Soai reaction

Kinetic Insight into Specific Features of the Autocatalytic Soai Reaction... 

Abstract The addition of diisopropylzinc to prochiral pyrimidine carbaldehydes (Soai reaction) is the only known example of spontaneous asymmetric synthesis in organic chemistry. It serves as a model system for the spontaneous occurrence of chiral asymmetry from achiral initial conditions. This review describes the possible kinetic origin of specific experimental features of this reaction. It is shown that generic kinetic models, including enantioselective autocatalysis and mutual inhibition between the enantiomers,... 

The first experimental invention of spontaneous asymmetric synthesis was achieved only a little more than a decade ago in an organic reaction system by Soai and coworkers [9-15]. The Soai reaction (Scheme 1) comprises the addition of diisopropylzinc to prochiral pyrimidine carbaldehydes yielding isopropylzinc alkoxides that, after hydrolysis, are usually converted into stable chiral pyrimidyl alkanols. 

Scheme 1 The Soai reaction Ar = 3-pyridyl, 3-quinolyl, 5-pyrimidinyl, ferrocenyl, 2-alkyl-5-pyrimidinyl (see Table 1)...

At first glance, the Soai reaction appears to be one of the prominent examples of catalytic asymmetric organozinc additions to carbonyl com-... 

In this contribution, we will try to give an overview of the possible mechanistic origin of chiral amplification in the Soai reaction. We will present a reaction network derived from simple theoretical models of chiral amplification that can give rise to a plausible description of the combined experimental observations of this reaction. Following our interest in describing the dynamic features of nonlinear reaction systems [20-23], we will emphasize the possible kinetic rea-... 

In recent years, the Soai reaction has been carried out with a number of variations in the starting aldehyde [9,24-31]. These attempts revealed a certain relationship between the structure of the aldehyde and the achievable ee, i.e., the difference between the eeo of the initially added autocatalyst and the ee/ of the produced autocatalyst (see Table 1). 

Using an empirical expression for the amplification capacity, Micskei et al. found that the amplification strength of the Soai reaction fluctuates over a wide range when the structure of the aldehyde is varied [32]. The authors excluded the possibility of simple substituent effects but rather assumed that important changes in the reaction mechanism are taking place. 

Scheme 2 Possible zinc alkoxide dimer formation in the Soai reaction by assuming a (ZnO)2 ring structure...

Scheme 3 Strong chiral amplification in the Soai reaction by using a starting ee of 0.00005% and obtaining the 2-alkynyl-5-pyrimidyl alkanol with an ee of 57% in the first reaction cycle...

Further remarkable experimental results have been obtained by Singleton and Vo [34] starting 48 trials of the Soai reaction with practically achiral initial conditions and conducting these experiments each in a series of four individual reaction cycles, the authors found that at the end of all 48 cases, the final ee ranged from 3 to 86%. 

In many cases, the Soai reaction is driven in reaction cycles by which the ee obtained in one cycle serves as the starting ee in a subsequent one. In the present case, the obtained ee was 57% (first cycle), 99% (second cycle), and > 99.5% (third cycle). 

Scheme 4 Soai reaction performed under achiral initial conditions giving rise in repeated experiments to a random distribution of the product enantiomers with significant nonzero final ee-, R = t-Bu-C=C-...

The results of Soai and coworkers [35] as well as those of Singleton and Vo [36] suggest the occurrence of mirror-symmetry breaking in the Soai reaction, which is a rare phenomenon that is basically limited to a few crystallization processes [37]. Under certain kinetic conditions, chiral autocatalysis... 

Figure 1 illustrates symmetry breaking in the Soai reaction that has been clearly documented in two cases by bimodal product distributions (black and... 

Fig. 1 Frequency distribution of the %ee in repeated experiments of the Soai reaction performed with different starting aldehydes but without initial addition of chiral substances. Cray bars 2-t-Bu-C=C-5-pyrimidinyl aldehyde ([35]) black bars 2-t-Bu-C=C-5-pyrimidinyl aldehyde with achiral silica gel ([40]) patterned bars (CH3)2-Si-C=C-5-pyrimidinyl aldehyde ([41])...

As listed In Tables 2 and 3, not only the initially added pyrimidyl alkanol but also a wide variety of other chiral substances can act as chiral initiators in the Soai reaction [42-63]. All the experiments reported below have been reproduced several times and were performed by using alternately the R and S enantiomer of the additives to confirm the inversion of the outcome. 

The origin of the various additive effects is still unknown. However, taking into account the wide variety of chiral additives that cause effects with considerable sensitivity, it can be assumed that unspecific rather than specific interactions between the additives and species involved in the reaction mechanism of the Soai reaction take place. These may cause small but directed chiral perturbations where advantage is taken of the extraordinarily strong autocatalytic amplification capacity of the system. As already demonstrated by Singleton and Vo [36], these perturbations can be extremely small without losing its enantiomeric direction. In fact, as we describe later, the assumption of interactions between these chiral additives and the Soai reaction product itself, i.e., the autocatalytic species, could provide a tentative explanation for such effects. 

Lutz et al. initiated a series of Soai reactions by simultaneously adding a pair of competing chiral (>-amino alcohol catalysts of opposite configurations to the initial reaction mixtures that were known to generate predominantly the... 

Table 2 Soluble chiral additives in the Soai reaction that act as chiral initiators...

Scheme 5 Enantioselectivity reversal in the Soai reaction in the presence of the chiral catalyst DMNE and the achiral additive DBAE...

As a first assumption to explain the unexpected enantioselectivity reversal, Lutz et al. proposed that the chiral and achiral additives interact to form a new dimeric species that catalyzes the formation of the opposite enantiomer of the chiral catalyst [65]. As described in a later section, the interaction between the chiral additive and the reaction product of the Soai reaction could represent a second possibility to explain the phenomenon of enantioselectivity reversal. 

Commenting their discovery of the first case of chiral autocatalysis in organic chemistry, Soai et al. stated that it seems conceivable that the [Soai] reaction. .. may be an example of the scheme proposed by Frank [9]. Indeed, the so-called Frank model that has been developed in 1953 predicts the spontaneous amplification of an initial enantiomeric excess by means of a simple set of coupled differential equations [1] ... 

According to Soai and coworkers [31], the strong chiral amplification sometimes observed in their system cannot be explained by so-called NLE alone since amplification effects in these cases remain at a more moderate level. Hence a more complex reaction mechanism than expressed by the reservoir or the ML model is indicated for the Soai reaction. 

A number of different kinetic attempts and strategies have been employed to obtain a closer understanding of the Soai reaction. The first efforts were made by Blackmond et al. using microcalorimetric studies [77]. The autocatalytic nature of the reaction was confirmed by the observation of the maxima of the reaction heat flows as a function of time. In particular, it was reported that the reaction rate depends on the enantiomeric purity of the initially added pyrimidyl alkanol, where the rate in the presence of the enantiopure alkanol was roughly twice of that using the racemic alkanol. 

Sato et al. confirmed the autocatalytic nature of the Soai reaction by showing the sigmoidal time evolution of the product formation and the acceleration of the reaction by initial addition of the pyrimidyl alkanol [19]. The authors also presented a modeling attempt by using fast pre-equilibrium... 

Rivera Islas et al. proposed an alternative approach, which should be generally employed for the study of nonlinear systems and was believed to respond better to the complexity of the Soai reaction than the consideration of single rate laws [69]. In such an attempt a priori approximations are usually avoided, all possible species are considered, the velocity of equilibria is especially taken into account, and the coupling of chemically realistic reaction steps is not disregarded. On the other hand, a larger number of variables and parameters have to be handled. Hence such an approach can only be conducted numerically but, in the best case, it can mimic the mechanics of the real system because of its similar coupled and multistep design. 

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