Kinetic versus Thermodynamic Control of Reactions

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Electrophilic addition to a conjugated diene at or below Toom temperature normally leads to a mixture of products in which the 1,2 adduct predominates over the 1,4 adduct. When the same reaction is carried out at higher temperatures, though, the product ratio often changes and the 1,4 adduct predominates. For example, addition of HBr to 1,3-butadiene at 0°C yields a 71 29 mixture of 1,2 and 1,4 adducts, but the same reaction carried out at 40 °C yields a 15 85 mixture. Furthermore, when the product mixture formed at 0 °C is heated to 40 °C in the presence of HBr, the ratio of adducts slowly changes from 71 29 to 15 85. Why  

To understand the effect of temperature on product distribution, let s briefly review what we said in Section 5.7 about rates and equilibria. Imagine a reaction that can give either or both of two products, B and C. 

Let s first carry out the reaction at a lower temperature so that both processes are irreversible and no equilibrium is reached. Since B forms faster than C, B is the major product. It doesn t matter that C is more stable than B, because the 

A reaction energy diagram for two competing reactions in which the less stable product (8) forms faster than the more stable product (C). 

Let s first carry out the reaction at some higher temperature so that both processes are readily reversible and an equilibrium is reached. That is, enough energy is supplied for reactant molecules to surmount the barriers to both products, and for both product molecules to climb the higher barriers back to reactant. Since C is more stable than B, C is the major product obtained. It doesn t matter that C forms more slowly than B, because the two are in equilibrium. The product of a readily reversible reaction depends only on thermodynamic stability. Such reactions are said to be under equilibrium control, or thermodynamic control. 

The electrophilic addition of HBr to 1,3-butadiene is a good example of how a change in experimental conditions can change the product of a reaction. The concept of thermodynamic control versus kinetic control is a useful one that we can sometimes take advantage of in the laboratory. 

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Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

This process illustrates the concept of kinetic versus thermodynamic control of a reaction, with naphthalene-1-sulfonic acid being the kinetic product and the 2-sulfonic acid the thermodynamic product. The energy changes associated with these processes are illustrated in Figure 12.1. 

Kinetic Versus Thermodynamic Control of Secondary Reactions... 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

A Kinetic Control Versus Thermodynamic Control of a Chemical Reaction... 

We include in Sections I,A and I,B some general features of the Tsuji-Trost reaction with comments on kinetic versus thermodynamic control in allylations and in alkylations in general. Then we review in Sections II, III, and IV all cases known to the authors of the application of the Tsuji-Trost reaction to ambident nucleophilic aromatic heterocycles. This leaves out of the review the allylation of such heterocyclic ambident nucleophiles as 2-piperidone and the like. By aromatic, we mean any heterocycle for which a tautomeric or mesomeric formula can be written that is aromatic in the normal structural sense of having 4n + 2n- electrons cyclically conjugated. 

Further studies by Brown and coworkers lent additional support to this mechanism and the absence of a free alkyl cation. Olah and coworkers have applied the concept of competitive alkylation to the case of naphthalene in order to study both positional and substrate selectivities, and to clarify the nature of kinetically versus thermodynamically controlled product composition. They explained the observed results by suggesting that a ir-complex, such as (1), was the intermediate involved when highly electrophilic catalysts or strongly basic aromatics were employed, and a o-complex (as proposed earlier by Brown) was involved in reactions with weakly electrophilic catalysts or less basic aromatics. 

Before commencing this discussion, it is appropriate to consider briefly the issue of kinetic versus thermodynamic control in the reactions of preformed Group I and Group II enolates and to summarize the structure-stereoselectivity generalizations that have emerged to date. It is now welt established that preformed lithium, sodium, potassium and magnesium enolates react with aldehydes in ethereal solvents at low temperatures (typically -78 °C) with a very low activation barrier. For example, reactions can often be quenched within seconds of the addition of an aldehyde to a solution of a lithium enolate. ... 

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