Noncovalent Interactions Accompanying Encapsulation of Resorcinol

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Non-Covalent Interactions Accompanying Encapsulation of Resorcinol Within Azacalix[4]pyridine Macrocycle Dipali N. Lande, Smita A. Bhadane, and Shridhar P. Gejji J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b12912 • Publication Date (Web): 27 Jan 2017 Downloaded from http://pubs.acs.org on January 30, 2017

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The Journal of Physical Chemistry

Non-covalent Interactions Accompanying Encapsulation of Resorcinol within Azacalix[4]pyridine Macrocycle. Dipali N. Lande, Smita A. Bhadane and Shridhar P. Gejji* Department of Chemistry, Savitribai Phule Pune University, Pune-411 007, India

Corresponding author: [email protected] Fax No.: +91-20-225691728 Telephone No.: +91-20 2560122

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Abstract Electronic structure and noncovalent interactions within the inclusion complexes of resorcinol and calix[4]pyridine (CXP[4]) or azacalix[4]pyridine (N-CXP[4]) macrocycles have been analyzed by employing the hybrid M06-2X density functional theory. It has been demonstrated that the substitution of hetero atom (-NH-) at the bridging position of the CXP[4] alters the shape of the cavity from ‘box shaped’ to funnel like one. The penetration of resorcinol guest within the CXP[4] cavity renders the “butter fly like” structure to the complex, whereas the NCXP[4] complex reveals distorted geometry with the guest being nearer to one of the pyridine rings at the upper rim of the host. Underlying hydrogen bonding, π···π and other weak interactions are characterized using the Quantum Theory of Atoms In Molecules (QTAIM) and Noncovalent Interactions Reduced Density Gradient (NCI-RDG) method. The coexistence of multiple intermolecular interactions are envisaged through the frequency shifts of the characteristics –NH and -OH vibrations in their calculated vibrational spectra. The guest protons confined to the host cavity exhibit shielding while those facilitating hydrogen bonding engender the downfield signals in their calculated 1H NMR spectra.


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Introduction A new generation of molecular scaffolds such as biphenarenes,1 pillararenes,2 oxatubarenes,3 calixarenes 4 and their modified analogs have been of growing interest in the field of host-guest chemistry.5-7 In particular the supramolecular hosts derived by substitution of the hetero atom(s) (commonly S, N and O but also Si, Ge, Se, Sn or P) for methylene linkages or arene carbons of calix[n]arenes, usually referred as heterocalixaromatics exhibiting superior physical or chemical properties have been focus of considerable recent research.8-17 The family of such macrocycles have opened up a plethora of applications in the area of sensors,18,19 material science,20 optical electronics21 and biological sciences.22 Interestingly the salient features for instance accessibility, rich molecular diversity, multiple binding sites and self-regulated cavity size offer certain advantages for their selective and efficient binding toward neutral organic guests,23 metal ions24-26 and biomolecules.27 Remarkably enough the size and cavity shape of these novel hosts can be “fine-tuned” due to presence of hetero atoms at bridging positions and those of the rims.28 To this direction, azacalix[4]arenes having four amino groups on its upper rim has been synthesized using one step cyclization.29 These authors demonstrated that such molecular containers are endowed with remarkable sensing ability toward anionic guests such as inositol phosphate in aqueous solution. Miyano et al.30 derived p-tert-butylthia[n]calixarenes (n=4, 6, 8) with sulfide linkages exhibit unique features which stem from the steric and electronic effects arising from sulphur atoms. The molecular container possessing hetero- and heteraunits has proven to be a quantum leap in the advancement of host-guest chemistry.31 Pursuance to this Chen et al.32 introduced triptycene units into oxacalix[4]arenes which yield enlarged cavities and rigid conformations. It has also been recognized that the



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oxacalix[4]arenes assembled tubular structures can encapsulate large sized guests such as fullerenes in solid state. Among different heterocalixaromatic families, aza (-NH-) derivatives have widely been explored as efficient receptors. One of the noticeable features of these being the ability of nitrogen atoms to adopt either sp2 or sp3 hybridization that provides more degrees of conjugation to adjacent aromatic moieties which in turn facilitates multiple binding sites. The stereo diversity and enhanced π-electron density of such hosts promote interactions with small organic molecules33 and transition metals.34 Moreover, such molecular containers serve as a versatile receptors for the hydrogen bond donors and display remarkable selectivity toward alcohol and diols, in particular resorcinol.29 The resorcinol is medicinally important anticancer, antifungal, antioxidant drug35 and finds potential applications in a diversity of areas including spectrofluorometric probing,36 agrichemicals,37 pharmaceuticals,38 clinical trials,39 electric and electronic devices.40 It therefore would be interesting how the clinically important resorcinol interact with heterocalixaromatic macrocycles. With this motif, Wang et al.33 studied the complexation phenomena of resorcinol with azacalix[4]pyridine. These author observed that this complex is enthalpy as well as entropy favoured and stabilized by multiple non-covalent interactions. It has been realized that strength, selectivity and directionality of these interactions profoundly influences the properties of inclusion complexes. In view of this the supramolecular interactions are analyzed with numerous experiments and computational methods. Theoretical investigations have proven successful in deriving deeper understanding, interpretation, and endorsement of experimental findings and yield molecular insights complementary to those accessible from the experiments. Density functional theory (DFT) can therefore be transpired as a


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stochastic method for describing reasonably accurate prediction of supramolecular interactions with affordable computational expense. Despite of afore mentioned studies, almost no endeavour, within DFT, appear to have been made toward the description of underlying noncovalent interactions in heterocalixaromatics. With this perspective DFT based investigations on the inclusion complexes of the calix[4]pyridine (CXP[4]) or azacalix[4]pyridine (N-CXP[4]) and resorcinol as a proto type example, exhibiting diverse supramolecular interactions, have been carried out and structures are shown in Scheme 1. The work further deals with understanding how substitution of -NH- groups at the bridging functionality of CXP[4] influence the noncovalent binding interactions have been studied. The theoretical investigations also shed light on conformational energetics and the ramifications of such interactions to vibrational as well as 1H NMR spectra. The computational strategy applied

is

outlined below.

(a)

(b)

Scheme 1. Structure of (a) calix[4]pyridine (X = CH2) and azacalix[4]pyridine (X=NH) hosts, (b) resorcinol guest.

Methodology Optimizations of CXP[4], NCXP[4] hosts, resorcinol as guest and their complexes were carried out with the GAUSSIAN-09 program package.41 Global hybrid meta GGA (M062X)42,43 functional design to handle weak interactions that include dispersion was used in conjucation with the 6-311++G(d,p) basis set.44 This level of theory is known to 5 ACS Paragon Plus Environment


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simulate the hydrogen bonding adequately typifying other weak interactions as demonstrated by extensive benchmarking in the recent literature.45-48 The local minima were confirmed from the vibrational frequencies by visualizing the displacement of atoms around their equilibrium (mean) positions using the GAUSSVIEW-5 program.49 Electron-rich regions in CXP[4] and N-CXP[4] hosts were inferred from the topography of Molecular Electrostatic Potential (MESP).50-54 The scalar field MESP V(r) is composed of terms those refer to the bare nuclear potential and electronic contributions. Accompanying molecular interactions between CXP[4] and N-CXP[4] complexes are elucidated with the help of QTAIM analyses employing the AIMALL software.55,56 Furthermore, the strength of underlying interactions was envisaged through Natural Bond Orbital (NBO) analysis.57 Additionally the Noncovalent interactions (NCI) were characterized in terms of reduced density gradients (RDG) defined through s=

|∇|

( ) / /

within the QTAIM approach which is derived by using the

Multifunctional Wavefunction Analyser software58 and the visual molecular dynamics program.59 The combination of s and ρ gives a rough partition of real space into bonding regions: the higher -s and lower-ρ parameters correspond to non-interacting density, low-s high-ρ imply covalent bonds, whereas low-s low-ρ evince the presence of noncovalent interactions. The chemical shifts (δH) and spin-spin coupling constants in 1H NMR of the lowest energy complexes were calculated by subtracting the nuclear magnetic shielding tensors of protons in the host, guest and complexes from those in the tetramethylsilane (reference) within the framework of the gauge-independent atomic orbital (GIAO) method.60 The effect of solvent (acetone) on the electronic structure and 1H

NMR chemical shifts were simulated by employing the self-consistent reaction field

(SCRF) theory incorporating the polarization continuum model (PCM).61


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Results and Discussion The substitution of phenol rings by pyridine moiety as well as bridging functionality emerge with a hetrocalixaromatic macrocycle possesessing intriguing structural characteristics than conventional calix[4]arene. Different conformers of calix[4]pyridine (CXP[4]) and azacalix[4]pyridine (N-CXP[4]) are generated by varying the orientation of pyridine rings relative to bridging substituents yielded cone, partial cone, 1,2-alternate and 1,3-alternate structures. Stationary point structures obtained from the M06-2X/6311++G(d,p) level of theory are illustrated in Figure S1 and Figure S2 of the Supporting Information. The relative stabilization energies (in kJ mol-1) are given along with in parentheses. The calixarene hosts comprised of phenol rings generally reveal cone conformer to be of the lowest energy owing to cooperative hydrogen bonding interactions. On the other hand substitution of pyridine ring as in the CXP[4] or NCXP[4] hosts are void of such cooperativity lead to the cone conformer to be largely destabilized and the 1,3-alternate structure is energetically favoured. Thus, it may be concluded that the minimized repulsions between lone pairs of nitrogen atoms of the pyridine moieties contribute to the conformational stability. The hierarchy for stabilization energies in the N-CXP[4] host follows the order: 1,3-alternate > 1,2alterrnate > partial cone > cone. In case of CXP[4] host, both 1,2 alternate and partial cone conformers are distorted significantly and the partial cone being stabilized over the 1,2 alternate structure. Optimized energy minimal structures of CXP[4], N-CXP[4] heterocalixarenes and isolated resorcinol are displayed in Figure 1 along with atomic labelling scheme. The highly symmetric 1, 3-alternate structures show two conjugated pyridine rings with edge-to-edge orientation or alternatively the isolated rings can be arranged with face to face parallel alignment. In case of CXP[4] all the isolated pyridine rings orient parallel to 7 ACS Paragon Plus Environment


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each other and renders ‘box’ shape cavity owing to the presence of methylene linkages. Substitution of N-H functionality at the bridging positions as in N-CXP[4] leads to increased separation between two conjugated pyridine rings and consequently transforms the ‘box’ shaped cavity to the ‘funnel’ shaped one. The nature of cavity and its dimensions play a vital role in its binding with complementary guests. To derive further molecular insights for such host guest binding from the apriori knowledge of the charge distribution within the CXP[4] hosts or its modified analogues are crucial and can be gauged through the MESP topography. The rich topographical features of MESP mapped isosurfaces brings out intense reactive sites, molecular shape, size and electrostatic potentials. The 3D MESP plots (electrostatic potential overlaid on 0.001 au) of CXP[4] and N-CXP[4] hosts are illustrated in Figure 2. The colour coding scheme of MESP isosurfaces: red representing electron-rich region (partially negative charge); blue shows electron deficient surface (partially positive charge); light blue depicts slightly electron deficient region and yellow indicates slightly electron rich region. The prevalence of green colour in the MESP isosurfaces corresponds to a potential halfway between the two extremes of red and blue. A careful observation of Figure suggests that electron-rich regions (bright red) attributed to the lone pair on nitrogen (electron donor) and delocalized π-cloud (reddish yellow) of the pyridine moieties in the hosts. A gradual depletion from red or blue areas to green located near pyridine rings is observed. The chemical equivalence of the pyridine protons in CXP[4] is evident from the maximum positive electrostatic potential (Vmax) parameters (~0.028 au). The cumulative effect of inner π-delocalized cloud reflects in dumbbell shaped portion (blood red) shown in Figure 2b and thus accumulation of electron density in the central part of the CXP[4] host can be noticed. In case of N-CXP[4] the π-cloud of isolated parallel rings as well as domain of lone pair of its nitrogen atoms are 8 ACS Paragon Plus Environment

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collectively concentrated in the core of the cavity and looks like a well-shaped as displayed in Figure 2. Such central electron rich regions are absent in the conventional bucket shaped cone conformer of the parent calix[4]arene. The pyridine A and A’ ring protons turn out to be relatively less electron deficient region (0.025 au) than those of the isolated parallel rings (B and B’) protons (0.030 au). The N-H bridge hydrogen atoms are rendered with the maximum brunt of positive charge. Thus it is speculated that, a weakly acidic resorcinol confined to CXP[4] and N-CXP[4] host within the energetically favored central electrophilic region. Taking cue from this the CXP[4] and N-CXP[4] complexes have been generated by rotation and translation of the resorcinol guest in neighbourhood of the MESP minima of the host. The resorcinol@CXP[4] and resorcinol@N-CXP[4] complexes were optimized using the M06-2X/6-311++G(d,p) level of theory, which are depicted in Figure 3. As may readily be noticed encapsulation of resorcinol within the cavity of CXP[4] receptor (cf. Figure 3a) led to a sandwiched π-complex in which the resorcinol is placed between two parallel pyridine A and A’ rings. On the other hand, the complexation of resorcinol with N-CXP[4] results in slightly distorted geometry due to acidic nature of guest.29 Remarkably, these complexes are stabilized through O1-H4···Na, C-H···π, π···π and van der Waal interactions. The O1-H4···Na interactions stem from the nitrogen atoms of the pyridine B & B’ rings with hydroxyl hydrogen of the resorcinol guest while the C-H···π and π···π interactions arise from aromatic moiety of resorcinol and the A & A’ pyridine rings in the molecular container. The accompanying interactions brings about significant alteration in electron density around the interacting moieties of the host and guest upon complexation which is transparent from the MESP mapped density. The pictorial representation of electrostatic potential in resorcinol and its complexes are given in Figure 4. The noticeable colour variation (red to yellow) in resorcinol@CXP[4] 9 ACS Paragon Plus Environment


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and resorcinol@N-CXP[4], depicts O1-H4···Na interactions with shallow MESP minima near nitrogen atoms (0.051 au to 0.027 au). A large diminution in electron density at central cavity of both the hosts are clearly visualized from Figure 3b and 3d signifying an effective host guest binding. Moreover the C-H···π and π···π interactions are manifested in the deeper MESP minima arising from π cloud of resorcinol ring. The interplay between host and guest also affect the structural parameters and the prominent changes in terms of bond distances, angles and dihedral angles as reported in Table 1. The O1−H4···Na interactions engender an elongation up to 0.023 Å and 0.018 Å for the O-H bond in CXP[4] and N-CXP[4] complexes, respectively. The C1-H3 bond in the resorcinol is shortened by ~0.002 Å compared to the free guest. It may readily be noticed that the bond angles between the conjugated pyridine rings are nearly insensitive to complexation of CXP[4] with resorcinol while a distortion in the geometry of N-CXP[4] upon the guest binding leads to a substantial deviation in ∠ C-N-C. The QTAIM analysis utilized as a tool for more detail inspection of the nature of weak supramolecular interaction in resorcinol and the CXP[4] or the N-CXP[4] host and pictured in Figure 5. These interactions are characterized and classified depending upon the properties of electron density (ρbcp) as well as energy (G, V, H) density at the bond critical point (bcp) which are listed in Table 2. According to Koch and Popelier62 the hydrogen bonding (O···H) interactions satisfied criteria: the ρbcp parameters in the range 0.002− 0.035 au, with the corresponding Laplacian ( ∇ ) values being 0.014−0.139 au. As may readily be noticed from Table 2, stronger hydrogen bonds (O1H4···Na) are inferred between the hydroxyl groups and pyridine nitrogen than those of C1-H3···Na bonding for the hitherto inclusion complexes. The presence of an intermolecular C···C bond path between the C atoms belonging to resorcinol and pyridine (A and A’) rings is an indication of the attractive through-space interactions 10 ACS Paragon Plus Environment

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between the diagonally stacked π−π* orbitals of sandwiched CXP[4] complex. In case of resorcinol@N-CXP[4] complex guest leans over one of the upper rim pyridine rings consequent to enlargement of cavity size upon bridging substitutions. These two rings facilitate Nb-Hc···O1, lone pair···π along with the π−π interactions and corresponding ρbcp value fall in the proposed range corresponds to weak interactions.62 Additionally, the existence of bcp between the carbon atoms of host rings (B and B’) suggest the presence of intramolecular π−π bonding (cf. Figure 5). The deeper insights for the atom-atom interactions can be derived using the basis of Virial theorem between energetic topological parameters and the Laplacian of electron density at bcp. Accordingly,

V = ∇ – 2G

H= G + V , where G, signifies the kinetic energy, which is directly proportional to mobility of the electron density at the bcp and reflects in the pressure exerted by electron density accumulated at bcp on other electrons while V represents potential energy of the electrons at bcp that provide a measure of pressure exerted on the electrons at the bcp by other electrons. The H refers to the total energy density with its sign showing the dependence on counterbalancing of G and V. The |V|/G ratio serves as a useful descriptor and indicates the nature and type of interactions: |V|/G < 1 representing the characteristic of closed interaction; when |V|/G > 2 is diagnostic for the share type interaction.55 Beside partially covalent and electrostatic interactions are observed for 1 < |V|/G < 2. For complexes studied herein, this ratio found to be ~1.11 indicating partially covalent and electrostatic character of O1-H4···Na hydrogen bonds. The rest of existing interactions with closed shell type (0.77-0.87) can be inferred. Further the strength of hydrogen bonding at the bcp was calculated by using the Espinosa-Molins11 ACS Paragon Plus Environment


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Lecomte formula (EHB = 0.5 x V).63 The strength of O1-H4···Na are predicted to be 42.6 kJ mol-1 for the CXP[4] complex (symmetrical geometry) whereas the corresponding hydrogen bond strengths in distorted N-CXP[4] complex are observed to be 35.2 kJ mol1

and 46.8 kJ mol-1. The bond strength of Nb-Hc···O1 arising from the bridging

functionality of N-CXP[4] turned out to be 10.1 kJ mol-1. These corollaries are corroborated from the ellipticity parameters (Ɛ=

− 1) with strong hydrogen bonding

relatively lower ellipticity (~0.02) while those originate from delocalized π- cloud display the weak molecular interaction. A quick glance at the electron density redistribution associated with nonlocalized dispersion as well as repulsive nonbonded interaction has been assured through the lens of NCI-RDG method. Therefore, it is serve as an effective tool to distinguish and visualize weak interactions: stabilized (hydrogen bonding), destabilized (steric repulsion) and delocalized weak (van der Waal). To probe the existence of weak interactions, the plots of the reduced density gradient versus the electron density multiplied by the sign of the second Hessian eigenvalue (λ2) has been utilized. Multiplication of electron density by the sign of the second Hessian eigenvalue distinguishes the repulsive (sign λ2)ρ > 0 and attractive (sign λ2)ρ < 0 interactions. The stronger attractive hydrogen bonding interactions, appear at the higher density values (ρ > 0.01 au), while dispersion interactions present at very low density values (ρ < 0.01 au) as shown in NCI plot. Supramolecular interactions in the NCI method can as well be visualized by gradient isosurfaces in real space for the molecule. The color coding scheme used for isosurfaces is as follows: blue for attractive, red for repulsive, and green for intermediate interactions. The 3D spatial visualization of NCI isosurfaces and 2D scatter plots between the resorcinol with parent CXP[4] and N-CXP[4] moiety are represented in Figure 6. As can be seen for resorcinol@CXP[4] complexes there is a 12 ACS Paragon Plus Environment

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small, flat, pill-shaped volume painted in dark blue in high critical density region (0.04 au) as measured in the 2D plot, appears between hydroxyl group and donor atom of pyridine rings B and B’. The resorcinol@N-CXP[4] complex reveal similar features except for the two troughs observed at higher density around the 0.032 au and 0.040 au as a result of asymmetrical structural environments (cf. Figure 6b). The higher ρ at the NCI critical point reflects the strength of the O1-H4···Na interaction contributing largely to stability of the complexes, the result parallel to the inferences drawn earlier. The additional stronger destabilized (steric crowding) interactions, are testified by a high ρ critical value (ρ = 0.025 au) appear in the central region of aromatic moiety (ring closure) represented by bright red cigar-shaped surfaces. These are elongated along direction of decreasing density. Moreover, there are other lower density isosurfaces between the overlap portion of resorcinol and the upper rim pyridine rings (A and A’), where π stacking can be inferred. The green sheet like extended form corresponds to π···π interaction is in both green and light brown, indicating weak attraction and repulsion, respectively. Interactions between the C1–H3 bond of resorcinol and the hydroxyl hydrogen (H4), is weak and found in real space by light brown colored isosurfaces. The almond-shaped bicolored isosurfaces manifests near the linkage unit of two conjugated pyridine rings. The attractive component of these surface has mainly been observed between the pyridine nitrogen and carbon atom, counterbalanced by destabilization originating from the induced four-membered ring closure. For the resorcinol@CXP[4] complex the shorter methylene linkages exert large ring strain compared to its N-CXP[4] analog (cf. Figure 6a and Figure 6b). These results demonstrate the presence of weak interactions between the host and guest and further shed light on unambiguous compatibility between QTAIM and NCI-RDG.



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To probe the origin and strength of weak interactions of resorcinol with CXP[4] and N-CXP[4], the NBO analysis was carried out. The second order perturbation energy ()

(→∗ ) gives a measure of the overlap integral between the lone pair and antibonding orbital of the donor and acceptor respectively. The NBO parameters for the resorcinol encapsulated complexes are provided in Table 3, which reiterates stronger hydrogen bonding interactions are involved in the → ∗ transition between lone pair of nitrogen and the antibonding orbital of the corresponding O-H bond. Interestingly the ()

(→∗ ) parameters in both the CXP[4] and N-CXP[4] complexes corresponding to π···π stacking interactions are lower by an order of magnitude imply that these interactions are not dominated by charge transfer or the electrostatic force. Additional lone pair

→ ∗ and Nb-Hc···O1 interactions in the resorcinol@N-CXP[4] are evident. In an effort to understand the effect of molecular interactions on the spectroscopic characteristics of hosts and guests, we computed vibrational activities and the 1H NMR spectra. Harmonic vibration frequencies of CXP[4], N-CXP[4] and their complexes with resorcinol are derived from the Hessian matrix computed within the framework of the M06-2X/6-311G(d,p) theory as pointed out in the preceding section. The molar absorption coefficient (or, molar absorptivity in units of 0.1 m2mol−1) versus the frequency (in cm−1) showing the -OH, -NH and -CH stretchings are portrayed in Figure 7. The frequencies pertaining to some prominent stretching vibrations are enumerated in Table 4. The following inferences are drawn. As showed in Figure 6, an isolated peak near 3924 cm-1 is assigned to O-H stretching of the isolated guest. The computed C1-H3 stretching modes of phenyl ring of guest lie between the two hydroxyl groups appears near 3128 cm-1. A large red shift (~511 cm-1) in the O-H stretching accompanying the complexation suggests the weakening of the corresponding bond


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owing to O1-H4···Na interactions with concomitant increase in its intensity. NBO analysis revealing the increase of electron density in its anti-bonding O-H natural orbital further corroborate these inferences. Noteworthy enough, the contraction of C1-H3 bond participating in C1-H3···Na interactions shows a blue shift for resorcinol@CXP[4] (3165 cm-1) and resorcinol@N-CXP[4] (3183 cm-1) complexes and accompanied with the diminutive intensity, consistent with earlier interpretation on the blue shifted hydrogen bonds. The π···π stacking between resorcinol and pyridine moieties shows signature as the characteristic C=C stretching in CXP[4] and N-CXP[4] complexes which reveal the wavenumber lowering ( ~53 cm-1) in the complexes. In case of N-CXP[4] the bridging N-H functionality facilitate Nb-Hc···O1 interactions and corresponding vibrations in the complex are observed at the 3575 cm-1. Thus the frequency shift and intensity patterns of characteristic vibrations in the infrared spectra serves as a “fingerprint” for typifying the noncovalent interactions in supramolecular chemistry. Underlying molecular interactions can be envisaged through chemical shifts (δ) and spin-spin coupling constants (J) in 1H NMR spectra from the GIAO method. Calculated δH values of an individual host or guest in the complex using acetone as the solvent are computed which are summarized in Table 5. Different types of protons in resorcinol labelled as H1 to H4 whilst the pyridine monomer in the hosts are designated by Ha, Hb (for N-CXP[4] Hb refers to A & A’ whereas Hb’ denotes B & B’ ring protons) and bridging protons are referred as Hc (cf. Figure 1). The confinement of H3 proton within electron rich host cavity engender shielding with its signal appearing near ~ 3.2 ppm. The hydroxyl protons (H4) manifest in a stronger intermolecular hydrogen bonding (O1-H4···Na) shows its signature with a downfield signal upto ~ 6.0 ppm in CXP[4] and N-CXP[4] complexes. As far as the host protons are concerned, δH values follow the order Ha > Hb > Hc in consistent with the one observed in the experimental 15 ACS Paragon Plus Environment


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1H

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NMR spectra. The N-H proton in the isolated N-CXP[4] observed at the 5.7 ppm

shows a signal near 6.2 ppm upon complexation with resorcinol, implying stronger NbHc···O1 hydrogen bonding. Further, the intermolecular spin-spin coupling constant (SSCs) enable one to unravel molecular interactions accompanying the hosts-guest complexation. To elucidate nature of hydrogen bond, indirect SSCCs 1hJ (H···N) and their components (PSO, DSO, FC, and SD) across the O1-H4···Na hydrogen bonds in the CXP[4] and N-CXP[4] complexes were calculated and are given in Table 6. It may be remarked here that the SSCCs parameters are strongly dependent on hydrogen bond separations and bond angle parameters. A large contribution from the FC term followed by the PSO term to J was noticed. Interestingly the negative one-bond coupling constants for

1hJ

(H···N) led to the magnetogyric ratio of 1H to be positive as oppose to 15N. Conclusions The density functional theory have been carried out to probe the underlying noncovalent interactions between the resorcinol and CXP[4] or N-CXP[4] molecular receptors. The 1,3-alternate conformer turns out to be of the lowest energy in both CXP[4] and N-CXP[4] hosts. Encapsulation of the weakly acidic resorcinol within the NCXP[4] results led to distorted host structure. It has been demonstrated that the minimum energy structure of resorcinol@CXP[4] complex is held by O1-H4···Na and π···π interactions whereas in N-CXP[4] the substitution results in additional Nb-Hc···O1 and lone pair···π interactions. Detail analysis of molecular interactions have been studied by the MESP topography, NBO analysis in conjuncture with the AIM and NCIRDG methods enables ones to distinguish attractive and repulsive interactions. A comprehensive analysis of the vibrational spectra confirm the noteworthy interactions from the frequency-shifts of characteristic -OH, -NH, -CH stretching vibrations.


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In summary, the present endeavor provides deeper insights to interpret supramolecular interactions at molecular level. This approach can further be extended to unravel interactions involved in the complex chemical and biological process. Acknowledgements SPG acknowledges support from the Research Project (37(2)/14/11/2015-BRNS) from the Board of Research in Nuclear Sciences (BRNS), India. DNL and SAB is thankful to Savitribai Phule Pune University for the award of research fellowship through the University of Potential excellence scheme from the University Grants Commission, New Delhi, India. Authors thank the Center for Development of Advanced Computing (CDAC), Pune for providing National Param Supercomputing Facility.

Supporting Information Different conformers of CXP[4] and N-CXP[4] from the M06-2X/6-311G(d,p) theory. The corresponding relative stabilization energies (in kJ mol-1) with respect to the lowest energy structure are shown along with.

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Figures:

4

(a)

(b)

(c)

(d)

(f) (e) Figure 1. Optimized structures of (a) host monomer (b) resorcinol (c) top view of CXP[4] (d) side view of CXP[4] (e) top view of N-CXP[4] (f) side view of N-CXP[4]



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(a)

(b)

Figure 2. Electron density isosurfaces (0.001 au) overlaid with MESP (from +0.045 au to 0.045 au) in (a) CXP[4] (b) N-CXP[4] hosts.


-

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(a)

(b) Figure 3. Optimized structure of (a) resorcinol@CXP[4] (b) resorcinol@N-CXP[4] complexes.



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(a)

(b)

(c)

Figure 4. Electron density isosurfaces (0.001 au) overlaid with MESP (from +0.045 au to -0.045 au) in (a) resorcinol (b) resorcinol@CXP[4] (c) resorcinol@N-CXP[4].


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(a)

(b) Figure 5. QTAIM topological analysis of NCI in (a) resorcinol@CXP[4] (b) resorcinol@NCXP[4] complexes. Bond critical points (bcp) are shown as pink. The ρbcp values are given along with.



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(a)

(b)

Figure 6. Colour-filled RDG isosurfaces depicting noncovalent interaction regions in the (a) resorcinol@CXP[4] and (b) resorcinol@N-CXP[4] complexes. 30

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(a)

(b) Figure 7. Vibration frequencies of (a) -CH stretching and (b) -OH, -NH stretching in the calculated infrared spectra of host, guest and their complexes.



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Table 1. Selected structural parameters (bond-distances in Å and angles in °) of CXP[4], N-CXP[4] hosts, resorcinol and their inclusion complexes. CXP[4]

N-CXP[4]

resorcinol

resorcinol@CXP[4]

resorcinol@N-CXP[4]

O1-H4

0.961

0.984

0.978, 0.981

C2-O1

1.357

1.354

1.360, 1.355

C1-C2

1.391

1.396

1.398

C1-C4

2.765

2.778

2.782

C2-C3

1.389

1.396

1.395

C3-C4

1.386

1.389

1.389

C1-H3

1.090

1.088

1.088

C3-H2

1.084

1.083

1.083

C4-H1

1.086

1.084

1.084

H3-H4

2.282

2.335

2.324, 2.349

Cb-Cc

1.393

1.399A, 1.390B

1.393A, 1.391B

1.396A, 1.390B

Cc-Na

1.333

1.328A, 1.329B

1.332A, 1.337B

1.327A, 1.419B

Cc-Cd

1.513

1.516A,

Cd-Hc

1.091

1.092A, 1.094B

Cc-Nb

1.405A, 1.421B

Nb-Hc

1.012

1.509B 1.404A, 1.409A’ 1.406B, 1.408B’ 1.013A, 1.012B

Cb-Cd-Na

89.7

108.8

Cc-Cd-Cc

107.8

111.2

Cc-Cd-Hc

110.3

109.6

Cb-Nb-Na

135.6

Cc-Nb-Cc

117.5

Cc-Nb-Hc

112.1

Cb-Cc-Cd-Hc

147.4A, 119.9A’, 144.2B, 117.4B’ 120.0A, 114.6A’, 119.8B, 113.8B’ 113.0A, 111.9A’ 113.2B, 112.3B’, -16.8A, 137.7B

11.5

cavity(Na-Na)

5.046

4.899A, 4.804B

5.025A, 4.760B

27.6A, 26.8A’, 158.3B,157.6B’ 4.866A, 4.674B

cavity(Ca-Ca)

4.081

9.029A, 3.371B

6.712A, 3.700B

8.657A, 3.472B

Cb-Cc-Nb-Hc

A, A’, B, B’

37.6A, 148.5B

refers to pyridine rings (cf. Figure 1).


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Table 2. QTAIM parameters corresponding to noncovalent interactions present in CXP[4], N-CXP[4] inclusion complexes.

resorcinol@CXP[4] O1-H4···Na C1-H3···Na Nb-Hc···O1 π···π Intra π···π Inter

LP(O1)···π

resorcinol@N-CXP[4]

r

ρ

∇2 ρ

G

V

H

Ɛ

|V|/

r

ρ

∇2 ρ

G

V

H

Ɛ

|V|/

1.816 1.816 2.797 2.883

0.039 0.039 0.007 0.006

0.106 0.106 0.021 0.020

0.030 0.030 0.005 0.004

-0.032 -0.032 -0.004 -0.003

0.003 0.003 -0.001 -0.001

0.023 0.023 1.025 0.838

1.099 1.099 0.829 0.814

1.801 1.887 2.785

0.041 0.033 0.006

0.109 0.100 0.017

0.031 0.026 0.004

-0.036 -0.027 -0.003

0.004 0.001 0.000

0.024 0.037 0.365

1.133 1.037 0.871

0.886 5.769 5.870 0.836 0.840

0.777 0.797 0.797 0.795 0.795

3.015 3.883

0.011 0.005

0.039 0.013

0.009 0.003

-0.008 -0.002

-0.001 -0.001

0.399 0.507

0.880 0.772

3.915 5.131

0.008 0.005

0.026 0.014

0.006 0.003

-0.005 -0.002

-0.001 -0.001

0.802 4.825

0.822 0.807

4.020

0.007

0.022

0.005

-0.004

-0.001

2.539

0.848

3.700 3.380 3.381 3.386 3.386

0.003 0.007 0.007 0.008 0.008

0.008 0.020 0.020 0.021 0.021

0.002 0.004 0.004 0.004 0.004

-0.001 -0.003 -0.003 -0.003 -0.003

0.000 -0.001 -0.001 -0.001 -0.001

33



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Table 3. NBO analysis of inclusion complexes of CXP[4], N-CXP[4] with resorcinol.

(kJ)

Name of complex

Donor

Acceptor

resorcinol@CXP[4]

LP(Na) BD(Cb-Cc) LP(Na)

BD*(O1-H4) RY*(C1) BD*(C1-H3)

27.O1 0.81 0.33

LP(Na) BD(C1-C2) BD(C2-C3) BD(C2-C3) BD(C2-O1)

BD*(O1-H4) BD*(Cc-Na) BD*(Ca-Cb) RY*(Ca) RY*(Cc)

91.84, 60.82 1.67 1.42 0.75 0.46

resorcinol@N-CXP[4]


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Table 4. Selected vibrational frequencies (cm–1) (ν = stretching, δ = bending) of CXP[4], N-CXP[4]hosts, resorcinol guest and the host-guest complexes. The corresponding intensities (in km mol-1) are given in parenthesies. Vibrational modes ν (O-H) ν (N-H) ν (C1-H3) ν(Cd-Hc) ν(CH=CH) ν (O-C2) ν(C2-C3) ν (Cc-Cd) δ (H3-C1=C2) δ (C1=C2-O-H4) δ (C1=C2-O) δ (H1-C4-C3-H2) Ring Breathing

CXP[4]

N-CXP[4]

resorcinol 3924(121)

resorcinol@CXP[4] 3419(1787)

3128(9)

3165(0) 3073; 3072; 3068; 3067 1685(90); 1670(90) 1688(35) 1678(108) 1372(10) 1228(7) 860(45) 393(0) 775(136) 878(10)

3609(122) 3098(30) 1671(207)

1670(368) 1711(55) 1707(233)

1358(25)

860(12) 816(23)

750(8) 741(14)

1250(210) 363(217) 340(5) 795(17)


resorcinol@N-CXP[4] 3413(1860) 3598; 3596; 3586; 3572 3162(0) 1702(57) 1669(55) 1654(223) 1555(19) 882(3) 385(10) 758(1) 820(63)


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.

Table 5.1H NMR chemical shifts (ppm) of CXP[4], N-CXP[4]hosts, resorcinol guest and their complexes. δH Ha Hb Hb’ Hc H1 H2 H3 H4

CXP[4] 8.3 7.8 7.8 4.1

N-CXP[4] 8.7 7.8 7.1 5.7

resorcinol

7.5 6.5 6.3 4.6

resorcinol@CXP[4] 7.7 4.5 4.5 7.8 8.0 6.5 3.0 10.6

resorcinol@N-CXP[4] 8.1 6.9 7.9 6.2 7.8 6.7 6.1 10.1


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Table 6. Calculated indirect spin-spin coupling constants 1hJ (H···N) across the intermolecular hydrogen bonds in CXP[4] and N-CXP[4]complexes.

resorcinol@CXP[4]

O1-H4···Na C1-H3···Na C1-H3···Na’

FC -4.88 0.18 0.23

SD 0.26 -0.01 -0.02

PSO -0.40 -0.09 -0.09

DSO 0.53 0.25 0.24

Total -4.49 0.32 0.36

resorcinol@N-CXP[4]

O1-H4···Na O1-H4···Na’ C1-H3···Na C1-H3···Na’ Nb-Hc···O1

-4.71 -4.61 0.31 0.38 0.92

0.25 0.19 -0.02 -0.02 0.07

-0.43 -0.41 -0.16 -0.18 0.51

0.55 0.51 0.24 0.25 -0.50

-4.35 -4.31 0.37 0.43 1.03



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Underlying non-covalent interactions in azacalix[4]pyridine and resorcinol. 249x114mm (96 x 96 DPI)


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Noncovalent Interactions Accompanying Encapsulation of Resorcinol

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