Thermodynamic and kinetic control

Many biochemical processes never reach equilibrium, so we need to distinguish between thermodynamic and kinetic factors that control the relative concentrations of reaction products. 

In some cases reactants can give rise to a Vcffiety of products. Suppose two products, Pi and P2, are produced by the following competing reactions  

The relative proportion in which the two products have been produced at a given stage of the reaction (before it has reached equilibrium) is given by the ratio of the two rates and therefore of the two rate constants  

This ratio represents the kinetic control over the proportions of products and is a common feature of biochemical reactions where an enzyme facilitates a specific pathway—one with a low activation energy—favoring the formation of a desired product. If a reaction is allowed to reach equilibrium, then the proportion of products is determined by thermodynamic rather than kinetic factors, and the ratio of concentrations is controlled by considerations of the standard Gibbs energies of all the reactants and products. 

---

The use of nitrogen anions in this process has not been well investigated. Nitrogen anion (36) readily substituted fluorine in perfluoroazaaromatics and the products could be rationalized on the basis of kinetic and thermodynamic control. With tetafluoropyridazine and CsF as a source of F, none of the expected 4,5-isomer was obtained. For 4,5 substitution a less... 

Scheme 30 Kinetically and thermodynamically controlled RCM in Fiirstner s total synthesis of herbarium I (163) [84]...

Variations in the proportions of the different components of product mixtures are observed in reactions that involve anhydrous HF31-80-82-84-85 and in pyridinium poly(hydrogen fluoride).86 These variations can also be explained in terms of kinetic and thermodynamic control. Thus, less stable, but more rapidly formed, dianhydrides isomerize under thermodynamic conditions to give more-stable products. It has also been noted that the starting isomeric forms of the ketose influence the kinetic outcome of the reaction.119... 

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

Dove, P. (1995). Kinetic and thermodynamic controls on silica reactivity in weathering environments. In "Chemical Weathering Rates of Silicate Minerals" (A. F. White and S. L. Brantley, eds), Mineralogical Society of America Washington, DC, Reviews in Mineralogy 31, 235-290. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

Double bond cis-trans isomerization occurs during hydrogenation with a relative rate dependent on structure. The less stable double bond isomerizes to the more stable one, but, of course, kinetics and thermodynamics control the extent of isomerization. In a linear carbon chain, one can expect the cis alkene to isomerize to trans and vice versa if the thermodynamics are favorable. However, in a strained cyclic system, trans will isomerize to cis (Fig. 2.13).117... 

For further evidence of kinetic and thermodynamic control in zirconocene-catalyzed diene cyclization, see Uesaka, N. Mori, M. Okamura, K. Date, T. J. Org. Chem. 1994, 59, 4542M547. 

Most helicates have linear axes, though a few helicates with circular axes are known - indeed the chiral (D4) molecular squares formed from Zn2+ and 2,5 -bis(2,2 -bipyridin- 6 -yl)pyrazine, 22, may be regarded as circular helicates (450). The formation of circular or linear forms seems to depend on balances between kinetic and thermodynamic control iron(II)-poly-2,2/-diimine systems with their substitutionally-inert metal centers provide useful systems for disentangling thermodynamic and kinetic contributions. The mechanism of formation of circular helicates of this type is believed to entail a kinetically favored triple helicate intermediate (484). Self-assembly of chiral-twisted iron(III)-porphyrin dimers into extended polynuclear species takes place through the intermediacy... 

A theoretical study at a HF/3-21G level of stationary structures in view of modeling the kinetic and thermodynamic controls by solvent effects was carried out by Andres and coworkers [294], The reaction mechanism for the addition of azide anion to methyl 2,3-dideaoxy-2,3-epimino-oeL-eiythrofuranoside, methyl 2,3-anhydro-a-L-ciythrofuranoside and methyl 2,3-anhydro-P-L-eiythrofuranoside were investigated. The reaction mechanism presents alternative pathways (with two saddle points of index 1) which act in a kinetically competitive way. The results indicate that the inclusion of solvent effects changes the order of stability of products and saddle points. From the structural point of view, the solvent affects the energy of the saddles but not their geometric parameters. Other stationary points geometries are also stable. 

Andres, J., Bohm, S., Moliner, V., Silla, E. and Tunon, I. Atheoretical study of stationary structures for the addition of azide anion to tetrafuranosides modeling the kinetic and thermodynamic controls by solvent effects, J. Phys. Chem., 98 (1994), 6955-6960... 

Intramolecular nitroaldol reactions are a useful choice for the conversion of sugars into polyhydroxylated nitro cyclopentanes, nitro cyclohexanes and their derivatives.46 Baer et al. in the course of their studies on the cyclization of 6-deoxy-6-nitrohexoses under kinetic and thermodynamic control,47 established the reaction pathway involved in the formation of nitroinositols mediated by intramolecular Henry reactions. Firstly, a nitronate is formed and then, under thermodynamic control conditions, an epimerization occurs before cyclization. But, under kinetic controlled conditions, the cyclization occurs first.48... 

Scheme 3.24. Silylcupration and stannylcupration of allenes under kinetic and thermodynamic control [37c, 67, 95, 96].

The and spectroscopy of a solution of 2-chloro-3,5-dinitropyridine in liquid ammonia at-40°C showed the formation of the C-6 adduct (10). This adduct is rather stable, since after 1 hr standing, no change in the spectrum was observed. It is interesting that at a somewhat lower temperature (-60°C) the addition takes place at C-4, i.e., formation of (9). Apparently one deals with the interesting concept of kinetically and thermodynamically controlled covalent adduct formation. At -60°C the addition is kinetically controlled, and at -40°C the addition is thermodynamically favored. The higher stability of the C-6 adduct compared to the C-4 adduct is probably due to the more extended conjugate resonance system (Scheme II.9). 

Scheme 13 MCRs under kinetic and thermodynamic control...

In another article, however, [59] it was shown that in the most case this reaction gave mixtures of two heterocycles 53 and 54. To develop procedures allowing regioselective synthesis of both heterocyclic systems, the authors of [59] studied an influence of temperature regime and catalyst type on the direction of this MCR. With application of ultrasonication and microwave irradiation it was estabhshed that the reaction studied can pass under kinetic and thermodynamic control. 

DMA) binds reversibly to Cjq. A similar effect was observed for 2,6-dimethoxy-anthracene [60], Use of, for example, a ten-fold excess of DMA results in an equilibrium between the various Cgg DMA adducts, with e,e,e-C5oDMA3 as the main component. Hence, synergetic combination of kinetic and thermodynamic control results in the generation of templates such as with incomplete... 

Dangles, O., Saito, N., and Brouillard, R., Kinetic and thermodynamic control of flavylium hydration in the pelargonidin-cinnamic acid complexation. Origin of the extraordinary flower color diversity of Pharbitis nil, J. Am. Chem. Soc., 115, 3125, 1993. 

The overall observed retention of the enantiomers, and thus the elution order, is based on several kinetically and thermodynamically controlled parameters concerned with stereorecognition nonstereoselective interactions of all partners SO(R), SA(R S), and particularly of the [SO(RI-SA(KI] and [SO(K)-SA(Si] complexes with the achiral stationary phase, also play a role (Figure 21). Therefore the retention order may be reversed for a specific pair of enantiomers depending on whether a covalently bound CSP or a CMPA is applied, but using the same chiral molecule (part) as chiral selector. These general principles, shown schematically for a CLEC system, are further complicated by the complexity of the entire system, hence they are difficult to anticipate and each case must be studied individually. 

N-alkylations and rearrangements are important for the synthesis of glycosides. N-3 and N-4 glycoside, e.g., of 5-oxo-TPs, are obtained under different conditions as the kinetically and thermodynamically controlled product, respectively [75BSF(2)2561] therefore a thermal rearrangement from an N-3 to an N-4 glycoside is possible. Table X lists these glycosides included are those derived from thioxo-TPs and mercaptomethyl-TPs. 

Rather than perform individual syntheses of all possible combinations of these nonpeptide units, members of each ring type or scaffold family were pooled in equimolar amounts prior to incorporation into the sequence DArg-Arg-X-Y-Arg. Since each individual member of a given pool was constructed on a similar carbocyclic scaffold, the chemical environment of the N-terminal amino group and C-terminal carboxylate groups were expected to follow similar kinetic and thermodynamic controls during the attachment of the nonpeptide residue to the growing peptide chain. The use of these smaller, directed libraries made it readily practical to obtain HPLC and mass spectral data for each and therefore confirm the composition of the library. 

Unfortunately, equilibrium and rate data in this area are practically nonexistent. However, sometimes it has been possible to obtain evidence for kinetically and thermodynamically controlled processes. 

The regioselective DoM effects can be rationalized in terms of kinetic and thermodynamic control of the reaction (83T2009). The relative thermodynamic acidity (NaNH2/NH3/-25°C) of pyridine hydrogens... 

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). 

---