Internal acidity scale and reactivity evaluation of chiral phosphoric acids with different 3,3'-substituents in Brønsted acid catalysis

Abstract

The concept of hydrogen bonding for enhancing substrate binding and controlling selectivity and reactivity is central in catalysis. However, the properties of these key hydrogen bonds and their catalyst-dependent variations are extremely difficult to determine directly by experiments. Here, for the first time the hydrogen bond properties of a whole series of BINOL-derived chiral phosphoric acid (CPA) catalysts in their substrate complexes with various imines were investigated to derive the influence of different 3,3'-substituents on the acidity and reactivity. NMR ¹H and ¹⁵N chemical shifts and ¹ J _NH coupling constants of these hydrogen bonds were used to establish an internal acidity scale corroborated by calculations. Deviations from calculated external acidities reveal the importance of intermolecular interactions for this key feature of CPAs. For CPAs with similarly sized binding pockets, a correlation of reactivity and hydrogen bond strengths of the catalyst was found. A catalyst with a very small binding pocket showed significantly reduced reactivities. Therefore, NMR isomerization kinetics, population and chemical shift analyses of binary and ternary complexes as well as reaction kinetics were performed to address the steps of the transfer hydrogenation influencing the overall reaction rate. The results of CPAs with different 3,3'-substituents show a delicate balance between the isomerization and the ternary complex formation to be rate-determining. For CPAs with an identical acidic motif and similar sterics, reactivity and internal acidity correlated inversely. In cases where higher sterical demand within the binary complex hinders the binding of the second substrate, the correlation between acidity and reactivity breaks down.

Fig. 1. (a) Proposed catalytic cycle for the asymmetric transfer hydrogenation with CPAs; (b) the influence of different 3,3′-substituents of the catalyst on the hydrogen bond of the ion pair (highlighted in grey) was investigated. In addition, the effect of the varying internal acidities of the binary complexes on the overall reaction rate of the shown transfer hydrogenation was the focus of this work.

Fig. 2. Structures of the investigated (a) phosphoric acids with different 3,3′-substituents and (b) imines. The hydrogen bonds of the binary complexes of TRIP 1a, TRIFP 1b, TiPSY 1c and TRIM 1d with the imines 3, 4 and 5 were investigated in detail by means of NMR. The other imines 2 and 6–13 are necessary to cover the complete hydrogen bond range of the Steiner–Limbach curve. The non-isomerizable imine 14 was used to investigate the influence of the Hantzsch ester concentration on the reaction rate. (c) The main focus of this work was the NMR-spectroscopic investigation of the binary CPA/imine-complexes. The imine exists either as E- or Z isomer.

Fig. 3. (a) In the Steiner–Limbach curve the δ_(OHN) is plotted versus δ_(OHN) of the hydrogen bonded complexes. All CPA/imine complexes are located on the left side of the curve (highlighted in grey) and form hydrogen-bond assisted ion pairs. The data for the complexes with TRIP, HBF₄, phenols and carboxylic acids were taken from ref. 42 All ¹⁵N chemical shifts are referenced to {δ(OHN)_ref = δ(OHN)_exp – 340 ppm} (for details and exact values see ESI Chapter 3); (b) the experimental δ(OHN) of the imines 3, 4 and 5 in the binary complexes with the CPAs 1a–1d are shown.

Fig. 4. The experimental CPA/imine ¹J_HN coupling constants are shown for E- and Z-imines of 3, 4 and 5. The following trend is observed for the E-imines: ¹J_HN TRIP < ¹J_HN TIPSY < ¹J_HN TRIM < ¹J_HN TRIFP. For Z-complexes slightly different trend was found: ¹J_HN TIPSY < ¹J_HN TRIP < ¹J_HN TRIM < ¹J_HN TRIFP. Due to overlap the ¹J_HN of TRIP/4Z was determined from HN-HMBC spectra (marked by an asterisk; for all values see ESI Chapter 3.3).

Fig. 5. (a) The reaction profiles for the symmetric transfer hydrogenation of imine 3 were done in situ in the NMR spectrometer with 1.4 equivalents of Hantzsch ester and 1 mol% catalyst (TRIP, TRIFP, TiPSY and TRIM) at 40 °C in CD₂Cl₂. (b) The slope of the linear ranges allows to access the rate constants.

Fig. 6. The catalytic cycle of the investigated transfer hydrogenation of imines is shown. Therefore, all possible rate determining steps are shown. The steps which could be neglected as rate-determining steps by experiments or calculations are shown in green, while the potential bottlenecks are shown in red. Finally, we assume a delicate equilibrium between the E- to Z-isomerization and the ternary complex formation to be the rate-determining step.

Fig. 7. (a) The comparison of the calculated structures of the binary (blue) and ternary (green) complex with TRIP and imine 3 shows that for the Hantzsch ester (HE) binding almost no reorganization is required. (b) The binary complex of TiPSY and imine 3 (red) revealed a sterical shield for the Hantzsch ester. Thus, before the ternary complex formation, a large reorganization is assumed.