Interplay between structural integrity and aromaticity on governing the nature of the non- covalent interactions within the mono and di-solvent clusters of 2-Hydroxypyridine and 2- Hydroxynicotionic acid: A topological description

Interplay between structural integrity and aromaticity on governing the nature of the non- covalent interactions within the mono and di-solvent clusters of 2-Hydroxypyridine and 2- Hydroxynicotionic acid: A topological description | 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 Interplay between structural integrity and aromaticity on governing the nature of the non- covalent interactions within the mono and di-solvent clusters of 2-Hydroxypyridine and 2- Hydroxynicotionic acid: A topological description Aniruddha Ganguly This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4931761/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Bader’s “Atoms in Molecules” formalism has been adopted to assess the non-covalent interactions present within the mono and di-solvent (water and methanol) clusters of 2-Hydroxypyridine and 2-Hydroxynicotionic acid in their Closed and Open conformations and to critically analyze the characteristics and the energetics of the interaction lines towards the planarity of the structural skeletons. Nucleus independent chemical shift (NICS) descriptor has also been exploited to delineate the role of aromaticity in dictating the structures and the characteristics of the non-covalent interactions present within the studied compounds. Both electrostatic and partially covalent Hydrogen bonding interactions (HB) are found within the clusters. Furthermore, apart from the typical O····H–O and N····H–O HBs, a weak albeit unique O····H–C interaction line of purely electrostatic origin is observed. The covalency of the HBs as well as the structural constraints are found to modulate the aromaticity of the associated pyridine nuclei. Atoms In molecules Non-covalent interactions Clusters Nucleus Independent Chemical Shift Covalency of the HBs Figures Figure 1 Figure 2 Figure 3 Introduction Non-covalent interactions are of crucial importance despite their so called “weaker” nature in contrast to typical ionic and covalent interactions considering their indispensable role in governing the spatial architectures and regulatory functions of biomolecules [ 1 – 5 ]. Hydrogen bonding (HB), the most fundamental among the non-covalent forces has always received extensive attention owing to its pervasive nature and critical importance to create and sustain life [ 1 – 6 ]. But the inherent complexities associated with the biological media often deem the unambiguous in vivo identification and characterization of the non-covalent interactions nearly impossible [ 7 , 8 ]. As a result, Hydrogen-bonded clusters, especially those of small aromatic molecules are becoming of paramount interest following the fact that, in these model systems, simply by changing the interacting molecules, selective isolation of these interactions are feasible, which can provide essential information about the function and dynamics of biomolecules with the additional advantage of conceivable outputs [ 9 – 11 ]. Furthermore, if the cluster is comprised of an aromatic molecule capable of HB formation either as a donor or an acceptor or both and a polar solvent molecule like water or methanol, it can serve as a potential model system for solvation in the condensed phase [ 9 – 13 ]. Since a “Chemical bond” does not qualify as a Dirac observable, an explicit quantum mechanical definition of the said term is unavailable leading to the relentless debate on the assessment of a particular pair of atoms to be considered as chemically bonded [ 14 , 15 ]. However, a rigorous quantum mechanical description formulated by Bader, viz. Atoms in molecules i.e. AIM formalism, which confides on the topological density operator \(\:\widehat{\rho\:\:}\) ( r ), having experimentally quantifiable expectation values, provides a distinctive platform to affirm and quantify the phenomenon of bonding of any manner between a pair of nuclei by a necessary and the sufficient condition of the existence of a “bond path” provided that the system is in stable electrostatic equilibrium [ 14 – 17 ]. As a bond path, i.e. the line following the ridge of maximum electronic density is invariably mirrored by another line of maximally negative potential energy density connecting the same nuclei, i.e. the virial path; Bader’s theory, strictly in an atomistic sense asserts a bond path to be always stabilizing [ 14 – 17 ]. The present contribution describes a thorough AIM-based investigation of the non-covalent interactions present within the mono and di-solvent (water and methanol) clusters of 2-Hydroxypyridine and 2-Hydroxynicotionic acid (Henceforth abbreviated as 2HP and 2HNA respectively) in their Closed and Open conformations (abbreviated as − C and − O conformations respectively, vide Schemes 1 and 2 ); and hence to inspect their roles in governing the structural motifs of the clusters. Besides, the role of aromaticity in dictating the structures and the energetics of the non-covalent interactions has also been analyzed exploiting the Nucleus Independent Chemical Shift (NICS) parameters [ 18 , 19 ]. Finally, the study also endeavors to establish whether structural impediments associated with maintaining a quasi-ring could affect the covalency of the HBs or not. Computational procedures Geometry optimization and frequency simulation Necessary geometry optimizations have been accomplished on Gaussian 09 suite of programs [ 20 ] utilizing the Møller–Plesset second order perturbation method (MP2) alongside the triple-ζ quality 6-311 + + G (d,p) basis set without imposing any symmetry restraints on the structures. The acquired structures have been subjected to compulsory vibrational analyses to authenticate the global minimization of the associated geometries as well as for necessary frequency assignments. Atoms-In-Molecules (AIM) analysis The AIM calculations have been performed on AIM2000 software suite [ 21 ] by virtue of the wavefunction files obtained from the optimized geometries at MP2/6-311 + + G(d,p) level using the Gaussian 09 suite. Calculation of aromaticity indices The Nucleus Independent Chemical Shift (NICS) index [ 18 , 19 ] has been applied to quantitatively assess the aromatic character of the pyridine rings associated with the studied systems. The necessary computations have been performed on the Gaussian 09 suite at MP2/6-311 + + G(d,p) level using the gauge-independent atomic orbital (GIAO) formalism, i.e. using the “Bq” probe atom to assign the spatial positions for the estimation of the index. However, it is worth mentioning that NICS(1) i.e. the negative values of absolute shielding measured at 1Å above the center of the ring and the corresponding zz tensor component (NICS (1) zz ) instead of the archetypal NICS(0) values computed at the centre of the ring itself has been opted in the present context as the latter analysis is fraught with spurious contributions from the in-plane σ–tensor components whereas the former asserts a better participation of the so called π-cloud [ 18 , 19 ]. Results and Discussions Geometrical and vibrational analyses The molecular frameworks relevant to this study, viz. 2HP and 2HNA (the numbering of the interacting atoms have been done according to Schemes 1 and 2 ) exhibit planar equilibrium structures in their Closed conformations; whereas although the Open conformation of 2HP is still planar, the –COOH functionality of 2HNA in its Open form exhibits a dihedral twist of ~ 29.74° with respect to the pyridine ring in an effort to minimize the destabilizing O 6 ····O a ( vide Scheme 1 and 2 ) Coulombic repulsion. This fact is supported by an augmented separation between the said O atoms on moving from the respective Closed conformation (~ 2.68 Å) to the Open conformation (~ 2.81 Å). However, the optimized geometries of the clusters furnish some atypical observations. For the mono-solvent (n = 1) clusters associated with the Closed conformations of 2HP ( viz. 2HP–C–ROH; R = H, CH 3 ), the frameworks remain nearly planar and the interacting –OH functionalities of the solvents reside in the same plane as that of the 2HP skeleton, whereas, for the Open conformations, the N 1 –C–O 5 –H 6 dihedrals display slight deviation from linearity, the corresponding angles being ~ 2.26° and 3.35° respectively for the water and MeOH clusters possibly owing to no or insignificant contribution of the –OH functionality in any bonding interactions. On the other hand, for the di-solvent (n = 2) clusters the deviation of the N 1 –C–O 5 –H 6 dihedral is comparatively significant which may be attributed to the flexibility of the geometries of the di-solvated clusters as compared to the corresponding mono-solvated ones; viz. the C α –O 5 –H 6 bond angle is found to discernibly amplify on moving from 2HP–C–H 2 O cluster (~ 109.1°) to the 2HP–C–(H 2 O) 2 cluster (~ 111.6°). The aforesaid rationale also accounts for the augmented N 1 –C α –O 5 –H 6 dihedrals in the di-solvent clusters of the Open conformation of 2HNA as compared to the corresponding mono-solvent clusters. Interestingly, the twist angle of the –COOH functionality of 2HNA in its Open form is found to increase in the clusters as compared to the framework itself; especially for the di-solvent clusters, which can be attributed to the aversion of the destabilizations associated with the O 5 ····O a Coulombic repulsions which otherwise would significantly enhance due to an increment in the atomic charges of the O 5 atoms as a result of HB formations. It is however worth mentioning here that in the 2HNA–O–H 2 O cluster, the –COOH functionality resides in the plane of the pyridine ring; the corresponding justification is to be substantiated later. In a chemical sense, the formation of an X····H–Y HB is typically perceived as a hyperconjugative charge transfer from the lone pair of the acceptor atom X to the σ* orbital of the donor bond H–Y [ 22 , 23 ]; an outcome of which is a reduction in the H–Y bond order as compared to the corresponding non-hydrogen bonded structure resulting a decrement in the H–Y stretching frequency in the H-bonded configuration, thoroughly substantiated by a ~ 83 cm –1 blue shift in the H 6 –O 5 stretching frequency on moving from the H-bonded Closed conformations to the Open conformations devoid of HBs for 2HNA ( vide Table S1 in the supplementary information). As far as the clusters are concerned, for the 2HP–C and the 2HNA–O clusters, evidence of strong HBs involving the –O 5 –H 6 functionality ( viz. the O 3 ····H 6 –O 5 HBs) is evident from the substantial decrements of the associated stretching frequencies ( vide Table S1 in the supplementary information); the order of strength being –H 2 O < –MeOH < –(H 2 O) 2 < –(MeOH) 2 for both the 2HP–C and 2HNA–O frameworks, which is readily attributable to a reduced spatial separation between the atoms involved in the HB; whereas for the 2HP–O clusters, the near constancy of the corresponding stretching frequency infers the O 5 –H 6 bond not being involved in any H-bonding interaction. It should however be mentioned at this point that there exists an O 5 ····H 7 –O 8 HB in the 2HP–O–(H 2 O) 2 cluster as concluded by the stretching frequency of the H 7 –O 8 bond being notably blue shifted ( vide Table S1 in the supplementary information) with respect to the H–O stretching frequency of water (~ 3887 cm –1 ). Interestingly, although the exact same orders of strength for the N 1 ····H 2 –O 3 HBs are noted for the 2HP–C and 2HNA–O frameworks as a result of a similar trend of spatial separation between the two atoms involved in the formation of the said HBs; the 2HP–O framework furnishes the order, –H 2 O ≈ –MeOH > –(H 2 O) 2 , which also seems rational as the separation between the involved atoms follow the exact same trend. For the di-solvent clusters, O 3 ····H 7 –O 8 HBs associated with the interaction between the two solvent molecules as proliferated in the blue shift of the H 7 –O 8 stretching frequency as compared to water (~ 3400 cm –1 ) is observed and the corresponding energetics agrees well with the internuclear separation between the bonded atoms. An analogous O 3 ····H 9 –O 8 HB for the 2HP–O–(H 2 O) 2 cluster with an amplified atomic separation is also noted in this regard. Moreover, the C 4 –H c stretching frequency in the 2HP–O–MeOH cluster shows a significant blue shift as compared to the C 4 –H c stretching frequency of methanol itself (~ 3191 cm –1 ), inferring the presence of a O 5 ····H c –C 4 HB in the aforesaid cluster. Topological analysis: Atoms-In-Molecule (AIM) study AIM analysis, proposed by Bader, depends principally on the scrutiny of the electron density (ρ( r )) of a molecule. As already has been pointed out, the theory predicts an interaction between two atoms by means of the existence of a critical point (CP) and an associated bond path linking the said atoms in a global minimum structure [ 6 , 14 – 17 , 22 , 23 ]. In the present contribution, AIM analyses have been employed to authenticate and enumerate the H–bonding interactions present within the concerned optimized structures ( vide Fig. 1 →3). The subsequent observations and pertinent discussions are summarized below. (i) All the clusters are found to contain N 1 ····H 2 –O 3 HBs ( vide Fig. 1 →3) in their optimized geometries. The corresponding data (summarized in Table 1 ) reveal that the magnitudes of the electron densities at the associated Bond Critical Points (ρ c ) are well within the Popelier limit of ~ 0.04 a.u. thereby demarcating them as conventional HBs, a fact further supported by the values of the associated Laplacians being within the threshold of ~ 0.13 a.u. [ 24 ]. Table 1 AIM parameters corresponding to the N 1 ····H 2 –O 3 , O 3 ····H 6 –O 5 and O 5 ····H c –C 4 HBs in the studied structures Compound d HB (Å) r HB (a.u.) ρ c (a.u.) ∇ 2 ρ c (a.u.) G c (a.u.) V c (a.u.) H c (a.u.) ρ RCP (a.u.) ellipticity E HB (kcal/mol) N 1 ····H 2 –O 3 HB 2HP–C–H 2 O 2.0329 3.9105 0.02416 0.09076 0.02059 – 0.01849 0.00211 0.01084 0.04211 – 5.8013 2HP–C–MeOH 1.9758 3.8011 0.02778 0.09849 0.02340 – 0.02229 0.00111 0.01314 0.03155 – 6.9936 2HP–C–(H 2 O) 2 1.8460 3.3936 0.03485 0.11234 0.02887 – 0.02993 – 0.00109 0.00435 0.04554 – 9.3907 2HP–C–(MeOH) 2 1.8204 3.4956 0.03751 0.11589 0.03109 – 0.03321 – 0.00212 0.00585 0.03782 – 10.4198 2HP–O–H 2 O 1.9723 3.7812 0.02517 0.09411 0.02125 – 0.01898 0.00227 — 0.07175 – 5.9551 2HP–O–MeOH 1.9648 3.7667 0.02616 0.09541 0.02192 – 0.01999 0.00193 0.00242 0.05615 – 6.2721 2HP–O–(H 2 O) 2 2.0806 3.9926 0.01950 0.07547 0.01602 – 0.01316 0.00286 0.00236 0.09421 – 4.1290 2HNA–O–H 2 O 2.1106 4.0778 0.02093 0.08057 0.01779 – 0.01544 0.00235 0.01098 0.02104 – 4.8444 2HNA–O–MeOH 2.0773 3.9011 0.02519 0.09117 0.02119 – 0.01959 0.00161 0.01317 0.03085 – 6.1465 2HNA–O–(H 2 O) 2 1.8693 3.5883 0.03282 0.10817 0.02728 – 0.02753 – 0.00025 0.00439 0.04961 – 8.6377 2HNA–O–(MeOH) 2 1.8379 3.5288 0.03586 0.11368 0.02984 – 0.03126 – 0.00142 0.00520 0.04408 – 9.8078 O 3 ····H 6 –O 5 HB 2HP–C–H 2 O 1.8346 3.5280 0.02599 0.12104 0.02704 – 0.02381 0.00322 0.01084 0.07583 – 7.4705 2HP–C–MeOH 1.7605 3.3862 0.03604 0.13604 0.03424 – 0.03446 – 0.00023 0.01314 0.03911 – 10.8120 2HNA–O–H 2 O 1.8076 3.4764 0.02779 0.12711 0.02885 – 0.02593 0.00293 0.01098 0.08389 – 8.1357 2HNA–O–MeOH 1.8069 3.3219 0.03904 0.14351 0.03715 – 0.03843 – 0.00013 0.01317 0.03745 – 12.0576 O 5 ····H c –C 4 HB 2HP–O–MeOH 2.9659 5.6797 0.00353 0.01387 0.00283 – 0.00219 0.00064 0.00242 0.03535 – 0.6871 Now, the Laplacian, which depends on the electronic kinetic and potential energy densities, viz. G ( r ) and V ( r ) respectively, can be expressed in terms of the Virial equation as [ 6 , 14 – 17 , 22 , 23 ]: Which immediately suggests that as G ( r ) > 0 and V ( r ) < 0, the sign of the Laplacian dictates the dominant energy density at the point r , i.e. a positive Laplacian at the BCP, as observed here, is indicative of the dominance of kinetic energy, which means that the electron density ρ( r ) is concentrated towards the nuclei, a typical trait of closed-shell (electrostatic) interactions whereas a negative Laplacian suggests the dominance of the potential energy; the electron density being concentrated within the bond path signifying covalent interaction [ 6 , 22 , 23 ]. The total energy density H ( r ) at the BCP represented as H c , which is the sum of the corresponding G ( r ) and V ( r ) at the BCP ( G c and V c respectively), is often considered as a more reliable parameter than the Laplacian itself to ascertain the nature of the associated bond path [ 6 , 22 , 23 ]; a positive H c (i.e. | G c | > | V c |) implies a closed-shell interaction and a negative H c (i.e. | V c | > | G c |) represents covalent interaction [ 6 , 22 , 23 ]. In the present scenario, although all the Laplacians are found to be positive, indicating closed-shell interactions, the corresponding H c s are not always positive ( vide Table 1 ). This apparent anomaly can be rationalized by a closer scrutiny of the Virial equation mentioned above. The equation simply shows that for a positive laplacian (i.e. | V c | < 2| G c |), two different situations may occur, (i) | V c | 0 and the interaction is purely electrostatic or (ii) | V c | > | G c | but | V c | < 2| G c |; i.e. H c 0 indicating electrostatic interaction, which is the situation here for the HBs present in a few of the studied clusters. So, as obvious, these types of HBs are partially covalent and partially electrostatic in nature [ 6 , 22 , 23 ]. However, it is imperative to note in this context that the model of resonance–assistance is not strictly applicable in the present scenario to account for the covalency associated with the HBs, as the said concept is typically invoked in cases where the donor and the acceptor moieties reside in the same nucleus. As can be seen from the tabulated data, for all the mono-solvent clusters (n = 1), and the Open conformation of the di-solvent cluster 2HP–(H 2 O) 2 , the N 1 ····H 2 –O 3 HBs are characterized by a positive Laplacian and a positive total energy density; viz. ∇ 2 ρ c > 0; and H c > 0, thereby inferring the interaction to be of electrostatic origin. However, the N 1 ····H 2 HBs associated with all the di-solvent clusters apart from the one mentioned above show negative total energy densities ( H c < 0), thus concluding a credible degree of covalency to the said HBs. The reason behind such an observation is to be substantiated later. A semi-quantitative description of the strengths of the concerned HBs ( vide Table 1 ), obtained using the relation E HB ≈ – V c /2 [ 6 , 22 , 23 ], divulges that the N 1 ····H 2 –O 3 HBs present in the concerned structures are moderately strong and the consequent energetics corroborate well with the separation between the two bonded atoms viz. N 1 and H 2 involved in the HBs [ 22 , 23 ]. The ellipticities (ε), defined as the ratio of the two largest negative eigenvalues of the Hessian of the electron density, are found to be remarkably small for the N 1 ····H 2 BCPs, indicating near isotropic distribution of the electron density in the directions normal to the bond path, i.e. a cylindrical symmetry of the HBs [ 14 – 17 , 22 , 23 ]. (ii) The mono-solvent clusters except for that associated with the Open conformation of 2HP ( viz. 2HP–O–H 2 O) also contain O 3 ····H 6 –O 5 HBs thoroughly preserving the Popelier criteria ( vide Table 1 ). However, although all these HBs are characterized by ∇ 2 ρ c > 0; when the solvent is water, the parameter H c is found to be > 0, thus ascertaining the interaction to be Coulombic in nature; whereas for MeOH, H c furnishes values < 0 supporting an involvement of the aromatic π-cloud in the interaction. The corresponding HBs are reasonably symmetric as is obvious from the values of the ellipticities at the respective BCPs; the HBs associated with the MeOH clusters being more symmetric as compared to the water clusters. (iii) The 2HP–O–MeOH cluster furnishes a unique O 5 ····H c –C 4 HB, the corresponding electron density parameters ρ c and ∇ 2 ρ c being one order in magnitude smaller than the Popelier threshold concluding exceptionally weak HB as substantiated by the associated energy and a significantly longer bond path ( vide Table 1 ). The interaction is purely electrostatic as supported by the conditions: ∇ 2 ρ c > 0; and H c > 0. Interestingly, the meager value of the ellipticity at the corresponding BCP is indicative of a symmetric HB although the corresponding RCP deviates significantly from the centroid of the formed quasi-ring. (iv) All the di-solvent clusters except for the Open conformation of 2HP ( viz. 2HP–O–(H 2 O) 2 ) demonstrate O 8 ····H 6 –O 5 HBs. As is evident from Table 2 , the magnitude of the electron densities as well as the corresponding Laplacians at the Bond Critical Points associated with the said HBs are noticeably greater than those suggested for conventional HBs [ 22 , 23 ] representing strong HBs with discernible covalency which is further substantiated from the corresponding H c s being < 0 and amplified values of the corresponding potential energy densities ( V c ). The associated ellipticities evince significant cylindrical symmetries of the HBs Table 2 AIM parameters corresponding to the O 8 ····H 6 –O 5 , O 5 ····H 7 –O 8 , O 3 ····H 7 –O 8 , O 3 ····H 9 –O 8 and O a ····H 6 –O 5 HBs in the studied structures Compound d HB (Å) r HB (a.u.) ρ c (a.u.) ∇ 2 ρ c (a.u.) G c (a.u.) V c (a.u.) H c (a.u.) ρ RCP (a.u.) ellipticity E HB (kcal/mol) O 8 ····H 6 –O 5 HB 2HP–C–(H 2 O) 2 1.7245 3.3140 0.03772 0.14314 0.03625 – 0.03672 – 0.00047 0.00435 0.05330 – 11.5211 2HP–C–(MeOH) 2 1.6513 3.1743 0.04741 0.15931 0.04461 – 0.04938 – 0.00477 0.00585 0.02980 – 15.4932 2HNA–O–(H 2 O) 2 1.6981 3.2639 0.04037 0.14921 0.03879 – 0.04028 – 0.00149 0.00439 0.05499 – 12.6381 2HNA–O–(MeOH) 2 1.6284 3.1309 0.04981 0.16470 0.04707 – 0.05296 – 0.00589 0.00520 0.04663 – 16.6162 O 5 ····H 7 –O 8 HB 2HP–O–(H 2 O) 2 1.9971 3.8262 0.01872 0.08581 0.01793 – 0.01441 0.00352 0.00236 0.06316 – 4.5211 O 3 ····H 7 –O 8 HB 2HP–C–(H 2 O) 2 1.7887 3.4376 0.03278 0.13447 0.03218 – 0.03074 0.00144 0.00435 0.02547 – 9.6448 2HP–C–(MeOH) 2 1.7682 3.4003 0.03565 0.14077 0.03483 – 0.03447 0.00036 0.00585 0.05530 – 10.8151 2HNA–O–(H 2 O) 2 1.7953 3.4503 0.02535 0.13325 0.03113 – 0.03014 0.00099 0.00439 0.02535 – 9.4566 2HNA–O–(MeOH) 2 1.7528 3.3696 0.03693 0.14450 0.03609 – 0.03606 0.00003 0.00520 0.04123 – 11.3138 O 3 ····H 9 –O 8 HB 2HP–O–(H 2 O) 2 2.1348 4.1061 0.01623 0.06337 0.01396 – 0.01208 0.00188 0.00236 0.04889 – 3.7901 O a ····H 6 –O 5 HB 2HNA–C 1.7790 3.4250 0.03644 0.13928 0.03502 – 0.03520 – 0.00019 0.01707 0.02546 – 11.0442 Instead of the aforementioned O 8 ····H 6 –O 5 HB, an O 5 ····H 7 –O 8 HB is observed for the 2HP–O–(H 2 O) 2 cluster ( vide Table 2 ) owing to the spatial orientation of the –O 5 –H 6 functionality. Interestingly, the corresponding HB is found to be significantly weaker as compared to the former ones, and is characterized by H c > 0, i.e. the interaction is of Coulombic origin. (v) For all the di-solvent clusters, symmetric HBs between the two solvent molecules ( viz. O 3 ····H 9 –O 8 HB for 2HP–O–(H 2 O) 2 and O 3 ····H 7 –O 8 HB for the rest; vide Table 2 ), of significant strength (2HP–O–(H 2 O) 2 being the only exception because of a larger separation between the interacting atoms) and electrostatic character (i.e. H c > 0) is observed. (vi) As can be inferred from the absence of the corresponding ring critical point (RCP), the 2HP–O–H 2 O cluster is the only non-cyclic structure. A distance of 3.94Å between the O 5 and the H 4 atoms is responsible for this observation. The magnitude of the electron densities at the RCPs for all the other relevant structures (ρ RCP ) indicate stable critical points which in turn demonstrate the geometries to be stable. (vii) The 2HNA–O–H 2 O and 2HNA–O–MeOH clusters contain O 5 ····O a interaction lines of Coulombic origin ( H c > 0) as can be seen from the relevant parameters ( vide Table S2 in the supplementary information). The increase in the distance between the interacting atoms (~ 2.71 Å in 2HNA–O–H 2 O to ~ 2.84 Å in 2HNA–O–MeOH) as a result of the non-planarity of the –COOH functionality in the latter is thoroughly reflected in the diminution of the electron densities at the respective BCPs, as well as in the significant elongation of the total bond path (~ 5.14 au in 2HNA–O–H 2 O to ~ 5.40 au in 2HNA–O–MeOH). The drastic increment in the ellipticity of the BCP on moving from 2HNA–O–H 2 O to 2HNA–O–MeOH immediately suggests a more unstable critical point in the latter, further substantiated by a reduced separation between the corresponding BCP and the RCP (from ~ 0.80 Å in 2HNA–O–H 2 O to ~ 0.22 Å in 2HNA–O–MeOH). The destabilization association with the said interaction line is evident from its absence in the di-solvent clusters of the Open conformation of 2HNA where the twisting angle of the –COOH functionality is comparatively higher as compared to 2HNA–O–MeOH cluster. Aromaticity analysis: Nucleus Independent Chemical Shift (NICS) study Although as previously stated, the general perception of resonance-assistance is not strictly applicable in our scenario, as the HB interactions are associated with atoms or functionalities directly of substitutionally attached to the aromatic nucleus; a modification of the global π-electron delocalization within the ring skeleton due to communication between the moieties responsible for the formation of HB as opposed to the nuclei devoid of such interactions is expected to occur, resulting in a modulation of the indices pertinent to the Hückel aromaticity of the nucleus [ 25 – 27 ]. The NICS parameters associated with the studied nuclei are collected in Table 3 , an inspection of which provides the subsequent observations. Table 3 NICS Parameters corresponding to the studied structures Compound NICS(1) NICS(1 zz ) 2HP–C – 9.7692 – 26.7188 2HP–C–H 2 O – 9.3891 – 25.4787 2HP–C–MeOH – 9.2779 – 25.0903 2HP–C–(H 2 O) 2 – 9.2264 – 24.8126 2HP–C–(MeOH) 2 – 9.0943 – 24.6028 2HP–O–H 2 O – 9.8851 – 26.7028 2HP–O–MeOH – 9.8369 – 26.4866 2HP–O–(H 2 O) 2 – 10.0512 – 27.1768 2HP–O – 9.9159 – 27.0328 2HNA–C – 9.2499 – 23.2789 2HNA–O–H 2 O – 9.0236 – 23.1409 2HNA–O–MeOH – 9.0929 – 23.3101 2HNA–O–(H 2 O) 2 – 8.9973 – 22.8119 2HNA–O–(MeOH) 2 – 8.8528 – 22.4226 2HNA–O – 9.5120 – 24.3218 (i) For the Closed forms of 2HP, the pyridine nucleus of the mono-solvent clusters which contain two HB interaction lines (N 1 ····H 2 –O 3 and O 3 ····H 6 –O 5 ) are found to be less aromatic as compared to 2HP itself. Since the N 1 ····H 2 –O 3 interaction lines for the aforesaid clusters are of electrostatic origin, their effect on the aromaticity of the 2HP nucleus should be minimal and thus the modulation of aromaticity of the concerned nuclei should be attributed to the O 3 ····H 6 –O 5 interaction lines. Interestingly, contrary to the case of water, for methanol the O 3 ····H 6 –O 5 HB furnish noteworthy covalent character confirming the involvement of the π-electrons of the ring, substantiated accordingly by a reduced magnitude of the NICS parameter in case of methanol. For the corresponding Open forms containing only the N 1 ····H 2 –O 3 interaction lines, the NICS parameters furnish almost identical magnitudes in comparison with the Open form of 2HP itself; the methanol cluster exhibiting slightly lesser aromaticity as compared to the water cluster, a fact corroborating well with the impression of a relatively stronger HB in the former case which also is the case for the Closed structures. Thus, for the 2HP–C–MeOH cluster, the quantitatively greater reduction in the extent of the aromatic character of the pyridine nucleus is a combined effect of two factors, (a) comparatively amplified strengths of the HBs and (b) the electronic assistance provided by the nucleus to the partially covalent O 3 ····H 6 –O 5 HB. However, it should be emphasized in this regard that although for the 2HP–C–H 2 O cluster both the HBs are of electrostatic origin, the corresponding NICS parameters are found to be discernibly reduced as compared to the Closed conformation of 2HP, the probable reason being the adjustments in the structural parameters to maintain a Closed geometry in order to sustain the two HB interaction lines, e.g. for the concerned structures, the C α – N 1 bond is found to increase in length on moving from 2HP–C to 2HP–C–H 2 O (from ~ 1.33 Å to 1.34 Å) whereas the C α – O 5 bond length decreases (from ~ 1.36 Å to 1.34 Å). (ii) For both the di-solvent clusters of the Closed conformation of 2HP, the observed HB interaction lines involving the pyridine nucleus; viz. N 1 ····H 2 –O 3 and O 8 ····H 6 –O 5 are perceived to have significant covalent character which confirms the involvement of the π-electrons of the ring, resulting a decrease in the aromaticity of the pyridine nucleus as compared to 2HP–C; the extent of decrement being greater for the methanol cluster as the corresponding HBs are comparatively stronger. Interestingly, since the N 1 atom is not involved in the aromatic sextet of pyridine, its participation in the formation of an HB as a donor atom is expected not to have any effect on the π-electron delocalization within the ring itself, which is in sharp contrast to the observed results, the probable reason being the fact that as the said structures are cyclic, i.e. the two intermolecular HBs (N 1 ····H 2 –O 3 and O 8 ····H 6 –O 5 ) are linked with each other through a third HB viz. O 3 ····H 7 –O 8 formed between the two solvent molecules; an extended resonance-assistance is operative here. For the di-solvent cluster corresponding to the Open conformation, 2HP–O–(H 2 O) 2 , where all the concerned HBs are electrostatic in nature, the corresponding NICS parameters are found to be somewhat amplified as compared to the Open conformation of 2HP itself, concluding an increase in the aromaticity of the pyridine nucleus. This observation has been connected to the electrostatic interaction between the O 5 atom and the adjacent ring carbon. An incremental electrostatic interaction associated with the ring carbon is expected to impede the aromatic sextet of the pyridine ring; an argument corroborated aptly by the fact that the order of the magnitude of the electrostatic interaction is found to follow the order: 2HP–O–(H 2 O) 2 < 2HP–O < 2HP–C, whereas the aromaticity of the corresponding pyridine rings follows exactly the reverse order. (iii)The presence of the conventional O a ····H 6 –O 5 HB of substantial covalency accounts for the reduced aromatic character of the Closed form of 2HNA as compared to the corresponding Open form as well as explains the structural obstructions associated with the formation of solvated clusters for the said Closed form. For the Open forms of 2HNA, the pyridine nucleus of the mono-solvent clusters comprising of two HB interaction lines (N 1 ····H 2 –O 3 and O 3 ····H 6 –O 5 ) analogous to that of the 2HP–C mono-solvated clusters are found be less aromatic as compared to the Open form of 2HNA. Although the characteristics and the energetics of the said HBs are exactly equivalent to those observed in case of the 2HP–C mono-solvated clusters, contrary to the latter, the MeOH cluster is identified to be slightly more aromatic as compared to the water cluster. The underlying reason is anticipated to be connected with the twisting out of the –COOH functionality out of the molecular plane for the 2HNA–O–MeOH cluster as compared to the near planar structure associated with the corresponding water cluster to obviate the destabilizations associated with the O 5 ····O a Coulombic repulsions as mentioned earlier. Now it’s appropriate to rationalize the planarity of the –COOH functionality in 2HNA–O–H 2 O cluster. As can be seen that for all of the studied pyridine derivatives, the MeOH clusters furnish stronger N····H–O and O····H–O HBs, leading to a decrease in the aromatic character of the associated pyridine nucleus as compared to the H 2 O clusters, i.e. two opposing factors, viz. the strengths of the formed HBs and the aromaticity of the associated nucleus, are at play here. Interestingly, for the 2HNA–O–H 2 O cluster, the C α –C β bond linking the two substituents (–COOH and –OH) is significantly longer as compared to that in the 2HNA–O– MeOH cluster (1.42 Å as compared to 1.34 Å respectively), which could be an exertion to minimize the O 5 ····O a interaction retaining the planarity of the structure intact in order to ensure an extended conjugation involving the –COOH functionality. However for the corresponding MeOH cluster and the di-solvent clusters, such attenuation of the O 5 ····O a interaction is not possible owing to an enhanced atomic charge on the O 5 atom for these clusters which rationalizes the out-of-plane twist of the –COOH functionality. For both the di-solvent clusters of the Open conformation of 2HNA, the observations are in line with those observed for the 2HP–C di-solvent clusters, i.e. both the HB interaction lines involving the pyridine nucleus; viz. N 1 ····H 2 –O 3 and O 8 ····H 6 –O 5 possess substantial covalency; thus a decrease in the aromaticity of the pyridine nucleus as compared to the Open form of 2HP is noticed; the extent of reduction being superior for the methanol cluster as the corresponding HBs are relatively stronger. In this regard, it is worth mentioning that the twist dihedral of the –COOH functionality is nearly identical for both the di-solvent clusters of the Open form of 2HNA. Conclusion The salient observations of the present study can be summarized as follows: (i) The N 1 ····H 2 –O 3 HB is ubiquitous in all the studied clusters. Although Ñ 2 ρ c > 0 is the general characteristic, for the mono-solvent clusters and the 2HP–O–(H 2 O) 2 cluster, the said HBs furnish H c > 0 whereas the other clusters display H c 0 when the solvent is water and H c < 0, when the solvent is MeOH. Interestingly, the 2HP–O–MeOH cluster shows a unique O 5 ····H c –C 4 HB which is purely electrostatic in nature and substantially weaker than conventional HBs. (iii) The O 8 ····H 6 –O 5 HBs demonstrated by the studied di-solvent clusters (except for the 2HP–O–(H 2 O) 2 cluster which contains an O 5 ····H 7 –O 8 HB) illustrate significantly amplified magnitude of the electron densities and the corresponding Laplacians as compared to the Popelier threshold signifying strong HBs with discernible covalency ( H c 0. (iv) The 2HNA–O–H 2 O and 2HNA–O–MeOH clusters contain O 5 ····O a interaction lines characterized by H c > 0. (v) For the 2HP–C systems, the pyridine nucleus of the mono-solvent clusters are found to be less aromatic as compared to 2HP as a result of the covalent O····H–O HBs (the order being: –MeOH < –H 2 O in accordance with the strengths of the said HBs). For the 2HP–C–H 2 O cluster, where both the HBs are electrostatic in nature, a reduced value of the NICS parameter as compared to the Closed conformation of 2HP has been associated with the impediments to maintain a Closed geometry to sustain the said interaction lines. The corresponding Open forms containing only the electrostatic N 1 ····H 2 –O 3 interaction lines furnish only nominal change in aromaticity in comparison to the Open form of 2HP. (vi) For the di-solvent clusters of the 2HP–C skeleton, the observed covalent HBs involving the pyridine nucleus result in a decrease in its aromaticity as compared to 2HP–C itself. For the 2HP–O–(H 2 O) 2 cluster where the concerned HBs are Coulombic in nature, an amplified aromaticity as compared to the 2HP–O conformation has been linked to the electrostatic interaction between the O 5 atom and the adjacent ring carbon C α . (vii) For the Open forms of 2HNA, the pyridine nucleus of the mono-solvent clusters are found be less aromatic as compared to the Open form of 2HNA due to the presence of covalent HBs. Contrary to the mono-solvated 2HP–C clusters, the 2HNA–C–MeOH cluster is found to be marginally more aromatic as compared to the water cluster, which has been rationalized on the basis of the twisting out of the –COOH functionality out of the molecular plane to avert the O 5 ····O a Coulombic repulsions. For both the di-solvent clusters, the NICS parameters corroborate well with those observed for the di-solvent 2HP–C clusters. Declarations Author Contribution A.G. has perceived the problem, done the calculations and wrote/edited the manuscript. Funding Declaration The author sincerely acknowledges the support received from Department of Science and Technology through the DST-FIST programme (Sanction no.: SR/FST/COLLEGE-/2023/1486). Acknowledgements The author conveys his utmost regards to Prof. Sławomir J. Grabowski, Ikerbasque Research Professor, Donostia International Physics Centre, Spain, for his kind gift of the AIM2000 software. Dr. Bijan K. Paul, Assistant Professor, Mahadevanada Mahavidyalaya, Barrackpore, India and Dr. Susmita Kar, Assistant Professor, Scottish Church College, Kolkata, India are gratefully acknowledged for stimulating discussions. References Bone RGA, Bader RFW (1996) Identifying and Analyzing Intermolecular Bonding Interactions In van der Waals Molecules. J Phys Chem 100: 10892–10911 Perrin CL, Nielson JB (1997) "Strong" hydrogen bonds in chemistry and biology.Annu Rev Phys Chem 48: 511–544 Černý J, Hobza P (2007) Non-covalent interactions in biomacromolecules. Phys Chem Chem Phys 9:5291–5303 Alkorta I, Rozas I, Elguero J (1998) Non-conventional hydrogen bonds. Chem Soc Rev 27:163–170 Desiraju GR, Steiner T (1999) The weak hydrogen bond in Structural Chemistry and Biology. Oxford University Press, New York Grabowski SJ (2001) Ab initio Calculations on Conventional and Unconventional Hydrogen Bonds–Study of the Hydrogen Bond Strength. J Phys Chem A 105:10739–10746 Müller-Dethlefs K, Hobza P (2000) Noncovalent Interactions: A Challenge for Experiment and Theory. Chem Rev 100:143–168 Johnson ER, Keinan S, Mori-Sánchez P, Contreras-García J, Cohen AJ, Yang W (2010) Revealing noncovalent interactions. J Am Chem Soc 132:6498–6506 Malloum A, Conradie J (2022) Structures, binding energies and non-covalent interactions of furan clusters. J Mol Graph Model 111:108102 Malloum A, Conradie J (2022) Non-covalent interactions in small thiophene clusters J Mol Liq 347:118301 Thomas JM, Thomas R (2023) Study of Non-Covalent Interactions Present in the Tapinarof–Ethanol System with Special Emphasis on Hydrogen-Bonding Interactions. J Phys Chem B 127:5933–5940 Macleod NA, Simons JP (2002) Conformation, structure and molecular solvation: a spectroscopic and computational study of 2-phenoxy ethanol and its singly and multiply hydrated clusters. Chem Phys 283:221–236 Zborowski KK, Poater J (2021) Pyrrole and Pyridine in the Water Environment—Effect of Discrete and Continuum Solvation Models. ACS Omega 6:24693–24699 Bader RFW (1991) A Quantum Theory of Molecular Structure and Its Applications . Chem Rev 91:893–928 Bader RFW (2009) Bond Paths Are Not Chemical Bonds. J Phys Chem A 113:10391–10396 Matta CF, Boyd RJ (2007) The Quantum Theory of Atoms in Molecules. Matta CF, Boyd RJ (ed), WILEY-VCH, Weinheim. Eskandari K, Alsenoy CV (2014) Hydrogen–Hydrogen Interaction in Planar Biphenyl: A Theoretical Study Based on the Interacting Quantum Atoms and Hirshfeld Atomic Energy Partitioning Methods J Comput Chem 35:1883–1889 Aihara J (2002) Nucleus-Independent Chemical Shifts and Local Aromaticities in Large Polycyclic Aromatic Hydrocarbons. Chem Phys Lett 365:34–39 Lazzeretti P (2004) Assessment of Aromaticity via Molecular Response Properties. Phys Chem Chem Phys 6:217–223 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr., Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision A.02-SMP, Gaussian, Inc., Wallingford, CT Biegler-König F, Schönbohm J, Bayles D (2001) AIM2000– A Program to Visualize and Analyze Atoms in Molecules. J Comput Chem 22:524–529 Grabowski SJ (2004) Hydrogen bonding strength—measures based on geometric and topological parameters J Phys Org Chem 17:18–31 Grabowski SJ (2011) What is the Covalency of Hydrogen Bonding? Chem Rev 111:2597–2625 Popelier PLA (1998) Characterization of a Dihydrogen Bond on the Basis of the Electron Density. J Phys Chem A 102:1873–1878 Randic M, Balaban AT (2006) Partitioning of π-electrons in rings for Clar structures of benzenoid hydrocarbons J Chem Inf Model 46:57–64 Gobre VV, Pinjari RV, Gejji SP (2010) Density functional investigations on the charge distribution, vibrational spectra and NMR chemical shifts in cucurbit[n]uril (n = 5-12) hosts. J Phys Chem A 114:4464–4470 Lande DN, Rao SS, Gejji SP, Deciphering Noncovalent Interactions Accompanying 7,7,8,8-Tetracyanoquinodimethane Encapsulation within Biphene[n]arenes: Nucleus-Independent Chemical Shifts Approach. ChemPhysChem 17:2197–2209 Tables Tables 1 to 3 are available in the Supplementary Files section Schemes Schemes 1-2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SupplementaryInformation.docx Scheme.docx Tables.docx Cite Share Download PDF Status: Posted Version 1 posted 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-4931761","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":351174541,"identity":"fa70ff73-2d44-4d42-b3bf-dc3b2f6e60b4","order_by":0,"name":"Aniruddha Ganguly","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYFACxgYQYmBj4AFyKoCYmbmBFC1nQFoYCWmB6AICoBbGNgQXJ+Cf3dzAXLjjsD0f+9mDj27Oq43mbwdq+VGxDacWiTsHG5hnnjmc2MaTl2ycu+147ozDjA2MPWdu47bmRmIDM2/b4QQ2CR4z6dxtx3IbgFqYGdtwa5GHarEHajH/nTvnWO58QloMoFoY24C2MOc21ORuIKTFEKjl8My2dKBfcoylc44dyN0I1HIQn1/kbqQ/fFzYZm0v337G8HNOTV3uvPOHDz74UYHH+0BwmIGhGYkNBAfwqgcCZgaGOhi7Dp/CUTAKRsEoGKEAAJAaW86kJvLEAAAAAElFTkSuQmCC","orcid":"","institution":"Scottish Church College","correspondingAuthor":true,"prefix":"","firstName":"Aniruddha","middleName":"","lastName":"Ganguly","suffix":""}],"badges":[],"createdAt":"2024-08-18 04:06:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4931761/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4931761/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":64432363,"identity":"cb6087a3-e285-4700-858e-21c863f4b42c","added_by":"auto","created_at":"2024-09-13 06:15:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":132807,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular graphs showing all the interaction lines corresponding to the clusters (a) 2HP–C–H\u003csub\u003e2\u003c/sub\u003eO (b) 2HP–C–MeOH (c) 2HP–O–(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e and (d) 2HP–O–(MeOH)\u003csub\u003e2\u003c/sub\u003e.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4931761/v1/b258d5a908f695ebb0133f4a.png"},{"id":64432364,"identity":"d38dc711-ae39-4279-8c0d-ea7583100d3a","added_by":"auto","created_at":"2024-09-13 06:15:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51724,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular graph of the 2HP–C–MeOH cluster showing all the interaction lines (the O\u003csub\u003e5\u003c/sub\u003e····H\u003csub\u003ec\u003c/sub\u003e–C\u003csub\u003e4\u003c/sub\u003e interaction line is noteworthy).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4931761/v1/f5a48d113bfed840d18caec3.png"},{"id":64432366,"identity":"c5792d0c-1563-4af4-bc7e-7ced62478eba","added_by":"auto","created_at":"2024-09-13 06:15:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1161908,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular graphs showing all the interaction lines corresponding to the clusters (a) 2HNA–O–H\u003csub\u003e2\u003c/sub\u003eO (b) 2HNA–O–MeOH (c) 2HNA–O–(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e and (d) 2HNA–O–(MeOH)\u003csub\u003e2\u003c/sub\u003e.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4931761/v1/1213d20d78e56010bff54d92.png"},{"id":69886100,"identity":"56fe2a2b-f396-4d29-bb0e-0df6797d0754","added_by":"auto","created_at":"2024-11-26 09:47:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2886965,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4931761/v1/33f69632-9f48-4b1f-97c9-578024580384.pdf"},{"id":64432963,"identity":"30bed5f1-7584-4110-80c7-c43dc9e338a0","added_by":"auto","created_at":"2024-09-13 06:23:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21097,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-4931761/v1/0e8dff61cda607a999a63811.docx"},{"id":64432964,"identity":"fc965119-c0c9-48f2-9833-729a8504dcf3","added_by":"auto","created_at":"2024-09-13 06:23:07","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":61554,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme.docx","url":"https://assets-eu.researchsquare.com/files/rs-4931761/v1/f28f96c87f3182d945f2d9a4.docx"},{"id":64432365,"identity":"5a33ee29-93eb-4686-b6c0-1c864be25264","added_by":"auto","created_at":"2024-09-13 06:15:07","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":34078,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-4931761/v1/1f5910e29ee017fe454c5549.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Interplay between structural integrity and aromaticity on governing the nature of the non- covalent interactions within the mono and di-solvent clusters of 2-Hydroxypyridine and 2- Hydroxynicotionic acid: A topological description","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNon-covalent interactions are of crucial importance despite their so called \u0026ldquo;weaker\u0026rdquo; nature in contrast to typical ionic and covalent interactions considering their indispensable role in governing the spatial architectures and regulatory functions of biomolecules [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Hydrogen bonding (HB), the most fundamental among the non-covalent forces has always received extensive attention owing to its pervasive nature and critical importance to create and sustain life [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. But the inherent complexities associated with the biological media often deem the unambiguous \u003cem\u003ein vivo\u003c/em\u003e identification and characterization of the non-covalent interactions nearly impossible [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. As a result, Hydrogen-bonded clusters, especially those of small aromatic molecules are becoming of paramount interest following the fact that, in these model systems, simply by changing the interacting molecules, selective isolation of these interactions are feasible, which can provide essential information about the function and dynamics of biomolecules with the additional advantage of conceivable outputs [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Furthermore, if the cluster is comprised of an aromatic molecule capable of HB formation either as a donor or an acceptor or both and a polar solvent molecule like water or methanol, it can serve as a potential model system for solvation in the condensed phase [\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince a \u0026ldquo;Chemical bond\u0026rdquo; does not qualify as a Dirac observable, an explicit quantum mechanical definition of the said term is unavailable leading to the relentless debate on the assessment of a particular pair of atoms to be considered as chemically bonded [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, a rigorous quantum mechanical description formulated by Bader, \u003cem\u003eviz.\u003c/em\u003e Atoms in molecules i.e. AIM formalism, which confides on the topological density operator \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\widehat{\\rho\\:\\:}\\)\u003c/span\u003e\u003c/span\u003e(\u003cb\u003er\u003c/b\u003e), having experimentally quantifiable expectation values, provides a distinctive platform to affirm and quantify the phenomenon of bonding of any manner between a pair of nuclei by a necessary and the sufficient condition of the existence of a \u0026ldquo;bond path\u0026rdquo; provided that the system is in stable electrostatic equilibrium [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. As a bond path, i.e. the line following the ridge of maximum electronic density is invariably mirrored by another line of maximally negative potential energy density connecting the same nuclei, i.e. the virial path; Bader\u0026rsquo;s theory, strictly in an atomistic sense asserts a bond path to be always stabilizing [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present contribution describes a thorough AIM-based investigation of the non-covalent interactions present within the mono and di-solvent (water and methanol) clusters of 2-Hydroxypyridine and 2-Hydroxynicotionic acid (Henceforth abbreviated as 2HP and 2HNA respectively) in their Closed and Open conformations (abbreviated as \u0026minus;\u0026thinsp;C and \u0026minus;\u0026thinsp;O conformations respectively, \u003cem\u003evide\u003c/em\u003e Schemes \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2\u003c/span\u003e); and hence to inspect their roles in governing the structural motifs of the clusters. Besides, the role of aromaticity in dictating the structures and the energetics of the non-covalent interactions has also been analyzed exploiting the Nucleus Independent Chemical Shift (NICS) parameters [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Finally, the study also endeavors to establish whether structural impediments associated with maintaining a quasi-ring could affect the covalency of the HBs or not.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eComputational procedures\u003c/h3\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eGeometry optimization and frequency simulation\u003c/h2\u003e \u003cp\u003eNecessary geometry optimizations have been accomplished on Gaussian 09 suite of programs [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] utilizing the M\u0026oslash;ller\u0026ndash;Plesset second order perturbation method (MP2) alongside the triple-ζ quality 6-311\u0026thinsp;+\u0026thinsp;+\u0026thinsp;G (d,p) basis set without imposing any symmetry restraints on the structures. The acquired structures have been subjected to compulsory vibrational analyses to authenticate the global minimization of the associated geometries as well as for necessary frequency assignments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAtoms-In-Molecules (AIM) analysis\u003c/h2\u003e \u003cp\u003eThe AIM calculations have been performed on AIM2000 software suite [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] by virtue of the wavefunction files obtained from the optimized geometries at MP2/6-311\u0026thinsp;+\u0026thinsp;+\u0026thinsp;G(d,p) level using the Gaussian 09 suite.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCalculation of aromaticity indices\u003c/h2\u003e \u003cp\u003eThe Nucleus Independent Chemical Shift (NICS) index [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] has been applied to quantitatively assess the aromatic character of the pyridine rings associated with the studied systems. The necessary computations have been performed on the Gaussian 09 suite at MP2/6-311\u0026thinsp;+\u0026thinsp;+\u0026thinsp;G(d,p) level using the gauge-independent atomic orbital (GIAO) formalism, i.e. using the \u0026ldquo;Bq\u0026rdquo; probe atom to assign the spatial positions for the estimation of the index. However, it is worth mentioning that NICS(1) i.e. the negative values of absolute shielding measured at 1\u0026Aring; above the center of the ring and the corresponding zz tensor component (NICS (1)\u003csub\u003ezz\u003c/sub\u003e) instead of the archetypal NICS(0) values computed at the centre of the ring itself has been opted in the present context as the latter analysis is fraught with spurious contributions from the in-plane σ\u0026ndash;tensor components whereas the former asserts a better participation of the so called π-cloud [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results and Discussions","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eGeometrical and vibrational analyses\u003c/h2\u003e\n \u003cp\u003eThe molecular frameworks relevant to this study, \u003cem\u003eviz.\u003c/em\u003e 2HP and 2HNA (the numbering of the interacting atoms have been done according to Schemes \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) exhibit planar equilibrium structures in their Closed conformations; whereas although the Open conformation of 2HP is still planar, the \u0026ndash;COOH functionality of 2HNA in its Open form exhibits a dihedral twist of ~\u0026thinsp;29.74\u0026deg; with respect to the pyridine ring in an effort to minimize the destabilizing O\u003csub\u003e6\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;O\u003csub\u003ea\u003c/sub\u003e (\u003cem\u003evide\u003c/em\u003e Scheme \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) Coulombic repulsion. This fact is supported by an augmented separation between the said O atoms on moving from the respective Closed conformation (~\u0026thinsp;2.68 \u0026Aring;) to the Open conformation (~\u0026thinsp;2.81 \u0026Aring;). However, the optimized geometries of the clusters furnish some atypical observations. For the mono-solvent (n\u0026thinsp;=\u0026thinsp;1) clusters associated with the Closed conformations of 2HP (\u003cem\u003eviz.\u003c/em\u003e 2HP\u0026ndash;C\u0026ndash;ROH; R\u0026thinsp;=\u0026thinsp;H, CH\u003csub\u003e3\u003c/sub\u003e), the frameworks remain nearly planar and the interacting \u0026ndash;OH functionalities of the solvents reside in the same plane as that of the 2HP skeleton, whereas, for the Open conformations, the N\u003csub\u003e1\u003c/sub\u003e\u0026ndash;C\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e\u0026ndash;H\u003csub\u003e6\u003c/sub\u003e dihedrals display slight deviation from linearity, the corresponding angles being ~\u0026thinsp;2.26\u0026deg; and 3.35\u0026deg; respectively for the water and MeOH clusters possibly owing to no or insignificant contribution of the \u0026ndash;OH functionality in any bonding interactions. On the other hand, for the di-solvent (n\u0026thinsp;=\u0026thinsp;2) clusters the deviation of the N\u003csub\u003e1\u003c/sub\u003e\u0026ndash;C\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e\u0026ndash;H\u003csub\u003e6\u003c/sub\u003e dihedral is comparatively significant which may be attributed to the flexibility of the geometries of the di-solvated clusters as compared to the corresponding mono-solvated ones; \u003cem\u003eviz.\u003c/em\u003e the C\u003csub\u003e\u0026alpha;\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e\u0026ndash;H\u003csub\u003e6\u003c/sub\u003e bond angle is found to discernibly amplify on moving from 2HP\u0026ndash;C\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO cluster (~\u0026thinsp;109.1\u0026deg;) to the 2HP\u0026ndash;C\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e cluster (~\u0026thinsp;111.6\u0026deg;). The aforesaid rationale also accounts for the augmented N\u003csub\u003e1\u003c/sub\u003e\u0026ndash;C\u003csub\u003e\u0026alpha;\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e\u0026ndash;H\u003csub\u003e6\u003c/sub\u003e dihedrals in the di-solvent clusters of the Open conformation of 2HNA as compared to the corresponding mono-solvent clusters. Interestingly, the twist angle of the \u0026ndash;COOH functionality of 2HNA in its Open form is found to increase in the clusters as compared to the framework itself; especially for the di-solvent clusters, which can be attributed to the aversion of the destabilizations associated with the O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;O\u003csub\u003ea\u003c/sub\u003e Coulombic repulsions which otherwise would significantly enhance due to an increment in the atomic charges of the O\u003csub\u003e5\u003c/sub\u003e atoms as a result of HB formations. It is however worth mentioning here that in the 2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO cluster, the \u0026ndash;COOH functionality resides in the plane of the pyridine ring; the corresponding justification is to be substantiated later.\u003c/p\u003e\n \u003cp\u003eIn a chemical sense, the formation of an X\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u0026ndash;Y HB is typically perceived as a hyperconjugative charge transfer from the lone pair of the acceptor atom X to the \u0026sigma;* orbital of the donor bond H\u0026ndash;Y [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]; an outcome of which is a reduction in the H\u0026ndash;Y bond order as compared to the corresponding non-hydrogen bonded structure resulting a decrement in the H\u0026ndash;Y stretching frequency in the H-bonded configuration, thoroughly substantiated by a\u0026thinsp;~\u0026thinsp;83 cm\u003csup\u003e\u0026ndash;1\u003c/sup\u003e blue shift in the H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e stretching frequency on moving from the H-bonded Closed conformations to the Open conformations devoid of HBs for 2HNA (\u003cem\u003evide\u003c/em\u003e Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e in the supplementary information). As far as the clusters are concerned, for the 2HP\u0026ndash;C and the 2HNA\u0026ndash;O clusters, evidence of strong HBs involving the \u0026ndash;O\u003csub\u003e5\u003c/sub\u003e\u0026ndash;H\u003csub\u003e6\u003c/sub\u003e functionality (\u003cem\u003eviz.\u003c/em\u003e the O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HBs) is evident from the substantial decrements of the associated stretching frequencies (\u003cem\u003evide\u003c/em\u003e Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e in the supplementary information); the order of strength being \u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO \u0026lt; \u0026ndash;MeOH \u0026lt; \u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e \u0026lt; \u0026ndash;(MeOH)\u003csub\u003e2\u003c/sub\u003e for both the 2HP\u0026ndash;C and 2HNA\u0026ndash;O frameworks, which is readily attributable to a reduced spatial separation between the atoms involved in the HB; whereas for the 2HP\u0026ndash;O clusters, the near constancy of the corresponding stretching frequency infers the O\u003csub\u003e5\u003c/sub\u003e\u0026ndash;H\u003csub\u003e6\u003c/sub\u003e bond not being involved in any H-bonding interaction. It should however be mentioned at this point that there exists an O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e HB in the 2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e cluster as concluded by the stretching frequency of the H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e bond being notably blue shifted (\u003cem\u003evide\u003c/em\u003e Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e in the supplementary information) with respect to the H\u0026ndash;O stretching frequency of water (~\u0026thinsp;3887 cm\u003csup\u003e\u0026ndash;1\u003c/sup\u003e). Interestingly, although the exact same orders of strength for the N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e HBs are noted for the 2HP\u0026ndash;C and 2HNA\u0026ndash;O frameworks as a result of a similar trend of spatial separation between the two atoms involved in the formation of the said HBs; the 2HP\u0026ndash;O framework furnishes the order, \u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO \u0026asymp; \u0026ndash;MeOH \u0026gt; \u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e, which also seems rational as the separation between the involved atoms follow the exact same trend. For the di-solvent clusters, O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e HBs associated with the interaction between the two solvent molecules as proliferated in the blue shift of the H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e stretching frequency as compared to water (~\u0026thinsp;3400 cm\u003csup\u003e\u0026ndash;1\u003c/sup\u003e) is observed and the corresponding energetics agrees well with the internuclear separation between the bonded atoms. An analogous O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e9\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e HB for the 2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e cluster with an amplified atomic separation is also noted in this regard. Moreover, the C\u003csub\u003e4\u003c/sub\u003e\u0026ndash;H\u003csub\u003ec\u003c/sub\u003e stretching frequency in the 2HP\u0026ndash;O\u0026ndash;MeOH cluster shows a significant blue shift as compared to the C\u003csub\u003e4\u003c/sub\u003e\u0026ndash;H\u003csub\u003ec\u003c/sub\u003e stretching frequency of methanol itself (~\u0026thinsp;3191 cm\u003csup\u003e\u0026ndash;1\u003c/sup\u003e), inferring the presence of a O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003ec\u003c/sub\u003e\u0026ndash;C\u003csub\u003e4\u003c/sub\u003e HB in the aforesaid cluster.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eTopological analysis: Atoms-In-Molecule (AIM) study\u003c/h2\u003e\n \u003cp\u003eAIM analysis, proposed by Bader, depends principally on the scrutiny of the electron density (\u0026rho;(\u003cstrong\u003er\u003c/strong\u003e)) of a molecule. As already has been pointed out, the theory predicts an interaction between two atoms by means of the existence of a critical point (CP) and an associated bond path linking the said atoms in a global minimum structure [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the present contribution, AIM analyses have been employed to authenticate and enumerate the H\u0026ndash;bonding interactions present within the concerned optimized structures (\u003cem\u003evide\u003c/em\u003e Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026rarr;3). The subsequent observations and pertinent discussions are summarized below.\u003c/p\u003e\n \u003cp\u003e(i) All the clusters are found to contain N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e HBs (\u003cem\u003evide\u003c/em\u003e Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026rarr;3) in their optimized geometries. The corresponding data (summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) reveal that the magnitudes of the electron densities at the associated Bond Critical Points (\u0026rho;\u003csub\u003ec\u003c/sub\u003e) are well within the Popelier limit of ~\u0026thinsp;0.04 a.u. thereby demarcating them as conventional HBs, a fact further supported by the values of the associated Laplacians being within the threshold of ~\u0026thinsp;0.13 a.u. [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAIM parameters corresponding to the N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e, O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e and O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003ec\u003c/sub\u003e\u0026ndash;C\u003csub\u003e4\u003c/sub\u003e HBs in the studied structures\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ed\u003csub\u003eHB\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(\u0026Aring;)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003er\u003csub\u003eHB\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026rho;\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026nabla;\u003csup\u003e2\u003c/sup\u003e\u0026rho;\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eG\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eV\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eH\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026rho;\u003csup\u003eRCP\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eellipticity\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eE\u003csup\u003eHB\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e(kcal/mol)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"11\"\u003e\n \u003cp\u003eN\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e HB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.01849\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01084\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 5.8013\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;MeOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9758\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.8011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09849\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02340\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.02229\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01314\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 6.9936\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.3936\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03485\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11234\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02887\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.02993\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00435\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 9.3907\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;(MeOH)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4956\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11589\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03321\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00212\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03782\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 10.4198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9723\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.7812\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02517\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09411\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.01898\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00227\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.07175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 5.9551\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u0026ndash;MeOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9648\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.7667\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02616\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09541\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.01999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05615\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 6.2721\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0806\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9926\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01950\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.07547\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01602\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.01316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00286\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09421\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 4.1290\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.0778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.08057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01779\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.01544\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00235\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01098\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 4.8444\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;MeOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0773\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02519\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02119\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.01959\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00161\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01317\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 6.1465\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8693\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5883\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03282\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.10817\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02728\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.02753\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04961\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 8.6377\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;(MeOH)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8379\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5288\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03586\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11368\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02984\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00520\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04408\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 9.8078\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"11\"\u003e\n \u003cp\u003eO\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02599\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.12104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02704\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.02381\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01084\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.07583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 7.4705\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;MeOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.7605\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.3862\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03604\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13604\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03424\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03446\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01314\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03911\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 10.8120\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4764\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02779\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.12711\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02885\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.02593\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00293\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01098\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.08389\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 8.1357\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;MeOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.3219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03904\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14351\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03715\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03843\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01317\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03745\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 12.0576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"11\"\u003e\n \u003cp\u003eO\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003ec\u003c/sub\u003e\u0026ndash;C\u003csub\u003e4\u003c/sub\u003e HB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u0026ndash;MeOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.9659\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.6797\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01387\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03535\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.6871\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eNow, the Laplacian, which depends on the electronic kinetic and potential energy densities, \u003cem\u003eviz. G\u003c/em\u003e(\u003cstrong\u003er\u003c/strong\u003e) and \u003cem\u003eV\u003c/em\u003e(\u003cstrong\u003er\u003c/strong\u003e) respectively, can be expressed in terms of the Virial equation as [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]:\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/p\u003e\n \u003cp\u003eWhich immediately suggests that as \u003cem\u003eG\u003c/em\u003e(\u003cstrong\u003er\u003c/strong\u003e)\u0026thinsp;\u0026gt;\u0026thinsp;0 and \u003cem\u003eV\u003c/em\u003e(\u003cstrong\u003er\u003c/strong\u003e)\u0026thinsp;\u0026lt;\u0026thinsp;0, the sign of the Laplacian dictates the dominant energy density at the point \u003cstrong\u003er\u003c/strong\u003e, i.e. a positive Laplacian at the BCP, as observed here, is indicative of the dominance of kinetic energy, which means that the electron density \u0026rho;(\u003cstrong\u003er\u003c/strong\u003e) is concentrated towards the nuclei, a typical trait of closed-shell (electrostatic) interactions whereas a negative Laplacian suggests the dominance of the potential energy; the electron density being concentrated within the bond path signifying covalent interaction [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. The total energy density \u003cem\u003eH\u003c/em\u003e(\u003cstrong\u003er\u003c/strong\u003e) at the BCP represented as \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e, which is the sum of the corresponding \u003cem\u003eG\u003c/em\u003e(\u003cstrong\u003er\u003c/strong\u003e) and \u003cem\u003eV\u003c/em\u003e(\u003cstrong\u003er\u003c/strong\u003e) at the BCP (\u003cem\u003eG\u003c/em\u003e\u003csub\u003ec\u003c/sub\u003e and \u003cem\u003eV\u003c/em\u003e\u003csub\u003ec\u003c/sub\u003e respectively), is often considered as a more reliable parameter than the Laplacian itself to ascertain the nature of the associated bond path [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]; a positive \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e (i.e. |\u003cem\u003eG\u003c/em\u003e\u003csub\u003ec\u003c/sub\u003e| \u0026gt; |\u003cem\u003eV\u003c/em\u003e\u003csub\u003ec\u003c/sub\u003e|) implies a closed-shell interaction and a negative \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e (i.e. |\u003cem\u003eV\u003c/em\u003e\u003csub\u003ec\u003c/sub\u003e| \u0026gt; |\u003cem\u003eG\u003c/em\u003e\u003csub\u003ec\u003c/sub\u003e|) represents covalent interaction [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the present scenario, although all the Laplacians are found to be positive, indicating closed-shell interactions, the corresponding \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003es are not always positive (\u003cem\u003evide\u003c/em\u003e Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). This apparent anomaly can be rationalized by a closer scrutiny of the Virial equation mentioned above. The equation simply shows that for a positive laplacian (i.e. |\u003cem\u003eV\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e| \u0026lt; 2|\u003cem\u003eG\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e|), two different situations may occur, (i) |\u003cem\u003eV\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e| \u0026lt; |\u003cem\u003eG\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e|, which implies that \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e \u0026gt; 0 and the interaction is purely electrostatic or (ii) |\u003cem\u003eV\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e| \u0026gt; |\u003cem\u003eG\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e| but |\u003cem\u003eV\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e| \u0026lt; 2|\u003cem\u003eG\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e|; i.e. \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e \u0026lt; 0 which implies a covalent interaction but \u0026nabla;\u003csup\u003e2\u003c/sup\u003e\u0026rho;\u003csub\u003ec\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0 indicating electrostatic interaction, which is the situation here for the HBs present in a few of the studied clusters. So, as obvious, these types of HBs are partially covalent and partially electrostatic in nature [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, it is imperative to note in this context that the model of resonance\u0026ndash;assistance is not strictly applicable in the present scenario to account for the covalency associated with the HBs, as the said concept is typically invoked in cases where the donor and the acceptor moieties reside in the same nucleus.\u003c/p\u003e\n \u003cp\u003eAs can be seen from the tabulated data, for all the mono-solvent clusters (n\u0026thinsp;=\u0026thinsp;1), and the Open conformation of the di-solvent cluster 2HP\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e, the N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e HBs are characterized by a positive Laplacian and a positive total energy density; \u003cem\u003eviz.\u003c/em\u003e \u0026nabla;\u003csup\u003e2\u003c/sup\u003e\u0026rho;\u003csub\u003ec\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0; and \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e \u0026gt; 0, thereby inferring the interaction to be of electrostatic origin. However, the N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e HBs associated with all the di-solvent clusters apart from the one mentioned above show negative total energy densities (\u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e \u0026lt; 0), thus concluding a credible degree of covalency to the said HBs. The reason behind such an observation is to be substantiated later. A semi-quantitative description of the strengths of the concerned HBs (\u003cem\u003evide\u003c/em\u003e Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), obtained using the relation E\u003csub\u003e\u003cem\u003eHB\u003c/em\u003e\u003c/sub\u003e \u0026asymp; \u0026ndash; \u003cem\u003eV\u003c/em\u003e\u003csub\u003ec\u003c/sub\u003e/2 [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e], divulges that the N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e HBs present in the concerned structures are moderately strong and the consequent energetics corroborate well with the separation between the two bonded atoms \u003cem\u003eviz.\u003c/em\u003e N\u003csub\u003e1\u003c/sub\u003e and H\u003csub\u003e2\u003c/sub\u003e involved in the HBs [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003eThe ellipticities (\u0026epsilon;), defined as the ratio of the two largest negative eigenvalues of the Hessian of the electron density, are found to be remarkably small for the N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e BCPs, indicating near isotropic distribution of the electron density in the directions normal to the bond path, i.e. a cylindrical symmetry of the HBs [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e(ii) The mono-solvent clusters except for that associated with the Open conformation of 2HP (\u003cem\u003eviz.\u003c/em\u003e 2HP\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO) also contain O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HBs thoroughly preserving the Popelier criteria (\u003cem\u003evide\u003c/em\u003e Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). However, although all these HBs are characterized by \u0026nabla;\u003csup\u003e2\u003c/sup\u003e\u0026rho;\u003csub\u003ec\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0; when the solvent is water, the parameter \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e is found to be \u0026gt;\u0026thinsp;0, thus ascertaining the interaction to be Coulombic in nature; whereas for MeOH, \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e furnishes values\u0026thinsp;\u0026lt;\u0026thinsp;0 supporting an involvement of the aromatic \u0026pi;-cloud in the interaction. The corresponding HBs are reasonably symmetric as is obvious from the values of the ellipticities at the respective BCPs; the HBs associated with the MeOH clusters being more symmetric as compared to the water clusters.\u003c/p\u003e\n \u003c/span\u003e \u003cspan\u003e\n \u003cp\u003e(iii) The 2HP\u0026ndash;O\u0026ndash;MeOH cluster furnishes a unique O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003ec\u003c/sub\u003e\u0026ndash;C\u003csub\u003e4\u003c/sub\u003e HB, the corresponding electron density parameters \u0026rho;\u003csub\u003ec\u003c/sub\u003e and \u0026nabla;\u003csup\u003e2\u003c/sup\u003e\u0026rho;\u003csub\u003ec\u003c/sub\u003e being one order in magnitude smaller than the Popelier threshold concluding exceptionally weak HB as substantiated by the associated energy and a significantly longer bond path (\u003cem\u003evide\u003c/em\u003e Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The interaction is purely electrostatic as supported by the conditions: \u0026nabla;\u003csup\u003e2\u003c/sup\u003e\u0026rho;\u003csub\u003ec\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0; and \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e \u0026gt; 0. Interestingly, the meager value of the ellipticity at the corresponding BCP is indicative of a symmetric HB although the corresponding RCP deviates significantly from the centroid of the formed quasi-ring.\u003c/p\u003e\n \u003c/span\u003e \u003cspan\u003e\n \u003cp\u003e(iv) All the di-solvent clusters except for the Open conformation of 2HP (\u003cem\u003eviz.\u003c/em\u003e 2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e) demonstrate O\u003csub\u003e8\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HBs. As is evident from Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, the magnitude of the electron densities as well as the corresponding Laplacians at the Bond Critical Points associated with the said HBs are noticeably greater than those suggested for conventional HBs [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e] representing strong HBs with discernible covalency which is further substantiated from the corresponding \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003es being \u0026lt;\u0026thinsp;0 and amplified values of the corresponding potential energy densities (\u003cem\u003eV\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e). The associated ellipticities evince significant cylindrical symmetries of the HBs\u003c/p\u003e\n \u003c/span\u003e \u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAIM parameters corresponding to the O\u003csub\u003e8\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e, O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e, O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e, O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e9\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e and O\u003csub\u003ea\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HBs in the studied structures\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ed\u003csub\u003eHB\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(\u0026Aring;)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003er\u003csub\u003eHB\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026rho;\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026nabla;\u003csup\u003e2\u003c/sup\u003e\u0026rho;\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eG\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eV\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eH\u003csub\u003ec\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026rho;\u003csup\u003eRCP\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e(a.u.)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eellipticity\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eE\u003csup\u003eHB\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e(kcal/mol)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"11\"\u003e\n \u003cp\u003eO\u003csub\u003e8\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.7245\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.3140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03772\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14314\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03625\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03672\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00047\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00435\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05330\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 11.5211\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;(MeOH)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.6513\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.1743\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04741\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.15931\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.04938\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00477\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02980\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 15.4932\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.6981\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.2639\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14921\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03879\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.04028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05499\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 12.6381\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;(MeOH)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.6284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.1309\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04981\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.16470\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04707\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.05296\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00589\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00520\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04663\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 16.6162\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"11\"\u003e\n \u003cp\u003eO\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e HB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9971\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.8262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01872\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.08581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01793\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.01441\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00352\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 4.5211\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"11\"\u003e\n \u003cp\u003eO\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e HB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.7887\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4376\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03278\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03218\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03074\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00435\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02547\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 9.6448\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;(MeOH)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.7682\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03565\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03483\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05530\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 10.8151\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.7953\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4503\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02535\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13325\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02535\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 9.4566\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;(MeOH)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.7528\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.3696\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03693\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03609\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03606\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00520\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04123\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 11.3138\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"11\"\u003e\n \u003cp\u003eO\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e9\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e HB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.1061\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01623\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06337\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01396\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.01208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04889\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 3.7901\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"11\"\u003e\n \u003cp\u003eO\u003csub\u003ea\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.7790\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03644\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13928\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03502\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.03520\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 0.00019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01707\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02546\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ndash; 11.0442\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eInstead of the aforementioned O\u003csub\u003e8\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HB, an O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e HB is observed for the 2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e cluster (\u003cem\u003evide\u003c/em\u003e Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) owing to the spatial orientation of the \u0026ndash;O\u003csub\u003e5\u003c/sub\u003e\u0026ndash;H\u003csub\u003e6\u003c/sub\u003e functionality. Interestingly, the corresponding HB is found to be significantly weaker as compared to the former ones, and is characterized by \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e \u0026gt; 0, i.e. the interaction is of Coulombic origin.\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e(v) \u0026nbsp;For all the di-solvent clusters, symmetric HBs between the two solvent molecules (\u003cem\u003eviz.\u003c/em\u003e O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e9\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e HB for 2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e and O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e HB for the rest; \u003cem\u003evide\u003c/em\u003e Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), of significant strength (2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e being the only exception because of a larger separation between the interacting atoms) and electrostatic character (i.e. \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e \u0026gt; 0) is observed.\u003c/p\u003e\n \u003c/span\u003e \u003cspan\u003e\n \u003cp\u003e(vi) As can be inferred from the absence of the corresponding ring critical point (RCP), the 2HP\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO cluster is the only non-cyclic structure. A distance of 3.94\u0026Aring; between the O\u003csub\u003e5\u003c/sub\u003e and the H\u003csub\u003e4\u003c/sub\u003e atoms is responsible for this observation. The magnitude of the electron densities at the RCPs for all the other relevant structures (\u0026rho;\u003csup\u003eRCP\u003c/sup\u003e ) indicate stable critical points which in turn demonstrate the geometries to be stable.\u003c/p\u003e\n \u003c/span\u003e \u003cspan\u003e\n \u003cp\u003e(vii) The 2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO and 2HNA\u0026ndash;O\u0026ndash;MeOH clusters contain O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;O\u003csub\u003ea\u003c/sub\u003e interaction lines of Coulombic origin (\u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sub\u003e \u0026gt; 0) as can be seen from the relevant parameters (\u003cem\u003evide\u003c/em\u003e Table S2 in the supplementary information). The increase in the distance between the interacting atoms (~\u0026thinsp;2.71 \u0026Aring; in 2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO to ~\u0026thinsp;2.84 \u0026Aring; in 2HNA\u0026ndash;O\u0026ndash;MeOH) as a result of the non-planarity of the \u0026ndash;COOH functionality in the latter is thoroughly reflected in the diminution of the electron densities at the respective BCPs, as well as in the significant elongation of the total bond path (~\u0026thinsp;5.14 au in 2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO to ~\u0026thinsp;5.40 au in 2HNA\u0026ndash;O\u0026ndash;MeOH). The drastic increment in the ellipticity of the BCP on moving from 2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO to 2HNA\u0026ndash;O\u0026ndash;MeOH immediately suggests a more unstable critical point in the latter, further substantiated by a reduced separation between the corresponding BCP and the RCP (from ~\u0026thinsp;0.80 \u0026Aring; in 2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO to ~\u0026thinsp;0.22 \u0026Aring; in 2HNA\u0026ndash;O\u0026ndash;MeOH). The destabilization association with the said interaction line is evident from its absence in the di-solvent clusters of the Open conformation of 2HNA where the twisting angle of the \u0026ndash;COOH functionality is comparatively higher as compared to 2HNA\u0026ndash;O\u0026ndash;MeOH cluster.\u003c/p\u003e\n \u003c/span\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eAromaticity analysis: Nucleus Independent Chemical Shift (NICS) study\u003c/h2\u003e\n \u003cp\u003eAlthough as previously stated, the general perception of resonance-assistance is not strictly applicable in our scenario, as the HB interactions are associated with atoms or functionalities directly of substitutionally attached to the aromatic nucleus; a modification of the global \u0026pi;-electron delocalization within the ring skeleton due to communication between the moieties responsible for the formation of HB as opposed to the nuclei devoid of such interactions is expected to occur, resulting in a modulation of the indices pertinent to the H\u0026uuml;ckel aromaticity of the nucleus [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003eThe NICS parameters associated with the studied nuclei are collected in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, an inspection of which provides the subsequent observations.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eNICS Parameters corresponding to the studied structures\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNICS(1)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNICS(1\u003csub\u003ezz\u003c/sub\u003e)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.7692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 26.7188\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.3891\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 25.4787\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;MeOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.2779\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 25.0903\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.2264\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 24.8126\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;C\u0026ndash;(MeOH)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.0943\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 24.6028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.8851\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 26.7028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u0026ndash;MeOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.8369\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 26.4866\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 10.0512\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 27.1768\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HP\u0026ndash;O\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.9159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 27.0328\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.2499\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 23.2789\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.0236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 23.1409\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;MeOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.0929\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 23.3101\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 8.9973\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 22.8119\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u0026ndash;(MeOH)\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 8.8528\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 22.4226\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2HNA\u0026ndash;O\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 9.5120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026ndash; 24.3218\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\u003cspan\u003e\n \u003cp\u003e(i) For the Closed forms of 2HP, the pyridine nucleus of the mono-solvent clusters which contain two HB interaction lines (N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e and O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e) are found to be less aromatic as compared to 2HP itself. Since the N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e interaction lines for the aforesaid clusters are of electrostatic origin, their effect on the aromaticity of the 2HP nucleus should be minimal and thus the modulation of aromaticity of the concerned nuclei should be attributed to the O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e interaction lines. Interestingly, contrary to the case of water, for methanol the O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HB furnish noteworthy covalent character confirming the involvement of the \u0026pi;-electrons of the ring, substantiated accordingly by a reduced magnitude of the NICS parameter in case of methanol. For the corresponding Open forms containing only the N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e interaction lines, the NICS parameters furnish almost identical magnitudes in comparison with the Open form of 2HP itself; the methanol cluster exhibiting slightly lesser aromaticity as compared to the water cluster, a fact corroborating well with the impression of a relatively stronger HB in the former case which also is the case for the Closed structures. Thus, for the 2HP\u0026ndash;C\u0026ndash;MeOH cluster, the quantitatively greater reduction in the extent of the aromatic character of the pyridine nucleus is a combined effect of two factors, (a) comparatively amplified strengths of the HBs and (b) the electronic assistance provided by the nucleus to the partially covalent O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HB. However, it should be emphasized in this regard that although for the 2HP\u0026ndash;C\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO cluster both the HBs are of electrostatic origin, the corresponding NICS parameters are found to be discernibly reduced as compared to the Closed conformation of 2HP, the probable reason being the adjustments in the structural parameters to maintain a Closed geometry in order to sustain the two HB interaction lines, \u003cem\u003ee.g.\u003c/em\u003e for the concerned structures, the C\u003csub\u003e\u0026alpha;\u003c/sub\u003e \u0026ndash; N\u003csub\u003e1\u003c/sub\u003e bond is found to increase in length on moving from 2HP\u0026ndash;C to 2HP\u0026ndash;C\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO (from ~\u0026thinsp;1.33 \u0026Aring; to 1.34 \u0026Aring;) whereas the C\u003csub\u003e\u0026alpha;\u003c/sub\u003e \u0026ndash; O\u003csub\u003e5\u003c/sub\u003e bond length decreases (from ~\u0026thinsp;1.36 \u0026Aring; to 1.34 \u0026Aring;).\u003c/p\u003e\n \u003c/span\u003e \u003cspan\u003e\n \u003cp\u003e(ii) For both the di-solvent clusters of the Closed conformation of 2HP, the observed HB interaction lines involving the pyridine nucleus; \u003cem\u003eviz.\u003c/em\u003e N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e and O\u003csub\u003e8\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e are perceived to have significant covalent character which confirms the involvement of the \u0026pi;-electrons of the ring, resulting a decrease in the aromaticity of the pyridine nucleus as compared to 2HP\u0026ndash;C; the extent of decrement being greater for the methanol cluster as the corresponding HBs are comparatively stronger. Interestingly, since the N\u003csub\u003e1\u003c/sub\u003e atom is not involved in the aromatic sextet of pyridine, its participation in the formation of an HB as a donor atom is expected not to have any effect on the \u0026pi;-electron delocalization within the ring itself, which is in sharp contrast to the observed results, the probable reason being the fact that as the said structures are cyclic, i.e. the two intermolecular HBs (N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e and O\u003csub\u003e8\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e) are linked with each other through a third HB \u003cem\u003eviz.\u003c/em\u003e O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e7\u003c/sub\u003e\u0026ndash;O\u003csub\u003e8\u003c/sub\u003e formed between the two solvent molecules; an extended resonance-assistance is operative here. For the di-solvent cluster corresponding to the Open conformation, 2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e, where all the concerned HBs are electrostatic in nature, the corresponding NICS parameters are found to be somewhat amplified as compared to the Open conformation of 2HP itself, concluding an increase in the aromaticity of the pyridine nucleus. This observation has been connected to the electrostatic interaction between the O\u003csub\u003e5\u003c/sub\u003e atom and the adjacent ring carbon. An incremental electrostatic interaction associated with the ring carbon is expected to impede the aromatic sextet of the pyridine ring; an argument corroborated aptly by the fact that the order of the magnitude of the electrostatic interaction is found to follow the order: 2HP\u0026ndash;O\u0026ndash;(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e \u0026lt; 2HP\u0026ndash;O\u0026thinsp;\u0026lt;\u0026thinsp;2HP\u0026ndash;C, whereas the aromaticity of the corresponding pyridine rings follows exactly the reverse order.\u003c/p\u003e\n \u003c/span\u003e \u003cspan\u003e\n \u003cp\u003e(iii)The presence of the conventional O\u003csub\u003ea\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e HB of substantial covalency accounts for the reduced aromatic character of the Closed form of 2HNA as compared to the corresponding Open form as well as explains the structural obstructions associated with the formation of solvated clusters for the said Closed form. For the Open forms of 2HNA, the pyridine nucleus of the mono-solvent clusters comprising of two HB interaction lines (N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e and O\u003csub\u003e3\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e) analogous to that of the 2HP\u0026ndash;C mono-solvated clusters are found be less aromatic as compared to the Open form of 2HNA. Although the characteristics and the energetics of the said HBs are exactly equivalent to those observed in case of the 2HP\u0026ndash;C mono-solvated clusters, contrary to the latter, the MeOH cluster is identified to be slightly more aromatic as compared to the water cluster. The underlying reason is anticipated to be connected with the twisting out of the \u0026ndash;COOH functionality out of the molecular plane for the 2HNA\u0026ndash;O\u0026ndash;MeOH cluster as compared to the near planar structure associated with the corresponding water cluster to obviate the destabilizations associated with the O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;O\u003csub\u003ea\u003c/sub\u003e Coulombic repulsions as mentioned earlier.\u003c/p\u003e\n \u003c/span\u003e\n \u003cp\u003eNow it\u0026rsquo;s appropriate to rationalize the planarity of the \u0026ndash;COOH functionality in 2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO cluster. As can be seen that for all of the studied pyridine derivatives, the MeOH clusters furnish stronger N\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u0026ndash;O and O\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u0026ndash;O HBs, leading to a decrease in the aromatic character of the associated pyridine nucleus as compared to the H\u003csub\u003e2\u003c/sub\u003eO clusters, i.e. two opposing factors, \u003cem\u003eviz.\u003c/em\u003e the strengths of the formed HBs and the aromaticity of the associated nucleus, are at play here. Interestingly, for the 2HNA\u0026ndash;O\u0026ndash;H\u003csub\u003e2\u003c/sub\u003eO cluster, the C\u003csub\u003e\u0026alpha;\u003c/sub\u003e\u0026ndash;C\u003csub\u003e\u0026beta;\u003c/sub\u003e bond linking the two substituents (\u0026ndash;COOH and \u0026ndash;OH) is significantly longer as compared to that in the 2HNA\u0026ndash;O\u0026ndash; MeOH cluster (1.42 \u0026Aring; as compared to 1.34 \u0026Aring; respectively), which could be an exertion to minimize the O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;O\u003csub\u003ea\u003c/sub\u003e interaction retaining the planarity of the structure intact in order to ensure an extended conjugation involving the \u0026ndash;COOH functionality. However for the corresponding MeOH cluster and the di-solvent clusters, such attenuation of the O\u003csub\u003e5\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;O\u003csub\u003ea\u003c/sub\u003e interaction is not possible owing to an enhanced atomic charge on the O\u003csub\u003e5\u003c/sub\u003e atom for these clusters which rationalizes the out-of-plane twist of the \u0026ndash;COOH functionality.\u003c/p\u003e\n \u003cp\u003eFor both the di-solvent clusters of the Open conformation of 2HNA, the observations are in line with those observed for the 2HP\u0026ndash;C di-solvent clusters, i.e. both the HB interaction lines involving the pyridine nucleus; \u003cem\u003eviz.\u003c/em\u003e N\u003csub\u003e1\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;O\u003csub\u003e3\u003c/sub\u003e and O\u003csub\u003e8\u003c/sub\u003e\u0026middot;\u0026middot;\u0026middot;\u0026middot;H\u003csub\u003e6\u003c/sub\u003e\u0026ndash;O\u003csub\u003e5\u003c/sub\u003e possess substantial covalency; thus a decrease in the aromaticity of the pyridine nucleus as compared to the Open form of 2HP is noticed; the extent of reduction being superior for the methanol cluster as the corresponding HBs are relatively stronger. In this regard, it is worth mentioning that the twist dihedral of the \u0026ndash;COOH functionality is nearly identical for both the di-solvent clusters of the Open form of 2HNA.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe salient observations of the present study can be summarized as follows:\u003c/p\u003e\n\u003cp\u003e(i) The\u0026nbsp;N\u003csub\u003e1\u003c/sub\u003e····H\u003csub\u003e2\u003c/sub\u003e–O\u003csub\u003e3\u003c/sub\u003e HB is ubiquitous in all the studied clusters. Although\u0026nbsp;Ñ\u003csup\u003e2\u003c/sup\u003eρ\u003csub\u003ec\u003c/sub\u003e \u0026gt; 0 is the general characteristic, for the mono-solvent clusters and the 2HP–O–(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e cluster, the said HBs furnish\u0026nbsp;\u003cem\u003eH\u003csub\u003ec\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u0026gt; 0 whereas the other clusters display\u0026nbsp;\u003cem\u003eH\u003csub\u003ec\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u0026lt; 0.\u003c/p\u003e\n\u003cp\u003e(ii) All cyclic mono-solvent clusters (2HP–O–H\u003csub\u003e2\u003c/sub\u003eO cluster is the only non-cyclic structure) furnish\u0026nbsp;O\u003csub\u003e3\u003c/sub\u003e····H\u003csub\u003e6\u003c/sub\u003e–O\u003csub\u003e5\u003c/sub\u003e HBs which are characterized by\u0026nbsp;\u003cem\u003eH\u003csub\u003ec\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u0026gt; 0 when the solvent is water and \u003cem\u003eH\u003csub\u003ec\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u0026lt; 0, when the solvent is MeOH. Interestingly, the 2HP–O–MeOH cluster shows a unique\u0026nbsp;O\u003csub\u003e5\u003c/sub\u003e····H\u003csub\u003ec\u003c/sub\u003e–C\u003csub\u003e4\u003c/sub\u003e HB which is purely electrostatic in nature and substantially weaker than conventional HBs.\u003c/p\u003e\n\u003cp\u003e(iii)\u0026nbsp;The\u0026nbsp;O\u003csub\u003e8\u003c/sub\u003e····H\u003csub\u003e6\u003c/sub\u003e–O\u003csub\u003e5\u003c/sub\u003e HBs demonstrated by the\u0026nbsp;studied di-solvent clusters\u0026nbsp;(except for the 2HP–O–(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e cluster which contains an\u0026nbsp;O\u003csub\u003e5\u003c/sub\u003e····H\u003csub\u003e7\u003c/sub\u003e–O\u003csub\u003e8\u003c/sub\u003e HB) illustrate significantly amplified\u0026nbsp;magnitude of the electron densities and the corresponding Laplacians as compared to the Popelier threshold signifying strong HBs with discernible covalency (\u003cem\u003eH\u003csub\u003ec\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u0026lt; 0). Conversely, the\u0026nbsp;O\u003csub\u003e5\u003c/sub\u003e····H\u003csub\u003e7\u003c/sub\u003e–O\u003csub\u003e8\u003c/sub\u003e HB\u0026nbsp;is realized be considerably weaker as compared to the former ones, and is characterized by \u003cem\u003eH\u003csub\u003ec\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u0026gt; 0.\u003c/p\u003e\n\u003cp\u003e(iv) The\u0026nbsp;2HNA–O–H\u003csub\u003e2\u003c/sub\u003eO and 2HNA–O–MeOH clusters contain\u0026nbsp;O\u003csub\u003e5\u003c/sub\u003e····O\u003csub\u003ea\u003c/sub\u003e interaction lines characterized by \u003cem\u003eH\u003csub\u003ec\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u0026gt; 0.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(v) For the 2HP–C systems, the pyridine nucleus of the mono-solvent clusters are found to be less aromatic as compared to 2HP as a result of the covalent\u0026nbsp;O····H–O HBs (the order being:\u0026nbsp;–MeOH \u0026lt;\u0026nbsp;–H\u003csub\u003e2\u003c/sub\u003eO in accordance with the strengths of the said HBs). For the 2HP–C–H\u003csub\u003e2\u003c/sub\u003eO cluster, where both the HBs are electrostatic in nature, a reduced value of the NICS parameter as compared to the Closed conformation of 2HP has been associated with the impediments to maintain a Closed geometry to sustain the said interaction lines.\u0026nbsp;The corresponding Open forms containing only the electrostatic\u0026nbsp;N\u003csub\u003e1\u003c/sub\u003e····H\u003csub\u003e2\u003c/sub\u003e–O\u003csub\u003e3\u003c/sub\u003e interaction lines furnish only nominal change in aromaticity in comparison to the Open form of 2HP.\u003c/p\u003e\n\u003cp\u003e(vi)\u0026nbsp;For the di-solvent clusters of the 2HP–C skeleton, the observed covalent HBs involving the pyridine nucleus result in a decrease in its aromaticity as compared to 2HP–C itself.\u0026nbsp;For the 2HP–O–(H\u003csub\u003e2\u003c/sub\u003eO)\u003csub\u003e2\u003c/sub\u003e cluster where the concerned HBs are Coulombic in nature, \u0026nbsp;an amplified aromaticity as compared to the 2HP–O conformation has been linked to the electrostatic interaction between the O\u003csub\u003e5\u003c/sub\u003e atom and the adjacent ring carbon C\u003csub\u003eα\u003c/sub\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(vii)\u0026nbsp;For the Open forms of 2HNA, the pyridine nucleus of the mono-solvent clusters are found be less aromatic as compared to the Open form of 2HNA due to the presence of covalent HBs. Contrary to the\u0026nbsp;mono-solvated 2HP–C clusters, the\u0026nbsp;2HNA–C–MeOH cluster is found to be marginally more aromatic as compared to the water cluster, which has been rationalized on the basis of the\u0026nbsp;twisting out of the –COOH functionality out of the molecular plane\u0026nbsp;to avert\u0026nbsp;the O\u003csub\u003e5\u003c/sub\u003e····O\u003csub\u003ea\u003c/sub\u003e Coulombic repulsions. For both the di-solvent clusters, the NICS parameters corroborate well with those observed for the di-solvent 2HP–C clusters.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.G. has perceived the problem, done the calculations and wrote/edited the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author sincerely acknowledges the support received from Department of Science and Technology through the DST-FIST programme (Sanction no.: SR/FST/COLLEGE-/2023/1486).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author conveys his utmost regards to Prof. Sławomir J. Grabowski, Ikerbasque Research Professor, Donostia International Physics Centre, Spain, for his kind gift of the AIM2000 software. Dr. Bijan K. Paul, Assistant Professor, Mahadevanada Mahavidyalaya, Barrackpore, India and Dr. Susmita Kar, Assistant Professor, Scottish Church College, Kolkata, India are gratefully acknowledged for stimulating discussions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBone RGA, Bader RFW (1996) Identifying and Analyzing Intermolecular Bonding Interactions In van der Waals Molecules. J Phys Chem 100: 10892\u0026ndash;10911\u003c/li\u003e\n\u003cli\u003ePerrin CL, Nielson JB (1997) \u0026quot;Strong\u0026quot; hydrogen bonds in chemistry and biology.Annu Rev Phys Chem\u003cem\u003e \u003c/em\u003e48: 511\u0026ndash;544\u003c/li\u003e\n\u003cli\u003eČern\u0026yacute; J, Hobza P (2007) Non-covalent interactions in biomacromolecules. Phys Chem Chem Phys 9:5291\u0026ndash;5303\u003c/li\u003e\n\u003cli\u003eAlkorta I, Rozas I, Elguero J (1998) Non-conventional hydrogen bonds. Chem Soc Rev 27:163\u0026ndash;170\u003c/li\u003e\n\u003cli\u003eDesiraju GR, Steiner T (1999) The weak hydrogen bond in Structural Chemistry and Biology. Oxford University Press, New York\u003c/li\u003e\n\u003cli\u003eGrabowski SJ (2001) Ab initio Calculations on Conventional and Unconventional Hydrogen Bonds\u0026ndash;Study of the Hydrogen Bond Strength. J Phys Chem A 105:10739\u0026ndash;10746\u003c/li\u003e\n\u003cli\u003eM\u0026uuml;ller-Dethlefs K, Hobza P (2000) Noncovalent Interactions: A Challenge for Experiment and Theory. Chem Rev 100:143\u0026ndash;168\u003c/li\u003e\n\u003cli\u003eJohnson ER, Keinan S, Mori-S\u0026aacute;nchez P, Contreras-Garc\u0026iacute;a J, Cohen AJ, Yang W (2010) Revealing noncovalent interactions. J Am Chem Soc 132:6498\u0026ndash;6506\u003c/li\u003e\n\u003cli\u003eMalloum A, Conradie J (2022) Structures, binding energies and non-covalent interactions of furan clusters. J Mol Graph Model 111:108102\u003c/li\u003e\n\u003cli\u003eMalloum A, Conradie J (2022) Non-covalent interactions in small thiophene clusters J Mol Liq 347:118301\u003c/li\u003e\n\u003cli\u003eThomas JM, Thomas R (2023) Study of Non-Covalent Interactions Present in the Tapinarof\u0026ndash;Ethanol System with Special Emphasis on Hydrogen-Bonding Interactions. J Phys Chem B 127:5933\u0026ndash;5940\u003c/li\u003e\n\u003cli\u003eMacleod NA, Simons JP (2002) Conformation, structure and molecular solvation: a spectroscopic and computational study of 2-phenoxy ethanol and its singly and multiply hydrated clusters. Chem Phys 283:221\u0026ndash;236\u003c/li\u003e\n\u003cli\u003eZborowski KK, Poater J (2021) Pyrrole and Pyridine in the Water Environment\u0026mdash;Effect of Discrete and Continuum Solvation Models. ACS Omega 6:24693\u0026ndash;24699\u003c/li\u003e\n\u003cli\u003eBader RFW (1991) A Quantum Theory of Molecular Structure and Its Applications\u003cstrong\u003e.\u003c/strong\u003e Chem Rev 91:893\u0026ndash;928\u003c/li\u003e\n\u003cli\u003eBader RFW (2009) Bond Paths Are Not Chemical Bonds. J Phys Chem A 113:10391\u0026ndash;10396\u003c/li\u003e\n\u003cli\u003eMatta CF, Boyd RJ (2007) The Quantum Theory of Atoms in Molecules. Matta CF, Boyd RJ (ed), WILEY-VCH, Weinheim.\u003c/li\u003e\n\u003cli\u003eEskandari K, Alsenoy CV (2014) Hydrogen\u0026ndash;Hydrogen Interaction in Planar Biphenyl: A Theoretical Study Based on the Interacting Quantum Atoms and Hirshfeld Atomic Energy Partitioning Methods J Comput Chem 35:1883\u0026ndash;1889 \u003c/li\u003e\n\u003cli\u003eAihara J (2002) Nucleus-Independent Chemical Shifts and Local Aromaticities in Large Polycyclic Aromatic Hydrocarbons. Chem Phys Lett 365:34\u0026ndash;39 \u003c/li\u003e\n\u003cli\u003eLazzeretti P (2004) Assessment of Aromaticity via Molecular Response Properties. Phys Chem Chem Phys 6:217\u0026ndash;223 \u003c/li\u003e\n\u003cli\u003eFrisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr., Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision A.02-SMP, Gaussian, Inc., Wallingford, CT \u003c/li\u003e\n\u003cli\u003eBiegler-K\u0026ouml;nig F, Sch\u0026ouml;nbohm J, Bayles D (2001) AIM2000\u0026ndash; A Program to Visualize and Analyze Atoms in Molecules. J Comput Chem 22:524\u0026ndash;529\u003c/li\u003e\n\u003cli\u003eGrabowski SJ (2004) Hydrogen bonding strength\u0026mdash;measures based on geometric and topological parameters J Phys Org Chem 17:18\u0026ndash;31\u003c/li\u003e\n\u003cli\u003eGrabowski SJ (2011) What is the Covalency of Hydrogen Bonding? Chem Rev 111:2597\u0026ndash;2625\u003c/li\u003e\n\u003cli\u003ePopelier PLA (1998) Characterization of a Dihydrogen Bond on the Basis of the Electron Density. J Phys Chem A 102:1873\u0026ndash;1878\u003c/li\u003e\n\u003cli\u003eRandic M, Balaban AT (2006) Partitioning of \u0026pi;-electrons in rings for Clar structures of benzenoid hydrocarbons J Chem Inf Model 46:57\u0026ndash;64\u003c/li\u003e\n\u003cli\u003eGobre VV, Pinjari RV, Gejji SP (2010) Density functional investigations on the charge distribution, vibrational spectra and NMR chemical shifts in cucurbit[n]uril (n = 5-12) hosts. J Phys Chem A 114:4464\u0026ndash;4470\u003c/li\u003e\n\u003cli\u003eLande DN, Rao SS, Gejji SP, Deciphering Noncovalent Interactions Accompanying 7,7,8,8-Tetracyanoquinodimethane Encapsulation within Biphene[n]arenes: Nucleus-Independent Chemical Shifts Approach. ChemPhysChem 17:2197\u0026ndash;2209\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1-2 are available in the Supplementary Files section.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Atoms In molecules, Non-covalent interactions, Clusters, Nucleus Independent Chemical Shift, Covalency of the HBs","lastPublishedDoi":"10.21203/rs.3.rs-4931761/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4931761/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBader’s “Atoms in Molecules” formalism has been adopted to assess the non-covalent interactions present within the mono and di-solvent (water and methanol) clusters of 2-Hydroxypyridine and 2-Hydroxynicotionic acid in their Closed and Open conformations and to critically analyze the characteristics and the energetics of the interaction lines towards the planarity of the structural skeletons. Nucleus independent chemical shift (NICS) descriptor has also been exploited to delineate the role of aromaticity in dictating the structures and the characteristics of the non-covalent interactions present within the studied compounds. Both electrostatic and partially covalent Hydrogen bonding interactions (HB) are found within the clusters. Furthermore, apart from the typical O····H–O and N····H–O HBs, a weak albeit unique O····H–C\u003csub\u003e \u003c/sub\u003einteraction line of purely electrostatic origin is observed. The covalency of the HBs as well as the structural constraints are found to modulate the aromaticity of the associated pyridine nuclei.\u003c/p\u003e","manuscriptTitle":"Interplay between structural integrity and aromaticity on governing the nature of the non- covalent interactions within the mono and di-solvent clusters of 2-Hydroxypyridine and 2- Hydroxynicotionic acid: A topological description","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-13 06:15:03","doi":"10.21203/rs.3.rs-4931761/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"88150a99-ed99-421b-b9bc-7bc8738dbe4b","owner":[],"postedDate":"September 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-26T09:38:59+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-13 06:15:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4931761","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4931761","identity":"rs-4931761","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}