Recent advances in click chemistry applied to dendrimer synthesis

Abstract

Dendrimers are monodisperse polymers grown in a fractal manner from a central point. They are poised to become the cornerstone of nanoscale devices in several fields, ranging from biomedicine to light-harvesting. Technical difficulties in obtaining these molecules has slowed their transfer from academia to industry. In 2001, the arrival of the "click chemistry" concept gave the field a major boost. The flagship reaction, a modified Hüisgen cycloaddition, allowed researchers greater freedom in designing and building dendrimers. In the last five years, advances in click chemistry saw a wider use of other click reactions and a notable increase in the complexity of the reported structures. This review covers key developments in the click chemistry field applied to dendrimer synthesis from 2010 to 2015. Even though this is an expert review, basic notions and references have been included to help newcomers to the field.

Keywords: Diels-Alder; Hüisgen cycloaddition; click; dendrimer; dendron; thiol-ene; thiol-yne.

Figure 1

Anatomy of a dendrimer. This example is an AB₂ type, where each branch is made of a monomer A that splits into two B monomers. “G” stands for generation.

Scheme 1

The Hüisgen [2 + 3] cycloaddition and the monomolecular version of the mechanism when it is catalyzed by copper. The alternative dinuclear transition state presented here is now widely accepted and explored by several groups [23,24,25,26].

Figure 2

Tris(3-hydroxypropyltriazolylmethyl)amine (THPTA) (left) and tris-(benzyltriazolylmethyl)amine (TBTA) (right). Similar ones have been developed and studied as CuAAC ligands [25].

Figure 3

Copper-free synthons used in dendrimer synthesis (A) fluorinated cyclooctyne (B) a dibenzoazocyclooctyne variant (C) acetylenediesters (D) propiolic esters.

Scheme 2

General schemes for the thiol-ene click reaction (Top) and for the thiol-yne click reaction (Bottom).

Scheme 3

General scheme for the Diels-Alder (DA) reaction (A), an example of rDA with furan and maleimide (B) and the cyclopentadienone popularized by the Mülllen group (C).

Figure 4

Complex dendritic architectures evolution from the pre-existing Janus (A) to the “onion peel” (B) and the three-faces strategies that rely on tri-orthogonality (C) or di-orthogonality (D).The structures of C and D are shown below to highlight how CuAAC was used only at the core for C and within the branches for D.

Scheme 4

Dendrons with an alkyne focal point are clicked on a nucleotide strand which ends bear azides. The global strategy where the Yne-D dendron is “clicked” on either a mono or di functionalized nucleotide strand is shown in (a). the structure of the Yne-D dendron is shown in (b) while (c) shows the detail of the nucleotide self-assembly around the metal ion. The resulting dendrimer self-assemble around a metal ion to form a cubic core with a total of four or eight dendrons. Reproduced with permission from Hamilton et al. [91].

Scheme 5

The global strategy of Malkoch et al. Through careful synthesis of starting synthons, they were able to use CuAAC and TEC without any transformation. This allowed for a very convenient and fast divergent synthesis [190].

Scheme 6

A metal-free dendrimer assembled through the EWG-alkyne-azide strategy [87]. If the substrates are oils at room temperature, no solvent is needed and the reaction can be self-heated.