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

doi:10.21203/rs.3.rs-4931761/v1

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–Cinteraction 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

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].

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 O₆····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, CH₃), 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 N₁–C–O₅–H₆ 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 N₁–C–O₅–H₆ 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–O₅–H₆ bond angle is found to discernibly amplify on moving from 2HP–C–H₂O cluster (~ 109.1°) to the 2HP–C–(H₂O)₂ cluster (~ 111.6°). The aforesaid rationale also accounts for the augmented N₁–C_α–O₅–H₆ 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 O₅····O_a Coulombic repulsions which otherwise would significantly enhance due to an increment in the atomic charges of the O₅ atoms as a result of HB formations. It is however worth mentioning here that in the 2HNA–O–H₂O 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 H₆–O₅ 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 –O₅–H₆ functionality (viz. the O₃····H₆–O₅ HBs) is evident from the substantial decrements of the associated stretching frequencies (vide Table S1 in the supplementary information); the order of strength being –H₂O < –MeOH < –(H₂O)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 O₅–H₆ bond not being involved in any H-bonding interaction. It should however be mentioned at this point that there exists an O₅····H₇–O₈ HB in the 2HP–O–(H₂O)₂ cluster as concluded by the stretching frequency of the H₇–O₈ 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 N₁····H₂–O₃ 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, –H₂O ≈ –MeOH > –(H₂O)₂, which also seems rational as the separation between the involved atoms follow the exact same trend. For the di-solvent clusters, O₃····H₇–O₈ HBs associated with the interaction between the two solvent molecules as proliferated in the blue shift of the H₇–O₈ 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 O₃····H₉–O₈ HB for the 2HP–O–(H₂O)₂ cluster with an amplified atomic separation is also noted in this regard. Moreover, the C₄–H_c stretching frequency in the 2HP–O–MeOH cluster shows a significant blue shift as compared to the C₄–H_c stretching frequency of methanol itself (~ 3191 cm^–1), inferring the presence of a O₅····H_c–C₄ 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 N₁····H₂–O₃ 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 N₁····H₂–O₃, O₃····H₆–O₅ and O₅····H_c–C₄ HBs in the studied structures
Compound	d_HB (Å)	r_HB (a.u.)	ρ_c (a.u.)	∇²ρ_c (a.u.)	G_c (a.u.)	V_c (a.u.)	H_c (a.u.)	ρ^RCP (a.u.)	ellipticity	E^HB (kcal/mol)
N₁····H₂–O₃ HB
2HP–C–H₂O	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–(H₂O)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–H₂O	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–(H₂O)₂	2.0806	3.9926	0.01950	0.07547	0.01602	– 0.01316	0.00286	0.00236	0.09421	– 4.1290
2HNA–O–H₂O	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–(H₂O)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
O₃····H₆–O₅ HB
2HP–C–H₂O	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–H₂O	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
O₅····H_c–C₄ 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_cs 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| < |G_c|, which implies that H_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 which implies a covalent interaction but ∇²ρ_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–(H₂O)₂, the N₁····H₂–O₃ HBs are characterized by a positive Laplacian and a positive total energy density; viz. ∇²ρ_c > 0; and H_c > 0, thereby inferring the interaction to be of electrostatic origin. However, the N₁····H₂ 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 N₁····H₂–O₃ HBs present in the concerned structures are moderately strong and the consequent energetics corroborate well with the separation between the two bonded atoms viz. N₁ and H₂ 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 N₁····H₂ 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–H₂O) also contain O₃····H₆–O₅ HBs thoroughly preserving the Popelier criteria (vide Table 1). However, although all these HBs are characterized by ∇²ρ_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 O₅····H_c–C₄ HB, the corresponding electron density parameters ρ_c and ∇²ρ_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: ∇²ρ_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–(H₂O)₂) demonstrate O₈····H₆–O₅ 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_cs 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 O₈····H₆–O₅, O₅····H₇–O₈, O₃····H₇–O₈, O₃····H₉–O₈ and O_a····H₆–O₅ HBs in the studied structures
Compound	d_HB (Å)	r_HB (a.u.)	ρ_c (a.u.)	∇²ρ_c (a.u.)	G_c (a.u.)	V_c (a.u.)	H_c (a.u.)	ρ^RCP (a.u.)	ellipticity	E^HB (kcal/mol)
O₈····H₆–O₅ HB
2HP–C–(H₂O)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–(H₂O)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
O₅····H₇–O₈ HB
2HP–O–(H₂O)₂	1.9971	3.8262	0.01872	0.08581	0.01793	– 0.01441	0.00352	0.00236	0.06316	– 4.5211
O₃····H₇–O₈ HB
2HP–C–(H₂O)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–(H₂O)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
O₃····H₉–O₈ HB
2HP–O–(H₂O)₂	2.1348	4.1061	0.01623	0.06337	0.01396	– 0.01208	0.00188	0.00236	0.04889	– 3.7901
O_a····H₆–O₅ 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 O₈····H₆–O₅ HB, an O₅····H₇–O₈ HB is observed for the 2HP–O–(H₂O)₂ cluster (vide Table 2) owing to the spatial orientation of the –O₅–H₆ 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. O₃····H₉–O₈ HB for 2HP–O–(H₂O)₂ and O₃····H₇–O₈ HB for the rest; vide Table 2), of significant strength (2HP–O–(H₂O)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–H₂O cluster is the only non-cyclic structure. A distance of 3.94Å between the O₅ and the H₄ 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–H₂O and 2HNA–O–MeOH clusters contain O₅····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–H₂O 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–H₂O to ~ 5.40 au in 2HNA–O–MeOH). The drastic increment in the ellipticity of the BCP on moving from 2HNA–O–H₂O 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–H₂O 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–H₂O	– 9.3891	– 25.4787
2HP–C–MeOH	– 9.2779	– 25.0903
2HP–C–(H₂O)₂	– 9.2264	– 24.8126
2HP–C–(MeOH)₂	– 9.0943	– 24.6028
2HP–O–H₂O	– 9.8851	– 26.7028
2HP–O–MeOH	– 9.8369	– 26.4866
2HP–O–(H₂O)₂	– 10.0512	– 27.1768
2HP–O	– 9.9159	– 27.0328
2HNA–C	– 9.2499	– 23.2789
2HNA–O–H₂O	– 9.0236	– 23.1409
2HNA–O–MeOH	– 9.0929	– 23.3101
2HNA–O–(H₂O)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 (N₁····H₂–O₃ and O₃····H₆–O₅) are found to be less aromatic as compared to 2HP itself. Since the N₁····H₂–O₃ 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 O₃····H₆–O₅ interaction lines. Interestingly, contrary to the case of water, for methanol the O₃····H₆–O₅ 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 N₁····H₂–O₃ 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 O₃····H₆–O₅ HB. However, it should be emphasized in this regard that although for the 2HP–C–H₂O 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 – N₁ bond is found to increase in length on moving from 2HP–C to 2HP–C–H₂O (from ~ 1.33 Å to 1.34 Å) whereas the C_α – O₅ 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. N₁····H₂–O₃ and O₈····H₆–O₅ 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 N₁ 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 (N₁····H₂–O₃ and O₈····H₆–O₅) are linked with each other through a third HB viz. O₃····H₇–O₈ 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–(H₂O)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 O₅ 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–(H₂O)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····H₆–O₅ 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 (N₁····H₂–O₃ and O₃····H₆–O₅) 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 O₅····O_a Coulombic repulsions as mentioned earlier.

Now it’s appropriate to rationalize the planarity of the –COOH functionality in 2HNA–O–H₂O 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 H₂O 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–H₂O 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 O₅····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 O₅····O_a interaction is not possible owing to an enhanced atomic charge on the O₅ 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. N₁····H₂–O₃ and O₈····H₆–O₅ 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.

The salient observations of the present study can be summarized as follows:

(i) The N₁····H₂–O₃ HB is ubiquitous in all the studied clusters. Although Ñ²ρ_c > 0 is the general characteristic, for the mono-solvent clusters and the 2HP–O–(H₂O)₂ cluster, the said HBs furnish H_c> 0 whereas the other clusters display H_c< 0.

(ii) All cyclic mono-solvent clusters (2HP–O–H₂O cluster is the only non-cyclic structure) furnish O₃····H₆–O₅ HBs which are characterized by 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 O₅····H_c–C₄ HB which is purely electrostatic in nature and substantially weaker than conventional HBs.

(iii) The O₈····H₆–O₅ HBs demonstrated by the studied di-solvent clusters (except for the 2HP–O–(H₂O)₂ cluster which contains an O₅····H₇–O₈ 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). Conversely, the O₅····H₇–O₈ HB is realized be considerably weaker as compared to the former ones, and is characterized by H_c> 0.

(iv) The 2HNA–O–H₂O and 2HNA–O–MeOH clusters contain O₅····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 < –H₂O in accordance with the strengths of the said HBs). For the 2HP–C–H₂O 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 N₁····H₂–O₃ 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–(H₂O)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 O₅ 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 O₅····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.

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.

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Tables 1 to 3 are available in the Supplementary Files section

Schemes 1-2 are available in the Supplementary Files section.

No competing interests reported.

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

Status:

Version 1

Abstract

Figures

Introduction

Computational procedures

Geometry optimization and frequency simulation

Atoms-In-Molecules (AIM) analysis

Calculation of aromaticity indices

Results and Discussions

Geometrical and vibrational analyses

Topological analysis: Atoms-In-Molecule (AIM) study

Aromaticity analysis: Nucleus Independent Chemical Shift (NICS) study

Conclusion

Declarations

Author Contribution

References

Tables

Schemes

Additional Declarations

Supplementary Files

Status:

Version 1