Thermodynamic vs. kinetic control

The terms kinetic control and thermodynamic control are concerned with the manner in which the ratios of products of a reaction are determined. When a reaction is under kinetic control, the ratio of two or more products is determined by the relative energies of the transition states leading to these products. The relative stabilities of the products do not matter. Under thermodynamic control, the ratio of the products is determined solely by the relative energies of the products. In this case the energies of the pathways leading to the products do not matter. In our discussion of the Curtin-Hammett principle, we only analyzed the energies of the transition states and not the energies of the products, and thus this principle applies to kinetic control. Thermodynamic control, which ultimately produces the equilibrium (thermodynamic) mixture of products, can only be achieved when it is possible for the products to interconvert (equilibrate) under the reaction conditions. The simplest way for the 

Diagrams used to explain kinetic control versus thermodynamic control. 

Lithium enolates exist as large aggregates and their approach to the electrophile is restricted by steric and electronic considerations, as well as by the relative geometry of the molecule. Despite the structural complexity remarkably good predictions for reactivity and diastereoselectivity can be made based on the steric requirements that would be present in a monomeric system. For example, in most reactions of enolate anions the electrophile will be delivered to the less hindered face of the enolate to give the major product. In all models used to describe reactivity (secs. 9.5.A.iii-9.5.A.v), a monomeric enolate will be shown but the facial and orientational bias of the enolate is clearly influenced by the state of aggregation in solution. 

The protons on both sides of the carbonyl in an unsymmetrical ketone are acidic. If the substitution pattern at those carbons is not identical, the pKa values of the hydrogens are different. When such a ketone is 

The base plays two roles in this reaction. First, it must react with the acid (42) quickly and efficiently (it must be a strong base). The base also generates a conjugate acid after deprotonation that plays a significant role in the position of the overall equilibrium. If the conjugate acid is more acidic than 42, it will reprotonate the conjugate base (the enolate anion), which drives the equilibrium back toward 42 and promotes the 

Reaction temperature is another important variable. If the reaction is kept cold, all reactions (including the forward and reverse reactions that constitute the equilibrium) are slowed. If there is enough energy at low temperatures to convert 42 to 43, the subsequent acid-base reactions (that will promote the equilibrium) will be slower and this favors kinetic control. The common reaction temperatures are -78°C (CO2 in acetone or 2-propanol) and -100°C. (ether in C02). Conversely, high reaction temperatures promote the equilibrium process. In most cases, the temperatures observed with thermodynamically controlled reactions are the reflux temperatures of the solvent (refluxing ethanol, water, methanol, tert-butanol). 

The final parameter in this process is the length of time the molecules are allowed to react. If the reaction time is short (typically min to h), it is more difficult for the equilibration process to develop. If the reaction is allowed to go for a long time (typically hours to days, although minutes can be a long time in some reactions), equilibration and thermodynamic control is more likely. The time factor is linked to the presence or absence of an acid in the system. When 43 is formed by reaction of LDA and 42. its conjugate acid is 

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Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

The product distribution may depend on the reaction conditions if the nucleophilic attack is reversible (kinetic vs. thermodynamic control). An additional complication arises from... 

The influence of the temperature. It has been established that the temperature has a dramatic effect on the occurrence of the Sn(ANRORC) process. Whereas participation of the Sn(ANRORC) mechanism in the amino-debromination of 4-t-butyl-6-bromopyrimidine at -75°C was found to occur for 77% according to the Sn(ANRORC) mechanism (79RTC5), it decreased to 33% when the amination was carried out at -33°C. Apparently at -75°C attack of the amide ion on C-2 is clearly favored over attack on C-6 (kinetic vs thermodynamic control) (78TL3841). Notice that 4-t-butyl-6-chloropyrimidine, when aminated at -33°C, reacts for nearly the... 

Another example of kinetic vs thermodynamic control is observed in an NMR-spectroscopic study of the ring opening of several 1-methoxy-3-carbamoylpyridinium salts by liquid ammonia. The study shows that... 

Furthermore, the organic functionalization studies have indicated that multiple reaction products can form even for simple systems. Kinetic and thermodynamic influences must be considered in any analysis of the product distribution. Moreover, the studies have revealed differences in the dominance of kinetic vs. thermodynamic control between the silicon and germanium surfaces. The dissimilarity primarily stems from the fact that adsorbate bonds are usually weaker on Ge than on Si. This difference in energetics leads to observable differences in the degree of selectivity that can be achieved on the two surfaces. Another important motif is the significance of interdimer bonding in the products. Many molecules, even as small as ethylene, have been observed to form products that bridge across two dimers. Consequently, each analysis of adsorption products should include consideration of interdimer as well as intradimer species. 

This review covers the Pd(0)-catalyzed allylations of aromatic ambident heterocyclic compounds, including all rings for which an aromatic tautomeric or resonance form can be written. Cases of C vs. O, C vs. N, N vs. O, and S vs. N allylation are discussed from all available viewpoints regioselectivity, kinetic vs. thermodynamic control, mechanism, stereo-... 

Understand the concept of kinetic vs. thermodynamic control of reactions. 

THE AVAILABILITY OF A REACTION CHANNEL. KINETIC VS. THERMODYNAMIC CONTROL... 

Suitably substituted isoxazolidines can undergo a thermally induced cycloreversion to nitrone and alkene. For example, the adducts of nitrones with alkylidene malonates or tolylsulfinylfuran-2(577)-ones suffer an easy cycloreversion, which determines significant changes in the diastereomeric composition of the cycloaddition mixtures depending on the reaction conditions (kinetic vs. thermodynamic control) <20040L1677, 2005JOC8825>. 

Wipf, P., Takahashi, H., Zhuang, N. Kinetic vs. thermodynamic control in hydrozirconation reactions. Pure Appl. Chem. 1998, 70, 1077-1082. 

Another example in which the regioselectivity of addition is different under kinetic vs thermodynamic control is the naphthalene series. In the addition of LiC(Me)2CN to naphthalene-Cr(CO)3 (53), a mixture of products is observed from addition at C-a and C-p 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 (54) [119]. 

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