Stepwise nucleophilic substitution

In this chapter we review published results of studies of the kinetics and products of stepwise nucleophilic substitution and elimination reactions of alkyl derivatives, and we present a small amount of unpublished data from our laboratory. Our review of the literature is selective rather than comprehensive, and focuses on work that provides interesting insight into the factors that control the rate constant ratio ks/kp for partitioning of carbocations, and that provides an understanding of how the absolute rate constants ks and kp that constitute this ratio change with changing carbocation structure. 

The thiadiazoline (50) (Ar = p-Tol) reacts with electron-deficient alkynes (51) to give arylimino-thiazoles (53). It has been suggested that the reaction proceeds via a 1,3-dipolar cycloadduct (52) (Scheme 13) <75TL459> or by a stepwise nucleophilic substitution reaction <84CHEC-I(6)463>. 

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. 

The authors of this review article suggest that the results indicated in Schemes 34, 35 and 36 are consistent with a stepwise nucleophile substitution mechanism (64JA107) as outlined in Scheme 37. When Z is nitrogen the driving force for the reaction is the ease of cleavage of the N—S bond by a soft nucleophile with a concerted elimination of phenylcyanamide. In the thiazole (Z = CH), however, the stable C—S bond precludes ring fission by a nucleophilic attack at sulfur and the initial adduct (79) (presumably trans) is obtained as a stable product. 

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>). 

Fig. 5.7. Mote O Ferrall-Jencks diagtam showing concerted, ion-pair and stepwise mechanisms for nucleophilic substitution.

Nucleophilic substitution has been used for the preparation of many thiophenes. For instance, 2-phenylthio-3,4-dinitro-5-piperidino-thiophene (155) has been prepared " through stepwise reaction of (150) with different nucleophiles. Nitrothienols and derivatives of them have been obtained from halogenated nitrothiophenes. " Allyl ethers have been prepared by the reaction of 5-chJoro-4-nitro-2-acetylthiophene, 3-nitro-2-chlorothiophene, and 2-nitro-3-bromothio-... 

Aliphatic substrates that contain a good leaving group and an a-CH group may undergo reactions by competing nucleophilic substitution and elimination pathways (Scheme l).1 A stepwise mechanism is favored for these reactions... 

Reactions and reactivity of nucleophiles with thiolsulfonates 137 Nucleophilic substitutions of sulfenyl derivatives general considerations 139 Bimolecular substitution at sulfenyl sulfur stepwise or concerted 140 Reversibility in reactions of nucleophiles with cyclic thiolsulfonates 145 Other reactions of thiolsulfonates 147... 

Reactivity toward nucleophiles and comparison with other electrophilic centers 152 Paths for nucleophilic substitution of sulfonyl derivatives 156 Direct substitution at sulfonyl sulfur stereochemistry 157 Direct substitution at sulfonyl sulfur stepwise or concerted 158 The elimination-addition path for substitution of alkanesulfonyl derivatives 166 Homolytic decomposition of a-disulfones 172 10 Concluding remarks 173 Acknowledgement 174 References 174... 

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-... 

Students of reaction mechanism will recognize intuitively that the difference between the narrow and broad borderline regions observed for nucleophilic substitution of azide ion at secondary and tertiary carbon (Fig. 2.2) is due to the greater steric hindrance to bimolecular nucleophilic substitution at the tertiary carbon. This leads to a large difference in the effects of an a-Me group on (s ) for the stepwise solvolysis and s ) for concerted bimolecular nucleophilic... 

The yield of the nucleophilic substitution product from the stepwise preassociation mechanism k[ = k. Scheme 2.4) is small, because of the low concentration of the preassociation complex (Xas 0.7 M for the reaction of X-2-Y). Formally, the stepwise preassociation reaction is kinetically bimolecular, because both the nucleophile and the substrate are present in the rate-determining step ( j). In fact, these reactions are borderline between S l and Sn2 because the kinetic order with respect to the nucleophile cannot be rigorously determined. A small rate increase may be due to either formation of nucleophile adduct by bimolecular nucleophilic substitution or a positive specific salt effect, whUe a formally bhnole-cular reaction may appear unimolecular due to an offsetting negative specific salt effect on the reaction rate. 

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... 

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