Synthesis of Redox-Active Macrocycles via Successive Ring Expansion

Interest in macrocycles has grown enormously in the last decade, in significant part due to their favourable properties in supramolecular chemistry. For example, some macrocycles can act as hosts for specific guest molecules and act as chemical sensors,¹ while others have been used as catalysts,² mimicking the active site of enzymes.³ There is also burgeoning interest in the synthesis of redox active macrocycles, as the redox state can control the supramolecular properties of the molecule and generate new modes of activity in catalysis or host-guest chemistry.⁴ Furthermore, there is significant interest in the development of cyclic molecular wires, as the multiple pathways for electron transfer in such molecules can lead to predictable variation in conductance.⁵

However, established synthetic methods to make macrocycles are typically inefficient, as large ring-closing reactions tend to be entropically unfavoured. This requires impractical, high dilution conditions to be used for their synthesis, negatively impacting scalability, and ultimately, their value in real-world applications.^6,7 In the last few years here in York, we have developed a series of ‘Successive Ring-Expansion’ (SuRE) methodologies, that allow functionalised macrocycles to be prepared more easily.^8–10 Using SuRE, diverse macrocycles can be ‘grown’ via the iterative insertion of amino acid and hydroxyacid-based linear fragments. To date, we have focused on using relatively simple linear fragments in SuRE. In this project, we plan to expand the SuRE methods to enable generation of novel ferrocene-containing redox-active macrocycles. This will be done by reacting ferrocene-containing acid chlorides with lactams via a simple N-acylation/ring expansion sequence to that used in our previous research on SuRE.⁸ As SuRE methods are designed to be performed successively, the lactam functionality will be regenerated as the product and therefore should then be amenable to further ring expansion in the same way, thus enabling the facile synthesis of highly functionalised macrocycles. Fully exploring the synthetic aspects in this reactivity, and discovering new variants, is a key goal of this PhD and as the project evolves, alternative redox-active components could be explored. Determining the electrochemical properties of the formed macrocycles is an additional important goal in this PhD, which will be done using a combination of electrochemical and spectroscopic techniques. As the redox state of the ferrocene may influence the conformation and/or reactivity of the macrocycle, this work is expected to have major implications for design of novel, tuneable and switchable catalysts with enzyme-like active sites.¹¹

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