1. Background

1.1. Historical Origins of dendimers

Towards the end of the 1970s, a great deal of interest was starting to be generated in the new areas of host-guest[1] and supramolecular[2] chemistry. In the quest for large, substrate-selective ligands, several research groups became interested in the synthesis of 'tentacle'[3] and 'octopus'[4,5] molecular compounds, where long branches radiate from a central hub or a macrocycle. Some of the 'octopus azaparacyclophanes'[5] (Figure 1) were found to act as shape-selective catalysts despite their highly flexible structures. The 'enzyme models' 1 and 2 could catalyse the hydrolysis of p-nitrophenyl esters with some selectivity towards alkyl chain length in the acyl moiety.

The success of this early research led to the first attempt at a dendrimer synthesis by Vögtle.[6] A 'cascade' synthesis was described, wherein an exhaustive Michael-type addition of acrylonitrile to an amine, followed by the reduction of the nitrile groups to primary amines, could theoretically be repeated ad infinitum to produce very highly branched macromolecular ligands (Scheme 1). Although this early research suffered from technical problems in the reduction step, these problems were later resolved,[7] allowing the synthesis of 'poly(propylene imine)' dendrimers to be achieved on a commercial scale.[8]

The field of highly branched macromolecules was also being addressed from the viewpoint of polymer chemists. The polymerisation of a monomer of the AB2 type had been suggested decades earlier by Flory,[9] and much theoretical work on the possible outcome of this type of reaction had been carried out.[10,11] Research groups led by Tomalia[12] (Scheme 2) and Denkewalter[13] devised routes whereby stepwise 'polymerisations' could be performed, giving highly branched polymers with extremely low polydispersities. The polyamidoamine (PAMAM) series that were synthesised by Tomalia were called 'starburst[14] dendrimers', after starbranched polymers and the Greek word dendra for a tree. The term 'dendrimer'[15] is now used almost universally to describe highly branched, monodisperse compounds.[16] Around the same time, Newkome[17,18] was developing a series of very highly branched molecules where each layer (or 'generation') had a different constitution. These molecules were called 'arborols',[19] and were investigated as covalently linked micelle analogues. Interest in dendrimers mushroomed after this early period to produce the wide range of structures we read about today. Indeed, a quick scan over the references quoted in this review reveals how activity in the field of dendrimers has 'taken off' in only the last few years.

1.2. The Dendritic Structure

One of the most interesting topological aspects of dendrimers is the concept of the 'starburst limit'.[11] If one considers that the number of branch ends on a dendrimer increases exponentially as a function of generation, while the surface area of the dendrimer only increases with the square of generation (and the volume with the cube of generation), it is apparent that there will come a point beyond which the dendrimer cannot grow as a consequence of a lack of space. This point is a function of the core multiplicity (nc), the branching multiplicity (nb), and the branch length (lb) as well as of the core and branch volumes and other quantities. A detailed analysis is given in Appendix 7.n. The increasing branch density with generation is also believed to have striking effects on the structures of dendrimers (Figure 2). At high generations, steric crowding of the branches at the surface of a dendritic molecule causes the adoption of a globular conformation.[17,20] The branch ends may lie either on the surface of the molecule, or throughout the entire structure, possibly determined by factors such as the solvent and the dendrimer constitution. If the former is the case, computer modelling experiments show[21] that the dendrimer will contain cavities and channels. Despite the dynamic nature of these voids, it might be anticipated that the microenvironment they create can be utilised in the entrapment of guest molecules.[22]

1.3. Applications of Dendrimers

A great many potential applications for dendrimers have been proposed. They have been stated and restated in the many articles and reviews[8,23] that have appeared in the scientific literature and popular press. Most of the ideas that have been investigated focus on the peculiarities of the dendritic interior for their rationalisation. The behaviour of dendrimers as hosts is essential if they are to find success as solubilising agents,[24] catalysts, and drug delivery[25] and slow release agents for perfumes, herbicides and drugs. Research is also active in applications as diverse as polymer additives[26] (for crosslinking and for processing), catalyst supports, thin films, laser-printing toners and MRI contrast agents.[27]

1.4. Nomenclature and Representation of Dendrimers

The size and complexity of dendrimers makes their representation difficult both on paper and by name. A systematic nomenclature has been developed for the naming of dendritic 'cascade' macromolecules.[28] However, while it has gained some popularity,[29] it is not yet in widespread usage. The depiction of dendrimers can be a somewhat more pressing problem, as many dendritic structures simply cannot be portrayed in more conventional ways. Although bent and elongated bonds can often be used to draw structures, when this practice becomes unacceptable, two possibilities are left. Either a cartoon representation can be used, or the structure can be drawn in part as shown in Figure 3. Both of these possibilities will be exploited here.