Klute
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Imine formation with Dean Stark (And other Dean Stark uses...)
After searching around, I found that alot of imines are made and sometimes isolated using an Dean Stark setup, to acheive maximum yield by
eliminating water... Generaly, the carbonyl compoud is dissolved in a hydrocarbon solvent (toluene, benzene, xylenes, cumene, etc) containing the
amine used, and everything refluxed for a long peroid of time in a dean stark setup.. Solvant can then be vacuum distilled, and imine isolated, or
next reactions done in the hydrocarbon solvant... In most applications I have found, either long aliphatic chaine primary amines or secondary amines
are used...
But, in the event of a small primary amine being used, as methylamine, which is hygroscopic, wouldn't a decent amount of the amine distill of with
the azeotrope before being able to react with the carbonyl and stay in the captured water? Seeing the great solubility of such amines in water...
Would adding the amine dissolved in a hydrocarbon solvant progressively help avoiding that? Being less excess, there is less unreacted amine to be
distilled off... and seeing that the equilibrium is constantly displaced with the elimination of the water, the need of an 2 or 3 fold excess of
amine to carbonyl might be avoided here... the amine is introduced as the same time as the water is eliminated, so the formed imine stays that way,
and the newly introduced amine reacts with the unreacted carbonyl.. and only minimal quantities of amine distills of with the water...
I've seen PTSA often used in catalytical amounts, but wouldn't it react with the amines and get neutralised?
Also, the use of an Dean Stark obviously implies reflux... I have seen alot of methylamine-imine reaction been done at room temperature or
lower... In a few apllications with methylamine, reflux temp. are used, but this is with aromatic aldehydes, of whom the imines are more stable
because conjugated... Would these temps (>100°C) be suitable? I guess it depends on the specific compound, but in general, for aliphatic saturated
ketones?
I know the use of molecular seives or even silica gel detroned the Dean Stark trap, but this isn't just for maximum yields and all, but more for
interest in the reaction, to be able to follow the reaction's completion by mesuring the volume of water... And to find another interesting reaction
to do with a Dean Stark... Fischer esterifications get boring after a while  and
aldol condensation aren't always possible as small chaine ketones (acetone, MEK, etc) often form azeotropes with toluene and such...
And if anyone knows of other interesting reactions to do in a Dean Stark, colorfull or nice-smelling products, please share!
Any backup or personal experience will be appreciated..
Thank you
[Edited on 23-2-2007 by Klute]
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stoichiometric_steve
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i think the trick with small aliphatic amines in imine formation in the dean-stark is to use a huge excess and let the stuff stir for a while until
you start the reflux.
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Klute
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Thank you for your reply!
Yes, that crossed my mine also, letting it stir for an hour or two at room temp, and then start refluxing.. To avoid using too much excess, I was
thinking dissolving 2xmolar in the solvant along with the carbonyl, then adding another 1 or 2xmolar during reflux...
Heating up wouldn't degrade any formed imine, no?
I found this, concerning formation of an imine and then it's reduction by NaBH4:
N-(2-Fluorophenyl)-2-(2-methylaminomethyl)pyrrole (10). To a solution of 1 g (4.90 mmol)of N-(2-fluorophenyl)pyrrole-2-carbaldehyde 9 in toluene (10
mL), methylamine (5 mL) and a catalytic amount of p-toluenesulfonic acid (PTSA) were added. The mixture was stirred at reflux using a refrigerant and
a Dean Stark system for 24 h. The reaction was monitored by TLC using hexane/ethyl acetate 7:3 as eluent. After complete consumption of the starting
aldehyde, the mixture was cooled to room temperature and the solvent was removed under vacuum. Then, methanol (12 mL) and 100 mg (2.64 mmol) of NaBH4
were added to the crude reaction mixture and the resulting mixture was stirred at room temperature for 2 h. Methanol was removed, water (15 mL) and
dichloromethane (20 mL) were added. The crude reaction mixture was extractedwith dichloromethane, the organic layers were dried over Na2SO4, filtered
and the solvent evaporated. The residue was purified by silica gel column chromatography using hexane/ethyl acetate 90/10 as eluent. Finally the
residue was recollected in methanol and the solvent wasremoved under vacuum to give 0.840 mg (4.11 mmol, yield 84 %) of the methylamine 10 as
colorless oil.
They use a very large excess of methylamine though, I guess this is also not to be bothered about MeNH2 loss during water removal... Also very long
reaction time... I really don't know how long would the formation of the imine/ water removal really take, as I have seen example where they reflux
for 3 hours until completion of the reaction by TLC like here... It must depend alot on the specific substrat...
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stoichiometric_steve
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the only way you could really tell if the imine was completely formed would be to do TLC.
whats that PTSA for in the reaction mix?
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Klute
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The PTSA serve as catalyst, I've seen that mentionned in other places too... That got me confused, because they said it was an acid-catalysed
reaction, but with all the amine freebase, I don't understand how the medium can be acidic...
Why wouldn't the quantity of water trapped indicated the following of the reaction? If all the reactants and solvant were anhydrous at the start?
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stoichiometric_steve
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yes, you are right, the amount of water collected would certainly be a measure for the progress of the reaction.
i was just thinking of using e.g. 40% aqueous methylamine, where the water would be azeoptroped off along with the amine.
with the PTSA, i remember reading somewhere that the protonated form of an imine is way more stable than the unprotonated form, so that might be what
it's used for.
talking about reductive amination...see isomeric_freds post containing some nice stuff about solventless red.amin. with PTSA or boric acid as modifiers for NaBH4 great stuff, highly recommended read!
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Klute
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I'm surprised I didn't see that before! Thanks, very good info
Concerning aqueuse reductions with Na Borohydride, Barium's methods of slowly titrating an concentrated aqueuse solution of the HCl salt of the amine
with the ketone dissolved in a organic solvant to push the amine out of solution to react with the ketone is more efficient than using straight 40%
solution IMHO. But again if 40% aq. is available, maybe it's not worth the hassle of titrating and reduce to rebase after...
But it isn't impossible that the 40% MeNH2 would simply distill off and go directly to the trap, with minimal amounts of amine dissolving in the
solvant...
Doing it ala Barium is nice in that a saturated solution of NaCl is obtained by neutrailsation of the HCl salt, and the little amount of water get
saturated very quickly by the amine which is forced out..
One thing that could be tried would be starting ala Barium, with the carbonyl compound in toluene, adding a conc. solution of the HCl salt of the
amine, slowly titrating with vigorous stirring, letting to stirr for an hour or two, and then seperating the 2 phases and adding the toluene layer in
a Dean Stark setup and eliminating residual water + water formed... Barium calls for 1-2 hours of R.T. stirring for the imine formation, before
seperation and reduction by basic NaBH4 aq. solution, so maybe the use of the Dean Stark would able maximum conversion to the imine before
reduction...
For the moment mixed results have been obtained with these methods (wet 2 layers, wet alcoholic) with different results, but then again the carbonyl
compounds weren't phenylacetones as Barium's used.. Maybe these ketone react better in these conditions...
[Edited on 25-2-2007 by Klute]
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stoichiometric_steve
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i can only tell you that out of every single method that me and an associate have tried that was authored by barium, none, absolutely NONE has worked
as advertised. i suspect that what he posted was nothing else than wishful thinking, a.k.a. imaginary bullshit. sorry.
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stoichiometric_steve
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i can only tell you that out of every single method that me and an associate have tried that was authored by barium, none, absolutely NONE has worked
as advertised. i suspect that what he posted was nothing else than wishful thinking, a.k.a. imaginary bullshit. sorry.
[]edit
erm. about what you posted: i think you wont get any less water in the reaction other than using 40% aq. methylamine or 70% aq. ethylamine. making a
HCl salt solution and titrating that with NaOH...you will end up with a lot more water in there.
i dont know where you want to go with your proposed procedure.
[Edited on 25-2-2007 by stoichiometric_steve]
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Klute
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My bad! I dunno where I made a mistake, but I was sure you would get an over
saturated solution by titrating a saturated solution of the HCl salt with 50% NaOH... After redoing the calculation, you end up indeed with a 25%
solution... Even if this is saturated in NACl, wich would help the MeNH2 leave the aq. , the imine must form much less easily because of less amine
present in the NP layer...
I guess the methods of gassing anhydrous MeNH2 gas must be used to get reasonable yields...
I dunno if Barium was posting BS or not, especially with his wet NaBH4 reductions, but he did seem to be a serious guy. Two of his wet methods were
tried, with very low yields:
When using MeOH instead of IPA, and the amine titration method, 9.7%, and using the toluene/aq. titrated amine, 6.2%.... Ketone was of very good
quality, fractionated over 3°c range, amine was recrystallized twice from abs. EtOH and washed with DCM.
I figured the method doesn't apply to all types of ketone, don't forget Barium used 2-fluorophenylacetone, which could have enough reactivity
difference from let's say MDP2P or even unsub.P2P to cause such difference in yield...
I, personally, don't see the point of publishing new methods with fake/boosted yields that no one can achieve, but what do I know about people
intentions.. Barium, by his posts and knowledge, see to me as a respectable researcher, but maybe I'm stupid, hey. Even Labtop was saying these
methods were more practicale than his on small scale.. I dunno if he tried them personally, though.
In the Hive's post, the maximum yield with MDP2P is 45%, and one bee gets 51% with unsub.P2P... IIRC.
Maybe working on PTC use can boost things up...
But I want to give anhydrous conditions a try... How many times have you and your associate tried these wet methods? What conditions (Alcoholic, 2
phase) did you use?
And did you have succes with anhydrous methods (ala Labtop)
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