Decomposition of acetonide protecting group in chloroform

Question

Today I purified my compound containing an acetonide protected diol. I took an NMR sample and it looked great, but because I have only little amount of the compound, I put the sample back into the flask and evaporated the $\ce{CDCl3}$.

In a while, the solution turned from yellow to brown, so I took another NMR and it looked a little bit more messy and the $\ce{CH3}$ signals from acetonide group had decreased intensity (integral from 6 to around 4.5).

Is it possible that the $\ce{CDCl3}$ is so acidic it causes acetonide removal? The compound survived silica chromatography. Have you ever experienced something similar?

Answer 1

Deuterochloroform (and indeed 'normal' chloroform) are known to be mildly acidic if left standing for any length of time:

Chloroform: It reacts slowly with oxygen, or oxidising agents, when exposed to air and light, giving, mainly, phosgene, Cl₂ and HCl.

_{Source: Purification of Laboratory Chemicals, 7 ed.}

To compensate for this, its common to add molecular sieves and a small amount of potassium carbonate to a new bottle of deuterochloroform to keep it dry and to minimise any acid that may be present/may be generated as the bottle ages.

If you look up the entry for acetonides in Greens' Protecting Groups in Organic Chemistry, you'll see that acetonices can come off under quite mild conditions, though personally I've never had an acetonide come off in an NMR tube of chloroform (I assume you didn't leave it standing for months in the tube...)

In order to cleave the acetonide under acidic conditions, you generally also need a nucleophile (methanol is common, water would do the trick), which if present should be very obvious on the NMR, and might go some way to explaining how you lost the acetonide. You should also consider other explanations, for instance you mentioned concentrating the chloroform- are you sure the rotary evaporator hadn't just been used to take off something wet and acidic?

Hopefully you can just put the acetonide back on without any issues, I suggest picking up a new bottle of chloroform-d and adding some sieves and potassium carbonate (you could try NMR-ing your old bottle to see if theres water/methanol etc in it, and then purify appropriately, but the stuff is sufficiently cheap that I wouldn't waste my time).