Radicals play a pivotal role in nature and are involved in many biochemical processes. However, until the late 20th century only minor attention was given to single electron processes in synthetic organic chemistry, due to the persistent notion of being difficult to control. With the development of new synthetic approaches to access such reactive open-shell intermediates in a practical fashion, radical chemistry has gained renewed interest. Photoredox catalysis (PRC) has emerged as the cornerstone in accessing these reactive open-shell intermediates under mild conditions. Key to the success of these strategies is the ability of chromophores to harvest visible light and reach long-lived excited states. Subsequently, the excited photocatalytic species can activate intermediates or reagents via single electron transfer (SET), energy transfer (ET), or hydrogen atom transfer (HAT) to yield radicals and enable chemical transformations. The mechanism of such photocatalytic systems often includes multiple catalytic species and reagents, which are actively involved in the catalytic cycle and render mechanistic investigations complicated. State-of-the-art methodologies to investigate photocatalytic systems mainly focus on the properties of the excited state species and consecutive quenching interaction with reagents, catalysts or intermediates. A more holistic picture of the overall process can be acquired via in situ monitoring techniques (Chapter 4). The value of real-time monitoring for gaining mechanistic insights was demonstrated during the development of a photocatalytic benzyl ether cleavage (Chapter 9). Due to their high stability, benzyl ethers are commonly used protecting groups in carbohydrate and natural product syntheses, though commonly utilized harsh deprotection strategies with poor functional group tolerance render them typically unattractive for multistep organic synthesis. Upon visible light irradiation, 2,3-dichlor-5,6-dicyano-1,4-benzoquinone (DDQ) reaches a highly oxidizing, long-lived excited triplet state (DDQ*), capable of oxidative cleavage of benzyl ethers.
A combination of DDQ and tert-butyl nitrite (TBN) cleaved benzyl groups from monosaccharides under ambient atmosphere and visible light irradiation with high functional group tolerance. Real-time monitoring using LED-NMR spectroscopy gave insights in the crucial role of TBN and light. The scale-up of light promoted reactions is typically detrimental to the efficiency of photocatalytic reactions, due to poor light penetration. Careful optimization of the reaction conditions for photooxidative debenzylations was required to access a deprotection methodology applicable on the gram scale (Chapter 6). The facile access to reactive open-shell intermediates enabled by photocatalysis has led to a myriad of new synthetic approaches, including photoredox catalyzed cross-coupling reactions. This is achieved using a combination of nickel and noble metal photocatalysts (PC). A more sustainable alternative to commonly used expensive and homogeneous iridium- and ruthenium polypyridyl complexes was found in graphitic carbon nitrides (gCN). The ability of CN-OA-m in combination with a nickel complex was showcased in an etherification and extended to the coupling of aryl iodides with thiols (Chapter 8). In situ IR-monitoring was applied for detailed kinetic analysis of the developed semi-heterogeneous system and the state-of-the-art photocatalyst tris(2-phenylpyridine)iridium(III) on a model O-arylation reaction. This indicated that different photocatalysts can result in different mechanistic scenarios, that result in the same product (Chapter 7). Incorporating fluorine into organic scaffolds increases the compounds physicochemical properties, such as lipophilicity and metabolic stability, resulting in improved active pharmaceutical ingredients and agrochemicals. Hence, the development of new safe and simple fluorination methodologies is of interest. A divergent benzylic radical fluorination reaction, initiated via a charge transfer complex that does not require visible-light activation, selectively yielded either benzyl fluorides or α-fluorophenylacetic acids depending on the conditions (Chapter 5). Charge transfer complex mediated in situ generation of a highly reactive radical species enabled hydrogen atom transfer (HAT) as well as single electron transfer (SET), solely depending on the pKa of the phenylacetic acid starting material.
