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Author: Subject: Novichoks and Related 3rd/4th Gen. OP Agents
Sauron
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[*] posted on 11-3-2010 at 04:18


Sorry but that is rather confused.

The hypothetical structure you posted is not "substituted VX" but rather analog of the 1930s British agent DFP.

Like DFP and unlike any V agent it contains no C-P bond

Its sole common stuctural element to V agents is the O=P-S-CH2-CH2-NR2 unit

VX contains no F

Persistance or nonpersistance in the environment is a deliberate design element of MOPs acccording to tactical requirements.





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[*] posted on 11-3-2010 at 21:33


I mean exactly this: (Attachment)

Where -O-N=CCl2 could be -O-N=CClF ; -O-CH=CCl2 ; Pinacolyl alcohol, etc - something that "ages" quickly... The first 3 mentioned give higher skin resorption, by the way.

Whether it is P-F or P-CH3 does not matter much in toxicity in this very case. Only P-CH3 variety is much more stable to environmental hydrolysis.

OP.bmp - 653kB

Compounds containing P-O-CH2-CH2-X ; X=Cl, F are generally not very toxic, because they do not match the enzyme. X=N(Et)2 is needed to match the enzyme. The oxygen should be substituted with sulphur that the P-S bond could be easily broken by the enzyme.


[Edited on 12-3-2010 by simply RED]




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[*] posted on 11-3-2010 at 23:49


Pinacolyl alcohol is slow to hydrolyse for reason os steric hindrance, as in GD soman a German gift to Stalin.

V agents are persistant without steric effects. VX is MeP(=O)(OEt)SCH2CH2N(iPr)2. It has a low vapor pressure, a high bp, the appearance and viscocity of motor oil.

Its toxicity is primarily percutaneous and the high lipophilicity is due to the thioester side chain.

The novichok oxime moiety is there to frustrate some older prophilaxis and treatment protocols.




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[*] posted on 12-3-2010 at 02:37


"The novichok oxime moiety is there to frustrate some older prophilaxis and treatment protocols. "

Indeed! Post VX OPs are designed to be untreatable by "VX-protocols". As it was mentioned earlier, enzymes phosphorylated by these - age very quickly and are unregeneratable.

I doubt any treatament exists for post VX OPs other than sympthomatic. Is there a new treatment for post VX OPs?

According to the book : "Modern Warfare Toxic Agents" by G.Kotov (1971) - Fast aging OPs like soman are aboslutely untreatable with a combination of attropine and obidoxime! Experiments are cited where attropine and obidoxime were injected in animals 10 minutes BEFORE intoxications with different OPs. For VX like chemicals the effect is 100-700 times higher LD-50s. For fast aging chemicals like soman the effcts is ...... 1.2-1.4 times LD50s.

So, fast aging OPs like Novichoks are absolutely untreatable with a combination of attropine and cholinesterase oxime reactivator.

Anyway, with the structure I posted as an attachment, I just wanted to show a real, complete, fast aging post VX OP formula.

[Edited on 12-3-2010 by simply RED]




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[*] posted on 12-3-2010 at 06:05


A lot has happened in this corner of military medicine since 1971 (hell since 1991!) and it is well known that atropine and older oximes like 2PAM are useless against VX (I do not recall re soman.)

However as soman has been aroundd for>70 years I am confident that there exist effective therapies and prophylaxis.

About the newcomers I simply do not know.




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[*] posted on 18-3-2010 at 02:44


Here is a "straight" idea of such "fast aging" compound synthesis:

Phos1.PNG - 15kB

Or directly:


untitled.gif - 3kB

[Edited on 18-3-2010 by simply RED]




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[*] posted on 18-3-2010 at 22:37


FC(CH3)=N-P(O)(-S-CH2-CH2-N(Et)2) geometry optimized with PM3 (Other methods will give the same conformational geometry).
Hydrogen atoms are deleted that the structure is clear.

Untitled-2.jpg - 26kB


F-P(O)(CH3)(-N=CF-CH2-N(Et)2 geometry optimized with PM3 (Other methods will give the same conformational geometry).
Hydrogen atoms are deleted that the structure is clear.

Untitled-1.jpg - 24kB


[Edited on 19-3-2010 by simply RED]




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[*] posted on 2-4-2012 at 14:18


also see the thread in this forum: "highly toxic acetylcholinesterase-inhibitor"
http://www.sciencemadness.org/talk/viewthread.php?tid=19571#...

While doing research for alternate routes for preparing an energetic plasticizer known as FEFO, I happened to find
some information relevent to the most deadly acetylcholine blockers. I am only posting this because the precursors are virtually impossible to obtain, and there are many non-obvious details being withheld which would be required for the reactions to work. This is for information purpsoes only, and does not contain sufficient information to actually conduct any of the reactions.

The nitration ... of 1,2-dichloro-1,2-difluoro ethylene, ClFC=CFCl, gives chlorofluoronitroacetic acid (40% yield), with a formula HOC(=O)CFCl(NO2). Chlorofluoronitroacetic acid reacts with red fuming nitric acid (HNO3 / NO2) to give chlorofluoronitronitrosomethane, with a formula O=N--CFCl(NO2), and which possesses a deep blue color.
This latter compound reacts with PCl3 to form one of the more potent Novichok agents.
Synthesis and pesticidal activity of chloronitroacetic acid esters. Martynov; Yurtanov; Ivanov; Martynov; Yurtanov; Ivanov; Kulish; Uvarova; Andreeva; Rozhkova; Zhirmunskaya; Veshchestv, Chernogolovka, USSR. Veshchestv, Chernogolovka, USSR. Doklady Akademii Nauk SSSR (1986), 289(1), 109-13 [Chem.]. Doklady Akademii Nauk SSSR (1986), 289 (1), 109-13 [Chem.].

Quote:
... track down all possible scientific articles about Novichok agents... Zhurnal Obshchei Khimii may be a good source...

in Tobiasons Scientific Principles, the chemical weapons volume, that the Soviets intentionally published large amounts of chemical weapons information in the open literature in the 1950s and 1960s with the hope some rogue nation would use the information to attack the US. The goal here was for the rogue state to finish the job for the Soviet Union, or at least inflict massive American casualities.

I. V. Martynov has published about 500 journal articles in his lifetime to date. Indeed there are many about phosphorus compounds, but those type of articles cease after 1972. He publishes many articles about molecular refraction after that. In 1984 he resumes publication of phosphorus related articles.

Synthesis and anticholinesterase activity of fluorochloronitroacetic acid esters. Ivanov, Yu. Ya.; Brel, V. K.; Postnova; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Khimiko-Farmatsevticheskii Zhurnal (1985), 19(8), 968-71.

There are a few earlier articles about fluorochloronitroacetic acid esters. These are important in the systhesis of Novichoks I would imagine. Samosa did mention in his paper that dihaloformaldoxime are critical parts of Novichok agents, and fluorochloronitroacetic acid should form those.

Here is another article of potential use in the preparation of Novichok agents. This compound is similar to fluorochloronitroacetic acid from which this substance is made:
Synthesis of chlorofluoronitronitrosomethane. Martynov, I. V.; Brel, V. K.; Uvarova, L. V. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1986), (4), 952-3.
Decarboxylation-nitrosation of ClFC(NO2)CO2H with HNO3 gave 52% ClFC(NO)NO2

Here is another possible tidbit as it relates to insecticides and plant growth regulation. We know they disguised their research under the guise of agrichemicals:
Synthesis and pesticidal activity of chloronitroacetic acid esters. Martynov, I. V.; Yurtanov, A. I.; Ivanov, Yu. J.; Kulish, E. V.; Uvarova, L. V.; Andreeva, E. I.; Rozhkova, N. G.; Zhirmunskaya, N. M. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Doklady Akademii Nauk SSSR (1986), 289(1), 109-13 [Chem.].
A series of 31 O2NCRR1CO2R [e.g., R, R1, R2 = H, Cl, n-C7H15 (I); F, Cl, ClCH2CH2; Br, Cl, Et] was tested for insecticidal and, in some cases, plant growth regulatory activity. Eight of the compds., e.g., I, were active insecticides. Twelve of the compds. were new but no preparation details were given.

Here is another possible Novichok variant:
Reaction of phosphorus trichloride with 1,1,2-trichloro-1-nitrosoethane in sulfur dioxide. Martynov, I. V.; Ivanov, A. N.; Epishina, T. A.; Sokolov, V. B. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1986), (9), 2158.
Reaction of ClCH2CCl2NO with PCl3 in SO2 gave 58% ClCH2CCl=NOP(=O)Cl2.

Here is yet another possible Novichok variant:
Reaction of dialkyl phosphites with 1,1-dichloronitrosoalkanes. Ivanov, A. N.; Epishina, T. A.; Goreva, T. V.; Sokolov, V. B.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1987), (1), 226-8.
(RO)2P(O)ON:CClR1 (R = Bu, Me2CHCH2, pentyl, Me, Et; R1 = Me, Et, Pr, Me2CH, Bu, Me2CHCH2) were prepd. in 44-67% yields by treating (RO)2POH with ONCCl2R1 in EtOH at 20.

Here is a toxicity study done on animals and humans for some "pesticides".
Delayed neurotoxicity from organophosphorus pesticides. Makhaeva, G. F.; Malygin, V. V.; Martynov, I. V.. USSR. Agrokhimiya (1987), (12), 103-24.
A review with 123 refs. on 8 clin. intoxication symptoms, pathmorphol., mechanisms of initiation of delayed neurotoxicity by organophosphorus pesticides (OPP) structure-activity relations of OPP, monitoring of the delayed neurotoxicity of OPP in animals and humans, etc.

Here is another possible Novichok variant:
Reaction of O-alkyl methylphosphonites with 1,1-dichloro-1-nitrosopropane. Sokolov, V. B.; Ivanov, A. N.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Zhurnal Obshchei Khimii (1987), 57(4), 952-3.
Reaction of ROP(O)HMe (R = Me2CH, Bu, pentyl) with EtCCl2NO in Et2O gave 50-52% ROP(O)MeON:CClEt (I; same R). Treating MeP(OR)2 with EtCCl2NO also gave I.

Here is an interesting reference, although I doubt this would have very high human toxicity due to the two large aryl groups attached to phosphorus. Still, it gives enlightenment as to where they are headed:
Reaction of diphenylphosphinous acid with 1,1-dichloro-1-nitrosoalkanes. Sokolov, V. B.; Epishina, T. A.; Ivanov, A. N.; Kharitonov, A. V.; Brel, V. K.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Zhurnal Obshchei Khimii (1987), 57(7), 1658-9.
Treating Ph2P(O)H with RCCl2NO (R = Et, Pr, Me2CH) in Et2O gave 62-75% Ph2P(O)ON:CClR (same R).


Another Novichok possibility:
Synthesis and the structure of dialkylfluoroformiminophosphates. Martynov, I. V.; Brel, V. K.; Uvarov, V. I.; Yarkov, A. V.; Novikov, V. P.; Chepakova, L. A.; Raevskii, O. A. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1987), (4), 857-60.
Syn- And anti-(RO)2P(O)N:CHF (R = Me, Et, Pr, Bu) were prepd. in 11-25% yields by treating (RO)3P with ClCHFNO2.

Here is some nasty looking stuff that may be of interest:
Reaction of (-aminoalkyl)phosphonates with perfluoro-2-azapropene. Aksinenko, A. Yu.; Pushin, A. N.; Sokolov, V. B.; Gontar, A. F.; Martynov, I. V.. Inst. Fiziol. Aktivn. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1987), (5), 1177-9.
(RO)2P(O)CMeR1N:C:NCF3 (R = Me, R1 = Et; R = Et, R1 = Et, Pr, Bu; R = Me2CHCH2, R1 = Et) were prepd. in 40-60% yields by condensing CF2:NCF3 with (RO)2P(O)CMeR1(NH2) in the presence of KF.

Here is another variant:
Reaction of polychloronitrosoethanes with phosphorous acid derivatives. Martynov, I. V.; Ivanov, A. N.; Epishina, T. A.; Sokolov, V. B. Inst. Fiziol. Akt. Veshchestv., Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1987), (5), 1086-9.
The title reaction gave 20-93% of 22 o-phosphorylated alkyl chloroformimines. Thus, treating ONCCl2R (R = Me, CH2Cl, CHCl2) with (R1O)3P (R1 = Me, Pr, Bu, Me2CHCH2, pentyl, ClCH2CH2) gave (R1O)2P(O)ON:CClR.

Of all the other compounds I have previously referenced this particular compound looks like it may be the deadliest. It has some similarities to most other nerve gasses in that it uses the simplest alkyl groups, and has a direct alkyl and a direct halogen attachment to phosphorus. I would replace those chlorines with fluorine to increase the toxicity:
Reaction of dichloromethylphosphine with 1,1-dichloro-1-nitrosoalkanes. Sokolov, V. B.; Ivanov, A. N.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Zhurnal Obshchei Khimii (1987), 57(7), 1659-60.
MePCl2 reacted with RCCl2NO (R = Et, Pr, Me2CH) in SO2 to give 27-37% RCCl:NOP(O)ClMe.

This compound looks like a good precursor for organophosphorus agents like the previous compound. The chlorines can be replaced by F, and one of the fluorines can form an ester or something else. The second compound is an example of what could be made, and I just bet that stuff is pretty toxic.
Interaction of 2,2,3,3-tetrafluoropropyl dichlorophosphite with 1,1,2-trichloro-1-nitrosoethane. Sokolov, V. B.; Ivanov, A. N.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1987), (6), 1422-3.
Refluxing CHF2CF2CH2OPCl2 (I) with CH2ClCCl2NO (II) in Et2O gave 67.8% Cl2P(O)ON:CClCH2Cl. Treating I with II in SO2 at 20 gave 48.2% (CHF2CF2CH2O)ClP(O)ON:CClCH2Cl.

We might have a real winner with this one as it has similarities with VX nerve gas. The second compound in particular has a =S group. If that could be isomerized, like it is done in making VX, then we have a thioester. The two isobutyl groups are probably too large to make this particular compound all that toxic. I am sure they could be replaced with methyls instead.
Reaction of diisobutylchlorophosphine with 1,1-dichloro-1-nitrosoalkanes in presence of sulfur dioxide and ethyl mercaptan. Sokolov, V. B.; Ivanov, A. N.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Aktivn. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1987), (11), 2586-8.
Treating (Me2CHCH2)2PCl with RCCl2NO (R = Me, Et, Pr, Me2CH) in Et2O contg. SO2 gave 61-74% (Me2CHCH2)2P(O)ON:CRCl (same R). When Et2SH was used instead of SO2, 44% (Me2CHCH2)2P(S)ON:CRCl (R = Me) was obtained.

Another phenyl attached compound:
Synthesis and molecular structure of (O-isopropylchloroformimino) diphenylphosphinate. Martynov, I. V.; Chekhlov, A. N.; Ivanov, A. N.; Epishina, T. A.; Makhaev, V. D.; Sokolov, V. B. Inst. Fiziol. Aktivn. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1987), (11), 2595-7.
Treating Ph2PH with Me2CHCCl2NO in C6H6 gave 58% Ph2P(O)ON:CClCHMe2, the structure of which was detd. by x-ray crystallog.

This compound has some VX similarities too:
O,O-Dialkyl O-(dialkylformimino) thiophosphates. Chepakova, L. A.; Brel, V. K.; Pushin, A. N.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Zhurnal Obshchei Khimii (1987), 57(12), 2716-19.
Twelve (R1O)2P(S)ON:CMeR (R = Me, Et, Pr; R1 = Me, Et, Pr, Bu) were prepd. in 41-62% yields by treating (R1O)2PHS with ONCClMeR or HON:CMeR.

These compounds are similar to the last journal reference except the R and R’ groups are switched. Isomerize that S and we may have something far more toxic.
O-(Alkylchloroformimino) O,O-dialkyl thiophosphates. Martynov, I. V.; Ivanov, A. N.; Epishina, T. A.; Sokolov, V. B. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1987), (12), 2854-5.
Seven (RO)2P(S)ON:CClR1 (R = Et, Me2CH; R1 = Me, Et, Pr, Me2CH, ClCH2) were prepd. in 33-54% yields by condensing (RO)2PSH with R1Cl2CNO in THF.

Martynov has 64 publications in 1988 alone, his best year. In no particular order here are some highlights:

Molecular and crystal structure of O,O-diethyl 1-[N2-(trifluoromethyl)fluoroformamidino]-1-methylethylphosphonate. Chekhlov, A. N.; Aksinenko, A. Yu.; Sokolov, V. B.; Korenchenko, O. V.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Doklady Akademii Nauk SSSR (1988), 302(4), 855-8 [Chem.].
The crystal and mol. structure of (EtO)2P(O)CMe2NHCFNCF3 was detd.

Reaction of (N-acetyl-N-ethylamido)alkylphosphonic acid chlorides with cesium fluoride. Krolevets, A. A.; Adamov, A. V.; Popov, A. G.; Martynov, I. V.. USSR. Zhurnal Obshchei Khimii (1988), 58(11), 2628-9.
RP(O)F(NEtCH:CH2) (R = Me, Me2CH) were prepd. in 45, 50% yields, resp., by treating RPCl(NEtAc) (I) with CsF. I were prepd. in 60, 65% yields, resp., by treating RPCl2 with Me3SiNEtAc.

Stable alkoxyfluorophosphoranes. Krolevets, A. A.; Popov, A. G.; Adamov, A. V.; Martynov, I. V.. USSR. Zhurnal Obshchei Khimii (1988), 58(11), 2626-7.
RPF2(OR1)2 (R = BuCHClCH2, R1 = Me3C; R = Me2CClCH2, R1 = Et) were prepd. in 45, 40% yields, resp., by treating RPF4 with Me3SiOR1.

O-(Alkylchloroformimidoyl) o-alkyl methylphosphonates. Sokolov, V. B.; Ivanov, A. N.; Goreva, T. V.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv., Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1988), (5), 1128-30.
Nine (RO)MeP(O)ON:CClR1 (R = Et, Pr, Bu, Me2CH, pentyl; R1 = Me, Et, Pr, Bu, Me2CH) were prepd. in 41-67% yields by treating R1CCl2NO with MeP(OR)2 or MeP(O)H(OR).

Reaction of 1,1-dichloro-1-nitrosoalkanes with phosphorus(III) chlorides. Martynov, I. V.; Ivanov, A. N.; Epishina, T. A.; Sokolov, V. B. Inst. Fiziol. Aktivn. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1988), (9), 2128-32.
The title reaction was studied. Thus, R1R2P(O)ON:CRCl (R = Me, Et, Pr, Me2CH; R1 = R2 = Cl, Me2CHCH2; R1 = Cl, R2 = Me) were prepd. in 34-74% yields by reaction of RCCl2NO with R1R2PCl in the presence of SO2.

Synthesis and x-ray diffraction study of N-(diisopropoxythiophosphoryl)thioacetamide. Solov'ev, V. N.; Chekhlov, A. N.; Zabirov, N. G.; Cherkasov, R. A.; Martynov, I. V.. Inst. Fiziol. Aktivn. Veshchestv, Chernogolovka, USSR. Doklady Akademii Nauk SSSR (1988), 300(6), 1386-9 [Chem.].
Treating MeCSNH2 with Me3COK in MeCN and then with ClP(S)(OCHMe2)2 gave 15% MeCSNHP(S)(OCHMe2)2, the structure of which was detd. by x-ray crystallog.

Reaction of 1,1-dichloro-1-nitrosoethane with phosphorus oxychloride in the presence of zinc. Sokolov, V. B.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1988), (7), 1691.
Cl2P(O)ON:CClMe was prepd. in 26.6% yield by treating MeCCl2NO with POCl3 in the presence of Zn.

Comparative studies on the interaction of acetylcholinesterases from human erythrocytes and housefly heads with phosphorylated alkylchloroformoxims. Shataeva, G. A.; Makhaeva, G. F.; Yankovskaya, V. L.; Sokolov, V. B.; Ivanov, A. N.; Martynov, I. V.. Inst. Physiol. Act. Subst., Chernogolovka, USSR. Zhurnal Evolyutsionnoi Biokhimii i Fiziologii (1988), 24(6), 791-6.
Among Valexon analogs, 6 (RO)2P(O)ON:CClMe (I), 6 (RO)2P(O)ON:C(Cl)CH2Cl (II), and 5 (RO)2P(O)ON:C(Cl)CHCl2 (III, R = Me, Et, Pr, iso-Bu, Bu, amyl), and 4 (EtO)2P(O)ON:C(Cl)R1 (IV, R1 = Me, Et, Pr, Bu), I-III (R = Et) were highly selective insecticides, having rate consts. of bimol. reaction with acetylcholinesterase (KII) of human erythrocytes (HE) lower by 1 magnitude order than with that from housefly heads (FL). Inhibition of both HE and FL followed the order I < II < III. Phosphorylation capacity of II 1.6-fold exceeded that of I. Replacing Me by Et, increased the effect of I-III on FL 3-8-fold and decreased that on HE 1.7-4-fold. Further increases in hydrophobicity abolished the specificity of I-III. The selectivity of IV decreased in order of R1: Me > Et > Bu; IV (R1 = Pr) showed no selectivity.

Fluorination of some phosphoric acid derivatives. Zavorin, S. I.; Lermontov, S. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka., USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1988), (5), 1174-6.
Dialkyl fluorophosphates were prepd. by the title fluorination with Et3N.3HF (I). Thus, fluorination of (EtO)2P(O)ON:CCl2 with I in MeCN gave 83.5% (EtO)2P(O)F.

Reaction of fluorine-containing acetylenic alcohols with phosphorus trichloride. Brel, V. K.; Chekhlov, A. N.; Ionin, B. I.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Zhurnal Obshchei Khimii (1988), 58(4), 750-7.
Treating RC.tplbond.CCMe(OH)CH2F (I; R = Ph) with PCl3 in Et2O gave 45% Cl2P(O)CR:C:CMeCH2F (II; R = Ph) and 24% E- and Z-Cl2P(O)CHPhCCl:CMeCH2F (III). Under the same conditions, I (R = MeOCH2) gave a mixt. of II (R = MeOCH2) and Cl2P(O)C(:CH2)CCl:CMeCH2F. Treating I (R = Ph) with MeOH and then with Br2 gave oxaphospholene IV. The structure of III was detd. by x-ray crystallog.

Synthesis and anticholinesterase activity of fluorochloronitroacetic acid thioesters. Ivanov, Yu. Ya.; Uvarov, V. I.; Brel, V. K.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Khimiko-Farmatsevticheskii Zhurnal (1988), 22(5), 538-40.
Treating O2NCFClCOX (I; X = OH) with PCl5 gave I (X = Cl), which reacted with RSH (R = Et, Bu) to give 35-55% I (X = SR; same R) (II). II were less effective acetylcholinesterase inhibitors than I (X = OR; same R) but had comparable activity vs. butyrylcholinesterase with lower toxicity.

Synthesis and antiesterase activity of sulfur-containing phosphorylated oximes. Chepakova, L. A.; Bret, V. K.; Makheva, G. F.; Yankovskaya, V. L.; Beznosko, B. K.; Malygin, V. V.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv., Chernogolovka, USSR. Khimiko-Farmatsevticheskii Zhurnal (1988), 22(2), 143-6.
Reaction of (RS)2POEt (R = Et, Pr, iso-Bu, Bu or amyl) with O:NCFCl2 gave the corresponding (RS)2P(:O)ON:CClF (I). An increase in the hydrophobicity of I did not alter the anticholinesterase activity of I, while the butyrylcholinesterase and carboxylesterase activity were increased.

O-substituted alkylchloroformoximes as substrates and inhibitors of cholinesterases. Ivanov Iu Ia; Sokolov V B; Epishina T A; Martynov I V Doklady Akademii nauk SSSR (1990), 310(5), 1253-5.

Inhibition of cholinesterase activity with fluorine-containing derivatives of alpha-aminophosphonic acid. Kuusk V V; Morozova I V; Agabekian R S; Aksinenko A Iu; Epishina T A; Sokolov V B; Kovaleva N V; Razdol'skiy A N; Fetisov V N; Martynov I V Bioorganicheskaia khimiia (1990 Nov), 16(11), 1500-8.
A series of O,O-diethyl-1-(N-alpha-hydrohexafluoroisobutyryl)aminoalkylphos phonates (APh) has been synthesized and their interaction with human erythrocyte acetylcholinesterase (AChE) and with horse serum butyrylcholinesterase (BuChE) studied. Most of the APhs inactivated the cholinesterases irreversible through formation of the enzyme-inhibitor intermediate. The inactivation rate constants and the enzyme-inhibitor intermediate dissociation constants are calculated. The quantitative structure-activity relationships including both hydrophobic and calculated steric parameters of substituents are developed for APh--ChE interactions. Molecular mechanics (programme MM2) was used for determining steric parameters (Es). On the basis of QSAR models analysis it was concluded that hydrophobic interactions play an essential role in APh--AChE binding, whereas for APh--BuChE binding steric interactions are essential. Presence of at least two APh binding centres on the surface of AChE and BuChE is suggested.

Reaction of 1,1-dichloro-1-nitrosobutane with (N,N-dimethylamido)dichlorophosphite. Sokolov, V. B.; Ivanov, A. N.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1989), (6), 1416-18.
Reaction of PrCCl2NO with Me2NPCl2 in Et2O or in SO2 gave 36% Me2NPCl4 or 30% Me2NP(O)ClON:CClPr, resp. Treating Me2NPCl4 with SO2 gave 91% Me2NP(O)Cl2. Reaction of PrCCl2NO with Me2NPCl2 in Et2O, and then with Ph3P and distn. gave Ph3PO and PrCN.

Alkyl chlorofluoroformimino perfluoroalkylphosphonates. Chepakova, L. A.; Brel, V. K.; Martynov, I. V.; Maslennikov, I. G. Inst. Fiziol. Akt. Veshchestv., Chernogolovka, USSR. Zhurnal Obshchei Khimii (1989), 59(6), 1455-6.
Treating RP(OR1)2 (R = CF3, R1 = Pr, Bu; R = CF3CF2, R1 = Me, Bu) with CFCl2NO in Et2O gave 76-88% title compds. R1OP(O)RON:CFCl.

Synthesis of dialkyl (3-alkyl-1,3-alkadien-2-yl)phosphonates. Brel, V. K.; Abramkin, E. V.; Martynov, I. V.; Ionin, B. I. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Zhurnal Obshchei Khimii (1989), 59(9), 2142-3.
(RO)2P(O)C(:CH2)CR1:CMe2 (R = Et, Pr; R1 = Me, Et) were prepd. in 41-73% yields by the Grignard reaction of (RO)2P(O)C(CH2OMe):C:CMe2 with R1X (X = halo).

Synthesis and antiesterase activity of O,O-dialkyl S-(ethoxycarboxyl)chloromethyl thiophosphates. Khaskin, B. A.; Makhaeva, G. F.; Torgasheva, N. A.; Ishmuratov, A. S.; Yankovskaya, V. L.; Fetisov, V. I.; Malygin, V. V.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovko, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1989), (12), 2741-6.
The title compds. (RO)2P(O)SCHClCO2Et (I; R = alkyl homologs) were prepd. in 82-95% yields in the reaction of (RO)2P(O)SCl with N2CHCO2Et at -25 (in Et2O) or 6-7 (in benzene), presumably via a noncarbene mechanism. I irreversibly inhibited acetylcholinesterase, butyrylcholinesterase, and carboxylesterase; antibutyrylcholinesterase activity increased in the homologous series of R, with max. at R = Bu. An antiesterase MSBAR of I was fulfilled with parameters representing hydrophobicity and steric properties of R.

Synthesis and cholinesterase hydrolysis of O-acylated alkylchloroformoximes. Sokolov, V. B.; Ivanov, Yu. Ya.; Epishina, T. A.; Agabekyan, R. S.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Khimiko-Farmatsevticheskii Zhurnal (1989), 23(11), 1317-20.
The title compds., RCO2N:CClR1 (R = Me, Et, Pr or CH2Cl and R1 = Me, Et, Pr, or iso-Pr) were prepd. e.g., by the reaction of 1,1-dichloro-1-nitrosobutane with AcCl in the presence of Zn. These compds. were good substrates for acetyl- and butyrylcholinesterases. The kinetic parameters (Km, Vmax and ac) of these compds. in the hydrolysis reactions were comparable to those with acetylcholine. The acute toxicity was 79-381 mg/kg in mice given drugs orally.

Synthesis and structure of O,O-dialkyl 2-[(ethoxycarbonyl)amino]hexafluoroisopropylphosphonates. Aksinenko, A. Yu.; Chekhlov, A. N.; Korenchenko, O. V.; Sokolov, V. B.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Zhurnal Obshchei Khimii (1990), 60(1), 61-5.
The title compds. (RO)2P(O)C(CF3)2NHCO2Et (I; R = Me, Et, CHMe2) were prepd. in 54-76% yields in the reaction of (RO)2P(O)H with (CF3)2C:NCO2Et. The crystal and mol. structure of I (R = Et) was detd.

O-Substituted alkylchloroformoximes as substrates and inhibitors of cholinesterases. Ivanov, Yu. Ya.; Sokolov, V. B.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Aktivn. Veshchestv, Chernogolovka, USSR. Doklady Akademii Nauk SSSR (1990), 310(5), 1253-5 [Biochem.].
The ability of O-substituted alkylchloroformoximes to serve as substrates for acetylcholinesterase (ACE, EC 3.1.1.7) and butyrylcholinesterase (BCE, EC 3.1.1.8) and to inhibit acetylcholine hydrolysis by these enzymes was detd., along with the LD50 of these compds. in mice. The compds. tested were O-acylated alkylchloroformoximes of the general formula R1C(O)ON:C(Cl)R2 [R1 = R2 = Me; R1 = Me, R2 = Et; R1 = Me, R2 = Pr; R1 = Et, R2 = Me; R1 = Et, R2 = iso-Pr; R1 = Pr, R2 = iso-Pr; R1 = CH2Cl, R2 = Pr (I); R1 = CH2Cl, R2 = iso-Pr (II)], O-carbonylated alkylchloroformoximes of the general formula EtOC(O)ON:C(Cl)R [R = Me (III), iso-Pr (IV)], and O-carbamoylated alkylchloroformoximes of the general formula (Me)2NC(O)ON:C(Cl)R [R = Me (V), iso-Pr (VI)]. All of the compds. except for I and II were good substrates for the enzymes, with Km values for ACE ranging (0.3-11.0)  10-4M and for BCE ranging (0.5-13.0)  10-4M (the Km values of ACE and BCE with acetylcholine were 1.3  10-4 and 5.4  10-4M, resp.). III and IV were competitive (Ki 1.6  10-4M) and mixed-type (Ki 4.2  10-4M) inhibitors, resp., of ACE. V and VI were effective inhibitors of both ACE and BCE, with bimol. rate consts. for inhibition (kII) of 5.7  103 and 1.4  105 M-1 min-1, resp., for ACE, and 9.8  103 and 5.4  106 M-1 min-1, resp., for BCE. The LD50 values for the tested compds. ranged 60-381 mg/kg body wt.

O-(alkylchloroformimino)(methyl)thiophosphonic acid chlorides. Lyashenko, Yu. E.; Sokolov, V. B.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1989), (12), 2865-6.
Treating the adduct from RCCl2NO and MePCl2 with H2S gave 21-35% MeP(S)ClON:CRCl.

Interaction of 1,1-dichloro-1-nitrosoalkanes with S-ethylmethylphosphonous chloride in the presence of sulfur dioxide. Sokolov, V. B.; Ivanov, A. N.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1990), (2), 464-5.
EtSP(O)MeON:CClR (R = Me, Et, Pr) were prepd. in 42-47% yields by treating RCCl2NO with EtSPMeCl in the presence of SO2.

O-(alkylchloroformimino)-O-alkylphosphoric acid chlorides. Sokolov, V. B.; Ivanov, A. N.; Goreva, T. V.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1990), (5), 1122-5.
Reaction of (ON)CCl2R with (R'O)2PCl (R, R' = alkyl) afforded the title compds. (R'O)ClP(O)ON:CRCl (I) in up to 69% yield. Hydrolysis of I led to substitution of P-, and not C-bound Cl, resulting in (R'O)(NH4O)P(O)ON:CRCl.

Reaction of the adduct of methyldichlorophosphine and 1,1-dichloro-1-nitrosoethane with thioacetic acid. Lyashenko, Yu. E.; Sokolov, V. B.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Zhurnal Obshchei Khimii (1990), 60(8), 1923-4.
Treating MePCl2 with MeCCl2NO in PhMe, followed by addn of 1 or 2 equiv AcSH gave 56% MeP(S)ClON:CMeCl or 32% MeP(S)ClON:CMeSAc, resp.

Inhibition of cholinesterase activity by fluorine-containing derivatives of -aminoalkylphosphonic acids. Kuusk, V. V.; Morozova, I. V.; Agabekyan, R. S.; Aksinenko, A. Yu.; Epishina, T. A.; Sokolov, V. B.; Kovaleva, N. V.; Razdol'skii, A. N.; Fetisov, V. I.; Martynov, I. V.. Inst. Physiol. Act. Subst., Chernogolovka, USSR. Bioorganicheskaya Khimiya (1990), 16(11), 1500-8.
A series of O,O-diethyl-1-(N--hydrohexafluoroisobutyryl)aminoalkylphosphonates (APh) has been synthesized and their interaction with human erythrocyte acetylcholinesterase (AChE) and with horse serum butyrylcholinesterase (BuChE) studied. Most of the APhs inactivated the cholinesterases irreversible through formation of the enzyme-inhibitor intermediate. The inactivation rate consts. and the enzyme-inhibitor intermediate dissocn. consts. are calcd. The quant. structure-activity relationships including both hydrophobic and calcd. steric parameters of substituents are developed for APh-ChE interactions. Mol. mechanics (program MM2) was used for detg. steric parameters (Es). On the basis of QSAR models anal. it was concluded that hydrophobic interactions play an essential role in APh-AChE binding, whereas for APh-BuChE binding steric interactions are essential. Presence of at least two APh binding centers on the surface of AChE and BuChE is suggested.

Synthesis and anticholinesterase activity of O-carbamoylated alkylchloroform oximes. Sokolov, V. B.; Ivanov, Yu. Ya.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshestva, Chernogolovka, USSR. Khimiko-Farmatsevticheskii Zhurnal (1991), 25(4), 33-4.
Treating ClCO2N:CClR (R = Me, Et, Pr, CHMe2) with NHR1R2 (R1 = R2 = H, Me, Et; R1 = H, R2 = Me) in Et2O gave 50-69% R1R2NCO2N:CClR (same R-R3), which are acetyl- and butyrylcholinesterase inhibitors (k11 = 1.1  10-2 to 5.4  10-6 M-1 min-1). Acute oral toxicity in mice ranged from 32 to 565 mg/kg.

O-Alkyl O-methylchloroformimino phenylphosphonates - effective inhibitors of the hen brain neurotoxic esterase. Makhaeva, G. F.; Kononova, I. V.; Malygin, V. V.; Lyashenko, Yu. E.; Sokolov, V. B.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, USSR. Doklady Akademii Nauk SSSR (1991), 317(4), 1009-12 [Biochem.].
The title phosphonates were effective inhibitors of neurotoxic esterase; with increasing hydrophobicity the compds. showed pronounced and selective biol. activity towards brain neurotoxic esterase compared to acetylcholinesterase. Thus, the structure of phenylphosphonate played a major role in the inhibitory effects of these potential pesticides towards neurotoxic esterase or acetylcholinesterase.

Synthesis and anticholinesterase activity of fluorine-containing -aminophosphoryl compounds. Korenchenko, O. V.; Ivanov, Yu. Ya.; Aksinenko, A. Yu.; Sokolov, V. B.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, Russia. Khimiko-Farmatsevticheskii Zhurnal (1992), 26(6), 21-3.
Reaction of R2P(O)H (R = MeO, EtO, PrO, Me2CHO, Ph) with (CF3)2C:NCOR1 (R1 = OEt, OCH2Ph, OPr, OBu, OCH2CH2CHMe2, CF3) in Et2O gave 44-93% R2P(O)C(CF3)2NHCOR1. Treating a 1,4,2-oxazaphospholine deriv. with alcs. gave Me(R)P(O)C(CF3)2NHCO2Et (R = BuO, Me2CHO). Bimol. rate consts. for inhibition of cholinesterases by these compds. were detd.

Synthesis and insecticidal and acaricidal activity of O-alkylchloroformimine O,O-dialkyl phosphates and O,O-dialkylthiophosphates. Ivanov, A. M.; Ivanova, G. B.; Sokolova, V. B.; Epishina, T. N.; Goreva, T. V.; Beznosko, B. K.; Martynov, I. V.. Inst. Fiziol. Okl. Veshchestv., Chernogolovka, Russia. Fiziologicheski Aktivnye Veshchestva (1991), 23 58-62.
Of 26 title compds., those having ethoxy group at P were both insecticides and acaricides, whereas those having their methoxy group showed insecticidal activity only. Increasing hydrophobicity of the alkoxy substituents decreased i.m. toxicity to mice, but also the effectiveness. O replacement by S also decreased toxicity. Synthesis is indicated.

Paradoxical toxic effect and calcium antagonism of the cholinesterase inhibitors O-(N-arylcarbamoyl)acylhydroximoyl chlorides. Ivanov, Yu. Ya.; Sokolov, V. B.; Epishina, T. A.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Chernogolovka, Russia. Doklady Akademii Nauk (1993), 328(6), 744-6 [Biochem.].
N-phenylcarbamates and aliphatic analogs of the formula R R1N(O)ON::C(Cl)R2 [where R = Et, Me, and Ph; R1 = H, Me; R2 = Et, Pr, iso-Pr] were examd. for their acetylcholinesterase and butyrylcholinesterase inhibition, for their acute toxicity and their action on selective organs. The enzyme inhibition depended on their molecular structure. Paradoxical effects (higher dose and low toxicity and vice versa) were noted.

Crystal and molecular structures and synthesis of O,O-diisopentyl 1-(phenylsulfonamido)-1-(trifluoromethyl)-2,2,2-trifluoroethylphosphonate. Chekhlov, A. N.; Aksinenko, A. Yu.; Sokolov, V. B.; Martynov, I. V.. Inst. Fiziol. Akt. Veshchestv, Ross. Akad. Nauk, Chernogolovka, Russia. Doklady Akademii Nauk (1995), 345(3), 360-363.
Reaction of (CF3)2C:NSO2Ph and (Me2CHCH2CH2O)2P(O)H in Et2O gave 85% title compd. (Me2CHCH2CH2O)2P(O)C(CF3)2NHSO2Ph, the structure of which was detd. by x-ray crystallog.



[Edited on 2-4-2012 by AndersHoveland]
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[*] posted on 2-4-2012 at 21:30


One more comment, the chlorofluoronitrosomethane, that was previously mentioned as a precursor to some of the Novichok agents, is very similar to another chemical weapon, phosgene oxime, which is a nettle agent (it is fast-acting and causes chemical burns upon skin contact)

chlorofluoronitrosomethane ClCHF(-N=O)
phosgene oxime Cl2C=NOH
(phosgene oxime is formed by the reduction of chloropicrin, Cl3CNO2, with stannous chloride SnCl2.

The nitroso compound may likey be just a tautomer of the oxime, meaning the two could be the same compound.
ClCHF(-N=O) <==> ClCF=NOH

Formaldoxime is known to have similar equilibrium (usually existing in the trimer actually, although this is likely not the case of phosgene oxime), sometimes forming a nitrosomethane monomer in solution (although the nitroso groups themselves can potentially dimerise).

With some of these experimental agents, it seems they were trying to somehow combine two different chemical weapons onto the same molecule. This does not really seem like a logical approach, as there are two separate mechanisms of action, and the acetylcholinesterase inhibitor effects are usually much more potent than the other.

Also, to comment on the (CH3)2NCH2CH2S- group bonded to the phosphorous atom, I think the tertiary amine helps facilitate the hydrolysis of this group with the alcohol group on the target enzyme. The amine grabs the hydrogen ion, while the sulfur attaches to the oxygen of the former alcohol.* I am not really sure what advantage there is to this over a conventional P-F bond.

*Although the amine is fairly separated on this molecular group from the sulfur atom, it can still have a big effect. An excellent example of this is found in the nitrogen mustard agents. Usually chloroalkanes are relatively unreactive as alkylating agents, but when an tertiary amine is also present on the molecule like this, it becomes more potent. A typical nitrogen mustard has the structure ClCH2CH2N(CH3)CH2CH2Cl. (a sulfur atom can also be in place of the nitrogen, as in normal mustard gas, but in this case the sulfur takes a positive charge, which would be just the opposite of the sulfur in the above mentioned groups in the Novochok agents, which could likely come off with a negetive charge) The precise chemistry is more complex, but will not be mentioned here.




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[*] posted on 10-4-2012 at 22:50


To quantitatively discuss the potency of Military Organophosphates (MOPs), it's important to understand the basics of their molecular toxicology.

Inside the binding pocket of acetylcholinesterase (AChE), the hydroxyl group on the active site serine residue displaces the leaving group on the organophosphate by nucleophilic acyl substitution [1]. Like any nucleophilic substitution reaction, the kinetics are determined both by the accessibility of the electrophilic site (P, in this case) and the leaving group's ability to stabilize the negative charge transferred to it. The basic idea is an extension of nucleophilic acyl substitution on esters, which is discussed in any introductory organic chemistry textbook.

Up until this point, the phosphorylated enzyme is inhibited reversibly. Reactivation is slow under ordinary circumstances but can be achieved through oxime reactivators--basically, another nucleophilic acyl substitution in which the active site serine is the leaving group. Secondary reactions, collectively called aging, result in irreversible inhibition. One of the more important aging reactions is the loss of the alkyl group to form a formally negatively charged O=P-O(-) moiety [1]. In the case of Sarin, Soman, and DFP, which all possess branched R groups, it has been proposed that this involves the heterolytic cleavage of the O-R bond to form an alkyl carbenium ion [1]. In the case of soman, the pinacolyl carbenium ion can undergo a methyl shift to place the positive charge on a tertiary center and gain added stability. The formed negative charge on the phosphoryl group inhibits further nucleophilic attack (i.e., reactivation) [4].

According to this mechanism, any interactions in the alkyl group that could stabilize the nascent positive charge ought to increase the rate of the dealkylation reaction. This consideration would be mitigated by steric factors such as how well the organophosphate molecule fits inside the binding pocket of AChE and how accessible the central phosphorus atom is to the serine hydroxyl group.

So with my simplified explanation, we have a measurable, quantifiable idea of "potency." It is a combination of the following factors:
#__The ability of the molecule to reach the target site (toxicokinetics), which is affected in part by its lipophilicity.
#__Kinetics of the phosphorylation of the catalytic serine residue in AChE, which is affected by the leaving group ability, electrophilicity of the P center (more on this later), and sterics around the central P atom.
#__Kinetics of the aging reaction that prevents reactivation of the enzyme-substrate complex.

The specific enzyme-substrate interactions of different AChE's has some unexpected variability: serine is not the only residue involved ([5] and [6]). In the case of chiral nerve agents, R and S isomers have slighly different molecular toxikodynamics but the end result is the same. For that matter, AChE is not the only enzyme targeted by organophosphate nerve agents. This discussion is basically a summary of a thread I'd started in the Biochemistry section a few years ago [7].

Quote:
With some of these experimental agents, it seems they were trying to somehow combine two different chemical weapons onto the same molecule. This does not really seem like a logical approach, as there are two separate mechanisms of action, and the acetylcholinesterase inhibitor effects are usually much more potent than the other.


Dihaloformaldoxime looks like one of those funky groups on molecules with highly tailored end-uses that have resulted from lots of structure-activity relationship studies. It actually reminds me a lot of the structure of the organophosphate insecticide DDVP. For all we know, this may not even be a moiety in the fabled Novichok agents.

Wikipedia has a page on the Novichok agents now [3]. It mentions a book by V.S. Mirzayanov, published after the start of this thread, State Secrets: An Insider's Chronicle of the Russian Chemical Weapons Program (ISBN 9781432725662), which gives different structures for the Novichok agents. They're duplicated at the bottom of the wiki page and I'm including them in this post (see attachment). There are a few subgroups here: phosphoriminofluoridates, methyl phosphoniminofluoridates, phosphonothionofluoridates, and methyl phosphonoselenofluoridates (!).

So we're back to the P-F bond. I guess F (HF, really) is just an awesome leaving group for volatile organophosphorus compounds intended to shutdown AChE. Maybe the O=P-N=C-N(R2) moiety rearranges to form a group that is particularly inert toward oxime reactivating agents or is itself inert to reactivation?

That P=Se group seems especially interesting. Phosphorothionates (OP's with P=S) groups are unable to inhibit AChE in and of themselves because the P is not electrophilic enough. Instead, they undergo a rearrangement (thiolo-thiono rearrangement) via an intramolecular Sn2 mechanism in which the phosphoryl S attacks the carbon in the P-O-C moiety, displacing the oxygen and forming the oxon analog. This, in turn, makes the central P atom electrophilic enough to be attacked by the serine hydroxyl group. A bit of background: Pearson's hard bases (e.g., -OH in the serine residue) preferentially attack the phosphorus atom while Pearson's soft bases (e.g., -SH, -SeH) preferentially attack tetrahedral carbon atoms in OP's [4]. Selenium, being larger and squishier than sulfur, may allow phosphoroselenates to readily undergo an analogous rearrangement while maintaining the lipophilicity/hydrophobicity of the original molecule.

(And on a further tangent, there was a great article on the use of HSAB Theory for describing toxicant-target interactions in Chemical Research in Toxicology : dx.doi.org/10.1021/tx2003257 )

And this is another tangent but the actual chemistry is too interesting to ignore:

Quote:
A typical nitrogen mustard has the structure ClCH2CH2N(CH3)CH2CH2Cl. (a sulfur atom can also be in place of the nitrogen, as in normal mustard gas, but in this case the sulfur takes a positive charge, which would be just the opposite of the sulfur in the above mentioned groups in the Novochok agents, which could likely come off with a negetive charge) The precise chemistry is more complex, but will not be mentioned here.


Sulfur mustards undergo an internal Sn2 reaction in which the S atom displaces a beta Cl and forms an intermediate with a three-membered ring. This strained ring, in turn, is opened by --NH2 group of a protein residue in a second Sn2 reaction. [2] Another cool use of three-membered heterocycles in biological chemistry!

References:

1. Biochemistry 1999, 38, 7032-7039.
2. McMurry, John. Organic Chemistry, 6th edition, pp 380-381. Thomson Brooks/Cole: 2004.
3. http://en.wikipedia.org/wiki/Novichok_agent
4. "Organophosphorus Insecticides. " Plimmer, Jack R.; Gammon, Derek W.; Ragsdale, Nancy N. (2003). Encyclopedia of Agrochemicals, Volumes 1-3.. John Wiley & Sons.
Online version available at:
http://www.knovel.com/web/portal/browse/display?_EXT_KNOVEL_...
5. Biochemistry 2006, 45, 74 81
6. J. Am. Chem. Soc. 1999, 121, 9883 9884
7. "Toxicity of AChE Inhibitors on a Quantitative, Molecular level." http://www.sciencemadness.org/talk/viewthread.php?tid=12913

Novichoks-Mirzayanov.png - 40kB

[Edited on 4-12-12 by DDTea]




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