Features and Requirements for Solid-Phase Synthesis

The requirements for solid-phase synthesis are diverse. The support must be insoluble, in the form of beads of sufficient size to allow quick removal of solvent by filtration, and stable to agitation and inert to all the chemistry and solvents employed. For continuous-flow systems, the beads also must be noncompressible. Reactions with functional groups on beads imply reaction on the inside of the beads as well as on the surface. Thus, it is imperative that there be easy diffusion of reagents inside the swollen beads and that the reaction sites be accessible. Accessibility is facilitated by a polymer matrix that is not dense and not highly functionalized. A matrix of defined constitution allows for better control of the chemistry. Easier reaction is favored by a spacer that separates the matrix from the reaction sites. Coupling requires an environment of intermediate polarity such as that provided by dichloromethane or dimethylformamide benzene is unsuitable as solvent. 

RB Merrifield. Solid-phase peptide synthesis. Endeavour 3, 1965. 

S Hancock, DJ Prescott, PR Vagelos, GR Marshall. Solvation of the polymer matrix. Source of truncated and deletion sequences in solid phase synthesis. J Org Chem 38, 774, 1973. 

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