Nucleophilic Substitution at a Tetrahedral Carbon Atom

Mechanisms of reactions of this type are broadly varied from the classical associative mechanism of bimolecular substitution Sn2 (I-+II-+III) to the classical dissociative mechanism SnI which requires the formation of the free carbocation VI, including the intermediate mechanisms of Winstein and Sneen where the contact IV or the solvent-separated V ion pairs serve as the active forms, see Ref. [12] for a detailed review. 

The geometry of the nucleophilic attack and the stereochemical outcome of a reaction are dictated by the type of the mechanism which in its turn, depends to a great extent on the solvent effects. The role of these factors has been the subject of a number of theoretical calculations which have led to a deeper understanding of the reactions in question. 

The reactions Sn2 are accompanied by the inversion of configuration of the tetrahedral carbon atom—Walden inversion, discovered as early as 1895 [13]. This result constituted the basis for the firmly established view regarding the concerted reaction mechanism whose important features are the rear-side approach of the nucleophile Y to the breaking bond C—X and the emergence of a trigonal-bipyramidal transition state structure II in Eq. (5.2)  

Energetical preferability of such a reaction path over any other has been confirmed by all semiempirical—CNDO/2 [14], INDO [15], MINDO/3 [16], MNDO [17,18]—as well as nonempirical [19-28] calculations. The principal reason for this is that the rear-side approach VII of the nucleophile provides for optimal possibilities of forming a new bond through overlapping of its lone-pair orbital with the lowest unoccupied MO of the substrate, which is, as follows from the calculations, primarily represented by the r -orbital of the C—X bond.  

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This order of reactivity correlates well with the electronegativity (induction constants) of these alkoxy groups. Compared to nucleophilic substitution at a tetrahedral carbon atom. 

It should be emphasized that these examples are not intended to show that the structures of transition states can never have the symmetry axes of the third, fifth and the higher odd orders. Thus, in the reaction of nucleophilic substitution at the tetrahedral carbon atom (Sect. 5.1) a transition state structure possessing C3-symmetry cannot be ruled out since the rotation about the C3-axis Y—C—X does not affect transformation of the reactants into the products and so corollary of Theorem 2 is not violated. 

Also the prediction has proved correct of a molecular configuration, in which intramolecular alkyl shifts are realized, i.e., an intramolecular nucleophilic substitution at the tetrahedral carbon atom. It has been found [6] that a fast (10 s at 25°C) bond-switching process associated with the rupture-formation of the C—S bonds of the anchored center does occur in the degenerate rearrangement of the l,8-fcis-(arylthio)-anthracene-9-carbinyl cation XIV in solution ... 

The electrophile shown in step 2 is the proton. In almost all the reactions considered in this chapter the electrophilic attacking atom is either hydrogen or carbon. It may be noted that step 1 is exactly the same as step 1 of the tetrahedral mechanism of nucleophilic substitution at a carbonyl carbon (p. 331), and it might be expected that substitution would compete with addition. However, this is seldom the case. When A and B are H, R, or Ar, the substrate is an aldehyde or ketone and these almost never undergo substitution, owing to the extremely poor nature of H, R, and Ar as leaving groups. For carboxylic acids and their... 

No gas-phase reactions of electrophilic substitution have been known so far, while the formation of the transition state structure of Eq. (5.9) in solution is greatly (often decisively) affected by medium factors, the specific solvation and the nucleophilic catalysis. Even though the true structure of a transition state of the Se2 reaction is much more complicated than XXIV, this structure correctly reflects the stereochemistry of substitution at the tetrahedral carbon atom, namely, the retention of configuration of the carbon atom bonds observed experimentally in most Se2 reactions (the Se2 rule. Ref. [1]). 

In many reactions at carbonyl groups, a key step is the addition of a nucleophile, which generates a tetracoordinate carbon atom. The overall course of the reaction is then determined by the fate of this tetrahedral intermediate. Addition occurs when the tetrahedral intermediate goes directly on to product. Condensation occurs if the carbonyl oxygen is eliminated and a double bond is formed. Substitution results when one of the groups is eliminated from the tetrahedral intermediate to re-form a carbonyl group. 

The net result is a substitution reaction in which the stoichiometry resembles that of an Sj 2 substitution reaction of haloalkanes. However, an Sj 2 reaction occurs in a single step in which the nucleophile bonds to the carbon atom as the leaving group leaves. Nucleophilic acyl substitution occurs in two steps, and the rate-determining step is usually nucleophilic attack at the carbonyl carbon atom to form a tetrahedral intermediate. The loss of the leaving group occurs in a second, faster step. 

The reactions of carboxylic acids and their derivatives are characterized by nucleophilic addition-elimination at their acyl (carbonyl) carbon atoms. The result is a substitution at the acyl carbon. Key to this mechanism is formation of a tetrahedral intermediate that returns to a carbonyl group after the elimination of a leaving group. We shall encounter many reactions of this general type, as shown in the following box. 

Unlike Sn2 displacements at saturated carbon, which proceed in a single step of synchronous bond-breaking and bond-formation, these substitutions have been discussed most frequently in terms of an intermediate complex, formed by addition of the nucleophile to the carbon atom undergoing substitution and converting that carbon atom to one with its substituents arranged in a tetrahedral configuration. For the reaction of 2,4-dinitrochlorobenzene and methoxide ion the intermediate complex would have a structure of the type indicated by II. It is, at this time, pertinent to consider in detail the nature of the evidence for such an intermediate. 

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