Synthesis of 2,4-D and 2,4,5-T Results in Formation of TCDD

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CHEM 151

Essay Code B11

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a carcinogenic congener that belonged to a group called dioxins, gained its popularity during the Vietnam War. Between 1962 and 1971, the United States military initiated Operation Ranch Hand where 11.2 million gallons of Agent Orange were sprayed over 10% of South Vietnam, consisting of an area equivalent to that of two-thirds the state of Massachusetts[1]. The herbicide and defoliant was employed to eliminate shieldingof their Vietnamese opponent provided by the dense tropical forest. Two main active ingredients in Agent Orange are 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), existing in approximately 1:1 proportion. In addition, trace amount of TCDD was detected in the herbicide. Monsanto Chemical Company, a major American manufacturer of Agent Orange, reported contamination of Agent Orange supplies by TCDD, an intermediate product in the synthesis of 2,4,5-T that remained as an undesired final product.

2,4-dichlorophenoxyacetic acid 2,4,5-trichlorophenoxyacetic acid 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Synthesis of 2,4-D and 2,4,5-T results in formation of TCDD.

Arthur Galston was investigating on various ways to accelerate the flowering and fruiting of soybeans throughout his graduate studies. He discovered that 2,3,5-triiodobenzoic acid (TIBA)can act asan effective growth regulator when applied at an appropriate amount. However, when excessive amount of TIBA is added, soybean plants will start to defoliate. High concentrations of TIBA prompt the plant to generate ethylene, which in turns trigger the enzyme responsible for the break down of cell wall. Through these observations, Galston deduced that TIBA will have harmful ecological effects to plants and suspected its negative effects to human.Galston’s work later serves as a prototype that ultimately led to the development of Agent Orange.

TCDD consists of two chlorinated benzene rings, joint by two oxygen atoms. It bears the chemical formula C12H4Cl4O2 and has a molar mass of 321.97 g/mol. Computational chemical studies suggests that the two oxygen atoms in TCDD have the most electron density[2]. The four carbons bearing a hydrogen atom have the second most electron density in the molecule. The four chlorine substituents bear the least electron density, creating an electron withdrawing nature of chlorines that makes the molecule susceptible to binding as it acts as a Lewis Acid to react with a Lewis Base, thus becoming more electron rich. Poland and Knutson previously established the correlation between high toxicity level and receptor binding[3] with the following requirements:

(1)Molecule must be planar.

(2)Molecule must be rectangular in shape.

(3)Molecule must have at least 3 out of 4 substituents in the lateral positions.

(4)Molecule must have at least one unsubstituted ring position.

TCDD satisfied all of the above requirements. The computation study that utilizes electrostatic potential of 12 halogenated dioxins was performedto deduce similarities between nontoxic dioxins and between toxic dioxins. Nontoxic dibenzo-p-dioxin has a positive electrostatic potential near the lateral hydrogen atoms and a strong negative potential above its two oxygen atoms[4]. On the other hand, TCDD has a negative electrostatic potential near the four chlorine atoms in the lateral positions and a weak negative potential near its two oxygen atoms. This can be summarized by the electrostatic potential map below where the blue regions have lower electron density and the red regions have higher electron density.

Mechanistic studies have been focusing on mapping out the complete metabolic pathway of the TCDD toxicity action. However, many specifics have yet to be discovered. Much of TCDD’s toxicity originated from its gene alteration effects by provoking defects during the gene transcription phase. TCDD utilizes the cytosolic protein known as aryl hydrogen receptor (AhR) to enter the nucleus, where it binds to a second protein known as aryl hydrogen receptor nuclear translocator (ARNT). TCDD activates an inactive AhR by acting as a ligand that binds to AhR. Upon binding to TCDD, the AhR-TCDD complex enters the nucleus where dimerization between the complex and the ARNT occurs. Lastly, it binds to the xenobiotic response element (XRE). Upon binding to XRE, the complex has control over the gene transcription. Deletion of Ah gene in mice allows immunity of various organ damages, including liver and lung[5]. In constrast, an active gene expression of AhR makes mice vulnerable to glandular and liver tumor.

Harmful properties of TCDD include carcinogenesis, immunotoxicity, chloracne, hepatotoxicity, dermal toxicity, adult neurotoxicity, acute weight loss, and various reproductive affects.TCDD is often associated with soft-tissue sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and chronic lymphocytic leukemia. TCDD intoxication data provided by Galston suggests that “concentration as low as 5 parts per trillion (ppt)–an amount roughly equivalent to one drop in 4 million gallons of water”[6] can instigate cancerous cells in rodents. TCDD concentration at 1 part per billion (ppb) can lead to premature death while concentration above 50 ppb can lead to death in adults. TCDD concentration in the remaining unused Agent Orange averages about 2 parts per million (ppm). It is estimated that approximately 240 pounds of TCDD was used from 1965 to 1971 on the Vietnamese homeland. Many American scientists, including Arthur Galston himself, opposed to the use of Agent Orange as a chemical warfare agent; they warn of the time-dependent side effects that will impair the health of the people andthe soil where they are exposed to high concentration of Agent Orange. Furthermore, TCDD dosage accumulates up the food chain. The projected half-life of TCDD in soil is approximately 10 years, while the half-life of TCDD in human fat tissues is approximately 7 years.

During the Vietnam War, about 3 million Americans were deployed in Vietnam. The American Cancer Society announced that approximately half of that population was on active duty during the times when Agent Orange was heavily sprayed around agricultural land in Vietnam[7]. Soldiers were constantly exposed to the highly concentrated Agent Orange that could potentially affect their health and well-being. Blood tests on Vietnam War veterans were carried out in the United States and data showed that veterans returning from Vietnam War had a significantly higher level of TCDD in their blood. The American Cancer Society also suggested several theories in which TCDD enters the human body. Two direct ways to acquire TCDD include inhalation by air andingestion of Agent Orange infected food and crops. In addition, TCDD is permeable through human skin and eyes. The carcinogenic property of TCDD has been proven in multiple studies, all of which suggests its contribution to the development of cancerous cells. It lowers the immune response in animals anddisrupts crucial cellular processes such as cell division. A mal-regulation of cell division can elicit tumor cell growth. Side effects include impaired development of sexual organs in rodents, obstetrical difficulties in human and animals and potential miscarriages[8].Newborns are susceptible to various health problems such as cleft palate, mental disabilities, hernias, polydactyl, and oligodactyly.

Works Cited

[1] Schneider, Brandon. Yale Scientific. Agent Orange: A Deadly Member of the Rainbow. (Accessed Feb 16, 2014).

[2] R. Fraser, Michael. 2,3,7,8-Tetrachlorodibenzodioxin, April 9, 2013. (Accessed Feb 16, 2014).

[3] Poland, A; Knulson, J.C. (1982). 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanisms of toxicity. Ann. Rev. Pharmacol. Toxicol. 22:517-554.

[4] Bultinck, Patrick; De Winter, Hans; Langenaeker, Wilfried; Tollenare, Jan P.. Computational Medicinal Chemistry for Drug Discovery. CRC Press: New York, 2003; p.220-222.

[5] Luch, Andreas. Medscape Multispecialty. Nature and Nurture – Lessons from Chemical Carcinogenesis. (Accessed Feb 16, 2014).

[6] Schuck, Peter H.. Agent Orange on Trial: Mass Toxic Disasters in the Courts. Harvard University Press: 1987, p.16-20.

[7] American Cancer Society. Agent Orange and Cancer. cancercauses/othercarcinogens/intheworkplace/agent-orange-and-cancer (Accessed Feb 16, 2014).

[8] Wikipedia. 2,3,7,8-Tetrachlorodibenzodioxin. (Accessed Feb 16, 2014).