Tuesday, October 14, 2014

LDA and its pesky bi-product

Who would have though that LDA can, instead of acting as a base in the presence of acidic protons, be oxidized to give some impurities which will make you pull your hear until you lose it or it turns grey?

Well, I would not but it did. It turns that a very very very small amount of this LDA actually can give you impurities (ca 0.28 area % in my case) due to oxidation of the base.
To give you a more specific example, if you have an ester, and you use LDA to pick a proton in another part of your target molecule, do not get puzzled if you get things like

Side reaction of esters and LDA

Of course, most of the LDA will act as a base and the desired product will be the major product you will obtain. But when looking at impurities is important, it is easy to overlook at this one.

So, what is actually happening. According to Férézou and Chevalley (Tetrahedron 68 (2012) 5882-5889), LDA can be oxidized by interaction with aldehydes and ketones (they have used benzophenone and benzaldehyde, among others, as oxidazers). A plausible mechanism is presented below:

First, the oxidative agent coordinates with Lithium, reducing the alcohol and oxidizing LDA, you get an imine
Another LDA molecule acts as base, attacking one of the nitrogens next to the imine carbon. An enamine is created. 
Through resonance, the enamine carbon acts as nucleophile, attacking the electrophilic carbonyl carbon. This would yield the bi-product. This mechanism is not confirmed but is fully possible.
As you can imagine, changing the reaction conditions could make this bi-product the mayor product. But that is a totally different story.

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