Handling reactives in the solubility database

The discovery that aromatic aldehydes bearing electron withdrawing groups react with alcohols has forced us to create a new category in the ONS Challenge SolubilitySum spreadsheet: solute reacts with solvent. There is now a column on the far right to flag these.

Since there is no meaningful number for these mixtures we are assigning the value of -0.1M in the solubility column of the SolSum sheet. That has the advantage that it will not break any web services currently querying the sheet. We can also put an explanation in the notes column for a reason, such as "forms hemiacetal".

One of the benefits of this approach is that all solutes reacting with solvents can be queried using Rajarshi's web query setting the solubility range from -1 to -0.01 M.

Complications with solubility measurements of aldehydes in alcohols

Last week I mentioned that we had started measuring temperature solubility curves. Since 4-nitrobenzaldehyde in methanol also got flagged by our Outlier Bot we picked it as the next one to process. This one has bothered me for some time because our values have systematically come out to about half of those published by Maccarone, E.; Perrini G. Gazetta Chimica Italiana. 1982, 112, p. 447. (private access) In this paper temperature curves for the solubilities were also provided and so I thought this would be a great opportunity to validate our sequential precipitation method.

This experiment (ONSC-EXP110) turned out to be very puzzling. On the day that we tried to make solutions we could not get as much material to go in as expected from the paper, even by sonicating at 40C. The next day some of these samples went into solution and then we could not get precipitation to occur for some samples even at 0C.

However, an examination of the NMRs of the samples with lowest concentration revealed the problem. It turns out that they were about 50% converted to the methanol hemiacetal. The NMR clearly shows the coupling between the benzylic and hydroxyl protons at 5.6 and 6.8 ppm, each integrating for 1H each compared with 2H for each of the new peaks in the aromatic region.



It turns out that the hemiacetal was present in all our previous measurements for 4-nitrobenzaldehyde in methanol but we didn't spot it. Furthermore we found significant hemiacetal formation for 2-chloro-5-nitrobenzaldehyde, 2,6-dichlorobenzadehyde and 4-chlorobenzaldehyde but only trace on none for others like veratraldehyde (ONSC-EXP033 has several of these NMRs). So it appears that if the aromatic ring bears sufficiently electron withdrawing groups hemiacetal formation is facilitated without the presence of a catalyst. This makes sense from a mechanistic standpoint.

Since the hemiacetal forms so easily in these cases I wonder why there was no mention made of it in the Maccarone paper. They assayed concentration using GLC - perhaps the hemiacetal decomposed quickly under those conditions? (PNBA is para-nitrobenzadlehyde):

From a practical standpoint is it even possible to measure the solubility of 4-nitrobenzaldehyde in alcohols? If you try to make up a solution for a reaction the concentration will be much less than calculated. With an excess of alcoholic solvent it seems unlikely that a reaction consuming the aldehyde will shift the equilibrium enough to make the formation of the hemiacetal inconsequential.

I think that for the Ugi reaction the implication of this is that alcoholic solvents should not be used for aldehydes bearing electron withdrawing groups.