Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on January 26, 2021, 04:27:49 PM
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We typically use roughly 50 mL of acetonitrile as the solvent and Masamune-Roush conditions. Today our aldehyde was not soluble, and I had to think quickly (and so might not have made the optimal choice). About 4 milliliters of DMF did dissolve the starting aldehyde, and the reaction appears to be running normally by TLC. We quench with ammonium chloride and extract the product into DCM. Typically, we purify over silica, although we often have to dissolve our crude product in a more polar solvent when we run the column. Can anyone see a problem with the presence of a few milliliters of DMF at any stage? I am thinking about trying to remove it at some point.
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I am assuming you are using the Masamune-Roush conditions because your starting material is sensitive. I see no reason why DMF would do anything, I think the amide might not be reactive enough to undergo the reaction. I have seen some examples in the literature where a ketone reacted in the presence of an amide and the amide was untouched so I wouldnt worry too much about using DMF.
Out of interest, how come you didnt use dry THF instead?
Edit:
See slide 8
https://hwpi.harvard.edu/files/myers/files/19-stereoselective_olefination_reactions.pdf
The example shows DMF as a solvent (though for a Wittig), so nothing to worry about.
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One reason that I use Masamune-Roush is that undergraduates without much experience in handling, say, NaH, are successful with it. But in some cases, we had methylesters present, which might not tolerate harsher conditions. In this case we had a benzamide derivative as our aldehyde. I was going to try THF first, but I thought that maybe I needed a solvent that was a H-bond donor. The linked summary of the Wittig and Horner-Wadsworth-Emmons reactions is a good one.
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I was worried that the DMF would interfere with silica chromatography, but it seems that we were able to remove much of the DMF by rotary evaporation, at least if the mass is any guide.
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If you rotovap DMF remember to trap, or else your pump seals will stink forever
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The Rf values of the time points were higher than the Rf value after rotary evaporation. I suspect that the presence of DMF in the reaction mixture caused this anomaly, which forced us to rethink the polarity of the solvent that we had been planning to use in the purification. Our yield was modest, but there are other factors to consider.
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Is there some reason you can't do the usual (multiple) aqueous washes to remove DMF? Even if checking aliquots I would do a quick water/EtOAc wash and spot the ethyl acetate layer. Sometimes like 5x washes are necessary to get it all. I check when its gone by using my nose, don't tell OSHA.
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If the question is "should I dissolve the product in DMF?" to load it on the column the answer is a resounding no. Dry load it if you must. Some people prefer dry loading in all situations.
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I thought about removing the DMF through extraction, which I have done but my students have not. Do you include LiCl in the aqueous rinses? I seem to recall seeing that in one recipe, but I could be mistaken. I was a little worried about how our product would partition in multiple rinses, and given our modest yield after the silica column (I will ask my students to calculate it today, but my guess is 30%), possibly my concerns were not wrong. Just to clarify, we used a more polar solvent in the silica column than we had thought we would, based on the time points.
I only saw one product by TLC; therefore, the low yield cannot easily be explained by forming a side product. We did make sufficient material to test. If I had this synthesis to do over again, I would have tried THF before trying DMF. One of the reasons that I attempted to remove (most of?) the DMF by rotary evaporation after the reaction was to minimize its presence in chromatography. I was worried that it would drive the product through the column too quickly. What, specifically, was the reason you think DMF is bad in chromatography? We used a model of Welch DryFast pump that was advertised as being able to pull a slightly higher vacuum than their base model.
My students tend to use a small portion of chloroform reflexively when they dissolve their crude product, and I wonder that it might have a negative effect on chromatography in some situations. The dry load technique is one that we need to put more regularly into our bag of tricks. Any tips on avoiding silica dust flying about in the rotary evaporator?
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There are adapters with glass filter you can attach when evaporating. Chloroform can contain a little ethanol that can affect chromatography, better use DCM or toluene. If you use Et2O in workup the DMF is easy washed out with water. If you use DCM the DMF is much more difficult to wash out. I think its important to get rid of the DMF before chromatography, it often makes everything come out too quickly.
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I have used ethyl acetate and isopropyl acetate when I extracted DMF in the past. In the present case, the mass of the crude product after rotary evaporation was consistent with most or all of the DMF having been removed, but I did not analyze the composition of the remainder, the material that went onto the column.
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I thought about removing the DMF through extraction, which I have done but my students have not. Do you include LiCl in the aqueous rinses? I seem to recall seeing that in one recipe, but I could be mistaken. I was a little worried about how our product would partition in multiple rinses, and given our modest yield after the silica column (I will ask my students to calculate it today, but my guess is 30%), possibly my concerns were not wrong. Just to clarify, we used a more polar solvent in the silica column than we had thought we would, based on the time points.
I only saw one product by TLC; therefore, the low yield cannot easily be explained by forming a side product. We did make sufficient material to test. If I had this synthesis to do over again, I would have tried THF before trying DMF. One of the reasons that I attempted to remove (most of?) the DMF by rotary evaporation after the reaction was to minimize its presence in chromatography. I was worried that it would drive the product through the column too quickly. What, specifically, was the reason you think DMF is bad in chromatography? We used a model of Welch DryFast pump that was advertised as being able to pull a slightly higher vacuum than their base model.
My students tend to use a small portion of chloroform reflexively when they dissolve their crude product, and I wonder that it might have a negative effect on chromatography in some situations. The dry load technique is one that we need to put more regularly into our bag of tricks. Any tips on avoiding silica dust flying about in the rotary evaporator?
a) yes LiCl in my experience is the best way to get rid of DMF. Normal water does not remove it all, neither does brine (or possibly they do after milion washes)
b) dry loading is my go-to technique since I dont have to try to dissolve my compounds in mobile phase which they might not be soluble (especially if you work with hexane:EA). As rolnor already said, there are adapters with filters that work well but simple splashguard / bumptrap or whatever you call it with cotton in the connection between the trap and your flask works well. Usually, low boiling solvents like DCM or MeOH are used. Evaporate to dryness, to the state of dry silica . In case you might have some DMF there, I suggest using gradient and wash with the less polar solvent first, neverhteless, after three LiCl washes you should have no DMF or only traces so it shouldnt be a big deal
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I load with ethyl acetate when needed. Decent polarity, but will get lost in the shuffle of a EtOAc/hexanes column. Honestly I seldom would dry load, only when necessary. DMF is the absolute worse choice though. Chloroform is probably ok.
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Just to clarify, when running a column I would never add DMF by choice. However, there is always a chance that some DMF might remain in a given reaction.
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I consulted Advanced Practical Organic Chemistry (John Leonard) and Practical Organic Synthesis (Reinhart Keese). Both have useful paragraphs on dry loading, but one point is not clear. Does one use sand, and if so, is the sand above or below the sample-impregnated silica?
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I consulted Advanced Practical Organic Chemistry (John Leonard) and Practical Organic Synthesis (Reinhart Keese). Both have useful paragraphs on dry loading, but one point is not clear. Does one use sand, and if so, is the sand above or below the sample-impregnated silica?
Sand on top of the sample loaded silica. So I make up the column, either wet or dry load, then add a bunch of sand, enough to protect the sample loaded silica so my cack-handed pouring of solvent doesnt disturb the sample layer.