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Organic Chemistry

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Martin Saltzman. Scientific Thought: In Context. Editor: K Lee Lerner & Brenda Wilmoth Lerner. Volume 2, Gale, 2009.

Introduction

Organic chemistry is the branch of chemistry that focuses on the properties and reactions of compounds that contain carbon atoms. The carbon atom is unique because it is the only element that can bond to itself, forming chains that can contain hundreds of atoms. Carbon can also combine with a wide variety of other elements.

Historical Background and Scientific Foundations

More than a million carbon compounds have been discovered, and new ones are constantly being synthesized. One reason for this large number is isomerism, particularly structural isomerism, first recognized in 1830 by the Swedish chemist Jöns Jakob Berzelius (1779-1848). In this arrangement, two or more compounds contain the same number of carbon and hydrogen atoms arranged in different ways to form unique compounds with distinct chemical and physical properties. A compound formed from five carbons and twelve hydrogen atoms (C5 H12) will, for example, produce three unique compounds. Other forms of isomerism distinguished by the spatial arrangements of their atoms were discovered later in the nineteenth century.

In the eighteenth and early part of the nineteenth centuries, when many carbon-based compounds were first isolated, they had only been extracted from plants and animals. For example, formic acid had been isolated from ants, salicylic acid had been isolated from willow bark, and urea had been found in urine. This entrenched the idea that organic molecules must be created by (or by the actions of) a living organism. This idea also fit with the doctrine known as vitalism, a theory that developed in reaction to the rise of the mechanistic approach to life being merely a physical process.

The Influence of Liebig and Wöhler

Two German chemists, Justus von Liebig (1803-1873) and Friedrich Wöhler (1800-1882), were responsible for the emergence of organic chemistry in the early nineteenth century. Their quantitative analytical methods helped establish the constitution of newly isolated and synthesized carbon compounds. Both were inspiring teachers who established laboratory work as the basic model for chemical education, teaching students who came from all over Europe and America. The pupils then emulated their methods when they returned home to train the next generation of chemists.

Liebig, the most prominent chemist in nineteenth-century Europe, studied chemistry at the Universities of Bonn and Erlangen, where he obtained his PhD in 1822. After further study in Paris, he chaired the chemistry department at the University of Giessen before moving to the University of Munich, where he spent the remainder of his life. Liebig’s major contributions were the development of new methods for the quick and precise measurement of the quantities of carbon, hydrogen, and nitrogen in organic compounds. This allowed Liebig and his students to identify a host of new organic compounds. Much of his work after 1840 was related to agricultural and biological chemistry, including a study of fermentation and methods for increasing soil fertility and yields through the use of artificial fertilizers.

The Synthesis of Urea and the Demise of Vitalism

Wöhler studied medicine at the Universities of Marburg and Heidelberg, obtaining his medical degree in 1823. He went on to study with Berzelius in Stockholm and to hold positions in technical schools in Berlin and Kassel. In 1836 he was appointed professor of chemistry in the medical faculty of Göttingen University, a position he held for the rest of his life. Wöhler’s major research interests were in inorganic chemistry, where he isolated the elements boron, silicon, aluminum, cerium, and just missed being the discoverer of vanadium and niobium. Like Liebig, he also established a school of research and teaching, but is best known for synthesizing urea.

In 1828 Wöhler synthesized the organic compound urea in the laboratory using the inorganic compound ammonium cyanate. Urea had previously been found only in urine—that is, from a biological source. While this dealt a blow to vitalism, it did not fully spell its demise. Skeptics believed that compounds associated with living organisms were produced by a “vital force” not available to the chemist. This idea persisted until 1844 when Hermann Kolbe (1818-1884) proved definitively that organic compounds could be produced under laboratory conditions by synthesizing acetic acid from the simple inorganic compounds carbon disulfide and chlorine.

Structural Theory and Its Development

In the early part of the nineteenth century a new problem emerged as chemists tried to classify and bring some order to the ever-increasing number of organic substances. This began a period of confusion and controversy that would last several decades, until the development of the structural theory of organic chemistry.

Analytical methods pioneered by both Liebig and Wöhler were able to determine the content of organic molecules, but did not show how their elements were arranged. The first attempt to solve the problem was known as radical theory. Berzelius proposed a way to understand the formation of inorganic compounds by assuming that some elements had a positive charge and others had a negative charge. Scientists knew that opposite electrical charges would attract; thus the formation of sodium chloride could be explained by assuming that sodium is positively charged and chlorine is negatively charged.

Radical theory was pioneered in the 1830s by Liebig and the French chemist Jean-Baptiste André Dumas (1800-1884). Radicals were thought to be a stable group of elements that were joined together to produce an electropositive group that was joined to an electronegative atom to form a compound. In the case of organic compounds the radical would contain carbon, hydrogen, and various other atoms in combination with an electronegative inorganic partner. Thus ethyl alcohol was represented as C2H4 H2O.

The electropositive radical was capable of transformation but should remain intact. This was demonstrated by Liebig and Wöhler in the case of benzaldehyde, which was extracted from almonds. The fact that compounds made from benzaldehyde all contained the radical C14H10O2 provided evidence for radical theory.

Radical theory lost its hold on organic chemistry, however, when scientists realized it was possible to substitute one atom for another in what was assumed to be a “stable” radical. This substitution was further shown by Dumas to be an atom of a different charge. For example, in some compounds the substitution of an electronegative chlorine for electropositive hydrogen did not significantly change the character of the product. Dumas was able to convert acetic acid to trichloroacetic acid, and the product still remained an acid.

Radical theory gave way in the 1840s to what became known as type theory. It was developed by two of Dumas’s students, Auguste Laurent (1808-1853) and French chemist Charles Frédéric Gerhardt (1816-1856), who proposed that organic (and even inorganic) substances were derived from simple molecules by substitution. Alexander Williamson (1824-1904) experimentally proved the existence of the water type with his synthesis in 1850 of diethyl ether from the potassium salt of ethyl alcohol and ethyl iodide.

In 1845 Laurent also introduced the concept of 2 homologous series—a group of similar compounds that differed by a single unit. The first three members of the alkane series, for example, are methane (CH4), ethane (CH6), and propane (C3H8); each succeeding molecule contains an additional CH2 group. The German chemist Hermann Kopp (1817-1892) showed that each additional CH2 increases the boiling point of each successive group member by a fixed number of degrees.

Three other types were proposed by Gerhardt in 1853, the ammonia (NH3), hydrogen (H2), and hydrogen chloride (HCl) types. These types together with the water type could be used to classify the already large number of organic compounds into four distinct groupings. Gerhardt wrote “By exchanging their hydrogens among certain groups, these types give rise to acids, to alcohols, to ethers, to hydrides, to radicals, to organic chlorides, to acetones, to alkalis.” Type theory was thus an advance—but because it still allowed multiple classifications for the same molecule, major problems remained to preoccupy chemists in the latter part of the nineteenth century.

Valences The concept of valence (the combining power of an element) slowly developed in the period from 1850 to 1870 through the work of the English chemist Edward Frankland (1825-1899) and the German August Kekulé (1829-1896). Frankland had begun his chemical studies in London and continued them in Germany with chemist Robert Wilhelm Bunsen (1811-1899) at Marburg. Frankland’s view of valence was derived from the earlier radical theory; Kekulé’s was based on type theory.

Frankland attempted to synthesize the hydrocarbon radical ethyl (C2H5) by reacting ethyl iodide with zinc. This produced not the desired result but butane, with diethyl zinc, the first example of an organometallic compound, as a byproduct. What was crucial about this discovery was that the diethyl zinc (C2H5)2Zn always contained twice as much ethyl as zinc. Frankland went on to show that in other organometallic compounds that a definite combining power existed between the organic portion and the metal. In 1852 Frankland proposed that inorganic and organic compounds both had 5 a combining power that came to be known as valence. Frankland also recognized multiple valences and gave examples where the valence was 3 or 5 such as in PCl3 & PCl5.

August Kekulé

Friedrich August Kekulé (1829-1896) was born in Darmstadt Germany, a descendent of a noble Bohemian family from Stradonitz, a city near Prague. Kekulé had studied architecture at Geissen, but because of Liebig’s influence he changed to chemistry, with additional studies in biological classification. Kekulé obtained his doctorate in Paris in 1851.

As a student in Paris, Kekulé had studied with Dumas and Gerhardt and was naturally drawn to type theory. Further study in London from 1854 to 1855 brought him into contact with two very original thinkers: Williamson and William Odling (1829-1921), chemists who studied chemical structure to understand chemical properties. Kekulé hypothesized that carbon was tetravalent, that is, could combine with four substituents to form organic molecules. His approach was purely mechanical and may have been influenced by his initial interest in architecture. In 1858 Kekulé proposed that carbon could form chains by using some of its valences to bond to other carbon atoms. Kekulé’s representations are not the familiar structural formulas we use today. Those were established by Scottish chemist Archibald Scott Couper (1831-1892) in 1858.

Couper had studied in Paris with the French chemist Charles-Adolphe Wurtz (1817-1884). He had ideas similar to those of Kekulé, but due to a series of mishaps his paper was published after Kekulé’s, and thus he failed to receive the credit he should have. In contrast to the conservative and cautious Kekulé, Couper drew formulas for molecules that used dotted lines to represent the bonds between carbon atoms.

The graphical structural formulas that are used today were introduced by Alexander Crum Brown (1838-1922) in 1861. Initially he wrote the elements using the letters such as C, H, O, etc., with circles around them, as Dalton had done in his exposition of the atomic theory in the first decade of the nineteenth century. The circles were connected with solid lines, with the number of lines equal to the valence—four in the case of carbon. The circles were eventually dropped to create the structural formulas we still use today.

Stereochemistry and Aromaticity

The idea that molecules are three dimensional was not realized until the latter part of the nineteenth century. Discoveries made by French scientist Louis Pasteur (1822-1895), Dutch chemist Jacobus van’t Hoff (1852-1911), and French chemist Joseph-Achille Le Bel (1847-1930) provided the keys to understanding the three-dimensional nature of many organic molecules.

Pasteur is best known for his microbiological research, but his initial training was in chemistry. In his doctoral research Pasteur studied the puzzling differences between two forms of the same compound: tartaric acid. Pasteur found that natural tartaric acid, isolated from the fermentation of grapes, rotated the polarization plane of light that passed through it. Racemic acid, a synthesized product that had an identical chemical formula, however, did not.

The French physicist Jean-Baptiste Biot (1774-1862) had observed this same phenomenon in 1815 with several organic liquids, including oil of turpentine. Salts of tartaric acid had been studied by other chemists as well, in particular the German chemist Eilhard Mitscherlich (1794-1863), who reported in 1844 that the physical properties of the sodium-ammonium salts of the optically active tartaric acid and the racemic acid were the same in every respect except their interaction with plane-polarized light.

Pasteur found that a comprehensive study of different tartrates showed that the optically active tartrates had an asymmetrical crystalline shape. All the racemic acid crystals were symmetrical. One particular compound, the sodium ammonium double salt of tartaric acid, produced very large well-defined crystals. Using a microscope and tweezers Pasteur was able to isolate two forms of the crystals. When subjected to plane polarized light, one bent the light to the right and the other to the left. The rotation was identical for both except the direction. If mixed in equal amounts there was no rotation at all. This phenomenon came to be known as stereoisomerism. Pasteur proposed that it was possible in nature for molecules to be asymmetric; by extension an association was made by Pasteur between asymmetry and life.

Pasteur and Kekulé had speculated that stereoisomerism might be caused by either the tetravalency of carbon itself or the way carbon is oriented in space as a result. This question was answered in 1874 by van’t Hoff and Le Bel, independently of each other.

At this time van’t Hoff was a professor in the veterinary school in Utrecht, Holland. His initial proposal, written in Dutch, attracted little attention. An extended form, La chimie dans l’espace (Chemistry in space) published in French in 1875, attracted much interest and controversy. He explained stereoisomerism by proposing that the four carbon valences were on the apexes of a tetrahedron. Four different substituents bonded to the central carbon atom could produce two structures that were mirror images of each other; this would then produce the asymmetry in carbon compounds.

Thus two mirror images could exist that were identical in all their properties except for the way they affected polarized light. These mirror images came to be known as enantiomers. Pasteur found that if a mixture contains equal amounts of each type, they cancel each other; this is why racemic acid did not affect polarized light and the natural tartaric acid did. Any mixture with equal numbers of enantiomers is now known as a racemic mixture.

Le Bel’s explanation was similar, but he started with a carbon that had four identical groups and looked at what happened with successively substituted atoms. With four different substituents, an asymmetry is produced in which the mirror image is no longer super-imposable on the original. Molecules that have more than one center of asymmetry (that is, more than one stereogenic center) will have 2n stereoisomers, where n is the number of sterogenic centers. In organic chemistry, each carbon atom to which four other atoms (or groups of atoms) are bonded constitutes a stereogenic center. Not every carbon atom in an organic molecule is necessarily a stereogenic center.

An example of how this rule applies is the glucose molecule (C 6H12 O 6), whose stereoisomers were first studied by German chemist Emil Fischer (1852-1919). Each glucose molecule has three centers of asymmetry, which allows the atoms to combine into 2 n = 8 (eight) unique compounds, which Fischer identified. One of the major achievements of twentieth-century synthetic organic chemistry has been to develop methods to produce particular stereoisomers when multiple routes are possible.

One major structural problem that remained to be solved was the structure of benzene (C 6 H6) and aromatic compounds in general. Benzene was a formidable challenge because its unusual properties could not be based on conventional ideas of structure. Many chemists had tried and failed to solve the benzene problem before Kekulé devised the first rational structure in 1865.

In a story of dubious authenticity, Kekulé is said to have had a daydream in which he envisioned a snake catching its tail; this led him to visualize benzene’s hexagonal structure, in which six carbon atoms alternate in single and double bonds. This model predicted that four unique isomers existed in disubstituted benzene molecules (benzene molecules containing two substituted atoms or groups of atoms), but only three were known. Kekulé proposed that one of these isomers has two forms that differ only by the locations of the single and double bonds. If an equilibrium exists between these two forms, all the carbon atoms become equivalent. This explanation became the basis of aromatic chemistry until the development of molecular orbital theory in the 1930s.

The Birth of the Synthetic Organic Chemical Industry

Organic compounds such as ethyl alcohol, found in beer and wine, and acetic acid, used in vinegar, have been produced since antiquity. Other naturally occurring organic compounds have been used for millennia as dyes and medicinal agents. But the production of organic substances in manufacturing plants did not being in earnest until the 1850s. The synthetic organic chemical industry began when a process was developed in the late-eighteenth century to produce gas from coal. This produced coal tar, a waste product that was considered a nuisance as it had only limited use, mainly as a water-proofing agent.

Organic chemists began to examine the constituents of coal tar in earnest in the 1840s. One of the primary investigators was the German chemist August Wilhelm Hofmann (1818-1892). A student of Liebig, he became the first professor of chemistry at the newly founded Royal College of Chemistry in London in 1844. Hofmann had begun to analyze coal tar in Liebig’s laboratory and continued this work when he moved to London.

Hofmann found that coal tar’s major components were aromatic hydrocarbons, a class of compounds based on the benzene molecule, first isolated by Michael Faraday (1791-1867) in 1825 from compressed oil gas. Hofmann and his students isolated at least 20 different substances from coal tar, the most important being aniline (C6 H5NH 2), an organic analog of ammonia, and phenol (C6 H5OH), which was used as one of the first antiseptics.

In 1856 William Henry Perkin (1838-1907), one of Hofmann’s students at the Royal College of Chemistry, tried to synthesize quinine, a drug used to treat malaria. At that time quinine could only be extracted from the bark of the cinchona, a tree that was native to the Dutch East Indies. Hofmann thought that quinine might be the aromatic hydrocarbon naphthalene. Perkin took a different approach and used an impure form of an aniline derivative called allyl toluidine and treated it with potassium dichromate. The reaction failed to produce quinine, and Perkin repeated the experiment using aniline itself.

This produced a brown substance which, when dissolved in alcohol, produced a vivid purple solution. Perkin was only 18 at the time, but he had the insight to see that this might be useful as a dye, especially since purple is a color with few natural sources. When Perkin’s samples were sent to a dyer, he found that it dyed silk a subdued purple that became known as mauve.

In partnership with his father and brother, Perkin built a plant to manufacture this synthetic dye on a commercial scale. Perkin’s genius was his ability to convert a laboratory process into a commercial product. His success led many English competitors to develop their own lines of aniline-based dyes. Using various derivatives of aniline and reaction conditions, the whole spectrum of colors became available, eliminating the need for natural dyes and dooming that industry.

Britain became the center of the synthetic organic chemical industry for the next two decades. The dye industry, in particular, became a magnet for many highly trained German organic chemists. The experience they gained in Britain had two distinct consequences. First, German chemists became masters of laboratory synthesis, developing synthetic replacements for the natural red dye alizarin and blue dye indigo. Second, Germany became the center of the organic chemical industry, founding of such companies as BASF, AGFA, Bayer, and Hoechst. Partnerships that developed between academia and the industry made Germany the world leader in chemical production by 1914. This became a problem for the United States during World War I, when exports of German organic chemicals were stopped by the British blockade.

Although synthetic dyes had been developed, pharmaceuticals were still derived mainly from natural sources. One key breakthrough was the synthesis of salicylic acid by Kolbe in 1853. A natural product derived from willow bark, salicylic acid was known for its pain-relieving abilities. Although one of Kolbe’s students converted the laboratory synthesis into a commercial product, salicylic acid taken internally produced unwanted side effects. The acetyl derivative prepared in 1897 by a chemist working for the Bayer Company in Germany was found to produce the same pain relief without the side effects. This compound was sold as aspirin beginning in 1899 and has remained a staple product for over a century.

In the latter part of the nineteenth century, German physician and bacteriologist Robert Koch’s (1843-1910) postulates proved the validity of the germ theory of disease and ushered in a more rational approach to the treatment of bacterial infections. Although synthetic dyes had previously been used to stain cells for medical studies, scientists such as German medical researcher Paul Ehrlich (1854-1915) thought that some dyes might actually destroy bacteria also. The dye methylene blue, for example, killed the parasite associated with malaria.

Ehrlich believed that a drug must be linked in a rational and systematic manner to its target. Ehrlich’s best-known work was on syphilis, which is caused by a spirochete, a type of bacterium. Ehrlich had been studying organic compounds that contained arsenic as a treatment against certain tropical diseases, only to find that most of these, although somewhat effective, had toxic side effects. Based on his knowledge of organic chemistry, Ehrlich synthesized a series of organoarsenic compounds, going through 605 before the next one, marketed under the trade name Salvarsan, proved successful. An even more effective compound called Neosalvarsan was produced in 1912; this remained the standard treatment until the beginning of the antibiotic era in the late 1940s.

Because little was known about how drugs actually worked, very few breakthroughs occurred between 1920 and 1940. If a drug proved effective it was purely by chance in most cases, not by design. A good example of this was the discovery of sulfa drugs by the Bayer division of I.G. Farben in Germany. Thousands of compounds were synthesized by Bayer chemists before one, whose structure was similar to a class of dyes known as azo compounds, showed any medicinal potential. The drug Prontosil was patented in 1932 and was the first synthetic antibacterial effective against streptococcal and staphylococcal bacteria (but not against enterobacteria).

What made Prontosil effective was that it decomposed in vivo to a compound called sulfanilamide, a relatively simple compound first synthesized in 1908. Thousands of sulfanilamide analogs were created in the 1930s, and several proved effective. This was the only antibacterial therapy available in any quantity through World War II. Penicillin, an antibiotic first used in 1942, was much more effective, but it was difficult to produce in large quantities, and much of what was made was intended for military use.

The era after 1945 marked the golden age of organic chemistry and the discovery of new drugs. New synthetic techniques and, most importantly, a revolution in instrumentation that included nuclear magnetic resonance, mass spectrometry, and various types of infrared, visible, and ultraviolet spectroscopy made it possible to determine the structures of both natural and synthetic products rapidly. Tremendous strides were made in finding medicinal agents to deal with a variety of conditions.

Industrial Advances

Prior to 1939 insecticides were mainly inorganic in nature and posed many health hazards, especially when used in the agricultural sector. In 1939 the organic insecticide DDT (dichloro-diphenyl-trichloroethane) was found to be very effective against many pests, especially those that carry diseases such as malaria. Spraying DDT saved an enormous number of lives during World War II because of its ability to prevent outbreaks of malaria and other tropical diseases. Various other chlorinated hydrocarbon pesticides were introduced when effectiveness and safety concerns made the use of DDT less desirable. These second-generation insecticides such as Chlordane, Lindane, and Dieldrin also had their problems and were replaced with an entirely new class of organophosphates.

In the post-World War II era, organic herbicides came to be an important addition to agriculture. One of the earliest commercial products, 2,4-D (2,4-dichloro-phenoxyacetic acid), highly effective against broad-leaf plants, improved agricultural yields. Agent orange is a 50-50 mixture of 2,4-D and 2,4,5,T (2,4,5-trichloro-phenoxyacetic acid) that was used extensively as a defoliant during the Vietnam war, sometimes creating serious health effects in those who came into contact with it. Trace amounts of dioxin, a highly carcinogenic material, are produced in the manufacture of 2,4,5-T. The manufacture of 2,4-D does not produce dioxin and is still used to control unwanted vegetation. Many new types of herbicides have been produced since then that are different in structure than the chloroacetic acids, and many are sold for use in both agriculture and for the home gardener.

Petroleum and Petrochemicals

The manufacture of chemicals from petroleum in the nineteenth century was spurred by the increasing need for new fuel sources to replace plant oils and animal tallow. The discovery that coal could be converted into a gas was promising, but mass distribution required large facilities for production and an infrastructure for distribution. A more convenient fuel was needed.

In the mid-nineteenth century a process devised by Scottish chemist James Young (1811-1883) heated certain forms of coal to produce a liquid that, after distillation and purification, proved to be an excellent illuminant. Sold under the trade name kerosene, it became the dominant method of lighting worldwide for the balance of the nineteenth and early part of the twentieth century.

In the United States, kerosene was mass-produced in plants using the Young process. However, the large amounts of industrial waste produced, the need to import special coal, and the required royalty payments led to the search for an alternative.

Crude oil seeps had been found in various parts of the United States, including one in Titusville, Pennsylvania. A New York-based business syndicate thought that it might be possible to drill into the earth, pump this crude oil to the surface, then distill it into a product similar to kerosene. The process worked, and after petroleum was found in other states and other countries, oil eventually became the world’s dominant energy source.

German chemists had pioneered the production of petrochemicals from both coal and natural gas (methane) from 1900 to 1930, devising processes to produce phenol, ethylene, ethylene oxide, acetone, vinyl acetate, and vinyl chloride. In the 1920s American chemists began to use the byproducts of the crude-oil refining process to produce many of the same products that German chemists had been able to make from coal.

Many of the products produced from petroleum form the basis of synthetic macromolecules. For example, ethylene can be converted directly into polyethylene, or transformed into styrene to produce polystyrene or vinyl chloride to produce polyvinyl chloride. Oil and natural gas have proved to be some of the most valuable of all organic substances for producing either other organic materials or intermediates. The petrochemical industry became the leading chemical industry in the United States after 1945; it remains an important part of the economy.

Organic Chemistry in the Twentieth Century

While the focus in the nineteenth century was on the synthesis of new molecules and the structure of natural products, research in the twentieth century centered on the reactions of organic molecules. By studying the processes involved in converting a reactant to a product, scientists hoped to follow the same path using a different reactant. A major step in this direction occurred with the development of the Lewis-Langmuir theory of covalent bonding, based upon the concept of the electron pair as the basis of the chemical bond as formulated by American physical chemist Gilbert N. Lewis (1875-1946) and Irving Langmuir (1881-1967).

This began the era of the electronic interpretation of reaction mechanisms. For a new generation of chemists, particularly those in Great Britain such as Robert Robinson (1886-1975) and Christopher Ingold (1893-1970), the Lewis-Langmuir theory became a way to understand the unique structure of molecules such as benzene and how reactions produced certain products and not others.

The tools of physical chemistry, such as thermodynamics and kinetics (the measurement of the rates of reactions) were used to validate electronic interpretation. This hybrid combination of organic and physical chemistry became known as physical organic chemistry, a term coined by the American physical chemist Louis Hammett (1894-1987) for his 1940 pioneering textbook in the new type of study.

Many significant investigations had been performed before 1940 by British and American chemists, including the British investigators Arthur Lapworth (1872-1941) and Kennedy J.P. Orton (1872-1930) and the Americans James Bryant Conant (1893-1978), Howard Lucas (1885-1963), and Frank C. Whitmore (1887-1947) among others. After 1945 American chemists became the preeminent practitioners of physical organic chemistry. Many reactions whose mechanisms had remained a mystery for decades were revealed by applying the techniques pioneered by individuals in the decades and centuries before.

Modern Cultural Connections

In the latter part of the twentieth century organic chemistry focused increasingly on the chemistry of life and biochemical processes. This usually involved developing methods to synthesize complex molecules, especially those with many centers for optical isomerism, and the structural elucidation of natural products found to be active against various conditions such as cancer.

Organic chemistry provides a host of useful products that have made the world more colorful with synthetic dyes, improved public health through pesticides and drugs, and increased the crop yields with fertilizers and pesticides. Synthetic fibers and engineered materials are also the products of organic chemistry.

Male Breast Cancer

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Teresa G Odle. The Gale Encyclopedia of Cancer. Editor: Jacqueline L Longe. 2nd Edition, Volume 2, Gale, 2006.

Definition

Male breast cancer is a malignant tumor that forms in a man’s breast.

Description

Breast cancer is rare in men, but can be serious and fatal. Many people believe that only women can get breast cancer, but men have breast tissue that also can develop cancer. When men and women are born, they have a small amount of breast tissue with a few tubular passages called ducts located under the nipple and the area around the nipple (areola). By puberty, female sex hormones cause breast ducts to grow and milk glands to form at the ends of the ducts. But male hormones eventually prevent further breast tissue growth. Although male breast tissue still contains some ducts, it will have only a few—or no—lobules. Near the breasts of men and women are axillary lymph nodes. These are underarm small structures shaped like beans that collect cells from lymphatic vessels. Lymphatic vessels carry lymph, a clear fluid that contains fluid from tissues, cells from the immune system, and various waste products throughout the body. The axillary lymph nodes are important to breast cancer patients, as they play a role in the spread and staging of breast cancer.

Breast cancer is much more common in women, mostly because women have many more breast cells that can undergo cancerous changes and because women are exposed to the effects of female hormones.

Infiltrating ductal carcinoma is the most common type of breast cancer in men. It is a type of adenocarcinoma, or a type of cancer that occurs in glandular tissue. Infiltrating ductal carcinoma starts in a breast duct and spreads beyond the cells lining the ducts to other tissues in the breast. Once the cancer begins spreading into the breast, it can spread to other parts of the body. This distant spread is called metastasis. When breast cancer metastasizes to other areas of the body, it can cause serious, life-threatening consequences. For example, breast cancer might spread to the liver or lungs. About 80% to 90% of all male breast cancers are infiltrating ductal carcinomas.

Ductal carcinoma in situ (DCIS) is not common; it accounts for about 10% of all male breast cancers. It also is an adenocarcinoma. In situ cancers remain in the immediate area where they began, so DCIS remains confined to the breast ducts and does not spread to the fatty tissues of the breast. This means it is likely found early. DCIS also may be called intraductal carcinoma.

Other types of breast cancer are very rare in men. Adenocarcinomas that are lobular (forming in the milk glands or lobules) only occur in about 2% of male breast cancer cases because men normally do not have milk gland tissues. Inflammatory breast cancer, a serious form of breast cancer in which the breast looks red and swollen and feels warm, also occurs rarely. Paget’s disease of the nipple, a type of breast cancer that grows from the ducts beneath the nipple onto the nipple’s surface, only accounts for about 1% of female breast cancers. However, slightly more men have this form of breast cancer than women. Sometimes, Paget’s disease is associated with another form of breast cancer.

Although not a form of cancer, but a benign condition, gynecomastia is important to mention. It is the most common of all male breast disorders and can be associated with male breast cancer in a rare condition called Klilnefelter’s syndrome. Gynecomastia most often occurs in teenage boys when their hormones change during puberty. Older men also may experience the condition when their hormone balance changes as they age. Gynecomastia is an increase in the amount of breast tissue, or breast tissue enlargement. If a man has Klinefelter’s syndrome, he can develop gynecomastia and increased risk of breast cancer.

Demographics

Breast cancer in men is rare, accounting for less than 1% of all breast cancers. Still, about 1,450 American men were diagnosed with the disease and 470 men died from it in 2004. Although studies show the number of breast cancer cases in women has decreased in the United States and Europe since the 1960s, the number of breast cancer cases in men have not decreased, but remained stable or slightly increased.

The rate of increase in cases begins and steadily rises at age 50 for men. However, the average age for male breast cancer is between 60 and 70 years old, with a median age of 67 years. Men often are diagnosed at a later stage than women.

Causes and symptoms

Scientists do not know what causes most cases of male breast cancer. However, excellent progress is being made in genetic research and in understanding how genes instruct cells to grow, divide, and die. For example, researchers have now mapped all of the genes in the human body. Genes are part of the body’s DNA, which is the chemical that instructs the cells. When DNA or genes carry defects (mutations), they activate changes in the cells, such as rapid cell division, that lead to cancer. Some genes, called tumor suppression genes, cause cells to die. Scientists have identified some genetic mutations that are risk factors for breast cancer. In other cases, environmental, or outside, factors are thought to increase a man’s risk for breast cancer.

Mutations of at least two versions of a tumor suppressor gene (BRCA1 and BRCA2) have been identified as causes of breast cancer in women. In men, the BRCA2 mutation is considered responsible for about 15% of breast cancers. Men can inherit genes from either parent. Studies have shown that BRCA1 also may increase a man’s risk for breast cancer, but its role is less certain. These mutations have been shown to increase other cancers in men, including prostate cancer. Klinefelter’s syndrome is a rare genetic cause of breast cancer in men. It results from inheriting an additional X chromosome.

Several other factors also may cause male breast cancer. Some conditions, such as the liver disease cirrhosis, can cause an imbalance in a man’s hormones, producing high levels of the female hormone estrogen, which can lead to breast cancer. Exposure to some substances such as high amounts of radiation may contribute to male breast cancer. A 2004 report studied why a cluster of breast cancer cases occurred among a small group of men who worked in the basement office of a multi-story office building. The study linked their breast cancer to exposure to high magnetic fields from a nearby electrical switchgear room in their work space.

Many men do not realize they can develop breast cancer; they ignore the symptoms. The most common symptom is a mass, or lump in the chest area, particularly around the nipple. The lump will be firm, not tender or painful. Other signs that may warn of male breast cancer include:

  • Skin dimpling or puckering
  • Changes in the nipple, such as drawing inward (retraction)
  • Nipple discharge of any kind
  • Redness or scaling of the nipple or breast skin
  • Abnormal swelling (or lump) of the breast, nipple, or chest muscle
  • Prolonged rash or irritation of the nipple, which may indicate Paget’s disease

Diagnosis

Physicians follow the same steps for diagnosing breast cancer in men as in women, except that routine screening of breast cancer is not done in men. Once symptoms are noticed, however, physicians will proceed in the same way. The physician will conduct a thorough medical history and examination, including questions that may identify risk factors for breast cancer, such as male or female relatives with the disease. The medical history also helps gather details on possible symptoms for breast cancer.

The physician also performs a clinical breast examination. This helps locate and study a lump or suspicious area. The physician will feel (palpate) a mass to get an idea of its size, texture, likely location and relation to surrounding skin, muscles and tissues. At this point, the physician already will begin to look for signs that the cancer may have spread to other organs and to the lymph nodes. The physician will palpate lymph nodes and the liver, for instance, to see if they are enlarged.

The next step in diagnosis usually is a diagnostic mammogram. Mammography is an x ray of the breast. Mammograms are performed by radiologic technologists who take special training in the procedure. Mammograms are evaluated by radiologists, physicians who receive medical training specifically in interpreting x rays. If the initial mammogram shows suspicious findings, the radiologist may order magnification views to more closely look at the suspicious area. Mammograms can accurately show the tissue in the breast, even more so in men than women, because men do not have dense breasts or benign cysts in their breasts that interfere with the diagnosis.

The radiologist also might recommend an ultrasound to follow up on suspicious findings. Ultrasound often is used to image the breasts. Also known as sonography, the technique uses high-frequency sound waves to take pictures of organs and functions in the body. Sound wave echoes can be converted by computer to an image and displayed on a computer screen. Ultrasound does not use radiation. A technologist will perform the ultrasound; it will be evaluated by the radiologist.

Biopsies, which involve removing a sample of tissue, are the only definite way to tell if a mass is cancerous. At one time, surgical biopsies were the only option, requiring removal of all or a large portion of the lump in a more complicated procedure. Today, fine-needle aspiration biopsy and core biopsies can be performed. In fine-needle aspiration biopsy, a thin needle is inserted to withdraw fluid from the mass. The physician may use ultrasound or other imaging guidance to locate the mass if necessary. The fluid is tested in a laboratory under a special microscope to determine if it is cancerous.

A core biopsy is similar, but involves removing a small cylinder of tissue from the mass through a slightly larger needle. Core biopsy may require local anesthesia. These biopsy techniques usually can be performed in a physician office or outpatient facility. The cells in biopsy samples help physicians determine if the lump is cancerous and the type of breast cancer. A tissue sample also may be used for assigning a grade to the cancer and to test for certain proteins and receptors that aid in treatment and prognosis decisions.

If there is discharge from the nipple, the fluid also may be collected and analyzed in a laboratory to see if cancer cells are present in the fluid.

Diagnosis of breast cancer spread may require additional tests. For example, a computed tomography (CT) scan may be ordered to check organs such as the liver or kidney for possible metastasized cancer. A chest x ray can initially check for cancer spread to the lungs. Bone scans are nuclear medicine procedures that look for areas of diseased bone. Magnetic resonance imaging (MRI) has been increasingly used in recent years as a follow-up study to mammograms when findings are not clear. However, for metastatic breast cancer, they are more likely to be ordered to check for cancer in the brain and spinal cord. Positron emission tomography (PET) scans also have become more common in recent years.

Treatment team

The treatment team for male breast cancer normally consists of a primary care physician, a medical oncologist (cancer specialist) and if radiation therapy is used, a radiation oncologist. Many other staff also are involved. For instance, special oncology nurses help guide patients through their care and recovery. Radiation therapists are specially trained technologists who deliver the radiation therapy treatments prescribed by the radiation oncologist.

Clinical staging, treatments, and prognosis

A technique called sentinel lymph node biopsy may be the first step in staging. The sentinel node is the first one the cancer cells are likely to reach, so it is the first one checked for cancerous cells. Using a radioactive substance and blue dye injected into the area around the tumor, physicians can track the path of the cells and stage the cancer. The technique has been used for many years on women with breast cancer; research in 2004 showed it worked well for predicting lymph node status in men as well.

Staging

Cancer staging systems help physicians compare treatments and research and identify patients for clinical trials. Most of all, they help physicians determine treatment and prognosis for individual patients by describing how severe a patient’s cancer is in relation to the primary tumor. The most common system used for cancer is the American Join Committee on Cancer (AJCC) TNM system, which bases staging largely on the spread of the cancer. T stands for tumor and describes the tumor’s size and spread locally, or within the breast and to nearby organs. The letter N stands for lymph nodes and describes the cancer’s possible spread to and within the lymph node system. In some descriptions below, the cancer may have been found by sentinel node biopsy as microscopic disease in nodes that are in the breasts (rather than the armpits). For simplification, these findings have been grouped with the axillary lymph nodes. M stands for metastasis to note if the cancer has spread to distant organs. Further letters and numbers may follow these three letters to describe number of lymph nodes involved, approximate tumor sizes, or other information. The following is a summary of breast cancer stages:

Stage 0: Tis, N0, M0: Ductal carcinoma in situ (DCIS). This is the earliest and least invasive form of breast cancer; the cancer cells are located within a duct and have not invaded surrounding fatty tissue.

Stage I: T1, N0, M0: The tumor is less than 1 in. in diameter (2 cm or less) and has not spread to lymph nodes or distant organs.

Stage IIA: T0, N1, M0/T2, NO, MO: No tumor is found or the tumor is smaller than 2 cm and cancer is found in one to three axillary lymph nodes (even if no tumor is found), or the tumor is between 2 and 5 cm in diameter but has not spread to the axillary lymph nodes. The cancer has not spread to distant organs.

Stage IIIB: T2, N1, M0/T3, NO, MO: The tumor is between 2 and 5 cm in diameter and has spread to one to three axillary lymph nodes or the tumor is larger than 5 cm, has not grown into the chest wall or spread to the lymph nodes or distant organs.

Stage IIIA: T0-2, N2, M0/T3, N1, MO: The tumor is smaller than 5 cm in diameter and has spread to four to nine axillary lymph nodes or the tumor is larger than 5 cm and has spread to one to nine axillary lymph nodes. The cancer has not spread to distant organs.

Stage IIIB: T4, N0-2, M0: The tumor has grown into the chest wall or the skin and may have spread to no lymph nodes or as many as nine lymph nodes. Cancer has not spread to distant sites.

Stage IIIC: T0-4, N3, MO: The tumor is any size, has spread to 10 or more axillary lymph nodes or to one or more lymph nodes under or above the collarbone (clavicle) on the same side as the breast tumor. The cancer has not spread to distant organs.

Inflammatory breast cancer: Classified as stage III, unless it has spread to distant organs or lymph nodes not near the breast (which would classify it as Stage IV).

Stage IV: T0-4, N0-3, M1: Regardless of the tumor’s size, the cancer has spread to distant organs, such as the liver, bones, or lung, or to lymph nodes far from the breast.

Treatment

If the axillary lymph nodes were identified as containing cancer at the time of the sentinel lymph node biopsy, they will be removed in an axillary dissection. Sometimes, this is done at the time of the biopsy.

For Stage I, surgery often is the only treatment needed for men. Women often have lumpectomies, which remove as little surrounding breast tissue as possible, to preserve some of their breast shape. For men, this is less of a concern, and mastectomy, or surgical removal of the breast, is performed in 80% of all male breast cancers. Men with Stage I tumors larger than 1 cm may receive additional (adjuvant) chemotherapy.

Men with Stage II breast cancer also usually receive a mastectomy. If they have cancer in the lymph nodes, they probably will receive adjuvant therapy. Those with estrogen receptor-positive tumors may receive hormone therapy with tamoxifen. The treatment team may recommend adjuvant radiation therapy if the cancer has spread to nearby lymph nodes and/or to the skin.

Stage III breast cancer requires mastectomy followed by adjuvant therapy with tamoxifen when hormones are involved. Most patients with Stage III disease also will require chemotherapy and radiation therapy to the chest wall.

Men with Stage IV breast cancer will require systemic therapy, or chemotherapy and perhaps hormonal therapy that works throughout the body to fight the cancer in the breast, as well as the cancer cells that have spread. Patients also may receive immunotherapy to help patients fight infection following chemotherapy. Radiation and surgery also may be used to relieve symptoms of the primary cancer and areas where the cancer may have spread. The treatment team also may have to diagnose specific treatments for the metastatic cancers, depending on their sites.

If male breast cancer recurs in the breast or chest wall, it can be treated with surgical removal and followed by radiation therapy. An exception is recurrence in the same area, where additional radiation therapy can damage normal tissue. Recurrence of the cancer in distant sites is treated the same as metasteses found at the time of diagnosis.

Prognosis

Prognosis for male breast cancer varies, depending on stage. Generally, prognosis is poorer for men than for women, because men tend to show up for diagnosis when their breast cancer has reached a later stage. The average five-year survival rate for Stage I cancers is 96%. For Stage II, it is 84%. Stage III cancers carry an average five-year survival rate of 52%, and by Stage IV, the rate drops to 24%.

Alternative and complementary therapies

Many alternative and complementary therapies can help cancer patients relax and deal with pain, though none to date have been shown to treat or prevent male breast cancer. For example, traditional Chinese medicine offers therapies that stress the importance of balancing energy forces. Many studies also show that guided imagery, prayer, meditation, laughter, and a positive approach to cancer can help promote healing. Early studies have shown that soy and flaxseed may have some preventive properties for breast cancer. However, these trials have been conducted in women. When looking for these therapies, cancer support groups suggest asking for credible referrals and working with the medical treatment team to coordinate alternative and complementary care.

Coping with cancer treatment

It is difficult for some men to accept and cope with a breast cancer diagnosis, since it is a relatively rare and unexpected disease among men. It is important that men work closely with their treatment team to talk about the their concerns and to carefully follow all instructions for care. Support groups and family support are critical in coping with a breast cancer diagnosis.

Eating a nutritious diet, stopping use of tobacco, and limiting use of alcohol, can help in recovery from breast cancer. Beginning a regular exercise program when the treatment team recommends also helps.

Clinical trials

Research currently is underway to test various chemotherapy combinations for male breast cancer at different stages. A clinical trial also is underway to investigate a vaccine for treating patients with metastatic breast cancer. The National Institutes of Health list clinical trials by disease type, including those for which they are recruiting patients. Choosing to participate in a clinical trial is a decision that involves the patient, family, and treatment team.

Prevention

Some forms of male breast cancer cannot be prevented. But detecting the cancer at an early stage can prevent serious complications, such as spread to distant organs. Men who have a history of breast cancer in their family should pay particular attention to the symptoms of breast cancer and seek immediate medical evaluation. Physicians may be able to test the blood of men with family history for presence of the BRCA2 gene so they may more carefully watch for early signs of breast cancer. Avoiding exposure to radiation also may help present some male breast cancers.

Special concerns

Men should remember that there are important difference between male and female breast cancers. Some experts say that specific guidelines and instructions for men with breast cancer are noticeably lacking, so men should not be afraid to ask questions or to push a physician for more information when he suspects he might have a suspicious lump or finding in his breast.