Advertisement

Chemistry of Mustard Compounds

  • Mahmood Sadeghi
  • Beeta Balali-MoodEmail author
Chapter

Abstract

The two main categories of mustard compounds are sulfur mustards and nitrogen mustards. Sulfur mustard was the first vesicant chemical weapon used. Its first widespread use was recorded in the World War One. After a number of sporadic military attacks, another widespread use of sulfur mustard occurred in the Iran-Iraq war. Nitrogen mustard derivatives are used in chemotherapy. HN-1, HN-2, HN-3 are the most important forms of nitrogen mustards. Nitrogen mustard HN-2 is chlormethine (Mechlorethamine) and has been used for treatment of multiple cancer diseases such as Hodgkin’s disease. Sulfur mustard has the chemical name bis(2-chloroethyl) sulfide and the IUPAC name 1-chloro-2-(2-chloroethylsulfanyl) ethane. It is also known as mustard, mustard gas, HD or Yperite. The compound is highly reactive and has carcinogenic, cytotoxic and powerful vesicant characteristics. Mustard gas was first synthesized from the reaction of ethylene and sulfur dichloride (Levinstein process) through an electrophilic addition mechanism. Later, it was prepared by the reaction of thiodiglycol with phosphorus trichloride (Meyer reaction) in a substitution reaction. Finally, reaction of concentrated hydrochloric acid (HCl) and thiodiglycol resulted in the production of sulfur mustard. Pure mustard is a viscous, colorless and odorless liquid which evaporates slowly in the atmosphere. Cytotoxicity of sulfur mustard stems from the formation of electrophilic species called sulfonium cation upon nucleophilic attack. This transient cation then readily reacts with macromolecules of DNA, RNA and proteins or with water to form the corresponding hydroxyl compounds. DNA Cross-linking of guanine by sulfur mustard and its interaction with imidazole are well studied. Nitrogen mustard (NM) and sulfur mustard (SM) slightly differ in properties. Like sulfur mustard, nitrogen mustard compounds are also alkylating agents and are reactive compounds that covalently bind to nucleophilic groups such as amine, carboxyl, sulfhydryl and imidazole moieties in DNA, RNA and proteins. Decontamination of SM can be achieved via hydrolysis in presence of aqueous solutions of sodium hypochlorite and or chloramine-T; in which HD decomposes into thiodiglycol non-poisonous product. No specific antidote for SM poisoning has been introduced. However, some formulations have been introduced as effective skin decontaminants.

Keywords

Sulfur mustard Nitrogen mustards HN-1 HN-2 HN-3 Mechlorethamine Synthesis Reaction Physical characteristics Chemical properties Mechanism of cytotoxicity DNA-crosslinking Aziridinium ion 

Notes

Glossary

Alkylation

Reaction involving a transfer of an alkyle group from one molecule to another for instance to a DNA molecule which can consequently result in cell death.

Antidotes

Medicines for counteracting/neutralizing the harmful effects of a poison

Carcinogenicity

Genetic alterations such as DNA strand breaks and unscheduled DNA synthesis that may lead to cancer development

Chemical Properties

The ability to undergo changes that alter a material’s composition and are observed during a reaction

CWA: chemical warfare agents

Toxic chemical compounds in munitions/devices causing death or harm to human beings.

Cytotoxic

Being toxic to cells which may result in cell death

Decontamination

Ways of detoxifying hazardous chemicals using specific compounds

Exposure

Being subjected to radiation or chemicals with potentially harmful effect.

Nitrogen Mustards

A family of mustard compounds with the central atom of nitrogen. Nitrogen mustards derivatives are used as chemotherapy drugs

Physical Properties

Properties that account for identifying substances. And are observed without changing the composition of matter

SM: Sulfur Mustard

A toxic and vesicant chemical warfare agent which is highly reactive and forms large blisters on the exposed skin

Spectroscopy

Study of the absorption and emission of light and matter. Spectral data shed light on the structure of compounds and can also be used in the analysis of a known analyte in a matrix

Synthesis

Production of chemical compounds

References

  1. Abrams JT, Barker RL, Jones WE, Val-Lender HW, Woodward FN (1949) The preparation of n-methyldiethanolamine and Nmethyl-2:2′- dichlorodiethylamine. J Soc Chem Ind 68:280–284CrossRefGoogle Scholar
  2. Agents SCRDSCW, Council NR, Studies DEL, Toxicology BES (1999) Review of the U.S. Army’s Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents. National Academies Press, Washington, DCGoogle Scholar
  3. Albrio PW, Fishbein L (1970) Gas chromatography of sulfur mustard and its analogs. J Chromatogr 46:202–203CrossRefPubMedGoogle Scholar
  4. Andacht TM, Pantazides BG, Crow BS, Fidder A, Noort D, Thomas JD, Blake TA, Johnson RC (2014) An enhanced throughput method for quantification of sulfur mustard adducts to human serum albumin via isotope dilution tandem mass spectrometry. J Anal Toxicol 38:8–15CrossRefPubMedGoogle Scholar
  5. Balali‐Mood M, Hefazi M (2006) Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol 99:273–282CrossRefPubMedGoogle Scholar
  6. Balali-Mood M, Hefazi M, Mahmoudi M, Jalali E, Attaran D, Maleki M, Razavi ME, Zare G, Tabatabaee A, Jaafari MR (2005) Long-term complications of sulphur mustard poisoning in severely intoxicated Iranian veterans. Fundam Clin Pharmacol 19:713–721CrossRefPubMedGoogle Scholar
  7. Balali-Mood M, Balali-Mood B, Moshiri M (2014) Sulfur mustard. In: Wexler P (ed) Encyclopedia of toxicology, 3rd edn. Academic Press, OxfordGoogle Scholar
  8. Ball CR, Roberts JJ (1972) Estimation of interstrand DNA cross-linking resulting from mustard gas alkylation of HeLa cells. Chem Biol Interact 4:297–303CrossRefPubMedGoogle Scholar
  9. Boëns B, Azouz M, Ouk T-S, Zerrouki R (2013) Synthesis and biological evaluation of nitrogen mustard derivatives of purine bases. Nucleosides Nucleotides Nucleic Acids 32:69–80CrossRefPubMedGoogle Scholar
  10. Bossle PC, Martin J, Sarver E, Sommer H (1984) High-performance liquid chromatography analysis of 2-chloroethyl ethylsulfide and itsdecomposition by-products by derivatization. J Chromatogr A 283:412–416CrossRefGoogle Scholar
  11. Boyer AE, Ash D, Barr DB, Young CL, Driskell WJ, Whitehead RD, Ospina M, Preston KE, Woolfitt AR, Martinez RA, Silks LA, Barr JR (2004) Quantitation of the sulfur mustard metabolites 1,1′-sulfonylbis[2-(methylthio)ethane] and thiodiglycol in urine using isotope-dilution gas chromatography-tandem mass spectrometry. J Anal Toxicol 28:327–332CrossRefPubMedGoogle Scholar
  12. Brown RS (1989) Design and synthesis of thiol-imidazole pairs as zwetterionic scavengers for sulfur mustard. Alberta University, EdmontonGoogle Scholar
  13. Brunton L, Blumenthal D, Buxton I, Parker K (2007) Goodman and Gilman’s manual of pharmacology and therapeutics. McGraw-Hill Education, New YorkGoogle Scholar
  14. Chabner BA, Roberts TG (2005) Chemotherapy and the war on cancer. Nat Rev Cancer 5:65–72CrossRefPubMedGoogle Scholar
  15. Chilcott R, Jenner J, Hotchkiss S, Rice P (2001) In vitro skin absorption and decontamination of sulphur mustard: comparison of human and pig‐ear skin. J Appl Toxicol 21:279–283CrossRefPubMedGoogle Scholar
  16. Cope AC, Gates M, Renshaw B (1946) Chemical warfare agents, and related chemical problems. National Defense Research Committee, WashingtonGoogle Scholar
  17. Crathorn AR, Roberts JJ (1966) Mechanism of the cytotoxic action of alkylating agents in mammalian cells and evidence for the removal of alkylated groups from deoxyribonucleic acid. Nature 211:150–153CrossRefPubMedGoogle Scholar
  18. D’agostino PA, Provost LR, Hancock JR (1998) Analysis of mustard hydrolysis products by packed capillary liquid chromatography-electrospray mass spectrometry. J Chromatogr A 808:177–184CrossRefGoogle Scholar
  19. Dacre JC, Goldman M (1996) Toxicology and pharmacology of the chemical warfare agent sulfur mustard. Pharmacol Rev 48:289–326PubMedGoogle Scholar
  20. Daniel T (2011) As an anti-cancer agent [online]. Available: http://jeanbont.pbworks.com/w/page/37089602/Present%20Uses
  21. De Alencar TA, Leitão AC, Lage C (2005) Nitrogen mustard- and half-mustard-induced damage in Escherichia coli requires different DNA repair pathways. Mutat Res/Genet Toxicol Environ Mutagen 582:105–115CrossRefGoogle Scholar
  22. Devita VT, Chu E (2008) A history of cancer chemotherapy. Cancer Res 68:8643–8653CrossRefPubMedGoogle Scholar
  23. Ede A (2006) The chemical element: a historical perspective, Greenwood guides to great ideas in science. Greenwood, WestportGoogle Scholar
  24. Flora SJ, Romano JA, Baskin SI, Sekhar K (2004) Pharmacological perspectives of toxic chemicals and their antidotes. Springer, New YorkGoogle Scholar
  25. Freemantle M (2014) The Chemists’ War: 1914–1918. Royal Society of Chemistry, CambridgeGoogle Scholar
  26. Fuson RC, Price CC, Burness DM, Foster RE, Hatchard WR, Lipscomb RD (1946) Levinstein mustard gas. IV. The bis(2-chloroethyl) polysulfides. J Org Chem 11:487–498CrossRefPubMedGoogle Scholar
  27. Gates M, Moore S (1946) Chemical warfare agents, and related chemical problems. National Defense Research Committee, Washington, DCGoogle Scholar
  28. Gilman A (1963) The initial clinical trial of nitrogen mustard. Am J Surg 105:574–578CrossRefPubMedGoogle Scholar
  29. Graef I, Karnofsky DA, Jager VB, Krichesky B, Smith HW (1948) The clinical and pathologic effects of the nitrogen and sulfur mustards in laboratory animals. Am J Pathol 24:1PubMedPubMedCentralGoogle Scholar
  30. Hallowell S, Yung Y, Bossle P, Rewter D (1986) Analysis of 2-chloroethyl sulphide and 2-hydroxyethyl ethyl sulfide in aqueous matrices by HPLC. Proc US Army Chem Res Dev 1:39–44Google Scholar
  31. Hanna DC, Gaisford JC, Goldwyn RM (1963) Intra-arterial nitrogen mustard for control ofpain in head and neck cancer. Am J Surg 106:783–785CrossRefPubMedGoogle Scholar
  32. Harvey SP, Szafraniec LL, Beaudry WT (1997) Neutralization and biodegradation of sulfur mustardGoogle Scholar
  33. Heather H (2005) Nitrogen. Rosen Pub Group, New YorkGoogle Scholar
  34. Hoenig SL (2002) Handbook of chemical warfare and terrorism. Greenwood Publishing Group, WestportGoogle Scholar
  35. Hoenig SL (2007) Compendium of chemical warfare agents. Springer, New YorkGoogle Scholar
  36. Kehe K, Szinicz L (2005) Medical aspects of sulphur mustard poisoning. Toxicology 214:198–209CrossRefPubMedGoogle Scholar
  37. Klaassen C (2007) Casarett & Doull’s toxicology: the basic science of poisons: the basic science of poisons. McGraw-Hill Education, New YorkGoogle Scholar
  38. Kort M (2010) Weapons of mass destruction. Infobase Publishing, New YorkGoogle Scholar
  39. Kumar P, Sharma U, Vijayaraghavan R (2013) Study of the efficacy ofCC-2 and Fuller’s earth combination as a decontaminant against sulphur mustard (mustard gas) dermal intoxication in mice. Defence Sci J 41:363–366CrossRefGoogle Scholar
  40. Ledgard J (2007) A laboratory history of chemical warfare agents, Columbus. Lulu.com
  41. Leikin JB, Mcfee RB, Kerscher R (2007) Handbook of nuclear, biological, and chemical agent exposures. CRC Press, Boca RatonCrossRefGoogle Scholar
  42. Lewis Sr, Richard J (2008) Hazardous chemicals desk reference. John Wiley & Sons, New JerseyGoogle Scholar
  43. Liebow AA, Waters LL (1959) Milton Charles Winternitz February 19, 1885–October 3, 1959. Yale J Biol Med 32:143.b1Google Scholar
  44. Logan TP, Sartori DA (2002) Proton nuclear magnetic resonance spectra of sulfur mustard and 2-chlorotheyl ethyl sulfide in selected solvents. U.S. Army Medical Research, Institute of Chemical DefenseGoogle Scholar
  45. Lomash V, Pant SC (2014) A novel decontaminant and wound healant formulation of N, N′‐dichloro‐bis [2, 4, 6‐trichlorophenyl] urea against sulfur mustard–induced skin injury. Wound Repair Regen 22:85–95CrossRefPubMedGoogle Scholar
  46. Lu Y, Mahato RI (2009) Pharmaceutical perspectives of cancer therapeutics. Springer, DordrechtCrossRefGoogle Scholar
  47. Lundin SJ, Stockholm International Peace Research Institute (1991) Verification of dual-use chemicals under the chemical weapons convention: the case of thiodiglycol. Oxford University Press, OxfordGoogle Scholar
  48. Malhotra RC, Ganesan K, Sugendran K, Swamy RV (1999) Chemistry and toxicology of sulphur mustard-a review. Defence Sci J 49:97–116CrossRefGoogle Scholar
  49. Maras, M.-H (1979) The CRC Press terrorism reader, Boca Raton, Taylor & Francis GroupGoogle Scholar
  50. Mazurek M, Witkiewicz Z, Popiel S, Śliwakowski M (2001) Capillary gas chromatography–atomic emission spectroscopy–mass spectrometry analysis of sulphur mustard and transformation products in a block recovered from the Baltic Sea. J Chromatogr A 919:133–145CrossRefPubMedGoogle Scholar
  51. Moore S, Stein WH, Fruton JS (1946) Chemical reactions of mustard gas and related compounds. II. The reaction of mustard gas with carboxyl groups and withthe amino groups of amino acids and peptides. J Org Chem 11:675–680CrossRefPubMedGoogle Scholar
  52. Muniandy PA, Liu J, Majumdar A, Liu S-T, Seidman MM (2010) DNA interstrand crosslink repair in mammalian cells: step by step. Crit Rev Biochem Mol Biol 45:23–49CrossRefPubMedPubMedCentralGoogle Scholar
  53. Pechura CM, Rall DP (1993) Veterans at Risk: The health effects of mustard gas and lewisite, Washington, D.C., National Academies PressGoogle Scholar
  54. Popiel S, Sankowska M (2011) Determination of chemical warfare agents and related compounds in environmental samples by solid-phase microextraction with gas chromatography. J Chromatogr A 121:8457–8479CrossRefGoogle Scholar
  55. Pratt WB (1994) The anticancer drugs. Oxford University Press, OxfordGoogle Scholar
  56. Price CC, Bullitt OH (1947) Hydrolysis and oxidation of mustard gas and related compounds in aqueous solution 1. J Org Chem 12:238–248CrossRefPubMedGoogle Scholar
  57. Puskar P (2011) History of mustard gas [online]. Available: http://jeanbont.pbworks.com/w/page/36495606/history%20of%20mustard%20gas
  58. Raghuveeran CD, Malhotra RC, Dangi RS (1993) Reversed-phase high-performance liquid chromatography of sulphur mustard in water. J Liq Chromatogr 16:1615–1624CrossRefGoogle Scholar
  59. Rohrbaugh DK, Yang YC (1997) Liquid chromatography/electrospray mass spectrometry of mustard-related sulfonium ions. J Mass Spectrom 32:1247–1252CrossRefGoogle Scholar
  60. Romano JA, Lukey BJ, Salem H (2007) Chemical warfare agents: chemistry, pharmacology, toxicology, and therapeutics, 2nd edn. Taylor & Francis, Boca RatonGoogle Scholar
  61. Rose HM, Gellhorn A (1947) Inactivation of influenza virus with sulfur and nitrogen mustards. Exp Biol Med 65:83–85CrossRefGoogle Scholar
  62. Ruff AL, Dillman JF (2008) Signaling molecules in sulfur mustard-induced cutaneous injury. Eplasty 8:8–22Google Scholar
  63. Saha P, Debnath C, Bérubé G (2013) Steroid-linked nitrogen mustards as potential anticancer therapeutics: a review. J Steroid Biochem Mol Biol 137:271–300CrossRefPubMedGoogle Scholar
  64. Sass S, Stutz MH (1981) Thin-layer chromatography of some sulfur and nitrogen mustards. J Chromatogr A 213:173–176CrossRefGoogle Scholar
  65. Shih ML, Korte WD, Smith JR, Szafraniec LL (1999) Reactions of sulfides with S‐330, a potential decontaminant of sulfur mustard in formulations. J Appl Toxicol 19:S83–S88CrossRefPubMedGoogle Scholar
  66. Spencer JN, Bodner GM, Rickard LH (2010) Chemistry: structure and dynamics. John Wiley & Sons, New YorkGoogle Scholar
  67. Stan’kov IN, Sergeeva AA, Sitnikov VB, Derevyagina ID, Morozova OT, Mylova SN, Forov VB (2004) Gas chromatographic determination of sulfur mustard and lewisite in community air. J Anal Chem 59:447–451CrossRefGoogle Scholar
  68. Stanford F (1967) Separation of mustard gas and hydroxy analogues by thin-layer chromatography. Analyst 92:64b–64bCrossRefGoogle Scholar
  69. Taysse L, Daulon S, Delamanche S, Bellier B, Breton P (2007) Skin decontamination of mustards and organophosphates: comparative efficiency of RSDL and Fuller’s earth in domestic swine. Hum Exp Toxicol 26:135–141CrossRefPubMedGoogle Scholar
  70. Teichert J, Sohr R, Baumann F, Hennig L, Merkle K, Caca K, Preiss R (2005) Synthesis and characterization of some new phase II metabolites of the alkylator bendamustine and their identification in human bile, urine, and plasma from patients with cholangiocarcinoma. Drug Metab Dispos 33:984–992CrossRefPubMedGoogle Scholar
  71. Tuorinsky SD (2008) Medical aspects of chemical warfare. Office of the Surgeon General at TMM Publications, WashingtonGoogle Scholar
  72. Ullmann F, Bohnet M (2003) Ullmann’s encyclopedia of industrial chemistry. Wiley-VCH, WeinheimGoogle Scholar
  73. Vaughan WE, Rust FF (1942) The photo-addition of hydrogen sulfide to olefinic bonds1. J Org Chem 07:472–476CrossRefGoogle Scholar
  74. Walker IG (1971) Intrastrand bifunctional alkylation of DNA in mammalian cells treated with mustard gas. Can J Biochem 49:332–336CrossRefPubMedGoogle Scholar
  75. Wormser U, Brodsky B, Green BS, Arad-Yellin R, Nyska A (1997) Protective effect of povidone-iodine ointment against skin lesions induced by sulphur and nitrogen mustards and by non-mustard vesicants. Arch Toxicol 71(3):165–170CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Medical Toxicology Research Center, School of Medicine, Mashhad University of Medical SciencesMashhadIran
  2. 2.MoodBioPharmLondonUK

Personalised recommendations