Noncovalent reactants

Catalysis occurs because the catalyst in some manner increases the probability of reaction. This may result from the reactants being brought closer together [catalysis by approximation, or the propinquity effect ], or somehow assisted to achieve the necessary relative orientation for reaction. Noncovalent interactions may be responsible for the effect. Covalent bond changes may also take place in catalysis. In a formal way, the manner in which catalysis occurs can be described by schemes such as Schemes I and II. 

In contrast to the reactions of the cycloamyloses with esters of carboxylic acids and organophosphorus compounds, the rate of an organic reaction may, in some cases, be modified simply by inclusion of the reactant within the cycloamylose cavity. Noncovalent catalysis may be attributed to either (1) a microsolvent effect derived from the relatively apolar properties of the microscopic cycloamylose cavity or (2) a conformational effect derived from the geometrical requirements of the inclusion process. Kinetically, noncovalent catalysis may be characterized in the same way as covalent catalysis that is, /c2 once again represents the rate of all productive processes that occur within the inclusion complex, and Kd represents the equilibrium constant for dissociation of the complex. 

Additive-Induced Stereoselectivity Stereoselectivity in a reaction between achiral reactants is additive induced when (a) stereogenic unit(s) is (are) stereoselectively generated under the influence of a noncovalently bound chiral compound (e.g., solvent, catalyst). 

Supramolecular control of reactivity and catalysis is among the most important functions in supramolecular chemistry. Since catalysis arises from a differential binding between transition and reactant states, a supramolecular catalyst is, in essence, chemical machinery in which a fraction of the available binding energy arising from noncovalent interactions is utilized for specific stabilization of the transition state or, in other words, is transformed into catalysis. 

It was Swain [15] who pointed out more than half a century ago that when a reaction between a nucleophile N and a substrate S is catalyzed by an electrophile E (case a), enhanced catalysis is expected if two of the components, either N and S (case b), S and E (case c), or N and E (case d) are bound together in the same molecule or in the same complex by covalent bonding or noncovalent interactions, respectively. An additional possibility is given by case e, where the two reactants and catalyst are held together in a ternary complex. 

Noncovalent interactions between the two separate molecules define, in the gas phase analogue of this reactive system, the preferential channels of approach (in the simpler cases there is just one channel leading to the reaction) with shape and strength determined only by these interactions. As a general rule, these channels carry the reactants to a stationary point on the potential energy surface called the initial reaction complex. 

Fig. 1 Equilibrium between reactants (E + I) and noncovalent complex (E- I ) in a typical enzyme-inhibitor binding process...

The role of water in governing the upper thermal limits for life also is based on covalent transformations in which water is a reactant. As emphasized earlier in this chapter, the removal of a molecule of water from reactants is common in diverse biosynthetic reactions, including the polymerization of amino acids into proteins and nucleotide triphosphates into nucleic acids. The breakdown of biomolecules often involves hydrolysis, and increased temperatures generally enhance these hydrolytic reactions. The thermal stabilities of many biomolecules, for instance, certain amino acids and ATP, become limiting at high temperatures. Calculations suggest that ATP hydrolysis becomes a critical limiting factor for life at temperatures between 110°C and 140°C (Leibrock et al., 1995 Jaenicke, 2000). Thus, at temperatures near 110°C, both the covalent and the noncovalent chemistries of water that are so critical for life are altered to the extent that life based on an abundance of liquid water ceases to be possible. 

In an enzyme-catalyzed reaction, the enzyme binds to the substrate (one of the reactants) to form a complex. The formation of the complex leads to the formation of the transition-state species, which then forms the product. The nature of transition states in enzymatic reactions is a large held of research in itself, but some general statements can be made on the subject. A substrate binds, usually by noncovalent interactions, to a small portion of the enzyme called the active site, frequently situated in a cleft or crevice in the protein and consisting of certain amino acids that are essential for enzymatic activity (Figure 6.3). The catalyzed reaction takes place at the active site, usually in several steps. 

The reaction catalyzed by ODCase is ostensibly quite simple—the decarboxylation of orotate ribose monophosphate (OMP) to produce uracil ribose monophosphate (see below). The problem with this reaction is that direct decarboxylation would lead to an anion whose lone pair of electrons is not aligned with any r-system that could lead to stabilization through delocalization. Various proposals have been put forth to overcome this apparent obstacle. These include selective stabilization of the transition state for direct decarboxylation by non-covalent interactions with ODCase, selective destabilization of the reactant by repulsive noncovalent interactions that are reduced or removed during direct decarboxylation, pre-protonation of the reactant on one of its carbonyl oxygens or alkene carbons such that decarboxylation would lead to a stabilized ylide, and concerted protonation-decarboxylation which would avoid the formation of a discrete uracil anion. The validity of these mechanistic proposals is analyzed from various viewpoints in this volume. 

The entropic cost of bringing reactants into noncovalent contact is treated as the cost of increasing the concentration of one reactant from the standard state value, typically 1M, to having the reactive atom of the reactant in one of a limited number of volumes equal to the volume of an atom and is given by... 

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