Theoretical Study on the Atom-Substituted Quinazoline Derivatives with Faint Emission as Potential Sunscreens.

Two novel compounds (HQS and HQSe) with excited-state intramolecular proton transfer (ESIPT) properties were designed based on the compound 2-(2-hydroxy-3-ethoxyphenyl)-3H-quinazolin-4-one (HQ). The parameters related to the ESIPT properties and electronic spectra of HQ and its derivatives were calculated using density functional theory and time-dependent density functional theory methods. The obtained geometric configurations, infrared vibrational spectra, and reduced density gradient scatter plots have shown that the intramolecular hydrogen bond O1···H1-N1 has been weakened upon photoexcitation. Moreover, from the scanned potential energy curves, it can be found that the ESIPT processes of the three compounds have no energy barriers. It is noteworthy that HQS and HQSe can strongly absorb light in the UVA region (∼340 nm) and exhibit weak fluorescence emission in the visible light region, which comes from the keto configuration. The special optical properties of HQS and HQSe can promote their application as potential sunscreen agents.

Introduction

Ultraviolet (UV) damage has been widely concerning because it can accelerate skin aging, cause melanin deposition, and induce skin cancer.[1−3] In general, UV rays can be classified as UVA, UVB, and UVC according to the difference in wavelength (320–400, 280–320, and 200–280 nm for UVA, UVB, and UVC, respectively),[4−6] in which UVA has intense penetration and is the most significant cause of skin aging. Therefore, the discovery, design, and synthesis of UV absorbers with special effects is significant to protecting the skin from UV damage.[7−9]

The UV absorber strongly and selectively absorbs high-energy UV rays. It then releases and consumes them with thermal energy or harmless low-energy radiation to avoid damage to the skin.[10,11] In the past few years, the applications of UV absorbers with excited-state intramolecular proton transfer (ESIPT) characteristics in sunscreen have been widely reported.[12−14] Under light excitation, compounds with ESIPT characteristics produce photoisomers through excited-state proton transfer, accompanied by double fluorescence.[15−17] Owing to their excellent application in sunscreen, they have attracted the interest of many researchers. Wu et al. reported a sunscreen molecule FPPO-HBr with ESIPT properties and found that the FPPO-HBr decays via the ESIPT process followed by the ultrafast structural distortion upon photoexcitation.[18] In addition, the ESIPT process of homosalate has been studied using time-resolved ultrafast laser spectroscopy, laser-induced fluorescence, and steady-state absorption spectroscopy methods to confirm the feasibility of homosalate as a sunscreen.[19] Moreover, the plant flavonoid compounds with ESIPT properties have been synthesized and investigated to provide a theoretical basis for sunscreen cosmetics.[20] Research on the properties of sunscreen still needs to be deeply explored.

In this work, two novel compounds, HQS and HQSe with ESIPT properties, were designed in theory by the homologous substitution (S and Se) on the synthesized molecule 2-(2-hydroxy-3-ethoxyphenyl)-3H-quinazolin-4-one (HQ).[21] The geometrical configurations of HQ, HQS, and HQSe in enol and keto forms are plotted in Scheme , and the significant atom associated with proton transfer is highlighted to aid understanding. Furthermore, the critical geometric structure parameters, infrared (IR) vibrational spectra, and RDG scatter plots of HQ, HQS, and HQSe are calculated to investigate the effect of atomic electronegativity on the intramolecular hydrogen bond (IHB). The potential energy curves (PECs) of HQ, HQS, and HQSe are calculated to study the influence of atomic substitution on the ESIPT process. It is worth noticing that the absorption and fluorescence peaks of HQS and HQSe are located in the range of UVA and visible light, respectively.

Scheme 1

Geometric Structures of HQ, HQS, and HQSe in (a) Enol and (b) Keto Forms

Methods

In this work, the geometric structure optimizations of HQ, HQS, and HQSe in enol and keto forms at ground and excited states were calculated using density functional theory (DFT)[22−24] and time-dependent density functional theory (TD-DFT)[25−27] methods with B3LYP/6-311G(d,p),[28−30] respectively. The optimization processes of HQ and its two derivatives are shown in Figure S1. The critical hydrogen bond parameters, absorption and fluorescence spectra, IR vibrational spectra, PECs, and RDG scatter plots of HQ, HQS, and HQSe were calculated based on the optimized structures. Considering that HQ, HQS, and HQSe are endowed with an obvious charge transfer process upon photoexcitation, range-separated functional CAM-B3LYP was used to simulate the absorption and fluorescence spectra in this work.[31] Moreover, all calculations exploited the integral equation formula polarized continuum model (IEFPCM)[32,33] of THF solvent to fit the experimental data better. The PECs of HQ, HQS, and HQSe at the S0 and the lowest excited (SL) states were scanned by steadily increasing the bond length of O1–H1. The analysis of hole–electron and frontier molecular orbitals (FMOs) all use the Multiwfn 3.8 program[34] and VMD 1.9.4.[35] All calculations were performed by using Gaussian 16 software[36] in this work.

Results and Discussion

Geometric Structure Parameters

The geometric structure parameters of HQ, HQS, and HQSe at the S0 and SL states were optimized by DFT and TD-DFT methods with B3LYP/6-311G(d,p), respectively. As numerous attempts to obtain the equilibrium structures of HQ and its two derivatives have culminated in failure and ended in their proton-transferred structures (HQ-k, HQS-k, and HQSe-k), herein, we only list the significant parameters associated with the IHBs of HQ-k, HQS-k, and HQSe-k, as shown in Table .[37] It can be found that the O1···H1 bond lengths are elongated from ∼1.552 Å in the S0 state to ∼1.689 Å in the SL state, whereas the H1–N1 bond lengths are decreased from ∼1.065 Å in the S0 state to ∼1.039 Å in the SL state. Furthermore, all of the bond angles δ(O1···H1–N1) are decreased from ∼144.8° in the S0 state to ∼141.1° in the SL state. Generally speaking, the shorter bond length, the more planar bond angle, the more robust the IHB, the more the molecule is prone to cause the proton transfer process.[38−40] Thus, it can be concluded that the IHB O1···H1–N1 is weakened at the SL state and verified that the reverse proton transfer (RPT) process prefers to proceed at the S0 state.[41] Most notably, the relative ordering of the IHB intensity at S0 and SL states for the three investigated compounds is as follows: HQ-k < HQS-k < HQSe-k. Based on the above analysis, it can be inferred that atomic electronegativity can alter the strength of IHB in the S0 and SL states and thereby affect the proton transfer process of HQ.[41]

Table 1

Critical Bond Lengths (Å) and Bond Angles (deg) of HQ, HQS, and HQSe at S0 and SL States

	state	O1···H1	H1–N1	δ(O1···H1–N1)
HQ-ka	S0	1.560	1.063	144.9
	SL	1.777	1.024	138.7
HQS-ka	S0	1.551	1.065	144.7
	SL	1.702	1.040	140.6
HQSe-ka	S0	1.546	1.067	144.9
	SL	1.588	1.055	144.2

The k represents the proton transfer structures of HQ and its derivatives.

Infrared Vibrational Spectra

The IR vibrational spectra of HQ, HQS, and HQSe in the keto form were obtained and are displayed in Figure . Apparently, the stretching vibrational mode of N1–H1 for HQ-k, HQS-k, and HQSe-k is separately located at 2726, 2696, and 2675 cm–1 in the S0 state, which shifts to 3321, 3094, and 2823 cm–1 in the SL state, implying that the IHB O1···H1–N1 is weakened upon photoexcitation and the RPT process is difficult to complete in the SL state. It can also be noticed that the blue shifts follow the decreased order of HQ-k > HQS-k > HQSe-k, indicating that the IHB intensity has gradually weakened as the atomic electronegativity decreased, which is consistent with the analysis of the geometric parameters.[42,43]

Figure 1

Simulated IR vibrational spectra in N1–H1 regions of HQ-k, HQS-k, and HQSe-k in the S0 and SL states.

RDG scatter plots

Reduced density gradient (RDG) is a dimensionless parameter used to describe electron heterogeneity in density functional theory. Its expression equation is[44,45]

As the electron density of the molecule decays exponentially, the RDG presents a large value far away from the molecule. On the contrary, the value of RDG in the interaction region is very minimal, in which the electron density and RDG in the noncovalent interaction region are relatively low.[46] Moreover, the IRI isosurface is a useful tool for rendering an intrinsic picture of intramolecular and intermolecular hydrogen bonding.[47] Like the RDG scatter plots, it can be used to discern distinct interaction strengths and types.

The RDG scatter plots and the interaction types of HQS-k and HQSe-k at the ground and excited states are shown in Figure ; it can be observed that the types of interactions of HQ-k, HQS-k, and HQSe-k at the ground and excited states are all hydrogen-bonding interactions. In RDG scatter plots, the enclosed place represents the IHB. The smaller the value here, the stronger the IHB. Obviously, for HQ-k, HQS-k, and HQSe-k, the IHB is weaker in the SL state compared to that in the S0 state, which is not favorable to the RPT process.[48−50] Moreover, the strengths of IHB are on the order of HQ-k < HQS-k < HQSe-k, verifying that IHBs are weakened with decreased atomic electronegativity.

Figure 2

RDG vs sign (λ2)ρ(r) scatter plots and the interaction types of HQ-k, HQS-k, and HQSe-k in S0 and SL states.

Absorption and Fluorescence Spectra

The absorption and fluorescence spectra of HQ, HQS, and HQSe were calculated using the CAM-B3LYP functional based on the optimized geometric structures and plotted in Figure . The relevant data are shown in Table and Table . The absorption peaks of HQ, HQS, and HQSe are situated at 277, 326, and 354 nm, respectively, in which wavelengths of HQS and HQSe are located in the range of UVA. Because HQ, HQS, and HQSe do not have stable structures in enol form in the SL state, they do not have fluorescence spectra in enol form. Moreover, in the keto form, HQ, HQS, and HQSe emit faint fluorescence and are located at 397, 402, and 422 nm, respectively, in which wavelengths of HQS and HQSe are located in the range of visible light.[51]

Figure 3

Absorption and fluorescence spectra of HQ, HQS, and HQSe in THF solvent.

Table 2

Absorption Peaks and Corresponding Transition Properties of HQ, HQS, and HQSe

	state	λabs (nm)	contribution MO	strength f
HQ-e	S1	314	(67.434%) H→L	0.2883
	S2	277	(59.745%) H-1→L	0.4623
	S3	267	(46.612%) H-1→L+1	0.1534
	S4	235	(62.840%) H-4→L+1	0.0003
	S5	233	(51.879%) H-2→L	0.0477
	S6	228	(64.107%) H-5→L	0.0007
HQS-e	S1	379	(67.110%) H-2→L	0.0000
	S2	326	(53.596%) H-1→L	0.4168
	S3	320	(55.701%) H→L+1	0.1756
	S4	289	(60.656%) H-1→L+1	0.2777
	S5	277	(43.460%) H-3→L	0.0458
	S6	263	(34.711%) H-3→L	0.0684
HQSe-e	S1	434	(68.200%) H-2→L	0.0000
	S2	354	(49.976%) H→L	0.3934
	S3	323	(58.589%) H→L+1	0.2271
	S4	302	(56.381%) H-1→L+1	0.1221
	S5	291	(45.846%) H-3→L	0.0013
	S6	281	(68.989%) H-2→L+1	0.0001

Table 3

Fluorescence Characteristics of HQ, HQS, and HQSe in the Keto Form in THF Solvent

	state	λflu (nm)	contribution MO	strength f
HQ-k	SL	397	(66.838%) H→L	0.0219
HQS-k	SL	402	(48.598%) H→L	0.0509
HQSe-k	SL	422	(65.888%) H→L	0.1032

As shown in Figure , it can be observed that the values of the absorption, fluorescence peaks, and Stokes shift of the three compounds are in the order of HQ > HQS > HQSe, indicating that atomic electronegativity can influence the optical characteristics of compounds. Moreover, it can be found that the absorption and fluorescence peaks of HQS and HQSe are located in the UVA range and the visible light range, respectively. Moreover, the oscillator strengths of fluorescence peaks are very weak, which is favorable for protecting human skin. Therefore, it can be concluded that HQS and HQSe can be used as sunscreen agents.

FMO Distribution and Hole–Electron Analysis

To further explore the fundamental reason for the proton transfer process, the FMO distributions associated with the SL state of HQ-k, HQS-k, and HQSe-k, and the corresponding energy gap values in THF were obtained and plotted in Figure . It can be seen that the electron density distributed on the O atom of HQ-k, HQS-k, and HQSe-k has decreased upon photoexcitation, indicating that IHB O1···H1–N1 will be weakened in the SL state. Moreover, the corresponding energy gaps of the three investigated proton-transferred tautomers are in the following order: HQ-k (3.603 eV) > HQS-k (2.839 eV) > HQSe-k (2.758 eV), which leads to the fluorescence peak following the order: HQ-k < HQS-k < HQSe-k, illustrating that atomic electronegativity can influence the optical characteristics of the molecules.[52]

Figure 4

Frontier molecular orbital distribution and the corresponding energy gap values of HQ-k, HQS-k, and HQSe-k in THF solvent.

In order to determine why the fluorescence strength is weakening, the isosurface of hole–electron distribution, Cele and Chole, the overlap of hole–electron (Sr), and charge density difference (CDD) of HQ-k, HQS-k, and HQSe-k in THF solvent were obtained and plotted in Figure .[53−55] The quantities of transferred electrons of HQ-k, HQS-k, and HQSe-k from ethoxyphenol to quinazoline are calculated and marked in the isosurface of hole–electron distribution. It can be found that the degree of charge transfer follows HQ-k (0.934 e) > HQS-k (0.634 e) > HQSe-k (−0.020 e), and the distance between the hole and the electron can also verify this conclusion. So the fluorescence strengths are in the following order: HQ-k < HQS-k < HQSe-k. In addition, the Sr and CDD can show that HQ, HQS, and HQSe have undergone a charge transfer process,[56] which explains the fundamental reason for proton transfer.

Figure 5

Isosurfaces of hole–electron distribution (a), Cele and Chole functions (b), overlap of hole–electron (Sr) (c), and charge density difference (d) of HQ, HQS, and HQSe in THF solvent. (a–c) Green represents holes and the orange represents electrons. (d) Green and orange correspond to the decrease and increase of the excited-state density relative to the ground state density, respectively.

Potential Energy Curves

To study the proton transfer process of HQ, HQS, and HQSe, the PECs of three compounds were scanned by increasing the O1–H1 bond length and are shown in Figure . In the S0 state, the energy barriers of the forward proton transfer (FPT) process for HQ, HQS, and HQSe are 5.496, 6.443, and 6.576 kcal/mol, respectively. Interestingly, we noticed that the FPT behavior has become an ultrafast process with no energy barriers in the SL state, which explains why the three molecules do not have a stable enol form in the SL state, and this result is consistent with the analysis of geometric structures.[57−59] For the RPT process, the negligible energy barriers (0.367, 0.194, and 0.178 kcal/mol) of HQ, HQS, and HQSe need to be surmounted in the S0 state, while the energy continues to rise in the SL state, implying that the RPT process prefers to proceed in the S0 state, which is in agreement with the relative stronger O1···H1–N1 IHB in the S0 state.

Figure 6

Potential energy curves of HQ, HQS, and HQSe in S0 and SL states along with the growing trend of O1–H1 bond length.

In addition, it can be found that the energy barriers of reverse ground-state intramolecular proton transfer (RGSIPT) of HQ, HQS, and HQSe are far lower than the energy barriers of ground-state intramolecular proton transfer (GSIPT) and ESIPT.[60−62] Thus, it can be found that the three compounds can quickly return to the enol form in the S0 state, and it is favorable to enhance the effective acting time of sunscreen.

Conclusion

In this work, the effects of atomic substitution on the ESIPT process of HQ have been comprehensively investigated by DFT and TD-DFT methods. From calculated results, it can be found that the IHBs of HQ, HQS, and HQSe are weakened in the SL state, indicating that it is difficult for RPT to occur in the SL states. The absorption and fluorescence peaks of HQS and HQSe are separately located in the range of UVA and visible light, which corresponds to sunscreen requirements, and it can be found that the quantity of transferred electrons can affect the strength of fluorescence peaks of molecules. Moreover, as a result of the analysis of the PECs, it can be concluded that HQ, HQS, and HQSe are not energy barrier processes, which is favorable for ESIPT to occur. Moreover, the energy barriers of RGSIPT of HQ, HQS, and HQSe are lower than the energy barriers of GSIPT, indicating the three compounds can quickly go back to the enol form at the ground state, and it is favorable to enhance the effective acting time of sunscreen. All in all, this provides a theoretical foundation for synthesizing the new compounds applied to sunscreen.