Diradical Chemistry: A Case Study of Reactive Intermediate Chemistry
When chemical reactions proceed in a stepwise manner, reaction intermediates always exist on potential energy surfaces between starting compounds and products. The structure and the reactivity of intermediates are quite important for the understanding of chemical reactions. However, the reactive intermediates are, in general, short-lived, so that it is quite difficult to experimentally clarify the chemistry. In the last century, chemists made great efforts to uncover the structure and reactivity of the energetically unstable intermediates such as cations,, anions, radicals,, and carbenes. The results of fundamental research studies have made a great contribution to the significant development in the field of not only mechanistic organic chemistry, but also organic synthesis, materials chemistry, and chemical biology. Since the reactive intermediates are short-lived, a number of analytical methods, including low temperature matrix spectroscopy and the laser flash photolysis technique, have also been developed to directly observe the intermediates. The developments of computational methods which can treat open-shell molecules including excited states are also significant. Thus, the fundamental research studies on reactive intermediates have influenced the development of the peripheral field of science, too. We are focusing on the chemistry of localized diradicals.
Localized diradicals (biradicals) are key intermediates in processes involving the homolytic bond-cleavage and formation reactions in cyclic compounds. There are two spin-multiplicities in the localized diradicals, singlet state (↑↓) and triplet state (↑↑), which are equilibrated with one another by the intersystem crossing process (ISC, a process of the multiplicity change). The chemistry of triplet diradicals is well-investigated not only as reactive intermediates, but also in materials chemistry, because the triplet diradicals frequently have lifetimes long enough to allow the diradicals to be detected under low temperature matrix conditions and are characterized using conventional spectroscopic techniques such as the EPR (Electron Paramagnetic Resonance) method. The paramagnetic character of triplet diradicals makes them potential building blocks for organic magnets and other materials with novel properties. Thus, the chemistry of triplet diradicals is very rich and the high-spin property has attracted continuous interest in many fields of chemistry. On the other hand, the singlet state of localized diradicals had been recognized as putative (undetectable) intermediates, because the intramolecular radical-radical coupling reactions are supposed to be barrier-less processes. In contrast to the rich chemistry of triplet diradicals, thus, the chemistry of localized singlet diradicals has been studied less, especially in experiments. It was necessary to generate detectable singlet diradicals, before thorough studies on the reactive intermediates were possible. The fundamental research studies on the hitherto unknown character of localized singlet diradicals was expected to provide not only new insights into the mechanisms of intramolecular homolytic reactions, but also opportunities to discover new concepts and novel functions of molecules.
The Paternó-Büchi Reaction: A Case Study of Organic Photochemistry
Oxetanes, four-membered cyclic ethers, have a ring-strain energy of ca. 110 kJ/mol and polar properties of the C-O bonds. Thus, similar to the synthetic utility of oxiranes (epoxides), the ring-opening reaction of oxetanes, accompanying bond-formation reactions, would be very useful for synthetic purposes. Furthermore, since the oxetane ring is an important structural component of biologically active compounds, such as merrilactone A, thromboxane A2, and oxetanocin, oxetin, taxane alkaloids, and laureacetal-B, efficient and selective methods for synthesis of the strained structure are active areas of research. Moreover, oxetane-ring-containing compounds are important industrial curing agents. Thus, there are over 2900 patents concerning "oxetanes". All those clearly indicate that the demand of synthetic oxetanes is high. The intramolecular nucleophilic substitution reactions, e.g. Williamson-type of reactions, should be one of the important methods for preparing the oxetane ring structures, and actually have been widely applied to the synthesis of oxetanes. Side reactions, e.g. the fragmentation from the intermediary alkoxide anion or the elimination from the intermediary carbocation, often decrease the chemical yields of the oxetane formation.
The photochemical reaction of carbonyl compounds and alkenes, so-called the Paternò-Büchi (PB) Reaction found in 1909, to give oxetanes is one of the most used methods for oxetane synthesis (Scheme 7.2). As exemplified in the PB reaction of benzophenone with 2-methylpropene, the selective formation of the oxetane is possible even in the photochemical reaction that involves highly unstable molecules, i.e. the excited state of carbonyls. Due to its synthetic importance and the mechanistic interest, the PB reaction is the most thoroughly studied synthetic method for oxetanes. Thus, a number of extensive reviews about the PB reaction were published in literatures since 1968. We are investigating the role of triplet conformation and hydroxyl group to allow for control of regio-, site-, and stereoselective formation of synthetically important oxetanes.
Caged Compounds: A Case Study of Chemical Biology
Caged compounds are important reagents in physiological studies, particularly in the field of neuroscience. Spatially and temporally controlled uncaging of neurotransmitters upon photolysis enables a better understanding of in vivo neuronal processes. For example, caged glutamates play a crucial role when studying mammalian learning and memory mechanisms. In engineering these probes, several well-defined properties of caged compounds must be considered. A fast and efficient uncaging of the biologically active molecule is important under irradiation conditions, and thermal stability of caged compounds is required in the physiological environment. However, affording both significant two-photon absorption (TPA) and good water solubility are among the most recent issues for in vivo studies of caged compounds. Using two photon (near-IR) as opposed to one (UV-vis) allows a deeper penetration depth and reduces scattering in biological tissues, and also reduces optical absorption by endogenous chromophores, causing less photodamage. Thus, the pertinent molecular design and synthesis of new caged compounds, based on chromophores with a high TPA cross-section (in GM), remains a challenge.
In the last two decades, several types of caged glutamates such as nitrobenzyl-, 7-aminocoumarinyl-, ruthenium-biphenyl-, and carboxymethylnitroindolinyl-caged compounds have been designed and synthesized for physiological studies. Here are numerous examples (including their reported two-photon uncaging cross-sections,), i.e., N-nitrophenethyloxycarbonyl (Noc-glu), carboxynitrobenzyl (CNB-glu), bromohydroxycoumarin (Bhc-glu, 1 GM/740 nm), methoxynitroindolinyl (MNI-glu, 0.06 GM/740 nm), carboxymethylnitroindolinyl (CDNI-glu, 0.06 GM/720 nm), propylmethoxynitrobiphenyl (PMNB-glu, 0.45 GM/800 nm), ruthenium bipyridine (RuBi, 0.14 GM/800 nm), and bisnitropropylstyrylfluorene (BNSF-glu, 5 GM/800 nm). Recently, we reported the synthesis and photochemical reactivity of caged glutamates with a pai-extended coumarin chromophore (HBC-glu) as a photolabile protecting group.
We are investigating the design and synthesis of new photolabile prtecting group with high TPA properties.