Structure and properties of hydrogen-active intermediates of aminoanionic metals in catalytic hydrogenation reactions

On September 12, 2022, Liu Qiang’s research group at Tsinghua University and Lan Yu’s research group at Zhengzhou University jointly published a research report entitled “Structure, reactivity and catalytic properties of manganese-hydride amidate complexes” at Nature Chemistry.

The study was the first to separate the amino anion metal hydrogen active intermediate (“M’N-MH”) in the catalytic hydrogenation reaction, and conducted an in-depth study of its reaction properties and catalytic performance, and found that this type of active intermediate has a higher catalytic efficiency than the classic amino metal hydrogen intermediate (“HN-MH”) in the metal ligand synergistic participation catalytic system. The corresponding authors of the paper are Liu Qiang and Lan Yu; The first authors are Wang Yujie and Liu Shihan.

Catalytic hydrogenation plays an important role in organic synthesis and chemical production, and is a key step in the synthesis of many basic organic chemicals, fine chemical products, and drug molecules. Conventional carbonyl hydrogenation reactions usually occur through the inner-sphere reaction mechanism (Figure 1b), and the reaction efficiency is not high due to the coordination of oxygen atoms with metal centers; In addition, the competitive coordination of carbonyl groups and olefin substrates makes C=O/C=C hydrogenation selectivity difficult to control. Since Nobel Laureate Professor Noyori reported in 1995 that the ruthenium bisphosphine diamine catalytic system with N-H structure and metal ligand synergistic participation effect, the catalytic efficiency and selectivity of the hydrogenation reaction of polar unsaturated substrates have been significantly improved. One of the most representative examples include the chiral spiroiridium catalyst containing N-H structure developed by Academician Zhou Qilin, a Chinese scientist, which has reached a catalyst conversion of 4.55 million (TON) in the asymmetric hydrogenation reaction of acetophenone, which is the highest record of homogeneous asymmetric catalytic reaction so far. The key active intermediates of such metal ligands in the synergistic participation of catalytic systems are amino metal hydrogen species (“HN-MH”), the N-H group activates the substrate by hydrogen bonding during the reaction process, and the negative hydrogen transfer process can be effectively promoted by the outer layer (outer-sphere) reaction mechanism (Figure 1c, X=H).

Figure 1: Catalytic hydrogenation and its reaction mechanism

Subsequent mechanism studies speculate that in the above-described catalytic hydrogenation reaction, the presence of excess alkali M’OR (M’ stands for alkali metal) may promote the deprotonation of N-H groups to form N-M’ structure, and the resulting aminoanionic metal hydrogen complex (“M’N-MH”) is the key catalytically active intermediate of this type of reaction (Figure 1c, X=M’). However, the current research on the formation and reaction properties of aminoanionic metal hydrogen intermediates is limited to theoretical calculations, which is due to the extreme difficulty of separating and characterizing aminoanionic metal hydrogen intermediates with catalytic hydrogenation activity, thus restricting the collaborative participation of novel and efficient metal ligands in the design and development of catalytic systems. Liu Qiang and Lan Yu’s research team envision the selection of 3D abundant metal manganese with a small atomic radius as the central metal, which can narrow the distance between negative hydrogen and alkali metal ions, and is expected to stabilize the amino anion metal hydrogen intermediate by using the auxiliary coordination effect of alkali metal ions with high negative hydrogen affinity (Figure 1d). Based on the above design ideas, they successfully isolated and obtained an aminoanionized manganese hydrogen intermediate (“LiN-MnH”) based on the clamp ligand skeleton, and conducted a comprehensive structural characterization as well as the reaction properties and catalytic properties.

Separation of amino anionic metal hydrogen active intermediates

Potassium tert-butanol is a commonly used base in catalytic hydrogenation reactions, and the authors first studied the equivalent reaction of the “HN-MnH” complex with potassium tert-butanol. The results of the study found that potassium tert-butanol can promote rapid isomerization of “HN-MnH” intermediates, and the corresponding “KN-MnH” active intermediates are not monitored by in situ NMR (Figures 2a, b). Further studies found that the more alkaline alkyl lithium reagent LiCH2SiMe3 was selected to react with the “HN-MnH” complex, and a new set of negative hydrogen signals and phosphine signals could be observed on the NMR (Figure 2b), but the resulting metal negative hydrogen species were unstable during solvent removal and partial decomposition occurred. To solve this problem, the authors performed this reaction in a hydrogen atmosphere, successfully isolated the active intermediate of the aminoanionic metal hydrogen “LiN-MnH” and obtained its single crystal structure (Figures 2c, d). The distance between Li and H in the crystal structure is only 1.81Å, and the bond angle of N-Li-H is 82.5° (Figure 2e), indicating that there is a bonding effect between Li and H, which plays an important role in stabilizing the aminoanionic metal hydrogen activity intermediate.

Figure 2: Synthesis, separation, and characterization of aminoanionic metal hydrogen active intermediates

Reactivity study of aminoanionic metal hydrogen active intermediates

The authors selected diarylone as the template substrate and conducted a reaction kinetic study by ultraviolet-visible spectroscopy, comparing the differences in reactivity between “LiN-MnH” and the corresponding “HN-MnH” complex. The results showed that the negative hydrogen transfer rate (0.22 M-1s-1) between diarylone and the “LiN-MnH” intermediate in the equivalent reaction was 24 times that of the reaction rate with the “HN-MnH” complex (0.0093 M-1s-1) (Figure 3), and the “LiN-MnH” and the corresponding “HN-MnH” complex and substrate could be calculated by the Eyring equation1aThe difference in activation energy of the reaction was 1.84 kcal/mol.

Figure 3: Reaction kinetics

In order to further understand the intrinsic causes of the difference in reactivity of the “LiN-MnH” and “HN-MnH” complexes, the authors studied the reaction potential energy surface of the above equivalent reaction process by DFT calculation. For the “HN-MnH” complex, the carbonyl substrate is coordinated with the N-H group to absorb heat by 2.3 kcal/mol, followed by a stepwise negative hydrogen and proton transfer with a total activation energy of 20.2 kcal/mol. In contrast, the coordination of the N-Li group of the carbonyl substrate with the “LiN-MnH” complex is a significant exothermic process (exothermic 6.1 kcal/mol) with a total reaction energy barrier of 18.6 kcal/mol (Figure 4). The theoretically calculated difference in reaction activation energy (1.6 kcal/mol) is well matched with the results measured by kinetic experiments (1.84 kcal/mol).

Figure 4: DFT study

By the analysis of the electron density Laplace function, it was found that the electrophilic index of li ions in the “LiN-MnH” complex was 0.659eV, which was significantly higher than the electrophilic index of protons in the “HN-MnH” complex of 0.034eV (Figure 4c). The above results show that the high reactivity of the “LiN-MnH” complex is due to the fact that the ability of Li ions in the N-Li structure as the Lewis acid electrophilic activation substrate is significantly better than that of the protons in the N-H structure, thereby effectively reducing the activation energy of the negative hydrogen transfer reaction.

Study on the catalytic properties of hydrogen active intermediates in aminoanionic metals

Although “LiN-MnH” has a higher reactivity in the equivalent reaction with carbonyl substrates than “HN-MnH” complexes, the two exhibit almost the same catalytic efficiency in the catalytic hydrogenation of ketone substrates (Fig. 5a), which is due to the fact that “LiN-MnH” complexes and ketone substrates are prone to hydrogen transfer reactions to generate amino metal intermediates and alkoxylium. Due to the lack of alkalinity of the latter, the regeneration of the active intermediate “LiN-MnH” cannot be completed, resulting in a reaction process with “HN-MnH” as the actual catalytic activity of the active species (Figure 5b). Therefore, maintaining the stability of the “LiN-MnH” active intermediate in the reaction is the key to achieving an efficient catalytic process. The authors envision N-alkylaldehydeimide as a suitable reaction substrate, because its hydrogenation product dialkylamine and “LiN-MnH” can construct an acid-base equilibrium reaction process, which can ensure that a certain amount of “LiN-MnH” active species are always present in the catalytic system, so that the advantage of “LiN-MnH” with higher negative hydrogen transfer reaction activity can be exerted in the catalytic reaction (Figure 5c, d).

Figure 5: Catalytic performance study

The “LiN-MnH” complex as an active catalyst does exhibit significantly better catalytic activity than the “HN-MnH” complex in the hydrogenation of various N-alkylaldehyde imides (Figure 6b). However, the catalytic activity of the complex in the hydrogenation reaction of N-alkyl ketoneimide remains undesirable (Figure 6e). Through further structural optimization, the authors found that the “AlN-MnH” complex (Figures 6c, d) can be easily prepared by reacting with alkyl aluminum hydrogen by an amino metal complex, and the amino anion manganese hydrogen active intermediate prepared by using The more acidic trivalent Al ion as a bridge metal showed better catalytic performance (Figures 6b, e).

Figure 6: Suitability of “AlN-MnH” synthetic and catalytic hydrogenation substrates

The above research results provide solid experimental evidence for the mechanism of bimetallic synergistic activation of negative hydrogen transfer reaction, and verify that this new reaction mode has higher reaction efficiency than the classical hydrogen bond collaborative negative hydrogen transfer mode, which has important reference significance for the rational design and evolution of metal ligand collaborative participation in catalytic system.

The experimental part of the above research work was completed by the team of Liu Qiang of Tsinghua University, and the theoretical calculation part was completed by the Lan Yu team of Zhengzhou University. (Source: Science Network)

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