Neurohormone melatonin has become a popular dietary supplement because it is a potent antioxidant, immune-active agent, and mitochondrial regulator and establishes healthy sleep. Melatonin could have many shared underlying mechanisms that can modulate and control the immune and oxidative response against COVID-19 infection. Despite its essential biological roles, a high-level ab initio conformational study has yet to be conducted more precisely on its most favored structural forms. We presented the conformational preferences of the five lowest energy structures of neutral melatonin derived from the First Principle Møller–Plesset Second-Order Perturbation Theory (MP2) and Density Functional Theory (DFT) ( M06-2X, and ωB97X-D) calculations that validated, Gauche-phenyl conformation (C), Gph (trans-in)/anti, as the most favored form, following experimental rotationally resolved spectroscopy and in contrast of two-photon IR and UV spectroscopy.[7, 25] The DFT-B3LYP evaluation of harmonic wave numbers allows us to make more precise vibrational assignments. Melatonin's ‘most remarkable’ fingerprint IR and Raman spectroscopic signatures were identified at 1212 and 1358 cm-1, respectively. The cis amide NH stretch frequency is lower than the trans amide counterpart. The CH2(α) and CH2(β) symmetric stretch vibrations have exhibited significant IR intensity and high Raman activity. Time-Dependent DFT calculations predict that the second-lowest excited state 1La (1ππ*) of Melatonin C is about 2129 cm-1 above the lowest excited 1Lb (1ππ*) state, and both states display a redshift on bulk hydration (mimicked by a polarizable continuum solvent model). Based on melatonin's prominent intrinsic vibrations/electronic excitations, the spectroscopic signatures can identify and distinguish from closely related indolic molecules.
Research Article
Spectroscopic signatures and conformational preferences in isolated melatonin: a computational study.
https://doi.org/10.21203/rs.3.rs-3210774/v1
This work is licensed under a CC BY 4.0 License
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Melatonin (N-acetyl-5-methoxy tryptamine)
MP2 and DFT calculations
Most favored structures
Infrared and Raman frequencies
TDDFT Vertical excitation energies
Melatonin (N-acetyl-5-methoxytriptamine) is a tryptophan-derived substituted indoleamine that appeared early during evolution, is extensive among living organisms, and involves multiple biological, hormonal, and physiological processes.[1, 2] It is a ubiquitous hormone initially extracted from the cow pineal gland in 1958 by Aaron B Lerner and his group in a remarkable attempt to characterize a skin lightening in amphibians after initial observations made by McCord and Allen in 1917.[1–4] Melatonin is a potent natural antioxidant, free radical scavenger,and light-sensitive hormone and controls several physiological processes, including the body's circadian rhythms and cardiovascular systems functions. [2–22] It is involved in the sleep-wake cycle and cell regulation and alleviates oxidative stress-induced degenerative diseases. [2, 5–18, 20–22] Melatonin is converted first from the amino acid tryptophan into serotonin, followed by acetylation via arylalkylamine N-acetyltransferase, and second, conversion to melatonin by hydroxy indole-O-methyl transferase.[5, 21] This molecule shares the core structure of serotonin (Fig. 1) and influences the immune and nervous systems. [21]
Oxidative stress is critical in the pathogenesis of aging and several diseases, such as cancer, cardiovascular disorders, atherosclerosis, and neurological disorders; therefore, an effective antioxidant therapy would be vital in these circumstances.[2,5−20] Melatonin effectively reduces oxidative cellular and molecular damage, reducing neuro-inflammation and treating neurological diseases. [20, 21] Its physiological processes exhibit antitumor, anti-diabetic, and anti-aging actions, prevention of a gain of body weight and fat depot mass, and anticancer effects by modulating the immune system. [10, 11, 15, 16, 18, 19, 21] Substantial research has defined melatonin as a remarkable molecule with pleiotropic effects on the immune system. [21, 22] Melatonin and its derivatives act as natural electron donors, highly efficient against oxidative stress; electron transfer and hydrogen transfer are the main mechanisms involved in the reactions of melatonin with free radicals (able to quench hydroxy and other radicals efficiently). [8–11] It induces significant changes in different immune cell proportions, enriches their viability, and remediates immune cell metabolism.[21] According to various experimental studies, melatonin possesses essential functions as an antiviral, antibiotic, anti-inflammatory, and anti-parasitic molecule; it reduces the level of pro-inflammatory cytokines, and this effect, therefore, could block the entry of SARS-CoV-2 into human cells.[17, 23, 24] The combined supplementation of vitamin D with melatonin could offer an attractive synergistic alternative for preventing and treating pulmonary infection by COVID-19.[17,23,24 ]
Melatonin is present in bacteria, unicellular eukaryotic organisms, invertebrates and vertebrates, algae, medicinal and food plants, fungi, and multiple edibles, such as vegetables, fruits, herbs, and seeds. [2, 16, 18] The plant's Mitochondria and chloroplasts are significant sources of the highest level of melatonin synthesis. [2] Dietary melatonin derived from plants may be an excellent supplementary source of antioxidants for animals. [2] It greatly maximizes the health-promoting effects of medicinal plants and healthy human foods. [2,16] The structure and biological function of Melatonin (N-acetyl-5-methoxytryptamine) has now become an exciting subject of research due to the pharmaceutical activities necessary for human life and particularly to the interest in immune health prompted by the COVID-19 pandemic and its lasting effects on mental health and sleep disturbances.[16, 17, 23, 24] Its physiological action, responsible for the pleiotropic effects, strongly depends on the interaction with specific receptors, binding to high-affinity G-protein-coupled receptors at the membrane level. [6] Therefore exact knowledge of the most favored form of structure of melatonin is crucial for performing and understanding experiments on structure-affinity relationships. Melatonin (NA-5-MT) molecule (See Fig. 1) has been subjected to several experimental and computational investigations regarding its conformational structures and spectroscopic properties. [25–35] It contains a single methyl-caped amide group and possesses two flexible side chains: the N-acetyl ethylamine side-chain at the 3-position on indole and the methoxy group at the 5-position. The conformational flexibility of the N-acetyl-ethylamine side chain in NA-5-MT plays an essential role in its binding to receptor sites. Spectroscopy is a powerful tool for providing characteristic signatures of molecules susceptible to their structure, and such signatures are isomer-specific. If more than one isomer is present in a mixture, the spectral signatures of the different isomers may overlap in the observed spectrum, preventing unambiguous spectral assignments. Spectroscopic signatures of isolated bio-molecules may provide insight into their preferred conformations, dynamical flexibility, and inter-and intra- molecular interactions determining their skeletal structures. Florio et al. [25] reported the conformational preferences of the isolated melatonin by studying the experimental infrared and ultraviolet spectra of individual conformations under jet-cooled conditions. They have observed five conformational isomers of isolated melatonin. [25] These five conformational isomers of melatonin can be classified into two families: trans-amide (three dominant conformers A, B, and C) and cis-amide (two minor conformers, D and E). There is a strong, energetic preference for trans amide over cis-amide conformation, with about 3 kcal/mole being more stable than the latter.[25] In all five conformers, the indole NH stretch fundamental appears very close to the corresponding mode frequency of bare indole, indicating that this fundamental is not sensitive to the conformations of the side chains. [25] Dian et al. [26] studied melatonin's infrared-induced conformational isomerization and vibrational dynamics using IR-UV hole-filling spectroscopy and IR-induced population transfer spectroscopy. Several other groups [7,12,15,27−35] reported IR, electronic spectroscopy, structural properties, and quantum chemical calculations for melatonin. Vasilescu and Broch [27] reported four minimal energy conformations of melatonin from ab initio and semi-empirical quantum computations. Conformational studies of the molecule using PM3, AM1, and wave-function-based methods have also been reported. [28–33] Bayard and Ide [32] reported its infrared spectrum. Gunasekaran et al. [15] computed the infrared absorption spectrum and calculated electronic excitations of melatonin using density functional theory (DFT). A comprehensive study of the conformational space of melatonin by Fogueri et al. [33] has also appeared in the literature. Singh et al. [12] recorded and studied melatonin's conventional infrared absorption spectra, Raman spectra, and UV-VIS spectra of melatonin in water in the 200–800 nm wavelength region. Further, they optimized the molecular structure of the three conformers of melatonin within density functional theory calculations and presented vibrational assignment and a few electronic excitations employing the DFT structures.The gas-phase photoelectron spectroscopic study of the neutral melatonin [35] found that the π- π and n- π orbital interactions depend strongly on its conformations. [9, 16] Fougueri et al. [33] have obtained reference quality conformational energies for the 52 unique conformers of melatonin, optimized with spin-component scaled MP2 method to assess the performance of ab initio and various DFT methods with and without empirical dispersion corrections. Basis set convergence is relatively slow due to internal C-H…O and C-H…N contacts. However, they probably did not precisely discuss experimental gas phase spectroscopy results regarding the energetic order of melatonin's lowest energy structures. Rotationally resolved electronic spectra of melatonin reported by Yi et al. [7] provide accurate ground state rotational constants for the most highly populated conformers of melatonin. The experimental rotationally resolved electronic spectra[7] have characterized the two lowest energy conformers, Gph(trans-in)/anti and Anti(trans-out)/anti. The Gph(trans-in)/anti was found to be the most stable conformer, followed by Anti(trans-out)/anti, [7] which was in contrast to the resonance-enhanced two-photon ionization (R2PI) and UV-UV hole burning (UVHB) spectroscopy results. [7, 25] The conformational preferences of melatonin reported by the group of Zwier [25, 26] and Yi et al. [7] were different. Unfortunately, while several experimental results were obtained for melatonin, none of the few computational papers consider employing the Moller-Plesset perturbation theory method using a modest/ higher basis set, which reliably accounts for dispersion interaction. The Second-order Moller-Plesset perturbation theory (MP2) offers a better approach for describing non-covalent interactions since it can be extended to much larger systems [36]. In the present work, we have optimized the geometries of the five experimentally observed conformers of neutral Melatonin by MP2 [36], Density functional theory with B3LYP [37–40], and M06-2X [40,41−43] and ωB97X-D [44, 45] employing the basis sets 6-311 + + G(d,p). The vibrational fundamentals of the observed five lowest energy conformers, determined from density functional theory calculations [37–40], invoking 6-311 + + G(2d, 2p) basis sets have systematically aided the interpretation of experimental IR and Raman spectra, and many previous incomplete and ambiguous assignments are analyzed and amended. The electronic absorption spectra were analyzed and re-assigned with Time-Dependent Density Functional Theory (TD-DFT) calculations. [46]
All the Electronic structure calculations for melatonin were carried out using Gaussian 09 rev. C01. [40] The Hartree-Fock method calculation has been carried out for initial structural optimization of experimentally observed ground state lowest energy melatonin conformers. Finally, the full optimization was performed employing the second-order Moller-Plesset (MP2) perturbation theory [36,40] and the density functional theory (DFT) calculations. [37–45] DFT calculations using Becke's three-parameter hybrid exchange functional (B3) [37, 38] with correlation functions such as one proposed by Lee, Yang, and Parr (LYP), [39] long-range corrected (LC) hybrid density functional with empirical dispersion corrections, wB97X-D and M06-2X exchange-correlation functional were performed. [41–45] For non-covalent systems, LC hybrid DFT-D functional, wB97X-D has shown generally satisfactory performance on an extensive basis set and a slight improvement over other empirical dispersion-corrected density functionals, where non-covalent interactions are expected to be significant. [41–45] The highly parameterized functional M06-2X, developed by Zhao and Truhlar, [41–43] has been shown to describe non-covalent interactions better than density functionals, which are currently in frequent use. Computations are performed with molecular geometry without symmetry restrictions, and all optimized structures were verified to ensure no imaginary frequency was present. Finally, 6-311 + + G(d, p) and 6-311 + + G(2d, 2p) basis sets were employed in the geometry optimization and harmonic wavenumbers calculations of melatonin conformers. All harmonic frequencies were obtained at the B3LYP/6-311 + + G(2d, 2p) level. The computed DFT harmonic frequencies were scaled by 0.977 and 0.9614 factors for NH and CH stretch fundamentals, respectively, to compare with experimental results. The Ionization potential of the different conformers of melatonin was computed with complete optimization at the M06-2X/6-311 + + G(d, p) level of theory without symmetry constraints. TD-DFT-B3LYP computation [46] employing the 6-311 + + G(d, p) basis set was performed to predict the electronic absorption wavelengths of the observed conformers of neutral melatonin. The electronic absorption spectra in aqueous solutions have also been calculated using the polarizable continuum (PCM) solvent models [47] using the same TDDFT-B3LYP method. [46, 47]
3.1 Optimized Geometries of Melatonin Conformers:
The melatonin (N-acetyl-5-methoxytriptamine) molecule (Fig. 1) contains four subunits methoxy group, an indole unit, a methylene unit, and an amide group. [7,25,26,33 ] It has two crucial functional groups that determine its specificity and amphiphilicity: the 5-methoxy group and the N-acetyl side chain (containing methylene and amide groups). The conformational flexibility of melatonin mainly arises from rotations of methoxy and the N-acetyl groups. The nomenclature for the melatonin conformers follows Florio et al. [25] For all experimentally observed conformers of melatonin, the N-acetyl side chain is perpendicular to the aromatic plane, which results in three possible conformations of the amide group: gauche to the pyrrole ring (Gpy), gauche position to the phenyl moiety (Gph) or pointing away from the indole chromophore (Anti).
The trans and cis refer to the anti and parallel orientation of NH and OH in the structure of the amide group. The anti or syn refers to the directions of the methoxy group pointing away or towards the indole NH. [7, 25] The 'in' or 'out' refers to whether the amide NH is pointed towards or away from the indole ring. [7] The geometry of experimentally observed [7, 25] three trans-amide structures, Gpy(trans-in)/anti (A), Anti (trans-out)/anti ( B), Gph(trans-in)/anti ( C) ]and the two cis-amide conformers [Gph(cis-in)/anti (D), Gpy(cis-out)/anti ( E)] of neutral Melatonin (See Fig. 2) were optimized using MP2 and DFT methods, employing the basis set 6-311 + + G(d, p). Table 1 lists the ZPE-corrected relative energies and the dipole moments of these five lowest energy conformers at the MP2 and DFT (M06-2X, ωB97X-D, and B3LYP) levels of theory, respectively, employing the basis set 6-311 + + G(d,p). The corresponding relative energies without ZPE correction are in Table S1 of ESI. Selected structural parameters of five experimentally observed conformers of melatonin computed at the MP2/6-311 + + G(d,p) level of theory are in Table S2 of ESI.
Table 1a Relative energies [Erel (kJ mol-1)] and dipole moments (Debye) in parenthesis of the five experimentally observed conformers of melatonin computed with basis set 6-311++G(d,p).
Table 1b Relative zero-point corrected energies (kJ mol-1) and dipole moments (Debye) in parenthesis of the five observed conformers of melatonin with basis set 6-311++G(d,p).
Present calculations confirm that the trans amide structures are preferred over cis-amide since it is evident that the anti(OH)-conformers are always more stable in the electronic ground state and less stable in the electronically excited state.[48] The trans amide conformer, Gph(trans-in)/anti (C), was found to be the global minimum at the MP2/6-311 + + G(d, p) level of theory, and the Gpy(trans-in)/anti (A) and Anti(trans-out)/anti (B) structures are slightly higher in energy at 7.89 and 10.42 kJ mol-1 respectively (See Fig. 2). The conformer C was also found to be most stable at the M06-2X/6-311 + + G(d, p) and ωB97X-D levels of theory. The present result is in accord with the experimental rotationally resolved electronic spectroscopy of melatonin [7], in which the Gph(trans-in)/anti (C) was found to be abundant. However, Florio et al. [25] have reported that the three trans-amide A, B, and C structures are more abundant with some preferences for Gpy(trans-in)/anti (A) and Anti(trans-out)/anti (B) structure over the Gph(trans-in)/anti (C) structure. Their DFT-B3LYP optimization yields, the Anti(trans-out)/anti (B) structure as the global minimum and the Gpy(trans-in)/anti (A) and Gph (trans-in)/anti (C) structures are slightly higher in energy at 0.30 and 0.69 kcal mol-1 respectively. Due to a lack of dispersion, the conventional DFT functional may not accurately involve the issues of intra-molecular non-covalent interactions of the flexible bio-molecules. In fact, the relative stabilities of flexible bio-molecule conformers may change from MP2 to the conventional DFT-B3LYP [50], so the relative energy of the isomer A is computed higher by 5.87 kJ mol-1 at the MP2/6-311 + + G(d, p) level than B3LYP/6-311 + + G(d,p) level. This may arise due to the inability of the B3LYP-functional to describe the dispersion energy quantitatively (See Figure S1 of ESI). Our MP2, M06-2X, and ωB97X-D results and the Yi et al. CC2 result [7] preferentially stabilizes the conformer C relative to A and B. Possibly since, in structure C, the oxygen lone pair is oriented away from the indole ring (See Fig. 1), and the CH3 and the amide N-H hydrogens are directed toward the π-cloud of indole moiety, providing additional stabilization ((See Figure S1 of ESI)). Like in melatonin, also for serotonin, our previous MP2 and CC2 calculations predict the Gph(out)/anti as the ground state lowest energy conformer. We have reported such correction in the energetic order for the lowest energy conformers of serotonin of the same laser spectroscopy group, [49, 50] which resembles, more precisely, serotonin rotational spectroscopy results. [48] Indeed, the stabilization of the Gph(trans-in)/anti-conformer C, at first, can be attributed to an electronic effect associated specifically with methyl (CH3) orientation, which does not occur for the other experimentally observed conformers. Secondly, in Gph(out) conformers of melatonin, like serotonin, additional internal hydrogen bonds are formed between the NH group's hydrogen and phenyl (Gph) π-cloud as well as due to CaromaticH···X interactions. [33] The increase of electron density at the C4 atom (of conformer C) increases the polarity of the CH-bond, which activates it for hydrogen bond formation.[48]The conformer Anti (trans-out)/anti (B) was found to be the second most stable at the M06-2X and ωB97X-D levels of the theory, which is also in agreement with Yi et al. [9] but is in contrast to present MP2 result (See Table 1). As seen in Table 1, the relative stability order of the conformers at the MP2 level, C > A > B > E > D, changes when going to M06-2X and ωB97X-D levels, C > B > A > D > E and to B3LYP level, B > A > C > D > E. The relative energy between the most stable and the least stable, experimentally observed conformers of melatonin also shows variations at different levels of theory [See Table 1].
The vertical and adiabatic ionization energies for the lowest energy structure A of the neutral Melatonin are found to be 7.36 and 7.76 eV, respectively, and for isomer C, these values are computed at 7.24 and 7.64 eV, respectively, at the M06/6-311 + + G(d,p) level of theory. These values for all five conformers are listed in Table S2 of ESI and in accordance with the experiment. [7, 25] The rotational constants and zero-point vibrational energy of the five observed conformers of melatonin are listed in Table 2. The values of the rotational constants in Table 2 allow us to classify the rotamers of melatonin as belonging to different families. Conformers of the same family have similar mass distributions, so their rotational constants are very similar. The first comparison of these predicted values of rotational constants given in Table 2 with those experimentally observed allows us to classify the observed rotamers as belonging to Gph/anti (C) and Gpy/anti (A) family, which is in consonance to results of Yi et al. [7] Table 2 displays that the rotational constants for the conformers Gph(trans-in)/anti (C) and Gph(cis-in)/anti (D) are very similar and belong to a 'Gph/anti' family. Whereas the rotational constants for Gpy(trans-in)/anti (A) and Gpy(cis-out)/anti (E) are very similar and belong to Gpy/anti-family. The NBO calculations at the MP2/6-311 + + G(d, p) level of theory led to negative charge densities of -0.725, -0.749, and − 0.626 (in melatonin C); -0.722, -0.740, and − 0.622 (in melatonin A) and − 0.716, -0.758, and − 0.627 ( in melatonin B) on amino N12, acetyl O1, and O5 (of methoxy) atoms, respectively (See Table 3). The negative charge densities on the N1 atom (indole NH) are also significant but insignificant as on the amino nitrogen atom.
|
Conf. A |
Conf. B |
Conf. C |
Conf. D |
Conf. E |
|
|---|---|---|---|---|---|
|
A(GHz) |
0.7936939 |
0.6262663 0.62762 b |
0.5550090 0.54199 b |
0.5627744 |
0.7842668 |
|
B(GHz) |
0.2939962 |
0.3327072 0.32750 b |
0.4840174 0.48703 b |
0.4337860 |
0.3123112 |
|
C(GHz) |
0.2515834 |
0.2232223 0.22141 b |
0.3074987 0.31226 b |
0.2626620 |
0.2754496 |
|
ZPVEc |
171.38000 |
171.42630 |
171.76792 |
171.69860 |
171.56710 |
| b Corresponding experimental values taken from the ref. [7]. c values obtained at | |||||
| B3LYP/6-311 + + G(d,p) level using MP2/6-311 + + G(d,p) level optimized geometries. | |||||
|
atom number a |
NBO Charge |
||||
|---|---|---|---|---|---|
|
Conf. A |
Conf. B |
Conf. C |
Conf. D |
Conf. E |
|
|
N1 |
-0.618 |
-0.618 |
-0.616 |
-0.613 |
-0.610 |
|
C2 |
0.061 |
0.058 |
0.051 |
0.061 |
0.080 |
|
C3 |
-0.135 |
-0.130 |
-0.128 |
-0.143 |
-0.154 |
|
C4 |
-0.287 |
-0.289 |
-0.292 |
-0.282 |
-0.287 |
|
C5 |
0.358 |
0.356 |
0.352 |
0.365 |
0.360 |
|
O5 |
-0.622 |
-0.627 |
-0.626 |
-0.625 |
-0.622 |
|
C6 |
-0.234 |
-0.229 |
-0.232 |
-0.226 |
-0.234 |
|
C7 |
-0.190 |
-0.199 |
-0.195 |
-0.196 |
-0.187 |
|
C8 |
0.155 |
0.158 |
0.155 |
0.156 |
0.152 |
|
C9 |
-0.072 |
-0.077 |
-0.079 |
-0.083 |
-0.081 |
|
C10 |
-0.135 |
-0.349 |
-0.359 |
-0.348 |
-0.349 |
|
C11 |
-0.099 |
-0.103 |
-0.091 |
-0.093 |
-0.095 |
|
N12 |
-0.722 |
-0.716 |
-0.725 |
-0.730 |
-0.726 |
|
C13 |
0.834 |
0.835 |
0.840 |
0.835 |
0.844 |
|
O13 |
-0.740 |
-0.758 |
-0.749 |
-0.740 |
-0.739 |
|
C14 |
-0.598 |
-0.594 |
-0.608 |
-0.610 |
-0.618 |
|
C15 |
-0.100 |
-0.102 |
-0.104 |
-0.114 |
-0.100 |
| a See Fig. 1 for the atom numbering. | |||||
3.2 Vibrational spectra:
Vibrational spectra can provide a more direct and sensitive probe of flexible bio-molecule conformations. Experimental wave numbers obtained from the gas phase IR spectra [25] and conventional IR and Raman spectra [12, 15, 32] are compared with the corresponding computed vibrational fundamentals of the five experimentally observed structures of neutral melatonin. Ab initio harmonic wave number values are typically higher than the corresponding experimental vibrational frequencies. The disagreement in this region is partly due to a large anharmonicity of NH and CH-stretching vibrations. The DFT values at the basis set 6-311 + + G(2d, 2p) better agree with the experimental values. The B3LYP wave numbers are close compared to the M06-2X wave numbers with the experimental values. A scaling factor (0.9614) for the predicted vibrational wave numbers in the NH stretching region was necessary to agree with the experimental values. The predicted IR intensities also agreed with the experiment for most of the vibrational fundamentals. The unscaled computed harmonic wave numbers and relative IR intensities at the DFT-B3LYP/6-311 + + G(2d,2p) level are shown in Fig. 3. The computed frequencies, intensities, and approximate description of vibration of selected fundamentals, including all the hydride stretch fundamentals are given in Table 4.
|
Approximate descriptions of vibrations |
Conformer A |
Conformer B
|
Conformer C
|
Conformer D
|
Conformer E
|
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
freq |
IR int |
Raman activity |
freq |
IR int |
Raman activity |
freq |
IR int |
Raman activity |
freq |
IR int |
Raman activity |
freq |
IR int |
Raman activity |
|
|
Indole NH str. |
3523 3522a |
74 |
144 |
3528 3525a |
77 |
174 |
3521 3524a |
75 |
164 |
3525 3523a |
81 |
166 |
3523 3523a |
84 |
129 |
|
Amide NH str. |
3481 3480a |
17 |
44 |
3516 3495a |
24 |
100 |
3490 3482a |
14 |
32 |
3435 3420a |
26 |
63 |
3440 3435a |
16 |
85 |
|
CH str. of pyrrole ring of indole |
3067 |
0 |
88 |
3065 |
1 |
125 |
3063 |
0 |
122 |
3064 |
0 |
120 |
3072 |
0 |
82 |
|
C4-H str. of phenyl ring |
3036 |
5 |
43 |
3028 |
15 |
70 |
3044 |
2 |
31 |
3056 |
2 |
49 |
3030 |
5 |
43 |
|
HCCH (+) str. in phenyl ring |
3028 |
5 |
180 |
3025 |
10 |
209 |
3025 |
6 |
180 |
3027 |
6 |
185 |
3028 |
5 |
180 |
|
HCCH (-) str. in phenyl ring |
3004 |
9 |
94 |
3002 |
9 |
101 |
3003 |
9 |
99 |
3004 |
9 |
104 |
3005 |
7 |
90 |
|
Asym. CH3 str. in acetyl group |
2987 |
9 |
85 |
2977 |
8 |
68 |
2987 |
6 |
51 |
2996 |
6 |
60 |
2991 |
5 |
50 |
|
Asym. CH3 str. in methoxy group |
2984 |
26 |
154 |
2982 |
31 |
141 |
2983 |
27 |
146 |
2986 |
23 |
128 |
2983 |
26 |
154 |
|
Asym. CH3 str. in acetyl group |
2954 |
11 |
35 |
2967 |
12 |
58 |
2951 |
7 |
39 |
2951 |
9 |
37 |
2957 |
4 |
63 |
|
CH2(α) asym. str. |
2951 |
19 |
57 |
2958 |
8 |
26 |
2947 |
14 |
82 |
2940 |
36 |
132 |
2947 |
18 |
25 |
|
CH2(β) asym. str. |
2933 |
5 |
57 |
2900 |
8 |
84 |
2926 |
17 |
64 |
2889 |
6 |
72 |
2900 |
16 |
78 |
|
Asym. CH3 str. in methoxy group |
2912 |
37 |
45 |
2926 |
29 |
37 |
2924 |
27 |
35 |
2937 |
17 |
68 |
2911 |
38 |
44 |
|
CH2(α) sym. str. |
2908 |
33 |
158 |
2913 |
31 |
63 |
2900 |
39 |
166 |
2906 |
52 |
143 |
2885 |
65 |
284 |
|
Sym. CH3 str. in acetyl group |
2898 |
5 |
151 |
2904 |
11 |
187 |
2894 |
7 |
167 |
2898 |
3 |
134 |
2899 |
17 |
183 |
|
CH2(β) sym. str. |
2872 |
34 |
143 |
2871 |
33 |
129 |
2881 |
30 |
142 |
2863 |
28 |
109 |
2866 |
27 |
111 |
|
Sym. CH3 str. in methoxy group |
2862 |
43 |
157 |
2873 |
42 |
180 |
2869 |
38 |
159 |
2865 |
50 |
180 |
2861 |
42 |
151 |
|
C = O str. Amide I) |
1639 1630b |
218 (s) |
10 |
1624 |
228 |
8 |
1633 |
186 |
6 |
1630 |
343 |
9 |
1634 |
345 |
14 |
|
Ring CC str. |
1631* 1619b |
42 (s) |
16 |
1634* |
40 |
13 |
1632* |
42 |
12 |
1632* |
26 |
11 |
1633* |
44 |
13 |
|
C = C str. in benzene ring |
1593* 1586b |
44 (m) |
9 |
1596* |
37 |
17 |
1593* |
39 |
9 |
1593* |
39 |
12 |
1594* |
48 |
8 |
|
C = C str. in pyrrole ring |
1550* |
12 |
65 |
1553* |
6 |
70 |
1546* |
24 |
44 |
1546* |
4 |
69 |
1548* |
2 |
69 |
|
CH2 Wagg O-CH3 str. |
1358 1222 1212b |
4 109 (vs) |
89 24 |
1353 1225 |
11 199 |
33 13 |
1355 1223 |
5 168 |
75 11 |
1357 1226 |
8 147 |
68 15 |
1360 1213 |
3 111 |
74 1 |
| Abbreviations used: s, strong; m, medium; vs very strong; sym., symmetric; asym., asymmetric; str., stretching; | |||||||||||||||
| .a ref. [25], b ref. [12], *unscaled wavenumbers. | |||||||||||||||
3.2.1 Region 4000 − 2000 cm− 1:
The harmonic vibrational frequencies and IR intensities of the five experimentally observed structures of neutral melatonin in this hydride stretch region are in remarkable agreement with corresponding experimental gas-phase IR spectra. [25] The complex vibrational spectra of neutral melatonin in this region can be divided into three groups. These are the heterocyclic indole system, the acetyl ethylamine side chain (or group), and a methoxy group OCH3. The melatonin conformers exhibit two NH stretch fundamentals (the indole NH and amide NH) in the 3400–3600 cm− 1 region and a collection of aromatic, alkyl, and methyl CH stretch fundamentals spread over the region from 2800 to 3100 cm− 1. In all five conformers, the indole NH stretch vibrational fundamental is predicted between 3521 cm− 1 and 3528 cm− 1, which appears very close to its frequency in the indole monomer (3525 cm− 1) and is in excellent agreement with gas-phase RDIR and FDIR spectra.[25] Not surprisingly, this fundamental is not sensitive to the conformations of the side chains of melatonin, as reported earlier. [25] Our calculations predict the amide NH stretch vibrational fundamental at 3481, 3516, 3490, 3438, and 3440 cm− 1 for conformers A, B, C, D, and E, respectively, which is close to the corresponding experimental gas-phase IR frequency 3480, 3495, 3482,3422, and 3435 cm− 1. [25] The predicted amide stretch fundamentals varying between 3438 to 3516 cm− 1 are much more sensitive to a conformational change in melatonin. Florio et al. [25 ] have also suggested that the amide NH stretch frequency, which is most susceptible to melatonin confirmation, will play a vital role in comparing experiments and theory in conformational assignments. The computed shift of the amide N-H stretching mode from the indole N-H stretch mode of the three trans-amide conformers, A, B, and C, indicates that the amide NH stretch mode frequencies of gauche N-acetyl positions, Gph and Gpy, are significantly lower than the corresponding anti position. Because the amide NH is free in the Anti(trans-out)/anti (B) conformer, in contrast, the trans amide gauche structure (A and C) points the amide NH towards the indole π cloud, producing a 42 and 31 cm− 1 computed redshift, respectively, compared to (B) in accordance the gas phase vibrational spectroscopy results.[25] The intensity of the amide NH stretch band is predicted to be lower in contrast to the indole NH stretch band (See Fig. 2), which aligns with the experiment. [25] In the conventional IR spectra, Singh et al. [12] reported the NH amide and NH indole stretching bands at 3280 and 3302 cm− 1 (and Raman bands at 3284 and 3304 cm− 1); large redshift in these observed frequencies may be due to close intermolecular interactions between neighboring melatonin molecules in the condensed phase; as the reported X-Ray spectra have already admitted the involvement of H atoms of two groups in the bonding between melatonin molecules in the solid phase. [34, 35], These bands represent the indole NH and amide NH stretching modes and are significantly red-shifted. Surprisingly Bayari and Ide [32] did not assign indole NH stretch in conventional IR spectra and ascribed a strong band observed at 3298 cm− 1 to amide NH-stretching mode. The strong band observed at 3298/3302 cm− 1 [12, 32] is attributed to be highly red-shifted indole NH fundamental (in condensed phase).
The CH stretch region of melatonin spectra consists of aromatic CH, alkyl CH2, methyl groups, and Fermi resonance with the overtones of lower vibrations.[25,50] The CH stretch region of each conformer of melatonin can serve as a confirming diagnostic of the molecular conformation. The assignment of the vibrations of -CH2 in the observed RIDIR and FDIR spectra was difficult because of the presence of the -CH3 group. [25] However, we have assigned the vibrational fundamentals observed in this region using our precise computed frequencies/intensity by comparing the gas phase spectra of similar molecules serotonin and 5-methoxy indole (See Table 4).[50, 51] The symmetric CH3-stretch fundamental of the methoxy group has the lowest frequency in the CH-stretching region. Its predicted value spreads over 2861–2873 cm− 1 region for the five conformers. The most intense band of the conformer A in the CH stretch region, observed at 2837 cm− 1 [25], was attributed to the symmetric CH3-stretching vibration mode of the methoxy group, as per earlier reports. [25, 51] The Computed IR intensity for this CH stretching mode agrees with the experiment; however, scaled harmonic frequency slightly overestimates the experimental value, probably due to its relatively high anharmonicity. Melatonin A's two "antisymmetric" methyl CH stretch bands are observed at 2912 and 2952 cm− 1. [25] Our calculated asymmetric methoxy methyl stretch frequencies for melatonin A are obtained at 2912 and 2984 cm− 1, respectively. The symmetric CH2(α) and CH2(β) stretching modes are predicted to occur between 2908–2913 cm− 1 and 2861–2881 cm− 1 region, respectively, with a significant IR intensity and high Raman activity for all the five conformers. In serotonin, these modes are reported in the regions 2846–2969 cm− 1 and 2882–2948 cm− 1 for eight experimentally observed conformers. [49, 50 ]Weak spectral features at the corresponding predicted frequencies are seen in the observed spectra of Florio et al. [25] ( shown in Figs. 5 and 6 of ref. 25). However, these authors do not report any band for the symmetric CH2(α) and CH2(β) stretch vibrations. Singh et al. [12] assigned these bands in the conventional IR and Raman spectra of melatonin; however, they have not used the optimized geometries of the experimentally observed lowest energy structures [7] of melatonin. The asymmetric CH2(α) and CH2(β) stretching vibrations are predicted to occur between 2940–2958 cm− 1 and 2889–2933 cm− 1 region, respectively, with relatively weak IR intensity and weak Raman activity, particularly for trans amide conformers. These two modes of vibrations are generally weakly coupled to each other.
The experimental gas-phase spectrum contains a dominant aromatic CH stretch band at 3010 cm-1 ascribable to the aromatic CH-stretch fundamental of the phenyl ring of the indole moiety. The CH-stretching mode of the pyrrole ring of indole was predicted at 3063–3071 cm− 1 with fragile IR intensity. In particular, the CH stretches of the melatonin A, B, and C shares standard features distinct from those of melatonin D and E, See Fig. 3), suggesting that the melatonin A, B, and C conformers have structural similarities not shared by melatonin D and E, as reported earlier.[25]
3.2.2 Region 2000 − 400 cm− 1 :
The vibrational spectral region between 800 and 1700 cm − 1 is mainly characterized by C–C, C–N, C = O stretching, and C–H and N–H bending vibrations. The Raman band celebrated at 1624 cm− 1 [12] also observed at 1624 cm− 1 and 1630 cm− 1 [12] in the conventional IR spectra recorded in KBr pellets, is ascribed to the Amide I (C = O stretching vibration mode) of neutral melatonin (See Fig. 3). As seen in Table 4, this computed C = O stretching (Amide I) fundamental for the conformers A, B, C, D, and E was found to be 1639, 1624, 1633, 1630, and 1634 cm− 1, respectively, is in remarkable agreement with the experiment. [12, 15, 32] The conventional IR spectrum [12] exhibits a strong band at 1554 cm− 1 and a medium-weak band at 1513 cm− 1 in this region, which is assigned to the CC ring and C = C stretching modes, respectively. The intense IR band observed at 1488 cm− 1 is ascribed mainly due to melatonin's Amide II band (amide NH bending mode). In the fingerprint region, the most intense Raman band experimentally observed at 1357 cm− 1 by Singh et al. and others [12, 15] is well identified theoretically for all the five conformers with very high Raman activity. However, the DFT calculations by singh et al. [12] incorrectly predicted Raman activity of this characteristic Raman melatonin peak in contrast to the experiment. This prominent Raman fundamental is ascribed to CH2 wagging vibration and aromatic CH bending. The high IR intensity of an IR band observed at 1212 cm− 1 by many groups is validated by our calculations and attributed to the C-OCH3 stretching mode coupled with ring stretch vibrations. These two prominent Raman and IR bands observed at 1357 and 1212 cm− 1 are validated vibrational spectroscopic signatures of neutral melatonin in the fingerprint region, and their computed frequency and Raman activity/IR intensity corroborate the experiment, as seen in Table 4. The methoxy unit's C–O stretching band coupled to the CH3 rocking motion occurs at 1175 and 1176 cm− 1 in the IR spectrum and Raman spectra, respectively. The IR intensity of this vibrational fundamental slightly decreases for the conformers D and E compared to A, B, and C (See Fig. 3). The observed bands at 796 cm− 1 and 769 cm− 1 in the IR spectra of melatonin [12] are attributed to the CH wagging mode. The CH wagging fundamentals, varying between 770 to 815 cm− 1 for the five conformers, also seem sensitive to conformational changes in melatonin.
3.3 Electronic Spectra and Vertical Electronic Excitation Energies:
The time-dependent formulation of density functional theory [46] yields electronic excitation energies close to the experiment. [25, 26, 12] Therefore, TD-DFT calculations have been again carried out to determine the vertical excitation energies of low-lying excited electronic states of all the melatonin's five conformers, employing a 6-311 + + G(d,p) basis set. As seen in Table 5, Melatonin's TD-DFT vertical electronic excitation energies are in accord with the experiment. [12] It is well known that the excited state dynamics of indole derivatives are described in terms of the low-lying ππ* and nπ* excited states. Much of what we currently know about the photochemistry of the indole derivative is based on the detailed spectroscopic study of its aromatic chromophore indole. It has been established that the 1Lb state is the lowest excited state in the gas phase, while the 1La state becomes the lowest-energy state in polar solvents. Present calculations predicted that the second-lowest singlet excited state is the 1La (1ππ*) state, about 1710, 2807, and 2129 cm− 1 above the 1Lb state for the lowest energy trans conformer A, B, and C, respectively. The difference in energy between 1Lb and 1La excited states of melatonin B is more consistent with the observed electronic absorption spectrum. [12] Based on TD-DFT calculations, the lowest energy singlet excitation can be assigned to S0 - S1 transition from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO) and corresponds to the observed electronic absorption shoulder peak at 301 nm of melatonin. [12] The excitation to the second excited singlet state 1La is mainly HOMO-1→LUMO character and corresponds to the observed intense electronic absorption peak at 278 nm of melatonin. [12]. Zwier's group [25] reported that the S0 → S1 origin transitions of methoxy indole and melatonin are shifted to the red of the indole by 2103 cm-1 and 2400–2800 cm-1, respectively. In a recent report on 5-methoxy indole [51], it was mentioned that the methoxy substituent introduces an additional node in the molecular orbital, which was formerly HOMO-1 in indole, and which becomes HOMO in 5-methoxy indole. This causes a change in energy ordering between indole, 5-methoxy indole, and Melatonin for the HOMO and HOMO-1, respectively, and is responsible for the altered excitation scheme of melatonin compared to indole. So it is clear that the excitation schemes for the 1La and 1Lb states in melatonin differ from those of indole. The presence of the methoxy group at the C5 position is responsible for the dramatic stabilization of the excited electronic state of melatonin concerning that of indole. [25]. The effect of hydration on 1Lb (1ππ*) and 1La (1ππ*) excited states due to the bulk water environment was mimicked by the polarizable continuum solvent model (PCM), which shows the redshift from the gas phase (See Table 5).
|
conformational state |
Experimental gas phase value (0–0 excitations) for 1Lb, a |
Calculated VEE at TD-DFT-B3LYP/6-311 + + G(d,p) level |
|||
|---|---|---|---|---|---|
|
in gas phase
|
in macro hydrated solvation (PCM method)
|
||||
|
1Lb |
1La |
1Lb |
1La |
||
|
Gpy(trans-in)/anti |
4.0436 |
4.343 (0.043) |
4.555 (0.081) |
4.315 (0.051) |
4.536 (0.151) |
|
4.119b |
4.460b |
||||
|
Anti (trans-out)/anti |
4.0445 |
4.301 (0.053) |
4.649 (0.074) |
4.301 (0.066) |
4.548 (0.146) |
|
Gph(trans-in)/anti |
4.0660 |
4.303 (0.052) |
4.567 (0.097) |
4.302 (0.057) |
4.491 (0.123) |
|
Gph(cis-in)/anti |
4.0273 |
4.281 (0.067) |
4.628 (0.0600) |
4.308 (0.066) |
4.528 (0.145) |
|
Gpy(cis-out)/anti |
4.0210 |
4.349 (0.048) |
4.575 (0.101) |
4.315 (0.052) |
4.543 (0.150) |
| a aref. [25]. b ref. [12]. | |||||
It should be noted that the experimentally observed electronic absorption peaks in water [12] are also redshifted compared to the corresponding gas-phase predicted VEE value. The redshift in Lb and La's lowest excited states due to the bulk water environment shows that S0-S1 and S0-S2 electronic transitions increase the strength of binding with water in these states. As seen in Table 5, the oscillator strength of the S0-S2 transition (electronic transition from a ground state to a 1La excited state) is significantly enhanced due to macro solvation with water.
The optimized geometries, harmonic vibrational wavenumbers, IR intensity, and Raman activity of the three most stable trans-amide structures, e.g., Gph(trans-in)/anti (C), Anti(trans-out)/anti (B), Gpy (trans-in)/anti (A) and the two cis-amide conformers, e.g., Gph(cis-in)/anti (D), Gpy(cis-out)/anti (E) of neutral Melatonin were computed by MP2 and DFT (employing M06-2X, ωB97X-D, and B3LYP functionals) methods with basis sets 6-311 + + G(d, p)/6-311 + + G(2d, 2p). The MP2, CC2, and DFT (using M06-2X, ωB97X-D functionals) predict the Gph(trans-in)/anti (C) as the most favored lowest energy structure of the neutral melatonin, following the experimental rotationally resolved electronic spectroscopy. [7] Like in melatonin, also for serotonin, the gauche phenyl conformer Gph(out)/anti was found the lowest energy conformer of serotonin in contrast to IR-UV laser spectroscopy results and resembles experimental rotational spectroscopy. [48–50] The stabilization of the Gph(trans-in)/anti-conformer C can be attributed to an electronic effect associated specifically with methyl (CH3) orientation and additional internal hydrogen bonds formed between the NH -π and to CH···X interactions.
The vertical and adiabatic ionization energies for the lowest energy structure of the neutral melatonin are determined at the M06-2X/6-311 + + G(d, p) level, which agrees with the experiment. The predicted values of rotational constants are found in consonance with the experiment. [7] Vibrational assignments are ascribed to each experimental IR fundamental of the hydride stretch region. Computed harmonic wave numbers and IR intensities were found very close to the corresponding experimental values in most cases. The amide NH stretch, alky CH stretch, and many other fundamentals provide the most apparent basis for distinguishing the five melatonin conformations. The trans-amide conformers' amide NH stretch fundamentals shifted to a higher frequency compared to their cis-amide counterparts. Raman and IR bands observed at 1357 and 1212 cm− 1 of neutral melatonin can provide a spectroscopic signature for melatonin. The second-lowest (singlet) excited state, 1La (1ππ*), was found above the 1Lb state to be the maximum for melatonin B, which agrees with the experiment. The effect of hydration shows the redshift of the vertical excitation energy of the 1Lb (1ππ*) and 1La (1ππ*) excited states.
Acknowledgment:
The authors are grateful to Research Projects [41-880/2012(SR)] of the University Grants Commission, Government of India, New Delhi, for support.
Notes:
The authors declare no competing interest.
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No competing interests reported.