Investigations into the generation and pleiotropic reactivity modes of the nitrile imine 1,3-dipole

  • Keith Livingstone

Student thesis: Doctoral Thesis


The nitrile imine 1,3-dipole is a versatile intermediate with a diverse range of applications from chemical biology to materials chemistry. In the 60 years since its initial discovery, this system has been found to undergo 1,3-dipolar cyclo addition with numerous dipolarophiles, while also engaging with various conventional heteroatomic nucleophiles through anelectrophilic addition mechanism. This pleiotropic reactivity profile makes the nitrile iminean especially unique motif within 1,3-dipole chemistry. The research detailed within this thesis relates to the manipulation of the nitrile imine 1,3-dipole and its role in the discovery of novel chemical transformations and works towards methods of harnessing its complex reactivity profile with the ultimate goal of improving the understanding of the species in its continued application within ligation chemistry. As aninitial investigation, a novel approach towards the popular 2,5-tetrazole nitrile imine precursor was developed. Employing robust Suzuki-hydrogenation methodology previously established within our laboratory, this protocol demonstrates a facile means of accessing abroad palette of 2,5-diaryl tetrazoles for application as a source of nitrile imines (Scheme0.1). Scheme 0.1: The development of a novel route towards 2,5-diaryltetrazoles employing Suzuki-debenzylation methodology [Scheme available in print and digital copies];With efficient access to the 1,3-dipole demonstrated, the extensive reactivity of the nitrileimine was investigated through its combination with arylboronic acids. Drawing mechanistic inspiration from the Petasis-Mannich reaction, a novel and metal-free approach towards C-C bond formation was developed, forming an array of aryl ketone hydrazone compounds (Scheme 0.2). The scope of the procedure was further expanded through the introduction of hydrazonyl chlorides as an alternative source of the nitrile imine. Exemplification of the transformation was accomplished through the metal-free synthesis of hypolipidemic agent fenofibrate, the adaption of the methodology to incorporate the nitrile oxide 1,3-dipole, and the integration of 2,5-tetrazole photolysis within a flow-chemistry manifold. ii Scheme 0.2: The development of a metal-free C-C bond-formation through the combination of nitrile imines and arylboronic acids [Scheme available in print and digital copies ];Finally, following extensive experience with the promiscuous reaction profile of nitrileimines, a series of competition experiments were undertaken to develop a comprehensive guide to the relative reactivity of the pleiotropic dipole (Scheme 0.3). The study investigated numerous potential substrates, spanning a selection of biomolecular residues, potent nucleophiles and bespoke dipolarophiles. Particular attention was paid to common NI bioorthogonal ligation agents that have been previously reported. Based on this, a definitive roadmap of NI reactivity was developed towards the more informed application of the versatile dipole within the field of chemical biology. Scheme 0.3: Quantitative investigations into the reactivity profile of the nitrile imine 1,3-dipole. [Scheme available in print and digital copies ]
Date of Award1 Jan 2021
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorCraig Jamieson (Supervisor) & Nick Tomkinson (Supervisor)

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