CHEMICAL NAME = 2-hydroxypropane-1,2,3-tricar-boxylic acid
CAS NUMBER = 77–92–9 MOLECULAR FORMULA = C6H8O7 MOLAR MASS = 192.1 g/mol
COMPOSITION = C(37.5%) H(4.2%) O(58.3%) MELTING POINT = 153°C
BOILING POINT = decomposes at 175°C DENSITY = 1.66 g/cm3
Citric acid is a white, crystalline, weak organic acid present in most plants and many animals as an intermediate in cellular respiration. Citric acid contains three carboxyl groups making it a carboxylic, more specifi cally a tricarboxylic, acid. Th e name citrus originates from the Greek kedromelon meaning apple of melon for the fruit citron. Greek works mention kitron, kitrion, or kitreos for citron fruit, which is an oblong fruit several inches long from the scrublike tree Citrus medica. Lemons and limes have high citric acid content, which may account for up to 8% of the fruit’s dry weight. Th e discovery of citric acid is credited to Jabir ibn Hayyan (Latin name Geber, 721–815). Citric acid was fi rst isolated in 1784 by the Swedish chemist Carl Wilhelm Scheele (1742–1786), who crystallized it from lemon juice.
Citric acid is a weak acid and loses hydrogen ions from its three carboxyl groups (COOH) in solution. Th e loss of a hydrogen ion from each group in the molecule results in the citrate ion, C3H5O(COO)33−. A citric acid molecule also forms intermediate ions when one or two hydrogen atoms in the carboxyl groups ionize. Th e citrate ion combines with metals to form salts, the most common of which is calcium citrate. Citric acid forms esters to produce various citrates, for example trimethyl citrate and triethyl citrate.
Industrial citric acid production began in 1860 and for the next 60 years was dominated by Italian producers. Th e original production method was based on extraction from the juice of citrus fruits by adding calcium oxide (CaO) to form calcium citrate, Ca3(C6H5O7)2, as an insoluble precipitate that can then be collected by fi ltration. Citric acid can be recovered from
86 | Th e 100 Most Important Chemical Compounds
its calcium salt by adding sulfuric acid. Citric acid production using sugar fermentation was fi rst reported in 1893 by Carl Wehmer. Wehmer fermented sugar using the fungi he named Citromyces. Wehmer was also studying oxalic acid production and attributed its production to the fungus Aspergillus niger. Wehmer published numerous articles on the production of acids from fungi and other researchers sought to commercialize the process. In 1917, James N.
Currie (1883–?), who worked as a food chemist for the U.S. Department of Agriculture, published an article on the production of citric acid using Aspergillus niger. Currie’s article presented the conditions that increased the yield of citric acid over oxalic acid during fermen-tation. Currie found that by controlling the cultures, culture medium, temperature, acidity, etc., he could obtain a high yield of citric acid. Th at same year Currie was hired by Pfi zer where he worked on the industrial fermentation process to produce citric acid.
Citric acid was Pfi zer’s leading product. Pfi zer had sold citric acid since the 1880s and was interested in acquiring an alternative to its Italian sources for raw materials (concentrated lemon and lime juice), which was prone to disruption because of wars, weather, and political instability. Pfi zer started to mass produce citric acid in 1919 using methods developed under Currie’s leadership. During the 1920s, Pfi zer refi ned and increased its citric acid produc-tion methods, and this led to the collapse of the Italian citric acid industry. In 1922, Italy controlled approximately 90% of the world citric acid market and by 1927 most exports had ceased. By 1929, Pfi zer was producing all of its own citric acid. Pfi zer’s development of citric acid production continued through the 1930s. In the original method of citric acid production, fermentation was carried out in trays on the surface of the sugar solution. Pfi zer developed a deep tank method in which fermentation could take place in a submerged envi-ronment using aeration inside a tank. Th e deep tank method resulted in greater productivity and effi ciency, further resulting in lower cost citric acid. In 1920, a pound of citric acid cost
$1.25 and 20 years later it was selling for about $0.20 cents per pound.
Both the surface tray and deep tank methods are used to produce citric acid today. In the surface process, sterilized air circulates over a layer of the medium consisting of sugar (typically dextrose or molasses), salts, and nutrients. Aspergillus niger spores introduced on the surface ferment the sugar over 6 to 10 days. Th is method is not used in the United States but is more common in less industrialized nations. Th e fermentation cycle runs 5 to 14 days. In the deep tank (submerged) process, fermentation takes place over 5 to 10 days in stirred stainless steel tanks or aerated towers. Th e deep tank process is preferred for large-volume production in the industrial world. It requires less labor and less space per volume of citric acid produced, is easier to maintain sterile conditions, and results in higher production capacity. One disad-vantage of the deep tank process is the higher energy costs. Citric acid yield from submerged culture fermentation processes can range between 80% and 95% per weight of sugar. After fermentation, the citric acid is separated from the broth by treating the broth with calcium hydroxide, Ca(OH)2 to precipitate calcium citrate. Citric acid is regenerated from the calcium citrate by treating it with sulfuric acid.
Citric acid and its citrate compounds are widely used in hundreds of applications. Global production of citric acid in 2005 was 1.6 million tons, with China producing approximately 40% of the world supply. In the United States, approximately 65% of citric acid use is in the food and beverage industry. Citric acid is used as an acidulant to impart tartness, to control pH, as a preservative and antioxidant, as a metal chelator, and to stabilize color and taste.
Citrate salts can be used as mineral and metal dietary supplement; for example, calcium citrate
Citric Acid | 87
is used as a calcium supplement. Th e second greatest use of citric acid is in detergents and cleaning products. Sodium citrate is used as a builder. Citric acid’s ability to chelate metals makes it useful as a water-softening agent, which can also assist in cleaning. Approximately 10% of citric acid production is used in the pharmaceutical industry. Citric acid’s largest use in pharmaceuticals is as an eff ervescent when combined with carbonates or bicarbonates such as in Alka-Seltzer. As an eff ervescent, it improves tastes, buff ers, and improves solubility of ingredients. It is also used in pharmaceuticals to impart tartness to mask unpleasant medicinal fl avors, maintain stability, and as a buff ering agent.
Citric acid is formed during cellular respiration in most organisms’ mitochondria through a series of chemical reactions called the citric acid or Krebs cycle. It is called the citric acid cycle because citric acid is the fi rst intermediate produced in the process. Th e key pathways in this cycle were determined by Hans Adolf Krebs (1900–1981) in 1937 for which he received the Nobel Prize in physiology or medicine in 1953. Th e cycle starts when acetyl coenzyme A, which is synthesized from digested food, combines with oxaloacetate to produce citryl coenzyme A, which then hydrolyzes to citrate. Th e citrate then goes through a set of reactions to change it to isocitrate. Further oxidation and reduction reactions result in overall energy production. Th e cycle ends with the regeneration of oxaloacetate, which can combine with another acetyl coenzyme A molecule and the process starts over. Each cycle of the process reduces three molecules of NAD+ to NADH (nicotinamide adenine dinucleotide), whereas a molecule of FAD (fl avin adenine dinucleotide) is converted to its reduced form, FADH2. NADH and FADH2 move to the electron transport chain, where they lose hydrogen and electrons in another series of reactions. Th e electron transport chain in turn releases energy synthesizing ATP through oxidative phosphorylation (see Adenosine Triphosphate).
28. Cocaine
CHEMICAL NAME = 8-Azabicyclo[3.2.1]
octane-22carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester
CAS NUMBER = 50–36–2
MOLECULAR FORMULA = C17H21NO4 MOLAR MASS = 303.4 g/mol COMPOSITION = C(67.3%) H(7.0%)
N(4.6%) O(21.1%) MELTING POINT = 98°C BOILING POINT = 187°C
DENSITY = 1.22 g/cm3 (calculated)
Cocaine is best known as an illegal drug that produces a euphoric “high” in individuals who use it. Cocaine is an alkaloid obtained from the leaves of the coca plant, Erythroxylum coca, which is native to northwestern South America and Central America. Native Indians in the Andes have chewed coca leaves for thousands of years, and early Spanish explorers noted the stimulating eff ect that chewing the leaves had on these people. Coca was traditionally reserved for royalty and religious ceremonies in many of these cultures. It was the most sacred plant for the Incas, and its use was reserved for priests and nobility. For many indigenous popula-tions coca was an important food that provided nourishment and essential nutrients and was therefore widely cultivated. Natives carried pouches of coca leaves called chuspas and distances and time would be measured by the length of a chew. Th e time of a chew was called a cocada.
Its traditional use among pre-Columbian cultures varied, but the subsequent conquest of these groups helped establish its general use among common people. Th is was related to the appar-ent ability of coca to provide stamina as well as induce insomnia to users.
Spanish conquistadors introduced coca to Europe and the original missionaries unsuccess-fully attempted to ban it use. Th e Catholic Church viewed its use as an act of paganism and a remnant of native religious ceremonies. Despite this position and the Church’s destruction of cultured coca crops, coca’s widespread use among many isolated cultures prevented signifi cant
Cocaine | 89
elimination. As conquered native populations were enslaved, Europeans saw the utility of coca as a stimulant to induce greater work out of people. Furthermore, control of coca plants provided early European settlers a valuable economic commodity to obtain goods and labors from natives. Subsequently, King Philip II of Spain (1527–1598) lifted any ban on coca, gave land grants to establish coca plantations, and imposed a tax on it. Discovery of Andean silver further stimulated coca use, as Europeans used coca leaves to boost slave labor.
Coca was touted in Europe as a great elixir and its use increased between the 16th and 19th centuries. In 1855, the German chemist Friedrich Gaedcke (1828–1890) succeeded in isolating the active ingredient in coca leaves and called it erythroxyline. An improved process for isolating cocaine was discovered by Albert Niemann (1834–1861) during his dissertation work in 1860. Soon after Niemann’s success, an explosion of cocaine in numerous therapeutic products ensued. It was widely used as a topical anesthetic in dentistry (Figure 28.1) and in ophthalmology; it also found use as an appetite suppressant, a drug used to treat morphine addiction, a stimulant, and a general elixir. Its popularity to treat depression was originally advanced by Sigmund Freud (1856–1939). In 1900, it was among the top fi ve medicinal products in the United States.
Coca extracts were also added to common food items. A popular wine called Vin Mariani was concocted by the chemist Angelo Mariani (1832–1914) in 1863. Mariani’s Bordeaux mixture used coca leaves. Cocaine from the coca leaves was extracted by the ethanol in the
Figure 28.1. Advertisement for cocaine tooth medicine from 1885. Cocaine was extensively used in the latter part of the 19th century in medicines, as a stimulant, as an anesthetic, and to treat morphine addiction. Source: National Library of Medicine of the National Institute of Health.
90 | Th e 100 Most Important Chemical Compounds
wine. After Mariani’s success a number of other vintners used coca leaves to infuse cocaine into their wines. One of these was a druggist from Atlanta named John Stith Pemberton (1831–1888). Pemberton produced his own version of a coca wine, but he also added the cola nut, which was also believed to have therapeutic properties. Reacting to the temperance movement, Pemberton sought to produce a nonalcoholic version of his beverage. Pemberton obsessively worked to fi nd a new formula using the coca leaf and cola nut ingredients. On May 8, 1886, the fi rst coke was served at Jacobs Pharmacy in Atlanta. In establishing his new drink, which was to be marketed as an invigorating tonic, Pemberton sought a unique name.
Frank Robinson was one of Pemberton’s partners and his bookkeeper. Robinson, who was a keen marketer, joined the names of the two ingredients Coca and Cola together and designed the unique script of Coca-Cola. Coca-Cola was not an instant success. Pemberton, who suf-fered from morphine addiction, sold his company interests and Coca-Cola’s formula during his last months and never realized the eventual success of the company. Although the cocaine extract of coca was eliminated from Coca-Cola in 1906 because of passage of the Pure Food and Drug Act, the formula still calls for other coca extracts for fl avoring.
At the end of the 19th century, people started to become aware of the addictive and medical problems associated with cocaine. Cocaine is a stimulant and its use produces a euphoric high accompanied by increased motivation, energy, and libido. Concurrently, it has physiological eff ects that include increased pulse rate, breathing, and blood pressure (it is a vasoconstrictor); muscle tension; loss of appetite; and insomnia. Unfortunately, after the initial euphoric high, which may last several minutes to several hours, the user experiences a letdown. Th is state of depression leaves the user craving another dose and the vicious cycle of drug addiction has begun. One theory for cocaine’s eff ect is related to its role in disrupt-ing the neurotransmitter dopamine. Cocaine occupies receptor areas on nerve cells blockdisrupt-ing dopamine from the cell. Th e dopamine in the cell discharges its signal in the synapse and leads to a prolonged and extended buildup of dopamine. Increased dopamine aff ects the pleasure center of the brain and the elevated dopamine produces the high. Th e neurons respond to cocaine use by reducing the number of dopamine receptors; therefore when the brain returns to normal conditions, the lack of receptors and decrease in dopamine results in depression.
Th e eff ects of cocaine vary according to how it is consumed, individual diff erences, dose, and frequency of use. Th e most common form is the crystalline salt cocaine hydrochloride.
Cocaine in this form is water-soluble and can be pulverized into a fi ne powder and can be
“snorted” or inhaled through the nose. Here it is adsorbed onto the mucous membranes and then absorbed into the bloodstream through mucous membranes. Cocaine can also be pre-pared as an aqueous solution and directly injected into the bloodstream. Th is method delivers cocaine quickly to the brain and the user can experience a high in a matter of minutes. Free base cocaine is cocaine in which the hydrochloride has been removed to produce a more pure product that can be used for smoking. Cocaine hydrochloride is not suitable for smoking because it vaporizes at too high a temperature. Free base is prepared by making an aqueous solution of cocaine hydrochloride with baking soda (sodium bicarbonate) or ammonia and then boiling the solution down to give the free base. Cracking sounds during the process led to the name “crack” for free-base cocaine.
Colombia is the world’s leading producer of cocaine, with about 75% of the world’s pro-duction. Coca is grown locally and is also imported from Peru and Bolivia. Th e processing of
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coca involves mashing the leaves with a base, kerosene, and sulfuric acid to produce a paste containing between 40% and 70% cocaine. It can then be exported where it is dried and purifi ed into cocaine hydrochloride. Estimates of global consumption of cocaine vary, but a reasonable approximation is roughly 750 tons. Of this amount, approximately one-third is imported into the United States, which is the leading consumer of cocaine.
Cocaine is used medicinally for local anesthesia and vasoconstriction, especially in surgery involving the ear, nose, and throat. It is the only naturally occurring anesthetic. Although it is still used in limited quantities for surgery, many surgeons and anesthesiologists have turned to safer alternatives such as lidocaine and benzocaine. Also, the use of alternatives eliminates the storage of a well-known addictive drug in clinics and hospital pharmacies.