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buffyj
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[*] posted on 13-2-2008 at 16:36
Hunig's base


Hey there,

Does anyone know where I could find data on the solubility of Hunig's base (N,N-diisopropylethylamine) in THF and dichloromethane at low temperatures (0° and -40°C)? I also need the solubility of triethylamine at the same conditions.

Thanks.
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Nicodem
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[*] posted on 14-2-2008 at 07:50


Both those amines are liquids in that temperature range and also fairly nonpolar, so your question makes little sense. It is like asking what is the solubility of ethanol in water. Why do you need such obsolete informations anyway?
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[*] posted on 14-2-2008 at 08:02


Although I don't know their solubilities, the question has some merits: Again in peptide synthesis DIPEA ((N,N-diisopropylethylamine) is usually dissolved in N-methyl pyrrolidone (NMP), and not in DMF because it doesn't dissolve terribly well.
As far as I know, DIPEA dissolves well in DCM but it isn't done much because non-chlorinated solvents are available that are easier to dispose of.




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[*] posted on 14-2-2008 at 09:21


Quote:
Originally posted by Nicodem
Both those amines are liquids in that temperature range and also fairly nonpolar, so your question makes little sense. It is like asking what is the solubility of ethanol in water. Why do you need such obsolete informations anyway?


Just because two liquids are miscible doesn't mean that they are miscible in all ratios (an example being bromine and water). Therefore, the concept of solubility still remains meaningful when dealing with two liquids.

Furthermore, the solubility of ethanol in water is an extremely nontrivial problem. The answer may seem obvious, but that is only because such a mixture is frequently encountered, and has been well documented. If, however, you had no experimental data and wanted to deduce the answer from first principles, it would be very difficult.

Also, when did the concept of solubility data become obsolete?




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Nicodem
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[*] posted on 14-2-2008 at 10:17


The point was that when two liquids are miscible in all ratios (like Et3N/THF, Et3N/CH2Cl2 , iPr2EtN/THF and iPr2EtN/CH2Cl2) there is no point in asking about solubility. I seriously doubt that the given temperature interval would change this. If something is obsolete in chemistry, than I bet an information of this type is. I mean, what good would a value like infinity of g/100g for solubility mean?
Ignored here is that Buffyj is probably asking because having a particular system in mind, like a reaction involving more than just the tertiary amine and solvent. So even if an absolute value for solubility would exist, it would still not apply to his system (and again the solubility information would be almost obsolete).

PS: I only encountered partial miscibility of diisopropylethylamine in highly polar, aprotic solvents like acetonitrile and beyond. Diisopropylethylamine is much like petroleum ether in regard to its nonpolarity.




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Dimitri
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[*] posted on 7-4-2008 at 09:19
Synthesis Of Diisopropylethylamine?


Unable to find much at all on the synthesis of this base otherwise known as Hunig's Base. Is it possible? Anyone tried it here? Much appreciate any help anyone can provide thanks!
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[*] posted on 7-4-2008 at 09:47


This is "Hunig's base."

There is a thread on this already. No need for another one.

Please relocate your post there and delete this one.

Dr.Hunig holds patents on this amine and doubtless they elaborate its preparation. Also there really ought to be plenty in the primary lit.

Have you tried Beilstein?

Houben-Weyl?

Anyway I am sure if you dig deeper you will be rewarded. I believe there is a website on Hunig's Base. Try Google.




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[*] posted on 8-4-2008 at 04:54


Tried google a hundred times over and nothing ever comes up. The beilstein website hasn't got any info on it either?
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[*] posted on 8-4-2008 at 05:04


I meant Beilstein's Handbuch, the set of books.

Which are in any good library. The first 15\6 volumes of the Hauptwerk are in pdf in References for free.

The Beilstein reference is: Beil. 4,IV,511


Ditto for Methoden (Houben-Weyl).

Then there's Chemical Abstracts.

Online: the ACS search engine for their journals.

The Wiley search engine for their journals.

Thieme, for Synthesis and Synthesis Letters

and so on.

RSC search engine for their journals.

ad infinitum.

Anyway you and I must be using different Googles.

http://www.google.co.th/search?hl=en&sa=X&oi=spell&a...

Try that, you get an eyefull.

If you want to do a CA search you will need the CAS registry number.

You can find that on Aldrich, use their FSE, search for DIEA, actually they have it listed as N-ethyldiisopropylamine.

It is not a very expensive compound. 1 L for about $200 US

[Edited on 8-4-2008 by Sauron]




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[*] posted on 8-4-2008 at 06:37


Dimitri, you will not find any preparation of diisopropylethylamine in any newer literature since it is too cheap, too available and too ubiquitous to be prepared in a laboratory environment. Also, for an amateur chemist any starting material would be nearly equally troublesome to get (for example, if you can get diisopropylamine you quite likely can get diisopropylethylamine as well).
Therefore, you should orient your searches into the patent literature. Surely a few papers on its synthesis should also exist, but I'm sure only in the old literature. In short, check the preparation methods described in Merck index and if you are not satisfied with that, do a thorough search as you were told going trough Beilstein and Chemical abstracts. Also, keep in mind that it can not be prepared by ethylating diisopropylamine via SN2 substitution since diisopropylamine is sterically too hindered. If I remember correctly it can however be prepared:
- by acetylating diisopropylamine followed by reduction (not used since economically irrational);
- reductive amination of acetaldehyde with diisopropylamine (for example, JP10081650);
- or reductive amination of acetone with ethylamine (for example, JP2180854).

PS: The thread has been merged with the previous Hunig's base related thread.




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[*] posted on 8-4-2008 at 08:34


I live in south wales and the library hasn't a book published in the 20th century! The only chemistry books I could find were a couple of very old Organic chemistry volumes. I'll do what you've said though and just keep searching but it's been weeks already.
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[*] posted on 8-4-2008 at 08:47


That beilstein reference is to volume 4 of the 4th Supplement which is I believe the combined 3rd and 4th supplements covering the literature of the 30s and 40s. If you search online you will find a number of useful websites on how to use Beilstein's Handbuch der Chemie.

I have only the Hauptwerk which stops at 1910 or so.

Anyway I will have a peek in Merck Index.

Damn. DIEA does not seem to be in Merck

I found it in Encyclopedia of Org.Reagents but, no preparative details were given.

[Edited on 9-4-2008 by Sauron]




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[*] posted on 9-4-2008 at 00:30


Quote:
Originally posted by Nicodem
Also, keep in mind that it can not be prepared by ethylating diisopropylamine via SN2 substitution since diisopropylamine is sterically too hindered.

I was wrong. Under harsh enough conditions ethylation of diisopropylamine with diethyl sulfate does indeed yield diisopropylethylamine (see Chemische Berichte 91 (1958) 380-392). It is however interesting in that it required almost 4 hours at 140°C to give 90% yield. Apparently some Chinese engineers were actually considering this approach for industrial preparation and researched the optimal reaction conditions:

From Jingxi Huagong, 20 (2003) 60-61:
Quote:
Abstract: (Me2CH)2NEt (DIPEA) was prepd. from (Me2CH)2NH (DIPA) and Et2SO4. The optimal reaction conditions include feed mol. ratio DIPA:Et2SO4 = 1.2:1, Et2SO4 addn. time 1 h and the reflux duration 4 h. The max. reaction temp. is 130, the mol. yield of DIPEA 81.4% and the DIPEA purity 99.8%.




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[*] posted on 10-4-2008 at 08:37


Too cheap and too available? I can't source it anywhere, you've got to be some massive company who's been dealing with the supplier for years and years to get anything in the UK.

I'd love to just buy Diisopropylethylamine and can't see why its not more readily available in the UK?
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[*] posted on 10-4-2008 at 11:03


Do you have a fume hood? I mean a real one, not some DIY job. Because without one, working with diethyl sulfate is a very bad idea.

A possible alternative prep would be to make ethylisopropylamine. This is less hindered than diisopropylamine. ow alkylate it with isopropyl halide. the chloride is probably best.

Kudos to Nicodem for finding that DIEA prep, I was never able to.

You might look for slightly more general approaches to hindered tertiary alkyl amines. Especially those of mixed structure,

I have no references, it's my own idea. But at least there's no dialkyl sulfate around to alkylate your brain.

[Edited on 11-4-2008 by Sauron]




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[*] posted on 20-12-2013 at 12:21
Preparation of diisopropylethylamine


Diisopropylamine can be ethylated with ethyl bromide to produce Hünig's base using mild reaction conditions in a ~50% conversion after a 26hr reaction time.

This procedure is based on the patent US2692285, the patent primarily concerns itself with di(sec-alkyl)-dialkylammonium salts
however it includes a preparation for diisopropylethylamine as an intermediate. The patent uses EtI in place of EtBr and claims that use of the bromide causes the formation of unsaturated products which are largely absent when the iodide was used.
However I have isolated the tertiary amine of the correct boiling point when using EtBr.
The patent also indicates a considerably shorter reaction time than is needed for a reasonable conversion although this was for EtI.

The required diisopropylamine is easily prepared by alkylating isopropylamine with isopropyl bromide (36hr reflux) [1].
Reductive alkylation of iPrNH2 with acetone would be quicker.

Preparation

In a 150ml RBF 28.9g DIPA (286mmol, 40ml) was combined with 43ml MEK to which was then added 15.6g EtBr (143mmol).

The mixture was set for reflux with magnetic stirring to prevent bumping later on.
Heating was raised slowly such that after 2hrs bath temperature was 45°C (ambient 4°C) and the reaction mixture had become turbid with a precipitate of DIPA·HBr. Bath temperature was slowly increased over 2hrs more until reflux became significant
(75°C, 1-2 drop/2sec) [2].

Reflux and stirring was maintained for an additional 26hrs (bath temperature raised to 85°C at 12hrs).

The reaction was cooled and the DIPA·HBr solids [3] were filtered and rinsed with MEK to yield 15.4g DIPA·HBr after drying.
The filtrate was acidified with 20.5g 36% HCl in 100ml H2O and the MEK distilled off.
The cooled residue in the flask was treated with 100ml 20% aqueous NaOH. The formed upper layer was separated, dried over NaOH and distilled, the distillate between 124-128°C was collected as the product, 8.9g DIPA was recovered.
Yield DIPEA 9.3g (50% of theoretical) [4].

[1] https://sciencemadness.org/talk/viewthread.php?tid=14442&...
[2] The slow heating run-up can be dispensed with as the reaction is quite slow and it appears to serve no purpose.
[3] It makes economic sense to recover the DIPA especially if you made it yourself, simply treat the DIPA·HBr with excess 10% NaOH.
and seperate the upper layer of freebase.
[4] The amount of DIPA·HBr recovered suggests a 59% of theoretical conversion.

--------------------

I am thinking of trying the ethylation using the OTC ethyl ethane sulphonate. If anyone has any suggestions e.g. regarding
reaction conditions or solvent they would be welcome.

It is of course cheaper to just buy the DIPEA and there is at least one European vendor selling it on eBay at present.
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[*] posted on 21-12-2013 at 06:26


It is quite simple to make di-isopropylamines from an amine and acetone with NaCNBH3, or NaH(OAc)3. So if you could get ethylamine (or the HCl salt) and just react it with acetone (in excess) in either MeOH, DCE, or other suitable solvent, add some HOAc, then add the reducing agent, you will get ethylisopropylamine forming quickly, then, the second isopropyl goes on slower. I did these years ago, and they worked OK.

More realistically, triethylamine will work in most cases where DIPEA works, and is much simpler to find/obtain. I have actually found several cases where TEA worked better, despite some claims that Hunigs is better for most reactions. So I would almost always try TEA before resorting to DIPEA unless there is a clear need for it.



[Edited on 21-12-2013 by Dr.Bob]
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[*] posted on 22-12-2013 at 03:09


Quote: Originally posted by Scr0t  
Diisopropylamine can be ethylated with ethyl bromide to produce Hünig's base using mild reaction conditions in a ~50% conversion after a 26hr reaction time.

Quite interesting that you can get such conversion using ethyl bromide at much milder conditions than those reported for the more reactive diethyl sulfate. Even when considering the much longer reaction time and lower yields, it is still remarkable.

Thank you for sharing your experience, but would you please consider taking the time to compile this report with your previous diisopropylamine report and post it in the Prepublication forum section? I think it would make for a good article.




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[*] posted on 22-12-2013 at 13:40


I'm not sure if this is of interest to you, however... I wrote a compilation of building syntheses (using known preparations) with an end/goal product of N,N-Diisopropylethylamine in a notebook quite a while ago that I've used on a few occasions. I don't have that on hand at the moment, but I'll type the gist of it for you and try to find references for it. I'm not going to include quantities, so use stoichiometric quantities and/or proportionate the quantities listed in each of the main three product's respective citations.

Product 1: Modified copper oxide, copper chromite, to serve as a catalyst of reductive amination prepared via thermal decomposition of copper ammonium chromate

Product 1a) Heated reactions to copper ammonium chromate (I prefer this as opposed to copper barium ammonium chromate for preparing copper chromite, as you do not get the barium yield to clean up) Combine ammonium dichromate and aqueous ammonia to yield ammonium chromate. Prepare a solution of copper nitrate trihydrate by stirring at 70°C. React this warm solution with the ammonium chromate previously prepared at stirring for 2-3 minutes. Copper ammonium chromate will precipitate. Filter the precipitate in a Buchner flask and dry at 110°C.

Product 1b) Thermal decomposition of copper ammonium chromate to copper chromite Heat product 1a at 300-350°C for one hour. As far as solid states go, this will yield copper chromite and copper oxide. This can be removed using an acid extraction, utilizing a wash with 10 % acetic acid twice. The resulting solid can be finally washed four times with deionized or distilled water. Finally, this can be filtered in a Buchner funnel and dried at 110°. Org. Synth. 1939, 19, 31

Product 2: Diisopropylamine by reductive amination of acetone with ammonia over hydrogenation and a copper chromite catalyst This can be done using a generic hydrogenation of a mixture of acetone, ammonia and previously prepared copper chromite heated at 140° to 200°. Patent US2686811 If this is done using a gas bubbler, syringe-septum techniques or like device to hydrogenate, it should be done under reflux. This can be distilled over potassium hydroxide.

Product 3: N,N-Diisopropylethylamine by alkylation of diisopropylamine via diethyl sulfate This has been discussed in the thread, please refer to prior posts. (As well as other routes from diisopropylamine to DIPEA)

[Edited on 22-12-2013 by TMCG]
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[*] posted on 23-12-2013 at 14:49


Quote: Originally posted by Nicodem  
would you please consider taking the time to compile this report with your previous diisopropylamine report and post it in the Prepublication forum section? I think it would make for a good article.

OK, I will do that. I do have a couple more experiments to do first though. I want to compare the results when using EtI instead and do scale-up with EtBr with a modified extraction procedure as I appear to have lost a fair bit of DIPA in the process.

[Edited on 23-12-2013 by Scr0t]
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[*] posted on 25-12-2013 at 14:30


As far as solubility, I've used DIEA regularly for peptide synthesis. The DIEA easily goes into solution with dichloromethane, and I typically use a large amount of DIEA as a base (>8 equivalents). It's a pretty ubiquitous compound, though I cannot find any "OTC" sources for it.
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