Structural and spectroscopic study of 5-cyanomethyl chromeno[4, 3-b]pyridine-3-carbonitrile (CCPC) using DFT and Thermodynamic: Computational and experimental analysis
Al-Shimaabadran1
MagdyA.Ibrahim1Phone+2 01007887204Emailmagdy_ahmed@edu.asu.edu.egEmailmagdy_ahmed1977@yahoo.com
ShimaaAbdelHalim1✉EmailShimaaquantum@ymail.comEmailshimaabdelhalim@edu.asu.edu.eg
1Department of Chemistry, Faculty of EducationAin Shams University11711RoxyCairoEgypt
2
A
+20 01090306455
Al-Shimaa badran, Magdy A. Ibrahim, Shimaa Abdel Halim*
Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, 11711, Cairo-Egypt
E-mail: magdy_ahmed@edu.asu.edu.eg and magdy_ahmed1977@yahoo.com
Tel.: +2 01007887204; fax: +2 022581243.
A
Abstract
The reaction of 3-(6,8-dimethylchromonyl)acrylonitrile (1) with cyanoacetamide (2) under basic conditions afforded a novel heterocyclic system: 5-cyanomethylchromeno[4,3-b]pyridine-3-carbonitrile (CCPC, 3). The transformation proceeds via a cascade mechanism involving initial Michael addition, retro-Michael-induced γ-pyrone ring opening and subsequent double recyclization steps. The structure of compound 3 was confirmed by analytical and spectral data. Its optimized molecular geometry and electronic properties were investigated using density functional theory (DFT/B3LYP) with the 6-311 + + G(d,p) basis set. Key global reactivity descriptors including electronegativity (χ), chemical potential (µ), electrophilicity index (ω), softness (S), and hardness (η) were calculated. Molecular electrostatic potential (MEP) maps provided insight into reactive sites. The experimental IR and NMR spectra exhibited strong agreement with theoretical predictions, validating the computational model. Swiss ADME analysis confirmed that all evaluated physicochemical parameters conform to Lipinski’s and Veber’s rules, indicating favorable drug-likeness. Additionally, non-linear optical (NLO) properties and quantum chemical descriptors were examined. Natural bond orbital (NBO) analysis revealed intramolecular charge transfer characteristics. Thermo kinetic behavior of CCPC was evaluated using the KiSThelP package across the temperature range 250–400 K in the gas phase and in various solvents (water, ethanol, acetone, dioxane, and DMSO). Rate constants (kuni) were estimated via transition state theory (TST) and unimolecular Eckart tunneling corrections. UV–Vis spectra were simulated using TDDFT-CAM-B3LYP/6-311 + + G(d,p), revealing solvent-dependent shifts in absorption maxima (λmax) and transition intensities. The nature of the electronic excitations was analyzed based on molecular orbital contributions.
Keywords:
Chromonylacrylonitrile
Chromeno [4,3-b]pyridine
Recyclization
Thermodynamic
NMR
NLO
NBO
*Corresponding Author
E-mail: Shimaaquantum@ymail.com and shimaabdelhalim@edu.asu.edu.eg (Shimaa Abdel Halim). Tel.: +20 01090306455
1. Introduction
Chromone is a versatile heterocyclic scaffold characterized by a benzopyran-4-one core structure and serves as a key building block in a wide range of natural products and synthetic compounds, particularly within the fields of medicinal chemistry and material science [1–3]. Naturally derived chromone analogs are abundantly found in plants and are associated with a wide spectrum of pharmacological activities [4, 5]. These biological properties include anti-inflammatory, antimicrobial, antioxidant, anticancer, antiproliferative, antiangiogenic, and antidiabetic effects [6–10]. Due to their structural adaptability, chromones have emerged as promising candidates in drug development. Moreover, their distinctive photophysical behavior has made them valuable in material science applications such as fluorescence-based sensing and organic electronic devices [11–13]. The structural simplicity of chromone, combined with its chemical reactivity, allows for extensive modification, enabling the generation of a broad library of derivatives with tailored properties [14–17]. Density Functional Theory (DFT) is a modelling technique recognized for its ability to accurately calculate the physicochemical properties of molecules while maintaining low computational costs [18–19].
Theoretical research using the DFT approach, computational studies, and electrical, optical, and photoelectrical characteristics is very important to find new drug candidates and understanding the electrical properties of different molecular structures [20–23]. The nonlinear optical (NLO) effect is at the forefront of current research because Chromeno[4,3-b]pyridines are crucial for providing the essential functions of frequency shifting, optical modulation, optical switching, optical logic, and optical memory for emerging technologies in fields like telecommunications, signal processing, and optical interconnections [24]. Molecular electrostatic potential (MEP), represented as a color-coded surface that reflects molecular size, shape, and charge distribution, is a powerful tool for analyzing the structural and physicochemical properties of molecules, including biomolecules and pharmaceutical compounds [25].
In this study, we aimed to explore the chemical reactivity of an electron-deficient chromone-linked acrylonitrile toward cyanoacetamide under mild basic conditions. The primary goal was to synthesize and characterize a novel compound, CCPC, and to investigate its physicochemical and electronic properties. Density Functional Theory (DFT) calculations at the B3LYP/6-311 + + G(d,p) level were utilized to optimize the molecular geometries of the target compounds and to compute key global reactivity descriptors, as well as their thermodynamic and kinetic stability parameters. Electronic absorption properties were examined via UV–Vis spectral simulations using time-dependent DFT (TDDFT-CAM-B3LYP/6-311 + + G(d,p)), which revealed solvent-induced red and blue shifts in the absorption maxima (λmax) and spectral intensities. The electronic nature of the excited states and the corresponding transitions were thoroughly analyzed. Natural Bond Orbital (NBO) analysis was carried out to investigate intramolecular charge transfer processes in CCPC. Furthermore, vibrational (IR) and nuclear magnetic resonance (NMR) spectra were theoretically predicted and compared with experimental results to validate the structural identity of the synthesized compound. Bioavailability parameters were evaluated through ADME analysis and molecular electrostatic potential (MEP) maps were constructed to identify electrophilic and nucleophilic sites, thereby supporting the proposed reaction mechanism and spectroscopic interpretations.
2. Experimental
2.1. General
A Perkin-Elmer CHN-2400 analyzer was used to conduct elemental microanalyses. A digital Stuart SMP3 device was used to measure melting points. Using KBr discs, infrared spectra were recorded on an FTIR Nicolet IS10 spectrophotometer (cm-1). Mercury-300BB was used to measure the 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra. The solvent used was DMSO-d6, and the internal standard was TMS (δ). The GC-2010 Shimadzu gas chromatography mass spectrometry equipment (70 eV) was used to obtain mass spectra. 3-(6,8-Dimethylchromonyl)acrylonitrile (1) was prepared according to the published method [26].
2.1.
Synthesis and characterization of compounds
4.2. 5-(Cyanomethyl)-7,9-dimethyl-2-oxo-1,5-dihydro-2H-chromeno[4,3-b]pyridine-3-carbonitrile (CCPC, 3)
A mixture of 3-(6,8-dimethylchromonyl)acrylonitrile (1) (0.68 g, 3 mmol) and cyanoacetamide (2) (0.25 g, 3 mmol) in absolute ethanol (25 mL) containing TEA (0.1 mL) was heated under reflux for 2 h. The yellow crystals deposited during heating were filtered off, air dried and crystallized from MeOH to give compound 3 as pale-yellow crystals, yield 0.56 g (65%), mp > 300 ºC. IR (KBr, cm− 1): 3242 (NH), 3027 (CHarom.), 2971, 2934 (CHaliph.), 2246, 2213 (2C ≡ N), 1652 (C = O), 1577 (C = C). 1H NMR (DMSO-d6, δ): 2.30 (s, 3H, CH3), 2.36 (s, 3H, CH3), 3.17 (d, 2H, J = 6.3 Hz, CH2CN), 5.47 (t, 1H, J = 6.3 Hz, H-5), 7.29 (s, 1H, H-8), 7.53 (s, 1H, H-10), 8.34 (s, 1H, H-4), 12.62 (bs, 1H, NH exchangeable with D2O). 13C NMR (DMSO-d6, δ): 17.5 (CH3), 20.4 (CH3), 22.3 (CH2), 70.4 (C-5), 108.2 (C-3), 112.8 (C-4a), 116.3 (C ≡ N), 117.2 (C ≡ N), 119.8 (C-10a), 125.4 (C-10b), 127.7 (C-9), 128.5 (C-7), 130.9 (C-8), 133.7 (C-10), 145.4 (C-4), 148.6 (C-6a), 162.4 (C-2). Mass spectrum, m/z (I%): 291 (M+, 57), 251 (M+ - CH2CN; 100), 223 (43), 172 (14), 122 (50), 108 (12), 94 (35), 77 (23), 65 (19). Analysis Calcd for C17H13N3O2 (291.31); C, 70.09; H, 4.50; N, 14.42%. Found: C, 69.87; H, 4.41; N, 14.36%.
2.2. Computational methods
Computational chemistry calculations for the synthesized compounds were carried out using the GAUSSIAN 09 W software, applying DFT at the B3LYP level with the 6-311 + + G(d,p) basis set. This method is well-suited for evaluating the stability and reactivity of molecules similar to those investigated in this study [27–29]. Visual representations were generated using Gauss-View 5.0 [30, 31]. Geometry optimizations were performed without imposing any symmetry constraints. Quantum chemical calculations provided results such as molecular electrostatic potential (MEP) maps and optimized geometries along with molecular orbital (MO) energies.
Additionally, the chemical shifts of the 1H and 13C NMR spectra were calculated using the Gauge-Including Atomic Orbital (GIAO) method at the B3LYP/6-311 + + G(d,p) level, and the results were compared with experimental values to validate the molecular structure [32]. Vibrational frequencies were also computed based on the optimized geometry to further support structural characterization.
The current work concentrated on the total dipole moment µtot, the average polarizability αtot and the first hyperpolarizability βtot, using the x, y and z components as follows [33–36]:
𝜇 = (𝜇2𝑥 + 𝜇2𝑦 + 𝜇2𝑧) 1/2, (1)
⟨𝛼⟩ = 1/3 (𝛼𝑥𝑥 + 𝛼𝑦𝑦 + 𝛼𝑧𝑧), (2)
Δ𝛼 = ((𝛼𝑥𝑥 − 𝛼𝑦𝑦) 2 + (𝛼𝑦𝑦 − 𝛼𝑧𝑧) 2 + (𝛼𝑧𝑧 − 𝛼𝑥𝑥) 2/2)1/2 (3)
⟨𝛽⟩ = (𝛽2𝑥 + 𝛽2𝑦 + 𝛽2𝑧) 1/2, (4)
Where
𝛽𝑥 = 𝛽𝑥𝑥𝑥 + 𝛽𝑥𝑦𝑦 + 𝛽𝑥𝑧𝑧,
𝛽𝑦 = 𝛽𝑦𝑦𝑦 + 𝛽𝑥𝑥𝑦+ 𝛽𝑦𝑧𝑧,
𝛽𝑧 = 𝛽𝑧𝑧𝑧 + 𝛽𝑥𝑥𝑧+ 𝛽𝑦𝑦𝑧.
Intrinsic Reaction Coordinate (IRC) calculations were performed using 20 points in both the forward and reverse directions, with a step size of 0.1 amu1/2 Bohr. The kinetic and statistical thermodynamics software package KiSThelP [37] was employed to determine the unimolecular rate coefficients (kuni, in s− 1) for CCPC in the gas phase and various solvents. To account for quantum mechanical tunneling effects, the tunneling correction factor χ(T) was estimated using the one-dimensional Eckart tunneling model (Eck) [38], which has been widely applied in prior studies [39]:
(5) |
Where, ΔHf ≠,0K represents the zero-point energy (ZPE)-corrected activation enthalpy in the forward direction, while p(E) denotes the transmission probability associated with the corresponding one-dimensional potential energy barrier at energy E. Orbital interactions, atomic charges, and their influence on molecular structure and stability were analyzed using the Natural Bond Orbital (NBO) method [40]. Additionally, the electronic absorption spectra (EAS) of the studied compounds were investigated using time-dependent density functional theory (TD-DFT) combined with the Coulomb-Attenuating Method (CAM-B3LYP), based on geometries optimized at the B3LYP/6-311 + + G(d,p) level in the gas phase [41, 42].
Results and discussion
3.1. Characterization of the synthesized compounds
The chemical reactivity of 3-(6,8-dimethylchromonyl)acrylonitrile (1) toward cyanoacetamide (2) was investigated in boiling ethanol using triethylamine (TEA) as a basic catalyst. This reaction yielded 5-(cyanomethyl)-7,9-dimethyl-2-oxo-1,5-dihydro-2H-chromeno[4,3-b]pyridine-3-carbonitrile (3, CCPC), as outlined in Scheme 1. The reaction proceeds via a cascade mechanism initiated by a Michael addition of the deprotonated cyanoacetamide at the C-2 position of the γ-pyrone ring, followed by a retro-Michael step leading to ring opening and formation of intermediate A. This intermediate undergoes free rotation around a single bond (intermediate B), which is then followed by intramolecular cyclocondensation (intermediate C) and subsequent cycloaddition, ultimately furnishing the final product 2, as depicted in Scheme 1. The electron-deficient sites in substrate 1 were further evaluated through theoretical calculations to support the proposed reaction mechanism. The computational results confirmed that the C-2 position of the γ-pyrone moiety is the most electron-deficient center, rendering it the most favorable site for nucleophilic attack in the initial Michael addition step.
Structure of product 3 was elucidated based on spectral results. The mass spectrum displayed the molecular ion peak at m/z 291 corresponding to the suggested molecular formula (C17H13N3O2) and the base peak at m/z 251, which attribute to loss of a CH2CN fragment from the molecular ion. The detailed fragmentation pathway of compound 3 is illustrated in Scheme 2. The IR spectrum of compound 3 exhibited distinctive absorption bands at ν 3242 (NH), 2246, 2213 (2C ≡ N), 1652 (C = O) and 1577 cm− 1 (C = C). The 1H NMR spectrum presented typical doublet and triplet signals at δ 3.17 and 5.47 ppm attributed to CH2-CN and H-5, respectively. Also, three singlet signals were recorded at δ 7.29, 7.53 and 8.34 ppm due to H-8, H-10 and H-4, respectively. A D2O-vanished signal due to NH proton was observed at δ 12.62 ppm. The 13C NMR spectrum of compound 3 showed characteristic signals at δ 70.4 (C-5), 108.2 (C-3), 112.8 (C-4a), 116.3 (C ≡ N), 117.2 (C ≡ N), 145.4 (C-4), 148.6 (C-6a), and 162.4 (C-2).
Scheme 1
Reaction of acrylonitrile 1 with cyanoacetamide
Scheme 2
Mass fragmentation patterns of compound 2 (CCPC)
3.2. Theoretical studies
3.2.1. Frontier molecular orbital energies and chemical reactivity
A
Frontier molecular orbitals (FMOs) are fundamental in assessing a molecule’s optical, electronic, and reactive behavior, as well as its overall chemical stability [43]. The molecular structures of the investigated compounds were fully optimized using the DFT/B3LYP/6-311 + + G(d,p) method. Figure 1 illustrates the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), and the optimized geometries of the studied compounds [44]. The HOMO reflects the electron-donating capability of a molecule, while the LUMO represents its potential to accept electrons. Corresponding energy values (EHOMO and ELUMO) are listed in Table 1. The energy gap (ΔE = ELUMO− EHOMO) serves as a critical indicator of chemical reactivity and kinetic stability; a larger ΔE denotes greater molecular stability. Among the evaluated compounds, compound 2 displayed the highest energy gap (ΔE = 6.947 eV), indicating superior chemical stability. In addition, several quantum chemical descriptors were computed—including chemical potential (µ), electronegativity (χ), hardness (η), softness (S), electrophilicity index (ω), nucleophilicity (ε), and the maximum charge transfer capacity (ΔNmax) using established theoretical formulas [45, 46].I = -EHOMO (6) Y = -ELUMO (7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
Ionization potential (I, eV) represents the energy required to remove an electron from a molecule [46], while electron affinity (Y, eV) quantifies the energy change when an electron is added. Chemical hardness (η, eV) reflects a molecule’s resistance to changes in its electron distribution, whereas softness (S, eV⁻¹) is its inverse [47]. Among the studied compounds, compound 2 has the highest hardness value (η = 3.473 eV), indicating that it is the least reactive and comparatively more rigid. In contrast, compound 3 shows the highest softness value (S = 0.560 eV− 1), making it the most reactive and chemically softer than the others. Additionally, electronegativity (χ, eV) describes a molecule’s tendency to attract electrons [48], with compound 3 displaying the highest value (χ = 4.757 eV), suggesting strong electron-withdrawing characteristics. Chemical potential (µ, eV) measures the tendency of electrons to escape from a system; the negative values observed for the studied compounds indicate overall molecular stability.
Moreover, Parr et al. [49] introduced the electrophilicity index (ω) as a parameter to quantify the decrease in energy when a molecule gains an additional electronic charge (ΔNmax) during interactions between electron donors and acceptors. Compound 3 exhibits a high ω value (6.338 eV) along with a significant ΔNmax (2.665), indicating its strong electrophilic nature. Conversely, nucleophilicity (ε, eV− 1) measures a molecule’s tendency to donate electrons [50], where compound 2 showing the highest ε value (0.342 eV− 1), making it the most potent nucleophile.
Parameters | Compound 1 | Compound 2 | Product 3 (CCPC) |
|---|---|---|---|
EHOMO | -6.719 | -7.981 | -6.542 |
ELUMO | -2.380 | -1.034 | -2.972 |
IP (eV) | 6.719 | 7.981 | 6.542 |
EA (eV) | 2.380 | 1.034 | 2.972 |
ΔE (eV) | 4.339 | 6.947 | 3.570 |
η (eV) | 2.169 | 3.473 | 1.785 |
µ (eV) | -4.549 | -4.508 | -4.757 |
ω (eV) | 4.771 | 2.925 | 6.338 |
ε (eV− 1) | 0.209 | 0.342 | 0.158 |
S (eV− 1) | 0.461 | 0.288 | 0.560 |
χ | 4.549 | 4.508 | 4.757 |
∆Nmax | 2.097 | 1.298 | 2.665 |
Figure 1. Molecular modeling and the electron density of HOMO and LUMO of compounds 1–3.
Compound 1 | Compound 2 | Compound 3 |
|---|---|---|
 Optimized Structures |  Optimized Structures |  Optimized Structures |
 ELUMO = -2.380 |  ELUMO= -1.034 |  ELUMO = -2.972 |
 EHOMO= -6.719 |  EHOMO = -7.981 |  EHOMO= -6.542 |
3.2.2. Molecular electrostatic potential (MEP)
Molecular electrostatic potential (MEP) mapping offers insights into a molecule’s size, hydrogen bonding interactions, and overall charge distribution resulting from electrons and nuclei. It helps predict sites of electrophilic attack (electron-rich regions with high electronegativity) and nucleophilic attack (electron-deficient regions with high positive electrostatic potential) [51, 52]. The electrostatic potential of the molecules was calculated using DFT at the B3LYP/6-311 + + G (d,p) level [53]. Figure 2 illustrates the MEP maps of the studied compounds.
The MEP map represents different electrostatic potentials through a color gradient: blue > green > yellow > orange > red. Blue areas indicate low electron density, while red regions represent high electron density [54]. The intense blue areas, primarily located on hydrogen and carbon atoms, signify the main electrophilic sites, suggesting a strong tendency to attract with nucleophilic reagents. Conversely, regions depicted in deep yellow and red colors mainly associated with nitrogen and oxygen atoms, indicating nucleophilic sites, suggesting a strong tendency to interact with electrophilic reagents. The presence of lone electron pairs as well as high electronegativity of these atoms may be the reasons for creating regions of negative electrostatic potential, affirming their nucleophilic character [55].
Herein, the MEP map for starting compound 1 supported the mechanism depicted in Scheme 1, where C-2 position has deep blue color indicating high suitability for nucleophilic attack by the reagent 2. The blue color at C-2 position was furnished due to low electron density (electrophilic site) achieved by electron withdrawing mesomeric effects of both C = O and C ≡ N, as well as the inductive effect of oxygen atom at position 1. In addition, the MEP map of the product 3 revealed deep blue color over C-4, and this mean low electron density (electrophilic nature) which achieved by electron withdrawing effect of both C = O and C ≡ N functions. Therefore, this map supports the 1H NMR results which displayed H-4pyridine at high chemical shift (δ) value as compared with other aromatic protons (see Table 3). Since, high δ value means low magnetic field (deshielding) due to low electron density (electrophilic nature in MEP map and therefore blue color, Fig. 2). On the other hand, a yellow color was seen at C-4a in the MEP of compound 3, and this may attribute to nucleophilic nature of this position due to electron repelling effect of NH group which increased the electron density over this site. Hence, high magnetic field (shielding) over C-4a position which leads to low chemical shift (δ) value in the 13C NMR spectra as compared with other aromatic carbons (see Table 3, Fig. 2).
1H NMR | 13C NMR | ||||
|---|---|---|---|---|---|
Atoms | Calculated | Experimental | Atoms | Calculated | Experimental |
17-H | 2.008296 | 2.30 | 20-C | 17.25262 | 17.5 |
23-H | 2.012475 | 2.36 | 16-C | 21.01514 | 20.4 |
21-H | 2.336835 | 2.36 | 29-C | 21.28556 | 22.3 |
22-H | 2.45021 | 2.36 | 8-C | 76.4621 | 70.4 |
18-H | 2.495781 | 2.30 | 13-C | 102.9234 | 108.2 |
19-H | 2.55246 | 2.30 | 9-C | 112.5739 | 112.8 |
30-H | 3.236307 | 3.17 | 26-C | 116.5117 | 116.3 |
31-H | 3.333138 | 3.17 | 32-C | 118.0458 | 117.2 |
35-H | 5.319709 | 5.47 | 3-C | 120.4037 | 119.8 |
14-H | 7.247692 | 7.29 | 7-C | 126.4159 | 125.4 |
15-H | 7.639213 | 7.53 | 1-C | 129.6899 | 127.7 |
34-H | 7.887824 | 8.34 | 5-C | 130.9913 | 128.5 |
28-H | 12.48683 | 12.62 | 6-C | 133.5516 | 130.9 |
2-C | 134.2141 | 133.7 | |||
11-C | 148.8349 | 145.4 | |||
4-C | 153.7202 | 148.6 | |||
24-C | 163.6628 | 162.4 | |||
Fig. 2
Molecular electrostatic potential of compounds 1–3
3.2.3. FT- IR Vibrational Analysis
The IR Vibrational Analysis is of considerable importance, as it enables accurate identification of molecules based on their distinctive infrared absorption profiles, thereby allowing precise determination of a substance’s chemical composition [56]. DFT calculations of vibrational frequencies have shown excellent agreement with the vibrational modes of organic compounds [56]. For the current study, the theoretical frequencies were computed using the B3LYP/6-311 + + G(d,p) level of theory and corrected using a scaling factor of 0.961 to minimize systematic errors. Table 2 present both the theoretical and experimental infrared vibrational frequencies for compound 3. The experimental and calculated FT-IR spectra are illustrated in Fig. S1.
In the IR spectra of compound 3, the NH stretching vibration was recorded experimentally at ν 3242 cm− 1, which was found theoretically at ν 3255 cm− 1. The experimental IR spectrum showed the absorption bands of the two C ≡ N groups at ν 2246 and 2213 cm− 1, while the theoretical values were observed at ν 2250 and 2220 cm− 1. Moreover, the measured stretching motion for C = O group was seen at ν 1652 cm− 1, which matched with the theoretical value at ν 1670 cm− 1.
Figure 3 showed a relationship between the wavenumbers derived from experimental observations and those computed theoretically for the functional groups; and exhibit a correlation coefficient (R²) of 0.99.
Compound 3 (CCPC) | |||
|---|---|---|---|
υexp.(cm− 1) | υthe.(cm− 1) | Assignment | |
3242 | 3255 | NH | |
3027 | 3081 | CHaromatic | |
2971, 2934 | 2981, 2936 | CHaliphatic | |
2246, 2213 | 2250, 2220 | 2C ≡ N | |
1652 | 1670 | C = O | |
1577 | 1578 | C = C | |
3.2.4. 1H NMR and 13C NMR spectroscopy
An effective strategy for investigating the structures of organic molecules involves integrating quantum computational chemistry methods with nuclear magnetic resonance (NMR) spectroscopy. The GIAO approach, combined with the B3LYP/6-311 + + G basis set, was employed to theoretically compute the ¹H and ¹³C NMR chemical shifts of the synthesized compounds [57, 58]. Table 3 presents a comparison between the calculated and experimental ¹H NMR chemical shifts, while Fig. S2 shows the ¹H NMR spectra recorded in DMSO.
In the 1H NMR spectra of compound 3, It was noted that, the three protons for each methyl group was recorded in the experimental chart as one signal, whereas three signals were recorded in the computed chart; and this may assign to different electron densities around each proton and hence different magnetic field (Table 3). Also, the two protons of CH2CN group were recorded experimentally at δ 3.17 ppm, whereas theoretically calculated as two signals at δ 3.23 and 3.33 ppm; and this may attribute to different orientation in space and consequently different chemical environments. The chemical shifts of the two benzo protons were seen experimentally at 7.29 and 7.53 ppm, whereas the calculated values were 7.25 and 7.64 ppm, respectively. The chemical shifts of H-5 and H-8 protons were observed experimentally at δ 5.47 and 8.34 ppm, while the computed values were at δ 5.32 and 7.89 ppm. The experimental chemical shift of the NH proton was found at δ 12.62 ppm, while the computed signal was determined at δ 12.48 ppm.
The 13C NMR spectra of compound 3 are displayed in Fig. S3. Table 3 shows the data of theoretical and experimental 13C-NMR chemical shifts. For example, the theoretical/experimental δ value of C = O was found at δ 163.6/ 162.4 ppm. In addition, the theoretical δ values of the two C ≡ N functions were found at δ 116.5 and 118.0 ppm, which closely agree with that experimentally recorded at δ 116.3 and 117.2 ppm. The experimental values for C-5 and C-4 were seen at δ 70.4 and 145.4 ppm, while the calculated values were δ 76.5 and 148.8 ppm. Moreover, the carbon atoms of the two CH3 groups were computed at δ 17.2 and 21.0 ppm which closed to the observed signals at δ 17.5 and 20.4 ppm. The relatively high chemical shift (δ) of C-5 as compared with other sp3 hybridized carbon may attribute to the deshielding achieved by the adjacent high electronegative oxygen atom.
The experimental 1H and 13C NMR chemical shifts were plotted with the theoretical chemical shifts and the correlation coefficients (R2) are 0.99 and 0.98, respectively, as shown in Fig. 3. Thus, the computed values are in good agreement with experimental values.
Fig. 3
Plots of the relationships of the calculated versus experimental (a) IR wavenumbers, (b) 1H NMR and (c) 13C NMR chemical shifts of CCPC, 3.
3.2.5. Drug similarity and in-silico ADME anticipation
Swiss ADME was utilized to carry out computational ADME analysis on the synthesized compounds to evaluate their physicochemical properties and drug-likeness characteristics [59, 60]. All compounds comply with Lipinski’s rule of five, which includes the following criteria: MlogP less than 5, no more than 5 hydrogen bond donors (HBD), no more than 10 hydrogen bond acceptors (HBA), and a molecular weight (MW) under 500 amu. The molecular weights of the current compounds range from 84 to 291 g/mol, which are within the acceptable range. The HBA values fall between 2 and 4, while HBD values between 0 and 1; hence both within the permissible limits. Furthermore, the predicted MlogP values range from − 1.36 to 1.21 (Table 4).
In addition to Lipinski’s criteria, Veber’s rule was also applied to assess drug-likeness. According to this rule: (a) the total polar surface area (TPSA), which is related to bioavailability, should not exceed 140 Ų. The TPSA values for the studied compounds range from 54 to 89.67 Ų. (b) The number of rotatable bonds should be fewer than 10, and all synthesized compounds meet this requirement (see Table 4). Collectively, the data indicate that all compounds possess favourable properties for oral bioavailability, as they satisfy both Lipinski’s and Veber’s guidelines.
Compound | HBA | HBD | MW | Log P | TPSA | Rotatable bond | Lipinski #violations | Veber violations |
|---|---|---|---|---|---|---|---|---|
1 | 3 | 0 | 225.24 | 1.21 | 54.00 | 1 | 0 | 0 |
2 | 2 | 1 | 84.08 | -1.36 | 66.88 | 1 | 0 | 0 |
3 | 4 | 1 | 291.30 | 1.06 | 89.67 | 1 | 0 | 0 |
3.2.6. Non-linear optical (NLO) properties
Nonlinear optical (NLO) properties refer to the ability of a material to interact with high-intensity light, such as that from a laser, and convert light of longer wavelengths into light of shorter wavelengths. One of the key NLO phenomena is second harmonic generation (SHG), in which incident light is effectively transformed so that its wavelength is halved. This occurs when the material absorbs the incoming light and, through a nonlinear optical process, emits light at twice the frequency (i.e., half the wavelength) of the original beam.
A
Fig. 4
The second harmonic generation.
Single crystals of nonlinear optical (NLO) materials have found widespread applications in various advanced technologies, including semiconductors, infrared detectors, solid-state lasers, photosensitive devices, and crystalline thin films used in microelectronics [61, 62]. To explore the correlation between the electronic structure and NLO properties of the studied compound, theoretical calculations were performed using the B3LYP/6-311 + + G(d,p) level of theory in the gas phase and in different solvents (water, ethanol, acetone, and DMSO). Key NLO parameters including the total static dipole moment (µ), mean polarizability (⟨α⟩), polarizability anisotropy (Δα), mean first-order hyperpolarizability (β), hyper-Rayleigh scattering coefficient (βHRS), and depolarization ratio (DR) are summarized in Table 5.
In this study, p-nitroaniline (PNA) was employed as a standard reference molecule for evaluating nonlinear optical (NLO) properties, due to the lack of experimental NLO data for the investigated compound. The values of the first-order hyperpolarizability (β), presented in Table 5, indicate that the studied compound (CCPC) exhibits β values approximately 3.5 times higher than those of PNA across all media. Notably, the β values in water and ethanol are significantly higher compared to those in the gas phase, acetone, and DMSO. For comparison, the reported first-order hyperpolarizability of PNA is 15.5 × 10⁻³⁰ esu, as documented by T. Gnanasambandan et al. [63]. The analysis further reveals that CCPC demonstrates a ~ 2.5-fold enhancement in β values over PNA in all solvents, with water and ethanol again showing the highest values. Additionally, the relatively lower β values observed in some environments suggest potential for increased optical selectivity. Overall, these findings suggest that the CCPC compound possesses promising nonlinear optical properties and may serve as a potential candidate for optoelectronic applications.
Medium | Property | CCPC |
|---|---|---|
Gas phase | µ, Debye a | 7.98 |
water | 12.22 | |
ethanol | 11.87 | |
acetone | 11.31 | |
DMSO | 11.62 | |
Gas phase | ˂α> ×10− 24 esub | 25.65 |
water | 36.55 | |
ethanol | 31.58 | |
acetone | 33.98 | |
DMSO | 34.28 | |
Gas phase | Δα × 10− 24 esu | 63.62 |
water | 64.65 | |
ethanol | 64.87 | |
acetone | 64.27 | |
DMSO | 64.29 | |
Gas phase | ˂β˃ × 10− 30 esuc | 85.53 |
water | 128.74 | |
ethanol | 126.32 | |
acetone | 120.78 | |
DMSO | 122.41 |
a, b, c PNA results (2.44, 22, 15.5) are taken from references [61–63]
3.2.7. NBO Analysis
Natural Bond Orbital (NBO) analysis was originally developed as a theoretical framework to investigate hybridization patterns and covalency within polyatomic wave functions, particularly in systems exhibiting hydrogen bonding and other strongly bound van der Waals interactions [64]. In this formalism, covalent interactions within molecules are represented by the filled NBOs (σ) that constitute the ‘‘natural Lewis structure’’ [65]. In contrast, noncovalent interactions are elucidated through the transformation of canonical molecular orbitals into NBOs, which also generate formally unoccupied orbitals absent in the idealized Lewis structure. Within this notation, σ and σ* are employed in a generalized manner to denote occupied and unoccupied orbitals, respectively. The occupied orbitals may correspond to core orbitals (CR), lone pairs (LP), or bonding orbitals (σ, π), whereas the unoccupied orbitals can represent antibonding orbitals (σ*, π*) or higher-energy Rydberg-type orbitals (RY*).
Also, NBO analysis provides insight into intra- and intermolecular interactions by identifying electron delocalization between donor and acceptor orbitals. These interactions occur specifically between filled orbitals of Lewis-type (bonding or lone pairs) and corresponding empty non-Lewis orbitals (antibonding or Rydberg). The stabilization energies arising from such donor–acceptor interactions are quantitatively evaluated using second-order perturbation theory [64]. The stabilization energy, E(2), which reflects the degree of electron delocalization from a donor orbital (i) to an acceptor orbital (j), is determined using the following expression [65].
𝐸 (2) = Δ𝐸𝑖j = 𝑞𝑖 (𝐹 (𝑖j) 2 /𝜀𝑗 –𝜀𝑖), | (15) |
where Fijis (𝑖j) denotes the off-diagonal element of the NBO Fock matrix, 𝑞𝑖 represents the occupancy of the donor orbital, and 𝜀𝑖 and 𝜀𝑗 correspond to the diagonal energies of the donor and acceptor NBOs, respectively.
This approach is highly effective for identifying charge delocalization pathways, such as transitions or conjugative interactions, within different regions of a molecular framework. The extent of hyper-conjugative interactions between donor and acceptor orbitals is directly correlated with the associated stabilization energy. In this context, the second-order perturbation stabilization energies provide a quantitative measure of conjugation throughout the system. For the current compound CCPC, nucleophilic hyper-conjugative interactions were found to generate stabilization energies of 112.7, 85.59, 58.81, 57.91, and 55.58 kJ·mol⁻¹ across all studied solvents. Notably, the stabilization energies in polar solvents (water and ethanol) are higher compared with those in less polar media (gas phase, acetone, and DMSO), reflecting enhanced charge delocalization in the former. These values correspond to transitions of the following types: LP(1)(O10)→π*(C4–C8), LP(1)(N27)→π*(C7–O25), LP(1)(N12)→π*(C24–O25), LP(1)(O25)→π* (C13–C24), and LP(1)(O25)→π* (C2–C6), (c.f. Table 6).
The electron delocalization process exhibits significant stabilization energy, with values up to 85.6 kJ·mol⁻¹, which can be attributed to resonance effects within the molecule. Remarkably, the investigated compound CCPC displays comparatively higher stabilization energies, highlighting the enhanced stability of its electronic molecular framework.
As a result, The NBO analysis confirmed significant donor–acceptor interactions and pronounced electron delocalization in compound CCPC. The relatively high stabilization energies, particularly in polar solvents, reflect strong hyper-conjugative and resonance effects that enhance the electronic stability of the molecular framework. These findings provide clear evidence of the conjugative nature of the system and its solvent-dependent stabilization behavior.
Compound | Donor | Acceptor | E(2)a(kcal/mol) | NBO | Population | ||||||||
Gas phase | water | ethanol | acetone | DMSO | Gas phase | water | ethanol | acetone | DMSO | ||||
CCPC | π C2-C6 | π* C1-O10 | 48.61 | 76.21 | 72.91 | 65.39 | 65.39 | C2-C6 | 1.87 | 1.78 | 1.79 | 1.82 | 1.82 |
LP (1) O10 | π C4-C8 | 112.7 | 75.21 | 71.91 | 64.37 | 64.38 | C4-C8 | 1.85 | 1.77 | 1.78 | 1.80 | 1.80 | |
LP(1) N12 | π* C24-O25 | 58.81 | 70.3 | 68.7 | 62.52 | 62.28 | LP(1) N12 | 1.70 | 1.68 | 1.68 | 1.68 | 1.68 | |
LP (1) O25 | π* C13-C24 | 57.91 | 69.3 | 67.7 | 61.52 | 61.28 | LP(1) N27 | 1.68 | 1.67 | 1.67 | 1.67 | 1.67 | |
LP (1) N27 | π* C7-O25 | 85.59 | 107.1 | 105.1 | 106.0 | 107.2 | LP (1)O10 | 1.10 | 1.99 | 1.99 | 1.99 | 1.99 | |
LP (1) N33 | RY*C1 | 23.35 | 22.81 | 23.00 | 23.29 | 23.30 | LP (2) O25 | 1.90 | 1.92 | 1.92 | 1.91 | 1.91 | |
LP (2) O10 | σ*C1-C2 | 24.63 | 20.10 | 20.71 | 22.11 | 22.11 | LP (1) N33 | 1.88 | 1.80 | 1.79 | 1.81 | 1.80 | |
LP (2) N27 | σ* C1-N27 | 45.55 | 37.10 | 38.41 | 41.44 | 41.55 | C1-O10 | 0.27 | 0.37 | 0.35 | 0.33 | 0.33 | |
LP (1) O25 | π* C2-C6 | 55.58 | 90.51 | 89.41 | 83.03 | 84.54 | C2-C6 | 0.27 | 0.34 | 0.33 | 0.33 | 0.33 | |
LP (2) N33 | π* N12-H28 | 139.4 | 133.8 | 132.5 | 134.8 | 135.1 | C4-C8 | 0.37 | 0.41 | 0.40 | 0.42 | 0.42 | |
π* C2-C6 | π* C1-O10 | 116.6 | 110.1 | 111.2 | 307.7 | 302.9 | |||||||
3.2.8. Potential energy diagram and intrinsic reaction coordinates (IRC)
As illustrated in Scheme 1, the suggested mechanism of CCPC can proceed via an intramolecular hydrogen atom transfer (HAT), indicative of a complex conversion pathway. The variations in bond lengths during this process for intermediates A, B, and C along the intrinsic reaction coordinate (IRC) in the gas phase are presented in Fig. 5. Correspondingly, Fig. 6 displays the potential energy profile of the CCPC decomposition calculated at the B3LYP/6-311 + + G (d,p) level. Barrier heights and reaction energies derived from this pathway are summarized in Table 7. Analysis of Figs. 5 and 6 reveals that, along the IRC pathway, the O–H bond gradually forms in tandem with the cleavage of the N–H bond, with both bond evolution curves intersecting at s = 0 amu1/2 bohr. Additionally, formation of the N–C bond and cleavage of the C–O bond occur smoothly throughout the reaction coordinate, indicating a well-coordinated intramolecular rearrangement.
According to the data in Table 7, structure A exhibits pronounced imaginary vibrational frequencies in the range of 1869.7 i to 1920.1 i, as calculated using the B3LYP/6-311 + + G(d,p) method. These high-magnitude imaginary frequencies suggest a significant contribution from quantum mechanical tunneling in this reaction pathway. Analysis of the corresponding energy profile indicates that although the pathway involving structure A is kinetically the least favorable, it is thermodynamically the most preferred—being the least endothermic route for the decomposition of CCPC. The computed activation barrier heights (along with reaction energies) are 39.2, 38.3, 38.8, 38.3, and 38.3 kcal/mol in the gas phase, water, ethanol, acetone, and DMSO, respectively, at the B3LYP/6-311 + + G(d,p) level of theory.
Among the investigated pathways for CCPC decomposition, the formation of structure B corresponds to the most endothermic route on the potential energy surface across all studied media. From a kinetic standpoint, intermediate B represents the second most favorable pathway in the gas phase, water, and ethanol; however, it becomes the least favorable route in acetone and DMSO. The calculated activation barrier heights (and reaction energies) for this pathway are 38.9, 37.6, 38.6, 39.2, and 39.3 kcal/mol in the gas phase, water, ethanol, acetone, and DMSO, respectively, as shown in Table 7, using the B3LYP/6-311 + + G(d,p) level of theory.
In contrast, the formation of structure C is associated with prominent imaginary frequencies of 1622.34 i, 1699.72 i, 1689.29 i, 1682.52 i, and 1685.92 i in the gas phase, water, ethanol, acetone, and DMSO, respectively (Table 7). This pathway is identified as the most kinetically favorable route for CCPC decomposition. The corresponding activation energies (and reaction enthalpies) for this route are 29.4, 34.2, 34.3, 34.6, and 34.9 kcal/mol in the gas phase, water, ethanol, acetone, and DMSO, respectively, calculated at the same level of theory.
A
Medium | species | B3LYP/6-311 + + G(d,p) | |||
Imiginary freqency(cm−1) | ΔE0K† | ΔH298K† | ΔG298K† | ||
Gas phase | A | -1869.70 | 39.24 | 39.14 | 39.33 |
water | -1920.14 | 38.28 | 38.12 | 38.40 | |
ethanol | -1910.16 | 38.81 | 38.70 | 38.85 | |
acetone | -1891.52 | 38.28 | 38.22 | 38.20 | |
DMSO | -1885.35 | 38.32 | 38.23 | 38.28 | |
Gas phase | B | -1606.95 | 38.87 | 38.78 | 38.94 |
water | -1684.14 | 37.58 | 37.38 | 37.82 | |
ethanol | -1674.26 | 38.56 | 38.44 | 38.70 | |
acetone | -1660.44 | 39.17 | 39.10 | 39.25 | |
DMSO | -1662.59 | 39.24 | 39.14 | 39.35 | |
Gas phase | C | -1622.34 | 29.43 | 29.33 | 29.54 |
water | -1699.72 | 34.20 | 34.12 | 34.19 | |
ethanol | -1689.29 | 34.29 | 34.42 | 33.31 | |
acetone | -1682.52 | 34.61 | 34.66 | 34.35 | |
DMSO | -1685.92 | 34.91 | 35.00 | 34.49 | |
ΔE0K | ΔH298K | ΔG298K | |||
Gas phase | CCPC | 10.14 | 10.13 | 10.21 | |
water | 6.59 | 6.73 | 6.18 | ||
ethanol | 7.37 | 7.55 | 6.92 | ||
acetone | 7.60 | 7.76 | 7.29 | ||
DMSO | 7.70 | 7.83 | 7.47 | ||
a energies calculated relative to the parent molecule.
Fig. 5
Change of bond lengths (angstroms) along reaction coordinates for CCPC at B3LYP/6-311 + + G(d,p) level.
Fig. 6
Potential energy diagram (△E0K, △E0K†, in kcal/mol) for different conversions of CCPC in different solvents using B3LYP/6-311 + + G(d,p) level (T = 0 K and P = 1 atm).
3.2.9. Chemical kinetics
The rate constants for all unimolecular hydrogen atom transfer (HAT) reactions involved in the formation of CCPC (Scheme 1) were computed using transition state theory (TST) in conjunction with the Eckart tunneling correction. These calculations were carried out under standard conditions (P = 1 atm) across a temperature range of 250–400 K. The results obtained from both methods—TST alone and TST with tunneling correction—were found to be closely aligned and comparable in magnitude. A summary of the forward and reverse rate constants for the various CCPC transformation pathways, incorporating Eckart tunneling corrections, is presented in Table 8 for the specified temperature range.
From Table 8, at T = 250 K and P = 1 atm, the total unimolecular rate constants are 6.30 × 103, 2.15 × 104, 1.66 × 104, 1.43 × 104, and 1.50 × 104s−1 in gas phase, water, ethanol, acetone, and DMSO, respectively. In T = 400 K, the obtained results increase gradually to become 6.42, 8.23, 7.92, 7.73, and 7.81 s− 1, respectively.
All elementary forward and reverse reactions show a positive temperature dependence, with total rate constants increasing progressively as the temperature rises. The computed rate constants further reveal that the reverse reactions proceed significantly faster than their corresponding forward counterparts. Among the various decomposition pathways, the transformation of CCPC into structure C is identified as the most kinetically favorable route, likely attributed to its relatively low activation energy barrier. In addition, the rates of CCPC conversions are partially higher in water and acetone mediums relative to other mediums. In general, the role of tunneling becomes significant at low temperatures. The contributions of Eckert correction are high for the forward and reverse reactions of the (R→A) reaction compared to (R→B) and (R→C) reactions.
T(K) | Medium | Forward reaction | Reverse reaction | ||||
k(R→A) | k(R→B) | k(R→C) | k(CCPC→A) | k(CCPC→B) | k(CCPC→C) | ||
250 | Gas phase | 8.91E + 05 | 2.54E + 03 | 6.30E + 03 | 9.20E + 05 | 2.79E + 03 | 5.21E + 03 |
water | 3.45E + 06 | 1.29E + 04 | 2.15E + 04 | 3.71E + 06 | 1.40E + 04 | 2.28E + 04 | |
ethanol | 2.84E + 06 | 9.53E + 03 | 1.66E + 04 | 3.04E + 06 | 1.04E + 04 | 1.72E + 04 | |
acetone | 1.72E + 06 | 6.63E + 03 | 1.43E + 04 | 1.80E + 06 | 7.23E + 03 | 1.50E + 04 | |
DMSO | 1.56E + 06 | 2.92E + 04 | 1.50E + 04 | 1.61E + 06 | 7.51E + 03 | 1.54E + 04 | |
275 | Gas phase | 2.73E + 04 | 3.01E + 02 | 5.33E + 02 | 2.76E + 04 | 3.18E + 02 | 4.73E + 02 |
water | 8.11E + 04 | 9.92E + 02 | 1.41E + 03 | 8.47E + 04 | 1.05E + 03 | 1.47E + 03 | |
ethanol | 6.90E + 04 | 8.00E + 02 | 1.17E + 03 | 7.33E + 04 | 8.46E + 02 | 1.19E + 03 | |
acetone | 4.60E + 04 | 6.17E + 02 | 1.05E + 03 | 4.78E + 04 | 6.51E + 02 | 1.08E + 03 | |
DMSO | 4.15E + 04 | 1.57E + 03 | 1.09E + 03 | 4.33E + 04 | 6.71E + 02 | 1.11E + 03 | |
298 | Gas phase | 2.47E + 03 | 7.76E + 01 | 1.12E + 02 | 2.48E + 03 | 8.01E + 01 | 1.04E + 02 |
water | 5.86E + 03 | 1.86E + 02 | 2.39E + 02 | 6.04E + 03 | 1.93E + 02 | 2.45E + 02 | |
ethanol | 5.17E + 03 | 1.60E + 02 | 2.08E + 02 | 5.34E + 03 | 1.66E + 02 | 2.11E + 02 | |
acetone | 3.69E + 03 | 1.33E + 02 | 1.91E + 02 | 3.78E + 03 | 1.37E + 02 | 1.95E + 02 | |
DMSO | 3.41E + 03 | 2.36E + 02 | 1.98E + 02 | 3.49E + 03 | 1.40E + 02 | 2.00E + 02 | |
325 | Gas phase | 3.15E + 02 | 2.64E + 01 | 3.30E + 01 | 3.17E + 02 | 2.69E + 01 | 3.17E + 01 |
water | 6.03E + 02 | 4.86E + 01 | 5.73E + 01 | 6.16E + 02 | 4.96E + 01 | 5.81E + 01 | |
ethanol | 5.44E + 02 | 4.40E + 01 | 5.21E + 01 | 5.57E + 02 | 4.48E + 01 | 5.24E + 01 | |
acetone | 4.24E + 02 | 3.87E + 01 | 4.91E + 01 | 4.29E + 02 | 3.94E + 01 | 4.96E + 01 | |
DMSO | 3.97E + 02 | 5.32E + 01 | 5.03E + 01 | 4.03E + 02 | 4.01E + 01 | 5.06E + 01 | |
350 | Gas phase | 8.34E + 01 | 1.35E + 01 | 1.56E + 01 | 8.35E + 01 | 1.37E + 01 | 1.53E + 01 |
water | 1.35E + 02 | 2.11E + 01 | 2.36E + 01 | 1.37E + 02 | 2.13E + 01 | 2.38E + 01 | |
ethanol | 1.25E + 02 | 1.96E + 01 | 2.21E + 01 | 1.26E + 02 | 1.99E + 01 | 2.22E + 01 | |
acetone | 1.03E + 02 | 1.79E + 01 | 2.12E + 01 | 1.04E + 02 | 1.81E + 01 | 2.13E + 01 | |
DMSO | 9.84E + 01 | 2.16E + 01 | 2.15E + 01 | 9.93E + 01 | 1.83E + 01 | 2.16E + 01 | |
375 | Gas phase | 3.28E + 01 | 8.42E + 00 | 9.32E + 00 | 3.28E + 01 | 8.47E + 00 | 9.19E + 00 |
water | 4.68E + 01 | 1.18E + 01 | 1.28E + 01 | 4.72E + 01 | 1.18E + 01 | 1.29E + 01 | |
ethanol | 4.40E + 01 | 1.12E + 01 | 1.22E + 01 | 4.44E + 01 | 1.13E + 01 | 1.22E + 01 | |
acetone | 3.83E + 01 | 1.04E + 01 | 1.18E + 01 | 3.85E + 01 | 1.05E + 01 | 1.18E + 01 | |
DMSO | 3.69E + 01 | 1.17E + 01 | 1.19E + 01 | 3.71E + 01 | 1.06E + 01 | 1.20E + 01 | |
400 | Gas phase | 1.69E + 01 | 5.95E + 00 | 6.42E + 00 | 1.69E + 01 | 5.98E + 00 | 6.36E + 00 |
water | 2.21E + 01 | 7.73E + 00 | 8.23E + 00 | 2.22E + 01 | 7.76E + 00 | 8.26E + 00 | |
ethanol | 2.11E + 01 | 7.43E + 00 | 7.92E + 00 | 2.12E + 01 | 7.46E + 00 | 7.93E + 00 | |
acetone | 1.90E + 01 | 7.06E + 00 | 7.73E + 00 | 1.91E + 01 | 7.09E + 00 | 7.74E + 00 | |
DMSO | 1.85E + 01 | 7.60E + 00 | 7.81E + 00 | 1.85E + 01 | 7.14E + 00 | 7.82E + 00 | |
3.2.10. UV–Vis spectral analysis.
A
The principal electronic transitions contributing to the UV–visible absorption spectrum of CCPC were identified through theoretical calculations and are summarized in Table 9. Figure 7 compares the experimental and simulated UV–visible spectra. As shown in Table 9, the computed absorption wavelengths in the gas phase were observed at 300, 230, 210, 200, and 190 nm, corresponding to energy gaps of 4.35, 5.65, 5.90, 6.09, and 6.40 eV, respectively. The associated oscillator strengths for these transitions were 0.2273, 0.1352, 0.4707, 0.1418, and 0.2892, indicating the intensity and probability of each electronic excitation.Based on the oscillator strength and absorption coefficient values, only the first transition exhibits significant absorption intensity, indicating that the band at 300 nm possesses the highest intensity, primarily attributed to a HOMO→LUMO transition with a 93% contribution. In ethanol, the calculated absorption wavelengths were 290, 260, 220, 210, and 195 nm, corresponding to energy gaps of 4.33, 4.85, 5.80, 5.85, and 6.30 eV, respectively. The corresponding oscillator strengths were 0.2416, 0.1769, 0.8833, 0.1536, and 0.2894. Notably, the first transition in ethanol also exhibited the most substantial HOMO→LUMO contribution at 96%, indicating it is the most dominant electronic excitation under these conditions.
The absorption wavelength of the first singlet excited state (S₀→S₁) in the gas phase is calculated to be 300 nm, with oscillator strength of 0.2273. Comparable absorption bands are observed at 290 nm and 295 nm in ethanol and dioxane, respectively, with corresponding oscillator strengths of 0.2416 and 0.2779. The increase in solvent polarity leads to a red shift in the absorption wavelength, indicating stabilization of the excited state in more polar environments. Experimentally, the UV-Vis absorption bands for the S₀→S₁ transition in ethanol and dioxane appear at 360 nm and 380 nm, respectively, demonstrating good agreement between theoretical predictions and experimental observations
Additionally, other singlet excited states were examined following the same approach. It was found that increasing solvent polarity generally induced a blue shift in the absorption wavelengths. The observed transitions, primarily of the n→π* type, involve HOMO→LUMO excitation in both the gas phase and solvents. In the gas phase, the second singlet excited state (S₀→S₂) appeared at 230 nm, while in ethanol and dioxane; it was observed at 260 and 265 nm, respectively. These calculated values align reasonably well with the experimental absorption bands located at 310 and 315 nm in ethanol and dioxane, respectively. As solvent polarity increases from dioxane to ethanol, the spectral bands corresponding to both ground and excited states converge. Moreover, the intensity of these bands enhances in more polar solvents, indicating a shift in the nature of the transitions from n→π* to π→π*.
Figure 7. Electronic absorption spectra of CCPC (a) experimental in ethanol, (b) experimental in dioxane (c) theoretical in gas phase (d) theoretical in ethanol, (e) theoretical in dioxane. The concentration of the solute in (all UV) is 2.036×10− 4 mol/L in polar solvent and 1.131×10− 4 mol/L in non-polar solvent.
Medium | Transition | Excitation energies | Type of transition | Ex. | Oscillator strengths (ƒ) | Configuration composition corresponding transition orbital |
|---|---|---|---|---|---|---|
Gas phase | S0—>S1 | 4.35 | n-π* | 300 | 0.2273 | -0.21 (49 ->51); -0.16 (49 ->53); 0.64 (50 ->51) |
S0—>S2 | 5.65 | π-π* | 230 | 0.1352 | -0.26 (49 ->51); 0.40 (50 ->52); 0.43 (50 ->53); 0.12(50 ->55); -0.12(50 ->56) | |
S0—>S3 | 5.90 | π-π* | 210 | 0.4707 | -0.20 (47 ->51); 0.21 (49 ->52); 0.54 (49 ->53); 0.17 (50 ->51); 0.16 (50 ->54); 0.11 (50 ->56) | |
S0—>S4 | 6.09 | π-π* | 200 | 0.1418 | 0.19 (47 ->51); 0.16 (47 ->53); 0.13 (49 ->53); 0.20 (50 ->53); 0.58 (50->56) | |
S0—>S5 | 6.40 | π-π* | 190 | 0.2892 | 0.61 (47 ->51); -0.23 (49 ->53); -0.17 (50 ->56) | |
Ethanol | S0—>S1 | 4.33 | n-π* | 290 360 | 0.2416 | -0.16 (49 ->51); 0.11 (49 ->52); -0.13 (49 ->53); 0.65 (50 ->51) |
S0—>S2 | 4.85 | n-π* | 260 310 | 0.1769 | 0.63 (49 ->51); 0.15 (50 ->51); -0.16 (50 ->52); 0.19 (50 ->53) | |
S0—>S3 | 5.80 | π-π* | 220 235 | 0.8833 | 0.16 (49 ->51); -0.25 (49 ->52); 0.31 (49 ->53); 0.14 (50 ->51); 0.36 (50 ->52); -0.13 (50 ->53) | |
S0—>S4 | 5.85 | π-π* | 210 | 0.1536 | 0.10 (45 ->51); 0.17 (49 ->52); 0.31(49 ->53); -0.23 (50 ->52); 0.38 (50 ->55); -0.13 (50 ->56) | |
S0—>S5 | 6.30 | π-π* | 195 | 0.2894 | 0.46 (47 ->51); -0.22 (48 ->51); 0.15 (49 ->52) -0.22 (49 ->53); -0.36 (50 ->56) | |
Dioxane | S0—>S1 | 4.38 | n-π* | 295 380 | 0.2779 | -0.18(49 ->51); -0.14(49 ->53); 0.65 (50 ->51) |
S0—>S2 | 4.91 | n-π* | 265 315 | 0.1882 | 0.61(49 ->51); 0.18(50 ->51); 0.26(50 ->53) | |
S0—>S3 | 5.78 | π-π* | 225 255 | 0.5596 | -0.27(49 ->51); -0.12(49 ->53); 0.20(50 ->52); 0.58(50 ->53) | |
S0—>S4 | 5.90 | π-π* | 215 | 0.1979 | 0.38(49 ->53); -0.11(49 ->54); -0.35(50 ->52); 0.18(50 ->53); -0.19(50 ->55); 0.21(50 ->56) | |
S0—>S5 | 6.36 | π-π* | 200 | 0.2654 | 0.59(47 ->51); -0.20(49 ->53); 0.11(49 ->56); 0.26(50 ->56) |
4. Conclusions
The chemical reactivity of 3-(6,8-dimethylchromonyl)acrylonitrile (1) was studied towards cyanoacetamide giving the novel chromeno[4,3-b]pyridine derivative (3, CCPC). The reaction mechanism was discussed in detail.
The synthesized compounds were geometrically optimized using the B3LYP/6-311 + + G(d,p) basis set in quantum chemical calculations. Based on frontier molecular orbital (FMO) analysis, CCPC exhibited a smaller energy gap and lower hardness, along with higher softness, indicating greater chemical reactivity and lower kinetic stability relative to the other compounds.
Molecular electrostatic potential (MEP) analysis supported the proposed mechanism through identifying the most reactive sites for electrophilic and nucleophilic attacks.
A strong correlation was observed between theoretical and experimental results for both infrared (IR) and nuclear magnetic resonance (NMR) spectra, with a correlation coefficient (R²) of 0.99.
In silico ADME evaluations revealed that all compounds demonstrated favorable drug-likeness, adhering to both Lipinski’s and Veber’s guidelines.
For the investigated compounds, the lowest values of β indicate increased selectivity. Therefore, the studied compounds exhibit promising nonlinear optical (NLO) properties.
Natural Bond Orbital (NBO) analysis of the investigated compounds revealed notable intermolecular charge transfer interactions between bonding and antibonding orbitals, associated with significant stabilization energies. These findings highlight the electronic stability of the molecular structures.
Intrinsic Reaction Coordinate (IRC) analysis demonstrated that the O–H bond formation occurs progressively alongside the cleavage of the N–H bond, with both energy profiles intersecting at s = 0 amu1/2bohr. Concurrently, the N–C bond forms while the C–O bond breaks gradually throughout the reaction pathway.
The conversion rates of CCPC were found to be comparatively higher in water and acetone, suggesting medium-dependent kinetic behavior. Additionally, quantum tunneling effects were observed to play a more prominent role at lower temperatures.
Density Functional Theory (DFT), coupled with Time-Dependent DFT using the CAM-B3LYP/6-311 + + G(d,p) solvation model, successfully reproduced the UV–Vis absorption spectra of the studied compounds. The results revealed solvent-dependent spectral shifts (both red and blue) in the absorption maxima (λ < sub > max</sub>) and intensities. Detailed excited state analysis provided valuable insight into the nature of the electronic transitions and their underlying molecular orbital contributions.
5- Availability of Data and Materials
Yes, availability of Data and Materials. The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
A
A
Author Contribution
Author contributionsAl-Shimaa badran: Formal analysis, Methodology, Writing-original draft & editingMagdy A. Ibrahim: Formal analysis, Methodology, Writing-original draft & editingShimaa Abdel Halim: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing-original draft, Writing-review & editing
Magdy A. Ibrahim
Formal analysis, Methodology, Writing-original draft & editing
Shimaa Abdel Halim
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing-original draft, Writing-review & editing
A
Funding
Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).
Competing interests
The authors declare no competing interests
Electronic Supplementary Material
Below is the link to the electronic supplementary material
A
Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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