Direct Measurement of the Visible to UV Photodissociation Processes for the PhotoCORM TryptoCORM

PhotoCORMs are light‐triggered compounds that release CO for medical applications. Here, we apply laser spectroscopy in the gas phase to TryptoCORM, a known photoCORM that has been shown to destroy Escherichia coli upon visible‐light activation. Our experiments allow us to map TryptoCORM’s photochemistry across a wide wavelength range by using novel laser‐interfaced mass spectrometry (LIMS). LIMS provides the intrinsic absorption spectrum of the photoCORM along with the production spectra of all of its ionic photoproducts for the first time. Importantly, the photoproduct spectra directly reveal the optimum wavelengths for maximizing CO ejection, and the extent to which CO ejection is compromised at redder wavelengths. A series of comparative studies were performed on TryptoCORM‐CH3CN which exists in dynamic equilibrium with TryptoCORM in solution. Our measurements allow us to conclude that the presence of the labile CH3CN facilitates CO release over a wider wavelength range. This work demonstrates the potential of LIMS as a new methodology for assessing active agent release ( e.g. CO, NO, H2S) from light‐activated prodrugs

Understanding Precatalyst Activation and Speciation in Manganese-Catalyzed C-H Bond Functionalization Reactions

An investigation into species formed following precatalyst activation in Mn-catalyzed C-H bond functionalization reactions is reported. Time-resolved infrared spectroscopy demonstrates that light-induced CO dissociation from precatalysts [Mn(C^N)(CO)4] (C^N = cyclometalated 2-phenylpyridine (1a), cyclometalated 1,1-bis(4-methoxyphenyl)methanimine (1b)) in a toluene solution of 2-phenylpyridine (2a) or 1,1-bis(4-methoxyphenyl)methanimine (2b) results in the initial formation of solvent complexes fac-[Mn(C^N)(CO)3(toluene)]. Subsequent solvent substitution on a nanosecond time scale then yields fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)], respectively. When the experiments are performed in the presence of phenylacetylene, the initial formation of fac-[Mn(C^N)(CO)3(toluene)] is followed by a competitive substitution reaction to give fac-[Mn(C^N)(CO)3(2)] and fac-[Mn(C^N)(CO)3(η2-PhC2H)]. The fate of the reaction mixture depends on the nature of the nitrogen-containing substrate used. In the case of 2-phenylpyridine, migratory insertion of the alkyne into the Mn-C bond occurs, and fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] remains unchanged. In contrast, when 2b is used, substitution of the η2-bound phenylacetylene by 2b occurs on a microsecond time scale, and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)] is the sole product from the reaction. Calculations with density functional theory indicate that this difference in behavior may be correlated with the different affinities of 2a and 2b for the manganese. This study therefore demonstrates that speciation immediately following precatalyst activation is a kinetically controlled event. The most dominant species in the reaction mixture (the solvent) initially binds to the metal. The subsequent substitution of the metal-bound solvent is also kinetically controlled (on a ns time scale) prior to the thermodynamic distribution of products being obtained

Chemodivergent Manganese-Catalyzed C–H Activation: Modular Synthesis of Fluorogenic Probes

Bioorthogonal diversification of peptides is generally dependent on impractical prefunctionalization methods. Here, the authors develop a manganese(I)-catalyzed C–H fluorescent labeling with BODIPY probes, which enables the development of activatable fluorophores to image cell function

Controlling cell behavior through the design of polymer surfaces

Polymers have gained a remarkable place in the biomedical fi eld as materials for the fabrication of various devices and for tissue engineering applications. The initial acceptance or rejection of an implantable device is dictated by the crosstalk of the material surface with the bioentities present in the physiological environment. Advances in microfabrication and nanotechnology offer new tools to investigate the complex signaling cascade induced by the components of the extracellular matrix and consequently allow cellular responses to be tailored through the mimicking of some elements of the signaling paths. Patterning methods and selective chemical modifi cation schemes at different length scales can provide biocompatible surfaces that control cellular interactions on the micrometer and sub-micrometer scales on which cells are organized. In this review, the potential of chemically and topographically structured micro- and nanopolymer surfaces are discussed in hopes of a better understanding of cell–biomaterial interactions, including the recent use of biomimetic approaches or stimuli-responsive macromolecules. Additionally, the focus will be on how the knowledge obtained using these surfaces can be incorporated to design biocompatible materials for various biomedical applications, such as tissue engineering, implants, cell-based biosensors, diagnostic systems, and basic cell biology. The review focusses on the research carried out during the last decade.The research leading to these results has received partial funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. NMP4-SL-2009-229292 and by the FCT projects PTDC/FIS/68517/2006, PTDC/QUI/69263/2006, PTDC/FIS/68209/2006, and PTDC/QUI/68804/2006

A comprehensive understanding of carbon-carbon bond formation by alkyne migratory insertion into manganacycles

Migratory insertion (MI) is one of the most important processes underpinning the transition metal-catalysed formation of C-C and C-X bonds. In this work, a comprehensive model of MI is presented, based on the direct observation of the states involved in the coupling of alkynes with cyclometallated ligands, augmented with insight from computational chemistry. Time-resolved spectroscopy demonstrates that photolysis of complexes [Mn(C^N)(CO)4] (C^N = cyclometalated ligand) results in ultra-fast dissociation of a CO ligand. Performing the experiment in a toluene solution of an alkyne results in the initial formation of a solvent complex fac-[Mn(C^N)(toluene)(CO)3]. Solvent substitution gives an η2-alkyne complex fac-[Mn(C^N)(η2-R1C2R2)(CO)3] which undergoes MI of the unsaturated ligand into the Mn-C bond. These data allowed for the dependence of second order rate constants for solvent substitution and first order rate constants for C-C bond formation to be determined. A systematic investigation into the influence of the alkyne and C^N ligand on this process is reported. The experimental data enabled the development of a computational model for the MI reaction which demonstrated that a synergic interaction between the metal and the nascent C-C bond controls both the rate and regiochemical outcome of the reaction. The time-resolved spectroscopic method enabled the observation of a multi-step reaction occurring over 8 orders of magnitude in time, including the formation of solvent complexes, ligand substitution and two sequential C-C bond formation steps

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)