Host-Guest Complexations of Amine Boranes and Isoelectronic / Isostructural Quaternary Alkylammonium Cations by Cucurbit [ 7 ] uril in Aqueous Solution

The host-guest complexation of six amine boranes (R3NBH3) by the macrocyclic host molecule cucurbit[7]uril (CB[7]) in aqueous solution has been investigated using 1H and 11B NMR spectroscopy. The limiting complexation-induced 1H and 11B chemical shift changes indicate that the amine boranes are included in the hydrophobic cavity of the host molecule. The host-guest stability constants for neutral {R3NBH3∙CB[7]} complexes (in the range of 10 5-107M-1) have been determined by 1H NMR competition experiments and are compared with the corresponding values for the isoelectronic/isostructural {R3NCH3∙CB[7]} + complexes. Ammonia borane (H3NBH3) does not form a host-guest complex with CB[7]. The trends in the host-guest stability constant with the guest molar volume are examined, and the stability is ascribed to the hydrophobic effect (packing coefficient) and quadrupoledipole interactions.

The cucurbit[n]urils (CB[n], n = 5-8, 10, 13-15) are a family of host molecules (Figure 1) which form stable hostguest complexes with organic cations in aqueous solution [20][21][22][23].The CB [n] hosts are oligomeric macrocycles comprised of n glycoluril units bridged by 2n methylene units.The hydrophobic cavity is accessible through two constrictive polar portals, each rimmed with n ureido carbonyl groups.With certain cationic guests, exceedingly stable host-guests complexes (up to 7 x 10 17 M -1 with CB [7] in water) can be formed when the size of hydrophobic portion of the guest (such as with ferrocene or diamantane groups [24,25]) matches the internal volume of the CB[n] cavity, displacing the high-energy waters within [26], and the cationic group(s) is placed adjacent to the carbonyl groups to maximize the iondipole interactions.
We have shown that CB [7] is selective towards the size of hydrophobic, charge-diffuse NR  is also very selective towards differing extents of the Nmethylation of lysines and arginines, with a 3500-fold preference for N,N,N-trimethyllysine (a histone biomarker) over the native lysine [29].The amine boranes with the formula R 3 NBH 3 are isoelectronic and isostructural with the R 3 NCH 3 + cations, which exhibit host-stability constants with CB [7] in the range of 10 4 -10 8 M -1 in aqueous solution [28].With neutral guests, which lack the capacity for iondipole interactions with the CB[n] host, the stability of the resulting host-guest complexes can be related to the packing coefficient of the guest within the host internal cavity, [30] which has been correlated with the number of heavy (nonhydrogen) atoms in the encapsulated portion of the guest [31][32][33].In addition, with polar neutral guests, the guest's dipole may align with the quadrupolar moment of the CB[n] cavity [31,34].
In the present study we have investigated the formations of host-guest complexes of cucurbit [7]uril with a series amine boranes R 3 NBH 3 (R = H, methyl, ethyl, t-butyl or R 3 = Nprotonated or N-methylated morpholine) and the isoelectronic/isostructural R 3 NCH 3 + cations in aqueous solution, using 1 H and 11 B NMR spectroscopy.The host-guest stability constants ( CB [7] ) have been determined and are compared with those measured for the isoelectronic R 3 NCH 3 + cations in aqueous solution.The values of  CB [7] are correlated with the packing coefficients and the octanol-water partition coefficients.

Results and Discussion
3.1. 1H and 11 B NMR Spectra.Nuclear magnetic resonance spectroscopy is very useful in examining both the qualitative and quantitative aspects of host-guest complex formation in solution.The magnitude and sign of the limiting complexation-induced chemical shift changes (û lim =  bound - free ) in the guest resonances are indicative of the average positions of the proton environments with respect to the cavity and portals of the CB [7] (Figure 1).An upfield shift (û lim < 0 ppm) indicates that the guest proton is located within the internal cavity, while a downfield shift (û lim > 0 ppm) results when the proton is near the carbonyl groups of a portal.For all of amine borane guest molecules, the 1 H and 11 B NMR resonances shift upfield with the addition of CB [7], as did the proton resonances for the quaternary alkylammonium cations.The values of û lim for the guest 1 H and 11 B nuclei are given in Figure 2.
The ammonia borane (H 3 NBH 3 ) itself does not appear to bind to CB [7] as there are no changes in the borane proton resonance with added host (Fig. S2).This is most likely due to its preference to be solvated by water, through hydrogen and dihydrogen (hydridic-to-protonic) [40] bonding, rather than residing in the CB [7] cavity.All of the other amine borane and quaternary alkylammonium guests exhibited 1:1 binding with the CB [7], based on the 1 H NMR titrations, with no evidence for other stoichiometries (see Fig. S4 for triethylamine borane).The exchange behaviour of the guest proton resonances (slow exchange vs. fast exchange) depended on the nature of the amine borane.The trimethylamine and triethylamine boranes exhibited slow exchange behaviour (separate resonances for the free and bound guests) in the presence of CB [7] (see Figure 3 for trimethylamine borane).
Other amine boranes exhibited intermediate to fast exchange behaviour (broadening and shifting of a resonance representing the average of the free and bound chemical shifts).In the case of morpholine borane (Figure 4) the addition of CB [7] results in a significant broadening of the guest proton resonances, maximizing at about 0.5 equivalent of the host, before sharpening again as the host-guest ratio reaches 1:1.
The CB [7] complexations of the isoelectronic/isostructural R 3 NCH 3 + cation guests, which correspond to the amine boranes in this study, were also investigated.These guests, including the tetramethylammonium cation [27] and the protonated N-methylmorpholinium and N,N'dimethylmorpholinium cations [41] investigated previously, also exhibit similar upfield shifts in the corresponding proton resonances (Figure 2) upon complexation by CB [7].All of the quaternary alkylammonium guest proton resonances exhibited fast exchange behaviour.

Host-Guest Stability Constants.
The host-guest stability constants ( CB [7] ) for the amine boranes and isostructural alkylammonium cations (R 3 NCH 3 + ) were determined by using competitive 1 H NMR binding experiments [38] using competitor guests for whom stability constants with CB [7] have been determined previously [27,38].The stability constants for the corresponding R 3 NCH 3 + guests for R = methyl (one of the competitor guests used in the present study) and for R 3 N = morpholine or N-methyl morpholine have been reported previously [41].The values for  CB [7] , presented in Table 1, fall into the range of 10 5 -10 8 M -1 for both sets of guests.Good agreement was achieved for the trimethylamine borane and triethylamine borane using two different competitor guests.Table 1 also includes the molar volumes and packing coefficients for the guests along with the exchange behaviour (slow/intermediate/fast) for the guest proton resonances in the presence of the CB [7].With neutral guests, such as the amine boranes, the reasonably high stability observed for CB[n] host-guest complexes may be achieved by maximizing the hydrophobic effect through an effective filling of the internal cavity, displacing some or all of the estimated eight "high-energy" water molecules in the process.Nau and coworkers [31-33, 35, 42-44] have used Mecozzi and Rebek's empirical determination [30] that a packing coefficient (PC) of 55 ± 9 % provides for optimal binding, to propose that the internal cavity of the CB [7] host (242 Å3 [31]) can encapsulate up to 12 heavy atoms (note that the aforementioned guest has heavy atoms in the diamantane core).
The molar volumes [39] and packing coefficients for the amine boranes and isostructural alkylammonium cations are presented in Table 1.With both sets of guests, there is a general increase in the host-guest stability constant with an increase in the packing coefficient, as depicted in Figure 5.It is interesting to note that with the amine boranes, the trimethylamine borane forms a slightly more stable complex than the triethylamine borane, whereas with the corresponding alkylammonium cations, the methyltriethylammonium complex with CB [7] is significantly more stable than that of the tetramethylammonium cation.The binding constants for the dimethylamine borane and trimethylamine borane are also comparable in magnitude to those for the isoelectronic/isostructural isobutane (2.7 x 10 5 M -1 , PC = 33%) and neopentane (1.0 x 10 6 M -1 , PC = 40%) [35].The similarities in binding constants between cationic R 3 NCH 3 + , dipolar R 3 NBH 3 , and neutral R 3 CCH 3 guests suggest that there may be offsetting differences in the desolvation and dispersion energies for the guests [35,43].The packing coefficient calculated for the triethylamine borane is 69%, outside the ideal range of 55 ± 9% for optimum binding.This is consistent with the smaller limiting chemical shift changes for the B-H and methyl protons on this guest, suggesting that these portions of the guest are located towards the portals of the host.We previously observed, for the NR 4 + cation complexes with CB [7], that the trend in the stability constants was R = Et > Me > n-Pr > n-Bu, reflecting suboptimal packing coefficients for the larger substituents, as fewer of the alkyl groups of the guest are included in the cavity.With R = nhexyl and n-heptyl, the increasing size of the included arm(s) of NR 4 + reversed the trend [28].The value of  CB [7] for NMeEt 3 + (Table 1) is higher than NEt 4 + , reflecting a slightly more compatible packing coefficient of 60% compared with 67% for the NEt 4 + cation [39].
for the antiseptic agent benzethonium chloride, while the more stable CB [7] binding ( CB [7] = (8.7 ± 1.3) x 10 7 M -1 ) is to the cationic benzyltrimethylammonium moiety, a second binding of CB [7] occurs over the neutral hydrophobic 2-(2,4,4-trimethylpentyl) tail with  CB [7] = (4.0 ± 1.9) x 10 3 M -1 [45].With eight heavy atoms in this group, a packing coefficient of 61% was calculated, accounting for the reasonable strength in binding.In addition to the hydrophobicity of its cavity, the CB[n] molecule has a quadrupole moment aligned with the nfold principal axis of symmetry, such that neutral polar solvent molecules will form host-guest complexes with CB [7] in which the guests may align their dipole with the host quadrupole [31,34].We have previously reported that neutral ketones and other polar solvent molecules, based on 1 H NMR û lim values and energy minimization calculations, orient themselves such that the dipole moment of the guest is aligned perpendicularly to the quadrupole moment of the CB [7] host [31].With the dipolar nature of the amine boranes, a similar guest orientation might be expected and would allow for all of the guest protons to be residing within the internal cavity of the host molecule, as observed.This additional interaction may account for the slower guest exchange behaviour observed in the 1 H NMR spectra.The structure of the morpholine borane complex with CB [7] has been calculated using a gas-phase MM2 energy minimization, and two views of the complex are shown in Figure 6.This dipolequadrupole alignment with this guest may be further assisted by the presence of the oxygen atom in the morpholine ring.

Conclusions
Amine boranes (R 3 NBH 3 ) form relatively stable host-guest complexes with cucurbit [7]uril in aqueous solution, with stability constants in the range of  CB [7] = 10 4 -10 7 M -1 .The trend in the host-guest stability constants and those of the isoelectronic/isostructural alkylammonium cations can be related to their abilities to fill the host internal cavity and displace some or all high-energy waters, as reflected in their packing coefficients.The slower guest exchange behaviour for the amine boranes, compared to the alkylammonium cations, as exhibited in the 1 H NMR spectra, may result from additional quadrupole-dipole interactions available.

Figure 2 :
Figure 2: Structures of amine borane guests (R 3 NBH 3 ) with the limiting chemical shift changes (û lim , ppm) of the guest proton (C-H in black and B-H in red) and boron (blue) resonances upon complexation by CB[7].The values in the square brackets are the û lim values for the corresponding quaternary alkylammonium cations (R 3 NCH 3 + ).

a
Error limits of ±15 %. b Calculated using Molinspiration software [39].c Calculated using NMe 4 + as the competitor.d Calculated using NEt 4 + as the competitor.e From [27].f From [40].g Calculated using TSP as the competitor.

Table 1 :
[7]t-guest stability constants, a molar volumes b and packing coefficients, and the 1 H NMR exchange behaviour for the CB[7]complexes with the H 3 BNR 3 and H 3 CNR 3 + guests.