Reactant-based design

Library design methods can be divided into reactant-based or product-based design. In reactant-based design, reactants are chosen without consideration of the products that will result. For example, diverse subsets of reactants are selected in the hope they will give rise to a diverse library of products. In product-based design, the selection of reactants is determined by analyzing the products that will be produced. 

Reactant-based design is computationally less demanding than product-based design, since there are fewer molecules to consider. Consider a two-component reaction where there are 100 examples of each type of reactant. Now assume that the aim is to design a library of 100 products with configuration 10 x 10, i.e., 10 examples of each reactant. There are approx 1013 different possible subsets of size 10 contained within 100 compounds, as determined by the equation below ... 

The compound selection methods described thus far can be used to select compounds for screening from an in-house collection, or to select which compounds to purchase from an external supplier. In combinatorial library design, however, it is necessary to select subsets of reactants for actual synthesis. The two main strategies for combinatorial library design are reactant-based selection and product-based selection. In reactant-based selection, optimized subsets of reactants are selected without consideration of the products that will result and any of the compound selection methods already identified can be used. An early example of reactant-based design is that already described by Martin and colleagues which is based on experimental design and where diverse subsets of reactants were selected for the synthesis of peptoid libraries [1]. 

Once the reactant pools have been filtered, the next step in product-based designs is usually to enumerate the full virtual library. This can be a very time-consuming step and hence a useful precursor can be to enumerate carefully chosen subsets that will give an indication of the success or otherwise of the full virtual experiment. Thus, in a two component reaction it can be useful to take the first reactant in the first pool and combine it with all the reactants in the second pool (to generate 1 x nB products). This should then be followed by the enumeration of one reactant in the second pool with all reactants in the first pool to give nA x 1 products. If either of these two partial enumeration steps fail, then the full enumeration will also fail. Thus, troublesome reactants can be identified early. 

Jamois, E. A., Hassan, M., and Waldman, M. (2000) Evaluation of reactant-based and product-based strategies in the design of combinatorial library subsets. 

To summarize, library design involves choices of diversity vs. similarity, product based vs. reactant based, and single objective vs. multiobjective optimizations. Chemoinformatics tools, such as various predictive models and chemoinformatics infrastructures, can be utilized to facilitate the selection process of library design. 

A variation of the one-pot approach that has, perhaps, been underdeveloped to date involves the use of multiple components (A and B), where the geometry of the reactants is designed to provide selectivity toward one macrocydic product, nA + nB An (Figure 6.1C). For example, Iyoda and coworkers exploited this approach to form selectively the cyclic trimer 8 based on the combination of a... 

The second possibility is a dissociation mechanism, involving not the reactant complex itself, but rather, its conjugate base (designated CB)... 

When structure-based strategies are used to help choose reactants for a combinatorial library, the strengths of both approaches complement each other. Although the structure-based design is not accurate, it statistically enhances and focuses the combinatorial library. Billions of possible library compounds can be generated on the computer in a virtual library and evaluated. From this, a smaller set of the order of thousands can be chosen... 

Although the objective is always to identify which reactants should be used to make the products, there are two fundamental approaches to library design reactant-based methods and product-based methods. Purely product-based methods, which select (or cherry pick) desired products without regard for the number of reactants required to form those products (as in standard similarity... 

Gillet, V. 1., Nicolotti, O. Evaluation of reactant-based and product-based approaches to the design of combinatorial libraries. Perspect. Drug Discov. Dev. 2000,20, 265—287. 

For reactors with single chemical reactions, it has been customary to write the species-based design equation for the limiting reactant A. Hence,... 

Equation 4.2.9 is the species-based design equation of a CSTR, expressed in terms of the conversion of reactant A. 

Adams et al. (/. Catalysis 3, 379, 1964) investigated these reactions and expressed the rate of each as second order (first order with respect to each reactant). Formulate the dimensionless, reaction-based design equations for an ideal batch reactor, plug-flow reactor, and a CSTR. 

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