How does the conformational landscape change on substitution in tetralin? A computational investigation with oxygen, sulphur and selenium

How does the conformational landscape change on substitution in tetralin? A computational investigation with oxygen, sulphur and selenium | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article How does the conformational landscape change on substitution in tetralin? A computational investigation with oxygen, sulphur and selenium Asif Iqubal Middya, Abhijit Chakraborty This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6622869/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Jul, 2025 Read the published version in Journal of Molecular Modeling → Version 1 posted 4 You are reading this latest preprint version Abstract Context: The oxygen, sulphur and selenium derivatives of tetralin termed as isochroman (IC), isothiochroman (ITC) and isoselenochroman (ISC) showed interesting conformational pattern. In particular ITC and IC have immense pharmacological significance. The twisted conformer is global minimum in IC, where the bent is a transition state (TS) and remains 1100 ± 100 cm -1 higher. The bent form in ITC and ISC possess the lowest energy. But, the twisted conformer lies higher by about 80 ± 20 cm -1 in ITC and 700 ± 50 cm -1 in ISC. The potential energy surfaces (PES) locate all the conformations and TSs. Molecular electrostatic potentials indicate the sites of electrophilic interactions and the small energy difference between the minima in ITC predict an interesting interplay of intermolecular interactions. The validity of maximum hardness principle and minimum electrophilicity principles are checked. Frontier molecular orbitals show the change in electron densities on excitation, which are mostly p®p * in nature. We suggest some experiments to corroborate our findings. Methods: Computations are performed with different functionals (B3LYP, M06-2X and ωB97X-D) in DFT as well as ab-initio methods (MP2 and CCSD) with 6-311G++ (2d, 3p) [55] and augmented cc-pVDZ as basis sets. Gaussian 09 is used for the above computations. PED analysis was performed by Veda 4 software. Ab-initio Calculations isochroman and isothiochroman Potential energy transition states Hardness and electrophilicity HOMO and LUMO vibrational frequencies Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Introduction The study of the conformational landscapes of a molecule becoming more and more important nowadays as it is a key factor in explaining the biological and pharmacological activities of it [ 1 – 6 ]. These landscapes were investigated both theoretically and experimentally [ 7 – 17 ] over the last couple of years providing us significant information. The pharmacologically important molecules possess an intrinsic floppy nature, which makes the search of their conformations a very challenging one. New methodologies are being developed to tackle these issues [ 18 – 19 ]. Amongst the large number of molecules, 1,2,3,4-tetrahydronaphthalene (THN) or tetralin possess different significance as many of its derivatives are extensively used in this industry. Its nitrogen substituted derivatives tetrahydoquinoline (THQ) and tetrahydroisoquinoline (THIQ) is substantially used in treating Parkinson’s disease [ 20 ] and as analgesic drugs [ 21 ]. On the other hand, THN and its family comprising its various substituted derivatives is also a fascinating object of considerable research from the perspective of their conformational landscape. Extensive high resolution molecular beam experiments by various groups [ 22 , 23 ] confirm that the twisted conformation, generated by the puckering of CH 2 –CH 2 groups is the global minimum. The different theoretical models and computations [ 24 ] also corroborate the experimental observations. Due to increased strain, the bent conformation and the planar form having C s and C 2V symmetries lie much higher in energy and both were confirmed to be a transition state (TS). Our group is engaged in finding the conformational landscape in different substituted derivatives of THN for quite some time. Initially we started with THQ [ 25 ] and THIQ [ 26 ]. The rationale behind this choice is stated earlier. Due to conjugation of the lone pair in THQ, the low energy conformations showed a different pattern than THN. Due to possible change in puckering the two lowest energy conformations were termed as half-twisted structures with the different orientations of the N lone pairs [ 25 , 27 ]. The bent conformations were either a TS or lie higher in energy. The high resolution rotational and vibronic spectra [ 27 ] corroborate the theoretical findings. The THIQ on the other hand displayed an interesting [ 26 ] pattern. We were able to locate a bent conformer as a local minimum apart from the global minimum of the “twisted” structures with different orientations of the lone pairs. The investigations prior to our works on THIQ, did not reveal any such bent conformer and we want to extend this method of conformational search for new as well as some other earlier studied molecules. On the other hand, the sulphur derivatives of benzopyran systems, namely thiochroman is well known for its numerous biological activities [ 28 ]. Vargas et. al. [ 29 ] had studied a large number of thiochroman derivatives and quantitatively identified the cytotoxic activities of them. It was observed that thiochroman and chroman derivatives can be used for treating carcinoma, particularly breast cancer for its enhanced level of antiestrogenic activities [ 30 ]. The growth rate of cancer cells are found to substantially reduce on application of some of the derivatives of these families [ 31 ]. In all these cases thiochroman and isothiochroman were the main precursors. It was also shown clearly that the biological and pharmacological activities are strongly dependent on conformations [ 13 ]. But, unfortunately very few studies were oriented in this direction in these molecules. In this article we will focus on three molecules, isothiochroman, isochroman and isoselenochroman. They are the mono substituted sulphur, oxygen and selenium derivatives of their parent THN molecule. The substitution is done in such a way that the new atom(s) are not in conjugation with the benzene ring. All the computations are performed in their ground states only. The earlier study of isochroman [ 32 ] in molecular beam experiments suggested the “twisted” structure to be the only contributor to all the experimental observations. Single point energy calculations of the assumed “twisted”, “bent” and “Planar” forms indicate the “twisted” form to be more stable by at least 1200 cm -1 with respect to the other two forms. But, there were no PES scan, which should have to be done to understand all the conformers and transition states (TS) of isochroman. It is also need to be mentioned that in THIQ [ 26 ], we observed a variation in computed results with the variation of basis sets. We will also check this issue in this article. To the best of our knowledge, we are yet to find out any work related to the search of all the conformers and transition states of isothiochroman as well as their vibrational characteristics. As the sulphur and oxygen belong to the same group with the former being heavier, we will extend our study to a heavier substituent like selenium in isoselenochroman. Apart from the aspect of locating conformers and TS’s, this article will also try to address the effect of substituents on the conformational landscape of the THN derivatives. The questions this article will try to answer are: 1. How does the substituents affect the conformational pattern in THN derivatives? 2. Whether the atomic weights of the substituents has any influence on this conformational landscape? 3. THN and its symmetrically substituted molecules like 1, 4-benzodioxan (BOD) [ 33 ] and tethydroqinoxaline (THQX) [ 34 ] possess identical symmetry. The three possible structures of THN and BOD molecules are twisted, bent and planar, which possess C 2 , C s and C 2v as its point group symmetry respectively. In THQX, the relative orientations of the H atom of the NH group produced a large number of conformers. All the monosubstituted derivatives lack these symmetry operations and the symmetry group of the conformers are transformed into C 1 , apart from the planar ones (C s ), which are observed to be much higher in energy in chroman [ 35 ], THQ [ 25 , 27 ], THIQ [ 26 ].Whether the relative energies and the nature of the different conformations show any drastic change in this case? The ordering of the stability of the different structures including conformers and transition states can also be assessed by computing some qualitative chemical concepts. This also help in understanding the chemical reactivity of the structures. Electronegativity [ 36 ], hardness [ 37 , 38 ] and electrophilicity [ 39 ] are the ones we will compute. Koopman’s theorem [ 40 ] is used to compute these parameters. The validity of maximum hardness principle (MHP) [ 41 ] and minimum electrophilicity principle (MEP) [ 42 ] will be checkedhere. These principles were found to be valid in a large number of cases, although a few violations were also observed [ 43 , 44 , 45 ] including the cases of structural stability [ 45 , 46 ]. Computational methods and choice of basis sets were found to be a key factor in some cases [ 41 ]. According to Koopman’s theorem, operational definition [ 40 ] of electronegativity (χ) and chemical hardness (η) are given by $$\:{\chi\:}=\:-\frac{1}{2}\left({\text{E}}_{\text{L}\text{U}\text{M}\text{O}}+{\text{E}}_{\text{H}\text{O}\text{M}\text{O}}\right)\:\:\:\:\text{a}\text{n}\text{d}\:\:{\eta\:}=\:\frac{1}{2}\left({\text{E}}_{\text{L}\text{U}\text{M}\text{O}}-\:{\text{E}}_{\text{H}\text{O}\text{M}\text{O}}\right)$$ where E HOMO and E LUMO are the energies of the highest occupied molecular orbital’s (HOMO) and lowest unoccupied molecular orbitals (LUMO) respectively. The electrophilicity (ω) is defined as \(\:{\omega\:}=\:{{\chi\:}}^{2}/2{\eta\:}\) Various computational methods and basis sets were used in this article; the underlying reasoning behind this is already outlined.We started with the popular density functional theory (DFT) [ 47 ]. Its popularity stems from its fast computational time, incorporation of electron correlations and above all satisfactory explanation of a large number of experimental observations [ 26 , 32 , 34 , 35 ]. Among all the functionals, our initial approach is to apply the three parameter hybrid exchange functional, B3LYP, which also incorporates correlation through Lee-Yang-Parr correlation functional [ 48 , 49 ]. Invarious instances B3LYP did not succeed to reproduce non-covalent interactions and a new functional M06-2X [ 50 ] accounts for this interaction more aptly. Dispersive interactions were further accounted for by introducing ωB97X-D [ 51 ] functional. The non-covalent interaction is a dominant one in the proton transfer process involved in the tautomerisation and in the situation where intermolecular interactions play a major role. e.g., during the formation of clusters with water, ammonia etc. Apart from DFT methods, we will also apply second order Møller-Plesset perturbation theory (MP2) [ 52 ]. The high-level ab-initio method is used by introducing coupled cluster (CC) [ 53 ] method. The electron correlation is well taken into account here. It is computationally too costly. In this paper, we will use this method including single and double excitations, (CCSD) [ 54 ]. These methods will try to find out the various structures in the ground state and consistency of computational results Computations and Methodology The functional B3LYP [ 48 , 49 ], M06-2X [ 50 ] andωB97X-D [ 51 ] were used within the Density Functional Theory (DFT) method to optimize the geometries of the molecules in various conformations in S 0 . The basis sets 6-311G++ (2d, 3p) [ 55 ] and augmented cc-pVDZ [ 56 ] were used for the above calculations. The latter one incorporates correlation corrections. Apart from DFT, MP2 [ 52 ] method was also used with the identical sets of basis. During the PEC scan the dihedral angle D1 = ∠C1-X-C3-C4 were kept fixed by a predetermined amount and the rest of the moleculewereallowed to optimize. We had cross-checked each individual dihedral angles to ascertain the minimum energy conformation corresponding to that particular angle. Then another dihedral angle D2 = ∠C5-C10-C1-Xwas varied to plot the PES. Vibrational frequencies of all the molecules were computed at the optimized structures. The frequencies were determined by computation of the second derivative of energy with respect to the variation of mass-weighted coordinates [ 57 ]. Potential Energy Distribution (PED) analysis [ 58 ] was done through Veda 4 software to determine the nature of the different vibrational modes. 6-311G++ (2d, 3p) [ 59 ] basis set was used for these computations. The transition states (TS) were identified by applying synchronous transit guided quasi-Newton (STQN) method [ 60 ] and were ascertained with the appearance of imaginary frequencies. Molecular Orbital (MO) calculations were performed with the same basis set. TDDFT method was further used to compute the vertical transition energy in the respective structures. All these computations are done with the program package GAUSSIAN 09 [ 61 ]. Results THN and its mono and di substituted oxygen and nitrogen derivatives showed a twisted configuration of the saturated ring as the global minimum. The other configuration where this ring is bent with respect to the benzene moiety was found [22] to be much higher in energy and quite inaccessible to experiments. Incidentally, they are yet to be observed. In THIQ [26], a bent conformer in a shallow well was identified, but it was higher by 900 cm -1 with respect to the global minima of the two twisted forms. It is to be kept in mind that nitrogen substituted THN derivatives like THQ, THIQ and THQX poses a more challenging problem as the orientation of H atom of the NH group yields more conformers. The “planar” configuration of the molecules where all the atoms are in the same plane with C S as molecular point group is a transition state (TS) for all these molecules and computed to be much higher in energy. Here, in isochroman (IC), isothiochroman (ITC) and isoselenochroman (ISC) we will search for all the configurations. In this case the substituent of the CH 2 group is a single atom (oxygen or sulphur or selenium).The energy of IC, ITC and ISC will primarily depend on the orientation of the saturated ring defined by the dihedral angle D1 = ÐC1-X-C3-C4 (X=O for IC, X=S for ITC and X=Se for ISC) of the saturated ring. The other important coordinate is the dihedral angle D2= ÐC5-C10-C1-S, which exhibits the relative orientations between the saturated and unsaturated rings. All the conformers and the TSs of all these molecules will be located in the potential energy surface (PES) drawn with D1 and D2 as the parameters. PES of all the three molecules is shown in figure 1. The variation of potential energy of these molecules with the change in D1 is shown in figure 2. This figure also includes THIQ. The comparison of PEC’s of different molecules will help us to understand the effect of substitution on the conformational landscape in respective electronic states. Analysis of the PES and PEC for individual molecules is the subject of our next chapter. While, the comparison of PEC’s in different states of a specific molecule will give us an idea of the changes in electronic structure on excitation. It will be the subject of our next work to be published soon [62]. Conformations Isochroman (IC) The “twisted” configuration is the global minimum from the analysis of PES and PEC in all the methods of calculation and with the variations of basis sets also. This structure is shown in Fig. 3(a).The equivalent minima are shown in Fig. 1(a) as C1T and C2T respectively. The transition states (TS) are designated as TS2A and TS2B and located in the Figures 1a, which is about 1100 ± 100 cm -1 higher in energy. TS correspond to the “bent” form of IC, where this dihedral angle is zero. The equivalent TS are also shown there. The planar form having C S symmetry is about 3550 ± 70 cm -1 higher in energy than the minimum. This is also confirmed to be a transition state (TS). Table 1 contains computed energies of all the structures of this molecule with various methods and variation of basis sets amongst them. Figure 4 shows all the conformations and transition states of isochroman. In the minimum energy twisted conformation the saturated ring is puckered by 34 0 ± 1 0 . If we compare this angle with that in THN (31 0 ) and THIQ (31 0 and 35 0 for the two minimum) it is found to be of the same order. In chroman, where the oxygen atom is in conjugation with the benzene ring, the lowest energy “twisted” conformer appeared with a twisting angle of 30 0 . In IC this angle increases to about 35 0 . If we compare the nitrogen substituted derivatives THQ and THIQ, the respective twisting angles were 29 0 and 31 0 & 35 0 respectively. Oxygen and nitrogen substitution at different places of the saturated ring of THN yields a common picture. Substitution at a position where the substituted atom is conjugated with the unsaturated ring showed a smaller twisting angle compared to the case where the substituted atom is unconjugated with the benzene ring. This might have arisen due to the interaction between the lone pair of the substituent with the pi electron cloud of the unsaturated ring. This interaction will exert a pull on the carbon atom adjacent to the substituent in the saturated ring decreasing the torsion of the adjacent carbon atoms in the ring. The geometrical parameters of the twisted configuration are given in Table T1 in the supplementary file. Isothiochroman (ITC) The global minimum of this molecule is found to be a “bent” configuration in DFT, MP2 and CCSD methods of computations, where we also varied basis sets to account for all possible aspects. This is the first time one observes a “bent” structure to be the most stable conformer of any THN derivatives investigated so far. The equivalent minima are designated as C1B and C2B in the PES shown in Figure 1(b). The “twisted” form is found to be close in energy. The relative energy difference is 60 ± 40 cm -1 . They are symbolized as C1T and C2T in the respective PES in Figure 1(b). Figure 2 also displays these conformations in the respective PEC. Figure 1 also identifies all the transition states (TS). Figure 2 contains the PEC of ITC along with that of IC, THIQ and ISC. We observed a “bent” conformer in THIQ, but it was quite high in energy by 900 cm -1 compared to the “twisted” form. In isochroman, “bent” form appears as TS. The conformation of the global minimum in THN derivatives are presumably determined by two interactions. The first one is the ring strain on the saturated ring which will try to reduce the interior angle from 120 0 resulting in a non-planar form. The torsional interaction of the –CH 2 -X- {X=O for IC, X=S for ITC and X=Se for ISC} part of the saturated ring tries to twist the saturated ring. The latter interaction depends inversely with inertia. So, substitution with comparatively heavier sulphur atom reduces the latter part in ITC, resulting in a “bent” global minimum close to the “twisted” form. For a comparative study, the potential energy curves are drawn for IC, ITC, ISC and THIQ in a same plot. The geometrical parameters of both the “bent” and “twisted” conformations are provided in Table T2 in the supplementary file. All the conformations and transition states are shown in Figure 4. The non-planarity of the saturated ring is measured by the twisting angle defined by Laane et.al. [24]. This angle is found to be 32 0 ± 1 0 is for the “twisted” form and about 6 0 for the “bent” form. The corresponding angle is found to be around 8 0 in the “bent” conformer of THIQ [26]. In the ideal case the dihedral angle {defined by D1 = C1-S-C3-C4} should be zero for the “bent” form and both the non-planar atoms/functional groups here, sulphur (S) and CH 2 should be at a same height from the molecular plane. Truly speaking this conformer is a mixture of “bent” and “twist” forms, but due to the contribution of the major part, this structural part is termed “bent” as done in THIQ [26]. The equivalent TSs TS1A and TS2A appear at D1 = ±47 0 , which lies about 1080 ± 60 cm -1 higher in energy than the global minimum. The other equivalent TSs termed TS1B and TS2B appear at D1= ± 41 0 . It signifies that it can neither be termed as “twist” nor “bent”. TS1B is about 650±100 cm -1 higher in energy. This barrier height for interconversion between the forms or between the two minima in the potential energy diagrams is much less compared to similar molecules like IC and THIQ. This might be interesting and need more high-resolution spectroscopic experiments to corroborate this important observation. The relative energy of all the computed structures are included in Table 1. It shows the consistency of our computations with the variation of basis sets and methods of calculations. The important structural parameters of the stable conformers are in Table 2, where we checked our consistency of computed values. Isoselenochroman(ISC) As discussed above, the relative energies between the “twisted” and “bent” conformations showed an important variation in IC and ITC. The “bent” form being TS in IC becomes global minimum in ITC. To look more into this problem, we replace the sulphur atom with heavier selenium (Se) to form isoselenochroman (ISC). Figure 1(c) includes the corresponding PES of the molecule. Here, the “bent” conformation is the global minimum with “twisted” form lies about 700 ± 50 cm -1 higher in energy. This “twisted” form is certainly different from the ealier ones observed in IC, ITC and THIQ. The dihedral angle D2 for the rest lies about 25 ± 5 0 . But, here in ISC it is about 7 0 . It indicates that selenium atom lies almost at the molecular plane, which the conformation may be termed as half-twist as observed in THQ [25]. The planar form lies about 3800 ± 150 cm -1 higher in energy. These results show that with the change in atomic number of the substituent in the iso position, the relative energies between these two conformations show a drastic change from IC to ISC. The respective TSs is also shown in Figure 1(c). The PEC plot of all the molecules is shown in Figure 2. The relative energy of all the possible structures of ISC is shown in Figure F2 in the supplementary file. The comparison of the different structural parameters of ISC and ITC (shown in Table 2), it shows a variation of around 2-3 0 degrees between the identical structures between them (apart from the twisted structure). Vibrational Frequencies : Isothiochroman The molecules in the THN family (including derivatives) are characterized by two low-frequency vibrations in 80-200 cm -1 region. The difference between these two frequencies are observed as well as computed to be in the order of around 50 cm -1 in S 0 for the molecules in the substituted THN family. For the nitrogen substituted THN’s, this difference was 48 cm -1 {98 and 156 cm -1 }in THQ [30], while 49 cm -1 { 96 and 145 cm -1 } in the TA form of THIQ and 50 cm -1 {95 and 145 cm -1 } in the TE conformer of THIQ [24]. In the oxygen substituted molecules, computations show this difference as 57 cm -1 {96 and 153 cm -1 } in chroman [35]. In isochroman [32] this difference was observed as 47 cm -1 {119 and 166 cm -1 } in the Raman Spectrum. Our computations predict the difference as 48 cm -1 {103 and 151 cm -1 }. In this aspect, this difference in the bent form of isothiochroman is 46 cm -1 {76 and 122 cm -1 } and 47 cm -1 {125 and 172 cm -1 } in the twisted form. These values seem to be consistent with the earlier observation on similar kind of molecules. The computed IR spectra of the two conformers of ITC are shown in Figure 5. The two characteristic low-frequency vibrations in the “bent” form appear at 75 and122 cm -1 , while in the “twisted” form these are predicted to appear at 125 and 172 cm -1 . The lower of the two frequencies (n 54 ) correspond to the butterfly motion of the aromatic rings as observed in nitrogen and oxygen substituted THN’s [24, 32, 35 ]. This is termed as ‘saturated ring bending’. The higher of these two (n 53 ) is termed ‘saturated ring twisting’. The strongest line (n 40 ) in the IR spectra is observed at 776 cm -1 and 768 cm -1 in the “bent” and “twisted” forms of ITC respectively. This is also a characteristic of the molecules belonging to THN family. This intense line was observed at 747 cm -1 in THIQ [25] while computation predict them to appear at 765 cm -1 and 768 cm -1 for the two low energy conformers. This is primarily a benzene ring mode of B 2g symmetry. Although in ITC this is the most intense line in computed IR spectra, this is not so in other THN derivatives. We observed a number of lines of comparable intensities in chroman [29], THQ [30] and THIQ [25]. The PED analyses of all the modes along with the frequencies of the different conformers are in the Table T4 in the supplementary file. There are 10 modes in 3000 – 3200 cm -1 range. The first five among these are different stretching modes of CH bonds of the saturated ring and the rest belongs to the CH stretching modes of the unsaturated ring. The low barrier height between the two forms suggests that both the forms would be sufficiently populated at room temperature. If we do not perform any conformer specific experiments like UV-UV hole burning spectroscopy and IR-UV double resonance spectroscopy [63], it will be difficult to separate their IR spectra. The difference in the vibrational signature of the two conformers can also be distinguished by the dispersed fluorescence spectra or single vibronic level luminescence spectra as observed earlier for molecules of THN family [64]. These experiments will also help in isolating the two forms. Isochroman In isochroman the characteristic low frequencies are predicted to appear at 103 and 151 cm -1 in S 0 , which were observed at 119 and 166 cm -1 in Raman spectra [35]. These are termed as ‘saturated ring bending’ and ‘saturated ring twisting’ modes respectively as earlier. Figure 6 shows the computed IR spectra of isochroman. This spectra of isochroman looks much different from that of isothiochroman. In isothiochroman the strongest mode is the one corresponding predominantly to the unsaturated ring mode of B 2g symmetry observed at 776 cm -1 , while in isochroman there are a number of lines having comparable intensity to that of the above mentioned mode. The one in-plane vibrational mode (n 29 ) of the unsaturated ring appearing at 1175 cm -1 also contributes strongly to the IR spectrum. There are a few more strong lines corresponding to the CH stretching modes of saturated ring appearing above 3000 cm -1 . In that respect this spectra resembles that of IR spectra of THIQ [25] and THQ [26]. The only difference among these molecules is the atomic weight of sulphur atom in isothiochroman and its dipole moment is presumably affecting the intensity profile of the IR spectrum of isothiochroman. The vibrational analysis including the PED analysis of isochroman in S 0 is given in Table T5 in supplementary file. Figure F1 compares our computation with the frequencies observed in Raman spectrum [32]. The linear regressional analysis yields the value of R 2 as 0.99954, indicating the success of our computations in corroborating the experimental spectra. Isoselenochroman The computed IR spectra of the two conformers of ISC are shown in Figure 7. The two characteristic low-frequency vibrations in the “bent” form appear at 78 and 126 cm -1 , while in the “twisted” form these are predicted to appear at 66 and 128 cm -1 . The strongest line (n 38 ) in the IR spectra is observed at 776 cm -1 and 769 cm -1 in the “bent” and “twisted” forms of ISC respectively. This is also a characteristic of the molecules belonging to THN family. There are 10 modes in 3000 – 3200 cm -1 range. The first six among these are different stretching modes of CH bonds of the saturated ring and the rest belongs to the CH stretching modes of the unsaturated ring. The PED analyses of ISC are given in Table T6 in supplementary file. HOMO-LUMO and ESP: HOMO-LUMO The electronic and optical properties of substances are intimately connected with the HOMO and LUMO of that molecules and it elucidates in understanding the nature of intermolecular interactions [65]. These orbitals also help in explaining the absorption spectra of substances and associate various molecular orbitals around HOMO and LUMO to the peaks in the observed spectra [32, 35]. HOMO and LUMO of the two conformers of isothiochroman are shown in Figure 8. It is evident from the figure that the electron density in HOMO is more on the saturated ring of ITC in both the forms. On excitation, this showed a shift more towards the unsaturated ring. The transition is mostly of π→π* in nature. It is an important point to note that in HOMO of both conformers there is a sufficient built up of electron density on sulphur atom. In LUMO on the other hand, the electron density shifts from this atom. The same kind of behaviour was also observed in case of thioanisole [66].In isoselenochroman (ISC) the corresponding plot shown in Figure 10, shows a shift in electron density from selenium atom to other region. This transition is also mostly π→π* in nature. This behaviour is quite different from the one observed in other molecules of THN family. In THIQ and here in isochroman( in Figure 9) , electron density mainly shifts from the unsaturated ring to the saturated ring on HOMO-LUMO transition. ESP The intermolecular interactions with a solvent can be predicted from the plot of Molecular Electrostatic potential (ESP) surface shown in Figure 11, Figure 12 and figure 13 for isothiochroman, isochroman and isoselenochroman respectively. The orientation of the saturated ring is different in the two conformers of ITC, indicating a difference in their surfaces. Three points are chosen on the respective surfaces to have a quantitative understanding of the nature of intermolecular interactions. The coloured surfaces are plotted in such a way that the blue regions are the positions of accumulation of maximum positive charges, while the red regions are the corresponding ones for negative charges. The negative charges are expected around the pi electron cloud of the unsaturated ring and the lone pair electrons of sulphur atoms. Three points A, B and C are chosen on the MEP, which are positioned at the center of the benzene ring and in the direction of the lone pairs on sulphur and selenium atoms in case of isothiochroman and isoselenochroman respectively. When isothiochroman will interact with water in its hydrated clusters, then the orientations of the different conformers can be predicted from these values. The values are included in Table 3 for the two conformers. There are three possible types of h-bonding is expected in the hydrated clusters of this molecule—i) π...H-O type, ii) S....H-O type and iii) H....O-H type. Similar cases will arise in ISC where S will be replaced by Se. Interplay between these different types of binding sites as well as the different conformers of ITC and ISC are expected to generate a fascinating landscape of conformers. Our preliminary studies yield that the monohydrates with the bent conformer is in the global minimum of the landscape with a large difference in the energy with the hydrated cluster of the twisted form. This work will be communicated shortly [67]. In isochroman, the corresponding ESP of the twisted conformer suggest that there might be abridged hydrated cluster involving pi electron clouds and the lone pairs of oxygen atoms. This will be subject of our study in near future. MHP and MEP The relative stability of the different conformers and transitions states can also be estimated from the variations in chemical reactivity parameters like hardness ( η ) and electrophilicity ( ω ). Maximum hardness principle (MHP) [37] suggests that the most stable conformer should be the hardest and transition states should have the least hardness. On the contrary, minimum electrophilicity principle (MEP) states that the most stable structure should have the least electrophilicity and the reverse is true for the transition states. There are some failures observed in the application of these principles in predicting the most stable conformer of a molecule [67]. In our recent works we found a mixed success in the application of these principles [25, 28, 68]. In case of homophthalic anhydride [69] the entire tautomerisation pathway is found to obey both these principles without any fluctuations or occasional deviations. But in other cases either one of these principles [25]was valid or one of the conformers or transition states [28] were found to follow the principles. ITC possess two close lying conformers and two transition states (TS). The values of hardness and electrophilicity for all the conformers and transition states are given in Table 4. If we scrutinize the data we may conclude that the transition state (TS1) having highest value of energy possess the least value of hardness among all the possible structures of ITC. The hardness of the other transition state (TS2) follows the order of stability. Thus transition states (TS1 and TS2) of ITC obey MHP in M06-2X, B3LYP and ωB97X-D calculations. But the most stable structure, i.e. the bent conformer is never found to be the hardest. In isochroman there are only two structures are of importance---minimum twisted and bent as the TS. From the table 4 one can easily conclude that MHP is completely violated both in isochroman and isoselenochroman. MEP states that transition states should have the highest electrophilicity. In the following table (Table8) only in B3LYP calculations shows that the relation between the stability of the conformers and their respective electrophilicities satisfy the above criteria for ITC. Otherwise, MEP does not go along with any levels of computations in ITC. In isochroman, this principle obeyed only by M06-2X and wB97X-D functionals. For isoselenochroman(ISC) MEP follows only in MP2 calculations. Conclusions Sulphur and selenium substitutions in tetrahydronaphthalene yields interesting results. The resulting molecule isothiochroman and isoselenochroman exhibits two minima and two transition states in its potential energy surface. The global minimum in each case is a “bent” conformation, which to the best of our knowledge is the first such reporting of this form to be a global minimum in any of the derivatives of THN. The other minima, the more popularly observed “twisted” conformation of the saturated ring is energetically very close to the “bent” conformation in isothiochroman, but was placed much higher (700 cm -1 ) in energy in isoselenochroman. The PEC has a symmetric distribution in S 0 around the origin. The computations yield a consistent result with variation of basis sets and methods. The highest TS structure follows the hardness principle. The comparison of molecular electrostatic potential surface of the two conformers clearly shows a difference. This will have an enormous effect when this molecule interacts with a solvent, where non-covalent interactions will be present. The oxygen substitution on the other hand shows a single twisted conformer as the sole minimum. The TS structure with a bent geometry is located at a height of 1200 cm -1 . The PEC of different derivatives of THN is compared. The appearance of a bent conformer was first observed in THIQ, where bent form was placed much higher in PEC. Sulphur and selenium substitution has a profound effect on the conformational landscape of the respective molecules. The atomic weight may presumably be the key factor, as the torsion of the saturated ringdecreaseswith the mass. The electron density is another factor. The low-frequency vibrations in the vibrationalspectra follows the same pattern for all of them. But IR spectra of isothiochroman look different from the other molecules in the THN family. MHP is completely violated in isochroman. MEP is obeyed by M06-2X functional in both the molecules. The substitution of THN with oxygen, sulphur and selenium shows a systematic change in the relative energies of the conformations. We suggest some high resolution experiments to corroborate our findings. Declarations Acknowledgements We are thankful to Niranjan Biswas and Prof. Santu Das for some fruitful discussion. The support from University Grants Commission and Department of Science and Technology (Govt. of India) is also gratefully acknowledged. Funding AC gratefully acknowledges the financial support received from University Grants Commission through a research Project (F. No. 37-560/2009(SR)) for conducting this work. The authors also acknowledge the instrumental support from DST (Govt. of India) under departmental FIST program of the University of Burdwan (Grant no: SR/FST/PS-II-001/2011) and University Grants Commission (UGC) for departmental CAS (Grant no. F.530/ 5/CAS/2011(SAP-I)) scheme Author Contribution A. I. M. : Literature Survey, editing, Software handling, Data handling,A. C. : Conceptualisation and Visualisation of the problem, Writing, Reviewing and editing the manuscript, Literature Survey, Presentation of Figures References I. Petterson and T. Liljefors, Structure-activity relationships for apomorphinecongeners..Conformational energies vs. biological activities.J.of Comp. 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Method Basis Set Structures Isochroman Isothiochroman Isoselenochroman Tw Bent Planar Tw Bent Planar TS1 TS2 Tw Bent Planar TS 1 TS 2 DFT-B3LYP G 0 1122 3517 98 0 3692 1140 562 698 0 3875 1628 571 G++ 0 1109 3581 68 0 3624 1060 555 714 0 3952 1565 540 aug .cc-pVDZ 0 1135 3512 59 0 3644 1056 560 705 0 3856 1590 530 DFT-M06-2X G 0 1202 3552 25 0 3932 1140 694 751 0 3901 1592 631 G++ 0 1211 3577 24 0 4000 1130 641 708 0 3940 1685 612 aug .cc-pVDZ 0 1204 3524 27 0 4022 1156 622 725 0 3954 1550 598 DFT wb 97xD G 0 1255 3606 47 0 3798 1089 520 692 0 3865 1462 612 G++ 0 1222 3587 35 0 3766 1050 694 663 0 3895 1562 584 aug.cc-pVDZ 0 1283 3632 39 0 3737 1142 482 751 0 3910 1570 599 MP2 G 0 1161 3532 107 0 3621 1130 720 795 0 3888 1489 605 G++ 0 1120 3503 79 0 3609 1125 757 713 0 3950 1586 685 aug.cc-pVDZ 0 1017 3567 78 0 3612 1098 735 722 0 3962 1653 645 CCSD G 0 1242 3677 122 0 3805 1160 708 730 0 3899 1652 625 G++ 0 1189 3708 98 0 3768 1180 697 715 0 3924 1563 601 G stands for 6-31 G(d) and G++ for 6-311 ++G(2d,3p) and cc for aug cc-pVDZ basis sets. Table 2.: The important structural parameters of bent and twisted conformations of isothiochroman and isoselenochroman over various methods. Basis set was 6-311G++(2d,3p) for all the computations. Method isothiochroman isoselenochroman Bent Twisted Bent Twisted D 1 D 2 D3 D 1 D 2 D 3 D 1 D 2 D 3 D 1 D 2 D 3 DFT-B3LYP -11.45 52.16 -55.38 -62.93 -24.85 -19.51 -11.72 55.25 -60.74 -63.82 -2.11 -18.11 DFT-M06-2X -11.29 53.83 -56.83 -64.74 -25.271 -18.48 -10.76 54.65 -59.35 -62.85 -7.54 -19.42 DFT- ωB97X-D -11.80 52.71 -55.51 -63.68 -24.62 -19.32 -11.78 56.12 -61.25 -64.12 -5.32 -18.60 MP2 -13.79 55.05 -56.05 -65.44 -26.89 -19.86 -12.01 52.25 -60.56 -62.50 -15.68 -18.98 CCSD -12.75 52.41 55.465 -63.58 -24.79 -18.46 -12.56 54.68 -59.87 -64.32 -19.21 D 1 = ÐC1-S-C3-C4 in degree, D 2 = ÐC5-C10-C1-S in degree, D3 = ÐC10-C5-C4-C3 Table 3. Values (in e/Å) of molecular electrostatic potential of different conformers of isothiochroman, isochroman and isoselenochroman at three critical regions indicated at Fig. 11.,12 and 13 (1e/Å = 332.1 kcal/mol) Molecule Conformer A B C Isothiochroman Bent -0.02587 -0.03146 -0.027715 Twisted -0.02591 -0.02962 -0.02697 Isochroman Twisted -0.02531 -0.04038 0.11876 Isoselenochroman Bent -0.02403 -0.02985 -0.0167 Twisted -0.02084 0.01206 -0.0232 Additional Declarations No competing interests reported. Supplementary Files Supplementaryfile1.docx Cite Share Download PDF Status: Published Journal Publication published 12 Jul, 2025 Read the published version in Journal of Molecular Modeling → Version 1 posted Editorial decision: Revision requested 16 May, 2025 Editor assigned by journal 16 May, 2025 Submission checks completed at journal 16 May, 2025 First submitted to journal 08 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6622869","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":457477058,"identity":"35482449-d749-45d9-8686-56d7454daad8","order_by":0,"name":"Asif Iqubal Middya","email":"","orcid":"","institution":"The University of Burdwan","correspondingAuthor":false,"prefix":"","firstName":"Asif","middleName":"Iqubal","lastName":"Middya","suffix":""},{"id":457477059,"identity":"7461b014-72d7-476f-a2fe-81b669a57a9f","order_by":1,"name":"Abhijit Chakraborty","email":"data:image/png;base64,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","orcid":"","institution":"The University of Burdwan","correspondingAuthor":true,"prefix":"","firstName":"Abhijit","middleName":"","lastName":"Chakraborty","suffix":""}],"badges":[],"createdAt":"2025-05-08 18:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6622869/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6622869/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00894-025-06432-6","type":"published","date":"2025-07-12T15:57:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83324333,"identity":"d580fdfd-e17d-4c70-b8f2-b3195d97f966","added_by":"auto","created_at":"2025-05-23 05:38:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":848946,"visible":true,"origin":"","legend":"\u003cp\u003ePotential Energy Surfaces (PES) of (a) isochroman, (b) isothiochroman and (c) isoselenochroman. Computations are performed at M06-2X / 6-311++G(2d,3p) level of theory\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/786ee4a02c10de784007de2a.png"},{"id":83323994,"identity":"8e3f45a1-238b-465d-a144-c6fc99bf29ab","added_by":"auto","created_at":"2025-05-23 05:30:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":217508,"visible":true,"origin":"","legend":"\u003cp\u003eVariation of Potential Energy with the respective dihedral angles for Isothiochroman (X=S), isochroman (X=O), isoselenochroman(X=Se) and THIQ (X=NH). Computations are performed at M06-2X / 6-311++G(2d,3p) level of theory\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/136b4b5ceb3c22352000cdde.png"},{"id":83323984,"identity":"38c3e9be-b8af-41d0-b2a2-86c66a7e339a","added_by":"auto","created_at":"2025-05-23 05:30:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":53027,"visible":true,"origin":"","legend":"\u003cp\u003eOptimised global minimum of (a) isochroman (b) isothiochroman and (c) isoselenochroman. Computations are performed at M06-2X/6-311 G++(2d,3p) level of theory\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/48e2870aa42d008994896db5.png"},{"id":83323976,"identity":"c87f16fb-98d7-4eeb-a401-f2c9f8c2f2f9","added_by":"auto","created_at":"2025-05-23 05:30:50","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":133674,"visible":true,"origin":"","legend":"\u003cp\u003eDifferent conformers and transition states (TS) along with their relative energies of isochroman and isothiochroman. Computations are performed at M06-2X/6-311G++(2d,3p) level of theory in the Ground State of the respective molecules.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/6bd795b7f331e0f1c565a1b3.png"},{"id":83323987,"identity":"e53f9121-eda3-4b0b-b491-23666908e7ed","added_by":"auto","created_at":"2025-05-23 05:30:51","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":67281,"visible":true,"origin":"","legend":"\u003cp\u003eComputed IR spectra of the different conformations of isothiochroman (a) Bent and (b)Twisted. Computations are done at M06-2X/6-311G++(2d,3p) level.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/f439e5bb86c243b6e32577bf.png"},{"id":83323985,"identity":"a72f5161-ddd2-4e50-b9c7-ff006ec3cf74","added_by":"auto","created_at":"2025-05-23 05:30:50","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":66961,"visible":true,"origin":"","legend":"\u003cp\u003eComputed IR spectra of isochroman. Computations are done at M06-2X/6-311G++(2d,3p) level.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/0b9fb40b7a43eb496a29c391.png"},{"id":83323992,"identity":"33a2cd2a-bbc8-4497-b973-2b3381a2aee2","added_by":"auto","created_at":"2025-05-23 05:30:51","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":61089,"visible":true,"origin":"","legend":"\u003cp\u003eComputed IR spectra of the different conformations of isoselenochroman (a)twisted and (b) bent. Computations are done at M06-2X/6-311G++(2d,3p) level.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/6e1382e8b8f2c2bf6965e599.png"},{"id":83324332,"identity":"13acde32-ec44-4ae1-b32b-741c8aebc975","added_by":"auto","created_at":"2025-05-23 05:38:51","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":109082,"visible":true,"origin":"","legend":"\u003cp\u003eHOMO and LUMO of the different conformers of isothiochroman. Computations are done at M06-2X/6-311G++(2d,3p) level of theory.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/c974e70773f8c4b4ad48ebbb.png"},{"id":83323979,"identity":"e3b8126c-2b52-471c-b373-9f34c8b4bf84","added_by":"auto","created_at":"2025-05-23 05:30:50","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":71486,"visible":true,"origin":"","legend":"\u003cp\u003eHOMO and LUMO of the twisted conformer of isochroman. Computations are done at M06-2X/6-311G++(2d,3p) level of theory.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/da052034d671218739747925.png"},{"id":83323982,"identity":"8e2f53fe-41ce-404b-b8f9-e38cac8b63a2","added_by":"auto","created_at":"2025-05-23 05:30:50","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":129679,"visible":true,"origin":"","legend":"\u003cp\u003eHOMO and LUMO of the different conformers of isoselenochroman. Computations are done at M06-2X/6-311G++(2d,3p) level of theory.\u003c/p\u003e","description":"","filename":"10.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/355650b574a48ba73e56f160.png"},{"id":83323997,"identity":"3bc7037d-6605-463c-bc2a-993cb43d5bb0","added_by":"auto","created_at":"2025-05-23 05:30:51","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":420206,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular electrostatic potential of Isothiochroman, a) Bent conformer, b) Twisted conformer. Calculations are performed at M06-2X / 6-311 ++G(2d, 3p) level of theory.\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/4872f8be9fef73a3ea4ffb74.png"},{"id":83323988,"identity":"1a120e6c-b76f-40d5-9787-cf28814c9dc7","added_by":"auto","created_at":"2025-05-23 05:30:51","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":379999,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular electrostatic potential of Isoselenochroman for the a) Bent and b) Twisted conformer. Computations are performed with M06-2X / 6-311 ++G(2d, 3p)level of theory.\u003c/p\u003e","description":"","filename":"12.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/89f08538b9938f6e33c3fdc6.png"},{"id":83324330,"identity":"56bb8f7d-0254-4fda-88bb-cbeaf4a79e11","added_by":"auto","created_at":"2025-05-23 05:38:51","extension":"png","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":324199,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular electrostatic potential of Isochroman, for the twisted conformer. Computations are performed with M06-2X / 6-311 ++G(2d, 3p)level of theory.\u003c/p\u003e","description":"","filename":"13.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/2298807720e2211d25047b4b.png"},{"id":83324952,"identity":"21f2e28c-d6bc-4d60-a6cb-00c68cd2b54e","added_by":"auto","created_at":"2025-05-23 06:02:51","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":15695,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Introduction section.\u003c/p\u003e","description":"","filename":"Unnumberfig.png","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/253edae3e55c6db8d98c4c4f.png"},{"id":86699402,"identity":"9f134419-3a89-4a3c-ab71-b885f7ea0b5d","added_by":"auto","created_at":"2025-07-14 16:09:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3939670,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/1b94647d-1039-4ab8-a179-bce0a01fcc28.pdf"},{"id":83323995,"identity":"ea5d0aea-29b1-4fe2-9c22-c60902a2b8e8","added_by":"auto","created_at":"2025-05-23 05:30:51","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":603182,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6622869/v1/37a599927d38e50e96913ef9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"How does the conformational landscape change on substitution in tetralin? A computational investigation with oxygen, sulphur and selenium","fulltext":[{"header":"Introduction","content":"\u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eThe study of the conformational landscapes of a molecule becoming more and more important nowadays as it is a key factor in explaining the biological and pharmacological activities of it [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]. These landscapes were investigated both theoretically and experimentally [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e] over the last couple of years providing us significant information. The pharmacologically important molecules possess an intrinsic floppy nature, which makes the search of their conformations a very challenging one. New methodologies are being developed to tackle these issues [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003eAmongst the large number of molecules, 1,2,3,4-tetrahydronaphthalene (THN) or tetralin possess different significance as many of its derivatives are extensively used in this industry. Its nitrogen substituted derivatives tetrahydoquinoline (THQ) and tetrahydroisoquinoline (THIQ) is substantially used in treating Parkinson\u0026rsquo;s disease [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e] and as analgesic drugs [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. On the other hand, THN and its family comprising its various substituted derivatives is also a fascinating object of considerable research from the perspective of their conformational landscape. Extensive high resolution molecular beam experiments by various groups [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e] confirm that the twisted conformation, generated by the puckering of CH\u003csub\u003e2\u003c/sub\u003e \u0026ndash;CH\u003csub\u003e2\u003c/sub\u003e groups is the global minimum. The different theoretical models and computations [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e] also corroborate the experimental observations. Due to increased strain, the bent conformation and the planar form having C\u003csub\u003es\u003c/sub\u003e and C\u003csub\u003e2V\u003c/sub\u003e symmetries lie much higher in energy and both were confirmed to be a transition state (TS).\u003c/p\u003e\n \u003cp\u003eOur group is engaged in finding the conformational landscape in different substituted derivatives of THN for quite some time. Initially we started with THQ [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e] and THIQ [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. The rationale behind this choice is stated earlier. Due to conjugation of the lone pair in THQ, the low energy conformations showed a different pattern than THN. Due to possible change in puckering the two lowest energy conformations were termed as half-twisted structures with the different orientations of the N lone pairs [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. The bent conformations were either a TS or lie higher in energy. The high resolution rotational and vibronic spectra [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] corroborate the theoretical findings. The THIQ on the other hand displayed an interesting [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e] pattern. We were able to locate a bent conformer as a local minimum apart from the global minimum of the \u0026ldquo;twisted\u0026rdquo; structures with different orientations of the lone pairs. The investigations prior to our works on THIQ, did not reveal any such bent conformer and we want to extend this method of conformational search for new as well as some other earlier studied molecules.\u003c/p\u003e\n \u003cp\u003eOn the other hand, the sulphur derivatives of benzopyran systems, namely thiochroman is well known for its numerous biological activities [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. Vargas \u003cem\u003eet. al.\u003c/em\u003e [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e] had studied a large number of thiochroman derivatives and quantitatively identified the cytotoxic activities of them. It was observed that thiochroman and chroman derivatives can be used for treating carcinoma, particularly breast cancer for its enhanced level of antiestrogenic activities [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. The growth rate of cancer cells are found to substantially reduce on application of some of the derivatives of these families [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. In all these cases thiochroman and isothiochroman were the main precursors. It was also shown clearly that the biological and pharmacological activities are strongly dependent on conformations [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. But, unfortunately very few studies were oriented in this direction in these molecules.\u003c/p\u003e\n \u003cp\u003eIn this article we will focus on three molecules, isothiochroman, isochroman and isoselenochroman. They are the mono substituted sulphur, oxygen and selenium derivatives of their parent THN molecule. The substitution is done in such a way that the new atom(s) are not in conjugation with the benzene ring. All the computations are performed in their ground states only. The earlier study of isochroman [\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e] in molecular beam experiments suggested the \u0026ldquo;twisted\u0026rdquo; structure to be the only contributor to all the experimental observations. Single point energy calculations of the assumed \u0026ldquo;twisted\u0026rdquo;, \u0026ldquo;bent\u0026rdquo; and \u0026ldquo;Planar\u0026rdquo; forms indicate the \u0026ldquo;twisted\u0026rdquo; form to be more stable by at least 1200 cm\u003csup\u003e-1\u003c/sup\u003ewith respect to the other two forms. But, there were no PES scan, which should have to be done to understand all the conformers and transition states (TS) of isochroman. It is also need to be mentioned that in THIQ [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e], we observed a variation in computed results with the variation of basis sets. We will also check this issue in this article. To the best of our knowledge, we are yet to find out any work related to the search of all the conformers and transition states of isothiochroman as well as their vibrational characteristics. As the sulphur and oxygen belong to the same group with the former being heavier, we will extend our study to a heavier substituent like selenium in isoselenochroman. Apart from the aspect of locating conformers and TS\u0026rsquo;s, this article will also try to address the effect of substituents on the conformational landscape of the THN derivatives.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eThe questions this article will try to answer are:\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e1. How does the substituents affect the conformational pattern in THN derivatives?\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e2. Whether the atomic weights of the substituents has any influence on this conformational landscape?\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e3. THN and its symmetrically substituted molecules like 1, 4-benzodioxan (BOD) [\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e] and tethydroqinoxaline (THQX) [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e] possess identical symmetry. The three possible structures of THN and BOD molecules are twisted, bent and planar, which possess C\u003csub\u003e2\u003c/sub\u003e, C\u003csub\u003es\u003c/sub\u003e and C\u003csub\u003e2v\u003c/sub\u003e as its point group symmetry respectively. In THQX, the relative orientations of the H atom of the NH group produced a large number of conformers. All the monosubstituted derivatives lack these symmetry operations and the symmetry group of the conformers are transformed into C\u003csub\u003e1\u003c/sub\u003e, apart from the planar ones (C\u003csub\u003es\u003c/sub\u003e), which are observed to be much higher in energy in chroman [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e], THQ [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], THIQ [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e].Whether the relative energies and the nature of the different conformations show any drastic change in this case?\u003c/p\u003e\n\u003c/span\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eThe ordering of the stability of the different structures including conformers and transition states can also be assessed by computing some qualitative chemical concepts. This also help in understanding the chemical reactivity of the structures. Electronegativity [\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e], hardness [\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e] and electrophilicity [\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e] are the ones we will compute. Koopman\u0026rsquo;s theorem [\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e] is used to compute these parameters. The validity of maximum hardness principle (MHP) [\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e] and minimum electrophilicity principle (MEP) [\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e] will be checkedhere. These principles were found to be valid in a large number of cases, although a few violations were also observed [\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e] including the cases of structural stability [\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e]. Computational methods and choice of basis sets were found to be a key factor in some cases [\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e]. According to Koopman\u0026rsquo;s theorem, operational definition [\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e] of electronegativity (\u0026chi;) and chemical hardness (\u0026eta;) are given by\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\n \u003cdiv class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e$$\\:{\\chi\\:}=\\:-\\frac{1}{2}\\left({\\text{E}}_{\\text{L}\\text{U}\\text{M}\\text{O}}+{\\text{E}}_{\\text{H}\\text{O}\\text{M}\\text{O}}\\right)\\:\\:\\:\\:\\text{a}\\text{n}\\text{d}\\:\\:{\\eta\\:}=\\:\\frac{1}{2}\\left({\\text{E}}_{\\text{L}\\text{U}\\text{M}\\text{O}}-\\:{\\text{E}}_{\\text{H}\\text{O}\\text{M}\\text{O}}\\right)$$\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003ewhere E\u003csub\u003eHOMO\u003c/sub\u003e and E\u003csub\u003eLUMO\u003c/sub\u003e are the energies of the highest occupied molecular orbital\u0026rsquo;s (HOMO) and lowest unoccupied molecular orbitals (LUMO) respectively. The electrophilicity (\u0026omega;) is defined as \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\omega\\:}=\\:{{\\chi\\:}}^{2}/2{\\eta\\:}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003eVarious computational methods and basis sets were used in this article; the underlying reasoning behind this is already outlined.We started with the popular density functional theory (DFT) [\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e]. Its popularity stems from its fast computational time, incorporation of electron correlations and above all satisfactory explanation of a large number of experimental observations [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. Among all the functionals, our initial approach is to apply the three parameter hybrid exchange functional, B3LYP, which also incorporates correlation through Lee-Yang-Parr correlation functional [\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e]. Invarious instances B3LYP did not succeed to reproduce non-covalent interactions and a new functional M06-2X [\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e] accounts for this interaction more aptly. Dispersive interactions were further accounted for by introducing \u0026omega;B97X-D [\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e] functional. The non-covalent interaction is a dominant one in the proton transfer process involved in the tautomerisation and in the situation where intermolecular interactions play a major role. e.g., during the formation of clusters with water, ammonia etc. Apart from DFT methods, we will also apply second order M\u0026oslash;ller-Plesset perturbation theory (MP2) [\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e]. The high-level \u003cem\u003eab-initio\u003c/em\u003e method is used by introducing coupled cluster (CC) [\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e] method. The electron correlation is well taken into account here. It is computationally too costly. In this paper, we will use this method including single and double excitations, (CCSD) [\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e]. These methods will try to find out the various structures in the ground state and consistency of computational results\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Computations and Methodology","content":"\u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eThe functional B3LYP [\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e], M06-2X [\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e] and\u0026omega;B97X-D [\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e] were used within the Density Functional Theory (DFT) method to optimize the geometries of the molecules in various conformations in S\u003csub\u003e0\u003c/sub\u003e. The basis sets 6-311G++ (2d, 3p) [\u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e] and augmented cc-pVDZ [\u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e] were used for the above calculations. The latter one incorporates correlation corrections. Apart from DFT, MP2 [\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e] method was also used with the identical sets of basis.\u003c/p\u003e\n \u003cp\u003eDuring the PEC scan the dihedral angle D1\u0026thinsp;=\u0026thinsp;\u0026ang;C1-X-C3-C4 were kept fixed by a predetermined amount and the rest of the moleculewereallowed to optimize. We had cross-checked each individual dihedral angles to ascertain the minimum energy conformation corresponding to that particular angle. Then another dihedral angle D2\u0026thinsp;=\u0026thinsp;\u0026ang;C5-C10-C1-Xwas varied to plot the PES. Vibrational frequencies of all the molecules were computed at the optimized structures. The frequencies were determined by computation of the second derivative of energy with respect to the variation of mass-weighted coordinates [\u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e]. Potential Energy Distribution (PED) analysis [\u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e] was done through Veda 4 software to determine the nature of the different vibrational modes. 6-311G++ (2d, 3p) [\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e] basis set was used for these computations. The transition states (TS) were identified by applying synchronous transit guided quasi-Newton (STQN) method [\u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e] and were ascertained with the appearance of imaginary frequencies. Molecular Orbital (MO) calculations were performed with the same basis set. TDDFT method was further used to compute the vertical transition energy in the respective structures. All these computations are done with the program package GAUSSIAN 09 [\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTHN and its mono and di substituted oxygen and nitrogen derivatives showed a twisted configuration of the saturated ring as the global minimum. The other configuration where this ring is bent with respect to the benzene moiety was found [22] to be much higher in energy and quite inaccessible to experiments. Incidentally, they are yet to be observed. In THIQ [26], a bent conformer in a shallow well was identified, but it was higher by 900 cm\u003csup\u003e-1\u003c/sup\u003e with respect to the global minima of the two twisted forms. It is to be kept in mind that nitrogen substituted THN derivatives like THQ, THIQ and THQX poses a more challenging problem as the orientation of H atom of the NH group yields more conformers. The \u0026ldquo;planar\u0026rdquo; configuration of the molecules where all the atoms are in the same plane with C\u003csub\u003eS\u003c/sub\u003e as molecular point group is a transition state (TS) for all these molecules and computed to be much higher in energy. Here, in isochroman (IC), isothiochroman (ITC) and isoselenochroman (ISC) we will search for all the configurations. In this case the substituent of the CH\u003csub\u003e2\u003c/sub\u003e group is a single atom (oxygen or sulphur or selenium).The energy of IC, ITC and ISC will primarily depend on the orientation of the saturated ring defined by the dihedral angle D1 = \u0026ETH;C1-X-C3-C4 (X=O for IC, X=S for ITC and X=Se for ISC) of the saturated ring. The other important coordinate is the dihedral angle D2= \u0026ETH;C5-C10-C1-S, which exhibits the relative orientations between the saturated and unsaturated rings. All the conformers and the TSs of all these molecules will be located in the potential energy surface (PES) drawn with D1 and D2 as the parameters. PES of all the three molecules is shown in figure 1. The variation of potential energy of these molecules with the change in D1 is shown in figure 2. This figure also includes THIQ. The comparison of PEC\u0026rsquo;s of different molecules will help us to understand the effect of substitution on the conformational landscape in respective electronic states. Analysis of the PES and PEC for individual molecules is the subject of our next chapter. While, the comparison of PEC\u0026rsquo;s in different states of a specific molecule will give us an idea of the changes in electronic structure on excitation. It will be the subject of our next work to be published soon [62].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConformations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIsochroman (IC)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe \u0026ldquo;twisted\u0026rdquo; configuration is the global minimum from the analysis of PES and PEC in all the methods of calculation and with the variations of basis sets also. This structure is shown in Fig. 3(a).The equivalent minima are shown in Fig. 1(a) as C1T and C2T respectively. The transition states (TS) are designated as TS2A and TS2B and located in the Figures 1a, which is about 1100 \u0026plusmn; 100 cm\u003csup\u003e-1\u003c/sup\u003e higher in energy. TS correspond to the \u0026ldquo;bent\u0026rdquo; form of IC, where this dihedral angle is zero. The equivalent TS are also shown there. The planar form having C\u003csub\u003eS\u003c/sub\u003e symmetry is about 3550 \u0026plusmn; 70 cm\u003csup\u003e-1\u003c/sup\u003e higher in energy than the minimum. This is also confirmed to be a transition state (TS). Table 1 contains computed energies of all the structures of this molecule with various methods and variation of basis sets amongst them. Figure 4 shows all the conformations and transition states of isochroman.\u003c/p\u003e\n\u003cp\u003eIn the minimum energy twisted conformation the saturated ring is puckered by 34\u003csup\u003e0\u003c/sup\u003e\u0026plusmn; 1\u003csup\u003e0\u003c/sup\u003e. If we compare this angle with that in THN (31\u003csup\u003e0\u003c/sup\u003e) and THIQ (31\u003csup\u003e0\u003c/sup\u003e and 35\u003csup\u003e0\u003c/sup\u003e for the two minimum) it is found to be of the same order. In chroman, where the oxygen atom is in conjugation with the benzene ring, the lowest energy \u0026ldquo;twisted\u0026rdquo; conformer appeared with a twisting angle of 30\u003csup\u003e0\u003c/sup\u003e. In IC this angle increases to about 35\u003csup\u003e0\u003c/sup\u003e. If we compare the nitrogen substituted derivatives THQ and THIQ, the respective twisting angles were 29\u003csup\u003e0\u003c/sup\u003e and 31\u003csup\u003e0\u003c/sup\u003e \u0026amp; 35\u003csup\u003e0\u003c/sup\u003e respectively. Oxygen and nitrogen substitution at different places of the saturated ring of THN yields a common picture. Substitution at a position where the substituted atom is conjugated with the unsaturated ring showed a smaller twisting angle compared to the case where the substituted atom is unconjugated with the benzene ring. This might have arisen due to the interaction between the lone pair of the substituent with the pi electron cloud of the unsaturated ring. This interaction will exert a pull on the carbon atom adjacent to the substituent in the saturated ring decreasing the torsion of the adjacent carbon atoms in the ring. The geometrical parameters of the twisted configuration are given in Table T1 in the supplementary file.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIsothiochroman (ITC)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe global minimum of this molecule is found to be a \u0026ldquo;bent\u0026rdquo; configuration in DFT, MP2 and CCSD methods of computations, where we also varied basis sets to account for all possible aspects. This is the first time one observes a \u0026ldquo;bent\u0026rdquo; structure to be the most stable conformer of any THN derivatives investigated so far. The equivalent minima are designated as C1B and C2B in the PES shown in Figure 1(b). The \u0026ldquo;twisted\u0026rdquo; form is found to be close in energy. The relative energy difference is 60 \u0026plusmn; 40 cm\u003csup\u003e-1\u003c/sup\u003e. They are symbolized as C1T and C2T in the respective PES in Figure 1(b). Figure 2 also displays these conformations in the respective PEC. Figure 1 also identifies all the transition states (TS).\u003c/p\u003e\n\u003cp\u003eFigure 2 contains the PEC of ITC along with that of IC, THIQ and ISC. We observed a \u0026ldquo;bent\u0026rdquo; conformer in THIQ, but it was quite high in energy by 900 cm\u003csup\u003e-1\u003c/sup\u003e compared to the \u0026ldquo;twisted\u0026rdquo; form. In isochroman, \u0026ldquo;bent\u0026rdquo; form appears as TS. The conformation of the global minimum in THN derivatives are presumably determined by two interactions. The first one is the ring strain on the saturated ring which will try to reduce the interior angle from 120\u003csup\u003e0\u0026nbsp;\u003c/sup\u003eresulting in a non-planar form. The torsional interaction of the \u0026ndash;CH\u003csub\u003e2\u003c/sub\u003e-X- {X=O for IC, X=S for ITC and X=Se for ISC} part of the saturated ring tries to twist the saturated ring. The latter interaction depends inversely with inertia. So, substitution with comparatively heavier sulphur atom reduces the latter part in ITC, resulting in a \u0026ldquo;bent\u0026rdquo; global minimum close to the \u0026ldquo;twisted\u0026rdquo; form. For a comparative study, the potential energy curves are drawn for IC, ITC, ISC and THIQ in a same plot. The geometrical parameters of both the \u0026ldquo;bent\u0026rdquo; and \u0026ldquo;twisted\u0026rdquo; conformations are provided in Table T2 in the supplementary file. All the conformations and transition states are shown in Figure 4. The non-planarity of the saturated ring is measured by the twisting angle defined by Laane \u003cem\u003eet.al.\u003c/em\u003e [24]. This angle is found to be 32\u003csup\u003e0\u003c/sup\u003e \u0026plusmn; 1\u003csup\u003e0\u003c/sup\u003e is for the \u0026ldquo;twisted\u0026rdquo; form and about 6\u003csup\u003e0\u003c/sup\u003e for the \u0026ldquo;bent\u0026rdquo; form. The corresponding angle is found to be around 8\u003csup\u003e0\u003c/sup\u003e in the \u0026ldquo;bent\u0026rdquo; conformer of THIQ [26]. In the ideal case the dihedral angle {defined by D1 = C1-S-C3-C4} should be zero for the \u0026ldquo;bent\u0026rdquo; form and both the non-planar atoms/functional groups here, sulphur (S) and CH\u003csub\u003e2\u003c/sub\u003e should be at a same height from the molecular plane. Truly speaking this conformer is a mixture of \u0026ldquo;bent\u0026rdquo; and \u0026ldquo;twist\u0026rdquo; forms, but due to the contribution of the major part, this structural part is termed \u0026ldquo;bent\u0026rdquo; as done in THIQ [26]. The equivalent TSs \u0026nbsp;TS1A and TS2A appear at D1 = \u0026plusmn;47\u003csup\u003e0\u003c/sup\u003e, which lies about 1080 \u0026plusmn; 60 cm\u003csup\u003e-1\u003c/sup\u003e higher in energy than the global minimum. The other equivalent TSs termed TS1B and TS2B appear at D1= \u0026plusmn; 41\u003csup\u003e0\u003c/sup\u003e. It signifies that it can neither be termed as \u0026ldquo;twist\u0026rdquo; nor \u0026ldquo;bent\u0026rdquo;. TS1B is about 650\u0026plusmn;100 cm\u003csup\u003e-1\u003c/sup\u003e higher in energy. This barrier height for interconversion between the forms or between the two minima in the potential energy diagrams is much less compared to similar molecules like IC and THIQ. This might be interesting and need more high-resolution spectroscopic experiments to corroborate this important observation. The relative energy of all the computed structures are included in Table 1. It shows the consistency of our computations with the variation of basis sets and methods of calculations. The important structural parameters of the stable conformers are in Table 2, where we checked our consistency of computed values.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIsoselenochroman(ISC)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs discussed above, the relative energies between the \u0026ldquo;twisted\u0026rdquo; and \u0026ldquo;bent\u0026rdquo; conformations showed an important variation in IC and ITC. The \u0026ldquo;bent\u0026rdquo; form being TS in IC becomes global minimum in ITC. To look more into this problem, we replace the sulphur atom with heavier selenium (Se) to form isoselenochroman (ISC). Figure 1(c) includes the corresponding PES of the molecule. Here, the \u0026ldquo;bent\u0026rdquo; conformation is the global minimum with \u0026ldquo;twisted\u0026rdquo; form lies about 700 \u0026plusmn; 50 cm\u003csup\u003e-1\u003c/sup\u003e higher in energy. This \u0026ldquo;twisted\u0026rdquo; form is certainly different from the ealier ones observed in IC, ITC and THIQ. The dihedral angle D2 for the rest lies about 25 \u0026plusmn; 5\u003csup\u003e0\u003c/sup\u003e. But, here in ISC it is about 7\u003csup\u003e0\u003c/sup\u003e. It indicates that selenium atom lies almost at the molecular plane, which the conformation may be termed as half-twist as observed in THQ [25]. \u0026nbsp;The planar form lies about 3800 \u0026plusmn; 150 cm\u003csup\u003e-1\u003c/sup\u003e higher in energy. These results show that with the change in atomic number of the substituent in the iso position, the relative energies between these two conformations show a drastic change from IC to ISC. The respective TSs is also shown in Figure 1(c). The PEC plot of all the molecules is shown in Figure 2. The relative energy of all the possible structures of ISC is shown in Figure F2 in the supplementary file. The comparison of the different structural parameters of ISC and ITC (shown in Table 2), it shows a variation of around 2-3\u003csup\u003e0\u003c/sup\u003e degrees between the identical structures between them (apart from the twisted structure).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVibrational Frequencies :\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIsothiochroman\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe molecules in the THN family (including derivatives) are characterized by two low-frequency vibrations in 80-200 cm\u003csup\u003e-1\u003c/sup\u003e region. The difference between these two frequencies are observed as well as computed to be in the order of around 50 cm\u003csup\u003e-1\u003c/sup\u003e in S\u003csub\u003e0\u003c/sub\u003e for the molecules in the substituted THN family. For the nitrogen substituted THN\u0026rsquo;s, this difference was 48 cm\u003csup\u003e-1\u003c/sup\u003e {98 and 156 cm\u003csup\u003e-1\u003c/sup\u003e}in THQ [30], while 49 cm\u003csup\u003e-1\u003c/sup\u003e { 96 and 145 cm\u003csup\u003e-1\u003c/sup\u003e } in the TA form of THIQ and 50 cm\u003csup\u003e-1\u003c/sup\u003e {95 and 145 cm\u003csup\u003e-1\u003c/sup\u003e } in the TE conformer of THIQ [24]. In the oxygen substituted molecules, computations show this difference as 57 cm\u003csup\u003e-1\u003c/sup\u003e {96 and 153 cm\u003csup\u003e-1\u003c/sup\u003e} in chroman [35]. In isochroman [32] this difference was observed as 47 cm\u003csup\u003e-1\u003c/sup\u003e {119 and 166 cm\u003csup\u003e-1\u003c/sup\u003e} in the Raman Spectrum. Our computations predict the difference as 48 cm\u003csup\u003e-1\u003c/sup\u003e {103 and 151 cm\u003csup\u003e-1\u003c/sup\u003e}. In this aspect, this difference in the bent form of isothiochroman is 46 cm\u003csup\u003e-1\u003c/sup\u003e{76 and 122 cm\u003csup\u003e-1\u003c/sup\u003e} and 47 cm\u003csup\u003e-1\u003c/sup\u003e{125 and 172 cm\u003csup\u003e-1\u003c/sup\u003e} in the twisted form. These values seem to be consistent with the earlier observation on similar kind of molecules.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe computed IR spectra of the two conformers of ITC are shown in Figure 5. The two characteristic low-frequency vibrations in the \u0026ldquo;bent\u0026rdquo; form appear at 75 and122 cm\u003csup\u003e-1\u003c/sup\u003e, while in the \u0026ldquo;twisted\u0026rdquo; form these are predicted to appear at 125 and 172 cm\u003csup\u003e-1\u003c/sup\u003e. The lower of the two frequencies (n\u003csub\u003e54\u003c/sub\u003e) correspond to the butterfly motion of the aromatic rings as observed in nitrogen and oxygen substituted THN\u0026rsquo;s [24, 32, 35 ]. This is termed as \u0026lsquo;saturated ring bending\u0026rsquo;. The higher of these two (n\u003csub\u003e53\u003c/sub\u003e) is termed \u0026lsquo;saturated ring twisting\u0026rsquo;. The strongest line (n\u003csub\u003e40\u003c/sub\u003e) in the IR spectra is observed at 776 cm\u003csup\u003e-1\u003c/sup\u003e and 768 cm\u003csup\u003e-1\u003c/sup\u003e in the \u0026ldquo;bent\u0026rdquo; and \u0026ldquo;twisted\u0026rdquo; forms of ITC respectively. This is also a characteristic of the molecules belonging to THN family. This intense line was observed at 747 cm\u003csup\u003e-1\u003c/sup\u003e in THIQ [25] while computation predict them to appear at 765 cm\u003csup\u003e-1\u0026nbsp;\u003c/sup\u003e and 768 cm\u003csup\u003e-1\u003c/sup\u003e for the two low energy conformers. This is primarily a benzene ring mode of B\u003csub\u003e2g\u003c/sub\u003e symmetry. Although in ITC this is the most intense line in computed IR spectra, this is not so in other THN derivatives. We observed a number of lines of comparable intensities in chroman [29], THQ [30] and THIQ [25]. The PED analyses of all the modes along with the frequencies of the different conformers are in the Table T4 in the supplementary file. There are 10 modes in 3000 \u0026ndash; 3200 cm\u003csup\u003e-1\u0026nbsp;\u003c/sup\u003erange. The first five among these are different stretching modes of CH bonds of the saturated ring and the rest belongs to the CH stretching modes of the unsaturated ring. The low barrier height between the two forms suggests that both the forms would be sufficiently populated at room temperature. If we do not perform any conformer specific experiments like UV-UV hole burning spectroscopy and IR-UV double resonance spectroscopy [63], it will be difficult to separate their IR spectra. The difference in the vibrational signature of the two conformers can also be distinguished by the dispersed fluorescence spectra or single vibronic level luminescence spectra as observed earlier for molecules of THN family [64]. These experiments will also help in isolating the two forms.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIsochroman\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn isochroman the characteristic low frequencies are predicted to appear at 103 and 151 cm\u003csup\u003e-1\u003c/sup\u003e in S\u003csub\u003e0\u003c/sub\u003e, which were observed at 119 and 166 cm\u003csup\u003e-1\u003c/sup\u003e in Raman spectra [35]. These are termed as \u0026lsquo;saturated ring bending\u0026rsquo; and \u0026lsquo;saturated ring twisting\u0026rsquo; modes respectively as earlier. Figure 6 shows the computed IR spectra of isochroman. This spectra of isochroman looks much different from that of isothiochroman. In isothiochroman the strongest mode is the one corresponding predominantly to the unsaturated ring mode of B\u003csub\u003e2g\u003c/sub\u003e symmetry observed at 776 cm\u003csup\u003e-1\u003c/sup\u003e, while in isochroman there are a number of lines having comparable intensity to that of the above mentioned mode. The one in-plane vibrational mode (n\u003csub\u003e29\u003c/sub\u003e) of the unsaturated ring appearing at 1175 cm\u003csup\u003e-1\u0026nbsp;\u003c/sup\u003ealso contributes strongly to the IR spectrum. There are a few more strong lines corresponding to the CH stretching modes of saturated ring appearing above 3000 cm\u003csup\u003e-1\u003c/sup\u003e. In that respect this spectra resembles that of IR spectra of THIQ [25] and THQ [26]. The only difference among these molecules is the atomic weight of sulphur atom in isothiochroman and its dipole moment is presumably affecting the intensity profile of the IR spectrum of isothiochroman. The vibrational analysis including the PED analysis of isochroman in S\u003csub\u003e0\u0026nbsp;\u003c/sub\u003eis given in Table T5 in supplementary file. Figure F1 compares our computation with the frequencies observed in Raman spectrum [32]. The linear regressional analysis yields the value of R\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eas 0.99954, indicating the success of our computations in corroborating the experimental spectra.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIsoselenochroman\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe computed IR spectra of the two conformers of ISC are shown in Figure 7. The two characteristic low-frequency vibrations in the \u0026ldquo;bent\u0026rdquo; form appear at 78 and 126 cm\u003csup\u003e-1\u003c/sup\u003e, while in the \u0026ldquo;twisted\u0026rdquo; form these are predicted to appear at 66 and 128 cm\u003csup\u003e-1\u003c/sup\u003e. The strongest line (n\u003csub\u003e38\u003c/sub\u003e) in the IR spectra is observed at 776 cm\u003csup\u003e-1\u003c/sup\u003e and 769 cm\u003csup\u003e-1\u003c/sup\u003e in the \u0026ldquo;bent\u0026rdquo; and \u0026ldquo;twisted\u0026rdquo; forms of ISC respectively. This is also a characteristic of the molecules belonging to THN family. There are 10 modes in 3000 \u0026ndash; 3200 cm\u003csup\u003e-1\u0026nbsp;\u003c/sup\u003erange. The first six among these are different stretching modes of CH bonds of the saturated ring and the rest belongs to the CH stretching modes of the unsaturated ring. The PED analyses of ISC are given in Table T6 in supplementary file.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHOMO-LUMO and ESP: \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHOMO-LUMO\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe electronic and optical properties of substances are intimately connected with the HOMO and LUMO of that molecules and it elucidates in understanding the nature of intermolecular interactions [65]. These orbitals also help in explaining the absorption spectra of substances and associate various molecular orbitals around HOMO and LUMO to the peaks in the observed spectra [32, 35]. HOMO and LUMO of the two conformers of isothiochroman are shown in Figure 8. It is evident from the figure that the electron density in HOMO is more on the saturated ring of ITC in both the forms. On excitation, this showed a shift more towards the unsaturated ring. The transition is mostly of \u0026pi;\u0026rarr;\u0026pi;* in nature. It is an important point to note that in HOMO of both conformers there is a sufficient built up of electron density on sulphur atom. In LUMO on the other hand, the electron density shifts from this atom. The same kind of behaviour was also observed in case of thioanisole [66].In isoselenochroman (ISC) the corresponding plot shown in Figure 10, shows a shift in electron density from selenium atom to other region. This transition is also mostly \u0026pi;\u0026rarr;\u0026pi;* in nature. This behaviour is quite different from the one observed in other molecules of THN family. In THIQ and here in isochroman( in Figure 9) , electron density mainly shifts from the unsaturated ring to the saturated ring on HOMO-LUMO transition.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eESP\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe intermolecular interactions with a solvent can be predicted from the plot of Molecular Electrostatic potential (ESP) surface shown in Figure 11, Figure 12 and figure 13 for isothiochroman, isochroman and isoselenochroman respectively. The orientation of the saturated ring is different in the two conformers of ITC, indicating a difference in their surfaces. Three points are chosen on the respective surfaces to have a quantitative understanding of the nature of intermolecular interactions. The coloured surfaces are plotted in such a way that the blue regions are the positions of accumulation of maximum positive charges, while the red regions are the corresponding ones for negative charges. The negative charges are expected around the pi electron cloud of the unsaturated ring and the lone pair electrons of sulphur atoms. Three points A, B and C are chosen on the MEP, which are positioned at the center of the benzene ring and in the direction of the lone pairs on sulphur and selenium atoms in case of isothiochroman and isoselenochroman respectively. When isothiochroman will interact with water in its hydrated clusters, then the orientations of the different conformers can be predicted from these values. The values are included in Table 3 for the two conformers. There are three possible types of h-bonding is expected in the hydrated clusters of this molecule\u0026mdash;i) \u0026pi;...H-O type, ii) S....H-O type and iii) H....O-H type. Similar cases will arise in ISC where S will be replaced by Se. Interplay between these different types of binding sites as well as the different conformers of ITC and ISC are expected to generate a fascinating landscape of conformers. Our preliminary studies yield that the monohydrates with the bent conformer is in the global minimum of the landscape with a large difference in the energy with the hydrated cluster of the twisted form. This work will be communicated shortly [67]. In isochroman, the corresponding ESP of the twisted conformer suggest that there might be abridged hydrated cluster involving pi electron clouds and the lone pairs of oxygen atoms. This will be subject of our study in near future.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMHP and MEP\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe relative stability of the different conformers and transitions states can also be estimated from the variations in chemical reactivity parameters like hardness (\u003cspan style=\"text-align: start;color: rgb(0, 0, 0);background-color: rgb(255, 255, 255);font-size: 11px;font-family: Verdana, Arial, Helvetica, sans-serif;\"\u003e\u0026eta;\u003c/span\u003e) and electrophilicity (\u003cspan style=\"text-align: start;color: rgb(0, 0, 0);background-color: rgb(255, 255, 255);font-size: 11px;font-family: Verdana, Arial, Helvetica, sans-serif;\"\u003e\u0026omega;\u003c/span\u003e). Maximum hardness principle (MHP) [37] suggests that the most stable conformer should be the hardest and transition states should have the least hardness. On the contrary, minimum electrophilicity principle (MEP) states that the most stable structure should have the least electrophilicity and the reverse is true for the transition states. There are some failures observed in the application of these principles in predicting the most stable conformer of a molecule [67]. In our recent works we found a mixed success in the application of these principles [25, 28, 68]. In case of homophthalic anhydride [69] the entire tautomerisation pathway is found to obey both these principles without any fluctuations or occasional deviations. But in other cases either one of these principles [25]was valid or one of the conformers or transition states [28] were found to follow the principles.\u003c/p\u003e\n\u003cp\u003eITC possess two close lying conformers and two transition states (TS). The values of hardness and electrophilicity for all the conformers and transition states are given in Table 4. If we scrutinize the data we may conclude that the transition state (TS1) having highest value of energy possess the least value of hardness among all the possible structures of ITC. The hardness of the other transition state (TS2) follows the order of stability. Thus transition states (TS1 and TS2) of ITC obey MHP in M06-2X, B3LYP and \u0026omega;B97X-D calculations. But the most stable structure, \u003cem\u003ei.e.\u003c/em\u003e the bent conformer is never found to be the hardest. In isochroman there are only two structures are of importance---minimum twisted and bent as the TS. From the table 4 one can easily conclude that MHP is completely violated both in isochroman and isoselenochroman.\u003c/p\u003e\n\u003cp\u003eMEP states that transition states should have the highest electrophilicity. In the following table (Table8) only in B3LYP calculations shows that the relation between the stability of the conformers and their respective electrophilicities satisfy the above criteria for ITC. Otherwise, MEP does not go along with any levels of computations in ITC. In isochroman, this principle obeyed only by M06-2X and wB97X-D functionals. For isoselenochroman(ISC) MEP follows only in MP2 calculations.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eSulphur and selenium substitutions in tetrahydronaphthalene yields interesting results. The resulting molecule isothiochroman and isoselenochroman exhibits two minima and two transition states in its potential energy surface. The global minimum in each case is a \u0026ldquo;bent\u0026rdquo; conformation, which to the best of our knowledge is the first such reporting of this form to be a global minimum in any of the derivatives of THN. The other minima, the more popularly observed \u0026ldquo;twisted\u0026rdquo; conformation of the saturated ring is energetically very close to the \u0026ldquo;bent\u0026rdquo; conformation in isothiochroman, but was placed much higher (700 cm\u003csup\u003e-1\u003c/sup\u003e ) in energy in isoselenochroman. The PEC has a symmetric distribution in S\u003csub\u003e0\u003c/sub\u003earound the origin. The computations yield a consistent result with variation of basis sets and methods. The highest TS structure follows the hardness principle. The comparison of molecular electrostatic potential surface of the two conformers clearly shows a difference. This will have an enormous effect when this molecule interacts with a solvent, where non-covalent interactions will be present.\u003c/p\u003e \u003cp\u003eThe oxygen substitution on the other hand shows a single twisted conformer as the sole minimum. The TS structure with a bent geometry is located at a height of 1200 cm\u003csup\u003e-1\u003c/sup\u003e. The PEC of different derivatives of THN is compared. The appearance of a bent conformer was first observed in THIQ, where bent form was placed much higher in PEC. Sulphur and selenium substitution has a profound effect on the conformational landscape of the respective molecules. The atomic weight may presumably be the key factor, as the torsion of the saturated ringdecreaseswith the mass. The electron density is another factor. The low-frequency vibrations in the vibrationalspectra follows the same pattern for all of them. But IR spectra of isothiochroman look different from the other molecules in the THN family. MHP is completely violated in isochroman. MEP is obeyed by M06-2X functional in both the molecules. The substitution of THN with oxygen, sulphur and selenium shows a systematic change in the relative energies of the conformations. We suggest some high resolution experiments to corroborate our findings.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are thankful to Niranjan Biswas and Prof. Santu Das for some fruitful discussion. The support from University Grants Commission and Department of Science and Technology (Govt. of India) is also gratefully acknowledged.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAC gratefully acknowledges the financial support received from University Grants Commission through a research Project (F. No. 37-560/2009(SR)) for conducting this work. The authors also acknowledge the instrumental support from DST (Govt. of India) under departmental FIST program of the University of Burdwan (Grant no: SR/FST/PS-II-001/2011) and University Grants Commission (UGC) for departmental CAS (Grant no. F.530/ 5/CAS/2011(SAP-I)) scheme\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. I. M. : Literature Survey, editing, Software handling, Data handling,A. C. : Conceptualisation and Visualisation of the problem, Writing, Reviewing and editing the manuscript, Literature Survey, Presentation of Figures\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eI. Petterson and T. Liljefors, Structure-activity relationships for apomorphinecongeners..Conformational energies vs. biological activities.J.of Comp. Aid. Mol. Design, 1 (1987) 143-152.\u003c/li\u003e\n\u003cli\u003eG. Malloci, G. Serra, A. Bosin, A. V. Vargiu. 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DOI: 10.1007/s00894-020-04411-7\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. : Calculated relative energies (cm\u003csup\u003e-1\u003c/sup\u003e) for different conformers and transition states of isochroman, isothiochroman and isoselenochroman.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eMethod\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eBasis Set\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"13\" valign=\"top\"\u003e\n \u003cp\u003eStructures\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003eIsochroman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\"\u003e\n \u003cp\u003eIsothiochroman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eIsoselenochroman\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePlanar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePlanar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTS1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePlanar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTS\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTS\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eDFT-B3LYP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1122\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3517\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e562\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e698\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3875\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1628\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e571\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eG++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3624\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e555\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3952\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1565\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e540\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eaug .cc-pVDZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3512\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3644\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1056\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e560\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e705\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3856\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1590\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e530\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eDFT-M06-2X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1202\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e694\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3901\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e631\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eG++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3577\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e641\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e708\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3940\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1685\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e612\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eaug .cc-pVDZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3524\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1156\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e622\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e725\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3954\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1550\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e598\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eDFT\u003c/p\u003e\n \u003cp\u003ewb 97xD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1255\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3606\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3798\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1089\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e520\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3865\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1462\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e612\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eG++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3587\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3766\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e694\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e663\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3895\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1562\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e584\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eaug.cc-pVDZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3632\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3737\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e482\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3910\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1570\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e599\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eMP2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1161\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3532\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3621\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e795\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1489\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e605\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eG++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3503\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3609\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e757\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e713\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3950\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1586\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e685\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eaug.cc-pVDZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3567\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1098\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e735\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e722\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3962\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1653\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e645\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eCCSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3677\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e122\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3805\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e708\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e730\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3899\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1652\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e625\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eG++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1189\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3708\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3768\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e697\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e715\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3924\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1563\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e601\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eG stands for 6-31 G(d) and G++ for 6-311 ++G(2d,3p) and cc for aug cc-pVDZ basis sets.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.:\u003c/strong\u003e The important structural parameters of bent and twisted conformations of isothiochroman and isoselenochroman over various methods. Basis set was 6-311G++(2d,3p) for all the computations.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"803\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 104px;\"\u003e\n \u003cp\u003eMethod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" style=\"width: 360px;\"\u003e\n \u003cp\u003eisothiochroman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eisoselenochroman\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 180px;\"\u003e\n \u003cp\u003eBent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 180px;\"\u003e\n \u003cp\u003eTwisted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eBent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eTwisted\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eD\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eD\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eD3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eD\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eD\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eD\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eD\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eD\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eD\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eD\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eD\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eD\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eDFT-B3LYP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-11.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e52.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-55.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-62.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-24.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-19.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-11.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e55.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-60.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-63.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e-2.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-18.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eDFT-M06-2X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-11.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e53.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-56.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-64.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-25.271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-18.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-10.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e54.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-59.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-62.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e-7.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-19.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eDFT-\u003c/p\u003e\n \u003cp\u003e\u0026omega;B97X-D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-11.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e52.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-55.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-63.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-24.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-19.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-11.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e56.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-61.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-64.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e-5.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-18.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMP2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-13.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e55.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-56.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-65.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-26.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-19.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-12.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e52.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-60.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-62.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e-15.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-18.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCCSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-12.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e52.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e55.465\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-63.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e-24.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e-18.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-12.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e54.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-59.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-64.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-19.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eD\u003csub\u003e1\u003c/sub\u003e=\u0026nbsp;\u0026ETH;C1-S-C3-C4 in degree, D\u003csub\u003e2\u003c/sub\u003e = \u0026ETH;C5-C10-C1-S in degree, D3 = \u0026ETH;C10-C5-C4-C3\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eValues (in e/\u0026Aring;) of molecular electrostatic potential of different conformers of isothiochroman, isochroman and isoselenochroman at three critical regions indicated at Fig. 11.,12 and 13 (1e/\u0026Aring; = 332.1 kcal/mol)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 131px;\"\u003e\n \u003cp\u003eMolecule\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eConformer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 131px;\"\u003e\n \u003cp\u003eIsothiochroman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eBent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e-0.02587\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e-0.03146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e-0.027715\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eTwisted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e-0.02591\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e-0.02962\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e-0.02697\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 131px;\"\u003e\n \u003cp\u003eIsochroman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eTwisted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e-0.02531\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e-0.04038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e0.11876\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 131px;\"\u003e\n \u003cp\u003eIsoselenochroman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eBent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e-0.02403\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e-0.02985\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e-0.0167\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eTwisted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e-0.02084\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e0.01206\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e-0.0232\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-molecular-modeling","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jmmo","sideBox":"Learn more about [Journal of Molecular Modeling](https://www.springer.com/journal/894)","snPcode":"894","submissionUrl":"https://submission.nature.com/new-submission/894/3","title":"Journal of Molecular Modeling","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Ab-initio Calculations, isochroman and isothiochroman, Potential energy, transition states, Hardness and electrophilicity, HOMO and LUMO, vibrational frequencies","lastPublishedDoi":"10.21203/rs.3.rs-6622869/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6622869/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eContext:\u003c/strong\u003e The oxygen, sulphur and selenium derivatives of tetralin termed as isochroman (IC), isothiochroman (ITC) and isoselenochroman (ISC) showed interesting conformational pattern. In particular ITC and IC have immense pharmacological significance. The twisted conformer is global minimum in IC, where the bent is a transition state (TS) and remains 1100 ± 100 cm\u003csup\u003e-1\u003c/sup\u003e higher. The bent form in ITC and ISC possess the lowest energy. But, the twisted conformer lies higher by about 80 ± 20 cm\u003csup\u003e-1\u003c/sup\u003e in ITC and 700 ± 50 cm\u003csup\u003e-1\u003c/sup\u003e in ISC. The potential energy surfaces (PES) locate all the conformations and TSs. Molecular electrostatic potentials indicate the sites of electrophilic interactions and the small energy difference between the minima in ITC predict an interesting interplay of intermolecular interactions. The validity of maximum hardness principle and minimum electrophilicity principles are checked. Frontier molecular orbitals show the change in electron densities on excitation, which are mostly p®p\u003csup\u003e*\u003c/sup\u003e in nature. We suggest some experiments to corroborate our findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Computations are performed with different functionals (B3LYP, M06-2X and ωB97X-D) in DFT as well as \u003cem\u003eab-initio\u003c/em\u003e methods (MP2 and CCSD) with 6-311G++ (2d, 3p) [55] and augmented cc-pVDZ as basis sets. Gaussian 09 is used for the above computations. PED analysis was performed by Veda 4 software.\u003c/p\u003e","manuscriptTitle":"How does the conformational landscape change on substitution in tetralin? A computational investigation with oxygen, sulphur and selenium","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-23 05:30:46","doi":"10.21203/rs.3.rs-6622869/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-16T07:50:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-16T04:26:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-16T04:25:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Molecular Modeling","date":"2025-05-08T17:52:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-molecular-modeling","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jmmo","sideBox":"Learn more about [Journal of Molecular Modeling](https://www.springer.com/journal/894)","snPcode":"894","submissionUrl":"https://submission.nature.com/new-submission/894/3","title":"Journal of Molecular Modeling","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"19bd08ce-449a-4bb4-8c3e-0131e875f78a","owner":[],"postedDate":"May 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T16:01:57+00:00","versionOfRecord":{"articleIdentity":"rs-6622869","link":"https://doi.org/10.1007/s00894-025-06432-6","journal":{"identity":"journal-of-molecular-modeling","isVorOnly":false,"title":"Journal of Molecular Modeling"},"publishedOn":"2025-07-12 15:57:34","publishedOnDateReadable":"July 12th, 2025"},"versionCreatedAt":"2025-05-23 05:30:46","video":"","vorDoi":"10.1007/s00894-025-06432-6","vorDoiUrl":"https://doi.org/10.1007/s00894-025-06432-6","workflowStages":[]},"version":"v1","identity":"rs-6622869","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6622869","identity":"rs-6622869","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}