Benzoin transition states

A mechanistic rationale for the observed cw-selectivity has been proposed based on preorganisation of the Breslow-type intermediate and imine through hydrogen bonding 253, with an aza-benzoin oxy-Cope process proposed. Reaction via a boat transition state delivers the observed cw-stereochemistry of the product (Scheme 12.57). Related work by Nair and co-workers (using enones 42 in place of a,P-unsaturated sulfonylimines 251, see Section 12.2.2) generates P-lactones 43 with fran -ring substituents, while the P-lactam products 252 possess a cw-stereo-chemical relationship. 

Oxidation of benzoin to benzil with Fe(III), in the presence of 2,2/-bipyridine or ferrozine is of first order in Fe(III) and benzoin. An inverse second-order dependence was observed with respect to hydrogen ions. For oxidation of substituted benzoins the reaction constant is p 1.2, indicating an electron-rich transition state and an inner sphere mechanism has been proposed.66 The order with respect to iodide, in the reaction of iodide ions with a diiron(III)-l,10-phenanthroline complex, is 2. The hydrolytic derivatives of the complex are not kinetically active. Both inner and outer sphere pathways are operative.67... 

Fig. 9.5 Possible transition states for the asymmetric benzoin condensation, as proposed by Enders et al. and Houk et al.

The stereochemical outcome of the reaction above is explained in terms of a structurally rigid 1,3-bridged six-membered chairlike transition state (Scheme 3.2i). Transition state B would be disfavored relative to transition state A because the phenyl group of benzoin is engaged in nonbonded interactions with the methyl and the hydrogen of the crotylsilane. 

Numerous organic reactions have been studied in aqueous solutions. It was observed that water is able to induce dramatic rate accelerations in Diels-Alder cycloadditions [66], benzoin condensation [67], Claisen rearrangements [68], Mu-kaiyama aldol reactions [57], Michael reactions [69], Baylis-Hillman reactions [70], and 1,3-dipolar cycloadditions [71], All these reactions are characterized by negative volume changes and negative volumes of activation. It is expected that ground state destabilization in aqueous media associated with transition state stabilization is one of the determining kinetic factors. 

These detailed mechanistic studies have led to the following generalized mechanism of enolate oxation by oxaziridine reagents. In the hydroxylation of deoxybenzoin 10 to benzoin 15, the enolate anion 11 is formed by kinetic deprotonation with LDA. The enolate anion then performs a nucleophilic attack on the oxygen of the oxaziridine 1 in a manner consistent with that proposed in transition state B. The hemiaminal 12 intermediate decomposes to form the alkoxide 14 and sulfonimine 13. The alkoxide is then quenched to provide alcohol IS.2... 

FIGURE 2.26. Transition state model for the NHC-catalyzed asymmetric benzoin reaction. 

The reaction of two molecules of benzaldehyde to form benzoin is generally referred to as the benzoin condensation. It is normally catalyzed by cyanide ion, although thiazolium ions will also catalyze it, as we have discussed above and shown in Fig. 1.2. The normal solvent for the benzoin condensation is ethanol, to dissolve all the components of the reaction. However, it seemed to us likely that there would be overlap of the phenyl rings in the transition state for the benzoin condensation, and thus that reaction in water could lead to hydrophobic accelerations. This proved to be the case. We saw that the rate of the cyanide-catalyzed benzoin condensation was 200-fold faster in water than in ethanol. Also, we saw that added LiCl increased the reaction rate, while added lithium perchlorate decreased it. Such salt effects are diagnostic of the presence of some acceleration by hydrophobic packing in the transition state for the reaction. 

In our first study, we examined the effect of added alcohols on the solubility of benzalde-hyde in water and on the rate of the benzoin condensation in water. We saw — in a plot with 15 points - that there was a good parallel between the log of the solubility and the log of the rate constant effect (increased solubility and decreased rate with added alcohols in water). Since the effect of added alcohols on the solubility ofbenzaldehyde simply reflects the antihydrophobic role of the additives, this must also be true of the rate effects. That is, apparently there was no extra effect relating to solvation of charges in the rate changes with additives they simply reflected the fact that the transition state for the benzoin condensation -under these conditions the transition state occurs during the addition of the cyanohydrin anion to the aldehyde - is less stabilized by additives than is the starting material. Some... 

A reaction pathway involving a concerted transition state of the type (210) has been shown to be compatible with the kinetic results and formation of 1,2-diarylethanones observed during the gas-phase pyrolysis of the formate ester of benzoin and the... 

We also detected a hydrophobic effect in the benzoin condensation [14]. In this case, in contrast to the Diels-Alder reaction, it is not formally required that the two hydrophobic phenyl groups come together in the transition state, but our studies indicated that they do. Again there was a large increase in rate when water was the solvent, but in an ionic reaction of this sort such solvent effects could well be related only to the effect on the ions of the polar character of the medium. However, we saw that the reaction rate was increased with LiCl, but decreased when LiC104 was added. In this system LiC104 is a salting... 

The conclusion that the two phenyl groups pack together in the benzoin condensation transition state was confirmed by the finding that this reaction is accelerated by y-cyclodextrin [14]. The cavity of this molecule is large... 

The hydrophobic interaction between hydrocarbons and water is a powerful ordering force in mixtures of lipophiles and hydrophiles [53, 54]. Domains of lipophiles provide a solubilizing phase for all like substances added to lipophile-water mixtures. These same forces have been successfully used to order water-insoluble organic molecules for enhancement of Diels-Alder reactions, the benzoin condensation and others which require molecular ordering in the transition state [55]. 

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