Thermodynamic control of product distribution

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. 

Similarly, reaction of chlorobenzene with isopropyl chloride imder Friedel—Crafts conditions produced primarily the ortho and para alkylation products after a short reaction period. Allowing the reaction mixture to stand for a week before workup, however, produced primarily the meta product. In both of these cases, the product isolated after a short time is said to be the product of kinetic control of the product distribution, since the product isolated is the one that is formed faster. The product isolated after a longer time is said to be the product of thermodynamic control of product distribution, since it is the more stable product. ... 

Thermodynamic Versus Kinetic Control of Product Distributions. 228... 

Figure 1 Free-energy profiles for organic reactions under kinetic and thermodynamic control. In reactions under kinetic control, it is the stability of the transition states (for example, AG g) that determines the product distribution. For reactions under thermodynamic control, the product distribution is determined by the stability of the products (for example, AGac)-...

Similar results are obtained from incineration of polymeric materials with octabromo- and pentabromodiphenyl ether (refs. 11,12). The temperature with the maximum PBDF-yield depends on the kind of polymeric matrix. All three bromo ethers 1-2 give the same isomer distribution pattern with preference for tetrabrominated dibenzofiirans. The overall yield of PBDF is lower for incineration of pentabromobiphenyl ether 2, 4 % at 700°C compared to 29 % for ether 1 at 500 °C (ref. 12). The preferred formation of tetrabrominated fiirans observed at all temperatures cannot be a result of thermodynamic control of the cyclisation reaction it is likely due to the special geometry of the furnaces. One explanation is that a spontaneous reaction occurs at approximately 400°C while the pyrolysis products are transferred to the cooler zones of the reactor details can be found elsewhere (ref. 12). 

Another area to which the MM method can be advantageously applied is the prediction of product distribution under thermodynamic control, where the errors in energy calculations tend to cancel if structurally related products are compared (120). A remarkable example is the dodecahydrogenation of phenanthrene, in which 25 structural isomer products are possible, each having one to four stable... 

In later chapters, we will encounter several other reactions where competition occurs between the formation of the kinetic product and the thermodynamic product. However, most reactions are conducted under conditions where only one of these factors controls the product distribution. In addition, the kinetic product and the thermodynamic product are often the same, so no competition occurs in these reactions either. 

With 1,5-dicarbonyl compounds, two modes of ring closure are often possible. In the example shown below, the more stable (higher-substituted) enone is formed preferentially (thermodynamic control). The observed distribution of products is the result of equilibration via retro-aldol reaction. 

Nevertheless, the product data have been exceptionally interpreted only in these terms. (1) An allylic carbocation can afford significant amounts of 1,2-products. For instance, in the above-mentioned DCl addition, 1,2-adducts were the major products whatever the solvent, (ii) In addition to the electrophile and substituent dependence of the charge distribution in the intermediate, solvent and steric effects probably play an important role in the product-forming step of these reactions, as they do in the reactions of monoenes . (iii) 1,2-Adducts isomerize frequently to the more stable 1,4-adducts. Therefore, the kinetic or thermodynamic control of the product distribution 2.i4 should be questioned. As a consequence, a number of early results were later revised when this problem was recognized, (iv) Finally, it has also been suggested " that 1,4-addition products do not necessarily arise from allylic intermediates but could also result from bridged intermediates via an Sn2 process implying a syn stereochemistry. 

For the kinetically controlled formation of 1,3-disubstituted tetrahydro-P-carbolines, placing both substituents in equatorial positions to reduce 1,3-diaxial interactions resulted in the cw-selectivity usually observed in these reactions." Condensation reactions carried out at or below room temperature in the presence of an acid catalyst gave the kinetic product distribution with the cw-diastereomer being the major product observed, as illustrated by the condensation of L-tryptophan methyl ester 41 with benzaldehyde. At higher reaction temperatures, the condensation reaction was reversible and a thermodynamic product distribution was observed. Cis and trans diastereomers were often obtained in nearly equal amounts suggesting that they have similar energies."... 

Even after a very short reaction time (001 sec) it is doubtful whether the isomer distribution (in the small amount of product that has as yet been formed) is purely kinetically controlled—the proportion of m-isomer is already relatively large—and after 10 sec it clearly is not m-benzyltoluene, the thermodynamically most stable isomer, predominating and the control now clearly being equilibrium or thermodynamic (p. 43). 

Cycloaddition of the cyclic nitrone derived from proline benzyl ester with alkenes proceeds readily to give isoxazolidines with good regio-and stereoselectivity (Eq. 8.47).68 The reaction favors exo-mode addition. However, certain cycloadditions are reversible and therefore the product distribution may reflect thermodynamic rather than kinetic control. 

In contrast to the examples of selectivity control discussed in the previous sections, the problem here is control of the regioselectivity of the individual reaction steps. This is evident from the Scheme 5. In the first reaction step the nickel-hydride species adds to propene forming a propyl- or isopropyl-nickel intermediate this step is reversible, and the ratio of the two species can be controlled both thermodynamically and kinetically. In the second step, a second molecule of propene reacts to give four alkylnickel intermediates from which, after j8-H elimination, 8 primary products are produced (Scheme 5). 2-Hexene and 4-methyl-2-pentene could be the products of either isomerization or the primary reaction. Isomerization leads to 3-hexene, 2-methyl-2-pentene (the common isomerization product of 2-methyl-1-pentene and 4-methyl-2-pen-tene), and 2.3-dimethyl-2-butene. It can be seen from the Scheme 5 that, if the isomerization to 2-methyl-2-pentene can be neglected, the distribution of the products enables an estimate to be made of the direction of... 

The distribution of products is dependant on the concentrations demonstrating that this is a truly thermodynamically controlled reaction. 

It has therefore been established170 from the product distributions that, while the oxymercuration is reversible, unless a base (e.g. sodium acetate) is added to the reaction medium, and gives almost exclusively the more stable compound 199, the aminomercu-ration takes place to give the kinetically controlled adduct 200, or under thermodynamic control the aminomercurial 201. Reactions are kinetically controlled when the mercurating species is a mercury(II) salt deriving from a weak acid such as mercury(II) acetate. Conversely, they are thermodynamically controlled with the covalent mercury(II) chloride. In the latter case, the presence of a strong acid in the medium allows the thermodynamically controlled product to be obtained. 

The influence of the classical anomeric effect and quasi-anomeric effect on the reactivity of various radicals has been probed. The isomer distribution for the deu-teriation of radical (48) was found to be selective whereas allylation was non-selective (Scheme 37). The results were explained by invoking a later transition state in the allylation, thus increasing the significance of thermodynamic control in the later reactions. Radical addition to a range of o -(arylsulfonyl)enones has been reported to give unexpected Pummerer rearrangement products (49) (Scheme 38).A mechanism has been postulated proceeding via the boron enolate followed by elimination of EtaBO anion. 

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