The Elusive Ternary Intermediates of Chiral Phosphoric Acids in Ion Pair Catalysis─Structures, Conformations, and Aggregation

Abstract

In ion-pair catalysis, the last intermediate structures prior to the stereoselective transition states are of special importance for predictive models due to the high isomerization barrier between E- and Z-substrate double bonds connecting ground and transition state energies. However, in prior experimental investigations of chiral phosphoric acids (CPA) solely the early intermediates could be investigated while the key intermediate remained elusive. In this study, the first experimental structural and conformational insights into ternary complexes with CPAs are presented using a special combination of low temperature and relaxation optimized ¹⁵N HSQC-NOESY NMR spectroscopy to enhance sensitivity. Combined NMR investigations and theoretical calculations revealed three conformers of the ternary complex, of which one also closely resembles the previously calculated transition states. In addition, a 2:1:1 ternary complex as well as an unprecedent [3:3] dimeric species consisting of two ternary complexes was revealed. Given the importance of the ground state energies for the transition state interpretation in ion pair catalysis we believe that the presented experimental insight into the structural and conformational variety of the ternary complexes is a key to the future development of predictive models in ion pair catalysis.

Figure 1

(A) Proposed catalytic cycle for the CPA-catalyzed transfer hydrogenation of imines. Prior studies elucidated structural details of the binary complexes but the ternary complex remained elusive for nearly a decade. (B) In this work, we accessed the ternary complex by using a HE derivate which is soluble even at 180 K needed for NMR investigations. The gathered measurements were used for a structural and conformational analysis in collaboration with computational methods.

Figure 2

Model compounds used in the screening for ternary complexes comprised of (R)-CPAs 1, imines 2 and HE 3. Twenty-five combination of imines 2a–g with CPAs 1a–f and 3b were screened.

Figure 3

(A) Structure of the ternary complex of 1a/2a/3b with the proton chemical shifts of the hydrogen bond signals. (B) ¹H NMR spectrum comparison of the binary (red, 1:1:0 stoichiometry, 40 mM, CD₂Cl₂, 180 K) and the ternary complex (blue, 1:1:1 stoichiometry, 40 mM, CD₂Cl₂, 180 K) of the system 1a/2a/3b. Upon addition of 3b, a highfield shift of both CPA/imine hydrogen bond signals is observed. (C) ¹H NMR spectrum of the 1a/2a/3b system in a 2:1:1 stoichiometry (40:20:20 mM, CD2Cl2, 180 K). This sample demonstrated that also for the dimeric 2:1 species (purple) it is possible to form a complex with 3b. The respective hydrogen bonds are underlined for each species. *3b hydrogen bond signals cannot be unambiguously assigned due to an overlap with other signals (marked in green).

Figure 4

(A) ¹H NMR spectrum of the OMe-CPA 1b/2a/3b system (1:1:1 stoichiometry, 40 mM, CD₂Cl₂, 180 K). The hydrogen bonds between CPA 1/imine 2 (orange) and CPA 1/3b (green) can be assigned to the ternary complex. The [CPA]_n aggregate is highlighted in pink. Additionally, two new hydrogen bond signals are observed ([E-2a/1a/3b]₂ in blue; [E-2a/1b/3b]₂ in purple; the respective hydrogen bond is underlined), which can be identified as a [3:3] dimeric species consisting of two ternary complexes. (B) One part of the ¹H–¹H NOESY/EXSY of this system is displayed showing the exchange between the [3:3] dimer and the 1b/E-2a hydrogen bond signal which reveals the [3:3] dimer as an E-imine species. (C) Schematic display of the [3:3] dimer (left) and calculated structure of the [3:3] dimer (right; see SI chapters 4.1 and 7.5).

Figure 5

(A) ¹⁵N-HSQC-NOESY spectrum of 1a/2a/3b (1:1:1 stoichiometry, 40 mM, CD₂Cl₂, 180 K). Separated rows for the CPA/E-imine (orange), CPA/Z-imine (red) and CPA/HE (green) hydrogen bonds can be observed. (B) Single rows can be displayed as 1D spectra for more detailed information to reveal the structural environment of each hydrogen bond, here exemplary displayed for the CPA/E-imine hydrogen bond (δ (¹⁵N) = 195 ppm).

Figure 6

Conformational analysis of the ternary complex. Three conformers were computed and validated by NMR spectroscopy. All three conformers coexist, with energetic stability (ΔG values) decreasing in the following order: C1 > C3 > C2. C1 and C2 are reactive in this state, while for C3 rearrangements are necessary to lead to a hydrogenation of the imine. The conformers are validated by distinct NOE cross signals of the 3b. For the sake of clarity out of a large NOE network only the NOEs characteristic for the individual conformation are depicted.