Catalyst nonlinear effects

Keywords Asymmetric catalysis, Asymmetric hydrogenation. Catalytic antibodies. Chiral Lewis acids. Chiral ligands. Enzymes, Organometallic catalysts. Organic catalysts. Nonlinear effects. History... 

Hie obsewation of nonlinear effects, botli witli dialcone and witli cydobexe-none, fiirdier supporis tliis catalyst stoidiiometry Hie nonlinear effects can be explained by tlie involvement of diasteteonieric complexes L2CL1R, witli two diiral ligands bound to copper fFig. 7.2) [45]. 

Jacobsen developed a method employing (pybox)YbCl3 for TMSCN addition to meso-epoxides (Scheme 7.22) [46] with enantioselectivities as high as 92%. Unfortunately, the practical utility of this method is limited because low temperatures must be maintained for very long reaction times (up to seven days). This reaction displayed a second-order dependence on catalyst concentration and a positive nonlinear effect, suggesting a cooperative bimetallic mechanism analogous to that proposed for (salen)Cr-catalyzed ARO reactions (Scheme 7.5). 

How relevant are these phenomena First, many oscillating reactions exist and play an important role in living matter. Biochemical oscillations and also the inorganic oscillatory Belousov-Zhabotinsky system are very complex reaction networks. Oscillating surface reactions though are much simpler and so offer convenient model systems to investigate the realm of non-equilibrium reactions on a fundamental level. Secondly, as mentioned above, the conditions under which nonlinear effects such as those caused by autocatalytic steps lead to uncontrollable situations, which should be avoided in practice. Hence, some knowledge about the subject is desired. Finally, the application of forced oscillations in some reactions may lead to better performance in favorable situations for example, when a catalytic system alternates between conditions where the catalyst deactivates due to carbon deposition and conditions where this deposit is reacted away. 

Kinetic resolution can also be accomplished via eliminative pathways. Thus, the enantiomerically enriched allylic alcohol 102 can be prepared from the meso epoxide 96 with up to 96% ee by the action of LDA in the presence of the chiral diamine 101 and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). The DBU is believed to function as an aggregation modifier, and the active catalyst is theorized to be a heterodimer of the lithium amide (deprotonated 101) and DBU, although some nonlinear effects have been observed at low DBU concentrations <00JA6610>. Dipyrrolidino derivatives (e.g., 104) have also demonstrated utility with regard to kinetic resolution <00H1029>. 

As shown in Figure 4.5, a remarkably high positive nonlinear effect was observed in the La-BINOL-Ph3PO complex-catalysed epoxidation of chalcone (either with CMHP or with TBHP as an oxidant)1121, which strongly suggests that the active catalyst leading to high enantioselection does not have a monomeric structure but may exist as a thermodynamically stable dinuclear complex. 

PhI=NTs in MeCN affords a copper species that is indistinguishable by ultraviolet-visible (UV-vis) spectroscopy from an identical solution derived from Cu(OTf)2. Given the strong oxidizing nature of PhI=NTs, it seems likely that both catalysts proceed through a Cu(II) species. Beyond this, little can be said with certainty. If nitrenoid formation proceeds by a two-electron oxidation of the catalyst, one would need to invoke Cu(IV) as an intermediate in this process (77). This issue is resolved if one invokes the intervention of a bimetallic complex in the catalytic cycle. However, attempted observation of a nonlinear effect revealed a linear relationship between ligand enantiopurity and product ee (77, 78). 

Catalytic amounts of this addend (4 equiv relative to Cu) increase the selectivity of the allylic oxidation when TBHP is used as the oxidant. No change was observed with terf-butyl perbenzoate. This observation suggests a dichotomy in the mechanism of this reaction when using the two oxidants. Furthermore, in the absence of anthraquinone, a small negative nonlinear effect (78) is observed while in its presence, a small positive nonlinear effect appears. The reasons for this reversal are not clear, although the authors observed that low enantiopurity catalysts lead to turbid... 

A study examining the relationship between ee of the catalyst and product revealed a strong nonlinear effect (Fig. 16) (78), suggestive of a complex relationship... 

Zhou and Pfaltz (149) note that complex 215 mirrors the behavior of van Koten s complex 210. The catalyst is trimeric in solution and solid state and displays an intricate nonlinear effect (78, 146) in the conjugate addition reaction, Fig. 19 (149). It seems likely that these ligand-metal complexes are structurally related. 

Tanaka et al. (152) demonstrated that a chiral copper alkoxide could be used substoichiometrically to deliver MeLi to an enone in conjugate fashion. The precatalyst is formed from amino alcohol 221, MeLi and Cul, Eq. 123a. Under stoichiometric conditions, this catalyst mediates the conjugate addition of MeLi to the macrocyclic enone, affording muscone in 91% ee. Lower enantioselectivity is observed using a substoichiometric amount of 222 (0.5 equiv), affording a 79% yield of muscone in 76% ee, Eq. 123b. These selectivities are attained by portion-wise addition of the substrate and MeLi to the alkoxy-cuprate. This catalyst also exhibits a complex nonlinear effect (78, 153). 

Blackmond pointed out that asymmetric amplification always has, as a consequence, a decrease in reactivity when compared to the enantiopure catalyst. This can be calculated on the various models proposed for the interpretation of nonlinear effects. It is qualitatively visible in the reservoir model above as well as in the ML2 model, where the asymmetric amplification given by g < 1 (low reactivity of the meso catalyst) has as consequence the overall slowdown in reaction rate. The generalized model ML has been discussed (for n = 2,3,4) when the various species are in equilibrium. The complexity of the curve can increase sharply as soon as n > 2. 

There are several reviews covering many aspects of nonlinear effects. The early examples of nonlinear effects almost exclusively dealt with organometallic catalysts. It is only very recently that some organocatalysts have been found to... 

Only a few cases of nonlinear effects have been reported some are listed in Table 7.2. Most of the examples involve proline as the catalyst. Chiral phosphora-mides and some phase transfer catalysts were also reported to give NLEs. 

The expression positive nonlinear effect reflects the fact that the observed ee (eCprod) is higher then the expected ee (eeiinear) calculated on the basis of Eq. (7.1). For example, let us consider an enantiopure catalyst that generates a product of 60% ee (eemax)- If the ligand is of 50% ee (eeaux), one now calculates eeprod = 30%. If instead the reaction provides a product of 58% ee, this can be considered as an excellent case of asymmetric amplification. 

TABLE 7.1. Nonlinear Effects Displayed by Some Organometallic Catalysts... 

The sensitivity of nonlinear effects to additives, catalyst preparation, or substrate structure have been noted, giving some mechanistic informations (see, e.g.. Refs. 50, 38, and 71 respectively). 

In summary, the origin of the chiral amplification is basically the difference in stability of the homochiral and heterochiral dinuclear Zn complexes. These complexes act as catalyst precursors, but differences in their kinetic behavior also affect the degree of the nonlinear effect. This investigation is probably the first example of elucidation of a molecular mechanism of catalytic chiral amplification (41) and may provide a chemical model of one means of propagation of chirality in nature. 

A similar nonlinearity is seen in the ene reaction of methyl glyoxylate and a-methylstyrene (Scheme 43) (69). Thus, the reaction catalyzed by a complex in situ formed from dibromo(diisopropoxy)titanium(IV) and (/ )-binaphthol in 33% ee affords the chiral adduct in 91% ee with the same enantioselectivity as would have been obtained had enantiomerically pure binaphthol been used. Molecular weight measurements suggest the catalyst is a dinuclear titanium compound, although the structure has not been elucidated. This nonlinear effect is interpreted by the difference in the dissociation constant of the diastereomeric dimers as... 

Recently, examples of catalytic asymmetric synthesis have been reported in which the enantiomeric purity of the product is much higher than that of the chiral catalyst. A positive nonlinear effect, that is, asymmetric amplification, is synthetically useful because a chiral catalyst of high enantiopurity is not needed to prepare a chiral product with high enantiomeric excess (% ee) (Scheme 9.1). 

Due to the intensive studies by many groups, the number of examples of asymmetric amplification has been substantially increasing. Aggregation state of the enantiomers of a chiral catalyst can be estimated based on the observation of a nonlinear effect between the enantiopurity of the chiral catalyst and that of the product. 

On some occasions an exception from this case can be observed by so-called nonlinear effects in asymmetric synthesis, in which the relation between the enantiomeric excess of the chiral catalyst or initiator and that of the product deviates from linearity (see Sect. 3.3)... 

It was soon recognized that in specific cases of asymmetric synthesis the relation between the ee of a chiral auxiliary and the ee of the product can deviate from linearity [17,18,72 - 74]. These so-called nonlinear effects (NLE) in asymmetric synthesis, in which the achievable eeprod becomes higher than the eeaux> represent chiral amplification while the opposite case represents chiral depletion. A variety of NLE have been found in asymmetric syntheses involving the interaction between organometallic compounds and chiral ligands to form enantioselective catalysts [74]. NLE reflect the complexity of the reaction mechanism involved and are usually caused by the association between chiral molecules during the course of the reaction. This leads to the formation of diastereoisomeric species (e.g., homochiral and heterochiral dimers) with possibly different relative quantities due to distinct kinetics of formation and thermodynamic stabilities, and also because of different catalytic activities. 

Empirical experimentation has revealed that the catalyst formed from a 1 1-1 1.4 ratio of Ln(0-i-Pr)3 (Ln = La or Yb) and 17 provides the maximum enantiomeric excesses for epoxidation (Figure 6). The 13C NMR spectrum of La-17 was not interpretable, suggesting that both the chiral Yb-17 catalyst and the La-17 catalyst exist as oligomers. Moreover, the catalytic epoxidation of 39 with Yb-17 displays a pronounced nonlinear effect (Figure 7). (For a treatment of nonlinear effects, see Chapter 5 in this volume.) Thus the oligomeric structure of these lanthanoid-BINOL catalysts may play a key role in the catalytic asymmetric... 

In order to achieve an amplification of chirality, it requires that/> 1. If P = 0 (no meso catalyst) or g = 1 (same reactivity of meso and homochiral catalysts), then/= 1. The condition/> 1 is achieved for 1 + p > 1 + g ), or g < 1. Thus the necessary condition for asymmetric amplification in the above model is for the heterochiral or meso catalyst to be less reactive than the homochiral catalyst. If the meso catalyst is more reactive, then/< 1, and hence a negative nonlinear effect is observed. The size of the asymmetric amplification is regulated by the value off, which increases as K does. The more meso catalyst (of the lowest possible reactivity) there is, the higher will be eeproduct. This is well illustrated by computed curves in Scheme 11. The variation of eeproduct with eeaux is represented for various values of g (the relative reactivity of the meso complex) with K = 4 (corresponding to a statistical distribution of ligands Scheme 11, top). The variation in the relative amounts of the three complexes with eeaux is also represented for a statistical distribution of ligands (Scheme 11, bottom). 

The presence of a nonlinear effect, either negative or positive, is a useful piece of information for the mechanistic study of a reaction. It implies that diastereomeric species are formed from the chiral auxiliary. If an asymmetric amplification is observed, it can be indicative of the formation of meso dimers (or tetramers etc.) of low reactivity. When the kinetic study of an asymmetric catalysis shows a rate second order with respect to catalyst concentration, it may be useful to investigate the possibility of nonlinear effects in the system. Jacobsen et al., for example, studied the... 

Enantioselective addition of (C2//5)2Z/i to CJlsCHOIn the presence of (— )-l, diethylzinc adds to C6H5CHO to provide the (R)-adduct. The optical purity of the catalyst (1) has a marked effect on the rate and also on the optical purity of the adduct. Thus (-)-PDB of only 10-20% ee provides (R)-l-phenylpropanol in 80-90% ee and about 95% chemical yield. This nonlinear effect in catalyzed asymmetric oxidations and aldolizations has been noted previously.2 It may be a result of the molecularity of the reaction or of the aggregation or ligand exchange of the catalyst. 

Experiments conducted in the mid-1980s by Agami indicated a small nonlinear effect in the asymmetric catalysis in the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.7). Agami proposed that two proline molecules were involved in the catalysis the first proline forms an enamine with the side chain ketone and the second proline molecule facilitates a proton transfer. Hajos and Parrish reported that the proline-catalyzed cyclization shown in Scheme 6.7 did not incorporate when run in the presence of labeled water. While both of these results have since been discredited—the catalysis is first order in catalyst and is incorporated into... 

Carbonyl-Ene Reaction. BINOL-TiX2 reagent exhibits a remarkable level of asymmetric catalysis in the carbonyl-ene reaction of prochiral glyoxylates, thereby providing practical access to a-hydroxy esters. These reactions exhibit a remarkable positive nonlinear effect (asymmetric amplification) that is of practical and mechanistic importance (eq 19). The desymmetrization of prochiral ene substrates with planar symmetry by the enantiofacial selective carbonyl-ene reaction provides an efficient solution to remote internal asymmetric induction (eq 20). The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative asymmetric induction (eq 21). Both the dibromide and dichloride catalysts provide the (2R,5S)-syn product with 97% diastereoselectivity and >95% ee. 

A complex of (M)-BINOL and Ti(0-t-Pr)4 has been used to catalyze additions of allyl and methallyl tributyltin to aldehydes (Table 19) [34], Yields and product ee are high with a variety of aldehydes. This catalyst also has a nonlinear effect suggestive of a dimeric structure [35]. 

The formation of 64 using catalyst (S,S)-62 exhibits a positive nonlinear effect, fitting well with Kagan s two ligand model [78] whereas the more hindered catalyst (S,S)-63 led to a perfect linear asymmetric induction suggesting that the product arose from a transition structure involving only one chiral phosphoramide. The kinetic study of this aldol reaction is in accordance with these re-... 

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