Direct displacement mechanism

The ionization and direct displacement mechanisms can be viewed as the extremes of a mechanistic continuum. At the 8 1 extreme, there is no covalent interaction between the reactant and the nucleophile in the transition state for cleavage of the bond to the leaving group. At the 8 2 extreme, the bond formation to the nucleophile is concerted with the bondbreaking step. In between these two limiting cases lies the borderline area, in which the degree of covalent interaction between the nucleophile and the reactant is intermediate between the two limiting cases. The concept of ion pairs is important in the consideration of... 

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... 

There is disagreement about the importance of the direct displacement mechanism in these reactions. Yet another mechanistic possibility is for reaction via the acylium ion. Scheme IV. 

Secondary bromides and tosylates react with inversion of stereochemistry, as in the classical SN2 substitution reaction.24 Alkyl iodides, however, lead to racemized product. Aryl and alkenyl halides are reactive, even though the direct displacement mechanism is not feasible. For these halides, the overall mechanism probably consists of two steps an oxidative addition to the metal, after which the oxidation state of the copper is +3, followed by combination of two of the groups from the copper. This process, which is very common for transition metal intermediates, is called reductive elimination. The [R 2Cu] species is linear and the oxidative addition takes place perpendicular to this moiety, generating a T-shaped structure. The reductive elimination occurs between adjacent R and R groups, accounting for the absence of R — R coupling product. 

Perhaps the most important conclusion to be drawn from this discussion of polar effects is that there is no evidence of extensive bond-breaking in the transition state, as there surely should be if a direct displacement mechanism were involved. But the evidence is entirely consistent with a mechanism involving the largely rate-determining formation of a tetrahedral addition intermediate. 

In experiments of major importance, first published in 1950, Melander found that in the nitration and bromination of a number of benzene derivatives the tritium isotope effect (kHlkT) is not 10-20 as is to be expected if carbon-hydrogen bond breaking occurs in the rate-determining step, but rather is less than 1.3. The direct displacement mechanism was thus ruled out, and the two-step mechanism of Equation 7.70 with the first step rate-determining was implicated.157... 

From the very limited evidence available, it appears that when an octahedral substitution proceeds via direct displacement, there is only a minor amount of d,l or cis-trans interconversion—that is, configuration is primarily retained. This is the case for a large number of conversions of the complexes of Pt(IV), and a smaller number of conversions involving complexes of Co(III), Cr(III), Rh(IlI). and Ir(III)—all of these may not involve the direct displacement mechanism, but some almost certainly do. Thus, we see a marked contrast to substitution reactions of tetrahedral carbon, where every act of displacement results in inversion of configuration. 

Evidence for a radical pathway includes the observation that the reaction is accelerated by radical initiators (such as oxygen or peroxides) and the presence of UV light. Moreover, the order of reactivity for the R group is IIP > II0 > 1°, which is inconsistent with a direct displacement mechanism, but is in accord with the stability of alkyl radicals. Radical inhibitors (such as steri-cally hindered phenols) retard the rate of reaction with sterically-hindered alkyl halides, but not when R = methyl, allyl, and benzyl. When stereoisomerically pure alkyl halides are used, OA results in the formation of a 1 1 mixture of stereoisomeric alkyl iridium complexes, consistent with the formation of an intermediate radical R-. 

In the acid-catalysed exchange of optically active s-butyl alcohol (1), Bunton et al. (1955b) found that kex(.hjkT c = 0-5 (see Table 1), which is compatible with the direct displacement mechanism (b). However, other... 

The general trends of reactivity of primary, secondary, and tertiary systems have already been discussed. Reactions that proceed by the direct displacement mechanism are retarded by increased steric repulsions at the TS. This is the principal cause for the relative reactivity of methyl, ethyl, and i-propyl chloride, which are in the ratio 93 1 0.0076 toward iodide ion in acetone. A statistical analysis of rate data for a... 

Adjacent carbonyl groups also affect reactivity. Substitution by the ionization mechanism proceeds slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 304, such substituents destabilize a carbocation intermediate, but substitution by the direct displacement mechanism proceeds especially readily in these systems. Table 4.10 indicates some representative relative rate accelerations. 

Recent computational work has suggested the existence of a mechanism for aminolysis that bypasses the tetrahedral intermediates. Transition structures corresponding to both stepwise addition-elimination through a tetrahedral intermediate and direct substitution were found for the reaction of methylamine with methyl acetate and phenyl acetate. There is considerable development of charge separation in the direct displacement mechanism because proton transfer lags rupture of the C—O bond. 

You have seen that nucleophilic acyl substitution reactions take place by a mechanism in which a tetrahedral intermediate is formed and subsequently collapses. The tetrahedral intermediate, however, is too unstable to be isolated. How, then, do we know that it is formed How do we know that the reaction doesn t take place by a one-step direct-displacement mechanism (similar to the mechanism of an Sn2 reaction) in which the incoming nucleophile attacks the carbonyl carbon and displaces the leaving group—a mechanism that would not form a tetrahedral intermediate ... 

To answer this question, Myron Bender investigated the hydroxide-ion-promoted hydrolysis of ethyl benzoate, with the carbonyl oxygen of ethyl benzoate labeled with 0. When he isolated ethyl benzoate from an incomplete reaction mixture, he found that some of the ester was no longer labeled. If the reaction had taken place by a one-step direct-displacement mechanism, all the isolated ester would have remained labeled because the carbonyl group would not have participated in the reaction. On the other hand, if the mechanism involved a tetrahedral intermediate, some of the isolated ester would no longer be labeled because some of the label would have been transferred to the hydroxide ion. By this experiment. Bender provided evidence for the reversible formation of a tetrahedral intermediate. 

It should be noted that alternative mechanisms, involving bimolecular displacement of DAG from PIP2, have not been ruled out. Dawson et al. (1971) noted that production of I(1,4,5)P3 may result from direct attack of hydroxide on the diester phosphorus atom of PIPj. This direct displacement mechanism (overall inversion) may be differentiated from the doubledisplacement mechanism via cyclic phosphate (retention) by stereochemical analysis using the chiral phosphate technique. Postulated pathways without the intermediacy of a cyclic 1,2-phosphate require a separate mechanism for production of cyclic inositol phosphates or alternatively a rapid cyclase reaction catalysed by the tissue extract used in in vitro studies. 

The limiting cases of nucleophilic substitution have been described as the ionization mechanism (SnI, substitution-nucleophilic-unimolecular) and the direct displacement mechanism (8 2, substitution-nucleophilic-bimolecular Gleave et al., 1935). The S l and Sn2 mechanisms describe the extremes in nucleophilic substitution reactions. Pure SnI and Sn2 reaction mechanisms, however, are rarely observed. More often a mix of these reaction mechanisms are occurring simultaneously. 

A concerted reaction must be stereospecific. The mechanism described by Fig. 5.2 requires inversion of configuration. An alternative direct displacement mechanism involving front-side attack would also exhibit second-order kinetics and respond similarly to structural and medium effects, but would require retention of configuration as the stereochemical course. As we shall see, the available data support fully the mechanism involving back-side displacement. Additionally, SCF-MO calculations of the hypothetical transition states for hydride displacement of hydride from methane indicate that the inversion geometry is 14.9 kcal/mol more favorable than the retention geometry ... 

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