One of our main fields of investigation is the generation, detailed examination and use of highly reactive species, focusing particularly upon diradicals and ion radicals. Since these intermediates can usually not be isolated, we use computational studies, isotope labeling experiments and EPR spectroscopy as indirect methods to gain a fundamental understanding of their nature. In many situations this approach has proven to be very useful in order to exploit the reactivity for synthetic purposes and to improve yield and selectivity of reactions involving certain of the reactive intermediates. 

Our interests are currently focused on the following groups of highly reactive intermediates:

1. Diradicals Related to Trimethylene Methane

2. Ion Radicals

1. Diradicals Related to Trimethylenemethane

The simple hydrocarbon called trimethylenemethane (TMM, 1) has been of great interest to  experimentalists and theoreticians for many years.[1] According to Hückel MO calculations and Hund´s rule, singlet and triplet electronic configurations are possible (see MO scheme below). The corresponding singlet and triplet states play an important role in the chemistry of TMM derivatives.

The isopropylidene diyls 2 are generated either thermally or photochemically from bicyclic azo compounds such as 3. The temperature required for extrusion of nitrogen varies as a function of the substituents A and B, and can be as low as –20 °C (A = B = OMe) to as high as refluxing toluene. Generally, simply refluxing in acetonitrile or THF suffices.

Intermolecular Diyl trapping

For preparative purposes, diyl 2 can be intercepted by a number of trapping agents, referred to as diylophiles. Diyl 3 acts as an electron rich system and undergoes cycloaddition to electron deficient trapping agents to afford fused and bridged adducts, 4 and 5. The early intermolecular cases were pioneered in the Berson research group at Yale.

Intramolecular Diyl Trapping

A very useful synthetic method is the intramolecular diyl trapping reaction depicted in the scheme shown below.[1] When a latent diylophile is tethered to a bicyclic diazene 6, intramolecular cycloaddition proceeds smoothly to form diyl 7. The versatility and reliability of this synthetic tool, including its incorporation in key steps of natural product total synthesis, was demonstrated by our group in numerous examples.

Using the Diyl Trapping in Natural Product Synthesis

For some time now, we have used the diyl trapping reaction as a key step in the assembly of natural products.[1-5] Our early efforts focused upon the possibility of constructing systems containing three or more five-membered rings including, for example, the linearly fused tricyclopentanoids, such as hirsutene, D(9,12)-capnellene, coriolin, and hypnophilin, as well as angularly fused systems like isocomene, and those with mixed linear and angular architectures, like crinipellin A. More recently, we have focused our attention upon other frameworks, including, for example, that of taxol analogue 8 [3], rudmollin (9) [4] and aphidicolin (10) [5].

Using Molecule-Assisted Homolysis as a Mechanistic Probe into the Chemistry of a Bicyclic Peroxide

In a recent study of our group the fate of bicyclic azo compounds described above in the presence of molecular oxygen is unveiled.[6] By pyrolysis of alkyl-substituted diazenes an unexpectedly complex product mixture is optained. Using deuterium labeling studies and quantum calculations, a reasonable mechanistic hypothesis for the decomposition of the resultant [3.3.0] peroxide, and subsequent formation of the keto-alcohol and Z-configured ?,?-unsaturated keto-aldehyde, is proposed. Surprisingly, molecule-assisted homolysis plays a key role in this transformation.

2. Ion Radicals

The focus of our research involving ion radicals is to gain a further understanding of the fundamental properties of these structures that form upon redox reactions, as well as the transformations they undergo. We usually apply what we learn to develop new synthetic methods and to prepare natural products or other useful compounds.

After generation of the ion radical, we are using the reactivity of this species for specific chemical transformations of the employed substrate (for instance rearrangements, trapping reactions, cyclizations). If the generation of the ion radical species is reversible, we are interested in the application of this process to redox mediation. The radical ion intermediates which are currently in our focus are depicted in the scheme below.[1,7]