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.

Back again, 2 years after last post

Well, I am back here to post some stuff about chemistry. I have a new job (Ok, been here for over 1 year now) at Cambrex as Process/Synthetic chemist and I love it.

Well, what has happened now is that we have been having a problem with a quench. We are using Dess-Martin Periodinane (DMP) for an oxidation and Sodium Thiosulfate for quenching DMP and its bi-products (IBA and possibly IBX).

We found a big problem in the process. Some of the batches that were produced contained elementary sulfur and first we though it could be alleviated by decreasing the amount of thiosulfate used for the quench. It did not work too well.

Second, we found a paper (DOI: 10.1021/op700227p) were they described a similar problem, and the recommendation was to add the quench solution to basified reaction mixture. We used Sodium bicarbonate to basify our solution and then started the addition of Sodium Thiosulfate. Sometimes it did work, sometimes it did not.

Further work demonstrated that the pH first increased upon addition of Sodium thiosulfate, but started to decrease over time. Experiment showed that longer quenching times increased the amount of sulfur formed in the reaction.

That is when I found this very useful paper (for me at this moment it is very useful at least). It is written by Takei et al,, DOI 10.1246/bcsj.49.70.

In this paper they make a series of experiments in acidic media, in which they observe and measure the disproportionation of thiosulfate and other sulfur containing species, at high temperatures (>70 °C). Although their reaction conditions do not match the ones in the oxidation I am performing, an interesting detail can be found in page 73. First some background.

Sodium thiosulfate is used to typically reduce idodine and bromine. In the reaction I am interesting to quench, I am using Sodium Thiosulfate to reduce Dess-Martin Periodinane (DMP) and its related bi-products (IBA and possibly IBX). 

If the reduction of DMP follows the same electronic pattern as the reduction of iodine (and is quite likely), Sodium Thiosulfate should oxidize to tetrathionate. Now, check page 73 in the publication from the 70's.Tetrahionate can disproportionate to sulfur, sulfate and acid. This would explain why, I am obtaining sulfur even though I am using alkaline solvents. 

This assumptions seems very likely, as when I measure the pH of my quenching, the pH first increases to 9-10, but then starts to decrease to 8 over time, and more sulfur is formed.

3SO4O62- + 2H2O --> 7S + 5SO42- + 4H+

Well, hope if someone encounters this problem this can be of help. If I am mistaking me hugely, please correct me.

Peace

/ Alejandro