Kinetic studies nucleophilic substitution

The kinetics of nucleophilic substitution reactions have been studied in greater detail than any other type of reaction because they don t always proceed through the same mechanism. Consider the reaction between the OH ion and t-butyl bromide, for example. 

The kinetics of nucleophilic substitution at the silicon atom assisted by uncharged nucleophiles have been studied by Corriu et at. (248-251). Hydrolysis of triorganochlorosilanes induced with HMPA, DMSO, and DMF was used as the model. The reaction proceeded according to the third-order kinetic law, first order with respect to the nucleophile, the silane, and the silylation substrate. Very low values of activation enthalpy and high negative entropy of activation were observed (Table VI). These results were taken as evidence for the intermediacy of silicon hypervalent species (249,251) however, they are also perfectly consistent with... 

In this chapter we report on an investigation of the kinetics of this reaction with several monomers. Bunnett and Levitt have studied the kinetics of nucleophilic substitution between p-substituted bromobenzenes and sodium methoxide (1) and found these reactions to be second order. Therefore, for a polymer-forming reaction between difunctional reactants, one would expect a second-order reaction with respect to the concentra-... 

Pearson and Sweigart have reported one of the first kinetic studies involving substitution at square-planar nickel(n), in Ni"-dithiolate complexes. They discuss nucleophilic reactivity, leaving group, and trans effects, and report that the reactions follow an associative pathway, as expected. The solvent path is not important and, although for Pt" the formation of a five-co-ordinate intermediate may be rate-determining, for Ni" this step is fast compared with subsequent steps. The formation constant of the five-co-ordinate intermediate does, however, markedly affect the overall rates, and it seems that the trans effect for nickel(ii) operates through the stability of this intermediate. 

The kinetics of nucleophilic substitution of the methoxy group in methoxy-butenone by the diethylamino group has been studied (91 Mil).Thus, the reactions of 4-heterobut-3-en-2-ones with amines presented below often involve the transamination step. 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

The mechanisms by which nucleophilic substitution takes place have been the subject of much study Extensive research by Sir Christopher Ingold and Edward D Hughes and their associates at University College London during the 1930s emphasized kinetic and stereochemical measurements to probe the mechanisms of these reactions... 

The first mechanistic studies of silanol polycondensation on the monomer level were performed in the 1950s (73—75). The condensation of dimethyl sil oxanediol in dioxane exhibits second-order kinetics with respect to diol and first-order kinetics with respect to acid. The proposed mechanism involves the protonation of the silanol group and subsequent nucleophilic substitution at the siHcone (eqs. 10 and 11). 

Nucleophilic Substitution. The kinetics of the bimolecular nucleophilic substitution of the chlorine atoms in 1,2-dichloroethane with NaOH, NaOCgH, (CH2)3N, pyridine, and CH COONa in aqueous solutions at 100—120°C has been studied (24). The reaction of sodium cyanide with... 

The reactivity of halogens in pyridazine N- oxides towards nucleophilic substitution is in the order 5 > 3 > 6 > 4. This is supported by kinetic studies of the reaction between the corresponding chloropyridazine 1-oxides and piperidine. In general, the chlorine atoms in pyridazine A-oxides undergo replacement with alkoxy, aryloxy, piperidino, hydrazino, azido, hydroxylamino, mercapto, alkylmercapto, methylsulfonyl and other groups. 

Kinetic studies have shown that the enolate and phosphorus nucleophiles all react at about the same rate. This suggests that the only step directly involving the nucleophile (step 2 of the propagation sequence) occurs at essentially the diffusion-controlled rate so that there is little selectivity among the individual nucleophiles. The synthetic potential of the reaction lies in the fact that other substituents which activate the halide to substitution are not required in this reaction, in contrast to aromatic nucleophilic substitution which proceeds by an addition-elimination mechanism (see Seetion 10.5). 

Most of the kinetic measures of solvent effects have been developed for the study of nucleophilic substitution (Sn) at saturated carbon, solvolytic reactions in particular. It may, therefore, be helpful to give a brief review of aliphatic nucleophilic substitution. Two mechanistic routes have been clearly identified. One of these is shown by... 

All the reactions discussed in this review are aromatic nucleophilic substitutions in the ordinary sense. These reactions are briefiy described in the following sections with respect to their general kinetic features and mainly involve aza-activated six-membered ring systems, although a few studies of other heteroaromatic compounds are also available. 

It is quite reasonable to expect the bimolecular two-stage mechanism Sj Ar ) to predominate in most aromatic nucleophilic substitutions of activated substrates. However, only in rare instances is there adequate evidence to rule out the simultaneous occurrence or predominance of other mechanisms. The true significance of the alternative mechanisms in azines needs to be determined by trapping the intermediates or by applying modem separation and characterization methods to the identification of at least the major portion of the products, especially in kinetic studies. 

It should be pointed out that the existence of stable structures of the intermediate-complex type (also known as a-complexes or Wheland complexes) is not of itself evidence for their being obligate intermediates in aromatic nucleophilic substitution. The lack of an element effect is suggested, but not established as in benzene derivatives (see Sections I,D,2 and II, D). The activated order of halogen reactivity F > Cl Br I has been observed in quantita-tivei36a,i37 Tables II, VII-XIII) and in many qualitative studies (see Section II, D). The reverse sequence applies to some less-activated compounds such as 3-halopyridines, but not in general.Bimolecular kinetics has been established by Chapman and others (Sections III, A and IV, A) for various reactions. 

In Scheme IV, intranuclejar activation is depicted. Kinetic studies with ionic nucleophiles show a variable relationship between the rates of reaction ortho and para to an azine-nitrogen (348 vs. 353 or 349) or nitro group due to entropy effects the energy of activation is expected on further study to be consistently lower for the para-position. The relative reactivity of 2- and 4-substituted bicyclic azines... 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

In contrast, Cozzi and Umani-Ronchi found the (salen)Cr-Cl complex 2 to be very effective for the desymmetrization of meso-slilbene oxide with use of substituted indoles as nucleophiles (Scheme 7.25) [49]. The reaction is high-yielding, highly enantioselective, and takes place exclusively at sp2-hybridized C3, independently of the indole substitution pattern at positions 1 and 2. The successful use of N-alkyl substrates (Scheme 7.25, entries 2 and 4) suggests that nucleophile activation does not occur in this reaction, in stark contrast with the highly enantioselective cooperative bimetallic mechanism of the (salen)Cr-Cl-catalyzed asymmetric azidolysis reaction (Scheme 7.5). However, no kinetic studies on this reaction were reported. 

A kinetic study of the nucleophilic substitution of Cl in [FeCp(PhCl)]+ BF by these different N-, O-, and S-anionic nucleophiles was performed using the titration of displaced Cl- by AgN03. The reactivity order increases according to the sequence ... 

A long series of studies of aromatic nucleophilic substitution included the kinetics of reactions of l-chloro-2,4-bis(trifluoromethylsulfonyl)benzene, 3-nitro-4-chlorophenyl trifluoromethyl sulfone and 2-chlorophenyl trifluoromethyl sulfone with sodium methox-ide or ammonia in methanol . The SO2CF3 group was found to have an enormous accelerating effect, in accord with the value of 1.65, based on the dissociation of anilinium ion. Further examples of the promotion of nucleophilic aromatic substitution by fluoro-substituted sulfonyl groups are given by Yagupol skii and coworkers . 

In basic aqueous media, a kinetic study of the reaction between stannate(II) ions and alkyl halide shows that mono- and disubstituted organotin compounds are formed (Eq. 6.12a).27 The monosubstituted organotin compound is obtained after a nucleophilic substitution catalyzed by a complexation between the tin(II) and the halide atom. The disubstituted compound results from an electrophilic substitution coupled with a redox reaction on a complex between the monosubstituted organotin compound and the stannate(II) ion. Stannate(IV) ions prevent the synthesis of the disubstituted compound by complexation. Similarly, when allyl bromide and tin were stirred in D2O at 60° C, allyltin(II) bromide was formed first. This was followed by further reaction with another molecule of allyl bromide to give diallyltin(IV) dibromide (Eq. 6.12b).28... 

Nucleophilic substitution reactions in the selenophene series have attracted some interest. Debromination of bromonitro compounds [(50, X = S, Se) and (53, X = S, Se)] with sodium thiophenoxide and sodium selenophen-oxide72 was studied. Selenophene compounds were four times more reactive than the thiophene derivatives. The position of attack, a or /), had very little influence on the rate ratio. The kinetics of the side-chain nucleophilic reactions of selenophene derivatives, shown in Scheme 4, has been reported.7 3... 

After 20 years pharmacological interest in nitrofurans is as strong as ever, and still prompts studies including nucleophilic substitutions. Kinetic studies of the replacement of halogen by dimethylamine in 5-halo-2-nitrofurans yield second order rate constants and disclose spectroscopic (IR, UV, and... 

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 results of a thorough study of the kinetics, products and stereochemical course for the nucleophilic substitution and elimination reactions of ring-substituted 9-(l-Y-ethyl)fluorenes ([31]-Y, Y = Br, I, brosylate) have been reported (Scheme 19).121,122. The reactions of the halides [31]-Br and [31]-I were proposed to proceed exclusively by a solvent-promoted ElcB reaction or an E2 reaction with a large component of hydron transfer in the transition state .122... 

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