Asymmetric hydrogenation mechanisms

This is the classical asymmetric hydrogenation mechanism, taught in every course on enantioselective homogeneous catalysis. By the end of 1990s, each step of this mechanism had been studied in detail, including the preparation and characterisation of all the intermediates, with the exception of dihydride complexes 14, whose detection remained elusive. ... 

In summary, the subtle details that govern the asymmetric hydrogenation mechanism of olefins catalyzed by cationic rhodium-diphosphine complexes depend on the specific combination of the ligand and the substrate (228). Further studies are needed to achieve a deeper understanding of the relationship between the nature of the intermediates and the transition states that determine the stereoselectivity (229). 

Halpern J 1982 Mechanism and stereoselectivity of asymmetric hydrogenation Soienoe 217 401-7... 

Chapter 9, on entropy and molecular rotation in crystals and liquids, is concerned mostly with statistical mechanics rather than quantum mechanics, but the two appear together in SP 74. Chapter 9 contains one of Pauling s most celebrated papers, SP 73, in which he explains the experimentally measured zero-point entropy of ice as due to water-molecule orientation disorder in the tetrahedrally H-bonded ice structure with asymmetric hydrogen bonds (in which the bonding proton is not at the center of the bond). This concept has proven fully valid, and the disorder phenomenon is now known to affect greatly the physical properties of ice via the... 

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

The asymmetric hydrogenation of acyclic imines with the ansa-titanocene catalyst 102 gives the chiral amines in up to 92% ee.684,685 This same system applied to cyclic imines produces the chiral amines with >97% ee values.684,685 The mechanism of these reductions has been studied 686... 

Halpern, J. Asymmetric catalytic hydrogenation Mechanism and origin of en-antioselection. In Morrison, J.D. (Ed.), Asymmetric Synthesis. Academic Press, Orlando, 1985, Vol. 5, p. 41. 

Figure 6-5. Proposed mechanism for weak-base-promoted Rh-catalyzed asymmetric hydrogenation. Reprinted with permission by Wiley-YCH Verlag GmbH, Ref. 4. 

For the mechanism of asymmetric hydrogenation, see Halpem, J. Asymmetric Catalytic Hydrogenation Mechanism and Origin of Enantioselection in Morri-sion, J. D. ed. Asymmetric Synthesis, Academic Press, New York, 1985, vol. 5. 

Figure 2. Mechanism of catalytic asymmetric hydrogenation. Adapted from Ref. [26].

Computation allows one to circumvent nature s reluctance to offer the dihydride to direct detection. The first papers using molecular mechanics to study asymmetric hydrogenation appeared in the late 80 s [53-55], However, molecular mechanics is not the ideal technique for any reaction that involves bond-breaking or bond-forming, such as all catalytic reactions, and only a limited amount of reliable information was obtained from these early studies. An MP2/QC/5IXT) study of (PH3)2Rh(olefin) structures was published in... 

Thus, additional experimental and computational studies will be needed to draw definitive conclusions regarding the mechanism of Ir-catalyzed asymmetric hydrogenation. The Ir(I)-Ir(III) and Ir(III)-Ir(V) cycles seem to be similar in energy, so it may well be that depending on the catalyst, substrate, and the hydrogenation conditions, one or the other pathway will be preferred or both cycles could operate in parallel. 

Chiral monodentate phosphites and phosphoramidites are also effective ligands for Rh-catalyzed asymmetric hydrogenation of enamide substrates. As seen in the structure of MonoPhos illustrated in Figure 1.2, combination of the mod-ihed BINOF backbone and the amine part gives a structural variety to this type of ligand. Combinatorial methods are effective for optimization of the chiral structures.Elucidation of the hydrogenation mechanism catalyzed by the MonoPhos-Rh complex is in progress." ... 

The dynamic behavior of the model intermediate rhodium-phosphine 99, for the asymmetric hydrogenation of dimethyl itaconate by cationic rhodium complexes, has been studied by variable temperature NMR LSA [167]. The line shape analysis provides rates of exchange and activation parameters in favor of an intermo-lecular process, in agreement with the mechanism already described for bis(pho-sphinite) chelates by Brown and coworkers [168], These authors describe a dynamic behavior where two diastereoisomeric enamide complexes exchange via olefin dissociation, subsequent rotation about the N-C(olefinic) bond and recoordination. These studies provide insight into the electronic and steric factors that affect the activity and stereoselectivity for the asymmetric hydrogenation of amino acid precursors. 

Noyori, R., Yamakawa, M. and Hashiquchi, S. Metal-Ligand Bifunctional Catalysis A Nonclassical Mechanism for Asymmetric Hydrogen Transfer between Alcohols and Carbonyl Compounds. J. Org. Chem. 2001, 66, 7931-7944. 

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