Formation of Breslow Intermediates from N‐Heterocyclic Carbenes and Aldehydes Involves Autocatalysis by the Breslow Intermediate, and a Hemiacetal

Abstract Under aprotic conditions, the stoichiometric reaction of N‐heterocyclic carbenes (NHCs) such as imidazolidin‐2‐ylidenes with aldehydes affords Breslow Intermediates (BIs), involving a formal 1,2‐C‐to‐O proton shift. We herein report kinetic studies (NMR), complemented by DFT calculations, on the mechanism of this kinetically disfavored H‐translocation. Variable time normalization analysis (VTNA) revealed that the kinetic orders of the reactants vary for different NHC‐to‐aldehyde ratios, indicating different and ratio‐dependent mechanistic regimes. We propose that for high NHC‐to‐aldehyde ratios, the H‐shift takes place in the primary, zwitterionic NHC‐aldehyde adduct. With excess aldehyde, the zwitterion is in equilibrium with a hemiacetal, in which the H‐shift occurs. In both regimes, the critical H‐shift is auto‐catalyzed by the BI. Kinetic isotope effects observed for R‐CDO are in line with our proposal. Furthermore, we detected an H‐bonded complex of the BI with excess NHC (NMR).


S1. General Experimental and Analytical Procedures
Tetrahydrofuran-d8 was passed through neutral aluminum oxide (Brockmann activity 1) and degassed by several freeze-pump-thaw cycles prior to use. The solvent tetrahydrofuran-d8 was stored over 4 Å molecular sieves in a glovebox over several weeks before usage. All samples for NMR experiments were prepared in a glovebox (UNILAB GLOVEBOX, 1200/780)W from M.Braun Inertgassysteme GmbH. For this glovebox, Argon BIP ® from AIR Products was used and the O2 and H2O levels were <1 ppm. The following NMR spectrometers were used: Bruker Avance II 600: 1 H (600.20 MHz), 13 C (150.92 MHz); Bruker DRX 500: 1 H (500.13 MHz), 13 C (125.76 MHz); Bruker Avance 400: 1 H (400.13 MHz), 13 C (100.61 MHz). Chemical shifts (δ) are given in parts per million (ppm) relative to tetramethylsilane (TMS) or solvent residual signals. [1] The following abbreviations are used for chemical shift multiplicities in 1  Based on a procedure by Louie [2] the azolium salt S1 was suspended in 100 mL anhydrous and degassed THF, and treated with KHMDS. The suspension was stirred for 2 h at r.t.. n-Pentane (50 mL) was added, and the mixture was filtered over cellite and washed several times with degassed and distilled n-pentane and THF. The filtrate was then treated with CO2 (balloon with cannula) for 2 h and a colorless precipitate was formed. The precipitate was filtered off and washed with little anhydrous and degassed THF and n-pentane. After removal of the solvent, the product was obtained as a colorless solid in 52 % (5.31 g, 12.2 mmol) yield over two steps.  3 JH-H = 6.9 Hz, 12H, H-8'/9' or 11'/12'), 1.28 (d, 3 JH-H = 6.9 Hz, 12H, H-8'/9' or 11'/12'), 13

S2 1a
The CO2 adduct of SIPr (SIPr•CO2, S2) was thermally decomposed according to the procedures by Delaude et al. [3] and Louie et al. [2] In a glovebox, a sublimation apparatus was charged with SIPr•CO2 S2 (2.32 g, 5.34 mmol) and sealed with PTFE tape. Under reduced pressure (0.2 mbar) the SIPr•CO2 was kept for 1 h at 130 °C to regenerate SIPr (1a). The temperature was then raised to 145°C to sublime the free SIPr (1a) formed. After sublimation, the SIPr (1a) product was obtained as a colorless solid in 82 % yield (1.71 g, 4.39 mmol) and was stored in a glovebox. The 1 H NMR spectra of SIPr (1a) thus prepared were identical to literature data. [2] 1a: C27H38N2, M = 390.60 g mol −1   Figure S1. 1  For a typical series of kinetic measurements, stock solutions of sublimed SIPr (1a), freshly distilled anisaldehyde (2b) and anisaldehyd-d1 (2b-d1) in THF-d8 were prepared in a glovebox. In a glovebox, the SIPr stock solution and additional THF-d8 were transferred into the NMR tube, which was then sealed with a septum and PTFE tape. The NMR tube was taken from the glovebox, thermostated to 298 K in the NMR spectrometer, and the first 1H NMR was recorded. For starting the reaction, the aldehyde stock solution was added by means of a syringe. The NMR tube was briefly shaken vigorously and reinserted into the spectrometer. 1 H NMR spectra were acquired using DS = 0, NS = 6, D1 = 20 s (400 MHz); DS = 0, NS = 6, D1 = 21 s (600 MHz). The use of these parameters was necessary to account for the long relaxation time of the aldehydic proton. The spectra obtained were processed using TopSpin 4.0.6 with multiintegration. The following 1 H NMR resonances were used for integration: 1a, 3.23 (sep., 4H); 2b, 7.76 (d, 2H); BI1a,2b, 6.37 (d, 2H). The ratios of the integrated signals were normalized by the number of protons measured and converted to concentrations over the course of the reaction. According to a procedure by Burès et al., calculations for VTNA analysis followed. [5] In the last step, the data were plotted in OriginPro 2016 and when necessary, a linear regression was fitted to the data.

S3.2.1. Time course of the Breslow Intermediate BI1a,2b Formation
In a glovebox SIPr (1a) was dissolved in 500 µL THF-d8 in a NMR tube. The aldehyde 2b was added via a Hamilton syringe and the course of the reaction was monitored by 1 H NMR.

S3.3.2. Attempt to Determine the Reaction Order in SIPr (1a)
In a glovebox, a NMR tube was charged with SIPr (1a), and the latter was dissolved in 500 µL THF-d8. Anisaldehyde (2b) was added to the NMR tube with a syringe, and the course of the reaction was monitored by 1 H NMR. The kinetic experiment was performed as described in the general procedure for kinetic measurements.

S3.3.3. Proton Inventory
The proton inventory study was carried out at 7-fold excess of SIPr (1a) relative to aldehyde (2b, 2b-d1), as described in the literature. [6] In a glovebox, stock solutions of SIPr (1a) (410.1 mg, 1.0 mmol in 5 mL THF-d8), anisaldehyde-d1 2b-d1 (14.6 µL, 0.12 mmol in 1 mL THF-d8) and anisaldehyde 2b (14.6 µL, 0.12 mmol in 1 mL THF-d8) were prepared. For the proton inventory, two sets of measurements (11 kinetic runs each) with different molar fractions n of anisaldehyde-d1 were monitored for 2 h by 1 H NMR. The molar fraction n of anisaldehyde-d1 was increased in a stepwise manner. The kinetic experiments were performed as described in the general procedure for kinetic measurements. The concentration of SIPr was 0.14 mol•L -1 (400 µL stock solution + 100 µL THF-d8) and for the aldehyde mixtures 0.02 mol•L -1 in every tube. The rate constant k was determined via the integrated rate equation from the slope by plotting

S11
A linear correlation with the fractional factor Φ indicates the transfer of one proton, and a quadratic one the transfer of two protons in the rate-limiting step: Equation for transfer of one proton: Equation for the transfer of two protons: For the proton inventory the inverse kinetic isotope effect kn/kH was calculated for every measurement and plotted against the molar fraction n (anisaldehyde-d1).    Figure S10. Proton Inventory, kn/kH plotted vs. molar fraction n (2b-d1), black full squares represent averaged values of the rate constants determined in the two individual sets of measurements (sets 1 and 2 above), together with the error margins. A linear regression (for the transfer of one proton) and a quadratic regression (transfer of two protons) were calculated. The inverse kinetic isotope effect kD/kH (fractionation factor Φ) was determined by using the data of the pure aldehydes, so the last and the first measurement of the proton inventory.

S3.4. Variable Time Normalization Analysis
For this method, the starting concentration of one reactant is constant. To determine the order in the other reactant, the concentration of this reactant is varied. By manipulation of the time scale and testing of different reaction orders, it is possible to achieve overlapping of the measurements. When the measurements overlap well, the right orders in the reactants are found.

Comparison of "Different Excess" Experiments
Here, ALW216, 217 and ALW215, 218 have the same initial concentration in 2b and are different excess experiments in 1a. They need to be compared to determine the order in 1a.The best overlap of the data was found for an order of 0.9 in 1a.  Here, ALW215, 217 and ALW216, 218 have the same initial concentration in 1a and are different excess experiments in 2b. They need to be compared to determine the order in 2b. The best overlap was found for an order of 1.2 in 2b.

Comparison of "Same Excess" Experiments
Here, ALW217, 218 and ALW219, 220 are same excess experiments with a difference in concentration of 0.02 mol L -1 in 1a and 2b. These reaction profiles need to be compared to analyze for product acceleration or inhibition. The reactions became faster in the presence of BI1a,2b/2b-d1, indicating product acceleration.

Determination of KIE by a KIE Normalization Factor fKIE
Introduction of a KIE normalization factor fKIE = 1.8 gave best overlap and best linearity for all measurements.

Comparison of "Same Excess" Experiments
Here, ALW221, 223 and ALW222, 224 are same excess experiments with a difference in concentration of 0.02 mol L -1 in 1a and 2b. These reaction profiles need to be compared to analyze for product acceleration or inhibition. The reactions became faster in the presence of BI1a,2b/2b-d1, indicating product acceleration.

S3.4.3. "Same Excess" Experiments with Reaction Product BI1a,2b added at t0
In a glovebox, stock solutions of SIPr (1a) (93.7 mg SIPr; 0.24 mmol in 1 mL THF-d8) and anisaldehyde (2b) (146 µL, 1.2 mmol in 1 mL THF-d8) were prepared. For sample ALW240, first 20 µL of the anisaldehyde stock solution were added to the SIPr solution and left for 6 h until the aldehyde was consumed completely. Then, additional 70 µL of the aldehyde stock solution were added, and the reaction was monitored by 1 H NMR spectroscopy. Here, ALW238, 223 and ALW239 are same excess experiments with a difference in concentration of 0.04 mol L -1 in 1a and 2b. An additional experiment with reaction product at t0 (0.04 mol L -1 ) was performed for additional probing of autocatalysis by BI1a,2b. After time shift the course of the reaction of ALW238 and 239 should give an overlay if the product has no effect on the reaction r ate. The reaction rate increases in the presents of BI1a,2b and an overlay of the reaction courses of ALW239 and 240 indicate product acceleration.