In principle, any chemistry and any reaction can be employed in solution-phase methods, including complex organometallic reagents, biocatalysis, etc. Few, if any, of the reactions and procedures documented in compendia of 'organic syntheses' and 'organic reactions' could not be adapted to solution-phase combinatorial chemistry if suitable time and effort were applied. Adapting viable reactions to solution-phase combinatorial chemistry entails a set of problems which can be routinely solved in a month or two. The problems are fairly standard and address aspects such as control of stoichiometry, capturing a broad range of reactivity within a single set of reaction conditions, and product quality assurance.
Complex molecule synthesis relies heavily on protecting groups. However their use in solution-phase library synthesis is restricted to situations where their removal gives volatile byproducts, e.g. Boc or Cbz groups. Certain synthetic transformations that produce nonvolatile coproducts are also a problem in solution. For example, Mitsunobu reactions, which produce phosphine oxide and hydrazide coproducts, work very well in solid phase but require major adaptation of procedures for use in solution. Multistep synthesis conducted in normal solution-phase parallel synthesis leads to rapid deterioration of product quality because of incomplete reactions and accumulating byproducts.
Compatibility with automated solution-handling devices is the only solvent and reagent restriction for solution-phase methods. Problems that may exist, such as loss of accuracy in dispensing small volumes of highly volatile solutions in ether or dichloromethane, can usually be overcome with less volatile alternatives such as dioxane or tetrachloroethylene.
Solution-phase systems equipped to prevent condensation of water vapor (or icing up) at the low end, or equipped to condense/reflux solvent vapor at the high end, can easily operate in the —20 °C to +150 °C range.
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