On formyl hydrogen bonds

We had a lively discussion regarding the ene reaction at our weekly group meeting today. This was done as part of a synthesis problem set and reminded me of an under-appreciated principle that should remain important in attempts to understand aldehyde reactivity. I refer to formyl hydrogen bonds, the likes of which are on display in a recent paper by Krische and Houk in JACS (http://pubs.acs.org/doi/abs/10.1021/jacs.5b04844). The appreciation of this interaction goes back to the foundational studies by Corey and co-workers. Here is a link to a great overview that covers some of the structural aspects of the formyl hydrogen bond: http://pubs.rsc.org/en/Content/ArticleLanding/2001/CC/B104800G. I have also included the accepted transition state model for the Lewis acid-catalyzed ene reaction developed by Mikami and colleagues. This constitutes a particularly striking example of the capacity of aldehydes to participate in hydrogen bond formation. There have been several X-ray structures that provide atomic level evidence for formyl hydrogen bonds. On various accounts, it is estimated to be worth between 6 and 9 kcal/mol, which is not insignificant. By all means, Lewis acid coordination to the aldehyde oxygen atom enhances the acidity of the aldehyde CH functionality.


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