TOXICOLOGICAL CHEMISTRY AND BIOCHEMISTRY - CHAPTER 17 pps

17.1.1 Classes of Organosulfur Compounds Substitution of alkyl or aryl hydrocarbon groups such as phenyl and methyl Figure 17.1 for H on hydrogen sulfide leads to a number of different o

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CHAPTER 17 Organosulfur Compounds 17.1 INTRODUCTION

Sulfur is directly below oxygen in the periodic table The sulfur atom has six valence electrons,

valence shell electron configurations, oxygen and sulfur behave somewhat alike chemically

expanded to more than eight electrons This makes sulfur’s chemical behavior more diverse than that of oxygen For example, sulfur has several common oxidation states, including –2, +4, and +6, whereas most chemically combined oxygen is in the –2 oxidation state

17.1.1 Classes of Organosulfur Compounds

Substitution of alkyl or aryl hydrocarbon groups such as phenyl and methyl (Figure 17.1) for H on hydrogen sulfide leads to a number of different organosulfur compounds These include thiols

hydrocarbon moieties can also be bonded to oxygen, adding to the variety of organosulfur com-pounds that can exist

of the compounds have strong, offensive odors that warn of their presence, which reduces their hazard

17.1.2 Reactions of Organic Sulfur

Organic sulfur undergoes a number of toxicological chemical reactions These include the following:

• Oxidation of sulfur

• Reduction of sulfur

• Removal of sulfur from a molecule

• Addition of sulfur-containing groups

Examples of these kinds of reactions, some of which are very important in xenobiotic metab-olism, are given below

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The same kind of reaction occurs with aminothiols, such as in the oxidation of cysteamine,

in organosulfide compounds:

(17.1.2) and sulfur on thioamides:

(17.1.3)

(17.1.4)

This reaction converts disulfiram, a therapeutic agent for the treatment of alcohol abuse, discussed

in Section 17.3, to dithiocarb (diethylthiocarbamate), a substance that strongly binds metals and is used for the treatment of nickel carbonyl poisoning

Desulfuration is the term given to removal of sulfur from a molecule One of the most common desulfuration reactions occurs with sulfur bonded to phosphorus A common desulfuration reaction

is the enzyme-mediated conversion of parathion to paraoxon (see discussion of organophosphate insecticides in Section 18.7):

(17.1.5)

Figure 17.1 Sulfur atom, compounds, and substituent groups.

C H H H

:

.

H

H S

Lewis symbol

of sulfur atom

Lewis structure of hydrogen sulfide

Carbon disulfide

Phenyl group Methyl group

Sulfoxidation

{O}

S

O

R C

S N H H

R C

S N

O H H

S-oxidation

Enzymatic reduction 2

Disulfiram Dithiocarb

S S

N

HS C N

S

{O}, enzymatic oxidation

Parathion Paraoxon

O P O

O

S

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The most significant instance of addition of a sulfur-containing group is the phase II conjugation

to sulfate of a xenobiotic compound or its phase I metabolite (see Section 7.4.3) by the action of adenosine 3'-phosphate-5'-phosphosulfate, a sulfotransferase enzyme that acts as a sulfating agent:

(17.1.6)

17.2 THIOLS, SULFIDES, AND DISULFIDES

Structural formulas of examples of these compounds are shown in Figure 17.2

17.2.1 Thiols

Thiols are also known as mercaptans The lighter alkyl thiols, such as methanethiol, are fairly common air pollutants with odors that may be described as ultragarlic Inhalation of even very low concentrations of the alkyl thiols in air can be very nauseating and result in headaches Exposure

Figure 17.2 Common low-molecular-mass thiols and sulfides All are liquids at room temperature, except for

methanethiol, which boils at 5.9°C.

H C SH H H

H H

H

H C C C SH H

H H

H C C SH H

H

H H

H

C C C SH H H

C

H H H

H H

C C C SH H

H H H

C SH H H

SH

H H H

S S

C C C H

H H

C H H H

H S

H

Methanethiol Ethanethiol 1-Propanethiol

2-Propene-1-thiol 1-Butanethiol 2-Butanethiol

1-Pentanethiol Alpha-toluenethiol Cyclohexanethiol

H C H

H

C C H H

H H

SH

3

H C H

H

C C H H

H H

SH

8

1-Decanethiol Benzenethiol Dimethyl sulfide

Thiophene (an unsaturated cyclic sulfide)

Thiophane

H C H

H

S C H

H

Methylbenzyl sulfide

S O O +

Phenol Phase II sulfate conjugate

S OH O O (Sulfating agent)

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to higher levels can cause increased pulse rate, cold hands and feet, and cyanosis With extreme cases, unconsciousness, coma, and death may occur The biochemical action of alkyl thiols likely

Volatile methanethiol from biogenic sources is released to the atmosphere in coastal and ocean

pesticide synthesis and odorants placed in lines and tanks containing natural gas, propane, and butane to warn of leaks Information about their toxicities to humans is lacking, although these compounds and 1-propanethiol should be considered dangerously toxic, especially by inhalation Also known as amyl mercaptan, 1-pentanethiol (bp, 124°C) is an allergen and weak sensitizer that causes contact dermatitis

Anaerobic bacteria in the colon produce significant quantities of methanethiol along with hydrogen sulfide Rodent studies indicate that these substances are detoxified to thiosulfate by the

The failure of this system may contribute to some diseases of the colon, such as ulcerative colitis

A typical alkenyl mercaptan is 2-propene-1-thiol, also known as allyl mercaptan It is a volatile liquid (bp, 68°C) with a strong garlic odor It has a high toxicity and is strongly irritating to mucous membranes when inhaled or ingested

Alpha-toluenethiol, also called benzyl mercaptan (bp, 195°C) is very toxic orally It is an experimental carcinogen

The simplest of the aryl thiols is benzenethiol, phenyl mercaptan (bp, 168°C) It has a severely repulsive odor Inhalation causes headache and dizziness, and skin exposure results in severe contact dermatitis

17.2.2 Thiols as Antidotes for Heavy Metal Poisoning

Toxic heavy metals, such as cadmium, lead, and mercury, are sulfur seekers that bind strongly with thiol groups, which is one of the ways in which they interact adversely with biomolecules, including some enzymes Advantage has been taken of this tendency to use thiols in chelation

17.2.3 Sulfides and Disulfides

Dimethylsulfide is an alkyl sulfide or thioether It is a volatile liquid (bp, 38°C) that is moderately toxic by ingestion Thiophene is the most common cyclic sulfide It is a heat-stable liquid (bp, 84°C) with a solvent action much like that of benzene It is used in the manufacture of pharma-ceuticals and dyes, as well as resins that also contain phenol or formaldehyde Its saturated analog

is tetrahydrothiophene, or thiophane

breath is a source of this compound in terrestrial atmospheres Dimethylsulfide is produced in enormous quantities by marine organisms This volatile compound is the largest source of biogenic sulfur in the atmosphere and is responsible for some of the odor emanating from coastal mud flats

SH

SH O

OH O

HO

meso -2,3-Dimercaptosuccinic acid

C

O C H

SH C H

SH

C O

O O

H

H C H

H C

H H

Diethyldimercapto succinate

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It, along with methylbenzyl sulfide and one or two other sulfides, is responsible for the nauseating

The organic disulfides contain the –SS– functional group, as shown in the following two examples:

These compounds may act as allergens that produce dermatitis in contact with skin Not much information is available regarding their toxicities to humans, although animal studies suggest several toxic effects, including hemolytic anemia

17.2.4 Organosulfur Compounds in Skunk Spray

Skunks are small animals that wage powerful defensive warfare in the form of spray that has

a sickening offensive odor The compounds that are responsible for skunk spray odor are organo-sulfur compounds Although seven or more such compounds have been isolated from the spray of

17.2.5 Carbon Disulfide and Carbon Oxysulfide

Carbon disulfide (CS2) is one of the most significant sulfur compounds because of its wide-spread use and toxicity This compound has two sulfur atoms, each separately bonded to a carbon atom This compound is a volatile, colorless liquid (mp, –111°C; bp, 46°C) Unlike most organo-sulfur compounds, it is virtually free of odor Although its uses are declining, it has numerous applications in chemical synthesis, as a solvent to break down cellulose in viscose rayon manufac-ture, and in the manufacture of cellophane It has also been used as an insecticide and fumigant Acute doses of carbon disulfide inhaled at 100 to l000 ppm irritate mucous membranes and affect the central nervous system, usually causing excitation as a first noticeable effect, followed

by restlessness, depression, and stupor Carbon disulfide intoxication causes reduced conduction velocity in the peripheral nerves, which can be detected by psychomotor tests that exhibit impaired

unconscious-ness and even death in cases of high exposure Symptoms experienced during recovery from severe acute carbon disulfide poisoning resemble those that occur following intoxication from ingestion

of ethanol in alcoholic beverages

H C C C C SS C C C C H

H H H H

SS

n-Butyldisulfide Diphenyldisulfide

Trans -2-butene-1-thiol

C

H H H

H H

C C HS

H H C

C

H H H

H H

C C S

H H

C C

O C H H H

Trans

-2-butenyl-1-thioacetate

3-Methyl-1-butane-thiol

HS C H H C H H

C C

H H H H

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Chronic carbon disulfide poisoning by absorption through the skin or respiratory tract involves the central and peripheral nervous systems and may cause anemia Symptoms include indistinct vision, neuritis, and a bizarre sensation of “crawling” on the skin Psychopathological symptoms may be varied and severe, including excitation, depression, irritability, and general loss of mental capabilities to the point of insanity Parkinsonian paralysis may result from chronic carbon disulfide poisoning

Carbon disulfide is metabolized by conjugating with the amino acid cysteine to form adducts that rearrange to produce 2-thiothiazolidine-4-carboxylic acid (TTCA):

(17.2.1)

TTCA is commonly determined by chemical analysis of urine as a biomarker of exposure to carbon disulfide Another metabolite of carbon disulfide that appears at levels of about 30% those of TTCA

(COS), a volatile liquid boiling at 50°C It can decompose to liberate toxic hydrogen sulfide Carbon oxysulfide vapor is a toxic irritant At high concentrations this compound has a strong narcotic effect

17.3 ORGANOSULFUR COMPOUNDS CONTAINING NITROGEN OR PHOSPHORUS

Several important classes of organosulfur compounds contain nitrogen or phosphorus These compounds are discussed in this section

17.3.1 Thiourea Compounds

Thiourea is the sulfur analog of urea Substitution of hydrocarbon moieties on the N atoms yields various organic derivatives of thiourea, as illustrated in Figure 17.3 Thiourea has been used

as a rodenticide It has a moderate to high toxicity to humans, affecting bone marrow and causing anemia It has been shown to cause liver and thyroid cancers in experimental animals

Phenylthiourea is likewise a rodenticide Its toxicity is highly selective to rodents relative to humans, although it probably is very toxic to some other animals The compound is metabolized extensively, and some of the sulfur is excreted as sulfate in urine

very high rodent:human toxicity ratio The lethal dose to monkeys is about 4000 mg/kg One

S C S

HS C H

H

C C OH O

H

N

Cysteine S NH

2-thioxothiazolidin-4-ylcarbonylglycine

S

C N

C H H

C OH O

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suicidal adult male human ingested about 80 g of 30% ANTU rat poison, along with a considerable

Dogs, however, are quite susceptible to ANTU poisoning

17.3.2 Thiocyanates

by hydrocarbon moieties, such as the methyl group Dating from the 1930s and regarded as the first synthetic organic insecticides, these compounds kill insects on contact Because of their volatilities, the lower-molecular-mass methyl, ethyl, and isopropyl thiocyanates are effective fumi-gants for insect control Insecticidal lauryl thiocyanate (below) is not volatile and is used in sprays

in petroleum-based solvents and in dusting powders

The toxicities of the thiocyanates vary widely by compound and route of administration Some metabolic processes liberate HCN from thiocyanates As discussed in Section 11.2.1, HCN is highly toxic, so its generation in the body can result in death Therefore, methyl, ethyl, and isopropyl thiocyanates should be regarded as rapid-acting, potent poisons

The isothiocyanate group is illustrated in the structure below:

Other compounds in this class include ethyl, allyl, and phenyl isothiocyanates Methylisothiocyan-ate, also known as methyl mustard oil, and its ethyl analog have been developed as military poisons Both are powerful irritants to eyes, skin, and the respiratory tract When decomposed by heat, these compounds emit sulfur oxides and hydrogen cyanide Methylisothiocyanate occurs in the environ-ment from some kinds of vegetables, as a breakdown product of some carbamate insecticides, and

Figure 17.3 Structural formulas of urea, thiourea, and organic derivatives of thiourea *At least one R group

is an alkyl, alkenyl, or aryl substituent.

Urea Thiourea Organic derivatives

of thiourea*

1-Naphthylthiourea (ANTU) Phenylthiourea

N C N H

H

H H

N C N H

H H

N C N R

R R S

N C N H

H H

S

N C N H

H H S

H

H C C C C C C C C C C C C S C

H H H H H H H H H H H H

H H H H H H H H H H H

N

Lauryl thiocyanate

C N

H H H

C S

Methylisothiocyanate

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17.3.3 Disulfiram

Disulfiram, is a sulfur- and nitrogen-containing compound with several industrial uses, includ-ing applications as a rubber accelerator and vulcanizer, fungicide, and seed disinfectant It is most commonly known as antabuse, a therapeutic agent for the treatment of alcohol abuse that causes nausea, vomiting, and other adverse effects when ethanol is ingested Disulfiram is an inhibitor of aldehyde dehydrogenase so that it allows for buildup of the acetaldehyde metabolite of ethanol, causing unpleasant effects that are a deterrent to the ingestion of alcohol Because of the buildup

of acetaldehyde, disulfiram should be given with extreme caution, especially to individuals suffering from liver cirrhosis

17.3.4 Cyclic Sulfur and Nitrogen Organic Compounds

The structural formulas of several cyclic compounds containing both nitrogen and sulfur are shown in Figure 17.4 Basic to the structures of these compounds is the simple ring structure of

thiazole It is a colorless liquid (bp, 117°C) One of its major uses has been for the manufacture

of sulfathiazole, one of the oldest of the sulfonamide class of antibacterial drugs The use of sulfathiazole is now confined to the practice of veterinary medicine because of its serious side effects

used in organic synthesis Thiazoles are used as rubber vulcanization accelerators Benzothiazole,

Figure 17.4 Cyclic compounds containing nitrogen and sulfur.

HS C

S

N C H H H

H

Vapam

C H H C H H

H C H H C H H

H C H H C H

N C SS C N

Disulfiram (antabuse)

N

S

N

N S

N

S H

N

Thiazole Benzothiazole 2-Aminothiazole 2-Mercaptobenzothiazole

Thiabendazole

N

H H

2-(Thiocyanomethylthio)-benzothiazole (fungicide)

N

2-(Methylthio)benzo-thiazole

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2-mercaptobenzothiazole, and 2-(methylthio)benzothiazole are breakdown products of fungicidal

2-(thiocyanomethylthio)benzothiazole and are common constituents of tannery wastewaters The

human toxicity of 2-(thiocyanomethylthio)benzothiazole is not known, although it has a high

carried through a plant and onto plant leaves Rats and dogs tolerate a relatively high dose of this

chemical, although it tends to make the latter vomit Acting as an adjuvant (a substance added to

a drug or insecticide to give it a desired form and enhance its action and effectiveness),

2-mercaptobenzothiazole is mixed with dithiocarbamate fungicides (see below) to increase their

potency It is an allergen that causes type IV (cell-mediated) hypersensitivity This condition is

manifested by contact dermatitis and a delayed hypersensitive reaction that follows a latent period

after exposure This cell-mediated process results from the sensitization of T lymphocytes

17.3.5 Dithiocarbamates

ethylenebis-dithiocarbamate anions, as shown in Figure 17.5 These fungicides are named in accordance with

the metal ion present For example, the manganese salt of dimethyldithiocarbamate is called maneb,

and the zinc and sodium salts are zineb and nabam, respectively The iron salt of

ethylenebisdithio-carbamate is called ferbam, and the zinc salt of this ion is called ziram These salts are chelates

(Section 2.3) in which two S atoms from the ethylenebisdithiocarbamate anion are bonded to the

same metal ion in a ring structure

The dithiocarbamate fungicides have been popular for agricultural use because of their

effec-tiveness and relatively low toxicities to animals However, there is concern over their environmental

breakdown products, particularly ethylenethiourea (2-imidazolidine thione; see Figure 17.5), which

is toxic to the thyroid and has been shown to be mutagenic, carcinogenic, and teratogenic in

experimental animals

17.3.6 Phosphine Sulfides

A number of toxicologically important organic compounds have sulfur bound to phosphorus

The simplest of these are the phosphine sulfides, containing only carbon, hydrogen, phosphorus,

and sulfur, as illustrated by the example below:

Phosphine sulfides tend to be toxic When burned, they give off dangerous phosphorus oxide and

sulfur oxide fumes

Figure 17.5 Dithiocarbamate anions and ethylenethiourea.

-S C N

S

-S C N

S H

-S

H H

N

N C

S H H

Dimethyldithiocar-bamate anion

Ethylenebisdithio-carbamate anion

Ethylenethiourea

S

Tributylphosphine sulfide

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17.3.7 Phosphorothionate and Phosphorodithioate Esters

The most toxicologically significant organic compounds that contain both phosphorus and sulfur

are the thiophosphate esters, which are used as insecticidal acetylcholinesterase inhibitors The

more complex structure, frequently aromatic Phosphorothionate and phosphorodithioate esters

contain the P=S (thiono) group, which increases their insect:mammal toxicity ratios and decreases

their tendency to undergo nonenzymatic hydrolysis, compared to their analogous compounds that

contain the P=O functional group The metabolic oxidative desulfuration conversion of P=S to P=O

in organisms (see Section 17.1) converts the phosphorothionate and phosphorodithioate esters to

species that have insecticidal activity

17.4 SULFOXIDES AND SULFONES

Numerous important organic compounds contain oxygen bonded to sulfur Among these

Figure 17.6 General formulas and specific examples of phosphorothionate and phosphorodithioate

organo-phosphate insecticides.

Figure 17.7 Sulfoxides and sulfones.

S

O R Ar

O O

O

Cl S

O

S P

O R

S P

C C H H

O P

H

S C

O S

O

S

O

H H

General formula of phosphorothionate insecticides

Parathion

General formula of phosphorodithioate insecticides Chlorothion

Malathion Disulfoton

H C S C H

O

S O O

H C S C H O O

H H

H

Dimethylsulfoxide Dimethylsulfone Sulfolane (DMSO)

Tiêu đề	Organosulfur Compounds
Trường học	CRC Press
Chuyên ngành	Toxicological Chemistry and Biochemistry
Thể loại	chapter
Năm xuất bản	2002
Thành phố	Boca Raton

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