Sciencemadness Discussion Board - Benzylamine via the delepine reaction

Benzylamine via the delepine reaction

gluon47 - 19-11-2016 at 21:59

I receintly made some benzyl chloride via the free-radical halogenation of toluene. I beleive my product to be fairly pure as I measured its density to be 0.921g/cm³ which is very close to density of pure benzyl chloride.

Anyway, I want to use the benzyl chloride to make benzylamine. The most feasible and interesting method I could find was the delepine reaction. I even managed to find a procedure.

So if I understand correctly, hexamine is benzylated by the benzyl chloride forming a hexaminium salt which is quite soluble in chloroform at high temperature but not at low temperatures. Upon cooling, the hexaminium salt precipitates. The salt is then hydrolysed with ethanolic hydrochloric acid forming benzylamine hydrochloride and ammonium chloride. Further workup yields fairly pure freebase benzylamine. A slight excess of benzyl chloride is used to prevent the sommelet reaction from occuring. Is this accurate?

It seems like chloroform is almost always used as the solvent for delepine reactions in general. Unfortunately chloroform is (for me anyway) very expensive to produce. Would solvents like toluene and dichloromethane work just as well?

Any help or advice would be greatly appreciated

.

[Edited on 20-11-2016 by gluon47]

j_sum1 - 19-11-2016 at 22:28

Chloroform is a doddle to make. Nilered and DougsLab have very good procedures on youtube. I would not let absence of CHCl3 stop you from performing what sounds like an interesting synth.

gluon47 - 19-11-2016 at 22:59

Thanks for the response!

I've tried making chloroform several times using the same reaction as nile red and dougs lab. My yields were absolutely pathetic with 1.5 L of 42g/L bleach producing only 9ml of chloroform! My bleach concentration was lower then the stuff nile red and dougs lab used, but I can't imagine this being the reason for the terrible yields. I would prefer to use chloroform for the reaction, but I just cant get a good enough yield for the process of making it to be cost effective.

Dichloromethane on the other hand, can be very easily and cheaply distilled from paint stripper. If this works just as well, I cant see the point in using absolutely massive amounts of bleach to produce minute amounts of chloroform.

I guess I could try the electrolytic method for producing chloroform, but no one seems to use this method so I figure there's a catch somewhere.

[Edited on 20-11-2016 by gluon47]

violet sin - 19-11-2016 at 23:14

Stronger bleach in pool maintenance supply may be helpful. 10$/gal 10-12.5% depending on the manufacturer. Never done the haloform though, so my knowledge is limited there.

But here is a discussion of a poor run.
http://www.sciencemadness.org/talk/viewthread.php?tid=62909

Good luck

CuReUS - 19-11-2016 at 23:46

you don't have to use CHCl₃,any solvent that will dissolve the adduct will do.Alcohol and dioxane have been used http://chemistry.mdma.ch/hiveboard/methods/000389457.html

j_sum1 - 20-11-2016 at 00:27

You can use calcium hypochlorite as a start material as well -- available as a pool chlorinator. I have tried using it directly but because it forms a sediment at the bottom of the vessel, separation of the chloroform is nigh impossible.

A better procedure is to use Ca(OCl)2 to make our own NaOCl solution by substitution reaction with Na2SO4 and decanting off the liquid. That allows you to get quite high concentration of NaOCl and you are not limited by the concentration of cleaners at your supermarket. And also you get to avoid the detergents and stuff that they inevitably throw in there.

OTOH, if chloroform is just a means to an end then CuReUS' advice sounds good.

gluon47 - 20-11-2016 at 10:36

Thanks all of you for your advice so far.

I think I'll use ethanol as the solvent for the reaction. From what I can tell, it actually seems to perform better then chloroform does.

To quote a post from the page CuReUS linked to

To a solution of 1 mole of hexamethylenetetramine in eight to ten times its weight of hot 95% alcohol slightly more than 1 mole of sodium iodide is added. One mole of the alkyl chloride or bromide is then added and the solution is allowed to stand until the precipitation is complete. The period of precipitation will vary from a few minutes to several weeks depending upon the substance. The longer the carbon chain the longer is the time required for the precipitation. The mixture containing the precipitate is saturated with hydrogen chloride gas, whereupon the precipitate dissolves and ammonium chloride precipitates. When the latter has been filtered off and the alcohol removed by distillation, the resultant impure hydrochloride is converted into the pure amine by distillation with an excess of sodium hydroxide.

This seems pretty good, but there are a few modification I would like to make.

1. Perform the initial reaction under reflux, just how its done with chloroform

2. Instead of using NaI (I don't have any), use a much smaller amount of NaBr. I don't understand why the procedure uses such a large amount of NaI when its purpose is purely catalytic

I could probably try this out next weekend, have I missed anything?

If I ever need chloroform for anything else, maybe I'll try with stronger bleach, thanks for the info.

[Edited on 20-11-2016 by gluon47]

gluon47 - 26-11-2016 at 11:31

I'm performing the reaction. Everything looks good so far. If anyone is interested and if I get any product, I could post a writeup.

aga - 26-11-2016 at 11:38

Definitely post a write up with photos !

A positive or negative result is irrelevant : all the details will be useful.

[Edited on 26-11-2016 by aga]

gluon47 - 26-11-2016 at 11:46

I've been taking plenty of photos along the way. I'll be sure to include them. Thanks!

gluon47 - 26-11-2016 at 22:29

I've attached the write up so I could include images.

I didn't manage to isolate the freebase, but I got some benzylamine hydrochloride.

Attachment: Benzylamine_web.pdf (248kB)
This file has been downloaded 610 times

CuReUS - 26-11-2016 at 23:11

You are correct,you will get some benzaldehyde as by product.You will also get some NH₃ and methylamine as well -http://gallica.bnf.fr/ark:/12148/bpt6k31103/f852.item.zoom

gluon47 - 27-11-2016 at 10:27

yes, I suspected so. Ammonia from the ammonium chloride. Methylamine from the ammonium chloride reacting with formaldehyde

AvBaeyer - 27-11-2016 at 21:17

I have run the Delepine reaction to make benzylamine generally following the procedure described in Organic Synthesis Coll.Vol. 5, p.121. My synthesis went as follows:

Hexamethylenetetramine (15.4 g, 0.11 mol) in chloroform (100 ml) was heated at 55 C to give a clear solution. Benzyl chloride (12.70 g, 0.10 mol) diluted with chloroform (15 ml) was then added dropwise during about 15 minutes. After about 30 minutes a crystalline product began to separate. After 4.5 hours reaction time, the reaction temperature was gradually raised to distill off about 50 ml of chloroform. The reaction mixture was cooled to room temperature then set aside overnight. Filtration gave 24.37 g of white solid after drying. Further concentration of the filtrate provided an additional 2.0 g of solid for a total yield of 26.37 g (99%) of intermediate product. (Note: virtually all the chloroform was recovered.)

The above intermediate was added to denatured ethanol (200 ml) at 35 C to give a slightly hazy solution. Hydrochloric acid (10M, 60 ml) diluted with water (30 ml) was then added and the reaction mixture was stirred at 25 C for 24 hours during which time solid material separated. The reaction was set for distillation to remove solvents. Distillation was discontinued when the head temperature reached 100 C. A total of 220 ml of distillate was collected. The syrupy pot residue mostly solidified on cooling. Water (25 ml) was added and the solid broken up with aid of slight warming. A cooled solution of sodium hydroxide (21 g, 0.52 mol) in water (40 ml) was added in portions with stirring which caused the separation of an oil. A small additional amount of sodium hydroxide was added to bring to pH 13. The cooled mixture was extracted with ether (3 x 25 ml). The combined ether extracts were washed with brine (50 ml) and dried over potassium carbonate. Distillation of the ether left behind a light yellow oil (8.91 g) which was distilled to give benzylamine (bp 39-40 C @ 1.8 mm, 7.47 g, 70% based on benzyl chloride).

Hope this is useful.

AvB

gluon47 - 27-11-2016 at 21:35

Thanks for sharing avbaeyer!

I'll definitely try making some chloroform more efficiently then try to recreate your synthesis. I did find another method for converting benzyl chloride to benzylamine but I really want to use the delepine reaction because its just so much more interesting.

[Edited on 28-11-2016 by gluon47]

gluon47 - 7-12-2016 at 22:02

I've had to change my plans a bit. Although Avbaeyer's write up looked very appealing, I'm currently out of hexamine and making a decent amount of chloroform is next to impossible since I cant find any source of concentrated bleach. I've decided to go with the other route to benzylamine I found http://chemistry.mdma.ch/hiveboard/methods/000399055.html.

To quote:

60g of benzyl chloride, 60 of urea and 40cc of water are refluxed for 5 hours, after which unreacted benzyl chloride is removed by steam distillation. The mixture is then allowed to cool and the crude benzyl urea is removed by filtration. The benzyl urea may be recrystallized from water. Benzyl urea thus obtained has; MP: 142-143°C, Yield: 42g

42g of benzyl urea and 50g of caustic soda are heated together to an internal temperature of the order of 250°C. and the crude benzylamine formed is distilled. The crude benzylamine can be purified by aspirating with nitrogen to remove ammonia and redistilling. Yield: 30g

Only problem is, the first step (preparation of benzylurea) makes no sense to me. Wouldn't benzylurea hydrochloride not free benzylurea be formed since hydrogen chloride is produced as a by product in the reaction?

Perhaps hydrogen chloride is not capable of protonating benzylurea for some reason.

Could someone please explain to me why no benzylurea hydrochloride is produced?

Any help would be greatly appreiciated

.

[Edited on 8-12-2016 by gluon47]

Metacelsus - 8-12-2016 at 05:45

Urea, like other amides, is only weakly basic (pKa of conjugate acid = 0.18). Interestingly, the oxygen will be protonated more readily than the nitrogens (this is due to resonance stabilization of the cation).

The HCl produced is likely distilled away with the water.

[Edited on 12-8-2016 by Metacelsus]

Amos - 8-12-2016 at 07:31

Since most compounds have similar solubility profiles in different chlorinated solvents, you could also try using dichloromethane or even the higher-boiling tetrachloroethylene (brakleen brake parts cleaner in red cans at most department or hardware stores in the US)

gluon47 - 8-12-2016 at 10:39

@Metacelsus thanks for the explanation! the whole thing makes a lot more sense to me now.

@Amos I was actually thinking that dichloromethane might work instead of chloroform. Maybe I'll go ahead and try it out if and when I retry the delepine reaction. Thanks for the suggestion.

I'll give the benzylurea a go once I've made enough benzyl chloride for an attempt. Thanks to both of you for your help

awlb2 - 12-12-2016 at 10:19

Could you perhaps make an ester from methanol and p-toluic acid (methylbenzoic acid). Then perform ammonolysis by addition of ammonia to make methylbenzamide. Then do Hoffman degredation wtih NaOCl to get the benzylamine ?

[Edited on 12-12-2016 by awlb2]

gluon47 - 12-12-2016 at 20:52

That would yield p-methylaniline (p-toluidine) not benzylamine. To make benzylamine this way, you would have to use phenylacetic acid rather then p-toluic acid.

Good thought though, it would certainly be interesting making benzylamine that way

awlb2 - 13-12-2016 at 13:24

Sorry about that mistake I made about what acid should be used. May I ask why are you attempting to make benzylamine: just for fun or will you synthesise other compounds from it or as a motion sickness treatment

. I am excited to hear your results (I am interested in hearing what the physical properties of benzylamine are: particularly smell as this info. is not widely available in detail) and may attempt it myself using methyl phenylethanoate if I can make some.

Well done for succeeding in the synthesis anyway, and nice write-up by the way!

[Edited on 13-12-2016 by awlb2]

gluon47 - 13-12-2016 at 20:03

To answer your question, there's not really any specific use I have for benzylamine, I just find the fact that its a motion sickness drug interesting

.

Currently I'm waiting for some benzyl alcohol I ordered online to arrive. Once I have that, I can make more benzyl chloride and try the other route to benzylamine. I'll post my results.

Thanks, my synthesis didn't exactly succeed but I certainly had a lot of fun and I hope I'll be able to try It again some time.

And good luck if you try the hoffman degradation route with phenylacetic acid. You wouldn't have to deal with benzyl chloride, that's a plus

.

[Edited on 14-12-2016 by gluon47]

CuReUS - 18-12-2016 at 00:37

gluon,when you have some benzyl chloride,could you try making benzylamine using Magnesium nitride ?
mix the Mg₃N₂ with benzyl chloride and drip the mixture slowly into a beaker of water.The Mg₃N₂ reacts with the water to form NH₃ which then reacts with the benzyl chloride to form benzylamine.And the best thing is that benzylamine is soluble in water whereas benzylchloride is not,so after the reaction the unreacted benzylchoride forms a separate later which can be removed via a separating funnel.

gluon47 - 19-12-2016 at 22:32

Wow, that sounds interesting, magnesium nitride far out!

However if the magnesium nitride forms ammonia in situ, I can't see it being any better then using ammonia directly. A massive excess of ammonia is required, otherwise large amounts of dibenzyl and tribenzylamine also form resulting in an extremely pour yield of benzylamine. This is why I didn't want to try using ammonia directly.

I might give it a go eventually, but I won't to try the method starting from urea first.

It certainly seems like a very interesting method, thanks for bringing it up

.

[Edited on 20-12-2016 by gluon47]

CuReUS - 20-12-2016 at 00:36

Quote: Originally posted by gluon47

However if the magnesium nitride forms ammonia in situ, I can't see it being any better then using ammonia directly.

because NH₃ is a stinky gas and a watched chemical.

Quote:

A massive excess of ammonia is required, otherwise large amounts of dibenzyl and tribenzylamine also form resulting in an extremely pour yield of benzylamine.

That's why I suggested adding the benzyl halide slowly instead of dumping it all in at once.Also don't forget the biphasic system in play.The moment the benzyl amine forms,it moves to the water layer,out of reach of any other benzyl halide

Another way to run the reaction,in case the nitride and benzyl halide don't mix, would be to mix Mg₃N₂ and IPA in a beaker and drip in a solution of benzyl halide and MeOH.Also,try using benzyl bromide instead of benzyl chloride.

gluon47 - 20-12-2016 at 10:31

OK, you've convinced me CuReUS. If I can make some magnesium nitride, I will probably give it a go.

There are a few other methods I would like to explore first though.

Mg3N2 looks very easy to prepare http://www.prepchem.com/synthesis-of-magnesium-nitride/

[Edited on 20-12-2016 by gluon47]

[Edited on 20-12-2016 by gluon47]

gluon47 - 21-1-2017 at 20:19

Quote: Originally posted by gluon47

60g of benzyl chloride, 60 of urea and 40cc of water are refluxed for 5 hours, after which unreacted benzyl chloride is removed by steam distillation. The mixture is then allowed to cool and the crude benzyl urea is removed by filtration. The benzyl urea may be recrystallized from water. Benzyl urea thus obtained has; MP: 142-143°C, Yield: 42g
[Edited on 8-12-2016 by gluon47]

I'm halfway through making some benzylurea at the moment. Looks good so far!

Here's a picture of the crystalline benzylurea separating after the reflux.
Due to the tragic necessity to sleep, I cannot continue for another 8 hours or so

.

At some point, I hope to post a write up.

[Edited on 22-1-2017 by gluon47]

gluon47 - 22-1-2017 at 22:08

Here is the final benzylurea product after recrystallization.

Will test the melting point to determine purity. I think I'll try making benzylurea a couple more times before I properly present my results though as the workup is a little messy and I believe I can make some improvements.

All that needs to be done now is to distill the benzylurea with sodium hydroxide and with a bit of luck, I'll get some benzylamine!