Cascade molecules, 2,41-70

Finally, Vogtle and his coworkers have prepared a number of cascade molecules which are structurally related to the aforementioned systems. These are repeating ring units of increasingly large cavity size and are prepared by repetitive synthetic procedures. Typically, an amine is cyanoethylated, the nitrile reduced to an amine which may then be further cyanoethylated and reduced or cyclized with a diacid halide. The rather elaborate scheme is illustrated in ref. 61 and examples of the structural type are shown in Table 8.4. 

The synthesis and study of dendrimers is a relatively new branch of macro-molecular chemistry. It began in 1985 with the publication of two landmark papers (D.A. Tomalia, H. Baker, J. Dewald, J.M. Hall, G. Kallos, R. Martin and J. Ryder, Polym. J., 1985,17,117-132 and G.R. Newkome, Z. Yao, G.R. Baker and V.K. Gupta, J. Org. Chem., 1985, 50, 2003-2004), and has grown to become a very vibrant research field. The word dendrimer comes from the Greek word dendra, meaning tree, and was applied to these compounds by Tomalia et al. in their very first paper. Newkome s team, by contrast, called their molecules arborols from the Latin word arbor, which also means a tree. The term cascade molecule has also been used, but the word dendrimer is the one that is used most widely throughout the literature, and is also used in the present chapter. 

This volume of Topics in Current Chemistry aims to highlight major developments in the field and it shows the efforts of chemists from various subdisciplines of chemistry to design new dendritic molecules focusing on novel properties, functions, and potential applications. Hyperbranched/dendritic molecules containing silicon, phosphorus, and other elements are reported apart from hydrocarbon, carbohydrate and nucleic acid cascade molecules. 

In 1978 we described a synthetic methodology as a repeating-step principle , which led us to the first cascade molecules , today known as dendritic molecules [17]. We recognized then that a synthetic pathway, which allows consecutive repetition, implies the advantage of likewise reactants and reaction conditions and is suited for the building of more or less structure perfect highly branched molecules, particularly of polyamines (Fig. 4). 

Fig. 4. Preparation of cascade molecules by a repeated addition of acrylonitrile to amines (according to Vogtle et al.)...

On the other hand, branched building blocks [30] possess inherent branching points remote from the site of connection. These monomers can be simple or complex in design and have been used in both divergent and convergent synthetic strategies. In addition, branched monomers can also be used to install utilitarian functionality within cascade molecules. 

The history of dendrimer chemistry can be traced to the foundations laid down by Flory [34] over fifty years ago, particularly his studies concerning macro-molecular networks and branched polymers. More than two decades after Flory s initial groundwork (1978) Vogtle et al. [28] reported the synthesis and characterization of the first example of a cascade molecule. Michael-type addition of a primary amine to acrylonitrile (the linear monomer) afforded a tertiary amine with two arms. Subsequent reduction of the nitriles afforded a new diamine, which, upon repetition of this simple synthetic sequence, provided the desired tetraamine (1, Fig. 2) thus the advent of the iterative synthetic process and the construction of branched macromolecular architectures was at hand. Further growth of Vogtle s original dendrimer was impeded due to difficulties associated with nitrile reduction, which was later circumvented [35, 36]. This procedure eventually led to DSM s commercially available polypropylene imine) dendrimers. 

The addition of ammonia to excess methyl acrylate (a linear monomer), followed by amidation with excess ethylenediamine afforded the resultant cascade molecule, and thus Tomalia [37] created the commercially available PAMAM starburst series of dendrimers (2, Fig. 2). Related core molecules such as ethylenediamine and aminoalcohols and other functionalizable groups such as thiol moieties were used to prepare similar dendrimers [38]. This methodology is applicable to most primary amines, resulting in a 1 —> 2 branching pattern. Recently, examples of related Si-, [39] P-, [40] and metallo systems [41], which follow this linear monomer protocol have been reported. 

Precise placement of metal complexing sites within the infrastructure of a cascade molecule is of importance from a variety of perspectives. In the construction of the above noted Micellane family (cf. Sect. 3.1), we reported the construction of dendrimers with four alkyne moieties at sites equidistant from each other in the interior (17, Fig. 8) [60]. These were treated with decaborane (B10H14) to afford 1,2-dicarba-closo-dodecaboranes (o-carboranes) [71]. Rendering boron clusters soluble in water is of interest because of their use in cancer treatment by Boron Neutron Cancer Therapy. First and second generation water-soluble dendrimers containing four and twelve precisely located boron cluster sites, respectively, were synthesized (e.g., 18). These water soluble dendrimers and their precursors were characterized by 13C-, and nB-NMR spectroscopy (Fig. 8). 

The concept of micelles consists of aggregation of amphiphilic molecules that contain polar and non-polar moieties, which associate in a manner that minimizes hydrophobic and lipophilic interactions. However, a cascade molecule consisting of an internal lipophilic framework and a external hydrophilic surface would effectively be a unimolecular micelle [59] capable of hosting molecular guest(s). 

For instance, some time ago Newkome et al. reported the synthesis of ruthenium based dendrimers [170]. A dendrimer (80) with twelve peripheral terpyridine ligands was built around a central quaternary carbon-based core. In the final step complexation between the terminal ligand of the dendrimer and a terpyridinyl ruthenium chloride building block afforded the dodecaruthenium cascade molecule 80 (Fig. 35). Thus, preconstructed cores and dendritic fragments were linked by Ru2+ as the connecting unit and this mode of connectivity could be denoted by [—(Ru)—]. 

Newkome, G.R., Moorefield, C.N., Keith, J.M., Baker, G.R., and Escamilla, G.H. (1994) Chemistry of micelles. 37. Internal chemical transformations in a precursor of a unimolecular micelle boron supercluster via site-specific addition of BioH14 to cascade molecules. Angew. Chem., Int. Ed. Engl. 33, 666-668. 

Recent literature contains many examples of the construction of cascades [56], Usually they are made by the covalent linking of monomer dyes, which allows strict control of their stoichiometry. The pyrene-Bodipy molecular dyads and triads are examples [57]. Efficient energy flow was reported in a purpose-built cascade molecule bearing three distinct chromophores attached to the terminal acceptor [58]. A combinatorial approach with the selection of the best hits can be applied using the assembly of fluorescent oligonucleotide analogs [59]. 

Harriman A, Mallon L, Ziessel R (2008) Energy flow in a purpose-built cascade molecule bearing three distinct chromophores attached to the terminal acceptor. Chemistry 14 11461-73... 

As discussed in the first section of this chapter, interest in dendrimers has increased rapidly since the successful synthesis of the first cascade molecules two decades ago. Much of this interest has been driven by the expectation that dendrimers will exhibit unique properties [2-5, 60]. Because dendrimers in many cases interact strongly with metal ions, it seems reasonable to expect that such composite materials might provide additional heretofore unknown or biomimetic functions. This is particularly true in hght of the high number of metal ions that can be complexed to a single dendrimer and (in some cases) their well-defined position in the dendrimer. For example, there has been much recent speculation that these materials will be useful for catalysis [3, 4, 53,... 

Newkome GR, Baker GR, Aral S, Saunders MJ, Russo PS, Theriot KJ, Moorefield CN, Rogers LE, Miller JE, Lieux TR, Murray ME, Phillips B, Pascal L. Cascade molecules. Part 6. Synthesis and characterization of two-directional cascade molecules and formation of aqueous gels. J Am Chem Soc 1990 112 8458-8465. 

Newkome GR, Yao Z, Baker GR, Gupta VK. Micelles. Part 1. Cascade molecules a new approach to micelles. A [27]-arborol. J Org Chem 1985 50 2003-2004. 

In this context, much attention is currently devoted to the preparation of highly branched tree-like species, variously called cascade molecules, arborols, or dendrimers. The reasons why such compounds are interesting from a fundamental viewpoint and promising for a variety of applications have been reviewed and highlighted by several authors. Many of the dendrimers obtained so far are organic in nature. This review describes a novel family of dendrimers containing metal ions, prepared in our laboratories over the last few years. 

Several years earlier (1974), the same group had already described manyarmed, albeit non-branched, molecules as octopus molecules [6], whose numerous arms were used for complexation with metal ions (Fig. 1.2). These octopus molecules can be regarded as forerunners of nitrogen-containing propylenamine cascade molecules since they already demonstrated the utility of many adjacent functional arms - all the more readily attainable by branching - for example for host-guest interactions [6]. 

The name dendrimers, which has meanwhile largely displaced the original designation of cascade molecules, is derived from the Greek words dendron and meros, and is meant to underscore the tree-like branched structure of this class of compounds (see Section 1.1). 

The first correctly dendritically branched molecules were termed cascade molecules and could be prepared divergently by a cascade synthesis (Section 1.1). 

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