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Reports: DNI753195-DNI7: Synthesis of Multivalent and Multimodal Nanoparticles by 'Clicking-To' Multiblock Dendrimers

Jonathan G. Rudick, PhD, State University of New York at Stony Brook

Introduction. The proposed research seeks to develop a "clicking-to" approach to novel multiblock dendrimers. Dendrimers are high-value materials derived from petroleum feedstocks whose development as monodisperse, multivalent and multimodal nanoparticles has been stymied by batch-to-batch variability during synthesis. Monodisperse dendrimers with blocks of orthogonally reactive end group functionalities are anticipated to yield, upon subsequent derivatization, multifunctional dendrimers without sacrificing structural perfection. We hypothesized that orthogonal click reactions would achieve the high reactivity needed to quantitatively functionalize each block of end groups (Figure 1).

Figure 1. Proposed "clicking-to" approach to functionalize triblock dendrimers.

Results and Discussion

Enhanced Reactivity of Dendrons in the Passerini Three-Component Reaction. Triblock dendrimers are prepared in a convergent strategy that culminates in a Passerini three-component reaction. The slow kinetics of the reaction with dendritic components has limited the size of the dendrimers that can be obtained in this manner. For triblock dendrimers to serve as precursors to monodisperse, multivalent and multimodal nanoparticles, we needed to increase the size of the components that successfully undergo the Passerini reaction. Our hypothesis was that short linkers at the apex of the dendrons would result in better reaction kinetics by relieving steric interactions that slow the reaction. Indeed, we have identified linkers that dramatically reduced the required time for the Passerini reaction of dendrons. To our surprise, we found that relief of steric crowding was not the reason for the increased reactivity. Instead, we determined that a previously unobserved electronic effect enhanced the reactivity of the aldehyde component (Figure 2). When X is an oxygen atom, the reactions are fast; whereas when X is a longer aliphatic group, the reactions are as slow as when no linker is present. As a result of this unprecedented structure-activity relationship, we have succeeded in synthesizing in a convergent manner the largest three-component dendrimer to date. These results have been submitted for publication.

Figure 2. An unprecedented substituent effect has been observed in the Passerini three-component reaction of dendrons, and been exploited to synthesize dendrimers up to third-generation.

Dendrons with Orthogonally Reactive Apex and Peripheral Groups. The proposed strategy to prepare triblock dendrimers involves a Passerini reaction of precursor dendrons with orthogonal, click reactive functional groups at the periphery. Dendrons that have functional groups for the Passerini reaction at the apex, and functional groups for click reactions at the periphery were needed. We have synthesized bifunctional dendron with orthogonally reactive apex and peripheral groups to serve as a common precursor for all the dendritic components. The synthesis of such a bifunctional dendron has been completed (Figure 3). Compound 1 is known compound that is prepared in three steps from commercially available materials. The apex alcohol is transformed to azide 3 in two steps by way of mesylate 2. The ketal protecting groups at the periphery of 3 are removed under acid catalysis to yield diols. The hydroxyl groups are orthogonal to the azide group, and can be alkylated without affecting the apex functional group (e.g., 4 to 5).

Figure 3. Compound 4 is a bifunctional dendron with orthogonally reactive peripheral and apex functional groups, which will be used as common precursor in the synthesis of the proposed Passerini reaction components. The alkylation of 4 to yield 5 demonstrates the planned approach to introduce peripheral groups with different click-reactive groups.

Broader Impacts. The award has enabled significant progress in developing our approach to prepare this novel class of dendrimers, and has had a tangible impact on two graduate student researchers. The graduate students each received 50% support from the ACS-PRF award. One of the students is the sole author of a recently submitted publication. The other student presented her research at the 248th ACS National Meeting. Both students have presented at local meetings. Presentations like these are essential for students to develop skills to succeed as a professional researcher. Support of this work by the ACS-PRF was instrumental in giving the students the resources to accumulate the data needed for those presentations.

Concluding Remarks. Two key project milestones were achieved during the present funding period. First, we have made advancements in the synthesis of triblock dendrimers via the Passerini reaction that have yielded the largest three-component dendrimers to date. Second, we have prepared a versatile intermediate from which we can diversify the peripheral groups of these three-component dendrimers to include a variety of functionalities that participate in click reactions. In the coming year we plan to identify click reactive groups that are orthogonal to each other and yield quantitative functionalization of the dendrimers.