Structures and energies
In the complex, IND-DC (Fig. 1), where the Cl atoms are attached to H10(NH), two relatively weaker hydrogen bonds (Cl …H10-N1) were formed with bond lengths of 2.8375 and 3.795Å. The DC to IND other interacting distances are: N1-H18 = 2.8147, N1-Cl21 = 3.5080, C2-H18 = 2.7405, C5-H18 = 1.9063, H10-C17 = 3.2546 and H12-Cl21 = 3.2962Å. Interaction of DC to the π-ring and NH bond of IND affect the vibration modes of IND [6]. The bond lengths, 1N-2C, 1N-10H, 2C-3C, 2C-5C show deviations of -0.001Å in the IND-DC complex (table 1). However in other IND-DC solvents significant variations are seen [26]. The angles C2-N1-H10 and C7-N1-H10 show slight change of 0.138 and 0.2098 upon complexation with DC. In solvent phases also there are changes in angles for some angles. The binding energy : E = EIND−DC - EIND - EDC [27, 28]. The binding energy in the gaseous phase is -14.28 kcal/mol while in the solvents, the energy is changed from − 9.26 to -9.55 kcal/mol.
Table 1
Geometrical parameters of IND and it’s complexes
(a) Bond lengths of IND and it’s complex in different solvents
|
IND
|
IND-DC
|
Gaseous
|
water
|
Ethanol
|
Methanol
|
DMSO
|
R(1,2)
|
1.3762
|
1.3772
|
1.3746
|
1.375
|
1.3749
|
1.3747
|
R(1,7)
|
1.3781
|
1.3778
|
1.3757
|
1.3759
|
1.3758
|
1.3759
|
R(1,10)
|
1.0065
|
1.0079
|
1.0087
|
1.0088
|
1.0088
|
1.0088
|
R(2,3)
|
1.4136
|
1.4146
|
1.4163
|
1.4163
|
1.4163
|
1.4163
|
R(2,5)
|
1.3959
|
1.3975
|
1.3985
|
1.3985
|
1.3985
|
1.3985
|
R(3,4)
|
1.4356
|
1.4354
|
1.4357
|
1.4357
|
1.4357
|
1.4357
|
R(3,6)
|
1.4018
|
1.4017
|
1.4032
|
1.403
|
1.403
|
1.4031
|
R(4,7)
|
1.3619
|
1.3621
|
1.3647
|
1.3645
|
1.3645
|
1.3646
|
R(4,11)
|
1.0805
|
1.0804
|
1.0808
|
1.0808
|
1.0808
|
1.0808
|
R(5,8)
|
1.3822
|
1.3832
|
1.3843
|
1.3841
|
1.3842
|
1.3841
|
R(5,12)
|
1.086
|
1.0859
|
1.0859
|
1.0859
|
1.0859
|
1.0859
|
R(6,9)
|
1.3815
|
1.382
|
1.3831
|
1.3831
|
1.3831
|
1.383
|
R(6,13)
|
1.0861
|
1.086
|
1.0863
|
1.0863
|
1.0863
|
1.0863
|
R(7,14)
|
1.0806
|
1.0805
|
1.0806
|
1.0806
|
1.0806
|
1.0806
|
R(8,9)
|
1.4066
|
1.4064
|
1.4078
|
1.4076
|
1.4077
|
1.4078
|
R(8,15)
|
1.0856
|
1.0856
|
1.0856
|
1.0856
|
1.0856
|
1.0856
|
R(9,16)
|
1.0855
|
1.0855
|
1.0856
|
1.0857
|
1.0857
|
1.0857
|
(b) Changes in Bond lengths
|
IND
|
Change in bond lengths of IND-DC
|
Gaseous
|
water
|
Ethanol
|
Methanol
|
DMSO
|
R(1,2)
|
1.3762
|
-0.001
|
0.0016
|
0.0012
|
0.0013
|
0.0015
|
R(1,7)
|
1.3781
|
0.0003
|
0.0024
|
0.0022
|
0.0023
|
0.0022
|
R(1,10)
|
1.0065
|
-0.0014
|
-0.0022
|
-0.0023
|
-0.0023
|
-0.0023
|
R(2,3)
|
1.4136
|
-0.001
|
-0.0027
|
-0.0027
|
-0.0027
|
-0.0027
|
R(2,5)
|
1.3959
|
-0.0016
|
-0.0026
|
-0.0026
|
-0.0026
|
-0.0026
|
R(3,4)
|
1.4356
|
0.0002
|
-0.0001
|
-0.0001
|
-0.0001
|
-0.0001
|
R(3,6)
|
1.4018
|
0.0001
|
-0.0014
|
-0.0012
|
-0.0012
|
-0.0013
|
R(4,7)
|
1.3619
|
-0.0002
|
-0.0028
|
-0.0026
|
-0.0026
|
-0.0027
|
R(4,11)
|
1.0805
|
0.0001
|
-0.0003
|
-0.0003
|
-0.0003
|
-0.0003
|
R(5,8)
|
1.3822
|
-0.0001
|
-0.0021
|
-0.0019
|
-0.002
|
-0.0019
|
R(5,12)
|
1.086
|
0.0001
|
0.0001
|
0.0001
|
0.0001
|
0.0001
|
R(6,9)
|
1.3815
|
0.0000
|
-0.0016
|
-0.0016
|
-0.0016
|
-0.0015
|
R(6,13)
|
1.0861
|
0.0001
|
-0.0002
|
-0.0002
|
-0.0002
|
-0.0002
|
R(7,14)
|
1.0806
|
0.0001
|
0
|
0
|
0
|
0
|
R(8,9)
|
1.4066
|
0.0002
|
-0.0012
|
-0.001
|
-0.0011
|
-0.0012
|
R(8,15)
|
1.0856
|
0
|
0
|
0
|
0
|
0
|
R(9,16)
|
1.0855
|
0
|
-0.0001
|
-0.0002
|
-0.0002
|
-0.0002
|
(c ) Bond angles of IND and it’s complex in different solvents
|
IND
|
IND-DC
|
Gaseous
|
water
|
Ethanol
|
Methanol
|
DMSO
|
A(2,1,7)
|
109.1689
|
109.0844
|
109.1749
|
109.1689
|
109.171
|
109.1694
|
A(2,1,10)
|
125.4538
|
125.3158
|
125.4936
|
125.5007
|
125.5019
|
125.4944
|
A(7,1,10)
|
125.3772
|
125.587
|
125.284
|
125.3071
|
125.3017
|
125.2863
|
A(1,2,3)
|
107.2839
|
107.3128
|
107.3707
|
107.3562
|
107.3598
|
107.3676
|
A(1,2,5)
|
130.3998
|
130.3631
|
130.3865
|
130.3965
|
130.3893
|
130.3869
|
A(3,2,5)
|
122.3163
|
122.323
|
122.2429
|
122.2472
|
122.2509
|
122.2455
|
A(2,3,4
|
106.8763
|
106.8436
|
106.7759
|
106.7832
|
106.7809
|
106.7786
|
A(2,3,6)
|
118.7999
|
118.7635
|
118.81
|
118.8109
|
118.8062
|
118.8136
|
A(4,3,6)
|
134.3238
|
134.3928
|
134.4141
|
134.4059
|
134.4129
|
134.4078
|
A(3,4,7)
|
106.9992
|
106.9985
|
106.8859
|
106.8986
|
106.8957
|
106.8921
|
A(3,4,11)
|
126.9066
|
126.9218
|
126.981
|
126.971
|
126.974
|
126.9662
|
A(7,4,11)
|
126.0942
|
126.0795
|
126.1331
|
126.1304
|
126.1303
|
126.1418
|
A(2,5,8)
|
117.4824
|
117.437
|
117.4969
|
117.4848
|
117.4866
|
117.4876
|
A(2,5,12
|
121.3206
|
121.2207
|
121.1568
|
121.1943
|
121.183
|
121.1824
|
A(8,5,12)
|
121.197
|
121.3413
|
121.3448
|
121.3198
|
121.3293
|
121.3285
|
A(3,6,9)
|
119.1336
|
119.1762
|
119.1664
|
119.1606
|
119.1618
|
119.1579
|
A(3,6,13)
|
120.2866
|
120.2774
|
120.3018
|
120.2994
|
120.3009
|
120.2948
|
A(9,6,13)
|
120.5798
|
120.5464
|
120.5318
|
120.54
|
120.5373
|
120.5472
|
A(1,7,4)
|
109.6716
|
109.7606
|
109.7918
|
109.7928
|
109.7923
|
109.7916
|
A(1,7,14)
|
120.3332
|
120.2516
|
120.1666
|
120.1648
|
120.1624
|
120.1516
|
A(4,7,14)
|
129.9952
|
129.9871
|
130.0416
|
130.0423
|
130.0453
|
130.0568
|
A(5,8,9)
|
121.2122
|
121.2205
|
121.2213
|
121.23
|
121.2259
|
121.2279
|
A(5,8,15)
|
119.4064
|
119.3808
|
119.3719
|
119.3683
|
119.371
|
119.3767
|
A(9,8,15)
|
119.3815
|
119.3982
|
119.4062
|
119.4014
|
119.4027
|
119.395
|
A(6,9,8)
|
121.0556
|
121.0796
|
121.0618
|
121.0662
|
121.0682
|
121.0669
|
A(6,9,16)
|
119.7251
|
119.6964
|
119.7178
|
119.7106
|
119.7105
|
119.7211
|
A(8,9,16)
|
119.2193
|
119.224
|
119.2204
|
119.2232
|
119.2212
|
119.212
|
(d)Changes in Bond angles
|
IND
|
IND-DC
|
Gaseous
|
water
|
Ethanol
|
Methanol
|
DMSO
|
A(2,1,7)
|
109.1689
|
0.0845
|
-0.006
|
0
|
-0.0021
|
0
|
A(2,1,10)
|
125.4538
|
0.138
|
-0.0398
|
-0.0469
|
-0.0481
|
-0.0406
|
A(7,1,10)
|
125.3772
|
-0.2098
|
0.0932
|
0.0701
|
0.0755
|
0.0909
|
A(1,2,3)
|
107.2839
|
-0.0289
|
-0.0868
|
-0.0723
|
-0.0759
|
-0.0837
|
A(1,2,5)
|
130.3998
|
0.0367
|
0.0133
|
0.0033
|
0.0105
|
0.0129
|
A(3,2,5)
|
122.3163
|
-0.0067
|
0.0734
|
0.0691
|
0.0654
|
0.0708
|
A(2,3,4
|
106.8763
|
0.0327
|
0.1004
|
0.0931
|
0.0954
|
0.0977
|
A(2,3,6)
|
118.7999
|
0.0364
|
-0.0101
|
-0.011
|
-0.0063
|
-0.0137
|
A(4,3,6)
|
134.3238
|
-0.069
|
-0.0903
|
-0.0821
|
-0.0891
|
-0.084
|
A(3,4,7)
|
106.9992
|
0
|
0.1133
|
0.1006
|
0.1035
|
0.1071
|
A(3,4,11)
|
126.9066
|
-0.0152
|
-0.0744
|
-0.0644
|
-0.0674
|
-0.0596
|
A(7,4,11)
|
126.0942
|
0.0147
|
-0.0389
|
-0.0362
|
-0.0361
|
-0.0476
|
A(2,5,8)
|
117.4824
|
0.0454
|
-0.0145
|
-0.0024
|
-0.0042
|
-0.0052
|
A(2,5,12
|
121.3206
|
0.0999
|
0.1638
|
0.1263
|
0.1376
|
0.1382
|
A(8,5,12)
|
121.197
|
-0.1443
|
-0.1478
|
-0.1228
|
-0.1323
|
-0.1315
|
A(3,6,9)
|
119.1336
|
-0.0426
|
-0.0328
|
-0.027
|
-0.0282
|
-0.0243
|
A(3,6,13)
|
120.2866
|
0.0092
|
-0.0152
|
-0.0128
|
-0.0143
|
-0.0082
|
A(9,6,13)
|
120.5798
|
0.0334
|
0.048
|
0.0398
|
0.0425
|
0.0326
|
A(1,7,4)
|
109.6716
|
-0.089
|
-0.1202
|
-0.1212
|
-0.1207
|
-0.12
|
A(1,7,14)
|
120.3332
|
0.0816
|
0.1666
|
0.1684
|
0.1708
|
0.1816
|
A(4,7,14)
|
129.9952
|
0.0081
|
-0.0464
|
-0.0471
|
-0.0501
|
-0.0616
|
A(5,8,9)
|
121.2122
|
-0.0083
|
-0.0091
|
-0.0178
|
-0.0137
|
-0.0157
|
A(5,8,15)
|
119.4064
|
0.0256
|
0.0345
|
0.0381
|
0.0354
|
0.0297
|
A(9,8,15)
|
119.3815
|
-0.0167
|
-0.0247
|
-0.0199
|
-0.0212
|
-0.0135
|
A(6,9,8)
|
121.0556
|
-0.024
|
-0.0062
|
-0.0106
|
-0.0126
|
-0.0113
|
A(6,9,16)
|
119.7251
|
0.0287
|
0.0073
|
0.0145
|
0.0146
|
0.004
|
A(8,9,16)
|
119.2193
|
-0.0047
|
-0.0011
|
-0.0039
|
-0.0019
|
0.0073
|
Electronic and spectroscopic properties
Table 2
Chemical descriptors (eV)
|
EHOMO
|
ELUMO
|
Energy gap
|
Hardness
|
Chemical potential
|
Electrophilicity index
|
IND
|
-8.8898
|
-4.9521
|
3.9377
|
1.9689
|
-6.9210
|
12.1640
|
IND-DC
gaseous
|
-8.1358
|
-4.9644
|
3.1714
|
1.5857
|
-6.5501
|
13.5284
|
IND-DC
Water
|
-8.1247
|
-4.9698
|
3.1549
|
1.5775
|
-6.5473
|
13.5868
|
IND-DC
Ethanol
|
-8.1257
|
-4.9679
|
3.1578
|
1.5789
|
-6.5468
|
13.5729
|
IND-DC
Methanol
|
-8.1255
|
-4.9685
|
3.1570
|
1.5785
|
-6.5470
|
13.5772
|
IND-DC
DMSO
|
-8.1252
|
-4.9687
|
3.1565
|
1.5783
|
-6.5469
|
13.5787
|
The HOMO and LUMO of IND-DC are − 8.1358 and − 4.9644 eV while that of IND is -8.8898 and − 4.9521 eV (Table 2). Energy gap of IND-DC show a lowering effect (from 3.9377 to 3.1714 eV) and due to salvation there is further decrease in HOMO-LUMO energy gap values. Significant changes are observed for the IND-DC complex for hardness and chemical potential values in comparison with that of IND. The electrophilicity index of IND-DC and its solvated values increases in comparison with that of bare IND. These shows the reactivity changes in the system [29]. The HOMO and LUMO are localized on IND with interchange in polarity while in all complexes, HOMO is over the DC and LUMO is over the IND [30, 31]. This shows strong charge transfer from DC to IND (Fig. 2).
In the potential surface plots (Fig. 3), rings show yellow - negative electrostatic potentials, electrophilic regions, and H atom of NH show blue, stronger positive potential, nucleophilic region. These are the most reactive sites in the molecule. Chlorine atoms also contribute to reactive sites in the systems [32–34]. Due to complexation with DC, the dipole moment of the drug changes from 2.1478 to 0.7353 Debye while in all solvents, the dipole moment increases from that of IND-DC value but less than that of IND. All the polarizability components are increasing order except for the first order polarizability in the case of methanol solvent (Table 3). Hence complexation of IND increases the NLO activity [35–37].
Table 3
|
Dipole
Moment (Debye)
|
Polarizability
(×10− 23 esu)
|
First order Polarizability
(×10− 30 esu)
|
Second order Polarizability
(×10− 37 esu)
|
IND
|
2.1478
|
1.190
|
0.907
|
2.131
|
IND-DC (gaseous)
|
0.7353
|
1.622
|
1.347
|
6.812
|
IND-DC (Water)
|
1.7971
|
2.137
|
3.529
|
6.516
|
IND-DC (Ethanol)
|
1.5877
|
2.110
|
3.320
|
6.643
|
IND-DC (Methanol)
|
1.6252
|
2.119
|
0.964
|
6.625
|
IND-DC (DMSO)
|
1.6726
|
2.128
|
3.433
|
6.595
|
The IND charges, C2 and C5 decreases by an amount 0.02359 and 0.01944e while the H10 and H12 increases by 0.01403 and 0.01487e due to complexation with DC (table S1). In solvents also, these charges show deviations from the pristine values with significant variations. All these show the charge transfer due to complexation with DC.
The theoretically predicted IR and Raman spectra of all complexes are depicted in Figs. 4 and 5. The NH stretching mode of parent is 3561.26, which is red shifted in DC complex by an amount of 15.58 and due to solvation, the red shift increases to lower wavenumbers which shows the hydrogen bonding of drug with DC (tables S2 and S3). Also the parent molecule’s vibrational modes at 1650.12, 1609.24, 1541.59, 1506.04, 1464.94, 1337.64 show lowering of wavenumber value in the DC complex and such lowering increases with salvation. Different vibrational modes of IND undergo red and blue shift due to DC complexation. All these shifts show the interaction between IND molecule and DC due to hydrogen bonding [6].