Electronic Structure and 1H NMR Chemical Shifts in Host-Guest

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Electronic Structure and 1H NMR Chemical Shifts in Host-Guest Complexes of Cucurbit[6]uril and sym-Tetramethyl Cucurbit[6]uril with Imidazole Derivatives Priyanka H. Dixit,† Rahul V. Pinjari,‡ and Shridhar P. Gejji*,† Department of Chemistry, UniVersity of Pune, Pune 411007, India, and Swami Ramanand Tirth Marathwada UniVersity, Nanded, 431606, India ReceiVed: August 3, 2010; ReVised Manuscript ReceiVed: September 4, 2010

Binding patterns and 1H NMR chemical shifts in the complexes of protonated N-(4-hydroxylphenyl)imidazole (g1), N-(4-aminophenyl)imidazole (g2), 2-phenylimidazole (g3) guests with cucurbit[6]uril (CB[6]), and symsubstituted tetramethyl cucurbit[6]uril (TMeCB[6]) in the gas phase as well as in water have been investigated using the density functional theory. It has been shown that the inclusion complexes of g1 and g2 with CB[6] or TMeCB[6] exhibit selective encapsulation of the phenyl moiety with its substituents binding to portal oxygens on the lower rim of the host and imidazole protons facilitate C-H · · · O interactions externally with upper rim ureido oxygens. On the other hand, the lowest-energy g3 complex encapsulates the imidazole ring within the host, engendering N-H · · · O interactions with portal oxygens on the upper rim of the host with the phenyl ring residing outside the cavity owing to an absence of para-substituent and show qualitatively different host-guest binding patterns. Calculated 1H NMR spectra of the complexes in water reveal shielding of phenyl ring protons within the host cavity which exhibit signals at 0.2-0.5 ppm, whereas the protons of the imidazole ring participating in hydrogen bonded interactions exhibit deshielding, and the corresponding 1 H NMR signals are downshifted by 1.1-1.5 ppm in the spectra compared to those in the unbound guest. 1H NMR chemical shifts of inclusion complexes thus obtained are in consonant with δH patterns observed in experiments reported in the literature. Introduction Cucurbit[n]uril (CB[n], n ) 5-10) macrocycle receptors consisting of glycoluril repeat units with each monomer joined to the next one by methylene bridges have been of growing interest in recent years. The specific arrangement of glycouril units render these hosts cagelike structure endowed with relatively large hydrophobic cavity and polar carbonyl groups surrounding its portals as characteristic features of the cucurbit family.1 Mock and co-workers characterized the structure of CB[6] from the infrared and 1H NMR spectra and X-ray diffraction experiments.2 The CB[6] host cavity exhibits selective and efficient binding toward organic as well as inorganic guest molecules; in particular, cationic or electron-deficient species. The relative hydrophobic nature of the CB[6] cavity with its molecular dimensions facilitate its use in separation technology,3,4 drug delivery vehicles,5-7 and supramolecular chemistry.8-18 Furthermore CB[6] also has been explored in molecular recognition,19,20 catalysis,21-23 and nanotechnology.24,25 In recent years, a series of CB[n] derivatives with alkyl groups substituted at equatorial positions26-28 (depicted on the right schematically), including fully or partially substituted cucurbiturils, have also been synthesized. The substituents (R) herein are cyclohexano, methyl, or hydroxyl groups, which show enhanced solubility in water and common organic solvents,28 allowing one to gain insights for host-guest binding patterns in water.29-31 Theoretical calculations based on quantum chemical or density functional methods have proven useful to understand host-guest interactions at the molecular level.32-34 The present work focuses on deriving the electronic structure and 1H NMR * Corresponding author. E-mail: [email protected]. † University of Pune. ‡ Swami Ramanand Tirth Marathwada University.

spectra of CB[6] or TMeCB[6] hosts with protonated imidazole derivatives. The protonated N-(4-hydroxylphenyl)imidazole (g1), N-(4-aminophenyl)imidazole (g2), and 2-phenylimidazole (g3) species are chosen as guest molecules, which consist of two unsaturated moieties, phenyl and imidazole rings. Interestingly, the amino acid histidine possesses an imidazole side chain that has been identified as an active site for enzymes and proteins. Moreover, these imidazole derivatives possess antifungal activity and, thus, are biologically important. Some of the complexes encapsulating imidazole derivatives within the CB[6] cavity show effective binding and therefore are utilized in designing strategies to incorporate nonmetallic DNA artificial nuclease, which in the physiological environment35 brings about effective cleavage of the DNA molecule by a proton transfer mechanism. As a pursuance to this, the following questions have been addressed in this work: How does the guest orient itself in the host cavity? Which molecular interactions govern the stability of these inclusion complexes? How do different binding patterns of the host-guest interactions manifest in 1H NMR chemical shifts? What is the influence of solvent on the structure and 1H NMR spectra? A density functional based approach is presented

10.1021/jp107289s  2010 American Chemical Society Published on Web 09/22/2010

CB[6]) Sym-Substituted TMeCB[6] to answer these questions and thus derive molecular level insights for host-guest interactions.

J. Phys. Chem. A, Vol. 114, No. 40, 2010 10907 The MESP at a spatial point, r, V(r), is given by N

Computational Method CB[6], TMeCB[6], the protonated imidazole derivatives (g1, g2, and g3), and three conformers each of their complexes were optimized using the density functional theory incorporating Becke’s three-parameter exchange36 coupled with Lee, Yang, and Parr’s (B3LYP) correlation functional.37 The internally stored 6-31G(d, p) basis set was employed. These conformers exhibit partial as well as complete encapsulation of imidazole derivatives within the cavities of CB[6] and TMeCB[6] hosts. Conformers herein include a phenyl ring accommodated in the cavity with the imidazole moiety interacting externally with the host portals (C1); alternatively, an imidazole moiety within the host cavity and the phenyl ring excluded (C2); and at last, complete encapsulation of the guest within the cavity of the host (C3). Optimizations using the Gaussian 09 program38 converged to two distinct conformers in each case, with the conformer C3 yielding a structure identical to the C1 complex, since incompatibility of the guest with the dimensions of the host cavity do not allow its complete penetration. The interaction energies in the gas phase of g1, g2, and g3 guests in the inclusion complexes with CB[6] or TMeCB[6] hosts were calculated by subtracting the sum of electronic energies of the host and guest from the SCF-derived energy of its complex within the B3LYP framework of theory.

V(r) )

∑ A

ZA

| | r-RA

-

∫ F(r′) d r′ 3

| |

(1)

r-r′

where N is the total number of nuclei in the molecule, ZA defines the charge of the nucleus located at RA, and F(r) is the electron density at location r. The two terms in the above eq 1 refer to the bare nuclear potential and the electronic contributions, respectively. Regions conducive to the electrophilic interactions are governed by substantial negative values of MESP. The topography in MESP was then mapped by examining eigenvalues of the Hessian matrix at the point where the gradient of V(r) vanishes, and the critical points (CPs) were thereby located using the program code written in our laboratory.39 The CPs are characterized in terms of an ordered pair (R, σ), where R and σ denote the rank and signature (the sum of algebraic signs of the eigenvalues) of the Hessian matrix, respectively, and fall into three categories: (3, +3), (3, +1), and (3, -1). The (3, +3) CP corresponds to the local minima, which represents potential binding sites for electrophilic interactions in their environs, whereas (3, +1) and (3, -1) refer to the saddle points. A locally written program UNIVIS-2000 was used for visualization of the MESP topography and isosurfaces.40 NMR chemical shifts (δ) were calculated by subtracting the nuclear magnetic shielding tensors of protons in hosts

Figure 1. Atomic numbering scheme in (a) CB[6], (b) TMeCB[6] host, (c) g1, (d) g2, and (e) g3.

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Figure 2. MESP isosurface (V) -240.23 kJ mol-1) along with the electrostatic potential mapped on the molecular surface of (a) CB[6] and (b) TMeCB[6].

TABLE 1: MESP Minima (in kJ mol-1) in CB[6] and TMeCB[6] Hosts CB[6] TMeCB[6]

w

x

y

-304.3

-276.7 -279.8

-68.8 -95.7

TABLE 3: Binding Energies (in kJ mol-1) of g1, g2, and g3 with CB[6] and TMeCB[6] Z

-299.0

CB[6] TMeCB[6]

and guests from those in the tetramethylsilane (as a reference) using the gauge-independent atomic orbital (GIAO) method.41 The effect of solvation on the structure and 1H chemical shifts in NMR spectra of CB[6] and TMeCB[6] hosts; g1, g2, and g3 guests; and 1:1 complexes thereof was modeled by selfconsistent reaction field (SCRF) theory incorporating the polarizable continuum model42 implemented in Gaussian 09. Results and Discussion Optimized geometries of host monomers in CB[6] and TMeCB[6] as well as protonated guests g1, g2, and g3 are

C1 C2 C1 C2

g1

g2

g3

195.5 185.6 205.4 189.3

205.3 173.2 215.5 186.1

233.2 235.1 245.1 245.7

shown in Figure 1, along with the atomic numbering scheme used. It has been pointed out that the MESP brings about effective localization of electron-rich regions42-49 in the molecular system that may be attributed to a delicate balance between the nuclear and electronic contributions given via eq 1 given in the computational method. Thus, the MESP exhibits rich topological features. An MESP isosurface of V ) -240.23 kJ mol-1 in CB[6] has been compared with those of the TMeCB[6] host in Figure 2. The electron-rich regions

TABLE 2: Selected Hydrogen Bond Distances in Inclusion Complexes of Imidazole Derivatives with CB[6] and TMeCB[6] (in Å) H7-O1 H9-O1 H4-O1 H4′-O1 H1′-O1 H2′-O1

g1@CB[6]

g1@TMeCB[6]

g2@CB[6]

g2@TMeCB[6]

2.047 2.047 1.997

2.029 2.121 2.020

2.105 1.994 2.400 2.341

2.106 2.002 2.495 2.289

g3@CB[6] C1

g3@TMeCB[6] C1

1.769 1.768

1.772 1.773

CB[6]) Sym-Substituted TMeCB[6]

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TABLE 4: B3LYP Calculated Geometrical Parameters of Inclusion Complexes of Protonated Imidazole Derivatives (g1, g2, and g3) with CB[6] and TMeCB[6] CB[6] TMeCB[6] O-O 7.045 O1O1* 3.523 O1C2N3C3 3.7 O1C2N5′C5′ 3.7 O1C2N3C4 -174.0 C2N3C4N5 -114.5 C2N3C4C4′ -2.3 C2N3C3H3 11.1 C2N5′C5′H3 13.4 C2H2 C3H3 C4H4 C5H5 C6H6 C7H7 C8H8 C9H9 N2H’2 O4H4 N4H4 C9N1C1C6 N1C9C1C6 C3C4O4H4 C3C4N4H4 a

7.152a 3.499 2.2 4.4 179.2 104.0 5.4 23.9 11.8

g1

g1@CB[6] g1@TMeCB[6]

7.801 3.480 0.8 1.9 -169.3 -121.2 -8.9 -8.2 16.4 1.089 1.079 1.089 1.081 1.088 1.089 1.083 1.083 1.085 1.033 0.986

1.082 1.078 1.078 1.077 1.080 1.011 0.978

7.959a 3.464 4.1 1.0 173.5 112.3 2.7 16.6 16.4 1.077 1.080 1.082 1.079 1.078 1.077 1.080 1.011 0.978

133.0

146.4

152.9

0.7

-14.6

11.1

g2

g2@CB[6] g2@TMeCB[6] 7.935a 3.438 2.2 -3.2 -171.6 -115.7 -5.9 -13.6 18.7 1.078 1.082

1.089 1.089

7.854 3.499 -0.8 0.9 170.7 118.2 5.9 9.8 14.3 1.078 1.082

1.089 1.089 1.083 1.083 1.085 1.032

1.083 1.079 1.078 1.077 1.081 1.011

1.082 1.079 1.078 1.077 1.080 1.011

1.017 133.9

1.014 146.0

1.014 153.3

22.7

25.3

24.2

g3

g3@CB[6] g3@TMeCB[6]

1.089 1.088 1.089 1.088 1.089 1.082 1.082

7.463 3.348 2.7 0.8 173.7 116.7 4.4 10.9 19.0 1.079 1.081 1.085 1.081 1.079 1.077 1.077

1.031

1.029

-153.5

-157.4

7.483a 3.559 2.1 0.8 -175.5 -110.8 -1.1 -21.1 14.9 1.079 1.081 1.085 1.081 1.079 1.077 1.077 1.029

-160.2

Distance between radially opposite methyl-substituted glycouril units that interact with guests.

Figure 3. Inclusion complex g1@CB[6] (a) C1 and (b) C2 from SCRF calculations.

in the CB[6] host have been largely localized near ureido oxygens on both the upper and lower rim of the host. The MESP minima near ureido oxygens and those near nitrogens within the host cavity designated as “x” (blue) and “y” (pink), respectively, are shown in Figure 2a. Thus, MESP investigations reveal the carbonyl-laced portals of CB[6] to be electron-rich relative to its cavity, and the minima near the

ureido oxygens (-276.7 kJ mol-1), reported in Table 1, are deeper than those identified near nitrogen atoms within the host cavity (-68.8 kJ mol-1) in this case. A simple plot of electrostatic potential on the molecular surface of the CB[6] host given also confirms this conclusion. An MESP isosurface of V ) -240.23 kJ mol-1 in the TMeCB[6] host shows each ureido oxygen of the methyl-

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Figure 4. Inclusion complex g1@TMeCB[6] (a) C1 and (b) C2.

substituted glycouril unit exhibits an MESP minimum (V ) -304.29 kJ mol-1), denoted by “w” (black) in Figure 2b. The remaining ureido oxygens of glycourils without methyl substituents exhibit distinct MESP features, and accordingly, radially opposite oxygens separated by 3.25 Å from the methylsubstituted glycouril emerge with the MESP minimum (V ) -299.04 kJ mol-1) denoted by “z” (green). The farthermost radially opposite ureido oxygens from the methyl-substituted monomer, on the other hand, possess two MESP minima shown by “x” (blue) in the figure. The MESP minima reported in Table 1, suggest that ureido oxygens of methyl-substituted glycouril monomer to be more electron-rich than those of unsubstituted glycouril. This can also be visualized from Figure 2b, that displays mapping of electrostatic potentials on the molecular surface of the isolated TMeCB[6]. Thus, it may be inferred that TMeCB[6] binds to the guest more strongly than CB[6], with the guest orienting equatorially within its cavity, which engenders interactions with ureido oxygens of methyl-substituted glycourils. As can be seen from Figure 1, two aromatic rings of g1 and g2 are connected through a nitrogen (N4) of the imidazole ring and differ only in the substituent at the para position of the phenyl ring. The two rings are connected by a carbon-carbon bond (C1-C9) in guest g3, and no substituent is attached to the phenyl ring in this case. Binding modes of these protonated imidazole derivatives g1, g2, and g3 to CB[6] and TMeCB[6] have been analyzed by considering different orientations of the guest within the host

cavity. Three conformers were thus considered for the inclusion complexes in each case, which finally converged to two distinct C1 and C2 structures with either a phenol or imidazole encapsulated within the host. Optimized geometries of C1 and C2 conformers of g1@CB[6] complexes are shown in Figure 1S(a) of the Supporting Information, along with the relative stabilization energies in kilojoules per mole in parentheses. The C1 conformer has been predicted to be 9.97 kJ mol-1 lower in energy, which may partly be attributed to hydrogen bonded interactions between the H7 and H9 of th guest and portal oxygens (O1) of opposite glycouril units on the upper rim of the host. In addition to these interactions, the hydroxyl substituent on the phenyl ring facilitates O-H · · · O interactions with the lower rim carbonyl oxygen O1′. The hydrogen bond distances of host-guest interactions are reported in Table 2. As shown in Figure 1S(b) of the Supporting Information, the C-H · · · O and O-H · · · O hydrogen bonded interactions render stabilization to the C1 conformer of g1@TMeCB[6] complex, which turns out to be 16.02 kJ mol-1 lower in energy than its C2 conformer. Optimized geometries of the C1 and C2 conformers of g2 complexed with CB[6] and TMeCB[6] hosts are displayed in Figure 2S of the Supporting Information. Host-guest binding patterns in the inclusion complexes of CB[6] and TMeCB[6] hosts are strikingly similar. Moreover, as noticed for the g1 complexes, encapsulation of the phenyl moiety with the exclusion of the imidazole ring yields the lowest-energy C1 conformer that possesses attractive O-H · · · O and N-H · · · O (two each)



Figure 5. Inclusion complex g2@CB[6] (a) C1 and (b) C2.

interactions. Moreover, the H7 and H9 imidazole protons facilitate hydrogen bonded interactions with portal oxygens (O1) of opposite glycouril units. The -NH2 substituent on the C4 of g2 engenders two additional hydrogen bond interactions with lower rim oxygens. Thus, these four attractive hydrogen bond interactions in the g2@CB[6] engender energy lowering of 32.04 kJ mol-1 for the C1 conformer. Similar arguments can be used to explain the energy lowering (of 29.42 kJ mol-1) for the C1 over its C2 conformer in the case of the TMeCB[6] complex. The corresponding hydrogen bond distances are reported in Table 2. Calculated interaction energies of g1 and g2 in different inclusion complexes are reported in Table 3. As may be inferred, the guest interacts more strongly when the phenyl ring penetrates inside the cavity and the imidazole moiety interacts externally. The binding of g3 to CB[6] or TMeCB[6] exhibits patterns different from those in g1 and g2 complexes. The lowest-energy g3@CB[6] complex displayed in Figure 3S of the Supporting Information shows partial encapsulation of the guest, wherein the imidazole ring accommodated in the host cavity participate in N-H · · · O interactions with carbonyl-laced portals. Because of the absence of a para substituent on the phenyl ring, g3 does

not bind to the lower rim of the host. Thus, the para substituent (hydroxyl or amino) holds the phenyl ring within the host cavity with concomitant exclusion of the imidazole ring, which interacts externally in the case of g1 and g2. Moreover, the complexes of g3 conformers with a phenyl ring encapsulated were also identified. This conformer however, has been predicted to be merely 2 kJ mol-1 higher in energy with the CB[6] host. It may be worth noting that the C1 conformer of the TMeCB[6] complex has been destabilized by 0.6 kJ mol-1 over its C2 conformer. Calculated interaction energies reported in Table 3 support these conclusions. Thus, stronger binding of protonated imidazoles to the TMeCB[6] host are in consonant with the inferences based on the MESP topography investigations, which revealed deeper minima near carbonyl oxygens of methyl-substituted glycourils in the TMeCB[6] host. It may, however, be remarked here that the binding constants determined from fluorescence emission experiments29 have shown that binding constants of g1 with CB[6] and TMeCB[6] hosts are comparable, whereas g2 shows a larger binding constant with CB[6]. In the case of g3, relatively stronger binding has been inferred for the CB[6] host.29

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On the other hand, electronic absorption experiments reveal that unlike g2, the guest g1 possesses a relatively larger binding constant with TMeCB[6], whereas the binding constants of g3 with CB[6] and TMeCB[6] are comparable. B3LYP/6-31G(d,p) calculated interaction energies predict guests g1, g2, and g3 bind relatively more strongly with the TMeCB[6] than with the unsubstituted CB[6] host; the difference in the case of g3, however, is merely less than 2 kJ mol-1. Thus, inferences from electronic absorption experiments that the g1 complex exhibits a larger binding constant in TMeCB[6] and the guest g3 engenders nearly equal binding constants with both CB[6] as well as TMeCB[6] hosts concur with those drawn from the present calculations. It should be noted here that a direct comparison of such binding abilities may be far from straightforward, since the calculations here refer to the single isolated molecules. As pointed out earlier, 1H NMR chemical shifts have been calculated by the GIAO method. In the case of g1, the H9 proton (8.52 ppm) has been noticed to be largely deshielded, while chemically equivalent protons H3 and H5 (7.19 ppm) engender large up-fielded signals. The order of chemical shifts for H7 (7.76 ppm) and H8 (7.82 ppm) protons in the calculated spectra are opposite to that observed in the experiment.29 Likewise, for g2, calculated δH values follow the trend H9 (8.44 ppm) > H8 (7.75 ppm) > H7 (7.68 ppm) > H2/H6 (7.46 ppm) > H3/H5 (6.72 ppm), which is qualitatively different from that observed in the

measured spectra (H9 > H7 > H2/H6 > H8> H3/H5). Moreover, δH values of the isolated g3 do not match with those from the measured spectra.29 To this end, Bagno et al.49 have pointed out that δH values of glucose obtained by employing the optimized geometry in solvent modeled via SCRF calculations within the framework of density functional theory agree better with those observed in the experimental NMR spectra than either in gas phase or derived by incorporating explicit water molecules. Thus, geometry relaxation in a solvent has primarily been important in deriving the δH values in the 1H NMR spectra. Pursuant to this, 1H NMR chemical shifts were calculated using optimized structures of host-guest complexes, individual hosts, and guests in the presence of water as the solvent. Optimized geometries of the host-guest complexes along with the individual hosts and guests derived from the SCRF calculations are outlined in the following. Selected bond distances and bond angles in g1-g3@CB[6] and g1-g3@TMeCB[6] inclusion complexes optimized in water are compared with those in unbound guests and pure hosts in Table 4. As shown in the table, ureido oxygens on radially opposite glycouril units of CB[6] are separated by 7.045 Å with nearly circular portals. Two adjacent ureido oxygens in CB[6] are 3.52 Å apart from each other, with two imidazole heterocycles of the same glycouril unit oriented mutually at an angle of ∼121°. The dihedral angle connecting glycouril units, for example,



Figure 7. Inclusion complex g3@CB[6] (a) C1 and (b) C2.

∠O1C2N3C3, deviates by ∼4° from planarity. Substitution of four methyl groups at equator position results in distortion of the CB[6] cavity, and thus, the largest separation of 7.251 Å for two oppositely lying portal oxygens was noticed the remaining O-O separated by 6.580 Å gives rise to an elliptical TMeCB[6] cavity. When the O-O separation of the ureido oxygens in the upper rim is largest, the lower rim concomitantly exhibits a least separation between corresponding glycouril units and vice versa. With substitution of methyl groups at equatorial positions, the portal oxygens are pushed farther apart compared with the parent CB[6], the separation of adjacent ureido oxygens being 3.33-3.61 Å. The mutual orientation of two adjacent glycouril units in TMeCB[6] is nearly the same as CB[6] (the O1C2N3C3 dihedral angle being 2.2° in TMeCB[6] compared with 4° for CB[6]). Furthermore, two methyl-substituted imidazole heterocycles in TMeCB[6] orient mutually at an angle of 125°. The C1 and C2 conformers of the g1@CB[6] complex optimized in water are shown in Figure 3. The portal oxygens on radially opposite glycouril units of CB[6] yield a larger separation (7.801 Å) on encapsulation of g1 compared with 7.045 Å in CB[6], signifying distortion of host cavity. A concomitant shortening of all C-H bonds in g1 on complexation

can be noticed. A change in the C9N1C1C6 dihedral angle from 133° to 147° suggests a relative orientation of the imidazole and phenyl rings has been affected significantly on complexation. The complexation of g1 with TMeCB[6] (cf. Figure 4) engenders distortion of the host cavity with an increased O-O separation (7.152 to 7.959 Å) of the radially opposite glycouril units and therefore, leads to conclusions similar to those drawn earlier for the g1@CB[6] complex. The C1 and C2 conformers of the g2@CB[6] complex optimized in water are shown in Figure 5. Here again, encapsulation of g2 induces expansion of the CB[6] cavity, and the mean ureido O-O separation of opposite glycouril units increases by 0.8 Å (cf. Table 4). As noted earlier, the C-H bonds in g2 are shortened on complexation. As inferred for the g1 complexes, the phenyl and imidazole axes herein are predicted to be nearly linear when g2 encapsulates within the CB[6] cavity. Similar conclusions may be drawn for the g2@TMeCB[6] complex, which is depicted in Figure 6. The expansion of the host cavity with simultaneous contraction of the C-H bonds in g2 may readily be noticed. The complexation of g3 yielding the C1 conformer, shown in Figure 7, induces expansion of the CB[6] cavity, as may be conjectured from the increased separation of the radially opposite

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ureido oxygens from 7.045 to 7.463 Å, which is, however, significantly smaller compared with that noticed for the g1 or g2@CB[6] complexes (cf. Table 4). Moreover, shortening of the C-H bonds in g3 may also be noticed. The inferences drawn can be extended further to the C1 conformer of TMeCB[6] (cf. Figure 8) complexes. In the following, we discuss calculated 1H NMR chemical shifts of the CB[6] and TMeCB[6] hosts and their inclusion complexes using the SCRF optimized geometries. The host CB[6] possesses three types of nonequivalent protons; namely, H1, H2, and H3. As may be noticed from Table 1S of the Supporting Information, H3 protons from a methylene group directed toward portal oxygens are deshielded and appear at δH ) 5.7 ppm, whereas the remaining methylene H1 protons directed outside the host cavity correspond to δH at 3.8 ppm in the spectra. The H2 protons on two imidazole heterocycles of the glycouril monomer emerge with δH to be 5.1 ppm in the spectra. Calculated δH values in the CB[6] protons follow the order H3 > H2 > H1 and thus agree with those reported in the work of Buschmann and co-workers.50 NMR chemical shifts of TMeCB[6] are shown in Figure 9e. As can be noticed from δH values reported in Table 1S of the Supporting Information, two methylene protons, H3a and H3b, directed toward the ureido oxygens are deshielded and yield distinct signals near δH ) 5.7 ppm, whereas the H1a and H1b methylene protons correspond to δH values at 3.9 and 3.7 ppm, respectively. Moreover, the signals displayed at δH 4.99 and 4.96 ppm arise from the H2a and H2b protons, respectively.

Likewise, the methyl H4 protons are largely shielded and correspond to δH ) 1.5 ppm, shown in Figure 9e. 1 H NMR spectra of unbound g1, the C1 conformer of the inclusion complex of g1 with CB[6] and TMeCB[6], are depicted in Figure 9. As can readily be noticed, the phenyl ring protons (H2, H6, H3, H5) exhibit shielding of ∼0.3 ppm and point to encapsulation of the phenyl ring in the shielding zone within the host cavity. The H7 and H9 imidazole protons participating in hydrogen bonded interactions with portal oxygens on the other hand are deshielded by ∼1.4 ppm (cf. Figure 9). Likewise, an upshift in the δH values of the phenyl protons of g1@TMeCB[6] complex can be predicted, and the imidazole protons (H7 and H9) exhibit deshielded δH signals compared with the unbound guest g1. Chemical shift values of unbound g1 and the C1 conformer of its inclusion complexes with both the hosts are compared with experimentally observed δH values in Table 2S of the Supporting Information. Since the experimental 1H NMR chemical shift data of g1 complexed with CB[6] engender broad signals (fast exchange of protons on the NMR time scale), a direct comparison of calculated 1H NMR chemical shifts in g1 complexed with CB[6] cannot be carried out. The trend of δH values for the g1@TMeCB[6] complex, therefore, observed to be accordance with the experimental data.29 1 H NMR data of the C1 conformer in the g2@CB[6] and g2@TMeCB[6] complexes shown in Figure 10 display shielded signals for phenyl ring protons H2, H6, H3, and H5 as a result of phenyl ring penetration within the host cavity. One of the



Figure 10. 1H NMR chemical shifts in water for (a) pure guest g2, (b) inclusion complex g2@CB[6], and (c) inclusion complex g2@TMeCB[6].

Figure 9. 1H NMR chemical shifts in water for (a) pure guest g1, (b) inclusion complex g1@CB[6], (c) pure host CB[6], (d) inclusion complex g1@TMeCB[6], and (e) pure host TMeCB[6].

imidazole protons (H8) is considerably shielded, while the H7 and H9 imidazole protons participating in hydrogen bonding are significantly downshifted in the 1H NMR spectra. Similar conclusions may be drawn for the g2@TMeCB[6] complex. Experimental 1H NMR measurements for g3 complexes by Tao and co-workers29 have shown that phenyl protons within the shielding zone of the cavity are up-shifted (0.4-0.9 ppm) and H7 or H8 (equivalent) imidazole protons emerge with deshielded signals near 7.8 ppm. For the g3@CB[6] complex, the C2 conformer predicts shielding of the imidazole protons (due to encapsulation within the cavity). Likewise, upfield NMR signals for H3, H4, and H5 (∆δH ) 0.6-0.7 ppm) phenyl protons can be inferred, unlike those for H2 and H6 (∆δH ) 0.5-0.6 ppm). On the other hand, encapsulation of the phenyl group in the C1 complex engenders shielding of the phenyl protons, and deshielded δH signals are predicted for the imidazole protons. Experimental 1H NMR spectra29 therefore, point to the C1 conformer (cf. Figure 11). The imidazole protons in the measured spectra, however, exhibit signals that imply significant deshielding, which can be attributed in part to intermolecular interactions between either two complexes or those with the host. These intermolecular interactions are not accounted for in the present density functional based calculations, which refer only to a single molecule. The change in the δH patterns on complexation of g3 with CB[6] and TMeCB[6] are qualitatively similar (cf. Table 2S of the Supporting Information).

Figure 11. 1H NMR chemical shifts in water for (a) pure guest g3, (b) inclusion complex g3@CB[6], and (c) inclusion complex g3@TMeCB[6].

Conclusions Binding patterns of hydroxyl- and amino-substituted imidazole derivatives (g1, g2, and g3) with CB[6] and sym-TMeCB[6] have been analyzed employing density functional theory. Electronic structures and 1H chemical shifts in partially encap-

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sulated complexes using water as a solvent have been obtained. The calculations predict that TMeCB[6] binds more strongly to protonated imidazole guests and engender qualitatively binding patterns similar to that of the CB[6] host in the inclusion complexes. The complexation brings about significant distortion of the host cavity, in particular for g1 or g2 complexes, pushing apart radially opposite ureido oxygens up to 0.8 Å. Unlike in the unbound guest, unsaturated phenyl and imidazole moieties tend to attain near linearity in the host-guest complexes. The O-H · · · O as well as N-H · · · O interactions, which stem from the para substituent of the phenyl ring and imidazole-host interactions, govern the stability of the inclusion complexes. The substituent holds the phenyl ring inside the host cavity via attractive interactions with the lower rim of the host. The absence of a para substituent on g3 leads to qualitatively different binding patterns between the host and guest. B3LYPderived 1H NMR chemical shifts of unbound guests and the inclusion complexes thereof in water agree well with experiment. The imidazole protons participating in hydrogen bonded interactions are deshielded, and all the remaining protons show significant shielding in the calculated spectra. The geometry relaxation in the presence of water does not alter the relative stabilization energies; however, influences significantly 1H NMR chemical shifts. Acknowledgment. S.P.G. is grateful to the University Grants Commission (UGC), New Delhi, India [Research Project F34370/2008(SR)] and University of Pune for disbursing the research grant under the potential excellence scheme. We thank the Center for Network Computing, University of Pune, for providing computational facilities. Supporting Information Available: B3LYP/6-31G(d,p) optimized geometries of isolated complexes of g1, g2, and g3 with CB[6] and TMeCB[6] hosts along with relative stabilization energies in kJ mol-1 given in parentheses, and the corresponding 1 H NMR chemical shifts in gas phase and in water. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew. Chem., Int. Ed. 2005, 44, 4844. (2) Freeman, W. A.; Mock, W. L.; Shih, N.-Y. J. Am. Chem. Soc. 1981, 103, 7367. (3) Wei, F.; Liu, S.-M.; Xu, L.; Cheng, G.-Z.; Wu, C.-T.; Feng, Y.-Q. Electrophoresis 2005, 26, 2214. (4) Xu, L.; Liu, S.-M.; Wu, C.-T.; Feng, Y.-Q. Electrophoresis 2004, 25, 3300. (5) Mohanty, J.; Pal, H.; Ray, A. K.; Kumar, S.; Nau, W. M. Chem. Phys. Chem. 2007, 8, 54. (6) Sindelar, V.; Cejas, M. A.; Raymo, F. M.; Chen, W.; Parker, S. E.; Kaifer, A. E. Chem.sEur. J. 2005, 11, 7054. (7) Lee, J. W.; Samal, S.; Selvapalam, N.; Kim, H.-J.; Kim, K. Acc. Chem. Res. 2003, 36, 621. (8) Wheate, N. J.; Taleb, R. I.; Krause-Heuer, A. M.; Cook, R. L.; Wang, S.; Higgins, V. J.; Aldrich-Wright, J. R. Dalton Trans. 2007, 5055. (9) Wheate, N. J.; Buck, D. P.; Day, A. I.; Collins, J. G. Dalton Trans. 2006, 451. (10) Wheate, N. J.; Day, A. I.; Blanch, R. J.; Arnold, A. P.; Cullinane, C.; Collins, J. G. Chem. Commun. 2004, 1424. (11) Mock, W. L. Top. Curr. Chem. 1995, 175, 1. (12) Kim, K. Chem. Soc. ReV. 2002, 31, 96. (13) Lehn, J.-M. Angew. Chem., Int. Ed. 1988, 27, 89.

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JP107289S

Electronic Structure and 1H NMR Chemical Shifts in Host-Guest

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