Introduction to "Novichok" Agents

While doing some research on the internet concerning Novichok agents, I came across an unusually informative review on Amazon.com for the Handbook of Chemical and Biological Warfare Agents. Being rather impressed by the liberal use of references and detailed information, including some formulas, I took it upon myself to edit the review (rephrased some things; basically put it in better English, since it was written by a Russian) and took the time to draw the formulas in MS Paint. I will not bother linking to the review itself, but will instead include my "improved" version, in MS Word form. It serves as a useful introduction to the "Novichok" series of Nerve Agents, and includes useful references (I suspect most are written in Russian..). I don't know if this is any new information to you, but it was new to me

Attachment: Novichoks, Dusty Agents, GV and GP agents.doc (38kB)
This file has been downloaded 7841 times

Just from looking at the structure of these agents, my guess to precursors are Phosphorus Oxychloride, Phosgene Oxime, some Fluorinating agent, and maybe Ethylene Chlorohydrin (looking at the second Novichok structure). The only other question is how to get the third group attached to the central Phosphorus-- the C-CC-X .

My guess is the synthesis would look something like this...I'm just throwing out ideas now to get discussion

HON=C(Cl2) + F --> HON=C(Cl)F + Cl

O=PCl3 + HON=C(Cl)F --> O=PCl2(-ON=C(Cl)F ) + HCl

O=PCl2(-ON=C(Cl)F) + HO-C2-Cl --> O=PCl(-ON=C(Cl)F)(-O-C2-Cl) + HCl

I'm thinking along the lines of the simple Tabun synthesis using Phosphorus Oxychloride, where the various groups are simply attached as shown above, with HCl or NaCl being the usual side-products. Following this logic, this could perhaps be a "simple" Novichok agent whose synthesis should not be much more complex than any G-Agent's:

O=P(-O-CC-Cl)(-O-N=C(Cl)(F))F

Another aspect of Novichoks worth noting are the unsaturated and halogenated side-chains. Perhaps this could explain their special toxicity, because they allow for multiple leaving-groups. However, I don't believe the Dihaloformaldoxime group is an active group--but rather a "stabilizing" group (I just made that term up, but it gets the point across).

One thing that is often brought up about treatment of Nerve Agent poisoning with Oximes-- the threat of forming highly toxic Phosphorylated Oximes. So to me, it looks like the Novichok agents play on this, but at the same time prevent Oxime treatment (as there is already an Oxime group attached).

What I am wondering is why two different halogens are used on the Dihaloformaldoxime group. Do you think that they are trying to take advantage of the difference in reactivities of the halogens, whereas if there is a F along side the Cl, the Cl may more readily react?

It wouldn't surprise me with the numbers of accidents the USSR has had-- Chernobyl, that Anthrax release, etc. I haven't heard of a nerve agent release, however...but if it did occur, the Russians would most likely cover it up. They were very secretive about their military, and they still are; and this makes it all the more difficult to get meaningful information about Novichok agents.

I am wondering, however: are there any Russian-speaking members on this forum, who would not mind doing a bit of translating of some of the books mentioned in the above Word file? Or, maybe give a list of useful words in Russian related to Novichok research...i.e.: the Cyrillic spelling for Novichok itself ( i believe it would be pronounced 'No-wee-shock', to at least allow us to do Google Searches? From there, we can easily Babelfish any Russian results.

I guess that is what we call good research . I am wondering--were most of your sources in English, or were much of them in German or Russian? I am having a hard time finding much in English, but if you feel like using it, the Russian word for "Novichok" is " Hoвичoк ," courtesy of my Russian friend . It is a rather common word, meaning "Rookie" or "New-Guy" , so you may get a lot of junk results. I guess I'll have to ask for some "qualifying" words from her next time I see her.

Now, on to the information. The big area of interest here seems to be about Phosphorylated Alkanoyl Chloride Oximes, from Zhurnal Obshchei Khimii. The Trialkyl Phosphate should be relatively easy to prepare, as it is seen in the syntheses of many nerve agents:

PCl3 + ROH --(CCl4)--> P(OR3) + RCl + HCl

As for the second reactant, X-C(R1)2-NO2, What if the two R1 groups were substituted with Cl and F, respectively? Alternately, if they were ALL substituted with Cl, then it becomes a very familiar compound--Chloropicrin. The question then is whether or not this would react in the same way.

If so, then the reaction to produce a very dangerous Nerve Agent looks to be unbelievably simple:

PCl3 + ROH --(CCl4)--> P(OR)3

P(OR)3 + CCl3NO2 --(CCl4)--> PO4R2(N=CCl2)

The product would then be distilled out.

[Edited on 3-27-04 by Samosa]

All of my sources were in english. And I was able to read the russian journal because there is an english form . unfortunatelly I´m not able to read russian so i also will have no use for russian information.
To your reaction-suggestions: Yes this synthesis looks very easy! The most complicated step seems to me the synthesis of Cl2FCNO2 or ClFC=NO. The reaction with chloropicrin is mentioned in the J.A.C.S.-article. But it doesn´t seem to be a good way to the novichok-compounds because the reaction is said to be very violent at -40°C producing smoke and flames!

Oh, that´s nice and may be very useful!
May I ask if you have already some informations about this class of chemicals?I have to admit that I´m a bit confused by the informations I have. It is said that the manufacture of these compounds should be very easy. But the chemistry-journals I looked up couldn´t confirm this! In fact the synthesis looks very difficult and uses some very strange compounds (e.g. Cl2FCNO2)

Well as you are I am sort of lost :/. Looking through various forums and articles I have gotten mixed results ranging from synthesis from simple and readily avalible substances like fertilizers and other things. But I have also read that it requires special equipment and it's not something as easy as that. Most sites however list them as being made from fertilizers (hence the secrecy since it's easy to hide production if it's made so simply) Some sites say soldiers carry the 2nd product with them and add alcohol. Not good for soldiers heh... I am still trying to see if the scientist who revealed this added any information through the years (Vil Mirzayanov)

My understanding of the nomenclature of OPs isn't so great, so could someone explain what 1,3,2-dioxapospholanes would look like?

Do a quick google search on Anatoly Kuntsevich... He is quite an interesting character. He is a former General and is the head of the Committee for Problems of the Chemical and Biological Weapons Convention. Beyond that, he was Boris Yeltsin's personal adviser on Chemical Weapons and was later assigned to abolishing Russia's Chemical and Biological Weapons program. I'm sure there is much to be learned from him; maybe if we could find an e-mail address or something (since he seems to frequen Amazon.com...), we could find something neat

As it turns out, fritz (not to be confused with FritzHaber) had this information in the little word file he uploaded... I suggest downloading it if you have not already--it mentions quite a few useful reactions. By the way, this forum has some rules about speaking in English, if I recall correctly... If you don't speak it well, I suggest using http://babelfish.altavista.com/ -- they have a Russian to English translator .

[Edited on 5-17-04 by Samosa]

whoops I must have competely overlooked this intresting converstion!
First of all i want to tell you I am preparing a new, revised information-paper about the novichok-stuff. Unfortunatelly I have too much other work to do so you have to wait a few days (I hope not weeks!)

I agree with souran, if Mr Kutsevich was a former general I doubt he would publicate informations about classified weapons under his own name (especially if he is dead since two years )
So I also think that care should be taken with his informations. All I read about the class of substances he described stands in opposite to the other informations I have from more or less official sources. But it may also be he HAS in fact some true informations and uses the pseudonym Kuntsevich as some kind of tip to his knowledge.
I have read about MeCN as a precursor but also I have no clue about how this may fit in a organophosphoros structure. Alcohols are mentioned too for the binary compounds but I guess these may react similiar as in the binary GB/VX mixtures.
I consider the suggestion of searching the RTECS-database about these compounds as a good idea! Lets look what could be found there!

well...presuming, that acetonitrile is a precursor, not solvent, I had this idea last night:

(R-)(X₁-)P=O(-X₂ + H₃C-CN ---> (R-)(X₁-)P=O(-N=C[-X₂]-CH₃,
where X1 = fluorine, cyanide, alkoxy, etc. radical, and X2 = chlorine, bromine, amino etc. radical, the bond P-X1 beeing more stable than that P-X2 or even P-N=C(X2)-CH3.
this would yield certainly interresting AChE-inhibitors...
further, I would consider this type of organophosphates to be much likely potent CW agents:
1)
(R,R'N-CH₂-CH₂-)(F-)P=O(-N=C(F)-CF₃
2)
(R,R'N-CH₂-CH₂-)(F-)P=O(-O-N=C(F)-CF₃

anyway, someone should contact some russian military chemist and buy the detailled formula for some $1.000

Yes this may be a great idea! But if all the secrets are revealed we will loose an intresting topic to discuss about. How boring! Hm, but on the other hand...

Nice first name Mr. Haber! And of course a very intresting person you got this pseudonym off!
I thought of a similiar way for the use of MeCN before I got the original literature. I thought of using it for creating the oxime function suggested in samosa´s paper. But I came to no solution of the problem because I don´t know how to get the oxygen between N and P.

Quote:

Originally posted by FritzHaber well...presuming, that acetonitrile is a precursor, not solvent, I had this idea last night: (R-)(X<sub>1</sub>-)P=O(-X<sub>2</sub> + H<sub>3</sub>C-CN ---> (R-)(X<sub>1</sub>-)P=O(-N=C[-X<sub>2</sub>]-CH<sub>3</sub>, where X1 = fluorine, cyanide, alkoxy, etc. radical, and X2 = chlorine, bromine, amino etc. radical, the bond P-X1 beeing more stable than that P-X2 or even P-N=C(X2)-CH3. this would yield certainly interresting AChE-inhibitors... further, I would consider this type of organophosphates to be much likely potent CW agents: 1) (R,R'N-CH<sub>2</sub>-CH<sub>2</sub>-)(F-)P=O(-N=C(F)-CF<sub>3</sub> 2) (R,R'N-CH<sub>2</sub>-CH<sub>2</sub>-)(F-)P=O(-O-N=C(F)-CF<sub>3</sub> anyway, someone should contact some russian military chemist and buy the detailled formula for some $1.000

To buy a state secret for 1000$ is daring idea. I am afraid to disillusion you but corrupt military chemists are so greedy for the most part. 1000$ is not quite sufficient. Moreover, I suppose the secret is sold already.
I mostly agree with Mr. FritzHaber, but if X2 = -OH, SH, amino I guess the reaction would look like this:

(CH3O)2P=O(SH) + MeCN --> (CH3O)2P=O(-S-C(CH3)=NH)

If X2 = Hal reaction would look like:

(CH3O)2P=O(Hal) + MeCN --> (CH3O)2P=O(-N=C(CH3)(Hal))

The product of first reaction is related to compound (CH3O)2P=O(-S-C(CH(CH3)2)=NH-CH3) which is highly toxic (http://wcb.ucr.edu/wcb/schools/CNAS/entm/tmiller/1/modules/p...)

Here are more examples of highly toxic related compounds(in ChemSketch smiles):

COP(=O)(OC)\N=C1/SC(CO1)C
CCOP(=O)(OCC)\N=C1/SCCS1 (Phospholane)
Clc1ccc(cc1)OP(=O)(Oc2ccc(cc2)Cl)\N=C\C (Phosacetim)

It is known two-step reaction of cholinesterase reactivation:

1. (R1-)(R2-)P=O(OR) + R3-CH=N-OH --> (R1-)(R2-)P=O(-O-N=CH-R3) + R-OH
2. (R1-)(R2-)P=O(-O-N=CH-R3) --> (R1-)(R2-)P=O(-OH) + R3-CN

May MeCN react with P-OH containing compounds?

[Edited on 28-5-2004 by souran]

I just searched on novichok agents, came up with this:

http://66.102.11.104/search?q=cache:v9FPKVzfKaAJ:www.cisworldservices.org/publications/CSM_FALL2002.pdf+novichok+agents&hl=en

Refers to "aconitrile", most likely, given the tone of the previous messages to be acetonitrile, mixed with the ubiquitous "common pesticide" in what is hinted to be something like a one-step procedure.

Could lead to a one pot synthesis of one of the nocichok agents maybe


Edit: found this, could someone maybe link to the references if they have access to the full article?

http://taylorandfrancis.metapress.com/app/home/contribution....

[Edited on 8-9-2004 by Reverend Necroticus Rex]

The reason organophosphorus nomenclature is confusing is that the first few workers on this subject didn't exactly have the same set of standards. For instance, one uses "phosphorothioate", while another uses "thiophosphate", and some go so far as to distinguish "phosphorothiolate" (>P-S) and "phosphorothionate" (>P=S).

Another source of confusion is that some workers tend to use a mix of the CAS and |IUPAC systems.

Here go some links on organophosphorus nomenclature:

http://www.acdlabs.com/iupac/nomenclature/93/r93_507.htm

http://www.chem.qmul.ac.uk/iupac/misc/phospho.html

sparky (~_~)

Quote: Originally posted by Conor579

But how successful WERE the current nerve agents we know about? What others had they tested? I like to ask questions xD

Quote: Originally posted by softbeard

Quote: Originally posted by Conor579   But how successful WERE the current nerve agents we know about? What others had they tested? I like to ask questions xD Nothing wrong with asking questions. The answer is that current nerve agents we know about are extremely "successful" at producing lethality in mammals, including humans. Just about every conceivable variation of (OR)2P=O-X (prototypically, X=F) type organo-phosphate compounds has been studied for non-reversible acetylcholine-esterase inhibitor activity. Some, like VX 'nerve gas', have been found to be extremely potent and environmentally persistant. Even some of the simplest organo-phosphate compounds of this type, like di-isopropyl phosphorofluoridate are quite toxic. The LC 50 for 10 min exposure of di-isopropyl phosphorofluoridate was 0.36 mg/l for rats and 0.44 mg/l for mice. This makes the compound more toxic than cyanogen chloride (1); on par, more or less, with HCN . And it's not even considered a 'real' nerve gas. There really is not very much interesting chemically about these compounds, aside from from them being able to be made very selective in their toxicity. So that potent insecticides can be made which have quite low toxicity in mammals (ie., Malathion). In general, these are not a fun group of chemicals to play with. 1. "Some Aspects Of The Chemistry of Organic Compounds Containing P and F", B. Saunders, A. Todd, 1957, Cambridge Press