Reversibility thermodynamic control

The stereoselectivity of cyclization reactions conducted under conditions of thermodynamic control can often be reliably predicted by estimation or calculation of the energy differences between the diastereomers of the cyclization product (H) or its immediate precursor (G). It has been shown that, even in cases where the (G) to (H) step is not reversible, thermodynamic control of the diastereomer ratio can be influenced through the use of cyclization substrates in which the neutralization step (G to H) is the slow step, thus allowing for equilibration of the diastereomers of (G). Thermodynamic equilibration of dia-stereomeric products will occur only if the reaction reverses to starting materials (A), or interconversion of the diastereomers of the intermediates (B) or (C) occurs in some other way (e.g. the C to D interconversion can equilibrate diastereomers if E = X). 

Alternatively, the use of reversible, thermodynamically-controlled synthetic methods - similar to those used to make the supramolecular polymers discussed in Figure 1 - can be used to assemble mechanically interlocked molecules in near quantitative yields (Figure 7)." However, imlike the supramolecular systems, once formed (after removal of the catalyst) the mechanically interlocked structures are robust and cannot be destroyed without breaking a (strong) covalent bond ... 

The para isomer can also form. However, the Kolbe reaction is reversible. Thermodynamic control favors the more stable ortho isomer. The stability of the ortho isomer may result from intramolecular hydrogen bonding. 

Betaine formation is reversible and the reaction becomes under thermodynamic control to give the most stable product. 

As in the nitration of naphthalene, sulfonation gives the 1-substituted naphthalene. However, because the reverse reaction (desulfonation) is appreciably fast at higher temperatures, the thermodynamically controlled product, naphthalene-2-sulfonic acid, can also be obtained. Thus it is possible to obtain either of the two possible isomers of naphthalene sulfonic acid. Under kineticaHy controlled conditions naphthalene-l-sulfonic acid [85-47-2] (82) is obtained thermodynamic control gives naphthalene-2-sulfonic acid [120-18-3] (83). 

For the other broad category of reaction conditions, the reaction proceeds under conditions of thermodynamic control. This can result from several factors. Aldol condensations can be effected for many compounds using less than a stoichiometric amount of base. Under these conditions, the aldol reaction is reversible, and the product ratio will be determined by the relative stability of the various possible products. Conditions of thermodynamic control also permit equilibration among all the enolates of the nucleophile. The conditions that permit equilibration include higher reaction temperatures, protic solvents, and the use of less tightly coordinating cations. 

The reaction proceeds by a multistep mechanism and normally is reversible. Therefore, we expect the reaction to be thermodynamically controlled. 

Thermodynamically-Controlled Reaction. A reaction the product ratio for which is determined solely by the relative thermochemical stabilities of the different products (product formation must be reversible, or separate low-energy pathways interconnecting the products must exist). 

Now let s carry out the same reaction at some higher temperature so that both processes are readily reversible and an equilibrium is reached. 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 stability, not on relative rates. Such reactions are said to be under equilibrium control, or thermodynamic control. 

Both primary and secondary amines add to a /S-unsaturated aldehydes and ketones to yield /3-amino aldehydes and ketones rather than the alternative imines. Under typical reaction conditions, both modes of addition occur rapidly. But because the reactions are reversible, they generally proceed with thermodynamic control rather than kinetic control (Section 14.3), so the more stable conjugate addition product is often obtained to the complete exclusion of the less stable direct addition product. 

The silicon- and sulfur-substituted 9-allyl-9-borabicyclo[3.3.1]nonane 2 is similarly prepared via the hydroboration of l-phenylthio-l-trimethylsilyl-l,2-propadiene with 9-borabicy-clo[3.3.1]nonane36. The stereochemistry indicated for the allylborane is most likely the result of thermodynamic control, since this reagent should be unstable with respect to reversible 1,3-borotropic shifts. Products of the reactions of 2 and aldehydes are easily converted inlo 2-phenylthio-l,3-butadienes via acid- or base-catalyzed Peterson eliminations. 

The basc-eatalyzcd addition of nilroalkancs to carbonyl compounds is a reversible reaction and proceeds under thermodynamic control. Thus low (R, R )/(R, S ) selectivities arc observed in the classical Henry reaction which leads to the silylated x-nitro alcohols 2. 

Lithiated areneacetonitriles react with a,/i-unsaturated ketones at low temperatures using short reaction times to give both 1,2- and 1,4-adducts. The 1,2-addition is reversible and under thermodynamic control (higher temperatures and longer reaction times) only the 1,4-adducts, i.e., <5-oxonitriles, arc obtained. When lithiated arylacetonitrile is added to 2-substituted 2-cy-cloalkenones in THF or in THF/HMPA mixtures at — 70-0°C, followed by protonation or alkylation under kinetically controlled conditions, predominantly cis- or fnms-2,3-disubstitut-ed cycloalkanones respectively, are obtained. 

Lubineau and coworkers [18] have shown that glyoxal 8 (Ri = R2 = H), glyoxylic acid 8 (Ri = H, R2 = OH), pyruvic acid 8 (Ri = Me, R2 = OH) and pyruvaldehyde 8 (Ri = H, R2 = Me) give Diels-Alder reactions in water with poor reactive dienes, although these dienophiles are, for the most part, in the hydrated form. Scheme 6.6 illustrates the reactions with (E)-1,3-dimethyl-butadiene. The reaction yields are generally good and the ratio of adducts 9 and 10 reflects the thermodynamic control of the reaction. In organic solvent, the reaction is kinetically controlled and the diastereoselectivity is reversed. 

D. Kinetic and Thermodynamic Control in the Reversible Carbonylation the 2-Norbomyl Cation. ... 

In Sections II and III the quantitative aspects have been summarized of the reversible carbonylation of secondary and tertiary alkyl cations as studied under thermodynamically controlled conditions. In Section IV the results have been reviewed of the irreversible carbonylation of the much less stable primary alkyl and vinyl cations as studied under kinetically controlled conditions. No kinetic details had been obtained in the latter case owing to the short-hved character of the ions. 

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

Figure 6.3 shows a free energy profile for a reaction in which B is thermodynamically more stable than C (lower AG), but C is formed faster (lower AG ). If neither reaction is reversible, C will be formed in larger amount because it is formed faster. The product is said to be kinetically controlled. However, if the reactions are reversible, this will not necessarily be the case. If such a process is stopped well before the equilibrium has been established, the reaction will be kinetically controlled since more of the faster-formed product will be present. However, if the reaction is permitted to approach equilibrium, the predominant or even exclusive product will be B. Under these conditions, the C that is first formed reverts to A, while the more stable B does so much less. We say the product is thermodynamically controlled.Of course. Figure 6.3 does not describe all reactions in which a Compound A can give two different products. In many cases, the more stable product is also the one that is formed faster. In such cases the product of kinetic control is also the product of thermodynamic control. 

C=C double bonds (15-62). The stereochemical difference in the behavior of 60 and 61 has been attributed to formation of the betaine 64 being reversible for 60 but not for the less stable 61, so that the more-hindered product is the result of kinetic control and the less hindered of thermodynamic control. ... 

The intramolecular version of ester condensation is called the Dieckmann condensation.217 It is an important method for the formation of five- and six-membered rings and has occasionally been used for formation of larger rings. As ester condensation is reversible, product structure is governed by thermodynamic control, and in situations where more than one product can be formed, the product is derived from the most stable enolate. An example of this effect is the cyclization of the diester 25.218 Only 27 is formed, because 26 cannot be converted to a stable enolate. If 26, synthesized by another method, is subjected to the conditions of the cyclization, it is isomerized to 27 by the reversible condensation mechanism. 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

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