[Anthasci]

Does anyone here have any experience with this relatively common reaction? Specifically I'm talking about acid hydrolysis, with 6M HCl (10% v/v) in AcOH under reflux at about 80°C for about 45 minutes after which TLC indicated starting material was almost depleted. To me it seemed a relatively straightforward procedure but the TLC was a bit messy and the yield low (high 30's). I would assume I may have gotten some dimer formation and possibly deprotected my other -OH groups (benzyl ether) due to relatively harsh conditions.
Has anyone perhaps found a useful tweak or trick for the described reaction that worked well for them?

Thanks!

[Dan]

Benzyl ethers should easily survive that, the problem is probably something else. I've found that low yields for reactions like this are usually attributable to problems in purification (loss of material to the aqueous layer during extractive workup, and/or streaking on silica gel). Though if you have a messy TLC, maybe there is a side reaction issue. I hate using AcOH as a solvent and avoid it whenever possible - smelly, difficult to remove, and concentrating your products in hot AcOH can cause unwanted reactions.

I've used pTSA or HCl (final acid concentration of 0.5-1 M is generally plenty) in aqueous dioxane at 80-90 °C to do this reaction before and yields were always good (at least 75%). The dioxane is only necessary if your starting material does not dissolve in water; only a minimum amount of dioxane should be used, just enough to dissolve the starting material at 80-90 °C, because it lowers the polarity of the medium and slows the rate of hydrolysis.

Another option, which is particularly useful if purification is difficult due to high product polarity, is an acidic resin (e.g. Dowex 50W) in aqueous dioxane (again, only enough dioxane to solublise the SM) at up to 80 °C (if you push the temp too high, the resins can start to slowly degrade). The hydrolysis tends to be a bit slower than with homogeneous catalysts, but all that is required post-reaction is filtration and concentration (assuming the reaction is clean).

[Anthasci]

Thanks for a comprehensive answer, Dan!

I do believe the work-up was pretty smooth and I obtained a relatively good separation on the column. There were some impure fractions (counting those, the yield would be around 40%) but all in all, I did not observe any streaking even with the relatively low Rf in the chosen mobile phase.

I shall consider attempting it in water/dioxane as all the events lead me to believe there was, in fact, something that went wrong during the reaction. I should also add that when performing the column, several fractions revealed spots which were not initially present in the TLC of the mixture after extraction, though I assume that is because they were dripping out in a fairly concentrated fashion.

[Dan]

all the events lead me to believe there was, in fact, something that went wrong during the reaction. I should also add that when performing the column, several fractions revealed spots which were not initially present in the TLC of the mixture after extraction, though I assume that is because they were dripping out in a fairly concentrated fashion.

How did you remove the acetic acid? Rotavap or base washing? I was assuming you evaporated most of it (because when AcOH is used as the solvent on a reasonable scale, the neutralisation is tedious) and I have occasionally seen side reactions occur during this process. You could also TLC your water layer from the extraction (though from what you say, it sounds like the product is not too polar).

Without seeing your structure or information on any identified side products, it's difficult to predict what the problem might be (I realise you may not be at liberty to reveal exact structures). An aqueous dioxane prep may or may not help, but it's probably worth a test reaction. You can also lower the temperature and leave it for longer.

[Anthasci]

First of all, apologies for a late reply.

The acid was indeed removed through extraction and washing of the organic phases with saturated NaHCO₃.

Dry mass after evaporation and before column was fine, so I do not think the problem lies in the work-up, but more in the reaction (and conditions). It seems to me that several side reactions are possible, such as dimer formation or perhaps the ring closing at a wrong C-atom?

[Dan]

It seems to me that several side reactions are possible, such as dimer formation or perhaps the ring closing at a wrong C-atom?

Dimer formation is unlikely in dilute solution (but may occur if the product is concentrated in AcOH, acetylation of free hydroxyls is possible). If you have the possibility of forming pyranose and furanose rings, then yes you will probably see both by NMR (and both anomers of each, i.e. 4 compounds in total, plus sometimes the free aldehyde form is detectable). The compound you isolate will show an equilibrium mixture of isomers which slowly interconvert in solution.