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Author: Subject: Preparation of Hünig's base (diisopropylethylamine)
Scr0t
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[*] posted on 9-1-2014 at 07:06
Preparation of Hünig's base (diisopropylethylamine)


Diisopropylamine (DIPA) can be ethylated with ethyl iodide to produce Hünig's base (DIPEA) under mild conditions.

The required DIPA was prepared by alkylating isopropylamine with isopropyl bromide (36hr reflux) [1], a procedure is given below. Isopropylamine (iPrNH2) itself can be economically extracted from the herbicide "Roundup" (isopropylamine salt of glyphosate) by treatment with excess aqueous NaOH and distillation in a 76% yield.
The EtI was obtained by the reaction of EtOH, Al (foil), I2 and H2O.
While this may not be the most efficient way of preparing DIPEA it's very simple and OTC.

The ethylation is based on the patent US2692285, the patent primarily concerns itself with di(sec-alkyl)-dialkylammonium salts and it includes a preparation for DIPEA as an intermediate.

Use of bromoethane as the ethylating agent was initially attempted and while it reacts, although more slowly with lower yield, it has been determined that it produces anomalous results which may be consistent with the patent's claim that "unsaturated" byproducts form with this reagent [2].


Preparation of diisopropylethylamine

49.3g (488mmol) DIPA, 74ml MEK and 38.0g (244mmol) EtI were mixed in a 250ml RBF and was heated to reflux while stirred magnetically (bath Temp. ~90°C) [3].

Within 15mins of heating a precipitate began to form, reflux and stirring was maintained for 24hrs [4].

When complete the reaction was cooled, filtered, solids washed with MEK and dried to yield 52.5g DIPA·HI [5].
The filtrate was treated with 40ml 36% HCl in 50ml H2O and stirred for ~30mins. The MEK was removed by distillation and the cooled residue treated with 40g NaOH in 100ml H2O. Seperation of the amber upper phase, drying over ~1g NaOH (perl) and distillation (124-128°C) yielded 27.6g DIPEA (88% of theoretical) as a clear colorless liquid.


Preparation of intermediate diisopropylamine

In a 500ml RBF 32.0g iPrNH2 (542mmol) and 80.0g iPrBr (650mmol, 1.2 eq) in 200ml IPA was refluxed for 36hrs while magnetically stirred.

Crystals began to form in the hot solution at about 15hrs.

When the reflux was done the reaction mixture was cooled in a freezer and the solids quickly filtered. After air drying 62.2g DIPA·HBr was obtained (yield 63% based on iPrNH2).

The DIPA freebase was liberated by adding the so obtained HBr salt to 30g NaOH in 60ml H2O, stirring until the solids had dissolved, separating the yellow upper phase, drying with NaOH and distilling (82-86°C) to yield 30.8g DIPA as a clear colorless liquid.


[1] Reductive alkylation of isopropylamine with acetone would be quicker.
[2] The purity of the presumed DIPA·HBr formed during the reaction with EtBr is suspect, also a middle fraction obtained during distillation of the presumed DIPEA likely contaminates it.
[3] An egg stir bar was used which had a little difficulty stirring the heavy iodide precipetate towards the end of the reaction.
[4] Precipitate formation with the iodide appeared to stop visibly at around 6-8hrs, 24hr reflux is likely excessive.
[5] The amount of DIPA·HI recovered suggests a 94% of theoretical conversion.


The ethylation was surprisingly efficient considering the steric hindrance that comes into play here.


[Edited on 18-1-2014 by Scr0t]
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plante1999
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[*] posted on 9-1-2014 at 14:43


Very nice synthesis. Great report, but it would be nice to know the yield of isopropyl amine from the round up. Pictures would be interesting, as usual.



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Scr0t
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[*] posted on 9-1-2014 at 15:25


You can expect a 76% yield of iPrNH2 from a Roundup concentrate.

https://www.sciencemadness.org/whisper/viewthread.php?tid=14...

I have yet to get decent digital camera, my old phone camera just wont cut it, anyway you aren't missing much... just some white solids forming in pale yellow liquids and biphasic liquid mixtures.
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UnintentionalChaos
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[*] posted on 13-1-2014 at 17:18


Excellent work. DIPEA is probably overkill for most preparations vs TEA but it's inability to form quaternary salts and the stepwise procedure makes the final alkylation smooth as opposed to any rather sloppy attempt at TEA with ammonia and lots of EtBr. I think I will have to try this procedure out.



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walruslover69
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[*] posted on 21-9-2020 at 05:16


Just wanted to give an update on this old procedure.

I used scr0t's 49.3g (488mmol) DIPA and 38.0g (244mmol) EtI in a 250ml RBF, but substituted 75ml of acetone for OP's MEK. I also simply let the reaction stand overnight at room temperature instead of refluxing. Withen 8 hours the reaction looked like it had gone to completion with the entire flask almost solidifying with perfect white crystals. I shook it up to break up some of the crystals which still filled about 1/2 the flask and left it overnight.

I haven't completed the workup yet, but when I do i will include the percent recovery.

out of curiosity, what is the point of adding 40ml of HCL and then distilling to remove MEK? IF you already have dried DIPA·HI, how can you remove MEK by distillation? Shouldn't you just be able to skip this and dissolve the DIPA·HI in water and add the NaOH solution?
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