Sciencemadness Discussion Board - Chlorination of Alkylamines to Nitrogen Mustards

Chlorination of Alkylamines to Nitrogen Mustards

DDTea - 29-12-2003 at 23:23

Nitrogen Mustards are Chlorinated derivatives of Alkylamines. Examples of potential amines to be chlorinated are Diethanolamine and Triethanolamine, but there are a few others.

From looking at E&W Archives, where I originally asked a very broad question concerning Nitrogen Mustards, NBK responded that the Chlorination of the Alkylamine is usually done with Thionyl Chloride in Trichloroethylene. The only truly difficult precursor to obtain is Thionyl Chloride. Trichloroethylene is readily available in hardware stores, and TEA is a bit more difficult, but far from impossible-- it has legitimate uses.

There are dozens of ways to Chlorinate, though. Surely there are ways to accomplish this particulary Chlorination. If one were to use the most readily available precursor amine, Triethanolamine ( (HO-C2H2)3-N ), the task at hand is to replace the three -OH groups with a -Cl, to synthesize HN-3. The trick is to find an alternative to Thionyl Chloride.

I imagine the reaction with Thionyl Chloride is as follows:

2 (C2H2OH)3-N + 3 SOCl2 --> 2 (C2H2Cl)3-N + 3 H2SO2

Could Chlorine gas, in the presence of Red Phosphorus, work? Or, instead of Red Phosphorus, Sulfur, the way Alkyl Halides are made? The Chlorine could be generated electrolytically, in the presence of UV light.

[Edited on 1-2-04 by Samosa]

blip - 31-12-2003 at 16:18

Thionyl chloride is present in some batteries in conjuction with lithium metal. Just search Google for "SOCl2".

[Edit: Typed smiley wrong.

]

[Edited on 1-1-2004 by blip]

DDTea - 31-12-2003 at 17:07

Well, that solves the problem of Thionyl Chloride. However, Lithium batteries can be very costly; and even with the small lab-amounts of Thionyl Chloride and Nitrogen Mustard that we'd want to work with, Lithium batteries may drive the price higher than it has to be.

Another solution, which completely slipped my mind as I wrote the original thread, is Sulfuryl Chloride; as produced by SO3 and HCl (thanks to the other recent post where this was mentioned). Sulfuryl Chloride is very similar to Thionyl Chloride, in that their formulas are SO2Cl2 and SOCl2, respectively. So, the reaction with Sulfuryl Chloride would be:

2 (C2H2OH)3-N + 3 SO2Cl2 --> 2 (C2H2Cl)3-N + 3 H2SO4

[Edited on 1-2-04 by Samosa]

Darkfire - 31-12-2003 at 17:25

Has anyone ever called you a crazy SOB Samosa?

DDTea - 31-12-2003 at 19:20

"There is no genius without some mixture of madness." - Seneca the Younger

Know what Darkfire? You really have made me stop and think a bit, just about the dangers of HN and such. You brought me back down to Earth again, and made me realize that I am a human, and that Nitrogen Mustards are designed to attack humans. Of course, what I'm discussing here is just the synthesis-- or at least, the sticking point in the synthesis. Beyond the lab glassware, the equipment, and the precursors, there will no doubt we dozens and dozens of safety precautions-- gas masks, full Chemical Protective suits, decontamination equipment, emergency dumping setups, etc... But, we speak about synthesis at the moment

The dangers are no greater than making Nitroglycerin or Acetone Peroxide, in my humble opinion-- just different. AP may explode because you touched it the wrong way, and it could permanently disable a man by removing a digit, blinding him, deafening him, or throwing sharpened projectiles that may cause nerve damage. Care and common-sense are a given with our hobby, because it is, very often, the more dangerous things that are the most interesting.

That is how it is for me-- things are relative, you see. Before, I used to be amazed by mixing Ammonia and Bleach and watching Chloramine fumes bubble up, or by the stinging power of Chlorine (from HCl and NaOCl)... but now, with my eyes focused on "stronger" chemicals (CX, HN, HCN, TEPP, etc...), Chlorine does not scare me at all. In fact, neither do NaOH (i used to be afraid of this, after it burned me), HCl gas, or even HF-- you just have to treat them with respect, and know their "personalities." This is the nature of our beast-- "mad science."

Anyhow, enough of that. Back to Chlorination of Alkylamines! Do you suppose Thionyl Chloride could be prepared by reacting SO2 (as produced by burning Sulfur) with dried HCl; much the same way Sulfuryl Chloride is prepared?

And yes, I have been called a crazy SOB a few times before

[Edited on 1-1-04 by Samosa]

[Edited on 1-2-04 by Samosa]

Darkfire - 31-12-2003 at 20:10

Im just messing with you man, in all honesty your my favorite poster on this board, in a totaly macho guy way haha

Mumbles - 1-1-2004 at 09:43

I'm pretty sure Thionyl Chloride can be made from SO2 and HCl. Water is the other product though, and water hydrolises Thionyl chloride. Perhaps running the gaseous products through a drying tube and condensing. Well, I'm assuming this could be done in a heated environment.

I'd probably go with SCl2 (or S2Cl2) and SO3 if I were to go about making it.

guaguanco - 1-1-2004 at 14:54

Quote:

Another solution, which completely slipped my mind as I wrote the original thread, is Sulfuryl Chloride; as produced by SO3 and HCl (thanks to the other recent post where this was mentioned). Sulfuryl Chloride is very similar to Thionyl Chloride, in that their formulas are SO2Cl2 and SOCl2, respectively. So, the reaction with Sulfuryl Chloride would be:

(C2H2OH)3-N + 3 SO2Cl2 --> (C2H2Cl)3-N + H2SO4

[Edited on 1-1-04 by Samosa]

You might want to think about competing dehydration/etherification reactions with SO2Cl2, and how to rule them out.
Also, assuming you had some SOCl2 and you reacted it with N(C2H4OH)3. How would you verify that you had actually produced what you expected?

DDTea - 1-1-2004 at 15:44

Well, the "ouch test" is always a possibility

More practically, though, qualitative analysis of the resulting compound would determine if it is the desired product. HN-3 is a yellow-brown liquid with pH of 4.2 at 25*C, whereas Triethanolamine has a pH of 7.3 - 7.7. It freezes at -4*C, and unlike TEA it is completely insoluble in Water (whereas TEA is miscible).

Sulfuryl Chloride tends to act as chlorinating agent. For example, it reacts with Benzene to form Chlorobenzene, with Acetone to form mono- and di-chloroacetones. This is from War Gases again, btw.

I'm assuming the main reaction would be chlorination, as Sulfuryl Chloride breaks down into SO2 and Cl2 quit easily.

guaguanco - 1-1-2004 at 21:02

Quote:

Originally posted by Samosa
Well, the "ouch test" is always a possibility

It's possible that SO2Cl2 would work, I don't know. SOCl2 is preferable because it's a lot cleaner: as soon as the initial OH - Cl exchange happens, the SO2 and HCl exit the reaction. With an excess of SO2Cl2, as the reaction progesses you'll have a pot containing Chlorosulfonic acid and Sulfuric Acid. I would expect significant side reactions, but I have no hard facts.
I recommend against the 'ouch' test.
I personally hope you veer away from this reaction, since the nitrogen mustards are not only powerful vesicants but are really toxic to all tissues, cause hair to fall out, major blood damage etc etc. Dosages used in chemotherapy are really small and still have really severe side effects. But it's your call, of course.
You're probably going to end up with a yellow-to-brown-to-black crude reaction mixture, especially if you don't start with really pure triethanolamine. Before you start jockeying this stuff around (as you try to to qualitatively determine that you actually created the stuff), you should be certain you have a really foolproof, absolutely safe method of destroying all traces of this stuff on your glassware, stirrers etc. You can't just throw this stuff away in any form!
Frankly, if I found out my nextdoor neighbor was screwing around with nitrogen mustards, I'd call the cops in a heartbeat.

I understand that you're mostly just speculating and theorizing.

unionised - 3-1-2004 at 08:55

There is an important difference between the hazards of explosives and these chemicals. The explosives won't (generally) kill you from cancer in 20 years.

[Edited on 3-1-2004 by unionised]

DDTea - 3-1-2004 at 12:51

We're talking Nitrogen Mustards here, I should stress-- Nitrogen Mustards are less toxic than Sulfur Mustard. Though it is "anticipated" to be a Carcinogen, it is not as potent one as Sulfur Mustard. As such, Nitrogen Mustards lend themselves to such uses as Chemotherapy ("Mustargen"

.

Oh, and just to say it-- the "ouch test" does have some uses. It is one of the best tests for Chloropicrin, and probably any potent lachrymator with a decent safety margin. But, it is not a valid test in this case

unionised - 4-1-2004 at 11:59

Being used as a drug does not rule out carcinogenicity. They may well be less likely to cause cancer than the sulphur mustards. I still think it's an important difference between explosives and nitrogen mustards.

guaguanco - 4-1-2004 at 14:13

Quote:

Originally posted by Samosa
We're talking Nitrogen Mustards here, I should stress-- Nitrogen Mustards are less toxic than Sulfur Mustard. Though it is "anticipated" to be a Carcinogen, it is not as potent one as Sulfur Mustard. As such, Nitrogen Mustards lend themselves to such uses as Chemotherapy ("Mustargen"

I suspect the distinction here is:
sulfur mustard: really, really, really, really nasty
nitrogen mustard: really, really, really nasty

unionised - 4-1-2004 at 15:45

Nicely put.

Thyionyl Chloride

Purple Haze - 9-1-2004 at 10:13

Actually I think that SO2+2HCl=H2O2+SCl

This could be your answer,although i wouldn't
want to have much of this stuff kicking
around.In Canada it is illegal to manufacture
or possess under the Chemical Weapons
Convention Implementation Act.

6. No person shall
(c)engage in any military preparations to
use a chemical weapon;
or
d) assist, encourage or induce,in any way,
anyone to engage in any activity prohibited
to a State Party under the Convention.
8.(1)Except as authorized by or pursuant to
any regulations made under paragraph 18(a),
no person shall produce, use, acquire or
possess a toxic chemical or precursor listed
in Schedule 1 of the
Schedules of Chemicals set out in the Annex
on Chemicals in the Convention.
(2) Except as authorized under the Export
and Import Permits Act, no person shall
export or import a toxic chemical or
precursor listed in Schedule 1 of the
Schedules of Chemicals set out in the
Annex on Chemicals in the Convention.
9. Except as authorized under the Export and
Import Permits Act, no person shall export or
import a toxic chemical or precursor listed
in Schedule 2 of the Schedules of Chemicals
set out in the Annex on Chemicals in the
Convention.
Schedule 1 (CAS registry number)

A. Toxic chemicals:
(1) O-Alkyl (<=C10, incl. cycloalkyl)alkyl
(Me, Et, n-Pr or i-Pr)-phosphonofluoridates
e.g. Sarin: O-Isopropyl methylphosphonofluoridate (107-44-8)

Soman: O-Pinacolyl methylphosphonofluoridate (96-64-0)

(2) O-Alkyl (<=C10, incl. cycloalkyl) N,N-dialkyl

(Me, Et, n-Pr or i-Pr) phosphoramidocyanidates

e.g. Tabun: O-Ethyl N,N-dimethyl

phosphoramidocyanidate (77-81-6)

(3) O-Alkyl (H or <=C10, incl. cycloalkyl) S-2-dialkyl

(Me, Et, n-Pr or i-Pr)-aminoethyl alkyl

(Me, Et, n-Pr or i-Pr) phosphonothiolates and

corresponding alkylated or protonated salts

e.g. VX: O-Ethyl S-2-diisopropylaminoethyl

methyl phosphonothiolate (50782-69-9)

(4) Sulfur mustards:

2-Chloroethylchloromethylsulfide (2625-76-5)

Mustard gas: Bis(2-chloroethyl)sulfide (505-60-2)

Bis(2-chloroethylthio)methane (63869-13-6)

Sesquimustard: 1,2-Bis(2-chloroethylthio)ethane (3563-36-8)

1,3-Bis(2-chloroethylthio)-n-propane (63905-10-2)

1,4-Bis(2-chloroethylthio)-n-butane (142868-93-7)

1,5-Bis(2-chloroethylthio)-n-pentane (142868-94-8)

Bis(2-chloroethylthiomethyl)ether (63918-90-1)

O-Mustard: Bis(2-chloroethylthioethyl)ether (63918-89-8)

(5) Lewisites:

Lewisite 1: 2-Chlorovinyldichloroarsine (541-25-3)

Lewisite 2: Bis(2-chlorovinyl)chloroarsine (40334-69-8)

Lewisite 3: Tris(2-chlorovinyl)arsine (40334-70-1)

(6) Nitrogen mustards:

HN1: Bis(2-chloroethyl)ethylamine (538-07-8)

HN2: Bis(2-chloroethyl)methylamine (51-75-2)

HN3: Tris(2-chloroethyl)amine (555-77-1)

(7) Saxitoxin (35523-89-8)

(8) Ricin (9009-86-3)

B. Precursors:

(9) Alkyl (Me, Et, n-Pr or i-Pr) phosphonyldifluorides

e.g. DF: Methylphosphonyldifluoride (676-99-3)

(10) O-Alkyl (H or <=C10, incl. cycloalkyl) O-2-dialkyl

(Me, Et, n-Pr or i-Pr)-aminoethyl alkyl

(Me, Et, n-Pr or i-Pr) phosphonites and

corresponding alkylated or protonated salts

e.g. QL: O-Ethyl O-2-diisopropylaminoethyl

methylphosphonite (57856-11-8)

(11) Chlorosarin: O-Isopropyl methylphosphonochlo-

ridate (1445-76-7)

(12) Chlorosoman: O-Pinacolyl methylphosphonochlo-

ridate (7040-57-5)

Schedule 2

A. Toxic chemicals:

(1) Amiton: O,O-Diethyl S-[2-(diethylamino)ethyl]

phosphorothiolate (78-53-5)

and corresponding alkylated or protonated salts

(2) PFIB: 1,1,3,3,3-Pentafluoro-2-(trifluoromethyl)-1-

propene (382-21-8)

(3) BZ: 3-Quinuclidinyl benzilate (*) (6581-06-2)

B. Precursors:

(4) Chemicals, except for those listed in Schedule 1,

containing a phosphorus atom to which is bonded

one methyl, ethyl or propyl (normal or iso) group but

not further carbon atoms,

e.g. Methylphosphonyl dichloride (676-97-1)

Dimethyl methylphosphonate (756-79-6)

Exemption: Fonofos: O-Ethyl S-phenyl

ethylphosphonothiolothionate (944-22-9)

(5) N,N-Dialkyl (Me, Et, n-Pr or i-Pr) phosphoramidic

dihalides

(6) Dialkyl (Me, Et, n-Pr or i-Pr) N,N-dialkyl

(Me, Et, n-Pr or i-Pr)-phosphoramidates

(7) Arsenic trichloride (7784-34-1)

(8) 2,2-Diphenyl-2-hydroxyacetic acid (76-93-7)

(9) Quinuclidin-3-ol (1619-34-7)

(10) N,N-Dialkyl (Me, Et, n-Pr or i-Pr) aminoethyl-2-chlorides

and corresponding protonated salts

(11) N,N-Dialkyl (Me, Et, n-Pr or i-Pr) aminoethane-2-ols

and corresponding protonated salts

Exemptions: N,N-Dimethylaminoethanol (108-01-0)

and corresponding protonated salts

N,N-Diethylaminoethanol (100-37-8)

and corresponding protonated salts

(12) N,N-Dialkyl (Me, Et, n-Pr or i-Pr) aminoethane-2-thiols

and corresponding protonated salts

(13) Thiodiglycol: Bis(2-hydroxyethyl)sulfide (111-48-8)

(14) Pinacolyl alcohol: 3,3-Dimethylbutan-2-ol (464-07-3)

Schedule 3

A. Toxic chemicals:

(1) Phosgene: Carbonyl dichloride (75-44-5)

(2) Cyanogen chloride (506-77-4)

(3) Hydrogen cyanide (74-90-8)

(4) Chloropicrin: Trichloronitromethane (76-06-2)

B. Precursors:

(5) Phosphorus oxychloride (10025-87-3)

(6) Phosphorus trichloride (7719-12-2)

(7) Phosphorus pentachloride (10026-13-8)

(8) Trimethyl phosphite (121-45-9)

(9) Triethyl phosphite (122-52-1)

(10) Dimethyl phosphite (868-85-9)

(11) Diethyl phosphite (762-04-9)

(12) Sulfur monochloride (10025-67-9)

(13) Sulfur dichloride (10545-99-0)

(14) Thionyl chloride (7719-09-7)

(15) Ethyldiethanolamine (139-87-7)

(16) Methyldiethanolamine (105-59-9)

(17) Triethanolamine (102-71-6)

Theoretic - 9-1-2004 at 10:43

"Actually I think that SO2+2HCl=H2O2+SCl"
No. That, and it's not balanced.

DDTea - 9-1-2004 at 11:50

One thing I love about the CWC is that it does not ban Phosgene Oxime, at least specifically

. Also, Triethanolamine is listed as a scheule 3 chemical, but it's readily available to soapmakers-- amateur or otherwise.

No doubt, Nitrogen Mustards are considered Chemical Weapons by anyone. As such, unless someone cares to become an individual chemical power, it is unlikely they would need to produce bulk quantities. Then there's the issue of weaponization, munitions, and dispersal. So, personally, i wouldn't consider lab sized quantities of a toxic chemical to be a "Chemical Weapon"-- just a toxic chemical; just like a few grams of Uranium is not considered a "Nuclear Weapon."

I'm not sure how well SCl2 would work for chlorinating Triethanolamine since I simply have not heard anything of it... I would say it's better used to generate Sulfur Mustard by reaction with Ethylene gas (which is another very simple preparation).

On that note, I have plenty of some sulfur allotrope (the purplish-black sulfur..is that S8?) lying around from a summer job...they were throwing so much of it away, that I couldn't help but reclaim some from a pile of cement cylindars in back. Could this perhaps be turned into SCl2 by addition of Chlorine gas? I am thinking this because I've heard Sulfur can be substituted for P in some halogenation reactions, such as to produce Methyl Iodidei...in effect, or at least I think, forming Sulfur halides in situ.

hinz - 6-5-2005 at 13:47

I'm also interested in HN-3, I thought about this synthesis.

NH3 + 3 HO-CH2-CH2-OH ==> (HO-CH2-CH2)3 N + 3 H2O

Normally this step would be done with ethene oxide instead of HO-CH2-CH2-OH, but I don't have it yet, so I'll try it with ethylene glycol. In my organic preparation book it's written that trietylamine (CH3-CH2)3 N is made by reaction of NH3 with 3 EtOH, so I think it will also work with ethylene glycol to yield triethanolamine.

I think, the chlorination could be done with HCl, because refering to Mario Sartori's ''War Gases'' ( It's a good book in the library, thanks !) the thiodiglycol is also chlorinated (German process) with HCl.

S(CH2-CH2-OH)2 + 2 HCl ==> S(CH2-CH2-Cl)2 + 2 H2O

The water is later removed by vaccum destillation.

[Edited on 7-5-2005 by hinz]

DDTea - 19-5-2005 at 01:46

If you have Ethylene Glycol, you have a route to Ethyle Oxide

. If I'm not mistaken, Ethylene Oxide is made from Ethyle Chlorohydrin--which, in turn, IS made from Ethylene Glycol:

HO-CH2CH2-OH + HCl --> Cl-CH2CH2-OH + H2O

The reaction is between the vapors of Ethylene Glycol and Hydrogen Chloride gas.
From there, the reaction between Sodium Hydroxide and Ethylene Chlorohydrin will yield Ethylene Oxide... I *think* it goes as such:

Cl-CH2CH2-OH + NaOH --> CH2CH2O + H2O + NaCl

Anyhow, the trouble with chlorinating triethanolamine with Hydrochloric Acid is that Amines are organic bases. As you know, reactions between acids and bases form salts... So the primary product will merely be Triethanolamine Hydrochloride. It may or may not be possible to chlorinate that further with HCl, but I don't know.

So what is needed is something that chlorinates the pesky Hydroxyl groups right away.

And on that note, what about Trichlorisocyanurate, as from pool stores?? It's an Acyl Chloride with 3 Chlorine atoms per molecule (as would be needed in chlorinating Triethanolamine). Aren't Acyl Chlorides good chlorinating agents? Or is there another reaction between these two chemicals that I'm not seeing?