Catalytic cycle asymmetric hydrogenation

In asymmetric hydrogenation, the pressure of hydrogen may have a substantial impact on both the rates and the stereoselectivities of the reaction. These effects may be attributed either to the formation of different catalytically competing species in solution or to the operation of kinetically distinct catalytic cycles at different pressures. 

The solvent employed in asymmetric catalytic reactions may also have a dramatic influence on the reaction rate as well as the enantioselectivity, possibly because the solvent molecule is also involved in the catalytic cycle. Furthermore, the reaction temperature also has a profound influence on stereoselectivity. The goal of asymmetric hydrogenation or transfer hydrogenation studies is to find an optimal condition with a combination of chiral ligand, counterion, metal, solvent, hydrogen pressure, and reaction temperature under which the reactivity and the stereoselectivity of the reaction will be jointly maximized. 

NMR spectroscopy has been used to study the species formed in solution by interaction of cinnamic add derivatives with asymmetric hydrogenation catalysts.257,258 Such studies are necessarily limited to those spedes which accumulate in adequate concentration and have sufficiently long lifetimes for observation by NMR. In catalytic reactions as rapid as those described here, such complexes appear likely to be outside rather than in the operating catalytic cycle.91... 

Three types of experiments have proved informative in the mechanistic study of asymmetric hydrogenation. These are, respectively, rate measurements and product analysis, X-ray crystallography and NMR-derived identification of stable and transient species involved in the catalytic cycle. The first two of these have been reviewed elsewhere (2, 3, 4) our own work has been concerned with NMR and has provided a surprising wealth of structural and mechanistic detail. A variety of chiral phosphine procatalysts have been used but the current discussion will be concerned largely with two. Thus (R,R)-1,2-ethanediylbis-[(2-methoxyphenyl)phenylphosphine] (1) (DiPAMP)... 

The discovery by the recent Nobel-laureate, Ryoji Noyori, of asymmetric hydrogenation of simple ketones to alcohols catalyzed by raras-RuCl2[(S)-binap][(S,S)-dpen] (binap = [l,l -binaphthalene-2,2/-diyl-bis(diphenylphosphane)] dpen = diphenylethylenediamine) is remarkable in several respects (91). The reaction is quantitative within hours, gives enantiomeric excesses (ee) up to 99%, shows high chemoselecti-vity for carbonyl over olefin reduction, and the substrate-to-catalyst ratio is >100,000. Moreover, the non-classical metal-ligand bifunctional catalytic cycle is mechanistically novel and involves heterolytic... 

Homogeneous catalytic hydrogenations—both racemic and asymmetric—proceed via catalytic cycles that involve many steps, as is illustrated below taking the Rh catalysis in Figure 17.78 and the Ru catalysis in Figure 17.79 as examples. Most probably, the intermediates given there are the appropriate ones. Not all the species discussed in these catalytic cycles have been proven completely, but it is very likely that these cycles are basically correct. 

Although a large number of asymmetric catalytic reactions with impressive catalytic activities and enantioselectivities have been reported, the mechanistic details at a molecular level have been firmly established for only a few. Asymmetric isomerization, hydrogenation, epoxidation, and alkene dihydroxylation are some of the reactions where the proposed catalytic cycles could be backed with kinetic, spectroscopic, and other evidence. In all these systems kinetic factors are responsible for the observed enantioselectivities. In other words, the rate of formation of one of the enantiomers of the organic product is much faster than that of its mirror image. 

Reaction 9.1 has been extensively studied to establish the mechanism of asymmetric hydrogenation. The catalytic cycle proposed for the asymmetric hydrogenation of the methyl ester of a-acetamido cinamic acid with 9.14 as the precatalyst is shown in Fig. 9.3. As mentioned earlier, this reaction is one of the early examples of industrial applications of asymmetric catalysis for the manufacture of L-DOPA (see Table 1.1). 

Figure 9.3 Catalytic cycles for the asymmetric hydrogenation of a-acetamido methyl acrylate (or cinamate). For clarity the detailed structure of the organic substrate is not shown. In 9.21 and 9.22 for ease of identification the carbon atom to which the metal hydride is transferred is marked by an arrow and the hydride is circled. Note that, excepting the chelating chiral phosphine, the stereochemistries around the rhodium in the left- and right-hand cycles have mirror-image relationships.

Transformations involving chiral catalysts most efficiently lead to optically active products. The degree of enantioselectivity rather than the efficiency of the catalytic cycle has up to now been in the center of interest. Compared to hydrogenations, catalytic oxidations or C-C bond formations are much more complex processes and still under development. In the case of catalytic additions of dialkyl zinc compounds[l], allylstan-nanes [2], allyl silanes [3], and silyl enolethers [4] to aldehydes, the degree of asymmetric induction is less of a problem than the turnover number and substrate tolerance. Chiral Lewis acids for the enantioselective Mukaiyama reaction have been known for some time [4a - 4c], and recently the binaphthol-titanium complexes 1 [2c - 2e, 2jl and 2 [2b, 2i] have been found to catalyze the addition of allyl stannanes to aldehydes quite efficiently. It has been reported recently that a more active catalyst results upon addition of Me SiSfi-Pr) [2k] or Et2BS( -Pr) [21, 2m] to bi-naphthol-Ti(IV) preparations. 

Scheme of the coupled catalytic cycles for the asymmetric hydrogenation of MAC. 

Later, Halpem conducted the same experiments using a Rh-DIPAMP complex to catalyze hydrogenation of methyl-(Z)-l-acetamidocinnamate (MAC), and the results were entirely analogous to the CHIRAPHOS system.11 The important lesson learned in Section 9-4-2 again applies in the mechanism for asymmetric hydrogenation—isolable intermediates such as 7 are typically not the active species involved in a catalytic cycle.12... 

One proposal for the catalytic cycle involves an Ir(III)-dihydride intermediate that forms after OA of H2 onto an Ir(I)-alkene complex. Experimental results seem to support this cycle,36 but computational studies suggest that the cycle involves Ir(III) and Ir(V) intermediates.37 The details of neither proposal have been elucidated. Work continues to expand the scope of this reaction to include asymmetric hydrogenation of any unfunctionalized alkene that could yield a chiral alkane. 

Propose a catalytic cycle for Ir-catalyzed asymmetric hydrogenation that Exercise 12-3... 

Scheme 12 Different catalytic cycles proposed for Ir-catalyzed asymmetric hydrogenation...

The mechanism for the asymmetric hydrogenation of enamides by Knowles catalyst is well understood due to the work of Halpern (Fig. 5) [20], The intermediates were identified by spectroscopy. The surprising finding was that two catalytic cycles were possible. The one that contains the lower concentrations of intermediates gives rise to the major product isomer as the reaction rates are faster compared with the cycle that has more detectable intermediates. 

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