Stepwise nucleophilic substitution intermediates

Benzotrichloride Method. The central carbon atom of the dye is supplied by the trichloromethyl group fromy>-chlorobenzotrichloride. Both symmetrical and unsymmetrical triphenylmethane dyes suitable for acrylic fibers are prepared by this method. 4-Chlorobenzotrichloride is condensed with excess chlorobenzene in the presence of a Lewis acid such as aluminium chloride to produce the intermediate aluminium chloride complex of 4,4, 4"-trichlorotriphenylmethyl chloride (18). Stepwise nucleophilic substitution of the chlorine atoms of this intermediate is achieved by successive reactions with different a.rylamines to give both symmetrical (51) and unsymmetrical dyes (52), eg, N-(2-chlorophenyl)-4-[(4-chlorophenyl) [4-[(3-methylphenyl)imino]-2,5-cyclohexadien-l-yhdene]methyl]benzenaminemonohydrochloride [85356-86-1] (19) from / -toluidine and a-chloroaniline. 

Imidoyl isothiocyanates 74 are readily available through stepwise nucleophilic substitution of iV-phenyl(phenyl-imino)methylchloromethanimidoyl chloride with secondary amines and potassium thiocyanate. Subsequent thermal intramolecular cyclization of intermediates 74 affords substituted 1,3,5-benzotriazocine derivatives 75 (Equation 8 <2005ARK96>). 

Similar qualitative relationships between reaction mechanism and the stability of the putative reactive intermediates have been observed for a variety of organic reactions, including alkene-forming elimination reactions, and nucleophilic substitution at vinylic" and at carbonyl carbon. The nomenclature for reaction mechanisms has evolved through the years and we will adopt the International Union of Pure and Applied Chemistry (lUPAC) nomenclature and refer to stepwise substitution (SnI) as Dn + An (Scheme 2.1 A) and concerted bimolecular substitution (Sn2) as AnDn (Scheme 2.IB), except when we want to emphasize that the distinction in reaction mechanism is based solely upon the experimentally determined kinetic order of the reaction with respect to the nucleophile. 

The benzylic substrates X-l-Y and X-2-Y have provided a useful platform for examining the changes in reaction mechanism for nucleophilic substitution that occur as the lifetime of the carbocation intermediate is decreased systematically by varying the meta- and para- aromatic ring substituents. When X is strongly resonance electron-donating, X-l-Y and X-2-Y react by a stepwise mechan-... 

The point of the change from a stepwise to a concerted mechanism for nucleophilic substitution at X-l-Cl may be detected as an upward break in the observed nucleophile selectivity nu/ s with decreasing stability of the putative intermediate X-1 (Fig. 2.2). Figure 2.5 shows that the position of this break and the change in mechanism shifts to more electron-withdrawing X as the reactivity of the nucleophile is decreased, from X = 4-F for... 

The change from a stepwise preassociation mechanism through a triple ion intermediate to an uncoupled concerted reaction occurs as the triple ion becomes too unstable to exist in an energy well for the time of a bond vibration ( 10 s). The borderline between these two reaction mechanisms is poorly marked, and there are no clear experimental protocols for its detection. These two reaction mechanisms cannot be distinguished by experiments designed to characterize their transition states, which lie at essentially the same position in the inner upper right hand corner of Figure 2.3. Only low yields of the nucleophilic substitution product are obtained from both stepwise preassociation and uncoupled concerted reactions, because for formation of the preassociation complex in water is small... 

Nucleophilic Substitution at Benzyl Derivatives. The sharp break from a stepwise to a concerted mechanism that is observed for nucleophilic substitution of azide ion at X-l-Y (Figs. 2.2 and 2.5) is blurred for nucleophilic substitution at the primary 4-methoxybenzyl derivatives (4-MeO,H)-3-Y. For example, the secondary substrate (4-MeO)-l-Cl reacts exclusively by a stepwise mechanism through the liberated carbocation intermediate (4-MeO)-T, which shows a moderately large selectivity toward azide ion ( az/ s = 100 in 50 50 (v/v) water/ trifluoroethanol). The removal of an a-Me group from (4-MeO)-l-Cl to give (4-MeO,H)-3-Cl increases the barrier to ionization of the substrate in the stepwise reaction relative to that for the concerted bimolecular substitution of azide ion. The result is that both of these mechanisms are observed concurrently for nucleophilic substitution of azide ion at (4-MeO,H)-3-Cl in water/acetone solvents. These concurrent stepwise and concerted nucleophilic substitution reactions of azide ion with (4-MeO,H)-3-Cl show that there is no sharp borderline between mechanisms for substitution at primary benzylic carbon, but instead a region of overlap where both mechanisms are observed. 

Generally, only a single stepwise or concerted pathway for aliphatic nucleophihc substitution is detected by experiment because of the very different activation barriers for formation of the respective reaction transition states for these reactions. The description of the borderline between stepwise and concerted nucleophilic substitution reactions presented in this chapter has been obtained through a search for those rare substrates that show comparable barriers to these two reactions and through the characterization of the barrier for nucleophile addition to the putative carbocation intermediate of the stepwise reaction in the region of this change in mechanism. 

The description of the borderline between stepwise and concerted nucleophilic substitution remains murky in cases where there is no significant stabilization of the transition state for the concerted reaction through the coupling of bond cleavage and formation. The reason is that there are no simple experimental protocols to detect the point at which the energy well for the carbocation intermediate of the stepwise reaction in the upper right hand corner of Figure 2.3 is transformed into... 

Stepwise pyrazine ring-formation using 5-nitropyrimidine was applied to the synthesis of 4a-hydroxytetrahydrobiopterin (95), which is an interesting intermediate in the metabolism of aromatic amino acids (see Sect. 5.2). As illustrated in Scheme 18, the 5-aminopyrimidine 97 prepared from chloroni-tropyrimidine 96 by nucleophilic substitution followed by catalytic hydrogenation was oxidized under acidic conditions to o-quinone derivative 98. 

Nucleophilic substitution reactions of dansyl chloride with anilines (entry 16)128 are reported in various protic solvents. Interestingly, the Px values are in parallel with the rates, which are dependent on the dielectric constant (e)49 of the solvent as can be seen from the data presented for each solvent in the order [e k2 (xlO4 M 1 s 1 at 30 °C for X = H) px], MeOH [32.66 107 0.67], EtOH [24.55 37.7 0.55], w-PrOH [20.45 8.71 0.50], 2-PrOH [19.92 5.33 0.41], n-BuOH [17.51 3.07 0.34], MeCN [35.94 13.7 0.72]. In the aprotic solvent MeCN, the rate is somewhat slow despite the largest s and Px values. Since the reactivity changes in parallel to the selectivity, the RSP is violated, and a stepwise mechanism through an intermediate can be excluded. Solvatochromic analysis also suggested that the reaction proceeds via an associative S 2 mechanism. 

Fig. 4.7. Two-dimensional reaction energy diagram showing concerted, ion pair intermediate, and stepwise mechanisms for nucleophilic substitution.

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