Proximity as a Binding Phenomenon

One form of binding that can occur between two reactants is simple proximity, a major tenet of the spatial temporal vision of catalysis. When a second order reaction ocairs in solution, two reactants must collide in the rate-determining step. This causes a loss in translational degrees of freedom in the reactants, thereby increasing the Gibbs free energy at the transition state due to the increased order of the system (look back at Section 2.1.2 to review this idea). The translational and rotational entropies of a freely moving molecule in solution are both around 30 entropy units (eu). 

To get an idea of how much the activation energy can be lowered by reducing the entropy of activation by tying two groups together, Benkovic and Bruice looked at a series of 40 reactions where the intramolecular version could be directly compared to intermolecular versions. On average, the TAS differed between the reactions by 4.6 kcal/mol at 25°C. This correlates to a roughly 2 X 10 rate enhancement for an intermolecular reaction to an intra- 

Many examples of proximity effects are known. In general, whenever an intramolecular acid or base is invoked in acid-base catalysis, proximity effects can be a factor. Further, when any catalyst holds a substrate near a catalytic group at its active site, or holds two separate substrates next to each other, proximity effects can be relevant. Proximity effects are definitely prevalent in organometallic catalysis, as we will see in Chapter 12. Hence, proximity effects are key to many forms of catalysis. 

Several attempts to measure the maximal rate enhancements that can be achieved through proximity effects alone have been performed. A typical example compares the in-termolecular aminolysis of phenyl acetate by trimethylamine (Eq. 9.3) to the intramolecular cyclization of phenyl 4-(N,N-dimethylamino)butanoate (Eq. 9.4). The intermolecular reaction has a rate constant = 1.3 X 10 M s , while the intramolecular reaction has ki = 0.17 s k This suggests a rate enhancement of 1200 for the intramolecular reaction. Even in pure trimethylamine, the pseudo-first order rate constant for the intermolecular reaction would be less than the intramolecular rate constant. 

There is a slight problem with the rate comparison just made. First, it is difficult to make completely fair comparisons, since inherently the structures of the compounds undergoing the intra- and intermolecular reactions are different, suggesting possible intrinsic reactivity differences. More importantly, the rate constants for the two reactions have different units, typically M s and s for the inter- and intramolecular reactions, respectively. What then is the meaning of the ratio in the previous paragraph  

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