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OPEN DFT study, and natural bond orbital

(NBO) population analysis of 2​‑
(2​‑Hy​dro​xyp​hen​yl)​‑1‑​azaazulene
tautomers and their mercapto
analouges
Shimaa Abdel Halim 1*, Asmaa B. El‑Meligy 2*, Ahmed M. El‑Nahas 2 &
Safinaz H. El‑Demerdash 2

Theoretical research on the keto-enol tautomerization of 2-(2-Hydroxyphenyl)-1-aza

azulene (2HPhAZ) and its thiol-thione (2MPhAZ) analouge has been performed using the density
functional B3LYP method with the 6–311 +  + G(2d,2p) basis set in gas and ethanol phases. The findings
of the MO computation on the energy scale and the prediction of the frontier molecular orbital (FMO)
energies demonstrate that the tautomeric structures exist in a static mixture in the ground state, with
the enol and thiol structure being more stable than the keto and thione structures in gas phase. The
ethanol solvent causes some reordering of the relative stability of 2HPhAZ and 2MPhAZ conformers.
The geometries created at the B3LYP/6–311 +  + G(2d,2p) level of theory were used for NBO analysis.
In the tautomerization of 2HPhAZ and its mercapto analogue 2-(2-Mercaptophenyl)-1-azaazulene
(2MPhAZ), it has been found that the O(S)-C sigma bond is weak due to nO(S) —> σ*C25-O26(S26) and nO(S)
—> σ*C15-N16 delocalization. It is also noted that the resulting p character of the corresponding oxygen
(sulfur) natural hybrid orbital (NHO) of σO(S)-C bond orbital is related to the decreased occupancy of the
localized σO(S)-C orbital in the idealized Lewis structure or the increased occupancy of σ*O(S)-C of the non-
Lewis orbital and their subsequent impact on molecular stability and geometry (bond lengths) in gas
phase and ethanol. Additionally, the energy of charge transfer decreases as the potential rotamers’
Hammett constants (R1–R3 for O(S) atoms) increase. The partial charge distribution on the skeleton
atoms demonstrates that the intra- and intermolecular interactions can be significantly influenced by
the electrostatic attraction or repulsion between atoms. Lastly, the currently applied NBO-based HB
strength indicator enables a fair prediction of the frequency of the proton donor NH stretching mode,
but this simple picture is hidden by abundant hype conjugative effects.

Azaazulenes, an azulene heterocyclic analogue (Fig. 1), have attracted concern due to their chemical and physical
properties and their biological a­ ctivity1,2 as anticancer ­agents3. 1-azaazulenes are the most stable of the several
azaazulene structures. When nitrogen and oxygen (sulphur) atoms in the heterocyclic ring change hydrogen
atoms, tautomers are produced. The proton transfer and hydrogen bonding of the hydrogen atom are significant
properties in chemistry. As a result, equilibrium between (enolimines/thiol and ketoenamines/thione forms) of
2HPhAZ and 2MPhAZ tautomeric forms is expected (Fig. 1).
Understanding the relative stabilities of tautomeric forms and their mutual conversion is a crucial topic
from the standpoint of structural chemistry. Oda et al.4 demonstrated that spectroscopic and X-ray crystal-
lographic investigations supported the structure of 2OHPhAZ. A reasonably substantial absorption in the vis-
ible light spectrum, as well as the X-ray diffraction ­data4, support the presence of its aromatic and coplanar
nature and an intramolecular hydrogen bond. The stability of 2OHPhAZ, the keto tautomer (2OPhAZ), and
various rotamers (2OHPhAZ-R1:R3) in the gas phase and ethanol was the subject of DFT research by El-
Meligy et al.5. Furthermore, to the best of our experience, we have not found any analysis of the nature of the

1
Chemistry Department, Faculty of Education, Ain Shams University, Cairo 1171, Egypt. 2Chemistry Department,
Faculty of Science, Menoufia University, Shebin El‑Kom 32512, Egypt. *email: [email protected];
[email protected]

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N N
HX H X
X=O enol keto
X=S thiol thione

Figure 1.  The tautomeric structure (enolimines/thiol and ketoenamines/thione form) of 2HPhAZ and
2MPhAZ.

bonding in the tautomerization of 2-(2-Hydroxyphenyl)-1-azaazulene (2HPhAZ) and its mercapto analogue

2-(2-Mercaptophenyl)-1-azaazulene (2MPhAZ).
The study of covalence and hybridization effects in polyatomic wave functions led to the development of the
natural bond orbital (NBO) analysis method. The work of Foster and W ­ inhold6 was expanded by Reed et al.7,
who utilized NBO analysis that showed mainly H-bonded and other strongly bound van der Waals complexes.
The "natural Lewis’s structure" has filled NBOs that are excellently suited to describing covalency effects in
­molecules7. However, the general conversion to NBOs also produces orbitals that are vacant in the official Lewis
structure and can be utilized to characterize non-covalent effects.
The terms filled and unfilled orbitals of the formal Lewis structure are denoted, respectively, by the symbols
σ and σ*, though the former orbitals may be core orbitals (CR), lone pairs (LP), σ or π bonds (σ, π), and so forth,
and the latter may be σ or π anti-bonds (σ*, π*), extra valence shell Rydberg (RY*) orbitals.
The NBO analysis focuses on the availability of a device of high quality, shedding light on both the HB-related
electron delocalization-induced hyper conjugative effects and the many effects found to influence the NH-stretch
spectral shift, i.e., the main measurable quantity on which most of the spectroscopic approaches are based.
The aim of this study is complementary to our work which is published in omega and Scientific reports
­journals5,8 to complete our work in this point that we study with the Natural Bond Orbital property to find the
mechanism of the stability of the tautomer and rotamers of 2-hydroxyl phenyl azaazulene and -mercapto phenyl
azaazulene.
In the current work, we attempt to investigate the electronic structure, stabilities, and bonding character-
istics of the 2HPhAZ and 2MPhAZ tautomers and rotamers in gas phase and ethanol at the theoretical level
B3LYP/6–311 +  + G(2d,2p). The hybridization of each atom, natural charges (Core, Valence, and Rydberg), the
second order perturbation energy (E (2)) of bonding and antibonding orbitals, exact configurations, and Lewis
and non-Lewis’s electrons have all been considered in the study of the results from natural bonding orbital
analysis in gas phase and ethanol.

Computational details
The gradient-corrected hybrid density functional B3LYP/DFT approach was used for all c­ omputations9,10. Using
this ­functional10 and the 6–311 +  + G (2d, 2p) basis ­sets11 as implemented in the Gaussian 09 ­program12, a com-
prehensive geometry optimization without symmetry constraints was carried out for each structure. Both Gauss
View 5.0.913 and Chem-Craft 1.614 were used to visualize all geometries. The natural bond orbital a­ pproach15 has
also been used to perform the population analysis at the B3LYP/6–311 +  + G (2d, 2p) level of theory using the
Gaussian 09 software package. In this process, sets of natural atomic orbitals (NAOs), natural hybrid orbitals
(NHOs), and natural boundary orbitals (NBOs) are successively changed from non-orthogonal atomic orbitals
(AOs).
Since electron density and other attributes are defined by the fewest number of filled orbitals in the fastest-
convergent manner, all these localized basis sets are complete and define the wavefunctions in the most practical
manner. The second-order perturbation interaction energy (E(2)), which is defined using the NBO technique,
can be used to quantitatively explain this noncovalent bonding-antibonding ­interaction16–18. The estimation of
the off-diagonal NBO Fock matrix elements is represented by this energy. From the second-order perturbation
method, it may be ­inferred15.

E (2) = �Eij = qi (F(ij)2 /εj −εi ), (1)

where qi is the donor orbital occupancy, εi and εj are diagonal elements and (ij) is the off-diagonal NBO Fock
matrix element.

Result and discussion

Geometry optimization
Figure 2 lists the tautomeric structures of 2HPhAZ and 2MPhAZ (enolimines/thiol and ketoenamines/
thione forms). Table 1 lists all the optimized structural properties determined in gas phase, and ethanol at the
B3LYP/6–311 +  + G(2d,2p) level of theory. Table 1 shows that the bond lengths in the tautomeric structure of
2HPhAZ (enolimines and ketoenamines form) are shorter than those in the thiol and thione forms of the mer-
capto homologue, but the estimated bond angles have shown the opposite in both gas and ethanol phases. The
mercapto analogue’s bond angles are less than those of hydroxy structures. Additionally, it has been discovered
that the HB length of the N–H–O(S) and the C–N–H bond angle are longer and smaller for the thiol and thione

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Figure 2.  The optimized structural for the tautomers and rotamers of 2HPhAZ and 2MPhAZ at B3LYP/
6–311 +  + G(2d,2p) level of theory.

forms than the enol and keto forms, respectively. The chemical differences between sulfur and oxygen atoms
are to blame for that. The longest hydrogen bond, O(S)…H, is between the enol and thione forms. The R3(O)
and R3(S) rotamers have the longest O(S)–C bonds among them. The R2(O) and R2(S) produce the biggest
C–O(S)–H bond angle by rotating the phenyl ring. An intriguing feature to note is how the bond length and angle
change when the tautomeric structure’s σF values ­change19–21. i.e., σF is the value of change in factor of the bond
length and bond angle when adding any para substituent on the benzene ring; in this case (our compounds),

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Bond lengths in Angstrom (Å) Bond angles in degrees (◦)

C-O/S O/S–H N–H < C-O/S–H < C-N–H
Compounds Gas Ethanol Gas Ethanol Gas Ethanol Gas Ethanol Gas Ethanol
Enol 1.343 1.356 0.993 1.000 1.703 1.669 107.775 107.329 152.633 152.408
Thiol 1.787 1.784 1.389 1.363 1.725 1.854 93.426 94.804 143.947 141.273
Keto 1.270 1.289 1.630 1.797 1.050 1.027 105.561 105.63 134.229 130.358
Thione 1.760 1.758 2.094 2.110 1.041 1.035 87.650 87.693 129.049 128.643
R1(O) 1.361 1.366 0.962 0.966 109.160 109.259
R1 (S) 1.797 1.792 1.353 1.346 93.888 94.157
R2(O) 1.366 1.367 0.964 0.961 109.605 111.33
R2(S) 1.794 1.789 1.348 1.343 97.887 98.073
R3(O) 1.369 1.366 0.962 0.966 109.020 109.541
R3(S) 1.797 1.792 1.349 1.344 95.499 95.446

Table 1.  The selected bond lengths in angstrom (Å) and angles in degrees (◦) calculated for the tautomer and
rotamers structures of 2HPhAZ and 2MPhAZ in gas phase, and ethanol using B3LYP/ 6–311 +  + G(2d,2p)
level of theory.

when changed to the tautomeric structures of 2HPhAZ and 2MPhAZ compounds, the value of factor of the
bond length and bond angle are changed.

Electronic structure
Enolimines/thiol and ketoenamines/thione are the two π-isoelectronic (tautomeric) structures in which the
2HPhAZ and 2MPhAZ are found. Additionally, research has been done on the three rotameric forms (R1, R2,
and R3). DFT calculations at B3LYP/ 6–311 +  + G(2d,2p) level of theory to determine which form is more stable
at the ground state by doing frequency calculations at the same level of calculation, the optimized geometry of
the investigated tautomeric structure was verified as a minimum on the potential energy surface. Figure 2 shows
the optimized structure for the investigated tautomeric structure.
The C1 symmetry point group is where the optimization structures are found (supporting information).
Table 2 displays the total energy and relative energy of the tautomeric and rotameric structures calculated at the
B3LYP/6–311 +  + G(2d,2P) in gas and ethanol phases. In case of 2HPhAZ, the studied DFT method qualitatively
gives similar tautomer stability orders in the gas phase and ethanol. The ethanol solvent causes some reordering
of the relative stability of 2MPhAZ conformers.
For tautomerization, the thiol form was found to be more stable than the thione form in the gas phase. The
relative energy difference between thiol and thione in the gas phase is 5.253 kJ at B3LYP/6–311 +  + G(2d,2P).
Stabilization of thiol in the gas phase is expected by the presence of a lower and stronger IHB of thione.
On the energy scale, the tautomeric structures are present in a static mixture in the ground state, with the
enol form being (29.492 and 7.737 kJ) more stable than the keto form in gas phase and ethanol, respectively
(Table 2). It has been found that keto/thione form has the lowest HOMO–LUMO gap (2.275/1.852 eV) followed
by enol/thiol forms (3.098/2.980 eV).
In the ground state of rotamers in statical mixes, the R3(O) structure is more stable than the R2(O) and R1(O)
structures, but the R1(S) structure is more stable than the R3(S) and R2(S) structures (Table 2). The stability
of R2(O) and R3(O) can be attributed to the possible intramolecular H bonding interaction of the C–H…N as

(ΔE0, kJ/mol) Eg(ev)

Compounds Gas phase Ethanol Gas phase Ethanol
Enol 0.000 0.000 3.098 3.322
Keto 29.492 7.737 2.275 2.617
R1 (O) 54.991 25.992 3.482 3.510
R2(O) 37.731 30.293 3.349 3.458
R3(O) 37.668 37.303 3.399 3.435
Thiol 0.000 19.854 2.980 3.288
Thione 5.254 0.000 1.852 2.299
R1(S) 8.026 24.561 3.189 3.396
R2(S) 10.035 28.004 3.308 3.475
R3(S) 9.178 25.860 3.388 3.510

Table 2.  Relative zero-point corrected energies (ΔE0, kJ/mol), and the energy gap ­(Eg), for the tautomer and
rotamers structures 2HPhAZ and 2MPhAZ in gas phase, and ethanol at B3LYP/ 6–311 +  + G(2d,2p) level of
theory.

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shown in Fig. 2. The slightly higher stability of R3(S) than R2(S) can be due to the anti-position present between
the S26-H28 group and the nitrogen of the azaazulene ring, given the possibility of H28 interaction with the
sulfur atom. The highest gap is in the rotamers. It is widely known that a molecule’s reactivity increases with
decreasing energy g­ aps22,23. As a result, it is anticipated that the keto/thione form will be more chemically reac-
tive than enol/thiol and their rotamer. The keto/thione compound can function as both an electron acceptor
and donor. The results of the MO calculation show that the computed reactivity in the gas phase and ethanol of
the studied compounds increases in the order.
For 2HPhAZ, enol > keto > R3(O) > R2(O) > R1(O) in gas phase but in ethanol the order of stability is Eno
l > keto > R1(O) > R2(O) > R3(O).
In case of 2MPhAZ, thiol > thione > R1(S) > R3(S) > R2(S) in gas phase. In ethanol, the order of stability
becomes thione > thiol > R1(S) > R3(S) > R2(S) in 2MPhAZ. Our results are agreeing with the previous results
that of 2-(2-Hydroxyphenyl)-1-aza azulene and 2-(2-Mercaptophenyl)-1-aza a­ zulene5,8.

Character of natural hybrid orbital (NHO) on the tautomeric structure

A natural atomic orbital (NAO) is a valence-shell atomic orbital that was created by diagonalizing the localized
block of a given molecule’s full density matrix, is connected to the atom in question via basis functions Xi (A), and
simultaneously satisfies the orthonormality and maximum occupancy conditions. While NAOs in a single atom
simply coincide with natural orbitals, in polyatomic molecules they largely maintain their one-center nature (as
opposed to natural orbitals, which get delocalized over all nuclear centers). Since a single center in polyatomic
molecules is surrounded by a molecular electron density, NAOs is regarded as offering the best explanation of this
position. Additionally, an NHO is produced via a unitary transformation of a directed hybrid orbital that is sym-
metrically orthogonalized and centered on a specific atom. Finally, an NBO is an orbital produced from NHOs
in the simple bond orbital diagram. Thus, for a localized σ-bond between atoms A and B, the NBO is defined as:
σAB = CA hA + CB hB (2)
where hA and hB are the natural hybrids centered on atoms A and B. Therefore, the NBOs thoroughly agree to
the representation of localized bonds and lone pairs as basic units of molecular structure, and hence it will be
probable to handily take ab initio wavefunctions in terms of the classical Lewis structure concepts by converting
these functions to the NBO f­ orms24. In Table 3, we produce the resulting natural atomic hybrids hA on some atoms
with the polarization coefficient CA for each hybrid (in explanations) in the equivalent NBO. The assessment of
the results described in Table 3 in gas phase, and ethanol shows that:
The p characteristics of sulfur NHO σC25-S26 and nitrogen NHO σC15-N16 bond orbitals increase with increas-
ing Hammett constant in gas phase, and ethanol due to stretching of the C25-S26 bond of the thiol and thione
tautomer. The C25-O26 bond of enolimines and ketoenamines tautomers shortens, in gas phase, and ethanol
causing orbitals to contract with increasing Hammett constant, in contrast to the p characteristics of oxygen
NHO σC25-O26 and nitrogen NHO σC15-N16. While the predicted d contributions of S atoms, which are insignificant
and nearly equal, determine that 3d orbitals are not important for the bonding of the thiol and thione tautomer
in gas phase, and ethanol.
The O(S)-C sigma bond’s interaction becomes weaker. These compounds exhibit strong delocalized nO(S)
—> σ*C25-O26(S26) and nO(S) —> σ*C15-N16 as well as significant hyper conjugative interaction, which results in partial
p character (Table 4). Additionally, Table 4 shows that E(2) rises in gas phase, and ethanol when the investigated
compounds’ Hammett constants rise, extending the (O)S-C bond as a result. Table 2’s stability order reveals
that the enol/thiol structure has higher Relative zero-point corrected energies (ΔE0, kJ/mol), values than the
keto/thione structure in gas phase. The enol and thiol structure being more stable than the keto and thione
structures in gas phase. The ethanol solvent causes some reordering of the relative stability of 2HPhAZ and
2MPhAZ conformers. The relative energy difference between thiol and thione in the gas phase is 5.253 kJ at

Bond C25-O26/ S26 C15-N16

O26/ S26 C25 C15 N16
Compounds Hybrids Gas phase Ethanol Gas phase Ethanol Gas phase Ethanol Gas phase Ethanol
Enol B3LYP sp1.79d0.01(0.8142) sp1.82d0.01(0.8159) sp2.90d0.00(0.5806) sp2.98d0.00(0.5782) sp2.54d0.00(0.6379) sp2.55d0.00(0.6371) sp1.97d0.01(0.7702) sp1.97d0.01(0.7708)
Thiol B3LYP sp4.55d0.02(0.6478) sp4.69d0.08(0.6757) sp2.62d0.02(0.7635) sp2.96d0.01(0.7372) sp2.88d0.00(0.6165) sp2.26d0.00(0.6325) sp2.05d0.00(0.7870) sp1.64d0.00(0.7746)
Keto B3LYP sp1.00d0.00(0.8640) sp1.61d0.01(0.8036) sp1.00d0.00(0.5034) sp2.43d0.00(0.5952) sp2.94d0.00(0.6164) sp2.94d0.00(0.6168) sp2.11d0.00(0.7874) sp1.50d0.00(0.7871)
Thione B3LYP sp4.78d0.02(0.6491) sp4.56d0.02(0.6535) sp2.42d0.02(0.7607) sp2.45d0.02(0.7569) sp2.82d0.00(0.6156) sp2.85d0.00(0.6173) sp2.00d0.00(0.7880) sp1.50d0.00(0.7867)
R1 (O) B3LYP sp1.87d0.01(0.8177) sp1.82d0.01(0.8184) sp3.05d0.00(0.5757) sp3.06d0.00(0.5747) sp2.36d0.00(0.6454) sp2.37d0.00(0.6428) sp1.97d0.01(0.7639) sp1.93d0.01(0.7660)
R1 (S) B3LYP sp4.60d0.06(0.6765) sp4.46d0.06(0.6800) sp2.97d0.01(0.7365) sp3.01d0.01(0.7332) sp2.42d0.00(0.6439) sp2.42d0.00(0.6426) sp1.98d0.01(0.7651) sp1.93d0.01(0.7662)
R2 (O) B3LYP sp3.67d0.02(0.8711) sp3.65d0.02(0.8721) sp2.25d0.01(0.5784) sp2.23d0.01(0.5774) sp2.64d0.00(0.6510) sp2.47d0.00(0.6436) sp2.03d0.01(0.7570) sp1.99d0.01(0.7654)
R2 (S) B3LYP sp4.55d0.02(0.6809) sp4.46d0.02(0.6811) sp3.07d0.02(0.7324) sp3.06d0.02(0.7322) sp2.44d0.00(0.6442) sp2.43d0.00(0.6427) sp2.01d0.01(0.7648) sp1.94d0.01(0.7661)
R3(O) B3LYP sp3.76d0.02(0.8601) sp3.74d0.02(0.8611) sp2.35d0.00(0.5775) sp2.32d0.00(0.5769) sp2.46d0.00(0.6439) sp2.48d0.00(0.6427) sp2.01d0.01(0.7651) sp1.98d0.01(0.7661)
R3(S) B3LYP sp4.51d0.02(0.6825) sp4.51d0.02(0.6825) sp3.08d0.02(0.7309) sp3.08d0.02(0.7309) sp2.44d0.00(0.6448) sp1.00d0.00(0.7991) sp2.03d0.01(0.7644) sp1.00d0.00(0.6011)

Table 3.  Calculated natural hybrid (NHOs) and the polarization coefficient for each hybrid in the equivalent
NBO (in explanations) for the studied the tautomers and rotamers structures of 2HPhAZ and 2MPhAZ in gas
phase, and ethanol at B3LYP/6–311 +  + G(2d,2p) level of theory.

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nO26/S26 — > σ*C25-O26/S26 nO26/S26 — > σ*C15-N16

Compounds Gas phase Ethanol Gas phase Ethanol
Enol 43.33 42.85 21.44 20.65
Keto 36.44 36.01 28.70 26.98
R1(O) 74.43 73.55 42.71 42.11
R2(O) 65.65 65.11 57.21 56.88
R3(O) 81.25 80.66 64.25 63.54
Thiol 44.35 43.31 50.62 51.01
Thione 56.31 56.10 42.42 40.98
R1(S) 66.87 65.77 64.11 65.02
R2(S) 78.88 77.54 75.69 77.10
R3(S) 80.48 82.09 82.82 80.11

Table 4.  Second order delocalization energies (E(2)) for the studied compounds in gas phase, and ethanol at
B3LYP/6–311 +  + G(2d,2p) level of theory, all values are in kcal/mol.

B3LYP/6–311 +  + G (2d,2P). For rotamer, R3(O) structure have higher stability than R2(O) and R1(O) struc-
tures, while R1(S) structure has higher stability than R3(S) and R2(S) structures (Table 2).

Donor–acceptor (bond–anti‑bond) interactions

Each valence bonding NBO (σAB) in the NBO ­analysis24 must be coupled with a corresponding valence antibond-
ing NBO (σ*AB), to compute the span of the valence space:
σ ∗AB = CA hA − CB hB (3)
For example, the Lewis σ-type (donor) NBOs are matched by the non-Lewis σ*-type (acceptor) NBOs that
are properly vacant in an ideal Lewis structure picture. The universal transformation to NBOs leaves vacant
orbitals in the formal Lewis structure. As a result, the filled NBOs of the natural Lewis’s structure can accurately
reflect covalency effects in molecules. Given that the non-covalent delocalization effects are linked to σ — > σ*
interactions between filled (donor) and empty (acceptor) orbitals, it is only logical to refer to them as being
of the donor–acceptor, charge transfer, or generalized "Lewis’s base-acid" Lewis’s type. The anti-bonds reflect
unutilized valence-shell capacity and span areas of the atomic valence spaces that are formally unsaturated by
covalent bond formation. Weak occupancies of the valence anti-bonds represent actual "delocalization effects," or
irreducible deviations from the idealized localized Lewis picture. To account for the donor–acceptor (bond-anti-
bonds) interactions, all potential interactions between "filled" (donor) Lewis-type NBOs and "empty" (acceptor)
non-Lewis NBOs are examined in the NBO analysis. The energies of these interactions are then estimated using
second-order perturbation theory. These interactions (or energy stabilization) are referred to as "delocalization"
corrections for the zeroth-order natural Lewis structure.
Table 5 reports the most significant interaction between "unoccupied" (acceptor) non-Lewis NBOs and
"occupied" (donor) Lewis-type NBOs. The lp (S or O) participates as a donor and the BD*(O(S)-C) anti-bond as
an acceptor [lp (S or O) — > BD*(O(S)-C)], with charge transfer energy values at the B3LYP level. These results
of the NBO analysis are collected in Table 5 in gas phase, and ethanol. This shows that increasing the Hammett
constants of these studied compounds leads to a decrease in charge transfer energy. It may be concluded that the
strength of the O(S)-C bond only minimally changes in the studied compounds because the amount of destabi-
lization energy predicted using the NBO technique does not significantly alter in each of the compounds, which
is consistent with our calculated r­ esults5 and the experimental r­ esults25.
The calculated natural orbital occupancy, repeatedly known as the orbital’s "natural population," is shown in
Table 6 in gas phase, and ethanol. It is observed that the maximum occupancy for σ C-O(S) and σ* C-O(S) bond orbit-
als is obtained for R1(O) and R3(S) 1.99338 (1.99348), 0.02224 (0.02295) in gas phase and in ethanol, respectively
and 1.98245 (1.98302), 0.02668 (0.02817), in gas phase, and, in ethanol, respectively. As we explained above,
small occupancies of the antibound orbitals relate, in Hartree Fock theory, to a complicated change from the

E(2) (kcal/mol)
Acc
Don. NBO NBO Enol Thiol Keto Thione R1(O) R1(S) R2(O) R2(S) R3(O) R3(S)
lp(O/S) in gas BD*(O/S -C26) in gas 23.33 26.87 18.54 29.32 45.90 41.25 25.14 25.69 31.25 32.12
lp(O/S) in ethanol BD*(O/S -C26) in ethanol 22.43 25.85 19.01 28.12 44.66 40.88 24.33 25.03 30.44 33.03
lp(N) in gas BD*(N-C15) in gas 14.24 17.21 12.08 22.10 12.21 16.32 18.22 28.88 19.78 23.65
lp(N) in ethanol BD*(N-C15) in ethanol 14.00 18.21 11.88 21.86 11.57 15.78 17.54 26.77 19.20 16.69

Table 5.  The second-order perturbation energies E(2) (kcal/mol) corresponding to the most important charge
transfer interactions (donor — > acceptor) in the studied compounds in gas phase, and ethanol by using
B3LYP/6–311 +  + G(2d,2p) method. lp is the lone pair NBO in the plane.

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Enol Thiol Keto Thione R1(O) R1(S) R2(O) R2(S) R3(O) R3(S)
σC25-O/S26 in gas phase 1.99236 1.97809 1.99291 1.98009 1.99338 1.98159 1.97658 1.98230 1.98704 1.98245
σC25-O/S26 in ethanol 1.99241 1.98202 1.99247 1.98006 1.99348 1.98206 197,628 1.98257 1.97659 1.98302
σC15-N16 in gas phase 1.98071 1.97429 1.98085 1.98219 1.97955 1.98000 1.98895 1.97879 1.97996 1.97893
σC15-N16 in ethanol 1.98092 1.95645 1.97556 1.97645 1.97990 1.98011 1.97972 1.97911 1.98030 1.97910
lp(O/S) in gas phase 1.97378 1.98458 1.96699 1.98348 1.97955 1.98941 1.96785 1.98699 1.97924 1.98825
lp(O/S) in ethanol 1.97559 1.98477 1.97239 1.98229 1.97969 1.98964 1.97839 1.98710 1.97850 1.98846
lp(N) in gas phase 1.88629 1.89328 1.89739 1.91608 1.93333 1.91908 1.91323 1.93496 1.93344 1.93493
lp(N) in ethanol 1.87803 1.89690 1.83173 1.91178 1.93738 1.92479 1.93603 1.93791 1.93724 1.93828
σ*C25-O/S26 in gas phase 0.02026 0.02328 0.01265 0.01238 0.02224 0.02582 0.01524 0.02530 0.01434 0.02668
σ*C25-O/S26 in ethanol 0.02209 0.02368 0.12318 0.01699 0.02295 0.02721 0.01487 0.02593 0.01473 0.02817
σ*C15-N16 in gas phase 0.54345 0.51578 0.02309 0.02572 0.49912 0.50768 0.01715 0.50287 0.01613 0.51806
σ*C15-N16 in ethanol 0.54488 0.51689 0.02487 0.02351 0.49649 0.50578 0.53287 0.50437 0.01854 0.51400
Valence non-Lewis in gas phase 1.99973 1.99978 1.99975 1.99921 1.99974 1.99989 1.99972 1.99979 1.99975 1.99989
Valence non-Lewis in ethanol 1.99974 1.99987 1.99978 1.99954 1.99972 1.99988 1.99975 1.99989 1.99975 1.99989
Rydberg non-Lewis in gas phase 0.00278 0.00264 0.00292 0.00346 0.00290 0.00438 0.00265 0.00479 0.00235 0.00476
Rydberg non-Lewis in ethanol 0.00246 0.00224 0.00289 0.00364 0.00229 0.00483 0.00266 0.00492 0.00255 0.00476

Table 6.  The important calculated valence non-Lewis and Rydberg non-Lewis, σ C-O(S) and σ*C-O(S) bond
orbital occupancies in gas phase, and ethanol at B3LYP/6–311 +  + G(2d,2p). lp is the lone pair NBO in the
plane.

idealized Lewis picture and thus to small non-covalent corrections to the picture of localized covalent bonds. The
resulting p character of the corresponding sulfur natural hybrid orbital (NHO) of the σC-O(S) bond orbital is also
related to the impact on molecular stability and geometry (bond lengths) of decreased occupancy of the local-
ized σC-O(S) orbital in the idealized Lewis structure or increased occupancy of σ*C-O(S) of the non-Lewis orbital.
In Table 3, for selected compounds at B3LYP level [thiol, thione, R1(S), R2(S), and R3(S)], the p characters of
sulfur σ C-S values are 4.55(4.69), 4.78(4.56), 4.60(4.46), 4.55(4.46), and 4.51(4.51), in gas phase, and ethanol,
respectively. Like this, the lengths of the C-S bonds are 1.787(1.784), 1.760(1.758), 1.797(1.792), 1.794(1.789),
and 1.797(1.792), in gas phase, and ethanol, respectively. For [enol, keto, R1(O), R2(O) and R3(O)], the p
characters of oxygen σ C-O values are 1.79(1.82), 1.00(1.61), 1.87(1.82), 3.67(3.65), and 3.76(3.74), in gas phase,
and ethanol, respectively. Like this, the lengths of the C-O bonds are 1.343(1.356), 1.270(1.289), 1.361(1.366),
1.366(1.367), and 1.369(1.366), in gas phase, and ethanol, respectively. Therefore, the results indicate that the
C-O(S) bond lengths of these compounds are basically controlled by the p character of these hybrid orbitals and
by the nature of the C-O(S) bond.

Natural population analysis

The natural population analysis (NPA) was evaluated using natural atomic orbital o ­ ccupancies26. Table 7 in
gas phase, and ethanol displays the molecular charge distribution on the skeletal atoms of the rotomeric and
tautomeric forms of 2HPhAZ and 2MPhAZ. In general, it is seen that the strong negative and positive par-
tial charges on the skeleton atoms—particularly O, N, and S—increase as the examined compounds’ Ham-
mett constants increase. The most electronegative center charges of [enol, keto, R1(O), R2(O), and R3(O)]
are −0.58236(0.60716), −0.53433(−0.52220), −0.48994(−0.55563), −0.5088(−0.56684), −0.5210(−0.57059), and
−0.69700(−0.74332), −0.71822(−0.83839), −0.65636 (−0.69924), −0.6867(−0.70641), and −0.6831(−0.70657),
in gas phase, and ethanol respectively, which are accumulated on N and O atoms. While [thiol, thione,
R1(S), R2(S), and R3(S)], the most electronegative center charges on N and S atoms are −0.60289(−0.56601),
−0.5412(−0.53769), −0.5132(−0.55665), −0.5113(−0.56395), −0.5129(−0.56467), and −0.02443(−0.01982),
−0.27762(−0.43861), −0.10941(−0.05444), −0.04712(−0.02862), and 0.0578(−0.02977), in gas phase, and etha-
nol respectively. According to the electrostatic point of view of the molecule, these electronegative atoms tend to
donate electrons. Also, it is found that the most electropositive center charges of [enol, keto, R1(O), R2(O), and
R3(O)] and [thiol, thione, R1(S), R2(S), and R3(S)] are accumulated on C7, C15, and C25 atoms (cf. Table 7).
These electropositive atoms have a propensity to accept electrons from the perspective of the molecule’s electro-
statics. Table 7 lists each electronegative and electropositive atom’s native electronic configuration. According
to the distribution of partial charges on the skeleton atoms, electrostatic attraction or repulsion between atoms
can contribute significantly to intra- and intermolecular interaction.

Conclusion
Using the DFT/B3LYP/6–311 +  + G (2d, 2p) level of theory, the electronic for tautomeric and rotameric structures
of 2HPhAZ and 2MPhAZ analogues is explored in gas phase, and ethanol. Enol/thiol is more stable than keto/
thione form for tautomer in the statically mixed ground state in gas phase, which is considered in all computa-
tions in this article. The ethanol solvent causes some reordering of the relative stability of 2HPhAZ and 2MPhAZ
conformers. For rotamer, R3(O) structure have higher stability than R2(O) and R1(O) structures, while R1(S)
structure has higher stability than R3(S) and R2(S) structures. According to our findings, an intriguing aspect

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Enol Thiol Keto Thione R1(O) R1(S) R2(O) R2(S) R3(O) R3(S)
C1 in gas phase -0.16588 –0.16422 –0.19673 –0.5690 –0.17080 –0.1695 –0.1613 -0.1584 –0.1727 –0.1672
C1 in ethanol –0.19941 –0.20172 –0.16537 –0.18866 –0.16690 –0.15447 –0.16307 –0.15853 –0.16709 –0.15176
C2 in gas phase –0.20506 –0.20645 –0.18806 –0.2014 –0.21512 –0.2138 –0.2071 –0.2127 –0.2142 –0.2138
C2 in ethanol –0.19959 –0.13607 –0.18607 –0.18011 –0.21285 –0.21304 –0.20808 –0.21026 –0.21256 –0.21107
C3 in gas phase –0.11955 –0.13963 –0.13884 –0.1349 –0.12243 –0.1215 –0.1234 –0.1125 –0.1236 –0.1120
C3 in ethanol –0.13183 –0.03984 –0.11380 –0.12132 –0.12298 –0.11808 –0.12148 –0.11567 –0.12317 –0.10876
C4 in gas phase –0.20004 –0.20313 –0.15073 0.73914 –0.18809 –0.1854 –0.1971 –0.2021 –0.1878 –0.1881
C4 in ethanol –0.10506 –0.20032 –0.15604 –0.07596 –0.18850 –0.21053 –0.19219 –0.19394 –0.19564 –0.20975
C5 in gas phase –0.06764 –0.25527 –0.04805 –0.0659 –0.07527 –0.0733 –0.0672 –0.0733 –0.0738 –0.0714
C5 in ethanol –0.06638 –0.12134 –0.05409 –0.05101 –0.08120 –0.07957 –0.07255 –0.07818 –0.07910 –0.07723
C6 in gas phase –0.14915 –0.14289 –0.20378 –0.2764 –0.14398 –0.1442 –0.1370 –0.1341 –0.1481 –0.1418
C6 in ethanol –0.19480 –0.14964 –0.16575 –0.18868 –0.15308 –0.14190 –0.14926 –0.14494 –0.15422 –0.13930
C7 in gas phase 0.21167 0.18890 0.22981 0.21355 0.18714 0.19214 0.19170 0.18670 0.19207 0.18711
C7 in ethanol 0.20011 0.16813 0.21993 0.21802 0.18056 0.18024 –0.18364 0.17780 0.18246 0.17875
C13 in gas phase –0.25869 –0.87975 –0.24933 –0.2413 –0.26482 –0.2618 –0.3094 –0.2803 –0.2543 –0.2655
C13 in ethanol –0.27109 –0.31545 –0.25853 –0.25116 –0.27539 –0.27226 –0.28988 –0.28425 –0.27459 –0.27778
C15 in gas phase 0.22868 0.05725 0.25384 0.25612 0.21258 0.21168 0.21496 0.20875 0.20507 0.20507
C15 n ethanol 0.20785 0.32704 0.24851 0.24771 0.19985 0.19580 –0.19179 0.19274 0.19051 0.19088
N16 in gas phase –0.58236 –0.60289 –0.53433 –0.5412 –0.48994 –0.5132 –0.5088 –0.5113 –0.5210 –0.5129
N16 in ethanol –0.60716 –0.56601 –0.52220 –0.53769 –0.55563 –0.55665 –0.56684 –0.56395 –0.57059 –0.56467
C17 in gas phase –0.24695 –0.24303 –0.26237 –0.2422 –0.23959 –0.2247 –0.2528 –0.2211 –0.2811 –0.2214
C17 in ethanol –0.25566 –0.22810 –0.28993 –0.25793 –0.25197 –0.22974 –0.26533 –0.26649 –0.28099 –0.22884
C18 in gas phase –0.13887 –0.61862 –0.14385 –0.1462 –0.14321 –0.1461 0.35002 –0.1338 0.34961 –0.1324
C18 in ethanol –0.15229 –0.16652 –0.15189 –0.15134 –0.15619 –0.15793 –0.34626 –0.06527 0.34849 –0.15498
C19 in gas phase –0.17230 –0.17539 –0.16098 –0.1697 –0.17461 –0.1778 –0.1663 –0.1776 –0.1708 –0.1782
C19 in ethanol –0.18804 –0.18657 –0.17880 –0.18282 –0.18591 –0.18805 0.18157 –0.18931 –0.18199 –0.23480
C22 in gas phase –0.16354 0.72442 –0.19917 –0.1527 –0.12282 –0.1101 –0.1623 –0.1105 –0.1229 –0.1077
C22 in ethanol –0.15962 –0.16897 –0.20667 –0.16102 –0.13693 –0.11513 –0.14816 –0.14456 –0.13562 –0.11493
C23 in gas phase –0.23910 –0.23362 –0.26583 –0.22041 –0.27668 –0.2269 –0.2548 –0.2299 –0.2335 –0.2325
C23 in ethanol –0.25555 –0.23438 –0.29957 –0.24746 –0.27993 –0.23643 –0.24481 –0.23739 –0.24919 –0.12436
C25 in gas phase 0.37617 –0.48595 0.43933 –0.12756 0.35734 –0.1174 –0.5649 –0.1310 –0.1398 –0.1270
C25 in ethanol 0.35354 –0.14899 0.40459 –0.13609 –0.34650 –0.13237 –0.16298 –0.14337 –0.16363 –0.18300
O26/S26 in gas phase –0.69700 0.02443 –0.71822 –0.27762 –0.65636 0.10941 –0.6867 0.04712 –0.6831 0.0578
O26/S26 in ethanol –0.74332 –0.01982 –0.83839 –0.43861 –0.69924 0.05444 –0.70641 0.02862 –0.70657 0.02977

Table 7.  Atomic charge distribution described in terms of natural population analysis (NPA) for the studied
compounds in gas phase, and ethanol by using B3LYP/6–311 +  + G(2d,2p) method.

to note is how the bond length and angle alter as a function of the tautomeric structure’s σF values. The examined
compounds’ increasing Hammett constants result in a rise in the p characteristics of the sulfur NHO σ C-S(O) bond
orbitals. There is a strong hyperconjugated interaction between nO(S)—> σ*C25-O26(S26) and nO(S) —> σ*C15-N16 in the
compounds studied. The weakness in the O(S)-C sigma bond is due to nO(S)— > σ*C25-O26(S26) and nO(S)—> σ*C15-N16
delocalization, which is responsible for the longer O(S)-C bond lengths and hence contributes to the tautomeriza-
tion of 2HPhAZ and 2MPhAZ. With an increase in the examined compounds’ Hammett constants, the charge
transfer energy reduces. The intra- and intermolecular interactions can be significantly influenced by the elec-
trostatic attraction or repulsion between atoms. The NBO analysis focuses on the availability of a device of high
quality, shedding light on both the HB-related electron delocalization-induced hyperconjugate effects and the
many effects found to influence the NH-stretch spectral shift, i.e., the main measurable quantity on which most
of the spectroscopic approaches are based.

Data availability
All data generated or analyzed during this study are included in this published article [and its supplementary
information files].

Received: 18 July 2023; Accepted: 22 December 2023

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Author contributions
S.A.H.: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing-
original draft, Writing-review & editing. A.B.E.-M. has reversed the writing for the article, Writing-review &
editing and Methodology. A.M.E.-N. find the point of the article, researches them, Formal analysis, and Meth-
odology. S.H.E.-D. prepared the studied compounds, and Methodology.

Funding
Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in coopera-
tion with The Egyptian Knowledge Bank (EKB).

Competing interests
The authors declare no competing interests.

Additional information
Supplementary Information The online version contains supplementary material available at https://​doi.​org/​
10.​1038/​s41598-​023-​50660-w.
Correspondence and requests for materials should be addressed to S.A.H. or A.B.E.-M.
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