Kinetic And Thermodynamic Control Of Reactions Pdf

[Gaetan Horton]

Thermodynamicreaction control or kinetic reaction control in a chemical reaction can decide the composition in a reaction product mixture when competing pathways lead to different products and the reaction conditions influence the selectivity or stereoselectivity. The distinction is relevant when product A forms faster than product B because the activation energy for product A is lower than that for product B, yet product B is more stable. In such a case A is the kinetic product and is favoured under kinetic control and B is the thermodynamic product and is favoured under thermodynamic control.[1][2][3]

The conditions of the reaction, such as temperature, pressure, or solvent, affect which reaction pathway may be favored: either the kinetically controlled or the thermodynamically controlled one. Note this is only true if the activation energy of the two pathways differ, with one pathway having a lower Ea (energy of activation) than the other.

Prevalence of thermodynamic or kinetic control determines the final composition of the product when these competing reaction pathways lead to different products. The reaction conditions as mentioned above influence the selectivity of the reaction - i.e., which pathway is taken.

Asymmetric synthesis is a field in which the distinction between kinetic and thermodynamic control is especially important. Because pairs of enantiomers have, for all intents and purposes, the same Gibbs free energy, thermodynamic control will produce a racemic mixture by necessity. Thus, any catalytic reaction that provides product with nonzero enantiomeric excess is under at least partial kinetic control. (In many stoichiometric asymmetric transformations, the enantiomeric products are actually formed as a complex with the chirality source before the workup stage of the reaction, technically making the reaction a diastereoselective one. Although such reactions are still usually kinetically controlled, thermodynamic control is at least possible, in principle.)

In the protonation of an enolate ion, the kinetic product is the enol and the thermodynamic product is a ketone or aldehyde. Carbonyl compounds and their enols interchange rapidly by proton transfers catalyzed by acids or bases, even in trace amounts, in this case mediated by the enolate or the proton source.

In the deprotonation of an unsymmetrical ketone, the kinetic product is the enolate resulting from removal of the most accessible α-H while the thermodynamic product has the more highly substituted enolate moiety.[7][8][9][10] Use of low temperatures and sterically demanding bases increases the kinetic selectivity. Here, the difference in pKb between the base and the enolate is so large that the reaction is essentially irreversible, so the equilibration leading to the thermodynamic product is likely a proton exchange occurring during the addition between the kinetic enolate and as-yet-unreacted ketone. An inverse addition (adding ketone to the base) with rapid mixing would minimize this. The position of the equilibrium will depend on the countercation and solvent.

If a much weaker base is used, the deprotonation will be incomplete, and there will be an equilibrium between reactants and products. Thermodynamic control is obtained, however the reaction remains incomplete unless the product enolate is trapped, as in the example below. Since H transfers are very fast, the trapping reaction being slower, the ratio of trapped products largely mirrors the deprotonation equilibrium.

The electrophilic addition reaction of hydrogen bromide to 1,3-butadiene above room temperature leads predominantly to the thermodynamically more stable 1,4 adduct, 1-bromo-2-butene, but decreasing the reaction temperature to below room temperature favours the kinetic 1,2 adduct, 3-bromo-1-butene.[3]

The first to report on the relationship between kinetic and thermodynamic control were R.B. Woodward and Harold Baer in 1944.[18] They were re-investigating a reaction between maleic anhydride and a fulvene first reported in 1929 by Otto Diels and Kurt Alder.[19] They observed that while the endo isomer is formed more rapidly, longer reaction times, as well as relatively elevated temperatures, result in higher exo / endo ratios which had to be considered in the light of the remarkable stability of the exo-compound on the one hand and the very facile dissociation of the endo isomer on the other.

C. K. Ingold with E. D. Hughes and G. Catchpole independently described a thermodynamic and kinetic reaction control model in 1948.[20] They were reinvestigating a certain allylic rearrangement reported in 1930 by Jakob Meisenheimer.[21] Solvolysis of gamma-phenylallyl chloride with AcOK in acetic acid was found to give a mixture of the gamma and the alpha acetate with the latter converting to the first by equilibration. This was interpreted as a case in the field of anionotropy of the phenomenon, familiar in prototropy, of the distinction between kinetic and thermodynamic control in ion-recombination.

Alkoxides are not as basic as ketone enolates, so the acid-base equilibrium tends to favor the starting ketone. However, they are still strong enough bases to set up an equilibrium between the starting ketone and the two different enolates.

The position of that equilibrium will favor the most thermodynamically stable enolate (i.e. the most substituted), even though it is slightly slower to form due to the fact that the C-H bond is more sterically hindered.

The equilibrium ratio of enolates will depend on the difference in energy between their heats of formation (which is typically 1-2 kcal/mol). As a rough rule of thumb, 4:1 is a good ballpark number but it can vary considerably. [Note 2]

Any time we form an enolate under thermodynamic control, we should expect that the major product will arise from the reaction of the more substituted enolate with the electrophile, such as in this halogenation reaction. [Note 3]

Note 1. A rough rule of thumb is that each C-H you replace with a C-C gets you an additional 1 kcal/mol of stability. This might not sound like a lot, but even 1 kcal/mol is enough to give you about 80:20 equilibrium ratio.

Note 4. For more on alkylation of ketones under thermodynamic conditions, see this classic study. It turns out the reaction of the ketone with NaOR/CH3I does indeed put CH3 on the more substituted enolate (in 41% yield), but there are lots of byproducts due to over-alkylation. For the purposes of our course, this is why procedures like the acetoacetic ester synthesis are preferred for enolate alkylation.

The reaction of one equivalent of hydrogen bromide with 1,3-butadiene gives different products at under different conditions and is a classic example of the concept of thermodynamic versus kinetic control of a reaction

At elevated temperatures, \(\ceB\) is still going to be the product that is formed faster. However, it also means that all the reactions will be reversible. This means that molecules of \(\ceB\) can revert back to \(\ceA\). Since the system is no longer limited by temperature, the system will minimize its Gibbs free energy, which is the thermodynamic criterion for chemical equilibrium. This means that, as the most thermodynamically stable molecule, \(\ceC\) will be predominantly formed.2 The reaction is said to be under thermodynamic control and \(\ceC\) is the thermodynamic product.

A simple definition is that the kinetic product is the product that is formed faster, and the thermodynamic product is the product that is more stable. This is precisely what is happening here. The kinetic product is 3-bromobut-1-ene, and the thermodynamic product is 1-bromobut-2-ene (specifically, the trans isomer).

Note that not every reaction has an energy profile diagram like Figure \(\PageIndex1\), and not every reaction has different thermodynamic and kinetic products! If the transition states leading to the formation of B were to be higher in energy than that leading to C, then C would simultaneously be both the thermodynamic and kinetic product. There are plenty of reactions in which the more stable product (thermodynamic) is also formed faster (kinetic).

It is perhaps simple enough to see why 4 is more stable than 3. It has an internal, disubstituted double bond, and we know that as a general rule of thumb, the thermodynamic stability of an alkene increases with increasing substitution. So, compared to the terminal, monosubstituted alkene 3, 4 is more stable.

Both the trans isomer 4 as well as the cis isomer 5 can be formed via attack of the nucleophile at the terminal carbon, and both are disubstituted alkenes. However, the trans isomer 4 is more stable than the cis isomer 5, because there is less steric repulsion between the two substituents on the double bond. As such, 4 is the thermodynamic product.

The most common argument is since resonance form 2a is more stable than 2b, is that it contributes more towards the resonance hybrid 2. As such, the positive charge on the internal carbon is greater than the positive charge on the terminal carbon. The nucleophile, being negatively charged, is more strongly attracted to the more positively charged or more electrophilic carbon, and therefore attack there occurs faster (the transition state being stabilized by greater electrostatic interactions). That's actually a very sensible explanation; with only the data that has been presented so far, we would not be able to disprove it, and it was indeed the accepted answer for quite a while.

In 1979, Nordlander et al. carried out a similar investigation on the addition of \(\ceDCl\) to a different substrate, 1,3-pentadiene.7 This experiment was ingenious, because it was designed to proceed via an almost symmetrical intermediate:

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