Singly occupied molecular orbital activation

Jang, H. -Y., Hong, J. -B., MacMillan, D. W. C. (2007). Enantioselective organocatalytic singly occupied molecular orbital activation the enantioselective a-enolation of aldehydes. Journal of American Chemical Society, 129, 7004-7005. 

Enamine, Iminium, and Singly Occupied Molecular Orbital Activation... 

We will look at thermal CDC processes first, both metal-catalyzed and metal-free, then briefly at photochemical CDC methods and so-called SOMO (Singly Occupied Molecular Orbital)-activation mechanisms and finally we will note an important stereo-electronic feature of some of these reactions that is likely responsible for their ability to produce very well-defined reaction outcomes. 

Fig. 9. Orbital pattern of singly occupied molecular orbital and Jahn-Teller active mode. Both SOMOs are antisymmetric with respect to the cr plane. For corannulene (top) the tangential direction along the pseudorotational path at the minimum corresponds to the antisymmetric vibration, while, for coronene (bottom), the symmetric vibration corresponds to the tangential direction at the minimum.

In contrast to the HOMO and LUMO, the singly occupied molecular orbital (SOMO) can be correlated both qualitatively and quantitatively with experimentally measurable EPR hyperfine couplings (hfcs). As a result, host-guest systems that have redox-active guests that are stable as radicals provide excellent tools for studying the effects of noncovalent interactions on redox properties. 

Comparing the activation mode of iminium and enamine catalysis, iminium catalysis is based on a LUMO-activation mode of the electrophile whereas enamine catalysis is based on a HOMO-activation of the nucleophile. Keeping in mind the fact that enamine and iminium species are rapidly interconverted via a two-electron redox process (proton abstraction of an iminium species results in an enamine), MacMillan and co-workers reasoned that it should be possible to interrupt this equilibrium chemically by carrying out just a one-electron oxidation of an enamine. This would then generate a three-7i-electron radical cation with a singly occupied molecular orbital (SOMO) that should be activated towards catalytic transfomiatirHis (racemic or asymmetric) not possible using classical enamine or iminium activation (Scheme 80) 316). 

In 2007, the groups of MacMillan and Sibi almost simultaneously introduced a new mode of organocatalytic activation, termed SOMO (singly occupied molecular orbital) catalysis, which was founded upon the transient production of a 37r-electron radical cation species that could function as a generic platform of induction and reactivity. This new mode of organocatalytic activation, was founded upon the mechanistic hypothesis that one-electron oxidation of a transient enamine intermediate, derived from the aldehyde and the chiral amine catalyst, rendered a 37i -electron SOMO-activated species, which could readily participate in asymmetric bond construction. 

Most of these reactions are accomplished using the singly occupied molecular orbital (SOMO) organocatalytic activation mode [34], The original example is devoted to the intramolecular radical cyclization of aldehydes using some imidazolidinone catalyst under oxidative conditions (Scheme 7.22) [35],... 

SOMO Activation Within the field of aminocatalysis, asymmetric organo-SOMO (singly occupied molecular orbital) catalysis has recently emerged as a powerful technique for the preparation of optically active compounds. In this context, MacMillan and coworkers described in 2008 the formation of y-oxyaldehydes from aldehydes and styrenes by organo-SOMO catalysis [25]. The condensation between the amine catalyst 46 and an aldehyde gave rise to an enamine intermediate, which was then oxidized by ceric ammonium nitrate (CAN) to give a radical cation. Reaction of this radical cation with a nonactivated olefin, namely styrene, led to the... 

So far, only catalytic heterocoupling of silicon enolates has been achieved by a singly occupied molecular orbital ( SOMO ) activation, as disclosed by MacMillan and coworkers [267]. The method is illustrated in Scheme 5.136 for a series of silyl enol ethers 556 that are reacted with octanal. Ceric(IV) ammonium nitrate (2 equiv.) serves as the oxidant and imidazolidinone 557 (20 mol%) as the... 

The ability of enamines to form in situ generated radicals gives rise to an entirely new principle of activation and thus to a series of very usefijl and highly selective previously unknown C-C bond formation processes. Thus, enamine catalysis changed into SOMOsingly occupied molecular orbital) (Figure 4.2) [24]. For direct experimental evidence of an enamine radical cation in SOMO catalysis see Reference [25]. These types of transformations were extensively elaborated by the MacMillan group. The first steps in this new concept were accomplished by the formation of radicals of enamines of imidazoHdin-4-ones. 

The vast majority of organocatalysis involves HOMO activation (such as enamine catalysis) or LUMO activation (such as iminium catalysis). However, a third type of organocatalytic activation has been reported by the MacMillan group which involves the single electron oxidation of transiently produced enamines, which is known as singly occupied molecular orbital (SOMO) catalysis. 

For example, in a 4-electron, 6-orbital CAS—specified as CASSCF 4,6)—performed on a singlet system, the active space would consist of the two highest occupied molecular orbitals (where the four electrons reside) and the four lowest virtual orbitals. Similarly, for a 6-electron, 5-orbital CAS on a triplet system, the active space would consist of the four highest occupied MO s— two of which are doubly-occupied and two are singly-occupied—and the LUMO (the keyword is CASSCF(6,5)). 

Compared to the analogous reactions of the parent molecules, many radical cation reactions show a dramatic decrease in activation barriers, one of the most striking aspects of radical cation chemistry. Intuitively, this observation can be ascribed to the fact that the highest occupied molecular orbital (HOMO) of a radical cation is occupied by a single electron. As a result, the bond strength of one or more key bonds must be reduced and the bonds more easily decoupled. However, the barriers to some radical cation rearrangements appear to lie even lower than might be expected on the basis of this simple model. 

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