Transition structure nucleophilic substitution

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Today it is widely accepted that fivefold coordinated silicon plays a key role in the reaction mechanisms of the nucleophilic substitution having a trigonal bipyramidal transition state species which ressemble these transition states can be isolated in some special cases. The structural features fit well to kinetic data and possibly explain the significantly higher reactivity (proved by experimental data) of Si-pentacoordinated compounds compared to their tetracoordinated analoga. 

Saunders10 and by Sims and coworkers11 have shown that the magnitude of the leaving-group heavy-atom isotope effect varies linearly with the extent of C—X bond rupture in the transition state for concerted elimination reactions and for nucleophilic substitution reactions, respectively. Since the magnitude of the isotope effect is directly related to the amount of C—X bond rupture in the transition state, these isotope effects provide detailed information about the structure of the transition state. 

The nucleophile in the S.v2 reactions between benzyldimethylphenylammonium nitrate and sodium para-substituted thiophenoxides in methanol at 20 °C (equation 42) can exist as a free thiophenoxide ion or as a solvent-separated ion-pair complex (equation 43)62,63. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for these Sjv2 reactions were determined to learn how a substituent on the nucleophile affects the structure of the S.v2 transition state for the free ion and ion-pair reactions64. 

Gas-phase nucleophilic substitution reactions of Y-benzyl chlorides and X-phenoxide or X-thiophenoxide nucleophiles have been investigated by using the PM3 semiempirical MO method. The structure of the transition state was examined. The values of the gas-phase Hammett constants px and py are much greater than for the solution reactions, but a theoretical cross-interaction constant pxy (ca —0.60 for both phenoxides and thiophenoxides) agrees well with an experimental value of —0.62 for the thiophenoxide reactions in MeOH at 20 °C. Other work by the same group has involved theoretical studies of competitive gas-phase 5 n2 and E2 reactions of NCCH2CH2CI with HO and An ab initio method at the 6-31-l-G level was... 

The presence of a stereogenic center on the aldehyde can strongly inlinence the diastereoselectivity in allylboration reactions, especially if this center is in the a-position. Predictive rules for nucleophilic addition on snch a-snbstitnted carbonyl substrates such as the Felkin model are not always snitable for closed transition structures.For a-substituted aldehydes devoid of a polar substituent, Roush has established that the minimization of ganche-ganche ( syn-pentane ) interactions can overrule the influence of stereoelectronic effects. This model is valid for any 3-monosubstituted allylic boron reagent. For example, althongh crotylboronate (E)-7 adds to aldehyde 39 to afford as the major prodnct the diastereomer predicted by the Felkin model (Scheme 2), " it is proposed that the dominant factor is rather the minimization of syn-pentane interactions between the Y-snbstitnents of the allyl unit and the a-carbon of the aldehyde. With this... 

Such supercomplexes may serve as models for the transition state of crown-assisted reactions, for example nucleophilic substitutions. The observed stereo-specifity could be caused by locally ordered structures in which the crown ether cation complex could act as the substrate and as the anion, as well. 

Despite its formal simplicity, the stepwise mechanism of the reaction between ketenes and imines raises a complex stereochemical situation since ketenes can be unsymmetrically substituted and imines can exist in either (E)- or -configurations [49]. As far as the first step of the reaction is concerned, the nucleophilic attack of the nitrogen atom of the imine can occur through the less hindered exo face, namely that which has the shortest substituent, or through the endo face, which incorporates the largest substituent (Scheme 8). In principle, the exo attack leads to second transition structures that exhibit the largest substituents at the 3-out position. 

Nucleophilic addition reactions of para-substituted benzylamines (XC6H4CH2NH2) to a-phenyl-/9-thiophenylacrylonitriles [Y(C4SH2)CH=C(CN)C6H4Y/] have been studied in acetonitrile at 25.0, 30.0, and 35.0 °C. The reactions apparently take place in a single step in which the C/ -N bond formation and proton transfer to C of a-phenyl-/3-thiophenyl acrylonitriles occur concurrently with a four-membered cyclic transition structure. These mechanistic conclusions were deduced from the following ... 

These conclusions have been confirmed experimentally,36 for both electrophilic and nucleophilic substitution. There seems no doubt that structures such as IH are stable entities rather than transition states. Moreover, as Melander and others have shown,36 the absence of deuterium isotope effects in most electrophilic substitutions indicates that in such cases the transition state must be VII rather than VIII. The rate-determining step in the reaction is the formation of the intermediate (III). 

S. S. Shaik, A. C. Reddy, A. Ioffe, J. P. Dinnocenzo, D. Danovich, J. K. Cho, J. Am. Chem. Soc. 117, 3205 (1995). Reactivity Paradigms. Transition State Structures, Mechanisms of Barrier Formation, and Stereospecificity of Nucleophilic Substitutions on a-Cation Radicals. 

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