Brønsted acid catalysis - the effect of 3,3'-substituents on the structural space and the stabilization of imine/phosphoric acid complexes

Abstract

BINOL derived chiral phosphoric acids (CPAs) are widely known for their high selectivity. Numerous 3,3'-substituents are used for a variety of stereoselective reactions and theoretical models of their effects are provided. However, experimental data about the structural space of CPA complexes in solution is extremely rare and so far restricted to NMR investigations of binary TRIP/imine complexes featuring two E- and two Z-imine conformations. Therefore, in this paper the structural space of 16 CPA/imine binary complexes is screened and 8 of them are investigated in detail by NMR. For the first time dimers of CPA/imine complexes in solution were experimentally identified, which show an imine position similar to the transition state in transfer hydrogenations. Furthermore, our experimental and computational data revealed an astonishing invariance of the four core structures regardless of the different steric and electronic properties of the 3,3'-substituent. However, a significant variation of E/Z-ratios is observed, demonstrating a strong influence of the 3,3'-substituents on the stabilization of the imine in the complexes. These experimental E/Z-ratios cannot be reproduced by calculations commonly applied for mechanistic studies, despite extensive conformational scans and treatment of the electronic structure at a high level of theory with various implicit solvent corrections. Thus, these first detailed experimental data about the structural space and influence of the 3,3'-substituent on the energetics of CPA/imine complexes can serve as basis to validate and improve theoretical predictive models.

Fig. 1. (a) Catalytic cycle of the transfer hydrogenation of imines with a chiral phosphoric acid catalyst and a Hantzsch ester as reducing agent. The binary complexed highlighted in grey is the focus of this work; (b) Brønsted acid catalysts with different 3,3′-groups.

Fig. 2. (a) Structure similarity of a crystal structure of a TiPSY/imine complex (green) and structure Type II E of a TRIP/imine complex identified in our previous work (black). (b) Structure deviation of the crystal structure of a TeBuP/imine complex (green) vs. both Type I E (black above) and Type II E (black below) of a TRIP/imine complex. The imine shows an intermediate position of Type I E and Type II E. (c) The four core structures of the binary complex identified in our previous work. The red arrows mark some of the identified NOE interactions.

Fig. 3. Chiral phosphoric acids and imines with different functional groups that were used for the NMR-spectroscopic investigations of CPA/imine complexes (PMP = p-methoxyphenyl). All screened CPA/imine combinations are shown in the table. A bold X marks complexes, which could be investigated in detail. For all systems, a 1 : 1 ratio of CPA and imine was used.

Fig. 4. Spectral resolution of the ¹H spectra of complexes between catalysts TRIP, TiPSY and TRIFP and imine 2 at 180 K in CD₂Cl₂; in all cases well separated signals of the hydrogen bonds indicate the E/Z populations, while deviations in linewidths and chemical shift overlap of key signals allow the structural investigations via NOE analysis only for complexes with TIPSY.

Fig. 5. ¹H spectra of the H-bond region of catalysts TRIM, 9-Phen and 1-Naph at 180 K in CD₂Cl₂ reveal the extended structural space of these catalysts including dimeric complexes and additional conformations due to asymmetric 3,3′-substituents in 9-Phen and 1-Naph.

Fig. 6. Section of a ¹H, ¹⁹F 2D HOESY spectrum of TiPSY/4 at 180 K in CD₂Cl₂ at 600 MHz; Red dashed lines correspond to the intermolecular HOEs identifying complex structure Type I E (for detailed NMR parameters see ESI S19†).

Fig. 7. Complex exchange processes in TiPSY/imine complexes; an exchange via tilting of the imine is observed between structures Type I E and Type II E as well as a disassociation and association process of the TiPSY/E-imine complexes; the exchange via tilting is fast on the NMR time-scale and leads to a different interaction pattern for each half of the catalyst; the dissociation and association process is slow on the NMR time-scale and leads to exchange peaks between the catalyst halves; in addition to an exchange via tilting of the imine, the reduced steric hindrance of the Z-imine enables an additional fast exchange between structures Type I Z and Type II Z via rotation, leading to a different signal pattern.

Fig. 8. Excerpt of the 2D NOESY spectrum of TiPSY/3 at 180 K in CD₂Cl₂ at 600 MHz; intermolecular cross-peaks (red numbers) detail the interaction between α-methyl group of 3 (blue spin 4) and BINOL backbone of the catalyst (for detailed parameters see ESI S25†).

Fig. 9. (a) Theoretically calculated dimer structure model on the example of the [TRIM/5E]₂ complex reveals the steric proximity of the protons A–C to phenyl entities which causes paratropic shielding effects and induces severe highfield shifts. (b) Excerpt of the ¹H spectrum of TRIM/7 at 180 K in CD₂Cl₂ at 600 MHz highlighting the highfield shift of proton A (red) and B (blue) of the dimer compared to the monomer. The significant highfield shifts of A–C compared to the monomeric structure (A: 1.10 ppm, B: 0.89 ppm, C: 1.56 ppm) experimentally corroborate the computed structure and indicate CH–π and π–π interactions.

Fig. 10. Theoretical calculations of the TiPSY, TRIP, TRIFP, TRIM/5 complex show the invariance of four core structures. Despite that, the E/Z ratios and the tendency towards dimerization vary strongly within the CPA/imine complexes. Moreover, quantum chemical calculations of E/Z-ratio showed a significant offset to the experimental values. Colour code: TiPSY red, TRIP blue, TRIFP orange, TRIM green.

Fig. 11. Reported crystal structure of a TeBuP/imine dimer (a) and calculated structure of a TRIM/imine dimer (b). The structures are similar despite comparing an aldimine (a) to a ketamine structure (b). (c) Comparison of the dimeric structure of a TRIM complex (black imine) with the calculated transition state consisting of a CPA (the 3,3′-substituents of the catalysts have been omitted to improve the visibility), an imine (purple) and a Hantzsch ester (purple, transparent). The steric influence of the second imine in the dimeric structure (b) is similar to the additional bulk of the Hantzsch ester in the transition state.