Nucleophilic substitution reactions second order kinetics

The points that we have emphasized in this brief overview of the S l and 8 2 mechanisms are kinetics and stereochemistry. These features of a reaction provide important evidence for ascertaining whether a particular nucleophilic substitution follows an ionization or a direct displacement pathway. There are limitations to the generalization that reactions exhibiting first-order kinetics react by the Sj l mechanism and those exhibiting second-order kinetics react by the 8 2 mechanism. Many nucleophilic substitutions are carried out under conditions in which the nucleophile is present in large excess. When this is the case, the concentration of the nucleophile is essentially constant during die reaction and the observed kinetics become pseudo-first-order. This is true, for example, when the solvent is the nucleophile (solvolysis). In this case, the kinetics of the reaction provide no evidence as to whether the 8 1 or 8 2 mechanism operates. 

A mechanism that accounts for both the inversion of configuration and the second-order kinetics that are observed with nucleophilic substitution reactions was suggested in 1937 by E. D. Hughes and Christopher Ingold, who formulated what they called the SN2 reaction—short for substitution, nucleophilic, birnolecu-lar. (Birnolecular means that two molecules, nucleophile and alkyl halide, take part in the step whose kinetics are measured.)... 

Now we get to the meaning of 2 in Sn2. Remember from the last chapter that nucleophilicity is a measure of kinetics (how fast something happens). Since this is a nucleophilic substitution reaction, then we care about how fast the reaction is happening. In other words, what is the rate of the reaction This mechanism has only one step, and in that step, two things need to find each other the nucleophile and the electrophile. So it makes sense that the rate of the reaction will be dependent on how much electrophile is around and how much nucleophile is around. In other words, the rate of the reaction is dependent on the concentrations of two entities. The reaction is said to be second order, and we signify this by placing a 2 in the name of the reaction. 

Cyanide is not the only nucleophile to effect reactions as in Scheme 35, C, but of those studied so far only benzenesulfinate and phenoxide are similar (and also show second order kinetics) while others give simple substitution with no rearrangement (and show first order kinetics). No doubt ionization to a furylium ion plays an important part in some of these transformations, but it is harder to account for the behavior of 70 which yields a lactone (71) and almost no cyano products.198... 

The usual kinetic law for S/v Ar reactions is the second-order kinetic law, as required for a bimolecular process. This is generally the case where anionic or neutral nucleophiles react in usual polar solvents (methanol, DMSO, formamide and so on). When nucleophilic aromatic substitutions between nitrohalogenobenzenes (mainly 2,4-dinitrohalogenobenzenes) and neutral nucleophiles (amines) are carried out in poorly polar solvents (benzene, hexane, carbon tetrachloride etc.) anomalous kinetic behaviour may be observed263. Under pseudo-monomolecular experimental conditions (in the presence of large excess of nucleophile with respect to the substrate) each run follows a first-order kinetic law, but the rate constants (kQbs in s 1 ruol 1 dm3) were not independent of the initial concentration value of the used amine. In apolar solvents the most usual kinetic feature is the increase of the kabs value on increasing the [amine]o values [amine]o indicates the initial concentration value of the amine. 

Hence Spj2 means that the reaction involves Substitution by a Nucleophile and that it follows second-order kinetics, i.e. two species are involved in the rate-determining step. The S 2 mechanism involves only one continuous step. 

If a reaction occurs by this first mechanism, it is commonly termed an SN2 reaction (i.e., substitution, nucleophilic, bimolecular). It represents an example of a simple elementary bimolecular reaction, as we discussed in Section 12.3, and it therefore follows a second-order kinetic rate law ... 

Experimental data from nucleophilic substitution reactions on substrates that have optical activity (the ability to rotate plane-polarized light) shows that two general mechanisms exist for these types of reactions. The first type is called an S 2 mechanism. This mechanism follows second-order kinetics (the reaction rate depends on the concentrations of two reactants), and its intermediate contains both the substrate and the nucleophile and is therefore bimolecular. The terminology S 2 stands for substitution nucleophilic bimolecular. ... 

The 5-position in 1,2,4-thiadiazoles is most reactive in nucleophilic substitution reactions. Chlorine, for example, may be displaced by nucleophiles (Nu) such as fluoride, hydroxide, thiol, amino, hydrazino, sulfite and azido groups (Scheme 11). Active methylene compounds such as malonic, acetoacetic and cyanoactic esters as their sodio derivatives also displace the 5-halo substituent (65AHC(5)ll9). The reaction follows second-order kinetics, the rate determining step being addition of the nucleophile at C-5 followed by rapid elimination of X. 

The kinetics of polycondensation hy nucleophilic aromatic substitution in highly polar solvents and solvent mixtures to yield linear, high molecular weight aromatic polyethers were measured. The basic reaction studied was between a di-phenoxide salt and a dihaloaromatic compound. The role of steric and inductive effects was elucidated on the basis of the kinetics determined for model compounds. The polymerization rate of the dipotassium salt of various bis-phenols with 4,4 -dichlorodiphenylsulfone in methyl sulfoxide solvent follows second-order kinetics. The rate constant at the monomer stage was found to be greater than the rate constant at the dimer and subsequent polymerization stages. 

Other cases in which second-order kinetics seemed to require an associative mechanism have subsequently been found to have a conjugate base mechanism (called S ICB, for substitution, nucleophilic, unimolecular, conjugate base in Ingold s notation ). These reactions depend on amine, ammine, or aqua ligands that can lose protons to form amido or hydroxo species that are then more likely to lose one of the other ligands. If the structure allows it, the ligand Irons to the amido or hydroxo group is frequently the one lost. 

If the reaction occurs by such a two-step reaction (break an old bond and make a new one) (Figure 11.21), one speaks of an S/ 2 reaction (substitution, nucleophilic bimolecular) and it is given by a second-order kinetic rate law ... 

The strength of the evidence for the two mechanisms, SnI and Sn2, lies in its consistency. Nucleophilic substitutions that follow first-order kinetics also show racemization and rearrangement, and the reactivity sequence 3 > 2° > 1 > CH3X, Reactions that follow second-order kinetics show complete stereochemical inversion and no rearrangement, and follow the reactivity sequence CHjX > r > 2" > 3°. (The few exceptions to these generalizations are understandable exceptions see Problem 16.5, p. 525.)... 

Reaction of an alkyl halide or tosylate with a nucleophile/base results either in substitution or in elimination. Nucleophilic substitutions are of two types Sn2 reactions and S l reactions. In the Sn2 reaction, the entering nucleophile attacks the halide from a direction 180° away from the leaving group, resulting in an umbrella-like Walden inversion of configuration at the carbon atom. The reaction shows second-order kinetics and is strongly inhibited by increasing steric bulk of the reactants. Thus, Sn2 reactions are favored for primary and secondary substrates. 

The nucleophilic substitution reactions of anilines with ero-2-norbomyl arenesulfonates, 2, present an interesting example of the preassociation mechanism55 (Scheme 1). The rate is faster with 2-exo (k2 = 15.9 x 10 4 and 3.24 x 10-5 M 1 s 1 when X = Z = H in MeOH and MeCN at 60.0 °C, respectively) than with 2-endo (k2 = 0.552 x 10 5 M 1 s 1 with X = Z = H in MeOH at 60.0 °C). These reactions are characterized by a large pz (1.8 and 1.2 for 2-exo and 2-endo) coupled with a small magnitude of px (—0.21 and —0.15 for 2-exo and 2-endo). The pz values for the aniline reactions are even larger than those for the SY 1 solvolysis in MeOH (pz =1.5 and 1.0 for solvolysis of 2-exo and 2-endo). Thus the abnormal substituent effect in the anilinolysis of 2 can only be accounted for by the preassociation mechanism of Scheme 1. The upper route is the normal S/v 1 pathway, and the lower route is the preassociation pathway. The preassociation step, Xass, and association of the Nu to the ion pairs, kn. occur in a diffusion limited or fast process and k is the rate-limiting step. This mechanism leads to second-order kinetics and therefore is an SY/2 process, but structural effects on rates are very similar to those of S l reactions, since the R+ Z pair consists essentially of the two free ions. 

The Role of Nucleophile Solvation. The value of = 0 for the reaction of substituted pyridines with 2,4-dinitrophenyl phosphate (76) is puzzling. If the value of is a measure of the amount of the bond formation to the nucleophile in the transition state, this value might be taken to mean that there is no bond formation to the nucleophile in the transition state. This is obviously not the case, because there is a large increase in the rate of disappearance of the phosphate ester with increasing concentration of the nucleophile the reactions follow simple second-order kinetics. 

Sj,j2 a bimolecular nucleophilic substitution reaction an important type of organic reaction seen in biochemistry, the rate of the reaction follows second-order kinetics (7.6)... 

S l stands for unimolecular nucleophilic substitution. The unimolecular part means that it obeys first-order kinetics. If the reaction is R X + Z R Z + X , with an S l reaction, the rate depends on the speed with which the X breaks away from the R. The Z group comes in later and quickly, compared with the breakdown of R X. S 2 stands for bimolecular nucleophilic substitution. This happens with the same reaction scheme if the Z attacks the R X molecule before it breaks down. Thus, the concentration of both R X and Z are important, and the rate displays second-order kinetics. 

Two processes consistent with second-order kinetics both involve hydroxide ion as a nucleophile but differ in the site of nucleophilic attack. One is an 8 2 reaction, the other is nucleophilic acyl substitution. 

As is the case with nucleophilic aliphatic substitution, nucleophilic aromatic substitution (SNAr) can occur by processes that exhibit either first- or second-order kinetics. In contrast to the aliphatic reactions, however, the first-and second-order aromatic reactions are quite different in character. 

Nucleophilic substitution reactions that follow second order kinetics and takes place in one step are called S 2 reactions. The rate determining step is the formation of intermediate transition state where both the reactant molecules undergo simultaneous covalency change, i.e., in an S 2 reaction, breaking of bond between the carbon atom and leaving nucleophile and making of bond between the carbon atom and incoming nucleophile occurs simultaneously. 

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