyanomethyl - perimidine revealed out the fact that the

enamine forms of the compounds are found to be stable.

Wang et al19 synthesized few 1H - 1, 2, 4 – diazaphospholes

(14) and characterized using spectral methods and single crystal X -

ray diffraction analysis. The molecules of all compounds are linked

into oligomers via the bridges of NH ...N hydrogen bonds in solid state.

To understand the nature of proton disorder and the intermolecular

hydrogen bonds, DFT calculations are utilized. The monomer and

dimer of the compounds are optimized at the B3LYP/ 6 - 311++G**

level. Both the experimental and theoretical results have suggested

that 1 H - 1, 2, 4 - diazaphospoles might be good candidate for

intermolecular solid state proton transfer (ISSPT). The calculated

linear distance N(1A) ... N(1B) between two diazaphosphole rings is

2.940 Ǻ longer than the experimental value (2.898 Ǻ) which is the

consequence of ISSPT.

Momany et al20 have reported DFT optimization and DFT - MD

studies of glucose surrounded by ten explicit water molecules and the

glucose/water super molecule is completely enclosed by an implicit

solvation model, COSMO. A set of twenty one starting configurations

of the explicit water molecules are first optimized empirically and

further optimized using reduced basis set (B3LYP/4 - 31G) on the

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sugar carbon atoms and the larger B3LYP /6 - 31+G* level on all other

atoms. The results of this study suggest that no water molecule

remains at any one specific site around glucose for a significant time

and it moves around the molecule within several picoseconds.

Curotto et al21 have reported that the structural and

spectroscopic study of the disulfide schiff base obtained from

condensation of 2 - aminothiophenol and o - vanillin. The structures

of the anhydrous and monohydrate forms of bis(3 - methoxy -

salicylidene - 2 - aminophenyl) dihydride (15) are resolved by X - ray

diffraction methods. The exploration of the conformational space and

optimized geometries are determined both in the gas phase and in

solvent phase using DFT methods with the triple - Zeta 6 - 311+G(d)

basis set. Geometries optimized from X - ray structures with solvent

effects are found to be the lowest energy structures. The calculated

geometry parameters are in very good agreement with those

parameters obtained experimentally. The exception is found in O - S

distances. The calculated O - S distance has been found to be 0.3Ǻ

larger than the experimental values.

1.1.2. Potential energy surface (PES) scan:

The PES is a vital concept in computational chemistry. A PES

is the relationship between the energy of a molecule and its geometry.

The concept of PES is made possible by focusing on the electronic

energy and then nuclear energy is added later. This makes the

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uncomplicated application of the Schrödinger equation to molecules

and this is based on Born - Oppenheimer approximation which

pictures out nuclei to be essentially stationary compared to electrons.

Dabbagh et al22 have studied a series of nine model primary

amides (16a – 16i) in gas phase at the DFT (B3LYP) and HF at 6 -

31+G/ 6 - 31+G** levels of theory in order to shed light on their

conformation, structure and intramolecular hydrogen bonding

network. A potential energy scan (Fig 2) has been performed on

optimized geometries by rotating the amide group with increments of

10o by rotating around the appropriate bond involving the - CO - NH2

group. The conformer corresponding to minimal energy and maximal

energy are extracted from the energy curve.

Singla et al23 have studied the excited state intramolecular

proton transfer (ESIPT) in Indole - 7 – carboxaldehyde (17). DFT, TD

DFT, CIS theories with B3LYP/ 6 - 311++G(d,p) basis set have been

used to obtain the structural parameters and energies of Indole - 7 -

carboxaldehyde in ground, excited states for cis, trans and

zwitterionic conformers. PES calculation has been used to study the

photo physics of the molecular system. The PES (Fig 3) are obtained

by forming Franck–Condon curves with TD DFT/B3LYP/6-311++G (d,

p) vertical excitation energies to the corresponding level of calculation

in the ground state and in the excited state. The reaction coordinate

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as variation of N15–H12 bond length along which the proton

undergoes translocation from N15 to O18.

Österman et al24 have investigated low energy singlet and

triplet excited state potential energy surfaces of two compounds Ru(II)

- bis tridentate complexes - [Ru(II)(tpy)2]2+ (tpy is 2,2‘:6‘,2‘‘-terpyridine)

(18a) and [Ru(II)(dqp)2]2+ (dqp is 2,6-di(quinolin-8-yl)pyridine) (18b).

Solvent effects have been considered. The 2D - PES calculations have

been performed with the same combination of the hybrid B3LYP

density functional with the 6-31G(d,p) basis set on H, C, and N and a

SDD basis set plus ECP description of Ru (Fig 4). The PES

constructed by calculation of excitations outside the Franck - Condon

region predicts qualitatively if a metal complex has useful excited

state properties. A significantly enhanced barrier for activated 3MLCT

state decay via the 3MC state in [RuII(dqp)2]2+ compared to

[RuII(tpy)2]2+ is here confirmed at the TD-DFT level.

Skorupska et al25 have initially determined Born-Oppenheimer

PESs at the B3LYP/3-21G level in order to localize stationary points

along minimum-energy paths for the main rotational motions in

molecules in their work on experimental and DFT dynamic 1H NMR

spectroscopic study of hindered internal rotation in selected N,N -

dialkyl isonicotinamides(19a – 19c). The PES scan has been

performed by stepwise rotation of 15o around the Cortho - Cipso - C - O

(θ1) and C - N - C - O(θ2) bonds. The generated PES picture of the

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conformational energy in the function of two torsion angles θ1 and θ2

is presented in this study (Fig 5). This approach permitted to find the

PES regions of global energy minima (GM) and saddle points reflecting

the three transition states (TSar, TS1, and TS2) of crucial importance

for this study.

Muthu et al26 have investigated the spectroscopic studies,

potential energy surface and molecular orbital calculations of

pramipexole(20), one of the newer drug approved for the treatment of

Parkinson disease. Molecular equilibrium geometries, electronic

energies, IR and Raman intensities, harmonic vibrational frequencies

have been computed for pramipexole molecule[(S)-N6-propyl-4,5,6,7-

tetrahydro-1,3-benzothiazole-2,6diamine]. One-dimensional relaxed

PES scan (Fig 6) of the N11-C12-C13-H28 dihedral angle using the

B3LYP/6-311G(d, p) method have been executed. During the

calculation, the N11-C12-C13-H28 angle has been varied in steps of

10o, 20o, 30o. . .360o. The structure has a minimum energy(948.741

Hartree), when the dihedral angle N11-C12-C13-H28 is 250o. A 2D

PES scan (Fig 6) has been performed for the dihedral angles N11-C12-

C13-H28 and C12-C13-C14-H29 at the B3LYP/3-21G level for the

pramipexole molecule. During the calculation all the geometrical

parameters were relaxed, while the N11-C12-C13-H28 and C12-C13-

C14-H29 angles were varied in steps of 20o, 40o . . . 360o. The line on

the surface is the lowest energy pathway linking the two minima, the

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reaction coordinate or intrinsic reaction coordinate which represents

the progress of reaction. A minimum is a minimum in all directions,

but a saddle point is a maximum along the reaction coordinate and a

minimum in all other directions.

Molecular geometry and anharmonic vibrational spectra of o-,

m-, p-iodonitrobenzene (21a – 21c) have been studied using DFT

calculations by Alam et al27. The stable structure on potential energy

surface is described by the energy profile (Fig 7) which has been

achieved as a function of C4–C5–N3–O1 dihedral angle. In the case of

o - iodonitrobenzene, two maxima are found at 0o and 90o with relative

energy values -4,597,341.675 and -4,597,335.400 kcal/mol

respectively. The values of dihedral angle, O–N–C–C show that

aromatic rings are co-planar with nitro group for m - iodonitrobenzene

and p - iodonitrobenzene. In o - iodonitrobenzene, the nitro group is

twisted by 31.7o with the plane of aromatic ring for obtaining stable

conformation. The angle of twist is confirmed by PES scan.

Beaula et al28 have carried out the PES study of herbicide 2-

phenoxy propionic acid in their FT IR, FT-Raman spectral study and

chemical computations of 2-phenoxy propionic acid(22). The PES scan

(Fig 8) has been performed on the torsional angle C7-C2-O1-C13 and

the energy curve for the rotations of the dihedral angle is presented.

The phenyl ring rotation energetically attains a global minimum

around 0 (or 360) degrees with barrier energy of -1508749.75 kJ/mol.

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A local minimum is located around 180o and 270o rotation with

barrier energy of 1508722.34 and -1508737.57 kJ/mol. Such a large

rotational barrier experienced by phenyl ring is due to strong

conjugation of ring p-electron system with the methyl and carboxyl

group, which stabilizes the molecule.

1.1.3. Vibrational frequency analysis:

Vibrational frequency analysis in DFT computes force

constants, the vibrational frequencies and the intensities. Vibrational

frequencies are computed by determining the second derivatives of the

energy with respect to the Cartesian nuclear coordinates and then

transforming to mass-weighted coordinates which is possible and

valid only for the geometry at a stationary point. It is futile to compute

frequencies at any geometry other than a stationary point for the

method used for frequency determination. And also computing 6-

311G(d) frequencies at a 6-31G(d) optimized geometry produces

meaningless results. It is also incorrect to compute frequencies for a

correlated method using frozen core at a structure optimized with all

electrons correlated or vice-versa. The recommended practice is to

compute frequencies following a previous geometry optimization using

the same method. This may be accomplished automatically by

specifying both Opt and Freq within the route section for a job.

There are two ways to interpret a theoretical vibrational

spectrum of a molecule - visualization of the atom movement and

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Potential Energy Distribution (PED) analysis. The PED analysis is

more accurate than visualization of atom movement and

quantitatively describes the contribution of movement of a given group

of atoms in a normal mode. The PED analysis results in presentation

of a normal mode coordinate as a superposition of local mode

coordinates. In consequence, we can find contributions of local mode

energy in overall energy of the normal mode. The PED analysis is

indispensible tool in serious analysis of the vibrational spectra. The

VEDA program29 made the automatic generation of the set of linearly

independent local coordinates possible.

Kibriz et al30 have investigated the experimental and theoretical

vibrational spectra of ethyl (2Z)-2-(2-amino-4-oxo-1,3-oxazol-5(4H)-

ylidene)-3-oxo-3-phenylpropanoate(23). Theoretical vibrational

frequencies and geometric parameters have been calculated using ab

initio Hartree Fock (HF), Density Functional Theory (B3LYP and

B3PW91) methods with 6-311++G(d,p) basis set by Gaussian 03

program. The computed values of frequencies are scaled using a

suitable scale factor to yield good coherence with the observed values.

The assignments of the vibrational frequencies are performed by

potential energy distribution analysis by using VEDA 4 program.

Sert et al31,32 have investigated the experimental and theoretical

harmonic and anharmonic vibrational frequencies of 4-chloro-3-

nitrobenzonitrile(24a) and 6-(2-methylpropyl)-4-oxo-2-sulfanylidene-

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1,2,3,4-tetrahydropyrimidine-5-carbonitrile(24b). Theoretical

vibrational frequencies and geometric parameters are calculated using

ab initio Hartree Fock (HF), density functional B3LYP and M06-2X

methods with 6-311++G(d,p) basis set by Gaussian 09W program. The

assignments of the vibrational frequencies were performed by

potential energy distribution (PED) analysis by using VEDA 4

program. The theoretical vibrational frequencies are compared with

the corresponding experimental data and are found to be in a good

agreement with each other.

Three similar bioactive molecules psoralens - 5-amino-8-

methoxypsoralen (25a), 5-methoxypsoralen (25b) and 8-

methoxypsoralen (25c) have been differentiated by Liu et al33 using

Raman spectra measurements and density functional theory (DFT)

calculations. All quantum chemical calculations are performed using

the DFT (B3LYP) method and 6-311++G(d,p) basis set by using the

Gaussian 03W program. Vibrational frequencies are scaled as 0.958

for the wavenumber range above 1700 cm-1 and 0.983 for the

wavenumber range below 1700 cm-1. Potential energy distribution

(PED) calculation, which has been performed by using Vibrational

Energy Distribution Analysis (VEDA) program. The Raman spectrum

between 1500 and 1650 cm-1 involved with aromatic ring stretching

vibrations is found to be identical for three psoralens which can be

used for psoralen system identification. 25b and 25c exhibit very

24

similar Raman spectra with small frequency differences at 651 and

795 cm-1, which are assigned to be out-of-plane torsion and stretching

vibrations of aromatic rings. The amino group in 25a caused a

significant change in the Raman spectrum. This demonstrates that

the Raman technique can be used to differentiate molecules with

similar structures.

Govindarajan et al34 have investigated the molecular structure

of 4-hydroxypteridine(26), its fundamental vibrational frequencies and

intensities of the vibrational bands have been interpreted with the aid

of structure optimizations and normal coordinate force field

calculations based on DFT and ab initio HF methods and different

basis sets combination. The complete vibrational assignments of

wavenumbers were made on the basis of potential energy distribution

(PED). The PEDs are computed from quantum chemically calculated

vibrational frequencies using VEDA program. The observed and

stimulated spectra are agreed for the good frequency fit in

DFT/B3LYP/6-311++G(d,p) method.

A study of the molecular structure and spectroscopic properties

of 3-hydroxy-2-quinoxalinecarboxylic acid(27) by experimental

methods and quantum chemical calculations has been studied by

Badoğlu et al35. The mid-IR and Raman spectra of 3-hydroxy-2-

quinoxalinecarboxylic acid (3HQC) are recorded and interpreted by

means of B3LYP/6-311++G(d,p) calculated harmonic frequencies

25

followed by potential energy distribution analysis. The stationary

structures are found by ascertaining that all the calculated

frequencies are real. The fundamental vibrational modes have been

characterized by their PED (potential energy distribution) obtained by

using the VEDA 4 program. The stable tautomeric forms are stabilized

by intramolecular O-H...O and O-H...N type hydrogen bonding. The

complex IR spectrum suggested the presence of several tautomers in

the solid sample. Among all the computed structures evidences of two

tautomers have been found in the experimental spectrum and

assigned. Based on the calculations on possible 3HQC dimers, several

unassigned bands are being interpreted as originating from a dimeric

structure which appear in condensed phase.

Koca et al36 have synthesized ethyl (2E)-3-amino-2-({[(4-benzoyl-

1,5-diphenyl-1H-pyrazol-3-yl) carbonyl] amino} carbon thioyl) but-2-

enoate(28) by the reaction of 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-

carbonyl chloride, ammonium thiocyanate and ethyl 3-aminobut-2-

enoate and then characterized by elemental analyses, IR, Raman, 1H

NMR, 13C NMR and X-ray diffraction methods. The molecular

structure of ethyl (2E)-3-amino-2-({[(4-benzoyl-1,5-diphenyl-1H-

pyrazol-3-yl)carbonyl]amino}carbonothioyl)but-2-enoate in the ground

state (in gas phase) has been optimized by HF and DFT (B3LYP)

methods with 6-311++G(d,p) basis set level and the optimized

structure is used in the vibrational frequency calculations. The

26

calculated harmonic vibrational frequencies are scaled by 0.9051 (HF)

and 0.9614 (B3LYP) for 6-311++G(d,p) level. The calculated vibrational

frequencies are clarified by means of the potential energy distribution

(PED) analysis of all the fundamental vibration modes by using VEDA

4 program. The results of B3LYP method in evaluating the vibrational

harmonic frequencies have shown better fit to the experimental data.

Any discrepancies noted between the observed and calculated

frequencies are due to the fact that the calculations have been

actually performed on isolated molecule in the gaseous state.

Several thermodynamic values like thermal energy, constant

volume molar heat capacity, entropy, free energy and enthalpy can be

computed at different temperature and pressure conditions during

vibrational analysis. The values obtained are based on ideal gas

assumptions. The thermochemistry parameters can be changed using

‗Freq = ReadIsotopes‘ in the route section.

The gas phase thermodynamic properties of 209 polybrominated

diphenyl ethers (PBDEs), 209 polybrominated biphenyls (PBBs), 19

polybrominated phenols (PBPs), hexabromocyclododecane (HBCD) and

tetrabromobisphenol A (TBBPA) including standard state entropy (So),

heat capacity (Cp), enthalpy (ΔHf ) and Gibbs free energy of formation

(ΔGf) are predicted using a combination of quantum mechanical

computations performed using the Gaussian 03 program at the

B3LYP/6-31G(d) level by Grabda et al37. The predicted results showed

27

that all of the thermodynamic properties considered in this study are

greatly dependent on the number and position of the bromine

substituents. The stability of congeners of PBDEs, PBBs and PBPs

decreases with increasing Br number, especially if substituted at the

ortho positions.

Jianting et al38 have calculated the gas phase thermodynamic

properties of 135 polychlorinated xanthones (PCXTs) using a

combination of quantum mechanical computations performed with

the Gaussian 03 program at the B3LYP/6-311G** level. It is found

that the chlorine substitution pattern strongly influences the

thermodynamic properties of the compounds. The enthalpies and

Gibbs energies of formation for 135 PCXT congeners are valuable for

further thermodynamic modeling. The values of molar heat capacities

at constant pressure from 200 to 1000 K for PCXT congeners are

calculated and the temperature dependence relation of this parameter

is obtained using the least-squares method.

Theoretical studies have been carried out on (+)-Varitriol(29)

using both the B3LYP/6-311+G and HF/6-311+G methods by Kumar

et al39. The vibrational spectra of (+)-Varitriol have been recorded in

solid state with FT-IR and Micro-Raman spectrometry. Nonlinear

optical properties like dipole moment, hyperpolarizabilities and

thermal properties like rotational constants, zero point vibrational

energies are calculated. Thermodynamic properties like total energy,

28

heat capacities, entropy and total thermal energy, rotational constants

and rotational temperatures have been calculated at constant

pressure using the B3LYP/6-311+G and HF/6-311+G optimized

geometries. Various thermodynamic properties have been calculated

at different temperatures using the B3LYP/6-311+G optimized

geometry. The thermodynamic function value increases with

increasing the temperature and this may be attributed to the fact that

the intensities of molecular vibration increases as the temperature

increases.

Parimala et al40 have investigated a complete vibrational

analysis of 2',4' –difluoroacetophenone(30) which is performed by HF

and DFT (B3LYP and LSDA) methods with 6-31G basis set. On the

basis of vibrational analyses and statistical thermodynamics, the

standard thermodynamic functions, heat capacity, entropy, enthalpy

and Gibb‘s free energy are calculated. The changes in the

thermodynamic functions have also been investigated for the different

temperatures. the values of heat capacity, entropy, enthalpy and

Gibb‘s free energy all increase with the increase of temperature from

100 to 1000 K, which is attributed to the enhancement of the

molecular vibration as the temperature increases. The correlation

equation among heat capacities, entropies, enthalpy changes, Gibb‘s

free energies and temperatures are fitted by quadratic formulas and

the corresponding fitting factors for these thermodynamic properties

29

are 0.996, 0.998, 0.995 and 0.999 for HF, 0.997, 0.998, 0.999 and

0.999 for B3LYP and 0.999, 0.998, 0.999 and 0.999 for LSDA

methods with 6-31G bases set, respectively.

Kumar et al41 have reported the combined experimental and

theoretical study on molecular structure, vibrational spectra,

hyperpolarizability, HOMO, LUMO, NMR analysis of 5-nitroindan.

Thermodynamic properties like heat capacity, entropy and enthalpy of

5-nitroindan are calculated. The values of thermodynamic parameters

such as zero-point vibrational energy, thermal energy, specific heat

capacity, rotational constants, entropy, and dipole moment of 5-

nitroindan by B3LYP method with 6-31G* and 6-31G** basis sets have

been calculated. The maximum dipole moment has been found to be

5.4086 Debye at B3LYP/6-31G** calculation levels.

1.1.4. NMR Chemical shift calculation:

NMR chemical shifts are an important tool in characterizing

molecular systems and structures. Accordingly, predicting NMR

spectra is an essential feature of computational chemistry software.

Gauge-Independent Atomic Orbital (GIAO) calculations include a

facility for predicting magnetic properties, including NMR shielding

tensors and chemical shifts. These calculations compute magnetic

properties from first principles, as the mixed second derivative of the

energy with respect to an applied magnetic field and the nuclear

magnetic moment. As a result, they can produce high accuracy

30

results for the entire range of molecular systems studied

experimentally via NMR techniques. Quantum mechanical chemical

shift calculations inherently require two fundamental steps. The first

is a geometry optimization calculation that produces a set of nuclear

coordinates corresponding to a minimum on the potential energy

surface. The second step is determination of the NMR shielding

constants themselves, referred to as an NMR single-point calculation.

Each of these calculations is performed utilizing a specific

computational method, basis set and the levels of theory for the two

steps need not be the same. Empirical scaling factors are dependent

on the levels of theory used for both steps and therefore can only be

utilized when the molecule of interest is computed with the same

levels of theory used to determine the factors. The important numbers

extracted from the output file are the isotropic values for each

numbered nucleus. Scaled chemical shift values (δ relative to TMS)

from the computed isotropic values (σ) are obtained using the scaling

factor obtained by linear regression analysis.

Castillo et al42 have synthesized two new 1-(2-methylpropenyl)-

2-methylbenzimidazoles(31a, 31b) by reaction of 2-

methylbenzimidazole with 3-chloro-2-methylpropene using a strong

base as a catalyst. The structures are confirmed by 1H and 13C

Nuclear Magnetic Resonance, elemental analysis and spectroscopic

methods such as FT-Raman, FT-IR and UV–VIS. Calculations on

31

proton and carbon magnetic shielding values were carried out in

solution(dimethylsulphoxide) using the gauge independent atomic

orbital (GIAO) approach. 13C/1H chemical shift values of two 1-(2-

methylpropenyl)-2-methylbenzimidazoles have been calculated using

B3LYP with the standard 6-311+G** basis sets. Correlations between

the proton and carbon-13 experimental chemical shifts and the GIAO

NMR calculations are found to be in good agreement.

Włostowski et al43 have examined the experimental NMR spectra

and theoretical GIAO – DFT calculations to obtain information about

the stereochemistry of the substituted inosine(32). The optimal

ground-state geometries for all the compounds have been calculated

using the density functional theory (DFT) and the proton and carbon

chemical shifts by the GIAO – DFT method. The B3LYP functional and

6-311G(2d,p) basis set are employed and the continuum model (PCM;

Gaussian 03W) is used in order to simulate the effects of the solvent.

The distance between C(O)6–H6 for all the compounds is predicted to

be greater than 3 Ǻ in syn conformation. Due to a negligible

intermolecular dipole–dipole (13C, 1H) interaction for distances greater

than 3–4 Ǻ, no heteronuclear overhauser effect (HOE by selective

irradiation of H - 6 proton) can be expected between these atoms in

syn-conformation. Hence, it has been concluded that the

diastereoisomers A and B form anti-conformation between purine and

32

aryl rings and three acetyl groups in positions 2, 3, 5 of the furanose

ring influence geometry of the molecule.

Sridevi et al44 have examined an integrated approach towards

understanding the vibrational, electronic, NMR, reactivity and

structural aspects of N-[acetylamino-(3-nitrophenyl)methyl]-acetamide

(33). Theoretical calculations are performed by ab initio HF and

density functional theory (DFT)/B3LYP method using 6-311++G(d,p)

basis sets. Tautomerism and the effect of solvent on the tautomeric

equilibria in the gas phase and in different solvents have been

studied. The theoretical chemical shift values are calculated by HF

and DFT/B3LYP methods using 6-311++G(d,p) basis set.. The

calculated 1Hand 13C NMR chemical shifts of 33 have been compared

with the experimental data. The predicted chemical shift values of HF

and DFT are found to be in closer agreement with the experimental.

The 1H and 13C Nuclear Magnetic Resonance (NMR) chemical

shifts of 1-ethyl-1,4-dihydro-7-methyl-4oxo-1,8-napthyridine-3-

carboxylic acid (34) have been calculated using B3LYP/6-311G (d,p)

GIAO method by Muthu et al45. The calculated 1H and 13C NMR

chemical shifts have been compared with the experimental data. The

predicted chemical shift values are found to be in closer agreement

with the experimental.

Singh et al46 have calculated 1H and 13C chemical shifts using

GIAO approach in DMSO - d6 using B3LYP functional and 6-31G(d,p)

33

basis set for newly synthesized ethyl 2-cyano-3-[5-(hydrazinooxalyl–

hydrazonomethyl)-1H-pyrrol-2-yl]-acrylate(35). The experimental 1H

NMR data was consistent with the calculated values from assigned

structure. Correlation graphs between the experimental and

calculated 1H NMR chemical shifts are drawn and the correlation

graph follows the linear equation: y = 1.2456x – 0.4481, where ‗x‘ is

the calculated 1H NMR chemical shift, ‗y‘ is the experimental 1H NMR

chemical shift (δ in ppm). The correlation coefficients (R = 0.89) shows

that there is an agreement between experimental and calculated

chemical shifts. The correlation graph of 13C NMR shows good

agreement between experimental and calculated chemical shifts with

correlation coefficients (R = 0.97) and follows the linear equation: y =

0.99152x _ 0.16491, where ‗x‘ is the calculated 13C NMR chemical

shift, ‗y‘ is the experimental 13C NMR chemical shift ( δ in ppm).

1.1.5. Hyperpolarizability calculations:

The 'polar' keyword requests the computation of dipole, electric

field polarizabilities and hyperpolarizabilities. The polarizability and

hyperpolarizability are presented in the output in the standard

orientation in lower triangular and lower tetrahedral order,

respectively: αxx, αxy, αyy, αxz, αyz, αzz and βxxx, βxxy, βxyy, βyyy, βxxz, βxyz,

βyyz, βxzz, βyzz, βzzz.

Kumar et al47 have revealed that the microscopic nonlinear

optical properties of m-nitroaniline(36) by evaluating the first-order

34

hyperpolarizability (β) by using the density functional theory (DFT)

quantum chemical calculations at B3LYP/3–21G (d,p) level. According

to the results of DFT calculations, the grown crystals exhibit non-zero

β values and it might have microscopic nonlinear optical behavior

which is seven times more than that of urea. The calculated first

hyperpolarizability (βtotal) of m-NA is 1.347006 X 10-30 esu, which is

nearly seven times that of urea (0.1947 X 10-30 esu).

Rajamani et al48 have calculated the first order

hyperpolarizability for 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]

pyrimidine(37) in order to show that the molecule is an attractive

molecule for future applications in non linear optics. The first

hyperpolarizability (β0) of this novel molecular system and the related

properties (β0, α0, μ) of 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-

piperazinyl] pyrimidine are calculated using the B3LYP/6-31G(d,p)

basis set, based on the finite field approach. The total molecular

dipole moment and first order hyperpolarizability are 0.6632 debye

and 4.545 X 10-30 esu respectively. First order hyperpolarizability of 2-

[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl] pyrimidine is 12 times

greater than those of urea (μ and β0 of urea are1.3732 debye and

0.3728 X 10-30 esu) obtained by B3LYP/6-31G(d,p) and B3LYP/6-

311G(d,p) method. So we conclude that 2-[4-(1,3-benzodioxol-5-

ylmethyl)-1-piperazinyl] pyrimidine is an attractive object for future

studies of non-linear optical properties.

35

Zaleśny et al49 have reported the results of computations of the

electronic and the vibrational contributions to the static first

hyperpolarizability (β) of m-dinitrobenzene molecule(38). Both

electronic and vibrational contributions to the static first

hyperpolarizability are considered. The extent to which electron

correlation is taken into account significantly influences the value of

the electronic first hyperpolarizability, i.e. the average value of first

hyperpolarizability is increased by 500% passing from the SCF to the

CCSD(T) level of theory. The use of DFT method in determination of

vibrational hyperpolarizabilities showed that the harmonic

contributions to β are substantially underestimated in comparison

with the wave function theory results. An important finding of this

study is that long-range corrected functionals tend to improve upon

traditional functionals both in determining electronic as well as

vibrational hyperpolarizabilities.

Dipole moment, polarizability, and first-order hyperpolarizability

of cyclic imides have been investigated using ab initio and density

functional theory calculations (HF/6-311++G(d,p), B3LYP/6-

311++G(d,p) and BH and HLYP/cc-pVDZ levels of theory) by

Khiavi et al50. It is observed that 4,5-dichloro- and 3,4,5,6-

tetrachlorophthalimide have highest mean polarizabilities and total

hyperpolarizabilities among the studied molecules. Moreover, a

reasonable agreement has been found between the experimental and

36

calculated dipole moments (μ) and average molecular polarizabilities

(α0) of several cyclic imides. Dependency of NLO properties on the

solvent polarity has also been studied. The first hyperpolarizability (β0)

of succinimide in vacuum is evaluated to be 559.43 X 10-33 esu. This

value increases to 764.19 X 10-33 esu in carbon tetrachloride and

1156.64 X 10-33 esu in water. In other words, β0 is found to be 1.4 and

2.1 times higher in carbon tetrachloride and water, respectively

compared with the related values in the vacuum.

Arivazhagan et al51 have investigated the first-order

hyperpolarizability (β) of p-fluorobenzonitrile (39) using DFT

calculations using ab initio and Becke-3-Lee-Yang-Parr (B3LYP)

functionals supplemented with the standard 6-311++G(d,p) basis set.

The calculated total dipole moment(μ) of the compound p-

fluorobenzonitrile is 2.402Debye. The calculated mean first

hyperpolarizability (β) of the compound p-fluorobenzonitrile is1.532 X

10-30 esu. The large value of hyperpolarizability, β is a measure of the

non-linear optical activity of the molecular system and it is associated

with the intramolecular charge transfer, resulting from the electron

cloud movement through π conjugated frame work from electron

donor to electron acceptor groups.

1.1.6. Natural Bond Orbital (NBO) calculations:

NBO analysis is based on a method for optimally transforming a

given wave function into localized form, corresponding to the one-

37

center ("lone pairs") and two-center ("bonds") elements of the chemist's

Lewis structure picture. In NBO analysis, the input atomic orbital

basis set is transformed via natural atomic orbitals (NAOs) and

natural hybrid orbitals (NHOs) into natural bond orbitals (NBOs). The

NBOs obtained in this fashion correspond to the widely used Lewis

picture, in which two-center bonds and lone pairs are localized. A full

NBO analysis is obtained in Gaussian when the POP=NBO keyword is

used. Natural bond orbital analysis is an essential tool for studying

intra- and intermolecular bonding and interaction among bonds and

also provides a convenient basis for investigating charge transfer or

conjugative interaction in molecular systems. The larger the

stabilization energy E(2) value, the more intensive is the interaction

between electron donors and electron acceptors,the more donating

tendency of electron transfer from electron donors to electron

acceptors and the greater is the extent of conjugation of the whole

system.

The natural bond orbital (NBO) calculations on the optimized

geometry of L-Phenylalanine L-Phenylalaninium Perchlorate(40) are

performed by Elleuch et al52 using NBO 3.1 program implemented in

the Gaussian 03 package at the DFT/B3LYP/6-31G(d) level in order to

understand various second order interactions between the filled

orbitals of one subsystem and vacant orbitals of another subsystem,

which is a measure of the intermolecular delocalization or hyper-

38

conjugation. The NBO analysis clearly explains the evidences of the

formation of strong H-bonded interaction between oxygen lone

electron pairs and σ* (N-H) anti bonding orbitals. The second order

perturbation theory analysis of Fock matrix in NBO shows strong

intermolecular hyper-conjugative interactions. The large stabilization

energy E(2) coupled with these interactions provides the stabilization

to the molecular structure and quantify the extent of intermolecular

N-H. . .O hydrogen bonding.

The non linear optical properties, NBO analysis,

thermodynamics properties and mulliken charges of pycolinaldehyde

oxime(41) are calculated and interpreted by Suvitha et al53. The strong

intramolecular hyperconjugative interaction of the σ electron of C3-C4

distribute to σ* C2-C3, C2-C11, C3-H7, C4-C5, C4-H8 and C5-H9 of

the ring. The conjugation of π (C3-C4) in the ring with the anti-

bonding orbital of π* (N1-C2) and (C5-C6) is evidenced by strong

delocalization energy of 26.18 and 17.32 kJ/mol. The π (C5-C6) bond

conjugation with the anti-bonding orbital of π* (N1-C2) and (C3-C4) is

contributed by energy of 18.19 and 22.66 kcal/mol.

Arjunan et al54 have clearly examined the picture of localized

bonds and lone pairs, stabilization energy of the delocalization of

electrons, the charge and hybridisation of the atoms of 4-hydroxy-1-

thiocoumarin (42) by NBO analysis (B3LYP/ 6 - 311G++(d,p)) in their

study on synthesis and characterization of an anticoagulant 4-

39

hydroxy-1-thiocoumarin by FTIR, FT-Raman, NMR, DFT, NBO and

HOMO–LUMO analysis. NBO analysis shows the intramolecular

charge transfer in 4-hydroxy-1-thiocoumarin from π(C3–C4) to π*(C2–

O16). NBO analysis shows that charge transfer mainly due to C–C

group and shows interaction between the ‗filled‘ donor-type NBO and

‗empty‘ acceptor-type NBO in the molecule and their stabilization

energies are estimated by second order Fock matrix. The

intramolecular charge transfer in 4-hydroxy-1-thiocoumarin from

π(C3–C4) to π(C2–O16) has the stabilization energy of 22.37 kcal mol-

1. The presence of intramolecular interaction and the frontier

molecular orbital energies are determined.

Karnan et al55 have investigated the Natural bond orbital

analysis, HOMO–LUMO and molecular electrostatic potential surface

on 5-chloro 4-nitro-o-toludine(43a), 5-bromo-4-nitro-o-toludine(43b)

and 5-fluoro-4-nitro-o-toludine(43c) for various intramolecular

interactions that are responsible for the stabilization of the molecule.

The number of intermolecular hyperconjugative interactions are

formed by π(C–C) and π*(C–C) in 5-chloro 4-nitro-o-toludine is more

than other halogen substitutions. This result indicates that

intramolecular charge transfer (ICT) in 43a is more than that of the

other substituents. The comparison of NBO values of 43a, 43b and

43c suggests the pharmaceutical properties of chlorinated nitro o-

toluidine are greater than other halogen substituted.

40

Nekoei et al56 have employed the second-order perturbation

theory at B3LYP/6-311G(d,p) and CCSD/6-31G(d,p)//B3LYP/6-

311G(d,p) levels of theory has been employed to evaluate the

stabilization energy for donor–acceptor interactions between the

orbitals in NBO analyses of eight α-chloro-O-oxime ethers(44a – 44h).

The NBO analysis reveals that the reason for the more stabilities of

the gauche forms, in which the Cl(1)–C(2) bond is in the gauche

position related to the O(3)–N(4) bond. It is attributed to the existence

of relatively strong interactions of kind LPO(3)-> σ*Cl(1)—C(2) and LPO(3) ->

π*N(4)—C(5) and less steric hindrance in these forms. NBO Calculations

well confirms that increasing the electron-donating nature of the

substitutions in R1 and/or R2 positions leads to an enhancement in

the amount of the anomeric effect and increasing their electron

withdrawing nature amplifies the LPO(3) -> π*N(4)—C(5) interaction and

reduces the anomeric effect.

1.1.7. Global and local reactivity indices:

Conceptual Density functional theory has been used to expose

the chemical reactivity and site selectivity of a variety of molecular

systems57. Chemical hardness, chemical potential and electrophilicity

are global reactivity indices that explain chemical reactivity and

quantities such as Fukui functions, local softness and local philicity

indices are local reactivity indices that explain site selectivity of a

molecular system.

41

Appropriate selection of population schemes used to derive the

local reactivity indices influences the calculated reactivity parameters.

Negative value of Fukui function indicates that electron density is

decreased in any particular site. Hence, it is good to look for positive

valued Fukui function. The substantial charge apportioning is needed

to obtain proper Fukui function from the condensed approach.

According to Koopmanns‘ theorem,58 the HOMO energy (EHOMO)

is related to the ionisation potential and the LUMO energy (ELUMO) is

related to the electron affinity of the molecule. If –EHOMO ≈ ionisation

potential and –ELUMO ≈ electron affinity, then the average value of

HOMO and LUMO energies is related to the Mulliken defined

electronegativity and the band gap between HOMO and LUMO is

related to the hardness.

The ionisation potential (I ) of the molecule is determined from

the difference between the energy of the cationic state of the molecule

(EM+) and the energy of the neutral state (EM). The electron affinity (EA)

of the molecule is assessed from the difference between the energy of

the anionic state of the molecule (EM-) and the energy of the neutral

state (EM).

MM EEI (7)

MM EEEA (8)

IEHOMO (9)

EAELUMO (10)

42

Hence, the electronegativity (χ) and the chemical hardness (η) of

the molecule can be predicted as follows,

2/2/ LUMOHOMO EEEAI (11)

LUMOHOMO EEEAI (12)

The chemical potential, μ, is the derivative of the energy with

respect to the number of electrons and corresponds to the negative of

the electronegativity. Hence,

2/LUMOHOMO EE (13)

The electrophilicity index (ω),59 is a measure of energy lowering

due to maximal electron flow. This new global reactivity index

measures the stabilization in energy when the system acquires an

additional electronic charge from the environment. The electrophilicity

which refers to the electrophilic power of a molecular system‘s ability

to accept electrons is defined as

2/2 (14)

The electrophilicity is a descriptor of reactivity that allows a

quantitative classification of the global electrophilic nature of a

molecule.

The Fukui function f(r)60, the widely used local density

functional descriptors to model chemical reactivity and site selectivity

is defined as

)()( ]/[ rvr Nrf (15)

43

where ρ(r) is the electron density at the point r, N is the number of

electrons and v(r) is the external potential in which the N electrons

move. The densities can be integrated over each atom and the

condensed fukui function is given as

Nk

qNk

qk

f 1 (16)

qNk

qNk

f k1 (17)

where qNk

refers to the gross charge on atom k in the molecule with N

electrons, qNk

1 denotes the gross charge on atom k in the molecule

with N + 1 electrons and qNk

1 denotes the gross charge on atom k in

the molecule with N – 1 electrons. k

f indicates the capacity of atom k

to undergo nucleophilic attack and f k indicates the tendency of atom

k to undergo electrophilic attack.

A dual descriptor (∆f)61 is defined as the difference between the

nucleophilic and electrophilic fukui functions and is given by

(18)

If ∆f > 0, then the site is favoured for a nucleophilic attack.

The local quantity called philicity ( ) associated with atomic

site k in a molecule with the help of the corresponding condensed

fukui function ( ) (where α = +, - and 0 representing nucleophilic,

electrophilic and radical attacks respectively) is given by

44

(19)

E. E. Porchelvi et al62 have calculated the fukui function values

in 6-Chloro-3,4dihydro-2H-1,2,4-benzothiazine-7-sulphonamide1,1-

dioxide molecule in order to identify the changes in the reactivity of

the molecule based on mulliken population at DFT/ B3LYP level. Out

of the three kinds of possible attacks, three kinds of attacks it is

possible to observe that electrophilic attack is bigger reactivity

compared with the nucleophilic and radical attack.

N. R. Sheela et al63 have calculated the electron density-based

local reactivity descriptor such as Fukui functions based on mulliken

charges at B3LYP/6-311++G(d,p) level to explain the chemical

selectivity or reactivity site in α-Phenyl-N-(4-Methyl Phenyl)

Nitrone(PN4MPN). The calculated value of electrophilicity index

describes the biological activity of PN4MPN. Nucleophilic attack is

found to be the bigger reactivity in the molecule.

R. Parthasarathi et al64 have analysed intermolecular reactivity

of some selected carbonyl systems and have proposed the concept of

group philicity. Group philicity values derived from both Mulliken

population analysis scheme and Hirshfeld population analysis scheme

have provided the expected reactivity trends in all sets of molecules

considered for evaluation.

45

1.2. Atoms In Molecules (AIM) analysis:

Bader theory65 of atoms in molecules (AIM) is a very useful tool

for analyzing the electronic charge density (ρb) its Laplacian (∇2ρ) and

hydrogen bonds, According to this theory, when two neighboring

atoms are chemically bonded, a bond critical point (BCP) appears

between them. Shorter bond length leads to increased overlap and a

larger value of ρb At the BCP, the sign of the laplacian of the electron

density ∇2ρ reveals whether the charge is concentrated as in covalent

bond (∇2ρ < 0) or depleted, as in electrostatic interactions (∇2ρ > 0) like

ionic bond or hydrogen bond.

The bond ellipticity is another proper at BCPs .It is defined as

ε = (λ1/λ2 – 1) (20)

Where,

λ1 = Largest curvature of the charge density perpendicular to the

bond path.

λ2 = Smallest curvature of the charge density perpendicular to the

bond path.

Bond ellipticity is a quantitative measure of the bond π –

Character. A ring critical point appears (RCP) in any bonded ring of

atoms.

In case of presence hydrogen bonding , the electron density at

the BCP of hydrogen bond will be relatively low, the laplacian (or) the

second derivative of the electron density will be positive indicating that

46

the interaction between the H and the bonded atom is dominated by

the contraction of charge away from the inter atomic surface toward

each nuclei.

Trendafilova et al66 have reported DFT and AIM studies of

intramolecular hydrogen bonds in dicoumarols. The calculated

electron density and Laplacian properties for the dicoumarols showed

the presence of two intra molecular hydrogen bonds in the compound.

The lower ρb and positive ∇2ρ values were obtained typically indicating

closed –shell interaction for O . . . H bondings. The calculated

ellipticity was consistent with π delocalization in both exocyclic rings

and is in full agreement with the differences in their structural

parameters obtained from structural X-ray analysis.

Sosa et al67 have performed ab initio calculations to analyze the

effect of C-H…. O hydrogen bonding interactions on the C – H bond

length. The topological properties of the electronic charge density are

analyzed employing the Bader‘s Atoms In Molecules (AIM) theory. They

have considered the methane derivatives for the study. The electron

density (ρb) it‘s second derivative (∇2ρ ) , eigen values λ1 , λ 2, λ 3 ,

value of |λ1|/λ3 are tabulated. The ρb value is less, ∇2ρ > 0, |λ1|/λ3

< 1 for the predicted hydrogen bonds in the compound were found to

be in contrast with the values predicted for covalent bonds.

The changes induced by perfluorination on the electron density

toplogical properties of dimethylether, methyl ether, diethyl ether and

47

their protonated forms have been anaysed by Vila et al68, under the

approach of the AIM. The variation of the polar character of the C – O

and C – C bonds with perfluorination and protonation is reflected by

the AIM atomic charges on the carbon and oxygen atoms. The study

lends support to consideration of protonation as a charge transfer

mechanism.

The substituent effects on the intramolecluar hydrogen bond in

1- hydroxyl anthraquinone were investigated within the AIM theory

and using NBO analysis by Li et al69. The topological properties of

BCP, RCP, the delocalization index DI and the integrated properties of

the interatomic surface can all be treated as indicators to measure the

strength of the intra molecular hydrogen bond. The introduction of

substituents at the ortho position strengthens the intra molecular

hydrogen bond while the introduction of substituents at the meta

position had only minor effects. Electron withdrawing substituents at

meta position reduces the covalent nature of the intra molecluar

hydrogen bond where as meta electron donating substituents

increases the covalent nature of the intramolecular hydrogen bond.

1.3. Azines:

Azines are compounds formed in the reaction of the carbonyl

group of aldehydes and ketones with hydrazine. The reaction of

hydrazine with the first mole of carbonyl group occurs through the

formation of the more familiar hydrazone, then reaction with a second

48

mole of the carbonyl compound. If two moles of same carbonyl

compounds are involved in the reaction, the azine formed is said to be

symmetrical and if one mole of two different carbonyl compounds are

involved in the reaction, the azine formed is said to be unsymmetrical

azines.

Azines are extremely useful compounds and they are receiving

attention due to their utility in a number of interesting reactions and

applications. They can be used in a variety of chemical reactions such

as 1, 3 – dipolar cycloadditions with dienophiles and [3 + 2]

cycloadditions in the construction of five – membered rings, which is

analogous to the Diels – alder reaction in construction of six –

membered rings. Azines are also been utilized because of their

biological properties, liquid crystalline properties. Azines are also

helpful in the synthesis of many compounds of pharmacological

interest. Recently azines are receiving attention as possible nonlinear

optical (NLO) materials, particularly the unsymmetrical azines with an

electron donor on one side and an electron acceptor on the other side.

Polyazines are being used as conducting polymers. Azines are also

used in coloring and dyeing processes.

Many research works have been performed earlier in

synthesizing azines by different approaches.

Shah et al70 have prepared azines by the thermolysis of

corresponding semicarbazones(Scheme 1). Thermolysis of

49

semicarbazones to azines occurs through reactive N – substituted

isocyanate intermediates which can be converted in situ to carbamates

and N – substituted urea. N – substituted isocyanate forms

symmetrical azines by going through a π2s + π2a cycloaddition which

gives an unstable isocyanate dimer that throws two molecules of

carbon monoxide and a nitrogen molecule to produce the symmetrical

azine.

Khouzani et al71 have reported an extremely fast method for the

reaction of hydrazine sulphate with a number of aldehydes and

ketones in the presence of anhydrous sodium acetate under solvent

free conditions and accelerating the process by microwave

irradiation(Scheme 2). The reaction is simpler, faster than the

classical methods of producing azines and provides a higher yield

(>90%) of pure desired products than classical methods that provides

low yield of the desired product with the mixture of other undesirable

products.

Khouzani et al72 have also reported a interesting, easy, novel

and solid state method for preparation of azines from aldehydes and

ketones using hydrazine sulphate, sodium hydroxide and alumina

under a solvent free condition(Scheme 3). This method is reported to

be the most preferable to other existing method of producing

symmetrical azines due to high yields of products, easier approach at

low cost.

50

Hopkins et al73 have examined the reactions (Fig 9) of the

nucleophilic carbene 1,3 – dimesityl – imidazol – 2 – ylidene with

diazofluorene, diphenyldiazomethane and azidotrimethylsilane.

Nucleophilic carbene 1,3 – dimesityl – imidazol – 2 – ylidene on

reaction with diazofluorene and diphenyldiazomethane yielded

unsymmetrical azines where else with azidotrimethylsilane it yielded

an imine after a subsequent hydrolysis reaction. The metrical

parameters of the formed unsymmetrical azines indicated the

presence of charge separation in them which predicted that they may

be NLO materials.

zhen et al74 have designed a new and environmentally benign

reaction route to symmetrical azines through reaction of aromatic

aldehydes with hydrazine sulphate by grinding under solvent free

conditions and in absence of catalysts. It was found that by following

this method the aldehydes that possess electron withdrawing group in

the para position of the phenyl group yielded high amount of azines

than other aldehydes used in this study because electron withdrawing

groups would support nucleophilic addition reaction.

Nanjundaswamy et al75 have studied the reaction of

hydrazinium formate with carbonyl compounds and the formed azines

are again converted to the corresponding carbonyls by stirring it with

triethylammonium chlorochromate for abou one hour

chemoselectively. An effort was made to get unsymmetrical azines by

51

using ketones along with aldehydes in the reaction with 1 equiv of

hydrazinium formate. But recovered only aldazines excluding the

presence of ketones which proves the selectivity of the method.

Nanjundaswamy et al76 have also reported the reaction of hydrazine

hydrate with carbonyl compounds in the presence of molecular iodine

at 0 – 10oC (Scheme 4). This reaction yielded high amount of

symmetrical azines in 1 to 4 minutes without any undesirable effect

on other substituents. This method does not require any solvent

extraction.

Eshghi et al77 have studied the selective and convenient

protection of aldehydes as azines under solvent free

conditions(Scheme 5). It is done in the presence of hydrazine

monohydrate and ferric chloride under solvent – free conditions. This

study also yields the symmetrical azines.

Simeonov et al78 have performed a fast, efficient, energy saving

and environmentally compassionate solvent – free one – pot

procedures for the synthesis of symmetrical aryl and heteroaryl azines

under microwave irradiation. The transformation goes via

semicarbazone or carbazate intermediates. If the aryl aldehydes

possess no substituents or electron releasing substituents the

intermediates are converted to the corresponding symmetrical azines.

If electron accepting groups are present in the aryl aldehydes then the

semicarbazone or carbazate becomes the only reaction product. The E,

52

E - configuration of the products are confirmed by the X – ray

analysis of a selected sample.

Galeta et al79 synthesized new non – symmetrical allenyl azines

with aliphatic and alicyclic substituents and have explained the

reaction of formation(Fig 10). The formed allenyl azines were refluxed

in xylene and bicyclics were produced. The combined intra –

intermolecular criss – cross cycloadditions of the new azines produced

fused five membered ring compounds. The new compounds formed in

this study were characterized NMR, IR and Mass spectral

measurements and X – ray structural analysis for some compounds.

Sauro et al80 have performed the electrochemical reduction of a

series of seven symmetrical and unsymmetrical 1, 4 –

dichloroazoethanes in N, N – dimethylformamide using cyclic

voltammetry and other electrochemical techniques. Bulk electrolysis

experiments revealed the loss of the two chlorine atoms by dissociative

electron transfer mechanism and formation of the azines in

quantitative yield.

Karimi et al81 have synthesized a series of new azines(45) by

reaction of 2 – ketoalkyl quinoline derivatives with some hydrazone in

solvent free reaction conditions using ultrasonic irradiation. The use

of ultrasonic radiation gave a good yield of azines in a short reaction

time. The tautomeric forms of the new azines from 2 – methylquinoline

were characterized by spectral studies. The cycloaddition reaction of

53

some of these azines with 2 – chloroacrylonitrile have also been

explained in this study.

Safari et al82 have designed a general, environmentally

concerned and useful method for the synthesis of symmetrical azines

from aromatic aldehydes and ketones in good yield. The reaction is

carried out in solvent free condition and in absence of catalysts. The

reaction was carried out by simply grinding the carbonyl compounds

with hydrazine sulfate and triethylamine with a pestle in a mortar at

room temperature. The obtained products were characterized using

spectral measurements. Lee et al83 have synthesized highly conjugated

symmetrical azines by solid state grinding of solid hydrazinium

carboxylate and carbonyl compounds without using solvents or

additives(Scheme 6). This method gave a higher yield and produced

water and carbon dioxide as waste. The yield of azines obtained by

this method is found to be high compared with the production of the

azines using hydrazine hydrate.

Ravi et al84 have prepared a new BiCl3 – loaded montmorillonite

K10 catalyst and have used that catalyst for the synthesis of azine

derivatives from benzophenone hydrazone and ketone or aldehydes by

simple physical grinding(Scheme 7). The BiCl3 – K10 gives an

excellent yield and is an inexpensive, easily recyclable catalyst.

Veena et al85 have synthesized 2-(3‘,5‘-dinitrobenzoyl)-3-

nitronaphtho[2,1-b]furan and the reaction of this compound with

54

hydrazine hydrate resulted in the formation of corresponding

hydrazone. Various azines(46) were obtained when the hydrazone was

treated with appropriate aldehydes by using different reaction

condition in absence and in presence of hydrochloric acid as a

catalyst. All the newly synthesized compounds have been

characterized by analytical and spectral studies and were screened for

antibacterial activity and antifungal activity.

Earlier researches have been committed to the studies on the

azine molecules.

O‘Relley et al86 have investigated the electrochemical reduction

of azabenzenes in acetonitrile and have presented the detailed

mechanism and rate constants for protonation of the radical anion.

The behavior of the cyclic monazine, diazines and the symmetrical

triazine in acetonitrile has been described in this study. The

techniques used in this study were polarography using dropping

mercury electrode, cyclic voltammetry, controlled electrode potential

electrolysis, coulometry and spectrophotometry.

Hagen et al87 has studied the electron diffraction pattern of

formalaldazine(47a) at -30o, 60o and 225oC. The molecules were found

to exist as a mixture of s – trans and gauche conformers with trans

conformer as the more stable conformer. In the radial distribution

curves obtained the peaks in the area relevant to the presence of trans

conformer from 2.5 – 3.0 Ao increased with increase in temperature.

55

Theoretical radial distribution curves were also calculated with models

containing different mixtures of the conformers at different

temperature and the theoretical result was found to be in good

agreement with experiment for the mixture which contained less

amount of gauche form at high temperature. Hagen et al88 has also

studied the molecular structure of gaseous

tetrabromoformaldazine(47b) at 112oC. It was found in this study

that the replacement of the hydrogen atoms in the formaldazine with

much larger atoms such as bromine did not push the molecular

structure to the expected planar anti form, instead it was found with a

single non – planar form with the CNNC equal to 72.1o deviating from

the planar form (0o).

Mom et al89 have reinvestigated the structure of benzalazine(48)

at 165K by X – ray crystallography experiment and the influence of

the thermal diffuse scattering on the determination of positional and

thermal parameters is examined. A comparison with the results of

other similar experiments was made.

Lai et al90 have halogenated acetophenone azines and have

studied their reactivities. The mono and dichlorinated derivatives

show an increase in the absorption maximum and are yellow in colour

and the trichlorinated derivative shows a decrease in the absorption

maximum and is colorless. The same study was carried out in the

brominated derivatives and chlorinated propiophenone azines and

56

same trend were observed in these azines too. The reactions of

hexachloro acetophenone azine have been reported.

Korber et al91 have examined the electronic structure and

conformational properties of the azine 2, 5 – Diacetyl – 3,4 – diazahexa

– 2,4 – diene(49). It predicts that the azine has two planar halves that

are twisted by an angle 102.7o. MNDO calculations were carried out

and the obtained structural parameters were compared with

experimental values and were found to be in good agreement.

Kholy et al92 have prepared hydrazones of 2, 6 – diaryl tetra

hydro – 1 – thio – 4 – pyrones and the hydrazones are converted to

azines(50). The structures of the new compounds have been

elucidated by hydrolysis, acylation reactions and spectroscopy

techniques like UV and IR spectroscopy. The symmetrical azines are

obtained easily by just keeping the hydrazone overnight at room

temperature itself.

Wiberg et al93 have examined the π – electron delocalization in

benzene and the monocyclic azines theoretically by an analysis of the

first π – π* transitions, calculation of hydrogenation energies and the

analysis of the wave functions. The distribution of π – electron density

around the rings does not get strongly disturbed by the replacement

of ‗CH‘ in benzene by ‗N‘ in the azines. The electronic transitions of the

compounds suggest that the delocalization energies are same for all

compounds considered for this study.

57

Bonaga et al94 have studied the gas chromatographic and mass

spectrometric behaviour of several 3 – methyl – 2 – benzothiazolone

azines(51). In the gas chromatographic analysis double peaks are

seen for all unsymmetric azines indicating the presence of E and Z

isomers. The GC/MS analysis of the azines showed double GC peaks

which are assigned for E and Z configuration.

Schweizer et al95 have studied the reaction of azines and have

synthesized pyrazolobenzoxazepines by treating azine

phospharanes(52) with benzalpthalide in xylene under reflux for 48

hours with a yield of 70% - 78%(Scheme 8). All the products obtained

were isolated as one isomer and the configuration about the exocyclic

bond in pyrazolobenzoxazepines is found to be ‗Z‘ configuration by the

nuclear overhauser effect difference experiments performed on the

product. This is also confirmed with X – ray crystallographic analysis.

The stereochemistries of benzoyl formate azines in the solid

state were studied using X – ray and IR methods, in solution using

the NMR techniques and theoretically in gas phase using ab initio

theory by Glaser et al96. Benzoyl formate azines are found to be

excellent phenyl conjugation system because of the presence of the

electron withdrawing ester substituent and in a conformation that

stops the π – back donation thereby making the azine ‗C‘ to be an

excellent electron acceptor. The X – ray crystallographic information of

ethyl benzoyl formate azine goes in accordance with the

58

stereochemistry predicted theoretically in gas phase. The NMR

studies too go in agreement with solid state studies and the ethyl

benzoyl formate azine is found to have Z, Z configuration.

Chen et al97 have analysed the stereochemistry and

stereoelectronics of symmetrical azines by the solid state analysis. The

azines taken under study are parent acetophenone azine, symmetrical

substituted acetophenone azines (H, F, Cl, Br and CN)(53). The

compounds are found to have (E, E) configuration consistent with the

steric demands of the substituents at the azine ‗C‘ atoms. The parent

and halogen substituted systems are assumed to have gauche

conformation and cyano system is found to have trans N – N

conformation. As the electronegativity of halogen increases the

halogen substituted azines seems to move towards more distinct trans

– gauche conformation. The torsion angle is increased in case of nitrile

substituent and reduced in case of halogen substituted azines

because nitrile substituents exihibits π – electron acceptor ability.

Shaw et al98 have used mixed mono azines`(54a,54b), α –

diazines(54c, 54d) and α – 2 – pyridyl azines(54e, 54f) containing (1R)

– (+) – camphor or (1R) – (-) – fenchone groups in a reaction with

Na2PdCl4 and have synthesized Palladium complexes [PdCl2L2] of

those azines. The azines were also made to react with [Pd2Cl4 (PR3)2]

and give complexes of types [{PdCl2 (PR3)} L] in which ligands are

bidentate bridging and [PdCl2 (PR3) L] in which the ligands are

59

monodentate. Most of above said complexes were found to be in

solution as mixture of isomers. But some complexes of type [PdCl2

(PR3) L] where L are α – 2 – pyridyl azine which contains camphor

residue, fenchone residue and monoazine with fenchone residue were

isolated. The crystal structure of [PdCl2L] 0.5.CH2Cl2 where L is α – 2

– pyridyl azine consisting of camphor residue is also obtained by X –

ray crystallography technique.

A comparative analysis of crystal structures of E, E configured

para substituted acetophenone azines with halogen, oxygen, nitrogen

and carbon functional groups have been made by Glaser et al99. The

crystal packing of the azines as the result of the difference in the

intrinsic electronic and steric effects due to the nature of the para –

substituent is discussed in this study. The molecules are analysed as

para – disubstituted benzenes X – C6H4 – azine group and compared

with X – C6H4 – Z systems and the electron withdrawing ability of the

azine group is ranked out.

Chen et al100 have synthesized the asymmetrical E, E –

configured para – disubstituted 4 – methoxy acetophenone azines(55)

with 4‘ – bromo, 4‘ – chloro and 4‘ – cyano substituents and their

crystal structures have been determined. The azines are assumed to

have 3 distinct gauche N – N conformation. The crystal packing is

structured out by offset T – shaped and parallel displaced face to face

arene – arene contacts. This study does not give any evidence of

60

conjugation in the structures but do not oppose the asymmetrization

effect in it.

Osborne et al101 have synthesized a series of ferrocenyl azines

by the reaction of the hydrazones of mono – and 1,1‘ – diacetyl

ferrrocene with mono and diketones. This resulted in the formation of

monobridged and dibridged ferrocenophane compounds. In

monobridged complex, the molecule is said to have centrosymmetric

eclipsed cyclopentadienyl rings and a planar – C = N – N = C – bridge

whereas the dibridged compound has staggered cyclopentadienyl rings

and non – planar bridges. The electrochemical behaviour of the

monobridged and dibridged compounds are also analysed with

respective two overlapping one electron oxidations and widely

separated one electron oxidations.

Glaser et al102 have proposed a comparative analysis of

asymmetrical and symmetrical azines. Structural parameters and the

natural population analysis of the asymmetrical azines which showed

no evidence for conjugation over the azine bridge. This conjugation

stopping character of the azine spacers (Fig 11) suggests a very small

dipole moment for the asymmetrical azines and introduces these

compounds to NLO world. The symmetrical azines analysed in this

study were the azines synthesized by G. S. Chen et al.

Lewis et al103 have reported the crystal structure of 4 – iodo

acetophenone azine(56). The azine showed a gauche conformation

61

with respect to the N – N bond and a large twist between the benzene

rings of each azine is observed. The long molecules are arranged

parallel within the layers and the azines in different layers deviate

from colinearity by 40o with the iodine atoms in the interface between

the layers. The surface of each layer can be viewed as a plane of iodine

atoms arranged in a kite shaped quadrilateral with two adjacent sides

of identical length and three unique angles.

Manas et al104 have synthesized 1,3 – dithiol – 2 – ylidene, a

donor – π – acceptor chromophores containing an azine spacer. These

derivatives showed μβ(0) values lower than those of similar derivatives

with ethylenic spacers. E – Z photomerization of the derivatives is also

reported in the study.

Sauro et al105 have estimated the extent of conjugation in

symmetrical and asymmetrical azines using electrochemical methods.

The electrochemical behqaviour of the azines was studied in

acetonitrile and N, N – dimethyl formamide solution using cyclic

voltammetry. The nitro substituted acetophenone azines exihibits an

Eo at a similar potential and the two – electron reversible wave which

indicates two localized, nonconjugated redox centers. The small ρ

values in combination with the other electrochemical data provide

support for single bond character of the N – N bond and support the

lack of conjugation between the two aryl centers through the

azomethine bonds.

62

Lewis et al106 have investigated the hypothesis that the azine

bridge is a conjugation stopper(Fig 12). The 1H and 13C NMR

spectroscopic data of the symmetric and unsymmetric acetophenone

azines support the hypothesis. NMR techniques was proved to be an

excellent tool to probe the degree of conjugation through the azine

bridge varying the donor group does not change the chemical shifts of

the aromatic hydrogen and ‗C‘ atoms on the acceptor substituted

phenyl ring and vice – versa.

Sauro et al107 have investigated a series of ferrocenyl

substituted azines(57) by electrochemical and photochemical

techniques. The electrochemical behavior of the ferrocenyl substituted

azine is governed by the ferrocenyl and aryl group attached to the

azine moiety. Electron withdrawing groups resulted in more positive

oxidation potentials and electron donating groups showed more

negative reduction potentials. The reduction and oxidation potentials

determined for the azine suggest that there is some electronic

communication between the two substituents of the azine moiety in

comparison with model compounds and suggest that azine bridge in it

is a conjugation limiter. The electrochemical behaviour of anthracenyl

azines consisting of ferrocenyl units are also studied and it exihibits

one electron reversible reduction followed by dimerization of the

radical anion. Photoisomerization of the anthracenyl azines from E/E

to E/Z and Z/Z forms were studied.

63

Frederickson108 has studied the infrared study of the C = N

stretching vibration in azine derivatives of aldehydes and ketones. The

C = N stretching vibration in azines is found to lie in the region 1610

to 1665 cm-1 with the intensity ranging from one third to one half

that of the carbonyl absorption of the parent compound. Hydrazones

of unsaturated aldehydes except trans cinnamaldehyde may undergo

ring closure to yield pyrazolines. The C = N stretching of

cyclobutanone azine is found at normal carbonyl position because of

the ring strain on the C = N frequency. This study was accompanied

with IR spectra of 18 azines that show the similarities and differences

between the original carbonyl compounds and their azine derivatives.

Manimekelai et al109 have reported a stereochemical study of

six t – 3 – methyl – r – 2,C – 6 – diphenyl piperidin – 4 – one azine

derivatives(58) in CDCl3 by NMR technique. In all the azines, the N –

N single bond is found to be anti to the methyl group in the piperidone

ring and the two C = N bonds are trans with respect to the N – N

single bond. The azomethine proton present in some azines is found to

be syn with respect to N – N bond.

Deun et al110 have outlined a synthetic route in which the rare

earth ion promotes the decomposition of habbe type ligand (N – (2 –

{2E – 2 – [2 – hydroxyl – 4 – (alkoxy) benzylidene] hydrazine} – 2 –

oxoethyl) benzamide) into symmetrical azine(Scheme 9). The thermal

behaviour of the habbe ligands and the azines are studied. The single

64

X – ray diffraction and NMR spectroscopy confirmed the formation of

symmetrical azines which showed nematic or smetic A phases. The

phase behavior was studied by High – temperature X – ray powder

diffraction study, Differential scanning calorimetry and Polarizing

optical microscopy. The habbe ligand gets decomposed to hydrazone

and hippuric acid molecule. Two of the hydrazone molecules combine

to form an azine by removing a hydrazine molecule.

Glaser et al111 have studied the solvent effect of some

symmetrical and unsymmetrical azines in CDCl3, Dimethyl

sulphoxide, Tetrahydro Furan, pyridine and benzene. Irrespective of

the solvent taken the electronic communication between the two

halves of unsymmetrical azines indicates that the azine bridge

functions as a ―conjugation stopper‖ and the spectroscopic properties

of the symmetrical azines are carried over to unsymmetrical azines.

The function of azine bridge as conjugation stopper is confirmed by

both theory and experimentation. DFT and MP2 computations show

iodine bonding in Iodoarenes. The absence of complexation shifts in

NMR spectra of haloarenes does not exclude the occurrence of halogen

bonding in solution(Fig 13).

Chandra et al112 have synthesized a series of new mono and

binuclear cationic complexes [RuH(CO)(PPh3)2(L)]+ and

[RuH(CO)(PPh3)2(- μ – L) RuH(CO)(PPh3)2]2+ where L = pyridine – 2-

carbaldehyde azine(59) or p – phenylene – bis(picoline) aldimine and p

65

– biphenylene – bis(picoline) aldimine as new DNA probes. The

products were characterized by microanalyses, spectral studies and

electrochemical studies. The crystallography of a representative

complex indicates the presence of intermolecular π – π stacking

resulting into a spiral network. Topoisomerase II inhibitory activity of

the complexes has been examined against filarial parasite. These

Ruthenium complexes with azine molecules show good interaction

with DNA.

Manimekalai et al113 have reported the spectral studies of four

cis – 2, 6 – diphenyl tetrahydrothiopyran – 4 – one azine

derivatives(60) in CDCl3. One of the azine which is stabilized by

intramolecular hydrogen bonding between OH proton of salicylidene

ring moiety with azomethine nitrogen and it is found to exist as one

single isomer and the other three azine derivatives are present in form

of two isomers in solution. In all the azines the two C = N bonds are

trans to N – N single bond.

Caballero et al114 investigated highly selective chromogenic and

redox or fluorescent sensors of Hg2+ in aqueous environment based on

1,4 – disubstituted azines. In this study they have synthesized and

characterized two azines, one is symmetrical azine with two redox

ferrocene groups and the other is a unsymmetrical azine with one

photoactive pyrene on one side and a p – methoxy phenyl group on

the other side. The metal recognition properties of these azines are

66

evaluated by electrochemical and optical analysis. The cyclic

voltammetric and differential pulse voltammetric analyses of the

azines in acetonitrile reveal that the voltammogram gets disturbed

only by the addition of Hg2+ ions. Moreover, the disturbance is well

pronounced in presence of water. Fluorescence emission spectra of

the azines also indicated the selective complexation of the azines with

Hg2+ ionswith the the increase in the excimer emission wavelength

Glaser et al115 have synthesized and evaluated the structural

and solid – state optical properties of the unsymmetrical

acetophenone azine 4 – decoxy – 4‘ – chloroacetophenone azine(61).

The crystals of 4 – decoxy – 4‘ – chloro acetophenone azine contain

parallel belamphiphile monolayers. The absorption and

photoluminescence studies of 4 – decoxy – 4‘ – chloro acetophenone

azine were conducted. Little or no absorption occurs at wavelengths

longer than 450 nm. The NLO behavior of 4 – decoxy – 4‘ – chloro

acetophenone azine is found experimentally. Its NLO response is 34

times larger than that of urea.

Zhao et al116 have synthesized 2‘ – chloro acetophenone azine

by the action of hydrazine with 2 – chloro acetophenone at room

temperature. The crystal structure of the azine is analysed and the

molecule is found to have C2 symmetry with the midpoint of the N – N

bond lying on the two fold axis. The reactions of 1, 4- di (N – methyl –

2‘ – pyrrolyl) – 2, 3 – diaza – 1, 3 – butadiene(62a), 1, 4 – di(6 – methyl

67

– 2‘ – pyridyl) – 2,3 – diaza 1,3 – butadiene (62b) and 3,6 – di – (2‘ –

thienyl) – 1, 2, 4, 5 – tetrazine with Fe2(CO)9 in toluene, Tetrahydro

furan and benzene have been studied by Wu et al117. It yielded

various types of hexacarbonyl diiron complexes. The complexes

exihibited five different coordination modes. N – N bond cleavage of 1,

4 – di ( N – methyl – 2‘ – pyrrolyl) – 2,3 – diaza – 1,3 – butadiene

yielded a complex with 2 – pyrrolyl methylidene amido bridging

ligands. Cyclometallated pyrrolyl and thienyl complexes are formed. A

diaza complex and two imine bridged complexes are formed. The

crystal structure of the ligands 1, 4 – di – (N – methyl – 2‘ – pyrrolyl) –

2,3 – diaza – 1,3 – butadiene and 3,6 – di – (2‘ – thienyl) – 1, 2, 4, 5 –

tetrazine and some of the iron complexes are determined by single

crystal X – ray crystallography.

A simple and robust reversible redox – fluorescence molecular

switch based on a unsymmetrical di substituted azine with ferrocene

and pyrene units(63) has been introduced by Martinez et al118. They

have taken the advantage of redox properties of ferrocene, an electron

donating unit and fluorescent activity of pyrene. The unsymmetrical

azine synthesized from those compounds shows a fast and reversible

redox – switchable fluorescence emission.

Fu119 has examined the crystal structure of 2 – methoxy

benzaldehyde azine(64). The molecule is seemed to locate on a centre

of inversion and it adopts a syn structure with respect to the methoxy

68

group and the aldehyde H atom. The benzene ring and adjacent N

atom are coplanar. The methoxy group deviates from the benzene

plane by 0.167 Ao for the methyl ‗C‘ atom.

Ziolek et al120 have investigated the photochromic cycle of the

salicylaldehyde azine with the help of the stationary and time –

resolved UV – Vis spectroscopy in a number of differently interacting

fifteen solvents and three different micro – heterogeneous micellar

systems. The properties of the enol, cis – keto and trans – keto

tautomer(Fig 14) are investigated in this study. The fluorescence

decay of the trans – keto tautomer have also been observed in this

study.

Tang et al121 have investigated the high pressure Raman spectra

and fluorescence spectra of acetophenone azine upto 17.7 GPa with a

diamond anvil cell in order to study the phase transition and

vibrational property at high pressure. The monoclinic structure is

found to undergo two possible crystalline to crystalline phase

transitions at pressures about 3.6 GPa and 5.8 GPa. At the pressure

range 8.7 GPa to 12.1 G Pa and some internal modes gets vanished.

This indicates the beginning of amorphization at 8.7 GPa. Above 12.1

GPa, an irreversible polymerization reaction occur. Upon releasing the

pressure, the new state remains stable as evident from its fluorescent

spectra.

69

A novel fluorescence turn – on detection method of human

serum albumin and Bovine serum albumin in aqueous solution is

investigated by X Chen et al122. They used substituted salicylaldehyde

azine for this study. The addition of the azine to the albumin solution

causes a fluorescence turn – on effect at 529 nm with large stokes

shift of 129 nm based on the hydrophobic binding mode between

protein and dye.

Grzegorzek et al123 have analysed 2‘ – hydroxyl acetophenone

azines‘(65) conformations by matrix isolation infrared spectroscopy

and quantum chemical calculations. The DFT/B3LYP/6 – 311++G (2d,

2p) calculation depicted two conformers for the azine. The two

conformers were a planar – trans form with – C = N – N = C – torsional

angle of 180o and a non – planar gauche form with torsional angle of

155o. The FTIR spectra of Argon matrix doped with the azine confirms

the presence of the two conformers. The experiment also depicted that

gauche conformer is more stable than a trans one.

Iwan et al124 have synthesized one series of symmetrical azine –

type liquid crystals(66a – 66c). The azines were characterized by

FTIR, NMR, high resolution mass spectrometry – electrospray

ionization and elemental analyses. The absorption,

photoluminescence and thermoluminescence features of the

compounds are reported. The mesomorphic properties were

investigated by polarizing optical microscopy and differential scanning

70

calorimetry. Azines with alkoxy semi perfluorinated end groups

showed smectic C phase, azine with octadecyloxy end chains

exihibited smectic C and smectic A phases.

Kim et al125 have synthesized an azine dye and it‘s boron

complex. Their structural elucidation was done by using elemental

analysis, UV – Vis, Fluorescence, Mass and 1H NMR spectroscopic

techniques. The effects of pH on their absorption /emission character

were studied and interpreted using electron density distribution

software. On decreasing the pH, the absorption peak of the dye azine

at 380 nm decreased and a new peak at 460 nm appeared. In case of

Boron complex the maximum peak at 380 nm is shifted to 395 nm.

The donor – acceptor – donor configuration of the dye is converted to

donor – acceptor configuration by the addition of acid. The HOMO and

LUMO energy gap calculated for the protonated azine fitted well with

the observed maximum absorption wavelengths.

Sek et al126 have synthesized azines and polyazines with

thiophene units(67) and have studied their light absorbing, emitting

redox and electrochromic properties. These azines and polyazines

were low molecular weight compounds and polymers consisting of one

and two thiophenes and double azomethine bonds. The effect of

number of thiophene rings on thermal, optical and electrochemical

properties were analysed. Bithiophene structured compound had

slightly higher glass transition temperature and decomposition

71

temperature. All the compounds exihibited blue light both in solution

and in solid state blended with polymer polymethylmeth acrylate. The

calculated energy gap decreased with the increase in the number of

thiophene rings. The theoretical energy gap value corresponded well

with the experimental value observed by DPV measurements.

Zheng et al127 have synthesized a series of azines which are a

class of novel nonsugar α – glucosidase inhibitors. The azines(68)

were formed by the reaction of polyhydroxy benzaldehydes and

hydrazine. The azines were investigated for their α – glucoside

inhibitory activity with p-Nitrophenyl-β-D-glucoside as substrate. The

compound with 2,4 – dihydroxy substituents seem to have more

inhibitory activity and those with fewer hydroxy groups have lower

activity. The activity was analysed in terms of IC50 values. This series

of azines may be used for development of new drugs in the treatment

of diabetes mellitus, hyperglycemia and cancer.

Sek et al128 have prepared two series of unsymmetrical azines

and their analogues by condensation of benzaldehyde, 2 – hydroxyl

benzaldehyde, 4 – pyridine carboxaldehyde, 2 – thiophene

carboxaldehyde and 4 – (diphenyamino) benzaldehyde with hydrazine

monohydrate and 1,4 – phenylene diamine. The structures were

analysed by FTIR and NMR spectroscopy along with elemental

analysis. The optical, electrochemical, thermal properties of all the

compounds were investigated by Differential scanning calorimetry, UV

72

– Vis spectroscopy, stationary and time resolved photoluminescence

spectroscopy and cyclic voltammetry.

Khouzani et al129 have analysed the tautomerism in 2 –

ketomethyl quinoline(Fig 15). A series of new 2 – ketomethyl quinoline

azines were prepared and their structure were analysed by

spectroscopic and elemental analysis. The presence of both methylene

and vinylic signals observed around 39 and 99 ppm indicates the

presence of mixture of tautomers in some compounds. Absence of any

signal indicate that only one tautomeric form exist for some

compounds.

Chen et al130 prepared some halogenated salicylaldehyde azines

(Scheme 10) and investigated the heavy atom effect on aggregation –

induced emission enhancement (AIEE) properties. Chloro and bromo

derivative display typical AIEE characteristics where as iodo derivative

is found to be external heavy atom quencher to salicylaldehyde azine

fluorescence in aggregated state. Iodo derivative has weak

fluorescence in aggregated state and relative strong fluorescence in

dispersed state and hence it can be used as a turn – on fluorescence

probe for egg albumin detection attributed to hydrophobic interaction.

1.3.1.Non – linear optical (NLO) activity of azines:

The optical parameters of a medium do not depend on the

intensity of the non – laser light propagating in the medium. This is

because the electric field strength of the non – laser light is of the

73

order of 103 v/cm and this cannot affect the interatomic fields of the

medium which is in the range of 107 to 1010 v/cm. Lasers generate

electric field strength varying from 105 to 109 v/cm which affect the

optical properties of the medium through which it propagates by

altering the phase, frequency, amplitude of the electric field. This

makes the medium through which it propagates by altering the phase,

frequency, amplitude of the electric field. This makes the medium to

enter into the NLO world.

NLO process can be considered as a dielectric phenomenon in

which the electrons that are bound to the nearby nuclei in the

medium get disturbed by the applied external electromagnetic field

and begins oscillating at the frequency of the applied field. This

induces polarization in the medium and it depends on the magnitude

of the applied electric field and polarizability of the medium.

P = χ1E (21)

Where P -> magnitude of polarization

E -> strength of applied electric field

χ1 -> polarizability of the medium

If the applied field is more intense, the above mentioned

linearequation becomes non – linear.

P = χ1E + χ2E2 + χ3E3 (22)

Where χ1, χ2, χ3 represents the second and third order susceptibilities

of the medium.

74

The above equation is written as

P = ΣαijE + ΣβijkE2 + ΣγijklE3 + … (23)

at molecular level, where,

αij -> polarizability

βijk -> First hyperpolarizability

γijkl -> Second hyperpolarizability

i, j, k, l -> molecular coordinates

A medium exhibiting NLO activity may consist of molecules with

asymmetric charge distribution. If a molecule is centrosymmetric, β

value is zero, indicating that centrosymmetric media do not show

SHG.

If a molecule has non – centrosymmetric electron donor(D)/

acceptor(A) the polarization takes place from D to A.. Organic

nonlinear optical materials show good and rapid NLO response

compared to the inorganic NLO materials . They are also called push-

pull chromophores, an electron donating group D conjugated to an

electron acceptor substituent A through a system of localized π -

bonds. These organic nonlinear optical materials possess large ground

state dipole moment large values of molecular first –order

hyperpolarazability (βtot). When it is excited, there is a large change in

the permanent dipole moment.

Asymmetrical azines with acceptor and donor groups in the

para positions of the benzene rings on opposing ends of the

75

hyperpolarizable π electron system are found to be efficient

candidate for NLO materials. Kleinpeter et al131 has quantified the

push – pull character of the azines by 13C, 15N chemical shift

differences of the partial C(1) N(1) and N(2) C(2) double bonds in

the central linking C(1) N(1)–N(2) C(2) unit and by the quotient of

the occupations of the bonding π and anti-bonding π* orbitals of these

bonds. Excellent correlation of the latter push–pull parameter with the

corresponding bond lengths dC N strongly recommend both the

occupation quotients π*/π and the corresponding bond lengths as

reasonable sensors for quantifying the push, pull character along the

C N–N C linking unit, for the donor–acceptor quality of the azines

and for the molecular hyperpolarizability βtot of the azines.

Dworczak et al132 have prepared a series of unsymmetrical

donor–acceptor substituted diazabutadienes and –hexatrienes and

investigated their linear optical (UV–vis) and nonlinear optical second

harmonic generation (SHG) properties. Among those synthesized

compounds, the one which contained a p-nitrophenyl group as

electron acceptor, the p-dimethylaminophenyl group was the most

powerful electron-donating group had the highest maximum

absorption wavelengths, as well as to the maximum SHG efficiency.

Theoretical and experimental results were in reasonable agreement.

Choytun et al133 have shown the strong polarization of the

azines impart structural features consistent with delocalization within

76

the azine fragment. The structural parameters that give insight into

the extent of delocalization within azines are the C – N and N – N bond

lengths. NLO properties for the azines are also reported. N –

heterocyclic carbenes are used as synthons to prepare azine molecule.

The azine link of the azine molecules under study is not perfectly

planar. It is clear from the study that the N – heterocyclic carbine

azines are strongly polarized materials that exihibits NLO behavior.

Azines with extreme push – pull substituents show structural trends

consistent with delocalization within the azine framework.

1.4. p – isobutyl acetophenone: (IBAP)

p – isobutyl acetophenone (69) has the pharmaceutical

importance in synthesizing Ibuprofen, a non - steroidal anti-

inflammatory (NSAID) drug that functions by reducing the hormones

that cause inflammation and pain in our body. Ibuprofen is the active

ingredient in a number of pain relievers e.g., Advil, Motrin, Nuprin.

Normally, hydrogenation of IBAP yields ibuprofen. Two of the most

popular ways to obtain Ibuprofen are the Boot process and the

Hoechst process. The Boot process is an older commercial process

developed by the Boot Pure Drug Company, United Kingdom and the

Hoechst process is a newer process developed by the Hoechst

Company, Germany. Most of these routes to Ibuprofen begin with

isobutyl benzene and use Friedel-Crafts acylation to produce IBAP. In

both the process IBAP is the antecedent to ibuprofen. After the

77

production of IBAP the Boot process (Scheme 11) requires five steps

to produce ibuprofen while the Hoechst process (Scheme 12), with

the assistance of catalysts, is completed in only two steps. Hence

many patented works and studies on the kinetics of hydrogenation of

IBAP using different catalysts were performed.

Elango134 has patented his work through Hoechst celanese

company . In the patented invention, A method is provided for the

preparation of ibuprofen by carbonylating 1-(4-isobutylphenyl) ethanol

with carbon monoxide in an acidic aqueous medium and in the

presence of a catalyst consisting essentially of a palladium compound

(Scheme 13) in which the palladium has a valence of zero to two

complexed with at least one monodentate phosphine ligand miscible

with the organic phase of the reaction medium. The carbonylation is

preferably integrated with a method of producing 1-(4-isobutylphenyl)

ethanol from isobutyl benzene wherein the latter compound is

subjected to Friedel-Crafts reaction with an acetylating agent to

produce 4ʹ-isobutylacetophenone, which is then reduced with

hydrogen in the presence of a hydrogenation catalyst, or with a

reducing agent containing available hydrogen, to obtain 1-(4-

isobutylphenyl) ethanol.

Many patent works are done in hydrogenating IBAP or involves

IBAP as an significant intermediate. Yoshiyaki135 has hydrogenated

IBAP with Raney Ni/ pyridine catalyst in his work on hydrogenation of

78

aromatic ketones with Raney Ni / amine catalyst. Ryan136 has IBAP

using activated Ni sponge as an intermediate during the preparation

of 1 – (4 – isobutyl phenyl) ethanol. Tadashi et al137 have

hydrogenated IBAP using Ru / C catalyst and converted it to p –

isobutyl phenyl – 2 – ethanol in their work on preparation of 1 – 1 –

hydroxyl ethyl) alkyl cyclohexanes by catalytic hydrogenation of alkyl

acetophenones. K. Saeki et al138 have prepared p – isobutyl phenyl – 2

– ethanol from IBAP using Pd/CaCO3 as catalyst and Pd/C in triethyl

amine as catalyst. Wagenknecht139 has patented his work for

Monsanto Company. The work was the electrochemical carboxylation

of IBAP. Hydroxyibuprofen is produced by the reduction of IBAP at the

cathode in the presence of carbon dioxide. Then hydroxyibuprofen is

hydrogenated to ibuprofen.

Cho et al140 have examined a precipitation and deposition

method to promote sodium on the Pd/ C catalyst used for the

hydrogenation of IBAP. The sodium content was varied and the yield

of the desired product 1 – (4 – isobutyl phenyl) ethanol was improved

greater than 96%. The reaction mechanism for the yield and selectivity

enhancement of the desired product induced by the promoted catalyst

Pd/C was elucidated in relation to the geometric and electronic effects

of the reactant molecules in the microporous support.

Zaccheria et al141 have obtained a selective hydrogenation of

different aryl ketones by using a heterogeneous copper catalyst under

79

very mild experimental conditions (Scheme 14), namely 90 °C and

1 atm. of hydrogen, without using any kind of additive or poisoning

agent. 1 – (4 – isobutyl phenyl) ethanol is obtained with 96% yield

from IBAP using this Cu / Al2O3 catalyst.

Thakar et al142 have investigated deactivation of Pd catalysts for

the hydrogenation of IBAP and for Pd/SiO2 an improved yield of nearly

80% of the desired product 1-(4-isobutylphenyl) ethanol was obtained.

However, severe catalyst deactivation was observed. The spent catalyst

was characterized using a wide variety of thermal, microscopic and

spectroscopic characterization techniques. This was not due to the

leaching of Pd but was due to the oligomerization of IBAP by

condensation reactions due to the acidity imparted by the presence of

isolated silanol groups on SiO2.

Hydrogenation of IBAP yields ibuprofen that has a chiral carbon

and can therefore exist as R (-) or S (+) enantiomeric forms. S (+)

enantiomer is the active form which performs the anti inflammatory

action by inhibiting the synthesis of prostaglandins which are the

cause of pain, inflammation, and fever. S (+) ibuprofen does this by

interfering with the action of an enzyme called cyclo-oxygenase which

catalyses the conversion of a compound called arachidonic acid into

prostaglandins. R(-) enantiomer is the inactive form and undergoes a

chiral inversion in vivo to the other S(+) form. This may cause some

disturbances in the punctual availability of the drug dosage in the

80

blood plasma quantitatively. This difficulty is overcome by controlled

release of ibuprofen from matrix tablets. This could be made better if

the hydrogenation of IBAP yields S (+) ibuprofen than the other

inactive form. Cleij et al143 have converted p – isobutyl acetophenone

to the corresponding epoxide and then used epoxide hydrolase

enzymes as tools for efficient synthesis of S (+) ibuprofen which has

the above mentioned therapeutic effect.

Maiorova et al144 have investigated the possibility of the

formation of inclusion complexes of IBAP with β – cyclodextrin during

the electrochemical reduction of IBAP on various cathodes – catalyst

in a two – phase water – organic system containing β – cyclodextrin.

This electrochemical reduction yielded the production of relevant

chiral alcohols.

Ikeda et al145 have synthesized 2 – hydroxy – 2 –(p – isobutyl

phenyl) – propionic acid in high yield (85%) by the electrolysis of IBAP

in a H – type glass cell equipped with a bubbler tube for introduction

of CO2 at the Hg pool cathode compartment and Pt was used as

anode. IBAP in a solution of N, N – Dimethyl formamide with Tetra

butyl ammonium iodide as the supporting electrolyte was added to the

cathode compartment where the electrolysis of IBAP to 2 – hydroxy – 2

– (p – isobutyl phenyl) – propionic acid which is confirmed by the

spectral studies.

81

Andy et al146 have investigated acylation of 2 – methoxy

naphthalene and isobutyl benzene in the liquid phase in the presence

of β – zeolite. This is the first industrial application of zeolite catalyst

in synthesis of aromatic ketones. The external surface of the zeolite

contributes significantly to the formation of 4 – isobutyl acetophenone

and the selectivity to the production of 4 – isobutyl acetophenone is

excellent (> 97%).

Bezouhanova147 has synthesized aromatic ketones in the

presence of zeolite catalysts. The swap of the classical acid catalysts

like AlCl3, HF by a zeolite avoids the environmental problems. The

mechanism of acylation on zeolites and the comparison of it with the

friedel – crafts acylation is presented in this study.

Mathew et al148 have studied the kinetics of hydrogenation of p

– isobutyl acetophenone using a 2 % Ru/Al2O3 catalyst experimentally

in a semi – batch slurry reactor over a temperature range of 373 – 398

K. The effect of catalyst loading, H2 partial pressure and IBAP

concentration and H2 consumption was studied and a rate equation

based on a Langmuir – Hinshelwood type mechanism was also

determined. A rate model based on the observed adsorption of

hydrogen in different liquid phase was found to fit well at all

temperatures. Rate parameters, activation energies, temperature

dependence of adsorption constants, heat of adsorption and entropy

values were also evaluated. Rajashekharam et al149 have studied the

82

kinetics of hydrogenation of p-isobutyl acetophenone using 10% Ni

supported on HY zeolite catalyst experimentally in a batch slurry

reactor over a temperature range of 373 – 413, K. The effect of

H2pressure, p-isobutyl acetophenone concentration, catalyst loading

and particle size on concentration-time and H2 consumption profiles

was studied.

IBAP is a precursor in the synthesis of ibuprofen. But the

presence of IBAP in the drug without conversion may cause adverse

effects in the central nervous system and also presents high dermal

absorption. This has to be controlled after proper detection of IBAP in

drugs. Shabir et al150 has developed a simple isocratic reversed –

phase high performance liquid chromatographic method for the

determination of 2 – (4 – isobutylphenyl) propionic acid and IBAP in a

gel formulation (a recent pharmaceutical preparation.Sodium

phosphate buffer and methanol were used as mobile phase and UV

detection was made at 220 nm. The analysis time was less than 10

minutes.

Zorita et al151 have developed a liquid -liquid extraction process

using a hollow fibre microporous membrane in order to determine the

free concentration of IBAP which is considered to be a toxic

degradation product of ibuprofen in river and sewage water of Sweden.

The liquid in the membrane pores were alone utilized in this approach

83

for a non-depleting extraction. IBAP was found to be 40ngL-1 or below

in sewage water for the first time after this procedure.

Matkovic et al152 have investigated the surface adsorption of

isobutyl benzene and IBAP on bulk fosfotungstic Wells – Dawson acid

H6P2W18O62.XH2O. The evolution of chemisorbed species towards

products was followed through infrared spectroscopy of systems at

various temperatures. The formation of chalcone type compound is

evidenced by the IR spectra and a mechanism is also proposed for the

aldol condensation of IBAP through enol formation.

Beghatto et al153 have used IBAP in the synthesis of 4 – isobutyl

benzaldehyde, an important intermediate for the fragrance (+) - and (-

)-Silvial which is a powerful, vibrant muguet ingredient with a slight

citrus under tone and a fresh aldehydic touch(Scheme 15). IBAP is

easily converted into the corresponding acid by the treatment with Br2

and NaOH. 4-Isobutylbenzoic acid may then react according to two

different reaction pathways to give the desired aldehyde, either by

reduction/oxidation via benzyl alcohol (yield = 73%) or by acylation

and reduction via acyl chloride (yield = 81%).

84

1.5. SCOPE OF THE PRESENT INVESTIGATION:

Pharmacologically important compound IBAP has been so far

used in the preparation of Ibuprofen. There are many number of

works been reported on the absorption of IBAP, kinetics of

hydrogenation of IBAP, production of ibuprofen from IBAP using

different catalysts. Such a pharmacologically significant compound

IBAP can be converted to azines which extend its area of application to

Material Science.

The azines, particularly asymmetrical azines derived from

carbonyl compounds are determined to have considerable NLO

response. Production of azines, asymmetrization effects present in

azines, electrochemical behavior, photochemical and fluorescence

reactivity, metal complexation reactions, tautomerism in azines and

computational DFT studies on conformational aspects of azines have

been reported. Hence, azines are a class of compounds that are

receiving increased interest for their bond formation reactions with

metal ions, biological applications like that of usage as DNA probes

and good electronic, linear and non-linear optical properties.

In the present work, pharmacologically important IBAP has

been converted to azines. The newly synthesized azines are

characterized by spectral techniques like IR, NMR and UV

spectroscopy. DFT and AIM studies are performed for the azines. The

present work comprises the following chapters

85

Chapter-3: DFT studies on IBAP.

Chapter-4: Synthesis, characterization and DFT Studies of Bis-1, 2-

(1-(4- isobutyl phenyl) ethylidene) hydrazine

Chapter-5: Synthesis, characterization and DFT Studies of 1-(1-(4-

isobutylphenyl) ethylidene)-2-((4-aryl) (phenyl) methylene) hydrazine

Chapter-6: Synthesis, characterization and DFT Studies of 1-(1-4-

isobutyl phenyl) ethylidene)-2-(1-aryl ethylidene) hydrazine

Chapter-7: Synthesis, characterization and DFT Studies of 1-(1-4-

isobutyl phenyl ethylidene)-2-(1-aryl methylidene) hydrazine.