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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on February 09, 2019, 02:29:30 PM
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I was looking over a synthesis recently in which a Weinreb amide was made and then reduced with DIBAL. It was done in the presence of a tertiary-butylester. Would there be some chance that the ester would also reduce? Are there any special tricks when making aldehydes with DIBAL? There was a thread here a few years ago, which mentioned this reduction, but there was not much discussion about it.
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tert-Butyl esters are less reactive in reduction compare to weinreb amide.
In my experience, reduction of weinreb amide to aldehyde requires low temperature (-78 to 0°C) to provent over reduction.
You can read this paper for more infomation.
https://onlinelibrary.wiley.com/doi/pdf/10.1002/bkcs.10571
You can check the table 3 in this paper to compare the reduction on ester and weinreb amide.
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Thank you; this paper looks quite helpful.
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Theoretically, DIBAL reduction occurs via formation of a >=O-Al Lewis complex that forces the hydride to attack from the less bulky side, which is impossible in case of a bulky tertiary ester, especially in low temperatures.
(But I have never worked with DIBAL and thus, I cannot know what happens in real life.)
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C. L. Bailey et al. / Tetrahedron Letters 56 (2015) 706–709. http://dx.doi.org/10.1016/j.tetlet.2014.12.066
This paper uses MgAB an alternative to DIBAL in reducing a Weinreb amide. The reaction takes place at room temperature. An ordinary ester is not reduced. So many reducing agents, so little time...
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Yes, indeed!
But is this reducing agent, conveniently being prepared?
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MgAB is prepared from dimethyamine-borane adduct and methyl magnesium chloride, and it can be stored for 3 months at room temperature. I suppose that there are particular circumstances where it would be handy, but I have no specific knowledge of it.
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Although not being a specialist of the issue, the overall preparation procedure of MgAB doesn’t seem very simple. Besides, MgAB doesn’t seem to be largely offered by suppliers.
Nevertheless, the article is very interesting because a chemoselective reducing agent that leads to aldehydes and works at room temperature within half an hour, is always a very useful and convenient tool.
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I am following a literature protocol, and the yield is 60% after column chromatography. I am inclined to try DIBAL and if I also obtain 60%, to stay with DIBAL.
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I am waiting on some reagents, but I will do this reaction as soon as I can. My question concerns the quench. DIBAL is in 1.5-fold excess. The protocol calls for potassium bisulfate to be added, then ethyl acetate. The temperature at this point is not specified, but it was -10 °C for the addition of DIBAL, and I assume that the temperature should remain there. KHSO4 is also used a washing solution. My question concerns whether or not I will see gas evolution (I assume that I will) and any other problems or issues that might happen in this quench and work-up. I looked up the pKa of HSO41-, and it is about 2.
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Obtaining the potassium bisulfate is proving more difficult than I expected. Are there other washing protocols that would perform equivalently? I have a feeling that if I tried phosphoric acid, I would form a precipitate with aluminum that could be problematic.
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KHSO4 is usually supplied as a mixture of KHSO4.xK2SO4 (x<1) crystals that are hydrites and have absorbed a little SO3 in their mass.
But I am afraid that with KHSO4, you will form the non-soluble potassium alum.
K2SO4.Al2(SO4)3.24H2O↓
Phosphoric acid will also form the insoluble AlPO4.
Alternatively, you could try saturated ammonium chloride solution that might form among others, a mixture of hexaminealuminium chloride and basic aluminium chlorides that all are water soluble.
[Al(NH3)6]Cl3 and AlCl3 + Al(OH)Cl2 + Al(OH)2Cl + Al(OH)3
But firstly, try this with a small amount, in order to see if it works.
Good luck.
1). Reaction study of aluminium chloride with ammonia and mechanisms leading to aluminium nitride, Journal of the European Ceramic Society, 16(5), 521-527, (1996)
https://www.sciencedirect.com/science/article/abs/pii/0955221995001689
2). Water-soluble basic aluminum compounds, United States Patent 2196016, (1940)
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Alternate ways to reduce a carboxyl is to make a acid chloride, this can be made near neutral with a complex DMAP/SOCl2, then reduce the acid chloride with Bu3SnH or by catalytic hydrogenation.
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I've always felt going the acid chloride route was a recipe for pain due to its hydorlytic stability making it much more of a pain to isolate and handle than any other carbonyl species.
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You make the acid chloride and reduce it one-pot, no isolation.
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About the quench: cant you use the protocols that are commonly used for LiAlH4? Rochelle salt, Na2SO4.10H2O or just NaOH/water?
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That is a good question. I don't know, because this is my first time working with DIBAL. Do you have any suggestions for the best quenching protocol?
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Last week I attempted the reduction of the Weinreb amide to the aldehyde using DIBAL in THF. The solvent was THF, and there was 0.1 mole of amide per liter of THF solvent before the addition of DIBAL. The protocol that I followed called for the addition of DIBAL to be done at -10 °C using an ice-salt bath, followed by stirring for 1.5 hours at that temperature. I stirred for a little longer (roughly 2 hours), and my temperature was close to -10 °C. I found that my temperature varied a bit, as I fiddled with adding salt. Purification over flash silica using 60:40 hexanes/ethyl acetate yielded mainly starting material and a small amount of the aldehyde. The aldehyde had a slightly higher Rf with respect to TLC. There was also a mixed fraction that was mostly starting material with roughly 6 percent of the aldehyde.
I can let the reaction run longer at 0 °C. I could also let it warm up to 25 °C. I am not sure whether or not I should worry about over-reduction. Thoughts about what to try next?
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Maybe monitor the reaction with TLC?
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Not that helpful right now, but a good trick for isolating aldehydes is to extract them from the other garbage as a hydrosulfite salt, then convert back to the aldehyde (with acid I think)
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Alternative No1:
Low yield and mainly starting material mean that the reduction has not been completed. Thus:
a). You let the reaction to run longer at 0 °C (say 1-2 h) with simultaneous reaction monitoring, or:
b). You let the reaction to run longer at 0 °C (say 1-2 h) and then add (equal to THF volume) anhydrous toluene that is preliminary frozen at 0 °C and let to reach room temperature.
Addition of toluene will delay over-reduction by dilution and by decreasing polarity because polar reactions like aldehyde to alcohol reduction, are favored in polar solvents.
PS: Try these in small amounts just to see if they work.
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Alternative No2: See these DIBAL derivatives that do not over-reduce esters to alcohols. They may work in Weinreb reaction, too and permit to let the reaction to run as long as necessary.
1). Lithium diisobutyl-t-butoxyaluminum hydride, a new and efficient reducing agent for the conversion of esters to aldehydes, Tetrahedron Letters, 48(29), 5061-5064, (2007)
https://www.sciencedirect.com/science/article/pii/S0040403907009689
2). Chemoselective Reduction of Esters to Aldehydes by Potassium Diisobutyl-t-butoxyaluminum Hydride (PDBBA), Bulletin of the Korean Chemical Society, 28(12), 2517-2518, (2007)
http://www.koreascience.or.kr/article/JAKO200702727022238.page
3). Partial Reduction of Esters to Aldehydes Using a Novel Modified, Red-Al Reducing Agent, Bull. Korean Chem. Soc., 35(7) 2169-2171, (2014)
http://koreascience.or.kr/article/JAKO201420947475644.page
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Beware Tet Letters papers!
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Maybe monitor the reaction with TLC?
TLC will be tricky owing to the closeness of the spots (Rf = 0.50 vs. Rf = 0.35), but I agree that it is necessary. Is there a trick for removing a small amount of material for TLC without introducing water vapor? I was thinking of using a tuberculin syringe with a small gauge needle or possibly a Hamilton syringe.
I was thinking in terms of holding at 0 °C for a number of hours. If the reaction were still incomplete, I was thinking of letting it come to room temperature overnight. Does that sound like a reasonable approach? Another idea is to use a smaller volume of solvent (presumably the kinetics are second-order), but I don't know what the solubility of the starting Weinreb amide is.
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Room temperature overnight sounds a good idea but you risk to over-reduce the Weinreb amide. Thus and in this case, you have to add lower excess of DIBAL, say 1.1-1.2 fold excess and optionally, dilute your THF solvent by adding more THF or anhydrous toluene, after temperature rise above 0 °C
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For TLC, I usually just pull a small aliquot out with a syringe and quickly do a mini-workup. Works well enough for most things just have to be aware that your reaction is warming in the syringe so it might not be 100% what is in the flask.
As long as your reaction is all in solution you can just seal it tight and put it in the fridge/freezer. Stirring makes us feel better, but unless its heterogeneous, stirring after the reaction is going and everything is added doesn't do much.
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Today I realized that I had mistakenly made the ratio of DIBAL to Weinreb amide to be 1:1, not the intended 1.5:1, in my first attempt to perform this reduction. I also realized that the paper that I have been following did two closely related reductions, one at roughly 50% higher concentration of Weinreb amide than the other one (0.15 moles per liter of solvent versus 0.10 moles per liter of THF), and I had used the lower concentration reaction as my model. Today I set up a second reaction, and I used the starting material that I had re-purified. I used the correct ratio of DIBAL, and I dissolved the amide into enough THF to mimic the higher concentration reaction. If the reaction follows second-order kinetics, then using the reduced volume of THF should increase the rate by a factor of approximately 2.25. The increased amount of DIBAL should also increase the rate. The DIBAL reagent is 1.0 M in THF.
I am monitoring by TLC. I tried simply spotting the reaction mixture without a micro-extraction. There is a strong spot at the baseline but there are other spots as well. The first time point, which was about 2.5 hours into the reaction, suggested to me that there was roughly a 25/75 ratio of aldehyde to starting material (the aldehyde has a higher Rf. Therefore, I decided to continue running the reaction, but I let it warm to about 2 °C, versus using an ice/salt bath at < 0 °C, which is what I had used for the first reaction and the first part of the second reaction. For the time being, I am tempted to avoid letting the reaction come to room temperature. Any further thoughts?
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My most recent time point has three spots by TLC. The third spot (in the sense of not having been visible before) is migrating with a lower Rf than starting material. I surmise that it is the alcohol, but I don't have a way to verify that yet.
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Mix the aloquot with some tbdms chloride and imidazole and see if its is replaced by something much more nonpolar?
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Alternative No2: See these DIBAL derivatives that do not over-reduce esters to alcohols. They may work in Weinreb reaction, too and permit to let the reaction to run as long as necessary.
1). Lithium diisobutyl-t-butoxyaluminum hydride, a new and efficient reducing agent for the conversion of esters to aldehydes, Tetrahedron Letters, 48(29), 5061-5064, (2007)
https://www.sciencedirect.com/science/article/pii/S0040403907009689
2). Chemoselective Reduction of Esters to Aldehydes by Potassium Diisobutyl-t-butoxyaluminum Hydride (PDBBA), Bulletin of the Korean Chemical Society, 28(12), 2517-2518, (2007)
http://www.koreascience.or.kr/article/JAKO200702727022238.page
3). Partial Reduction of Esters to Aldehydes Using a Novel Modified, Red-Al Reducing Agent, Bull. Korean Chem. Soc., 35(7) 2169-2171, (2014)
http://koreascience.or.kr/article/JAKO201420947475644.page
Thank you very much. I am reading through these references, but I converted most of my acid into its Weinreb amide; therefore, I am committed to reducing it until I succeed or run out of it. At the moment I am thinking about trying some model chemistry with phenylacetic acid, after converting it into its Weinreb amide.
EDT
I am also re-reading the 2015 Tetrahedron Letters paper by Bailey. It mentions (citing footnote 23) that reduction with DIBAL at room temperature "... gives a mixture of products, including alcohols, amines, and aminals." I have just skimmed reference 23 (Davies IW, JOC 2000 65, 25, 8415 https://pubs.acs.org/doi/10.1021/jo000870z.) It used DIBAL in toluene and mentioned seeing a small amount of aminal. However, I don't see a discussion of room temperature products. BTW I have been holding the reaction near 4 °C overnight, but the last couple of TLC plates look similar or identical.
My present plan is to work this up (either now or after I let it run at room temperature) and then run a silica column with >40 grams of silica per gram of product. This is not very efficient, but I should be able to isolate a small amount of the aldehyde, which is better than no aldehyde at all.
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Mix the aloquot with some tbdms chloride and imidazole and see if its is replaced by something much more nonpolar?
That is a creative idea, but I do not have those reagents on hand.
EDT
Would an aminal hydrolyze during the workup with KHSO4?
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One reagent which came up on page 1 of this thread was LDBBA (An JA Bull Korean Chem Soc 2015 36 2928. DOI: 10.1002/bkcs.10571). The reaction is performed at 0 °C. Millipore Sigma offers this reducing agent as a 0.25 M solution in THF/hexanes. Although pricey, one might argue that it is cheap if it works.
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This is an update on my second attempt at the reduction of a Weinreb amide. This reaction was let run for about 24 hours at 0-5 °C, then for about the same amount of time at room temperature. My reason for doing so was that I wanted to see the starting material disappear entirely, but that never happened. Either there was some unreacted starting material, or there was a side-product that had a similar Rf value. The last several TLC plates, which were run over these two days, looked similar. There was a less intense spot with a higher Rf than the starting material, a more-intense spot with about the same Rf as starting material, and a faint spot with a lower Rf than starting material. I worked the reaction up with KHSO4 and purified over silica (50:1 w/w) using 60:40 hexanes/ethyl acetate. I was able to isolate two products, but I did not see a product corresponding to the slowest-moving spot by TLC. One fraction was a mixed product by TLC, and I did not combine this with either pool.
I have analyzed the 1H NMR of the two chromatographic pools in a preliminary way Pool 1 has a main product that has a characteristic aldehyde proton. However, there appears to be a second product in which there are two singlets that might correspond to the fragment -N(CH3OCH3. The chemical shift of one of these is close to the predicted shift for the Weinreb amine that would be produced upon over-reduction. Based on the integration, here is 70-85% presumed aldehyde, and 15-30% presumed Weinreb amine. Pool 2 has two singlets at the same chemical shift of the two methyl groups as the starting material.
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Use my bisulfite trick to seperate the aldehyde from the other stuff. You can use sodium bicarb to convert it back I think. I would actually say that it might be possible to do the workup without a column using this technique.
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By mass I recovered about 72% of what I applied to the column. Pool 1 was about 16% of the recovered mass, and pool 2 was about 84% of the recovered mass. In other words, I am getting very little aldehyde, because pool 1 is in the minority and is not pure.
BTW, here is a reference to non-aqueous regeneration after bisulfite isolation: Kjell DP et al., J. Org. Chem. 1999, 64, 5722-5724, in case anyone needs it. It provides a little bit of background on the general subject.
ETA
One person with specific experience in this area has told me not to attempt a purification of the aldehyde on silica, because the silica will cause decomposition.
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Indeed, silica or alumina may catalyze the autoxidation of aldehydes to the corresponding carboxylic acids in the column and TLC plates. But this does not happen always. It mainly depends on the aldehyde structure and the working conditions. Consequently, the chromatographic purification of aldehydes figures in the literature from time to time.
Alternatively and in order to be sure, you can try the bisulfite adduct (as wildfyr suggests) and regenerate your aldehyde by alkaline treatment or/and in non-aqueous conditions:
Purification process for 3-phenoxybenzaldehyde, US Patent 4162269, (1979)
2-Methyl-3-phenylpropanal, Organic Syntheses, 61, 82, (1983) or in: Organic Syntheses, Collective volume 7, 361, (1990)
http://www.orgsyn.org/demo.aspx?prep=CV7P0361
A Novel, Nonaqueous Method for Regeneration of Aldehydes from Bisulfite Adducts, J. Org. Chem., 64(15), 5722-5724, (1999)
https://pubs.acs.org/doi/abs/10.1021/jo990543v
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Thank you very much. The first thing that I have to do is to produce a high percentage of the aldehyde, which I do not seem to be doing. So far I have tried DIBAL/THF twice, both following a literature protocol for a derivative of an amino acid that differed only in the protecting group (they used FMOC and I used BOC). The first time I used 1.0 equivalents of DIBAL (I had intended to use 1.5) and kept the temperature below zero (this was close to the procedure that I was trying to follow). The second time I used 1.5 equivalents and gradually increased the temperature over a couple of days (see above). I followed the reaction by spotting the reaction mixture onto a TLC plate, but what appeared to be starting material was always the major spot. It could be something else with a very similar Rf and NMR spectrum.
Right now I do not know what to try next. I could try DIBAL/THF again, and I am open to suggestions on how to change the conditions. DIBAL in toluene has precedent, but I do not have this reagent on hand. Lithium aluminum hydride has been recommended to me and has precedent in the literature. There is also a paper cited upthread that uses LDBBA. I would like to spare the BOC-protected material because it is the most valuable. I also have the FMOC-protected Weinreb amide of the same compound, and that is somewhat less valuable. I can also make a simple model Weinreb amide.
It is also possible that spotting onto a TLC plate is producing results that are misleading in some way.
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The problem is that if your aldehyde is destroyed in the column and the TLC plate, you will obtain low yields, whatever the reduction method is. Thus, it would be better to initially focus to a non-chromatographic monitoring/purification method of the final product.
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The problem is that if your aldehyde is destroyed in the column and the TLC plate, you will obtain low yields, whatever the reduction method is. Thus, it would be better to initially focus to a non-chromatographic monitoring/purification method of the final product.
Are aldehydes inert to alumina? I am not sure how I would monitor by TLC if alumina also decomposes aldehydes. The only other thing that comes to mind is for each time point to do a mini-conversion into the sulfite-adduct and then run the adduct on a TLC plate.
EDT
The protocol I am following used a flash column and hexanes/EtOAc. However, I realize that I may have to depart from the script...
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Alumina may further catalyze the autoxidation of aldehydes to the corresponding esters (Tishchenko Reaction).
So at the beginning, you can run the reduction overnight without monitoring, as described above and purify the final product via the bisulfite adduct, in order to get an idea about the “real" reaction yield.
In a next trial, monitoring can be effectuated by HPLC, where degassed eluents are used and columns are packed under pressure and theoretically, there is no air (oxygen) trapped therein.
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Have you taken NMR of the crude and just seen the conversion of weinreb amide to aldehyde? This will tell you if the reaction is actually low conversion, or just falling apart on silica.
You can also run a 2D TLC to see if your product falls apart on silica.
I've never understood why people want to column everything, I avoid it as much as possible. Expensive, requiring high expertise, and most of all, time consuming. Clever washes and precipitations are by far the best (and most scalable) methods. You'd be surprised what you can accomplish, such as removing PPh3O with a zinc chloride wash! https://pubs.acs.org/doi/pdf/10.1021/acs.joc.7b00459
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For the second reaction I checked the crude product (after washes but before the column) with H-1 NMR, and it was suggestive of about 15% aldehyde, which is not that different from what I guessed, based on TLC.
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For the second reaction I checked the crude product (after washes but before the column) with H-1 NMR, and it was suggestive of about 15% aldehyde, which is not that different from what I guessed, based on TLC.
This experiment rules out decomposition on silica as being the sole problem. Although decomposition is a possibility, it was not mentioned in the paper I am following.
It has been suggested to me that the presence of the BOC or FMOC group could cause the consumption of one equivalent of DIBAL through removal of the carbamate proton. If this happened, the work-up would reprotonate it. I am in the process of looking over other examples that used DIBAL. Thoughts?
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I tried the reaction on a smaller scale using the FMOC-protected Weinreb amide and 2.5 equivalents of DIBAL. I do not have the NMR in front of me at the moment, but my recollection is that by integrating the aldehyde peak, I saw about 20% conversion. Some literature searching that I did suggested to me that LAH will work. I thought that I cancelled my order of lithium diisobutyl-tert-butoxyaluminum hydride in THF/hexanes, but it showed up last week. Under the circumstances I am inclined to try LDBBA next and LAH after that.
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The Fmoc is base-labile so this is maybe a problem?
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One of the papers I am following claimed a 60% yield in this reaction, and their substrate was FMOC-protected. My first attempts were with BOC-protected substrate, and I obtained only a little product.
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I hope to return to this work soon. I plan to follow the reaction using TLC, but this time I plan to use some sort of mini-extraction on any time points. One possibility is to use ethyl acetate vs. KHSO4. I have also heard that with aluminum-based reagents, the Rochelle salt is a possibility. Does anyone have any advice on what mini-extraction conditions are best, or more generally on using mini-extractions in conjunction with TLC?
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Its difficult to give advice with so little info about your compound.
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The desired product is an alkyl aldehyde. The two protecting groups are BOC on a nitrogen and tert-butyl (on a carboxylic acid).
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I get the impression that you have worked for some time with this, is it possible to change the strategy? Two good ways to create an aldehyde is to oxidize a alcohol, Dess Martin is good, or to cleave a double bond with osmium tetroxide/NaIO4.
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I set this work aside in favor of reactions where I could use commercial aldehydes, but I want to come back to it now. I have two reducing agents, and I still have some of the Weinreb amide that I made. If that runs out, I will try another strategy, such as the Dess-Martin reagent.
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If you do the DIBAL reduction, keep it cold until the quench, that will help protect the ester. Your quench may turn into a frozen mess, due to the temperatures, but just add the quench at a moderate speed at first to control the temps, and once some is added, then the further quench will warm the reaction. Maybe take it out of the cold bath just before quench. I have done some reactions like that where the quenched reaction is an icy mess, but the yield was great, so just let it thaw some under nitrogen and then extract once thawed some.
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How does one deal with the gelatinous mess after the quench? I tried an extraction, but I could not see the line between the aqueous layer and the ether layer. I tried to filter through papers but it took forever, and the ether evaporated. I am wondering about filtering in vacuo through diatomaceous earth.
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Wernic D et al., J. Org. Chem. 1989, 54, 4224-4228.
Zhang G et al, Organic Biomol. Chem 2015 13(14):4149 DOI: 10.1039/c5ob00120j
These two procedures are almost identical.
We tried to reduce the Weinreb with Dibal-H again this week. We worked at -70 °C (dry ice/acetone) By NMR the crude material looks like 45% aldehyde and 33% Weinreb amide. What is odd is that the reaction seemed to be more complete at 2 hours than after 4-5 hours. The separation between spots in our TLC solvents (35-40% ethyl acetate in hexanes) was poor. We will need to find a different system for silica chromatography. We found that dipping the plate into DNP solution gave a yellow spot for crude product and a white spot for starting material.
Let's say that we can get 25% yield after purification. We can live with that, but we would like to improve this significantly.
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I would not be surpriced if the reaction is very fast, Dibal is a potent reagent. If so it could be good to quench after say 5 min. I think acetic acid can be OK to use. Its possible that the aldehyde breaks down in the reaction mixture if run too long.
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At least one author mentioned moving ahead with their aldehyde without further purification, but that was not an option for us. We were able to purify the aldehyde away from the remaining Weinreb amide via a relatively large column of silica in modest yield. After we had done so, I read an old email from a chemist who was worried about decomposition of the aldehyde and had recommended not attempting to purify it. I suppose fortune was on our side, but I seem to recall other workers who also indicated the sensitivity of aldehydes to decomposition, meaning that I suspect the email raised a real possibility. I may need to start reading at the top of this thread to see what I have forgotten...
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At least one author mentioned moving ahead with their aldehyde without further purification, but that was not an option for us. We were able to purify the aldehyde away from the remaining Weinreb amide via a relatively large column of silica in modest yield. After we had done so, I read an old email from a chemist who was worried about decomposition of the aldehyde and had recommended not attempting to purify it. I suppose fortune was on our side, but I seem to recall other workers who also indicated the sensitivity of aldehydes to decomposition, meaning that I suspect the email raised a real possibility. I may need to start reading at the top of this thread to see what I have forgotten...
Schwartz reagent one should expect quant. yield if it is keept dry :-)
di cyclopentadienyl chloro zirconium hydride you just filter through silica gel quickly to get the product (standard workup). The hemi aminal chelate decomposes on silica gel
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We performed the reaction twice more, on increasing scales. I don't know the exact yields yet, but I believe that the yields were good, and the products looks clean by NMR. I am not sure where the difference lies. It could be just using a different bottle of Dibal-H, but I am far from certain.
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Great! Often oxygen or moisture is less of a problem when running larger scale.