Transition states nucleophilic substitution

If the ring becomes more strained in the transition state nucleophilic substitution should proceed more slowly than with similar, non-cyclic electrophiles. Thus, cyclopropyl derivatives are highly resistant towards nucleophilic substitution because the RCR angle is fixed at 60°, and only rarely can products of an Sn2 reaction at cyclopropyl derivatives be obtained [109]. Instead, allyl derivatives are usually the main products (Scheme4.23). 

A reaction described as Sn2, abbreviation for substitution, nucleophilic (bimolecular), is a one-step process, and no intermediate is formed. This reaction involves the so-called backside attack of a nucleophile Y on an electrophilic center RX, such that the reaction center the carbon or other atom attacked by the nucleophile) undergoes inversion of stereochemical configuration. In the transition-state nucleophile and exiphile (leaving group) reside at the reaction center. Aside from stereochemical issues, other evidence can be used to identify Sn2 reactions. First, because both nucleophile and substrate are involved in the rate-determining step, the reaction is second order overall rate = k[RX][Y]. Moreover, one can use kinetic isotope effects to distinguish SnI and Sn2 cases (See Kinetic Isotope Effects). 

Reactions (109) and (110) as well as nitroalkane deprotonation are all examples of central substitution so that for these reactions a does not measure the earliness or lateness of the transition state. End substitution, such as in the nucleophile or leaving group of SN2 reactions, in which the formal charge does vary between reactants and products generates -values which may be utilized as a relative measure of transition state charge this, provided that the reaction is composed of three configurations. Such applications were discussed in Section 3, p. 152. 

Stereochemistry chi 4 Intermediates and transition states in substitution reactions How substitution reactions affect stereochemistry What sort of nucleophiles can substitute, and what sort of leaving groups can be substituted The sorts of molecules that can be made by substitution, and what they can be made from fragmentation reactions ch36... 

Kinetic, steric, and thermodynamic results have been reviewed to argue that the rate-determining step in some aliphatic nucleophilic substitutions is the transfer of an electron. The same group carried out a systematic ranking of different nucleophiles with respect to their ability to stabilize the transition states of substitution reactions, acetonitrile and dimethyl sulfoxide being the solvents involved. The nucleophiles included enolates, phenolates, thiophenolates, hydroxide, and cyanide. The method is based on a comparison of the rate coefficient, ksm, for the substitution reaction between a given nucleophile and benzyl chloride with the rate coefficient, A et for the corresponding electron transfer from an aromatic radical anion to benzyl chloride. The ratio ksuB/ ET expresses the rate enhancement due to electronic interaction in the transition state of the substitution reaction. 

Section 4 9 The potential energy diagrams for separate elementary steps can be merged into a diagram for the overall process The diagram for the reac tion of a secondary or tertiary alcohol with a hydrogen halide is charac terized by two intermediates and three transition states The reaction is classified as a ummolecular nucleophilic substitution, abbreviated as SnI... 

Hughes and Ingold interpreted second order kinetic behavior to mean that the rate determining step is bimolecular that is that both hydroxide ion and methyl bromide are involved at the transition state The symbol given to the detailed description of the mech anism that they developed is 8 2 standing for substitution nucleophilic bimolecular... 

The 8n2 mechanism is believed to describe most substitutions m which simple pri mary and secondary alkyl halides react with anionic nucleophiles All the examples cited in Table 8 1 proceed by the 8 2 mechanism (or a mechanism very much like 8 2— remember mechanisms can never be established with certainty but represent only our best present explanations of experimental observations) We 11 examine the 8 2 mecha nism particularly the structure of the transition state in more detail in 8ection 8 5 after hrst looking at some stereochemical studies carried out by Hughes and Ingold... 

Nucleophilic substitution had occurred with inversion of configuration consistent with the following transition state... 

Although nucleophilic participation at the transition state is slight it is enough to ensure that substitution proceeds with inversion of configuration... 

The sp hybridized carbon of an acyl chloride is less sterically hindered than the sp hybridized carbon of an alkyl chloride making an acyl chloride more open toward nude ophilic attack Also unlike the 8 2 transition state or a carbocation intermediate m an Stvfl reaction the tetrahedral intermediate m nucleophilic acyl substitution has a stable arrangement of bonds and can be formed via a lower energy transition state... 

Two modified sigma constants have been formulated for situations in which the substituent enters into resonance with the reaction center in an electron-demanding transition state (cr+) or for an electron-rich transition state (cr ). cr constants give better correlations in reactions involving phenols, anilines, and pyridines and in nucleophilic substitutions. Values of some modified sigma constants are given in Table 9.4. 

Alkyl groups under nonacidic conditions sterically deflect nucleophiles from C, but under acidic conditions this steric effect is to some extent offset by an electronic one the protonated oxirane opens by transition states (Scheme 40) which are even more 5Nl-like than the borderline Sn2 one of the unprotonated oxirane. Thus electronic factors favor cleavage at the more substituted carbon, which can better support a partial positive charge the steric factor is still operative, however, and even under acidic conditions the major product usually results from Cp attack. 

For many secondary sulfonates, nucleophilic substitution seems to be best explained by a concerted mechanism with a high degree of carbocation character at the transition state. This has been described as an exploded transition state. Both the breaking and forming bonds are relatively weak so that the carbon has a substantial positive charge. However, the carbocation per se has no lifetime because bond breaking and fonnadon occur concurrently."... 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

In this reaction I" is the nucleophile, and Br" is called the leaving group (or nucleofuge). Beyond this, the classification symbolism may include a designation of the molecularity of the reaction. Molecularity is the number of reactant molecules included in the transition state. The above reaction is an 8 2 reaction, because both reactants are present in the transition state. On the other hand, this substitution... 

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