[kriggy]

About the quench: cant you use the protocols that are commonly used for LiAlH4? Rochelle salt, Na₂SO₄.10H₂O or just NaOH/water?

[Babcock_Hall]

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?

[Babcock_Hall]

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?

[rolnor]

Maybe monitor the reaction with TLC?

[wildfyr]

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)

[pgk]

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.

[pgk]

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

[wildfyr]

Beware Tet Letters papers!

[Babcock_Hall]

Maybe monitor the reaction with TLC?

TLC will be tricky owing to the closeness of the spots (R_f = 0.50 vs. R_f = 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.

[pgk]

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

[TheUnassuming]

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. 

[Babcock_Hall]

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 R_f.  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? 

[Babcock_Hall]

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 R_f than starting material.  I surmise that it is the alcohol, but I don't have a way to verify that yet.

[wildfyr]

Mix the aloquot with some tbdms chloride and imidazole and see if its is replaced by something much more nonpolar?

[Babcock_Hall]

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.