Sciencemadness Discussion Board

Best Conditions For N-Alkylation?

Bestbmc - 3-3-2022 at 15:27

Hello Everyone,

I recently prepared some Bromoethane and a concentrated solution of ammonia in ethanol.
My goal is to produce triethylamine and diethylamine by N-alkylation of the ammonia using bromoethane.
I know that the reaction will produce a a mixture of primary, secondary, tertiary and possibly a quaternary amine, but I have uses for these in the future.

I could not find many procedures on the topic, with most of them requiring a sealed ampoule under high pressure.
Because of this, my current plan is to stir the bromoethane with the ammonia at room temperature for several days with sodium iodide as a catalyst.

I have several ideas in mind to help improve the speed or yield of the reaction but I do not know if they are worth it, or detrimental.

I can add sodium carbonate or bicarbonate, to neutralize the HBr formed but I am unsure whether it will react with the bromoethane and destroy it during the reaction.

I also do not know if the reaction is going to proceed at a meaningful rate at room temp and whether it is worth to to reflux the mixture, with the possibilty of ammonia escaping.

If anyone has any procedures or experience relating to this, it would help me a lot.

Dr.Bob - 4-3-2022 at 05:14

You will need to use sodium, or even better, potassium carbonate (its slightly more soluable), as the base, otherwise the reaction will quickly tie up the ammonia as the hydrochloride salt. You could even just use most any ammonium salt and a few equivalents of potassium carbonate, which is easier than ammonia to find. The best solvents for this reaction are acetone, acetonitrile, and DMF (which is a pain to deal with). For the room temp reaction, I would do it in a sealable bottle, that way your ammonia and amines won't all evaporate. If glass, just keep in shielded if you warm it. Good stirring will help dissolve enough carbonate to speed up the reaction. A trace of cesium carbonate is great, as the cesium counterion is even more soluable in organics, so that helps speed it up as well.

I would start with 2.6 equivalents of bromoethane, which in theory would produce about half diethylamine, and half triethylamine. You would have a hard time isolating any monoethylamine, it is very low boiling. Some of the bromide won't react, but some ammonia will evaporate, so the exact ratio needed will be be hard to predict. If you can't get it to work, you can simply free base triethylamine HCl and then distill the product to get pure triethylamine. I have some crude triethylamine HCl material that I could share with anyone in the US.

Bestbmc - 4-3-2022 at 10:35

Thanks for the quick reply,

I was prepared to use all of my ammonia solution in ethanol if it needed to act as a base for the reaction, but now that I know I can use a carbonate as a base, I will be able to save some of my solution.

I dont have access to a high pressure bottle, so anything I would be doing sealed would be in round bottom flasks if possible.

Over the couse of the reaction, the bromoethane and ammonia will turn into higher boiling point components reducing their overall partial pressure making them not a problem. The only thing I am concerned about doing this in a sealed system is the ammonia interacting with the carbonate to form a ammonium carbonate salt and then decomposing into co2 and water. I don’t think this will happen, and if it does, the water and co2 should theoretically react with another amine and redissolve.

I just want to be sure that I am not building a bomb because of co2 build up.

Jenks - 4-3-2022 at 11:42

Mixing ammonium hydroxide with a base could increase pressure by evolving ammonia gas, particularly if heated. A way to prevent this from being a hazard would be to mix the ammonium hydroxide with the base without enclosing it. Once it is at room temperature, it should be safe to seal if the reaction is also carried out at room temperature. If it is sealed with a stopper then, even if pressure did increase, it would only dislodge the stopper.

Some ethanol or other water-miscible alcohol may help the bromoethane to dissolve. This would bring it into contact with the ammonia, helping it react, and should also reduce its vapor pressure.

Two important variables I foresee are the number of equivalents of ammonia you will want to use and how long to wait before assuming that the reaction is complete. You could use 2.5 equivalents of ammonia to hope for a mixture mostly of diethylamine and triethylamine. Completion of the reaction could be confirmed by showing that there is no more bromoethane in the vapor above the reaction mixture. Maybe a silver halide test could show this - or maybe not, since the vapor will also be rich in ammonia and/or amines.

Antigua - 4-3-2022 at 11:59

How has no one mentioned so far that this isn't going to work? Sterically unhindered alkyl bromides will alkylate the nitrogen atom to the quaternary ammonium salt almost exclusively. Maybe you can get a 10% yield out of that.

Jenks - 4-3-2022 at 13:28

Quote: Originally posted by Antigua  
How has no one mentioned so far that this isn't going to work? Sterically unhindered alkyl bromides will alkylate the nitrogen atom to the quaternary ammonium salt almost exclusively. Maybe you can get a 10% yield out of that.

I think there is more hope than that.

Even the Wikipedia page on Amine Alkylation says, "For example, reaction of 1-bromooctane with ammonia yields almost equal amounts of the primary amine and the secondary amine."

I found experimental results in a Quora post:

From the post:


This is copied from MARCH’S ADVANCED ORGANIC CHEMISTRY 6th edition p556

The limitations of this approach can be seen in the reaction of a saturated solution of ammonia in 90% ethanol with ethyl bromide in a 16:1 molar ratio, under which conditions the yield of primary amine was 34.2% (at a 1:1 ratio the yield was 11.3% (Werner, E.A. J. Chem. Soc. 1918, 113, 899.)

I checked the primary data of the reference (please note that it is from 1918!) They got 57.5% diethylamine using this procedure and minor amounts of triethylamine but please note that they added the Ethylbromide in portions if they did it in one portion mainly triethylamine was formed.

My conclusion is that alkylation of ammonia with methyl halide might give the simple result of preferring quaternization, but as the alkyl groups grow there will be increasing compensation by their bulkiness, counteracting their electron donation, so that the outcome is not simple, particularly if there is a large excess of amine.

Bestbmc - 4-3-2022 at 13:53

I just started a test run of the reaction, using a 500ml round bottom flask with some sodium carbonate, ammonia in ethanol and bromoethane. I stoppered it, and it is going to run over the weekend at room temp with stirring. I’m going to test the solution on monday to see how much bromoethane is remaining.

As for the products, the documents I read seem to point to triethylamine being the major product, and I should be able to heat any tetra ethyl amine salt to decompose it to a the tertiary amine and a alkyl halide (reportedly).

But the only true way to find out is to do it, so in the next week I will likely be able to come back with results of what is produced and how much of each.

S.C. Wack - 4-3-2022 at 17:46

Would y'all believe that the subjects of diethylamine and triethylamine have come up HERE before?

"This file has been downloaded 37226 times"

(BTW EA Werner trivia: Very few chemistry professors even in his time have ever had his academic credentials; he never attended college, except for working in one.)