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. 2022 Nov 22;126(48):10156–10163. doi: 10.1021/acs.jpcb.2c05064

Relevance of the Cation in Anion Binding of a Triazole Host: An Analysis by Electrophoretic Nuclear Magnetic Resonance

Pascal Steinforth †, Melania Gómez-Martínez ‡, Lukas-Maximilian Entgelmeier ‡, Olga García Mancheño ‡, Monika Schönhoff †,*
PMCID: PMC9744096  PMID: 36409921

Abstract

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Triazole hosts allow cooperative binding of anions via hydrogen bonds, which makes them versatile systems for application in anion binding catalysis to be performed in organic solvents. The anion binding behavior of a tetratriazole host is systematically studied by employing a variety of salts, including chloride, acetate, and benzoate, as well as different cations. Classical nuclear magnetic resonance (1H NMR) titrations demonstrate a large influence of cation structures on the anion binding constant, which is attributed to poor dissociation of most salts in organic solvents and corrupts the results of classical titration techniques. We propose an approach employing electrophoretic NMR (eNMR), yielding drift velocities of each species in an electric field and thus allowing a distinction between charged and uncharged species. After the determination of the dissociation constants KD for the salts, electrophoretic mobilities are measured for all species in the host-salt system and are analyzed in a model which treats anion binding as a consecutive reaction to salt dissociation, yielding a corrected anion binding constant KA. Interestingly, dependence of KA on salt concentration occurs, which is attributed to cation aggregation with the anion-host complex. Finally, by the extrapolation to zero salt concentration, the true anion-host binding constant is obtained. Thus, the approach by eNMR allows a fully quantitative analysis of two factors that might impair classical anion binding studies, namely, an incomplete salt dissociation as well as the occurrence of larger aggregate species.

Introduction

Host–guest chemistry is still of growing scientific interests, despite already more than 30 years of research since Cram, Lehn, and Pedersen were awarded with the Nobel Prize for their work in this field.1 It features various applications, such as biomedicine,2−4 self-assembly,5−7 and catalysis. Noncovalent anion binding through hydrogen bond (HB)-donor catalysts is a widespread tool in organocatalysis for activating ionic or polarizable substrates and is used in several reactions like enantioselective dearomatization,8−10 acylation,11 and many more.12−15

In recent years, triazole-based host–guest systems made by click-chemistry gained increasing attention.16,17 A cooperative binding of anions by several triazole groups induced structural changes like folding or helix inversion.17,18 In a previous study, a tetratriazole host was introduced and applied in several reactions like the dearomatization of heteroarenes or asymmetric Reissert reactions of isoquinolines.8,9,19−21 Furthermore, this host was investigated with respect to its binding and folding mechanism.8 By DFT computations, the anion binding initialization could be attributed to the central triazoles.22

For all application fields of host–guest complexation, a quantification of the binding characteristics is required in order to improve its functionality. Therefore, a variety of methods has been developed over the last decades. Isothermal titration calorimetry is especially prevalent when protein interactions are investigated,23−25 while UV/vis26−28 and fluorescence29,30 methods provide binding constants of host–guest systems of photoactive substances. NMR measurements are established for investigating cyclodextrines,31,32 pillar[n]arenes,33,34 and other host systems.28,35,36 For example, employing Job’s plot, the stoichiometry and binding constants are available. However, methodological improvement continues with the contribution of Hibbert and Thordarson who stated Job’s plot to be error-prone and launched their open science online tool bindfit to process NMR and UV/vis titration data.4,37 When ionic systems are considered, additional care has to be taken as in common NMR titrations, the ionic strength is varied under the titration. Schulz et al. showed that in addition to ion binding, the chemical shifts may be severely affected by the ionic strength, thus compromising the obtained binding constants.38

The use of conventional methods to determine ion binding constants still neglects the fact that there are more factors in binding processes than only the two desired binding partners. The binding process of ions to a host is a two-step process of salt dissociation and host–guest complexation. However, the pre-equilibrium of dissociation is often ignored in binding studies.18,39−42 It is, on the other hand, highly relevant, as in organocatalysis, anion binding commonly occurs in organic, apolar solvents. Replacing the apolar solvent by a polar one is often no suitable alternative, as the solubility of many hosts is limited in polar solvents. Moreover, polar solvents may reduce the free energy of the free, solubilized ions, causing ion solvation to compete with ion complexation to the host. Thus, for anion binding in organic solvents, solvent choice is a complex topic, and knowledge of dissociation and binding equilibria is essential to evaluate the eligibility of specific solvents.

With the aim to take into account all the factors involved in anion binding, electrophoretic NMR (eNMR) has been chosen as an advanced characterization technique. eNMR is a species-selective method, providing drift velocities of charged molecules or complexes in an electric field and thus delivering detailed information on ionic association.43−46 The experiment is based on diffusion measurements by pulsed field gradient (PFG) NMR but includes additional electrical field pulses, which induce a collective ion drift motion evident as a shifting phase angle φ, dependent on the respective electrophoretic mobility μ. The method has been applied to ion binding in solution, as demonstrated, for example, by Giesecke et al., who investigated the binding of cations to poly(ethylene oxide) chains, exploiting the increased charge of the polymer introduced by cations bound to the chain.47,48 Along similar lines, eNMR has also been applied to quantify cation binding to crown ether hosts.49

In this work, a wide variety of salts are investigated in terms of their binding capacity toward a chiral host featuring cooperative binding by four triazole groups. In comparison to our previous study,22 the focus here is set on experimental results to unveil cation and functional group effects. Therefore, binding constants and stoichiometries are studied by conventional 1H NMR titration, while a more detailed analysis through eNMR techniques is performed. By measuring electrophoretic mobilities, a differentiation between the uncharged host and the charged host–guest complex is possible. This enables to characterize ion pairing in solution and to determine the dissociation constants KD as important binding criteria for the prevalent host–guest system. Employing this methodology, we analyze the effect of poor salt dissociation on anion-host binding constants by the effective charge εc. We show that within a model of consecutive equilibria of salt dissociation and anion-host binding, electrophoretic mobilities can serve to yield true binding constants. The method even allows to compensate for additional complexation effects, namely, a complexation of cations with the anion-host complex.

Materials and Methods

Materials

Acetone-d6 (99.9%), tetrabutylammonium benzoate (TBA B, 99.0%), tetrabutylammonium acetate (TBA Ac, 97%), tetraethylammonium benzoate (TEA B, 99.0%), tetraethylammonium chloride (TEA Cl, 99.0%), and ammonium benzoate (NH4 B, 98%) were all purchased from Sigma Aldrich Germany. Tetrabutylammonium chloride (TBA Cl, 97%) is purchased from Carbolution Chemicals Germany. Tetrabutylammonium trifluoroacetate (TBA TFA) is synthesized by anion exchange from TBA OH.50 Acetone-d6 is dried over molecular sieves (3 Å, AppliChem Germany) for at least 24 h; TBA B, TBA Cl, TBA Ac, and TBA TFA are dried in high vacuum at 50 °C overnight. All other salts were used as received. Tetrakis-Triazole TT1a is prepared as previously published.21

NMR Titrations

Each titration series consists of 23 single samples. TT1a host concentration is kept constant at 2 mM, while the salt concentration is varied from 0 to 10 equivalents (equiv). All preparational work is done in an argon atmosphere to avoid moisture. Stock solutions of TT1a (c = 5 mM) and salt (c = 10 mM and c = 50 mM, respectively) are prepared; solutions of TEA Cl and NH4 B are stirred overnight because of low solubility. Finally, samples are filled into 5 mm NMR tubes and sealed with laboratory film to prevent evaporation. 1H NMR spectra are performed on a 60 MHz benchtop spectrometer (Magritek Spinsolve) equipped with an autosampler and a magnetic field gradient unit (up to 0.5 T/m). Single pulse experiments (32 scans, 30 s repetition time, 26.5 °C) grant the desired spectra. For evaluation, the four signals of the cavity protons 1 to 4 (see Scheme 1) are chosen, and chemical shift δ is extracted by a self-written python script. The binding constant KA is obtained using bindfit software employing a binding model with a 1:1 stoichiometry.4,37,51

Scheme 1. Structure of Tetrakis-Triazole TT1aa.

Scheme 1

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Bold numbers indicate cavity protons for later evaluation. Because of symmetry, signals of unlabeled cavity protons are indistinguishable in NMR spectra.

Pulsed Field Gradient-NMR Diffusion

Diffusion coefficients D are conducted on a 400 MHz Bruker Avance Neo spectrometer using a broad band gradient probe head (Bruker diffBBO, up to 17 T/m) and employing a stimulated echo pulse sequence with field gradient pulses. By stepwise incrementing the gradient strength g in a series of spectra, D is obtained by a fit of the Stejskal–Tanner equation to the echo intensity I:

graphic file with name jp2c05064_m001.jpg 1

with γ as the gyromagnetic ratio of the measured nucleus (1H or 19F). The gradient pulse duration δ is 1 ms and the diffusion time Δ is 20 ms for all measurements. The measurement temperature is 298.2 K. Evaluation is performed with Topspin (Bruker) using eq 1.

Electrophoretic NMR

eNMR measurements are conducted on the same 400 MHz spectrometer and broad band gradient probe head. Solutions (c = 20 mM) of the respective salt dissolved in acetone-d6 are used in a sample geometry from P&L Scientific (Sweden) containing Pd electrodes in a 5 mm NMR tube (see the SI, Figure S1) to measure eNMR. For obtaining the electrophoretic mobility μ, a series of spectra is taken under variation of the applied voltage U, resulting in an electric field strength E = U/d. U is alternatingly stepwise increased to −100 and +100 V using a pulse generator (P&L Scientific, Sweden). The effective electrode distance d is calibrated by 1H eNMR on a tetramethylammonium bromide solution (10 mM, D2O).52 The phase shift ϕ is linearly dependent on the gradient pulse duration δ = 1 ms, the gradient pulse strength g = 50 G/cm, the gyromagnetic ratio γ, and the migration time Δ = 50 ms according to

graphic file with name jp2c05064_m002.jpg 2

All eNMR experiments are conducted at 298.2 K; temperature control is ensured via the water cooling of the gradient coils, that is, without any gas flow to minimize convection in the sample. A double-stimulated echo pulse sequence with additional electric field pulses is employed (Figure S2) with a relaxation delay of 90 s to allow dissipation after Joule heating. Minor contributions from convection amount to less than 5% of uncharged solvent drift relative to the ion drift. In case of 1H measurements, this is compensated by referencing the phase angles of the ion signals to those of the acetone solvent, as suggested previously.53 Phase angles ϕ for each spectrum are obtained fitting the peaks to Lorentzian shapes, as described earlier.46 Finally, the mobilities are obtained from the slope of linear regressions of plots of ϕ/E (see eq 2). Mobility values are averaged over at least two measurements, and the error is estimated to 10%, or the standard deviation, if the latter is larger.

Results and Discussion

Binding Constants Obtained via 1H NMR Titrations

Anion binding constants to TT1a were determined in previous work using TBA Cl and TBA B, while TBA triflate (TBA OTf) exhibited no binding to TT1a.22 In the present work, we complement the anion binding data to analyze a systematic variation of the anion structure as well as the structure of the cation. TEA B and NH4 B are chosen to clarify a potential influence of the cation structure on the anion binding process. In addition, the corresponding chloride salts are investigated, even though NH4 Cl is not soluble in acetone-d6 and hence could not be measured. Further variations of the anion include using TBA Ac, which features the same functional carboxylic group, but with a smaller methyl group attached. At last, with TBA TFA, an electron-withdrawing −CF3 group is introduced to the anion. Binding constants in TT1a solutions containing different salts are determined by 1H NMR titration.

Figure 1 exemplarily shows chemical shift variations for the case of TBA TFA; results of the other salts are given in the Supporting Information, Figures S3–S5. The 1:1 binding model fits the data well in all cases, as evidenced by the absence of systematic deviations in the residuals (see Figure 1 (top) and SI Figures S3–S5). For all anions, the chemical shift variation is the largest for the triazole protons H1 and H3, indicating larger shifts of the electron distributions of these protons. Interestingly, both triazoles exhibit very similar shift differences, the same holds for both protons on the phenyl rings (see Scheme 1 and Figure S6). This shows that all inner cavity protons are involved in anion binding. This is consistent with results of the host conformation obtained from DFT calculations for the case of Cl– binding, as published earlier.22

Figure 1.

Figure 1

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Bottom: NMR titration data of four cavity protons (for assignment, see Scheme 1) from TT1a (c = 2 mM). Added salt is TBA TFA. Lines are the resulting fits from the determination of the binding constant KA via bindfit with a model assuming a 1:1 stoichiometry. Top: Residuals of the KA fit.

The resulting binding constants for all salts are compiled in Figure 2. All tetraalkylammonium salts of benzoate and chloride show moderate binding toward the host molecule, while binding constants are the same within error. This proves the flexibility of the helical host structure allowing binding of different anion species. Other triazole-based hosts exhibit similar to stronger binding, partially due to a more defined structure.16,54−56 Identical binding constants for different salts with the same anion are also consistent with expectation. However, ammonium benzoate can be considered as nonbinding with log(KA/M–1) ≈ −1.0, providing a huge difference in anion binding in dependence on the cation choice, which is investigated in detail further below. In addition, TBA Ac, containing also a carboxylic group like benzoate, binds significantly better toward TT1a. Superior binding toward triazole hosts of acetate compared to chloride was also shown before.57 However, replacing the three hydrogens of the methylene-group by fluorine in TBA TFA, a significant weakening of the binding behavior is observed. This observation can be explained by the +I-effect of the −CH3 being replaced by an −I-effect of −CF3, thus draining electron density from the carboxylic group and reducing the strength of the hydrogen bonds. This underlines the importance of the steric and electronical properties of the functional groups attached to the negatively charged groups.

Figure 2.

Figure 2

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Binding constants of all investigated salts determined by NMR titrations. Square: TBA salts, triangle upward: TEA salts, triangle downward: NH4 salts.

The binding constants obtained by 1H NMR titrations are determined under the assumption of full salt dissociation. While this assumption is reasonable for polar solvents like water, organic solvents like acetone used here can deviate significantly. Incomplete salt dissociation causes an underestimation of binding constants obtained by 1H NMR titrations because the ion concentrations are overestimated. Hence, the dissociation equilibrium is of importance for the determination of anion binding constants. However, at this point, a discrimination of the effects of salt dissociation or anion binding, respectively, is difficult. Therefore, we separately investigate the salt dissociation equilibrium by eNMR and will use the dissociation constant in the interpretation of apparent cation-dependent anion binding constants.

Mobilities and Dissociation in Salt Solutions

Measuring the electrophoretic mobility of the salt constituents can grant insight into the association or dissociation of different species. Thus, mobilities are determined for cations (based on 1H eNMR) and anions (based on 1H or 19F eNMR, rsp.). An example of the evaluation procedure of voltage-dependent eNMR spectra is given in the SI Figures S7 and S8. In Figure 3, the cation and anion mobilities for solutions of the series of salts are summarized. As expected, the mobilities of the TBA+ cations are the same in the margin of errors for all corresponding three salts. The same holds for the TEA+ cations, which display mobilities in the same range as TBA+. The proton peak of NH4+ is not observable in the spectrum. Comparing the anion mobilities, benzoates in TEA B and TBA B solution have equal mobilities as expected, but surprisingly, the benzoate mobility in NH4 B is close to zero. This is an indicator for associated ions, for example, ion pairs, which are present in solution. As neutral ion pairs exhibit a net charge of zero, they are not migrating in the electric field, yielding zero mobility.

Figure 3.

Figure 3

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Electrophoretic mobilities of the ions of different salts (c = 20 mM) in acetone-d6, without the addition of TT1a. Squares: TBA salts, up triangle: TEA salts, down triangle: NH4+ salt. Chloride mobilities could not be determined because of too short spin relaxation time.

Any salt in dilute solution may occur in two different sites, that is, dissociated ions and undissociated ion pairs. Because exchange between either site is rapid, in diffusion or electrophoretic NMR, the NMR signal consists of a fast exchange average over both sites, weighted by their fractions, and it is

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and

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with p as the pair fraction, indices (+, −, p) referring to cation, anion, and pair, respectively, and the superscript “0” denoting the free ion properties as opposed to the averaged experimental observables μ± and D±. Because neutral pairs do not migrate in the field, it is μp = 0 and thus μ± = (1 – p)μ±0. As this set of four equations contains five unknowns, the degree of dissociation (1 – p) cannot be directly calculated. We therefore employ a procedure combining diffusion coefficient measurements (results for cations and anions, see the SI, Table S3) with well-documented Stokes radii of the cations in acetone from the literature.58,59 From the latter, we calculate D+ by the Stokes–Einstein equation and subsequently resolve eqs 3 and 4 to yield the pair fraction p. Details are given in the SI Section D, eqs S1–S4. The resulting pair fraction is given in Figure 4, and the numerical values are given in Table S4.

Figure 4.

Figure 4

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Degree of dissociation of all salt species (c = 20 mM) in acetone, as determined by eq S4, employing cation Stokes radii from the literature (see the SI section D). Errors are determined by error propagation.

The fraction of dissociated ions is clearly below one for all salts employed. With the exception of NH4 B, which shows almost no dissociation, typically, a large fraction of the order of 55 to 70% of anions is present as ion pairs and thus not available for anion binding. The effective concentration ceff of anions available for binding to the host is then calculated by eq 5.

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We note that the same information can also be obtained from conductivity measurements of the salt solutions. DC conductivities are given in the SI Figure S9, where values from impedance spectroscopy show excellent agreement with those obtained from electrophoretic mobilities after summation of partial conductivities. In conclusion, the effective concentration available for anion binding is far lower than the total salt concentration. The salt dissociation is a preceding equilibrium, which has to be accounted for when determining anion binding constants to the host.

Influence of the Cation on Anion Binding

The mobility of about 0 for NH4 B proves that there are very few free anions in solution, but almost all anions are complexed as ion pairs with NH4+, resulting in pair fraction close to unity. DC conductivity, however, is still not equal to pure acetone; therefore, we assume p(NH4 B) to be 0.99. This explains the missing binding of the benzoate to TT1a when NH4 B is used because there are no relevant amounts of free benzoate anions available for the host to bind to.

Even for the other salts, fractions of free ions are rather low, that is, between 0.3 and 0.45. Surprisingly, 1 – p of TBA TFA is higher than that for the other salts, while the anion-host binding is weaker, as evidenced in Figure 2. Therefore, we conclude that the electron-withdrawing effect of the −CF3 group in TFA reduces the binding constant even more than suggested by the titration results in Figure 2.

Relevance of the Dissociation Equilibrium, Determination of KD

At this point, we will use the knowledge about dissociation equilibria to treat anion binding under consideration of both equilibrium constants, KA for anion binding and KD for salt dissociation, see Scheme 2.

Scheme 2. Two-Step Binding Process of Anions to Hosta.

Scheme 2

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H: host, AC: undissociated salt, A: anion, C: cation, HA: anion-host complex, KD: salt dissociation constant, and KA: anion binding constant to host.

While binding constants obtained by NMR titrations are underestimated because the free anion concentration is overestimated, we expect to obtain a higher anion binding constant with the correction for the dissociation equilibrium. Now, recognizing that the mobilities as well as the diffusion coefficients are dependent on the salt dissociation, a closer look to the dissociation constants KD of the salts is necessary.

Salt dissociation is a simple one-step reaction, and the determination of KD requires the concentrations of three species - anion A, cation C, and ion pair AC - in equilibrium. The dissociated fractions are taken from salt solutions without the presence of TT1a.

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with

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and

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where [AC]0 is the total salt concentration. Hence, KD is determined by eq 7 and depicted in Figure 5, where we test it for a correlation with the binding constant, as determined by 1H NMR titrations.

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Figure 5.

Figure 5

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Dissociation constants of salts in acetone-d6 versus binding constant toward TT1a determined by 1H NMR titrations. Red line: linear fit of all data points except TBA TFA.

There is a linear trend for all salts except TBA TFA, linking the host binding constant to the dissociation constant of the respective salt. For TBA TFA, the binding is diminished by the reduced electron density of the carboxylic group, as discussed above, and thus, TBA TFA is shifted to the left. The linearity for all other salts leads to the conclusion that in the present system, the ion pair dissociation of the salts is the limiting factor for the binding constant. Thus, employing classical 1H NMR titrations, different binding constants determined for salts with different anions might easily be misinterpreted, as they might only reflect different dissociation constants of the respective salt. This is an important finding for anion binding catalysis in organic solvents because it highlights that a more accurate evaluation of the eligibility of solvents for a given targeted transformation is required.

Treatment of Anion Binding with Preceding Dissociation Equilibrium

In the following, we treat both equilibria (see Scheme 2) in order to obtain a true anion-host binding constant KA. This analysis is performed exemplarily for the salt TBA B because here, a 1H eNMR measurement delivers the mobilities of all three molecules. Obtaining the electrophoretic mobility of the host via 1H eNMR, it is possible to distinguish between the uncharged catalyst and the charged host–guest complex. To this end, an instructive quantity is the effective charge defined as the quotient of the mobility μ of a species as measured by eNMR and the apparent mobility calculated by the Nernst–Einstein equation using the host diffusion coefficient Dhost (eqs 8 and 9, see SI Table S3 for host diffusion). We calculate the effective charge for the host according to

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with

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Note that the host diffusion coefficient Dhost is assumed to be not altered by anion binding. Then, with z = 1, the charge number of the host–anion complex, εc, equals the fraction of host molecules with a bound anion, which yields the equilibrium concentrations [HA] and [H] of the host–anion complex and the host, respectively.

graphic file with name jp2c05064_m012.jpg 10
graphic file with name jp2c05064_m013.jpg 11

This yields the equilibrium concentrations of the different species and finally KA.

graphic file with name jp2c05064_m014.jpg 12

Concerning the anion, there are three different species present in the solution: a free fraction xf, a bound fraction xb, and a fraction of anions existing in ion pairs p(eqs 13, 14).

graphic file with name jp2c05064_m015.jpg 13
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p can be derived from the fraction of bound cations as these only occur as two species, that is, ion pairs or free ions, see also eq S3, yielding eq 15, with μ+0 as the mobility obtained from the Nernst–Einstein equation. Furthermore, eq 16 allows to calculate the bound fraction of anions.

graphic file with name jp2c05064_m017.jpg 15
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Replacing the concentrations in eq 12 by these expressions yields KA in dependence on the host effective charge and the cation mobility (eq 17).

graphic file with name jp2c05064_m019.jpg 17

Effective charges are determined from electrophoretic mobilities determined for 2 mM host concentration and 10 equiv of guest. This ratio is chosen to achieve host saturation and thus maximum host mobility and minimal errors. According to eq 17, the binding constant results as log(KA/M–1) = 1.94 ± 0.22. This value is far lower than the value obtained from NMR titrations (log(KA/M–1) = 2.84 ± 0.08), although the latter is expected to be reduced due to the incomplete dissociation equilibrium.

To resolve this discrepancy, the same measurements and evaluation are performed at different salt concentrations. Effective charges of the cation and host and the resulting binding constants are given in Table S5 for a series of single experiments. The binding constants are plotted in Figure 6. There is a clear dependence of the binding constant on salt concentration.

Figure 6.

Figure 6

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Concentration-dependent determination of the binding constant of benzoate to TT1a by eNMR evaluated within the model of subsequent equilibria (Scheme 2). Different data points result from individual eNMR measurements at the given ratio of TBA benzoate to TT1a. Errors are calculated by error propagation.

However, within the model of subsequent equilibria (Scheme 2), the binding constant should be a concentration-independent property. In addition, for high salt concentrations, it is lower than the value obtained by NMR titrations (log(KA/M–1) = 2.84 ± 0.08); this is opposite to the expectation of the consequence of low salt dissociation, which should result in an enhanced true binding constant. However, for decreasing salt concentration, the binding constant increases. We attribute the apparent decrease of KA with salt concentration as a consequence of the cation being capable of associating to the complex, forming a host-anion-cation complex, which is consistent with the results of the molecular dynamics (MD) simulations published earlier.55 Effective charges determined by eNMR revealed a similar addition of TBA cations to other types of anionic complexes before.60 Such a complex is uncharged; thus, it causes a zero contribution to the electrophoretic mobilities, such that, in particular, the host mobility is reduced with strong decreasing influence on KA, see eq 15. It is important to highlight that there are minor differences in the chemical shift of the TBA cation at different concentrations, also indicating a (weak) association of the cation. With the argument that in the regime of low salt concentration the fraction of triple complexes is negligible, we perform a linear regression, see red line in Figure 6. Extrapolating this linear regression to 0 equiv, a binding constant of log(KA/M–1) = 3.20 ± 0.04 is obtained. This value is well above that obtained from NMR titration, as expected because of the incomplete salt dissociation mentioned above.

In summary, the true binding constant turns out larger than that obtained in classical 1H NMR titration when the dissociation equilibrium is accounted for. Cation complexation, however, reduces the apparent KA to a degree which strongly depends on the salt concentration.

Careful analysis provided, the method proposed here is valuable especially for ion-binding hosts in organic solvents, which cannot dissociate the salt completely, and therefore, the effective ion concentration is lowered to an unknown degree. We emphasize that both effects, poor salt dissociation and cation complexation, can be accounted for by employing eNMR experiments in dependence on the salt concentration, such that finally, a correct anion-host binding constant is obtained.

Conclusions

Employing eNMR in binding studies is a powerful tool to further investigate ionic host–guest systems. In this work, we have studied the effective anion binding association through eNMR techniques of a prototypical anion binding catalyst, which allows to consider additional factors influencing the apparent binding constant in conventional titration methods. Classical 1H NMR titrations result in binding constants of (alkyl)ammonium salts toward a tetratriazole bearing host, which appear to depend on the type of cations in a series of benzoates, ranging from a good binding guest to almost no binding at all. By eNMR, it is shown that a poor salt dissociation is responsible for the low binding constant obtained for NH4 B. Applying mobility measurements of each constituent, a model considering the preceding salt dissociation equilibrium delivers corrected binding constants. It is further found that binding of the cation to the host-anion-complex, consistent with MD simulations,22 has an effect on the apparent anion binding constant because it results in an additional fraction of neutral complexes. This cation influence can be taken into account by mobility measurements in dependence on salt concentration and their extrapolation to zero. Applying this method yields anion binding constants, which are corrected for cation complexation effects. This is valuable for any ion binding host systems in organic solvents, for example, in anion binding catalysis. In addition, this method solves the problem of varying ionic strength and its effect on chemical shifts in NMR titrations.38

Acknowledgments

We gratefully acknowledge the German Science Foundation (DFG) for funding of this project, project number 433682494–CRC1459, project A05. We thank Chiara Weiß for performing some of the impedance measurements and Florian Ostler for providing the TBA TFA salt for the binding studies.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpcb.2c05064.

  • eNMR experimental sketches (Figures S1 and S2); NMR titration data for all salts (Figures S3–S6); binding constants (Table S1); eNMR raw data and results (Figures S7 and S8, Table S2); diffusion coefficients (Table S3) and calculation of pair fraction (Table S4); impedance spectroscopy experimental procedures and comparison of results to eNMR (Figure S9); and mobilities, effective charges, and binding constants of host–guest systems (Table S5) (PDF)

The authors declare no competing financial interest.

Supplementary Material

jp2c05064_si_001.pdf (1.5MB, pdf)

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