Experimental IR, Raman, and UV-Vis Spectra DFT Structural and Conformational Studies: Bioactivity and Solvent Effect on Molecular Properties of Methyl-Eugenol

Highlights What are the main findings? The ME molecule has 21 stable configurations. For all the tops (except =CH2), the barrier heights are of the same order, while the =CH2 top has a barrier height one order of magnitude higher. Like estragole and eugenol, ME also has the same Fermi doublets for the following modes: νs(–CH2) and 2 × βs(–CH2); νs(CH3) and 2 × δs(CH3). The ME molecule has three active sites. Vibrational analysis suggests that the solvents affect the internal modes of both OCH3 moieties strongly. What is the implication of the main finding? The methyl-eugenol molecule could be a good choice for the pharmacological applications The OCH3 moieties of methyl-eugenol play significant role in interaction with other molecules. Abstract Structural, conformational, and spectroscopic investigations of methyl-eugenol were made theoretically at the B3LYP-6-311++G**level. Experimental IR, Raman, and UV-vis spectra were investigated and analyzed in light of the computed quantities. Conformational analysis was carried out with the help of total energy vs. dihedral angle curves for different tops, yielding 21 stable conformers, out of which only two have energies below the room temperature relative to the lowest energy conformer. The effect of the solvent on different molecular characteristics was investigated theoretically. MEP and HOMO-LUMO analysis were carried out and barrier heights and bioactivity scores were determined. The present investigation suggests that the molecule has three active sites with moderate bioactivity. The solvent–solute interaction is found to be dominant in the vicinity of the methoxy moieties.


•
The ME molecule has 21 stable configurations. • For all the tops (except =CH 2 ), the barrier heights are of the same order, while the =CH 2 top has a barrier height one order of magnitude higher. • Like estragole and eugenol, ME also has the same Fermi doublets for the following modes: ν s (-CH 2 ) and 2 × β s (-CH 2 ); ν s (CH 3 ) and 2 × δ s (CH 3 ).

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The ME molecule has three active sites. • Vibrational analysis suggests that the solvents affect the internal modes of both OCH 3 moieties strongly.
What is the implication of the main finding?
• The methyl-eugenol molecule could be a good choice for the pharmacological applications • The OCH 3 moieties of methyl-eugenol play significant role in interaction with other molecules.

Introduction
Methyl-eugenol (ME) is a member of the family of phenylpropenes. A total of 450 plant species from across 80 families were found to contain ME in essential oils from plant leaves, roots, stems, flowers, or whole plant extracts [1]. The oils constituting more than 0.1% of methyl eugenol are calamus, rose, tea tree oil, green myrtle, citronella, lemon balm, camphor oil. Common herbs and spices containing ME are basils [2], lemongrass, bay leaves, cloves, tarragon, allspice, nutmeg, and mace [3,4]. ME is also present in fruits such as banana, grapefruit, and some other forest fruits. It is a natural product balm, camphor oil. Common herbs and spices containing ME are basils [2], lemongrass, bay leaves, cloves, tarragon, allspice, nutmeg, and mace [3,4]. ME is also present in fruits such as banana, grapefruit, and some other forest fruits. It is a natural product and bears strong potential in medicinal and agriculture areas like aromatherapy, massage, and liver injury [5], for its anti-cancer [6], anti-allergic [7], and anti-oxidative effects [8], as an anesthetic agent for rodents [9], in insecticides, and for its antifungal and antibacterial actions [10], etc. It has flavor and fragrance properties occurring naturally in various plants including some herbs, distinct food resources, and essential oils. Natural ME is used as a flavoring agent in food and as a fragrance in cosmetic products [11]; synthesized ME is used as an insect attractant but not used as a flavoring agent in food and fragrance in cosmetic products as it may cause cancer in humans/animals [12,13]. It is also used in low/high concentration for fruit fly attractant/replant [14]. It is a safe anesthetic agent as well as anti-depressive and reduces anxiety level for rats [9,15] because of its capability of inducing partial or total loss of sensation. Rietjens et al. [16] studied the metabolic and toxic behaviors of ME in different orientation of the functional groups.
Structural and vibrational investigations of ME were carried out by Chowdhry et al. [17], in which they considered only the three lower energy conformers. The vibrational assignments proposed by these authors are also doubtful in several cases. In the present paper, structural and spectroscopic investigations were carried out for the ME molecule at the level B3LYP-6-311++G**, in addition to the experimental IR, Raman, and UV-vis spectral studies. The structural and vibrational computations were carried out also with water and ethanol as solvents. We have determined the barrier height, MEP, HOMO-LUMO analysis, and bioactive scores. To determine the total number of possible conformers, we scanned total energy vs. dihedral angle curves for different tops. A total of 21 pairs of stable conformers were found. In each pair, one conformer is the enantiomer of the other conformer. Out of these 21 conformers, only 2 conformers are found to exist below 300 K relative to the lowest energy conformers, as also reported by earlier workers [17].

Result and Discussion
The optimized structure of the ME molecule is shown in Figure 1 (C-I). There are seven tops in ME molecule. By scanning the total energy vs. dihedral angles surfaces, we search the total number of possible conformers.

Determination of Conformers
To search the total number of possible conformers of ME, we scanned the total energy vs. dihedral angle curves for different tops. The rotations of the two CH3 tops about their respective O-C axes do not yield any new structures. However, each of the rotations of the OCH3 tops about their respective C-O axes gives rise to 3-fold potential barrier, yielding

Determination of Conformers
To search the total number of possible conformers of ME, we scanned the total energy vs. dihedral angle curves for different tops. The rotations of the two CH 3 tops about their respective O-C axes do not yield any new structures. However, each of the rotations of the OCH 3 tops about their respective C-O axes gives rise to 3-fold potential barrier, yielding only nine structures, out of which two structures are not stable due to strong steric hindrance. Therefore, the two OCH 3 tops on rotating would yield seven possible stable structures. Similarly, the rotation of the =CH 2 top about the C=C axis does not produce a new structure. However, rotations of the -CH=CH 2 and -CH 2 -CH=CH 2 tops about their respective axes result in 3-and 2-fold potential barriers, giving rise to six possible different structures. Therefore, the total number of possible stable structures comes out to be 7 × 6 = 42. Out of these 42 possible conformers, there are 21 pairs with different energies and in each pair one structure is the mirror of the other structure. One structure of such a pair is called the enantiomer of the other structure. The total energy and their energy differences with respect to the lowest energy conformer are listed in Table 1. The first three lower energy conformers of the ME molecule are shown in Figure 1. The conformers C-II and C-III are at higher energies by 215 and 312 K, respectively, above the conformer C-I. According to the orientations of the three functional groups, the 21 conformers could be classified into two categories: (i) conformers with the same allyl group orientation and (ii) conformers with the same methoxy groups orientations. According to the allyl group orientations, the conformers could be divided into three categories, each of which contains seven conformers. Similarly, according to the methoxy groups orientations the conformers could be divided into seven categories, each of which contains three conformers (Table S1). The calculated relative abundances of all the 21 conformers were listed in Table 1. For the conformer C-I, C-II, and C-III, the abundances are 32.1, 16.2, and 11.2, respectively. Assuming the presence of only these three conformers-C-I, C-II, and C-III-below room temperature, the relative abundances are 53.9, 27.2, and 18.9, respectively, with an approximate ratio of 6:3:2.

Molecular Geometries
The optimized geometrical parameters of the three lower energy conformers (C-I, C-II, and C-III) are collected in Table S2. In going from one low energy conformer to another, a few geometrical parameters are found to change considerably. The C 12 -C 15 /C 1 -C 12 bond length is found to enhance/reduce by 0.006 Å/0.008 Å in conformer C-II. The phenyl ring C-C bond lengths show small changes in going from C-I to C-III. The largest C-C bond length is found to be C 1 -C 12 (1.520 Å) for the three conformers. The largest C-H bond lengths were found for the C-H bonds of the methyl groups lying in the ring plane. The bond angles α(C 2 -C 3 -O 8 ) (124.8 • ) and α(C 5 -C 4 -O 9 ) (125.1 • ) are found to be much larger and the bond angles α(C 4 -C 3 -O 8 ) (115.6 • ) and α(C 3 -C 4 -O 9 ) (115.1 • ) have much lower values as compared to the other α(C-C-H) and α(C-C-C) angles associated with phenyl ring moieties due to excess electrostatic repulsive force between the two O atoms. For the H atoms of the two methyl groups lying in the ring plane, the α(O-C-H) bond angle for both methoxy groups is found to be smaller (105.7) than the other two α(O-C-H) angles (111.5 • ).

Barrier Heights
Referring to the Figure 1, the ME molecule has seven tops; namely, the two OCH 3 , two CH 3 , a CH 2 CHCH 2 , a CHCH 2 , and a =CH 2 top. The total energy vs. dihedral angle curves for the four tops, which generate different conformers, are shown in Figure 2, and the three tops, which do not generate any new conformers, are shown in Figure S2. The number of minima in each curve gives the foldness of the corresponding barrier. The computed barrier heights are listed in Table  length is found to enhance/reduce by 0.006 Å/0.008 Å in conformer C-II. The phenyl ring C-C bond lengths show small changes in going from C-I to C-III. The largest C-C bond length is found to be C1-C12 (1.520 Å) for the three conformers. The largest C-H bond lengths were found for the C-H bonds of the methyl groups lying in the ring plane. The bond angles α(C2-C3-O8) (124.8°) and α(C5-C4-O9) (125.1°) are found to be much larger and the bond angles α(C4-C3-O8) (115.6°) and α(C3-C4-O9) (115.1°) have much lower values as compared to the other α(C-C-H) and α(C-C-C) angles associated with phenyl ring moieties due to excess electrostatic repulsive force between the two O atoms. For the H atoms of the two methyl groups lying in the ring plane, the α(O-C-H) bond angle for both methoxy groups is found to be smaller (105.7) than the other two α(O-C-H) angles (111.5°).

Barrier Heights
Referring to the Figure 1, the ME molecule has seven tops; namely, the two OCH3, two CH3, a CH2CHCH2, a CHCH2, and a =CH2 top. The total energy vs. dihedral angle curves for the four tops, which generate different conformers, are shown in Figure 2, and the three tops, which do not generate any new conformers, are shown in Figure S2. The number of minima in each curve gives the foldness of the corresponding barrier. The computed barrier heights are listed in Table 2. The rotations of the CH3 and =CH2 tops do not yield new structures. Each of the two CH3 tops has the barrier height of 3.34 kcal/mole, while the =CH2 top has the barrier height of 93.13 kcal/mole.   The remaining four tops CH 2 CHCH 2 , CHCH 2 , 8 OCH 3 , and 9 OCH 3 are responsible for the formation of different conformers. The total energy vs. dihedral angle plot for the top CH 2 CHCH 2 about the C 1 -C 12 axis is shown in the Figure 2a, in which the points A and E correspond to the same configuration. The points A/E and C and, similarly, the points B and D are energetically different points. The transition A → C via B needs more energy than the transition E → C via D. The reverse transitions (C → A and C → E) follow a similar pattern but require less energy. This difference is a result of substituent OCH 3 groups at the meta-and para-positions relative to the allyl group. Referring to Figure 2b, the points A/G, C, and E and similarly the points B, D, and F are energetically different points. The energies required for the transitions A → C, C → E, and E → G are found to be 2.36, 2.00, and 3.62 kcal/mole, respectively; for the reverse transitions, the required energies are 1.27, 1.98, and 4.73 kcal/mole, respectively. From Figure 2c, it could be seen that the points A/G and C/E and, similarly, the points B/F and D are energetically different points. The transitions A → C and G → E through the points B and F need the same amount (1.13 kcal/mole) of energy. For the lowest energy conformer, allyl moiety does not affect the barrier heights for the 8 OCH 3 and 9 OCH 3 tops. However, the transition C → E through the point D is found nearly six times higher than the energy required for the transitions A → C or G → E. Similarly, for Figure 2d, the local minima points A/G and C/E separated by the peak points B/F and D are energetically different points. The transitions from A → C and G → E through the points B and F are found to be~2.36 kcal/mole, however, the transition C → E through the point D is found to be~2.72 kcal/mole.

Bioactive Scores
The bioactivity of a molecule is directly connected to the medicinal/pharmaceutical activity of the molecule. It is calculated in term of the bioactive scores, which are related to the binding preference of the molecule with the biological targets. The bioactive scores of the ME molecule are computed using the online software Molinspiration available at the site-www.molinspiration.com (accessed on 10 March 2023). The most common biological targets are the proteins like G protein-coupled receptor and nuclear receptor ligand, ion channel modulation, kinase inhibition, protease inhibition, and enzyme activity inhibition. The computed bioactive scores of the ME molecule are given in Table 3. These scores suggest that ME is a moderately bioactive molecule.

APT Charge
Atomic polar tensor (APT) charges at different sites of the three lower energy conformers are given in Table 4. The APT charges at various sites retain their polarity excepting the sites C 1 and H 16 . The polarity of C 1 and H 16 atoms are found to be positive in conformers C-I and C-II and are found to be negative in the conformer C-III. The magnitudes of the APT charges are found to show variation in phenyl ring and allyl moieties, excepting the C atoms of the methyl groups. The C atoms of the phenyl ring attached to the substituents bear positive APT charges since all the three substituents are electron withdrawing in nature and the remaining C atoms of the phenyl ring bear negative APT charges. The magnitudes of the APT charges are found to be much higher at the C and O atoms of both the OCH 3 groups as compared to the rest atoms. The highest negative charge is found to be at the O atom of the OCH 3 group attached at the para-position relative to the allyl moiety. The H atoms attached to the C 15 and C 17 atoms have positive APT charges; however, the H atoms attached to the C 12 atom bears negative APT charge in the allyl moiety. In going from one low energy conformer to another, a few sites show noticeable changes in the magnitudes of the APT charges. The enhancement in the magnitudes of the APT charges at the sites C 6 and H 11 in the conformer C-II and the site H 19 in C-III is a result of steric hindrance with the allyl moiety. There is decrease in the APT charge at the site H 7 in C-II and the sites C 2 and C 5 in the conformers C-II and C-III. Table 4. APT charges (in e unit) at different atomic sites of ME.

Atoms C-I C-II C-III C-I In Solvent Effect
Water Ethanol  Table 5 presents the 75 normal modes of vibration of ME. The computed and experimental Raman and IR spectra are shown in Figures 3 and S3. The observed IR and the Raman spectra of ME agree with the observed spectrum reported by the earlier authors [17]. The observed Raman and IR bands along with the corresponding computed scaled IR and Raman frequencies and their relative intensities, depolarization ratios of the Raman bands, PEDs, and the proposed mode assignments for the three lower energy conformers are collected in Table S3. Vibrational analysis has been made in light of the computed vibrational spectra and related quantities for the allyl and methoxy-benzenes. To correlate the experimental and computed scaled frequencies, help has also been taken from the vibrational assignments of the observed frequencies for the allyl-benzene (AB) [18], anisole [19], estragole (EG) [20], and eugenol (EU) [21] molecules. In order to correlate the normal modes of the phenyl ring moiety with benzene, the form of a normal mode, observed from the animation available with the Gauss View 05 software and the PEDs, was of considerable help. Table 5. Normal mode distribution of ME.

Methoxy (-OCH 3 ) Group Modes
There is no observed frequency for the mode υ s (a ) in both the IR and Raman spectra of ME. For benzene derivatives with a methoxy group {anisole [19], EG [20], and EU [21]}, two frequencies are observed around 2835 and 2900 cm −1 , which are explained to arise due to the Fermi resonance (FR) between the fundamental mode υ s (CH 3 ) and the 1st overtone of the mode δ s (CH 3 ). In the present case, the two frequencies 2834 and 2905/2907 cm −1 are observed in both the IR and Raman spectra. The computed (scaled) frequencies for the modes υ s (CH 3 ) and δ s (CH 3 ) are found to be 2867/2870 and 1447/1438 cm −1 . Therefore, the average (2870 cm −1 ) of the two observed frequencies-2834 and 2905 cm −1 -is assigned to the mode υ s (CH 3 ) and the two frequencies 2834 and 2905 cm −1 are explained to arise due to the FR between υ s (CH 3 ) and 2 × δ s (CH 3 ). The δ s (CH 3 ) modes for both OCH 3 groups are observed at 1441(IR)/1449(R) cm −1 .
correlate the experimental and computed scaled frequencies, help has also been taken from the vibrational assignments of the observed frequencies for the allyl-benzene (AB) [18], anisole [19], estragole (EG) [20], and eugenol (EU) [21] molecules. In order to correlate the normal modes of the phenyl ring moiety with benzene, the form of a normal mode, observed from the animation available with the Gauss View 05 software and the PEDs,was of considerable help. The discussion of the vibrational assignments for the methyl eugenol molecule could be divided into three groups: (i) Methoxy (-OCH3) moiety modes (12 + 12), (ii) Allyl (-CH2-CH=CH2) moiety modes (21), and (iii) Phenyl moiety modes (30).  The modes υ as (CH 3 )(a ) and υ as (CH 3 )(a ) were correlated with the observed frequencies 2905(IR)/2908(R) and 3001(IR)/3002(R) cm −1 and the a and a components of the anti-symmetric deformation modes are observed at 1464(IR/R) and 1452(IR) cm −1 , respectively. The CH 3 torsional modes corresponding to the OCH 3 groups attached to the metaand para-C atoms relative to the C atom to which the allyl group is attached are computed to be 225 and 250 cm −1 . In estragole, the OCH 3 group is attached to the para-C atom, while in eugenol it is attached to the meta-C atom relative to the allyl attached C atom of the ring. Moreover, the τ(CH 3 ) mode is found to have magnitudes 223 and 246 cm −1 for the eugenol and the estragole molecule. Therefore, the magnitudes of the τ(CH 3 ) modes of ME also agree with those of eugenol and estragole considering the position of the C atom of the ring to which the OCH 3 group is attached relative to the allyl C atom of the ring.
The modes υ s (a ), υ as (a ), δ as (a ), ρ(a ), and τ(CH 3 ) of one OCH 3 group are found to be coupled with the corresponding modes of the other OCH 3 group. Moreover, the δ s (CH 3 ) mode of both the CH 3 groups appear to be coupled with the β s (-CH 2 ) mode of the allyl moiety. The frequencies corresponding to the modes υ s (a ), υ as (a ), υ as (a ), δ s (a ), and ρ(a ) of the 9 OCH 3 group are computed to be lower than the corresponding modes of the 8 OCH 3 group.
In and 1039(R) cm −1 , respectively. Likewise, the modes α(C-O-CH 3 ) and τ(C-OCH 3 ) of one OCH 3 group are also found to couple with the corresponding modes of the other OCH 3 group as well as some other modes of the allyl and phenyl moieties. The mode α(C-O-CH 3 ) is observed at 538(IR)/382(R) cm −1 with weak intensity in the Raman spectrum. The mode τ(C-9 OCH 3 ) is observed as a strong Raman band of 60 cm −1 . The assignment of the modes ν(O-CH 3 ) and τ(C-OCH 3 ) are in support with assignment of the modes in the anisole [19], the estragole [20], and the eugenol [21] molecules. The mode α(C-O-CH 3 ) shows variation in going from one molecule to another as well as surrounding of the substituent groups.
Out of the 12 modes of each OCH 3 group, the 3 modes α(C-O-CH 3 ), τ(C-OCH 3 ), and τ(CH 3 ) show a noticeable change in computed frequencies in going from one low energy conformer to another. The mode τ(CH 3 ) of the CH 3 group attached to the meta-C atom relative to the C atom attached with allyl group is reduced by 17 cm −1 in the conformer C-III relative to the conformers C-I and C-II. (6) The modes ν s and ν as were found to be pure modes with the scaled frequencies 2879 and 2911 cm −1 , respectively. The mode β s (1439 cm −1 ) has strong coupling with the mode δ s (CH 3 ) of the 8 OCH 3 group. Similar to the case of the OCH 3 group(s), the ν s and 2× β s of the methylene group are found to be in FR with each other, giving rise to the two observed component frequencies as 2905(IR)/2907(R) and 2834(IR, R) cm −1 . The average of these two frequencies, i.e., 2870 cm −1 is assigned to the mode ν s and the observed frequency 1444 cm −1 to the mode β s of the methylene group. It is noteworthy that both the modes ν s (-CH 3 ) and ν s (-CH 2 ) are correlated to the same pair of the observed frequencies 2906 and 2834 cm −1 . Likewise, the modes δ s (-CH 3 ) and β s (-CH 2 ) are correlated to the same observed frequencies 1445(IR)/1449(R) cm −1 . The observed frequency corresponding to the mode ν as (-CH 2 -) is computed to be 2911 cm −1 and appears to be obscured with the higher frequency component (2906 cm −1 ) of the FR doublet.

Allyl (-CH 2 -CH=CH 2 ) Group Modes (21) Methylene (-CH 2 -) Group Modes
The modes ω, ρ, and t of methylene group were computed to be 1297, 1203, and 889 cm −1 , respectively, and appear to be strongly coupled with the other modes (Table S3). The t mode is not a usual torsional mode, which makes its magnitude considerably high (889 cm −1 ) compared to the usual torsion modes (<500 cm −1 ). For the EU [21], it is observed at 894 cm −1 in the Raman spectrum. The modes ω and ρ are observed in the Raman spectrum at the frequencies 1293 and 1206 cm −1 . The assignments of these modes are in agreement with the corresponding modes of the EG [20] and EU [21] molecules.
The three C-H planar bending modes β s (=CH 2 ), δ(=C-H), and ρ(=CH 2 ) of the vinyl group are correlated to the computed frequencies 1414, 1287, and 1092 cm −1 , respectively. The modes β s (=CH 2 ) and ρ(=CH 2 ) are found to be strongly coupled with the other modes of the allyl moiety; however, the δ(=C-H) mode has strong coupling with the ring β(C-H) modes and weak coupling with other allyl moiety modes. The observed frequencies corresponding to these modes are identified as 1418(IR)/1412 (R), 1285 (IR), and 1101 (IR) cm −1 , respectively.
The computed frequencies 1005, 920, and 600 cm −1 arise due to non-planar bending motions of the three C-H bonds of the vinyl moiety. The frequency 1004 cm −1 is found to arise due to the opc of the τ(=CH 2 ) mode with the γ(=C-H) mode, whereas the ipc between these two modes yields the frequency 600 cm −1 . The remaining ω(=CH 2 ) mode has a strong coupling with the ν(C 12 -C 15 ) mode. These frequencies are correlated to the observed frequencies 995(IR)/994(R), 913(IR)/923(R), and 601(IR)/596(R) cm −1 , respectively. The present assignments for the allyl group modes are in agreement with the corresponding assignments reported earlier [18,20,21].
The three modes ν(C=C), α(C 12 -C 15 =C 17 ), and τ(C 12 -C 15 ) are computed to be 1650, 279, and 75 cm −1 , respectively. The modes α(C 12 -C 15 =C 17 ) and τ(C 12 -C 15 ) are found to be strongly coupled with the other modes. The vibrational frequencies show the variation in going from one low energy conformer to another for a few modes of the allyl moiety (Table S3). (30) The phenyl ring moiety consists of three parts: (i) phenyl ring, (ii) C-H bonds, and (iii) 2 C-O(CH 3 ) and C-C(H 2 CHCH 2 ) bonds. The assignments for these three parts are discussed separately in the following three sub-sections.

Phenyl Moiety Modes
Phenyl Ring Modes (12) The magnitudes of the ring stretching modes 8a, 8b, 19a, and 19b are found to be similar to those for the estragole, eugenol, and ME molecules. For the ME molecule, these modes were computed to be 1600, 1581, 1507, and 1407 cm −1 with the respective observed frequencies 1605(IR, w)/1604(R, s), 1591(IR, m)/1591(R, m), 1514(IR, s)/1511(R, m), and 1418(IR, m)/1412(R, w) cm −1 . Kekule ring stretching mode 14 shows variation and is found to have frequencies of 1325, 1367, and 1340 cm −1 for the estragole, eugenol, and ME molecules, respectively. The ring breathing mode 1 is computed to be 765 cm −1 with the observed frequency 766 cm −1 in both the IR and Raman spectra with good intensities. The present assignments are in agreement with the corresponding assignment made by Chowdhry et al. [17] for the ME molecule.
For the ME molecule, the modes 4, 16a, and 16b are computed to be 728, 748, and 463 cm −1 , respectively, with the observed frequencies of 724(IR)/722(R), 748(IR)/745(R), and 460(IR/461(R) cm −1 . The assignments for the modes 4 and 16b are in agreement with eugenol; however, the mode 16a is found to have a higher frequency (748 cm −1 ) compared to eugenol (597 cm −1 ). The modes 6a, 6b, and 12 are computed to have frequencies of 473, 534, and 642 cm −1 , respectively, with the corresponding observed frequencies of 483(IR)/473(R), 542(IR)/547(R), and 646(IR)/647(R) cm −1 . Mode 12 is found to involve two frequencies: 1028 and 642 cm −1 . The higher frequency also involves the O-CH 3 stretching of both the methoxy groups and is more suitable for the opc O-CH 3 stretching mode. Therefore, the lower frequency is assigned to mode 12 of ME. Mode 12 is found to be lower (645 cm −1 ) in ME as compared (743 cm −1 ) to the eugenol molecule. For the other two modes, the present assignments agree with those of the eugenol molecule. (9) The computed stretching frequencies for the three C-H bonds C 5 -H 10 , C 2 -H 7 , and C 6 -H 11 are 3063, 3056, and 3026 cm −1 , respectively, with the observed frequencies of 3061(IR), 3049(R), and 3037(R) cm −1 , respectively. The highest frequency β(C-H) mode is computed to be 1269 cm −1 and is not observed in both the IR and Raman spectra and corresponds to the mode 3 of benzene. The computed frequencies 1149 and 1134 cm −1 result due to the two β(C-H) modes assigned to the observed frequencies 1153(IR)/1152(R) and 1122(R) cm −1 , respectively. Both these frequencies are found to couple with other modes. The frequency 1149 cm −1 is found to couple strongly with the mode ν(C 1 -C 12 ) and weakly with the modes ν(C-O) and ν(O-CH 3 ) of both the methoxy groups.

C-H Modes
The computed frequencies for the three γ(C-H) modes are 903, 851, and 800 cm −1 , the latter two being observed at 850(IR)/853(R) and 806(IR)/805(R) cm −1 having weak Raman and medium IR intensities. The highest/lowest γ(C-H) mode arises due to the opc/ipc of the C-H bending motions at the positions C 5 and C 6 with a small contribution from the ring deformation modes. The remaining γ(C-H) mode arises due to non-planar bending of the C 3 -H bond. The present assignments of the modes ν(C-H), β(C-H), and γ(C-H) are supported by the assignments proposed by Chowdhry et al. [17] for ME.
C-O(CH 3 ) and C-C(H 2 CHCH 2 ) Group Modes (9) The two ν(C-O(CH 3 )) modes are computed to be 1231 and 1255 cm −1 . These modes are coupled with each other as well as with the ring modes. The frequencies 1231 and 1255 cm −1 arise due to the opc and ipc of the stretching motions of the C-OCH 3 bonds of both the methoxy groups and are observed at 1235(R) and 1260(IR)/1259(R) cm −1 , respectively. The frequency 1231 cm −1 arises due to the ipc of the modes ν(C 3 -O(CH 3 )) and ν(C 4 -O(CH 3 )) with the contributions 9% and 24%, respectively, whereas the frequency 1255 cm −1 arises due to the opc of the same modes with the contributions 16% and 11%, respectively. The assignments for these modes are in agreement with the assignments reported by Chowdhry et al. [17] for ME. The ν(C 1 -C 12 ) mode is calculated to be 928 cm −1 and could not observed in both the IR and Raman spectra of ME. The assignment of this mode is in agreement with the assignment for this mode in estragole [20]. The β(C 1 -C 12 ) and γ(C 1 -C 12 ) modes are computed to be 345 and 122 cm −1 , respectively, and lie outside the investigated IR range and could not be observed in Raman spectrum. The planar and non-planar bending modes for both the C-O(CH 3 ) groups attached to the sites C 3 and C 4 are computed to be 354/185 and 204/166 cm −1 with the corresponding observed frequencies of 361/196 and -/170 cm −1 .
For the C-C(H 2 CHCH 2 ) bond, the ν(C-C(H 2 CHCH 2 )) mode is computed to be 939 cm −1 . From the PEDs, this mode is found to couple strongly with the modes of the allyl moiety and trigonal ring deformation mode 12. The planar and non-planar bending modes are computed to be 291 and 174 cm −1 and observed at 300 and 179 cm −1 , respectively, in the Raman spectrum. The assignments of these modes are in agreement with the assignments of the corresponding modes for the estragole molecule [20].

Conformer Dependent Modes
The computed IR and Raman spectra for the three lower energy conformers are shown in Figure S4. The corresponding computed frequencies for the conformers C-I and C-II are very close to each other. However, the conformer C-III has 15 fundamental modes with computed frequencies having difference greater than 10 cm −1 as compared with the corresponding modes of the conformers C-I/C-II. Only two of these modes are observed separately, while the remaining 13 cannot be observed for C-III. These two modes are the α(C 14 -C 15 =C 17 ) and α(R)-6a, which could be correlated to the observed frequencies 420 and 553 cm −1 , respectively, for the conformer C-III. These two modes were observed at 403 and 542(IR)/538(R) cm −1 for the conformers C-I/C-II. The frequencies 420 and 553 cm −1 correlated to the C-III modes could also be interpreted as a combination (165 + 250 = 415 cm −1 ) and overtone (2 * 279 cm −1 ) bands of the conformer C-I. Thus, the entire experimental IR and Raman spectra could be explained in terms of the computed IR and Raman spectra of the lowest energy conformer C-I.

Solvent Effects
The two solvents water and ethanol are found to have almost same influence on different molecular properties. In the presence of water and ethanol as solvents, the geometrical parameters do not change as compared to their gas phase structure, excepting the parameters related to the two C-OCH 3 moieties. For each OCH 3 group, the bond lengths C-O and O-CH 3 were found to be increased by 0.003 and 0.008 Å, respectively, relative to the gas phase values. The angles of the CH 3 moieties are found to show variations in the range 0.2-0.4 • . The magnitudes of APT charges at different sites are found to enhance significantly in several cases, the largest enhancement being at the sites of the twp O atoms. The sites of the H-atoms are found to show minimum enhancement. The computed IR and Raman spectra for the lowest energy conformer C-I in gas phase and solvent medium are shown in Figure 4. The computed vibrational frequencies and related parameters in gas and solvent medium are listed in Table 6. This table shows that the major of the modes show a change in frequencies. Out of 75 modes, 3 modes-τ(C 1 -C 12 Figure 5. (a-c) MEP plots of the three lower energy conformers of ME.

MEP Plots
Molecular electrostatic potential (MEP) plot is helpful in locating the active sites near the molecule [22][23][24]. The MEP plots for the first three lower energy conformers are depicted in Figure 5. The blue color represents the highest positive charge density and the red color represents the highest negative charge density. The blue color is the most suitable site for the nucleophilic substitution and the red color is the most suitable site for the electrophilic substitution. For the ME molecule, the red color is spread between the O atoms of both methoxy moieties. The light green color is spread near the H atoms of both methoxy groups. Thus, the strong electrophilic substitution would take place in the proximity of the O atoms of the OCH 3 groups. The proximity of the H atoms of the methoxy moieties is suitable for a weak nucleophilic substitution ( Figure 5).

HOMO-LUMO Plots
Energies of HOMO (E H ) and LUMO (E L ) are used to estimate the chemical parameters like chemical softness, ionization potential, electron affinity, and electrophilicity index, etc. The energies (-E H ), (-E L ) and their gap (E H -E L ) represent the ionization potential, electron affinity, and chemical hardness, respectively [25][26][27][28][29]. The magnitude of the energy gap (E H -E L ) gives the reactive behavior of the molecule. The HOMO-LUMO plot of the ME molecule is given in Figure 6. The E H , E L , and E H -E L and the calculated parameters from these are given in Table 7. The value of E H -E L suggests that the molecule is chemically soft in nature. From the HOMO plot, it could be seen that the electron density is delocalized mainly over the phenyl ring and O atoms of the OCH 3 groups. However, in the LUMO, the charge density is shifted from the methoxy moieties towards the allyl moiety.
Molecules 2023, 28, x FOR PEER REVIEW 15 of 19 from these are given in Table 7. The value of EH-EL suggests that the molecule is chemically soft in nature. From the HOMO plot, it could be seen that the electron density is delocalized mainly over the phenyl ring and O atoms of the OCH3 groups. However, in the LUMO, the charge density is shifted from the methoxy moieties towards the allyl moiety.  The computed and observed UV-vis spectra of ME are shown in Figure 7. The computed peak positions, related quantities, the possible transitions for the computed peaks and the observed peaks are listed in Table 8. The contribution of the HOMO → LUMO + 3 transition to the computed peak 248 nm is 45%. This computed peak could be correlated with the observed peak 265 nm. The remaining two computed peaks 223 and 220 nm have major contributions from the transitions HOMO → LUMO+1 and HOMO → LUMO + 10 and appear to merge into a single band with peak at 222 nm which correspond to the observed band with peak at 219 nm.  The computed and observed UV-vis spectra of ME are shown in Figure 7. The computed peak positions, related quantities, the possible transitions for the computed peaks and the observed peaks are listed in Table 8. The contribution of the HOMO → LUMO + 3 transition to the computed peak 248 nm is 45%. This computed peak could be correlated with the observed peak 265 nm. The remaining two computed peaks 223 and 220 nm have major contributions from the transitions HOMO → LUMO + 1 and HOMO → LUMO + 10 and appear to merge into a single band with peak at 222 nm which correspond to the observed band with peak at 219 nm.   Figure 7. Observed and computed UV-vis spectra of ME. Table 8. UV-vis absorption bands and the corresponding transitions for ME.