Doctor of Philosophy
Mark S. Workentin
This thesis explores the preparation of thiolated gold nanoparticles (AuNPs) and thiolated gold nanoclusters (AuNCs) capable of undergoing post-assembly surface modifications using two common “bioorthogonal” click reactions: the strain-promoted alkyne-azide cycloaddition (SPAAC) reaction (which occurs between a strained-alkyne and an azide) and the strain-promoted alkyne-nitrone cycloaddition (SPANC) reaction (which occurs between a strained-alkyne and a nitrone). Due to their rapid and modifiable reaction kinetics, high chemoselectivity, and stability of the reactive partners, these reactions were originally designed to tether functional substrates to biologically sensitive biomolecules, without altering their structure or perturb the biologically sensitive environments in which they operate in. The research presented herein explores using the SPAAC and SPANC reactions as “nanoorthogonal” click reactions, translating their advantageous characteristics towards surface modifications of thiolated AuNPs and AuNCs in an efficient and straightforward manner without perturbing their chemically sensitive structures.
Chapter 2 describes the development of a reactive AuNP platform with an aliphatic strained-alkyne (specifically, bicyclo[6.1.0]nonyne (BCN)) tethered to its surface. This platform could undergo both interfacial SPAAC (I-SPAAC) and interfacial SPANC (I-SPANC), whose reaction kinetics could be tuned through structural alterations to the complementary azide/nitrone dipolar species, respectively. When highly electron-deficient dipolar species were used, rapid surface modifications could be accomplished. Such predictable alterations to the kinetic profiles of I-SPAAC and I-SPANC allows exclusive reactivity with one highly reactive dipolar species in the presence of a less reactive dipolar species, which altogether provides an efficient and versatile route towards derivatizing AuNP surfaces. To further expand the scope of such rapid modifications of AuNP surfaces, Chapter 3 explores the development of a nitrone-terminated AuNP platform, in which the surface nitrone dipolar species are delocalized into highly electron deficient pyridinium groups. In a prototype kinetic study, nitrones with pyridinium groups on the Nα of the nitrones exhibited rapid reaction kinetics with BCN, whose reaction kinetics could be altered through modifications of the Cα substituents of the nitrone. Unfortunately, due to the high reactivity of the pyridinium-functionalized nitrone group, attempts to incorporate this rapidly reactive moiety to the AuNP surface was not successful due to the synthetic incompatibilities between pyridinium-functionalized nitrones and thiols. However, the development of such rapid SPANC chemistry serves as a promising tool for modifications of other nanomaterial systems in which thiols are not present.
Chapter 4 describes the first example of an azide-modified AuNC system (specifically, the [Au25(SR)18]-1 system) that could undergo post-assembly cluster-surface SPAAC (CS-SPAAC) chemistry with complementary strained-alkynes. The molecular structure of this azide-modified platform (specifically [Au25(SCH2CH2-p-C6H4-N3)18]-1 with p-azidophenylethanethiolate as the surface ligand) is reported. Whereas larger AuNP systems tend to be more rigid, the structures and integrity of smaller AuNC systems are more chemically sensitive, and the ability to conduct CS-SPAAC in a nanoorthogonal manner without altering the internal structure represents an exciting new paradigm towards AuNC surface modifications. Chapter 5 explores how the reactivity, structure and physical properties of azide-modified [Au25(SR)18]-1 platforms are affected by changing the regioisomeric form of the azide-modified surface ligands. Two isomeric forms of [Au25(SCH2CH2-p-C6H4-N3)18]-1 were developed: [Au25(SCH2CH2-m-C6H4-N3)18]-1 and [Au25(SCH2CH2-o-C6H4-N3)18]-1. The molecular structures of the neutrally charged forms of these three isomers are reported. It was found that although the physical properties appeared to be largely unaffected, the structure and reactivity of these azide-modified platforms appear to be dependent on the regioisomeric form of the azide-modified surface ligand. Chapter 6 describes the first example of a ferrocene-modified [Au25(SR)18]-1 system, which could be accomplished through a CS-SPAAC reaction between the azide-modified [Au25(SCH2CH2-p-C6H4-N3)18]-1 platform and BCN-terminated ferrocene, which highlights the true power of conducting CS-SPAAC chemistry on the surface of [Au25(SR)18]-1 frameworks to incorporate large, functional substrates.
In total, this work describes and explores innovative methodologies that can be used to conduct chemical modifications of AuNP and AuNC surfaces using SPAAC and SPANC, in an efficient and nanoorthogonal manner without altering the parent structures. Using such versatile and effective strategies, it will be possible to develop functional variants of these popular nanomaterial systems more easily for application-based research.
Summary for Lay Audience
Gold nanoparticles (AuNPs) and gold nanoclusters (AuNCs) are popular nanomaterial frameworks that are promising candidates for application-based research in nanomedicine, bioimaging and catalysis. Both material frameworks have internal gold-containing cores in the nanometer size regime, which are stabilized by an external monolayer of surface ligands. The key distinction between them is that AuNPs are larger (> 2 nm) and typically polydisperse (i.e. broad size range), while AuNCs are smaller (< 2 nm) and typically monodisperse (i.e. narrow size range). To optimize the practicality of these nanomaterial systems, it is important to modify the chemical composition of their external surfaces with functional substrates that can tailor them for desired applications. Common methodologies that are currently employed to achieve such surface modifications share many mutual drawbacks that limit the ability to effectively modify their surfaces. This is caused by the chemical sensitivity of these nanomaterials and the synthetic challenges in developing functional substrates that can be incorporated onto the AuNP and AuNC surfaces. For these reasons, there is a need to explore alternate strategies to incorporate functionality to the surfaces of AuNPs and AuNCs.
This thesis explores the preparation of AuNPs and AuNCs with surface ligands that are capable of undergoing post-assembly surface modifications using the strain-promoted alkyne-azide cycloaddition reaction (SPAAC) and strain-promoted alkyne-nitrone cycloaddition reaction (SPANC). These “bioorthogonal” reactions are largely reserved for tethering functional substrates to biologically sensitive biomolecules in an efficient, chemoselective manner without perturbing the biologically sensitive environments in which the biomolecules reside and operate in. The goal of this thesis is to demonstrate that the SPAAC and SPANC reactions can also be used as “nanoorthogonal” reactions, which can be used to efficiently modify the surfaces of chemically sensitive AuNPs and AuNCs in a straightforward and robust manner without the limitations of other common surface modification strategies.
Gunawardene, Praveen N., "Nanoorthogonal Surface Modifications of Gold Nanoparticles and Nanoclusters through Strain-Promoted Cycloaddition Chemistry" (2021). Electronic Thesis and Dissertation Repository. 8013.
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