Exploring Chimeric Calix[4]tetrolarene Molecular Scaffolds

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A: Molecular Structure, Quantum Chemistry, and General Theory

Exploring Chimeric Calix[4]tetrolarene Molecular Scaffolds: Theoretical Investigations Dipali N. Lande, and Shridhar P. Gejji J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b01686 • Publication Date (Web): 04 Apr 2018 Downloaded from http://pubs.acs.org on April 4, 2018

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The Journal of Physical Chemistry

Hybrid structures of calixarene (lower rim) and pyrogallolarene (upper rim) 194x193mm (96 x 96 DPI)

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Exploring Chimeric Calix[4]tetrolarene Molecular Scaffolds: Theoretical Investigations Dipali N. Lande and Shridhar P. Gejji* Department of Chemistry, Savitribai Phule Pune University, 411 007, India

Corresponding author: [email protected] Fax No.: +91-20-225691728, Telephone No.: +91-20 2560124

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Abstract Structure and spectral characteristics of chimeric mixture

of calixarene and

pyrogallolarene (usually referred as calix[4]tetrolarene) and its derivatives are studied employing the M06-2X based density functional theory. Different conformers viz., cone, partial cone 1,2-alternate and 1-3-alternate, were identified as the stationary point structures on their potential energy surfaces. Amongst these, the symmetric C4V cone conformer is found to be energetically favorable which can be attributed to cyclic array of hydrogen bonding network in the calix[4]tetrolarene or its thia analogue. The substitution of methoxy groups at the upper rims of calix[4]tetrol- and thicalix[4]tetrol -arenes influences significantly the cooperative hydrogen bonding network and conformational behavior of these hosts. The methoxy substituted macrocycles showed lowering in symmetry from C4v to C2v engendering the pinched cone conformer as the lowest energy structure. The enhanced solubility of the modified calix[4]tetrolarene macrocycles have further been explained from diminutive cooperative hydrogen bonding in its top rim than the pyrogallolarene, which is evidenced from the quantum theory of atoms in molecule and non-covalent interaction reduce density gradient method. Discernibly the underlying cooperative hydrogen bonding emerge with signature in the characteristic vibrational patterns of the calixarene based molecular scaffolds. The chemical shift parameters of their 1H

NMR spectra have further been characterized.



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1. Introduction Arene based molecular scaffolds such as calix[n]arene,1 resorcin[n]arenes, 2pyrogallol[n]arenes,3

pillar[n]arenes,4

biphen[n]arenes,5

corona[n]arenes,6

asar[n]arenes,7 oxatub[4]arenes8-10 are play a pivotal role in the domain of host-guest chemistry. The structural attributes for example their shape, size, and electronic properties facilitate their use in countless scientific field encompassing: molecular machine,11 supramolecular polymer,12 catalysis,13 and drug delivery14 and makes them fascinating. Amongst these one of the more explored cavitand is calix[n]arenes which has chalice-like structure and derived by condensation of para-substituted phenol derivatives in the presence of formaldehyde. A family of this host usually is endowed with three dimensional hydrophobic cavity that can accommodate a variety of organic and cationic guests.15-18 Modification of these hosts by nucleophilc and electrophilic aromatic substitutions at the endo- or exo- positions of its central annulus makes them largely flexible and paves a way to develop a strategy to devise the newer cavitands which exhibit efficient molecular recognition.19-22 Besides the methylene linkage of calix[n]arenes has led to newer families of molecular containers categorized as hetero- and hetera-calixarenes.23-26 A particular branch of calixarenes designed by varying the nature of starting phenol by 1,2,3-trihydroxybenzene is Pyrogallol[4]arene. To characterized the pyrogallolarenes possessing a concave surface and 12 peripheral hydroxyl groups, the solid state analytical methods particularly, X-ray crystallography, are utilized.

To this direction Mattay,27

Atwood,28 and Rissanen29 inaugurated structures of the “cone” or “rccc” conformers for the isolated scaffolds. Pursuance to this Dakanale30 and coworkers elucidated the conformation and configuration of these cavitands using the NMR experiments. 3 ACS Paragon Plus Environment

The

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preparation, physico-chemical characterization, and mesomorphic properties of such new class of pyrogallol[4]arene-based columnar liquid crystals have also been illustrated in the literature.30-32 The pioneering works of Cram et al.33-38 considered pyrogallol[4]arenes as the building block for the synthesis of hemicarcerands in which the covalently bonded dimeric capsules provide impetus for further investigations accompanying the host–guest complexation. With this view the strategies to modulate the binding behavior of pyrogallolarene have been developed in the literature, for instance, Reinhoudt et al.39-43 combined the calix[4]arene and pyrogallol[4]arene subunits via incorporation of linkers which yielded rigid container endowed with nanometer-size cavity, usually referred by ‘carceplexes’. These authors further studied immobilization of pyrogallol[4]arene based carceplexes on a gold surface and subsequently analyzed their complexes with the neutral as well as cationic guests. Discernibly blooming of these synthetic receptors has further opened up plethora of applications in interdisciplinary areas and accelerated expansion of the field of supramolecular chemistry.

In this light the chimeric calixtetrolarenes

synthesized by Cohen and coworkers44 which may as well be considered as a fruit of the perfect combination of calixarene (lower rim) and pyrogalloarene (upper rim) molecular receptors. This chimeric cavitand was obtained by simple and efficient one step reaction between partially methylated 1,2,3,5-benzenetetrol with paraformaldehyde using trifluroacetic acid as a catalyst using dichloroethane as the solvent. These authors combined the NMR, HRMS analyses and X-ray diffraction experiments and elucidated its structure. A detailed molecular level understanding of the electronic structure, conformational behavior, cavity size (dimensions) and charge distributions in such synthetic macrocycles is expected to shed light on the rationale on its complexation 4 ACS Paragon Plus Environment


behavior. These hosts offer certain advantages for design of efficient experimental systems. Inspired by this in the present endeavor we seek to explore the impact of chimeric mixture of calixarene and pyrogallolarene. The following questions have been addressed How substitution at the bridging positions or at the upper rim of the calix[4]tetrolarene influence the conformational energies and the electronic structure of these macrocycles? How topography of scalar fields such as molecular electrostatic potential characterize the charge distribution within their cavity and shed light on the complexation apriorily? How underlying cooperative hydrogen bonding interactions reflect in the vibrational and 1H NMR spectra? Schematic representation of these macrocycles structures are displayed in scheme 1. The computational strategy adopted is outlined below.

Scheme 1. Atomic labeling and abbreviations used herein.

2. Computational Strategy The present work analyze the energy rank order of calix[4]tetrolarene conformers and their derivatives. The density functional theory (DFT) incorporating the global hybrid meta GGA (M06-2X) functional, which simulates well the hydrogen bonding and adequately typifying other weak interactions, have been applied in conjunction with the 65 ACS Paragon Plus Environment

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311++G(d,p) basis set (the polarized and diffuse functions being added to all atoms).45-50 Stationary point structures exhibiting qualitatively different hydrogen bonded patterns were optimized using the Gaussian 09 suite of programs.51 Normal vibrational frequencies in various conformers were computed for the stationary point structures which were confirmed to be the local minima on multi-dimensional potential energy surfaces. The normal vibrations were assigned by visualization of the displacements of atoms around their equilibrium (mean) positions using the GAUSSVIEW-5 program.52 The electrophilic and nucleophilic reactive sites were predicted from the MESP comprising of the bare nuclear and electronic contributions which bring forth effective electron-rich regions in the host.53-56 Subsequent MESP topography was mapped by examining eigenvalues of the Hessian matrix where the gradient of V(r) vanishes. Quantum Theory of Atoms in Molecules (QTAIM), proposed by Bader57 was employed to study the molecular electron density topography and accordingly the bond critical points (bcp) were characterized with the AIMAll software.58

The nonlocalized dispersion as well as repulsive nonbonded

interactions are certain from the NCI-RDG method.59 The RDG defined through s =

|∇ |

( )/ /

within the QTAIM approach and obtained using the Multiwfn program60 and

visualized through the visual molecular dynamics51 software. The chemical shift parameters (δH) in NMR spectra were obtained for the lowest energy conformers by subtracting the nuclear magnetic shielding tensors of protons in the host from those in the tetramethylsilane (reference) within the framework of the gauge-independent atomic orbital (GIAO) method.62 Furthermore the effect of solvent (chloroform) on electronic structure and 1H NMR chemical shifts were simulated using the self-consistent reaction field (SCRF) theory that incorporates the polarization continuum model (PCM).63 6 ACS Paragon Plus Environment


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3. Results and Discussion 3.1 Structural characteristics Calix[4]tetrolarene and its thia derivatives comprising of benzenetetrol (1,2,3,5tetrahydroxybenzene) monomer units can be envisaged as the chimeric mixture of calixarene and pyrogallolarene hosts. Like calix[4]arenes such artificial receptors possess four stereo-centers at the bridging position and different isomeric arrangements led to various conformers showing different arrangements for the hydroxyl groups on the lower (narrow) rim: all four hydroxyls pointing along the same direction (cone structure); one hydroxyl pointing in the opposite direction (partial cone); two neighboring monomers directed in different directions (1,2 conformer) and lastly, two radially opposing monomers pointing in different directions (1,3 conformer), have been optimized. The structures thus derived were subjected to earlier screening using the M06-2X theory with the lower 6-311G basis set. The minimum energy and next low lying structures of these hosts are shown in Figure S1 to S4 of the supporting information. The hierarchy of relative stabilization energies of molecular receptors (I to V) follows the order: cone > partial cone > 1,2-alterrnate > 1,3-alternate.

Subsequently the minimal energy conformers of

calix[4]tetrolarene and its modified analogue subjected to optimizations with the extended 6-311++G(d,p) basis set. The optimized structures are displayed in Figure 1 along with the atomic labelling scheme. As can be inferred

C4v symmetrical cone structure of the

calix[4]tetrolarene (I) possess intramolecular hydrogen bonding interactions between the OH groups (oriented in clockwise direction) at its narrower lower rim

which are

effectively locked in a cyclic network of cooperative hydrogen bonding, contribute to its larger stability over the remaining conformers. Additionally the upper rim (wider) consists 7 ACS Paragon Plus Environment

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of hydroxyl groups oriented in anticlockwise direction which bring forth interactions between neighboring hydroxyl functionalities. The bridging sulphur atoms (-S-) in II brings about expansion of the host cavity subsequently weakening the cooperative hydrogen bonding network, engenders the shortening of C-O and O-H bonds ( ~0.014 Å and ~0.005 Å respectively) compared to the cone conformer of calix[4]tetrolarene. Substitution of meta methoxy group on the upper rim of parent calix[4]tetrolarene causes larger steric repulsions between the meta methoxy substituents in the symmetrical C4v cone conformer. Thus, III and IV reveal lowering of symmetry concomitantly minimizing steric hindrance, which in turn, transforms to the ‘pinched cone’ structure, wherein the two opposite aromatic rings orient nearly parallel with methoxy substituents directing inside (endo) the cavity whereas the remaining methoxy substituent protruding outside the host cavity; the other two aromatic rings adopt flattened positions with the substituents showing the opposite arrangement compared to parallel ones (cf. Figure 1). The flattened aromatic rings in III revealed a separation of 10.19 Å, which compares well with 10.07 Å observed in the X-ray structure reported by Zafrani and Cohen.44 3.2 Molecular electrostatic potential (MESP) In an effort to predict reactive sites in molecular scaffolds studied herein the MESP topography was used as a puissant descriptor. Figure 2 represents the maps of the electrostatic potential overlaid on 0.001 au isodensity surface of calix[4]tetrolarene and its derivatives. The electrostatic potential intensifications are displayed on the color scale as: red (more negative) < orange < yellow < green< blue (positive). A prevalence of green shows the potential midway between the two extreme ends. As may readily be discernible the negative potential has largely been localized near hydroxyl oxygens of the cavitand 8 ACS Paragon Plus Environment


which partly can be attributed to lone pair of oxygen and the π-electron clouds of aromatic rings.

An inner surface within its cavity is less electron rich than the calix[4]arene

receptor. Maximal brunt of a positive charge (dark blue) near the hydroxyl protons can be noticed. The bridging hetero atoms in II pulls the π-electron density of aromatic moiety concomitantly weakening the negative π potential inside its cavity, as evidenced from figure. The methoxylation of upper rim hydroxyl functionalities renders more electro-rich character to the cavity (reddish yellow) and the oxygen centers (dark red) which can be attributed to the disruption hydrogen bond network. Moreover, the lower rim oxygen atoms of the parallel rings render large negative potential. It may, therefore be concluded that MESP topography provides a concise tool for clarifying the substituent effect. Furthermore electron-rich regions around the bridging sulphur atoms in II and IV macrocycles render multiple coordinating sites for effective host-guest binding. In summary, the wide variety of guest molecules can coordinate to interior of bowl (I and II) and funnel (in III and IV) either by hydrophobic effect or various electrostatic interactions. 3.3 Quantum theory of atoms in molecules (QTAIM) An in-depth analysis of hydrogen bonding enables one to rationalize molecular recognition ability and should prove useful for design of task-specific host–guest complexes. In this sense the Bader QTAIM methodology has been proven advantageous to segregate the underlying molecular interactions which tie-up the various chemical concepts related to structure, bonding and reactivity to topological parameters of the electron density distribution function. The negative value of Laplacian of electron density ( ∇ ) at bcp indicates concentration of electronic charge in the internuclear region suggesting sharing of electronic charge between two nuclei ascertaining the covalent bond 9 ACS Paragon Plus Environment

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(polar). The closed shell type interactions for example, hydrogen bond, ionic bond or van der Waal interactions are recognized from depletion of the electronic charge in the internuclear region. A demarcation of hydrogen bonding from van der Waal interactions can be carried out using the criteria set by Koch and Popelier.64 Accordingly the ρbcp parameters fall in the range 0.002− 0.035 au, whereas the corresponding Laplacian (∇2ρ) parameter lie between 0.014−0.139 au. The correlation between the ∇2ρ and energetic parameters at the bcp can be established with the use of the Virial theorem 0.25 ∇2ρ = 2 Gbcp + Vbcp, where Gbcp, denotes the kinetic energy (conventionally >0) component which is directly proportional to mobility of the electron density, whereas the Vbcp term refers to the potential energy (< 0) of the electrons at bcp and provides a measure of pressure exerted on the electrons at the bcp by other electrons. To comprise such energetic parameters in a system of classification of interatomic contacts, Cremer and Kraka65 suggested a criterion on the basis of the sign of ∇2ρ and total electron energy density Hbcp of the charge distribution which can be expressed as Hbcp = Gbcp + Vbcp . As pointed out earlier, the ∇2ρ < 0 suggests covalent and greater than zero indicates closed-shell interactions. However, sometimes the negative Vbcp value greater than the positive value of Gbcp results in negative Hbcp , but the ∇2ρ is still positive implying relatively stronger hydrogen bonding rendered with partial covalent character. Weak and medium hydrogen bonds show both positive ∇2ρ and Hbcp values. QTAIM topological parameters and the corresponding bond distances are enumerated in Table 1. The stronger cooperative hydrogen bonding (O-H···O) interactions between the hydroxyl groups at lower rim are evident from the presence of bcp with larger electron density of 0.04314 au with the corresponding Laplacian being positive, however the total electron density (Hbcp) turns out be a negative (-0.0032 au) in case of the 10 ACS Paragon Plus Environment


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calix[4]tetrolarene (I) host. It may, therefore, be conjectured that these hydrogen bonding interactions have partially covalent character.

The intramolecular hydrogen bonding

arising from –OH group at the C1 and C3 positions can be ascertained from the corresponding QTAIM topological parameters as opposed to the hydroxyl group at C2 position which do not participate in the hydrogen bonding. The substitution of –S- at linking position engenders larger separation between the hydroxyl groups with smaller ρ (0.0248 au) values implying the weaker hydrogen bonding. The minimum energy pinched cone conformer of host III and IV possess varying hydrogen bond strengths at their lower rims; the parallel ring hydroxyl group reveal stronger interaction than flatten ones. As shown in Table 1, for II to IV both ∇2ρ and H parameter turn out to be > 0 which imply closed shell type interactions. Additionally the correlation of hydrogen bond separation and electron density can also be deciphered from the plot of ln(ρbcp) as a function of hydrogen bond distance d(O-H···O) portrayed in Figure 3. A linear correlation (correlation coefficient 0.98) shows the reciprocal relation between ρbcp and the interatomic distances. Further the variation of G and V as a function of interatomic separation (A···B) is portrayed in Figure 4. Beside this the strength of hydrogen bonding at the bcp was determined by using the Espinosa-Molins-Lecomte formulae (EHB =0.5 x Vbcp). Calculated strength of OH···O interactions thus were estimated to be 56 kJ mol-1 and 41 kJ mol-1 corresponding to the lower and upper rims, respectively, for the calix[4]tetrolarene receptor. The rest of macrocycles (II to IV) hydrogen bond strength falls in the range 15.3 - 26.7 kJ mol-1. These inferences are corroborated through the ellipticity parameters ( =

− 1) with strong

hydrogen bonding displaying relatively lower elliptical value (0.07) whilst the weaker hydrogen bonding correspond to the larger values. 11 ACS Paragon Plus Environment

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3.4 Noncovalent interactions reduced density gradient (NCI-RDG) The weak intramolecular interactions should not necessarily indicate the presence of the bcp (critical point where the density gradient vanish) within the regime of QTAIM theory. To scrutinize these interactions particularly, the O1H1 and O2H2 hydroxyl group in addition to nonlocalized dispersion and repulsive non-bonded interactions, we apply the NCI-RDG method which has emerged as a powerful tool to categorize and envisaged weak interactions: stabilized (hydrogen bonding), destabilized (steric repulsion) and delocalized weak (van der Waal). The 2D plots of the reduced density gradient (s) versus the electron density multiplied by the sign of the second Hessian eigenvalue (λ2) and 3D RDG isosurfaces in real space by color mapping providing the fingerprint region of close contact within the molecular system. A color coding scheme used is as follows: strong repulsive non-bonded overlap shown in red, attractive interactions in blue and the green regions suggest electrostatic interactions. The 3D spatial visualization of NCI isosurfaces and 2D stiletto-heel shape scatter plots of host I to IV are portrayed in Figure 5. The appearance of a small, flat, pilled shaped dark blue isosurfaces between the O-H···O interactions at the lower rim of host at high critical density region in 2D plot (-0.045au) in calix[4]tetrolarene corroborates the earlier inferences on the stronger hydrogen bonding. The bluish green isosurfaces are observed between the O3-H3···O1 interactions with trough at -0.035 au. The bicolored (green and red) isosurfaces are observed between the O1H1, O2H2 and O3H3 groups of all monomer. Here the attractive component of the surface between the oxygen and hydrogen atoms, is counterbalanced by destabilization originating from the induced five-membered ring closure. The bright red cigar-shaped surfaces which are elongated along the direction of decreasing density appear between the central core of 12 ACS Paragon Plus Environment


aromatic rings indicating destabilized (steric crowding) interactions and reflect as trough for high ρ critical values (ρ = 0.020 au) in the 2D scatter plot. Similar inferences are drawn for the rest of molecular scaffolds. 3.5 Infrared and 1H NMR spectra Understanding the molecular mechanism of cooperative self-assembly is a key component for modeling self-assembled supramolecular architectures and analyzed through the lens of the vibrational spectroscopy. Underlying cooperative interactions reflect in the characteristic vibrations of their infrared spectra. Normal vibration frequencies of calix[4]tetrolarene and its derivatives (I to IV) were calculated within the regime of the M06-2x/6-311++G(d,p) theory. The molar absorption coefficient (or, molar absorptivity in units of 0.1 m2mol−1) versus the frequency (in cm−1) showing the -OH stretchings in I to V are illustrated in Figure 6. All these molecular receptors possess four hydroxyl groups at the lower rim. The stretching vibration corresponding to all OH groups in the parent calix[4]tetrolarene coincide; the highly symmetrical C4v cone conformer renders all benzenetetrol units to be equivalent. Theoretical calculations demonstrated that stronger dynamic interactions within all four oscillators stem from circular network of cooperative intramolecular hydrogen bonding. Consequently their vibrations are not precisely vibrations of individual hydroxyl groups and were assigned to stretching vibrations of cyclic (O–H···)4 system with four distinct frequency bands. Out of these ʋ1 near 3513 cm-1 has zero intensity by symmetry rules, the ʋ2 and ʋ3 bands are doubly degenerate intense bands those appear at 3470 cm-1, and the symmetrical stretching ʋ4 shows up near 3378 cm-1 again with the negligible intensity. Similar inferences are drawn for the upper rim hydroxyl groups. For II molecular receptor, pattern of group vibrations of cyclic 13 ACS Paragon Plus Environment

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tetramer system still preserve, despite the weakening of cooperativity in hydrogen bonding network. The 3716 cm-1 band was assigned to hydroxyl vibrations of parallel aromatic rings and 3594 cm-1 arise from those of flattened rings in the pinched cone conformer (C2V) in III. The ʋ(OH) stretching vibration shows a upshift (blue shift) on modification via substitution at the linkage as in IV due to transfer of electron density from sulphur atom to aromatic rings of the host. Natural bond orbital analysis revealed diminutive electron density in its anti-bonding O-H natural orbital in consonance with the earlier corollaries. In other words the number and intensity patterns of OH vibrations in the infrared spectra serves as an indicator of cooperativity effects in the intramolecular hydrogen bonding. Moreover, the vibration near 3132 cm-1 of the spectra of calix[4]tetrolarene stem from methylene linkage and corresponds to lower wavenumber bands near the 3987 cm-1 in III. Alternatively the cooperativity of hydrogen bonding can be envisaged from the frontier molecular constituting the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). Subsequently the charge distribution within macrocycle are characterized through frontier orbitals the form of electron density (isosurface ±0.04 a. u. ) depicted in Figure 7. It may readily be discernible that HOMO largely resides over the aromatic rings and near hydroxyl oxygen in host I to IV invoking cooperative hydrogen bonding interactions arising from the hydroxyl groups. On the other hand the LUMO is delocalized over the π cloud of the aromatic rings and also near the sulphur atoms. The proton NMR chemical shifts are computed from the GIAO method which serves as criterion for probing the intramolecular interactions. To take into account bulk solvent effects the NMR calculations were performed employing the SCRF-PCM theory with 14 ACS Paragon Plus Environment


chloroform as the solvent. Calculated δH values of calix[4]tetrolarene and its derivatives from the M06-2X/6-311++G(d,p) theory are summarized in Table 2. The protons of receptor I to IV derivatives can be classified as: hydroxyl protons at upper rim as H1, H2 and H3 whereas at lower rim as H5; the H6 protons from methyl linkage and H7 refers to those from the methoxy group. The hydroxyl protons at the lower rim (H5) of parent calix[4]tetrolarene facilitate stronger cooperative intramolecular hydrogen bonding interactions engendering largely deshielded (10.83 ppm) signals. The hydrogen bonded H3 protons at the upper rim emerge with δH values near 8.28 ppm whilst the H2 and H1 protons show signals at the 6.11 ppm and 5.61 ppm, respectively. The distinct δH signals of methylene linkage protons, differing by ~ 0.24 ppm, were further noticed. For thia analog of host I the concerned, δH parameters follow the order H5 > H3 > H1 > H2. The H5 protons reveal shielding by 2.66 ppm which reaffirm the weakening of the cooperative hydrogen bonding. The lowest energy pinched cone conformer of host III display the δH signal for the H5 hydroxyl protons near 8.10 ppm (parallel ring); 8.98 ppm (flatten ring); the corresponding δH in the measured spectra was observed at 8.90 ppm. The methylene bridge signals emerge with doublets at 5.33 ppm and 3.44 ppm typifying respectively, the axial and equatorial protons. The methoxy protons chemical shift from the present theory turns out to be 3.75 ppm, which agrees well with its experimental counterpart (near 3.76 ppm). As compared to III, the hydroxyl protons at the lower rim (H5) in IV revealed upfield signals. It may be speculated that conformational behavior, substitution effect and underlying interactions reflect in their δH parameters.


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Conclusions In nut shell, the electronic structure, conformational energetics, charge distribution, vibrational and 1H NMR spectra of the Calix[4]tetrolarene and its derivatives, which represent chimers of calixarene (lower rim) and pyrogallolarene (upper rim) have been analyzed in the present endeavor. A systematic conformational search on the molecular scaffolds yields the cone, partial cone, 1,2-alternate and 1,3-alternate conformers. The cooperativity in hydrogen bonding at the lower rim engenders the symmetrical cone conformer to be of the lowest energy for I and II while in case of receptors III and IV the pinched-cone is favored. A disruptions in cooperative hydrogen bonding network of the upper rim of these chimers than the individual pyrogallolarene host, may be expected that enhancing the solubility. Furthermore the methoxy substitution renders largely electronrich cavity in III and IV than the calix[4]tetrolarene or its thia derivative suggesting its favorable binding for the electron deficient or neutral guests. The hydroxyl protons at the lower rim facilitating circular array of hydrogen bonding network reflect as largely deshielded signals in the calculated 1H NMR spectra. Lastly the characteristic patterns in the hydrogen bonded OH vibrations are noticed from the infrared spectra. Supporting Information Different conformers of calix[4]tetrolarene and its derivatives from M06-2X/6-311G(d,p) theory. 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 is thankful to UPE Phase-II (UPE 262 (A) 3) project from the University Grand Commission (UGC). Authors thank the Centre 16 ACS Paragon Plus Environment


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for Development of Advanced Computing (CDAC), Pune for providing the National Param Supercomputing Facility.

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Figures: Lower Rim

Host Cavity

I

II

III

IV

Figure 1. Optimized geometry of the calix[4]tetrolarene and its derivatives.


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Host cavity

Lower rim

I

II

III

IV

Figure 2. Electron density isosurfaces (0.001 au) overlaid with MESP (±0.03 au)



Figure 3. The ρbcp parameters for O-H···O hydrogen bonds for host I to IV along with the fitted logarithmic relation is given. See text for details.


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Figure 4. A plot of kinetic and potential electron density as a function of intramolecular hydrogen bond distances. See text for details



I

II


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III

IV

Figure 5. Color-filled RDG isosurfaces depicting intramolecular interaction regions in the host I to IV.



Figure 6. OH vibration frequencies in the calculated infrared spectra of I-IV receptors.


Page 32 of 35

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HOMO

LUMO

I

II

III

IV

Figure 7. Frontier orbitals (± 0.04 a.u) in calix[4]tetrolarene and modified macrocycles.



Page 34 of 35

Table 1. QTAIM parameters for the nonbonding interactions in I to IV macrocycles. Interactions

r

ρ

∇2 ρ

ε

V

G

H

O5-H5---O5

1.707

0.043

0.145019

0.067704

-0.04255

0.039401

-0.00315

O3-H3---O1

1.794

0.034

0.13001

0.081922

-0.03105

0.031776

0.000727

II

O5-H5---O5

1.931

0.025

0.096959

0.098211

-0.02036

0.022301

0.00194

O3-H3---O1

1.979

0.022

0.086768

0.110237

-0.01699

0.019341

0.00235

III

O5-H5a---O5

1.797

0.035

0.125284

0.052716

-0.03169

0.031506

-0.00018

O5-H5b--O5

1.877

0.029

0.115807

0.112546

-0.02595

0.027451

0.001502

O5-H5a---O5

2.073

0.018

0.069758

0.074231

-0.01333

0.015386

0.002053

2.257 0.014 0.052457 0.240044 and b refers to parallel and flattened position rings respectively.

-0.01027

0.011693

0.001421

Hosts I

IV

O5-H5b--O5

a


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Table 2. 1H NMR chemical shifts (ppm) in calix[4]tetrolarene and their derivatives. δH H1 H2 H3 H5 H6 H7

I 6.11 5.61 8.28 10.83 3.80,3.56

II 6.20 5.45 8.47 8.17


III

IV

8.54 5.33, 3.44 3.75

7.50 3.73

Exploring Chimeric Calix[4]tetrolarene Molecular Scaffolds

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