Leaving group solvent effects

The most comprehensive examination of the Rokita kinetic procedure from a synthetic standpoint was carried out by Barrero and coworkers.6 They examined the effects of various leaving groups, solvents, nucleophiles, and their equivalents on subsequent [4 + 2] cycloadditions. Avast excess of the intended nucleophile (50-100 equiv) must be employed, because the fluoride triggered (3-elimination proves nearly instantaneous at room temperature resulting in a high concentration of a species that is prone to undergo dimerization and other undesired side reactions that are irreversible at these low temperatures (Fig. 4.7). Use of fewer equivalents of the intended nucleophile led to a rapid drop off in yield. For example, 5-10 equivalents of ethoxy vinyl ether (EVE) affords only a 5-10% yield of the desired benzopyran... 

The effects of leaving group, solvent, and nucleophile, on the kinetics of aminolysis of a series of substituted aryl diphenylphosphinates and their mono and dithio analogues have been investigated. ... 

SN1 Very strong effect reaction favored by polar solvents Weak effect reaction favored by good nucleophile/weak base Strong effect reaction favored by good leaving group Strong effect reaction favored by 3°, allylic, and benzylic substrates... 

Reactions of (ii)-l-decenyl(phenyl)iodonium salt (6a) with halide ions have been examined under various conditions. The products are those of substitution and elimination, usually (Z)-l-halodec-l-ene (6b) and dec-l-yne (6c), as well as iodobenzene (6d), but F gives exclusively elimination. In kinetic studies of secondary kinetic isotope effects, leaving-group substituent effects, and pressure effects on the rate, the results are compatible with the in-plane vinylic mechanism for substitution with inversion. The reactions of four ( )-jS-alkylvinyl(phenyl)iodonium salts with CP in MeCN and other solvents at 25 °C have been examined. Substitution with inversion is usually in competition with elimination to form the alk-l-yne. 

Table III-52 indicates the kinetic data for quatemization of 2- and 4-alkylthiazoles. The 8 value shows that the 4-positioiH more sensitive than the 2-position to steric effects, the bond angle HjCjN (123°6) being greater than that of HjQN (119 4). This result has been confirmed for all solvents and leaving groups (256).

Winstein suggested that two intermediates preceding the dissociated caibocation were required to reconcile data on kinetics, salt effects, and stereochemistry of solvolysis reactions. The process of ionization initially generates a caibocation and counterion in proximity to each other. This species is called an intimate ion pair (or contact ion pair). This species can proceed to a solvent-separated ion pair, in which one or more solvent molecules have inserted between the caibocation and the leaving group but in which the ions have not diffused apart. The free caibocation is formed by diffusion away from the anion, which is called dissociation. 

We will discuss shortly the most important structure-reactivity features of the E2, El, and Elcb mechanisms. The variable transition state theoiy allows discussion of reactions proceeding through transition states of intermediate character in terms of the limiting mechanistic types. The most important structural features to be considered in such a discussion are (1) the nature of the leaving group, (2) the nature of the base, (3) electronic and steric effects of substituents in the reactant molecule, and (4) solvent effects. 

In the El mechanism, the leaving group has completely ionized before C—H bond breaking occurs. The direction of the elimination therefore depends on the structure of the carbocation and the identity of the base involved in the proton transfer that follows C—X heterolysis. Because of the relatively high energy of the carbocation intermediate, quite weak bases can effect proton removal. The solvent m often serve this function. The counterion formed in the ionization step may also act as the proton acceptor ... 

The leaving group in the alkylating reagent has a major effect on whether C- or O-alkylation occurs. In the case of the lithium enolate of acetophenone, for example, C-alkylation is predominant with methyl iodide, but C- and O-alkylation occur to approximately equal extents with dimethyl sulfate. The C- versus O-alkylation ratio has also been studied for the potassium salt of ethyl acetoacetate as a function of both solvent and leaving group. ... 

When a positively charged substituent such as the trimethylam-monio group is anywhere on the ring, but most effectively when it is ortho to the leaving group, it can favorably affect the entropy of activation with anionic nucleophiles and accelerate reaction. A recent example of reagent-substituent interaction is the electrophilic substitution of 2-carboxybiphenyl, nitration (non-polar solvent) of which occurs only at the 2 -position and not the 4 -position and has been postulated to be due to the interaction of the nitronium ion with the carboxyl group. 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

The effects on SN2 reactions of the four variables—substrate structure, nucleophile, leaving group, and solvent—are summarized in the following statements and in the energy diagrams of Figure 11.7 ... 

Figure 11.7 Energy diagrams showing the effects of (a) substrate, (b) nucleophile, (c) leaving group, and (d) solvent on Sn2 reaction rates. Substrate and leaving group effects are felt primarily in the transition state. Nucleophile and solvent effects are felt primarily in the reactant ground state.

For Sn2 reactions in solution, there are four main principles that govern the effect of the nucleophile on the rate, though the nucleophilicity order is not invariant but depends on substrate, solvent, leaving group, and so on. 

---