And the leaving group

Because adjacent bonds are eclipsed when the H—C—C—X unit is syn coplanar a transition state with this geometry is less stable than one that has an anti coplanar rela tionship between the proton and the leaving group... 

The ionization mechanism for nucleophilic substitution proceeds by rate-determining heterolytic dissociation of the reactant to a tricoordinate carbocation (also sometimes referred to as a carbonium ion or carbenium ion f and the leaving group. This dissociation is followed by rapid combination of the highly electrophilic carbocation with a Lewis base (nucleophile) present in the medium. A two-dimensional potential energy diagram representing this process for a neutral reactant and anionic nucleophile is shown in Fig. 

Front-side approach is disfavored both because the density of the a orbital is less in the region between the carbon and the leaving group and because front-side approach would involve both a bonding and an antibonding interaction with the tr orbital since it has a nodal surface between the atoms. 

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. 

Attack ty acetate at C-1 of C-2 would be equally likely and would result in equal amounts of the enantiomeric acetates. The acetate ester would be exo because reaction must occur from the direction opposite the bridging interaction. The nonclassical ion can be formed directly only from the exo-brosylate because it has the proper anti relationship between the C(l)—C(6) bond and the leaving group. The bridged ion can be formed from the endo-brosylate only after an unassisted ionization. This would explain the rate difference between the exo and endo isomers. 

This valence bond description leads to an interesting conclusion. Because the transition state occurs at the point where the initial and final state VB configurations cross, the transition state receives equal contributions from each. This is so whether the transition state is early or late. Thus, the nucleophile Y and the leaving group X possess about equal charge densities in the transition state. This conclusion means that an early transition state is not (in this sense) reactantlike , for a reactantlike transition state should have most of the charge on Y. Similarly, a late transition state is not necessarily productlike. This view is at variance with other interpretations. 

The anti periplanar requirement for E2 reactions overrides Zaitsev s rule and can be met in cyclohexanes only if the hydrogen and the leaving group are trans diaxial (Figure 11.19). If either the leaving group or the hydrogen is equatorial, E2 elimination can t occur. 

E2 reaction (Section 11.8) A bimolecular elimination reaction in which both the hydrogen and the leaving group are lost in the same step. 

Substitutions. A name consists of the entering group, the syllable de , and the leaving group. If the leaving group is hydrogen, it may be omitted (in all examples, the substrate is written on the left). 

In nucleophilic substitution the attacking reagent (the nucleophile) brings an electron pair to the substrate, using this pair to form the new bond, and the leaving group (the nucleofuge) comes away with an electron pair ... 

The decarbonylation of aromatic aldehydes with sulfuric acid" is the reverse of the Gatterman-Koch reaction (11-16). It has been carried out with trialkyl- and trialkoxybenzaldehydes. The reaction takes place by the ordinary arenium ion mechanism the attacking species is H and the leaving group is HCO, which can lose a proton to give CO or combine with OH from the water solvent to give formic acid." Aromatic aldehydes have also been decarbonylated with basic catalysts." When basic catalysts are used, the mechanism is probably similar to the SeI process of 11-38. See also 14-39. 

Note that these mechanisms are the reverse of those involved in the acid-catalyzed hydration of double bonds (15-3), in accord with the principle of microscopic reversibility. With anhydrides (e.g., P2O5, phthalic anhydride) as well as with some other reagents such as HMPA, it is likely that an ester is formed, and the leaving group is the conjugate base of the corresponding acid. In these cases, the mechanism can be El or E2. The mechanism with AI2O3 and other solid catalysts has been studied extensively but is poorly understood. 

So far, we have explored the substrate, the nucleophile, and the leaving group. This takes care of all of the parts of the compounds that are reacting with each other. Let s summarize substitution reactions in a way that allows us to see this ... 

So, by talking about the substrate, the nucleophile, and the leaving group, we have covered almost everything. But there is one more thing to take into account. What solvent are these compounds dissolved in It can make a difference. Let s see how. 

Next, we need to draw the conformation in which the H (on the front carbon) and the leaving group (Cl) are antiperiplanar ... 

In contrast to the lability of certain dN adducts formed by the BHT metabolite above, amino acid and protein adducts formed by this metabolite were relatively stable.28,29 The thiol of cysteine reacted most rapidly in accord with its nucleophilic strength and was followed in reactivity by the a-amine common to all amino acids. This type of amine even reacted preferentially over the e-amine of lysine.28 In proteins, however, the e-amine of lysine and thiol of cysteine dominate reaction since the vast majority of a-amino groups are involved in peptide bonds. Other nucleophilic side chains such as the carboxylate of aspartate and glutamate and the imidazole of histidine may react as well, but their adducts are likely to be too labile to detect as suggested by the relative stability of QMs and the leaving group ability of the carboxylate and imidazole groups (see Section 9.2.3). 

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