Indian Journal of Chemistry Vol. 45A, January 2006, pp. 100-105

Model chemistry of hydrazides. II. Electronic structure of five-membered aromatic hydrazides

V Ananta Ramam, V V Panakala Rao, K Rama Krishna & R Sambasiva Rao*

School of Chemistry, Andhra University, Visakhapatnam 530003, India Email: rscchem@yahoo.com

Received 6 October 2004; revised 5 December 2005

The model chemistry of five-membered aromatic hydrazides at SEMO level of theory employing AM I, PM3, SAMl and MNDO Hamiltonians has been studied using AMPAC 6.7 package. The effect of heteroatom (0, S or N) in cyclopentadiene and the position (2- or 3-) of hydrazide fragment on quantum chemical parameters are reported in the gaseous phase. The stability based on total energy follows the order furoic > thiophene> pyrrole hydrazides. The heat of formation (HoF) is exothermic for furoic hydrazide only. Pyrrole with hydrazide fragment in the second position has the lowest dipole moment of 1.93 Debye whereas the 3-analogue has 4.9 units. The second order hyperpolarizabilities are smaller, but greater than urea and thiourea. Based on the present values of third order hyperpolarizabilities, the effect of substituents throws light on utility of these compounds with non-linear optical properties. The shapes of these molecules, electrophilic centers and charge distribution are derived from 3D-surfaces and 2D-contours of total electron density (TO), electrostatic potential (ESP) and energies of frontier molecular orbitals (FMOs). Logarithm of partition coefficient, molecular refractivity and Henry's constants are also computed . These results offer complementary information In understanding the apparently contradictory physico-chemical properties and biological response of the hydrazides.

A compound in bio-system or in environment undergoes: (a) 'transformation into isomers, (b) a chemical reaction leading to new species or (c) decomposition. The geometric, kinetic/thermo­dynamic stability, electronic/topological/geometric structure of all possible species and their dynamic behaviour in vitro has a pivotal role in understanding the complex phenomenon 1,2, It involves chemical forces, hydrogen bonding, van der Waals and stacking interactions. In spite of the fact that minimum energy conformer was looked for reactivity, unequivocally it is proved that higher energy analogues are prefelTed in several instances. Thus, it is a challenging problem with combinatorial possibilities.

Although QSAR3, model chemistry in silic04 and/or

artificial intelligence tools5 are not a panacea, they provide complementary information, etc. data to fix the pit falls in rationalizing apparently contradictory behaviour of similar compounds.

The model chemistry of isonicotinic acid hydrazide (INH), its valence isomers and their iso-propyl derivatives at SEMO level are reported6

. It was observed that electrophilic character increased on introducing isopropyl group at terminal nitrogen of hydrazide fragment and INH has higher hyperpolarizability compared to its isomers.

2-Furoic acid hydrazide (FAH) is one of the starting materials in the synthesis of anti-bacterial, anti­leukemic7

, anti-micophasmal durgs. FAH has CNS activity als08

,9 and is used in low density foams and fungicides lo. Co-ordination through amide or imide in divalent metal complexes of FAH was reported under different experimental conditions II. The mixed ligand complexes of cobalt thiocyanate with adipic acid hydrazide, glutamic and nonane dioic and sebatic acid hydrazides have different physico-chemical properties.

The model chemistry of five-membered hydrazides with different heteroatoms, fragment position and substituents throw light on the electronic structure, reactivity and biological response. We report here, the electronic structure and quantum chemical parameters of FAH and other five-membered aromatic hydrazides with 0, S or N as heteroatom along with cydopentadiene hydrazide.

Theoretical Hardware and software

An IBM Pentium III (800 MHz processor) with Windows98 OS is employed. AMPAC 6.7 version l2

, a GUI based semi empirical quantum chemical computational package is used for numerical and multidimensional graphical output.

ANANTA RAMAM ef al.: ELECTRONIC STRUCTURE OF 5-MEMBERED AROMATIC HYDRAZIDES 101

MATLAB I3, a numerical computation and

visualization environment was adopted to develop MATLAB (.m) functions to generate input files for different functions like geometry optimization with different Hamiltonians, frequency analysis by different algorithms, etc. from given z matrix. The AMPAC package employs BFGS l

4-17 modification of DFP algorithm I 8. Energy minimum for· geometry of the molecule in gas phase was arrived at based on SCF-MO at RHF level. The Hamiltonians at semi­empirical level are MNDO I9

-22

, and their modifications23

.24

, AM1 25.26 and PM327.28. A hybrid

semi empirical ab initio procedure, SAM 129 was also employed as a prelude to ab initio and DFT methods.

Results and Discussion The model chemistry of pyrrole-2-hydrazide

(Py2Hy), 2-furoic acid hydrazide (Fu2Hy), 2-thiophene hydrazide (Th2Hy), pyrrole-3-hydrazide (Py3Hy), 3-furoic acid hydrazide (Fu3Hy), 3-thiophene hydrazide (Th3Hy), and cyclopentadiene-3-hydrazide (CP3Hy) has been investigated.

Minimum energy geometry was located with respect to all geometric coordinates, viz. bond length (BL), bond angle (BA) and dihedral angle (DA) with six Hamiltonians, viz. M.NDO, MND03, MNDOC, AMI, PM3 and SAMl implemented in AMPAC 6.7 software. The bond lengths obtained with different Hamiltonians agree well while, dihedral angles differ considerably. This is due to the improvement in semi­empirical algorithms from MNDO to PM3 in an attempt to approach the reality. The point group is automatically determined in AMPAC.

SCF convergence It is based on multiple criteria, viz. difference in

electronic energy and diagonal elements of the density matrix. The default value of SCFCRT in the software is le-8 and optionally it can be decreased to le-ll (with AMPAC key word SCFCRT=O). SELCON (kcallmol) is calculated based on an internal estimate

of the accuracy of the computer and SCFCRT. The threshold in PL TEST is obtained from an empirical equation, which considers round off level and wave­function employed. The multilevel convergence criteria of SCF in AMPAC are depicted in the form of a knowledge base are described below:

Knowledge base for SCF convergence in SEMO methods of AMPAC

If Difference between electronic energy & between two successive iterations < SELCON

Then SCF _Convergence_1 (SELCON) is achieved

Limitation Although energy appears to be stationary, the density matrix may be still oscillating

Remedy PL-test

If Diagonal elements of density matrix < & threshold

Then SCF _convergence_2(PL-test) is achieved

If SELCON test is converged & PLTEST test is converged

Then Self consistence both in energy & density matri x (SCF _convergence) achieved

After SCF convergence, heat of formation (HoF) calculated is minimized for the system. It also involves multiple convergence criteria involving RMS gradient norm, relative change in geometry and change in HoF in successive cycles. In the present investigation, the geometries are optimized within 0.1 kcallmole. Further, RMS gradient/relative change in geometry norm and HoF are minimized to 0. leA A and 0.2e-3 kcal/mol, respectively. Standard deviations and gradient norm for optimized geometries with PM3 are given in Table 1, which indicate the accuracy of computation.

Table I--Gradient norm (and its RMS) of optimized geometric parameters

Compo MW NFL SCF IIGrli RMS IIGRII

Cp3Hy 124.14 24 115 0.140 0.020 Py3Hy 125 .13 24 70 0.178 0.027 Fu3Hy 126.12 24 67 0.097 0.015 Th3Hy 142.18 24 66 0.116 0.019 Py2Hy 125.13 24 72 0.153 0.024 Fu2Hy 126.12 24 67 0.092 0.015 Th2Hl' 142.18 24 66 0.083 0.013

102 INDIAN J CHEM. SEC A. JANUARY 2006

Table 2-Heat of formati on and energy components at PM3 level

Camp. HoF

Total energy (eV) kcal/mol

Cp3Hy 16.1 4 -1450.7555

Py3 Hy 9.7 1 -1479.575 1

Fu3Hy -19.86 -1594.9358

Th3Hy 16.34 -1487.7739

Py2Hy 9.81 -1479.5706

Fu2Hy 14.92 -1594.721 4

Th2Hy 20.9 1 -1487.5759

Stability of S-membered aromatic hydrazides

The quantum chemically computed total energy increases in the order: Fu3Hy > Th3Hy >Py3Hy > Cp3Hy reflecting the decrease in the stability of the compounds. The heat of formation is exothermic for 3-furoic acid hydrazide, while small but endothermic for all other derivatives. The endothermic (Table 2) character increased in the order [Cp3Hy = Th3Hy] > Py3 Hy > Fu3Hy for compounds with hydrazide in 3-position, while the corresponding analogues in 2-position followed the pattern Th2Hy > Fu2Hy > Py2 Hy. The stabilities based on electronic energy are in the order: CpxH > Thx H > FuxH > PyxH (x : 2- or 3-positi on) at PM3 level. It reflects the order of physico-chemical properti es derivable from electronic component of the energy.

For compounds with hydraz ide frag ment in the second position HoF is positive indicating instability from enthalpy values alone.

Atomic and ESP charges

Although electrostatic potential (ESP) and net atomic charges for the optimized geometry with all Hami ltonians are computed, on ly ESP30 charges at PM3 level are indicated for the three hydrazides, Cp3Hy, Pyxh, Fuxh and Thxh (x : hydrazide fragment in 2- or 3- position).

The most negative charge is concentrated on C2 with furan moiety while C4 for thiophene and pyran skeletons . The hydrazide at C2 position and the negative charges follow the order [Fu3Hy "" Py3Hy] > Th3Hy . . The positive charge on the heteroatoms increases in the order.:Fu3Hy < Th3Hy < Py3Hy. In all these three substituted compounds, there is a hi gh negative charge on 010, N il and N 13 forming an envelope of negati vely charged cloud, a facile region for interaction with an electrophile. The charges on the hydrogens of the ring and hydrazide moiety are significantly positive.

ZPE Electronic Core-core

85.60 -6695.8792 5245.1237

78.37 -6743.0000 5263.4249

70.73 -6879.7532 5284.8174

68.63 -6594. 1990 5106.4250

79.24 -6821.6407 5342 .070 1

71.10 -6977.5817 5382.8602

68.91 -6635 .5442 5147.9683

Fig. I- Total electron density (TD) on (a) Py3Hy, (b) Py2 Hy, (c) Fu3Hy and (d) Fu2Hy.

Total electron density and ESP surfaces/contours

The 2D-contour of ESP reveals the quantitative distribution of charge in the plane when a unit charge approaches the molecule . The outer contour of 3-D electron density surface plots reveals the shape of the molecule. It also throws light on the limit of influence of electron density of the molecule.

For cyclopentadiene hydrazide, 2D-contour of total density (TD) mapped on 3D-surface shows zero total electron density around C6-C9, C II and broad clouds enveloping NI3-NI5-HI7 and H5-C4-Cl atoms. In the case of Py3Hy, small white regions at H9, H6, C l , NI2 and N14, while a large diffused white marking in the case of 2-substituted analogue. For Fu3Hy, the neutral electron density is found at H7, ring 0 , imino N whereas for Fu2Hy, there is no white patch on either imino or amino nitrogens. However, neutral charge region is around S5 and H8 of thi ophene 2-hydrazide ~Fig. 1).

ANANTA RAMAM et al.: ELECTRONIC STRUCTURE OF 5-MEMBEREO AROMATIC HYORAZIDES 103

The electrophilic and nucleophilic reactivities of the hydrazides are analyzed from ESP on TD plots both in three- and two-dimensions. For cyclopentadiene hydrazide, higher negative charge is around oxygen of the fragment (CONHNH2) in 3-position. However, in the case of all other hydrazides with heteroatoms, 3-substituted compounds are found to be better electrophiles compared to those in the 2-position. Diffused charges or long patches indicate lower polar interactions around N13-NlS of Py3Hy and amino N of Fu3Hy .

A perusal of the spread of HOMO (Fig. 2) differs with the position of the hydrazide fragment especially ~'ith sulphur or oxygen (heteroatom). HOMO does not exist on ring oxygen or sulphur with Fu2Hy and Th2Hy, while it is present in Fu3Hy and Th3Hy. In the case of Th3Hy, Py3Hy and Fu3Hy, HOMO spreads on imino- and amino-nitrogens rendering them susceptible for orbital based interactions. LUMO covers the entire heterocyclic ring for Th2Hy and Py2Hy. However, C3 of the ring is not well covered in Fu2Hy.

Fig . 2- Frontier molecul ar orbita ls of typica l hydrazides: HOMOs (a) Th3Hy, (c) Fu3Hy; LUMOs (b) Th3Hy, (d) Fu3Hy.

Some of the physico-chemical parameters viz. logarithm of partition coefficient (P), molecul ar refractivity (MR) and Henry's constant are described in Table 3. The minimum (-0.82) and, maximum (0.68) values of log (P) are found for Py3Hy and . Th2Hy. The trend observed is Th3Hy > Cp3Hy > . Fu3Hy > py3Hy and Th2Hy > Py2Hy > Fu2Hy when ; the hydrazide fragment is in 3- and 2-po~itions .

respectively .

Compo

Cp3Hy Py3Hy Fu3Hy Th3Hy Py2Hy Fu2Hy Th2Hy

Compo

Cp3Hy

Py3Hy

Fu3Hy

Th3Hy

Py2H y

Fu2Hy

Th2Hy

Table 3--Typical physico-chemical parameters

log P MR Henry ' s cm3/mol constant

-0.20 37.69 4.04 -0.82 33.96 6.74 -0.75 32.37 4.48 0.62 37.84 4.74 -0.76 33.01 6.74 -0.69 3 1.43 4.48 0.68 36.90 4.74

Dipole moment and polarizability

Th . d' 1 3J -JJ b . d ~le statIc IpO e moments- are 0 tame employing semi-empirical RHF MO calculations employing PM3 Hamiltonian (Table 4). Among the hydrazides with nitrogen, oxygen and sulfur in the heterocyclic ring, 2-substituted pyrrole hydrazide has

Table 4--Total dipole moment and its point charge and hybrid orbital contributions

Dipole moment (Oebye)

Total Point charge Hybrid orbi tal

Xpc Ypc Zpc Tpe Xho Yho Zho Tho

2.76 1.22 1.42 -2.62 3.22 -0.44 -1.09 0.00 1.1 8

4.39 - 1.40 3.64 -0.32 3.91 -1.40 -0.29 -0.23 1.42

2.44 0.59 2.79 -0.32 2.87 -0.99 -0.44 -0.2 1 1.08

2.22 -0.46 3.17 0.34 3.22 0.56 -0.95 -0.48 1. I 1

1.93 1.41 0.97 0.42 1.76 0.22 0.06 -0.40 0.24

3.49 2.33 0.34 -1.68 2.89 0.79 0.06 0.18 0.80

3.61 0.50 1.58 -2.18 2.73 2.22 -0.51 0.06 2.28

104 INDIAN J CHEM, SEC A, JANUARY 2006

Table 5-Polarizability (a) and second (~) and third (y) order hyperpolarizabilities at PM3 level

Compo Polarizability Hyper polarizability

a x 10-24 ~ X 10-30 y x 10-36

Cp3Hy 18.91 1.46 7.01 Py3Hy 18.37 0 .26 5.53 Fu3Hy 17.12 0.37 4.60 Th3Hy 20.50 1.25 5.91 Py2Hy 18.76 2. 11 6.28 Fu2Hy 17.40 0.89 5.37 Th2Hy 20.32 -0.06 4.29

lowest dipole moment of 1.93 Debye, while 3-substituted analogue is highly polar with a value of 4.39 Debye.

A perusal of Table 4 reveals that the total static point dipole moments follow the order Py3Hy » Cp3Hy > Fu3Hy > Th3Hy. However, the sulfur (2.2 Debye) and oxygen (2.4 Debye) analogues have closer dipole moments. In the case of 2-subtituted hydrazides, a change in order has been noticed and sulfur analogue has the highest dipole moment, while that with nitrogen has a lower dipole moment (1.93 Debye) compared with Py3Hy.

The contribution of dipole moment from point charges and hybrid orbitals also follow the same trend Py3Hy » Cp3Hy > Th3Hy > Fu3Hy like the total moment. The magnitudes in X, Y and Z directions (Table 4) throw light on orientation, direction of the dipole with respect to the molecular plane.

Table 5 depicts polarizability (ex) and second (~) and third (y) order hyperpolarizability values for the compounds studied. The polarizability is highest for thiophene hydrazide and the trend for 3- and 2-substituted compounds are Th3Hy > Cp3Hy >Py3Hy >Fu3Hy and Th2Hy > Py2Hy >Fu2Hy, respectively. The second order hyper polarizabilities (~) are small but greater than those for urea (0.39) and thiourea (0.80). The third order polarizabilities are not large enough for employing these materials with non-linear optical susceptibilities. A systematic investigation with experimental design34 is under progress to increase yS-38 by introducing substituents to undertake a feasibility study for employing these compounds in optical information processing, integrated optics and telecommunications.

,Acknowledgements One of the authors (RSR) sincerely thank~ Prof R

M Leblanc, University of Miami, USA for kindling

interest III electronic modeling of bioactive compounds. DR DE, Gwalior is acknowledged for financial support to procure the AMPAC 6.7 package. KRK expresses his gratitude to UGC for a research award.

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