Chemical & Chemical Engineering News (80th Anniversary Issue), Vol. 81, No. 36, 2003, Sept. Edited by X. Lu Introduction

Throughout my time in the chemical industry, I have been fascinated by the prevalence of nitrogen in the most important and essential components of life on Earth. Imagine a world without nucleic acids and DNA for recording the program of life; without amino acids and peptides to carry out the instructions of the genome; or without the alkaloids, a source of inspiration to synthetic and medicinal chemists and the basis of many pharmaceuticals of use and abuse.

Amino acids, the building blocks of the cell's protein factory, occur in only 20 different types in mammalian proteins, yet from these 20 simple molecules an almost infinite variety of structural proteins and enzymes can be built, and they can catalyze chemical processes far more efficiently and selectively than our chemical efforts. The natural amino acids are also remarkable in that they all are constructed by nature in the l form in proteins. What event early in the history of life on Earth led to the chirality of amino acids is a question that has always intrigued me. It may be that catalysis on a primitive inorganic surface favored the l form over the d, or the selection of l amino acids could have been an effect of polarized light.

There is also a theory that life on Earth was seeded by complex molecules from the interstellar void. Indeed, a variety of simple nitrogen compounds, such as cyanides, isocyanides, and formamide, have been found in interstellar gas. More evidence has recently emerged to show that the simplest amino acid, glycine, is also present in outer space.

Another vital property of nitrogen as a basic element of life is its ability to form hydrogen bonds. Hydrogen bonds between amino acids control the folding of proteins into a-helices and -sheets. In DNA, the hydrogen bonds to nitrogen are of even more importance. The realization that adenine only paired with thymine and that cytosine only paired with guanine (Watson-Crick pairing) was one of the keys to deciphering the structure of DNA. Base pairing through the hydrogen bonds of the nitrogen bases is also essential for the transmission of genetic information from DNA to messenger RNA and hence to instruct the protein synthesis factory.

Nitrogen is essential to life, but we must always remember that nitrogen can be destructive as well. Haber's work on ammonia synthesis was not undertaken to manufacture cheap fertilizer, although this was one of the outcomes of his discovery. Rather, it was the need for nitric acid to manufacture explosives when wartime blockades prevented importation of natural potassium nitrate from Chile that drove Haber to find an alternative process. This Janus-like aspect of nitrogen to be an element for good and for evil had already been recognized by Alfred Nobel. Having made his fortune from the manufacture of dynamite from nitroglycerine and kieselguhr, he left it to found the prizes which bear his name, and which a number of researchers in the chemistry of nitrogen compounds have received. The search for ever more potent explosives for both peaceful and military purposes continued after Nobel's death, and led in 2000 to the preparation by Philip Eaton of octanitrocubane, perhaps the most powerful explosive ever to be made. Both the good and the dark side of the chemistry of nitrogen continue to fascinate chemists today, and this essential element will surprise researchers studying its compounds well into the future.

Peter Nagler is head of the fine chemicals business unit at Degussa AG. After many years working with amino acids, he is, like nitrogen, generally noncombustible and nontoxic.

NITROGEN AT A GLANCE

Name: From the Greek nitron genes, nitre (potassium nitrate) forming.

Atomic mass: 14.01

History: Discovered by Scottish physician Daniel Rutherford in 1772.

Occurrence: Nitrogen makes up about 78% of Earth's atmosphere by volume. Nitrogen is "fixed" from the atmosphere by bacteria in the roots of certain plants such as clover. It is obtained commercially through the fractional distillation of liquid air.

Appearance: Colorless, odorless gas.

Behavior: The gas is largely inert, but its compounds are vital components of foods, fertilizers, and explosives.

Uses: Liquid nitrogen is used to freeze foods and preserve biological specimens. The gas is used as a nonreactive "blanket gas" in the semiconductor industry and welding.

PHOSPHORUS

C. DALE POULTER ,UNIVERSITY OF UTAH

Phosphorus, an element of tremendous importance in commerce and research, was first isolated by Hennig Brandt in 1669. Following the standard practice of alchemists of his era, he protected his invention as a "trade secret" in hopes that he had discovered the Philosopher's Stone. Brandt's monopoly was broken a decade later by Robert Boyle, often regarded as the father of chemistry for his insistence on publishing experiments in sufficient detail so they could be reproduced by others. The description that Boyle and his assistant Abrose Godfrey Hanckwitz gave to the Royal Society of London is a fascinating account of their research with phosphorus. It begins with "As is before shewed, take Urine well putrefied in a Tub" and concludes with "If the Privy Parts be therewith rubb'd, they will be inflamed and burning for a good while after." I wonder who volunteered for that experiment!

MAGICAL Joseph Wright's "The Alchemist in Search of the Philosopher's Stone Discovers Phosphorus."

I was introduced to the wonders of phosphorus at the tender age of three. This was near the end of World War II, when Mom and I were living with my grandmother and three aunts, one of whom I convinced to give me a few kitchen matches. My combustion experiment soon got out of control, and I spent the next hour or so at the front window of my grandmother's house nervously watching firemen fight a grass fire in the field across the street. At the same time, phosphate, from Coca-Cola, was an important component in an unrelated set of experiments to develop a concoction I called "chemical dog food." Numerous formulations, most of which featured coffee grounds floating on a highly colored liquid, were prepared from as many different ingredients as I could find in the kitchen. The consumer evaluations I conducted with my grandmother's dog Mitzi were negative, and I eventually dropped the project.

In grade school, my research activities became more organized. Several of my playmates and I formed a "chemistry club." We combined our chemistry sets and set up a laboratory under the front porch of my house--I don't think Mom and Dad ever knew about it. By and large our experiments, many of which were more advanced versions of the earlier combustion study, were successful. We had fun, actually taught ourselves some chemistry, and survived with no permanent injuries. The house survived as well!

I didn't learn very much about phosphorus in college or in graduate school. Phosphorus played a minor role in my graduate and postdoctoral research--P₂O₅ to dry solvents and Wittig reagents to synthesize olefins. Imagine: nine years of advanced education and training with five years of specialization in organic chemistry--the chemistry of compounds from living organisms--and virtually no mention of phosphorus.

I was reintroduced to phosphorus by Hans Rilling, a biochemist at the University of Utah, when we began a long, productive collaboration to study the mechanisms of the reactions used by nature to join isoprene units. The substrates for our enzymes were diphosphate esters--molecules beautifully designed to be stable at physiological pH, but easily activated once inside the active site of an enzyme. One of the first hurdles I faced was how to prepare substrate analogs for mechanistic studies from precious, lovingly synthesized alcohols. The reactions used then gave miserable yields of at most a few milligrams of product. Over the next several years, my students and I developed a practical solution based on a simple displacement using inorganic pyrophosphate. We published a detailed description of the procedure in Organic Syntheses over the objections of a member of the editorial board who regarded our use of a vortex mixer, lyophilization, and chromatography on cellulose to purify the nonvolatile water-soluble products as being "too unfamiliar and biochemical" for organic chemists. Since then, my organic colleagues have become much less hydrophobic.

Over the years, my group has become increasingly dependent on phosphorus. In addition to the isoprenoid diphosphates, we rely heavily on recombinant DNA technology. Consider a few of the beauties of phosphate esters in this regard: reverse transcription for making cDNA libraries from RNA, polymerase chain reaction for synthesizing customized DNA, cutting and pasting of DNA to make templates for generating recombinant proteins, chemical synthesis of DNA, and high-throughput DNA sequencing. These "tools of the trade" for today's chemist studying biosynthesis were unimaginable only three decades ago when I entered the field.



C. Dale Poulter is the John A. Widtsoe Distinguished Professor of Chemistry at the University of Utah. He has received the ACS Ernest Guenther and Repligen Awards for his work on isoprenoid biosynthesis and is editor-in-chief of the Journal of Organic Chemistry.

PHOSPHORUS AT A GLANCE

Name: From the Greek phosphoros, bringer of light.

Atomic mass: 30.97.

History: Discovered in 1669 by German physician Hennig Brandt.

Occurrence: Widely distributed in many minerals. Phosphate rock, containing apatite, is an important source.

Appearance: Solid nonmetal. Ordinary phosphorus is a waxy white solid. Phosphorus has white, red, and black allotropes. White phosphorus is soft, while red phosphorus is powdery.

Behavior: White phosphorus catches fire spontaneously in air. When exposed to damp air, it glows in the dark in a process known as chemiluminescence. It reacts vigorously with all the halogens.

Uses: An essential component of living systems found in nervous tissue, bones, cell protoplasm, and DNA, mostly as phosphate. Compounds are also used in fertilizers, insecticides, detergents, and foods.

ARSENIC

M. FEROZE AHMED, BANGLADESH UNIVERSITY OF ENGINEERING & TECHNOLOGY

Arsenic was known to me as a homeopathic medicine from my boyhood. I learned that arsenic is a poison but in small doses builds resistance against the common cold, asthma, coughs, scabies, and a variety of other diseases. My chemistry teacher then introduced arsenic as the third element in Group VA in the periodic table. The presence of arsenic in lethal doses in food, water, or air is not noticeable to human senses of sight, smell, and taste, which makes arsenic a perfect homicidal and suicidal agent. In the late 1980s, I further studied the element while deriving environmental quality standards for Bangladesh, but my understanding was limited to its evil reputation as a poison and its inhibitory effects on biological activities.

Arsenic is a ubiquitous element in nature and is widely distributed in air, water, soils, rocks, plants, and animals in variable concentrations. It is the 20th most abundant element in Earth's crust and the 12th most abundant element in the biosphere. The cycling of arsenic in the environment is regulated by natural processes and human activities. Thus, humans all over the world are exposed to small amounts of arsenic, mostly through food, water, and air.

POISONED Arsenic contamination of drinking water is wreaking havoc in Bangladesh, prompting many scientists such as Bibudhendra Sarkar to help.

But the presence of high levels of arsenic in groundwater, the main source of drinking water in many countries around the world, has drawn the attention of the scientific community. As an environmental engineer with an interest in water supplies, I became fully involved in arsenic research in 1995. My international links with Massachusetts Institute of Technology, the University of Cincinnati, Columbia University, and the United Nations University in Japan helped me to conduct intensive work on arsenic-release mechanisms in groundwater, arsenic removal technologies, and the fate of arsenic in the environment. In addition, I extensively studied the status of arsenic problems in Bangladesh and regional countries; participated in, as well as organized, several international events; conducted advanced training on arsenic; and edited, published, and distributed five documents on arsenic, most of which are available free online.

The status of arsenic changed in 1987 when inorganic arsenic present in drinking water was classified as carcinogenic. Arsenic is known to be nonessential for plants but an essential trace element in several animal species, while its presence in humans is an issue of debate. On the basis of an epidemiological study conducted in Taiwan, arsenic content in drinking water associated with an excess lifetime skin cancer risk of 10^–5 was calculated to be 0.17 mg per L--too low for measurement. The joint Food & Agriculture Organization of the United Nations/World Health Organization (WHO) Expert Committee on Food Additives confirmed a provisional tolerable weekly intake of 15 mg per kg of body weight for inorganic arsenic in 1988. WHO, therefore, recommended a provisional guideline value of 10 mg per L for arsenic in drinking water in 1993, which has been adopted as a standard for arsenic in drinking water in many developed countries. Many developing countries, including Bangladesh, for technical and economical reasons, have retained the earlier WHO guideline value of 50 mg per L as the national standard or as an interim target. The estimated number of people exposed to arsenic exceeding 50 mg per L from drinking water in Bangladesh, India, China, and Nepal is 29 million, 5.3 million, 5.6 million, and 0.6 million, respectively. Concerns have been raised about arsenic contamination in the food chain through irrigation with contaminated water.

I have visited various places in Bangladesh, India, Pakistan, and Nepal; lectured on arsenic; and exchanged views with the regional scientists. Thousands of arsenicosis cases have been confirmed in Bangladesh and West Bengal. The common adverse effects of chronic arsenic exposure are melanosis, keratosis, hyperkeratosis, some cases of skin cancer, gangrene, peripheral vascular disorder, and other adverse health effects. Fortunately, the arsenicosis prevalence rate is still much lower than the estimated risk at the present level of contamination. The poorest people are most likely to be worst affected by arsenicosis, not only physically, but also socially and economically. My present activities at the government and nongovernment levels are targeted toward providing sustained access to arsenic-safe drinking water.

Much remains to be learned about arsenic. The interindividual variation in susceptibility to arsenic toxicity is still a puzzle. The precise mechanism of action of arsenic in human systems is yet to be fully understood. The silent presence of arsenic in the environment, particularly in drinking water and the food chain, is a potential threat to humankind and deserves greater attention from the scientific community around the world.

M. Feroze Ahmed is a professor of civil/environmental engineering at Bangladesh University of Engineering & Technology, Dhaka. He received the Dr. Rashid Gold Medal in 2001.

ARSENIC AT A GLANCE

Name: From the Greek arsenikon, yellow orpiment (a powdered pigment).

Atomic mass: 74.92.

History: Arsenic compounds were mined by the ancient Chinese, Greeks, and Egyptians. The element was first isolated by Albertus Magnus, a German alchemist, in 1250.

Occurrence: Occasionally found as a free element, but mostly it is found in a number of minerals.

Appearance: Either yellow or steel gray, very brittle crystalline, nonmetal solid.

Behavior: Arsenic is stable in dry air. Its gray form tarnishes and burns in oxygen. Arsenic salts and arsine gases are poisonous. Arsenic is carcinogenic and possibly teratogenic.

Uses: In alloys, arsenic is used in semiconductors, pesticides, wood preservatives, and glass. It is also used in bronzing.

ANTIMONY

NINA ULRICH, UNIVERSITY OF HANNOVER, GERMANY

Antimony is one of the least famous chemical elements. If you ask someone on the street about it, you'll be met with a blank stare. Not like the response you would get if you mentioned everyday elements such as oxygen or elements famous for their toxicity, such as arsenic. Even a chemist might respond: "Well, antimony, it's just like arsenic. Toxic, you know. Its chemical properties are quite similar, fifth main group. But less useful, except maybe for some alloys."

That was also my point of view when I started antimony speciation analysis 10 years ago. But I quickly realized that this element has been part of history for a long time and has many important functions in the present. In the future, there could be even more applications, especially in the medical field.

Antimony's use is first documented by the ancient Egyptians. They loved the beautiful colors of compounds like the bright orange antimony sulfide, especially for cosmetic purposes. But even in that period, antimony was taken as medicine for different fevers and skin irritations, as old papyri show. And medicine stayed one of the main fields for antimony application (besides alchemy). In the 13th century, Roger Bacon described several of its properties, and in the 17th century, Theodor Kerckring wrote the first monograph of a chemical element about antimony. In addition, antimony is part of the canon of homeopathy and has been widely applied in the past few centuries.

AFFLICTED A young Sudanese boy with visceral leishmaniasis.

Back in the early-20th century, antimony was discovered to be extremely useful in the therapy of tropical diseases, especially leishmaniasis. This is a deadly parasitic infection; there are millions of people at risk and, according to the World Health Organization, an estimated 2 million cases occur every year. In some areas of South America, leishmaniasis is endemic and its cutaneous form is simply viewed as a children's disease. The more severe form, visceral leishmaniasis, however, leads to fever and massive enlargement of the intestines, liver, and spleen and, sadly, when untreated it has a mortality rate of 98%. The vector is a small insect, a sand fly, that lives in human houses, and the reservoir contains not only humans but also many kinds of mammals and even some reptiles like crocodiles. Therefore, it is nearly impossible to exterminate the disease.

Although the mechanism of antimony toxicity to the parasite remained unclear, several therapeutic agents have been developed. In the early years, mainly trivalent antimony had been applied, which showed a nice ability to kill the parasite but unfortunately also to kill the human host. So the antimony was switched to the pentavalent oxidation state in the 1950s, resulting in much lower toxicity. Nowadays, mainly sodium stibogluconate (pentostam) and meglumine antimonite (glucantime) are used.

In the past decade, health officials noted that the disease was becoming resistant to antimony treatment. That led to increased efforts for the development of new therapeutic agents and the understanding of their mode of action. New techniques--both on the biomedical and on the chemical side--were developed for cell samples. Scientists succeeded in cultivating the parasite cells, the amastigotes, on media, giving the opportunity for direct investigation of antimony toxicity on them.

Meanwhile, in analytical chemistry, advances were being made in the field of speciation analysis, which deals with different oxidation states and the chemical bindings of metals and metalloids. Ideally, the conformation of the chemical compounds can directly be determined. Although there are numerous problems--for example, the stability of the compounds, the low concentrations of the species, and insufficient separation--much progress has been made in the past few years. It has been possible to differentiate between trivalent and pentavalent antimony in cell samples. In addition, the formation of chemical bindings between organic compounds in the cells, such as enzymes or proteins, and antimony has been observed.

The chemical analysis led to these results for the biological processes: The pentavalent antimony is reduced in the amastigote cells to the trivalent oxidation state. Afterward, the trivalent antimony takes effect on the parasite. The antimony resistance of some strains of the leishmaniasis parasite is possibly caused by the inability of these cells to effect the reduction, thereby interrupting the chemical reactions. In addition, some cell groups show a reduced antimony uptake or accelerated antimony excretion.

Speciation analysis in combination with biomedical experiments has helped explain much about the biochemistry of antimony in leishmaniasis. But much more research is needed before the mode of action of antimony in the parasite is fully understood. This knowledge then might be used as a basis for the development of new therapeutic agents that are more toxic to the parasites and cause fewer side effects.

Nina Ulrich is a professor of inorganic chemistry at the Institute of Inorganic Chemistry, University of Hannover, Germany.

ANTIMONY AT A GLANCE

Name: From the Greek anti and monos, not alone. The symbol is from the Latin stibium, mark.

Atomic mass: 121.76.

History: Antimony was recognized in compounds by ancient civilizations and was known as a metal at the beginning of the 17th century.

Occurrence: Found in many minerals.

Appearance: Bluish white, solid metal.

Behavior: Antimony is highly toxic.

Uses: Addition of antimony to alloys increases the hardness and mechanical strength of lead and other metals.

BISMUTH

NEIL BURFORD, DALHOUSIE UNIVERSITY

Bismuth is the heaviest nonradioactive element and is essentially a nontoxic neighbor of lead and thallium in the periodic table. It is mined as bismuth oxide (Bi₂O₃, also known as bismite) or bismuth sulfide (Bi₂S₃, bismuthinite), and the brittle, silvery elemental form is one of a few substances (water is another) for which the solid is less dense than the liquid.

Although bismuth has been extensively used in alloys, pharmaceuticals, electronics, cosmetics, pigments, and organic synthesis ("Chemistry of Arsenic, Antimony, and Bismuth," N. C. Norman, editor, Kluwer Academic Publishers, 1997; "Organobismuth Chemistry," Hitomi Suzuki and Yoshihiro Matano, editors, Elsevier, 2001), the chemistry of bismuth is perhaps the least well established of the group-15 elements (known as the pnictogens). Compounds of bismuth typically have low solubility in most solvents, so that definitive formula assignments are usually based on X-ray diffraction studies of crystalline samples that have been isolated in small or indefinite quantities. Most isolated compounds are unique rather than members of a series of related compounds illustrating fundamental chemical trends.

	CRYSTAL CLEAR Crystals of bismuth have a pink sheen that is unusual among metals.

The bioutility of bismuth compounds has a 250-year history that includes numerous medicinal applications [Chem. Rev., 99, 2601 (1999)]; however, the mechanisms of bioactivity are not understood. Moreover, as for most compounds of bismuth, the chemical characterization of biorelevant complexes remains incomplete. Although the "heavy metal" designation has impeded application of bismuth chemistry in medicine, two compounds have been extensively used for gastrointestinal medication for decades. Pepto-Bismol contains bismuth subsalicylate (BSS), and De-Nol contains colloidal bismuth subcitrate (CBS). The use of these compounds for the treatment of travelers' diarrhea, non-ulcer dyspepsia, nonsteroidal anti-inflammatory drug damage, and various other digestive disorders extends from the previous use of bismuth compounds in the treatment of syphilis and tumors, in radioisotope therapies, and in the reduction of the renal toxicity of cisplatin.

Systematic synthetic studies coupled with bioactivity assessments of tropolone derivatives [Coord. Chem. Rev., 163, 345 (1997)] and thiobismuth compounds [Dig. Dis. Sci., 43, 2727 (1998)] have revealed relationships between specific structural features and bioactivity. Assessments have included antimicrobial behavior against Clostridium difficile, Helicobacter pylori (a bacterium associated with the pathogenesis of gastroduodenal ulcers), Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis, as well as gastric ulcer healing efficacy studies in rats.

The binding of bismuth to proteins of exposed ulcer tissue and the formation of a protective coating is proposed as a mode of action for the ulcer-healing behavior of some bismuth compounds. In this context, the chemistry of bismuth complexes involving biomolecules as ligands represents an important component in understanding aspects of the bioactivity. The thiophilicity of bismuth has prompted speculation that sulfur-containing biomolecules represent the primary target for pharmaceuticals such as CBS and BSS.

Bismuth complexes involving biomolecules have been characterized by ¹³C NMR spectroscopy and X-ray absorption spectroscopy [Coord. Chem. Rev., 185­186, 689 (1999); Pure Appl. Chem., 70, 863 (1998)]. More definitive data are obtained using mass spectrometry, which enables formula assignments for molecules and molecular fragments, and, specifically, the identification of new bismuth complexes involving weakly donating functional groups [Inorg. Chem., 42, 3136 (2003)]. Most important is the identification of glutathione and cysteine complexes of bismuth, which provide support for the thiolation of bismuth as the primary biochemical fate of bismuth pharmaceuticals [Chem. Commun., 2003, 146].

The array of medicinal uses for bismuth compounds indicates a diverse biorelevance for the element that has not yet been unequivocally defined. The indisputable antimicrobial activity of various bismuth compounds at appropriate concentrations, the relatively low elemental human-cell cytotoxicity, and the apparent gastric cytoprotective properties of certain bismuth salts highlight the chemistry of bismuth as an important focus for the development or discovery of new gastrointestinal pharmaceutical agents. The efficiency of such developments will depend on the systematic assessment of bismuth chemistry as a foundation for understanding biochemical interactions.

Neil Burford is the Harry Shirreff Professor of Chemical Research and a Canada Research Chair in the department of chemistry at Dalhousie University in Halifax, Nova Scotia. He received his B.Sc. from the University of Cardiff and a Ph.D. from the University of Calgary in 1983.

BISMUTH AT A GLANCE

From the German weisse masse, white mass.

Atomic mass: 208.98.

History: Known since the 15th century; was often confused with tin and lead.

Occurrence: Found in the ores bismite and bismuthinite.

Appearance: Mostly white, heavy, brittle metal with a pinkish tinge at room temperature.

Behavior: The most diamagnetic metal. One of the few species that expands from a liquid to a solid.

Uses: Metallurgists often use it in alloys so that a metal's volume will remain the same when it solidifies. Bismuth alloys are also used extensively in fire alarms and fuses; a large electrical current will melt the alloy, breaking the circuit.

OXYGEN

CARL DJERASSI, STANFORD UNIVERSITY

Oxygen is a tricky subject to be offered on a silver platter. No such platter is large enough to cope with any but the smallest morsels from the giant pantry filled with oxygen-containing goodies. Rather different from an element with a three-digit atomic number, where modest hors d’oeuvres suffice.
One need not be a chemist to know that without oxygen a human life would cease in seconds or minutes rather than decades. But as an organic chemist who has practiced his art for more than half a century, I must concede that without oxygen I would not have published a single paper, because most of my chemical life was spent grazing in steroid pastures. Few classes of organic molecules are as interesting as steroids—covering the gamut from sex hormones, oral contraceptives, bile acids, corticoids, vitamin D, and cardiac glycosides to anabolic drugs of abuse—yet this panoply of biological diversity is based on a single chemical template: the tetracyclic C₁₇H₂₈ steroid skeleton. A thin paperback written solely in two letters (C and H) becomes the steroid “Bible of Life” through addition of a third letter, O, that nature—and occasionally clever chemists—introduce into select places on that template. I shall cite one example.
Arguably the hottest topic in synthetic organic chemistry around 1950 was cortisone—the glamour steroid that had been anointed with the 1950 Nobel Prize in Physiology or Medicine. Pictures of helpless arthritics dancing within days of cortisone administration flooded the media. The fierce competition was described in breathless prose by Harper’s Magazine in 1951: “The new ways of producing cortisone come as the climax to an unrestrained, dramatic race involving a dozen of the largest American drug houses, several leading foreign pharmaceutical manufacturers, three governments, and more research personnel than have worked on any medical problem since penicillin.” In chemical shorthand, it meant discovering how to introduce oxygen into the inaccessible C-11 position of ring C of some readily available plant sterol. And while a single issue in the 1951 Journal of the American Chemical Society recorded the completion of no less than three such successful solutions, the earliest submission date bore the unlikely address, “Syntex, S.A., Laguna Mayran 413”—an industrial area of Mexico City across from a tortilla stand—in marked contrast to the fancy Rahway, N.J., and Cambridge, Mass., addresses of our competitors.

The following year at a Gordon Conference, Robert B. Woodward from Harvard, Lewis H. Sarett from Merck, Gilbert Stork from Columbia, and I from Syntex demonstrated the inherent collegiality of science by composing a spoof under the authorship of F. Nathaniel Greene and Alvina Turnbull titled “Partial Synthesis of Cortisone from Neohamptogenin” (a putative constituent of a potentially inexhaustible source: New Hampshire maple syrup). Whereas our earlier, testosterone-drenched claims in JACS had each trumpeted the “first successful introduction of a C-11 oxygen function into a steroid devoid of functionality in ring C,” we now jointly proclaimed “the first successful introduction of a 3-keto group into an 11-oxygenated steroid devoid of functional groups in ring A.”

The subsequent 40 years of my research career featured a shift from synthesis to the application of physical methods. But even here, steroids were the focus of all our studies and oxygen the key to our successes. If it had not been for our choice of the carbonyl function and its associated strong Cotton effect, we never would have arrived at the generalizations derivable from optical rotatory dispersion and circular dichroism or drawn many mechanistic conclusions from the mass spectra of such oxygen-containing substrates.

ACTING UP Scheele, Mme. Lavoisier, and Priestley in “Oxygen” simulate Lavoisier’s famous experiment on oxygen’s role in respiration.