Sciencemadness Discussion Board

n chloro butylamine

mr_bovinejony - 27-5-2024 at 01:01

I've been searching for a while but can't find anything about making a chloramine, specifically from hypochlorite and butylamine, that isn't di chlorinated to some extent. Is this just a product I have to accept and remove somehow or is there some way to only mono chlorinate? The mono chlorinated product can be cyclized into pyrrolidine, separation can probably be best achieved at this step.

[Edited on 27-5-2024 by mr_bovinejony]

bnull - 27-5-2024 at 05:32

What about protecting the amino group? Protection would reduce reactivity and leave only one hydrogen to be attacked. A protecting group that is removed only in acidic conditions, such as triphenylmethyl, may work.

mr_bovinejony - 27-5-2024 at 05:59

Interesting idea, the trityl group looks huge though. I wonder how sterics would affect that. Cbz and boc are the only groups I'm familiar with

Keras - 27-5-2024 at 06:51

If you have acetic anhydride, you can use it to produce an actylamine, that you can then chlorinate, and then remove the acetyl group by hydrolysis?

[EDIT: Might not work for aliphatic amines, though.]

[Edited on 27-5-2024 by Keras]

bnull - 27-5-2024 at 06:58

BOC looks better. Or maybe you can make an amide. Trityl could end up being chlorinated too; a naphthalene oxidation to phthalic acid using hypochlorite gave me lots of chloronaphthalene and next to zero phthalic acid.

What about TCCA in place of hypochlorite?

Your N-chlorobutylamine is a little hard to find, as a matter of fact. Did you try patents?

mr_bovinejony - 27-5-2024 at 07:45

I haven't looked into tcca but chlorination with gaseous chlorine and uv chlorinated the chain somewhere, I assumed tcca would do the same like it does in other reactions.

I've tried patents and even looked for other mono chloramines but no luck.

Page 445 of the hilgetag book preparation organic chemistry has some references I'm interested in but they're all old as shit or not in English sadly

https://scholarworks.uni.edu/cgi/viewcontent.cgi?article=409...

Here's the amide being used but can't find a synthesis for it. Chloroacetamide then alkylation with butyl bromide?

[Edited on 27-5-2024 by mr_bovinejony]

bnull - 27-5-2024 at 08:50

I read the section "N-Halo-de-hydrogenation" from March's Advanced Organic Chemistry (7th), pages 729-730. Reference 760 seems to be what you want: De Luca, Giacomelli and Nieddu, "A Simple Protocol for Efficient N-Chlorination of Amides and Carbamates".

haloamines.png - 39kB
Quote:

Typical Procedure for the Preparation of N-Chloroamides.
Trichloroisocyanuric acid (5.25 mmol) was added at 0 °C to a well stirred solution of the amide (5 mmol) in CH2Cl2 (30 mL) and the mixture was kept at r.t. for the required time, monitoring (TLC) till completion. Then the mixture was filtered on Celite and the solution evaporated under reduced pressure affording the N-chloro derivative.


Protect it as amide, chlorinate it, then deprotect it.

Attachment: s-2004-836061.pdf (94kB)
This file has been downloaded 131 times

Edit: So you're after pyrrolidine. Why didn't you say it before?

You could also try electrolysis of a solution of sodium chloride in waterNote. Butylamine is slowly added close to the anode. You would have to calculate how much current and time.

There is this paper: Lyalin, B.V., Petrosyan, V.A. Developing Principles for an Electrochemical Low-Waste Production of Chloramines T, B, and KhB. Russ J Electrochem 36, 1246–1256 (2000).

Note: It was one of my procedures to make chloronaphthalenes. Why do I keep having ideas after editing?

Edit2: Editing again. Do you think you can chlorinate butylamine to 4-chlorobutyl-1-amine? This way you could close the ring by dehydrohalogenation with, say, alcoholic KOH or sodium ethoxide.

[Edited on 27-5-2024 by bnull]

mr_bovinejony - 27-5-2024 at 15:51

Is it not mentioned in the first post that pyrrolidine is made this way? Here is the chlorination paper, not very selective though

https://pubs.acs.org/doi/pdf/10.1021/ja01148a024

Alright so if I understand this correctly acetic anhydride reacts with butylamine, then tcca voodoo, then hydrolysis.
@Keras why do you think this might not work with aliphatic amines?

[Edited on 28-5-2024 by mr_bovinejony]

bnull - 28-5-2024 at 03:04

Quote: Originally posted by mr_bovinejony  
Is it not mentioned in the first post that pyrrolidine is made this way?

No. You wrote
Quote:
The mono chlorinated product can be cyclized into pyrrolidine,

which is not the same as
Quote:
I want to cyclize the mono chlorinated product into pyrrolidine.

I'm being pedantic. Anyway.

Pyrrolidine can be made the other way around, with the chlorine atom in the other extreme of the molecule. From March's same book as above, page 482:
Quote:
Thus, 4-chloro-1-aminobutane treated with base gives pyrrolidine.

Assuming that this is the way pyrrolidine is made, I searched for anything about chlorination of aliphatic amines. I found this patent: US2763610, "Aliphatic Chain Chlorination of Amine Hydrochlorides". I suppose you can use a solvent other than carbon tetrachloride.

On the other hand, March's, pages 1426-1427, describe the Hofmann-Löffler reaction, which explains why you want the N-chloro-n-butylamine. It goes
Quote:
When N-haloamines in which one alkyl group has a hydrogen in the 4 or 5 position are heated with sulfuric acid, pyrrolidines, or piperidines are formed, in a reaction known as the Hofmann–Löffler reaction (also called the Hofmann–Löffler–Freytag reaction). The R' group is normally alkyl, but the reaction has been extended to R' = H by the use of concentrated sulfuric acid solution and ferrous salts.925 The first step of the reaction is a rearrangement, with the halogen migrating from the nitrogen to the 4 or 5 position of the alkyl group. It is possible to isolate the resulting haloamine salt, but usually this is not done, and the second step, the ring closure (Reaction 10-31), takes place.

hofmann-loffler.png - 21kB

Reference 925 is Schmitz and Murawski's paper, which is in German and is also given in page 445 of Hilgetag's book.

In both cases, the chlorine ends up in the extreme of the aliphatic chain.

Not yet satisfied as to the process, I read Schmitz and Murawski's paper. They forward a reference on the preparation of N-chloro-alkylamines: Schmitz and Schinkowski, "Diaziridine VI. Synthese von N.N’-Dialkyl-hydrazinen über Diaziridine". The preparation is buried in page 8 under "Beschreibung der Versuche". My German is horrible, but here is a translation (corrected by @EF2000, thank you again) with the original below, and the link to the cursed paper.
Quote:
N-Chloro-alkylamine: 1 mol of a 10-20% solution of the primary amine in water is cooled in a salt/crushed ice bath. 0.9 mol of a 1.5 mol/L of sodium hypochlorite (11%, I believe) is added to the amine solution under stirring during 5-10 minutes. The solution is extracted with ether, in the case of N-chloro-metilamine several times, and dried with potassium carbonate. The yield, as given by iodometry, is 90-98% of the theoretical.

Quote:
N-Chlor-alkylamine: 1 Mol einer 10-20-proz. wässrigen Lösung des primären Amins wurde unter Eis/Kochsalz-Kühlung und Rühren innerhalb von 5-10 Min. mit 0.9 Mol einer ca. 1.5 molaren Natriumhypochlorit-Lösung versetzt. Man ätherte aus, beim N-Chlor-methylamin mehrmals, und trocknete mit Kaliumcarbonat. Die jodometrisch bestimmten Ausbeuten an N-Chlor-alkylaminen betrugen 90-98 % d. Th.

I would appreciate if someone could correct the translation. Or convert from equivalents to mass or volumes because I suck at this.

Edit: @EF2000: Thank you very much. I was wondering why one should wash the product with N-chloro-methylamine. I'll fix the translation.

[Edited on 28-5-2024 by bnull]

EF2000 - 28-5-2024 at 08:21

Quote: Originally posted by bnull  

Not yet satisfied as to the process, I read Schmitz and Murawski's paper. They forward a reference on the preparation of N-chloro-alkylamines: Schmitz and Schinkowski, "Diaziridine VI. Synthese von N.N’-Dialkyl-hydrazinen über Diaziridine". The preparation is buried in page 8 under "Beschreibung der Versuche". My German is horrible, but here is a free translation with the original below, and the link to the cursed paper.
Quote:
N-Chloro-alkylamine: 1 equivalent of a 10-20% solution of the primary amine in water is cooled in a salt/crushed ice bath. 0.9 equivalent of a 1.5 mol/L of sodium hypochlorite (11%, I believe) is added to the amine solution under stirring during 5-10 minutes. The solution is etherified, then the product is washed several times with N-chloro-metilamine, and dried with potassium carbonate. The yield, as given by iodometry, is 90-98% of the theoretical.

Quote:
N-Chlor-alkylamine: 1 Mol einer 10-20-proz. wässrigen Lösung des primären Amins wurde unter Eis/Kochsalz-Kühlung und Rühren innerhalb von 5-10 Min. mit 0.9 Mol einer ca. 1.5 molaren Natriumhypochlorit-Lösung versetzt. Man ätherte aus, beim N-Chlor-methylamin mehrmals, und trocknete mit Kaliumcarbonat. Die jodometrisch bestimmten Ausbeuten an N-Chlor-alkylaminen betrugen 90-98 % d. Th.

I would appreciate if someone could correct the translation. Or convert from equivalents to mass or volumes because I suck at this.

One small correction: "Mol" is mole, equivalent is "Val". (Equivalence factor here is 1/1 anyway).

If primary amine is n-butylamine then one needs 73 grams of n-butylamine (730-365 g of 10-20% solution). And 600 ml of 10% sodium hypochlorite solution.

Another correction: the second sentence should be "The solution was etherified [extracted with ether, richtig?], in the case of N-chloromethylamine several times, and dried with potassium carbonate."
The synthesis of N-chloromethylamine required several extractions with ether, perhaps because it is more soluble in water.
So one doesn't need to wash one chloramine product with another chloramine, zum Glück.


[Edited on 28-5-2024 by EF2000]

mr_bovinejony - 28-5-2024 at 09:59

Thank you very much for all your help. I looked into the hoffman-loffler as well when I read it in hilgetag, hoping it was useful for 6 and 7 membered rings. But I may go 4 chloro butylamine instead, I have come across a few mentions that chloramines are not the nicest things to work with. Decomposition, sometimes explosively, has been known to happen.