Insights on Potential Photoprotective Activity of Two Butylchalcone Derivatives: Synthesis, Spectroscopic Characterization and Molecular Modeling

Abstract

The development of photoprotective agents presents a growing interest due to skin disorders, e.g., cancer. In order to obtain natural-based compounds with potential photoprotective activity, we promote the synthesis and extensive characterization of a butylchalcone derivative (E)-3-(4-butylphenyl)-1-(4-methylphenyl)-prop-2-en-1-one (BMP). Moreover, we carried out a comparative analysis of two chalcones bearing a methyl (BMP) and bromo (BBP) substituent groups (at para position), on respective electronic structures and supramolecular arrangement, using density functional theory (DFT). Through theoretical calculations carried out by DFT, it was possible to verify its antioxidant property by the mechanisms of free radical scavenging, H-atom transfer (HAT), and one-electron transfer (ET), and their stabilities. Finally, from the analysis of chalcone’s electronic transitions in the excited state calculated by the time-dependent (TD)-DFT method as well as UV-vis absorption spectra of the BMP and BBP (200–390 nm), it is possible to highlight their potential use as organic photoprotective agents.

1. Introduction

Due to health challenges of skin diseases, such as cancer and actinic keratoses, there is great interest in the development of photoprotective agents to avoid damaging the skin [1,2]. Moreover, these photoprotective agents should present low cost/toxicity and ultraviolet (UV) absorption property [3]. In this regard, natural product derivatives have been shown as promising photoprotective agents, e.g., plant extracts (i.e.,: Ginkgo biloba and Lippia sp.), green propolis, caffeic acids derivatives [4], and chalcones (1,3-diaryl-2-propen-1-ones) [5]. Among these natural products, chalcones represent a versatile class of natural-based compounds possessing a set of pharmacological properties, such as antioxidant [6], anticancer [7], antidiabetic [8], larvicidal [9], antibacterial [10], antiparasitic [11], anti-inflammatory [12], neuroprotective agents [13], and insecticidal [14], as well as optic properties [15,16,17], including photoprotective activity [18], due to their UV-absorbing and antioxidant properties.

In order to obtain chalcone-based sunscreen agents with ideal physical and chemical properties, the understanding of their molecular structure as well as structure–activity relationship plays a pivotal role. By the way, there are several examples in literature reporting the molecular design of chalcones with different groups (electron-donating and withdrawing), such as bromine, butyl, methyl, nitro, and dimethylamino [19,20]. These modulations on molecular structures of chalcone modify their pharmacokinetic and pharmacodynamics properties as well as the properties of cosmetic agents (e.g.,: sunscreen) [5].

Herein, we described the synthesis of a butylchalcone derivative (E)-3-(4-butylphenyl)-1-(4-methylphenyl)-prop-2-en-1-one (BMP) and its structural description by X-ray diffraction. Moreover, we promoted a comparative analysis of two chalcones bearing methyl (BMP) and bromine (BBP) [21] substituent groups (at para position) on the molecular and electronic structures and on the supramolecular arrangement through density functional theory (DFT). Additionally, BMP chalcone was fully characterized by a set of spectroscopy and thermal characterizations, namely Ultraviolet–visible (UV-vis) spectroscopy, ¹H-¹³C-nuclear magnetic resonance (NMR) spectroscopy, Raman spectroscopy, infrared (IR) spectroscopy, DSC analysis, and mass spectrometry (MS). The use of BMP and BBP chalcone derivatives as a potential sunscreen agent (Figure 1) was proposed on the basis of their observed optical properties.

2. Materials and Methods

2.1. Synthesis and Crystallization

All solvents and chemicals were commercially obtained from Sigma-Aldrich. Initially, 4-methylacetophenone (1 mmol; 134 mg) or 4′-bromo-acetophenone (1 mmol; 199.0 mg), 4-butylbenzaldehyde (1 mmol; 162 mg), and ethanol (1 mL) were added to a volumetric flask. Subsequently, pulverized KOH (1 mmol; 56.1 mg) was also added and the reaction was mixed by manual shaking for 3 min at 25 °C. White precipitate products were obtained, filtrated by vacuum filtration, and crystallized using ethanol. (E)-3-(4-butylphenyl)-1-(4-methylphenyl)prop-2-en-1-one (BMP) and (E)-3-(4-butylphenyl)-1-(4-bromophenyl)-prop-2-en-1-one (BBP) were obtained in 92% yield (0.92 mmol; 256 mg) and in 95% yield (0.95 mmol; 326.0 mg), respectively. Then, in a conical flask, the crystal growth of BMP and BBP were performed using dichloromethane. The BMP and BBP crystals were obtained by the slow evaporation method, keeping the mixture at 25 °C for 80 h. BMP crystals: C₂₀H₂₂O (278.40 g/mol); white prism solid; and m.p.: 71.2 °C. BBP crystals: C₁₉H₁₉BrO (343.26 g/mol); white prism solid; and m.p.: 109.8 °C.

2.2. Characterization

A UV-Vis spectrum was obtained using a Cary 5000 UV-Vis-NIR spectrometer and DMSO as solvent. ¹H and ¹³C NMR spectra were obtained on a Bruker Avance 500 MHZ NMR spectrometer using TMS and CDCl₃ as the internal standard and solvent, respectively. Raman analysis was performed using a WITec Alpha 300 RAS microscope (WITec, Ulm, Germany), excitation wavelength at 785 nm, and a detection range of 100–4000 cm⁻¹. The spectra were collected with a 20× magnification objective (Zeiss, Jena, Germany). Spectra were recorded with the integration time of 30 s and 2 accumulations. Obtained spectra were processed and analyzed using WITec Project FOUR and Origin 2016 software. DSC analysis was performed in a 214 Polyma, Netzsch equipment equipped with platinum crucibles. BMP sample (5.08 mg) was added in the crucibles and the following program was applied: temperature range: 20–200 °C; heating rate of 10 °C·min⁻¹, under a N₂ atmosphere with a flow of 40 mL·min⁻¹. GC-MS spectrum was obtained in a Shimadzu (QP2010 Ultra) spectrometer, EI mode, and equipped with a CBP-5 (30 × 0.25 × 0.25) column. Moreover, the following parameters were used: injection volume: 1.0 μL (split mode) and helium as drag gas (1.0 mL.min⁻¹); injector temperature: 280 °C; detector temperature: 310 °C; initial oven temperature: 100 °C (for 2 min) followed by a heating ramp of 30 °C.min⁻¹ until 300 °C. The IR analysis was carried out using a Perkin Elmer (8400S FT-IR) spectrometer using the wavenumber range of 400–4000 cm⁻¹ and KBr technique.

2.3. X-ray Diffraction Analysis

A suitable crystal of BMP was selected, kept at 273 K, and the X-ray diffraction was collected on a Bruker APEX-II CCD diffractometer with wavelength radiation MoKα λ = 0.71073 Å. The crystal size used was 0.21 × 0.23 × 0.04 mm³. The structure was solved by direct methods with the intrinsic phasing method (SHELXT) [22] using Olex2 1.3 version [23] and refined by least-squares minimization with SHELXL [24]. All hydrogen atoms were fixed at the calculated position, and potential hydrogen bond interactions were verified through Platon [25] and Crystal Explorer software [26]. The BMP and BBP structures data were deposited in the Cambridge Crystallography Data Centre (CCDC) under codes 2232935 and 2069836, respectively.

2.4. Molecular Modeling

Theoretical calculations were carried out by DFT [27,28], implemented in the G16 [29] software package, using the hybrid exchange and correlation functional with long range correction, M06-2X [30], combined with the basis set 6-311++G(d,p), in gas phase. The obtained geometric parameters were compared to the experimental ones. The chalcones have substituent groups –CH₃ (electron-donating) and –Br (electron-withdrawing) at the para position of the aromatic B ring. Moreover, the molecular structures were compared to verify the effects of these groups on their molecular conformations. Frontier molecular orbitals (FMO) [31], highest occupied molecular orbital (HOMO), and lowest unoccupied molecular orbital (LUMO) were obtained. The kinetic stabilities and chemical reactivity of the butylchalcone derivatives were compared. Molecular electrostatic potential maps contributed to the global electrophilicity analysis through their electronic isodensity surfaces. The electrostatic potential $V\left(r\right)$[32] at point $r$ is defined as

$$V\left(r\right)={\displaystyle \sum }_{\alpha }^{}\frac{Z_{\alpha }}{\left|r_{\alpha }-r\right|}-{\displaystyle \int }\frac{\rho \left(r^{\prime }\right)}{\left|r^{\prime }-r\right|}d{r}^{\prime },$$

(1)

where $Z_{\alpha }$ is the charge of nuclei $\alpha$ at point $r_{\alpha }$ and $\rho \left(r^{\prime }\right)$ is the charge density at point $r^{\prime }$. Furthermore, from the MEP map it is possible to predict the possible regions where intermolecular interactions occur.

The local electrophilicity of both molecules was determined by the Fukui function [33,34] and then it was possible to predict the molecular regions in which chalcones act as antioxidant agents. Based on Fukui indices, the possible radicals formed in the free radical scavenging processes were analyzed through spin density calculations [35,36]. This was started from the BMP- and BBP- optimized structures to optimize the respective radicals using the same level of theory used previously. The radical structures deformation energies were included in the results we obtained for the analysis of the chalcones antioxidant potential [37]. NBO [38] analysis was carried out to determine the radicals stability by the hyperconjugation energy [39], estimated by the second-order perturbation formula,

$$E_{i\to j^{*}}^{\left(2\right)}=-n_{\sigma }\frac{\langle {\sigma }_i\left|\widehat{F}\right|{\sigma }_j^{*}\rangle {}^2}{{\epsilon }_{j^{*}}-{\epsilon }_i}=-n_{\sigma }\frac{F_{ij}^2}{{\epsilon }_{j^{*}}-{\epsilon }_i},$$

(2)

where $\langle \sigma \left|F\right|{\sigma }^2\rangle$ or $F_{ij}^2$ is the Fock matrix element between the natural bond orbitals $i$, and $j$; ${\epsilon }_{{\sigma }^{*}}$ is the energy of the antibonding orbital ${\sigma }^{*}$, and ${\epsilon }_{\sigma }$ is the energy of the bonding orbital $\sigma$; $n_{\sigma }$ stands for the population occupation of the $\sigma$ donor orbital.

2.5. Supramolecular Arrangement

The butylchalcone derivatives (BMP and BBP) supramolecular arrangements were determined by the Hirshfeld surfaces (HS) [40] and 2D fingerprint plots [41], providing information about the intermolecular interaction patterns by color mapping, in addition to describing the specific properties of the surfaces. The HS indicates the partition of the crystal electron density and the molecular fragments of the space occupied. The 2D fingerprint plots indicate the percentages of the strength of interactions involved in the crystal packing modes [42]. The donor and recipient regions are based on the normalized function of the distance to the nearest inner surface nucleus. The distance from the point to the nearest nucleus outside the surface represents the regions of space where molecules are in contact with each other. Furthermore, quantum theory of atoms in molecules [43] (QTAIM) calculations showed the character of these interactions, through the analysis of the topological parameters. For these theoretical calculations, the inputs were constructed from the crystallographic data at the M06-2X/6-311++G(d,p) level of theory, in which the atomic coordinates were kept fixed. The NBO analysis was carried out to determine the interactions stability by the hyperconjugation energy, (Equation (2)).

2.6. Analysis of Photoprotective Property

To understand the BMP and BBP electronic transitions, calculations of the electronic absorption spectra were carried out using implicit solvation (DMSO) by polarizable continuum model (PCM) as implemented in G16 [29]. From the optimized structure, the TD-DFT method was used, with the functional CAM-B3LYP with the basis set 6-311++G(d,p), and the data obtained for the electronic transitions were compared to the data experiments of both chalcones. UV-Vis spectra of the chalcones (BMP and BBP) were obtained using a Cary 5000 UV-Vis-NIR spectrometer and DMSO as solvent. The analysis of the range of UV-vis absorption was performed using Origin 2016 software.

3. Results

3.1. Synthesis and Characterization

The BMP chalcone was obtained in 92% yield according to Section 2.1 via the Claisen–Schmidt condensation approach (Scheme 1).

Figure S1 shows UV spectrum of BMP with an absorption band between 293 and 385 nm and a maximum absorption at 308 nm. Raman spectroscopy also was used to characterize and determine the quality of the BMP crystals (Figure S2). Spectra for each crystal type were normalized to a certain peak (the exact position of the peak is indicated by arrows on the graphs and in the figure legends). For the Raman spectrum of BMP, the C–H stretching vibrations were observed at 1300–1000 cm⁻¹, showing a strong Raman intensity. The C-H out-of-plane deformations were observed at 740, 759, 800, 836, 896, 965, and 984 cm⁻¹ for the BMP crystal (Figure S2). Moreover, peaks at 1256, 1303, 1333, 1376, 1425, and 1432 cm⁻¹ for BMP crystal were observed and assigned to C–C stretching vibrations. A sharp band at 1604 cm⁻¹ was also observed and assigned to ethylenic bridge vibrations for BMP. The C=O vibrations also were observed as a weak Raman band at 1666 for BMP. The C=O stretching vibration is further influenced by intermolecular hydrogen bonding between the C=O group and phenyl ring, which may explain the weak Raman band observed for the BMP chalcone.

Moreover, aiming to characterize the molecular structure of the BMP and its purity, ¹H-NMR (Figure S3) and ¹³C-NMR (Figure S4) were carried out. The chemical shifts are shown below: ¹H NMR (500 MHz, CDCl₃) δ 7.97 (d, J = 8.2 Hz, 2H), 7.8 (d, J = 15.7 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 15.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 2.68 (d, J = 7.8 Hz, 2H), 2.46 (s, 3H), 1.64 (dq, J = 12.9, 7.6 Hz, 2H), 1.45–1.35 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 190.15, 146.01, 144.59, 143.54, 135.78, 132.46, 129.34, 129.31, 129.08, 128.66, 128.50, 121.07, 35.65, 33.44, 22.38, 21.72, 13.99.

Figure S5 presents the DSC thermogram of the BMP crystals which show a sharp exothermic peak (at 71.2 °C). This peak indicates direct melting of the BMP crystal phase to the isotropic liquid phase. Furthermore, Figure S6 shows the MS spectrum of BMP chalcone presenting the following data: GC-MS (EI): r.t./min (m/z) = 9.3 min (277, 263, 235, 221, 192, 165, 131, 119, 91, 65, and 41). BMP chalcone also was characterized by IR spectroscopy (Figure S7). From the analysis of the IR spectrum, the following typical bands are presented: 2967 υ(Csp2-H); 2923 υ(C-H); 1657 υ(C=O); 1595 υ(C=C); 1422 υ(C=C) aromatic ring; 987 υ(CH=CH). In addition, the BBP chalcone was also fully characterized by ¹H- and ¹³C-NMR spectroscopy, Raman spectroscopy, IR spectroscopy, DSC analysis, and MS and the data are described in our publication [21].

3.2. Solid State Description

The BMP molecule has a –CH₃ group linked in the para position of the A ring and an n-butyl group, also in the para position attached to the B ring of the chalcone. The structural information and interactions of the BMP and the ORTEP graph were generated using the Olex2 [23] software (Figure 2), so that the atomic ellipsoids are similar in size, indicating the absence of disorder [44]. The BMP molecule was crystallized in the orthorhombic crystalline system. Unusual bond lengths and angles and torsions were based on conformation observed by the statistical analyzer Mogul software. The main crystallographic refinement data are presented in

Table 1. Crystallographic data and structure refinement for BMP and BBP.

Crystal Data	BMP	BBP
Chemical formula	C20H22O	C19H19OBr
Molecular weight (g/mol)	278.37	343.25
Crystal system	orthorhombic	orthorhombic
Space group	Pbca	Pbca
a (Å)	11.341(3)	11.3065(12)
b (Å)	8.1445(19)	8.1831(9)
c (Å)	33.628(8)	33.892(4)
α (°)	90	90
β (°)	90	90
γ (°)	90	90
Volume (Å3)	3106.2(12)	3135.8(6)
Z	8	8
Radiation type	Mo Kα$\left(\lambda =0.71073\right)$	Mo Kα $\left(\lambda =0.71073\right)$
R[F2 > 2σ(F2)]; wR(F2)	R1 = 0.0545, wR2 = 0.1346	R1 = 0.0317, wR2 = 0.0620
S	1.025	1.035
Dimentions (mm)	0.23 × 0.21 × 0.04	0.226 × 0.197 × 0.044

.

Chemically, molecular planarity in chalcones is a parameter that is related to donor–acceptor interactions through its main chain and through π conjugation along the charge transfer [45]. This parameter is closely related to molecular properties, such as electron transfer, non-linearity, solubility, molecular packing, and melting point. However, we observed that the BMP molecule has a non-planar structure (Figure S8a), so that the angle formed between the aromatic rings is 47.38°. In the case of the BBP molecule [21], which is also non-planar (Figure S8b), the observed angle between the aromatic rings is 0.7% smaller compared to BMP. The non-planarity of the molecules decreases the crystal packing energy and the melting point, in addition to contributing to a better aqueous solubility of the chalcones.

The conformational between chalcone structures showed that the substituent group does not change significantly their molecular geometry. For bond lengths (see the graph in Figure 3a), compression of the C₈=C₉ bond of the BMP bridge by 3.82% was observed, by the substitution of the Br atom by the –CH₃ group. Furthermore, as expected, the volume of the Br atom directly impacts the C₁–Br length by approximately 20.86%. In the case of bond angles (Figure 3b), it was observed that C₁–C₂–C₃ and C₅–C₆–C₁ of the benzene ring A increased by 1.98 and 1.89%, respectively, while C₆–C₁–C₂ decreased by 3.08%. The torsional angles also did not change significantly along the carbon chains of the chalcones. A small decrease of 2.13 and 1.14% was observed in C₅–C₄–C₇–O₁ and C₁₅–C₁₀–C₉=C₈, respectively. In the case of bond angles, it was observed that C₁–C₂–C₃ and C₅–C₆–C₁ of the benzene ring A increased by 1.98 and 1.89%, respectively, while C₆–C₁–C₂ decreased by 3.08%. The torsional angles also did not change significantly along the carbon chains of the chalcones. A small decrease of 2.13 and 1.14% was observed in C₅–C₄–C₇–O₁ and C₁₅–C₁₀–C₉–C₈, respectively. The chalcone bridge is 28° out of the plane of ring A and 19° out of the plane of ring B, and both rings form planes of 47° to each other. Through the overlap of BMP and BBP molecules, shown in Figure 2c, it is possible to observe that the torsional angles vary little in both structures.

The theoretical geometric parameters of the results were compared to the experimental data, through the mean absolute percentage deviation,

$$\mathrm{MADP}=\frac{100}{n}{\displaystyle \sum }_{i=1}^n\left|\frac{{\chi }_{DFT}-{\chi }_{XRD}}{{\chi }_{XRD}}\right|,$$

(3)

where ${\chi }_{DFT}$ and ${\chi }_{XRD}$ represent the theoretical and experimental geometric parameters, respectively. The results showed that the level of theory used is adequate to describe the chalcones BMP and BBP. The MADP values for bond lengths were, respectively, 0.388% in BMP, with Pearson’s correlation coefficient equal to R² = 0.9981, and 0.499%, with R² = 0.9954, in BBP. Figure 4a,c show the scattering of the bond lengths in chalcones, comparing theoretical and experimental values. The graphs show that the deviations were very small, highlighting the C₈=C₉ bond in BBP, which is approximately 3.4% smaller for the molecule maintained in a vacuum. In the case of bond angles, the MADP values were 0.565% (R² = 0.9233) in BMP and 0.516% (R² = 0.9329) in BBP. Figure 4b,d show the scattering of the theoretical versus experimental bond angles. The largest deviations occurred with average increases of 1.8% and 3.7% in C₁₄–C₁₃–C₁₆ and C₁₃–C₁₆–C₁₇, respectively, and with the average decreases of 1.6%, 1.6%, and 1.4% in C₁₂–C₁₃–C₁₆, C₁₆–C₁₇–C₁₈, and C₁₇–C₁₈–C₁₉. Figure 4b,d show the theoretical angles behavior compared to experimental ones.

3.3. Molecular Modeling Analysis

From the calculations of electron density$\rho \left(r\right)$, it was possible to determine some electronic properties of the molecules of the chalcones BMP and BBP. The delocalized FMO isosurfaces are shown in Figure 5 and the HOMO and LUMO energies are shown in

Table 2. Reactivity indices for BMP and BBP chalcones, obtained at M06-2X/6-311++G(d,p) level of theory.

DESCRIPTORS	CNP-OM (kcal/mol)	CNP-CL (kcal/mol)
EHOMO	−175.993	−179.499
ELUMO	−31.931	−37.462
ΔEHOMO-LUMO *	144.062	142.036
Ionization Energy ($I$)	175.993	179.499
Electronic Afinity ($A$)	31.931	37.462
Electronegativity ($\chi$)	103.962	108.480
Chemical potential ($\mu$)	−103.962	−108.480
Chemical hardness ($\eta$)	144.062	142.036
Electrophilicity index ($\omega$)	37.512	41.426

* The energy gap is the difference between the HOMO and LUMO energies, ΔE_HOMO-LUMO = E_LUMO − E_HOMO.

. The data showed that the HOMO energy in BMP is $\approx$2.0% lower than the HOMO energy in BBP. A slight difference infers a slightly more basic character to the brominated chalcone. On the other hand, the energy of the LUMO of BMP is $\approx$14.8% lower than that of the LUMO of BBP, conferring a character that is consequently more acidic to the former. The energy gaps (ΔE_HOMO-LUMO) of the HOMO and LUMO orbitals also indicated that the –CH₃ substituent group makes the BMP molecule slightly more stable than BBP (Table 2).

Based on the FMO energies values, the chemical hardness,

$$\eta =\frac{1}{2}{\left(\frac{{\partial }^{2}E}{\partial N^2}\right)}_{\upsilon }=\frac{I-A}{2},$$

(4)

of the chalcones was determined, which showed that the orbitals in BMP are 1.4% harder. This difference indicates that the orbitals of this molecule are less polarizable than the orbitals of BBP. In addition, the calculated values for the chemical potential,

$$\mu ={\left(\frac{\partial E}{\partial N}\right)}_{\upsilon }=-\frac{I+A}{2}=-\chi ,$$

(5)

showed that BMP has a greater ability to transfer charge during chemical processes since it has a 4.2% higher $\mu$ value, which also justifies its slightly more basic character. In Equations (4) and (5), $E$ is the energy of the system, $N$ is the number of electrons, $\upsilon$ is the external potential, $I=-E_{HOMO}$ is the ionization potential, and $A=-E_{LUMO}$ is the electron affinity.

To measure the electrophilic nature of molecules, global electrophilicity indices were also calculated by the expression,

$$\omega =\frac{{\mu }^2}{2\eta }.$$

(6)

A quantitative characterization was carried out for several organic molecules, in which the theoretical results showed that, for strong electrophiles $\omega >$ 1.5 eV (or $\omega >$ 35 kcal/mol), for moderate electrophiles 0.8 eV $<\omega <$ 1.5 eV (or 18 kcal/mol $<\omega <$ 35 kcal/mol) and, finally, for marginal electrophiles $\omega <$ 0.8 eV (or $\omega <$ 18 kcal/mol) [46,47]. The BMP and BBP compounds are strong electrophiles, so the latter is about 9.4% more electrophilic. These results make sense since the substituent –Br atom is a more electronegative atom than the carbon of the –CH₃ group, resulting in a molecule with higher electronegativity, $\chi$. To determine the localized electrophilicity in both compounds, the Fukui function was used to determine the sites of nucleophilic,

$$f^{+}={\left[\frac{\partial \rho \left(r\right)}{\partial N}\right]}_{\upsilon }^{+},$$

(7)

electrophilic,

$$f^{-}={\left[\frac{\partial \rho \left(r\right)}{\partial N}\right]}_{\upsilon }^{-},$$

(8)

and radical

$$f^0={\left[\frac{\partial \rho \left(r\right)}{\partial N}\right]}_{\upsilon }^0.$$

(9)

attacks. The most commonly used theory for the determination of Fukui indices is the finite difference approach, proposed by Parr and Yang [48], which determines that the Fukui indices are obtained from the calculations of the independent molecular orbitals for the neutral species and two ionic species, maintained under fixed external potential.

The isosurfaces obtained from the $f^{+}$, $f^{-}$, and $f^0$ functions are shown in Figure 6. Through these results, it is possible to observe that, in both chalcones, the charge density is high in the carbonyl O and C₇ atoms, in the C₁ atom of ring A, and the C₁₃ atom of ring B, making these regions susceptible to nucleophilic attack (Figure 6a,d). In the case of C₁, the –CH₃ and –Br substituent groups throw electrons to the benzene ring by inductive and mesomeric effects, respectively. By MEP map (Figure 7a), it was possible to verify that the charge density is reduced on the –CH₃ group in BMP (blue color), due to the electron donor effect; in the Br region, in BBP, we observed that the charge density is reduced on the side opposite the C–Br bond, but slightly increased on the bond (Figure 7b), since the –Br substituent group attract electrons from the ring by induction and throws by resonance. In the carbonyl of the aliphatic portion, the high charge density is due to the resonance effect produced by the π electrons present in this region. The MEP maps showed that the charge density is high in the O atom region (red surface color), resulting in a nucleophilic region of the molecules, both in BMP and BBP. In ring B, the n-butyl substituent group also throws electrons to the benzene ring by an inductive effect, increasing the charge density on the C₁₃ atom.

According to the isosurfaces generated by the $f^{-}$ function, electrophilic attacks can occur on the C₈ atoms of the aliphatic portion of the chalcones and on the C₁₀ and C₁₃ atoms of the B ring (Figure 6b,e). The π electrons present in the C₈–C₉ bond of the aliphatic portion of the chalcones resonate with the π electrons of the respective B rings, forming a conjugated π system. This electronic effect, together with the mesomeric effect produced by the O atom of the carbonyl group, minimizes the charge density on the C₈ atom, making it an electrophilic region of the BMP and BBP molecules. The Mulliken atomic charges show that the C₈ atom is positive, which means that the charge density on it is low. The same occurs on the C₁₀ and C₁₃ atoms of the benzene ring, whose atomic charges are positive. These data confirm the electrophilic character of the molecules in these regions.

Finally, the isosurfaces produced by the $f^0$ function showed that O, C₈, C₉, and C₁₃ atoms are susceptible to radical attacks on BMP and BBP molecules. Researchers have reported that chalcones, as well as their analogues, have antioxidant activity [49], due to the keto-vinylene group –(CO)–CH=CH– in the aliphatic region [50], in addition to hydroxyl and phenyl substituents on the benzene ring. Thus, the Fukui indices for radical attacks corroborate the data in the literature.

There are two main mechanisms that describe the antioxidant activity of compounds [51]. The first mechanism is related to the H-atom transfer (HAT) from the antioxidant molecule (A$-$H) to a free radical (R$·$), such that the antioxidant becomes a radical,

Thus, based on the results for the $f^0$ function, we observed the formation of two radicals that are possibly formed in the free radical scavenging activity of our chalcones, by the HAT mechanism (Scheme 2). The first (radical 1) arises from homolytic scission of the C_α–H bond (C_α = C₈), while the second (radical 2) arises from homolytic scission of the C_β–H bond (C_β = C₉). These radicals are shown in Scheme 2. The spin densities isosurfaces showed that the respective unpaired electrons are delocalized in the radicals 1 of both chalcones (Figure 8a,d). Thus, they can migrate from the C_α atom to the carbonyl O atom by resonance, so that the ground state of these radicals can then be represented as a superposition of two structures

whose wave functions are represented by the linear combination

$$\mathsf{\Psi }=c_1{\psi }_{{\mathrm{C}}_{\alpha }}+c_2{\psi }_{\mathrm{O}}.$$

(10)

However, the spin density calculations showed that the unpaired electron probability being located on the C_α atom is, on average, 2.8 times greater than on the O atom. In both chalcones, the unpaired electron on the C_α and O atoms are housed in a p orbital, whose occupancies are, respectively, 0.74e and 0.95e. NBO analysis showed that the stabilizing energies $E^{\left(2\right)}$ obtained for radicals 1 are very low, indicating that radicals are electronically unstable. The hyperconjugation that most contributes to radical stability is $\pi$(C₁₀–C₁₅) $\to$ ${\pi }^{*}$(C₈–C₉). However, the $E^{\left(2\right)}$ values obtained for the stability of radicals 1, with the unpaired electron housed to the C_α atom, were 7.06 kcal/mol in BMP and 7.45 kcal/mol in BBP. For the unpaired electron housed to the O atom, the hyperconjugation that most contributes to the stability of radicals 1 is $\pi$(C₇–C₈) $\to$ ${\pi }^{*}$(C₇–O), whose stabilizing energies were 3.62 kcal/mol in BMP and 3.61 kcal/mol in BBP. $E^{\left(2\right)}$ values justify the greater unpaired electron probability being on the C_α atom. Furthermore, data from the NBO analyses in Table S1 (supplementary material) showed that BBP is slightly more stable than BMP.

In the case of radicals 2, the spin density calculations showed that the unpaired electrons are allocated preferentially over the C_β atom, where $\rho$(C_β) $\approx$ 0.76. However, these electrons are also delocalized, being able to resonate with the B ring of chalcones (Figure 8b,e), forming a conjugated π system, and being able to be allocated in atoms C₁₁, C₁₃, and C₁₅. The unpaired electron on the C_β atom is housed in the hybrid orbitals sp^10.31 in BMP and sp^10.72 in BBP, where the occupancies are 0.82e. The low $E^{\left(2\right)}$ values obtained indicate that the radicals 2 of both chalcones are also electronically unstable. The hyperconjugation that most contributes to the stability of these radicals is $\sigma$(C₈–H) $\to$ ${\sigma }^{*}$(C₉–C₁₀), where the stabilizing energies obtained are 2.35 kcal/mol in BMP and 4.02 kcal/mol in BBP. From $E^{\left(2\right)}$ values, shown in Table S1, we can conclude that radical 2 in BBP is slightly more stable.

In the HAT mechanism, the reactivity of an antioxidant compound can be estimated by calculating the C–H bond dissociation enthalpy,

$$\Delta {\mathrm{H}}^0\left(\mathrm{C}-\mathrm{H}\right)={\mathrm{H}}^0\left(\mathrm{A}-\mathrm{H}\right)-\left[{\mathrm{H}}^0\left(\mathrm{A}·\right)+{\mathrm{H}}^0\left(\mathrm{H}·\right)\right].$$

(11)

where C is the C_α and C_β atoms. The lower the $\Delta {\mathrm{H}}^0$ value, the higher the expected antioxidant activity for the compound. In the case of BMP and BBP, the $\Delta {\mathrm{H}}^0$ values obtained for the C_α–H bond homolytic cleavage for the formation of radical 1 were 98.8 and 97.4 kcal/mol, respectively, and for the C_β–H bond homolytic cleavage for the formation of radical 2 were 97.7 and 96.5 kcal/mol. It was verified that by the $\Delta {\mathrm{H}}^0\left(\mathrm{O}-\mathrm{H}\right)$ values, for a group of phenols, that the O–H bonds homolytic cleavage varied between 78.2 and 88.3 kcal/mol, and for a group of phenolic chalcones the values of $\Delta {\mathrm{H}}^0$(O–H), for the cleavage of the same bond, varied between 72.9 and 84.6 kcal/mol [52]. Therefore, despite having presented $\Delta {\mathrm{H}}^0$ values slightly higher than those observed in the literature, we noticed that chalcones BMP and BBP have antioxidant potential. Furthermore, homolytic cleavage of O–H bonds is not the only way for chalcones to exhibit free radical scavenging activity.

The second mechanism describes the one-electron transfer (ET) from the antioxidant (A) to the free radical (R$·$), such that A becomes a cation radical (A${·}^{+}$)

The spin density calculations showed that, by the ET mechanism, the unpaired electrons in the chalcones radicals 3 (Scheme 2) are preferentially allocated over the respective C_α atoms, where $\rho$(Ca) $\approx$ 0.52. However, the isosurfaces showed that they can also be found located on atoms of O, where $\rho$(O) $\approx$ 0.11, and of C₁₃, where $\rho$(C₁₃) $\approx$ 0.27. These data corroborate the regions of radical attacks obtained by the $f^0$ function. For the ET mechanism, the evaluation of the antioxidant activity of the compound must be carried out through the ionization potential (IP), by the expression

$$\mathrm{IP}=E_0\left(\mathrm{A}{·}^{+}\right)-E_0\left(\mathrm{A}-\mathrm{H}\right),$$

(12)

where $E_0\left(\mathrm{A}-\mathrm{H}\right)$ is the total energy of the antioxidant and $E_0$(A${·}^{+}$) is the total energy of the corresponding radical cation. The lower the IP values, the greater the antioxidant activities of a molecule. The values calculated for the IP of the chalcones were 185,351 kcal/mol (BMP) and 188,732 kcal/mol (BBP). Phenolic chalcones showed a mean IP value of 174 kcal/mol [53], the IP experimental value for phenol is 196 kcal/mol, and for glutathione, the IP value is 212 kcal/mol [53]. Thus, we can infer that the chalcones evaluated in this work are potential antioxidant agents.

The BMP supramolecular arrangement on bc plane has a zig-zag form with no classic hydrogen bonds. Similarly, the molecules in BBP also assume this structural configuration, performing no classic hydrogen bonds. It was observed that both arrangements carry out C₃–H$\cdots$O₁, C₈–H$\cdots$O₁, C₁₅–H$\cdots$C₁₃, and C₁₇–H$\cdots$H–C₁₈ interactions. By BMP HS, it was possible to verify that in the first two interactions (Figure 9a), the contacts between the H and O atoms correspond to the sum of the van der Waals radii and occur at 2753 and 2767 Å, respectively. Such contacts are also present in the supramolecular arrangement of BBP (Figure 9b). However, in the first interaction (C₃–H$\cdots$O₁), the contacts occur at a distance smaller than the sum of the van der Waals radii, being 3.3% smaller than the same interaction in BMP. The C₈–H$\cdots$O₁ interaction is also lower in BBP ($\approx$1.6%). In both compounds, the Hirshfeld surface showed that, in the normalized distance in the C₁₅–H$\cdots$C₁₃ interaction, the contacts are smaller than the sum of the van der Waals radii, so the interaction length in BMP is 2.877 Å, being about 1.1% higher than in BBP. Through the shape index map (Figure 10), it was observed that such an interaction is configured as a C–H $\cdots$ π in both compounds. Finally, it was observed that the C₁₇–H$\cdots$H–C₁₈ interaction is formed by contact, whose atomic distances correspond to the van der Waals separation. In BMP, the interaction length is 2391 Å, whereas in BBP this interaction is only 0.76% smaller. The C₅–H$\cdots$C₁₁ interaction also occurs in both chalcones. However, the Hirshfeld surfaces showed that the normalized distance for the contacts in this interaction comprises the van der Waals separation. Their lengths in the respective supramolecular arrangements differ by 1.4%, which is greater in BMP.

According to the fingerprint plot (Figure 11), it was observed that the C⋯H and H⋯H contacts are 9.4% and 27.6% larger in BMP supramolecular arrangement, while the C⋯C and O⋯H are 8.3% and 1.5% higher in BBP [8]. Theoretical solubility calculations [https://biosig.lab.uq.edu.au/pkcsm/prediction] (accessed on 14 February 2023) showed that both chalcones are lipid soluble, so the solubility in water, at 25 °C, is in the ratio of 0.96:1, from BMP to BBP. These data showed that the presence of the substituent group –CH3 in the chalcone chain increases the hydrophilicity of BMP, compared to BBP.

The topological parameters obtained by QTAIM showed that the electron density at the bond critical point of each observed interactions is very low ($\rho \left(r\right)<$ 0.1 a.u.). The values of these typological parameters are shown in

Table 3. Hydrogen-bond geometry and topological parameters calculated for the BMP and BBP molecular interactions at the bond critical point.

Interaction	H$\cdots$A (Å)	D–H$\cdots$A (°)	${{\mathit{\rho }}_{\mathit{B}\mathit{C}\mathit{P} }}^{\left(\mathit{a}\right)}$ (a.u.)	${\nabla }^2{{\mathit{\rho }}_{\mathit{B}\mathit{C}\mathit{P} }}^{\left(\mathit{b}\right)}$ (a.u.)	${\mathit{G}\left(\mathbf{r}\right)}^{ \left(\mathit{c}\right)}$ (a.u.)	${\mathit{v}\left(\mathbf{r}\right)}^{ \left(\mathit{d}\right)}$ (a.u.)	${\mathit{h}\left(\mathbf{r}\right)}^{ \left(\mathit{e}\right)}$ (a.u.)	$\frac{\left|\mathit{v}\left(\mathbf{r}\right)\right|}{\mathit{G}\left(\mathbf{r}\right)}$
BMP
C3–H$\cdots$O1	2.753	148.44	0.0219	0.0504	0.0107	−0.0089	0.0019	0.8
C8–H$\cdots$O1	2.767	158.31	0.0194	0.0217	0.0060	−0.0066	−0.0006	1.1
C15–H$\cdots$C13	2.877	148.87	0.0264	0.0388	0.0121	−0.0144	−0.0024	1.2
C5–H$\cdots$C11	2.884	138.40	-	-	-	-	-	-
C5–H$\cdots$C12	2.886	121.22	0.0215	0.0314	0.0078	−0.0078	0.0000	1.0
C17–H$\cdots$H–C18	2.391	140.07	0.0048	0.0179	0.0034	−0.0022	0.0011	0.7
C7=O1$\cdots$C8	3.467	85.93	0.0286	0.0040	0.0033	−0.0056	−0.0023	1.7
BBP
C3–H$\cdots$O1	2.666	147.47	0.0060	0.0202	0.0043	−0.0035	0.0008	0.8
C8–H$\cdots$O1	2.723	157.43	0.0046	0.0166	0.0035	−0.0028	0.0007	0.8
C15–H$\cdots$C13	2.846	146.19	0.0058	0.0160	0.0034	−0.0028	0.0006	0.8
C5–H$\cdots$C11	2.845	135.33	0.0058	0.0184	0.0037	−0.0028	0.0009	0.8
C17–H$\cdots$H–C18	2.373	140.37	0.0051	0.0149	0.0032	−0.0027	0.0005	0.8
C11–H$\cdots$O1	2.929	140.32	0.0039	0.0134	0.0028	−0.0022	0.0006	0.8
C3–H$\cdots$H–C3	2.397	120.68	0.0054	0.0178	0.0036	−0.0028	0.0008	0.8

^(a) Total electronic density on BCP; ^(b) Laplacian of electron density on BCP; ^(c) Lagrangian Kinect energy; ^(d) Potential energy density; ^(e) Total energy density.

and molecular graphs are shown in Figure 12. Through the results, it is possible to observe that the electron densities of C₃–H⋯O₁, C₈–H⋯O₁, and C₁₅–H⋯C₁₃ interactions are 3.6, 4.2, and 4.6 times higher in BMP, respectively. Furthermore, the values obtained for ${\nabla }^2\rho \left(r\right)$ were positive, indicating that the electronic charge is depleted in the BCPs [54]. This indicates that intermolecular interactions are closed-shell. The total electronic energy density, $h\left(r\right)$, is another topological parameter that helps to characterize the type of interaction in the BCP. The value of $h\left(r\right)$ is directly related to ${\nabla }^2\rho \left(r\right)$ through the equation

$$h\left(r\right)=\frac{{\hslash }^2}{8m}{\nabla }^2\rho \left(r\right)+\frac{1}{2}v\left(r\right)$$

(13)

where $v\left(r\right)$ is the local potential energy density⁵⁹. In general, strong interactions present large $\rho \left(r\right)$ and ${\nabla }^2\rho \left(r\right)$ and $h\left(r\right)$ negative, while in weak interactions, the values of $\rho \left(r\right)$ are small and ${\nabla }^2\rho \left(r\right)$ and $h\left(r\right)$ are positive. The data presented in Table 3 show that all interactions in BBP resulted in values of $h\left(r\right)>0$. On the other hand, C₈–H⋯O₁, C₁₅–H⋯C₁₃, and C₇=O₁⋯C₈ interactions in BMP showed negative values of $h\left(r\right)$, and in the other interactions the values are also positive. Based on the results of Nakanishi and coworkers [55,56], we may infer that C₃–H⋯O₁ and C₈–H⋯O₁ interactions are classified as weak hydrogen bonds in BMP, while they are van der Waals interactions in BBP. The values obtained for the ratio $\left|v\right|/G$ indicate that the electron flow in the respective BCPs is very low in these interactions ($\left|v\right|/G<1.0$), except for C₈–H⋯O₁, whose value is at the limit, indicating that the electron flow is slightly higher. In both chalcones, C₁₇–H⋯H–C₁₈ are classified as van der Waals interactions. In the contact between the A and B rings of BMP, a single bond path was formed, resulting in the C₅–H⋯H–C₁₂ interaction, corresponding to C₅–H⋯C₁₂. On the other hand, in BBP, the same contact was observed from the bond path that connects the C₅–H portion of the A ring of an asymmetric unit to the C₁₁–C₁₂ portion of the B ring of another asymmetric unit. This interaction is similar to a C–H ⋯ π interaction. Although it seems redundant to mention the C₈–H⋯O₁ and C₇=O₁⋯C₈ interactions, it was observed that in the first one there is the formation of a bonding path between the H and O₁ atoms, while in the second interaction, the bonding path is formed between the C₇=O₁ bond and the C₈ atom, as shown in the molecular graph of BMP. C₇=O₁⋯C₈ interaction caught our attention due to the topological parameter values found, which indicate that it is a hydrogen bond, despite being a long-distance interaction. The value of the ratio $\left|v\right|/G$ indicates that the electron flux is high in the intranuclear region of the interaction, resulting in a partially covalent character ($1.0<\left|v\right|/G<2.0$).

Tables S1 and S2 (supplementary material) contain the NBOs data for the interactions observed in BMP and BBP. NBO analysis showed that the C₃–H⋯O₁ interactions in both chalcones are formed from low values of stabilizing energies. However, the number of hyperconjugations between the donor orbital (Lewis type) and the acceptor orbital (non-Lewis type) differs in each compound, being higher in BMP. The orbital of the O₁ lone pair, ${\eta }_1$(O₁), hyperconjugates with the antibonding ${\sigma }^{*}$ orbital of the C₃–H bond, where the value of $E^{\left(2\right)}$ is about 70.1% lower in BMP. The occupancy of the ${\eta }_1$(O₁) orbital is 1.98e, so the O₁ atom is a hybrid sp^0.74 in BMP and sp^0.75 in BBP. The occupancy of the antibonding ${\sigma }^{*}$ orbital of C₃–H is 0.012e, where in BMP it is formed by the contribution of 40.7% of the sp^2,11 hybrid orbital of C₃ and 59.3% of the s orbital of H, while in BBP it is formed by the contribution of 40.1% of the sp^2,14 hybrid orbital of C₃ and 59.9% of the s orbital of H. However, the formation of this bond, in BMP, also occurs by the hyperconjugations ${\eta }_1$(O₁) $\to$ ${\sigma }^{*}$(C₃–H), $\sigma$(C₃–H) $\to$ ${\sigma }^{*}$(C₇–O₁) and $\sigma$(C₃–H) $\to$ ${\pi }^{*}$(C₇–O₁), while in BBP, also by the hyperconjugation ${\eta }_1$(O₁) $\to$ ${\sigma }^{*}$(C₃–C₄). In other words, the greater number of hyperconjugations that form the C₃–H⋯O₁ interaction makes it more stable in BMP compared to BBP. The hyperconjugation $\sigma$(C₃–H) $\to$ ${\pi }^{*}$(C₇–O₁) in BMP presented a value of $E^{\left(2\right)}$ = 12.02 kcal/mol, indicating that the interaction presents greater stability.

In the case of the C₈–H⋯O₁ interaction, we observed that the bonding s orbital of the C₈–C₉ bond hyperconjugates with the antibonding ${\pi }^{*}$ orbital of the C₇=O₁ bond in BMP and the $\pi$ orbital bonding the C₈–C₉ bond with the orbital ${\pi }^{*}$ antibonding of the C₇=O₁ bond on BBP. In both cases, the $E^{\left(2\right)}$ value is 0.16 kcal/mol. In BMP, the bonding $\sigma$ orbital, $\sigma$(C₈–C₉), has an occupancy equal to 1.98e, being formed by 50.15% of the sp^1.75 hybrid orbital of C₈ and 49.85% of the sp^1.76 hybrid orbital of C₉ and the antibonding ${\pi }^{*}$ orbital has an occupancy of 0.18e, being formed by the contribution of 68.34% and 31.66% of the p orbitals of the respective C₇ and O₁ atoms. In BBP, the occupancy of the bonding $\pi$ orbital is 1.86e, being formed by 54.66% and 45.34% of the pure p orbitals of C₈ and C₉ atoms, respectively, while the antibonding ${\pi }^{*}$ orbital is formed by 67.98% and 32.02% of the p orbitals of atoms C₇ and O₁. Furthermore, we observed that, in BBP, there is an extra hyperconjugation that contributes to the stabilization of this interaction, $\pi$(C₇–O₁) $\to$ ${\pi }^{*}$(C₈–C₉), with a value of $E^{\left(2\right)}$ = 0.06 kcal/mol. The C₇=O₁⋯C₈ interaction observed in the QTAIM results in BMP is formed by the same hyperconjugation as the C₈–H⋯O₁ interaction, i.e., $\sigma$(C₈–C₉) $\to$ ${\pi }^{*}$(C₇–O₁).

The C₁₇–H⋯H–C₁₈ interaction in BMP was shown to be 11 times more stable in BMP compared to BBP. In both compounds, $\sigma$(C₁₇–H) $\to$ ${\sigma }^{*}$(C₁₈–H) hyperconjugation was observed, in which the values obtained for $E^{\left(2\right)}$ were, respectively, 17.78 and 1.61 kcal/mol. The $\sigma$(C₁₇–H) orbitals have an occupancy of 1.98e. In BMP, this orbital is formed by 60.44% of the sp^2.91 hybrid orbital of C₁₇ with 39.56% of the s orbital of H, while in BBP, it is formed by 59.17% of the sp^3,11 hybrid orbital of C₁₇ with 40.83% of the s orbital of H. The ${\sigma }^{*}$(C₁₈–H) orbital in BMP has an occupancy of 0.011e and is formed by the contribution of 39.73% of the sp^2.97 hybrid orbital of C₁₈ with 60.27% of the s orbital of H, while in BBP, its occupancy is 0.014e, being formed by 41.15% of the sp^3,19 hybrid orbital of C₁₈ with 58.85% of the s orbital of H. Other hyperconjugations were observed in BMP, such as $\sigma$(C₁₆–C₁₇) $\to$ ${\sigma }^{*}$(C₁₈–H), $\sigma$(C₁₈–H) $\to$ ${\sigma }^{*}$(C₁₇–H), and $\sigma$(C₁₈–C₁₉) $\to$ ${\sigma }^{*}$(C₁₇–H), all with low $E^{\left(2\right)}$ values (0.11, 0.32, and 0.48 kcal/mol, respectively). In BBP, only the extra $\sigma$(C₁₇–H) $\to$ ${\sigma }^{*}$(C₁₇–C₁₈) hyperconjugation was observed, with $E^{\left(2\right)}$ value equal to 0.28 kcal/mol.

It was observed that eight hyperconjugations stabilize the C₅–H⋯C₁₁ interaction in BMP, while in BBP, only three. In BMP, $\sigma$(C₅–H) $\to$ ${\sigma }^{*}$(C₁₀–C₁₁) hyperconjugation occurs, with $E^{\left(2\right)}$ = 0.06 kcal/mol, and in BBP, hyperconjugation of the same ligand $\sigma$ orbital occurs with the antibonding ${\pi }^{*}$ orbital of the C₁₀–C₁₁ bond, $\sigma$(C₅–H) $\to$ ${\pi }^{*}$(C₁₀–C₁₁), with $E^{\left(2\right)}$ = 0.10 kcal/mol. In both compounds, the $\sigma$(C₅–H) orbital has an occupancy of 1.98e. However, the acceptor orbitals are formed by different contributions, since they are different orbitals in the chalcones. In BMP, this orbital is formed by 59.41% of the sp^2.08 hybrid orbital of C₅ and 40.59% of the s orbital of H. In BBP, it is formed by the contribution of 60.07% of the sp^2,11 hybrid orbital of C₅ and 39.93% of the s orbital of H. In the case of the acceptor orbital, in BMP, ${\sigma }^{*}$(C₁₀–C₁₁) is formed by 49.39% of the sp^1.96 hybrid orbital of C₁₀ and 50.66% of the sp^1,96 hybrid orbital of C₁₁, while in BBP the ${\pi }^{*}$(C₁₀–C₁₁) orbital is formed by 47.59% and 52.41% of pure p orbitals of C₁₀ and C₁₁, respectively. The hyperconjugations that best contribute to the stabilization of the C₅–H⋯C₁₁ interaction in BMP are $\sigma$ (C₅–C6) $\to$ ${\pi }^{*}$(C₁₁–C₁₂), with $E^{\left(2\right)}$ = 5.72 kcal/mol, followed by $\pi$(C₁₁–C₁₂) $\to$ ${\sigma }^{*}$(C₅–H), where $E^{\left(2\right)}$ = 1.83 kcal/mol.

In BBP, two hyperconjugations contribute to the stabilization of the C₃–H⋯H–C₃ interaction: $\sigma$(C₃–H) $\to$ ${\sigma }^{*}$(C₃–H), with $E^{\left(2\right)}$ = 0.11 kcal/mol, and $\pi$(C₃–C₄) $\to$ ${\sigma }^{*}$(C₃–H), with $E^{\left(2\right)}$ = 0.06 kcal/mol. The $\sigma$(C₃–H) donor orbital is formed by 59.18% of the sp^2,17 hybrid of C₃ and 40.82% of the s orbital of H and has an occupancy of 1.98e. The donor $\pi$(C₃–C₄) orbital is formed by 47.96% and 52.04% of the pure p orbitals of atoms C₃ and C₄, respectively, and its occupancy is 1.65e. The acceptor orbital is formed by 40.82% of the sp^2,17 hybrid orbital of C₃ and 59.18% of the s orbital of H, whose occupancy is 0.012e. We take the hyperconjugations with the most considerable values of hyperconjugation energies that stabilize the interactions observed in the supramolecular arrangements of the studied chalcones. However, other hyperconjugations are shown in Tables S1 and S2 of the supplementary material.

3.4. Analysis of Photoprotective Property

The experimental UV-vis spectra (Figure 13a,c) showed that BMP and BBP molecules have an absorption band in the range of 300–350 nm, with this absorption range being typical of chalcones [5,18]. This absorption range can be attributed to π → π transitions, which are similar to chalcone-type molecules [57,58]. The maximum wavelengths, ${\lambda }_{max}$, obtained were 308 and 331 nm, respectively. The sunscreen agents are classified according to the range wavelength of protection: UV-B (290–320 nm) and UV-A (320–400 nm), and broad-spectrum (290–400 nm). In this regard, according to their UV-vis spectra, the BMP and BBP appear to be promising organic sunscreen agent candidates as an alternative to p-aminobenzoic acid (PABA), ethylhexylmethoxycinnamate derivatives, and others [59].

The BMP theoretical UV-vis spectrum (Figure 13b) showed absorption in the same range so the ${\lambda }_{max}$ value is only 0.6% displaced from the experimental one. For this value, we observed a single electronic transition (H→L) that occurs in the second excited state (S₂). The vertical excited energy (

Table 4. Vertical excitation energies ($E$), absorption wavelength (λ), oscillator strength ($f$) and the corresponding electronic transition of the twelve excited states of BMP and BBP calculated by TD-DFT/CAM-B3LYP/6-311++G(d,p) level of theory in DMSO.

Excited State	$\mathit{E}$ (kcal/mol)	λtheor (nm)	λexper (nm)	f	Excitation	Transition	%
BMP
S1	87.878	325.36		0.0148	H–4 $\to$ L	σ →π*	80.03
S2	92.299	309.78	308	1.1349	H $\to$ L	π →π*	90.45
S3	110.757	258.15		0.0506	H–2 $\to$ L	π →π*	36.6
					H–1 $\to$ L	π →π*	32.81
					H $\to$ L + 5	π →π*	13.94
S4	111.075	257.41		0.1487	H–1 $\to$ L	π →π*	49.6
					H–2 $\to$ L	π →π*	25.01
S5	111.947	255.41		0.0419	H–3 $\to$ L	π →π*	65.58
					H–3 $\to$ L + 1	π →π*	12.06
					H–1 $\to$ L + 4	π →π*	11.68
S6	130.488	219.12		0.0812	H $\to$ L + 1	π →π*	45.77
					H $\to$ L + 5	π →π*	22.32
					H–2 $\to$ L	π →π*	15.32
S7	133.024	214.94	214	0.1035	H $\to$ L + 5	π →π*	41.96
					H $\to$ L + 1	π →π*	22.58
					H–2 $\to$ L	π →π*	13.85
S8	136.039	210.17		0.1243	H–1 $\to$ L + 4	π →π*	38.8
					H-3 $\to$ L	π →π*	25.35
					H–1 $\to$ L + 1	π →π*	11.57
S9	140.109	204.07		0.0024	H $\to$ L + 2	π →σ*	60.69
S10	142.413	200.77		0.1578	H–1 $\to$ L + 1	π →π*	26.2
					H–3 $\to$ L + 4	π →π*	23.39
S11	144.223	198.25		0.0848	H–5 $\to$ L	π →π*	49.33
S12	147.428	193.94		0.0118	H–4 $\to$ L + 1	σ →π*	67.71
BBP
S1	87.216	327.83	331	0.0805	H–4 $\to$ L	π →π*	62.58
					H–3 $\to$ L	π →π*	13.56
					H $\to$ L	π →π*	11.61
S2	91.545	312.33		1.0669	H $\to$ L	π →π*	80.49
S3	110.162	259.55		0.0039	H–2 $\to$ L	π →π*	61.74
S4	111.439	256.57		0.2825	H–1 $\to$ L	π →π*	81.83
S5	113.612	251.66		0.0264	H–3 $\to$ L	π →π*	50.84
					H–1 $\to$ L + 2	π →π*	16.85
					H–4 $\to$ L	π →π*	11.39
					H–3 $\to$ L + 1	π →π*	11.03
S6	128.744	222.08		0.038	H $\to$ L + 1	π →π*	61.96
S7	132.137	216.38		0.1495	H $\to$ L + 6	π →σ*	51.22
					H–2 $\to$ L	π →π*	20.01
					H $\to$ L + 1	π →π*	11.13
S8	134.069	213.26	213	0.0007	H–1 $\to$ L + 6	π →σ*	44.9
					H–1 $\to$ L + 2	π →π*	11.49
S9	136.592	209.32		0.1464	H–1 $\to$ L + 2	π →π*	43.55
					H–3 $\to$ L	π →π*	26.25
S10	140.725	203.18		0.0034	H $\to$ L + 2	π →π*	55.62
					H $\to$ L + 8	π →σ*	19.42
S11	142.182	201.09		0.2044	H–6 $\to$ L	π →π*	58.15
					H $\to$ L + 1	π →π*	11.05
S12	142.855	200.15		0.0016	H–1 $\to$ L + 1	π →π*	45.17
					H–3 $\to$ L + 2	π →π*	14.57

) required for this transition is 92.3 kcal/mol and the oscillator strength is 1.1349, so it contributes 90.45% in that state. This electronic transition is characterized as π→π*, contributing to 90.45% of the transitions in this excited state. For the BBP UV-vis spectrum, two excited states were observed. The first, corresponding to the S₁ state, appears at 327.83 nm and has vertical excited energy of 87.2 kcal/mol. This is displaced from the experimental ${\lambda }_{max}$ by 0.4%. However, the oscillator strength is only 0.0805. In this excited state, four electronic transitions were observed, H-4→L, H-3→L, H→L, and H-1→L, with the first contribution of 62.58%. The second excited state (S2) appears at 312.33 nm, with vertical excited energy of 91.5 kcal/mol, being displaced 5.6% from the experimental ${\lambda }_{max}$. However, the strength of the oscillator is 1.0669. In this state, four electronic transitions were also observed, with H→L presenting the highest contribution. All electronic transitions cited for BBP are characterized as π→π*.

4. Conclusions

Aiming to produce potential photoprotective agents, the butylchalcone derivative BMP was synthetized and fully characterized by UV-vis, Raman, IR, ¹H-, and ¹³C-NMR spectroscopies, DSC analysis, and mass spectrometry (MS). Moreover, its structural description was performed by X-ray diffraction. A comparative analysis was performed for the two chalcones bearing methyl (BMP) and bromo (BBP) substituent groups (at para position) on the molecular and electronic structures, and on the supramolecular arrangement through DFT. Both butylchalcone derivatives are in the same space group (Pbca), and the substituent groups do not significantly change their molecular conformations. Although BMP is slightly more stable than BBP, the chemical reactivity descriptors obtained showed that the molecules are electronically similar. Furthermore, the intermolecular interactions patterns in the supramolecular arrangement are very similar, containing mostly van der Waals interactions and weak hydrogen bonds. NBO analysis showed that all interactions are weakly hyperconjugated, giving little stability. The Fukui indices pointed out the regions where possible radical attacks can happen in both chalcones, and the spin density calculations showed the probability densities in these regions. The calculations showed that the formed radicals have low stability, but BMP and BBP are potential antioxidant agents. The UV-vis spectra showed that both chalcones also have potential as organic sunscreens due to the presence of chromophores, associated with p electrons along their entire carbon chain, in addition to being capable of absorbing radiation in the UVA and UVB range. Additionally, regarding the structure–activity relationship of the chalcones (BMP and BBP) with phototoprotective property, the C-4 butyl chain was chosen as a starting point for molecular modeling evaluation (X-ray, spectroscopy characterization, theoretical studies). Moreover, aiming to evaluate and modulate the UV-vis absorption profile (a pivotal property for sunscreen agent), two substituent groups, –CH₃ (electron-donating) and –Br (electron-withdrawing), at para position on the aromatic ring were studied. These structural modifications resulted in a change in UV-vis absorption of the chalcones, which can be explored further. As a future perspective, both chalcones (BMP and BBP) could be added as organic photoprotective agents in topical sunscreens formulations or in combination with inorganic photoprotective agents, such as titanium dioxide and zinc oxide [60], in order to improve the efficiency of the commercial sunscreens.