CHEMICAL NAME = ascorbic acid CAS NUMBER = 50–81–7 MOLECULAR FORMULA = C6H8O6 MOLAR MASS = 176.1 g/mol
COMPOSITION = C(40.92%) H(4.58%) O(54.50%) MELTING POINT = 192°C
BOILING POINT = decomposes DENSITY = 1.95 g/cm3
Ascorbic acid, a water-soluble dietary supplement, is consumed by humans more than any other supplement. Th e name ascorbic means antiscurvy and denotes the ability of ascorbic to combat this disease. Vitamin C is the l-enantiomer of ascorbic acid. Ascorbic acid defi ciency in humans results in the body’s inability to synthesize collagen, which is the most abundant protein in vertebrates. Collagen is the fi brous connective tissue found in bones, tendons, and ligaments. Scurvy produced from a lack of vitamin C results in body deterioration, producing tender joints, weakness, and ruptured blood vessels. Th e rich supply of blood vessels in the gums, coupled with the wear associated with eating, produces one of the fi rst visible signs of scurvy: bleeding, sensitive gums eventually leading to the loss of teeth.
Signs of scurvy have been found in the human remains of ancient civilizations. Scurvy aff ected soldiers, Crusaders, and settlers during the winter months, but it is mostly associ-ated with sailors. Long sea voyages where crews were isolassoci-ated from land for extended periods increased during the age of exploration. Th ese voyages relied on large staples of a limited vari-ety of foods that were eaten daily, and it was typically several weeks to several months before staples could be replenished. Th e lack of fruits, vegetables, and other foods containing vitamin C in sailors’ diets ultimately resulted in high occurrences of scurvy. For example, it is believed that approximately 100 of 160 of Vasco da Gama’s crew that sailed around the Cape of Good Hope died of scurvy. Th e fi rst extensive study of scurvy was conducted by the Scottish naval surgeon James Lind (1716–1794) in response to the high death rate of British sailors. In 1747, Lind varied the diets of sailors suff ering from scurvy during a voyage and discovered that
Ascorbic Acid | 31
sailors who consumed citrus fruit recovered from the disease. Lind published his fi ndings in his Treatise on Scurvy in 1753. Although Lind’s work provided evidence that citrus fruit could combat scurvy, the disease continued to plague sailors and explorers into the 20th century.
Many people discounted Lind’s work, sailors were reluctant to change their standard diet, and it was diffi cult or expensive to provide the necessary foods to combat scurvy. Although there were notable exceptions, such as the voyages of Captain James Cook (1728–1779), and although certain foods were known as antiscorbutic, scurvy persisted throughout the 19th century.
During the fi rst decades of the 20th century, researchers discovered the need for essential vitamins and the relation between diet and defi ciency diseases. Between 1928 and 1933, research teams led by Albert Szent-Györgyi (1893–1986), a Hungarian-born researcher work-ing at Cambridge, and Charles G. Kwork-ing (1896–1988), workwork-ing at Columbia University in the United States, isolated ascorbic acid. Szent-Györgyi obtained the substance from the adrenal gland of bovine kidneys (King isolated it from lemons) and called it hexuronic acid.
Subsequent research in which he isolated hexuronic acid from paprika and conducted experi-ments on guinea pigs demonstrated that hexuronic acid alleviated scurvy. Hexuronic acid was shown to be the same as vitamin C, which had been identifi ed as Lind’s antiscorbutic substance by the two researchers Alex Holst (1861–1931) and Th eodore Frohlich in 1907.
In 1934, Norman Haworth (1883–1950), working with Edmund Hirst (1898–1975) in England, and Poland’s Th adeus Reichstein (1897–1996) succeeded in determining the struc-ture and synthesis of vitamin C. Vitamin C was the fi rst vitamin to be produced synthetically.
Szent-Györgyi received the Nobel Prize in medicine or physiology in 1937, and during the same year Haworth received the Nobel Prize in chemistry, in a large part for their work on vitamin C.
Until the 20th century, it was thought that scurvy was confi ned to humans. Most plants and animals have the ability to synthesize ascorbic acid, but it was discovered that a limited number of animals, including primates, guinea pigs, the Indian fruit bat, and trout, also lack the ability to produce ascorbic acid. In vertebrates, ascorbic acid is made in the liver from glu-cose in a four-step process. Each step requires a specifi c enzyme and humans lack the enzyme required for the last step, gulonolactone oxidase.
Ascorbic acid is produced synthetically using the Reichstein process, which has been the standard method of production since the 1930s. Th e process starts with fermentation followed by chemical synthesis. Th e fi rst step involves reduction of D-glucose at high temperature into D-sorbitol. D-sorbitol undergoes bacterial fermentation, converting it into L-sorbose.
L-sorbose is then reacted with acetone in the presence of concentrated sulfuric acid to produce diacetone-L-sorbose, which is then oxidized with chlorine and sodium hydroxide to produce di-acetone-ketogulonic acid (DAKS). DAKS is then esterifi ed with an acid catalyst and organ-ics to give a gulonic acid methylester. Th e latter is heated and reacted with alcohol to produce crude ascorbic acid, which is then recrystallized to increase its purity. Since the development of the Reichstein process more than 70 years ago, it has undergone many modifi cations. In the 1960s, a method developed in China referred to as the two-stage fermentation process used a second fermentation stage of L-sorbose to produce a diff erent intermediate than DAKS called KGA (2-keto-L-gulonic acid), which was then converted into ascorbic acid. Th e two-stage process relies less on hazardous chemicals and requires less energy to convert glucose to ascorbic acid. Th e annual global production of ascorbic acid is approximately 125,000 tons.
32 | Th e 100 Most Important Chemical Compounds
Sodium, potassium, and calcium salts of ascorbic acids are called ascorbates and are used as food preservatives. Th ese salts are also used as vitamin supplements. Ascorbic acid is water-soluble and sensitive to light, heat, and air. It passes out of the body readily. To make ascorbic acid fat-soluble, it can be esterifi ed. Esters of ascorbic acid and acids, such as palmitic acid to form ascorbyl palmitate and stearic acid to form ascorbic stearate, are used as antioxidants in food, pharmaceuticals, and cosmetics.
As noted, vitamin C is needed for the production of collagen in the body, but it is also essential in the production of certain hormones such as dopamine and adrenaline. Ascorbic acid is also essential in the metabolism of some amino acids. It helps protect cells from free radical damage, helps iron absorption, and is essential for many metabolic processes.
Th e dietary need of vitamin C is not clearly established, but the U.S. National Academy of Science has established a recommended dietary allowance (RDA) of 60 mg per day. Some groups and individuals, notably Linus Pauling in the 1980s, recommend dosages as high as 10,000 mg per day to combat the common cold and a host of other ailments. Table 10.1 lists the amount of vitamin C in some common foods.
Table 10.1 Vitamin C Content of Foods
Food
Vitamin C in mg/100g
Rose hip 2,000
Red pepper 200
Broccoli 90
Beef liver 30
Orange 50
Lemon 40
Apple 6
Banana 9
Cabbage 30
Grapefruit 30
Appreciable amounts of vitamin C are loss when fruits and vegetables are cooked. When using heat to process foods such as in canning and preserving, vitamin C is lost.
11. Aspartame
CHEMICAL NAME = N-L-a-aspartyl-L-phenylalanine 1-methyl ester
CAS NUMBER = 22839–47–0 MOLECULAR FORMULA = C14H18N2O5 MOLAR MASS = 294.3 g/mol
COMPOSITION = C(57.1%) H(6.2%) N(9.5%) O(27.2%)
MELTING POINT = 246°C BOILING POINT = decomposes DENSITY = 1.3 g/cm3 (calculated)
Aspartame is the most popular artifi cial sweetener in the United States. It is sold as sweeteners such as NutraSweet and Equal, but it is also incorporated into thousands of food products.
Aspartame was discovered accidentally in 1965 during a search for drugs to treat gastric ulcers.
James M. Schlatter, an organic chemist working for G. D. Searle & Company, was using aspartyl-phenylalanine methyl ester (aspartame) in a synthesis procedure and inadvertently got some of the compound on his hands. Later in the day Schlatter noticed a sweet taste when he licked his fi ngers to pick up a piece of paper. Initially, he thought the taste was from sugar on a doughnut he had eaten that morning but then realized he had washed his hands since eating the doughnut. He was curious about the sweet taste and traced its origin back to the aspartyl-phenylalanine methyl ester. Schlatter did not believe aspartame, which was composed of amino acids found in humans, was toxic, so he tasted it and noticed the same sweet taste. Schlatter brought his discovery to the attention of his group leader Robert Henry Mazur (1924–), who then led investigations to commercialize the discovery. Publications on aspartame appeared soon after Schlatter’s discovery, but its ability to act as an artifi cial sweetener was not reported until 1969 in an article authored by Mazur. Searle applied for a patent in 1969.
Searle researchers continued to pursue the usefulness of aspartame as an artifi cial sweetener in the 1970s. Animal and human studies were conducted and in 1973 Searle applied for Food and Drug Administration (FDA) approval. In July 1974, the FDA approved the use
34 | Th e 100 Most Important Chemical Compounds
of aspartame in powder form for limited uses such as cereals, powdered drinks, and chewing gum. FDA’s approval brought immediate complaints from individuals and consumer groups claiming that Searle’s studies were fl awed, and that the FDA had ignored studies that showed harmful eff ects of aspartame. In December 1975, the FDA rescinded its approval of aspartame.
After this action, charges were brought against Searle & Company, claiming that certain nega-tive studies on aspartame were concealed from the FDA. Th e FDA requested that the U.S.
Attorney investigate Searle’s action. Searle refuted the charges, and it was during this time that they hired Washington insider and former Secretary of Defense Donald Rumsfeld (1932–) to serve as their CEO. Th e investigation lasted several years and because of delays, the statue of limitations ran out. When the Reagan Administration assumed power in January 1981, a more favorable climate for the approval of aspartame was in place. Even though a Public Board of Inquiry did not recommend its approval and a six-member FDA internal review board was split on the issue, Reagan’s newly appointed FDA Commissioner Arthur Hayes (1933–) approved aspartame for limited use in 1981. Two years later it was approved for use in car-bonated beverages. In 1985, G. D. Searle & Company was bought by Monsanto. Monsanto formed the NutraSweet Company and marketed aspartame under the same name.
Claims on aspartame’s safety continue to be controversial among some individuals and groups. Part of the problem in deciphering information on aspartame’s safety is due to its controversial approval process as well as a plethora of studies from numerous groups. Although animal studies have bearing on aspartame’s eff ects on humans, they must be interpreted cau-tiously because they may be based on excessive doses applied to species that respond diff erently than do humans. Safety concerns are also promulgated over the Internet by unreliable, bias sources. Th e FDA continues to support aspartame’s safety. In May 2006, the European Food Safety Authority recommended that the use of aspartame not be modifi ed after reviewing an Italian study that raised questions about tumors produced in rats ingesting modest amounts of aspartame. A number of health organizations such as the American Heart Association, American Diabetes Association, and American Cancer Society agree with the FDA’s current stand on aspartame and generally support the use of artifi cial sweeteners.
Aspartame is synthesized using the L enantiomer of phenylalanine. Th e L enantiomer is separated from the D enantiomer, the racemic mixture, by reacting it with acetic anhydride (CH3CO)2O) and sodium hydroxide. Th e product of this reaction is then treated with the enzyme porcine kidney acylase. An organic extraction with acid yields the L enantiomer in the aqueous layer and the D enantiomer in the organic layer. Th e l-phenylalanine is reacted with methanol and hydrochloric acid to esterify the COOH group on phenylalanine. Th e esterifi ed l-phenyalanine is then reacted with aspartic acid, while using other chemicals to prevent unwanted side reactions, to produce aspartame.
Today aspartame is used in more than 6,000 food products. Aspartame is 160 times as sweet as sucrose based on mass equivalents. Approximately 16,000 tons are consumed annu-ally on a global basis, with approximately 8,000 tons used in the United States and 2,500 tons in Europe. In the body aspartame is metabolized into its three components: aspartic acid, phenylalanine, and methanol (Figure 11.1). Aspartic acid is a nonessential amino acid and phenylalanine is an essential amino acid. Th e condition called phenylketonuria (PKU) is a genetic disorder that occurs when a person lacks the enzyme phenylalanine hydroxylase and cannot process phenylalanine. Th is results in high phenylalanine blood levels that are metabolized into products; one of these is phenylpyruvate, which contains a ketone group and
Aspartame | 35
Figure 11.1 Metabolites of aspartame.
gives the disorder its name. PKU can result in brain damage and mental retardation. Because aspartame is a source of phenylalanine, individuals with PKU must consider this source in managing the disease. People with PKU are placed on a diet that restricts phenylalanine. In the United States, the FDA requires that foods containing aspartame must have the warning label: “Phenylketonurics: Contains Phenylalanine.” Another health concern voiced by certain individuals relates to aspartame’s methanol component. Methanol is metabolized in the body into formaldehyde and formic acid, which are both toxic (see Methanol, Formaldehyde, Formic
Acid). Th e scientifi c view on this issue is that normal aspartame consumption levels are much too low to have a methanol toxic eff ect.
In addition to the warning label for phenylketonurics, the federal government has other regulations concerning aspartame’s use. When aspartame is used in baked goods and baking mixes, it should not exceed 0.5% by weight. Packages of the dry, free-fl owing aspartame are required to prominently display the sweetening equivalence in teaspoons of sugar. Aspartame for table use should have a statement on the label indicating that it is not to be used for cook-ing or bakcook-ing.
12. Benzene
CHEMICAL NAME = 1,3,5-cyclohexatriene CAS NUMBER = 71–43–2
MOLECULAR FORMULA = C6H6 MOLAR MASS = 78.1 g/mol
COMPOSITION = C(92.3%) H(7.7%) MELTING POINT = 5.5°C
BOILING POINT = 80.1°C DENSITY = 0.88 g/cm3
Benzene is a colorless, volatile, highly fl ammable liquid that is used extensively in the chemical industry and received wide interest in the early days of organic chemistry. Benzene was dis-covered in 1825 by Michael Faraday (1791–1867), who identifi ed it in a liquid residue from heated whale oil. Faraday called the compound bicarburet of hydrogen, and its name was later changed to benzin by Eilhardt Mitscherlich (1794–1863), who isolated the compound from benzoin (C14H12O2). Benzene’s formula indicates that it is highly unsaturated. Th is would suggest that benzene should readily undergo addition reactions like the aliphatic compounds.
Th at benzene did not undergo addition puzzled chemists for a number of years.
Th e discovery of benzene’s structure is credited to August Kekulé von Stradonitz (1829–
1896), but Kekulé’s structure was based on the work of other chemists such as Archibald Scott Couper (1831–1892). Couper wrote an article in 1858 entitled “On a New Chemical Th eory.” Couper’s article showed that carbon acted as a tetravalent (capable of combining with four hydrogen atoms) or divalent (capable of combining with two hydrogen atoms) atom. Couper also explained how tetravalent carbon could form chains to produce organic molecules. He also presented diagrams in his article depicting the structure of organic com-pounds and even proposed ring structures for some organic comcom-pounds. Unfortunately for Couper the presentation of his article was delayed, and in the meantime Kelulé’s similar, but less developed, ideas were published. Kekulé, who originally studied architecture but switched to chemistry, had close contacts with the great chemists of his day, and his work on organic structure was readily accepted as a solid theory. Kekulé showed that organic molecules could
Benzene | 37
be constructed by carbon bonding to itself and other atoms. He proposed that benzene oscil-lated back and forth between two structures so that all carbon-carbon bonds were essentially equivalent. His model for the structure of benzene is represented as:
Kekulé proposed that the structure for benzene resonated between two alternate structures in which the position of the double and single bonds switched positions. In the fi gure, ben-zene is depicted as changing back and forth between two structures in which the position of the double bonds shifts between adjacent carbon atoms. Th e two structures are called resonance structures.
A true picture of benzene’s structure was not determined until the 1930s when Linus Pauling produced his work on the chemical bond. Benzene does not exist as either of its resonance structures, and its structure should not be considered as either one or the other.
A more appropriate model is to consider the structure of benzene as a hybrid of the two resonance structures. Each carbon atom in the benzene ring is bonded to two other carbon atoms and a hydrogen atom in the same plane. Th is leaves six delocalized valence electrons.
Th ese six delocalized electrons are shared by all six carbon atoms, as demonstrated by the fact that the lengths of all carbon-carbon bonds in benzene are intermediate between what would be expected for a single bond and a double bond. Rather than consider a structure that exists as one resonance form or the other, benzene should be thought of as existing as both resonance structures simultaneously. In essence, 1.5 bonds are associated with each carbon in benzene rather than a single and double bond. Using the hexagon symbol with a circle inside is more representative of the delocalized sharing of electrons than using resonance structures, although benzene is often represented using one of its resonance structures.
Because of its structure, benzene is a very stable organic compound. It does not readily undergo addition reactions. Addition reactions involving benzene require high temperature, pressure, and special catalysts. Th e most common reactions involving benzene involve substitution reactions. Numerous atoms and groups of atoms may replace a hydrogen atom or several hydrogen atoms in benzene. Th ree important types of substitution reactions involving benzene are alkylation, halogenation, and nitration. In alkylation, an alkyl group or groups substitute for hydrogen(s). Alkylation is the primary process involving benzene in the chemi-cal industry. An example of alkylation is the production of ethylbenzene by reacting benzene, with ethylchloride and an aluminum chloride catalyst:
38 | Th e 100 Most Important Chemical Compounds
Th e greatest use of benzene is in the production of ethylbenzene, which consumes approximately 50% of all benzene produced. Ethylbenzene is in turn converted to styrene (polystyrene), plastics, and rubber products. In halogenation, halogen atoms are substituted for hydrogen atoms. Th e process of nitration produces a number of nitro compounds, for example, nitroglycerin. Nitration involves the reaction between benzene and nitric acid in the presence of sulfuric acid. During the reaction the nitronium ion (NO2+) splits off from nitric acid and substitutes on to the benzene ring, producing nitrobenzene:
Millions of organic chemicals are derived from benzene. Several common benzene derivatives are shown here.
After styrene production, approximately 20% of benzene production is used to produce
After styrene production, approximately 20% of benzene production is used to produce