Odd Alternant Hydrocarbon Catalysed C-C and C-N Cross-Coupling Reactions

Sil, Swagata (2025) Odd Alternant Hydrocarbon Catalysed C-C and C-N Cross-Coupling Reactions. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (Phd thesis of Swagata Sil (18RS096)) 18RS096.pdf - Submitted Version Restricted to Repository staff only Download (25MB)

Abstract

C-C and C-N cross-coupling reactions are two fundamental pillars holding the vast area of organic synthesis. These two cross-coupling reactions are widely applicable due to their usage in the synthesis of different structural motifs, which are attractive as pharmaceuticals, agrochemicals, natural products, materials, etc. Cross-coupling reactions are traditionally catalysed by palladium, whereas recent improvisations replaced it with lighter transition metals like nickel, iron, cobalt, copper, etc. The standard pathway of cross-coupling revolves around the coordination of the electrophile with the palladium(0) center, transmetalation of the nucleophile, often through complexation with magnesium/zinc or deprotonation, followed by reductive elimination delivering the desired products, along with regeneration of the catalyst. Elevated temperature and sophisticated ligand systems are crucial for carrying out such reactions. Though chemically driven processes have dominated the fields of these transition metal-catalysed cross-couplings so far, new methodologies have introduced the implementation of Ru or Ir-based photosensitizers under light irradiation. Along with this, Nickel-mediated electrocatalytic pathways are gradually becoming significant as effective alternatives to the several decades-old cross-coupling reactions. Despite the indispensable participation of transition metals, some methodologies were also devised to acquire C-C and C-N cross-coupling reactions without any transition metals. These reaction protocols, loaded with very high concentrations of strong bases coupled with high temperatures, suffered from the limitation of poor functional group tolerance which eventually narrowed the substrate scope. Burdened with the use of organometallic reagents and multiple steps, such protocols could never be executed catalytically. Hence attaining catalytic transition metal-free C-C and C-N cross-coupling reactions avoiding external stimuli are indeed extremely difficult and rare to accomplish. Additionally, cross-electrophilic methylation falls in a different section of C-C cross-coupling where, unlike conventionally known cross-couplings, two electrophilic coupling partners with the same polarity get connected. For example, the incorporation of methyl groups in organic structural motifs led to a dramatic rise in pharmacological and physiochemical activities, well-recognized as the ‘Magic Methyl Effect’ in medicinal and pharmaceutical science. This catalytic technique for installing methyl groups into arene frameworks mandatorily requires transition metals. While chemically driven processes are controlled by palladium, nickel-based complexes, the combination of photo and chemoredox catalysis has also been implemented to facilitate methylated arenes from aryl halides upon light stimulation. As far as the literature is concerned, there is no chemical catalytic finding on cross-electrophilic methylation of aryl halides, that can work flawlessly without transition metals. In this scenario, we are introducing the phenalenyl (PLY) system, the 70-year-old odd alternant hydrocarbon, the transition metal-mimicking catalyst which can operate without any extrinsic excitation. This polycyclic aromatic hydrocarbon can exist in three different redox states, depending on the electronic occupancy in the NBMO (non-bonding molecular orbital)- the cationic state possesses a vacant NBMO (12 π-electrons), while the radical (13 π-electrons) and the anionic state (14 π-electrons) could house one and two electrons rendering the NBMO singly-occupied and fully-filled, respectively. The unique trait of the PLY system, unlike other aromatic hydrocarbons, is the reversibility of electronic acceptance and liberation using the NBMO, without compromising its aromaticity during each fold of skeletal reduction, as evident from NICS calculation. Though the radical and cationic states were already vastly applied catalytically, the anionic state remained quite under-explored. Previous DFT studies and subsequent control experiments demonstrated the dianionic PLY system capable of reducing the aryl halides through single-electron-donation, resulting in the generation of the aryl radical, which can be further functionalized in the presence of other coupling partners. Hence this single-electron-transfer-based catalyst has been implemented to achieve Sonogashira alkynylation and Buchwald-Hartwig amination to provide the desired cross-coupled products without any external stimuli. In the case of the transition metal-free C(sp)-C(sp²) cross-coupling, the catalytic protocol was further extended towards mechanochemical solid-state cross-coupling between solid aryl halides and alkynes, under ball-milling grinding. Both PLY-mediated catalytic findings were the first reports of transition metal-free Sonogashira and Buchwald-Hartwig cross-couplings under ambient conditions. Regardless of its efficiency of cleaving the Ar-Cl bonds at room temperature, the phenalenyl system never exhibited any capability of activating the strongest Ar-F bond. In the process of conducting transition metal-free methylation of aryl halides with methyl iodide, this redox-active direduced PLY species cleaved C-F bonds as well with other C-halogen bonds to deliver methylated arenes. Additionally, the stepwise single-electronic reduction of iodomethane into the alkyl radical to anion was also achieved by this super-electron-donor PLY molecule, promoting a triple-electron-transfer catalysis operated by this aromatic hydrocarbon. Apart from late-stage functionalization of drug molecules and one-pot sequential trimethylation, the versatility of this organocatalyst was further depicted in the integration of cross-couplings with cross-electrophilic methylation in a single reaction vessel. This study could establish that the redox-non-innocent phenalenyl molecule could replace transition metals from some of the most significant cross-coupling reactions to establish a unique radical-mediated pathway. In future, the phenalenyl molecule can be tuned to higher redox states to functionalize various inert molecules such as CO₂ and other gas molecules, producing more value-added feedstocks.

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