Stereochemical effects mechanistic studies

The use of metals for prearranging reaction centers as neighboring groups has a special value in the production of macrocycles (template effect). Although these ligands can be sometimes prepared directly, the addition of metal ion during the synthesis will often increase the yield, modify the stereochemical nature of the product, or even be essential in the buildup of the macrocycle. There have been few mechanistic studies of these processes. The alkali and alkaline-earth metal ions can promote the formation of benzo[18]crown-6 in methanol ... 

The use of DMSO as a mechanistic tool is not restricted to rate variation effects (Section 4). Advantage can also be taken of its unique molecular properties which enable it to stabilize certain types of structures, such as the anionic intermediates in SnAt reactions. Moreover, as a consequence of its influence on ion association constants, it is found to affect the product distribution and the stereochemical course of bimolecular olefin-forming eliminations. These two illustrative systems which have been chosen for discussion are intended to demonstrate the versality of this solvent in mechanistic studies and may suggest other avenues of investigation. 

Esters of cinnamic acid and ring-substituted derivatives (12) have received considerable attention for decades from a preparative point of view [2,61], as model compounds for early kinetic studies [10,11,62] and for examination of effects of medium [63], cations [63], proton donors [64], and complexing agents [65] on products, mechanisms, or kinetics. Series of cinnamates have more recently been the subject of systematic stereochemical, kinetic and mechanistic studies [16,66,67]. 

The solvent exerts a strong influence on the product distribution. Starting from the same tetrahydrobenzylisoquinoline in MeCN, 82% XXXV are fonned. In MeCN-MeOH the intermediate can be effectively trapped by methanolysis and 58% XXXVI are obtained [159]. A major mechanistic study seeking common denominators in the oxidations leading to XXIV, XXVI, and XXVIII has been published [152b]. A stereochemical study indicated that the yield in the cyclization is independent on the pseudoequatorial or pseudoaxial position of the benzyl substituent in the benzyltetrahy-droisoquinoline [160]. 

The stereochemical similarity between the additive and the crystal structure of one of the enantiomorphic substrates was found to be of paramount importance [8], while parameters like temperature, concentration or nature of the medium had only a quantitative effect on the induction in this system. Further kinetic and mechanistic studies resulted in the formulation of a mechanism according to which the additive is enantioselectively adsorbed in small amounts at the surface of the growing crystal of the same absolute configuration. The adsorption of the chiral additive causes a drastic decrease in the rate of growth of this same crystal, thus shifting the crystallization equilibrium towards the unaffected enantiomorphous phase. This is illustrated in Scheme 2, where the achiral monomer is represented as a fast racemizing... 

Although the rationalization of the reactivity and selectivity of this particular substrate is distinct from that for chiral ketals 92-95, it still agrees with the mechanistic conclusions gained throughout the study of Simmons-Smith cyclopropa-nations. StOl, the possibility of the existence of a bimetallic transition structure similar to v (see Fig. 3.5) has not been rigorously ruled out. No real changes in the stereochemical rationale of the reaction are required upon substitution of such a bimetallic transition structure. But as will be seen later, the effect of zinc iodide on catalytic cyclopropanations is a clue to the nature of highly selective reaction pathways. A similar but unexplained effect of zinc iodide on these cyclopro-panation may provide further information on the true reactive species. 

The successful mechanism for a reaction is a theory that correlates the many facts which have been discovered and is fruitful for the prediction of new experiments (1). One approach to mechanism is the study of stereochemistry which seeks information concerning the geometrical relationships between the reactants at the critical stages in the reaction. Information is gleaned from the examination of the products, if several isomers differing only in configuration may be formed, or from a study of the reactivity of closely related substances whose molecular shapes are varied in a specific manner. Occasionally a stereochemical fact places a considerable restraint upon the allowable mechanistic postulates, but the most effective employment of stereochemistry generally depends upon its detailed correlation with other experimental methods. 

In these reactions, retention can only be accommodated by formation of a phosphorane intermediate, followed by pseudorotation, before loss of the leaving group. Inversion could result either from a concerted reaction, or a stepwise process, if the phosphorane collapses before pseudorotation can occur. The stereochemical and LFER data indicate that both mechanisms occur. In a study of similar cyclic triesters (Fig. 12c and d) that combined LFER studies, stereochemical analysis, and solvent isotope effects, Rowell and Gorenstein found a trend in / g values as a function of attacking nucleophile.61 These, and the stereochemical data, are strong evidence for a mechanistic continuum from concerted to stepwise reactions of six-membered cyclic phosphate triesters.61... 

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