What about Fluorous Substrates and Products ?
Fluorous Technology Primer - Part VI
Introduction
The term "fluorous synthesis" is often used to describe techniques in which the substrates and/or desired products are rendered fluorous. This technique is a phase tagging strategy that is conceptually analogous to "solid phase synthesis", but with major operational differences. Making substrates and products fluorous necessarily involves cleavable tags (since the final product will not be tagged), and fluorous protecting groups or traceless tags can be used. Fluorous synthesis concepts were introduced with liquid-liquid separation methods coupled with very large fluorous tags (60-120 fluorines). These early "heavy" fluorous techniques are quickly being superceded by "light" techniques where tags with many fewer fluorines are used coupled with solid-liquid extraction.
Example
Amino acids are readily coupled to make amides by first tagging the amine with a fluorous acyl group or a fluorous Boc group and then coupling the acids with amines under standard conditions. In general, only about 15-19 fluorines are needed, and the resulting tagged molecules have solubility properties that are largely dominated by the organic domain. In other words, they are soluble in organic not fluorous solvents. However, the solid phase extraction properties of the molecule are still dominated by the fluorous domain. The protected acids are coupled with amines under standard conditions. The desired tagged products are then retained on the column in the first pass of the solid phase extraction (MeOH/water) while all the coupling reagents, reactants and byproducts are eluted off. The coupled fluorous products are then eluted off in a second pass (MeCN) and are obtained in excellent purity.
Features
Fluorous synthesis is attractive because a single protecting group or tag can be used to render a library of organic molecules fluorous. The resulting library of soluble molecules can then be separated from broad classes of organic and inorganic reagents, reactants, side products, etc. by solid phase extraction. Unlike polymer-bound molecules, the fluorous-tagged compounds are small molecules that can be analyzed and characterized by standard small molecule techniques. The tagging methods are ideal for expedited parallel synthesis and for the gram-scale preparation of chemical intermediates in parallel. Because the tagged compounds have relatively few fluorines, they can be reacted under typical conditions for non-tagged molecules and the solid phase extraction gives a fast yet substantive separation. In the final detagging step, solid phase extraction can again be used to separate the organic product from the remnant of the fluorous tag. The tag can often be recovered in a form suitable for reuse, if desired. In addition to fluorous acyl and Boc groups, there are now a number of fluorous silyl groups, fluorous THP groups, fluorous benzyl groups, etc.
Our Technology Primer - Table of Contents
1. Introduction: What are Fluorous Molecules ?2. Fluorous Separation Methods
3. Fluorous Biphasic Catalysis
4. Fluorous Triphasic Reactions
5. Fluorous Reagents, Reactants and Catalysts
6. Fluorous Substrates and Products (Fluorous Synthesis)
7. Fluorous Mixture Synthesis
8. Summary