Professor Michael J. Krische: The Properties of Organic Molecules Depend Upon Their Structures

Organic Chemistry In Our Everyday Life
Professor Michael J. Krische
A Broad Scientific Question: What is the nature of matter? Organic Chemistry: The study of carbon containing compounds. Since virtually all naturally occurring compounds contain carbon, organic chemistry is inextricably tied to living systems.
O O H 3C Plant Extraction H 3C O H 3C O H 3C Purple Foxglove, i.e. Digi tal is P urpur ea HO OH O O OH O OH O H 3C H H Steroidal Aglycon The "War-Head" of Digitoxin H OH Digitoxin - A Drug Based on Digitalis Extract Used to Treat Congestive Heart Failure and Atrial Fibrillation H
Glycone - Modulates Drug Delivery and Metabolism
The properties of organic molecules depend upon their structures

Some Familiar Naturally Occurring Substances or Natural Products
N N O Popcorn Aroma Me
N N
OMe Me
N N
OMe Me Me
Raw Potato Aroma
Bell Pepper Aroma
OH OMe
OH OMe
O OMe NH2
O OMe OH Wintergreen Aroma
O H Vanilla Aroma
Clove Aroma
Grape Aroma
Subtle Differences in Structure Confer Differences in Properties

Naturally Occurring Fragrant Esters
O O CH3 H3 C CH3 Rasberry Aroma O O Rum Aroma CH3 CH3 Banana Aroma H3C O O CH3 CH3
O H3C O Pear Aroma O H3C O(CH2)7CH3 Orange Aroma H3C CH3 H3C O
O CH3 H3C O
O CH3
Apple Aroma O O Honey Aroma
Pineapple Aroma O H3C O Peach Aroma
Subtle Differences in Structure Confer Differences in Properties

Organic Molecules Can Have Handedness - They Can Be Chiral. Pair of Chiral Molecular are Referred to as Enantiomers.
Mirror Plane Mirror Plane
O C H
Left Hand Right Hand (+)-Carvone (Caraway)
O C H
(-)-Carvone (Spearmint)
Tetrahedral Carbon Centers Possessing Four Different Groups Can Exist as NonSuperimposable Mirror Images They are Enantiomers.

Different Enantiomers Can Have Wildly Different Biological Profiles
Mirror Plane Mirror Plane
O N O H C O N H O O
O N C H O N H O H 3C H 3C
NH2 O
H 2N O
SH OH
HO HS
CH3 CH3
(+)-Thalidomide (Sedative, anti-Nausea)
(-)-Thalidomide (Severe Birth Defects)
Antidote for Hg Poisening
Optical Atrophy (Blindness)
If a molecule has n-chiral centers, there are 2n possible combinations possible, termed stereoisomers. The FDA now requires that chiral molecules be prepared as single entities. Over 50% of the worlds top-selling drugs are single enantiomers and it is estimated that 80% of all drugs currently entering development are chiral and will be marketed as single-enantiomer entities.
H 3C O NH O O OH OH O O H O O O CH3 O O O OH
Taxol - Bark of Pacific Yew Tree Potent Anti-Cancer Agent 11 Stereocenters 2048 Possible Isomers!

Professor Michael J. Krische Where Do Drugs Come From?
61% of the 877 small molecules introduced as drugs worldwide from 19812002 were inspired by Natural Products (J. Nat. Prod. 2003, 1022). Hence, the discovery, biological profiling (SAR), and preparation of natural products is of paramount importance in terms of public health.
HO O H CH3 H CO2 H CH3

The Structures of Natural Products are Shaped by Selective Pressure. They Evolve.
O O CH3 H H
OH
CH3 CH3
Hirsutic Acid-C (Anti-Biotic Properties)
Coriolin (Anti-Tumor Properties)

Digitoxin A drug based on digitalis extract used to treat congestive heart failure and atrial fibrillation. The extracts of purple foxglove, i.e. digitalis purpurea, have been used in folk-medicine since 1500 B.C. In 1775, the Scottish doctor Withering determined that the extract of purple foxglove was the active ingredient in a folk remedy treatment for heart conditions prepared by a local gypsy woman. In this way, digitoxin was introduced to the mainstream medical community. It is still in broad use today.
O O H3C
Plant Extraction
H3C H3C O H3C O H3C O O OH H O H
H OH
Purple Foxglove, i.e. Digitalis Purpurea
O HO OH
OH
Steroidal Aglycon The "War-Head" of Digitoxin
Glycone - Modulates Drug Delivery and Metabolism

Cardiovascular Drugs - Antihypertensive Agents:
Angiotensin-converting enzyme (ACE) plays a key role in regulating blood pressure. ACE cleaves the peptide angiotensin I to give angiotensin II, which is a strong vasoconstrictor. The venom of the Brazilian pit viper was found to inhibit ACE cleavage. Even though the snake venom peptides were not orally active, the realization that peptides could inhibit ACE initiated the search for smaller peptide based inhibitors which could be administered orally. In this way, the venom of the Brazilian Pit Viper served as inspiration for the blockbuster antihypertensive agents Vasotec and Zestril.
Venom of the Brazilian Pit Viper
Teprotide is a 9-Amino Acid Peptide

Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro
O HN N OEt CH3 O CO2H HN N
O OH NH2
2
O CO2H
Vasotec - Merck & Co. $2.3 Billion in Sales (1999)
Zestril - AstraZeneca Plc. $1.2 Billion in Sales (1999)

Diabetes - Exenatide (marketed as Byetta):
Diabetes afflicts 23.6 million children and adults in the United States (7.8% of the population). Type 2 Diabetes (adult-onset diabetes) is a metabolic disorder that is primarily characterized by insulin resistance, insulin deficiency, and hyperglycemia. It is often managed by increasing exercise and dietary modification, although medications and insulin are often needed, especially as the disease progresses. Exenatide, a 39-amino-acid peptide, is a synthetic version of exendin-4, a hormone in the saliva of the Gila monster that regulates glucose metabolism and insulin secretion.

Halichondrin B Analogue Eribulin (Halaven): Halichondrin B
is a naturally-occurring polyether macrolide originally isolated from the marine sponge Halichondira okadai by Hirata and Uemura in 1986. It was found to exhibit extraordinary in vitro and in vivo anti-cancer activity. The first total synthesis was completed by Yoshito Kishi and co-workers at Harvard University in 1992. Later, a simplified analogue of Halichondrin B was developed named Eribulin (marketed as Halaven). Eribulin has an IC50 value of 13.0 nM for DLD-1 human colon cancer cell and exhibits antitumor activities in melanoma, breast and other cell lines. Eribulin disrupts microtubule assembly during mitosis, which inhibits cell division. Eribulin was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease.

Analgesics - Morphine:
Used as early as 4000 BC, the main ingredient of opium, it was not until 1803 that Morphine was first identified and isolated by the German pharmacist Serturner. He called this alkaloid "Morphia" after Morpheus, the Greek God of Dreams. Morphine is used medicinally to alleviate severe pain. Morphine was used during the American Civil War as a surgical anesthetic and was sent home with many soldiers for relief of pain. At the end of the war, over 400,000 people had the army disease, morphine addiction.
HO O NMe HO Morphine
MeO O NMe HO Codeine
AcO O NMe AcO Heroin
From the opium poppy pod, used as early as 4000 BC
Has potent analgesic and euphoric properties

Composes 10-15% of dry weight of the poppy 95% of morphine extracted is converted to codeine Illicit production of morphine exceeds licit production by a factor of 10.

Analgesics - Aspirin and the Willow Tree:
The father of modern medicine, Hippocrates, who lived sometime between 460 B.C and 377 B.C. left historical records of pain relief treatments, including the use of powder made from the bark and leaves of the willow tree to heal headaches, pains and fevers. The active ingredient in willow bark, termed salicin, was isolated in 1828, by Buchner, a pharmacy professor of at the University of Munich. By 1829, the French chemist Leroux improved the extraction procedure, obtaining ~30g of salicin from 1.5kg of willow bark. Later, in 1838, the Italian chemist Piria split salicin into a sugar and an aromatic component (salicylaldehyde) and converted the latter, by hydrolysis and oxidation, to a crystalline, colorless acid, that he named salicylic acid. However, salicylic acid was tough on stomachs. In 1853, Gerhardt neutralized salicylic acid by buffering it with sodium (sodium salicylate) and acetyl chloride, creating acetylsalicylic acid. Gerhardt had no desire to market his product and abandoned his discovery. In 1899, the German chemist Hoffmann, who worked for Bayer, rediscovered Gerhardt's formula, and gave it to his father who was suffering from arthritis. With good results, Felix Hoffmann convinced Bayer to market the new wonder drug. Aspirin was patented on March 6, 1889.
O OH O O CH3
Acetosalicylic Acid

Warfarin: An anti-coagulant that is the top prescribed blood thinning agent in the world.
In the 1930s, a cow farmer in Deer Park, Wisconsin, brought samples of the sweet clover his cows were eating to the University of Wisconsin, searching for an explanation for his cows death by excessive bleeding after minor procedures. Upon analysis of the cows blood, low levels of blood coagulation proteins were found. Extraction and isolation of products in the sweet clover silage produced the compound later known as warfarin, which inhibits the production of blood coagulation factors. In the 1940s, warfarin first was patented as a highly effective rat poison and soon became the highest used rat poison in the world. A decade later, its therapeutic anticoagulant potential was realized, now as the most utilized anticoagulant for treatment for thrombosis and prevention of embolisms, especially post cardiac surgery.
Warfarin Rat Poison to Top-Selling Anticoagulant

Physostigmine:
This alkaloid acts as a cholinesterase inhibitor and is naturally found in the calabar bean plant, native to Nigeria. Its biological activity results from blocking the breakdown of acetylcholine, a chemical responsible for nerve signal transmission. Ingesting large quantities of physostigmine results in death by asphyxiation, but small quantities have been found to have a wide range of therapeutic applications, including treatment of glaucoma, Alzheimers disease, myasthenia gravis (an autoimmune disease causing muscle weakness), and as an antidote for several toxins.
One important side effect is nausea and vomiting, which plays an important role in the historical significance of physostigmine and calabar bean. In the past, calabar bean was used in trial by ordeal by the Efik Uburutu people in Nigeria to determine if a suspected person was guilty of a crime. After ingesting an herbal drink containing ground calabar bean, if the suspect vomited, they were declared innocent. If they didnt vomit, the suspect was declared guilty, and would die soon after. Medicinal applications of physostigmine-containing calabar bean were first studied in 1864, and further development has resulted in a powerful therapeutic agent.

Analgesics - Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):
NSAIDs are analgesic and antipyretic drugs that inhibit the enzymes cyclooxgenase 1 and 2 (COX-1/COX-2) from synthesizing prostaglandins, chemicals in cells that promote inflammation, pain and fever. This mechanism of prostaglandins inhibition was discovered by Sir John Robert Vane (1927-2004), a British pharmacologist, who was later awarded a Nobel Prize for his work in 1982. NSAIDs are used in the treatment of conditions where pain and inflammation are present, e.g. arthritis, osteoarthritis, dysmenorrhea, gout etc. Since prostaglandins support blood clotting function of the platelets, heavy or frequent use of NSAID can result in an ulcer or prolonged bleeding, especially after an injury or a surgery. NSAIDs are mostly weak acids with a pka of 3-5. The first class of anti-inflammatory, analgesic and antipyretic drugs in the family of NSAID were the salicylates (e.g. aspirin). NSAIDs can be differentiated by their potency, duration of action, methods of administration and rate of elimination, and can be classified based on their chemical structures. Most NSAIDs are available over-the-counter without prescription; in 2001, it was reported that NSAIDs account for 70 million prescriptions and 30 billion over-the-counter medications sold in the United States.

Analgesics - Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Ibuprofen (Advil, Motrin, etc.): Phenylpropionic acid derivative that was derived from propionic acid and was discovered by Boots Group (Steward Adams and coworkers); it was patented in 1961. It originally marketed as Brufen; it is commonly used as an analgesic and anti-inflammatory medicine especially for the treatment of rheumatoid arthritis. It was listed as one of the essential medicines for a basic health system by the World Health Organization (WHO) in 2005.
Naproxen (Aleve etc.): Phenylpropionic acid derivative that is commonly used for the treatment of moderate to severe pain and inflammation associated with arthritis. It was first marketed as a prescription drug (Naprosyn) in 1976 and became available over-thecounter as naproxen sodium (Aleve) in 1994.
Ketoprofen (Orudis, Oruvail, etc.): Phenylpropionic acid derivative that is commonly used for treatment of inflammatory pain associated with arthritis. It is a racemate with only the (S)-enantiomer possessing pharmacological activities. It is also a common analgesic and is used fever-reducing in horses and some small animals.
Diclofenac (Voltaren, Olfen, etc.): Phenylacetic acid derivative that is commonly used for the treatment of inflammation and joint pain caused by rheumatoid arthritis, osteoarthritis, ankylosing spondylitis etc. It was developed by Ciba Geigy (now Novartis) in 1973 and was first introduced into the UK in 1979.
Ketorolac (Toradol, Acular): Heterocyclic acetic acid derivative that was approved by FDA in 1989. Recent studies showed that it is effective for reducing post-operative pain. This drug is not available over-the-counter in the United States and a prescription is required for administration.

Antiseptics (external infection):
Carbolic acid, also known as phenol, was introduced by the English surgeon Lister the first effective anti-septic in 1867. In the middle of the nineteenth century, post-operative sepsis infection accounted for the death of approximately 50% of the patients undergoing major surgery. By cleaning wounds and dressing them using carbolic acid solutions, he was able to announce at a British Medical Association meeting, in 1867, that his wards at the Glasgow Royal Infirmary had remained clear of sepsis for nine months. Phenol is caustic to skin, so subsequently the milder antiseptic boric acid (H3BO3) was used. Antisepsis was one of the two most significant medical discoveries in the 19th century (the second was anesthesia).
HO
Carbolic Acid Phenol

Professor Michael J. Krische Anti-Bacterials (internal infection):
Antibiotics are natural substances that are released by bacteria and fungi as a means of inhibiting other organisms - it is chemical warfare on a microscopic scale. Paul Ehrlich, a German medical professor, was fascinated that aniline and other synthetic dyes stain specific microbes. This led him to predict that one could create "magic bullets," agents that would "be able to exert their full action exclusively on the parasite harbored within the organism." Focusing on syphilis, a bacterial infection that afflicted over 10% of the European population, he screened compounds that contained aniline substructures (for delivery) and arsenic (the warhead), he identified arshpenamine or Salvarsan in 1909. His search for a specific drug to treat a specific disease marked the beginning of targeted chemotherapy. Salvarsan was the world's first blockbuster drug. Earlier, syphilis was treated using mercury salts. In 1932, the German biochemistry Domagk discovered that the sulfanilimide dye, later named prontosil, killed bacteria without serious toxic side effects. At this time, Domagks 6-year old daughter received a streptococcal infection from a needle prick and was near death. Domagk tested the drug on his daughter, who made a complete recovery. Later it was found that the much simpler substance, sulfanilamide, is superior and much cheaper to produce also, it doesnt lead to red skin! The discovery of sulfanilamide greatly attenuated the mortality rate during WWII. Penicillin was discovered of by Alexander Fleming in 1928, but it wasn't until ten years later, in 1939, that Chain, Florey and Abraham of Oxford University were able to purify and stabilize a form of penicillin, enabling demonstration of its therapeutic potential. Penicillin is produced from a soil mold via fermentation. When penicillin became widely available during the second world war, it was a medical miracle, rapidly vanquishing the biggest wartime killer - infected wounds. Penicillin has saved countless lives and is considered the greatest discovery in medical history.
ClH3N HO As As Arsphenamine Salvarsan
NH3Cl OH H 2N
NH2 N N SO2NH2
OPh H N O O N CO2H Penicillin V
Sulfa-Drugs Prontosil (Sulfonilamide)
Green Chemistry for Organic Synthesis

Streptomycin and Tuberculosis The White Plague:
Prof. M. J. Krische
Despite its wonders, penicillin is not effective against tuberculosis a bacterial infection of the lung. During the 19th century, up to 25 per cent of deaths in Europe were caused by this disease (although 90% of infections are asymptomatic). Over the past two centuries, TB has claimed over 2 billion lives. A third of the world's population are thought to be infected with M. tuberculosis, and new infections occur at a rate of about one per second. Streptomycin is antibiotic produced by soil bacteria originally isolated by Waksman and Schatz in 1947. It is a mainstay of tuberculosis therapy. Because streptomycin-resistance arises during treatment, the antibiotic is usually used in combination with other drugs, such as isoniazid or rifampicin, another natural product from soil bacteria isolated in 1957. Despite all the drugs available today, TB is still a problem in developing nations. The highest incidences (up to 80%) are in countries in Africa, Asia, and Latin America only 5 10% of the US population tests positive for TB. The World Health Organization estimates that each year 3 million people die from TB. Today, there are strains of TB resistant to any known antibiotic. In New York City, 19% of TB is resistant to the two most powerful drugs. It is now feared that the disease will spread to other areas in the U.S. before there is a cure.

Erythromycin:
Erythromycin is another natural product made by soil bacteria that has anti-biotic activity similar to penicillin. Indeed, it is often given to people who are allergic to penicillin. Erythromycin was discovered by the pharmaceutical company Eli Lilly. Erythromycin is constructed via polypropionate biosynthesis, which involves formal aldol-type bond constructions. The aldol reaction ranks among the most important methods for the stereoselective synthesis of polyketide natural products both in Nature and in synthetic organic chemistry. Azithromycin is a synthetic analogue of erythromycin, and one of the words top-selling drugs. It is used to treat bacterial infections such as ear infections, tonsillitis, throat infections, laryngitis, bronchitis, and pneumonia.
Me O Me HO HO Me HO O Me O
NMe2 HO Me O Me O O Me Me O Me Me OH OMe Me Me
OH OH O
OH OH O OH Me N Me HO HO Me HO O Me O
Me HO Me O Me O O Me Me
NMe 2
Me Me Me Me Me Me Erythromycin A Seco Acid
Me Me
OH OH O
OH OH O OH
OH OMe
Erythromycin A
Azithromycin
Me Me Me Me Me Me 7 polypriopionate units
Green Chemistry for Organic Synthesis

Quinine & Malaria:
Prof. M. J. Krische
The Cinchona tree was originates from the slopes of the Andes. Its ability to cure malaria was discovered by Jesuit monks and the anti-malarial value of Cinchona became more widely recognized. So valuable was the bark that at one time, bark powder was often matched by its weight in gold. Indeed, over-harvesting of the bark nearly decimated the population of the tree in its native habitat. Fortunately, Dutch adventurers smuggled a few seedlings out of Peru in the 1860s, and used them to set up large plantations in Java. In WWII, the Japanese military conquest cut off access to quinine from Java, which accounted for 95% of the world supply. This led to the death of over 60,000 US troops died in WWII due to malaria infection.
Currently, an estimated 200 million to 300 million malaria infections occur each year, with 2 million to 3 million deaths one death every 12 seconds. 90% of all cases occur in Africa. 5% of African children (3,000 each day) die of malaria. The World Health Organization (WHO) ranks malaria first among human parasitic diseases in terms of socio-economic and public health importance. Due to global warming and drug-resistantance, malaria is undergoing a dramatic resurgence. Since recorded history until today, more human deaths are attributed to malaria than any other cause.

Sugar Substitutes:
A total of 3,920 products containing artificial sweeteners were launched in the U.S. between 2000 and 2005. Artificial sweeteners are much less expensive than sucrose or corn syrup. Saccharin: Synthesized in 1879 by Remsen and Fahlberg, it is 300-500 times as sweet as sugar and is often used to improve the taste of toothpastes, dietary foods, and dietary beverages. It is marketed as Sweet n Low.
Cyclamate: Discovered in 1937 at the University of Illinois by graduate student Michael Sveda, the FDA banned its sale in the United States in 1969 because intestinal bacteria could desulfonate cyclamate to produce cyclohexylamine, a compound suspected to have some chronic toxicity.
Aspartame: Discovered in 1965 by James M. Schlatter, it is 180 times sweeter than sucrose. This sweetener is marketed under a number of trademark names, including Equal, NutraSweet, and Canderel. It is used in approximately 6,000 consumer foods and beverages.
Sucralose: Discovered in 1976 by Leslie Hough, sucralose was first approved for use in in 1998. It is 600 times as sweet as sucrose and can be found in more than 4,500 food and beverage products. It is used because it is a no-calorie sweetener and is safe for consumption by diabetics. It is marketed as Splenda.

Cyclopamine: Cyclopamine is an alkaloid identified as 11-deoxojervin that is found in Veratrum
californicum, the California corn lily. It was named for one-eyed lambs, real-world Cyclopes, at a farm in Idaho. The U.S. Department of Agricultures Poisonous Plant Research Laboratory in Utah began an investigation on this alkaloid after World War II due to the 40% loss of sheep resulting from the cyclopean defect in this region. It was found that if pregnant sheep ate the plant on their 14th day of gestation, they would give birth to lambs with a single eye in the middle of their foreheads. Ingestion of this plant during the later days of gestation induces limb and tracheal malformations. Upon further study, it was revealed that cyclopamine inhibits the hedgehog (Hh) signaling pathway that regulates embryogenesis. This finding attracted the attention of many developmental biologists and cancer researchers. An organic chemist from the University of Leipzig in Germany, Athanassios Giannis, reported that aberrant activation of this Hh-pathway in adults leads to malignances. As a result, cyclopamine could be a potential therapeutic agent for the treatment of some challenging forms of cancer.

Coniine: Coniine is a toxic alkaloid found in poisonous hemlock (conium
maculatum). It is a neurotoxin that targets the peripheral nervous system. Coniine causes ascending muscle paralysis by blocking the nicotinic receptors on the post-synaptic membrane of the neuromuscular junction. Once paralysis reaches the respiratory muscles, death occurs due to lack of oxygen to the heart and brain. In ancient Greece, the philosopher Socrates was poisoned by hemlock after being condemned to death for impiety. Coniine also is found in the nectar of the yellow pitcher plant (Sarracenia flava), where it is used to intoxicate prey. Made by Albert Ladenburg in 1886, coniine is the first alkaloid prepared via total synthesis. For an adult, the ingestion of more than 100 mg of coniine (6 to 8 fresh leaves, or a smaller dose of seeds or root) may result in fatality.
Organic Chemistry and Drug Discovery

Atropa belladonna: Atropa belladonna is a botanical name for plants that are commonly known as
belladonna; other common names include deadly nightshade, atropa, deaths herb and witchs berry. Atropa belladonna belongs to the Solanaceae family, which is commonly known as the nightshade or potato. Belladonna has been used for its hallucinogenic effects, cosmetic, poison and medicine. The word Belladonna comes from the Italian words that mean beautiful lady, this is probably because italian women used to dilate their pupils by means of a drop of belladonna in each eye. The name atropa bella donna is derived from a warning in Italian and Greek meaning do not betray a beautiful lady. Active ingredients in Belladonna are atropine, hyoscine, and hyoscyamine, which possess anticholinergic properties. All parts of this plant may prove to be poisonous even in small dosage, especially the black berry. 10 to 20 ingestions of the black berry will kill most adults, and two to three will be sufficient to kill the children. Belladonna poisoning has symptoms such as fever, dry mouth, loss of balance, sensitivity to light, rash, hallucination, urinary retention, constipation, convulsion as well as staggering headache.

Oenanthotoxin:
Oenanthotoxin is a toxin extracted from Oenanthe crocata; it is a central nervous system poison that causes facial muscles spasm resulting in a grinning appearance, a trait that is anciently known as risus sardonicus the sardonic smile. This plant was used in ritual killings in ancient pre-Rome times in Sardinia. Elderly citizens who were unable to support themselves were seen as a burden to society. Hence, they were intoxicated with this sardonic herb prior to being killed by beating or dropping from a high rock, so they would have a defiant grin in the face of death. Researchers later discovered that the plant toxins oenanthotoxin and dihydrooenanthotoxin block the receptors to the neurotransmitter aminobutyric acid (GABA), which is directly involved in muscle tone regulation. The sardonic smile could be explained on the basis of this observation.

Poison Dart Frogs: Skin secretions from certain frogs are used by
Amerindian tribes to prepare poison darts. The golden poison arrow frog (Phyllobates terribilis) is most deadly to humans. Its skin secretions contain the potent cardio- and neurotoxic steroidal alkaloid batrachotoxin. Frogs raised in captivity do not produce this toxin, as they acquire the poison from eating insects in their native habitat, which obtain the poison from a plant source. Approximately 136 micrograms of batrachotoxin, equivalent to 2-3 grains of table salt, is a lethal dosage. Compounds isolated from these frogs have potential medicinal value. For example, the alkaloid epibatidine, isolated from the skin secretions of the frog Epipedobates tricolor, is a painkiller 200 times as potent as morphine. Many of these frogs are now endangered due to habitat loss.

Ergotism and Witchcraft: The fungus Claviceps
purpurea infects rye and produces metabolites known as the ergot alkaloids, which are used to produce lysergic acid and its infamous diethylamide, known as LSD. Ingesting infected rye bread causes a form of food poisoning called ergotism, which is characterized by violent muscle spasms, vomiting, hallucinations, paranoia, crawling sensations on the skin, and even a form of gangrene known as St. Anthonys fire. Plagues of Holy Fire (gangrenous ergotism) are responsible for certain geographical boundaries in modern Europe. For example, France suffered many waves of ergotism in the 8th and 9th centuries. Thousands died, which made France an easy target for Vikings. These Northmen took the northwest coast of France, which ceded to them and would become Normandy. Ergot thrives in warm, damp, rainy springs and summers. There is considerable evidence that ergotism is linked to medieval witch trials. Bouts of bewitchment tended to be seasonal and would recur in geographical regions where rye is a staple. Additionally, witch trials were more common in years when the spring and summer months were colder and wetter. Ergot alkaloids were found in the stomachs of Iron Age human remains from peat bogs northeastern Europe.

Industrial Chemistry: Where do chemical products come from? Is their production sustainable?
One major feedstock for the production of organic compounds is methane, the primary component of natural gas. In the chemical industry, methane is the feedstock of choice for the production of hydrogen, methanol, acetic acid, and acetic anhydride. In fact, 2% of global energy consumption is due to methane-steam reforming to produce the hydrogen needed for the Haber-Bosch reaction the reduction of atmospheric nitrogen to furnish ammonia. Ammonia is the limiting nutrient in terrestrial plant growth and NH4NO3 produced using the Haber-Bosh process is a potent fertilizer that bolstered worldwide food production to unprecedented levels. As natural sources of methane are depleted, efforts toward the production and capture of methane from landfills and other renewable sources has become the topic of intensive investigation.

An Example of Industrial Synthesis on Scale: Di(2-Ethylhexyl) Phthalate
> 50% Plasticizer!
4 Linear Steps, H2O is Only Stoichiometric Byproduct Catalytic Chemistry versus Stoichiometric Reagent Abundant Starting Materials - Minimal Preactivation

Professor Michael J. Krische: The Properties of Organic Molecules Depend Upon Their Structures

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Professor Michael J. Krische: The Properties of Organic Molecules Depend Upon Their Structures

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Organic Chemistry In Our Everyday Life