Kinetic and Thermodynamic Control of a Reaction

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Oniy one product is formed in many of the reactions you will study in organic chemistry. However, sometimes two (or more) different products may be formed from competing reactions. If two products are formed, the inquiring scientist wants to know which is formed faster and which is more stable. While the product that forms faster is frequently also the more stable, this is not always the case. Sometimes it is possible to favor the formation of one product or another by modifying the conditions under which the reaction is conducted. The two experimental parameters that are most commonly varied to favor formation of one product over another are reaction time and the temperature at which the reaction is conducted. By performing the experimentai procedures in this chapter, you will have an unusual opportunity to discover different means of controlling the course of chemical reactions using some of the same techniques that are practiced in industry for the production of compounds of practicai interest. 

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We will start our analysis by assuming that both of the reactions are exothermic and that Y is thermodynamically less stable than Z. These assumptions mean that 

Reaction profile that predicts different products from kinetic and thermodynamic control of competing reactions. 

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Distinguish between kinetic and thermodynamic control of a reaction. Suggest criteria for expecting one over the other. 

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. 

The studies by the methods of radiolysis provided a wealth of knowledge about the kinetic and thermodynamic controls of radical reactions, the importance of which is no more questioned. Indeed, it is known that the chemical events initiated by ionizing radiation, are the same as those that take place in normal and deleterious events of every day s life. In this review we focus on some ofthe major knowledge that was acquired by the use of pulse radiolysis and steady-state gamma radiolysis of aqueous solutions of amino acids, peptides and proteins (Inset). The potential role of pulse radiolysis (Chapter 2) for studying biomolecules has been acknowledged rather early. In most cases, pulse radiolysis... 

The reactions of elemental fluorine with inorganic compounds are exothermic and often have little or no reaction associated activation energies. Most often the major synthetic problem is kinetic and thermodynamic control of these vigorous reactions. It is therefore a very unusual synthetic situation when reactions must be activated by methods such as high temperatures, plasmas, or photochemical means. Examples of such cases are the synthesis of NO+BF4 by the photochemically activated reaction of fluorine and oxygen with boronnitride (52) and the plasma-activated synthesis of (CF112)n from graphite (53). 

We shall consider reactions catalysed by two different types of pro-catalyst the first (type A) employs Pd-allyl cations ([Pd(a]lyl)(PCy3)]+/Et3SiH or [Pd(allyl)(MeCN)2] + ), and the second (type B) employs Pd-alkyl or chloro complexes ([(phen)Pd(Me)(MeCN)]+, where phen = phenanthroline, and [(RCN)2PdCl2]). These two types of catalysts give very different products in the cyclo-isomerisation of typical 1,6-dienes such as the diallyl-malonates (10), Scheme 12.6. Since there is known to be a clear order of thermodynamic stability 11 < 12 <13, with a difference of ca. 3-4 kcal mol 1 between successive pairs, any isomerisation of products under the reaction conditions will tend towards production of 12 and 13 from 11 and 13 from 12. Clearly, when 11 is the major product (as with pro-catalysts of type A), it must be the kinetic product (see Chapter 2 for a discussion of kinetic and thermodynamic control of product distributions). However, when 12 is generated selectively, as it is with pro-catalysts of type B, there is the possibility that this is either generated by rapid (and selective) isomerisation of 11 or generated directly from 10. 

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. 

Polysubstitution raises some complications for three reasons (a) when two polyfluoroalkyl groups are already present these can, in some cases, control the position of further substitution (b) some of the reactions are reversible and (c) substitution at the position most activated to attack sometimes results in crowding and therefore not the most thermodynamically stable system. This can lead to a competition between kinetic and thermodynamic control of reaction products [116, 122-128]. 

The fluoropyridazines have been intensively investigated by Musgrave and co-workers. Earlier work or nucleophilic substitutions in perfluoro-pyridazines has been reviewed. Tetrafluoropyridazine reacts with hexa-fluoropropene to give products formed from both kinetic and thermodynamic control of the polyfluoroalkylation, i.e., the fluoride ion-induced reaction between a fluoroolefin and an activated polyfluoroaromatic compound. The reaction with tetrafluoroethylene is kinetically controlled. Products arising only from thermodynamic control are formed, however, in the reaction with octafluoroisobutene. 

Since AG° is negative for this process, diamond should spontaneously change to graphite at 25°0 and 1 atm. Elowever, the reaction is so slow under these conditions that we do not observe the process. This is another example of kinetic rather than thermodynamic control of a reaction. We can say that diamond is kinetically stable with respect to graphite even though it is thermodynamically unstable. 

Figure 6.28. Reprinted with permission from "A New Perspective on Kinetic and Thermodynamic Control of Reactions," by Snadden, R. B. /. Chem. Educ. 1985, 62, 653-655. Copyright 1985 American Chemical Society. 

The maximum rates of the reactions of most aldehydes and ketones with semi-carbazide occur in the pH range of 4.5-5.0. For the purpose of making derivatives of carbonyl compounds (Sec. 25.7), semicarbazide is best used in an acetate buffer (CH3CO2H/CH3CO2 ) solution, which maintains a pH in the maximum rate range of 4.5-5.0. However, to demonstrate the principle of kinetic and thermodynamic control of reactions, buffers that maintain higher pHs, and thus produce lower rates, are more desirable. Parts A-C of the experimental procedure involve a phosphate buffer system, whereas the bicarbonate system is used in Part D. It is then possible to compare how the difference in rates in the two buffer systems affects the product ratio. Analysis of the products from the various parts of these experiments provides strong clues as to which of the semicarbazones is the product of kinetic control and which is the product of thermodynamic control. 

Horita, K., Hachiya, S., Nagasawa, M., Hikota, M., and Yonemitsu, O. (1994) Synthetic studies of halichondrin B, an antitumor polyether macrolide isolated from a marine sponge. 1. Stereoselective synthesis of the C1-C13 fragment via construction of the B and A rings by kinetically and thermodynamically controlled intramolecular Michael reaction. Synlett, 38—40. 

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