Chapter 1

Dendrimer Chemistry: Supramolecular Perspectives and Applications

Charles N. Moorefield, Sujith Perera, and George R. Newkome

“There are many beautiful molecular architectures, it is just that some are easier to access than others.”

Roald Hoffman, Nobel Prize in Chemistry, 1981

1.1 Introduction

1.1.1 Historical Background

Dendritic chemistry, from its initial development to its application in the construction of utilitarian devices and materials, has provided a great amount of proverbial cement for interdisciplinary integration. Similar to polymer (or macromolecular) chemistry, conceptualized and postulated by luminaries such as Flory [1–3] (Nobel—1974) and Staudinger (Nobel—1953) who provided a new foundation for material sciences, dendrimer chemistry has generated another new level of scaffolding upon which a myriad of potential uses are being explored and exploited.

First introduced as “cascade” molecules due to their repeating motif by Vögtle and coworkers [4] in 1978, materials analogously termed arborols (derived from the Latin word arbor for tree) and dendrimers (derived from the Greek word dendro for tree) were reported by Newkome et al. [5] and Tomalia et al. [6] both in 1985, respectively. While these reports specifically addressed the potential to craft branching molecular architectures with multiple terminal functionality and repetitive branch junctures (Tomaila, 1 → 2 branching based on linear building blocks; Newkome, 1 → 3 branching based on modular building blocks with preconstructed branching centers) another notable report appeared by Aharoni and coworkers [7] in 1982 describing the “Size and Solution Properties of Globular tert-Butoxycarbonyl-poly(α,ε-l-lysine).” Their study involved the characterization of 1 → 2, asymmetrically branched materials that were termed “nondraining globular biopolymers” that were iteratively prepared and reported in 1981 (U.S. patent 4289872, Denkewalter et al. [8]). Other notable and interesting reports prior to the explosive advent of dendritic chemistry, include the iterative synthesis of ultralong, linear paraffins reported by Bidd and Whiting [9], the early observation by Ingold and Nickolls [10] of the entrapment of gas molecules by methanetetraacetic acid, and Lehn's elegant modular approach [11] to cryptate syntheses.

1.1.2 Architectural Concepts

Dendritic molecules can be envisioned by considering the repetitive layering of multifunctional building blocks based on a protection and deprotection scheme or the addition of increasing numbers of linear, complementary monomers. This generally results in a branched, tree- or fractal-like, molecular motif whereby each incorporated layer provides a foundation for the successive layer. Since the number of reactive sites and branching centers increases with each layer, a “mushrooming” framework is produced. The synthetic protocol can be visualized (Scheme 1.1) by considering the attachment of a generic 1 → 3 branched building block 1 that possesses three reactive sites differentiated from the 4th. Thus, treatment of monomer 1 with three equivalents of a like monomer produces a new monomer 2 with the same functional group characteristics as the starting materials, except that the periphery has now grown and expanded to a 1 → 9 branched construct.

Scheme 1.1 Divergent and convergent routes to branched architecture.

The iterative dendritic strategy has developed into two general modes of construction. The divergent route, initially introduced by Vögtle et al. [4], whereby molecular growth essentially proceeds from the “inside outward” and the convergent route, introduced in 1990 by Fréchet et al. [12], resulting in growth from the “outside inward.” Differences in the two methods arise from building block order of addition and can be affected by the control over functional group activation and deactivation. Thus, logical choices of protection–deprotection strategies derived from classical synthetic chemistry are a prime importance in dendritic chemistry. Addition of nine equivalents of a triprotected monomer 1 to the surface of a growing specie 2 will lead to the progressively greater branched construct 3. The same material (i.e., 3) can be derived convergently by inverting the process to add three equivalents of the 1 → 9 higher–order, branched monomer to the simple monomer. Both methods allow the construction of dendritic material and also have their individual strengths and weaknesses. For example, divergent syntheses requires an ever increasing number of monomer attachment reactions leading to a higher probability of incomplete reactions at the ever-expanding periphery leading to a greater number of imperfections; whereas, convergent methods instill a greater probability to generate perfect structures due to few required reactions for layer construction, albeit at lower molecular weights. The potential to locate and connect at a single site within a growing multifunctional monomer diminishes with size and the attendant steric hindrance. Predicated on these features and a comprehensive mass spectrometry analysis, divergent and convergent methods have been compared to polymer and organic syntheses, respectively, by Meijer et al. [13].

As with most other unique areas that attract much attention, descriptive terminology has been developed within the dendritic chemistry community. While much is intuitive, a brief discussion is warranted. The central point from which all branching emanates is described as a core; whereas, the outer surface, or peripheral region, is populated with terminal groups (4; Fig. 1.1). Branching centers define the branching multiplicity based on the number of functional groups or reactive sites that they possess (i.e., 2, 3, or greater) and layers are often referred to as generations to easily denote the number of iterations used in construction. Notably, dendritic void volume is a valuable and useful property and has been employed by many research groups for purposes such as micellar entrapment, host–guest interactions, and catalytic site construction, to mention but a few. This feature has given rise to a new area of study upon which this book is largely based—drug delivery and pharmacological agents using dendritic species.

Figure 1.1 2D and 3D representations of dendritic components.

Branched monomers, or building blocks, used in dendritic construction are now commonly referred to as dendrons, in analogy to synthons in classical organic chemistry. Many dendrimers have been reported [14] using nonbranched monomers; however, their monomers are usually not described as dendrons owing to their linear characteristic. Arising from the convergent protocol, the single reactive site on a multifunctional dendron is described as the focal site. The individual layers of building blocks that comprise dendritic structures are generally denoted as generations, which in turn allow for easy descriptive terminology and a ready understanding of the potential number of surface moieties provided the multiplicity of the core and dendron(s) are known. The concept of dense packing arises from the consideration of increasing numbers of surface groups and a proportionately decreasing amount of available surface area; hence, at some level of construction there will not be enough surface area to accommodate a stoichiometric number of building blocks. This aspect may or may not be problematic and will depend on the desired end characteristics of the material(s) in question.

Ultimately, consideration of dendritic generation leads to the question – structurally, what constitutes a dendrimer? Numerous reports in the literature describe new dendritic species comprising only a single generation. In many cases, a zeroth-generation construct is reported. The importance, elegance, and usefulness of these materials notwithstanding, they are not dendrimers in an historical or idealized sense. They do not possess repeating architectural details at different generations. Therefore, we will herein only describe those materials possessing the attributes of greater than two generations as belonging to a dendrimer family and they must be structurally characterized.

1.1.3 Initial Reduction to Practice

In 1978, a branched covalent molecular architecture was initially reported (Scheme 1.2) by Vögtle et al. [4]. Their scheme represented the first report of a repetitively branched, polyfunctional molecule whereby all to the intermediates were isolated, purified, and substantially characterized in contrast to the traditional synthesis of a polymer whereby only the starting materials and products are isolated and verified. The synthetic protocol utilized Michael-type, nucleophilic amine addition to an electron-poor cyanoalkene followed by reduction of the cyano groups to generate new amine moieties used for further reaction. Thus, for example, amine 5 was treated with acrylonitrile in the presence of glacial acetic acid to give bis-nitrile 6 that was then reduced with NaBH4 and CoCl2·6H2O to afford diamine 7. Repetition of the sequence generated polynitrile 8 and subsequently polyamine 9 possessing 3 tertiary and 4 primary amino moieties. The procedure was also undertaken with diamines such...