Divergent synthesis refers to the sequential "growth" of a dendrimer layer by layer, starting with a core "initiator" molecule which contains functional groups capable of acting as active sites in the initial reaction. Each subsequent reaction in the series increases the number of available surface groups exponentially. Core molecules which give rise to PAMAM dendrimers can vary, but the most basic initiators are ammonia and ethylene diamine. Outward growth of PAMAM dendrimers is accomplished by alternating between two reactions:
# Michael addition of the amino-terminated surface onto methyl acrylate, resulting in an ester-terminated outer layer, and
# Coupling with ethylene diamine to achieve a new amino-terminated surface.
Each round of reactions forms a new "generation", and PAMAM dendrimers are often classified by generation number; the common shorthand for this classification is "GX" or "GX PAMAM", where X is a number referring to the generation number. The first full cycle of Michael addition followed by coupling with ethylene diamine forms Generation 0 PAMAM, with subsequent Michael additions giving rise to "half" generations, and subsequent amide coupling giving rise to "full" (integer) generations.
With divergent synthesis of dendrimers, it is extremely important to allow each reaction to proceed to completion; any defects caused by incomplete reaction or intramolecular coupling of new surface amines with unreacted methyl ester surface groups could cause "trailing" generations, stunting further growth for certain branches. These impurities are difficult to remove when using the divergent synthetic approach because the molecular weight, physical size, and chemical properties of the defective dendrimers are very similar in nature to the desired product. As generation number increases, it becomes more difficult to produce pure products in a timely fashion due to steric constraints. As a result, synthesis of higher-generation PAMAM dendrimers can take months.