Bambusurils as a mechanistic tool for probing anion effects

Bambusuril macrocycles have high affinity towards anions (X−) such as PF6− and SbF6− or BF4− and ClO4−. Therefore, addition of bambusurils to reaction mixtures containing these anions effectively removes the free anions from the reaction process. Hence, comparing reactions with and without addition of bambusurils can demonstrate whether the anions actively participate in the reaction mechanism or not. We show this approach for gold(i) mediated addition of methanol to an alkyne. The reaction mechanism can proceed via monoaurated intermediates (e.g., in catalysis with [(IPr)AuX]) or via diaurated intermediates (e.g., in catalysis with [(PPh3)AuX]). We show that anions X− slightly affect the reaction rates, however the effect stays almost the same even after their encapsulation in the cavity of bambusurils. We also demonstrate that X− affects the overall reaction rate in the very same way as the reaction rate of the protodeauration step. All results are consistent with the indirect effect of X− by the acidity of the conjugated acid HX on the rate-determining step. There is no evidence that a direct involvement of X− would affect the reaction rate.


II) Experiments with [(IPr)AuX] Bn-BU
The stock solution A was prepared by mixing of AgX (Table S1) dissolved in 0.2 ml of CD 3 OD and 15.4 mg of AuCl(IPr) dissolved in 0.6 ml CD 2 Cl 2 . The reaction mixture was mixed for 30 minutes and filtered through a PTFE filter (pore size 0.2 μm) to remove precipitated AgCl.

S3
Final reaction mixtures without Bn-BU were prepared by mixing of 200 µl of the stock solution A, 62 µl of PhCCCH 3 , 53 µl of toluene, 350 µl of CD 2 Cl 2 , and 166 µl of CD 3 OD. Reaction mixture was immediately monitored by NMR spectroscopy.
Final reaction mixtures with Bn-BU were prepared by mixing of 12.5 mg of Bn-BU, 200 µl of the stock solution A, 62 µl of PhCCCH 3 , 53 µl of toluene, 350 µl of CD 2 Cl 2 , and 166 µl of CD 3 OD. Reaction mixture was immediately monitored by NMR spectroscopy.

III) Experiments with [(PPh 3 )Au(SbF 6 )] and different concentration of ptoluenesulfonic acid (TsOH)
The stock solution A was prepared by mixing of 10.2 mg of AgSbF 6 dissolved in 0.6 ml of CD 3 OD and 12.3 mg of AuCl(PPh 3 ) dissolved in 0.2 ml CD 2 Cl 2 . The reaction mixture was mixed for 30 minutes and filtered through a PTFE filter (pore size 0.2 μm) to remove precipitated AgCl.
Final reaction mixtures were prepared by mixing of 200 µl of the stock solution A, 100 µl of the stock solution of TsOH (for the composition of the solution see Table S2), 62 µl of PhCCCH 3 , 53 µl of toluene, and 416 µl of CD 3 OD. Reaction mixture was immediately monitored by NMR spectroscopy.

IV) Experiments with [(PPh 3 )Au(SbF 6 )] and iPr-BU*H 2 SO 4
The stock solution A was prepared by mixing of 10.2 mg of AgSbF 6 dissolved in 0.6 ml of CD 3 OD and 12.3 mg of AuCl(PPh 3 ) dissolved in 0.2 ml CD 2 Cl 2 . The reaction mixture was mixed for 30 minutes and filtered through a PTFE filter (pore size 0.2 μm) to remove precipitated AgCl.

S4
Final reaction mixtures were prepared by mixing of 138 µl of the stock solution A, 69 µl of the stock solution of iPr-BU*H 2 SO 4 (for the composition of the solution see Table   S3), 43 µl of PhCCCH 3 , 36 µl of toluene, and 287 µl of CD 3 OD. Reaction mixture was immediately monitored by NMR spectroscopy.

Results of NMR spectroscopy experiments
The NMR experiments were recorded using a Varian NMR System (300 MHz) and the δ scale was referenced to the solvent residual peak at δ = 3.31 ppm. We used toluene as an internal standard. The solutions of a catalyst and reactants were mixed and immediately probed by the NMR instrument.
We have fitted the time-dependence of the intensities of reactant and products using rate equations based on Scheme S1. For reactions catalyzed by (IPr)Au + , we have evaluated all rate constants (k 1 , k 2 , k 11 , k 22 ). The reactions catalyzed by (PPh 3 )Au + are slower, therefore we have evaluated only the rate of concentration decrease of the alkyne.
Based on Scheme S2 following differential equation was suggested: This equation was used as a kinetic model for the fitting of experimental data with mathematic software GNU Octave. Rate constant k NMR was free fit parameter and equation was solved numerically. We used the least squares method for the fitting of experimental data. Obtained rate constants are shown in Table S5.
Figure S1_part 1: Explanation of the measured data. The kinetic data in the figures below show relative concentrations of 1-phenylpropyne (the concentration decreases with time) and concentrations of the products of methanol addition to the C(1) and C(2) carbon atoms of 1-phenylpropyne. We will not color-code the individual channels, because we color-code addition of bambusurils. However, the rate constants for all channels describing the fitted curves are summarized in Table 1.
Figure S1_part 2 (the next page). Relative ratios of 1-phenylpropyne, the products of C1 and C2 additions as a function of the reaction time as monitored by NMR spectroscopy for 1.25 mol% [AuCl(IPr)]/1.5 mol% a,b) AgSbF 6 , c,d) AgPF 6 , e,f) AgClO 4 . The solid lines correspond to fits obtained by the Octave program assuming the Scheme S1; the corresponding rate constants are listed in Table 1.

Preparation of reaction mixtures for mass spectrometry experiments I) Different concentration of 1-phenylpropyne
The stock solution A was prepared by mixing of 4.0 mg of AgSbF 6 or 2.9 mg AgPF 6 or 3.0 mg AgOTf dissolved in 1.4 ml of CH 3 OH and 4.8 mg of AuCl(PPh 3 ) dissolved in 0.2 ml CH 2 Cl 2 . The reaction mixture was mixed for 30 minutes and filtered through a PTFE filter (pore size 0.2 μm) to remove precipitated AgCl.  Table S6) and left to react for a time delay 5 minutes. After a time delay elapsed, 320 µl of solution CD 3 OH was added. Reaction mixture was immediately monitored by ESI-MS.

II) Different concentration of p-toluenesulfonic acid (TsOH)
The stock solution A was prepared by mixing of 4.0 mg of AgSbF 6 dissolved in 1.4 ml of CH 3 OH and 4.8 mg of AuCl(PPh 3 ) dissolved in 0.2 ml CH 2 Cl 2 . The reaction mixture was mixed for 30 minutes and filtered through a PTFE filter (pore size 0.2 μm) to remove precipitated AgCl.
Stock solution B was prepared by mixing of 120 µl of phenylpropyne and 2 ml of CH 3 OH.
Stock solution of p-toluenesulfonic acid (TsOH) was prepared by dissolving of 3.8 mg of TsOH in 1.6 ml CH 3 OH.  Table S7) and left to react for a time delay 5 minutes. After a time delay elapsed, 320 µl of solution CD 3 OH was added. Reaction mixture was immediately monitored by ESI-MS.

III) Different concentration of iPr-BU*H 2 SO 4
The stock solution A was prepared by mixing of 4.0 mg of AgSbF 6 or 2.9 mg AgPF 6 or 3.0 mg AgOTf dissolved in 1.4 ml of CH 3 OH and 4.8 mg of AuCl(PPh 3 ) dissolved in 0.2 ml CH 2 Cl 2 . The reaction mixture was mixed for 30 minutes and filtered through a PTFE filter (pore size 0.2 μm) to remove precipitated AgCl.
Stock solution B was prepared by mixing of 60 µl of phenylpropyne and 1.5 ml of CH 3 OH.
Stock solution of iPr-BU*H 2 SO 4 was prepared by dissolving of 5.2 mg of 1 in 0.3 ml of CH 3 OH.  Table S8) and left to react for a time delay 5 minutes. After a time delay elapsed, 300 µl of solution CD 3 OH was added. Reaction mixture was immediately monitored by ESI-MS.

Delayed reactant labelling method
The method is based on the monitoring of the reaction mixture that contains one of the reactants as a mixture of isotopically labeled and unlabeled molecules in time. In mass spectrum we can see couple of peaks that contain reactant. One of these peaks contains labeled reactant and the other peaks contain unlabeled reactant. The key trick is the time delay (t D ) for the addition of the labeled reactant to the reaction mixture. This allows us to follow the kinetics of all ions that contain this particular reactant. We assume that labeling does not affect effectivity of ion ionization. We evaluate the signals only relative to each other, thus overall intensity is not important.

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The evolution of the intensity of signals that corresponds to the reaction intermediate (Int) and to the labeled intermediate (Int label ) in time reflects reestablishment of the steady-state conditions and can be described by following equation: [ In the real experiment a precise ratio of the labeled and unlabeled intermediates is obtain by fitting experimental data. For the half-life of the intermediates the following equation can be used: The intermediates formation rate (k I ) does not influence a shape of the curves if we assume that the rate constant for the formation of labeled and unlabeled intermediates is the same. Further we assume that labeled and unlabeled intermediates react with the same rate constant. 1,3-Diisopropyl urea (10.00 g, 69.34 mmol) was dissolved in mixture of MeOH (100 mL) and conc. HCl (2.0 mL), and heated to 80 °C. 4,5-Dihydroxyimidazolidin-2-one (10.24 g, 86.68 mmol, 1.25 eq.) was added in two portions over 1 h. The warm reaction mixture was filtered after 6 h of heating to obtain 8.96 g of material containing traces of unsubstituted glycoluril. The impurity was removed by reflux in water (100 ml) and filtration to give product in yield 8.00 g (51 %). 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.39 (s, 2H), 5.27 (d, J = 1.0 Hz, 2H), 3.95 -3.68 (m, 2H), 1.10 (dd, J = 6.9, 5.5 Hz, 12H). 13 Figure S17: 13 C NMR spectrum of iPr-BU*H 2 SO 4 . Figure S19: 13 C NMR spectrum of anion-free iPr-BU. Figure S20: 1 H NMR spectra of iPrBU*H 2 SO 4 in the presence of 0.5 equivalent (unless stated otherwise) of CF 3 SO 3 ˉ, SbF 6 ˉ, PF 6 ˉ, BF 4 ˉ, and ClO 4 ˉ, compared to the spectra of iPrBU complexes with corresponding anions. All spectra measured in CD 3 OD at 30°C. TBA = tetrabutylammonium, BMIM = 1-butyl-3-methylimidazolium. Figure S21: 1 H NMR spectra of iPrBU*H 2 SO 4 in the presence of 0.5 equivalent (unless stated otherwise) of CF 3 SO 3 ˉ, SbF 6 ˉ, PF 6 ˉ, BF 4 ˉ, and ClO 4 ˉ. All spectra measured in CD 3 OD at 30°C. TBA = tetrabutylammonium, BMIM = 1-butyl-3-methylimidazolium.