This paper describes spectral, non-linear optical (NLO), and biological activity variation of pyrrole hydrazones as a result of structural variation. In order to study structure-property variation, pyrrole hydrazones (3A, 3B, and 3C) were synthesized in both solid and solution phases. The grinding solvent-free method becomes rapid, easy, convenient, useful, sustainable, and eco-friendly green synthesis as compared to the classical solution phase reactions. The structure of pyrrole hydrazones has been elucidated by microanalysis and quantum chemical calculations. The intense emission at λem 521 nm (3A and 3B) and 617 nm (3C) in the visible (green and orange) region with Stokes shifts at 195, 160, and 282 nm reveals that the studied compounds work as good photoluminescent materials. All compounds show strong n-π* and charge transfer (π-π*) transitions in the UV-vis region with high extinction coefficients. In the studied systems (3A, 3B, and 3C), the orbital overlap between σ(NH-O) → σ*(NH-O) is found due to intra-molecular charge transfer. The first hyperpolarizabilities were found to be 48.83 × 10-30 esu for 3B and 63.89 × 10-30 esu for 3C, showing variation with structure. Their high values indicate more suitability for NLO application. Incorporation and/or change in position of electron-withdrawing groups increase the β0 values of 3B and 3C compared to 3A. The β value also increases monotonically as the polarity of the solvents increases. The red shift in N-H and C=O stretching Fourier-transform infrared bonds is due to the formation of dimers. The synthesized 3A, 3B, and 3C show good antimicrobial activity and are predicted to be potential antibacterial and antifungal drugs. The 3B has more molar refractivity (122.16 esu) than 3A and 3C and correlates well with the calculated binding affinity and experimental antimicrobial data.
This paper describes spectral, non-linear optical (NLO), and biological activity variation of pyrrole hydrazones as a result of structural variation. In order to study structure-property variation, pyrrole hydrazones (3A, 3B, and 3C) were synthesized in both solid and solution phases. The grinding solvent-free method becomes rapid, easy, convenient, useful, sustainable, and eco-friendly green synthesis as compared to the classical solution phase reactions. The structure of pyrrole hydrazones has been elucidated by microanalysis and quantum chemical calculations. The intense emission at λem 521 nm (3A and 3B) and 617 nm (3C) in the visible (green and orange) region with Stokes shifts at 195, 160, and 282 nm reveals that the studied compounds work as good photoluminescent materials. All compounds show strong n-π* and charge transfer (π-π*) transitions in the UV-vis region with high extinction coefficients. In the studied systems (3A, 3B, and 3C), the orbital overlap between σ(NH-O) → σ*(NH-O) is found due to intra-molecular charge transfer. The first hyperpolarizabilities were found to be 48.83 × 10-30 esu for 3B and 63.89 × 10-30 esu for 3C, showing variation with structure. Their high values indicate more suitability for NLO application. Incorporation and/or change in position of electron-withdrawing groups increase the β0 values of 3B and 3C compared to 3A. The β value also increases monotonically as the polarity of the solvents increases. The red shift in N-H and C=O stretching Fourier-transform infrared bonds is due to the formation of dimers. The synthesized 3A, 3B, and 3C show good antimicrobial activity and are predicted to be potential antibacterial and antifungal drugs. The 3B has more molar refractivity (122.16 esu) than 3A and 3C and correlates well with the calculated binding affinity and experimental antimicrobial data.
Hydrazones possess the
−CH=NNH– frame, representing
an important class of compounds for drug development and material
applications. It contains a C=N double bond and two connected
nitrogen atoms of different nature. These structural frames are mainly
responsible for variation of physical and chemical properties of hydrazones,
thereby attracting researchers to synthesize them as target structures
for various applications. Difference in nature of nitrogen atoms provides
capability to react with electrophilic and nucleophilic reagents;
hence, majority of the hydrazine derivatives are used in the synthesis
of heterocyclic compounds and nitrogen-containing organic compounds.
Hydrazones display a range of biological spectra.[1−7] The chemical structures of materials and their variety of biological
effects are scientifically significant and have been responsible for
the development of many technologically relevant fields of interest.The finding of hidden data and trends is encouraged and facilitated
by machine learning (ML). ML allows us to model patterns and correlate
data for relationships and predictions. Material properties such as
melting point, glass transition temperature, hardness, ionic conductivity,
molecular atomization energy, and lattice constant are all used macroscopically
and microscopically.[8] To identify a material
with better performance from the candidate sets, screening and a probabilistic
model are utilized. It is a project that aims to use computational
tools to find new materials and assess their properties. To anticipate
material attributes, quantitative structure–property relationships
(QSPRs) use basic physicochemical features. Density functional theory
(DFT) constructs molecular structures using ab initio calculations.[9] In DFT,[10] validation
is used to find and forecast interatomic potentials. Validation is
used in DFT[10] to search for and forecast
interatomic potentials. The various properties are critical for the
creation of novel medications, as they determine the pharmacokinetic
profile. In chemistry and physics, the DFT approach[11] is used to find the lowest energy state, electronic structure,
chemical reactivity, and material properties.[12−16] Chemical information included in a symbolic representation
of a molecule is converted into a meaningful number of molecular descriptors
that are used to correlate the outcome of a standardized experiment
using logic and mathematics. The objective of the present paper is
to design and synthesize new organic compounds—pyrrole hydrazones
for production of properties. The electro-optical and non-linear optical
(NLO) materials have received considerable attention due to their
wide range of potential applications.[16−18] When donor and acceptor
groups are present at opposite ends, it leads to significant change
and plays an important role in material field, and such materials
serve as critical components in several advanced technologies, such
as NLO devices, organic light-emitting diodes, photovoltaic cells,
and so forth.[17−21]In light of the preceding literature review, pyrrole hydrazones
were produced by reacting formyl pyrrole with aromatic hydrazides
containing nitro and carbonyl groups as acceptors and analyzing them
using spectroscopic, quantum chemical, and microanalysis. The results
show increase in first static hyperpolarizability and activity with
incorporated acceptors being responsible for structural variation.
Experimental Section
The analytical
grade chemicals were used as such without further
purification. The infrared (IR) spectra were recorded in KBr disc
using a Nicolet MX-1 FTIR spectrophotometer. On a Bruker spectrometer, 1H NMR spectra were acquired at 300 MHz (in DMSO-d6 or methanol solvent), and chemical shifts were reported
in parts per million (ppm) units relative to an internal standard,
TMS. The UV–vis spectra were recorded using a Shimadzu UV 2100
UV–vis recording spectrophotometer in the 200–800 nm
range. UV patterns were recorded in a DMSO solution with a concentration
of 10–5 M. The mass spectra were recorded using
an EI a Micromass Quattro II triple quadrupole mass spectrometer.
The melting points were determined using the open capillary tube method,
and the data were uncorrected.
Conventional Method of Synthesis
An ice cold stirring solution of ethyl-4-formyl-3,5-dimetyl-1H-pyrrole-2-carboxylate (0.200 g, 1.0251 mmol) (1) in methanol was added dropwise to the corresponding hydrazide derivatives
(2A, 2B, 2C) (0.139 g, 1.025
mmol) in 15 mL of methanol with stirring. After stirring at room temperature,
the precipitates of cream, orange, and yellow colors were obtained,
respectively. The precipitates were filtered off, washed with methanol,
and dried in air. Yield: 3A, 75%, 3B, 82%,
and 3C, 85%. All compounds decomposed above 250 °C
without melting.
Compounds
(3A, 3B, 3C) and reactants
(phenyl hydrazine 2A, para nitro phenyl hydrazine 2B, and para nitro benzoic acid hydrazide 2C)
dissolved in DMSO were investigated for their biological activity.
As a pharmacological control, DMSO was employed. All chemicals and
reactants were tested for bactericidal activity at concentrations
of 100 and 200 g/mL. The substance dispersed into the medium’s
concentration gradient. After the incubation period, the inhibitory
zones were measured in centimeters. The actual reading control is
represented by the tabulated results. The compounds were tested against Escherichia coli, Pseudomonas aeruginosa (Gram negative bacteria), Staphylococcus aureus, Streptococcus pyogenes (Gram positive
bacteria), Candida albicans, and Aspergillus niger (fungi). The plates were placed
in an incubator for bacterial growth at 37 °C and for fungal
growth at 22 °C within 30 min of preparation. After 48 h of incubation
for bacteria and 7 days for fungus, the diameter of the zone (including
the diameter disc) was measured in mm and recorded. The measurements
were taken from the bottom of the plate using a ruler without opening
the lid.
Computational Detail
DFT has progressed
from a rising star to a key player in computational quantum chemistry
during the last few decades. DFT was used to calculate the conformational
geometries of the target molecule.[11] For
all calculations, the Gaussian 09 program package[22] was utilized. The global and local indices were calculated
using Koopman’s approach.[23−25] To obtain the aforementioned
indexes, we used single-point computations of the anion and cation
at the neutral molecule’s optimal geometry, ensuring that the
external potential remained constant. The development of new and more
accurate density functionals is a very active research subject. Although
efforts are being made to construct more “general-purpose”
capabilities, it is understood that some functionalities are better
suited to certain applications than others. With a favorable balance
of accuracy and computational cost, the B3LYP functional, which uses
the basis set 6-311++G(d,p), has been effectively used in reactivity
investigations.[11−15] The original geometry constructed from traditional geometrical parameters
was reduced at the DFT level without any constraints in the potential
energy surface using the standard 6-31G(d,p)/6-311++G(d,p) basis set.
The time-dependent DFT was used to determine electronic absorption
spectra on the optimized structure (TD-DFT). An online Ramachandran
(RC) plot server was used to construct the RC plot.[26] The online Achilles blind docking server application[27] was used to execute the molecular docking investigation.
The docking findings were observed using a PYMO visualizer.[28]
Results and Discussion
Structural Elucidation and Thermodynamics
Consideration
Finding novel materials with good performance
is a constant issue in materials research. Elements are being replaced
and structures are being transformed in current experimental and computational
screenings for discovery of novel materials. Compositional search
space, structural search space, or both are, on the other hand, frequently
restricted. Both screening approaches may necessitate a significant
amount of calculation or testing, and they usually result in an “exhaustive
search” that consumes a significant amount of time and resources.
In light of these facts and the benefits of ML, a completely adaptive
method combining ML and computational simulation is offered for the
“in silico” evaluation and screening of new materials
to provide proposals for new and better materials. The route for formation
of (3A, 3B, 3C) is shown in Scheme , and characteristic
values for identification are given in Table . The classical solvated method requires
more hours at reflux temperature in order to obtain good yields.
Scheme 1
Formation of Pyrrole Hydrazones (3A, 3B, 3C)
Table 1
Yields and 1H NMR, 13C NMR, MASS, and IR Data of Pyrrole Hydrazones; T = Theoretical
Calculated Value, E = Experimental Value, S = Solution Phase, G =
Grinding Method
chemical
shifts
prod.
yield (%)
1H
13C
mass
IR (cm–1)
3A
75S, 97G
–NH (11.50)E
286.18
NH= (M 3506T)
(D 3271E, 3341T)
=NNH (11.40)E
COCH2CH3 (158.68)E
–CH=NNH (M 3010T)
(3002E, D 3011T)
–CH=N– (7.89)E
–CH=N (149.94)E
–C=N (M 1599)
(1566E, D 1551T)
–CH2CH3 (4.18–4.25)E
–CH2 (59.35)E
COCH2 (M 1688T)
(1663E, D 1655T)
3B
82S, 99G
–NH (11.51)E
330.21
NH= (M 3500T)
(3228E, D 3341T)
=NNH (11.79)E
COCH2CH3 (161.01)E
–CH=N (8.75)E
–CH=N (149.94)E
–C=N (M 1594T)
(1589E, D 1601T)
–CH2CH3 (4.20–4.271)E
–CH2 (61.59)E
COCH2 (M 1691T)
(1660E, D 1654T)
–CH2CH3 (1.28–1.33)E
–CH3 (14.35)E
3C
85S, 99G
–NH (11.67)E
–CO
(160.64)E
359.13
NH= (M 3498T)
(3342E, D 3337T)
=NNH–CO (11.76)E
COCH2CH3 (160.51)E
–CH=N (8.48)E
–CH=N (148.94)E
–C=N (M 1604T) (1489E D 1507T)
–CH2CH3 (4.21–4.28) E
–CH2 (59.26)E
COCH2 (M 1691T)
(1668E, D 1655T)
–CH2CH3 (1.27–1.32)E
–CH3 (14.35)E
–NHC=O (1717)
Next, the grinding method was used for the formation
of (3A, 3B, 3C) compounds.
In this method,
manual grinding of (2A, 2B, 2C) with 1 can be carried out by using a mortar and pestle.
The chemical reaction proceeds due to collisions between the reacting
molecules. Pyrrole hydrazones were synthesized in higher yields using
this approach. The most frequent method for inducing mechanochemical
reactions is grinding using a mortar and pestle.The geometrical
parameters of (3A, 3B, 3C)
have been calculated by DFT/B3LYP levels with
the 6-31G**(d,p) basis set and are listed in the Supporting Information Table 1, and the optimized configuration
of monomer and conformers is shown in Figure . The optimized configuration of dimers along
with numbering and labeling is given in the Supporting Information Figure 1. Because these compounds lack crystal
structures, the best structures can only be compared to other related
systems with optimized configurations. In good percentage yields,
new pyrrole hydrazone compounds were produced. The synthesized derivatives
are stable, and they can be kept at room temperature for longer periods
of time. The structures of synthesized compounds were not only confirmed
by IR, 1H and 13C NMR, elemental analysis, UV–vis,
and mass spectrometry but also with the electronic descriptors. Further
conformational analysis has been performed without imposing any symmetry
constraints on the molecule to understand the conformers’ stability.
The potential energy of 3A, 3B, and 3C was determined by the variation in the total energy of
the molecule with change in dihedral angles (C3C2C9O10)/(C5C4C13N14) 3A, (C3C2C9O13)/(C5C4C7N10) 3B, and (C3C2C22O24),
(C5C4C7N9) in 3C, as shown in Figure . Two minima were observed in the potential
energy curve around the dihedral angles (C3C2C9O10)/(C5C4C13N14) 3A, (C3C2C9O13)/(C5C4C7N10) 3B, and (C3C2C22O24),
(C5C4C7N9) 3C which correspond to the conformers 3A/3A/3A, 3B/3B/3B, and 3C/3C/3C The 3A, 3B,
and 3C are lower in energy than the latter one and thus
represent the more stable conformers. The enthalpy differences between
conformers 3A/3A/3A, 3B/3B/3B, 3C/3C/3C are 0.251, 0.7275, 0.323, 0.773,
0.252, and 1.281 kcal/mol. All calculations have been performed on
stable conformers which would correspond to lower energy value that
is the conformers 3A, 3B, and 3C. The calculated thermodynamic parameters are listed in Table . The calculated negative
values show that reactions 3A, 3B, and 3C are spontaneous and exothermic at room temperature.
Figure 1
Optimized ground
state geometry along with conformers of pyrrole
hydrazones (3A, 3B, 3C).
Table 2
Calculated Enthalpy (au), Gibbs Free
Energy (au), and Entropy (Cal (mol Kelvin)−1) for 1, 2A/B/C, Products (3A, 3B, 3C), and Water
1
2A/B/C
product (3A, 3B, 3C)
water
reaction
reaction (kcal/mol)
Compound A
enthalpy (H)
–669.1265
–342.7912
–935.5271
–76.3945
–0.0040
–2.5301
Gibbs free energy (G)
–669.1858
–342.8299
–935.6022
–76.4160
–0.0023
–1.4846
entropy (S)
124.946
81.569
157.893
45.116
–3.506
Compound B
enthalpy (H)
–669.1265
–547.2897
–1140.0275
–76.3945
–0.0058
–3.6690
Gibbs free energy (G)
–669.1858
–547.3354
–1140.1084
–76.4160
–0.0031
–1.9628
entropy (S)
124.946
96.122
170.23
45.116
–5.722
Compound C
enthalpy (H)
–669.1265
–660.6235
–1253.3507
–76.3945
0.0047
2.9894
Gibbs free energy (G)
–669.1858
–660.6743
–1253.4367
–76.4160
0.0075
4.7201
entropy (S)
124.946
107.039
181.065
45.116
–5.804
Optimized ground
state geometry along with conformers of pyrrole
hydrazones (3A, 3B, 3C).
Assignments of Vibrational Frequencies Based
on Experimental Values and Theoretical Calculations
For the
identification of functional groups in organic compounds, vibrational
spectroscopy is used extensively.[29] The
frequency agreement between estimated harmonics and observed fundamental
modes can be used to propose complicated system assignment. The simulated
IR spectra are shown in Figure , and experimental spectra are given in the Supporting Information Figure 2. The resulting vibrational
wave numbers for the optimized geometries of (3A, 3B, 3C) and the proposed brief assignments are
given in Table . The
detailed vibrational analysis carried out with the help of PED for
(3A, 3B, 3C) is given in the Supporting Information Table 2a–c, respectively.
Figure 2
FT-IR
simulated spectra of 3A, 3B, and 3C.
FT-IR
simulated spectra of 3A, 3B, and 3C.In the experimental FT-IR spectra of (3A, 3B, 3C), the N–H stretching vibrations
of pyrrole
(νN–H) are observed at 3271, 3269, and 3342
cm–1 and calculated as 3341, 3342, and 3337 cm–1 in the dimer and 3506, 3507, and 3498 cm–1, respectively, in the monomer. The observed wavenumbers are in good
agreement with the calculated wavenumber of dimer than monomer, and
similar observation has been found in our earlier studies and also
reported in the literature for the hydrogen-bonded dimer of pyrrole.[30−33] As a result, the vibration of the hydrogen-linked N–H group
is attributed to the solid-state spectra of (3A, 3B, 3C). The stretching wavenumber of the hydrogen
bond donor (N–H) in the dimer is redshifted due to the elongation
of the conventional hydrogen bond donor (N–H bond) compared
to the free N–H group in the monomer due to the elongation
of the conventional hydrogen bond donor (N–H bond). The computed
and observed spectra are found to be very close to each other. Deformation
of N–H has appeared at 1517 cm–1 and calculated
as 1535 cm–1. The solid-state spectrum of (3A, 3B, 3C) attributes to the vibration
of the hydrogen-bonded N–H group, and the observed wagging
mode at 774 cm–1 also confirms the involvement of
pyrrole N–H group in intermolecular attraction. The dimerization
tendency enhances in pyrrole species having 3,5-dimethyl substituent
along with 2-carbonyl substituent.
NMR Spectroscopy
The experimental
values of 1H and 13C chemical shifts of (3A, 3B, 3C) are given in Table , and experimental
spectra are given in the Supporting Information Figure 2. The comparison between experimental and calculated 1H and 13C NMR chemical shifts is given in the Supporting Information Table 3a–f. The
pyrrolic NH appears as singlets at 9.81, 11.51, and 11.67 ppm in 3A, 3B, and 3C, respectively. The
azomethine proton (−CH=N−) and NH proton of the
hydrazone (−CH=NNH−) exhibited the expected singlets
at 7.89, 8.75, 8.48 and 11.50, 11.79, and 11.74 ppm in DMSO, respectively,
in (3A, 3B, 3C). The higher
frequency signal for NH indicates a greater acidity of this hydrogen,
which is more susceptible to attack by the solvent. The ethyl ester
group attached to the pyrrole ring at α position of (3A, 3B, 3C) resonated as a quartet (CH2) in the range of 4.52–4.59 ppm and a triplet (CH3) at 1.93 ppm.Given that a comparable molecule’s 13C NMR chemical shift range is typically more than 100 ppm,
precision ensures that spectroscopic parameters may be reliably interpreted.
The synthesis of compounds 3A–3C may be seen in
the carbon NMR spectra once more. Supporting Information Table 2 shows 13C NMR spectra. Supporting Information Tables 3b, d, and f show detailed 13C NMR assignments for 3A, 3B, and 3C. The existence of peaks at 158.68, 161.01, and 160.515
ppm in the 13C NMR spectral data of 3A, 3B, and 3C confirms the presence of carbonyl
carbon in the ester group. The C=O group connected to the nitro
phenyl ring in (3C) molecule is confirmed by the peak
at 160.64 ppm. In 3A, 3B, and 3C, the C=N–N linked carbon emerges at 149.84, 135.60,
and 139.49 ppm, confirming the production of the hydrazone linkage.
The estimated 1H and 13C NMR chemical shifts
match the observed results very well. In material property prediction
research, regression analysis methods are often used, and both macroscopic
and microscopic properties can be predicted. The regression correlation
between experimental 1H/13C NMR chemical shift
(y) and calculated 1H/13C NMR
chemical shift (x) (δ in ppm) follows the linear
equation, y = 1.09322x + 0.23132/y = 1.09432x + 0.23232, and the value of
correlation coefficient (R2 = 0.9298/0.9529)
shows that there is good agreement between experimental and calculated
results.Mass spectrometry has also corroborated more evidence
for the production
of 3A, 3B, and 3C. Supporting Information Figure 2 shows the mass
spectra. The M+ and M + 1 peak in the mass spectra of the
pyrrole hydrazones (3A, 3B, and 3C) correspond to the molecular weight of the molecules.
NBO and UV–vis Spectroscopy
From a theoretical standpoint, characterization of excited states
can be accomplished by solving the eigenvalue issue using either a
multiconfigurational ansatz or the single-particle Kohn–Sham
equations in the density functional theory’s time-dependent
formalism (TDDFT). The transition dipole moment and the accompanying
transition density define an excited state. The former informs about
the likelihood of exciting an electron from the ground state and the
most efficient light polarization direction, whereas the transition
density informs about the shift in electronic density from the ground
state to the excited state. Both of these features are particularly
sensitive to polarization caused by the environment, and the spectroscopic
fingerprint of the isolated molecule in vacuum is frequently insufficient
even for a qualitative description. The singlet excited states for
the studied compounds are listed in Table and shown in Figure . The molecular orbital plots are shown in Figure . The UV–visible
spectrum analysis reveals that (3A, 3B)
are transparent throughout the visible range, with absorption values
at 326 and 361 nm, respectively. Molecules with high extinction coefficients
allow for strong π–π*, n−π*, and charge
transfer transitions in the UV–vis range. In comparison to 3A and 3B, compound 3C has the strongest
acceptor and the smallest energy difference between the ground and
excited states; thus, absorption occurs in the longer wavelength zone.
Table 3
Comparison between Experimental and
Calculated Electronic Transitions: E/eV, Oscillatory
Strength (f), (λmax in nm)
si. no.
excitation
E (eV)
(f)
λcal
λexp.
assignment
Compound
3A
1
76 → 77
3.7774
0.6249
328.23
326
π → π* (CT)
2
76 → 78
3.9717
0.3061
312.17
π → π*
3
75 → 77
5.149
0.2854
240.79
238
π → π**
Compound 3B
1
87 → 88
3.2315
0.7857
383.68
361
π → π* (CT)
2
86 → 88
4.0323
0.1438
307.48
286
n → π*
3
86 → 90
5.2254
0.3828
237.27
235
n → π*
Compound 3C
1
94 → 95
2.6813
0.1248
462.4
468
π → π* (CT)
2
94 → 96
4.1127
0.6275
301.47
335
π → π*
3
93 → 96
4.7851
0.2469
259.11
265
n → π*
Figure 3
Experimental
UV–visible spectra of 3A, 3B, and 3C.
Figure 4
Molecular orbital plots of (3A, 3B, and 3C) compounds.
Experimental
UV–visible spectra of 3A, 3B, and 3C.Molecular orbital plots of (3A, 3B, and 3C) compounds.The calculated λmax of 3B has been
observed at longer wavelength leading to an increase of molecular
hyperpolarizability of 3B compound in comparison to 3A and 3C. The hyperconjugative interaction and
electron density transfer from the filled lone pair electron were
interpreted using the NBO analysis. Nowadays, theoretical methods
are utilized to examine various second-order interactions between
the filled orbitals of one sub-system and the unfilled orbitals of
another sub-system, as well as to anticipate delocalization or hyperconjugation.[34]Supporting Information Table 4a–c reveals substantial intra- and intermolecular
hyperconjugative interactions in the second-order perturbation theory
analysis of the Fock Matrix in the NBO basis for (3A, 3B, 3C). In (3A, 3B, 3C), the intramolecular interaction is created by
the orbital overlap between σ(NH–O) and σ*(NH–O),
resulting in intramolecular charge transfer (ICT) and system stability.
The interactions π(C2–C3) → π2*(C4–C5),
π(C2–C3) → π2*(C9–C15), π(C4–C5)
→ π2*(C2–C3), and π(C4–C5) →
π2*(C2–C3) have high stabilization energy in the range
of 15.77–25.80 kcal/mol, according to NBO analysis. The ICT
can make the molecule more polarized by moving the π-electron
cloud from the donor to acceptor, and the ICT must be accountable
for the NLO features of the molecule. As a result, the (3A, 3B, 3C) may be used in the future for
NLO material applications. The selected Lewis (bond or lone pair)
NBO orbitals of (3A, 3B, 3C) with their valence hybrids corresponding to the various bonds and
lone pairs (lp) are listed in Supporting Information Table 4a–c.
Emission (Photoluminescence) Spectroscopy
Photoluminescence (PL) is a process in which a substance absorbs
and then re-radiates electromagnetic energy (photons). Photoexcitation
initiates luminescence (light emission), which is one of many types
(excitation by photons). Figure shows the experimental PL spectra of (3A, 3B, 3C) in dioxane excited at λex.max = 252, 415, and 301 nm. The most striking feature is
that (3A, 3B) give an intense PL emission
at λex.max = 521 nm in the green region upon irradiation
by ultraviolet light (λex.max = 252 and 415 nm),
whereas in (3C), a weak emission at λex.max = 478 nm in the blue region and another intense PL emission at λex.max = 617 nm in the orange region were observed upon irradiation
by visible light (λex.max = 301 nm). As a result
of the intense emission in the visible (green and blue) area with
Stokes shifts of 195, 160, and 282 nm, the emission spectrum reveals
that the examined compounds are a good photoluminescent material.
Figure 5
Experimental
PL spectra of 3A, 3B, and 3C.
Experimental
PL spectra of 3A, 3B, and 3C.
NLO Properties
The use of computational
calculations to investigate the broad properties of materials is an
alternate method of investigation. Polarizabilities and hyperpolarizabilities
define a system’s behavior in the presence of an applied electric
field.[35] As a result, the molecules under
study will have a better NLO response and may be suitable for use
as a NLO material. The dipole moment is used to investigate the nonbonded
type dipole–dipole interactions between molecules; the bigger
the dipole moment, the more powerful the intermolecular interactions. Table shows the calculated
dipole moment, polarizability, and first static hyperpolarizability
values in gas phase and solvents. The dipole moment of (3B) is the greatest of them all. According to the dipole moment vector,
the pyrrole side acts as a donor, while the benzene side acts as an
acceptor. The attachment of nitro-acceptor increases the dipole moment
from 3A to 3B. Because of the carbonyl-acceptor, 3C has a lower dipole moment than 3B, in which
the vector sum is responsible for the decrease. Due to its maximum
softness value, (3B) has the highest polarizability value
of any. From chloroform to ethanol and DMSO, the dipole moment and
polarizability of substances increased monotonically as the solvent
polarity of the medium increased. The effects of solvents on NLO characteristics
have been explored, and they have been found to change with solvent
polarity to varying degrees. In the gas phase, 3C has
the highest first static hyperpolarizability, but 3B has
the highest hyperpolarizability in chloroform, ethanol, and DMSO solvent
media. Compounds (3B) and (3C) have greater
first static hyperpolarizability than the commonly used standard p-NA.
As a result, the molecules under investigation are anticipated to
have a NLO response and could be employed as a NLO material. The UV–visible
spectrum analysis reveals that the compounds are nearly transparent
in the visible region, with absorption near 300 and 350 nm in the
UV range due to the π–π* and charge transfer transitions.
Table 4
Static Dipole Moment (μ0), Mean
Polarizability (|α0|), Anisotropy of Polarizability (Δα),
First Hyperpolarizability (β0), and Their Components
Vacuum
dipole moment (μ0)
polarizability
first hyperpolarizability
(β0)
α0
Δα
3A
1.66
30.12
118.05
17.71
3B
8.72
35.41
143.54
48.83
3C
6.100
33.80
130.81
63.89
PNA
7.169
5.987
25.871
11.548
CHCl3
3A
1.9631
26.089
122.78
27.986
3B
10.088
44.444
181.09
139.772
3C
6.5181
40.431
154.09
117.118
PNA
8.6890
14.6410
53.2540
28.2031
MeOH
3A
2.119
27.863
130.47
32.037
3B
10.658
48.223
196.61
195.918
3C
6.889
43.045
162.22
137.598
PNA
9.266
16.107
59.177
38.5141
DMSO
3A
2.129
27.971
130.914
32.266
3B
10.691
48.450
197.546
199.669
3C
6.913
43.200
162.68
138.763
PNA
9.300
16.1963
59.5405
39.2014
Molecular Electrostatic Potential Map and
Electronic Reactivity Descriptor
The reactivity map known
as the molecular electrostatic potential (ESP) map reveals where charged
point-like reagents are most likely to attack organic molecules electrophilically
or nucleophilically. The relative polarity of a molecule is visualized
via ESP. It can also be used to explain electronegativity, partial
charges, chemical reactivity sites, structure–activity correlations,
hydrogen bonding, and other molecular interactions, such as biomolecules
and pharmaceuticals. In the Supporting Information Figure 3, the ESP map for the monomer and dimer of (3A, 3B, 3C) is displayed. The color code
of MEP map is in the range between −0.0511 au (deepest red)
and +0.0511 (deepest blue). Negative ESP is frequently associated
with the lone pair of electronegative N and O atoms (red or orange
blob). ESPs have been equalized, as seen by the decrease in negative
potential around the carbonyl group’s O oxygen atom and the
increase in positive potential around the pyrrole’s H hydrogen
atom N–H. In the MEP map of monomer, positive potential is
only localized over the H hydrogen atom (deep blue blob) of pyrrolic
NH, while negative potential is only localized over the O oxygen atom
(red blob). The ESP is important in explaining how the examined chemicals
(3A, 3B, 3C) interact with
biomolecules such as proteins in the living system.
Global Reactivity Descriptors
To
comprehend the link between structure, stability, and global chemical
reactivity, conceptual DFT-based global reactivity descriptors are
applied. Quantitative structure activity (QSAR), QSPR, and structure
toxicity connections are also developed using descriptors. Stability,
reactivity, dynamics, and other characteristics are all aided by descriptors.
Global reactivity descriptors are essential because they are linked
to various electrical structural principles. Electronegativity (χ),
chemical potential (μ), global hardness (η), global softness
(S), and electrophilicity index (ω) are all
global reactivity descriptors that are very good at forecasting global
reactivity trends. On the basis of Koopman’s theorem,[35,36] global reactivity descriptors are calculated using the energies
of frontier molecular orbitals εHOMO and εLUMO and given by eqs –5.The electrophilicity index (ω)
is a global reactivity index similar to chemical hardness and chemical
potential, according to Parr et al.[35,36] This is a
quantifiable quantity that is both positive and definite. When the
system acquires an additional electronic charge (N) from the environment, this new reactivity index evaluates the energy
stabilization. Because an electrophile is a chemical species capable
of accepting electrons from the environment, its energy must drop
when accepting an electronic charge, the direction of charge transfer
is fully dictated by the electronic chemical potential of the molecule.
As a result, its electronic chemical potential must be lower than
that of reactants 1 and 2. Electrophilic charge transfer (ECT)[35] is defined as the difference between the ΔNmax values of interacting molecules. If we consider
two molecules A and B approach to each other (i) if ECT > 0, charge
flow from B to A (ii) if ECT < 0, charge flow from A to B. ECT
is calculated using eq where, (ΔNmax)A = μA/ηA (ΔNmax)B = μB/ηB.ECT for the reactant system [(1) ↔ (2A, 2B, 2C)] is listed in Table . The global electrophilicity
index (ω = 5.994 eV) of (3C) shows that it behaves
as a strong electrophile. ECT is calculated as 0.524 for reactant
molecules (1) and (2A), which indicates
that charge flows from (2) to (1). Therefore,
(1) acts as the electron acceptor (electrophile) and
(2) acts as the electron donor (nucleophile). The low
value of chemical potential and high value of electrophilicity index
for (1) favor its electrophilic behavior. In the same
way, the high value of chemical potential and low value of electrophilicity
index for (2A) favor its nucleophilic behavior.
Table 5
Calculated εHOMO,
εLUMO, Energy Band Gap (εL –
εH), Chemical Potential (μ), Electronegativity
(χ), Global Hardness (η), Global Softness (S), and Global Electrophilicity Index (ω) for (1), (2), and
(3)
molecules
εH
εL
εH – εL
X
μ
H
S
ω
ECT
Compound 3A
(1)
–6.1609
–1.0164
5.1446
3.5887
–3.5887
2.5723
0.1944
2.5033
0.52445
(2a)
–5.2542
0.36327
5.6176
2.4455
–2.4455
2.8088
0.1780
1.0646
(3A)
–4.8110
–0.6531
4.1579
2.732
–2.7320
2.0790
0.2405
1.7951
Compound 3B
(1)
–6.1609
–1.0164
5.1446
3.5887
–3.5887
2.5723
0.1944
2.5033
–0.4782
(2b)
–6.0603
–1.842
4.2183
3.9511
–3.9511
2.1092
0.2371
3.7008
(3B)
–5.4363
–1.959
3.4774
3.7341
–3.7341
1.5123
0.3306
4.6101
Compound 3C
(1)
–6.1609
–1.0164
5.1446
3.5887
–3.5887
2.5723
0.1944
2.5033
–0.8518
(2C)
–7.3275
–2.8140
4.5136
5.0707
–5.0707
2.2568
0.2216
5.6967
(3C)
–5.7558
–2.7285
3.0273
4.2422
–4.2422
1.5136
0.3303
5.9445
Local Reactivity Descriptors
One
of the most extensively utilized local density functional descriptors
to characterize chemical reactivity and site selectivity is the Fukui
function (FF).[37] The local (condensed)
FFs (fk+, fk–, fk0) are determined using the approach described by Yang and
Mortier[38] based on a finite difference
method employing eqs –9 using the same calculation method
B3LYP/6-311G++(d,p).where N, N – 1, and N + 1 are the total electrons present
in neutral, cation, and anion states of molecule, respectively.In addition, local softnesses (sk+, ,)(39) and local electrophilicity indices (ωk+, ωk–, ωk0)[39] describe the reactive atoms
present within the molecule. These local reactivity descriptors associated
with a site k in a molecule are defined with the help of the corresponding
“condensed to atom” variants of FF, using the following eqs and 11.where +, −, and 0 signs show nucleophilic,
electrophilic, and radical attacks, respectively. Equations and 11 predict that the most electrophilic (nucleophilic) site in a molecule
is the one providing the maximum value of sk+ (sk–),
ωk+ (ωk–), respectively.The selected local reactivity descriptors
for reactants (2A, 2B, 2C) are given in Table . Using Hirshfeld
charges, the maximum values of local electrophilic reactivity descriptors
(fk+, sk+, ωk+) at aldehyde
carbon C6 of reactant (1) indicates that this is the
most electrophilic site. The nucleophilic reactivity descriptor (fk–, sk–, ωk–) analysis of reactants (2A, 2B, 2C) shows that N20 is the most nucleophilic site.
Therefore, the nucleophilic attack of N20 site of reactants (2A, 2B, 2C) at the most electrophilic
site C6 of reactant (1) confirms the formation of product
molecules (3A, 3B, 3C) or Schiff
base linkage (C=N) in hydrazone.
Table 6
Selected Reactivity Descriptors as
FFs (fk+, fk–), Local Softnesses (sk+, sk–), and Local Electrophilicity Indices (ωk+, ωk–) for (3A, 3B, 3C) Using Hirshfeld Atomic Charges
atom
fk+
sk+
ωk+
atom
fk–
sk–
ωk–
Compound 3A
C8
0.0652
0.0156
0.1170
N1
0.0494
0.0119
0.0888
C13
0.1030
0.0247
0.1850
N15
0.1270
0.0305
0.2281
Compound 3B
C7
0.0926
0.0266
0.3641
N1
0.0493
0.0141
0.1939
C9
0.0236
0.0068
0.0931
N11
0.1129
0.0324
0.4441
Compound 3C
C7
0.0586
0.0193
0.3485
N1
0.0550
0.0181
0.3270
C11
0.0349
0.0115
0.2080
N10
0.0880
0.0290
0.5234
C22
0.0117
0.0038
0.0699
The global parameters for (1), (2A, 2B, 2C), (3A, 3B, 3C) and selected reactivity descriptors as
FFs (fk+, fk–), local softnesses (sk+, sk–), and local electrophilicity
indices (ωk+, ωk–) for (3A, 3B, 3C) are given in Table . Using Mulliken charges, the maximum values of local electrophilic
reactivity descriptors (fk+, sk+, ωk+) at C8, C13, C7, C9, C7, C11, and C22 for (3A, 3B, 3C) indicate that this site is more
prone to nucleophilic attack and favor formation of the larger number
of heterocyclic compounds.
Evaluation of Antimicrobial Activity and Molecular
Docking
Table reports the antibacterial and antifungal activities of the reactants
and products (3A, 3B, 3C). Figure shows the bar diagram
representation of zone of inhibition, in mm, (a) against bacterial
strains (b) and fungal strains. The products (3A, 3B, 3C) show good antibacterial activity in comparison
to pyrrole and hydrazide derivatives (reactants).
Table 7
Antimicrobial Activity of Reactants
(1, 2A, 2B, 2C) and Products (3A, 3B, 3C) at Different Concentrations
zone of inhibition(mm)
antibacterial
activity
antifungal activity
Gram positive
Gram negative
S.
aureus (μg/mL)
S. pyogenes (μg/mL)
E. coli (μg/mL)
P. aeruginosa (μg/mL)
C. albicans (μg/mL)
A. niger (μg/mL)
comp
100
200
100
200
100
200
100
200
100
200
100
200
1
4
11
3
5
4
4
4
6
6
7
6
8
2A
5
12
5
8
5
6
5
7
7
8
8
9
2B
7
10
6
9
6
7
5
7
7
8
8
9
2C
7
9
7
8
6
7
6
8
8
9
9
13
3A
10
14
9
14
7
9
9
8
8
14
8
15
3B
11
17
11
17
8
9
10
10
11
16
10
16
3C
12
19
10
18
7
10
9
10
10
17
9
19
control chloramphenicol/nystatin
14
20
13
20
13
23
13
19
12.5
22
14
25
Figure 6
Bar diagrams representing
the inhibition zones against (A) bacterial
and (B) fungal strains.
Bar diagrams representing
the inhibition zones against (A) bacterial
and (B) fungal strains.The products (3A, 3B, 3C) were found to be more active against Gram positive S. aureus and S. pyogenes bacterial strains at 200 μg/mL concentration. The reactant
(r1) found in most of the cases is less active against both Gram positive
and Gram negative bacteria. The results of preliminary antifungal
activity screening reveal that (3A, 3B, 3C) have a significant effect on C. albicans and A. niger, even at 100 μg/mL
concentration, though the best results come only at 200 μg/mL,
respectively. In all cases, the assayed substances showed an activity
level against bacterial and fungal lower than that of chloramphenicol
and Nystatin, the reference drug.
Molecular Docking
Molecular docking
is a powerful tool for investigating the behavior of small molecules
in the binding site of target proteins to elucidate fundamental biochemical
processes and confirm bioactivity in any chemical structure.[40] PYMOL is used to visualize protein–ligand
interactions.[28] The docking study in this
paper used the bacterial PDB ID 3U2D-1 and the fungus PDB ID 1KS5. Both proteins’
crystal structures were retrieved from the RSCB protein database.[41,42] The pi and psi angles of the RC plot were used to analyze protein–ligand
interaction characteristics with bacterial and fungal proteins.[26] The RC plot in Figure is used to predict the structure and stability
of proteins.
Figure 7
2D RC plots for receptor proteins (a) 3U2D-1 and (b) 1KS5.
2D RC plots for receptor proteins (a) 3U2D-1 and (b) 1KS5.The residues in the most favored region, allowed
region, and generously
allowed region are shown by black dark gray, gray light gray, green,
and brown patches on the plot, showing the stability of proteins chosen
for docking simulation. The majority of the amino acid residues in
both proteins are in the permitted zone. The bonded residues in all
three derivatives (3A, 3B, 3C) lie in the permitted region of the RC plot. These findings indicated
that all three 3A, 3B, and 3C derivatives have a high affinity for the target protein, implying
antibacterial and -fungal activities. The chosen proteins are well-docked
with the three examined ligands, and the atoms of the studied compounds
bind with several bacterial protein residues, particularly GLU′68,
GLN′66, THR′80, ASN′82, THR′171, HIS′143,
VAL′174 (3A), VAL′130, VAL′131,
GLU′50, GLU′58, ASN′54, ASP′57 (3B), and ILE′102, ASN′54, ASP′57, VAL′131,
and GLU′50 (3C). Protein–ligand interacted
images/H bond-interacting images are shown in Figure with bacterial receptor protein and fungal
protein interactions with ligands are shown in Figure for 3A, 3B, and 3C compounds.
Figure 8
H bond interacting images of the studied compounds (3A, 3B, 3C) with bacterial receptor
protein.
Figure 9
H bond interacting images of the studied compounds (3A, 3B, 3C) with fungal receptor
protein.
H bond interacting images of the studied compounds (3A, 3B, 3C) with bacterial receptor
protein.H bond interacting images of the studied compounds (3A, 3B, 3C) with fungal receptor
protein.The atoms of the studied compounds are interacted
with different
residues of fungal proteins, namely, GLN′153, GLN′158,
TRP′22, ASN′20 (3A), GLN′153, GLN′158,
TRP′22, SER′111, PHE′101, GLN′200, ASN′20,
ASN′63 (3B), and GLN′200, GLN′158,
ASN′20, ASN′63, THY′61, TRP′22, PHE′101,
THR′151 (3C). The molecular docking study result
reveals that the 3A, 3B, and 3C compounds have good interaction properties with the receptor molecules
and they are predicted to be potential antibacterial and antifungal
drugs.
Molar Refractivity
Molar refractivity
(MR) is a property that is determined by the refractive index, molecular
weight, and density of steric bulk and is responsible for the lipophilicity
and binding properties of the examined system. It can be calculated
by the Lorentz–Lorentz equation[43,44] and defined
aswhere n—refractive
index, MW—molecular weight, ρ—density, (MW/ρ)—molar
volume, N—Avogadro number, and α0—polarizability of molecular system. This equation
holds for both liquid and solid states of the system.The MR
property is a crucial one in the QSPR connection. The true volume
of the molecule is represented by the MR. MR is affected by the London
dispersive forces that work in the drug–receptor interaction,
as well as the volume of the molecules. In QSAR investigations for
drug design, RM is often used. The calculated MRs for (3A, 3B, and 3C) are 70.25, 122.16, 108.92
esu, respectively, which are responsible for the binding property
of pyrrole hydrazone molecules for treatment of microbial infections.
The MR value of 3B is greater than those of 3A and 3C. The maximum bacterial and fungal strains’
zone of inhibition was seen in the case of 3B. The calculated
binding affinity correlates well with the experimental antimicrobial
result of 3B.
Conclusions
In this study, pyrrole
hydrazones of different structures were
synthesized and analyzed using spectral, quantum chemical, and biological
methods. Grinding has proven to be a versatile, easy-to-use, highly
functional, and environmentally benign method for solid-state synthesis
of the 3A, 3B, and 3C. The
results revealed that 3A, 3B, and 3C could be obtained with a transformation rate of more than
99%, with no by-products. This is well-suited to the production of
active medicinal substances, which necessitates a high level of purity.
The computed chemical shifts for 1H and 13C
NMR agree with the experimental chemical shifts. The presence of the
intermolecular hydrogen bonding N–H···O is confirmed
by the red shift in the wavenumber of both the proton donor as pyrrole
N–H and the proton acceptor as C=O. The molecular orbital
coefficient analysis suggests the nature of all the electronic excitations
as π → π* and n → π*. The compounds
(3A and 3B) show emission at λem 521 nm, whereas 3C shows emission at 617 nm
in the visible (green and orange) region. The Stokes shifts for 3A, 3B, and 3C are 195, 160, 282
nm, respectively. The NBO analysis indicates that the maximum conjugation
stabilization energy is ∼22.68 kcal/mol through π →
π* interactions in the pyrrole ring. The interaction n →
π* also stabilizes the molecule to a greater extent of 50.68
kcal/mol. The global electrophilicity index for (3A, 3B, 3C) shows that these molecules behave as
strong electrophiles. The electrophilic reactivity descriptor (fk+, sk+, ωk+) analysis for (3A, 3B, 3C) indicates that the investigated
molecules might be used as the precursor for the target synthesis
of new heterocyclic derivatives. The compound exhibits strong and
effective ICT due to transfer of π-electron cloud from donor
to acceptor and shows high hyperpolarizability. The calculated first
hyperpolarizabilities (β0 = 17.71, 48.83, and 63.89
× 10–30 esu) demonstrates that the target compounds
are attractive materials for NLO applications. The gradual increase
in β0 values of products 3B and 3C compared to 3A is due to the incorporation
of electron-withdrawing groups. The products (3A, 3B, and 3C) display good antimicrobial activity.
Scheme 1
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9