Host–guest complexation of HMeQ[7] with alkyldiammonium ions and alkyldiamines: a comparative study

Abstract

This work presents the host–guest complexation of HMeQ[7] with a series of alkyldiammonium ions and the corresponding uncharged alkyldiamines (H₂N(CH₂)_nNH₂, n = 2, 4, 6, 8, 10, 12) in aqueous solution. ¹H NMR data indicate that all alkyldiamines and alkyldiammonium ions have inclusion interactions with HMeQ[7] except for the ethanediamine. The driving force for the formation of HMeQ[7]–alkyldiammonium inclusion complexes appears to be the ion–dipole interaction, while the complexation of HMeQ[7] with alkyldiamines mostly depends on the hydrophobic effect. ITC study points out that the host–guest complexation of HMeQ[7] with alkyldiammonium ions is driven by enthalpy and entropy, while the host–guest complexation of HMeQ[7] with alkyldiamines is driven exclusively by enthalpy. The features of weak basicity and absence of charged groups of the alkyldiamines are responsible for the large negative entropy and large enthalpy change in the complexation process of HMeQ[7] with alkyldiamines.

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Introduction

Host–guest complexation or molecular recognition has gained increasing current interest.^1–13 The interest is for fundamental and practical reasons. Fundamentally, the host–guest complexation depends on not only the complementarity of size and shape between host and guest, but also appropriate intermolecular interactions, including CH–p, hydrogen-bonding, and ion–dipole interactions as well as hydrophobic effects. Understanding how and why molecules fit together is an intellectual challenge in supramolecular chemistry.^14–16 From a practical standpoint, the host–guest complexation can be exploited in molecular sensing, drug delivery, supramolecular polymers, and the fabrication of molecular switches and molecular machines.^17–23 A large number of macrocyclic molecules, such as crown ethers, cyclodextrins, calixarenes, and pillar[n]arenes have been utilized for the study of host–guest complexation.^24–28

Cucurbit[n]urils^29–36 (Q[n], n = 5–8, 10) are synthetic macrocyclic host molecules, featuring a rigid hydrophobic cavity and two carbonyl-laced portals. In the past two decades, numerous literature reports have already demonstrated how Q[n] molecules recognize various organic guests to form host–guest complexes. For example, Kaifer et al. systematically investigated the host–guest interactions of Q[7] with viologen derivatives and ferrocene derivatives.³⁷ Using host-stabilized charge-transfer (CT) interactions Kim and co-workers prepared a variety of supramolecular assemblies based on Q[8].³⁸ The host–guest complexation of Q[n] with alkyl(di)ammonium ions and their derivatives have been studied by Mock,^39–43 Kim^44–48 and other groups.^49–57 It should be noted here that the guest in above mentioned host–guest complexes features with positively charged residues, in particular ammonium groups. Not surprisingly, ion–dipole interaction is studied most and well documented in host–guest complexes: it is easily visualized and computed by modeling. By contrast, other interactions are less studied.^58,59 It seems as if the ion–dipole interaction is primarily responsible for the formation of the normal host–guest complexes. Is ion–dipole interaction necessary to the formation of host–guest complexes? In other words, can uncharged organic molecules be encapsulated into Q[n]?

Since alkyldiammonium ions are well-known guests for host–guest complexation by Q[n],^39–57 we decided to study the host–guest interactions of HMeQ[7] (Fig. 1),⁶⁰ a water-soluble Q[7] derivative with seven substituent methyl groups at the waist synthesized in our laboratory, with a series of alkyldiammonium ions and the corresponding uncharged alkyldiamines (H₂N(CH₂)_nNH₂, n = 2, 4, 6, 8, 10, 12, Fig. 1) in aqueous solution by ¹H NMR spectroscopy and isothermal titration calorimetry (ITC) techniques. Comparing the ¹H NMR spectra would reveal the differences of the binding of HMeQ[7] with positively charged and neutral guests. Investigating the thermodynamic data of HMeQ[7] binding with alkyldiammonium ions and alkyldiamines would reveal the contributions of different driving forces to the host–guest complexation. In a word, this study will help us to understand the nature of the host–guest complexation of HMeQ[7] with alkyldiammonium ions and alkyldiamines. We report here the interesting results of this study.

Fig. 1 Crystal structures of HMeQ[7] (left) and the guests (right) used in this study.

Results and discussion

Encapsulation behaviors in aqueous solution

¹H NMR was utilized to investigate the host–guest interactions of HMeQ[7] with alkyldiammonium ions. It has been reported that alkyldiammonium guests have different binding behavior to Q[n] and Q[n] derivatives based on their alkyl chain lengths.^{44–48,53–57} Previous publications reported that guest 1²⁺ is externally complexed with TMeQ[6]⁵⁶ and guest 2²⁺ does not form a stable complex with normal Q[7].⁴⁸ However, in the presence of HMeQ[7], all the alkyl chain protons on the guests 1²⁺ and 2²⁺ moved upfield (Fig. 2 and 3), indicating that the guests 1²⁺ and 2²⁺ are encapsulated into the HMeQ[7] cavity, forming stable inclusion complexes. The guests 1²⁺ and 2²⁺ must take extended conformations within the HMeQ[7] cavity because the cavity dimension of HMeQ[7] is much larger than the alkyl chain lengths of the guests 1²⁺ and 2²⁺. Given that only one set of signals was observed for the guests 1²⁺ and 2²⁺, in-out guest exchange must be fast on the NMR time scale.

Fig. 2 ¹H NMR spectra (400 MHz, D₂O) of guest 1²⁺ (A) in the absence and in the presence of (B) 1.02 and (C) 2.20 equiv. of HMeQ[7] in D₂O at 20 °C.

Fig. 3 ¹H NMR spectra (400 MHz, D₂O) of guest 2²⁺ (A) in the absence and in the presence of (B) 0.18 and (C) 1.00 equiv. of HMeQ[7] in D₂O at 20 °C. (D) shows the ¹H NMR spectrum (400 MHz) of HMeQ[7] in 0.50 mL D₂O at 20 °C.

At a first glance, the binding behavior of the guests 3²⁺ and 4²⁺ with HMeQ[7] are similar with that of the guests 1²⁺ and 2²⁺ because the entire alkyl chains of the guests 3²⁺ and 4²⁺ experience upfield shifts too (Fig. 4 and 5). Further analysis reveals that the alkyl chain lengths of the guests 3²⁺ and 4²⁺ (6 and 8 carbons, length of 10.0 and 12.5 Å in extended conformation)⁶¹ are longer than the height of HMeQ[7], it is reasonable to presume that the guests 3²⁺ and 4²⁺ have to adopt non-extended conformations when bound within the HMeQ[7] cavity.

Fig. 4 ¹H NMR spectra (400 MHz, D₂O) of guest 3²⁺ (A) in the absence and in the presence of (B) 0.35, and (C) 1.39 equiv. of HMeQ[7] in D₂O at 20 °C.

Fig. 5 ¹H NMR spectra (400 MHz, D₂O) of guest 4²⁺ (A) in the absence and in the presence of (B) 0.74 and (C) 1.36 equiv. of HMeQ[7] in D₂O at 20 °C.

The changes induced by HMeQ[7] in the ¹H NMR spectra of longer guests 5²⁺ (Fig. 6) and 6²⁺ (Fig. 7) clearly depart from that observed with the shorter guests 1²⁺–4²⁺. Here, guest 6²⁺ is taken as a representative to depict this type of binding behavior in detail. As can be seen in Fig. 7, upon addition of the HMeQ[7] host, two kinds of shifts are observed. The a protons of 6²⁺ experience a small downfield shift, while the other protons undergo a considerable upfield shift. This HMeQ[7]-induced shift pattern suggests that the methylene units adjacent to ammonium ions are situated outside of the HMeQ[7] portals, while the central portion of the alkyl chain is included inside the HMeQ[7] cavity. Since the length of the HMeQ[7] cavity is only 9.1 Å, the buried alkyl chains, 8 carbons (length of 12.5 Å in extended conformation) for the guest 5²⁺ and 10 carbons (length of 15.0 Å in extended conformation)⁶¹ for the guest 6²⁺, can only take compressed conformations. For the guests 3²⁺–6²⁺, any exchange between bound and free guests is slow on the NMR time scale, since signals from both species were distinguishable when an excess amount of the guest is present.

Fig. 6 ¹H NMR spectra (400 MHz, D₂O) of guest 5²⁺ (A) in the absence and in the presence of (B) 0.18 and (C) 1.79 equiv. of HMeQ[7] in D₂O at 20 °C.

Fig. 7 ¹H NMR spectra (400 MHz, D₂O) of guest 6²⁺ (A) in the absence and in the presence of (B) 0.45 and (C) 2.20 equiv. of HMeQ[7] in D₂O at 20 °C.

The host–guest interactions of HMeQ[7] with uncharged alkyldiamines in aqueous solution have also been investigated by ¹H NMR spectroscopy. The ¹H NMR spectra of 1 and 1 binding to HMeQ[7] are shown in Fig. S1.† The downfield chemical shift for the a protons of 1 indicates that the guest 1 were located out side of the portal of HMeQ[7]. In other words, the guest 1 is externally complexed with HMeQ[7], forming an exclusion complex. For the guests 2 and 3, all the resonances for the alkyl chain protons shifted upfield, indicative of their positioning within the cavity of HMeQ[7] (Fig. S2 and S3†). In the case of other three guests 4–6 (Fig. S4, S5† and 8), ¹H NMR induced shifts of methylene groups upon complexation with HMeQ[7] are similar to those of guests 6²⁺. In other words, as the alkyl chains get larger than 8 carbons, they can no longer fit completely inside the HMeQ[7] cavity. The terminal methylene groups stick out from the HMeQ[7] portals and the alkyl chains buried in the HMeQ[7] cavity take compressed conformations. When an excess amount of the guests 3–6 is present, a new set of signals was observed in the ¹H NMR spectra due to the formation of micellar aggregates, which benefits the reduction of the hydrophobic surfaces of the guests.

Fig. 8 ¹H NMR spectra (400 MHz, D₂O) of guest 6 (A) in the absence and in the presence of (B) 0.89 and (C) 1.13 equiv. of HMeQ[7] in D₂O at 20 °C.

In summary, the ¹H NMR spectroscopy measurements indicate that all alkyldiammonium ions and alkyldiamines form stable inclusion complexes with HMeQ[7] in aqueous solution except for the guest 1. The major driving force for the formation of the HMeQ[7]–alkyldiammonium complexes appears to be the ion–dipole interactions between the positive charge of the guest and the portal oxygen atoms of HMeQ[7]. For the formation of the HMeQ[7]–alkyldiamine complexes, including exclusion and inclusion complexes, the major driving force should be the hydrophobic effect. If the alkyl chains of the guest is larger than the dimension of the HMeQ[7] cavity, the guest adopts compressed conformation within the HMeQ[7] cavity.

Enthalpic and entropic contributions to host–guest complexation

Isothermal titration calorimetry (ITC) is one of the most effective techniques in investigating the host–guest interactions, because it not only determines the thermodynamic parameters (ΔS° and ΔH°) but also provides the association constant (K). To further understand the nature of host–guest complexations of HMeQ[7] with alkyldiammonium ions and alkyldiamines, we carried out ITC experiments (Fig. S6†). Since the guest 1 failed to form stable inclusion complexes with HMeQ[7] as the others, it is excluded in the present discussion. From the data in Table 1, the host–guest complexations of HMeQ[7] with alkyldiammonium ions were driven mainly by enthalpy and to some extent by entropy (|ΔH°| > |ΔS°|), while the host–guest complexations of HMeQ[7] with alkyldiamines were exclusively enthalpy driven.

Table 1 The association constants and thermodynamic parameters for the host–guest complexation of HMeQ[7] with alkyldiammonium ions and alkyldiamines

Experiment	K (M^−1)	ΔH° (J mol^−1)	TΔS° (J mol^−1)
1^2+·HMeQ[7]	(2.06 ± 0.21) × 10^5	(−1.79 ± 0.03) × 10^4	1.25 × 10^4
2^2+·HMeQ[7]	(2.01 ± 0.19) × 10^6	(−1.96 ± 0.05) × 10^4	1.64 × 10^4
3^2+·HMeQ[7]	(1.15 ± 0.25) × 10^7	(−2.79 ± 0.07) × 10^4	1.34 × 10^4
4^2+·HMeQ[7]	(1.08 ± 0.16) × 10^7	(−3.42 ± 0.03) × 10^4	5.98 × 10^3
5^2+·HMeQ[7]	(8.61 ± 0.43) × 10^6	(−3.31 ± 0.05) × 10^4	6.51 × 10^3
6^2+·HMeQ[7]	(8.18 ± 0.20) × 10^6	(−2.72 ± 0.04) × 10^4	1.23 × 10^4
1·HMeQ[7]	(6.62 ± 0.73) × 10^5	(−1.08 ± 0.01) × 10^5	−7.50 × 10^4
2·HMeQ[7]	(2.53 ± 0.22) × 10^5	(−1.01 ± 0.02) × 10^5	−6.97 × 10^4
3·HMeQ[7]	(1.52 ± 0.22) × 10^5	(−1.19 ± 0.03) × 10^5	−8.98 × 10^4
4·HMeQ[7]	(2.49 ± 0.25) × 10^4	(−1.56 ± 0.09) × 10^5	−1.31 × 10^5
5·HMeQ[7]	(3.85 ± 0.26) × 10^4	(−8.36 ± 0.39) × 10^4	−5.75 × 10^4
6·HMeQ[7]	(3.40 ± 0.15) × 10^4	(−1.29 ± 0.04) × 10^5	−1.03 × 10^5

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It is well known that the reaction enthalpy for the host–guest complexation is derived from different contributions: ion–dipole interactions, van der Waals interactions and the solvation effect. The solvation effect includes the desolvation of the host and the guest, and the solvation of the host–guest complex. In the case of the complexation of HMeQ[7] with alkyldiamines, the ion–dipole interaction should be neglected because the alkyldiamines are uncharged. However, due to the absence of the ion–dipole interactions, the alkyldiamines can flex to the surface of the cavity to fill the available space properly, which optimizes the van der Waals interactions. As a result, the van der Waals interactions between the alkyldiamines and the inner wall of the HMeQ[7] cavity are larger than those of HMeQ[7]–alkyldiammonium complexes. On the other hand, due to the weak basicity of the alkyldiamines, the enthalpic losses originating from the desolvation of the alkyldiamines are smaller than those of the alkyldiammonium ions. Taken together, the complexations of HMeQ[7] with alkyldiamines appear to be enthalpically more favorable than those of HMeQ[7] with alkyldiammonium ions.

Generally speaking, the entropy change of the host–guest complexation involves two events: (1) entropic gain by the removal of the water molecules from the cavity and the portals of the host, and from the solvated shell of the guest. (2) entropic loss by the host–guest association.^62–64 The observed positive entropy values for the formation of HMeQ[7]–alkyldiammonium complexes imply that the entropy loss originating from the host–guest association are overcompensated by the entropy gain from the desolvation of the HMeQ[7] and the alkyldiammonium ions. The large negative entropy values for the formation of HMeQ[7]–alkyldiamine complexes arise from two main reasons. (1) Given that the alkyldiamines belong to weakly basic guests, hydrogen bonding of the guests with the water molecules shouldn't be taken into account. Therefore, entropic gain by the removal of the water molecules from the solvated shell of the guests should be neglected. (2) The strongly van der Waals interactions between the alkyldiamines and the inner wall of the HMeQ[7] cavity restrict the movement of the guests, including rotation and translation, which leads to large entropic losses.

Although the enthalpies of the HMeQ[7]–alkyldiamines complexations are higher than those of the HMeQ[7]–alkyldiammoniums complexations, the entropies for the HMeQ[7]–alkyldiamines complexations are large negative. As a result, according to the van't Hoff equation:

ln K = −ΔH°/RT + ΔS°/R

The association constants of the HMeQ[7] with alkyldiamines are 1–3 orders of magnitude lower than those of with alkyldiammonium ions. Kim group reported a similar investigation of the host–guest complexation between Q[7] and the same series of alkyldiammonium ions.⁴⁸ The comparison of the thermodynamic data of the HMeQ[7] and the Q[7] with alkyldiammonium ions is considerably interesting. Obviously, the enthalpic gains are greater in HMeQ[7] complexes compared to those in Q[7] complexes. This results may be attributed to the electron-donating effect of the seven substituted methyl groups at the waist of the HMeQ[7], which enhances the ion–dipole interactions between the ammonium groups of the guest and the carbonyl groups of the HMeQ[7] portals. In contrast, the entropic gains are smaller for HMeQ[7] than for Q[7] upon complex formation. As a result we observed that the association constants are greater in HMeQ[7] complexes compared to those in Q[7] complexes.

Conclusions

In summary, we have investigated the host–guest complexation of HMeQ[7] with a series of alkyldiamines and the corresponding protonated alkyldiammonium ions in aqueous solution by ¹H NMR spectroscopy and ITC techniques. Experimental data indicate that all the guests can form inclusion complexes with HMeQ[7] except for the guest 1. If the alkyl chains of the guest is larger than the dimension of the HMeQ[7] cavity, the guest adopt compressed conformation within the HMeQ[7] cavity. The host–guest complexations of HMeQ[7] with alkyldiammonium ions were driven mainly by enthalpy and to some extent by entropy, while the host–guest complexations of HMeQ[7] with alkyldiamines were exclusively enthalpy driven. The features of weak basicity and absence of charged group of the alkyldiamines are main reasons for large negative entropy values and large enthalpy changes of the complexation of HMeQ[7] with alkyldiamines. The investigation of the same host reacts with protonated and neutral guests not only help us further understanding the nature of the host–guest complexation, but also provide us new idea in designing and constructing molecular switches and machines based on the control of the pH values.

Experimental section

Materials and methods

Guests 1–6 were purchased from Aldrich and used without further treatment. Their pH values in 1 mM aqueous solution are 9.87, 11.08, 11.02, 10.67, 10.77 and 9.67, respectively. Guests 1²⁺–6²⁺ were obtained by protonation of the corresponding diamines with HCl in water. The pH values of the guests 1²⁺–6²⁺ (1 mM) are 5.42, 5.82, 6.03, 5.17, 5.91 and 6.02, respectively. HMeQ[7] was prepared according to a literature method.⁶⁰ All the NMR data were recorded on a Bruker DPX 400 spectrometer in D₂O at 293.15 K.

Isothermal titration calorimetry (ITC) experiments

All titrations were carried out on a Nano ITC instrument (TA, USA). All solutions were prepared in purified water and degassed prior to titration experiments. An aqueous solution (0.1 mm) of HMeQ[7] was placed in the sample cell (1.3 mL). A typical ITC titration was carried out by titrating 25 aliquots of guest solution (1 mm, 8 μL) into a HMeQ[7] solution. The heat evolved was recorded at T = 298.15 K. The heat of dilution was corrected by injecting the guest solution into deionized water and subtracting these data from those of the host–guest titration. Computer simulations (curve fitting) were performed using the Nano ITC analyze software. The first data point was always removed from the data set prior to curve fitting. The data were analyzed with ORIGIN 8.0 software using the independent model.

Acknowledgements

We thank the National Natural Science Foundation of China (Grant No. 21272045, 21371004) and graduate student innovative funding of Guizhou Unversity (No. 2015038) for support of this work.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, ¹H NMR spectroscopic data of HMeQ[7] with guests 1–5 in D₂O, NOESY NMR spectra of HMeQ[7] with guests 3²⁺ and 4²⁺, and ITC profile of HMeQ[7] with all guests. See DOI: 10.1039/c5ra23758k

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