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(BQ) Part 2 book Organic chemistry has contents: Aromatic compounds; reactions of substituted benzenes, carbonyl compounds I; more about oxidation–reduction reactions; more about amines heterocyclic compounds, carbohydrates, catalysis,... and other contents.
BRUI15-593_621r3 27-03-2003 2:51 PM Page 593 FIVE In Chapter 15, we will examine the structural features that cause a compound to be aromatic We will also look at the features that cause a compound to be antiaromatic Then we will take a look at the reactions that benzene undergoes You will see that although benzene, alkenes, and dienes are all nucleophiles (because they all have carbon–carbon p bonds), benzene’s aromaticity causes it to undergo reactions that are quite different from the reactions that alkenes and dienes undergo Aromatic Compounds PA R T The two chapters in Part Five deal with aromaticity and the reactions of aromatic compounds Aromaticity was first introduced in Chapter 7, where you saw that benzene, a compound with an unusually large resonance energy, is an aromatic compound We will now look at the criteria that a compound must fulfill in order to be classified as aromatic Then we will examine the kinds of reactions that aromatic compounds undergo In Chapter 21, we will return to aromatic compounds when we look at the reactions of aromatic compounds in which one of the ring atoms is an atom other than a carbon Chapter 15 Aromaticity • Reactions of Benzene Chapter 16 Reactions of Substituted Benzenes In Chapter 16, we will look at the reactions of substituted benzenes First we will study reactions that change the nature of the substituent on the benzene ring; and we will see how the nature of the substituent affects both the reactivity of the ring and the placement of any incoming substituent Then we will look at three types of reactions that can be used to synthesize substituted benzenes other than those discussed in Chapter 15—reactions of arene diazonium salts, nucleophilic aromatic substitution reactions, and reactions that involve benzyne intermediates You will then have the opportunity to design syntheses of compounds that contain benzene rings 593 BRUI15-593_621r3 27-03-2003 2:51 PM Page 594 15 Aromaticity • Reactions of Benzene Benzene Michael Faraday (1791–1867) was born in England, a son of a blacksmith At the age of 14, he was apprenticed to a bookbinder and educated himself by reading the books that he bound He became an assistant to Sir Humphry Davy in 1812 and taught himself chemistry In 1825, he became the director of a laboratory at the Royal Institution, and, in 1833, he became a professor of chemistry there He is best known for his work on electricity and magnetism Eilhardt Mitscherlich (1794–1863) was born in Germany He studied oriental languages at the University of Heidelberg and the Sorbonne, where he concentrated on Farsi, hoping that Napoleon would include him in a delegation he intended to send to Persia That ambition ended with Napoleon’s defeat Mitscherlich returned to Germany to study science, simultaneously receiving a doctorate in Persian studies He was a professor of chemistry at the University of Berlin 594 T he compound we know as benzene was first isolated in 1825 by Michael Faraday, who extracted the compound from a liquid Pyrrole Pyridine residue obtained after heating whale oil under pressure to produce a gas used to illuminate buildings in London Because of its origin, chemists suggested that it should be called “pheno” from the Greek word phainein (“to shine”) In 1834, Eilhardt Mitscherlich correctly determined benzene’s molecular formula (C6H 6) and decided to call it benzin because of its relationship to benzoic acid, a known substituted form of the compound Later its name was changed to benzene Compounds like benzene, which have relatively few hydrogens in relation to the number of carbons, are typically found in oils produced by trees and other plants Early chemists called such compounds aromatic compounds because of their pleasing fragrances In this way, they were distinguished from aliphatic compounds, with higher hydrogen-to-carbon ratios, that were obtained from the chemical degradation of fats The chemical meaning of the word “aromatic” now signifies certain kinds of chemical structures We will now examine the criteria that a compound must satisfy to be classified as aromatic 15.1 Criteria for Aromaticity In Chapter 7, we saw that benzene is a planar, cyclic compound with a cyclic cloud of delocalized electrons above and below the plane of the ring (Figure 15.1) Because its p electrons are delocalized, all the C ¬ C bonds have the same length—partway between the length of a typical single and a typical double bond We also saw that benzene is a particularly stable compound because it has an unusually large resonance energy (36 kcal>mol or 151 kJ>mol) Most compounds with delocalized electrons BRUI15-593_621r3 27-03-2003 2:51 PM Page 595 Section 15.2 Aromatic Hydrocarbons 595 > Figure 15.1 a b c have much smaller resonance energies Compounds such as benzene with unusually large resonance energies are called aromatic compounds How can we tell whether a compound is aromatic by looking at its structure? In other words, what structural features aromatic compounds have in common? To be classified as aromatic, a compound must meet both of the following criteria: It must have an uninterrupted cyclic cloud of p electrons (often called a p cloud) above and below the plane of the molecule Let’s look a little more closely at what this means: For the p cloud to be cyclic, the molecule must be cyclic For the p cloud to be uninterrupted, every atom in the ring must have a p orbital For the p cloud to form, each p orbital must overlap with the p orbitals on either side of it Therefore, the molecule must be planar The p cloud must contain an odd number of pairs of p electrons Benzene is an aromatic compound because it is cyclic and planar, every carbon in the ring has a p orbital, and the p cloud contains three pairs of p electrons The German chemist Erich Hückel was the first to recognize that an aromatic compound must have an odd number of pairs of p electrons In 1931, he described this requirement by what has come to be known as Hückel’s rule, or the 4n ؉ rule The rule states that for a planar, cyclic compound to be aromatic, its uninterrupted p cloud must contain 14n + 22p electrons, where n is any whole number According to Hückel’s rule, then, an aromatic compound must have 1n = 02, 1n = 12, 10 1n = 22, 14 1n = 32, 18 1n = 42, etc., p electrons Because there are two electrons in a pair, Hückel’s rule requires that an aromatic compound have 1, 3, 5, 7, 9, etc., pairs of p electrons Thus, Hückel’s rule is just a mathematical way of saying that an aromatic compound must have an odd number of pairs of p electrons (a) Each carbon of benzene has a p orbital (b) The overlap of the p orbitals forms a cloud of p electrons above and below the plane of the benzene ring (c) The electrostatic potential map for benzene shows that all the carbon–carbon bonds have the same electron density Aromatic compounds are particularly stable For a compound to be aromatic, it must be cyclic and planar and have an uninterrupted cloud of P electrons The P cloud must contain an odd number of pairs of P electrons Erich Hückel (1896–1980) was born in Germany He was a professor of chemistry at the University of Stuttgart and at the University of Marburg PROBLEM ◆ a What is the value of n in Hückel’s rule when a compound has nine pairs of p electrons? b Is such a compound aromatic? 15.2 Aromatic Hydrocarbons Monocyclic hydrocarbons with alternating single and double bonds are called annulenes A prefix in brackets denotes the number of carbons in the ring Cyclobutadiene, benzene, and cyclooctatetraene are examples cyclobutadiene [4]-annulene benzene [6]-annulene cyclooctatetraene [8]-annulene 3-D Molecules: Cyclobutadiene; Benzene; Cyclooctatetraene BRUI15-593_621r3 27-03-2003 2:51 PM Page 596 596 CHAPTER 15 Aromaticity • Reactions of Benzene Cyclobutadiene has two pairs of p electrons, and cyclooctatetraene has four pairs of p electrons Unlike benzene, these compounds are not aromatic because they have an even number of pairs of p electrons There is an additional reason why cyclooctatetraene is not aromatic—it is not planar but, instead, tub-shaped Earlier, we saw that, for an eight-membered ring to be planar, it must have bond angles of 135° (Chapter 2, Problem 28), and we know that sp carbons have 120° bond angles Therefore, if cyclooctatetraene were planar, it would have considerable angle strain Because cyclobutadiene and cyclooctatetraene are not aromatic, they not have the unusual stability of aromatic compounds Now let’s look at some other compounds and determine whether they are aromatic Cyclopropene is not aromatic because it does not have an uninterrupted ring of p orbital-bearing atoms One of its ring atoms is sp hybridized, and only sp and sp hybridized carbons have p orbitals Therefore, cyclopropene does not fulfill the first criterion for aromaticity cyclopropene Tutorial: Aromaticity When drawing resonance contributors, remember that only electrons move, atoms never move + − cyclopropenyl cation cyclopropenyl anion The cyclopropenyl cation is aromatic because it has an uninterrupted ring of p orbital-bearing atoms and the p cloud contains one (an odd number) pair of delocalized p electrons The cyclopropenyl anion is not aromatic because although it has an uninterrupted ring of p orbital-bearing atoms, its p cloud has two (an even number) pairs of p electrons + + + resonance contributors of the cyclopropenyl cation δ+ δ+ δ+ resonance hybrid Cycloheptatriene is not aromatic Although it has the correct number of pairs of p electrons (three) to be aromatic, it does not have an uninterrupted ring of p orbitalbearing atoms because one of the ring atoms is sp hybridized Cyclopentadiene is also not aromatic: It has an even number of pairs of p electrons (two pairs), and it does not have an uninterrupted ring of p orbital-bearing atoms Like cycloheptatriene, cyclopentadiene has an sp hybridized carbon sp3 cycloheptatriene 3-D Molecules: Phenanthrene; Naphthalene sp3 cyclopentadiene The criteria for determining whether a monocyclic hydrocarbon compound is aromatic can also be used to determine whether a polycyclic hydrocarbon compound is aromatic Naphthalene (five pairs of p electrons), phenanthrene (seven pairs of p electrons), and chrysene (nine pairs of p electrons) are aromatic naphthalene phenanthrene chrysene BRUI15-593_621r3 27-03-2003 2:51 PM Page 597 Section 15.2 BUCKYBALLS AND AIDS In addition to diamond and graphite (Section 1.1), a third form of pure carbon was discovered while scientists were conducting experiments designed to understand how long-chain molecules are formed in outer space R E Smalley, R F Curl, Jr., and H W Kroto, the discoverers of this new form of carbon, shared the 1996 Nobel Prize in chemistry for their discovery They named this new form buckminsterfullerene (often shortened to fullerene) because it reminded them of the geodesic domes popularized by R Buckminster Fuller, an American architect and philosopher The substance is nicknamed “buckyball.” Consisting of a hollow cluster of 60 carbons, fullerene is the most symmetrical large molecule known Like graphite, fullerene has only sp hybridized carbons, but instead of being arranged in layers, the carbons are arranged in rings, forming a hollow cluster of 60 carbons that fit together like the seams of a soccer ball Each molecule has 32 interlocking rings (20 hexagons and 12 pentagons) At first glance, fullerene would appear to be aromatic because of its benzene-like rings However, it does not undergo electrophilic substitution reactions; instead, it undergoes electrophilic addition reactions like an alkene Fullerene’s lack of aromaticity is apparently caused by the curvature of the ball, which prevents the molecule from fulfilling the first criterion for aromaticity—that it must be planar Buckyballs have extraordinary chemical and physical properties They are exceedingly rugged and are capable of surviving the extreme temperatures of outer space Because they are essentially hollow cages, they can be manipulated to make materials never before known For example, when a buckyball is “doped” by inserting potassium or cesium into its cavity, it becomes an excellent A geodesic dome e + f c cycloheptatrienyl cation d g cyclononatetraenyl anion − PROBLEM C60 buckminsterfullerene "buckyball" Richard E Smalley was born in 1943 in Akron, Ohio He received a B.S from the University of Michigan and a Ph.D from Princeton University He is a professor of chemistry at Rice University Which of the following compounds are aromatic? b 597 organic superconductor These molecules are presently being studied for use in many other applications, such as new polymers and catalysts and new drug delivery systems The discovery of buckyballs is a strong reminder of the technological advances that can be achieved as a result of conducting basic research Scientists have even turned their attention to buckyballs in their quest for a cure for AIDS An enzyme that is required for HIV to reproduce exhibits a nonpolar pocket in its threedimensional structure If this pocket is blocked, the production of the virus ceases Because buckyballs are nonpolar and have approximately the same diameter as the pocket of the enzyme, they are being considered as possible blockers The first step in pursuing this possibility was to equip the buckyball with polar side chains to make it water soluble so that it could flow through the bloodstream Scientists have now modified the side chains so that they bind to the enzyme It’s still a long way from a cure for AIDS, but this represents one example of the many and varied approaches that scientists are taking to find a cure for this disease PROBLEM ◆ a Aromatic Hydrocarbons h CH “ CHCH “ CHCH “ CH SOLVED Robert F Curl, Jr., was born in Texas in 1933 He received a B.A from Rice University and a Ph.D from the University of California, Berkeley He is a professor of chemistry at Rice University Sir Harold W Kroto was born in 1939 in England and is a professor of chemistry at the University of Sussex a How many monobromonaphthalenes are there? b How many monobromophenanthrenes are there? SOLUTION TO 3a There are two monobromonaphthalenes Substitution cannot occur at either of the carbons shared by both rings, because those carbons are not bonded to a hydrogen Naphthalene is a flat molecule, so substitution for a hydrogen at any other carbon will result in one of the compounds shown Br Br 3-D Molecules: 1-Chloronaphthalene; 2-Chloronaphthalene BRUI15-593_621r3 27-03-2003 2:51 PM Page 598 598 CHAPTER 15 Aromaticity • Reactions of Benzene PROBLEM The [10]- and [12]-annulenes have been synthesized, and neither has been found to be aromatic Explain 15.3 Aromatic Heterocyclic Compounds A compound does not have to be a hydrocarbon to be aromatic Many heterocyclic compounds are aromatic A heterocyclic compound is a cyclic compound in which one or more of the ring atoms is an atom other than carbon A ring atom that is not carbon is called a heteroatom The name comes from the Greek word heteros, which means “different.” The most common heteroatoms found in heterocyclic compounds are N, O, and S benzene pyridine heterocyclic compounds N N H O S pyridine pyrrole furan thiophene Pyridine is an aromatic heterocyclic compound Each of the six ring atoms of pyridine is sp hybridized, which means that each has a p orbital; and the molecule contains three pairs of p electrons Don’t be confused by the lone-pair electrons on the nitrogen; they are not p electrons Because nitrogen is sp hybridized, it has three sp orbitals and a p orbital The p orbital is used to form the p bond Two of nitrogen’s sp orbitals overlap the sp orbitals of adjacent carbon atoms, and nitrogen’s third sp orbital contains the lone pair this is a p orbital pyrrole N these electrons are in an sp2 orbital perpendicular to the p orbitals orbital structure of pyridine It is not immediately apparent that the electrons represented as lone-pair electrons on the nitrogen atom of pyrrole are p electrons The resonance contributors, however, show that the nitrogen atom is sp hybridized and uses its three sp orbitals to bond to two carbons and one hydrogen The lone-pair electrons are in a p orbital that overlaps the p orbitals on adjacent carbons, forming a p bond—thus, they are p electrons Pyrrole, therefore, has three pairs of p electrons and is aromatic − N H + N H − − + N H + N H resonance contributors of pyrrole − + N H BRUI15-593_621r3 27-03-2003 2:51 PM Page 599 Section 15.4 Some Chemical Consequences of Aromaticity these electrons are in a p orbital these electrons are in a p orbital H N O orbital structure of pyrrole these electrons are in an sp2 orbital perpendicular to the p orbitals orbital structure of furan Similarly, furan and thiophene are stable aromatic compounds Both the oxygen in the former and the sulfur in the latter are sp hybridized and have one lone pair in an sp orbital The second lone pair is in a p orbital that overlaps the p orbitals of adjacent carbons, forming a p bond Thus, they are p electrons − − + O − O + + O O + − O resonance contributors of furan Quinoline, indole, imidazole, purine, and pyrimidine are other examples of heterocyclic aromatic compounds The heterocyclic compounds discussed in this section are examined in greater detail in Chapter 21 N N N H N quinoline indole N NH N H N imidazole purine N N pyrimidine PROBLEM ◆ In what orbitals are the electrons represented as lone pairs when drawing the structures of quinoline, indole, imidazole, purine, and pyrimidine? PROBLEM Answer the following questions by examining the electrostatic potential maps on p 598: a Why is the bottom part of the electrostatic potential map of pyrrole blue? b Why is the bottom part of the electrostatic potential map of pyridine red? c Why is the center of the electrostatic potential map of benzene more red than the center of the electrostatic potential map of pyridine? 15.4 Some Chemical Consequences of Aromaticity The pKa of cyclopentadiene is 15, which is extraordinarily acidic for a hydrogen that is bonded to an sp hybridized carbon Ethane, for example, has a pKa of 50 + H+ − H H cyclopentadiene pKa = 15 CH3CH3 ethane pKa = 50 H cyclopentadienyl anion − CH3CH2 + H + ethyl anion 599 BRUI15-593_621r3 27-03-2003 2:51 PM Page 600 600 CHAPTER 15 Aromaticity • Reactions of Benzene Tutorial: Aromaticity and acidity Why is the pKa of cyclopentadiene so much lower than that of ethane? To answer this question, we must look at the stabilities of the anions that are formed when the compounds lose a proton (Recall that the strength of an acid is determined by the stability of its conjugate base: The more stable its conjugate base, the stronger is the acid; see Section 1.18.) All the electrons in the ethyl anion are localized In contrast, the anion that is formed when cyclopentadiene loses a proton fulfills the requirements for aromaticity: It is cyclic and planar, each atom in the ring has a p orbital, and the p cloud has three pairs of delocalized p electrons The negatively charged carbon in the cyclopentadienyl anion is sp hybridized because if it were sp hybridized, the ion would not be aromatic The resonance hybrid shows that all the carbons in the cyclopentadienyl anion are equivalent Each carbon has exactly one-fifth of the negative charge associated with the anion − − − − − resonance contributors of the cyclopentadienyl anion δ− δ− δ− δ− δ− resonance hybrid As a result of its aromaticity, the cyclopentadienyl anion is an unusually stable carbanion This is why cyclopentadiene has an unusually low pKa In other words, it is the stability conveyed by the aromaticity of the cyclopentadienyl anion that makes the hydrogen much more acidic than hydrogens bonded to other sp carbons PROBLEM ◆ Predict the relative pKa values of cyclopentadiene and cycloheptatriene PROBLEM a Draw arrows to show the movement of electrons in going from one resonance contributor to the next in the cyclopentadienyl anion pyrrole b How many ring atoms share the negative charge in the cyclopentadienyl anion? pyrrole? Another example of the influence of aromaticity on chemical reactivity is the unusual chemical behavior exhibited by cycloheptatrienyl bromide Recall from Section 2.9 that alkyl halides tend to be relatively nonpolar covalent compounds— they are soluble in nonpolar solvents and insoluble in water Cycloheptatrienyl bromide, however, is an alkyl halide that behaves like an ionic compound—it is insoluble in nonpolar solvents, but readily soluble in water Br covalent cycloheptatrienyl bromide + Br− ionic cycloheptatrienyl bromide tropylium bromide BRUI15-593_621r3 27-03-2003 2:51 PM Page 601 Section 15.4 Some Chemical Consequences of Aromaticity Cycloheptatrienyl bromide is an ionic compound because its cation is aromatic The alkyl halide is not aromatic in the covalent form because it has an sp hybridized carbon, so it does not have an uninterrupted ring of p orbital-bearing atoms In the ionic form, however, the cycloheptatrienyl cation (also known as the tropylium cation) is aromatic because it is a planar cyclic ion, all the ring atoms are sp hybridized (which means that each ring atom has a p orbital), and it has three pairs of delocalized p electrons The stability associated with the aromatic cation causes the alkyl halide to exist in the ionic form + + + + + + + resonance contributors of the cycloheptatrienyl cation δ+ δ+ δ+ δ+ δ+ δ+ δ+ resonance hybrid PROBLEM-SOLVING STRATEGY Which of the following compounds has the greater dipole moment? O C O C Before attempting to answer this kind of question, make sure that you know exactly what the question is asking You know that the dipole moment of these compounds results from the unequal sharing of electrons by carbon and oxygen Therefore, the more unequal the sharing, the greater is the dipole moment So now the question becomes, which compound has a greater negative charge on its oxygen atom? Draw the structures with separated charges, and determine their relative stabilities In the case of the compound on the left, the three-membered ring becomes aromatic when the charges are separated In the case of the compound on the right, the structure with separated charges is not aromatic Because being aromatic makes a compound more stable, the compound on the left has the greater dipole moment O− C+ O− C+ PROBLEM Draw the resonance contributors of the cyclooctatrienyl dianion a Which of the resonance contributors is the least stable? b Which of the resonance contributors makes the smallest contribution to the hybrid? 601 BRUI15-593_621r3 27-03-2003 2:51 PM Page 602 602 CHAPTER 15 Aromaticity • Reactions of Benzene 15.5 Antiaromaticity Antiaromatic compounds are highly unstable An aromatic compound is more stable than an analogous cyclic compound with localized electrons In contrast, an antiaromatic compound is less stable than an analogous cyclic compound with localized electrons Aromaticity is characterized by stability, whereas antiaromaticity is characterized by instability relative stabilities aromatic compound > cyclic compound with localized electrons > antiaromatic compound increasing stability A compound is classified as being antiaromatic if it fulfills the first criterion for aromaticity but does not fulfill the second criterion In other words, it must be a planar, cyclic compound with an uninterrupted ring of p orbital-bearing atoms, and the p cloud must contain an even number of pairs of p electrons Hückel would state that the p cloud must contain 4n p electrons, where n is any whole number—a mathematical way of saying that the cloud must contain an even number of pairs of p electrons Cyclobutadiene is a planar, cyclic molecule with two pairs of p electrons Hence, it is expected to be antiaromatic and highly unstable In fact, it is too unstable to be isolated, although it has been trapped at very cold temperatures The cyclopentadienyl cation also has two pairs of p electrons, so we can conclude that it is antiaromatic and unstable + cyclobutadiene cyclopentadienyl cation PROBLEM 10 ◆ a Predict the relative pKa values of cyclopropene and cyclopropane b Which is more soluble in water, 3-bromocyclopropene or bromocyclopropane? PROBLEM 11 ◆ Which of the compounds in Problem are antiaromatic? 15.6 A Molecular Orbital Description of Aromaticity and Antiaromaticity Why are planar molecules with uninterrupted cyclic p electron clouds highly stable (aromatic) if they have an odd number of pairs of p electrons and highly unstable (antiaromatic) if they have an even number of pairs of p electrons? To answer this question, we must turn to molecular orbital theory The relative energies of the p molecular orbitals of a planar molecule with an uninterrupted cyclic p electron cloud can be determined—without having to use any math—by first drawing the cyclic compound with one of its vertices pointed down The relative energies of the p molecular orbitals correspond to the relative levels of the vertices (Figure 15.2) Molecular orbitals below the midpoint of the cyclic structure are bonding molecular orbitals, those above the midpoint are antibonding molecular orbitals, and any at the midpoint are nonbonding molecular orbitals This scheme is sometimes called a Frost device (or a Frost circle) in honor of Arthur A Frost, an BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1214 1214 CHAPTER 30 The Organic Chemistry of Drugs 30.6 Receptors Many drugs exert their physiological effects by binding to a specific cellular binding site called a receptor That is why a small amount of a drug can bring about a measurable effect Drug receptors are often glycoproteins or lipoproteins, which explains why different enantiomers of a drug have different effects (Section 5.15) Some receptors are part of cell membranes, while others are found in the cytoplasm—the material outside the nucleus Because not all cells have the same receptors, drugs have considerable specificity For example, epinephrine has intense effects on cardiac muscle, but almost no effect on muscle in other parts of the body Nucleic acids—particularly DNA—also act as receptors for certain kinds of drugs A drug interacts with its receptor by means of the same kinds of bonding interactions—hydrogen bonding, electrostatic attractions, and van der Waals interactions—that we encountered in other examples of molecular recognition (Section 24.8) The most important factor in bringing together a drug and a receptor is a snug fit: The greater the affinity of a drug for its binding site, the higher is the drug’s potential biological activity Two drugs for which DNA is a receptor are chloroquine (an antimalarial) and 3,6-diaminoacridine (an antibacterial) These flat cyclic compounds can slide into the DNA double helix between base pairs—like a card being inserted into a deck of playing cards—and interfere with the normal replication of DNA CH2CH3 HNCHCH2CH2CH2N CH2CH3 Cl H2N N chloroquine N NH2 3,6-diaminoacridine Knowing something about the molecular basis of drug action—such as how a drug interacts with a receptor—allows scientists to design and synthesize compounds that might have a desired biological activity For example, when excess histamine is produced by the body, it causes the symptoms associated with the common cold and allergic responses This is thought to be the result of the protonated ethylamino group anchoring the histamine molecule to a negatively charged portion of the histamine receptor − + N CH2CH2NH3 N H histamine histamine receptor BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1215 Section 30.6 Drugs that interfere with the natural action of histamine—called antihistamines— bind to the histamine receptor but not trigger the same response as histamine Like histamine, these drugs have a protonated amino group that binds to the receptor The drugs also have bulky groups that keep the histamine molecule from approaching the receptor antihistamines CH3 + CHOCH2CH2NH(CH3)2 + S NCH2CHNH(CH3)2 diphenhydramine Benadryl promethazine Promine S + NCH2CH2CH2NH(CH3)2 promazine Talofen Acetylcholine is a neurohormone that enhances peristalsis, wakefulness, and memory and is essential for nerve transmission A deficiency of brain cell receptors that bind acetylcholine—cholinergic receptors—contributes to the characteristic loss of memory in Alzheimer’s disease Cholinergic receptors are structurally similar to those that bind histamine Therefore, antihistamines and cholinergic agents show overlapping activities As a result, the antihistamine diphenhydramine has been used to treat insomnia and to combat motion sickness − O + CH3COCH2CH2N(CH3)3 acetylcholine cholinergic receptor Excess histamine production by the body also causes the hypersecretion of stomach acid by the cells of the stomach lining, leading to the development of ulcers The antihistamines that block the histamine receptors—thereby preventing the allergic responses associated with excess histamine production—have no effect on HCl production This fact led scientists to conclude that a second kind of histamine receptor triggers the release of acid into the stomach Because 4-methylhistamine was found to cause weak inhibition of HCl secretion, it was used as a lead compound About 500 molecular modifications were performed over a 10-year period before four clinically useful antiulcer agents were found Two of these are Tagamet ® and Zantac ® Notice that steric blocking of the receptor site is not a factor in these compounds Compared with the antihistamines, the effective antiulcer drugs have more polar rings and longer side chains Receptors 3-D Molecules: Histamine; Diphenhydramine; Promethazine; Promazine 1215 BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1216 1216 CHAPTER 30 The Organic Chemistry of Drugs + CH2CH2NH3 N CH3 N H 4-methylhistamine H CH2SCH2CH2NH + C N C N H + NHCH3 CH3NHCH2 O N N H Tutorial: Structural similarities in classes of drugs C CH2SCH2CH2NH NO2 NHCH3 ranitidine Zantac CH3 CH3 C cimetidine Tagamet Tagamet ® has the same imidazole ring as 4-methylhistidine, but it has a sulfur atom and a functional group based on guanidine (Section 23.1) Zantac ® has a different heterocyclic ring, and although its side chain is similar to that of Tagamet ®, it does not contain a guanidino group Observations that serotonin was implicated in the generation of migraine attacks led to the development of drugs that bind to serotonin receptors Sumatriptan, introduced in 1991, relieved not only the pain associated with migraines, but also many of migraine’s other symptoms, including sensitivity to light and sound and nausea CH3 CH2CH2NH2 CH2CH2NCH3 O HO CH3NH N H S N H O serotonin sumatriptan Imitrex The success of sumatriptan spurred a search for other antimigraine agents by molecular modification, and three new triptans were introduced in 1997 and 1998 These second-generation triptans showed some improvements over sumatriptan—specifically, a longer half-life, reduced cardiac side effects, and improved CNS penetration CH3 CH2CH2NCH3 O O CH3 CH2CH2NCH3 N N H N zolmitriptan Zomig CH3NH NCH3 S O N N H O N H N H rizatriptan Maxalt naratriptan Amerge In screening modified compounds, it is not unusual to find a compound with a completely different pharmacological activity than the lead compound For example, a molecular modification of a sulfonamide, an antibiotic, led to tolbutamide, a drug with hypoglycemic activity (Section 25.8) O H2N S O NH O a sulfonamide R H3C S O NH C NHCH2CH2CH2CH3 O tolbutamide BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1217 Section 30.7 Drugs as Enzyme Inhibitors Molecular modification of promethazine, an antihistamine, led to chlorpromazine, a drug that, although lacking antihistamine activity, lowered the body temperature This drug found clinical use in chest surgery, where patients previously had to be cooled down by wrapping them in cold, wet sheets Because wrapping in cold, wet sheets had been an old method of calming psychotic patients, a French psychiatrist tried the drug on some of his patients He found that chlorpromazine was able to suppress psychotic symptoms to the point that the patients assumed almost normal behavioral characteristics However, they soon developed uncoordinated involuntary movements After thousands of molecular modifications, thioridazine was found to have the appropriate calming effect with less problematic side effects It is now in clinical use as an antipsychotic SCH3 Cl CH3 N S NCH2CH2CH2N(CH3)2 S chlorpromazine Thorazine NCH2CH2 thioridazine Mellaril Sometimes a drug initially developed for one purpose is later found to have properties that make it a better drug for a different purpose Beta-blockers were originally intended to be used to alleviate the pain associated with angina by reducing the amount of work done by the heart Later, they were found to have antihypertensive properties, so now they are used primarily to manage hypertension, a disease that is prevalent in the Western world 30.7 Drugs as Enzyme Inhibitors In earlier chapters, we discussed several drugs that act by inhibiting enzymes (Sections 25.8 and 25.9) Penicillin, for example, destroys bacteria by inhibiting the enzyme that synthesizes bacterial cell walls (Section 17.15) O RCNH HC C OH S N O O CH3 RCNH CH3 HC O COO− C N H O S CH3 CH3 COO− penicillin active enzyme inactive enzyme Bacteria develop resistance to penicillin by secreting penicillinase, an enzyme that destroys penicillin by hydrolyzing its b -lactam ring before the drug can interfere with bacterial cell wall synthesis inactive hydrolysis product active drug HC CH2OH + C CH N CH CH2O O penicillinase penicillin CH N H C CH H2O CH2OH + C − N H O O O penicillinase CH penicillinase penicilloic acid 1217 BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1218 1218 CHAPTER 30 The Organic Chemistry of Drugs Chemists have developed drugs that inhibit penicillinase If such a drug is given to a patient along with penicillin, the antibiotic is not destroyed This is an example of a drug that has no therapeutic effect itself, but acts by protecting a therapeutic drug One penicillinase inhibitor is a sulfone, which is easily prepared from penicillin by oxidizing the sulfur atom with a peroxyacid (Section 20.4) O RCNH S HC C N CH3 O O O CH3 RCOOH RCNH O HC C COO− S N O penicillin O CH3 CH3 COO− a sulfone Because the sulfone looks like the original antibiotic, penicillinase accepts it as a substrate, forming an ester, as it does with penicillin If the ester were then hydrolyzed, penicillinase would be liberated and, therefore, would be free to react with penicillin However, the electron-withdrawing sulfone provides an alternative pathway to hydrolysis that forms a stable imine Because imines are susceptible to nucleophilic attack, an amino group at the active site of penicillinase reacts with the imine, forming a second covalent bond between the enzyme and the inhibitor The covalently attacked group inactivates penicillinase, thereby wiping out the resistance to penicillin The sulfone is another example of a mechanism-based suicide inhibitor (Section 25.8) O O RCNH S HC C O CH3 RCNH CH3 N CH2O COO− O O O S HC C O CH3 CH3 NH penicillinase CH2OH COO− O CH2OH ester hydrolysis penicillinase an ester imine formation penicillinase −SO O −SO O RCNH NH O NH CH RCNHCH CH3 C COO− O CH3 C CH2O NH2 O O −SO RCNH O CH +NH C CH CH3 CH3 COO− an imine CH3 C N + CH CH3 H2N O COO− penicillinase inactive What makes the sulfone such an effective inhibitor is that the reactive imine group does not appear until after the sulfone has been bound to the enzyme that is to be inactivated In other words, the inhibitor has a specific target In contrast, if an imine were BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1219 Section 30.7 Drugs as Enzyme Inhibitors administered directly to the patient, it would be nonspecific, reacting with whatever nucleophile it first encountered When two drugs are given simultaneously to a patient, their combined effect can be additive, antagonistic, or synergistic That is, the effect of two drugs used in combination can be equal to, less than, or greater than the sum of the effects obtained when the drugs are administered individually Administering penicillin and the sulfone in combination results in drug synergism: The sulfone inhibits the penicillinase, so penicillin won’t be destroyed and will be able to inhibit the enzyme that synthesizes bacterial cell walls Another reason to administer two drugs in combination is that if some bacteria are resistant to one of them, the second drug will minimize the chance that the resistant strain will proliferate For example, two antimicrobial agents, isoniazid and rifampin, are given in combination to treat tuberculosis NHNH2 O CH3 CH3 HO CH3 OH O CH3COO CH3 OH OH CH3 CH3 NH CH3O CH O O CH3 N N N N CH3 OH O isoniazid Nydrazid rifampin Rifadin Typically, it takes a bacterial strain 15 to 20 years to evolve resistance to antibiotics The fluoroquinolones, the last class of antibiotics to be discovered until very recently, were discovered more than 30 years ago, so drug resistance has become an increasingly important problem in medicinal chemistry More and more bacteria have become resistant to all antibiotics—even vancomycin, until recently the antibiotic of last resort The antibiotic activity of the fluoroquinolones results from their ability to inhibit DNA gyrase, an enzyme required for transcription (Section 27.10) Fortunately, the bacterial and mammalian forms of the enzyme are sufficiently different that the fluoroquinolones inhibit only the bacterial enzyme There are many different fluoroquinolones All have fluorine substituents, which increase the lipophilicity of the drug, enabling it to penetrate into tissues and cells If either the carboxyl group or the double bond in the 4-pyridinone ring is removed, all activity is lost By changing the substituents on the piperazine ring, excretion of the drug can be shifted from the liver to the kidney, which is useful to patients with impaired liver function The substituents on the piperazine ring also affect the halflife of the drug NH2 O O piperazine ring COOH F N N H3C pyridinone ring HN COOH F N N F HN CH3 ciprofloxacin Cipro active against gram-negative bacteria sparfloxacin Zagam active against gram-negative bacteria and gram-positive bacteria 3-D Molecules: Rifampin; Isoniazid 1219 BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1220 1220 CHAPTER 30 The Organic Chemistry of Drugs The approval of Zyvox ® by the FDA in April 2000 was met with great relief by the medical community Zyvox ® is the first in a new family of antibiotics: the oxazolidinones In clinical trials, Zyvox ® was found to cure 75% of the patients infected with bacteria that had become resistant to all other antibiotics O O O CH3CNHCH2 N H linezolid Zyvox N O F Zyvox ® is a synthetic compound designed by scientists to inhibit bacterial growth at a point different from that at which any other antibiotic exerts its effect Zyvox ® inhibits the initiation of protein synthesis by preventing the formation of the complex between the first amino-acid-bearing tRNA, mRNA, and the 30S ribosome (Section 27.13) Because of the drug’s new mode of activity, resistance is expected to be rare at first and, hopefully, slow to emerge 30.8 Designing a Suicide Substrate It is important for a drug to have a minimum of undesirable side effects A drug must be administered in sufficient quantity to achieve a therapeutic effect; however, too much of a drug can be lethal The therapeutic index of a drug is the ratio of the lethal dose to the therapeutic dose The higher the therapeutic index, the greater is the margin of safety of the drug Penicillin is an effective antibiotic that has a high therapeutic index because it interferes with cell wall synthesis—and bacterial cells have walls, but human cells not What else is characteristic about cell walls that could lead to the design of an antibiotic? We know that enzymes and other proteins are polymers of L-amino acids Cell walls, however, contain both L-amino acids and D-amino acids Therefore, if the racemization of naturally occurring L-amino acids to mixtures of L- and D-amino acids could be prevented, D-amino acids would not be available for incorporation into cell walls, and bacterial cell wall synthesis could be stopped We have seen that amino acid racemization is catalyzed by an enzyme that requires pyridoxal phosphate as a coenzyme (Section 25.6) What we need, then, is a compound that will inhibit this enzyme Because the natural substrate for the enzyme is an amino acid, an amino acid analog should be a good inhibitor The first step in racemization is removal of the a-hydrogen of the amino acid If the inhibitor has a leaving group on the b -carbon, the electrons left behind when the proton is removed can displace the leaving group instead of being delocalized into the pyridine ring (Compare the mechanism shown here with that shown for racemization in Section 25.6.) Transimination with the enzyme forms an a,b -unsaturated amino acid that reacts irreversibly with the imine formed by the enzyme and the coenzyme Because the enzyme is now bound to the coenzyme in an amine linkage rather than in an imine linkage, the enzyme can no longer undergo a transimination reaction with its amino acid substrate The enzyme has thus been irreversibly inactivated This is another example of an inhibitor that does not become chemically active until it is at the active site of the targeted enzyme BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1221 Section 30.9 an elimination reaction an α, β-unsaturated amino acid − B Cl− H O Cl CH2 C C O− CH2 +N R CH3 H C C O− O− C C NH2 E (CH2)4 N N HC H O R CH2 O +N H H O CH3 HC H O R transimination with E−(CH2)4NH2 +N CH3 H E O R = 1221 O BH N HC Quantitative Structure–Activity Relationships (QSAR) an amine (CH2)4 linkage P − O −O OCH2 O − O C NH C CH2 R CH NH2 H O + +N H CH3 inactivated enzyme 30.9 Quantitative Structure–Activity Relationships (QSAR) The enormous cost involved in synthesizing and testing thousands of modified compounds in an attempt to find an active drug led scientists to develop a more rational approach—called rational drug design—to the design of biologically active molecules They realized that if a physical or chemical property of a series of compounds could be correlated with biological activity, they would know what property of the drug was related to that particular activity Armed with this knowledge, scientists could design compounds that would have a good chance of exhibiting the desired activity This strategy would be a great improvement over the random approach to molecular modification that traditionally had been employed The first hint that a physical property of a drug could be related to biological activity appeared almost 100 years ago when scientists recognized that chloroform (CHCl 3), diethyl ether, cyclopropane, and nitrous oxide (N2O) were all useful general anesthetics Clearly, the chemical structures of these diverse compounds could not account for their similar pharmacological effects Instead, some physical property must explain the similarity of their biological activities In the early 1960s, Corwin Hansch postulated that the biological activity of a drug depended on two processes The first is distribution: A drug must be able to get from the point where it enters the body to the receptor where it exerts its effect For example, an anesthetic must be able to cross the aqueous milieu (blood) and penetrate the lipid barrier of nerve cell membranes The second process is binding: When a drug reaches its receptor, it must interact properly with it Chloroform, diethyl ether, cyclopropane, and nitrous oxide were each put into a mixture of 1-octanol and water 1-Octanol was chosen as the nonpolar solvent because, Corwin H Hansch was born in North Dakota in 1918 He received a B.S from the University of Illinois and a Ph.D from New York University He has been a professor of chemistry at Pomona College since 1946 BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1222 1222 CHAPTER 30 The Organic Chemistry of Drugs with its long chain and polar head group, it is a good model of a biological membrane When the amount of drug dissolving in each of the layers was measured, it turned out that they all had a similar distribution coefficient (the ratio of the amount dissolving in 1-octanol to the amount dissolving in water) In other words, the distribution coefficient could be related to biological activity Compounds with lower distribution coefficients— more polar compounds—could not penetrate the nonpolar cell membrane; compounds with greater distribution coefficients—more nonpolar compounds—could not cross the aqueous phase This meant that the distribution coefficient of a compound could be used to determine whether a compound should be tested in vivo The technique of relating a property of a series of compounds to biological activity is known as a quantitative structure–activity relationship (QSAR) Determining the physical property of a drug cannot take the place of in vivo testing because how the drug will behave once it reaches a suitable receptor cannot be predicted by the distribution coefficient alone Nevertheless, QSAR analysis provides a way to lead chemists to structures with the greatest probability of having the desired biological activity In this way, molecular modification that would lead to compounds without the desired activity can be avoided In the following example, QSAR was useful not only in determining the structure of a potentially active drug but also in determining something about the structure of the receptor site A series of substituted 2,4-diaminopyrimidines, used as inhibitors of dihydrofolate reductase (Section 25.8), was investigated NH2 R N H2N N R′ a 2,4-diaminopyrimidine The potency of the inhibitors could be described by the equation potency = 0.80p - 7.34s - 8.14 Tutorial: Quantitative structure– activity relationship (QSAR) where s and p are substituent parameters The s parameter is a measure of the electron-donating or electron-withdrawing ability of the substituents R and R¿ The negative coefficient of s indicates that potency is increased by electron donation (Chapter 17, Problem 75) The fact that increasing the basicity of the drug increases its potency suggests that the protonated drug is more active than the nonprotonated drug The p parameter is a measure of the hydrophobicity of the substituents Potency was found to be better related to p when the p value for the more hydrophobic of the two substituents was used, rather than the sum of the p values for both substituents This finding suggests that the receptor has a hydrophobic pocket that can accommodate one, but not both, substituents In a search for a new analgesic, the potency of the drug was found to be described by the following equation, where HA indicates whether R is a hydrogen bond acceptor and where B is a steric factor: COOH R N O potency = − 4.45 − 0.73HA + 6.5B − 1.55(B)2 Analysis indicated that the vinyl substituted compound should be prepared In a search for a drug to be used to treat leukemia, a QSAR analysis showed that the antileukemic activity of a series of substituted triazines was related to the electron- BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1223 Section 30.11 Combinatorial Organic Synthesis 1223 donating ability of the substituent When, however, another QSAR analysis showed that the toxicity of these compounds was also related to the electron-donating ability of the substituent, it was decided that it would be fruitless to continue synthesizing and testing this class of compounds In addition to solubility and substituent parameters, some of the properties that have been correlated with biological activity are oxidation–reduction potential, molecular size, interatomic distance between functional groups, degree of ionization, and configuration 30.10 Molecular Modeling Because the shape of a molecule determines whether it will be recognized by a receptor and, therefore, whether it will exhibit biological activity, compounds with similar biological activity often have similar structures Because computers can draw molecular models of compounds on a video display and move them around to assume different conformations, computer molecular modeling allows more rational drug design There are computer programs that allow chemists to scan existing collections of thousands of compounds to find those with appropriate structural and conformational properties Any compound that shows promise can be drawn on a computer display, along with the three-dimensional image of a receptor site For example, the binding of netropsin, an antibiotic with a wide range of antimicrobial activity, to the minor groove of DNA is shown in Figure 30.1 The fit between the compound and the receptor may suggest modifications that can be made to the compound that result in more favorable binding In this way, the selection of compounds to be synthesized for the purpose of screening for biological activity can be more rational and will allow pharmacologically active compounds to be discovered more rapidly The technique will become more valuable as scientists learn more about receptor sites 30.11 Combinatorial Organic Synthesis The need for large collections of compounds that can be screened for biological activity in the constant search for new drugs has led organic chemists to a synthetic strategy that employs the concept of mass production This strategy, called combinatorial organic synthesis, involves the synthesis of a large group of related compounds— known as a library—by covalently connecting sets of building blocks of various structures For example, if a compound can be synthesized by connecting three different building blocks, and if each set of building blocks contains 10 interchangeable compounds, then 1000 110 * 10 * 102 different compounds can be prepared This approach clearly mimics nature, which uses amino acids and nucleic acids as building blocks to synthesize an enormous number of different proteins and nucleic acids The first requirement in combinatorial synthesis is the availability of an assortment of reactive small molecules to be used as building blocks Because of the ready availability of amino acids, combinatorial synthesis made its first appearance in the creation of peptide libraries Peptides, however, have limited use as therapeutic agents because they generally cannot be taken orally and are rapidly metabolized Currently, organic chemists create libraries of small organic molecules for use in a combinatorial approach for modifying lead compounds or as a complement to rational drug design An example of the approach used in combinatorial synthesis is the creation of a library of benzodiazepines These compounds can be thought of as originating from three different sets of building blocks: a substituted 2-aminobenzophenone, an amino acid, and an alkylating agent ▲ Figure 30.1 The antibiotic netropsin (turquoise atoms) bound in the minor groove of DNA BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1224 1224 CHAPTER 30 The Organic Chemistry of Drugs R4 O N NH2 R R − O R R2 X an alkylating agent H3N+ an amino acid R2 a benzodiazepine R4 R O N O a 2-aminobenzophenone The 2-aminobenzophenone is attached to a solid support in a manner that allows it to be readily removed by acid hydrolysis (Figure 30.2) The amino acid—N-protected and activated by being converted into an acyl fluoride—is then added After the amide is formed, the protecting group is removed and the seven-membered ring is created as a result of imine formation A base is added to remove the amide hydrogen, forming a nucleophile that reacts with the added alkylating agent The final product is then removed from the solid support In order to synthesize a library of these compounds, the solid support containing the 2-aminobenzophenone can be divided into several portions, and a different amino acid can then be added to each portion Each ring-closed product can also be divided into several portions, and a different alkylating agent can be added to each portion In this way, many different benzodiazepines can be prepared Note that while a combinatorial synthesis does not have to have one of the reactants anchored to a solid support, such a support improves yields because none of the product is lost during the purification step R3 O NH2 R1 NH R1 O R3 R2 Pr NH CH N H Pr H N R1 O R3 N O C F piperidine, DMF R2 O R2 5% acetic acid, DMF base R4 X resin R4 R4 O N R1 Tutorial: Combinatorial synthesis O N R3 N R2 ▲ Figure 30.2 Combinatorial organic synthesis of benzodiazepines H+ H2O R1 R3 N R2 BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1225 Section 30.13 Economics of Drugs • Governmental Regulations 30.12 Antiviral Drugs Relatively few clinically useful drugs have been developed for viral infections This slow progress is due to the nature of viruses and the way they replicate Viruses are smaller than bacteria A virus consists of nucleic acid—either DNA or RNA— surrounded by a coat of protein A virus penetrates a host cell or merely injects its nucleic acid into the cell In either case, the nucleic acid is transcribed and is integrated into the host genome Most antiviral drugs are analogs of nucleosides, interfering with DNA or RNA synthesis In this way, they prevent the virus from replicating For example, acyclovir, the drug used against herpes viruses, has a three-dimensional shape similar to guanine Acyclovir can, therefore, fool the virus into incorporating it instead of guanine into the virus’s DNA Once this happens, the DNA strand can no longer grow, because acyclovir lacks a 3¿-OH group The terminated DNA binds to DNA polymerase and inactivates it irreversibly (Section 27.7) Cytarabine, used for acute myelocytic leukemia, competes with cytosine for incorporation into viral DNA Cytarabine contains an arabinose rather than a ribose (Table 22.1) The 2¿-OH group in the b -position prevents the bases in DNA from stacking properly (Section 27.7) Ribarvirin is a broad-spectrum antiviral agent that inhibits viral mRNA synthesis (Section 27.10) A step in the metabolic pathway responsible for the synthesis of guanosine triphosphate (GTP) converts inosine monophosphate (IMP) into xanthosine monophosphate (XMP) Ribarvirin is a competitive inhibitor of the enzyme that catalyzes that step Thus, ribarvirin interferes with the synthesis of GTP and, therefore, with all nucleic acid synthesis Idoxuridine is approved in the United States only for the topical treatment of ocular infections, although it is used for herpes infections in other countries Idoxuridine has an iodo group in place of the methyl group of thymine The drug is incorporated into DNA in place of thymine Chain elongation can continue because idoxuridine has a 3¿-OH group The DNA that has incorporated idoxuridine, however, is more easily broken and is also not transcribed properly O NH2 N H2N N N HOCH2CH2OCH2 acyclovir Aclovir used against herpes simplex infections O HO O NH2 N N O HN C N O HO OH cytarabine Cytosar used against acute myelocytic leukemia N I HN N O O HO N O HO HO OH ribavirin Viramid a broad-spectrum antiviral agent OH idoxuridine Herplex approved for topical ophthalmic use 30.13 Economics of Drugs • Governmental Regulations The average cost of launching a new drug is $100–$500 million This cost has to be amortized quickly by the manufacturer because the starting date of a patent is the date the drug is first discovered A patent is good for 20 years from the date it is applied for, but because it takes an average of 12 years to market a drug after its initial discovery, the patent protects the discoverer of the drug for an average of only years It is only during the years of patent protection that marketing the drug can provide enough profit so that costs can be recovered and income can be generated to carry out research 1225 BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1226 1226 CHAPTER 30 The Organic Chemistry of Drugs on new drugs In addition, the average lifetime of a drug is only 15 to 20 years After that time, it is generally replaced by a newer and improved drug Only about in drugs actually makes a profit for the company Why does it cost so much to develop a new drug? First of all, the Food and Drug Administration (FDA) has very high standards that must be met before it approves a drug for a particular use Before the U.S government became involved with the regulation of drugs, it was not uncommon for charlatans to dispense useless and even harmful medical preparations Starting in 1906, Congress passed laws governing the manufacture, distribution, and use of drugs These laws are amended from time to time to reflect changing situations The present law requires that all new drugs be thoroughly tested for effectiveness and safety before they are used by physicians An important factor leading to the high price of many drugs is the low success rate in progressing from the initial concept to an approved product: Only or of every 100 compounds tested become lead compounds; out of a 100 structural modifications of a lead compound, only is worthy of further study; and only 10% of these compounds actually become marketable drugs ORPHAN DRUGS Because of the high cost associated with developing a drug, pharmaceutical companies are reluctant to carry out research on drugs for rare diseases Even if a company were to find a drug, there would be no way to recoup its expenditure, because of the limited demand In 1983, the U.S Congress passed the Orphan Drugs Act The act creates public subsidies to fund research and provides tax credits for up to 50% of the costs of developing and marketing drugs—called orphan drugs—for diseases or conditions that affect fewer than 200,000 people In addition, the company that develops the drug has four years of exclusive marketing rights if the drug is nonpatentable In the 10 years prior to the passage of this act, fewer than 10 orphan drugs were developed Today, there are more than 100, and some 600 others are in development Drugs originally developed as orphan drugs include AZT (to treat AIDS), Taxol® (to treat ovarian cancer), Exosurf Neonatal® (to treat respiratory distress syndrome in infants), and Opticrom® (to treat corneal swelling) Summary A drug is a compound that interacts with a biological molecule, triggering a physiological response Each drug has a proprietary name that can be used only by the owner of the patent, which is valid for 20 years Once a patent expires, other drug companies can market the drug under a generic name that can be used by any pharmaceutical company Drugs that no one wants to develop because they would be used for diseases or conditions that affect fewer than 200,000 people are called orphan drugs The Food and Drug Administration (FDA) has very high standards that must be met before it approves a drug for a particular use The average cost of launching a new drug is about $230 million The prototype for a new drug is called a lead compound Changing the structure of a lead compound is called molecular modification A random screen (or blind screen) is a search for a pharmacologically active lead compound without having any information about what structures might show activity The technique of relating a property of a series of compounds to biological activity is known as a quantitative structure–activity relationship (QSAR) Many drugs exert their physiological effects by binding to a specific cellular binding site called a receptor Some drugs act by inhibiting enzymes or by binding to nucleic acids Most antiviral drugs are analogs of nucleosides, interfering with DNA or RNA synthesis and thereby preventing the virus from replicating A bacteriostatic drug inhibits the further growth of bacteria; a bactericidal drug kills the bacteria In recent years, many bacteria have become resistant to all antibiotics, so drug resistance has become an increasingly important problem in medicinal chemistry The therapeutic index of a drug is the ratio of the lethal dose to the therapeutic dose The higher the therapeutic index, the greater is the margin of safety of the drug The effect of two drugs used in combination is called drug synergism Large collections of compounds that can be screened for biological activity are prepared by combinatorial organic synthesis—the synthesis of a group of related compounds by covalently connecting sets of building blocks BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1227 AU: Add terms to list? or change to lightface in text? Problems 1227 Key Terms antiviral drug (p 1225) bactericidal drug (p 1212) bacteriostatic drug (p 1212) biological activity (p 1221) blind screen (p 1211) brand name (p 1207) combinatorial organic synthesis (p 1223) distribution coefficient (p 1222) drug (p 1204) drug resistance (p 1220) drug synergism (p 1219) generic name (p 1208) lead compound (p 1208) molecular modeling (p 1223) molecular modification (p 1208) orphan drug (p 1226) proprietary name (p 1207) quantitative structure–activity relationship (QSAR) (p 1222) random screen (p 1211) rational drug design (p 1221) receptor (p 1214) suicide inhibitor (p 1218) therapeutic index (p 1220) trademark (p 1207) trade name (p 1207) Problems What is the chemical name of each of the following drugs? a benzocaine b procaine Based on the lead compound for the development of procaine and lidocaine, propose structures for other compounds that you would like to see tested for use as anesthetics Which of the following compounds is more likely to exhibit activity as a tranquilizer? CH3 CH3 O N N N CH3O or CH3C O N O Which compound is more likely to be a general anesthetic? CH3CH2CH2OH or CH3OCH2CH3 What accounts for the ease of imine formation between penicillinase and the sulfone antibiotic that counteracts penicillin resistance? For each of the following pairs of compounds, indicate the compound that you would expect to be a more potent inhibitor of dihydrofolate reductase: a NH NH N H2N CH2CHCH3 NO2 N or N H2N Cl N CH3 b CH3 NH2 H2N NH2 CH2CH3 N CH2CHCH3 CH3 CH3 N or N CH2CHCH3 H2N N CH2CHCH2CH3 CH3 The lethal dose of tetrahydrocannabinol in mice is 2.0 g>kg, and the therapeutic dose is 20 mg>kg The lethal dose of sodium pentothal in mice is 100 mg>kg, and the therapeutic dose is 30 mg>kg Which is the safer drug? BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1228 1228 CHAPTER 30 The Organic Chemistry of Drugs The following compound is a suicide inhibitor of the enzyme that catalyzes amino acid racemization: O CCHCO− HC NH2 Propose a mechanism that explains how this compound irreversibly inactivates the enzyme Explain how each of the antiviral drugs shown in Section 30.12 differs from the naturally occurring nucleoside that it most closely resembles 10 Show a mechanism for the formation of a benzodiazepine 4-oxide from the reaction of a quinazoline 3-oxide with methylamine 11 Show how Valium® could be synthesized from benzoyl chloride, para-chloroaniline, methyl iodide, and the ethyl ester of glycine CH3 O C Cl NH2 + O + Cl O N C H2NCH2 OCH2CH3 Cl + CH3I N Valium 12 Show how Tagamet ® could be synthesized from the indicated starting materials C N N C CH2OH N N H + CH3 HSCH2CH2NH2 N + CH2CH2SCH2CH2NH N C CH3S C N SCH3 + CH3NH2 N H CH3 NHCH3 ... CCH2CH2CH2Cl CH2CH2CCl c AlCl3 H2O H2O O O b CCH2CH2Cl CH2CH2CH2CCl d AlCl3 32 Which compound in each of the following pairs is a stronger base? Why? NH2 NH b CH3CHCH3 or CH3CNH2 or N AlCl3 H2O... catalytic hydrogenation (H 2/ Pd) O O + CH3CH2CH2CCl AlCl3 H2O CCH2CH2CH3 acyl-substituted benzene H2 Pd CH2CH2CH2CH3 alkyl-substituted benzene 615 BRUI15-593_ 621 r3 27 -03 -20 03 2: 51 PM Page 616 616... rearranged alkyl substituent CH3 + CH2CH2CH2CH3 AlCl3 °C CH3CH2CH2CH2Cl 1-chlorobutane CHCH2CH3 + 1-phenylbutane 35% + 2- phenylbutane 65% 1 ,2- hydride shift CH3CH2CHCH2 CH3CH2CHCH3 + H a primary carbocation