HostâGuest Interactions Accompanying the Encapsulation of 1,4

Article pubs.acs.org/JPCA

Host−Guest Interactions Accompanying the Encapsulation of 1,4Diazabicyclo[2.2.2]octane within endo-Functionalized Macrocycles Dipali N. Lande, Maneesha N. Shewale, and Shridhar P. Gejji* Department of Chemistry, Savitribai Phule Pune University, Pune 411 007, India ABSTRACT: The binding of novel endofunctionalized bis-urea/thiourea molecular receptors toward neutral 1,4-diazabicyclo[2.2.2]octane (DABCO) demonstrates stronger binding of the bis-thiourea macrocycles than for their urea analogues by employing M06-2X/6-31+G(d,p)-based density functional theory. The formation of such inclusion complexes is spontaneous, thermodynamically favorable, and facilitated via bifurcated N−H···N···H−N hydrogen bonding and C−H···π, dipole−dipole, and other noncovalent interactions, which are reflected in the frequency shift of their characteristic N−H vibrations in the calculated vibrational spectra of these complexes. The underlying noncovalent interactions are analyzed using the molecular electrostatic potential topography and quantum theory of atoms in molecules in conjunction with the noncovalent interactions reduced density gradient method. It has also been shown that the encapsulation of DABCO within the π-electron-rich cavity of such hosts brings about shielding of the guest protons confined within the host cavity whereas those facilitating hydrogen bonding engender the downfield signals in their calculated 1H NMR spectra.

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discernible here that the flipping of naphthalene rings in such hosts renders a large conformational flexibility with the deeper, well-defined cavity of varying size that exhibits distinct preferences toward cation binding. It was also realized that oxatub[n]arene (n = 5,6) macrocycles assemble as tubular structures capable of encapsulating large guests such as C60 and C70.29 Subsequently, these authors successfully synthesized dynamic imine molecular scaffolds33 and tweezers based on a bis-naphthalene cleft with perfect curvature. Moreover, these authors introduced converging functional groups such as urea and thiourea into the bis-napthalene cleft cavity in order to mimic the biological functionalities, and they are known as endofunctionalized bis-urea/thiourea molecular tubes.34,35 In addition to this, the configurational isomerism and neutral molecular recognition of these molecular tubes have been studied by employing X-ray diffraction and spectroscopy experiments. It is noticeable that the hydrogen atoms in urea/thiourea linkages serve as potential hydrogen bond donors that are directed inward towards the guest. The cooperativity between the deep cavity of the host and bridging urea group with a nonzero dipole moment was responsible for the binding of neutral guests, for instance, 1,4-dioxane, 1,2-dinitro benzene, and 1,4-diazabicyclo[2.2.2]octane. Such macrocycles are highly reminiscent of enzyme binding pockets and prove useful for understanding the binding of natural receptors possessing hydrophobic cavities/inwardly directed functional groups.

INTRODUCTION The advent of synthetic molecular scaffolds such as crown ethers1 to cyclodextrins,2 calixarenes,3 and cucurbiturils4 has spurred significant interest in the discipline of host−guest chemistry.5−8 The past few decades have witnessed the development of novel macrocyclic arenes, viz., heterocalix[n]aromatics,9 pillar[n]arene,10 hybrid[n]arenes,11 biphen[n]arene,12 corona[n]arene,13 and asar[n]arenes14 endowed with special host−guest properties such as easy synthesis, selectivity, and highly tunable functionalities with potential applications in diverse areas spanning molecular machines,15 supramolecular polymers,16 stimuli-responsive materials,17 drug-delivery systems,18,19 and catalysis.20,21 A family of newer molecular receptors possessing cyclic arrays of the naphthalene framework in their architecture have become the focus of considerable attention in recent years.22−32 These macrocycles are endowed with unique features such as deep or wide hydrophobic cavities with the enhanced πelectron density within their cavities. In this light, Georghiou and co-workers22 successfully synthesized the calix[n]naphthalene composed of methylene linkages by the direct cyclocondensation reaction between 1-naphthol and formaldehyde under basic conditions. In the same way, Glass et al.23,24 demonstrated that molecular receptors possessing the naphthalene backbone linked through amide and allyl functionalities improve their binding efficiency compared to that of those having methylene bridges, and such hosts have been widely used as fluorescent sensors. Recently, Jiang and coworkers25−28 reported flexible naphthalene-based molecular cavitands, viz., oxatub[n]arene (n = 4, 5, and 6), zorb[4]arne, and tweezers that possess interconvertible cavities. It is © XXXX American Chemical Society

Received: March 9, 2017 Revised: April 25, 2017 Published: April 26, 2017 A

DOI: 10.1021/acs.jpca.7b02238 J. Phys. Chem. A XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry A

Figure 1. Optimized structures of (a) the DABCO guest, (b) the bis-napthalene cleft monomer, (c) SBU, (d) ABU, (e) SBTU, and (f) ABTU molecular tubes.

terized in the recent literature.39 Hunter and co-workers40 studied the complexation of DABCO with metalloporphyrin through 1H NMR spectroscopy and also measured the magnitude of π···π interactions. Ogoshi et al.41 showed that DABCO conduces the host−guest complex with pillar[6]arene exclusively and not with pillar[5]arene. It should therefore be interesting to study how the encapsulation of DABCO within the endofunctionalized molecular tubes affects the physicochemical and spectral behavior.

These play a vital role in the recognition of biologically or environmentally important neutral molecules. 1,4-Diazabicyclo[2.2.2]octane (DABCO), a diazabicyclic molecule with a cagelike structure, has been widely used in organic synthesis as a nontoxic catalyst with high selectivity and serves as a weak base and ligand.36,37 The antioxidant nature of DABCO further helps to improve the lifetime of dyes, which makes it useful in dye lasers and for mounting samples in fluorescence microscopy.38 The inclusion complexes of DABCO and cucurbituril or pillararenes have been characB


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The Journal of Physical Chemistry A On the theoretical front recently, Shewale et al.42 studied the structural features of inclusion complexes between the neutral guests and endofunctionalized urea hosts. It has been shown that syn (SBU) and anti (ABU) configurational isomers of the macrocyle exhibit distinct selectivity toward guest binding, and the complexation of the centrosymmetric guest with the centrosymmetric ABU host is energetically favored over the SBU isomer. The present work focuses on the molecular tubes possessing converging thiourea functionalities and the syn and anti configurational isomers of thiourea (denoted by SBTU and ABTU). Density functional theory (DFT)-based calculations were employed to derive molecular insights for the binding selectivity and structural characteristics of the inclusion complexes among four endofunctionalized molecular tubes (SBU, ABU, SBTU, and ABTU) and the DABCO guest as a prototype example. The underlying noncovalent interactions accompanying encapsulation within bis-urea/thiourea macrocycles have been analyzed through the molecular electrostatic potential (MESP) topography and quantum theory of atoms in molecules (QTAIM) in conjunction with the noncovalent interactions reduced density gradient (NCI-RDG) method. The ramifications of these interactions in vibrational and 1H NMR spectroscopy are discussed. The computational method is outlined in the following text.

the Multiwfn program,60 and visualized through the visual molecular dynamics software.61 Furthermore, the chemical shift (δH) parameters in the 1H NMR spectra were calculated by subtracting the nuclear magnetic shielding tensors of protons in the individual host, guests, and their complexes from those in the tetramethylsilane (reference) within the framework of the gauge-independent atomic orbital (GIAO) method.62 The effect of solvent (chloroform) on the structure and 1H NMR chemical shifts was simulated by employing the self-consistent reaction field (SCRF) theory incorporating the polarization continuum model (PCM).63

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RESULT AND DISCUSSION The bis-urea macrocycle and its thia analogue (bis-thiourea) are made up of bis-napthalene cleft units linked together by urea and thiourea, respectively. Different configurations of these hosts were generated by the rotation of the naphthalene cleft around the bridging functionality: one with both clefts oriented parallel and the other with those in an antiparallel manner referred as syn and anti isomers, respectively. Optimized structures of DABCO and syn and anti isomers of bis-urea (SBU and ABU) macrocycles and its thia-derivatives (SBTU and ABTU) obtained from the M06-2X/6-31+G(d,p) theory are displayed in Figure 1 along with the atomic labeling scheme. As can be seen from the figure, the hosts with urea and thiourea groups differ by only one atom; therefore, the syn isomers of both molecular receptors as well as anti isomers have an almost similar spatial arrangement of clefts and thus reveal a similar cavity shape. The syn isomers facilitating O···O and the C−H···O interactions at the lower rim render bowl-shaped architecture to their cavities. On the other hand, the absence of such interactions as in anti isomers endows these hosts with tubular-shaped cavities. To understand the complexation mode of SBU or ABU macrocycles or their thia analogs with respect to the DABCO guest, a priori knowledge of the charge distribution and reactive sites is crucial and can be gauged through the MESP topography. For a vivid representation of electrophilic and nucleophilic regions, the MESP overlaid on electron isodensity contours (0.001 au) has been portrayed in Figure 2. The 0.001 au molecular surface contains more than ∼96% of the electronic density of the molecule, which is typically just beyond the van der Waals radii of the constituent atoms. The variation in electrostatic potential is shown by the color scheme red (lowest) → orange → yellow → green → blue (highest), indicating whether a particular region is electron-rich (red) or electron-deficient (blue). As far as hosts are concerned, it may readily be noticed that the negative MESP appearing around heteroatoms (N, O, and S) is attributed to the domain of the lone pair (bright red) and the delocalized π cloud corresponding to the bis-naphthalene cleft (reddish yellow), whereas the positive MESP observed for the most acidic urea/ thiourea hydrogen atoms (dark blue) as well as aromatic and alkyl chain protons are shown as light blue (cf. Figure 2a−d). Further quantitative assessment of the positive and negative electrostatic potentials on the surfaces can be carried out from the Vmax and Vmin parameters. The NH acidic protons in SBTU and ABTU isomers of thiourea turn out to be largely electrondeficient with the corresponding Vmax being in the range of 191 to 186 kJ mol−1 compared to the urea isomers subsequent to the accommodation of large negative charges on sulfur rather than on oxygen atoms. This can be partially attributed to a larger atomic radius and the valence shell expansion of the

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METHODOLOGY The quantum chemical calculations of four endofunctionalized molecular tubes (hosts), DABCO (guest), and their complexes were performed with the Gaussian 09 suite of programs.43 In the present work, the Minnesota M06-2X,44,45 a hybrid metaGGA exchange-correlation functional, which is designed to handle weak interactions that include dispersion, was used in conjugation with the Pople’s 6-31+G(d,p) basis set. The hydrogen bonding and dispersive interactions typifying noncovalent host−guest binding are simulated well with the use of this level of theory.46−50 To derive molecular insights accompanying the complexation of bis-urea/thiourea cavitands, the charge distribution within the cavity was characterized in terms of MESP topography.51−55 The MESP, V(r) generated by a molecule at a point r is given by N

V (r ) =

∑ A=1

ZA − |r − RA|

∫ |rρ−(r′r)′| d3r′

The positive potential produced by N nuclei with nuclear charges (ZA), located at RA, are represented by the first term, whereas the second term refers to the negative potential generated by continuous electron density ρ(r) centered at r. Thus, it is observed that from this equation the MESP can attain positive as well as negative values and the balancing of two such terms emerges with the effective electron-rich regions in the molecular system. The vibrational frequencies in the stationary-point structures of the hosts as well the complexes turned out to be real, which confirms the local minima on the multivariate potential energy surfaces. The Gaussian output wfn file was subsequently subjected as an input to the AIMAll 2000 software56 to perform QTAIM analysis to elucidate the nature and strength of the underlying noncovalent interaction of complexes studied herein.57,58 Additionally, the nonlocalized dispersion and repulsive nonbonded interactions are assured from the NCI-RDG method.59 The RDG is defined through |∇ ρ| 1 s = 2 1/3 4/3 within the QTAIM approach, obtained using 2(3π )

ρ

C


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Figure 3. Optimized structures of (a) DABCO@SBU, (b) DABCO@ ABU, (c) DABCO@SBTU, and (d) DABCO@ABTU macrocycles.

Binding energies were calculated by subtracting the sum of electronic energies of the isolated guest and host from that of the host−guest complexes. The hierarchy of relative stabilization energies follows the order DABCO@ABTU > DABCO@ ABU > DABCO@SBTU > DABCO@SBU. Interestingly, the complexation of centrosymmetric DABCO with centrosymmetric anti hosts ABU and ABTU is energetically more favored over the SBU and SBTU isomers, and stronger binding can further be attributed to intermolecular hydrogen bonding (bifurcated N−H···N···H−N leads to six-membered-ring formation) and C−H···π interactions as well. Table 1 shows the selected geometrical parameters of hosts, guests, and their lowest-energy complexes. As may be observed, the bifurcated hydrogen bonding interactions engender an elongation for the N−H bond in ABU and ABTU complexes, respectively. The C−H protons of DABCO participating in C−H···π interactions emerge with their signature in separation distance, which is up to ∼0.003 Å longer. The cavity size (dimensions) can be estimated by knowing the separation of radially opposite atoms at the rims of the macrocycles. The encapsulation of DABCO within the ABU and ABTU hosts leads to a contraction of the cavity size consequent to stronger hydrogen bonding arising from the bridging functionality. In summary, structural parameters and binding energies data suggest that the ATBU molecular tube binds effectively to the DABCO guest, which is consistent with the inferences drawn from the work of Huang and co-workers.35 Within DFT-based investigations, the molecular-level understanding of the nature of supramolecular interactions underlying the complexes is identified and specified through an array of quantum tools incorporating QTAIM, NCI-RDG, and MESP. In view of this, Bader’s QTAIM has been employed extensively to examine hydrogen bonding, dihydrogen bonding,

Figure 2. Electron density isosurfaces (0.001 au) overlaid with the MESP (−0.05 to +0.05 au) in (a) SBU, (b) ABU, (c) SBTU, and (d) ABTU hosts and (e) the DABCO guest.

sulfur atom. It is evident that the bis-naphthalene cleft renders the host cavity with an electron-rich nature and protons from bridging urea/thiourea functionalities are electron-deficient whereas the free DABCO guest (cf. Figure 2e) revealed the −N− atoms to be electron-rich, with the hydrogen atoms being electron-deficient. It was therefore easy to deduce that −N− atoms of the guests would be located near the bridging functionality of the host through electrostatic interaction conducing host−guest complexes with the guest protons being attracted to the π-cloud of clefts. In other words, the binding of the neutral guests can be attributed to electrostatic complementarity. Taking a cue from these considerations, the complexes of bis-urea/thiourea macrocycles with the DABCO guest were generated. Energy-minimal structures of the DABCO@SBU, DABCO@ ABU, DABCO@SBTU, and DABCO@ABTU complexes from the M06-2X/6-31+G(d,p) theory are depicted in Figure 3. Calculated free energy change (ΔG) parameters accompanying the formation of the inclusion complexes turned out to be in the range −15.7 to −16.8 kJ mol−1, indicating the exergonic or spontaneous formation of the host−guest complex in all cases. D


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Table 1. Selected Geometrical Parametersa in the Guests and Hosts and Their Inclusion Complexes from M06-2X/6-31+G(d,p) Theory DABCO C−H

1.095

C−N C−C N−H14

1.468 1.559

ABU

ATBU

1.011

C−O

DABCO@ATBU

1.098 1.096 1.474 1.554 1.013 1.026 1.225 1.229

1.096 1.098 1.475 1.554 1.015 1.027

1.012

1.226

C−S C−N−C

DABCO@ABU

1.682 108.8

108.9 109.1

N−C−N

114.2

114.5

H14−N−C

119.2

118.9 119.3

H14−N−C−O

168.3 160.3

H14−N−C−S

113.8 114.1 118.0 114.4 114.8 119.1 172.0 170.3 −170.9 174.7

179.6

179.6 176.2 177.3

172.2 N−C−C−N C−Cb a

−3.9 10.396

10.277

1.682 1.685 108.2 108.4 108.8 113.5 113.3 118.0 115.7 114.3 118.1

13.7 10.044

14.5 10.118

Bond distances are in angstroms, and angles are in degrees. bRefers to the distance between two readily opposite carbonyls of urea.

Subsequently, more detail information regarding the atom− atom interactions can be derived on the basis of virial theorem at critical points correlating ∇2ρ to the total electron energy density (Hbcp) and the terms of latter values, the kinetic electron energy density (Gbcp) and the potential electron energy density (Vbcp), as follows:

C−H···π, and other weak interactions. These interactions are envisaged through the electron density at the bond critical point (ρbcp) and its Laplacian (∇2ρ) as well as through the local energy density parameters (G, V, and H) that provide a measure of strength and covalency therein. The selected QTAIM topological parameters are reported in Table 2. A negative Laplacian value suggests that the interatomic bond exists as a covalent characteristic whereas the hydrogen bonds, ionic bonds, and van der Waals interactions are analyzed from the positive value of the Laplacian. Also, according to Koch and Popelier64 the hydrogen bonding interactions must satisfy the following criteria: (i) existence of bcp with ρbcp parameters in the range of 0.002 to 0.035 au and (ii) the corresponding Laplacian (∇2ρ) values being 0.024−0.139 au. From the data listed in Table 2, it may readily be noticed that the ABTU complex engenders stronger bifurcated hydrogen bonds (N−H···N···H−N) between the linked thiourea group and the nitrogen of DABCO. In addition to this, ABU and ABTU complexes are stabilized through dihydrogen bonding present between the NH protons of hosts and CH protons of guests. The values of ρbcp and its Laplacian indices are typical of those found for weak hydrogen bonds, being somewhat larger in value than van der Waals interactions. The delocalized π cloud of aromatic rings of ABU and the ABTU isomer of hosts and DABCO guest protons brings about C−H···π interactions with the corresponding ρbcp values falling in the interval of 0.005− 0.008 au for ABU and between 0.005 and 0.009 au for ABTU.

0.25∇2 ρ = 2G bcp + Vbcp

(1)

Hbcp = G bcp + Vbcp

(2)

Conventionally Gbcp is always positive whereas Vbcp is always negative. Thus, if the absolute value of Vbcp outweighs 2 times the Gbcp, then the Laplacian (∇2ρ) is negative (eq 1). This indicates the covalent character of interaction, and it may concern stronger hydrogen as well as covalent bonds.65,66 Nonetheless, there are such interactions, particularly hydrogen bonds, where the modulus of Vbcp only one time outweighs Gbcp; in that case, ∇2ρ is positive but Hbcp is negative (eq 2). The signs of ∇2ρ and Hbcp characterize the strength of hydrogen bonding. Weak and medium-strength hydrogen bonds have both positive ∇2ρ and Hbcp values. For strong hydrogen bonds, ∇2ρ is positive and Hbcp is negative. A decrease in Hbcp toward negative values implies a stronger interaction arising from the increased electrostatic contribution to the total interaction energy. In the complexes studied herein, two out of the four N−H···N···H−N hydrogen bonds show negative Hbcp values, evidencing the existence of strong hydrogen bond formation and engendering more stable E


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Table 2. QTAIM Parameters for the Nonbonding Interactions in the DABCO@ABU and DABCO@ABTU Complexes r C−H···π

N−H···N

N−H···H

C−H···π

N−H···N

C−H···H

ρ

∇2ρ

2.7533 2.8537 2.8913 3.0779 2.7573 2.7617 2.0228 2.8221 2.2040 2.4089 2.2181 2.6483

0.0070 0.0060 0.0061 0.0045 0.0079 0.0078 0.0275 0.0060 0.0190 0.0127 0.0070 0.0031

0.0216 0.0172 0.0183 0.0133 0.0255 0.0251 0.0667 0.0180 0.0486 0.0371 0.00274 0.0099

3.1194 2.8087 2.7068 5.2681 3.0119 3.5582 4.4499 2.7452 2.0911 2.1076 2.4221 3.7935

0.0078 0.0059 0.0087 0.0083 0.0049 0.0080 0.0065 0.0258 0.0091 0.0215 0.0110 0.0035

0.0078 0.0163 0.0280 0.0267 0.0146 0.0263 0.0199 0.0616 0.0297 0.0528 0.0324 0.0112

G DABCO@ABU 0.0044 0.0035 0.0037 0.0027 0.0053 0.0052 0.0179 0.0033 0.0128 0.0091 0.0054 0.0019 DABCO@ABTU 0.0051 0.0033 0.0058 0.0055 0.0030 0.0054 0.0040 0.0166 0.0068 0.0142 0.0078 0.0021

V

H

G/|V|

ε

−0.0034 −0.0026 −0.0028 −0.0021 −0.0042 −0.0041 −0.0191 −0.0024 −0.0135 −0.0089 −0.0039 −0.0012

0.0010 0.0008 0.0009 0.0006 0.0011 0.0011 −0.0012 0.0009 −0.0007 0.0002 0.0015 0.0006

1.2841 1.3149 1.3154 1.2913 1.2642 1.2625 0.9863 1.1041 0.9489 1.0222 1.3829 1.4940

1.3797 0.9085 2.9849 2.1778 3.4625 3.1601 0.0184 2.9849 0.0110 0.1002 0.3252 0.3314

−0.0040 −0.0026 −0.0046 −0.0044 −0.0023 −0.0043 −0.0031 −0.0179 −0.0062 −0.0151 −0.0075 −0.0014

0.0011 0.0008 0.0012 0.0011 0.0007 0.0012 0.0009 −0.0012 0.0006 −0.0010 0.003 0.0007

0.7901 0.7698 0.7897 0.7974 0.7707 0.7880 0.7654 1.0742 0.9113 1.0678 0.9626 0.6687

0.8004 0.6442 2.7484 2.1628 1.0146 6.7810 1.7337 0.0115 0.8330 0.0112 0.2265 0.2484

of electron density in the plane normal to the interaction coordinate, whereas the λ3 eigenvalue denotes accumulation/ depletion about the internuclear direction and is always > 0 for the closed-shell interactions. The region with λ2 < 0 classifies the bonding interaction whereas the point with λ2 > 0 suggests a nonbonding interaction. Thus, 2D plots of the reduced density gradient(s) versus the electron density multiplied by the sign of the second Hessian eigenvalue (λ2) provide a fingerprint region of close contact within the molecular system through a series of troughs that approach near s = 0 for the finite ρ parameter. Moreover, (sign λ2)ρ can be utilized to enrich the information provided by 3D RDG isosurfaces in real space by color mapping. (If (sign λ2)ρ > 0 represents repulsive, then (sign λ2)ρ < 0 suggests attractive and (signλ2)ρ ≈ 0 for van der Waals interactions.) The color-coding scheme used is as follows: the strong repulsive nonbonded overlap is shown in red, attractive interactions are shown in blue, and the green regions suggest electrostatic interactions. The 3D spatial visualization of NCI isosurfaces and 2D scatter plots between DABCO with the ABU and ABTU moieties is illustrated in Figure 4. The appearance of small, flat, pill-shaped bluish-green isosurfaces between the N−H proton of the host and the nitrogen atom of DABCO in the high critical density region in the 2D plot (−0.020 and −0.015 au) for the ABU complex (cf. Figure 4a) signifies the presence of hydrogen bonding. Similar inferences may be drawn for the ABTU complexes except that troughs are observed at the higher critical density values (−0.025 and −0.020 au) as a result of stronger hydrogen bonding than for ABU (cf. Figure 4b). The bright red cigarshaped surfaces that are elongated along the direction of decreasing density appear between the central region of aromatic and nonaromatic rings, implying destabilized (steric crowding) interactions, which are further reflected as troughs at

structures (cf. Table 2). Another useful parameter in analyzing the strength of interactions is the ellipticity (ε = λ1/λ2 − 1) at the bcp, which measures the extent to which density is accumulated preferentially in a given plane containing the bond path of interaction. Grabowski67 showed that X−H···π bonds exhibit larger ellipticities than do other hydrogen bonds. Likewise, the stronger N−H···N···H−N hydrogen bonds (negative Hbcp) have ellipticity values of ∼0.02 for the ABU and ABTU complexes whereas those of C−H···π bonds turn out to be relatively large (>1.0). The (G/|V|) ratio serves as a useful descriptor and indicates ionic or covalent interactions. For the host−guest interactions studied here, this ratio was found to be greater than 1.0, and thus partially covalent and electrostatic C−H···π and N−H···N···H−N hydrogen bonds can be inferred. Furthermore, the strength of hydrogen bonding at the bcp was estimated from the Espinosa68 correlation (EHB = 0.5V). The hydrogen bonds in ABU and ABTU have bond energies of between 17 and 25 kJ mol−1. It has been realized that the weak intramolecular interactions should not necessarily imply the presence of the bcp (critical point where the density gradient vanishes) within the framework of QTAIM theory.69 To examine these interactions as well as nonlocalized dispersion and repulsive nonbonded interactions, we implemented the NCI-RDG approach, which generalizes the concept and focuses on the loci of lower RDG(s) or in the region of space around the critical point. Hence, it serves as an effective method to discriminate and visualize weak interactions: stabilized (hydrogen bonding), destabilized (steric repulsion), and delocalized (van der Waals). In this method, the sign of the second eigenvalue of the electron density Hessian matrix (λ2) discriminates the bonding or nonbonding noncovalent interactions and characterizes (along with the first eigenvalue λ1) the accumulation/depletion F


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Figure 4. Color-filled RDG isosurfaces depicting noncovalent interaction (NCI) regions in (a) DABCO@ABU and (b) DABCO@ABTU complexes.

high ρ critical values (ρ = 0.025 and 0.020 au) in the 2D scatter plot of ABU and ABTU complexes. Likewise, the green sheetlike extended form corresponding to the C−H···π interactions between guest protons and the bis-naphthalene cleft at the low isodensity isosurfaces are represented as both green and light-brown colors, signifying weak attraction and repulsion, respectively. Bicolored isosurfaces are observed between the heteroatoms (N, O) and nearest methylene protons of the ABU and ABTU molecular receptors. The attractive component (green) here indicates weak intramolecular hydrogen bonding interactions and is counterbalanced by the destabilized component (red) originating from the induced five-membered ring closure. A quick glance at the electron density redistribution associated with supramolecular interactions between DABCO and ABU or ABTU molecular containers is envisaged from Figure 5. The MESP textured on electron density isosurfaces (0.001 au) is shown. A noteworthy color variation from dark blue to green around N−H protons of urea/thiourea groups as well as red to green near guest nitrogen atoms in DABCO@ ABU and DABCO@ABTU predicts bifurcated N−H···N···H− N interactions that are manifest as the disappearance of MESP minima near guest nitrogen atoms. Besides, the C−H···π interactions are attributed to the stability of the complex, which

Figure 5. Electron density isosurfaces (0.001 au) overlaid with the MESP (−0.05 to +0.05 au) in (a) DABCO@ABU and (b) DABCO@ ABTU complexes.

is manifested in the Vmin parameters corresponding to a π delocalized electron cloud of the naphthalene moiety as well as being clearly visualized from the MESP density maps shown in Figure 5a,b. G


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The Journal of Physical Chemistry A The vibrational spectroscopy provides a fingerprint for typifying the underlying molecular interactions of the host− guest complexes. We therefore derived the harmonic vibrational frequencies within the framework of M06-2X/6-31G (d,p) theory for the free host, guests, and their complexes. The molar absorption coefficient (or molar absorptivity in units of 0.1 m2 mol−1) versus the frequency (in cm−1) of DABCO@ABU and DABCO@ABTU in the 3700−3300 cm−1 region for −NH stretches is given in Figure 6. As shown in the figure, two strong

Table 3. 1H NMR Chemical Shifts in the Hosts, Guests, and Their Complexes Using Chloroform as a Solvent at M062X/6-31+G(d,p) Theory H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 H11 H12 H13 H14 H (DABCO)

ABU

DABCO@ABU

ATBU

DABCO@ATBU

8.46 9.02 7.70 9.10 6.47 3.35 4.19 3.55 2.06 1.27 1.34 4.75 5.05 4.33 2.62

8.06 8.81 7.96 9.05 6.53 3.50 4.02 3.96 1.98 1.66 1.25 4.66 5.45 4.37 0.68

8.22 8.53 7.42 8.68 6.03 2.98 4.34 3.72 1.65 1.54 1.04 4.81 5.61 4.72

8.07 8.78 8.07 9.20 6.33 3.40 4.17 3.19 2.02 1.48 1.29 4.97 5.45 6.24 −0.50

urea ABU macrocycle. The corresponding signals in the ABTU receptor were predicted to be near 4.72 ppm upon substitution of the thiourea. Furthermore, the methylene protons (H12 and H13) in the ABTU host next to thiourea groups showed large downfield signals. The N−H protons of facilitating bifurcated intermolecular hydrogen bonding interactions show up deshielding by ∼0.4 ppm in the ABU complexes compared to the downfield from 4.72 to 6.24 ppm for the DABCO@ABTU complexes, which reaffirms the stronger binding of guest suggested earlier. The methylene protons in the isolated DABCO appear at 2.62 ppm, and the confinement of DABCO within ABU and ABTU cavities brings about the shielding in 1 H NMR. These corollaries are found to be in agreement with the experimental findings.35 The electronic properties of DABCO@ABU and DABCO@ ABTU complexes at the molecular level can be characterized through frontier orbitals constituting the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) in the form of electron density (isosurface ±0.04 au). Plots of the most representative molecular frontier orbitals in the ground state of the bisurea/thiourea molecular receptor and their complexes are shown in Figure 7. From an inspection of the molecular plots, it is observed that the HOMO of the ABU host has largely been localized near the naphthalene moiety and partially near the nitrogen atoms (with diminutive intensity) of urea linkages. Interestingly, in the ABTU receptor the HOMOs are delocalized over the sulfur atoms of thiourea and on the aromatic naphthalene rings. The penetration of the guest within a host cavity revealed the HOMO on one of the bisnaphthalene clefts and heteroatoms (O, S) of the urea/thiourea group whereas the LUMO was located near another cleft. The complementarity of electron-rich regions within HOMO and LUMO points to intramolecular charge transfer. It may therefore be concluded that the confinement of the DABCO guest does not alter the electronic structure of ABU and ABTU hosts and that guest encapsulation occurs by a physical adsorption process. Moreover, the HOMO and LUMO reside mainly on the receptors, indicating that the guest is shielded by the hosts against potential chemical reactions from others species, demonstrating the advantage of such hosts as trapping agents for the guest. To understand the kinetic stability of such

Figure 6. Vibrational frequencies of −NH stretching in the calculated infrared spectra of ABU, ABTU molecular tubes, and their complexes.

peaks are observed at ∼3663 and 3636 cm−1, assigned to the −NH vibrations of the isolated ABU isomer that corresponding vibrations of the ABTU isomer predicted near 3629 and 3623 cm−1. The C−H stretching vibrations in bis-napthalene clefts are located in the interval of 3292−3212 cm−1 for both the ABU and ABTU macrocycles. A significant red shift of the N− H stretching mode relative to the free hosts can be explained from the intermolecular bifurcated N−H···N···H−N hydrogen bonding interactions in the DABCO@ABU and DABCO@ ABTU complexes. The C−H···π interactions emerge with the signature in the vibrational spectra as a blue shift (49 cm−1) for the C−H vibration of the guest. The direction of the frequency shift accompanying the complexation can further be rationalized from the NBO analysis, which shows increased electron density in the corresponding antibonding natural orbital for the N−H σ* of complexes, engendering bond weakening leading to the frequency downshift. Chemical structure, conformational behavior, and underlying molecular interactions in a guest embedded with the four endofunctionalized molecular tubes can be monitored through chemical shifts (δH) in their 1H NMR spectra. Thus, the δH values (using the CDCl3 as the solvent) in the isolated ABU or ABTU hosts, guest and their inclusion complexes obtained from the M06-2X/6-31+G(d, p) theory are given in Table 3. The protons of molecular receptors can broadly be classified as naphthalene cleft protons (H1 to H7), butoxy groups (H8− H11), methylene linkages (H12 and H13), and N−H from the urea/thiourea linkages (H14) as shown in Figure 1a. The aromatic H1−H4 protons of the naphthalene moiety reveal deshielding whereas the butoxy protons led to an upfield signal. The H14 protons yield the δH signal near 4.33 ppm in the bisH


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global index parameters. The lowering of the ΔEg values upon complexation suggests that the complexation is reversible and kinetically controllable. The negative chemical potential parameters further support the inferences about the spontaneity of encapsulation.

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CONCLUSIONS The present work provides insight into the in-depth understanding of the binding selectivity of four endo-functionalized molecular tubes of the urea/thiourea functional group converging toward the neutral DABCO guest at the molecular level. The syn isomers (SBU and SBTU) are endowed with a bowl-shaped cavity whereas anti isomers (ABU and ABTU) have tubular architecture. The complexation of centrosymmetric DABCO with centrosymmetric anti hosts ABU and ABTU is favored over their syn configurational isomers. The bifurcated N−H···N···H−N hydrogen bonding, C−H···π, and van der Waals forces contribute to the stability of the complexes. The replacement of urea by thiourea groups improves the hydrogen bonding and other noncovalent interactions, further revealing stronger binding toward the guest. Comprehensive investigations of the vibrational spectra confirm the noteworthy interactions from the frequency shifts of the characteristic −NH and − CH stretching modes. Finally, the frontier molecular orbital plots suggest that these hosts can be utilized as trapping agents for the guest.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +91-20-225691728. Tel: +91-20 25601225. ORCID

Dipali N. Lande: 0000-0002-7219-1286 Shridhar P. Gejji: 0000-0003-3305-2475 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS S.P.G. acknowledges support from a research project (37(2)/ 14/11/2015-BRNS) from the Board of Research in Nuclear Sciences (BRNS), India. D.N.L. is thankful to the University of Pune for the award of a research fellowship through the University of Potential excellence scheme from the University Grants Commission, New Delhi, India. M.N.S. is thankful to the University Grants Commission, India, for the faculty development programme. The authors thank the Center for Development of Advanced Computing (CDAC), Pune, India, for providing access to the National Param Supercomputing Facility.

Figure 7. Frontier orbitals (±.04 a.u) in (a) isolated DABCO, (b) ABU, (c) DABCO@ABU, (d) ABTU, and (e) DABCO@ABTU.

inclusion complexes, the band gap energy (ΔEg), which serves as a stability index, was calculated. Larger ΔEg engenders a high molecular stability and hence a lower reactivity in chemical reactions. Calculated ΔEg values of the free host, guest, and their inclusion complexes are summarized in Table 4 along with

Table 4. HOMO, LUMO Gap (in eV), and Global Indices in the Individual Host, Guest, and Their Complexes molecular properties

DABCO

ABU

ATBU

DABCO@ABU

DABCO@ATBU

ΔEHOMO−LUMO global hardness (η) softness (S) electronic chemical potential (μ) electronegativity (χ) global electrophilicity index (ω) ionization potential electron affinity

−7.3 3.6 0.1 −3.0 3.0 1.2 6.6 −0.6

−6.0 3.7 0.1 −3.0 3.0 1.2 6.7 −0.7

−5.8 2.9 0.2 −3.8 3.8 2.4 6.7 0.9

−5.7 2.8 0.2 −3.8 3.8 2.5 6.6 0.9

−5.5 2.8 0.2 −3.8 3.8 2.6 6.6 1.1

I


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