Regioselective cycloadditions on fullerenes and endohedral metallofullerenes
Creators: name: Sun, Yue
Publisher: name: No Publisher Supplied
Year: 2024

description: Over the past few decades, fullerenes and endohedral metallofullerenes (EMFs) have attracted increasing attention for their potential applications of nanomaterials and biomedicine. Chemical functionalization reactions provide fullerene derivatives with substantially improved solubility and modified chemical and physical properties, broadening the scope of applications. Due to the formation of relatively stable cycloadducts in good yields and easy access of reactants, cycloadditions have been one of the most intensively used reactions in the synthesis of fullerene derivatives. This dissertation explores the chemical reactivity and regioselectivity of fullerenes and EMFs in cycloaddition reactions.Chapter 1 provides a general introduction to the fundamental concepts of fullerenes and EMFs, outlining their discovery and structural characteristics. Next, it describes the most common cycloaddition reactions used for the functionalization of fullerenes, including [2+1], [3+2], and [4+2] cycloadditions. Furthermore, it introduces the production, classification, and functionalization of EMFs, with a focus on their chemical reactivity, regioselectivity, and also the challenges associated with multi-functionalization. The chapter concludes with a summary of the current limitations hindering the broad use of fullerenes and EMFs, emphasizing the need for further research to overcome these challenges and unlock the full potential of these materials.In Chapter 2 and 3, an inverse-electron-demand Diels-Alder reaction was developed on both fullerenes (C60 and C70) and EMFs (Sc3N@C80 and Lu3N@C80). The oxidative [4 + 2] reaction of o-phenylenediamine-derived disulfonamides with C60 or C70 was investigated first in Chapter 2, which we found to be an oxidation reaction followed by an IEDDA reaction. Electron withdrawing groups (EWGs) in the disulfonamides were shown to facilitate the reaction experimentally and computationally, which is the opposite of most fullerene cycloadditions. Indeed, a [4 + 2] adduct on the [5,6]-junction of C70 was isolated as a major product for the first time, which was confirmed by NMR and X-ray diffraction. DFT studies revealed that the dd-[5,6]-C70 adduct is a kinetically favored product.Next, in Chapter 3, the scope of this reaction was extended to M3N@C80 (M=Sc or Lu). In this reaction, EMFs exhibit higher reactivity compared to empty fullerenes due to the inverse electron demand. Moreover, a complete retro-reaction can be achieved upon thermal treatment. The distinctive reactivity and reversibility of the IEDDA reaction enable a new concept in the chemical separation methodology for EMFs, where the desired EMFs that typically “remain last” in traditional chemical separation methods “react first” and are regenerated by retro-additions. The new chemistry and processing approach provide a key step towards the various applications of fullerenes and EMFs.In Chapter 4, a new multi-component reaction of alkyl isocyanide, dimethyl acetylenedicarboxylate (DMAD) or terminal alkynes with C60 or Lu3N@C80 were investigated. The three-component cycloaddition reaction of C60, alkyl isocyanide, and DMAD is firstly investigated to afford cyclopent-2-en-1-imino- and ketenimine methano-[60]fullerene derivatives, as confirmed by X-ray single-crystal analysis. Hydration of the ketenimine methanofullerene in the presence of acid gives the corresponding fullerene amides. Additional versions of alkynes have been tested as reactants under similar conditions, which suggests that the reaction requires an ester group on one side and a substituent providing both inductive and resonance effects on the other side of the triple bond. The reaction of t-butyl isocyanide (tBuNC), EWG-bearing terminal alkynes or DMAD with Lu3N@C80 was then investigated. A series of unexpected [6,6]-open metallofulleroids were obtained and fully characterized. The distinct reactivity and selectivity difference between EMFs and empty fullerenes was explored. The difference underscores the influence of the encapsulated metal cluster on the reaction pathway, leading to products with unique electronic and structural characteristics.In Chapter 5, a highly regioselective bis-addition was achieved by the isocyanide-induced reactions using a two-step strategy. The reaction of tBuNC, terminal alkyne and Lu3N@C80 resulted in a [6,6]-open monoadduct in the first step. The reaction of tBuNC and DMAD was performed on the resulted monoadduct. A series of bis-adducts was obtained as the major products and characterized by HPLC, MS, NMR and X-ray crystallography. Surprisingly, the second addition occurs on the adjacent site of the previous addition site, resulting in a [6,6]-closed structure. This addition shows unique regioselectivity being the opposite of previously reported cases. The computational study on the plausible mechanism and driving force behind the bis-addition is on-going.Lastly, in Chapter 6, a novel synthetic platform "metallobuckytrio" (MBT) was introduced, which enabled the precise and modular development of water-soluble EMF derivatives. The synthesis of the MBT framework was detailed, which combines a C60 hexakis-adduct with two EMF monoadducts, allowing for controlled addition of functional groups and enhanced solubility. By incorporating polyethylene glycol ligands, the derivatives maintain the electronic and photophysical properties of the EMF cage, providing a promising basis for future development of bio-specific rare-earth element drugs.