BASIC MECHANISTIC CONCEPTS

1. equilibrium thermodynamics thermodynamic control kinetic control competing rates of formation of products BASIC MECHANISTIC CONCEPTS There are many organic reactions in which the energy requirements for competing reaction paths are rather similar. It is important to be able to analyze the factors that may permit a particular reaction path to dominate. The key issue is the relative activation energies of competing pathways because they determine the outcome of the reaction. KINETIC VERSUS THERMODYNAMIC CONTROL Product composition may be governed by the equilibrium thermodynamics of the system. When it is true, the product composition is governed by thermodynamic control. Alternatively,product composition may be governed by competing rates of formation of products. This is called kinetic control. product composition governed by

2. A kA R kB B G [A] kA = [B] kB REACTION PROGRESS In this case the DG‡ for formation of the competing transition states TSA and TSB from R are much less than the DG‡’s for A and B come back to TSA and TSB respectively. The formation of A and B is irreversible, because they cannot come back to R, once formed. • The ratio of products A and B at the end of the reaction will not depend on the relative stabilities, but only on their relative rates of formation. The relative amounts of A and B depends on the heights of the activation barriers DG‡A andDG‡B, not on the relative stability of A and B. TSA TSB DGA‡ DGB‡ KINETIC CONTROL R DG B A

3. DGA‡ G DGB‡ DG REACTION PROGRESS In this case the lowest DG‡ is that for formation of TSA from R, but the DG‡ for formation of TSB from A is not much larger. This system might be governed by either kinetic or thermodynamic factors. Conversion of R to A will be only slightly more rapid than conversion of A to B. • If the reaction condition are carefully adjusted, it will be possible for A to accumulate and not to proceed to B. • Under such conditions, A will be the dominant product and the reaction will be under kinetic control. TSA • Under somewhat more energetic conditions, for example at higher temperature, A will be transformed to B and the reaction will be under thermodynamic control. • A and B will equilibrate, and the product ratio will depend on the equilibrium constant determined by DG. R TSB A B

4. A kA R K DGB‡ kB B DG K = G [A] [B] DGA‡ REACTION PROGRESS In this case, the barrier separating A and B is small, with respect to that for the formation of TSA from R. In this case A and B will equilibrate more rapidly than R is converted to A. • This means that the A:B ratio is governed by the inherent stability of A and B and is independent from the rate of conversion. Adjustment of reaction conditions would have little effect on product composition, because the latter is entirely governed by the inherent thermodynamic stability of the two compounds. TSA TSB A B THERMODYNAMIC CONTROL R

5. HAMMOND’S POSTULATE The rates of chemical reactions are controlled by the free energy of the transition state and it means that information about the structure of transition states is crucial to understand reaction mechanism. • However, because transitions states have only transitory existence, it is not possible to make experimental mesurements that provide direct information about their structure. Hammond has discussed the circumstances under which it is valid to relate transition state structure to the structure of reactants, intermediate and products. His statements concerning transition state structure are known as Hammond’s postulate. Discussing individual steps in a reaction mechanism, Hammond’s postulate states: if two states as, for example, a transitions state and an unstable intermediate, occur consecutively during a reaction process and have nearly the same energy content, their interconversion will involve only a small reorganization of molecular structure. nearly the same energy content small reorganization of molecular structure

6. This is a highly hexotermic step with a low activation energy. “EARLY” TRANSITION STATE • It follows from Hammond’s postulate that, in this step, the transition state will structurally resemble the reactant, because they are close in energy and interconverted by a small structural change. TS R G • This is depicted as a small displacement toward product along the reaction coordinate. P REACTION PROGRESS

7. TS • This is a step in which the transition state is a good deal higher in energy than either the reactant or the product. G • In this case, neither the reactant nor the product will be a good model of the transition state. R P REACTION PROGRESS

8. “LATE” TRANSITION STATE This is an endothermic step such as might occur in the formation of an unstable intermediate. TS P • In this case the energy of transition state is similar to that of the intermediate, and the transition state should be similar in structure to the intermediate. G R REACTION PROGRESS

9. The significance of the concept incorporated in Hammond’s postulate is that in appropriate cases, it permits discussion of transition-state structure in terms of the reactants, intermediates or products in a multistep reaction sequence. • The postulate indicates that such comparison is appropriate in the cases in which the transition state is close in energy to the reactant, intermediate or product. • Chemists sometimes speak of “early” or “late” transition states. An “early” transition state is reactant-like, whereas a “late” transition-state is product-like. “early” transition state reactant-like “late” transition-state product-like

10. A good example: electrophilic aromatic substitution • The ortho-, para- and meta-directing effects of aromatic substituents were among the first structure-reactivity relationships to be developed in organic chemistry. • Let us take in exam bromination of methoxybenzene, benzene and nitrobenzene. • These reactions are kinetically controlled, so the rate effects and the substituent’s directing effects can be explained interms of DG‡.

11. G DG‡ REACTION PROGRESS Electrophilic aromatic substitution involves a distinct intermediate and two less well defined states. By application of the Hammond Postulate it is possible to conclude that the rate-determining step involves the formation of a transition state that should closely resemble the intermediate s complex. Consequently the effects of the substituents on the transition state are discussed in terms of this intermediate. s complex intermediate p complex resembles reactants p complex resembles products

12. The product composition is kinetically controlled, so the isomer ratio will be governed by the relative magnitudes of DG‡o, DG‡m and DG‡p. The attack of the electrophile developes a positive charge in the ring at the transition state What is the effect of the different substituents on the intermediate? • The electron releasing-methoxy group can interact directly to delocalize the charge and stabilize the intermediate, leading to o- and p-bromobenzene. It cannot stabilize the intermediate leading to m-bromomethoxybenzene • The o- and p- intermediate are therefore stabilized with respect to benzene, but the m-intermediate is not. As a result, methoxybenzene reacts faster than benzene and the products are mainly the ortho- and para-isomers

13. In the case of nitrobenzene, the electronwithdrawing nitro group strongly destabilizes the intermediate, because it is not able to stabilize the positive charge in the s-complex intermediate. • This destabilization is greatest in the o- and p-intermediates, which place positive charge on the nitro-substuted carbon. • The meta transition state is also destabilized, with respect to that of benzene, but not as much as the ortho and para transition states. • As a result nitrobenzene is less reactive than benzene, and the product is mainly the meta isomer

14. methoxybenzene reacts more quickly with respects to benzene to the attack of electrophiles and formation of ortho- and para-substituted products is more favored. nitrobenzene reacts more slowly with respects to benzene to the attack of electrophiles and formation of meta-substituted products is less disfavored. All these considerations can be represented in this diagram

15. PA A B PB DG G conformational equilibrium REACTION PROGRESS The Curtin-Hammett principle Let us consider in a general way the effect that conformational equilibria can have on a chemical reaction. Under what circumstances can the position of the conformational equilibrium for a reactant determine which of two competing rection paths will be followed? TSB TSA G‡B-G‡A DGc‡ DGPB‡ DGPA‡ B A PA PB

16. In most cases the energy of activation for a chemical reaction will be greater than that of a conformational equilibration. If this is the case DGA‡ and DGB‡ >> Gc. • The conformers of the reactant are in equilibrium and are interconverted at a rate much faster than that at which the competing reactions occur.

17. The conformers of the reactant are in equilibrium, so: The rates of formation of products PA and PB are: and at any moment product ratio is expressed by

18. According to transition state theory, the rate constant can be expressed by: and the equilibrium constant as consequently the product ratio can be rewritten as

19. TSB G‡B - G‡A TSA G‡B-G‡A DG‡PB DGPB‡ DGPA‡ DG‡PA DG DG B G A PA PB REACTION PROGRESS The free energy diagram shows that DG‡PB + DG - DG‡PA = G‡B - G‡A = The product ratio is therefore determined not by DG, but by the relative energy of the two transition states TSA and TSB.

20. The rate of formation of the products is dependent upon the relative concentration of the two conformers, since one conforme has even less free energy than the other, but the conformational equilibrium is established rapidly, relative to the two competing product-forming steps. • The position of conformational equilibrium cannot control the product ratio. The reaction may proceed through a minor conformation if it is the one that provides access to the lowest-energy transition state. • The conclusion that the ratio of products formed from conformational isomers in not determined by the conformation population ratio is known as Curtin-Hammet principle.