A Mechanistic Investigation into Mn(I)-Catalysed C-H Bond Functionalisation: from Pre-Catalyst Activation to Substrate Coordination and Transformation

This thesis describes mechanistic investigations into Mn(I)-mediated C–H bond activation and functionalisation processes, with an additional focus on the factors influencing the reactivity of the manganese complexes. Initially, an investigation into Mn(I)-catalysed C–H bond alkenylation of 2-phenylpyridines was performed, utilising the distinct IR bands of the manganese carbonyl species to monitor the catalyst in situ (Chapter 2). The mechanistic studies allowed for a comprehensive reaction mechanism to be derived, where pre-catalyst activation was found to be substrate-dependent, leading to two distinct pathways. Furthermore, two new catalytic cycles (involving protonation by the 2-phenylpyridine and water) were discovered, in addition to the confirmation of the previously proposed cycle. Time-Resolved InfraRed (TRIR) spectroscopy provided an opportunity to study the processes underpinning C–C bond formation in further detail, observing short-lived (0.5 ps – 1 ms) reaction intermediates and their respective kinetic behaviour (Chapter 3). Photochemical initiation led to the utilisation of a range of manganese complexes and unsaturated substrates. The uni- and bimolecular behaviour of the intermediates and their kinetics were probed from experiments diluted in toluene. Carboxylic acid additives were employed to increase the efficiency of Mn(I)-catalysis using terminal alkynes, while inhibiting reactions with acrylates (Chapter 4). Mechanistic studies revealed that a change in catalyst resting-state explains the different effects. TRIR spectroscopy allowed for the observation of the protonation by carboxylic acids, leading to an observation of the steps underpinning the CMD/AMLA-6 mechanism. Investigation into the fluorine-induced regioselectivity of Mn(I)-mediated C–H bond functionalisation of 2-phenylpyridines showed that the cyclomanganation reaction is kinetically driven and irreversible. Addition of benzoic acid led to a reversible mechanism, where the regioselectivity is thermodynamically controlled. It was additionally revealed that the regioselectivity likely arises from the relative thermodynamic stability of the manganacycles, where the trend follows the order: ortho>meta>para (with respect to the fluorine substituent)

Mechanistic insight into catalytic redox neutral C-H bond activation involving manganese(I) carbonyls: Catalyst activation, turnover and deactivation pathways reveal an intricate network of steps

Manganese­(I) carbonyl-catalyzed C–H bond functionalization of 2-phenylpyridine and related compounds containing suitable metal directing groups has recently emerged as a potentially useful synthetic methodology for the introduction of various groups to the ortho position of a benzene ring. Preliminary mechanistic studies have highlighted that these reactions could proceed via numerous different species and steps and, moreover, potentially different catalytic cycles. The primary requirement for typically 10 mol % catalyst, oftentimes the ubiquitous precursor catalyst, BrMn­(CO)5, has not yet been questioned nor significantly improved upon, suggesting catalytic deactivation may be a serious issue to be understood and resolved. Several critical questions are further raised by the species responsible for providing a source of protons in the protonation of vinyl–manganese­(I) carbonyl intermediates. In this study, using a combination of experimental and theoretical methods, we provide comprehensive answers to the key mechanistic questions concerning the Mn­(I) carbonyl-catalyzed C–H bond functionalization of 2-phenylpyridine and related compounds. Our results enable the explanation of alkyne substrate dependencies, i.e., internal versus terminal alkynes. We found that there are different catalyst activation pathways for BrMn­(CO)5, e.g., terminal alkynes lead to the generation of MnI–acetylide species, whose formation is reminiscent of CuI–acetylide species proposed to be of critical importance in Sonogashira cross-coupling processes. We have unequivocally established that alkyne, 2-phenylpyridine, and water can facilitate hydrogen transfer in the protonation step, leading to the liberation of protonated alkene products

Mild and Regioselective Pd(OAc)2-Catalyzed C–H Arylation of Tryptophans by [ArN2]X, Promoted by Tosic Acid

A regioselective Pd-mediated C–H bond arylation methodology for tryptophans, utilizing stable aryldiazonium salts, affords C2-arylated tryptophan derivatives, in several cases quantitatively. The reactions proceed under air, without base and at room temperature in EtOAc. The synthetic methodology has been evaluated and compared against other tryptophan derivative arylation methods using the CHEM21 Green Chemistry Toolkit. The behavior of the Pd catalyst species has been probed in preliminary mechanistic studies, which indicates that the reaction is operating homogeneously, although Pd nanoparticles are formed during substrate turnover. The impact of these higher order Pd species on catalysis, under the reaction conditions examined, appear to be minimal, e.g. acting as a Pd reservoir in the latter stages of substrate turnover or as a moribund-form (derived from catalyst deactivation). We have determined that TsOH shortens the induction period observed when employing [ArN2]BF4 salts with Pd(OAc)2. Pd(OTs)2(MeCN)2 was found to be a superior precatalyst (confirmed by kinetic studies) to Pd(OAc)2

Insight into the mechanism of CO-release from trypto-CORM using ultra-fast spectroscopy and computational chemistry

Photolysis of trypto-CORM, fac-[Mn(tryp)(CO)3(NCMe)] (tryp = tryptophanate) at 400 nm results in controlled CO-release which may be utilised to inhibit the growth of Escherichia coli (E. coli). An investigation into the fundamental processes which underpin the CO-release event is described. Time-dependent density functional theory (TD-DFT) indicates that irradiation at 400 nm results in an LMCT from the indole group of the amino acid to orbitals based on the metal as well as the carbonyl and NCMe ligands. Ultra-fast time-resolved infra-red spectroscopy (TRIR) demonstrates that in NCMe solution, photolysis (400 nm) results in loss of CO in under 3 ps with the sequential generation of three new states with two carbonyl ligands and a coordinated tryptophanate. The first species is assigned to vibrationally hot 3[Mn(tryp)(CO)2(NCMe)] which undergoes cooling to give the complex in its v = 0 state. This triplet state then undergoes solvation ( ≈ 20 ps) with a concomitant change in spin to give [Mn(tryp)(CO)2(NCMe)2] which persists for the remainder of the experiment (800 s). These data indicate that following the initial photochemically induced loss of CO, any thermal CO loss is much slower. Related experiments with trypto-CORM in a mixture of DMSO and D2O gave analogous data, indicating that this process also occurs in the medium used for the evaluation of biological properties