3.1. Experimental work investigation
As shown in Fig. 2 the huge number of short contacts in the Pd-complex crystal structure gives evidence about the perfect arrangement of molecules in the unit cell and that leading to think about formation of other metal complexes of parallel arrangement including the same chelating ligand species. Atom speciation short contacts occupy an important space including intramolecular C..H, intermolecular O..H and intramolecular besides intermolecular Cl..H contacts, but the investigated results not show N..H and S..H either intra or intermolecular contact type. This is attributed to the chelating bidentate ligand (coordinate with N and S) face most of its electronic density around the core of Pd metal.
3.2. DFT crystallographic modulation
To compare between the modulated metal structures with the experimental data, Table 1 presents some important geometrical bond lengths and bond angles of the studied complexes. The observed X-ray geometrical indices were compared with the calculated results using DFT/B3LYP/LanL2DZ effective method in gas phase. The experimental Pd1-S2, pd1-Cl3, Pd1-Cl4 and Pd1-N5 bond lengths have values 2.260, 2.328, 2.293 and 2.102 Å, respectively. There is a satisfied computational result with the experimental ones except in case of Zn-morpholine complex in which Zn1-S2 bond length is 2.692Å. This difference may be attributed to the weak bond formed between Zn atom and S atom of the ligand destroying the molecular stability of the unit cell structure. X-ray bond angles of S2-M1-Cl3, S2-M1-Cl4, S2-M1-N5, Cl3-M1-Cl4, Cl3-M1-N5 and Cl4-M1-N5 are 169.0, 88.1, 89.1, 91.0, 92.7 and 174.3o, respectively. evaluating the bond angles of the studied complexes, it was found the computational results of Pd- complex move in the same trend leading to formation of a square planar structure, also, in case of Ni-complex the data calculated are relatively closer to P-complex indicating a square planar Ni-complex formation. On the contrary, the data investigated for Zn-complex not as the same in both Pd- and Ni structures. Bond angles values in Zn-complex insight a tetrahedral structure formation. Fig. 3 illustrates theoptimized structures of the studied complexes with full labeled atoms.
Table 1
Geometrical parameters of X-ray Pd complex and the modulated structures (Pd, Zn and Ni) using DFT/LanL2DZ method
|
Experimental
X-ray
|
Pd-complex
DFT/B3LYP/
LanL2DZ
|
Zn-complex
DFT/B3LYP/
LanL2DZ
|
Ni-complex
DFT/B3LYP/
LanL2DZ
|
Bond Length(Å)
|
M1-S2
|
2.260
|
2.356
|
2.692
|
2.355
|
M1-Cl3
|
2.328
|
2.387
|
2.292
|
2.238
|
M1-Cl4
|
2.293
|
2.373
|
2.294
|
2.231
|
M1-N5
|
2.102
|
2.182
|
2.198
|
2.056
|
S2-C21
|
1.820
|
1.907
|
1.911
|
1.902
|
S2-C24
|
1.787
|
1.87
|
1.862
|
1.872
|
N5-C6
|
1.496
|
1.523
|
1.519
|
1.526
|
N5-C15
|
1.500
|
1.522
|
1.521
|
1.524
|
N5-C18
|
1.513
|
1.516
|
1.509
|
1.517
|
C9-O35
|
1.423
|
1.464
|
1.464
|
1.464
|
C12-O35
|
1.424
|
1.461
|
1.463
|
1.461
|
Bond angle
|
S2-M1-Cl3
|
169.0
|
174.2
|
97.3
|
169.6
|
S2-M1-Cl4
|
88.1
|
88.2
|
111.9
|
86.03
|
S2-M1-N5
|
89.1
|
88.5
|
87.4
|
89.8
|
M1-S2-C21
|
97.3
|
106.5
|
84.9
|
94.9
|
M1-S2-C24
|
110
|
93.3
|
113.8
|
107.5
|
Cl3-M1-Cl4
|
91.0
|
92.0
|
134.5
|
91.8
|
Cl3-M1-N5
|
92.7
|
91.6
|
107.1
|
93.1
|
Cl4-M1-N5
|
174.3
|
175.8
|
109.6
|
173.5
|
M1-N5-C6
|
108.9
|
109.7
|
107.3
|
109.9
|
M1-N5-C15
|
110.0
|
107.4
|
107.1
|
107.4
|
M1-N5-C18
|
108.5
|
108.7
|
109.6
|
110.3
|
*M = Pd, Ni, Zn |
To examine the natural bond orbital analysis, the atomic charges of the compound must be in the full optimized state till reach the ground state stationary point.
Table 2 present the atomic charges calculated with NBO method for the studied complexes optimized in gas state. Imaginarily about the electronic behavior around the central metal atom increase according to the affinity of the metal to electrons. The atomic partial charge around Pd is 0.187 and around Ni atom is 0.242, these values are positive small compared with Zn atom (1.043). This difference in charges indicate the atomic orbitals of Pd and Ni become strongly combined with the atomic orbitals of coordinated ligands that can lead to a markedly increasing in metal-ligand charge transfer but the atomic orbitals combination is considered as a weak metal-ligand charge transfer reaction. Also, the strong combination in atomic orbitals of Pd and Ni can be proved by the high positive charge value on S2 atom (0.381 and 0.369) compared with the value (0.198) in Zn-complex. The charges on Cl atoms are small with negative values in both Pd and Ni complexes, on the contrary, charges on Cl atoms are higher with negative values. As the same comparison for N atom, but for O atom the charges mostly as the same in the three complexes.
Table 2
NBO charges of the studied M-complexes using computational analysis.
Atom
|
Pd-complex
DFT/LanL2DZ
|
Zn-complex
DFT/LanL2DZ
|
Ni-complex
DFT/LanL2DZ
|
M1
|
0.187
|
1.043
|
0.242
|
S2
|
0.381
|
0.198
|
0.369
|
Cl3
|
-0.396
|
-0.626
|
-0.397
|
Cl4
|
-0.367
|
-0.625
|
-0.374
|
N5
|
-0.532
|
-0.664
|
-0.553
|
C6
|
-0.238
|
-0.244
|
-0.240
|
H7
|
0.261
|
0.241
|
0.261
|
H8
|
0.230
|
0.240
|
0.228
|
C9
|
-0.079
|
-0.079
|
-0.078
|
H10
|
0.176
|
0.180
|
0.176
|
H11
|
0.234
|
0.232
|
0.234
|
C12
|
-0.078
|
-0.079
|
-0.078
|
H13
|
0.234
|
0.233
|
0.234
|
H14
|
0.175
|
0.178
|
0.175
|
C15
|
-0.244
|
-0.251
|
-0.246
|
H16
|
0.223
|
0.239
|
0.222
|
H17
|
0.261
|
0.242
|
0.262
|
C18
|
-0.227
|
-0.229
|
-0.228
|
H19
|
0.239
|
0.236
|
0.237
|
H20
|
0.223
|
0.219
|
0.222
|
C21
|
-0.508
|
-0.510
|
-0.511
|
H22
|
0.246
|
0.254
|
0.243
|
H23
|
0.250
|
0.250
|
0.251
|
C24
|
-0.168
|
-0.177
|
-0.164
|
C25
|
-0.233
|
-0.226
|
-0.233
|
H26
|
0.225
|
0.230
|
0.227
|
C27
|
-0.201
|
-0.203
|
-0.201
|
H28
|
0.227
|
0.226
|
0.227
|
C29
|
-0.203
|
-0.204
|
-0.204
|
H30
|
0.227
|
0.226
|
0.227
|
C31
|
-0.193
|
-0.198
|
-0.194
|
H32
|
0.232
|
0.231
|
0.231
|
C33
|
-0.206
|
-0.217
|
-0.208
|
H34
|
0.254
|
0.251
|
0.252
|
O35
|
-0.612
|
-0.617
|
-0.613
|
Quantitative structure activity relationship (QSAR) mainly depends on the core indices construct the activity versus stability framework of complexes. The insight to energy leading to investigation the highest occupied and lowest unoccupied molecular orbital energies (EHOMO and ELUMO) which control the electronic properties of the studied complexes.
Some important reactivity parameters were calculated as the following:
I = - EHOMO (1)
A = - ELUMO (2)
η = (I-A)/2 (3)
µ = - (I+A)/2 (4)
σ = 1/ η (5)
EGAP = ELUMO- EHOMO (6)
The data calculated present in Table 3 where the dipole moment values indicate whether is most polarizable compound. Pd-complex show higher dipole moment value (13.335) then Ni-complex (12.838) and the the lower is of Zn-complex (10.877). the relation between these parameters and stability of compounds can mainly help in the chemical reactions whose these compounds associated [25]
The frontier molecular orbitals (FMOs) of Pd-complex occur in levels with energies enough to motivate compound stabilization (EGAP = 5.74 ev) through electron transition where it is relatively small compared with the other complexes. Also, other parameters significantly control the compounds stability and reactivity such as ionization potential (I), electron affinity (A), chemical potential (µ), chemical hardness (η) and global softness (σ) were calculated and tabulated. Also, a helpful polarizability index (α) was calculated and indicated that Pd-complex is the most polarizable molecular structure (207.089).
Figure 4 shows the FMOs of the studied complexes with the energy of each level where the highest occupied molecular orbital (HOMO) contribution is mainly on the whole coordinated N ring bearing O atom in both Pd and Ni complexes, but this contribution not appear in Zn-complex. This aimed to that Pd and Ni-morpholine derivative complexes mostly act in the same as structural and electronic behavior.
Table 3
Reactivity parameters of the studied complexes in gas phase with B3LYP/6-311g (d,p)
Parameter
|
Pd- complex
|
Zn-complex
|
Ni-complex
|
E (Hartee)
|
-764.206
|
-703.110
|
-806.778
|
D (debye)
|
13.335
|
10.877
|
12.838
|
EHOMO (ev)
|
-6.80
|
-7.05
|
-7.10
|
ELUMO (ev)
|
-1.06
|
-0.93
|
-0.73
|
EGAP (ev)
|
5.74
|
6.12
|
6.37
|
I
|
6.80
|
7.05
|
7.10
|
A
|
1.06
|
0.93
|
0.73
|
η
|
2.87
|
3.06
|
3.19
|
µ
|
-3.93
|
-3.99
|
-3.92
|
σ
|
0.348
|
0.327
|
0.313
|
α (a.u.)
|
207.089
|
180.825
|
196.643
|
3.3. IR Spectroscopic analysis
Differences in spectroscopic data analysis between the modulated and reported structures seem to be simple. Fig. 5 shows DFT/IR and Raman spectral bands obtained for the reported Pd complex and the modulated Zn-, Ni- complexes. Vibrational frequencies were taken in the range of 500-4000 cm-1 and were performed by normal modes that corresponding to the ground state molecular electronic structure [26, 27].
The characteristic bands of the three studied molecular structures varies in their absorbance and scatter intensity from strong into weak contribution. Very simple variations in the peak position and intensity especially the position of M-coordinated atom peak due to the electronic environment surrounded by the band group. Mostly in all studied cases, the peaks appear in the position range 3238cm-1 – 3216cm-1 are corresponding to =C-H aromatic group, whereas the peaks located at 3181cm-1 - 3007cm-1 are characteristic to -C-H aliphatic group. C=C stretching peak appear at 1626 cm-1. The observed peak at 1313 cm-1 is attributed to C-O stretching bond analysis. There are also some weak peaks appear in the range 1081cm-1 – 1057cm-1 that corresponding to C-C and C-N stretching single bonds. The band at 614 cm-1 is corresponding to C-S bond. A strong peak appears at 1523 cm-1 is corresponding to -C-H bending. Pd-N stretching band appears at 549 cm-1. Pd-Cl appears at 346 cm-1 but not occur in the computational scale. Ni-N band occurs at 552 cm-1, while Zn-N band appears at 536 cm-1.
3.4. UV-Vis spectra detection (TD-DFT)
CPCM model in DT-DFT method is best describe the behavior of electronic transitions in the molecular structure. Fig. 6 shows the different transition states for the studied optimized Pd, Zn and Ni complexes. It was observed that there are three transitions with different excitation environment. Mentioned to UV/Vis spectra of Pd-complex, the orbital contribution in the three transitions involve HOMO-2, HOMO-1 and HOMO to only LUMO state. This case indication about the limitation of electron transfer to higher unoccupied states and that must need higher absorption energy for successive electronic transitions. In case of Ni-complex, the peaks appear in higher wavelength range with small absorbance values, that may be increasing the difficulty for Ni-morpholine derivative crystal structure formation in the same condition of Pd-complex synthesis. The orbital contribution as the same in Pd-complex in transition to only LUMO level while there are successive transitions between HOMO and its lower states. In case of Zn-complex, UV/Vis spectra appeared at lower wavelength higher absorbance. These transitions are allowed for the ligand intra-excitation states (n-π* and π-π*) but d-d transition, that distinguish the metal-ligand transition, not observed. The excitation energy for each transition and orbital contribution are tabulated in Table 4.
Table 4. Excitation energies, maximum wavelengths, oscillator strengths and % orbital contribution for the studied experimental and modulated crystal structures.
Compound
|
Spectral line
number
|
Excitation
energy (eV)
|
λmax (nm)
|
F
|
Type of transition
|
contribution % orbital
|
Pd-complex
|
1
|
2.128
|
582.72
|
0.0023
|
HOMO→LUMO
|
64.8
|
2
|
2.295
|
540.31
|
0.0001
|
HOMO-1→LUMO
|
63.7
|
3
|
2.408
|
514.82
|
0.0041
|
HOMO-2→LUMO
|
56.2
|
Ni-complex
|
1
|
1.071
|
1157.41
|
0.0001
|
HOMO→LUMO
|
60.37
|
2
|
1.372
|
903.92
|
0.0001
|
HOMO-2→LUMO
|
43.40
|
HOMO-1→LUMO
|
37.65
|
3
|
1.429
|
867.74
|
0.0001
|
HOMO-3→LUMO
|
52.10
|
HOMO-2→LUMO
|
20.04
|
Zn-complex
|
1
|
5.227
|
237.18
|
0.0024
|
HOMO-2→LUMO
|
48.71
|
HOMO-1→LUMO
|
47.40
|
2
|
5.372
|
230.81
|
0.0610
|
HOMO-1→LUMO
|
53.20
|
HOMO→LUMO
|
35.60
|
3
|
5.469
|
226.70
|
0.0369
|
HOMO-1→LUMO
|
33.99
|
HOMO→LUMO
|
60.39
|
3.5. Hirschfeld surface analysis of Pd-complex structure
This type of analysis discusses the percent quantity of crystal structure intermolecular contacts represented with red spots. Fig. 7 shows these surface analytical contacts for Pd-complex. 3D-fingerprint plots in Fig. 8 give evolution about the percent atom pairs contacts where all the contact atom pair types present as a whole percent 100%. The close contact between the inside Cl layered atom to the outside H atom gives 18.4%. The inside O to outside H gives 3.5%, while the inside S atom to outside H atom gives 2.5% contact.
The crystal packing of Pd-complex (unit cell dimensions 1:1:1) present in Fig. 9 as the close intermolecular contacts are represented in red lines. The maximum bond distance of these contacts was chosen as 2.70 Ǻ where there are different types of atom pair intermolecular contacts. Increasing the contact distance (> 2.70 Ǻ), larger types of interactions appear around the crystal structure of Pd-complex. Due to different types of heteroatoms, the crystal structure packing is strong between the molecules and that lead to a significant arrangement of the crystal structure [28].
3.6. Molecular docking simulation
As a part of molecular behavior for complexes toward the biological inhibition process, the studied metal-morpholine derivative complexes were docking investigated in binding with 1O6S and 2BHM receptor codes.
Figure 10 visualizes the molecular docking of the three studied metal-complexes with either 1O6S and 2BHM protein receptors. Furthermore, the best explored 1O6S results of molecular docking for Ni- and Zn-morpholine derivative complexes located in the same position pocket with total fitting energy of -59.80 Kcal/mol and -58.70 kcal/mol while the previously synthesized Pd-morpholine derivative complex in other protein position with total docking score of -60.300 kcal/mol. For the three complexes, the docking score energies are significantly the same but the difference in the type and number of bound protein amino acids. As shown from Table 5, Pd-complex binds with 7 amino acids and the mode of binding either H-bond or VdW interaction through different heteroatoms of morpholine derivative ligand. While Ni-complex and Zn-complex bind with11 and 10 amino acids respectively with variation in binding site energy. In case of docking with 2BHM protein target, the best docked score found that Pd- and Zn- complexes bind with protein amino acids closely in similar position while Ni-complex bind in other position. This may depend on the electronic behavior on the surface of the complex where this is obvious from the ultra-folding of morpholine derivative ligand of Zn-complex during docking analysis. Molecular docking data are present in Table 6, the total score energy for Pd-,Ni- and Zn-complexes are -64.800, -65.400 and -61.200 kcal/mol. Pd-complex is surrounded by 7 types of binding amino acids, but Ni- and Zn- complexes are surrounded by 6 binding amino acids in the target pocket.
Table 5
the total energy score (fitting) of the studied M-complexes with 1O6S target
M- Complex
|
Pd- morpholine derivative
|
Ni- morpholine derivative
|
Zn- morpholine derivative
|
Energy (kcal/mol)
|
-60.300
|
-59.800
|
-58.700
|
H- ASN-282
|
-2.780
|
0.000
|
0.000
|
H- ASP-67
|
0.000
|
-3.500
|
-1.578
|
H- TYR-74
|
0.000
|
-2.500
|
0.000
|
V- GLN-82
|
0.000
|
-0.656
|
-4.506
|
V- ARG-85
|
0.000
|
-4.651
|
-0.336
|
V- ASN-282
|
-4.911
|
0.000
|
0.000
|
V- LYS-25
|
-5.858
|
0.000
|
0.000
|
V- LYS-33
|
-5.100
|
0.000
|
0.000
|
V- VAL-34
|
-4.596
|
0.000
|
0.000
|
V- TYR-36
|
-4.592
|
0.000
|
0.000
|
V-THR-57
|
-4.945
|
0.000
|
0.000
|
V-S-GLU-64
|
0.000
|
-4.157
|
-9.861
|
V- PRO-65
|
0.000
|
-2.206
|
-4.286
|
V- LEU-66
|
0.000
|
-5.541
|
-5.389
|
V- ASP-67
|
0.000
|
-1.877
|
-5.712
|
V- ASP-67
|
0.000
|
-3.689
|
-6.278
|
V- ARG-70
|
0.000
|
-8.589
|
-7.038
|
V- ILE-71
|
0.000
|
-5.637
|
-0.976
|
Table 6
the total energy score (fitting) of the studied M-complexes with 2BHM target
complex
|
Pd-morpholine derivative
|
Ni- morpholine derivative
|
Zn- morpholine derivative
|
Energy (kcal/mol)
|
-64.800
|
-65.400
|
-61.200
|
H- GLY-174
|
0.000
|
-3.500
|
0.000
|
H- ASN-225
|
-2.604
|
0.000
|
-2.453
|
V- PRO-135
|
-4.590
|
0.000
|
-0.091
|
V- ASN-225
|
-7.136
|
0.000
|
0.000
|
V- ASP-99
|
0.000
|
-4.397
|
0.000
|
V-ASP-99
|
0.000
|
-6.596
|
0.000
|
V-ASP-103
|
0.000
|
-5.550
|
0.000
|
V- TYR-204
|
0.000
|
-6.886
|
0.000
|
V- TYR-206
|
0.000
|
-18.614
|
0.000
|
V- MET-131
|
-0.997
|
0.000
|
-5.511
|
V- MET-131
|
-0.024
|
0.000
|
-4.745
|
V- MET-212
|
-0.237
|
0.000
|
-6.061
|
V- ASN-225
|
-6.858
|
0.000
|
-2.754
|