Structural Biochemistry/Kinetic and Thermodynamic Control

Background
Product ratios of reactions can be changed according to the conditions in which the reaction occurs. Depending on the kinetic and thermodynamic control of the reaction, product ratios can vary dramatically. An example of this is the hydrobromination of 1,3-butadiene at 40oC v.s 0oC. At 0oC, the reaction is under kinetic control and the products favor 3-Bromo-1-butene over 1-Bromo-2-butene in a 70:30 mixture. However at 40oC, the reaction is under thermodynamic control and favors the 1-Bromo-2-butene product with a 15:85 ratio.

Chemical reactions can be controlled by thermodynamic or kinetic means. When a reaction can yield two different products, the reaction conditions change the outcome and therefore the products. When conditions of a reaction changes, the reaction itself may change. Some conditions to be considered are temperature, pressure, light, or even solvent. The difference between thermodynamic and kinetic conditions is that thermodynamic factors associate with the relative stability of the molecules while the kinetic factors are associated with the rate of product formation. This phenomena of different products can only occur when there are two different paths with two different activation energies or energy required to make the reaction progress. In essence, when temperature is low the reaction undergoes kinetic control where the major product is the one that comes from the quickest reaction. When temperature is high, the reaction undergoes thermodynamic control which provides the more stable system and product. Under kinetic control the reaction is rate based and is not reversible, but under thermodynamic control the reaction is in equilibrium and is also reversible under the correct conditions.

Thermodynamic Control
When the product ratio of a reaction depends upon the thermodynamic stability of the products, a reaction is said to be under thermodynamic control. In the hydrobromination of 1,3-Butadiene at 40oC, the ratio of the products favors the more stable isomer, as it is under thermodynamic control. At higher temperatures or over long periods of time, the more stable isomer will dominate as the two isomers will be in equilibrium and rapidly interconvert.

Thermodynamic control of a reaction favors the more thermodynamically stable molecule. This reaction pathway is selected for by using long reaction times or high temperatures. Long reaction times or high temperatures will give the molecules more energy to surpass the lower kinetic pathway to eventually make its way over to the more stable thermodynamic product. Even though molecules have already taken the kinetic pathway, with enough time or high enough temperatures, the molecules will have the energy to go back and overcome the higher activation energy in order to rest in the more stable state or product. Essentially, with enough time or temperature molecules will select for the thermodynamically controlled pathway and end as the more stable product.

Kinetic Control
A product ratio that follows the relative rates of formation, such as the hydrobromination of 1,3-butadiene at 0oC, is said to be under kinetic control. The reason 3-Bromo-1-butene dominates is because at 0oC, the reverse formation is much slower than at 40oC so the isomers are not rapidly inter-converting.

Kinetic control favors shorter reaction times. This is also the path that requires less energy or has a lower activation energy. This is because at the start of a fast reaction more molecules will go towards the kinetic lower energy path and if stopped short, the molecules will not have a chance to return and take the thermodynamic path. Also, low temperature favors the kinetic pathway because it does not give the molecules that already took the kinetic path enough energy to return back to the starting material and then take the thermodynamic path. The way to get the kinetic product is to use short times for reactions to trap the kinetic product or use high temperatures.