15 October 2012 Review
Oxidation in organic synthesis
In 1991, Jeremy Knowles of Harvard University in the US wrote that enzyme catalysis is ‘not different, just better’ than small molecule equivalents.1 Nearly 25 years later, this comparison still holds in general. But small molecules are making significant inroads – with reactivity and selectivity approaching levels previously thought unachievable.
One area where enzymes maintain the upper hand is selective C–H functionalisation. Nature’s catalysts are adept at picking out certain of the multiple C–H bonds in complex molecules to react with, guided by their highly organised protein machinery. Christina White from the University of Illinois in Urbana–Champaign, US, is one of the leaders in developing molecular catalysts for this process. Her group’s catalyst systems are beginning to distinguish C–H bonds on the basis of relatively subtle steric and/or electronic differences.
Figure 1 - Bulkier ligands restrict access to the catalytic centre, increasing steric selectivity
The team has introduced bulky aryl groups bearing two ortho-CF3 substituents onto the pyridine part of the catalyst ligand (figure 1). This modified iron complex maintains its activity, but restricts the trajectory at which substrates can approach the iron centre. The team proposed that this would confer intrinsic selectivity for less hindered C–H bonds.
To examine this hypothesis, they compared the selectivity of the original and modified catalysts for a number of substrates (figure 2). Oxidising a linear aliphatic ester shows that the modified catalyst is much more selective for the less hindered secondary carbon over the inherently more electron rich (and hence reactive) tertiary carbon. In contrast, the original catalyst shows no selectivity at all. The modified catalyst can also override the inherent reactivity of a substituted cyclohexane – the original catalyst shows a 2:1 preference for the tertiary C–H site, whereas the modified version selectively oxidises the secondary carbon, giving a 1:2 ratio of products.
Figure 2 - The modified catalyst overturns inherent substrate selectivity
The team has also developed a theoretical model for the catalyst’s selectivity based on substrate structure. The model encompasses both steric and electronic parameters to quantify how susceptible different sites are to oxidation. In line with their hypothesis, the model indicates that steric factors dominate the origin of the selectivity for the modified catalyst, and that the electronics have a negligible influence.
Figure 3 - Oxidising (-)-triacetoxytricalysiolide B shows the modified catalyst is also less prone to over-oxidation
Figure 4 - A predictive framework makes the system more powerful when dealing with more complex substrates
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