NMR Determination of the Binding Constant of Ionic Species: A

Article Cite This: J. Org. Chem. 2018, 83, 10881−10886

pubs.acs.org/joc

NMR Determination of the Binding Constant of Ionic Species: A Caveat Nils Schulz,† Severin Schindler,† Stefan M. Huber,*,† and Mate Erdelyi*,∥ †

Faculty of Chemistry and Biochemistry, Organic Chemistry I, Ruhr-Universität Bochum, Universitätsstraße 150, Bochum 44801, Germany ∥ Department of Chemistry, BMC, Uppsala University, Uppsala SE-752 37, Sweden

J. Org. Chem. 2018.83:10881-10886. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/21/18. For personal use only.

S Supporting Information *

ABSTRACT: Determination of the dissociation constant of ionic complexes with the standard NMR titration and NMR dilution techniques may yield a severely compromised result, due to the typically unconsidered chemical shift alteration induced by the gradual change of the ionic strength during the experiment. We show that the reliability of an NMR titration experiment is markedly improved upon keeping the overall ionic strength constant.

■

INTRODUCTION Noncovalent interactions, mediating all molecular recognition phenomena, are of tremendous importance for chemistry and biology. The most valuable descriptor of interaction strength is the binding constant K, or alternatively, its reciprocal, the dissociation constant Kd. It is commonly determined by NMR, optical (IR, fluorescence, and UV−vis) spectroscopies, or thermodynamic methods, such as isothermal titration calorimetry (ITC).1 To avoid false interpretation of the binding situation, the accuracy of the binding event’s characterization is of the highest importance. Whereas the characterization of the dissociation constants of neutral complexes is typically straightforward, the accurate determination of those of charged species, that are of at least as fundamental importance for chemical and biological processes, is more challenging. This fact is rarely considered, or even discussed, 2 although its neglect may have detrimental consequences.3 We demonstrate this herein for the two NMR techniques that are most typically applied to quantify ion pairing using a charged halogen bonding model system as an example.4 The model system used herein interacts primarily by halogen bonding (XB); however, the highlighted challenge is independent of the nature of the interaction and is thus universal for charged species.

nucleus throughout the titration is the average signal of the bound and the unbound states, in case of fast equilibration.1a,5a This can be exemplified by the titration of a cationic 2haloimidazolium-based Lewis acid with a halide salt (Figure 1) that forms a halogen bonded complex. Interaction, here halogen bond formation (Figure 2), is typically assessed by the detection of chemical shift changes, Δδ, close to the XB donor.6 As the chemical shift is sensitive to any changes in the environment of a nucleus, the distinction between Δδ induced by a specific intermolecular interaction and by nonspecific

Figure 1. 2-Iodoimidazolium salt 1-BAr F (tetrakis(3,5-bis(trifluoromethyl)-phenyl)borate) and 2-OTf (triflate) were used as model systems to demonstrate the challenge of the determination of association constants of ionic species. BArF is commonly seen as noncoordinating, whereas OTf is seen as a weakly coordinating anion.

■

RESULTS AND DISCUSSION The most common NMR experiment to determine dissociation constants is the titrand/titrant titration. This involves complex formation upon a gradual increase of the titrant/ titrand ratio at a constant titrand and increasing titrant concentration. The NMR chemical shift of the observed © 2018 American Chemical Society

Received: June 22, 2018 Published: August 15, 2018 10881

DOI: 10.1021/acs.joc.8b01567 J. Org. Chem. 2018, 83, 10881−10886

Article

The Journal of Organic Chemistry

Figure 2. 1H NMR titration of 1-BArF against TBA (tetrabutyl ammonium) bromide in CD3CN. Chemical shift changes of the backbone protons upon (left) a gradual addition of TBA bromide to a constant concentration of XB donor, resulting in an increasing ionic strength, and upon (right) a gradual increase in ratio of TBA bromide at a constant ionic strength. The data to the left could easily be misinterpreted to reflect cooperative binding of 1 to bromide via halogen bonding (blue) and hydrogen bonding (orange); it, however, reflects the consequence of ionic strength alteration. The data to the right, obtained at a constant ionic strength, allows reliable determination of the binding constant of the halogen bonding interaction of 1 and bromide ion.

effects is not trivial. Figure 2 illustrates the Δδ observed in a conventional 1H NMR titration of the XB donor 1-BArF (titrand, or host, constant concentration of 0.02 M) with an increasing ratio of tetrabutyl ammonium (TBA) bromide (titrant, or guest). This standard experimental setup for titration, with a titrand of virtually constant concentration and an increasing titrant/titrand ratio upon the addition of titrant,1a,7 is attractive as it circumvents subsequent data correction with a dilution factor. As it is apparent from its concentration-dependent variation, shown in Figure 2 (left), the chemical shift of the observed iodoimidazolium ring proton is affected by at least two opposing influences, evidently making Kd determination difficult, if not infeasible. The observed concentration dependence of Δδ may be interpretable as the result of two competing interactions, i.e., binding of bromide ion via halogen bonding (Figure 2, blue) until a 1:1 stoichiometry followed by hydrogen bonding (Figure 2, orange) to the imidazolium backbone at a higher halogen bond donor−acceptor ratio. Although this may seem to be a reasonable explanation, it is oversimplistic and misleading. Using a charged titrant in the titration, this standard measurement technique implies a gradually increasing ionic strength, I, throughout the experiment (0.02−0.12 M). As an essential part of the Debye− Hückel theory,8 the ionic strength, defined as half of the sum of the product of charge number, zi, over all ionic species and concentration, ci, of each ion9, is an important factor that influences the activities of ions. Ion pairing is prone to follow nonideal behavior and is highly sensitive toward alteration of the medium.5b Thus, the unfavorable influence of the increasing ionic strength on the chemical shift throughout the titration by far outweighs the advantage gained by elimination of a possible dilution induced chemical shift change by the use of a concentrated titrand solution. The above mistake is avoidable by keeping the ionic strength constant during the course of the titration, as indicated by the titration curve obtained in an alternative experiment using the same titrand/titrant system (Figure 2, right). This method requires the preparation of multiple NMR samples at a

constant total volume, containing varying volume fractions of equimolar stock solution of the titrand, here the XB donor ([H]0 = 1 mM), and tetrabutyl ammonium bromide ([G]0 = 1 mM). The ionic strength is kept constant by keeping the sum of the concentrations of [H]0 and [G]0 constant throughout all samples. (For details, see Tables S7−S9 in the Supporting Information.) As both salts are composed of monovalent ions, even if their relative concentration varies throughout the sample series, the overall ionic strength of each individual sample remains comparable. The chemical shift of the tetrabutylammonium ion remains constant throughout the titration, indicating that it does not form a strong ion pair with Br− or 1 (Table S8, Supporting Information). Data analysis of the resulting curve (Figure 2, right) using standard equations for titrand/titrant titration1a yielded ΔG0 = 24.9 kJ mol−1, which is in line with that obtained by ITC titration4b for the same system (Table 1). Here, it should be noted that ITC is Table 1. NMR- and ITC-Derived Dissociation Constants (Kd) and Free Energy (ΔG0) Obtained from Titrand/ Titrant Titrations of Haloimidazolium Salts (Titrand) with TBA Bromide (Titrant) in Acetonitrilea 4b titrand 1BArF 2BArF a

Kd (NMR) [M]

Kd (ITC)3 [M]

ΔG0 (NMR) [kJ mol−1]

ΔG0 (ITC) [kJ mol−1]

4.6 × 10−5

8.6 × 10−5

24.9

23.3

2.2 × 10−4

4.7 × 10−4

21.0

19.2

For details, see the Supporting Information.

less dependent on ionic strength alteration as it only requires the addition of 2−3 equiv of the titrant, whereas NMR titrations may easily require the addition of 15−50 equiv. NMR titration at 20 mM total ion concentration, comparable with the concentration used in the conventional titration experiment (Figure 2, left), provided a titration curve (Figure S15, Supporting Information) that resembles that obtained by titration at 1 mM total ion concentration (Figure 2, right). Hence, at a constant total ion concentration, the titration curve 10882


Article


Figure 3. C2−I (left) and C5-backbone carbon (right) chemical shift changes of 2-OTf (blue, +) and 2-BArF (orange, +) in a dilution experiment, performed in CD2Cl2 solution.

as in the alternative titration experiment above, providing a sigmoidal chemical shift alteration upon stepwise dilution of the sample. A constant chemical shift plateau is expected at considerably high concentrations, representing the paired ions state (δpaired), and at low concentrations, representing the unpaired, separately solvated ions state (δunpaired). In between these extremes, the observed chemical shift, δexp, depends on the molar fraction of the paired ions (eq 1). When [cation+anion−]exp is the known total salt concentration, the experimentally inaccessible concentrations of the paired ions [cation+anion−] as well as the concentration of the unpaired ions [cation+] and [anion−] can be calculated from χpaired using eqs 3 and 4, and Kd from eq 4, at each concentration.

remains to show simpler concentration dependence, independent of the overall concentration, as compared to the titration performed at a constant titrand concentration (Figure 2, left). This consistency suggests that ionic strength change, rather than hydrogen bonding or aggregation, is behind the unexpected shape of the titration curve shown in Figure 2, left. Conventional NMR titration, as described above, is popular to obtain binding/dissociation constants. However, the technique may suffer from a conceptual problem, namely, the presence of counterions, which obviously may interact with the studied ions in some fashion. In the most extreme case, i.e., for strong ion pairs of an ion and its counterion (weak electrolyte) prior to titration, essentially the difference in ion pairing between the original ion pair and the newly formed one is measured. For intermediate cases, it is difficult to estimate the influence of “unwanted” ion pairing to the detected overall binding energy. An alternative approach to determine Kd uses serial dilution of a concentrated solution of a weakly binding complex.10 The ever-increasing dilution in this experiment counteracts ion pair formation and accordingly is expected to allow the determination of “pure” dissociation constants without disturbance from potentially interfering counterions. It also allows examination of non-coordinating or weakly coordinating ion pairs (BArF and triflate salts), which pose a fundamental problem for thermodynamic methods, such as ITC, by reaching the detection limit. The influence of ionic strength alteration on this technique is illustrated on the model system 2-iodoimidazolium triflate (2-OTf), a complex analogous to 2BArF. Such 2-iodoimidazolium salts with weakly coordinating or non-coordinating counterions are typically applied as halogen bond-mediated organocatalysts, for which the reduced competition of the counterion toward the substrate is of vast importance.11 Accordingly, the knowledge of the dissociation constants of these systems is vastly valuable. We have studied the concentration dependence of the chemical shift changes of iodoimidazolium C2−I, the nucleus nearest to the proposed binding site, of 2-OTf in CD2Cl2. χpaired =

[cation+anion−] = χpaired × [cation+anion−]exp

[cation+] = [anion−] = (1 − χpaired) × [cation+anion−]exp (3) Kd =

(1 − χpaired)2 [cation+][anion−] = × [cation+anion−]exp + − [cation anion ] χpaired

(4)

Using this technique, the accuracy of the determined Kd crucially depends on the precise determination of the chemical shifts of δpaired and δunpaired. This is most difficult for the lowdilution end as measurements at low concentrations require high-sensitivity detection and are time-consuming, especially for 13C NMR experiments. To circumvent this, a sample that may serve as a chemical shift reference for the unpaired, “naked” iodoimidazolium with a presumably non-coordinating BArF anion may be applied. However, this approximation is misleading and invalid, as demonstrated by the discrepancy of the chemical shifts obtained for 2-OTf and its “reference”, the corresponding 2-BArF salt (Figure 3, left). Hence, the C2−I carbon shift changes upon dilution of the triflate salt (blue), reaching its minimum plateau at 97.16 ppm and indicating fully solvated ions at 250 μM, whereas the corresponding BArF salt showed a concentration-dependent shift of 97.5−97.7 ppm. (The ionic strength alteration during the dilution experiment is 2.5 × 10−4 M to 0.1 M.) The latter weakly coordinating salt would be a sufficient chemical shift reference for the naked cation if its C2−I carbon chemical shift had been consistent with that of the minimum shift plateau observed for 2-OTf. However, the difference between the

δexp − δunpaired δpaired − δunpaired

(2)

(1)

A rapid association−dissociation equilibrium process yields an averaged signal of paired and unpaired ions in solution, just 10883


Article


data interpretation. Furthermore, the degree of dissociation of titrand and titrant may differ. Ion pairs are typically associated to a larger extent in solvents of low polarity as compared to aqueous solutions or to more polar solvents. The addition of ion pairs to the solution of neutral substances may therefore have a larger influence on the overall ion strength in a polar solvent. However, strong ion pairing and ion pairing equilibria may also severely influence the quantification of association constants, and thus independently of the solvent, the influence of ions on Kd determination cannot be neglected.2a As the ionic strength is defined as the sum of the product of charge number and concentration of each ion present in a solution,8,9 the influence of multiple charged ions is expected to be larger than that of monocharged ones. The susceptibility of the solvent or the reaction field effect may serve reasonable explanations but does not provide a straightforward quantitative estimation, as the corresponding models are based on descriptions of monoatomic spherical ions.12,13 This results in questionable interpretability as well as high and ionic strength-dependent inaccuracy of the determination of binding constants, with increasing uncertainties at increasing ionic strengths. There is no known correction factor. The use of an external reference may be expected to provide reliable approximation; however, the accuracy of this approach depends on the precise determination of the magnetic susceptibilities.14,15 Overall, there is no obvious experimental or theoretical solution to avoid or compensate the influence of ionic strength alteration in dilution experiments. Even under the presumption that at low concentration and in a solvent of low dielectric constant the chemical shift is less affected, the determination of dissociation constants remains ambiguous, as the maximum chemical shift, δpaired, has to be estimated. Possible aggregation affecting the chemical shifts may further influence the estimated Kd’s. Overall, great care should be taken when using the dilution-based technique for Kd determination.

chemical shifts of the plateau and the reference represents a considerable fraction of the overall shift difference Δδ(OTf)C,paired/unpaired detectable over the total dilution range. Accordingly, using the chemical shift of 2-BArF as reference for δunpaired would give a Kd ≈ 9 × 10−4 M (at a concentration of 30 mM, Table 2), which is a factor of 10 smaller as compared Table 2. Estimation of Kd with and without Using BArF as a Reference for δunpaired χpaireda conc [M] 2.0 1.5 1.0 5.0 3.0 1.0 5.0 2.5 1.0 2.5

× × × × × × × × × ×

−1

10 10−1 10−1 10−2 10−2 10−2 10−3 10−3 10−4 10−5

Kd [M]

δexp [ppm]

without refb

BArF refc

98.08 98.03 97.94 97.78 97.67 97.45 97.35 97.26 97.19 97.16

1.00 0.94 0.85 0.67 0.55 0.31 0.20 0.11 0.03 0.00

1.00 0.98 0.95 0.88 0.84 0.76 0.72 0.69 0.66 0.65

without ref 6.2 2.8 8.1 1.1 1.5 1.6 1.8 3.2

× × × × × × × ×

10−4 10−3 10−3 10−2 10−2 10−2 10−2 10−3

BArF ref 7.3 3.1 7.5 8.9 7.6 5.5 3.5 1.8

× × × × × × × ×

10−5 10−4 10−4 10−4 10−4 10−4 10−4 10−5

δpaired was estimated to 98.08 ppm. bδunpaired = 97.16 ppm. cδunpaired = 95.45 ppm.

a

to the Kd determined using the minimum shift detected in the dilution experiment (Kd ≈ 1 × 10−2 M at the same concentration, Table 2). This example demonstrates the magnitude of the error of the dissociation constant that may be introduced by the use of non-coordinating anions as a chemical shift reference for “naked” cations. It is important to underline that this is not just a technical but rather a conceptual problem of the NMR experiments typically utilized for determination of association constants! Although commonly neglected, the ionic strength has a significant influence on the chemical shift of the solutes, as demonstrated in the first example, with the magnitude of the influence varying among the nuclei of a molecular system (Figure 4). It should be noted that at the typical concentrations of dilution experiments, the dissociation of non-coordinating ions, such as BArF, might be incomplete and might vary throughout the experiment, further influencing the observed chemical shifts and complicating the

■

CONCLUSIONS

In conclusion, the determination of dissociation constants of ionic species by NMR titration or NMR dilution experiments may be severely compromised by the alteration of ionic strength. The reliability of NMR titration experiments is markedly improved when the overall ionic strength is kept

Figure 4. Chemical shift changes of C2−I (left) and C5-backbone carbon (right) of 2-OTf in a concentration-dependent 13C NMR experiment in CD3CN. 10884



■

ACKNOWLEDGMENTS This work was supported by the Cluster of Excellence RESOLV (EXC1069) by the Deutsche Forschungsgemeinschaft. We also thank the Swedish NMR Centre for access to NMR instrumentation.

constant. Dilution experiments, which are commonly seen to provide a more reliable, “pure” dissociation constant, must be interpreted with caution.

■

EXPERIMENTAL SECTION

■

2-Iodoimidazoliumsalts 1-BArF and 2-BArF and 2-OTf were synthesized according to literature procedures.4a,b Solvents were chosen based on the solubility of the studied compounds and were purchased from commercial suppliers. They were of 99.8% or higher purity and were used without purification. Solutions were prepared at room temperature, 21 °C. NMR spectra were acquired on a Bruker Avance III HD 800 MHz spectrometer equipped with a TXO cryogenic probe, at 25 °C, and were processed with the software MestreNova version 11. Chemical shifts were referenced indirectly to TMS via the residual solvent signal (CD2Cl2, δΗ = 5.320 ppm and δC = 54.000 ppm; CD3CN, δΗ = 1.940 ppm and δC = 118.260 ppm). The spectroscopic data, shown in the Supporting Information, was in agreement with that previously published.4a,b N,N′-1,3-Bis(2,6-diisopropylphenyl)-2-iodoimidazolium Bis(tetrakis(3,5-bis(trifluoromethyl)phenyl)-borate (1-BArF):3 1H NMR (800 MHz, CD2Cl2, 100 mM) δ 7.83 (s, 2H, H-4 and H-5), 7.75 (m, 8H, BArF), 7.70 (t, J = 7.8 Hz, 2H, H-9), 7.58 (m, 4H, BArF), 7.46 (d, J = 7.8 Hz, 4H, H-8), 2.22 (sept, J = 6.8 Hz, 4H, H12), 1.31 (d, J = 7.0 Hz, 12H), 1.25 (d, J = 7.0 Hz, 12H); 13C NMR (201 MHz, CD2Cl2) δ 162.9 (q, 1JCB = 49.7 Hz, BArF), 145.5 (C-6), 135.4 (BArF), 133.9 (C-9), 131.8 (C-7), 129.5 (m, J = 30.2 Hz; BArF), 128.9 (C4−5), 127.2 (q, 1JCF = 272.3 Hz; BArF, CF3), 126.3 (C-8), 118.1 (BArF), 104.3 (C-2), 30.2 (C-12), 24.9, 23.5 (C11−12). 2-Iodo-1-methyl-3-octyl-imidazolium Trifluoromethanesulfonate (2-OTf): 3 1H NMR (800 MHz, CD2Cl2, 150 mM) δ 7.75 (d, J = 2.1 Hz, 1H, H-4), 7.64 (d, J = 2.1 Hz, 1H, H-5), 4.16 (t, J = 7.5 Hz, 2H, H7), 3.92 (s, 3H, H-6), 1.84 (p, J = 7.2 Hz, 2H, H-8), 1.34 (m, 4H, H-9 and H-10), 1.30 (m, 2H, H-13), 1.27 (m, 4H, H-11 and H-12), 0.88 (t, J = 6. Hz, 3H, H-14); 13C NMR (201 MHz, CD2Cl2) δ 127.5 (C4), 125.9 (C-5), 123.6−118.9 (q, CF3-15), 98.0 (C-2), 53.7 (C-7), 40.4 (C-6), 32.2 (C-12), 30.2 (C-8), 29.5 (C-11), 29.4 (C-10), 26.7 (C-9), 23.10 (C-13), 14.3 (C-14); 19F NMR (235 MHz, CD2Cl2) δ −78.14 ppm. 2-Iodo-1-methyl-3-octyl-imidazolium Bis(tetrakis(3,5-bis(trifluoromethyl)phenyl)-borate (2-BArF): 3 1H NMR (300 MHz, CD2Cl2, 50 mM) δ 7.73 (m, 8H, BArF), 7.57 (m, 4H, BArF), 7.45 (m, 2H, H4 and H5), 4.11 (t, 2H, H-7), 3.84 (s, 3H, H-6), 1.84 (m, 2H, H-8), 1.35, 1.28, 0.88 (t, 3H, H-14); 13C NMR (101 MHz, CD2Cl2) δ 163.08−161.59 (m, BArF), 135.38, 129.5 (m, BArF), 129.2 (q, BArF), 127.4 (C-4), 126.2 (C-5), 118.1 (m, BArF), 95.3 (C-2), 54.4 (C-7), 40.6 (C-6), 32.2 (C-12), 30.2 (C-8), 29.5 (C-11), 29.3 (C-10), 26.7 (C-9), 23.1 (C-13), 14.3 (C-14).

■

REFERENCES

(1) (a) Thordarson, P. Determining association constants from titration experiments in supramolecular chemistry. Chem. Soc. Rev. 2011, 40, 1305−1323. (b) Connors, K. A. Binding Constants; John Wiley & Sons Inc, 1987; pp 141−355. (2) (a) Rolens, A.; Vacca, A.; Venturi, C. Binding of Ionic Species: A General Approach To Measuring Binding Constants and Assessing Affinities. Chem. - Eur. J. 2009, 15, 2635−2644. (b) Hua, Y.; Ramabhadran, R. O.; Uduehi, E. O.; Karty, J. A.; Raghavachari, K.; Flood, A. H. Aromatic and Aliphatic CH Hydrogen Bonds Fight for Chloride while Competing Alongside Ion Pairing within Triazolophanes. Chem. - Eur. J. 2011, 17, 312−321. (3) No references to studies reporting inaccurate dissociation constants are given here to avoid pointing out specific investigations or researchers. (4) (a) Jungbauer, S. H.; Walter, S. M.; Schindler, S.; Rout, L.; Kniep, F.; Huber, S. M. Activation of a carbonyl compound by halogen bonding. Chem. Commun. 2014, 50, 6281−6284. (b) Schulz, N.; Sokkar, N. P.; Engelage, E.; Schindler, S.; Erdelyi, M.; SanchezGarcia, E.; Huber, S. M. XB, or not XB, that is the question: The Interaction Modes of Haloimidazolium Salts in Solution. Chem. - Eur. J. 2018, 24, 3464−3473. (5) (a) Connors, K. A. Binding Constants; John Wiley & Sons Inc, 1987; pp 193 ff. (b) Connors, K. A. Binding Constants; John Wiley & Sons Inc, 1987; p 94. (6) (a) Serpell, C. J.; Kilah, N. L.; Costa, P. J.; Félix, V.; Beer, P. D. Halogen Bond Anion Templated Assembly of an Imidazolium Pseudorotaxane. Angew. Chem., Int. Ed. 2010, 49, 5322−5326. (b) Caballero, A.; White, N. G.; Beer, P. D. A Bidentate HalogenBonding Bromoimidazoliophane Receptor for Bromide Ion Recognition in Aqueous Media. Angew. Chem., Int. Ed. 2011, 50, 1845− 1848. (c) Cametti, M.; Raatikainen, K.; Metrangolo, P.; Pilati, T.; Terraneo, G.; Resnati, G. 2-Iodo-imidazolium receptor binds oxoanions via charge-assisted halogen bonding. Org. Biomol. Chem. 2012, 10, 1329−1333. (d) Takeda, Y.; Hisakuni, D.; Lin, C.-H.; Minakata, S. 2-Halogenoimidazolium Salt Catalyzed Aza-Diels−Alder Reaction through Halogen-Bond Formation. Org. Lett. 2015, 17, 318−321. (7) Hirose, K. Analytical Methods in Supramolecular Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA, 2007; p 41. (8) Debye, P.; Hückel, E. Zur Theorie der Elektrolyte. II. Das Grenzgesetz für elektrische Leitfähigkeit Phys. Z. 1923, 24, 185, 305. (9) Lewis, G. N.; Randall, M. The activity coefficient of strong electrolytes 1. J. Am. Chem. Soc. 1921, 43, 1112−1154. (10) (a) Ammer, J.; Nolte, C.; Karaghiosoff, K.; Thallmair, S.; Mayer, P.; de Vivie-Riedle, R.; Mayr, H. Ion-pairing of phosphonium salts in solution: C-Hhalogen and C-Hpi hydrogen bonds. Chem. Eur. J. 2013, 19, 14612−14630. (b) Larsen, D. W.; Wahl, A. C. Nuclear Magnetic Resonance Study of Ion Association between Quaternary Ammonium Ions and Hexacyanoferrate(III) Ion. Inorg. Chem. 1965, 4, 1281−1286. (c) Buckson, R. L.; Smith, S. G. Concentration Effects on the Nuclear Magnetic Resonance of Quaternary Ammonium Salts 1. J. Phys. Chem. 1964, 68, 1875−1878. (11) Bulfield, D.; Huber, S. M. Halogen Bonding in Organic Synthesis and Organocatalysis. Chem. - Eur. J. 2016, 22, 14434− 14450. (12) Buckingham, A. D.; Schaefer, T.; Schneider, W. G. Solvent Effects in Nuclear Magnetic Resonance Spectra. J. Chem. Phys. 1960, 32, 1227−1233. (13) Becconsall, J. K.; Hampson, P. Solvent effects in proton and 13C N.M.R. chemical shifts of polar compounds. Mol. Phys. 1965, 10, 21− 32.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01567. Syntheses, experimental setup, and NMR data (PDF)

■

Article

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Stefan M. Huber: 0000-0002-4125-159X Mate Erdelyi: 0000-0003-0359-5970 Notes

The authors declare no competing financial interest. 10885


Article

The Journal of Organic Chemistry (14) Homer, J. Solvent Effects on Nuclear Magnetic Resonance Chemical Shifts. Appl. Spectrosc. Rev. 1975, 9, 1−132. (15) Mizuno, K.; Tamiya, J.; Mekata, M. External Double Reference Method to Study Concentration and Temperature Dependences of Chemical Shifts Determined on a Unified Scale. Pure Appl. Chem. 2004, 76, 105−114.

10886


NMR Determination of the Binding Constant of Ionic Species: A

Recommend Documents