Thermodynamic versus Kinetic Control

Basic Mechanistic Concepts Kinetic versus Thermodynamic Control, Hammond s Postulate, the Curtin-Hammett Principle 

SECTION 4.4. BASIC MECHANISTIC CONCEPTS KINETIC VERSUS THERMODYNAMIC CONTROL, HAMMOND S POSTULATE. THE CURTIN-HAMMETT PRINCIPLE 

Product composition may be governed by the equilibrium thermodynamics of the system. When this is true, the product composition is governed by thermodynamic control. Alternatively, product composition may be governed by competing rates of formation of products. This is called kinetic control. 

Let us consider cases 1-3 in Fig. 4.4. In case 1, AG s for formation of the competing transition states A and B from the reactant R are much less than AG s for formation of A and B from A and B, respectively. If the latter two AG s are sufficiently large that the competitively formed products B and A do not return to R, the ratio of the products A and B at the end of the reaction will not depend on their relative stabilities, but only on their relative rates of formation. The formation of A and B is effectively irreversible in these circumstances. The reaction energy plot in case 1 corresponds to this situation and represents a case of kinetic control. The relative amounts of products A and B will depend on the heights of the activation barriers AG and G, not the relative stability of products A and B. 

In case 2, the lowest AG is that for formation of A from R, but the AG for formation of B from A is not much larger. System 2 might be governed by either kinetic or thermoifynamic factors. Conversion of R to A will be only slightly more rapid than conversion of A to B. If the reaction conditions are carefully adjusted, it will be possible for A to accumulate and not proceed to B. Under such conditions, A will be the dominant product and the reaction will be under kinetic control. Under somewhat more energetic conditions, for example, at a higher temperature, A will be transformed to B, and under these conditions the reaction will be under thermoifynamic control. A and B will equilibrate, and the product ratio will depend on the equilibriiun constant determined by AG. 

Physical Organic Chemistry, McGraw-Hill, New York, 1962, pp. 95-98 P. R. Wells, Linear Free Energy Relationships, Academic Press, New York, 1968, pp. 35-44 M. Charton, Prog. Phys. Org. Chem. 10, 81 (1973). 

CHAPTER 4 STUDY AND DESCRIPTION OF ORGANIC REACTION MECHANISMS 

The product composition will reflect thermodynamic control. The terms kinetic and thermodynamic control are especially useful in discussing situations in which changes in the reaction conditions may shift the product composition from kinetic to thermodynamic control. 

In Case 3, the barrier separating A and B is very small relative to that for formation of A from R. A and B will equilibrate rapidly relative to formation of A. The product mixture will reflect thermodynamic control. 

For a reaction that can give rise to more than one product, the amount of each of the different products can depend on the reaction temperature. This is because, although all reactions are reversible, it can be difficult to reach equilibrium, and a non-equilibrium ratio of products can be obtained. 

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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. 

FIGURE 6.3 Free energy profile illustrating kinetic versus thermodynamic control of product. The starting compound (A) can react to give either B or C. 

Another example in which the regioselectivity of addition is different under kinetic versus thermodynamic control is the naphthalene series. In the addition of LiCMe2CN to [(naphthalene)Cr(CO)3] (41), a mixture of products is observed from addition at C-a and C-(3 in the ratio 42 58 under conditions where equilibration is minimized (0.3 h, -65 C, THF-HMPA). With the same reactants, but in THF and at 0 °C, the product is almost exclusively the a-substituted naphthalene (equation Sti).84-83 92... 

In order that all chapters be self-contained and comprehensible without detailed knowledge of the content of others, some topics (e.g. the steady state approximation and kinetic versus thermodynamic control) crop up in several places. The coverage is not the same in different chapters, however, and is developed in each according to the context and the perspectives of different authors. 

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. 

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. 

The palladium-allylation of ambident aromatic heterocycles is covered by Professor Moreno-Mafias and Dr. Pleixats (Barcelona, Spain) in the second chapter of this volume. The preference for carbon versus oxygen, nitrogen, and sulfur allylation is discussed from the diverse viewpoints of regioselectivity, kinetic versus thermodynamic control, mechanisms, stereochemistry, and synthetic targets in the first general survey of this topic. 

Kinetic versus Thermodynamic Control in the Addition of HBr to Buta-1,3-diene... 

Kinetic versus thermodynamic control in the isomerization of alkenes... 

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