Nucleophilicity kinetic concept

Now we can understand the difference between nucleophilicity and basicity. Nncleophilicity measures how fast things happen, which is called kinetics. Basicity measnres stability and the position of equilibrium, which is called thermodynamics. Throughout your course, you will see many reactions where the prodnct is determined by kinetic concepts, and yon will also see many reactions where the prodnct is determined by thermodynamic concepts. In fact, there will even be times where these two factors are competing with each other and you will need to make a choice of which factor wins kinetics or thermodynamics. 

We saw in Chapter 8 (Section 8.3) that the difference between bases and nucleophiles is function. We even saw the difference between the terms nucleophilic-ity (which is a kinetic concept) and basicity (which is a thermodynamic concept). But there is another important difference between the strengths of bases and nucleophiles that you must know. Students rarely see this difference, and it causes them much unnecessary anguish when doing problems that involve substitution and elimination reactions at the same time (we will do problems like this in Chapter 12). Let s avoid the anguish by clearing up the difference now. 

Nucleophilicity and basicity are inherently related, because both involve donation of electrons. Although one definition is that a nucleophile is "an electron pair donor, i.e., a Lewis base," we often consider nucleophilicity to be a kinetic concept (equation 8.34), whereas basicity is usually considered to be an equilibrium concept (equation 8.35). ° ... 

Nucleophilicity and electrophilicity are closely related to Lewis basicity and acidity, respectively. Nucleophiles are Lewis bases (electron-pair donors) and electrophiles are Lewis acids (electron-pair acceptors). Now, as discussed previously, nucleophilicity is measured in terms of the rate of a nucleophilic attack, so it s a kinetic concept. Basicity, on the other hand, is measured in terms of the equilibrium constant for protonation (or for association with some Lewis acid), so it is a thermodynamic concept. Another difference is that. 

An elaboration of the ion-pair concept includes an ion sandwich in which a preassociation occurs between a potential nucleophile and a reactant. Such an ion sandwich might be a kinetic intermediate which accelerates dissociation. Alternatively, if a caibocation were quite unstable, it might always return to reactant unless a nucleophile was properly positioned to capture the caibocation. 

In general, the reaction between a phenol and an aldehyde is classified as an electrophilic aromatic substitution, though some researchers have classed it as a nucleophilic substitution (Sn2) on aldehyde [84]. These mechanisms are probably indistinguishable on the basis of kinetics, though the charge-dispersed sp carbon structure of phenate does not fit our normal concept of a good nucleophile. In phenol-formaldehyde resins, the observed hydroxymethylation kinetics are second-order, first-order in phenol and first-order in formaldehyde. 

Much of the study of kinetics constitutes a study of catalysis. The first goal is the determination of the rate equation, and examples have been given in Chapters 2 and 3, particularly Section 3.3, Model Building. The subsection following this one describes the dependence of rates on pH, and most of this dependence can be ascribed to acid—base catalysis. Here we treat a very simple but widely applicable method for the detection and measurement of general acid-base or nucleophilic catalysis. We consider aqueous solutions where the pH and p/f concepts are well understood, but similar methods can be applied in nonaqueous media. 

Like the kinetic evidence, the stereochemical evidence for the SnI mechanism is less clear-cut than it is for the Sn2 mechanism. If there is a free carbocation, it is planar (p. 224), and the nucleophile should attack with equal facility from either side of the plane, resulting in complete racemization. Although many first-order substitutions do give complete racemization, many others do not. Typically there is 5-20% inversion, though in a few cases, a small amount of retention of configuration has been found. These and other results have led to the conclusion that in many SnI reactions at least some of the products are not formed from free carbocations but rather from ion pairs. According to this concept," SnI reactions proceed in this manner ... 

Reaction mechanisms divide the transformations between organic molecules into classes that can be understood by well-defined concepts. Thus, for example, the SnI or Sn2 nucleophilic substitutions are examples of organic reaction mechanisms. Each mechanism is characterized by transition states and intermediates that are passed over while the reaction proceeds. It defines the kinetic, stereochemical, and product features of the reaction. Reaction mechanisms are thus extremely important to optimize the respective conversion for conditions, selectivity, or yields of desired products. 

Entries 1—4 in Scheme 2.3 represent cases in which the nucleophilic component is converted to the enolate under kinetically controlled conditions by the methods discussed in Section 1.2. Such enolates are usually highly reactive toward aldehydes so that addition occurs rapidly when the aldehyde is added, even at low temperature. When the addition step is complete, the reaction is stopped by neutralization and the product is isolated. The guiding mechanistic concept for reactions carried out under these conditions is that they occur through a cychc transition state in which lithium or another metal cation is coordinated to both the enolate oxygen and the carbonyl oxygen. i. 4... 

It is well known from structural and kinetic studies that enzymes have well-defined binding sites for their substrates (3), sometimes form covalent intermediates, and generally involve acidic, basic and nucleophilic groups. Many of the concepts in catalysis are based on transition state (TS) theory. The first quantitative formulation of that theory was extensively used in the work of H. Eyring (4, 5 ). Noteworthy contributions to the basic theory were made by others (see (6) for review). As an elementary introduction, we will apply the fundamental assumptions of the TS theory in simple enzyme catalysis as follows. 

Since Swain s and Scott s efforts [217] to quantify the kinetic term nu-cleophilicity, chemists have continued to search for a quantitative concept of nucleophilic reactivity [218]. Most of this work has dealt with Sn2 type reactions, however, and the marked dependence of the relative strengths of nucleophiles on the nature of the electrophile and the polarity of the solvent has become textbook knowledge. 

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