Unexpected Reaction Pathways Leading to Thiodiglycol During the

Subscriber access provided by University of Sunderland

Article

Unexpected Reaction Pathways Leading to Thiodiglycol During the Degradation of Long-Chain Sulfur Mustards Esther Gómez-Caballero, Roberto Martinez-Alvarez, and Miguel A. Sierra J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01670 • Publication Date (Web): 19 Sep 2018 Downloaded from http://pubs.acs.org on September 20, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Unexpected Reaction Pathways Leading to Thiodiglycol During the Degradation of Long-Chain Sulfur Mustards

Esther Gómez-Caballero,b Roberto Martínez-Álvarez,*,a Miguel A. Sierra*,a

Dedicated to the memory of Prof. Jiří Matoušek and his tireless efforts to eradicate chemical weapons

a

Departamento de Química Orgánica, Facultad de Química and Centro de Innovación en Química

Avanzada (ORFEO-CINQA), Universidad Complutense, 28040 Madrid, Spain. b

Laboratorio de Verificación de Armas Químicas (LAVEMA), Área de Defensa Química.

Departamento NBQM, Subdirección General de Sistemas Terrestres. INTA-Campus La Marañosa. M-301, km 10.5, 28330, Madrid, Spain.

Abstract: Degradation of long-chain sulfur mustards with various commercial decontaminants unexpectedly forms thiodiglycol (TDG) through unreported reaction pathways. Chemical warfare agents (CWAs) degradation products have to be unambiguously related to their reference compounds in order to fulfil international verification protocols. Thus, the formation of TDG using water based decontaminants introduce an uncertainty in the origin of this chemical that has been systematically used to unambiguously demonstrate the presence of yperite in environmental and biomedical samples. Therefore, these novel and unprecedented degradation pathways will result either in modifications of the international verification protocols for forensic purposes, or in the exclusion of TDG as an exclusive marker of yperite.

ACS Paragon Plus Environment

1

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 26

Introduction. The purpose of decontamination of Chemical Warfare Agents (CWAs) is to neutralize the threat imposed by their use, either on purpose (war or terrorism) or accidental (leakage from laboratories using CWAs for research or within the goals allowed by the Chemical Weapons Convention).1 Additionally, the decontamination process has to secure areas like former facilities of CWA production, facilities for the destruction of CWAs stockpiles, as well as old and abandoned chemical weapons. Since CWAs possess an extremely high risk not only for human life but also for the environment,2,3 fast and efficient decontamination systems are always required.4-6 One century ago, the use of sulfur mustard (mustard gas, yperite or HD), 1, in the WWI European theatre initiated the modern chemical warfare era.7 In parallel, decontamination methods had to be developed urgently.3 Mustard gas has been used recursively in different war conflicts; the most recent, the Iran-Iraq conflict (1980-1988)

8

and the Syria civil-war (2011 to present).9 In

consequence, the behavior of sulfur mustard against several decontamination systems and its impact in the environment has been profusely studied. 3,6,10-19 The alleged use of CWAs is supervised by the Organization for the Prohibition of Chemical Weapons (OPCW) through a very restrictive verification protocol.20,21 This protocol establishes that to unambiguously determine the use of a CWA, the identification of unaltered agent or any of its degradation products must be based on at least two different analytical techniques giving consistent results; the primary technique must be a data rich spectrometric technique.22 From a forensic


2

Page 3 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


approach, should a degradation compound originate from two different CWAs, the identification of this compound must be traced to more than one chemical. In the absence of additional proofs, the results of the verification process will be ambiguous. Therefore, a deep understanding about the conditions and mechanism of formation of such degradation chemicals is required. We report herein that one of the accepted markers for the presence of yperite, 1, namely thiodiglycol (TDG), 2, can be formed from long-chain sulfur mustards by different reaction pathways during their treatment with several commercial decontaminants, and even during the synthesis of some of these CWAs. TDG, is formed during the degradation of sulfur mustard by well-stablished pathways, and thence, it has been used as a marker of the use of this CWA.23 In fact, the presence of this degradation product (either by decontamination or by environmental evolution) has been considered a proof of the use of mustard gas. TDG is originated by hydrolysis of a cyclic sulfonium intermediate 3 formed by the intramolecular SN displacement (in water SN1-type) of the chlorine by the sulfur atom in the yperite, 1. A second similar reaction on intermediate 4 forms thiodiglycol through cation 5. Alternatively, cation 5 may undergo an intramolecular nucleophilic displacement forming 1,4-thioxane, 6 (Scheme 1).


3


S

Cl

Cl

Cl

1, mustard gas, yperite or HD

Page 4 of 26

ClH 2O

S

3 - HCl

ClH 2O

S

Cl

OH

S

OH

4

5 - HCl

- HCl

S S

HO

OH 2 (TDG)

O 6

Scheme 1. Formation of sulfur mustard degradation products.

During an ongoing project

24

directed towards determining the efficiency of several commercial

preparations for military and civil use to decontaminate long-chain sulfur mustards, that contrary to yperite have been not extensively studied.25-27 We became aware that, under certain circumstances, TDG was formed, in the absence of sulfur mustard and of reagents that could form this product during the decontamination process. Since these observations are of relevance, not only as novel reaction pathways for the degradation of sulfur mustards, but also in the context of homeland and world safety, as well as for the OPCW verification regime, we pursued the study of the conditions and reaction pathways in which TDG may be formed. Results and Discussion. Long-chain sulfur mustards 7 and 8 are the higher homologues of sulfur mustard, 1, (Scheme 2). These compounds have been weaponized and they are included in the schedule 1.A.04 of the Chemical Weapons Convention (CWC).1 The preparation of long-chain sulfur mustards was first reported in 1921.28 For the purposes of this study, compounds 7 were prepared from 2-


4

Page 5 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


chloroethanol and 1,n-alcanedithiols (n = 2-5) in the presence of sodium ethoxide, followed by treatment of the diols thus obtained with thionyl chloride. Oxymustard 8 was prepared by reaction of 2-mercaptoethanol and 1-bromo-2-(2-bromoethoxy) ethane in the presence of sodium ethoxide, followed by treatment with thionyl chloride (Scheme 2). Further purification of compounds 7 and 8 was not pursued to mimic a real scenario of synthesis of these CWAs for terrorist use. The purity of compounds 7 and 8 was determined by 1H NMR using either methyldiethanol amine or 2,6dimethylphenol as internal standards (see the Experimental Section). OH

Cl

1.EtOH, Na +

HS

Cl

2. SOCl2

Cl

nS

7a, n = 2 7b, n = 3 7c, n = 4 7d, n = 5

SH n

n = 2,3,4,5 OH

HS

1.EtOH, Na +

Br

S

O

Cl

S

2. SOCl2 Br

O

S

Cl

8

Scheme 2. Synthesis of long-chain sulfur mustards 7 and 8.

Compounds 7 and 8 were treated with water based and organic based commercial decontaminants. Water based formulations were in general, less efficient than organic based decontaminants due to poorer solubility of long-chain sulfur mustards 7 and 8 in water. In fact, heavy mustards 7 and 8 were detected in some water-based decontaminants even after seven days of decontamination while no traces of these mustards were detected in organic decontaminants after twenty four hours of degradation.29 The GC-MS analysis of the degradation mixtures resulting from the treatment of long-chain sulfur mustard 7a with water based formulations RM21, RM31, BX24, BX29, and BX40

30

shows

hydrolysis products 9 and 10, condensation products 11 and 12 and TDG 2, (Scheme 3).31 TDG


5


appears from the beginning of the degradation process (measured after 90 minutes) and steadily increases with time (Figure 1, left graphic). Chemical 11 is formed with all decontaminant solutions tested but compound 12 was not formed either with RM21 or RM31 and increased slowly with time with formulations BX24, BX29 and BX40 (Figure 2).

Cl

RM21,RM31,

7a

HO

S

S

S

S

HO

OH +

S

S

S

OH

S

11

10 HO

OH

9

BX24,BX29,BX40

S

S

S

OH +

HO

12

S

OH

2

Scheme 3. Main degradation products obtained in the degradation of 7a with water-based formulations.

Oxymustard 8 behaves similarly to mustard 7a (Figure 1, right graphic), but, in this case, apart from the expected hydrolysis products 13 and 14 and TDG no condensation products were observed (Scheme 4). % 2 in the decontamination of 8

% 2 in the decontamination of 7a 8

30 25

6

20 15 10 5 0

4

90 min

24 hours

2

24 hours

7 days

0

90 min

RM21 RM31 BX24

BX29

BX40

%2

%2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 26

7 days RM21 RM31 BX24

Decontaminants

BX29

BX40

Decontaminants

Figure 1. Formation of TDG, 2, in the degradation of 7a and 8.


6

Page 7 of 26

% 11 in the decontamination of 7a

% 12 in the decontamination of 7a 4

30 20

% 12

% 11

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


90 min

10

3

24 hou rs

0 BX 24

90 min

1

24 hours

0

7 days

RM21

2

RM21 RM31

BX 40

Decontaminants

7 days BX 24 BX 29 BX 40

Decontaminants

Figure 2. Formation of condensation products 11 and 12 during the degradation of 7a. Mustards 7b-d originated the expected hydrolysis products analogous to 9 and 10. However, TDG was not observed in these cases.

The formation of TDG during the degradation of mustards 7a and 8 is not easily explained within the framework of the established mechanisms for the degradation of yperite 1.6,10-15 Moreover, the formation of TDG is crucial in the formation of condensation products 11 and 12. Therefore, a different reaction mechanism should be proposed to explain the apparition of this product, and by extension of compounds 11 and 12 (see below). 8

RM21,RM31

S

Cl

O 13

BX24,BX29,BX40

HO

S

O

S

OH + HO

S

OH

S

OH

2

14

Scheme 4. Main degradation products obtained in the decontamination of 8 with water-based formulations We propose the following mechanism to explain the formation of thiodiglycol 2 in the degradation of mustard 7a with formulations RM21, RM31, BX24, BX29 and BX40. Intermediate 15 reacts with the aqueous basic media by attack of the hydroxyl anion to the a-carbon attached to the sulfur


7


Page 8 of 26

of the thiirane cation. This process yields thiirane together with TDG Further hydrolysis of thiirane will form 2-mercaptoethanol (Scheme 5). This pathway will be, not only competitive with the “standard” hydrolysis pathway leading to 10 but also responsible of the formation of condensation products 11 and 12 (see below). Cl

RM21,RM31,

7a

S

S

HO

OH +

S

S

S

S

OH

11

10 HO

OH

9

BX24,BX29,BX40 HO

S

S

S

S

S

OH +

HO

12

S

OH

2

Scheme 5. Mechanism of the formation of TDG 2 and mercaptoethanol from 9.

To rationalize these competitive reaction pathways, we computed the formation of thiodiglycol 2 from 15.32 We began with the preformed cyclic sulfonium intermediate 15, which will evolve to the “expected” hydrolysis product 10 through TS16-1 (pathway A in Figure 3) derived from the attack of HO– to the carbon of the three membered ring, or to TDG through TS16-2, produced by attack of the HO– to the a-carbon to the thiirane ring (pathway B in Figure 3) together with thiirane. The computed energy for both reaction pathways is very similar (9.9 kcal mol-1 for path A vs 9.1 kcal mol-1 for path B) and both pathways are strongly exergonic (-66.9 kcal mol-1 for path A vs -58.3 kcal mol-1 for path B). In consequence, both degradation pathways are competitive under the degradation conditions used.


8

Page 9 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


OH HO

S

HO

S

S

HO

TS16-1

TS16-2

+9.9

HO

S

S

S

+9.1

+ HO–

15

-58.3

Path A Path B

HO

-66.9 HO

S

S 10

S

OH

2 OH

+ S

Figure 3. Computed reaction pathways (B3LYP/6-31G**,GD3 in H2O) for the formation of TDG, 2, and hydrolysis product 10.

The degradation of oxymustard 8 (Scheme 4) follows a different reaction pathway. In fact, now the intermediate cyclic sulfonium cation 17 could not form TDG. Evolution of this cation 17, formed by reaction of the sulfur atom with the chlorine in a SN1-type reaction, may occur by attack of the hydroxyl anion to the thiirane cation to form the “standard” hydrolysis product 14. Alternatively, reaction of the base on the a-carbon attached to the sulfur will form compound 18 together with thirane, which by hydrolysis will form 2-mercaptoethanol. However, there is an alternative reaction pathway that occurs through 1,4-thioxane cationic intermediate 19 formed by the intramolecular


9


Page 10 of 26

displacement of chlorine by the oxygen of intermediate 13. Intermediate 19 will evolve to TDG and 1,4-thioxane, 6 by reaction of HO– with the a-carbon attached to the oxygen. Obviously, the attack of the HO– to the ring oxygen a-carbon will form the “standard” hydrolysis product 14 (Scheme 6). S

HO

O

S

Cl

13 HO– S

HO

19

S

HO

S

S

HO

S

S

O 17

HO–

HO–

OH

2 + O

O

14

HO

S

O

OH

14

18 + S

6

Scheme 6. Mechanisms of formation of 14 and TDG, 2 from 13. The viability of the mechanisms depicted in Scheme 6 depends on the relative energies involved in the formation of intermediates 17 and 19 from intermediate 13. Should be the energies required to form 17 and 19 very different, it will be difficult to assume that both pathways are competitive. Therefore, we first computed both reaction pathways (Figure 4). Formation of thiirane intermediate 17 through TS20-1 requires 23.8 kcal mol-1, (path A) an energy barrier accessible in the decontamination conditions. This barrier is casually identical to the one required for the formation of 1,4-thioxane cation 19 (23.8 kcal mol-1) through TS20-2 (path B). Thus, it is reasonable to assume that in the conditions used, the formation of both intermediates is competitive. Moreover, based in the reaction profiles in Figure 4 it is reasonable to assume that the reaction should occur exclusively through a six-membered intermediate, since formation of the intermediate


10

Page 11 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


17 is clearly reversible. Support for this asseveration is the absence of condensation products in the degradation of 8. These polycondensation products require 2-mercaptoethanol formed by extrusion of thiirane from 17. Since thiirane should not be formed according to this hypothesis, these products are not present in the degradation of oxymustard 8, as it was experimentally demonstrated. Cl

Cl R

S

O

O R

TS20-1 -0.2 23.8 R

S

S

S

TS20-2 23.8

17 + Cl–

-8.9

O R

S 19

+ Cl–

Cl

S

O

Path A Path B

R

13 R = CH2SCH2CH2OH

Figure 4. Computed reaction pathways (B3LYP/6-31G**,GD3 in H2O) for the formation of 17 and 19 Finally, we computed the energies involved in the evolution of 19 to TDG, 2, and 1,4-thioxane, 6, through TS21-2 (path A in Figure 5), and to the “expected” hydrolysis product 14 through TS21-1 (pathway B in Figure 5). Path A is 3.6 kcal mol-1 higher in energy than path B, being both pathways strongly exergonic and showing accessible energy barriers (12.5 kcal mol-1 and 8.9 kcal mol-1, respectively). Therefore, the production of TDG by this alternative reaction pathway accounts for its detection in the degradation of oxymustard 8.


11


Page 12 of 26

S

OH O

O

R HO

TS21-2

S

12.5

R TS21-1 8.9

S + HO–

O R

19

R = CH2SCH2CH2OH

-55.4

R O

S

OH

-67.2

14

S

HO Path A Path B

OH

2 +

O

S

Figure 5. Computed reaction pathways (B3LYP/6-31G**,GD3 in H2O) for the formation of TDG, 2, from 8. Formation of thiirane and hence of 2-mercaptoethanol in the degradation of mustard 7a accounts for the observation of polycondensation products 11 and 12 in these processes. The formation of these products occurs by attack of the more nucleophilic thiol moiety (as thiolate in the basic decontamination media) to the cyclic sulfonium

intermediates 21 and 22. Thus, the three

membered ring of cyclic sulfonium intermediate 21 will be opened to form 23 which upon transformation into a new thiirane 22 will form 11 and 12, by hydrolysis or reaction with 2-


12

Page 13 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mercaptoethanol, respectively (Scheme 7). This is a reasonable pathway and supports the mechanisms for the degradation of long-chain sulfur mustards proposed throughout this work. S

Cl

S

S

Cl

21 + HO

S

S

OH

23 SH S

S

S

OH

22 H 2O 11

HS

OH

12

Scheme 7. Mechanism of formation of 11 and 12 from 21.

The key point for the formation of condensation products 11 and 12, during the degradation of heavy mustards is the formation in the media of 2-mercaptoethanol. This compound is produced by the ring opening of thiirane in the aqueous media. However, while the formation of cyclic sulfonium intermediates is common to the degradation of all the studied mustards, formation of condensation products occurs exclusively during the degradation of the heavy mustard 7a. The degradation of this mustard occurs through intermediates like 22 having a sulfur atom at the b position of the thiiranium group. The remaining heavy mustards studied (7b-d) have the sulfur atom located at g, d etc positions. These data pointed to the anchimeric assistance of the b-sulfur to the extrusion of thiirane in intermediates like 15. As it is well known this assistance is less effective when the sulfur moiety is located in more remote positions.33 Therefore, condensation products are not expected in the degradation of heavy mustards 7b-d.34,35 Conclusions. In conclusion, long-chain sulfur mustards 7a and 8 form TDG during degradation processes with different commercial formulations used to neutralize CWAs. The degradation of mustard 7a


13


Page 14 of 26

occurred through two nearly isoenergetic competitive reaction pathways sharing a common intermediate (15 in Figure 3). The formation of TDG, occurs through an SN2 attack with extrusion of thiirane. The hydrolysis of the cyclic sulfonium intermediate yields 2-mercaptoethanol, that by ulterior reaction with different intermediates of the hydrolysis of mustard 7a accounts for the formation of polycondensation products 11 and 12. On the contrary, degradation of oxymustard 8 occurred through the formation of a six-membered 1,4-thioxane intermediate 19 rather than a threemembered episulphonium intermediate 17 (Scheme 6). This pathway leads to TDG by reaction of the intermediate 19 with base in a SN2 process with extrusion of 1,4-thioxane, 6. Formation of the six membered cyclic intermediate is more favorable than the pathways occurring through cyclic sulfonium intermediate like 17. Therefore, the formation of 2-mercaptoethanol is not expected in this case, and polycondensation products are not experimentally observed. This set of results obtained with commercial decontaminants in the degradation of long-chain sulfur mustards questions the use of TDG as an exclusive marker for the use of yperite. Since the degradation products of CWAs have to be unambiguous in their origin to be used in the international verification protocols for forensic purposes, our results introduce an uncertainty element that may result either in modifications of the verification systems, or in the exclusion of TDG as an exclusive marker for yperite (both in the analysis of environmental and biomedical samples). Experimental Section. General Information. Unless otherwise stated, all reagents were used as received from commercial sources. The synthesis of long-chain mustards were effected under argon using standard Schlenk techniques. Solvents used in decontamination samples were of GC quality for trace analysis. Decontaminant agents were used as


14

Page 15 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


received from commercial suppliers, except for BX24 that was solved in water following recommendations of use in technical literature. 1

H-RMN were recorded at 400 MHz in CHCl3 (7.26 ppm). GC-MS analyses were carried out in EI

mode at 70 eV or CI (using NH3). Columns used forGC experiments were DB5-ms (30 m, 0.25 mm, 0.25 µm) and OV1701-ms (30 m, 0.25 mm, 0.25 µm). Mass spectra were recorded in a MSD 5973 spectrometer coupled to a 6890 GC (Agilent Technologies). The obtained results are given as m/z. The values in brackets (%) are given related to the base peak (100%). Computational Methods. Geometry optimizations without symmetry constraints were carried out by using the Gaussian 09 suite of programs 36 using the B3LYP functional 37-39 in conjunction with the D3 dispersion correction suggested by Grimme.40 The 6-31G** basis set was used for the H, C, O, and S atoms. All structures of the reactants, intermediates, transition states, and products were fully optimized in H2O as the solvent and using the polarizable continuum model (PCM) method.41-43 Reactants and products were characterized by frequency calculations,44 and have positive definite Hessian matrices. Transition structures (TS’s) show only one negative eigenvalue in their diagonalized force constant matrices, and their associated eigenvectors were confirmed to correspond to the motion along the reaction coordinate under consideration using the Intrinsic Reaction Coordinate (IRC) method.45 All energies collected in the text are Gibbs energies at 298 K. Synthesis of long-chain mustards, 7a-d and 8. Mustards 7a-d and 8 were prepared following the methods reported by Gupta

46

and Kaushik

47

with modifications. WARNING: Long-chain mustards 7a-d and 8 are strong vesicant chemical warfare agents controlled by the OPCW. The synthesis of these compounds must be carried out by specialized chemists using appropriate protection equipment in approved installations to manipulate CWC Schedule 1 chemicals.


15


Page 16 of 26

1,2-bis(2-Chloroethylthio)ethane, 7a. To a solution of metallic sodium (23.4 mmol, 0.54 g) in 20 mL of absolute EtOH, 1,2-ethanedithiol was added dropwise (net, 10.6 mmol, 1g) under argon atmosphere. The resulting mixture was heated during 1 hour and cooled to rt. 2-Chloroethanol (22.3 mmol, 1.80 g) was added dropwise to this solution, and the resulting mixture was refluxed with constant stirring for 1.5 hours. To 1 g (5.5 mmol) of the product obtained by solvent removal, solved in 5 mL of anhydrous DCM and cooled to 0ºC (ice bath), a solution of SOCl2 (22 mmol, 1.6 mL) in 5 mL of DCM was added dropwise. The mixture was stirred for 1 hour at rt and the solvent was removed. Mustard 7a was obtained as a white solid (1.16 g, 5.3 mmol, yield 91%; 96.4% purity determined by 1H NMR). Traces of yperite, 1, were also detected. 1H NMR (CDCl3) δ: 2.79 (s, 4H, CH2), 2.90 (t, J=7.8Hz, 4H, CH2), 3.65 (t, J=7.8Hz, 4H, CH2). MS(EI,70eV) m/z (%B): 218(M.+,7), 182(21), 123(100), 109(67), 73(30), 63(59), 45(33). MS(CI,NH3) m/z (%B): 236[M+NH4]+(89), 183(100), 155(16), 140(13), 123(29) 1,3-(2-Chloroethylthio)propane, 7b. Following an analogous procedure from 1.8 g (9.2 mmol) of the intermediate obtained from 0.47 g (20.4 mmol) of metallic sodium, 1 g (10.64 mmol,) of 1,3propanethiol and 1.64 g (20.38 mmol) of 2-chloroethanol, 1.26 g of 7b were obtained as a yellow oil (1.27 g, 5.45 mmol, 59 % yield, 77% purity as determined by 1H NMR). 1H NMR (CDCl3) δ: 1.88 (q, J=6Hz, 2H, CH2], 2.69 (t, J=6Hz, 4H, CH2), 2.86 (t, J=6Hz, 4H, CH2), 3.64 (t, J=6Hz, 4H, CH2) MS(EI,70eV) m/z (%B): 232(M.+,8), 196(9), 169(100), 133(17), 107(33), 87(20), 73(34), 63(23), 45(21). MS(CI,NH3) m/z (%B): 250[M+NH4]+(52), 169(100) 1,4-(2-Chloroethylthio)butane, 7c. Following an analogous procedure from 1.72 g (8.18 mmol) of the intermediate obtained from 0.41 g (18.0 mmol) of metallic sodium, 1 g (8.18 mmol,) of 1,4butanethiol and 1.45 g (18.0 mmol) of 2-chloroethanol, 1.26 g of 7c were obtained as a dark brown oil (1.26 g, 5.13 mmol


16

Page 17 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


, 63 % yield, 93.3% purity as determined by 1H NMR). 1H NMR (CDCl3) δ: 1.71 (m, 4H, CH2), 2.59 (m, 4H, CH2), 2.86 (t, J=6Hz, 4H, CH2), 3.66 (t, J=6Hz, 4H, CH2). MS(EI,70eV) m/z (%B): 246(M.+,4), 210(15), 183(100), 151(52), 109(88), 87(67), 73(27), 63(39), 55(43), 45(30). MS(CI,NH3) m/z (%B): 264[M+NH4]+(61), 183(100) 1,4-(2-Chloroethylthio)pentane, 7d. Following an analogous procedure from 1.64 g (7.3 mmol) of the intermediate obtained from 0.37 g (16.1 mmol) of metallic sodium, 1 g (7.3 mmol,) of 1,5pentanethiol and 1.23 g (16.1 mmol) of 2-chloroethanol, 0.73 g of 7d were obtained as a dark brown oil (0.93 g, 3.57 mmol, 43 % yield, 81.8% purity as determined by 1H NMR). 1H NMR (CDCl3) δ: 1.44-1.65 (m, 6H, CH2), 2.57(t, J=6Hz, 4H, CH2), 2.85(t, J=9Hz, 4H, CH2), 3.63(t, J=9 Hz, 4H). MS(EI,70eV) m/z (%B): 260 (M.+, not detected), 224(32), 197(23), 165(49), 129(64), 109(94), 101(87), 87(24), 69(100), 63(50), 45(29). MS(CI,NH3) m/z (%B): 278[M+NH4]+(100), 225(46) Bis(2-chloroethylthioethyl)ether, 8. To a solution of metallic sodium (17 mmol, 0.39 g) in 20 mL of absolute EtOH, 2-mercaptoethanol (net, 16 mmol, 1.25 mL) was added dropwise under argon atmosphere. The resulting mixture was heated during 0.5 hours and cooled to rt. Bis(2bromoethyl)ether (8 mmol, 2.0 g) was added to this solution, and the resulting mixture was refluxed with constant stirring for 2.0 hours. After this time, a white solid appeared. The resulting slurry was cooled, the solid filtered and washed with 15 mL of DCM. The solvent of the resulting solution was evaporated, the residue dissolved in 20 mL of Cl3CH and the solution washed with brine. The organic layer was dried (Na2SO4) and the solvent removed. The expected diol was obtained as a pale yellow solid. To 0.83 g (3.67 mmol) of the diol in 20 mL of anhydrous DCM and cooled to 0ºC (ice bath), a solution of SOCl2 (14.7 mmol, 1.05 mL) in 5 mL of DCM was added dropwise. The mixture was stirred for 1 hour at rt and the solvent was removed. Mustard 8 was obtained as a


17


Page 18 of 26

brown oil (0.68 g, 2.6 mmol, yield 72%; 95% purity determined by 1H NMR). 1H NMR (CDCl3) δ: 2.75 (m, 4H, CH2), 2.92(m, 4H, CH2), 3.65(m, 4H, CH2), 3.65(m, 4H, CH2). MS(EI,70eV) m/z (%B): 262(M.+, not detected), 226(6), 199(6), 123(100), 63(51), 45(29). MS(CI,NH3) m/z (%B): 280[M+NH4]+(100) Procedure for the decontamination of 7a-d and 8 with water-based formulations: 3 mL decontaminant was added to 20 mg of the mustard. 1 mL of acetone was added to enhance the solubility of the mustard in the reaction media. The mixture was stirred for 90 minutes in an ultrasonic bath (mixture A). 500 µL of the mixture A was added to 3 mL of milli Q water (mixture B) 300 µL of the mixture B was evaporated to dryness under gentle N2 stream. The residue was redisolved in MeCN and 50 µl of BSTFA and heated at 60ºC for 30 minutes. The same procedure was performed with mixture A after 24 hours and 7 days. Chromatographic analysis. The aliquots have been analyzed by GC-MS (EI, CI), using a DB5-ms or OV1701-ms (30 m, 0.25 mm, 0.25 µm) columns. The temperature program was 40ºC, 1 minute, 10ºC/minute, 280ºC, 10 minutes. Splitless mode, temperature injector 250ºC. Injection volume 1 µL, and delay solvent 6.5 minutes. The MS parameters in EI mode were: source temperature 230ºC and analyzer 150ºC, and in CI mode, source temperature 250ºC and analyzer 150ºC. Associated Content. Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxx. GC and MS data of degradation mixtures, and Cartesian coordinates.


18

Page 19 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Author Information. Corresponding Authors: E-mail: MAS: [email protected]; RMA: [email protected] ORCID: Roberto Martínez-Álvarez: 0000-0002-4185-7698 Miguel A. Sierra: 0000-0002-3360-7795

Notes. The authors declare no competing financial interest. Acknowledgements. Support for this work under grants CTQ2016-77555-C2-1-R and CTQ2016-81797- REDC (Programa Redes Consolider) from the MINECO (Spain) is gratefully acknowledged. We also thank Fundación Ramón Areces for financial support. The authors gratefully acknowledge the assistance of Ms. Gema de Rivas and Clara Nova for their help with sample preparation; Drs. María Sierra, Daniel Pellico and Margarita Altable for the synthesis of long chain sulfur mustards; and Juan Manuel Moreno, Nerea Picazas and Nuria Aboitiz for their help with GC analyses. Continuous support and encouragement by Col. Fernández and Gen. Monforte are also acknowledged.

References and Notes. 1 Chemical Weapons Convention (CWC) https://www.opcw.org/chemical-weaponsconvention/ (Accessed September 10, 2018) 2

Romano, J. A.; Lukey, B. J.; Salem H. Chemical Warfare Agents Chemistry, Pharmacology, Toxicology, and Therapeutics; CRC Press: Boca Ratón, 2008.

3

Talmage, S.;.Munro, N. B; Watson, A. P.; King, J. F.;. Hauschild, V. The Fate of Chemical Warfare Agents in the Environment in Chemical Warfare Agents:


19


Page 20 of 26

Toxicology and Treatment, 2nd ed.; Marrs, T.C.; Maynard, R. L.; Sidell, F. R., Ed.; John Wiley & Sons:Chichester, U.K., 2007. 4

Giannakoudakis, D. A.; Bandosz, T. J. Detoxification of Chemical Warfare Agents: From WWI to Multifunctional Nanocomposite Approaches; Springer: Berlin, Germany, 2018.

5

Altmann, H. J.; Richardt, A. Decontamination of Chemical Warfare Agents in Decontamination of Warfare Agents: Enzymatic Methods for the Removal of B/C Weapons; Richardt, A.; Blum, M. M., Eds; Wiley-VCH: Weinheim, Germany, 2008.

6 Yang, Y. C.; Baker, J. A.; Ward, J. R. Decontamination of chemical warfare agents. Chem. Rev. 1992, 92, 1729-1743. 7

The first mustard gas bombardment by the German army on British troops in Ypres occurred the night of 12-13 of July, 1917. Some 50,000 shells containing 125 tons of yperite were used on this night. See: Hanslian, R. Der Chemische Krieg; Mittler, E S & Sohn: Berlin, Germany, 1937. See, also ref 3 page 375.

8 United Nations, Security Council. Report of the Specialists Appointed by the Secretary-General to Investigate Allegations by the Islamic Republic of Iran Concerning the Use of Chemical Weapons. New York, NY: United Nations. Documents 5/15834 (June 2, 1983), 5/16433 (March 26, 1984), 5/18852 (May 8, 1987), 5/19823 (April 25, 1988), 5/20063 (July 25, 1988), and 5/20134 (August 19, 1988).Accessed September 10, 2018

9 http://www.un.org/zh/focus/northafrica/cwinvestigation.pdf (Accessed September 10, 2018)


20

Page 21 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


10 Popiel, S.; Witkiewicz, Z.; Szewczuk, A.J. The GC/AED studies on the reactions of sulphur mustard with oxidants. J. Hazard. Mater. 2005, 123, 94-111. 11 Popiel, S.; Witkiewicz, Z.; Nalepa, T. The reactions of sulphur mustard with the active components of organic decontaminants. J. Hazard. Mater. 2005, 123, 269-280. 12 Talmage, S.S.; Watson, A.P.; Hauschild, V.; Munro, N.B.; King, J. Chemical Warfare Agent Degradation and Decontamination. Curr. Org. Chem. 2007, 11, 285298. 13 B. Singh, G.K. Prasad, K.S. Pandey, R.K. Danikhel and R. Vijayaraghavan. Decontamination of chemical warfare agents. Defence Sci. J. 2010, 60(4), 428-441. 14 A.W. Kahn, S. Kotta, S.H. Ansari, J. Ali and R.K. Sharma. Recent advances in decontamination of chemical warfare agents Defence Sci. J. 2013, 63(5), 487-496. 15 Sachin, L.S.; Karthikra, R.; Kumar, K.K.; Sony, T.; Raju, P.; Prabhakar, S. Mass Spectral Studies on Vinylic Degradation Products of Sulfur Mustards under Gas Chromatography/Mass Spectrometry Conditions Eur. J. Mass Spectrom. 2015, 21, 791-800. 16 Hung, H.; Kah, D.; Lim, K. Ch.; Lee, J.Y. Fate of sulfur mustard on soil: Evaporation, degradation, and vapor emission. Environ. Poll. 2017, 220, 478-486. 17 Medvedevaa, N.; Polyaka, Y.; Kuzikova, L.; Orlova O.; Zharikov, G. The effect of mustard gas on the biological activity of soil. Environ. Res. 2008, 106, 289-295. 18 Popiel, S.; Nawała, J.; Dziedzic, D.; Söderström, M.; Vanninen P. Determination of Mustard Gas hydrolysis Products Thiodiglycol and Thiodiglycol Sulfoxide by Gas Chromatography-Tandem Mass Spectrometry after Trifluoroacetylation. Anal. Chem. 2014, 86, 5865-5872.


21


Page 22 of 26

19 Brevett, C.A.S.; Sumpter K.B.; Nickol, R.G. Kinetics of the degradation of sulfur mustard on ambient and moist concrete. J. Hazard. Mat. 2009, 162, 281-291 and the pertinent references therein. 20 https://www.opcw.org/chemical-weapons-convention/annexes/verification–annex/ (Accessed September 10, , 2018). 21 Sassolini, A.; Brinchi, G.A.; Di Gennaro, S.; Dionisi, C.; Dominici, L.; Fantozzi, G.; Onofri, R.; Piazza M.; Guidotti, M. Evaluation of Molecular Markers and Analytical Methods Documenting the Occurrence of Mustard Gas and Arsenical Warfare Agents in Soil. Bull. Environ.Contam Toxicol. . 2016, 97, 432-438. 22 QDOC_LAB_WI_PT04_iss2_rev3.pdf 23 Determination of TDG 2 and TDGO (thiodiglycol sulfoxide) arising from the oxidation of TDG is routinely employed to prove the use or the presence of sulfur mustard. See references 20-21and the pertinent references cited therein. 24 Gómez-Caballero. E. Study of the behavior of heavy sulfur mustards against commercial decontaminants. PhD Thesis, Universidad Complutense, Madrid July, 2017. 25 Timperley, C.M.; Black, R.M.; Bird, M.; Holden, I.; Mundy, J.L.; Read, R.W. Hydrolysis and Oxidation Products of the Chemical Warfare Agents 1,2-Bis[(2chloroethylthio)]ethane

Q

and

2,2´-Bis(2-chloroethylthio)diethyl

Ether

T.

Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 2027-2046. 26 D´Agostino, P.A.; Provost. P.R. Capillary column electron impact and ammonia chemical ionization gas chromatographic-mass spectrometric and chromatographictandem mass spectrometric analysis of mustard hydrolysis products J. Chromatogr. A 1993, 645, 283-292.


22

Page 23 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


27 D´Agostino, P.A.; Provost P.R.; Hancock, J.R. Analysis of mustard hydrolysis products by packed capillary liquid chromatography-electrospray mass spectrometry J. Chromatogr. A. 1998, 808, 177-184. 28 Bennett, G.M.; Whincop, E.M. Some derivatives of monothioethylene glycol J. Chem. Soc. Trans. 1921, 119, 1860-1864. 29 The behavior of long-chain sulfur mustards in their decontamination processes with organic based decontaminants will be published in due time. 30 These commercial decontaminants are water based and they have pH>7 in all cases. See de SI for the specific formulations. 31 Traces of HD 1 were observed during the synthesis of long-chain sulfur mustard 7a. The anomalous formation of compound 1 can be explained by chlorination of TDG 2, formed by degradation of 7a during the synthetic procedure. However, these traces did not account either for the amounts of TDG 2 observed or for the polycondensation products obtained. See text. 32 DFT calculations were carried out at the PCM (H2O)-B3LYP/6-31G**, D3 level of theory using the Gaussian 09 suite of programs. 33 This clever explanation for the formation of condensation products 11 and 12 was proposed by a reviewer. In fact, anchimerically assisted extrusion of thioxane may be also a competitive reaction pathway in the formation of TDG from intermediate 19. Further work to disentangle the origin of these and related classes of condensation products is underway in our laboratories. We thank to the anonymous reviewer for his/her insight.


23


Page 24 of 26

34 S. Y. Bae, M. D. Winemiller. Mechanistic insights into the hydrolysis of 2-chloroethyl ethylsulfide: the expanded roles of sulfonium salts. J. Org. Chem. 2013, 78, 64576470 35 . Aricò, A. S. Aldoshin, P. Tundo. Mustard carbonate analogues: influence of the leaving group on the neighnoring effect. ACS Sustainable Chem.Eng. 2016, 4, 28432851 36 Gaussian 09, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2009. 37

Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange J. Chem. Phys. 1993, 98, 5648-5652;

38 Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density Phys. Rev. B 1998, 37, 785-789;


24

Page 25 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


39 Vosko, S. H.; Wilk, L.; Nusair, M. Accurate spin-dependent electron liquid correlation energies for local spin density calculations: a critical analysis Can. J. Phys. 1980, 58, 1200-1211. 40 Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu J. Chem. Phys. 2010, 132, 154104. 41 Miertuš, S.; Scrocco, E.; Tomasi, J. Electrostatic interaction of a solute with a continuum. A direct utilizaion of AB initio molecular potentials for the prevision of solvent effects Chem. Phys. 1981, 55, 117-129; 42 Pascual-Ahuir, J. L.; Silla, E.; Tuñón, I. GEPOL: An improved description of molecular surfaces. III. A new algorithm for the computation of a solvent-excluding surface J. Comp. Chem. 1994, 15, 1127-1138; 43 Barone, V.; Cossi, M. Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model J. Phys. Chem. A, 1998, 102, 1995-2001. 44 McIver, J. W.; Komornicki, A. K. Structure of transition states in organic reactions. General theory and an application to the cyclobutene-butadiene isomerization using a semiempirical molecular orbital method J. Am. Chem. Soc. 1972, 94, 2625-2633. 45 González, C.; Schlegel, H. B. Reaction path following in mass-weighted internal coordinates J. Phys. Chem. 1990, 94, 5523-5527. 46 A. K. Gupta, D. K. Dubey, M. P.; Kaushik, A simple and economical chemical neutralization method for the destruction of sulfur mustard and its analogues J. Hazard. Mater. B. 2007, 139, 154-159.


25


Page 26 of 26

47 M. Kaushik, H. Rana, H. Facile one-step synthesis of dithiaalkanediols OPPI Briefs. 2005, 37, 268-272.


26

Unexpected Reaction Pathways Leading to Thiodiglycol During the

Recommend Documents