# Structural, Electronic, and Vibrational Properties of Isoniazid and Its Derivative N-Cyclopentylidenepyridine-4-carbohydrazide: A Quantum Chemical Study

Authors: Anoop kumar Pandey; Abhishek Bajpai; Vikas Baboo; Apoorva Dwivedi
Journal: Journal of Theoretical Chemistry
 (2014)

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## Abstract

Isoniazid (Laniazid, Nydrazid), also known as isonicotinylhydrazine (INH), is an  organic  compound that is the first-line medication in prevention and treatment of  tuberculosis. The optimized geometry of the isoniazid and its derivative N-Cyclopentylidenepyridine-4-carbohydrazide molecule has been determined by the method of density functional theory (DFT). For both geometry and total energy, it has been combined with B3LYP functionals having LANL2DZ and 6-311 G (d, p) as the basis sets. Using this optimized structure, we have calculated the infrared wavenumbers and compared them with the experimental data. The calculated wavenumbers by LANL2DZ are in an excellent agreement with the experimental values. On the basis of fully optimized ground-state structure, TDDFT//B3LYP/LANL2DZ calculations have been used to determine the low-lying excited states of isoniazid and its derivative. Based on these results, we have discussed the correlation between the vibrational modes and the crystalline structure of isoniazid and its derivative. A complete assignment is provided for the observed FTIR spectra. The molecular HOMO, LUMO composition, their respective energy gaps, and MESP contours/surfaces have also been drawn to explain the activity of isoniazid and its derivative.


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## Body

## 1. Introduction

Tuberculosis remains a major worldwide health problem with at least 10 million new cases and 3 million deaths estimated to occur annually. Isoniazid (Laniazid, Nydrazid), also known as isonicotinylhydrazine (INH), is an organic compound that is the first-line medication in prevention and treatment of tuberculosis. The compound was first synthesized in the early 20th century [1] but its activity against tuberculosis was first reported in the early 1950s, and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug [2]. With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable. Isoniazid is available in tablet, syrup, and injectable forms (given intramuscularly or intravenously). It is available worldwide, is inexpensive, and is generally well tolerated. It is manufactured from isonicotinic acid, which is produced from 4-methylpyridine [3].A previous investigation was done on determination of microquantities of isoniazid (INH), either in pure form or in pharmaceutical formulations by calorimetric method [4]. In another work, studies on the 4-benzoylpyridine-3-carboxamide entity as a fragment model of the isoniazid-NAD adduct were carried out [5]. A previous work on vibrational analysis of isoniazid was done by Gunasekaran et al. [6] by Wilson G.F. method which is a classical method, so it is necessary to work again with quantum chemical method to reduce the inaccuracy in previous work. The title compound, N-cyclopentylidenepyridine-4-carbohydrazide, C11H13N3O, is a derivative of the antituberculosis drug isoniazid. The XRD analysis of this compound was done recently by Lemmerer et al. [7]. It is a derivative of such an important biological isoniazid molecule so comparative study of these two compounds is necessary for discovery of new drugs.In the present communication, the molecular structure of well-known drug isoniazid and its derivative has been analyzed using the density functional theory. The equilibrium geometry, harmonic vibrational frequencies, and HOMO-LUMO gap have been calculated by the density functional B3LYP method employing LANL2DZ and 6-311 G (d, p) as the basis sets. The detailed interpretation of the infrared spectra of isoniazid and its derivative in terms of the normal mode analysis has been reported. The main objective of the present study is to investigate in detail the vibrational spectra of important biological molecules (isoniazid and its derivative) by DFT [8] method, which can presumably help in understanding its dynamical behavior. To the best of our knowledge no detailed DFT calculations have been performed on isoniazid and its derivative so far in the literature. Here we have discussed only results from LANL2DZ because these results are closer to experimental data than 6-311 G (d, p). So, here LANL2DZ shows supremacy over 6-311 G (d, p) basis set.


## 2. Experimental and Computational Methods

### 2.1. Structure and Spectra

The molecular structures of the title compounds isoniazid and its derivative are made by molecular modeling. The model molecular structures of the compounds are given in Figures1 and 2. Fourier transform infrared spectrum was recorded with FTIR Perkin Elmer spectrometer in KBr dispersion in the range of 400 to 4000 cm−1 for the title molecule. Fourier transform Raman spectrum was recorded in the range of 50 to 3500 cm−1 for isoniazid [6].Figure 1
Model molecular structure of isoniazid.Figure 2
Model molecular structure of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).


### 2.2. Computational Methods

Initial geometry was generated from standard geometrical parameters and was minimized without any constraint in the potential energy surface. The gradient corrected density functional theory (DFT) with the three-parameter hybrid functional (B3) [9] for the exchange part and the Lee-Yang-Parr (LYP) correlation function [10] has been employed for the computation of molecular structure, vibrational frequencies, HOMO-LUMO, and energies of the optimized structures, using GAUSSIAN 09 [11]. The calculated vibrational frequencies have also been scaled by a factor of 0.963 [12]. By combining the results of GaussView’s program [13] with symmetry considerations, vibrational frequency assignments were made with a high degree of accuracy. We used this approach for the prediction of IR frequencies of title compound and found it to be very straightforward. Density functional theory calculations are reported to provide excellent vibrational frequencies of organic compound if the calculated frequencies are scaled to compensate for the approximate treatment of electron correlation, for basis set deficiencies and for anharmonicity. A number of studies have been carried out regarding calculations of vibrational spectra by using B3LYP methods with LANL2DZ and 6-311 G (d, p) basis sets. The scaling factor was applied successfully for B3LYP method and was found to be easily transferable in a number of molecules. Thus, vibrational frequencies calculated by using the B3LYP functional with LANL2DZ as basis set can be utilized to eliminate the uncertainties in the fundamental assignment in the IR spectra.


## 2.1. Structure and Spectra

The molecular structures of the title compounds isoniazid and its derivative are made by molecular modeling. The model molecular structures of the compounds are given in Figures1 and 2. Fourier transform infrared spectrum was recorded with FTIR Perkin Elmer spectrometer in KBr dispersion in the range of 400 to 4000 cm−1 for the title molecule. Fourier transform Raman spectrum was recorded in the range of 50 to 3500 cm−1 for isoniazid [6].Figure 1
Model molecular structure of isoniazid.Figure 2
Model molecular structure of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).


## 2.2. Computational Methods

Initial geometry was generated from standard geometrical parameters and was minimized without any constraint in the potential energy surface. The gradient corrected density functional theory (DFT) with the three-parameter hybrid functional (B3) [9] for the exchange part and the Lee-Yang-Parr (LYP) correlation function [10] has been employed for the computation of molecular structure, vibrational frequencies, HOMO-LUMO, and energies of the optimized structures, using GAUSSIAN 09 [11]. The calculated vibrational frequencies have also been scaled by a factor of 0.963 [12]. By combining the results of GaussView’s program [13] with symmetry considerations, vibrational frequency assignments were made with a high degree of accuracy. We used this approach for the prediction of IR frequencies of title compound and found it to be very straightforward. Density functional theory calculations are reported to provide excellent vibrational frequencies of organic compound if the calculated frequencies are scaled to compensate for the approximate treatment of electron correlation, for basis set deficiencies and for anharmonicity. A number of studies have been carried out regarding calculations of vibrational spectra by using B3LYP methods with LANL2DZ and 6-311 G (d, p) basis sets. The scaling factor was applied successfully for B3LYP method and was found to be easily transferable in a number of molecules. Thus, vibrational frequencies calculated by using the B3LYP functional with LANL2DZ as basis set can be utilized to eliminate the uncertainties in the fundamental assignment in the IR spectra.


## 3. Results and Discussion

### 3.1. Molecular Structure

In the case of isoniazid, the molecule has only one pyridine ring. The optimized bond length of C–C in six membered pyridine ring ranges between 1.403 Å and 1.414 Å. The optimized bond length of C–C outside the ring is 1.509 Å. The optimized bond lengths of C–N in ring range between 1.356 Å and 1.359 Å. The optimized bond length of C–N outside the ring is found to be 1.390 Å. The optimized C–H bond lengths attached to the ring are found to be 1.080 Å −1.087 Å. The optimized C=O bond length adjacent to ring is found to be 1.262 Å. The optimized N–H bond lengths adjacent to ring are found to be 1.016 Å–1.020 Å.When a five-membered carbon ring is also attached to isoniazid, it becomes N-cyclopentylidenepyridine-4-carbohydrazide. For N-cyclopentylidenepyridine-4-carbohydrazide, it has one six-membered pyridine ring (A) and one five-membered carbon ring. The optimized bond length of C–C in six-membered pyridine ring A ranges between 1.405 Å and 1.411 Å, while for another ring B it ranges between 1.521 Å and 1.553 Å. The optimized bond lengths of C–N in pyridine ring A range between 1.356 Å and 1.359 Å. The optimized bond length of C–N in between both rings is found to be 1.392 Å. The optimized C–H bond lengths attached to the ring A are found to be 1.084 Å–1.086 Å while for ring B it ranges between 1.094 Å and 1.101 Å. The optimized C=O bond length in between both rings is found to be 1.249 Å. The optimized N–H bond length in between the rings is found to be 1.017 Å. All the optimized bond lengths are in good agreement with the experimental values given in the literature and summarized in Table1 [7]. This difference in the bond lengths is attributed to the difference in bond strength. The length of a chemical bond is the result of equilibrium of attractive and repulsive forces between the atoms which are bonded. In fact, the distance between the atoms of a bond is not constant since the atoms are always vibrating in molecules; the measured bond distance is, therefore, an average value. Although the measurements may vary in accuracy, still similar bonds have fairly constant lengths in different molecules, variation generally being much less.Table 1
Optimized geometrical parameters of isoniazid and N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) by (B3LYP)/ 6-311 G (d, p) and (B3LYP)/LANL2DZ methods.
Isoniazid
N-Cyclopentylidenepyridine-4-carbohydrazide parameters
Bond lengths
Parameters
Calculated
Parameters
Calculated
Exp.
LANL2DZ
6-311 G (d, p)
Wilson GF (literature)
LANL2DZ
6-311 G (d, p)
R(1, 2)
1.4036
1.3933
(1.470)
R(1, 2)
1.4054
1.3905
(1.3801)
R(1, 6)
1.3599
1.3355
(1.358)
R(1, 6)
1.3596
1.3381
(1.3309)
R(1, 7)
1.0866
1.0866
(1.100)
R(1, 7)
1.0865
1.0862
(0.95)
R(2, 3)
1.4146
1.3965
(1.420)
R(2, 3)
1.4100
1.3954
(1.3836)
R(2, 8)
1.0845
1.0788
(1.100)
R(2, 8)
1.0850
1.0824
(0.95)
R(3, 4)
1.4124
1.3972
(1.420)
R(3, 4)
1.4119
1.397
(1.3904)
R(3, 11)
1.5098
1.5067
(1.517)
R(3, 11)
1.5114
1.5098
(1.4973)
R(4, 5)
1.4088
1.3903
(1.420)
R(4, 5)
1.4079
1.3937
(1.3768)
R(4, 9)
1.0806
1.0822
(1.100)
R(4, 9)
1.0868
1.084
(0.95)
R(5, 6)
1.3563
1.3373
(1.358)
R(5, 6)
1.3564
1.3346
(1.3360)
R(5, 10)
1.0872
1.0864
(1.100)
R(5, 10)
1.0870
1.0866
(0.95)
R(11, 12)
1.2625
1.2198
(1.208)
R(11, 12)
1.2496
1.2106
(1.2249)
R(11, 13)
1.3903
1.377
(1.369)
R(11, 13)
1.3920
1.3825
(1.3484)
R(13, 16)
1.0203
1.0161
(1.012)
R(13, 14)
1.3977
1.369
(1.3961)
R(13, 17)
1.4052
1.402
(1.352)
R(13, 15)
1.0175
1.0129
(0.889)
R(14, 17)
1.0170
1.0152
(—)
R(14, 16)
1.2980
1.275
(1.2759)
R(15, 17)
1.0170
1.0142
(—)
R(16, 17)
1.5220
1.5146
(1.5076)
—
—
—
—
R(16, 20)
1.5329
1.5238
(1.5035)
—
—
—
—
R(17, 18)
1.5495
1.5388
(1.5243)
—
—
—
—
R(17, 21)
1.1002
1.0975
(0.99)
—
—
—
—
R(17, 22)
1.0942
1.0904
(0.99)
—
—
—
—
R(18, 19)
1.5529
1.5413
(1.5227)
—
—
—
—
R(18, 23)
1.0985
1.0952
(0.99)
—
—
—
—
R(18, 24)
1.0955
1.0915
(0.99)
—
—
—
—
R(19, 20)
1.5537
1.5438
(1.5333)
—
—
—
—
R(19, 25)
1.0955
1.0915
(0.99)
—
—
—
—
R(19, 26)
1.0983
1.0946
(0.99)
—
—
—
—
R(20, 27)
1.1020
1.0983
(0.99)
—
—
—
—
R(20, 28)
1.1001
1.0955
(0.99)
Bond angles
Parameters
LANL2DZ
6-311 G (d, p)
Wilson GF
Parameters
LANL2DZ
6-311 G (d, p)
Exp.
A(2, 1, 6)
123.156
124.085
(128.1)
A(2, 1, 6)
123.207
123.7612
(124.11)
A(2, 1, 7)
120.854
119.882
(115.9)
A(2, 1, 7)
120.864
120.2359
(117.9)
A(6, 1, 7)
115.989
116.031
(115.9)
A(6, 1, 7)
115.927
116.0026
(117.9)
A(1, 2, 3)
119.423
118.609
(113.4)
A(1, 2, 3)
119.086
118.8914
(118.76)
A(1, 2, 8)
121.333
121.238
(123.3)
A(1, 2, 8)
121.357
121.5728
(120.6)
A(3, 2, 8)
119.243
120.148
(123.3)
A(3, 2, 8)
119.553
119.5347
(120.6)
A(2, 3, 4)
117.688
117.644
(120.0)
A(2, 3, 4)
118.003
117.7332
(118.04)
A(2, 3, 11)
115.580
116.359
(119.9)
A(2, 3, 11)
117.887
117.7499
(119.94)
A(4, 3, 11)
126.731
125.851
(119.9)
A(4, 3, 1)
124.079
124.4757
(121.87)
A(3, 4, 5)
118.793
116.359
(120.0)
A(3, 4, 5)
118.940
118.7973
(118.51)
A(3, 4, 9)
120.388
119.095
(119.90)
A(3, 4, 9)
122.012
121.7783
(120.7)
A(5, 4, 9)
120.818
119.585
(119.9)
A(5, 4, 9)
119.000
119.3816
(120.7)
A(4, 5, 6)
123.709
121.315
(123.5)
A(4, 5, 6)
123.267
123.7549
(124.23)
A(4, 5, 10)
120.395
120.222
(118.2)
A(4, 5, 1)
120.733
120.095
(117.9)
A(6, 5, 10)
115.895
116.119
(118.2)
A(6, 5, 1)
115.997
116.1492
(117.9)
A(1, 6, 5)
117.229
116.890
(115.9)
A(1, 6, 5)
117.480
117.0429
(116.34)
A(3, 11, 12)
120.109
120.608
(123.5)
A(3, 11, 12)
121.407
121.7922
(121.01)
A(3, 11, 13)
123.160
120.465
(113.2)
A(3, 11, 13)
114.386
113.8995
(115.24)
A(12, 11, 13)
116.730
116.119
(123.10)
A(12, 11, 13)
124.194
124.3057
(123.71)
A(11, 13, 16)
112.897
110.815
(118.3)
A(11, 13, 14)
120.222
120.4885
(117.90)
A(11, 13, 17)
127.415
123.657
(120.9)
A(11, 13, 15)
119.204
118.6787
(120.9)
A(16, 13, 17)
119.687
120.608
(120.9)
A(14, 13, 15)
120.413
120.0841
(121.2)
A(13, 17, 14)
113.970
112.315
(—)
A(13, 14, 16)
117.618
117.4204
(116.39)
A(13, 17, 15)
113.972
109.553
(—)
A(14, 16, 17)
120.864
121.3315
(120.59)
A(14, 17, 15)
115.002
109.146
(—)
A(14, 16, 20)
129.064
128.9664
(129.82)
—
—
—
—
A(17, 16, 20)
110.061
109.6831
(109.59)
—
—
—
—
A(16, 17, 18)
103.828
103.7083
(103.49)
—
—
—
—
A(16, 17, 21)
109.558
109.1963
(111.1)
—
—
—
—
A(16, 17, 22)
111.559
111.673
(111.1)
—
—
—
—
A(18, 17, 21)
110.424
110.1309
(111.1)
—
—
—
—
A(18, 17, 22)
114.254
114.7737
(111.1)
—
—
—
—
A(21, 17, 22)
107.188
107.2821
(109)
—
—
—
—
A(17, 18, 19)
103.849
103.6438
(103.09)
—
—
—
—
A(17, 18, 23)
110.096
109.8783
(111.1)
—
—
—
—
A(17, 18, 24)
112.690
113.1144
(111.1)
—
—
—
—
A(19, 18, 23)
110.044
109.8696
(111.1)
—
—
—
—
A(19, 18, 24)
112.485
112.7897
(111.1)
—
—
—
—
A(23, 18, 24)
107.663
107.5175
(109.1)
—
—
—
—
A(18, 19, 20)
104.367
104.3214
(103.63)
—
—
—
—
A(18, 19, 25)
112.900
113.1836
(111)
—
—
—
—
A(18, 19, 26)
109.818
109.665
(111)
—
—
—
—
A(20, 19, 25)
112.372
112.7006
(111)
—
—
—
—
A(20, 19, 26)
109.763
109.5735
(111)
—
—
—
—
A(25, 19, 26)
107.597
107.3627
(109)
—
—
—
—
A(16, 20, 19)
104.150
104.3483
(103.78)
—
—
—
—
A(16, 20, 27)
109.9266
109.6136
(111)
—
—
—
—
A(16, 20, 28)
112.6795
112.4489
(111)
—
—
—
—
A(19, 20, 27)
110.6596
110.8512
(111)
—
—
—
—
A(19, 20, 28)
112.2491
112.6471
(111)
—
—
—
—
A(27, 20, 28)
107.209
106.9667
(109)


### 3.2. Vibrational Assignments

The molecules isoniazid and its derivative (CPPC) contain 17 and 28 atoms and they have 45 and 78 normal modes of vibration, respectively. All the fundamental vibrations are active IR. The harmonic vibrational frequencies are calculated for both the molecules at B3LYP/LANL2DZ and 6-311 G (d, p) level and experimental frequencies (FTIR) have been compared in Tables2 and 3 for isoniazid and its derivative (CPPC), respectively. Tables 2 and 3 also include the vibrational assignments of the normal modes. Vibrational assignments are based on the observation of the animated modes in GaussView and assignments reported in the literature.Table 2
Comparison of the observed and calculated vibrational spectra of isoniazid with (B3LYP)/6-311 G (d, p) and B3LYP/LANL2DZ.
B3LYP
FTIR (exp.)
FT Raman (exp.)
Vibrational assignments
LANL2DZ
IR (Int.)
6-311 G (d, p)
IR (Int.)
27
4.4893
39
2.1136
—
—
Whole molecule twists from joint
136
0.1522
121
3.0144
—
—
Twist NH2
163
0.0223
134
2.9603
—
—
Rock NH2
200
2.6928
198
2.2873
—
—
Whole molecule bends from joint
281
9.3909
261
15.6415
—
—
β(C–N–N)
343
64.239
306
54.4552
—
—
Twist NH2
380
4.8231
370
2.1727
—
—
τ(C–C–C=O)
385
3.0767
377
0.0835
—
—
γ(C–C–C) + γ(C–C–H)
457
3.736
452
5.6374
504
504
γ(C–C–C) + γ(C–C–H)
528
2.5885
544
17.1188
—
—
Rock NH2 +β(C–C=O)
578
142.03
588
52.8091
—
—
Rock NH2
658
23.445
636
26.3687
660
666
τ(C–C–C–C) + τ(C–N–C–C)
659
28.530
659
0.79
Twist NH2
668
162.33
702
45.9836
674
682
Rock NH2
701
110.45
720
3.2826
—
—
γ(C–N–H)
710
0.1352
745
774.0493
—
—
β(C–N–C) + β(C–C–C)
758
29.601
836
13.6245
745
750
γ(C–C–C) + γ(C–C–H)
854
37.843
865
0.5422
845
849
γ(C–C–H)
904
0.0237
874
143.4664
—
—
γ(C–C–H)
953
4.925
956
0.4745
—
—
Ring breathing
998
2.1689
970
3.0528
—
—
γ(C–C–H)
1005
2.381
977
3.1906
1020
1002
γ(C–C–H)
1046
9.4117
1052
17.7683
β(C–C–H) + β(C–C=O)
1049
20.656
1060
5.0938
1061
1057
β(C–N–C) + β(C–C–C)
1072
1.5593
1071
3.1435
—
—
β(C–C–H)
1170
69.756
1154
50.7026
—
—
β(C–C–C) + β(C–C–H)
1200
1.2477
1198
1.8033
1200
1187
β(C–C–H)
1223
0.006
1227
3.1093
—
—
Twist NH2
1249
5.3368
1268
3.7348
—
—
ν(C–N) + ν(C–C)
1305
3.9465
1301
3.2532
—
—
β(C–C–H)
1353
177.39
1334
194.7891
1334
1331
β(O=C–N) + β(C–C–H)
1383
56.249
1386
31.6275
—
—
β(C–C–H)
1416
48.473
1427
19.6455
1412
1410
β(C–N–H)
1448
2.1058
1465
1.3185
—
—
β(C–C–H)
1517
56.958
1535
28.9279
1472
—
ν(C–C)
1560
11.455
1574
9.7845
—
—
ν(C–C)
1577
87.192
1634
30.7552
1556
1551
ν(C=O)
1642
55.629
1684
235.7803
1635
1642
S(NH2)
3079
32.086
3030
34.8746
3050
3065
ν(C–H)
3085
9.0201
3035
14.6458
—
—
ν(C–H)
3121
4.9876
3089
2.9337
—
—
ν(C–H)
3153
8.4279
3119
3.3617
—
—
ν(C–H)
3381
1.8185
3341
1.8712
—
—
ν(N–H)
3389
17.234
3387
16.6022
3303
3300
ν(N–H)
3509
9.0098
3426
4.449
—
—
ν(N–H)
ν: stretching; β: in plane bending; γ: out of plane bending; S: scissoring; w: wagging; τ: torsion.Table 3
Comparison of calculated vibrational spectra of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) with (B3LYP)/6-311 G (d, p) and B3LYP/LANL2DZ.
B3LYP
Vibrational assignments
LANL2DZ
IR (Int.)
6-311 G (d, p)
IR (Int.)
29
0.189
29
0.0368
Whole molecule twists from middle
44
0.0329
43
0.0041
Whole molecule twists from middle
55
1.0643
56
0.5335
Ring B bends from middle
65
2.6343
64
1.7946
Twisting in ring B
115
1.2256
113
0.2943
Twisting in ring B
155
9.5443
152
8.6203
Both rings twist from middle
189
11.479
187
10.7292
Bending in whole molecule
221
0.5418
226
0.7907
γ(C–C–C) ring B
239
1.4716
243
1.22
τ(C–C–N–N)
284
4.2682
285
4.0485
τ(N–N–C=O)
324
4.6942
325
0.6016
Twist CH2 ring B
376
0.124
374
0.0949
Out of plane bending in ring A as a whole
395
2.2666
382
7.9387
τ(C–C–C=O)
453
8.0728
443
26.6387
ω(N–H)
466
11.181
464
11.8231
Out of plane bending in whole molecule
542
4.2055
492
20.6542
Whole molecule bends from middle
554
52.148
546
8.846
Twist CH2 ring B
573
25.912
559
0.4785
Twist CH2 ring B
588
7.2812
593
9.2922
β(C–C=N)
654
1.136
657
0.8099
Ring A deformation
660
43.182
663
50.3605
Ring A breathing
690
28.825
696
16.6761
γ(C–C–C) ring A
739
0.3987
736
0.1654
Twist in ring B
750
13.234
746
10.518
γ(C–C–C) ring A
811
0.675
806
0.01
γ(CH2) ring B
835
12.940
825
13.797
γ(C–C–C)rRing B
837
25.375
830
1.1714
γ(C–C–C) ring A
873
2.6331
866
2.3196
γ(C–C–C) ring B
885
25.947
867
0.4876
β(N–C=O) joint to both rings
887
3.846
889
4.1429
γ(C–C–H) ring A
906
5.1907
907
22.5923
Twist CH2 ring B
947
5.0577
933
2.7875
γ(C–C–H) ring B
951
5.9695
951
0.2745
Ring A breathing
966
2.0181
973
4.7925
γ(C–C–C) ring A
986
18.651
974
0.9688
γ(C–C–C) ring A
990
12.259
985
0.3854
γ(C–C–C) ring A
1002
2.3552
995
0.0806
Twist CH2 ring B
1027
5.8621
1021
12.9074
γ(C–C–C) ring B
1048
14.225
1050
17.0033
β(C–C–H) ring A
1072
17.410
1067
8.9467
β(C–C–H) ring A
1104
73.216
1105
114.2174
β(C–C–H) ring A
1127
0.6851
1118
0.8245
Twist CH2 ring B
1144
9.5501
1144
23.861
γ(C–C–H) ring B
1184
15.684
1174
13.5043
β(C–C=N) ring A + β(C–C–C) ring B
1196
6.0684
1188
9.5816
γ(C–C–H) ring B
1203
3.3536
1195
23.0436
β(C–C–H) ring A
1222
62.461
1209
146.2051
Twist CH2 ring B
1237
163.03
1217
51.1901
β(C–C–C) ring A + twist CH2 ring B
1249
10.424
1232
34.5492
Ring A deformation
1266
9.0924
1256
4.27
Twist CH2 ring B
1283
2.845
1279
0.3718
Rock CH2 ring B
1305
0.2089
1295
0.4946
Twist CH2 ring B
1306
0.0683
1297
1.5912
Twist CH2 ring B
1312
0.6944
1301
0.9643
β(C–C–H) ring A
1381
13.894
1385
14.4629
β(C–C–H) ring A
1436
34.372
1416
17.0927
S(CH2) ring B
1441
13.808
1420
7.2964
S(CH2) ring B
1447
11.264
1442
5.421
β(C–C–H) ring A
1461
9.7004
1456
3.4055
S(CH2) ring B
1469
1.2504
1463
17.0394
S(CH2) ring B
1487
313.60
1489
318.044
β(C–N–H)
1529
37.617
1538
23.3689
Ring A deformation
1563
7.4055
1573
17.1708
ν(C–C) ring A
1604
227.40
1654
22.9328
ν(C=O)
1623
2.596
1715
302.3136
ν(C=N) joint ring B
2902
18.706
2890
12.407
ν(C–H) ring B
2925
15.584
2900
12.3498
ν(C–H) ring B
2938
21.950
2917
25.4822
ν(C–H) ring B
2939
41.648
2923
12.8395
ν(C–H) ring B
2954
38.945
2934
41.6752
ν(C–H) ring B
3001
42.309
2975
40.8297
ν(C–H) ring B
3009
30.010
2981
39.1011
ν(C–H) ring B
3017
50.383
2990
14.2807
ν(C–H) ring B
3072
8.0634
3031
21.1113
ν(C–H) ring A
3086
26.263
3038
23.6222
ν(C–H) ring A
3095
16.702
3061
12.3221
ν(C–H) ring A
3118
4.5408
3088
3.1852
ν(C–H) ring A
3416
17.207
3412
13.2313
ν(N–H)
ν: stretching; β: in plane bending; γ: out of plane bending; S: scissoring;
ω: wagging; τ: torsion.In isoniazid, the N–H functional group is present at 3389 cm−1 in calculated spectra which is in good agreement with the experimental data. The C–H functional group is present at a number of positions. The stretching vibration, ν(C–H), is expected to occur in the region 2800–3200 cm−1. The ν(C–H) functional group is present at 3079 cm−1 in calculated spectra which is in good agreement with the experimental data, that is, 3050 cm−1. The calculated values of the ν(C–H) vibration lie within this spectral range. The calculated (scaled) and experimental frequencies are deviated by a large amount, which may be explained by the presence of hydrogen bonding in the solid sample. The theoretical calculations have been done on gas-phase molecule.The –NH2 functional group is important constituents of isoniazid and vibrations corresponding to these groups are present in a number of modes. The stretching modes corresponding to these groups are of two types: symmetric and asymmetric stretching. In the symmetric stretching vibration, both the arms of the functional group are stretching in-phase with each other, whereas, in the asymmetric stretching mode, the atomic hydrogen motions are out-of-phase. The twisting and rocking vibrations for both the functional groups are present mixed with other vibrations in middle region. As expected, the ring torsion modes along with wagging modes appear in the low frequency range. An intense band due to torsion of C–C–C–C is at 658 cm−1 in calculated spectrum which matches well with the experimental one, that is, 560 cm−1. There are some frequencies in lower region having appreciable IR intensity. Furthermore, the study of low frequency vibrations is of great significance, because it gives information on weak intermolecular interactions, which take place in enzyme reactions [14]. Knowledge of low frequency mode is also essential for the interpretation of the effect of electromagnetic radiation on biological systems [15].In CPPC, the N–H functional group is present at 3416 cm−1 in calculated spectra having appreciable IR intensity. The C–H functional group is present at a number of positions. The ν(C–H) functional group is present at 2939, 2954, and 3001 cm−1 in calculated spectra having substantial IR intensity. The region 1600–2000 cm−1 is generally considered as the double bond stretching region for C=O, C=C, and C=N bonds [16–19]. The C=O stretching vibration, ν(C=O), appears as a prominent mode in the calculated spectra at 1604 cm−1.The –CH2 functional groups are important constituents of CPPC and vibrations corresponding to these groups are present in a number of modes. Due to twist –CH2 mode an intense peak is present at 554 cm−1 in calculated spectra as a prominent mode. The twisting and rocking vibrations for the functional group are present mixed with other vibrations in middle region. Here, we are discussing only most IR active modes present in calculated spectra for both the molecules. The aim of this section is to obtain direct information on lower and higher frequency vibrations of such biologically active molecules. No experimental FTIR spectrum is available for comparison so it will be a suitable path for experimental researchers.


### 3.3. Electronic Spectra and Electronic Properties

On the basis of fully optimized ground-state structure, TDDFT//B3LYP/LANL2DZ calculations have been used to determine the low-lying excited states of isoniazid and CPPC. The calculated results involving the vertical excitation energies, oscillator strength(
f
), and wavelength are carried out using the Gaussian 09W program. Experimental wavelengths are not available so these calculated data can help the experimental researchers. Electronic transitions determined from excited state calculations are listed in Table 4 for the three lowest energy transitions of the molecule. For isoniazid, TD-DFT calculation predicts three intense electronic transitions at 5.7714 eV (214.82 nm), 6.8565 eV (180.83 nm), and 6.7948 eV (159.44 nm) with oscillator strengths of 0.1780, 0.5155, and 0.2444, respectively. For CPPC and TD-DFT calculation predicts three intense electronic transitions at 5.7716 eV (214.82 nm), 6.6955 eV (185.18 nm), and 7.0662 eV (175.46 nm) with oscillator strengths of 0.3239, 0.2676, and 0.1706, respectively. The calculated UV spectrum of isoniazid and its derivative CPPC are shown in Figures 3 and 4.Table 4
Calculated parameters for isoniazid and CPPC using TDDFT//B3LYP/LANL2DZ.
Excitation
CI coefficient
Expansion wave length (nm)
Oscillator strength
Energy (eV)
calculated
Isoniazid
Excited state 1
31
→
37
0.63973
214.82
0.1780
5.7714
34
→
38
0.27134
Excited state 2
34
→
38
0.50322
180.83
0.5155
6.8565
31
→
38
−0.13282
Excited state 3
34
→
39
0.53619
159.44
0.2444
7.7762
29
→
38
−0.11809
CPPC
Excited state 1
49
→
55
0.45328
214.82
0.3239
5.7716
53
→
57
0.10859
52
→
57
0.10042
Excited state 2
47
→
55
0.26652
185.18
0.2676
6.6955
50
→
56
0.50556
53
→
58
0.22945
Excited state 3
49
→
56
0.45774
175.46
0.1706
7.0662
50
→
57
0.41085Figure 3
Calculated UV spectrum of CPPC.Figure 4
Calculated UV spectrum of isoniazid.The frontier orbitals, HOMO and LUMO, determine the way the molecule interacts with other species. The frontier orbital gap helps to characterize the chemical reactivity and kinetic stability of the molecule. A molecule which has a larger orbital gap is more polarized having more reactive part as far as reaction is concerned [20]. According to the present calculations, the frontier orbital gap in case of the given molecules is 4.9531 and 4.7835 eV, respectively, for isoniazid and CPPC given in Table 5. So we can say that CPPC is more reactive than isoniazid. The plots of the HOMO, LUMO, and electrostatic potential for both the molecules are shown in Figures 5–10. For isoniazid, HOMO (Figure 5) is located over the whole molecule. LUMO is located (Figure 6) at the same place as HOMO excluding hydrogen atoms. For CPPC, HOMO (Figure 7) is located nearby and on ring B. LUMO is located (Figure 8) nearby and on ring A. The importance of MESP lies in the fact that it simultaneously displays molecular size, shape, and positive, negative, and neutral electrostatic potential regions in terms of colour grading (shown in Figures 9 and 10) and is very useful in investigation of molecular structure with its physiochemical property relationship [21–25]. We have also plotted 3D MESP structures of the title compound as shown in Figures 11 and 12. For isoniazid and CPPC, the electronegative region is outside of the molecule near the oxygen atoms. The energy equal to the shielded potential energy surface is required for any substitution reaction near oxygen. The electronegative lines (in between −0.08 a.u. and −0.02 a.u.) form a closed contour which clearly indicates that total flux passing in between these curves are not equal to zero. For any nucleophilic substitution reaction near oxygen (closed contour area), an amount of energy equal to shielded potential energy surface is required; however, the remaining part of the molecule is suitable for electrophilic substitution reaction. Thus, it can be asserted that MESP values have been shown to be well related to biological properties. [26–28].Table 5
Lowest energy, HOMO-LUMO gap (frontier orbital energy gap) and dipole moment of isoniazid and N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) by (B3LYP)/6-311 G (d, p) and (B3LYP)/LANL2DZ methods.
Parameters
Isoniazid
N-Cyclopentylidenepyridine-4-carbohydrazide
LANL2DZ
6-311 G (d, p)
LANL2DZ
6-311 G (d, p)
Energy (in au)
−472.2226
−472.4245
−666.3336
−666.6202
Dipole moment (in Debye)
5.49
4.94
6.25
5.37
HOMO
−6.8353
−6.8852
−6.7673
−6.7821
LUMO
−1.8800
−1.9129
−1.9815
−1.9875
Frontier orbital energy gap (eV)
4.9552
4.9723
4.7857
4.7946Figure 5
HOMO picture of isoniazid.Figure 6
LUMO picture of isoniazid.Figure 7
HOMO picture of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).Figure 8
LUMO picture of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).Figure 9
MESP picture of isoniazid.Figure 10
MESP picture of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).Figure 11
Contour plot of isoniazid.Figure 12
Contour plot of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).


### 3.4. Reactivity Descriptors

#### 3.4.1. Global Reactivity Descriptors

The energies of frontier molecular orbitals (εHOMO, εLUMO), energy band gap (εLUMO − εHOMO), electronegativity (
χ
=
-
(
1
/
2
)
(
LUMO
ε
+
HOMO
ε
)
), chemical potential (
μ
=
-
χ
), global hardness (
η
=
(
1
/
2
)
(
LUMO
ε
-
HOMO
ε
)
), global softness (
S
=
1
/
2
η
), and global electrophilicity index (
ω
=
μ
2
/
2
η
) [29–32] of isoniazid and CPPC have been listed in Table 6. It is found that the gap between HOMO and LUMO is smaller in CPPC than isoniazid.Table 6
Calculatedε
HOMO, ε
LUMO, energy band gap (ε
L
-
ε
H), chemical potential (μ), electronegativity (χ), global hardness (η), global softness (S), and global electrophilicity index (ω) for isoniazid and CPPC at B3LYP/LANL2DZ level.
Molecules
ε
H
ε
L
ε
L
-
ε
H
χ
μ
η
S
ω
CPPC 2
−6.7673
−1.9815
4.7857
4.3744
−4.3744
2.3929
0.2090
3.9984
ISO 2
−6.8353
−1.8800
4.9552
4.3577
−4.3577
2.4776
0.2018
3.8322


#### 3.4.2. Local Reactivity Descriptors

Fukui function (FF) of a molecule provides information of the local site reactivity within the molecule and as such it provides a method for understanding and categorizing chemical reactions. These values represent the qualitative descriptors of reactivity of different atoms in the molecule. Ayers and Parr [33] have elucidated that molecules tend to react where the FF is the largest when attacked by soft reagents and in places where the FF is smaller when attacked by hard reagents. The use of Fukui functions for the site selectivity of isoniazid and CPPC molecules for nucleophilic and electrophilic attacks has been made with special emphasis on the dependence of Fukui values on the basis of B3LYP/6-311G(d,p) level of theory. Using Mulliken atomic charges of cationic and anionic states of isoniazid and CPPC, local Fukui functions (
f
k
+
,
f
k
-
), local softness (
s
k
+
,
s
k
-
), and local electrophilicity indices (
ω
k
+
,
ω
k
-
) [30, 31] have been calculated using the following equation:
(1)
f
k
+
=
[
q
(
N
+
1
)
-
q
(
N
)
]
for
nucleophilic
attack
,
f
k
-
=
[
q
(
N
)
-
q
(
N
-
1
)
]
for
electrophilic
attack
,
f
k
0
=
1
2
[
q
(
N
+
1
)
+
q
(
N
-
1
)
]
for
radical
attack
.
Local softness and electrophilicity indices are calculated using the following equation:
(2)
s
k
+
=
S
f
k
+
,
s
k
-
=
S
f
k
-
,
ω
k
+
=
ω
f
k
+
,
ω
k
-
=
ω
f
k
-
,
where + and − signs show nucleophilic and electrophilic attacks, respectively.Fukui functions, local softness, and local electrophilicity indices for selected atomic sites in isoniazid and CPPC have been listed in Tables7 and 8. For CPPC, the maximum values for local nucleophilic reactivity descriptors (
f
k
-, s
k
-, ω
k
-
) at N13 and N14 indicate that these two sites are more prone to electrophilic attack. But on comparison with N17 of isoniazid it is found that the N14 of CPPC has lower affinity towards electrophile. This situation changes because the nitrogen of CPPC is bonded through a double bond to the C16 of a pentagonal ring; hence, the charge density around N14 decreases.Table 7
Fukui functions (f
k
+, f
k
-), local softness (s
k
+, s
k
-), and local electrophilicity indices (ω
k
+, ω
k
-) for selected atomic sites of CPPC, using Mulliken population analysis at B3LYP/LANL2DZ level.
CPPC
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
N6
0.063725
0.047259
0.013319
0.009877
0.254798
0.18896
C11
0.088784
0.050459
0.018556
0.010546
0.354994
0.201755
N13
0.016223
0.049147
0.003391
0.010272
0.064866
0.196509
N14
0.023381
0.043409
0.004887
0.009072
0.093487
0.173567
H15
0.018967
0.032456
0.003964
0.006783
0.075838
0.129772
CPPC (full)
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
C1
0.037085
0.053511
0.007751
0.011184
0.148281
0.213958
C2
0.079194
0.038498
0.016552
0.008046
0.316649
0.15393
C3
0.037105
0.018265
0.007755
0.003817
0.148361
0.073031
C4
0.056432
0.033863
0.011794
0.007077
0.225638
0.135398
C5
0.046093
0.054106
0.009633
0.011308
0.184298
0.216337
N6
0.063725
0.047259
0.013319
0.009877
0.254798
0.18896
H7
0.05017
0.048264
0.010486
0.010087
0.2006
0.192979
H8
0.024605
0.022564
0.005142
0.004716
0.098381
0.09022
H9
0.025706
0.012418
0.005373
0.002595
0.102783
0.049652
H10
0.048308
0.046734
0.010096
0.009767
0.193155
0.186861
C11
0.088784
0.050459
0.018556
0.010546
0.354994
0.201755
O12
0.10292
0.103102
0.02151
0.021548
0.411515
0.412243
N13
0.016223
0.049147
0.003391
0.010272
0.064866
0.196509
N14
0.023381
0.043409
0.004887
0.009072
0.093487
0.173567
H15
0.018967
0.032456
0.003964
0.006783
0.075838
0.129772
C16
0.07141
0.083266
0.014925
0.017403
0.285526
0.332931
C17
-
0.01717
-
0.0153
-
0.00359
-
0.0032
-
0.06865
-
0.06118
C18
0.000227
-
0.00052
4.74
E
-
05
-
0.00011
0.000908
-
0.00206
C19
0.000575
0.001021
0.00012
0.000213
0.002299
0.004082
C20
-
0.02038
-
0.0215
-
0.00426
-
0.00449
-
0.08147
-
0.08597
H21
0.03456
0.04074
0.007223
0.008515
0.138185
0.162895
H22
0.039332
0.053361
0.00822
0.011152
0.157265
0.213359
H23
0.02873
0.033782
0.006005
0.00706
0.114874
0.135074
H24
0.028555
0.033136
0.005968
0.006925
0.114174
0.132491
H25
0.029499
0.033406
0.006165
0.006982
0.117949
0.133571
H26
0.025818
0.029323
0.005396
0.006129
0.103231
0.117245
H27
0.034231
0.046674
0.007154
0.009755
0.136869
0.186621
H28
0.025909
0.028557
0.005415
0.005968
0.103595
0.114182Table 8
Fukui functions (f
k
+, f
k
-), local softness (s
k
+, s
k
-), and local electrophilicity indices (ω
k
+, ω
k
-) for selected atomic sites of isoniazid, using Mulliken population analysis at B3LYP/LANL2DZ level.
ISO
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
N6
0.087184
0.075685
0.017594
0.015273
0.334107
0.29004
C11
0.045066
0.105331
0.009094
0.021256
0.172702
0.403649
O12
0.125455
0.097778
0.025317
0.019732
0.480769
0.374705
N13
0.104399
−0.09059
0.021068
−0.01828
0.400078
−0.34714
H14
0.07228
0.027223
0.014586
0.005494
0.276991
0.104324
H15
0.045876
0.053631
0.009258
0.010823
0.175806
0.205525
H16
0.066534
0.058946
0.013427
0.011895
0.254972
0.225893
N17
−0.07824
0.12441
−0.01579
0.025106
−0.29982
0.476764
ISO (full)
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
C1
0.070332
0.074531
0.014193
0.01504
0.269526
0.285618
C2
0.086439
0.065308
0.017443
0.013179
0.331252
0.250273
C3
0.098962
−0.00059
0.019971
−0.00012
0.379242
−0.00226
C4
0.068608
0.080752
0.013845
0.016296
0.26292
0.309458
C5
0.061734
0.096349
0.012458
0.019443
0.236577
0.369229
N6
0.087184
0.075685
0.017594
0.015273
0.334107
0.29004
H7
0.068036
0.06207
0.01373
0.012526
0.260728
0.237865
H8
0.03037
0.040116
0.006129
0.008095
0.116384
0.153733
H9
−0.02115
0.070626
−0.00427
0.014252
−0.08104
0.270653
H10
0.068106
0.05842
0.013744
0.011789
0.260996
0.223877
C11
0.045066
0.105331
0.009094
0.021256
0.172702
0.403649
O12
0.125455
0.097778
0.025317
0.019732
0.480769
0.374705
N13
0.104399
−0.09059
0.021068
−0.01828
0.400078
−0.34714
H14
0.07228
0.027223
0.014586
0.005494
0.276991
0.104324
H15
0.045876
0.053631
0.009258
0.010823
0.175806
0.205525
H16
0.066534
0.058946
0.013427
0.011895
0.254972
0.225893
N17
−0.07824
0.12441
−0.01579
0.025106
−0.29982
0.476764


### 3.5. Dipole Moment, Polarizability, Hyper Polarizability, and Thermodynamic Properties

Dipole moment(
μ
), polarizability 〈
α
〉, and total first static hyper polarizability β [31, 32] are also calculated in Tables 5 and 9 by using density functional theory. They can be expressed in terms of x, y, z components and are given by the following equation:
(3)
μ
=
(
μ
x
2
+
μ
y
2
+
μ
z
2
)
1
/
2
,
〈
α
〉
=
1
3
[
α
x
x
+
α
y
y
+
α
z
z
]
,
β
Total
=
(
β
x
2
+
β
y
2
+
β
z
2
)
1
/
2
=
[
(
β
x
x
x
+
β
x
y
y
+
β
x
z
z
)
2
+
(
β
y
y
y
+
β
y
x
x
+
β
y
z
z
)
2
+
(
β
z
z
z
+
β
z
x
x
+
β
z
y
y
)
(
β
x
x
x
+
β
x
y
y
+
β
x
z
z
)
2
2
+
(
β
z
z
z
+
β
z
x
x
+
β
z
y
y
)
(
β
x
x
x
+
β
x
y
y
+
β
x
z
z
)
2
2
]
1
/
2
.
The β components of Gaussian output are reported in atomic units, where 1 a.u. = 8.3693 × 10−33 e.s.u. For isoniazid and CPPC, the calculated dipole moment values are 5.49 and 6.25 Debye. Having higher dipole moment than water (2.16 Debye), isoniazid and CPPC both can be used as better solvents. For isoniazid, we see a greater contribution of α
z
z in molecule which shows that molecule is elongated more towards Z direction and more contracted to X direction. Perpendicular part contributes less part of polarizability of molecule. Β
x
x
x, β
y
y
y contribute a larger part in hyper polarizability. This shows that molecule is more optical active in X-axis and Y-axis directions. For CPPC, we see a greater contribution of α
y
y in molecule which shows that molecule is elongated more towards Y direction and more contracted to X direction. Perpendicular part contributes less part of polarizability of molecule.Table 9
Polarizability and hyper polarizability of isoniazid and N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) by (B3LYP)/LANL2DZ methods.
Isoniazid
N-Cyclopentylidenepyridine-4-carbohydrazide
LANL2DZ
6-311 G (d, p)
LANL2DZ
6-311 G (d, p)
Polarizability
α
x
x
−54.4243
−53.1504
−87.0159
−86.5468
α
x
y
−13.9175
−11.3119
8.2530
6.5995
α
y
y
−57.0302
−56.9567
−96.2129
−95.0135
α
y
z
0.0007
2.9339
4.6341
4.0900
α
z
z
−58.4664
−57.4167
−88.0328
−87.9161
α
z
x
0.0006
2.8602
1.0289
0.8897
α
56.6403
55.8412
90.4205
89.8254
Hyper polarizability
β
x
x
x
104.6160
92.6426
−133.3584
−99.8131
β
x
x
y
−9.7260
−11.3252
50.4571
40.4792
β
x
y
y
−5.2048
−2.4771
−9.9876
−5.2677
β
y
y
y
−28.2262
−20.4938
−30.0106
−21.2944
β
z
z
z
0.0026
4.0365
−0.0107
−0.6537
β
x
x
z
0.0029
8.9620
6.7905
5.7162
β
x
z
z
13.6068
11.5672
−9.3808
−4.2219
β
y
z
z
−3.0727
−2.3332
1.3678
2.3214
β
y
y
z
−0.0001
2.6541
1.3952
0.9832
β
x
y
z
−0.0020
−3.8704
12.4376
10.8998
β total
120.2335
115.5787
154.1308
111.5623Β
x
x
x, β
x
x
y contribute a larger part in hyper polarizability. This shows that molecule is more optical active in X-axis and X
Y-plane directions. The connection between the electric dipole moments of an organic molecule having donor-acceptor substituent and first order hyper polarizability is widely recognized in the literature. Standard thermodynamic functions such as free energy, constant volume heat capacity C
V, and entropy S have also been calculated for both the molecules and are given in Table 10. These functions can provide helpful information for further study of the title compounds.Table 10
Calculated thermodynamic properties of isoniazid and N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) by (B3LYP)/LANL2DZ and 6-311 G (d, p) methods.
E (thermal) (k cal mol−1)
CV (cal K−1 mol−1)
S (cal K−1 mol−1)
Iso
CPPC
Iso
CPPC
Iso
CPPC
Total
89.150
152.971
32.161
49.600
92.375
116.973
(88.749)
(151.836)
(32.206)
(50.109)
(92.452)
(117.377)
Translational
0.889
0.889
2.981
2.981
40.658
41.830
(0.889)
(0.889)
(2.981)
(2.981)
(40.658)
(41.830)
Rotational
0.889
0.889
2.981
2.981
29.577
32.607
(0.889)
(0.889)
(2.981)
(2.981)
(29.490)
(32.545)
Vibrational
87.373
151.194
26.199
43.638
22.141
42.537
(86.972)
(150.059)
(26.244)
(44.147)
(22.304)
(43.002)


## 3.1. Molecular Structure

In the case of isoniazid, the molecule has only one pyridine ring. The optimized bond length of C–C in six membered pyridine ring ranges between 1.403 Å and 1.414 Å. The optimized bond length of C–C outside the ring is 1.509 Å. The optimized bond lengths of C–N in ring range between 1.356 Å and 1.359 Å. The optimized bond length of C–N outside the ring is found to be 1.390 Å. The optimized C–H bond lengths attached to the ring are found to be 1.080 Å −1.087 Å. The optimized C=O bond length adjacent to ring is found to be 1.262 Å. The optimized N–H bond lengths adjacent to ring are found to be 1.016 Å–1.020 Å.When a five-membered carbon ring is also attached to isoniazid, it becomes N-cyclopentylidenepyridine-4-carbohydrazide. For N-cyclopentylidenepyridine-4-carbohydrazide, it has one six-membered pyridine ring (A) and one five-membered carbon ring. The optimized bond length of C–C in six-membered pyridine ring A ranges between 1.405 Å and 1.411 Å, while for another ring B it ranges between 1.521 Å and 1.553 Å. The optimized bond lengths of C–N in pyridine ring A range between 1.356 Å and 1.359 Å. The optimized bond length of C–N in between both rings is found to be 1.392 Å. The optimized C–H bond lengths attached to the ring A are found to be 1.084 Å–1.086 Å while for ring B it ranges between 1.094 Å and 1.101 Å. The optimized C=O bond length in between both rings is found to be 1.249 Å. The optimized N–H bond length in between the rings is found to be 1.017 Å. All the optimized bond lengths are in good agreement with the experimental values given in the literature and summarized in Table1 [7]. This difference in the bond lengths is attributed to the difference in bond strength. The length of a chemical bond is the result of equilibrium of attractive and repulsive forces between the atoms which are bonded. In fact, the distance between the atoms of a bond is not constant since the atoms are always vibrating in molecules; the measured bond distance is, therefore, an average value. Although the measurements may vary in accuracy, still similar bonds have fairly constant lengths in different molecules, variation generally being much less.Table 1
Optimized geometrical parameters of isoniazid and N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) by (B3LYP)/ 6-311 G (d, p) and (B3LYP)/LANL2DZ methods.
Isoniazid
N-Cyclopentylidenepyridine-4-carbohydrazide parameters
Bond lengths
Parameters
Calculated
Parameters
Calculated
Exp.
LANL2DZ
6-311 G (d, p)
Wilson GF (literature)
LANL2DZ
6-311 G (d, p)
R(1, 2)
1.4036
1.3933
(1.470)
R(1, 2)
1.4054
1.3905
(1.3801)
R(1, 6)
1.3599
1.3355
(1.358)
R(1, 6)
1.3596
1.3381
(1.3309)
R(1, 7)
1.0866
1.0866
(1.100)
R(1, 7)
1.0865
1.0862
(0.95)
R(2, 3)
1.4146
1.3965
(1.420)
R(2, 3)
1.4100
1.3954
(1.3836)
R(2, 8)
1.0845
1.0788
(1.100)
R(2, 8)
1.0850
1.0824
(0.95)
R(3, 4)
1.4124
1.3972
(1.420)
R(3, 4)
1.4119
1.397
(1.3904)
R(3, 11)
1.5098
1.5067
(1.517)
R(3, 11)
1.5114
1.5098
(1.4973)
R(4, 5)
1.4088
1.3903
(1.420)
R(4, 5)
1.4079
1.3937
(1.3768)
R(4, 9)
1.0806
1.0822
(1.100)
R(4, 9)
1.0868
1.084
(0.95)
R(5, 6)
1.3563
1.3373
(1.358)
R(5, 6)
1.3564
1.3346
(1.3360)
R(5, 10)
1.0872
1.0864
(1.100)
R(5, 10)
1.0870
1.0866
(0.95)
R(11, 12)
1.2625
1.2198
(1.208)
R(11, 12)
1.2496
1.2106
(1.2249)
R(11, 13)
1.3903
1.377
(1.369)
R(11, 13)
1.3920
1.3825
(1.3484)
R(13, 16)
1.0203
1.0161
(1.012)
R(13, 14)
1.3977
1.369
(1.3961)
R(13, 17)
1.4052
1.402
(1.352)
R(13, 15)
1.0175
1.0129
(0.889)
R(14, 17)
1.0170
1.0152
(—)
R(14, 16)
1.2980
1.275
(1.2759)
R(15, 17)
1.0170
1.0142
(—)
R(16, 17)
1.5220
1.5146
(1.5076)
—
—
—
—
R(16, 20)
1.5329
1.5238
(1.5035)
—
—
—
—
R(17, 18)
1.5495
1.5388
(1.5243)
—
—
—
—
R(17, 21)
1.1002
1.0975
(0.99)
—
—
—
—
R(17, 22)
1.0942
1.0904
(0.99)
—
—
—
—
R(18, 19)
1.5529
1.5413
(1.5227)
—
—
—
—
R(18, 23)
1.0985
1.0952
(0.99)
—
—
—
—
R(18, 24)
1.0955
1.0915
(0.99)
—
—
—
—
R(19, 20)
1.5537
1.5438
(1.5333)
—
—
—
—
R(19, 25)
1.0955
1.0915
(0.99)
—
—
—
—
R(19, 26)
1.0983
1.0946
(0.99)
—
—
—
—
R(20, 27)
1.1020
1.0983
(0.99)
—
—
—
—
R(20, 28)
1.1001
1.0955
(0.99)
Bond angles
Parameters
LANL2DZ
6-311 G (d, p)
Wilson GF
Parameters
LANL2DZ
6-311 G (d, p)
Exp.
A(2, 1, 6)
123.156
124.085
(128.1)
A(2, 1, 6)
123.207
123.7612
(124.11)
A(2, 1, 7)
120.854
119.882
(115.9)
A(2, 1, 7)
120.864
120.2359
(117.9)
A(6, 1, 7)
115.989
116.031
(115.9)
A(6, 1, 7)
115.927
116.0026
(117.9)
A(1, 2, 3)
119.423
118.609
(113.4)
A(1, 2, 3)
119.086
118.8914
(118.76)
A(1, 2, 8)
121.333
121.238
(123.3)
A(1, 2, 8)
121.357
121.5728
(120.6)
A(3, 2, 8)
119.243
120.148
(123.3)
A(3, 2, 8)
119.553
119.5347
(120.6)
A(2, 3, 4)
117.688
117.644
(120.0)
A(2, 3, 4)
118.003
117.7332
(118.04)
A(2, 3, 11)
115.580
116.359
(119.9)
A(2, 3, 11)
117.887
117.7499
(119.94)
A(4, 3, 11)
126.731
125.851
(119.9)
A(4, 3, 1)
124.079
124.4757
(121.87)
A(3, 4, 5)
118.793
116.359
(120.0)
A(3, 4, 5)
118.940
118.7973
(118.51)
A(3, 4, 9)
120.388
119.095
(119.90)
A(3, 4, 9)
122.012
121.7783
(120.7)
A(5, 4, 9)
120.818
119.585
(119.9)
A(5, 4, 9)
119.000
119.3816
(120.7)
A(4, 5, 6)
123.709
121.315
(123.5)
A(4, 5, 6)
123.267
123.7549
(124.23)
A(4, 5, 10)
120.395
120.222
(118.2)
A(4, 5, 1)
120.733
120.095
(117.9)
A(6, 5, 10)
115.895
116.119
(118.2)
A(6, 5, 1)
115.997
116.1492
(117.9)
A(1, 6, 5)
117.229
116.890
(115.9)
A(1, 6, 5)
117.480
117.0429
(116.34)
A(3, 11, 12)
120.109
120.608
(123.5)
A(3, 11, 12)
121.407
121.7922
(121.01)
A(3, 11, 13)
123.160
120.465
(113.2)
A(3, 11, 13)
114.386
113.8995
(115.24)
A(12, 11, 13)
116.730
116.119
(123.10)
A(12, 11, 13)
124.194
124.3057
(123.71)
A(11, 13, 16)
112.897
110.815
(118.3)
A(11, 13, 14)
120.222
120.4885
(117.90)
A(11, 13, 17)
127.415
123.657
(120.9)
A(11, 13, 15)
119.204
118.6787
(120.9)
A(16, 13, 17)
119.687
120.608
(120.9)
A(14, 13, 15)
120.413
120.0841
(121.2)
A(13, 17, 14)
113.970
112.315
(—)
A(13, 14, 16)
117.618
117.4204
(116.39)
A(13, 17, 15)
113.972
109.553
(—)
A(14, 16, 17)
120.864
121.3315
(120.59)
A(14, 17, 15)
115.002
109.146
(—)
A(14, 16, 20)
129.064
128.9664
(129.82)
—
—
—
—
A(17, 16, 20)
110.061
109.6831
(109.59)
—
—
—
—
A(16, 17, 18)
103.828
103.7083
(103.49)
—
—
—
—
A(16, 17, 21)
109.558
109.1963
(111.1)
—
—
—
—
A(16, 17, 22)
111.559
111.673
(111.1)
—
—
—
—
A(18, 17, 21)
110.424
110.1309
(111.1)
—
—
—
—
A(18, 17, 22)
114.254
114.7737
(111.1)
—
—
—
—
A(21, 17, 22)
107.188
107.2821
(109)
—
—
—
—
A(17, 18, 19)
103.849
103.6438
(103.09)
—
—
—
—
A(17, 18, 23)
110.096
109.8783
(111.1)
—
—
—
—
A(17, 18, 24)
112.690
113.1144
(111.1)
—
—
—
—
A(19, 18, 23)
110.044
109.8696
(111.1)
—
—
—
—
A(19, 18, 24)
112.485
112.7897
(111.1)
—
—
—
—
A(23, 18, 24)
107.663
107.5175
(109.1)
—
—
—
—
A(18, 19, 20)
104.367
104.3214
(103.63)
—
—
—
—
A(18, 19, 25)
112.900
113.1836
(111)
—
—
—
—
A(18, 19, 26)
109.818
109.665
(111)
—
—
—
—
A(20, 19, 25)
112.372
112.7006
(111)
—
—
—
—
A(20, 19, 26)
109.763
109.5735
(111)
—
—
—
—
A(25, 19, 26)
107.597
107.3627
(109)
—
—
—
—
A(16, 20, 19)
104.150
104.3483
(103.78)
—
—
—
—
A(16, 20, 27)
109.9266
109.6136
(111)
—
—
—
—
A(16, 20, 28)
112.6795
112.4489
(111)
—
—
—
—
A(19, 20, 27)
110.6596
110.8512
(111)
—
—
—
—
A(19, 20, 28)
112.2491
112.6471
(111)
—
—
—
—
A(27, 20, 28)
107.209
106.9667
(109)


## 3.2. Vibrational Assignments

The molecules isoniazid and its derivative (CPPC) contain 17 and 28 atoms and they have 45 and 78 normal modes of vibration, respectively. All the fundamental vibrations are active IR. The harmonic vibrational frequencies are calculated for both the molecules at B3LYP/LANL2DZ and 6-311 G (d, p) level and experimental frequencies (FTIR) have been compared in Tables2 and 3 for isoniazid and its derivative (CPPC), respectively. Tables 2 and 3 also include the vibrational assignments of the normal modes. Vibrational assignments are based on the observation of the animated modes in GaussView and assignments reported in the literature.Table 2
Comparison of the observed and calculated vibrational spectra of isoniazid with (B3LYP)/6-311 G (d, p) and B3LYP/LANL2DZ.
B3LYP
FTIR (exp.)
FT Raman (exp.)
Vibrational assignments
LANL2DZ
IR (Int.)
6-311 G (d, p)
IR (Int.)
27
4.4893
39
2.1136
—
—
Whole molecule twists from joint
136
0.1522
121
3.0144
—
—
Twist NH2
163
0.0223
134
2.9603
—
—
Rock NH2
200
2.6928
198
2.2873
—
—
Whole molecule bends from joint
281
9.3909
261
15.6415
—
—
β(C–N–N)
343
64.239
306
54.4552
—
—
Twist NH2
380
4.8231
370
2.1727
—
—
τ(C–C–C=O)
385
3.0767
377
0.0835
—
—
γ(C–C–C) + γ(C–C–H)
457
3.736
452
5.6374
504
504
γ(C–C–C) + γ(C–C–H)
528
2.5885
544
17.1188
—
—
Rock NH2 +β(C–C=O)
578
142.03
588
52.8091
—
—
Rock NH2
658
23.445
636
26.3687
660
666
τ(C–C–C–C) + τ(C–N–C–C)
659
28.530
659
0.79
Twist NH2
668
162.33
702
45.9836
674
682
Rock NH2
701
110.45
720
3.2826
—
—
γ(C–N–H)
710
0.1352
745
774.0493
—
—
β(C–N–C) + β(C–C–C)
758
29.601
836
13.6245
745
750
γ(C–C–C) + γ(C–C–H)
854
37.843
865
0.5422
845
849
γ(C–C–H)
904
0.0237
874
143.4664
—
—
γ(C–C–H)
953
4.925
956
0.4745
—
—
Ring breathing
998
2.1689
970
3.0528
—
—
γ(C–C–H)
1005
2.381
977
3.1906
1020
1002
γ(C–C–H)
1046
9.4117
1052
17.7683
β(C–C–H) + β(C–C=O)
1049
20.656
1060
5.0938
1061
1057
β(C–N–C) + β(C–C–C)
1072
1.5593
1071
3.1435
—
—
β(C–C–H)
1170
69.756
1154
50.7026
—
—
β(C–C–C) + β(C–C–H)
1200
1.2477
1198
1.8033
1200
1187
β(C–C–H)
1223
0.006
1227
3.1093
—
—
Twist NH2
1249
5.3368
1268
3.7348
—
—
ν(C–N) + ν(C–C)
1305
3.9465
1301
3.2532
—
—
β(C–C–H)
1353
177.39
1334
194.7891
1334
1331
β(O=C–N) + β(C–C–H)
1383
56.249
1386
31.6275
—
—
β(C–C–H)
1416
48.473
1427
19.6455
1412
1410
β(C–N–H)
1448
2.1058
1465
1.3185
—
—
β(C–C–H)
1517
56.958
1535
28.9279
1472
—
ν(C–C)
1560
11.455
1574
9.7845
—
—
ν(C–C)
1577
87.192
1634
30.7552
1556
1551
ν(C=O)
1642
55.629
1684
235.7803
1635
1642
S(NH2)
3079
32.086
3030
34.8746
3050
3065
ν(C–H)
3085
9.0201
3035
14.6458
—
—
ν(C–H)
3121
4.9876
3089
2.9337
—
—
ν(C–H)
3153
8.4279
3119
3.3617
—
—
ν(C–H)
3381
1.8185
3341
1.8712
—
—
ν(N–H)
3389
17.234
3387
16.6022
3303
3300
ν(N–H)
3509
9.0098
3426
4.449
—
—
ν(N–H)
ν: stretching; β: in plane bending; γ: out of plane bending; S: scissoring; w: wagging; τ: torsion.Table 3
Comparison of calculated vibrational spectra of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) with (B3LYP)/6-311 G (d, p) and B3LYP/LANL2DZ.
B3LYP
Vibrational assignments
LANL2DZ
IR (Int.)
6-311 G (d, p)
IR (Int.)
29
0.189
29
0.0368
Whole molecule twists from middle
44
0.0329
43
0.0041
Whole molecule twists from middle
55
1.0643
56
0.5335
Ring B bends from middle
65
2.6343
64
1.7946
Twisting in ring B
115
1.2256
113
0.2943
Twisting in ring B
155
9.5443
152
8.6203
Both rings twist from middle
189
11.479
187
10.7292
Bending in whole molecule
221
0.5418
226
0.7907
γ(C–C–C) ring B
239
1.4716
243
1.22
τ(C–C–N–N)
284
4.2682
285
4.0485
τ(N–N–C=O)
324
4.6942
325
0.6016
Twist CH2 ring B
376
0.124
374
0.0949
Out of plane bending in ring A as a whole
395
2.2666
382
7.9387
τ(C–C–C=O)
453
8.0728
443
26.6387
ω(N–H)
466
11.181
464
11.8231
Out of plane bending in whole molecule
542
4.2055
492
20.6542
Whole molecule bends from middle
554
52.148
546
8.846
Twist CH2 ring B
573
25.912
559
0.4785
Twist CH2 ring B
588
7.2812
593
9.2922
β(C–C=N)
654
1.136
657
0.8099
Ring A deformation
660
43.182
663
50.3605
Ring A breathing
690
28.825
696
16.6761
γ(C–C–C) ring A
739
0.3987
736
0.1654
Twist in ring B
750
13.234
746
10.518
γ(C–C–C) ring A
811
0.675
806
0.01
γ(CH2) ring B
835
12.940
825
13.797
γ(C–C–C)rRing B
837
25.375
830
1.1714
γ(C–C–C) ring A
873
2.6331
866
2.3196
γ(C–C–C) ring B
885
25.947
867
0.4876
β(N–C=O) joint to both rings
887
3.846
889
4.1429
γ(C–C–H) ring A
906
5.1907
907
22.5923
Twist CH2 ring B
947
5.0577
933
2.7875
γ(C–C–H) ring B
951
5.9695
951
0.2745
Ring A breathing
966
2.0181
973
4.7925
γ(C–C–C) ring A
986
18.651
974
0.9688
γ(C–C–C) ring A
990
12.259
985
0.3854
γ(C–C–C) ring A
1002
2.3552
995
0.0806
Twist CH2 ring B
1027
5.8621
1021
12.9074
γ(C–C–C) ring B
1048
14.225
1050
17.0033
β(C–C–H) ring A
1072
17.410
1067
8.9467
β(C–C–H) ring A
1104
73.216
1105
114.2174
β(C–C–H) ring A
1127
0.6851
1118
0.8245
Twist CH2 ring B
1144
9.5501
1144
23.861
γ(C–C–H) ring B
1184
15.684
1174
13.5043
β(C–C=N) ring A + β(C–C–C) ring B
1196
6.0684
1188
9.5816
γ(C–C–H) ring B
1203
3.3536
1195
23.0436
β(C–C–H) ring A
1222
62.461
1209
146.2051
Twist CH2 ring B
1237
163.03
1217
51.1901
β(C–C–C) ring A + twist CH2 ring B
1249
10.424
1232
34.5492
Ring A deformation
1266
9.0924
1256
4.27
Twist CH2 ring B
1283
2.845
1279
0.3718
Rock CH2 ring B
1305
0.2089
1295
0.4946
Twist CH2 ring B
1306
0.0683
1297
1.5912
Twist CH2 ring B
1312
0.6944
1301
0.9643
β(C–C–H) ring A
1381
13.894
1385
14.4629
β(C–C–H) ring A
1436
34.372
1416
17.0927
S(CH2) ring B
1441
13.808
1420
7.2964
S(CH2) ring B
1447
11.264
1442
5.421
β(C–C–H) ring A
1461
9.7004
1456
3.4055
S(CH2) ring B
1469
1.2504
1463
17.0394
S(CH2) ring B
1487
313.60
1489
318.044
β(C–N–H)
1529
37.617
1538
23.3689
Ring A deformation
1563
7.4055
1573
17.1708
ν(C–C) ring A
1604
227.40
1654
22.9328
ν(C=O)
1623
2.596
1715
302.3136
ν(C=N) joint ring B
2902
18.706
2890
12.407
ν(C–H) ring B
2925
15.584
2900
12.3498
ν(C–H) ring B
2938
21.950
2917
25.4822
ν(C–H) ring B
2939
41.648
2923
12.8395
ν(C–H) ring B
2954
38.945
2934
41.6752
ν(C–H) ring B
3001
42.309
2975
40.8297
ν(C–H) ring B
3009
30.010
2981
39.1011
ν(C–H) ring B
3017
50.383
2990
14.2807
ν(C–H) ring B
3072
8.0634
3031
21.1113
ν(C–H) ring A
3086
26.263
3038
23.6222
ν(C–H) ring A
3095
16.702
3061
12.3221
ν(C–H) ring A
3118
4.5408
3088
3.1852
ν(C–H) ring A
3416
17.207
3412
13.2313
ν(N–H)
ν: stretching; β: in plane bending; γ: out of plane bending; S: scissoring;
ω: wagging; τ: torsion.In isoniazid, the N–H functional group is present at 3389 cm−1 in calculated spectra which is in good agreement with the experimental data. The C–H functional group is present at a number of positions. The stretching vibration, ν(C–H), is expected to occur in the region 2800–3200 cm−1. The ν(C–H) functional group is present at 3079 cm−1 in calculated spectra which is in good agreement with the experimental data, that is, 3050 cm−1. The calculated values of the ν(C–H) vibration lie within this spectral range. The calculated (scaled) and experimental frequencies are deviated by a large amount, which may be explained by the presence of hydrogen bonding in the solid sample. The theoretical calculations have been done on gas-phase molecule.The –NH2 functional group is important constituents of isoniazid and vibrations corresponding to these groups are present in a number of modes. The stretching modes corresponding to these groups are of two types: symmetric and asymmetric stretching. In the symmetric stretching vibration, both the arms of the functional group are stretching in-phase with each other, whereas, in the asymmetric stretching mode, the atomic hydrogen motions are out-of-phase. The twisting and rocking vibrations for both the functional groups are present mixed with other vibrations in middle region. As expected, the ring torsion modes along with wagging modes appear in the low frequency range. An intense band due to torsion of C–C–C–C is at 658 cm−1 in calculated spectrum which matches well with the experimental one, that is, 560 cm−1. There are some frequencies in lower region having appreciable IR intensity. Furthermore, the study of low frequency vibrations is of great significance, because it gives information on weak intermolecular interactions, which take place in enzyme reactions [14]. Knowledge of low frequency mode is also essential for the interpretation of the effect of electromagnetic radiation on biological systems [15].In CPPC, the N–H functional group is present at 3416 cm−1 in calculated spectra having appreciable IR intensity. The C–H functional group is present at a number of positions. The ν(C–H) functional group is present at 2939, 2954, and 3001 cm−1 in calculated spectra having substantial IR intensity. The region 1600–2000 cm−1 is generally considered as the double bond stretching region for C=O, C=C, and C=N bonds [16–19]. The C=O stretching vibration, ν(C=O), appears as a prominent mode in the calculated spectra at 1604 cm−1.The –CH2 functional groups are important constituents of CPPC and vibrations corresponding to these groups are present in a number of modes. Due to twist –CH2 mode an intense peak is present at 554 cm−1 in calculated spectra as a prominent mode. The twisting and rocking vibrations for the functional group are present mixed with other vibrations in middle region. Here, we are discussing only most IR active modes present in calculated spectra for both the molecules. The aim of this section is to obtain direct information on lower and higher frequency vibrations of such biologically active molecules. No experimental FTIR spectrum is available for comparison so it will be a suitable path for experimental researchers.


## 3.3. Electronic Spectra and Electronic Properties

On the basis of fully optimized ground-state structure, TDDFT//B3LYP/LANL2DZ calculations have been used to determine the low-lying excited states of isoniazid and CPPC. The calculated results involving the vertical excitation energies, oscillator strength(
f
), and wavelength are carried out using the Gaussian 09W program. Experimental wavelengths are not available so these calculated data can help the experimental researchers. Electronic transitions determined from excited state calculations are listed in Table 4 for the three lowest energy transitions of the molecule. For isoniazid, TD-DFT calculation predicts three intense electronic transitions at 5.7714 eV (214.82 nm), 6.8565 eV (180.83 nm), and 6.7948 eV (159.44 nm) with oscillator strengths of 0.1780, 0.5155, and 0.2444, respectively. For CPPC and TD-DFT calculation predicts three intense electronic transitions at 5.7716 eV (214.82 nm), 6.6955 eV (185.18 nm), and 7.0662 eV (175.46 nm) with oscillator strengths of 0.3239, 0.2676, and 0.1706, respectively. The calculated UV spectrum of isoniazid and its derivative CPPC are shown in Figures 3 and 4.Table 4
Calculated parameters for isoniazid and CPPC using TDDFT//B3LYP/LANL2DZ.
Excitation
CI coefficient
Expansion wave length (nm)
Oscillator strength
Energy (eV)
calculated
Isoniazid
Excited state 1
31
→
37
0.63973
214.82
0.1780
5.7714
34
→
38
0.27134
Excited state 2
34
→
38
0.50322
180.83
0.5155
6.8565
31
→
38
−0.13282
Excited state 3
34
→
39
0.53619
159.44
0.2444
7.7762
29
→
38
−0.11809
CPPC
Excited state 1
49
→
55
0.45328
214.82
0.3239
5.7716
53
→
57
0.10859
52
→
57
0.10042
Excited state 2
47
→
55
0.26652
185.18
0.2676
6.6955
50
→
56
0.50556
53
→
58
0.22945
Excited state 3
49
→
56
0.45774
175.46
0.1706
7.0662
50
→
57
0.41085Figure 3
Calculated UV spectrum of CPPC.Figure 4
Calculated UV spectrum of isoniazid.The frontier orbitals, HOMO and LUMO, determine the way the molecule interacts with other species. The frontier orbital gap helps to characterize the chemical reactivity and kinetic stability of the molecule. A molecule which has a larger orbital gap is more polarized having more reactive part as far as reaction is concerned [20]. According to the present calculations, the frontier orbital gap in case of the given molecules is 4.9531 and 4.7835 eV, respectively, for isoniazid and CPPC given in Table 5. So we can say that CPPC is more reactive than isoniazid. The plots of the HOMO, LUMO, and electrostatic potential for both the molecules are shown in Figures 5–10. For isoniazid, HOMO (Figure 5) is located over the whole molecule. LUMO is located (Figure 6) at the same place as HOMO excluding hydrogen atoms. For CPPC, HOMO (Figure 7) is located nearby and on ring B. LUMO is located (Figure 8) nearby and on ring A. The importance of MESP lies in the fact that it simultaneously displays molecular size, shape, and positive, negative, and neutral electrostatic potential regions in terms of colour grading (shown in Figures 9 and 10) and is very useful in investigation of molecular structure with its physiochemical property relationship [21–25]. We have also plotted 3D MESP structures of the title compound as shown in Figures 11 and 12. For isoniazid and CPPC, the electronegative region is outside of the molecule near the oxygen atoms. The energy equal to the shielded potential energy surface is required for any substitution reaction near oxygen. The electronegative lines (in between −0.08 a.u. and −0.02 a.u.) form a closed contour which clearly indicates that total flux passing in between these curves are not equal to zero. For any nucleophilic substitution reaction near oxygen (closed contour area), an amount of energy equal to shielded potential energy surface is required; however, the remaining part of the molecule is suitable for electrophilic substitution reaction. Thus, it can be asserted that MESP values have been shown to be well related to biological properties. [26–28].Table 5
Lowest energy, HOMO-LUMO gap (frontier orbital energy gap) and dipole moment of isoniazid and N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) by (B3LYP)/6-311 G (d, p) and (B3LYP)/LANL2DZ methods.
Parameters
Isoniazid
N-Cyclopentylidenepyridine-4-carbohydrazide
LANL2DZ
6-311 G (d, p)
LANL2DZ
6-311 G (d, p)
Energy (in au)
−472.2226
−472.4245
−666.3336
−666.6202
Dipole moment (in Debye)
5.49
4.94
6.25
5.37
HOMO
−6.8353
−6.8852
−6.7673
−6.7821
LUMO
−1.8800
−1.9129
−1.9815
−1.9875
Frontier orbital energy gap (eV)
4.9552
4.9723
4.7857
4.7946Figure 5
HOMO picture of isoniazid.Figure 6
LUMO picture of isoniazid.Figure 7
HOMO picture of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).Figure 8
LUMO picture of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).Figure 9
MESP picture of isoniazid.Figure 10
MESP picture of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).Figure 11
Contour plot of isoniazid.Figure 12
Contour plot of N-cyclopentylidenepyridine-4-carbohydrazide (CPPC).


## 3.4. Reactivity Descriptors

### 3.4.1. Global Reactivity Descriptors

The energies of frontier molecular orbitals (εHOMO, εLUMO), energy band gap (εLUMO − εHOMO), electronegativity (
χ
=
-
(
1
/
2
)
(
LUMO
ε
+
HOMO
ε
)
), chemical potential (
μ
=
-
χ
), global hardness (
η
=
(
1
/
2
)
(
LUMO
ε
-
HOMO
ε
)
), global softness (
S
=
1
/
2
η
), and global electrophilicity index (
ω
=
μ
2
/
2
η
) [29–32] of isoniazid and CPPC have been listed in Table 6. It is found that the gap between HOMO and LUMO is smaller in CPPC than isoniazid.Table 6
Calculatedε
HOMO, ε
LUMO, energy band gap (ε
L
-
ε
H), chemical potential (μ), electronegativity (χ), global hardness (η), global softness (S), and global electrophilicity index (ω) for isoniazid and CPPC at B3LYP/LANL2DZ level.
Molecules
ε
H
ε
L
ε
L
-
ε
H
χ
μ
η
S
ω
CPPC 2
−6.7673
−1.9815
4.7857
4.3744
−4.3744
2.3929
0.2090
3.9984
ISO 2
−6.8353
−1.8800
4.9552
4.3577
−4.3577
2.4776
0.2018
3.8322


### 3.4.2. Local Reactivity Descriptors

Fukui function (FF) of a molecule provides information of the local site reactivity within the molecule and as such it provides a method for understanding and categorizing chemical reactions. These values represent the qualitative descriptors of reactivity of different atoms in the molecule. Ayers and Parr [33] have elucidated that molecules tend to react where the FF is the largest when attacked by soft reagents and in places where the FF is smaller when attacked by hard reagents. The use of Fukui functions for the site selectivity of isoniazid and CPPC molecules for nucleophilic and electrophilic attacks has been made with special emphasis on the dependence of Fukui values on the basis of B3LYP/6-311G(d,p) level of theory. Using Mulliken atomic charges of cationic and anionic states of isoniazid and CPPC, local Fukui functions (
f
k
+
,
f
k
-
), local softness (
s
k
+
,
s
k
-
), and local electrophilicity indices (
ω
k
+
,
ω
k
-
) [30, 31] have been calculated using the following equation:
(1)
f
k
+
=
[
q
(
N
+
1
)
-
q
(
N
)
]
for
nucleophilic
attack
,
f
k
-
=
[
q
(
N
)
-
q
(
N
-
1
)
]
for
electrophilic
attack
,
f
k
0
=
1
2
[
q
(
N
+
1
)
+
q
(
N
-
1
)
]
for
radical
attack
.
Local softness and electrophilicity indices are calculated using the following equation:
(2)
s
k
+
=
S
f
k
+
,
s
k
-
=
S
f
k
-
,
ω
k
+
=
ω
f
k
+
,
ω
k
-
=
ω
f
k
-
,
where + and − signs show nucleophilic and electrophilic attacks, respectively.Fukui functions, local softness, and local electrophilicity indices for selected atomic sites in isoniazid and CPPC have been listed in Tables7 and 8. For CPPC, the maximum values for local nucleophilic reactivity descriptors (
f
k
-, s
k
-, ω
k
-
) at N13 and N14 indicate that these two sites are more prone to electrophilic attack. But on comparison with N17 of isoniazid it is found that the N14 of CPPC has lower affinity towards electrophile. This situation changes because the nitrogen of CPPC is bonded through a double bond to the C16 of a pentagonal ring; hence, the charge density around N14 decreases.Table 7
Fukui functions (f
k
+, f
k
-), local softness (s
k
+, s
k
-), and local electrophilicity indices (ω
k
+, ω
k
-) for selected atomic sites of CPPC, using Mulliken population analysis at B3LYP/LANL2DZ level.
CPPC
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
N6
0.063725
0.047259
0.013319
0.009877
0.254798
0.18896
C11
0.088784
0.050459
0.018556
0.010546
0.354994
0.201755
N13
0.016223
0.049147
0.003391
0.010272
0.064866
0.196509
N14
0.023381
0.043409
0.004887
0.009072
0.093487
0.173567
H15
0.018967
0.032456
0.003964
0.006783
0.075838
0.129772
CPPC (full)
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
C1
0.037085
0.053511
0.007751
0.011184
0.148281
0.213958
C2
0.079194
0.038498
0.016552
0.008046
0.316649
0.15393
C3
0.037105
0.018265
0.007755
0.003817
0.148361
0.073031
C4
0.056432
0.033863
0.011794
0.007077
0.225638
0.135398
C5
0.046093
0.054106
0.009633
0.011308
0.184298
0.216337
N6
0.063725
0.047259
0.013319
0.009877
0.254798
0.18896
H7
0.05017
0.048264
0.010486
0.010087
0.2006
0.192979
H8
0.024605
0.022564
0.005142
0.004716
0.098381
0.09022
H9
0.025706
0.012418
0.005373
0.002595
0.102783
0.049652
H10
0.048308
0.046734
0.010096
0.009767
0.193155
0.186861
C11
0.088784
0.050459
0.018556
0.010546
0.354994
0.201755
O12
0.10292
0.103102
0.02151
0.021548
0.411515
0.412243
N13
0.016223
0.049147
0.003391
0.010272
0.064866
0.196509
N14
0.023381
0.043409
0.004887
0.009072
0.093487
0.173567
H15
0.018967
0.032456
0.003964
0.006783
0.075838
0.129772
C16
0.07141
0.083266
0.014925
0.017403
0.285526
0.332931
C17
-
0.01717
-
0.0153
-
0.00359
-
0.0032
-
0.06865
-
0.06118
C18
0.000227
-
0.00052
4.74
E
-
05
-
0.00011
0.000908
-
0.00206
C19
0.000575
0.001021
0.00012
0.000213
0.002299
0.004082
C20
-
0.02038
-
0.0215
-
0.00426
-
0.00449
-
0.08147
-
0.08597
H21
0.03456
0.04074
0.007223
0.008515
0.138185
0.162895
H22
0.039332
0.053361
0.00822
0.011152
0.157265
0.213359
H23
0.02873
0.033782
0.006005
0.00706
0.114874
0.135074
H24
0.028555
0.033136
0.005968
0.006925
0.114174
0.132491
H25
0.029499
0.033406
0.006165
0.006982
0.117949
0.133571
H26
0.025818
0.029323
0.005396
0.006129
0.103231
0.117245
H27
0.034231
0.046674
0.007154
0.009755
0.136869
0.186621
H28
0.025909
0.028557
0.005415
0.005968
0.103595
0.114182Table 8
Fukui functions (f
k
+, f
k
-), local softness (s
k
+, s
k
-), and local electrophilicity indices (ω
k
+, ω
k
-) for selected atomic sites of isoniazid, using Mulliken population analysis at B3LYP/LANL2DZ level.
ISO
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
N6
0.087184
0.075685
0.017594
0.015273
0.334107
0.29004
C11
0.045066
0.105331
0.009094
0.021256
0.172702
0.403649
O12
0.125455
0.097778
0.025317
0.019732
0.480769
0.374705
N13
0.104399
−0.09059
0.021068
−0.01828
0.400078
−0.34714
H14
0.07228
0.027223
0.014586
0.005494
0.276991
0.104324
H15
0.045876
0.053631
0.009258
0.010823
0.175806
0.205525
H16
0.066534
0.058946
0.013427
0.011895
0.254972
0.225893
N17
−0.07824
0.12441
−0.01579
0.025106
−0.29982
0.476764
ISO (full)
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
C1
0.070332
0.074531
0.014193
0.01504
0.269526
0.285618
C2
0.086439
0.065308
0.017443
0.013179
0.331252
0.250273
C3
0.098962
−0.00059
0.019971
−0.00012
0.379242
−0.00226
C4
0.068608
0.080752
0.013845
0.016296
0.26292
0.309458
C5
0.061734
0.096349
0.012458
0.019443
0.236577
0.369229
N6
0.087184
0.075685
0.017594
0.015273
0.334107
0.29004
H7
0.068036
0.06207
0.01373
0.012526
0.260728
0.237865
H8
0.03037
0.040116
0.006129
0.008095
0.116384
0.153733
H9
−0.02115
0.070626
−0.00427
0.014252
−0.08104
0.270653
H10
0.068106
0.05842
0.013744
0.011789
0.260996
0.223877
C11
0.045066
0.105331
0.009094
0.021256
0.172702
0.403649
O12
0.125455
0.097778
0.025317
0.019732
0.480769
0.374705
N13
0.104399
−0.09059
0.021068
−0.01828
0.400078
−0.34714
H14
0.07228
0.027223
0.014586
0.005494
0.276991
0.104324
H15
0.045876
0.053631
0.009258
0.010823
0.175806
0.205525
H16
0.066534
0.058946
0.013427
0.011895
0.254972
0.225893
N17
−0.07824
0.12441
−0.01579
0.025106
−0.29982
0.476764


## 3.4.1. Global Reactivity Descriptors

The energies of frontier molecular orbitals (εHOMO, εLUMO), energy band gap (εLUMO − εHOMO), electronegativity (
χ
=
-
(
1
/
2
)
(
LUMO
ε
+
HOMO
ε
)
), chemical potential (
μ
=
-
χ
), global hardness (
η
=
(
1
/
2
)
(
LUMO
ε
-
HOMO
ε
)
), global softness (
S
=
1
/
2
η
), and global electrophilicity index (
ω
=
μ
2
/
2
η
) [29–32] of isoniazid and CPPC have been listed in Table 6. It is found that the gap between HOMO and LUMO is smaller in CPPC than isoniazid.Table 6
Calculatedε
HOMO, ε
LUMO, energy band gap (ε
L
-
ε
H), chemical potential (μ), electronegativity (χ), global hardness (η), global softness (S), and global electrophilicity index (ω) for isoniazid and CPPC at B3LYP/LANL2DZ level.
Molecules
ε
H
ε
L
ε
L
-
ε
H
χ
μ
η
S
ω
CPPC 2
−6.7673
−1.9815
4.7857
4.3744
−4.3744
2.3929
0.2090
3.9984
ISO 2
−6.8353
−1.8800
4.9552
4.3577
−4.3577
2.4776
0.2018
3.8322


## 3.4.2. Local Reactivity Descriptors

Fukui function (FF) of a molecule provides information of the local site reactivity within the molecule and as such it provides a method for understanding and categorizing chemical reactions. These values represent the qualitative descriptors of reactivity of different atoms in the molecule. Ayers and Parr [33] have elucidated that molecules tend to react where the FF is the largest when attacked by soft reagents and in places where the FF is smaller when attacked by hard reagents. The use of Fukui functions for the site selectivity of isoniazid and CPPC molecules for nucleophilic and electrophilic attacks has been made with special emphasis on the dependence of Fukui values on the basis of B3LYP/6-311G(d,p) level of theory. Using Mulliken atomic charges of cationic and anionic states of isoniazid and CPPC, local Fukui functions (
f
k
+
,
f
k
-
), local softness (
s
k
+
,
s
k
-
), and local electrophilicity indices (
ω
k
+
,
ω
k
-
) [30, 31] have been calculated using the following equation:
(1)
f
k
+
=
[
q
(
N
+
1
)
-
q
(
N
)
]
for
nucleophilic
attack
,
f
k
-
=
[
q
(
N
)
-
q
(
N
-
1
)
]
for
electrophilic
attack
,
f
k
0
=
1
2
[
q
(
N
+
1
)
+
q
(
N
-
1
)
]
for
radical
attack
.
Local softness and electrophilicity indices are calculated using the following equation:
(2)
s
k
+
=
S
f
k
+
,
s
k
-
=
S
f
k
-
,
ω
k
+
=
ω
f
k
+
,
ω
k
-
=
ω
f
k
-
,
where + and − signs show nucleophilic and electrophilic attacks, respectively.Fukui functions, local softness, and local electrophilicity indices for selected atomic sites in isoniazid and CPPC have been listed in Tables7 and 8. For CPPC, the maximum values for local nucleophilic reactivity descriptors (
f
k
-, s
k
-, ω
k
-
) at N13 and N14 indicate that these two sites are more prone to electrophilic attack. But on comparison with N17 of isoniazid it is found that the N14 of CPPC has lower affinity towards electrophile. This situation changes because the nitrogen of CPPC is bonded through a double bond to the C16 of a pentagonal ring; hence, the charge density around N14 decreases.Table 7
Fukui functions (f
k
+, f
k
-), local softness (s
k
+, s
k
-), and local electrophilicity indices (ω
k
+, ω
k
-) for selected atomic sites of CPPC, using Mulliken population analysis at B3LYP/LANL2DZ level.
CPPC
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
N6
0.063725
0.047259
0.013319
0.009877
0.254798
0.18896
C11
0.088784
0.050459
0.018556
0.010546
0.354994
0.201755
N13
0.016223
0.049147
0.003391
0.010272
0.064866
0.196509
N14
0.023381
0.043409
0.004887
0.009072
0.093487
0.173567
H15
0.018967
0.032456
0.003964
0.006783
0.075838
0.129772
CPPC (full)
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
C1
0.037085
0.053511
0.007751
0.011184
0.148281
0.213958
C2
0.079194
0.038498
0.016552
0.008046
0.316649
0.15393
C3
0.037105
0.018265
0.007755
0.003817
0.148361
0.073031
C4
0.056432
0.033863
0.011794
0.007077
0.225638
0.135398
C5
0.046093
0.054106
0.009633
0.011308
0.184298
0.216337
N6
0.063725
0.047259
0.013319
0.009877
0.254798
0.18896
H7
0.05017
0.048264
0.010486
0.010087
0.2006
0.192979
H8
0.024605
0.022564
0.005142
0.004716
0.098381
0.09022
H9
0.025706
0.012418
0.005373
0.002595
0.102783
0.049652
H10
0.048308
0.046734
0.010096
0.009767
0.193155
0.186861
C11
0.088784
0.050459
0.018556
0.010546
0.354994
0.201755
O12
0.10292
0.103102
0.02151
0.021548
0.411515
0.412243
N13
0.016223
0.049147
0.003391
0.010272
0.064866
0.196509
N14
0.023381
0.043409
0.004887
0.009072
0.093487
0.173567
H15
0.018967
0.032456
0.003964
0.006783
0.075838
0.129772
C16
0.07141
0.083266
0.014925
0.017403
0.285526
0.332931
C17
-
0.01717
-
0.0153
-
0.00359
-
0.0032
-
0.06865
-
0.06118
C18
0.000227
-
0.00052
4.74
E
-
05
-
0.00011
0.000908
-
0.00206
C19
0.000575
0.001021
0.00012
0.000213
0.002299
0.004082
C20
-
0.02038
-
0.0215
-
0.00426
-
0.00449
-
0.08147
-
0.08597
H21
0.03456
0.04074
0.007223
0.008515
0.138185
0.162895
H22
0.039332
0.053361
0.00822
0.011152
0.157265
0.213359
H23
0.02873
0.033782
0.006005
0.00706
0.114874
0.135074
H24
0.028555
0.033136
0.005968
0.006925
0.114174
0.132491
H25
0.029499
0.033406
0.006165
0.006982
0.117949
0.133571
H26
0.025818
0.029323
0.005396
0.006129
0.103231
0.117245
H27
0.034231
0.046674
0.007154
0.009755
0.136869
0.186621
H28
0.025909
0.028557
0.005415
0.005968
0.103595
0.114182Table 8
Fukui functions (f
k
+, f
k
-), local softness (s
k
+, s
k
-), and local electrophilicity indices (ω
k
+, ω
k
-) for selected atomic sites of isoniazid, using Mulliken population analysis at B3LYP/LANL2DZ level.
ISO
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
N6
0.087184
0.075685
0.017594
0.015273
0.334107
0.29004
C11
0.045066
0.105331
0.009094
0.021256
0.172702
0.403649
O12
0.125455
0.097778
0.025317
0.019732
0.480769
0.374705
N13
0.104399
−0.09059
0.021068
−0.01828
0.400078
−0.34714
H14
0.07228
0.027223
0.014586
0.005494
0.276991
0.104324
H15
0.045876
0.053631
0.009258
0.010823
0.175806
0.205525
H16
0.066534
0.058946
0.013427
0.011895
0.254972
0.225893
N17
−0.07824
0.12441
−0.01579
0.025106
−0.29982
0.476764
ISO (full)
f
k
+
f
k
-
s
k
+
s
k
-
ω
k
+
ω
k
-
C1
0.070332
0.074531
0.014193
0.01504
0.269526
0.285618
C2
0.086439
0.065308
0.017443
0.013179
0.331252
0.250273
C3
0.098962
−0.00059
0.019971
−0.00012
0.379242
−0.00226
C4
0.068608
0.080752
0.013845
0.016296
0.26292
0.309458
C5
0.061734
0.096349
0.012458
0.019443
0.236577
0.369229
N6
0.087184
0.075685
0.017594
0.015273
0.334107
0.29004
H7
0.068036
0.06207
0.01373
0.012526
0.260728
0.237865
H8
0.03037
0.040116
0.006129
0.008095
0.116384
0.153733
H9
−0.02115
0.070626
−0.00427
0.014252
−0.08104
0.270653
H10
0.068106
0.05842
0.013744
0.011789
0.260996
0.223877
C11
0.045066
0.105331
0.009094
0.021256
0.172702
0.403649
O12
0.125455
0.097778
0.025317
0.019732
0.480769
0.374705
N13
0.104399
−0.09059
0.021068
−0.01828
0.400078
−0.34714
H14
0.07228
0.027223
0.014586
0.005494
0.276991
0.104324
H15
0.045876
0.053631
0.009258
0.010823
0.175806
0.205525
H16
0.066534
0.058946
0.013427
0.011895
0.254972
0.225893
N17
−0.07824
0.12441
−0.01579
0.025106
−0.29982
0.476764


## 3.5. Dipole Moment, Polarizability, Hyper Polarizability, and Thermodynamic Properties

Dipole moment(
μ
), polarizability 〈
α
〉, and total first static hyper polarizability β [31, 32] are also calculated in Tables 5 and 9 by using density functional theory. They can be expressed in terms of x, y, z components and are given by the following equation:
(3)
μ
=
(
μ
x
2
+
μ
y
2
+
μ
z
2
)
1
/
2
,
〈
α
〉
=
1
3
[
α
x
x
+
α
y
y
+
α
z
z
]
,
β
Total
=
(
β
x
2
+
β
y
2
+
β
z
2
)
1
/
2
=
[
(
β
x
x
x
+
β
x
y
y
+
β
x
z
z
)
2
+
(
β
y
y
y
+
β
y
x
x
+
β
y
z
z
)
2
+
(
β
z
z
z
+
β
z
x
x
+
β
z
y
y
)
(
β
x
x
x
+
β
x
y
y
+
β
x
z
z
)
2
2
+
(
β
z
z
z
+
β
z
x
x
+
β
z
y
y
)
(
β
x
x
x
+
β
x
y
y
+
β
x
z
z
)
2
2
]
1
/
2
.
The β components of Gaussian output are reported in atomic units, where 1 a.u. = 8.3693 × 10−33 e.s.u. For isoniazid and CPPC, the calculated dipole moment values are 5.49 and 6.25 Debye. Having higher dipole moment than water (2.16 Debye), isoniazid and CPPC both can be used as better solvents. For isoniazid, we see a greater contribution of α
z
z in molecule which shows that molecule is elongated more towards Z direction and more contracted to X direction. Perpendicular part contributes less part of polarizability of molecule. Β
x
x
x, β
y
y
y contribute a larger part in hyper polarizability. This shows that molecule is more optical active in X-axis and Y-axis directions. For CPPC, we see a greater contribution of α
y
y in molecule which shows that molecule is elongated more towards Y direction and more contracted to X direction. Perpendicular part contributes less part of polarizability of molecule.Table 9
Polarizability and hyper polarizability of isoniazid and N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) by (B3LYP)/LANL2DZ methods.
Isoniazid
N-Cyclopentylidenepyridine-4-carbohydrazide
LANL2DZ
6-311 G (d, p)
LANL2DZ
6-311 G (d, p)
Polarizability
α
x
x
−54.4243
−53.1504
−87.0159
−86.5468
α
x
y
−13.9175
−11.3119
8.2530
6.5995
α
y
y
−57.0302
−56.9567
−96.2129
−95.0135
α
y
z
0.0007
2.9339
4.6341
4.0900
α
z
z
−58.4664
−57.4167
−88.0328
−87.9161
α
z
x
0.0006
2.8602
1.0289
0.8897
α
56.6403
55.8412
90.4205
89.8254
Hyper polarizability
β
x
x
x
104.6160
92.6426
−133.3584
−99.8131
β
x
x
y
−9.7260
−11.3252
50.4571
40.4792
β
x
y
y
−5.2048
−2.4771
−9.9876
−5.2677
β
y
y
y
−28.2262
−20.4938
−30.0106
−21.2944
β
z
z
z
0.0026
4.0365
−0.0107
−0.6537
β
x
x
z
0.0029
8.9620
6.7905
5.7162
β
x
z
z
13.6068
11.5672
−9.3808
−4.2219
β
y
z
z
−3.0727
−2.3332
1.3678
2.3214
β
y
y
z
−0.0001
2.6541
1.3952
0.9832
β
x
y
z
−0.0020
−3.8704
12.4376
10.8998
β total
120.2335
115.5787
154.1308
111.5623Β
x
x
x, β
x
x
y contribute a larger part in hyper polarizability. This shows that molecule is more optical active in X-axis and X
Y-plane directions. The connection between the electric dipole moments of an organic molecule having donor-acceptor substituent and first order hyper polarizability is widely recognized in the literature. Standard thermodynamic functions such as free energy, constant volume heat capacity C
V, and entropy S have also been calculated for both the molecules and are given in Table 10. These functions can provide helpful information for further study of the title compounds.Table 10
Calculated thermodynamic properties of isoniazid and N-cyclopentylidenepyridine-4-carbohydrazide (CPPC) by (B3LYP)/LANL2DZ and 6-311 G (d, p) methods.
E (thermal) (k cal mol−1)
CV (cal K−1 mol−1)
S (cal K−1 mol−1)
Iso
CPPC
Iso
CPPC
Iso
CPPC
Total
89.150
152.971
32.161
49.600
92.375
116.973
(88.749)
(151.836)
(32.206)
(50.109)
(92.452)
(117.377)
Translational
0.889
0.889
2.981
2.981
40.658
41.830
(0.889)
(0.889)
(2.981)
(2.981)
(40.658)
(41.830)
Rotational
0.889
0.889
2.981
2.981
29.577
32.607
(0.889)
(0.889)
(2.981)
(2.981)
(29.490)
(32.545)
Vibrational
87.373
151.194
26.199
43.638
22.141
42.537
(86.972)
(150.059)
(26.244)
(44.147)
(22.304)
(43.002)


## 4. Conclusion

This paper reports a comprehensive computational structural study on antituberculosis drug isoniazid and its new derivative N-cyclopentylidenepyridine-4-carbohydrazide. The frequency assignments for isoniazid and its derivative N-cyclopentylidenepyridine-4-carbohydrazide have been done for the first time by employing density functional theory (DFT) with LANL2DZ and 6-311 G (d, p) as the basis sets. Normal modes analysis provides detailed description of the vibrational spectra of the molecules in question. Reactivity reflects the susceptibility of a substance towards a specific chemical reaction and plays a key role in, for example, the design of new molecules and understanding biological systems and material science. The lower value of frontier orbital energy gap and a higher dipole moment in case of CPPC suggest a more reactive nature as compared to isoniazid. Hyper polarizability is mainly controlled by the planarity of the molecules, the donor and accepter strength, and bond length alteration. The values of hyper polarizability indicate a possible use of these compounds in electrooptical applications.We have also discussed global and local reactivity descriptors sites for both molecules during electrophilic, nucleophilic, and radical attacks. These values represent the qualitative descriptors of reactivity of different atoms in the molecule. The present work might encourage the need for an extensive study by the experimentalists interested in the vibrational spectra and the structure of these compounds. The results reported in the present paper can help in the experimental investigations on the origin of the biological activity of these molecules.



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*Source: 894175-2014-02-24.xml*