Sidmadra
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Lithiation reaction of an Aniline... gooey yield problems, uncrystalizable, not sure where I went wrong
I don't have the exact paper on hand but saved the rough procedure. It's a very straight forward procedure... Lithiate an Aniline under Argon, add the
alkyl halide, workup, recrystallize. I didn't bother including weights/molar in my writeup because I was completely unable to determine yield, however
my reaction was performed on a similar scale. Yield ended up being a sticky goo, that was unable to be dissolved in the solvent system that the papers
authors used for recrystallization, nor able to be weighed.
I followed the procedure almost exactly, all proper molar ratios, except I used Heptane(stored over molecular sieves) instead of Hexane, and 11M
Butyllithium instead of 2.4M (molar ratios accounted for). I purged my flask with argon very thoroughly, and was able to add the Butyllithium
apparently without issue. Butyllithium was confirmed to be active by the notable sparks flashing off the syringe when removed from the flask seal. For
my Aniline I used N,N-Diisopropyl-3-methoxyaniline, which is a sterically crowded tertiary aniline similar to the one used in the
paper. Not exact with the amount of carbons, but all the same functional groups and spacing. For my Alkylhalide, I used
1-Bromoheptane, which is what was used in the paper.
The procedure in paper:
| Quote: | To a flame dried 2 neck flask were added 3g (12mmol) of Compound A(Aniline Compound), and 30ml of dry hexane under Argon. After that, n-butyllithium
(5ml, 2.4M in hexane) was added at room temperature. The mixture was allowed to stir at 85 C for 2 hours.
To the mixing flask was added 1.5ml (12.09mmol) of Compound B(Alkyl Halide), and the mixture was allowed to stir at 85 C for 12 hours.
After 12 h of stiring at 85 C, the mixture was quenched with 150ml of water. 100ml of CH2Cl2 and HCl solution (25ml, 5%) were added. The resulting
mixture was then extracted with additional CH2Cl2, organic layers combined, and washed with saturated NaHCO3 solution. After filtration, evaporation
and recrystallization from Methanol, resulted in a 60% yield of the alkylated compound as a white solid.
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My Writeup:
| Quote: |
All Flask and Syringes were washed with acetone and allowed to dry to remove residual water. Reaction was performed on a gram scale (3g of my aniline)
First I stirred my aniline into Heptane, resulting in a white suspension. I then purged the septum sealed flask with Argon for 10 minutes. I prepared
to add my butyllithium with proper handling, withdrawing it under argon, etc.
When I added the butyllithium through syringe at room temperature, the flask temperature rose by about 20-30C, and the white suspension of my reagent
initially became cakey/filmy at points, indicating something was happening, but this evened out after about 5 minutes of stirring, at which point the
solution was creamy/milky white. I thought it was odd that the procedure called for heating at 85c, especially considering some reaction did appear to
happen upon immediate addition, but figured it was because the reagent doesn't dissolve in the Hexane, so additional time/heat was given due to it
being heterogeneous in nature. I let this stir 2 hours per the procedure.
After this, I then used a syringe to add my Bromoheptane compound. The original paper did not indicate that airfree techniques were used during this
step, but I decided to do so anyways to hopefully eliminate any potential oxygen reaction. Prior to this addition, some of the
material on the walls of the flask began to turn green, which I assumed was from degradation of the lithiation reagent from heat, however this was
relatively minor, but did become more green over the 12 hours. The overall stirring mixture remained relatively white.
Workup: I first added a slight amount of water through syringe to ensure there was no risk of fire and all lithium reagent destroyed.
I then added the full amount as specified and worked up exactly according to procedure. The solution/mixture was notably greenish at this point, and
when concentrated in the Rotary Evaporator it took on a very dark green / near black apperance. Resulting a slime which was not able to be
recrystallized at all in the solvent used in the paper, and hardly able to be poured out of the flask to be weighed.
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So, I'm not really sure what went wrong. There were no air leaks in my system, and I even kept the system airfree during steps which the paper did not
specify needed to be airfree, just to be safe. Is it note worthy that the system had such a rise in temperature upon addition of the butyllithium? Is
this potentially indicating that the butyllithium was reacting with water, or that the lithium reagent simply forms rapidly?
If there was water in my heptane, I could definitely see how this would go wrong, but that would mean the molecular sieves did not do their job. I'm
working on getting more heptane to try again, but figured I would ask here to see if anyone spots anything obviously wrong. I haven't conducted many
Lithiation reactions so I'm not sure where I messed up.
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Dr.Bob
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Did they not cool the reaction before adding the BuLi? That is pretty standard to avoid spikes in temperature during the addition. Did they add it
dropwise or at what rate, again, BuLi reactions can get hot fast, and that can decompose the anion formed in some cases. Usually the solvent is
dried by distilling from sodium, but sometimes that can be skipped, especially if an excess of the buLi is used. Does the paper you mention suggest
which hydrogens are abstracted? I would guess ortho to the methoxy, but not sure. And aminoanilines like that are hard to dry, so the aniline may
contain substantial moisture as well. If you can TLC the product and see how many spots there are, that is the main key, as if you have a mixture,
it is not likely to crystallize, even if pure, I would not expect that type of aniline (DiisoProaniline)to be easy to crystallize. I made some years
ago, and they were all oils and goos that often looked like used motor oil, even after purification.
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zed
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I was unsure about drying non-polar solvents over molecular sieves. But, some of the guys say it works pretty well.
https://webcache.googleusercontent.com/search?q=cache:0LISE7...
How about a link, or a picture?
Crud? Short path vacuum distillation. This will generally produce a crud free product, that may or may not...refuse to crystallize. But, hence,
perhaps it's HCl salt will crystalize.
[Edited on 11-6-2018 by zed]
[Edited on 11-6-2018 by zed]
[Edited on 11-6-2018 by zed]
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12thealchemist
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You mentioned that you used 11 M BuLi instead of 2.4 M. Is it possible that due to the far higher concentration that you ended up "adding the BuLi too
quickly" so to speak? I remember a similar sort of problem from a lab in 2nd year where I think I went wrong by adding the BuLi too quickly. I assume
you went dropwise, but perhaps "slow-dropwise" is what is required for such a concentration difference?
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Sidmadra
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DrBob,
In the paper I recall they added the Lithium at RT. There was other compounds that they lithiated at -78c however for some reason they said this
addition was done at RT. I'm assuming that the lithiated compound is just extra stable or something, perhaps because it is stabilized by two DMG
groups.
My starting reagent actually crystallized very well in methanol. I started with yellow powder, heated in methanol, and crystalized within 10 minutes
upon cooling to very beautiful white crystals, which were subsequently crushed in a pestle mortar before using in the reaction. I lost about 10% of
the bulk weight during the crystallization. I don't think there was water in this compound because it was crystallized from methanol, unless it
absorbed a substantial amount from the air.
Can water be trapped in crystals like that formed in methanol? The methanol itself wasn't dried, but was distilled under vacuum a few days prior.
Maybe it would be worth while for me to put all of my crystals in the rotovap without a solvent just to dry it on max vacuum for a while? That way to
remove any possible residual water or methanol.
Right now I'm currently working under the assumption that perhaps my Heptane had residual alcohols in it. I thought I was using fresh, but I fear it
may have been polluted from a past reaction that I forgot about. In any case, I purchased some Fresh Heptane and I plan to try the reaction again.
Quote: Originally posted by zed  |
How about a link, or a picture?
Crud? Short path vacuum distillation. This will generally produce a crud free product, that may or may not...refuse to crystallize. But, hence,
perhaps it's HCl salt will crystalize.
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I've already cleaned all my glass and trashed the gunk. I plan to try again with fresh heptane in case what I used before was somehow contaminated
with alcohols from a past reaction I forgot about. The HCl salt of this aniline was actually rather hard to work with. The salt itself actually isn't
water soluble, and despite the HCl component, prefers to stick to DCM/Chloroform layer. I speculate it is because of the non-polar bulkiness of the
compound.
| Quote: Originally posted by 12thealchemist | | You mentioned that you used 11 M BuLi instead of 2.4 M. Is it possible that due to the far higher concentration that you ended up "adding the BuLi too
quickly" so to speak? I remember a similar sort of problem from a lab in 2nd year where I think I went wrong by adding the BuLi too quickly. I assume
you went dropwise, but perhaps "slow-dropwise" is what is required for such a concentration difference? |
Can it be added too quickly? I didn't do drop wise for the entire addition. I did the first few drops slowly to make sure the Argon atmosphere was
intact so no fire, and then just deposited the rest in over the next 15 seconds. The temperature spike wasn't too major, and in any case the paper
authors said it took 2 hours at 80 degrees celcius for the lithiated compound to form, indicating it is perhaps limited by steric hindrance or some
other factor.
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Dr.Bob
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Usually BuLi is added slowly, over many minutes. Often at low temps, so that seems unusual to go quickly and at RT. I would suggest adding it
slowly, with good stirring, and let it stir an hour at RT before heating. I know that may seem unneeded, and it may be, but hard to be sure. It
shouldn't hurt to run it slower. Just my suggestions.
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Sidmadra
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| Quote: Originally posted by Dr.Bob | | Usually BuLi is added slowly, over many minutes. Often at low temps, so that seems unusual to go quickly and at RT. I would suggest adding it
slowly, with good stirring, and let it stir an hour at RT before heating. I know that may seem unneeded, and it may be, but hard to be sure. It
shouldn't hurt to run it slower. Just my suggestions. |
Dr.Bob, do you know if aryl lithiations like this typically proceed fairly quickly with the DOM groups, or is the steric bulk of the molecule likely
to inhibit the rate? Can you think of a reason why they would feel the need to heat it at this temperature? To be fair, I do know the starting reagent
does not have any solubility in hexane/heptane until it is heated to about 40-50c (at which point it melts and becomes miscible), and in the paper
they just stirred the reaction on an Oil Bath 85c - with the BuLi still added at RT. Frankly it didn't even say they were stirring when they added the
BuLi. As well, the lithiated compound is thermally stable enough if it can withstand 85c for many hours.
From what I've noticed, it seems low temperatures are mostly used with BuLi when there is an ether being used as the solvent, mostly to limit
competing reactions with the ether and decomposition, from what I understand.
Another concern that remains unanswered is why exactly the paper authors let the alkylation reaction run for 12h. I imagine aryl lithiums are pretty
reactive and would probably react very rapidly even with a weak alkyl halide. Maybe they just let it run 12h because they were letting it go
overnight, and perhaps maybe even 1h would more than suffice.
I plan to make the following changes when I next run this reaction:
* Use fresh Heptane, stirred over fresh 3a sieves for 1 hr prior to use
* Use mild heat on the aniline under vacuum for an hour on rotary evaporator, to remove any remaining methanol or perhaps water in the crystals.
* Add the BuLi more slowly.
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