Stability of Conjugated Dienes: Molecular Orbital Theory Conjugated dienes can be prepared by some of the methods previously discussed for preparing alkenes ( – ). The base-induced elimination of HX from an allylic halide is one such reaction. Simple conjugated dienes used in polymer synthesis include 1,3-butadiene, chloroprene (2-chloro-1,3-butadiene), and isoprene (2-methyl-1,3-butadiene). Isoprene has been prepared industrially by several methods, including the acid-catalyzed double dehydration of 3-methyl-1,3-butanediol. One of the properties that distinguishes conjugated from nonconjugated dienes is that the central single bond is shorter than might be expected. The C2–C3 single bond in 1,3-butadiene, for instance, has a length of 147 pm, some 6 pm shorter than the C2–C3 bond in butane (153 pm). Another distinctive property of conjugated dienes is their unusual stability, as evidenced by their heats of hydrogenation ( ). We saw in that monosubstituted alkenes, such as 1-butene, have Δ H ∘ hydrog near –126 kJ/mol (–30.1 kcal/mol), whereas disubstituted alkenes, such as 2-methylpropene, have Δ H ∘ hydrog near –119 kJ/mol (–28.4 kcal/mol), which is approximately 7 kJ/mol less negative. We concluded from these data that more highly substituted alkenes are more stable than less substituted ones. That is, more highly substituted alkenes release less heat on hydrogenation because they contain less energy to start with. A similar conclusion can be drawn for conjugated dienes. Heats of Hydrogenation for Some Alkenes and Dienes Alkene or diene Product ∆ H ° hydrog (kJ/mol) (kcal/mol) –126 –30.1 –119 –28.4 –253 –60.5 –236 –56.4 –229 –54.7 Because a monosubstituted alkene has a Δ H ∘ hydrog of approximately –126 kJ/mol, we might expect that a compound with two monosubstituted double bonds would have a Δ H ∘ hydrog approximately twice that value, or –252 kJ/mol. Nonconjugated dienes, such as 1,4-pentadiene ( Δ H ∘ hydrog = − 253 kJ/mol ), meet this expectation, but the conjugated diene 1,3-butadiene ( Δ H ∘ hydrog = − 236 kJ/mol ) does not. 1,3-Butadiene is approximately 16 kJ/mol (3.8 kcal/mol) more stable than expected. What accounts for the stability of conjugated dienes? According to valence bond theory ( and ), their stability is due to orbital hybridization. Typical C–C single bonds, like those in alkanes, result from σ overlap of sp 3 orbitals on both carbons, but in a conjugated diene, the central C–C single bond results from σ overlap of sp 2 orbitals on both carbons. Because sp 2 orbitals have more s character (33% s ) than sp 3 orbitals (25% s ), the electrons in sp 2 orbitals are closer to the nucleus and the bonds they form are somewhat shorter and stronger. Thus, the “extra” stability of a conjugated diene results in part from the greater amount of s character in the orbitals forming the C–C single bond. According to molecular orbital theory ( ), the stability of conjugated dienes arises because of an interaction between the π orbitals of the two double bonds. To review briefly, when two p atomic orbitals combine to form a π bond, two π molecular orbitals (MOs) result. One is lower in energy than the starting p orbitals and is therefore bonding; the other is higher in energy, has a node between nuclei, and is antibonding. The two π electrons occupy the low-energy, bonding orbital, resulting in formation of a stable bond between atoms ( ). Two p orbitals combine to form two π molecular orbitals. Both electrons occupy the low-energy, bonding orbital, leading to a net lowering of energy and formation of a stable bond. The asterisk on ψ 2 * indicates an antibonding orbital. Now let’s combine four adjacent p atomic orbitals, as occurs in a conjugated diene. In so doing, we generate a set of four π molecular orbitals, two of which are bonding and two of which are antibonding ( ). The four π electrons occupy the two bonding orbitals, leaving the antibonding orbitals vacant. Four π molecular orbitals in 1,3-butadiene. Note that the number of nodes between nuclei increases as the energy level of the orbital increases. The lowest-energy π molecular orbital (denoted ψ 1 , Greek psi) has no nodes between the nuclei and is therefore bonding. The π MO of next-lowest energy, ψ 2 , has one node between nuclei and is also bonding. Above ψ 1 and ψ 2 in energy are the two antibonding π MOs, ψ 3 * and ψ 4 * . (The asterisks indicate antibonding orbitals.) Note that the number of nodes between nuclei increases as the energy level of the orbital increases. The ψ 3 * orbital has two nodes between nuclei, and ψ 4 * , the highest-energy MO, has three nodes between nuclei. Comparing the π molecular orbitals of 1,3-butadiene (two conjugated double bonds) with those of 1,4-pentadiene (two isolated double bonds) shows why the conjugated diene is more stable. In a conjugated diene, the lowest-energy π MO ( ψ 1 ) has a favorable bonding interaction between C2 and C3 that is absent in a nonconjugated diene. As a result, there is a certain amount of double-bond character to the C2–C3 single bond, making that bond both stronger and shorter than a typical single bond. Electrostatic potential maps show clearly the additional electron density in the central single bond ( ). Electrostatic potential maps of 1,3-butadiene (conjugated) and 1,4-pentadiene (nonconjugated). Additional electron density is present in the central C−C bond of 1,3-butadiene, corresponding to partial double-bond character. In describing 1,3-butadiene, we say that the π electrons are spread out, or delocalized, over the entire π framework, rather than localized between two specific nuclei. Delocalization allows the bonding electrons to be closer to more nuclei, thus leading to lower energy and greater stability. Problems

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Electrophilic Additions to Conjugated Dienes: Allylic Carbocations One of the most striking differences between conjugated dienes and typical alkenes is their behavior in electrophilic addition reactions. To review briefly, the addition of an electrophile to a carbon–carbon double bond is a general reaction of alkenes ( ). Markovnikov regiochemistry is observed because the more stable carbocation is formed as an intermediate. Thus, addition of HCl to 2-methylpropene yields 2-chloro-2-methylpropane rather than 1-chloro-2-methylpropane, and addition of 2 equivalents of HCl to the nonconjugated diene 1,4-pentadiene yields 2,4-dichloropentane. Conjugated dienes also undergo electrophilic addition reactions readily, but mixtures of products are invariably obtained. Addition of HBr to 1,3-butadiene, for instance, yields a mixture of two products (not counting cis–trans isomers). 3-Bromo-1-butene is the typical Markovnikov product of 1,2-addition to a double bond, but 1-bromo-2-butene seems unusual. The double bond in this product has moved to a position between carbons 2 and 3, and HBr has added to carbons 1 and 4, a result described as 1,4-addition . Many other electrophiles besides HBr add to conjugated dienes, and mixtures of products are usually formed. For example, Br 2 adds to 1,3-butadiene to give a mixture of 3,4-dibromo-1-butene and 1,4-dibromo-2-butene. How can we account for the formation of 1,4-addition products? The answer is that allylic carbocations are involved as intermediates (recall that the word allylic means “next to a double bond”). When 1,3-butadiene reacts with an electrophile such as H + , two carbocation intermediates are possible—a primary nonallylic carbocation and a secondary allylic cation. Because an allylic cation is stabilized by resonance between two forms ( ), it is more stable and forms faster than a nonallylic carbocation. When the allylic cation reacts with Br – to complete the electrophilic addition, the reaction can occur either at C1 or at C3 because both carbons share the positive charge ( ). Thus, a mixture of 1,2- and 1,4-addition products results. You might recall that a similar product mixture was seen for NBS bromination of alkenes in , a reaction that proceeds through an allylic radical. An electrostatic potential map of the allylic carbocation produced by protonation of 1,3-butadiene shows that the positive charge is shared by carbons 1 and 3. Reaction of Br – with the more positive carbon (C3) predominantly yields the 1,2-addition product. Predicting the Product of an Electrophilic Addition Reaction of a Conjugated Diene Give the structures of the likely products from reaction of 1 equivalent of HCl with 2-methyl-1,3-cyclohexadiene. Show both 1,2 and 1,4 adducts. Strategy Electrophilic addition of HCl to a conjugated diene involves the formation of allylic carbocation intermediate. Thus, the first step is to protonate the two ends of the diene and draw the resonance forms of the two allylic carbocations that result. Then, allow each resonance form to react with Cl – , generating a maximum of four possible products. In the present instance, protonation of the C1–C2 double bond gives a carbocation that can react further to give the 1,2 adduct 3-chloro-3-methylcyclohexene and the 1,4 adduct 3-chloro-1-methylcyclohexene. Protonation of the C3–C4 double bond gives a symmetrical carbocation, whose two resonance forms are equivalent. Thus, the 1,2 adduct and the 1,4 adduct have the same structure: 6-chloro-1-methylcyclohexene. Of the two possible modes of protonation, the first is more likely because it yields a more stable, tertiary allylic cation rather than a less-stable, secondary allylic cation. Solution Problems

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Kinetic versus Thermodynamic Control of Reactions Electrophilic addition to a conjugated diene at or below room temperature normally leads to a mixture of products in which the 1,2 adduct predominates over the 1,4 adduct. When the same reaction is carried out at higher temperatures, however, the product ratio often changes and the 1,4 adduct predominates. For example, addition of HBr to 1,3-butadiene at 0 °C yields a 71 : 29 mixture of 1,2 and 1,4 adducts, but the same reaction carried out at 40 °C yields a 15 : 85 mixture. Furthermore, when the product mixture formed at 0 °C is heated to 40 °C in the presence of HBr, the ratio of adducts slowly changes from 71 : 29 to 15 : 85. Why? To understand the effect of temperature on product distribution, let’s briefly review what we said in about rates and equilibria. Imagine a reaction that can give either or both of two products, B and C . Let’s assume that B forms faster than C (in other words, Δ G ‡ B < Δ G ‡ C ) but that C is more stable than B (in other words, Δ G ∘ C > Δ G ∘ B ). An energy diagram for the two processes might look like that shown in . An energy diagram for two competing reactions in which the less stable product B forms faster than the more stable product C . Let’s first carry out the reaction at a lower temperature so that both processes are irreversible and no equilibrium is reached. Because B forms faster than C , B is the major product. It doesn’t matter that C is more stable than B , because the two are not in equilibrium. The product of an irreversible reaction depends only on relative rates, not on stability. Such reactions are said to be under kinetic control . Now let’s carry out the same reaction at some higher temperature so that both processes are readily reversible and an equilibrium is reached. Because C is more stable than B , C is the major product obtained. It doesn’t matter that C forms more slowly than B , because the two are in equilibrium. The product of a readily reversible reaction depends only on stability, not on relative rates. Such reactions are said to be under equilibrium control, or thermodynamic control . We can now explain the effect of temperature on the electrophilic addition reactions of conjugated dienes. At low temperature (0 °C), HBr adds to 1,3-butadiene under kinetic control to give a 71 : 29 mixture of products, with the more rapidly formed 1,2 adduct predominating. Because these low-temperature conditions don’t allow the reaction to reach equilibrium, the product that forms faster predominates. At higher temperature (40 °C), however, the reaction occurs under thermodynamic control to give a 15 : 85 mixture of products, with the more stable 1,4 adduct predominating. The higher temperature allows the addition process to become reversible, so an equilibrium mixture of products results. shows this situation in an energy diagram. Energy diagram for the electrophilic addition of HBr to 1,3-butadiene. The 1,2 adduct is the kinetic product because it forms faster, but the 1,4 adduct is the thermodynamic product because it is more stable. The electrophilic addition of HBr to 1,3-butadiene is a good example of how a change in experimental conditions can change the product of a reaction. The concept of thermodynamic control versus kinetic control is a useful one that we can sometimes take advantage of in the laboratory. Problems

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The Diels–Alder Cycloaddition Reaction Perhaps the most striking difference between conjugated and nonconjugated dienes is that conjugated dienes undergo an addition reaction with alkenes to yield substituted cyclohexene products. For example, 1,3-butadiene and 3-buten-2-one give 3-cyclohexenyl methyl ketone. This process, named the Diels–Alder cycloaddition reaction after its discoverers, is extremely useful in the laboratory because it forms two carbon–carbon bonds in a single step and is one of the few general methods available for making cyclic molecules. (As the name implies, a cycloaddition reaction is one in which two reactants add together to give a cyclic product.) The 1950 Nobel Prize in Chemistry was awarded to Otto Diels and Kurt Alder in recognition of the importance of their discovery. The mechanism of Diels–Alder cycloaddition is different from that of other reactions we’ve studied because it is neither polar nor radical. Rather, the Diels–Alder reaction is a pericyclic process. Pericyclic reactions, which we’ll discuss in more detail in Chapter 30, take place in a single step by a cyclic redistribution of bonding electrons. The two reactants simply join together through a cyclic transition state in which the two new C–C bonds form at the same time. We can picture a Diels–Alder addition as occurring by head-on ( σ ) overlap of the two alkene p orbitals with the two p orbitals on carbons 1 and 4 of the diene ( ). This is, of course, a cyclic orientation of the reactants. Mechanism of the Diels–Alder cycloaddition reaction. The reaction occurs in a single step through a cyclic transition state in which the two new C−C bonds form simultaneously. In the Diels–Alder transition state, the two alkene carbons and carbons 1 and 4 of the diene rehybridize from sp 2 to sp 3 to form two new single bonds, while carbons 2 and 3 of the diene remain sp 2 -hybridized to form the new double bond in the cyclohexene product. We’ll study this mechanism in more detail in Section 30.5 but will concentrate for the present on learning about the characteristics and uses of the Diels–Alder reaction.

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Characteristics of the Diels–Alder Reaction The Dienophile The Diels–Alder cycloaddition reaction occurs most rapidly if the alkene component, called the dienophile (“diene lover”), has an electron-withdrawing substituent group. Thus, ethylene itself reacts sluggishly, but propenal, ethyl propenoate, maleic anhydride, benzoquinone, propenenitrile, and similar compounds are highly reactive. Note also that alkynes, such as methyl propynoate, can act as Diels–Alder dienophiles. In all cases, the double or triple bond of the dienophile is adjacent to the positively polarized carbon of an electron-withdrawing substituent. As a result, the double-bond carbons in these substances are substantially less electron-rich than the carbons in ethylene, as indicated by the electrostatic potential maps in . Electrostatic potential maps of ethylene, propenal, and propenenitrile show that electron-withdrawing groups make the double-bond carbons less electron-rich . One of the most useful features of the Diels–Alder reaction is that it is stereospecific , meaning that a single product stereoisomer is formed. Furthermore, the stereochemistry of the dienophile is retained. If we carry out cycloaddition with methyl cis -2-butenoate, only the cis-substituted cyclohexene product is formed. With methyl trans -2-butenoate, only the trans-substituted cyclohexene product is formed. Another stereochemical feature of the Diels–Alder reaction is that the diene and dienophile partners orient so that the endo product, rather than the alternative exo product, is formed. The words endo and exo are used to indicate relative stereochemistry when referring to bicyclic structures like substituted norbornanes ( ). A substituent on one bridge is said to be endo if it is syn (cis) to the larger of the other two bridges and is said to be exo if it is anti (trans) to the larger of the other two. Endo products result from Diels–Alder reactions because the amount of orbital overlap between diene and dienophile is greater when the reactants lie directly on top of one another, so that the electron-withdrawing substituent on the dienophile is underneath the diene double bonds. In the reaction of 1,3-cyclopentadiene with maleic anhydride, for instance, the following result is obtained: Predicting the Product of a Diels–Alder Reaction Predict the product of the following Diels–Alder reaction: Strategy Draw the diene so that the ends of its two double bonds are near the dienophile double bond. Then form two single bonds between the partners, convert the three double bonds into single bonds, and convert the former single bond of the diene into a double bond. Because the dienophile double bond is cis to begin with, the two attached hydrogens must remain cis in the product. Solution Problems The Diene Just as the dienophile component has certain constraints that affect its reactivity, so too does the conjugated diene component. The diene must adopt what is called an s -cis conformation , meaning “cis-like” about the s ingle bond, to undergo a Diels–Alder reaction. Only in the s -cis conformation are carbons 1 and 4 of the diene close enough to react through a cyclic transition state. In the alternative s -trans conformation, the ends of the diene partner are too far apart to overlap with the dienophile p orbitals. Two examples of dienes that can’t adopt an s -cis conformation, and thus don’t undergo Diels–Alder reactions, are shown in . In the bicyclic diene, the double bonds are rigidly fixed in an s -trans arrangement by geometric constraints of the rings. In (2 Z ,4 Z )-2,4-hexadiene, steric strain between the two methyl groups prevents the molecule from adopting s -cis geometry. Two dienes that can’t achieve an s -cis conformation and thus can’t undergo Diels–Alder reactions. In contrast to these unreactive dienes that can’t achieve an s -cis conformation, other dienes are fixed only in the correct s -cis geometry and are therefore highly reactive in Diels–Alder cycloaddition. 1,3-Cyclopentadiene, for example, is so reactive that it reacts with itself. At room temperature, 1,3-cyclopentadiene dimerizes. One molecule acts as diene and a second molecule acts as dienophile in a self-Diels–Alder reaction. Biological Diels–Alder reactions are also known but are uncommon. One example occurs in the biosynthesis of the cholesterol-lowering drug lovastatin (trade name Mevacor) isolated from the fungus Aspergillus terreus. The key step is the intramolecular Diels–Alder reaction of a triene, in which the diene and dienophile components are within the same molecule. Problems

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Diene Polymers: Natural and Synthetic Rubbers Conjugated dienes can be polymerized just as simple alkenes can ( ). Diene polymers are structurally more complex than simple alkene polymers, however, because double bonds occur every four carbon atoms along the chain, leading to the possibility of cis–trans isomers. The initiator (In) for the reaction can be either a radical, as occurs in ethylene polymerization, or an acid. Note that the polymerization is a 1,4 addition of the growing chain to a conjugated diene monomer. Rubber is a naturally occurring diene polymer of isoprene (2-methyl-1,3-butadiene) and is produced by more than 400 different plants. The major source is the so-called rubber tree, Hevea brasiliensis, from which the crude material, called latex, is harvested as it drips from a slice made through the bark. The double bonds of rubber have Z stereochemistry, but gutta-percha, the E isomer of rubber, also occurs naturally. Harder and more brittle than rubber, gutta-percha has a variety of applications, including use in dental endodontics and as the covering on some golf balls. A number of different synthetic rubbers are produced commercially by diene polymerization. Both cis - and trans -polyisoprene can be made, and the synthetic rubber thus produced is similar to the natural material. Chloroprene (2-chloro-1,3-butadiene) is polymerized to yield neoprene, an excellent, although expensive, synthetic rubber with good weather resistance. Neoprene is used in the production of industrial hoses and gloves, among other things. Both natural and synthetic rubbers are too soft and tacky to be useful until they are hardened by heating with elemental sulfur, a process called vulcanization. Vulcanization cross-links the rubber chains by forming carbon–sulfur bonds between them, thereby hardening and stiffening the polymer. The exact degree of hardening can be varied, yielding material soft enough for automobile tires or hard enough for bowling balls (ebonite). The unusual ability of rubber to stretch and then contract to its original shape is due to the irregular structure of the polymer chains caused by the double bonds. These double bonds introduce bends and kinks into the polymer chains, thereby preventing neighboring chains from nestling together. When stretched, the randomly coiled chains straighten out and orient along the direction of the pull but are kept from sliding over one another by the cross-links. When the tension is released, the polymer reverts to its original random state. Problems

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Ultraviolet Spectroscopy As we’ve seen, mass spectrometry, infrared spectroscopy, and nuclear magnetic resonance spectroscopy are techniques of structure determination applicable to all organic molecules. In addition to these three generally useful methods, there is a fourth— ultraviolet (UV) spectroscopy —that is applicable only to conjugated compounds. UV is less commonly used than the other three spectroscopic techniques because of the specialized information it gives, so we’ll only discuss it briefly. Technique Examines Mass spectrometry Molecular size and formula IR spectroscopy Functional groups present NMR spectroscopy Carbon–hydrogen framework UV spectroscopy Conjugated π electron systems The ultraviolet region of the electromagnetic spectrum extends from the short-wavelength end of the visible region (4 × 10 –7 m) to the long-wavelength end of the X-ray region (10 –8 m), but the narrow range from 2 × 10 –7 m to 4 × 10 –7 m is the part of greatest interest to organic chemists. Absorptions in this region are usually measured in nanometers (nm), where 1 nm = 10 –9 m. Thus, the ultraviolet range of interest is from 200 to 400 nm ( ). The ultraviolet (UV) and neighboring regions of the electromagnetic spectrum. We saw in that when an organic molecule is irradiated with electromagnetic energy, the radiation either passes through the sample or is absorbed, depending on its energy. With IR irradiation, the energy absorbed corresponds to the amount needed to increase molecular vibrations. With UV radiation, the energy absorbed corresponds to the amount needed to promote an electron from a lower-energy orbital to a higher-energy one in a conjugated molecule. The conjugated diene 1,3-butadiene, for instance, has four π molecular orbitals, as shown previously in . The two lower-energy, bonding MOs are occupied in the ground state, and the two higher-energy, antibonding MOs are unoccupied. On irradiation with ultraviolet light ( hυ ), 1,3-butadiene absorbs energy and a π electron is promoted from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO) . Because the electron is promoted from a bonding π molecular orbital to an antibonding π * molecular orbital, we call this a π → π * excitation (read as “pi to pi star”). The energy gap between the HOMO and the LUMO of 1,3-butadiene is such that UV light of 217 nm wavelength is required to effect the π → π * electronic transition ( ). Ultraviolet excitation of 1,3-butadiene results in the promotion of an electron from ψ 2 , the highest occupied molecular orbital (HOMO), to ψ 3 *, the lowest unoccupied molecular orbital (LUMO). An ultraviolet spectrum is recorded by irradiating a sample with UV light of continuously changing wavelength. When the wavelength corresponds to the energy level required to excite an electron to a higher level, energy is absorbed. This absorption is detected and displayed on a chart that plots wavelength versus absorbance (A), defined as A = log I 0 I where I 0 is the intensity of the incident light and I is the intensity of the light transmitted through the sample. Note that UV spectra differ from IR spectra in how they are presented. For historical reasons, IR spectra are usually displayed so that the baseline corresponding to zero absorption runs across the top of the chart and a valley indicates an absorption, whereas UV spectra are displayed with the baseline at the bottom of the chart so that a peak indicates an absorption ( ). The ultraviolet spectrum of 1,3-butadiene, λ max = 217 nm. The amount of UV light absorbed is expressed as the sample’s molar absorptivity ( ϵ ) , defined by the equation ε = A c × l where A = Absorbance c = Concentration in mol/L l = Sample pathlength in cm Molar absorptivity is a physical constant, characteristic of the particular substance being observed and thus characteristic of the particular π electron system in the molecule. Typical values for conjugated dienes are in the range ε = 10,000 to 25,000. The units for molar absorptivity, L/(mol · cm), are usually dropped. A particularly important use of this equation comes from rearranging it to the form c = A /( ε · l ), which lets us measure the concentration of a sample in solution when A , ε , and l are known. As an example, β -carotene, the pigment responsible for the orange color of carrots, has ε = 138,000 L/(mol · cm). If a sample of β -carotene is placed in a cell with a pathlength of 1.0 cm and the UV absorbance reads 0.37, then the concentration of β -carotene in the sample is c = A ε l = 0.37 1.38 × 10 5 L mol ⋅ cm ( 1.00 cm ) = 2.7 × 10 − 6 mol/L Unlike IR and NMR spectra, which show many absorptions for a given molecule, UV spectra are usually quite simple—often only a single peak. The peak is usually broad, and we identify its position by noting the wavelength at the top of the peak— λ max , read as “lambda max.” Problems

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Interpreting Ultraviolet Spectra: The Effect of Conjugation The wavelength necessary to effect the π → π * transition in a conjugated molecule depends on the energy gap between HOMO and LUMO, which in turn depends on the nature of the conjugated system. Thus, by measuring the UV spectrum of an unknown, we can derive structural information about the nature of any conjugated π electron system present in a molecule. One of the most important factors affecting the wavelength of UV absorption by a molecule is the extent of conjugation. Molecular orbital calculations show that the energy difference between HOMO and LUMO decreases as the extent of conjugation increases. Thus, 1,3-butadiene absorbs at λ max = 217 nm, 1,3,5-hexatriene absorbs at λ max = 258 nm, and 1,3,5,7-octatetraene absorbs at λ max = 290 nm. (Remember: longer wavelength means lower energy.) Other kinds of conjugated systems, such as conjugated enones and aromatic rings, also have characteristic UV absorptions that are useful in structure determination. The UV absorption maxima of some representative conjugated molecules are given in . Ultraviolet Absorptions of Some Conjugated Molecules Name Structure λ max (nm) 2-Methyl-1,3-butadiene 220 1,3-Cyclohexadiene 256 1,3,5-Hexatriene H 2 C=CH―CH=CH–CH=CH 2 258 1,3,5,7-Octatetraene H 2 C=CH–CH=CH–CH=CH–CH=CH 2 290 3-Buten-2-one 219 Benzene 254 Problems

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Conjugation, Color, and the Chemistry of Vision Why are some organic compounds colored while others are not? β -Carotene, the pigment in carrots, is yellow-orange, for instance, while cholesterol is colorless. The answer involves both the chemical structures of colored molecules and the way we perceive light. The visible region of the electromagnetic spectrum is adjacent to the ultraviolet region, extending from approximately 400 to 800 nm. Colored compounds have such elaborate systems of conjugation that their “UV” absorptions extend into the visible region. β -Carotene, for instance, has 11 double bonds in conjugation, and its absorption occurs at λ max = 455 nm ( ). Ultraviolet spectrum of β -carotene, a conjugated molecule with 11 double bonds. The absorption occurs in the visible region. “White” light from the sun or from a lamp consists of all wavelengths in the visible region. When white light strikes β -carotene, the wavelengths from 400 to 500 nm (blue) are absorbed while all other wavelengths are transmitted and can reach our eyes. We therefore see the white light with the blue removed, which we perceive as a yellow-orange color for β -carotene. Conjugation is crucial not only for the colors we see in organic molecules but also for the light-sensitive molecules on which our visual system is based. The key substance for vision is dietary β -carotene, which is converted to vitamin A by enzymes in the liver, oxidized to an aldehyde called 11- trans -retinal, and then isomerized by a change in geometry of the C11–C12 double bond to produce 11- cis -retinal. There are two main types of light-sensitive receptor cells in the retina of the human eye: rod cells and cone cells. The 3 million or so rod cells are primarily responsible for seeing dim light and shades of gray, whereas the 100 million cone cells are responsible for seeing bright light and colors. In the rod cells of the eye, 11- cis -retinal is converted into rhodopsin, a light-sensitive substance formed from the protein opsin and 11- cis -retinal. When light strikes the rod cells, isomerization of the C11–C12 double bond occurs and trans -rhodopsin, called metarhodopsin II, is produced. In the absence of light, this cis–trans isomerization takes approximately 1100 years, but in the presence of light, it occurs within 2 × 10 –13 seconds! Isomerization of rhodopsin is accompanied by a change in molecular geometry, which in turn causes a nerve impulse to be sent through the optic nerve to the brain, where it is perceived as vision. Metarhodopsin II is then recycled back into rhodopsin by a multistep sequence involving cleavage to all- trans -retinal and cis–trans isomerization back to 11- cis -retinal. Photolithography Fifty years ago, someone interested in owning a computer would have paid approximately $150,000 for 16 megabytes of random-access memory that would have occupied a volume the size of a small desk. Today, anyone can buy 60 times as much computer memory for $10 and fit the small chip into their shirt pocket. The difference between then and now is due to improvements in photolithography, the process by which integrated-circuit chips are made. Photolithography begins by coating a layer of SiO 2 onto a silicon wafer and further coating with a thin (0.5–1.0 μ m) film of a light-sensitive organic polymer called a resist. A mask is then used to cover those parts of the chip that will become a circuit, and the wafer is irradiated with UV light. The nonmasked sections of the polymer undergo a chemical change when irradiated, which makes them more soluble than the masked, unirradiated sections. On washing the irradiated chip with solvent, solubilized polymer is selectively removed from the irradiated areas, exposing the SiO 2 underneath. This SiO 2 is then chemically etched away by reaction with hydrofluoric acid, leaving behind a pattern of polymer-coated SiO 2 . Further washing removes the remaining polymer, leaving a positive image of the mask in the form of exposed ridges of SiO 2 ( ). Additional cycles of coating, masking, and etching then produce the completed chips. Manufacturing the ultrathin circuitry on this computer chip depends on the organic chemical reactions of special polymers. (credit: “Integrated circuit on microchip” by Jon Sullivan/Wikimedia Commons, Public Domain) Outline of the photolithography process for producing integrated circuit chips. The polymer resist currently used in chip manufacturing is based on the two-component diazoquinone–novolac system. Novolac resin is a soft, relatively low-molecular-weight polymer made from methylphenol and formaldehyde, while the diazoquinone is a bicyclic (two-ring) molecule containing a diazo group =N=N) adjacent to a ketone carbonyl (C=O). The diazoquinone–novolac mix is relatively insoluble when fresh, but on exposure to ultraviolet light and water vapor, the diazoquinone component undergoes reaction to yield N 2 and a carboxylic acid, which can be washed away with dilute base. Novolac–diazoquinone technology is capable of producing features as small as 0.5 μ m (5 × 10 –7 m), but further improvements in miniaturization are still being developed. 1,2-addition 1,4-addition conjugated Diels–Alder cycloaddition reaction dienophile endo exo highest occupied molecular orbital (HOMO) kinetic control lowest unoccupied molecular orbital (LUMO) molar absorptivity ( ε ) s -cis conformation stereospecific thermodynamic control ultraviolet (UV) spectroscopy Summary The unsaturated compounds we’ve looked at previously have had only one double bond, but many compounds have numerous sites of unsaturation, which gives them some distinctive properties. Many such compounds are common in nature, including pigments and hormones. A conjugated diene or other compound is one that contains alternating double and single bonds. One characteristic of conjugated dienes is that they are more stable than their nonconjugated counterparts. This stability can be explained by a molecular orbital description in which four p atomic orbitals combine to form four π molecular orbitals. Only the two bonding orbitals are occupied; the two antibonding orbitals are unoccupied. A π bonding interaction in the lowest-energy MO introduces some partial double-bond character between carbons 2 and 3, thereby strengthening the C2–C3 bond and stabilizing the molecule. Conjugated dienes undergo several reactions not observed for nonconjugated dienes. One is the 1,4-addition of electrophiles. When a conjugated diene is treated with an electrophile such as HCl, 1,2- and 1,4-addition products are formed. Both result from the same resonance-stabilized allylic carbocation intermediate and are produced in varying amounts depending on the reaction conditions. The 1,2 adduct is usually formed faster and is said to be the product of kinetic control . The 1,4 adduct is usually more stable and is said to be the product of thermodynamic control . Another reaction unique to conjugated dienes is Diels–Alder cycloaddition . Conjugated dienes react with electron-poor alkenes ( dienophiles ) in a single step through a cyclic transition state to yield a cyclohexene product. The reaction is stereospecific, meaning that only a single product stereoisomer is formed, and can occur only if the diene is able to adopt an s -cis conformation. Ultraviolet (UV) spectroscopy is a method of structure determination applicable specifically to conjugated π -electron systems. When a conjugated molecule is irradiated with ultraviolet light, energy absorption occurs and a π electron is promoted from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO) . For 1,3-butadiene, radiation of λ max = 217 nm is required. The greater the extent of conjugation, the less the energy needed and the longer the wavelength of radiation required. Summary of Reactions Electrophilic addition reactions ( and ) Diels–Alder cycloaddition reaction ( and ) Additional Problems Visualizing Chemistry Mechanism Problems Conjugated Dienes Diels–Alder Reactions Diene Polymers UV Spectroscopy General Problems

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Why This Chapter? A fennel plant is an aromatic herb used in cooking. A phenyl group—pronounced exactly the same way—is the characteristic structural unit of “aromatic” organic compounds. (credit: modification of work “Fennel” by Ruth Hartnup/Flickr, CC BY 2.0) The reactivity of substituted aromatic compounds, more than that of any other class of substances, is intimately tied to their exact structure. As a result, aromatic compounds provide an extraordinarily sensitive probe for studying the relationship between structure and reactivity. We’ll examine this relationship here and in the following chapter, and we’ll find that the lessons learned are applicable to all other organic compounds, including important substances such as the nucleic acids that control our genetic makeup. In the early days of organic chemistry, the word aromatic was used to describe such fragrant substances as benzaldehyde (from cherries, peaches, and almonds), toluene (from Tolu balsam), and benzene (from coal distillate). It was soon realized, however, that substances grouped as aromatic differed from most other organic compounds in their chemical behavior. Today, the association of aromaticity with fragrance has long been lost, and we now use the word aromatic to refer to the class of compounds that contain six-membered rings with three alternating double bonds. Many naturally occurring compounds are aromatic in part, including steroids such as estrone and well-known pharmaceuticals such as the cholesterol-lowering drug atorvastatin, marketed as Lipitor. Benzene itself causes a depressed white blood cell count (leukopenia) on prolonged exposure and should not be used as a laboratory solvent.

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Naming Aromatic Compounds Simple aromatic hydrocarbons come from two main sources: coal and petroleum. Coal is an enormously complex mixture consisting primarily of large arrays of benzene-like rings joined together. Thermal breakdown of coal occurs when heated to 1000 °C in the absence of air, and a mixture of volatile products called coal tar boils off. Fractional distillation of coal tar yields benzene, toluene, xylene (dimethylbenzene), naphthalene, and a host of other aromatic compounds ( ). Some aromatic hydrocarbons found in coal tar. Unlike coal, petroleum contains few aromatic compounds and consists largely of alkanes (see Chapter 3 Chemistry Matters ). During petroleum refining, however, aromatic molecules are formed when alkanes are passed over a catalyst at about 500 °C under high pressure. Aromatic substances, more than any other class of organic compounds, have acquired a large number of nonsystematic names. IUPAC rules discourage the use of most such names but do allow some of the more widely used ones to be retained ( ). Thus, methylbenzene is known commonly as toluene; hydroxybenzene as phenol; aminobenzene as aniline; and so on. Common Names of Some Aromatic Compounds Structure Name Toluene (bp 111 °C) Phenol (mp 43 °C) Aniline (bp 184 °C) Acetophenone (mp 21 °C) Benzaldehyde (bp 178 °C) Benzoic acid (mp 122 °C) ortho -Xylene (bp 144 °C) Styrene (bp 145 °C) Monosubstituted benzenes are named systematically in the same manner as other hydrocarbons, with - benzene as the parent name. Thus, C 6 H 5 Br is bromobenzene, C 6 H 5 NO 2 is nitrobenzene, and C 6 H 5 CH 2 CH 2 CH 3 is propylbenzene. Alkyl-substituted benzenes are sometimes referred to as arenes and are named in different ways depending on the size of the alkyl group. If the alkyl substituent is smaller than the ring (six or fewer carbons), the arene is referred to as an alkyl-substituted benzene. If the alkyl substituent is larger than the ring (seven or more carbons), the compound is referred to as a phenyl-substituted alkane. The name phenyl , pronounced fen -nil and sometimes abbreviated as Ph or Ф (Greek phi ), is used for the –C 6 H 5 unit when the benzene ring is considered a substituent. The word is derived from the Greek pheno (“I bear light”), commemorating the discovery of benzene by Michael Faraday in 1825 from the oily residue left by the illuminating gas used in London street lamps. In addition, the name benzyl is used for the C 6 H 5 CH 2 – group. Disubstituted benzenes are named using the prefixes ortho ( o ) , meta ( m ) , or para ( p ) . An ortho-disubstituted benzene has its two substituents in a 1,2 relationship on the ring, a meta-disubstituted benzene has its two substituents in a 1,3 relationship, and a para-disubstituted benzene has its substituents in a 1,4 relationship. The ortho, meta, para system of nomenclature is also useful when discussing reactions. For example, we might describe the reaction of bromine with toluene by saying, “Reaction occurs at the para position,” meaning at the position para to the methyl group already present on the ring. As with cycloalkanes ( ), benzenes with more than two substituents are named by choosing a point of attachment as carbon 1 and numbering the substituents on the ring so that the second substituent has as low a number as possible. If ambiguity still exists, number so that the third or fourth substituent has as low a number as possible, until a point of difference is found. The substituents are listed alphabetically when writing the name. Note in the second and third examples shown that - phenol and - toluene are used as the parent names rather than - benzene . Any of the monosubstituted aromatic compounds shown in can serve as a parent name, with the principal substituent (–OH in phenol or –CH 3 in toluene) attached to C1 on the ring. Problems

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Structure and Stability of Benzene Benzene (C 6 H 6 ) has six fewer hydrogens than the six-carbon cycloalkane cyclohexane (C 6 H 12 ) and is clearly unsaturated, usually being represented as a six-membered ring with alternating double and single bonds. Yet it has been known since the mid-1800s that benzene is much less reactive than typical alkenes and fails to undergo typical alkene addition reactions. Cyclohexene, for instance, reacts rapidly with Br 2 and gives the addition product 1,2-dibromocyclohexane, but benzene reacts slowly with Br 2 and gives the substitution product C 6 H 5 Br rather than the addition product. We can get a quantitative idea of benzene’s stability by measuring heats of hydrogenation ( ). Cyclohexene, an isolated alkene, has Δ H ° hydrog = –118 kJ/mol (–28.2 kcal/mol), and 1,3-cyclohexadiene, a conjugated diene, has Δ H ° hydrog = –230 kJ/mol (–55.0 kcal/mol). As noted in , this value for 1,3-cyclohexadiene is a bit less than twice that for cyclohexene because conjugated dienes are more stable than isolated dienes. Carrying the process one step further, we might expect Δ H ° hydrog for “cyclohexatriene” (benzene) to be a bit less than 3 × 118 = 354 kJ/mol, or three times the cyclohexene value. The actual value, however, is –206 kJ/mol, some 148 kJ/mol (35.4 kcal/mol) less than expected. Because of this difference in actual and expected energy released during hydrogenation, benzene must have 148 kJ/mol less energy to begin with. In other words, benzene is more stable than expected by 148 kJ/mol ( ). A comparison of the heats of hydrogenation for cyclohexene, 1,3-cyclohexadiene, and benzene. Benzene is 148 kJ/mol (35.4 kcal/mol) more stable than might be expected for “cyclohexatriene.” Further evidence for the unusual nature of benzene is that all its carbon–carbon bonds have the same length—139 pm, which is intermediate between typical single (154 pm) and double (134 pm) bonds. In addition, an electrostatic potential map shows that the electron density in all six C–C bonds is identical. Thus, benzene is a planar molecule with the shape of a regular hexagon. All C–C–C bond angles are 120°, all six carbon atoms are sp 2 -hybridized, and each carbon has a p orbital perpendicular to the plane of the six-membered ring. Because all six carbon atoms and all six p orbitals in benzene are equivalent, it’s impossible to define three localized π bonds in which a given p orbital overlaps only one neighboring p orbital. Rather, each p orbital overlaps equally well with both neighboring p orbitals, leading to a picture of benzene in which all six π electrons are free to move about the entire ring ( b). In resonance terms ( and ), benzene is a hybrid of two equivalent forms. Neither form is correct by itself; the true structure of benzene is somewhere in between the two resonance forms but is impossible to draw with our usual conventions. Because of this resonance, benzene is more stable and less reactive than a typical alkene. (a) An electrostatic potential map of benzene and (b) an orbital picture. Each of the six carbon atoms has a p orbital that can overlap equally well with neighboring p orbitals on both sides. As a result, all C–C bonds are equivalent and benzene must be represented as a hybrid of two resonance forms. Chemists sometimes represent the two benzene resonance forms by using a circle to indicate the equivalence of the carbon–carbon bonds, but this representation has to be used carefully because it doesn’t indicate the number of π electrons in the ring. (How many electrons does a circle represent?) In this book, benzene and other aromatic compounds will be represented by single line-bond structures. We’ll be able to keep count of π electrons this way but must be aware of the limitations of the drawings. Having just seen a resonance description of benzene, let’s now look at the alternative molecular orbital description. We can construct π molecular orbitals for benzene just as we did for 1,3-butadiene in . If six p atomic orbitals combine in a cyclic manner, six benzene molecular orbitals result, as shown in . The three low-energy molecular orbitals, denoted ψ 1 , ψ 2 , and ψ 3 , are bonding combinations, and the three high-energy orbitals are antibonding. The six benzene π molecular orbitals. The bonding orbitals ψ 2 and ψ 3 have the same energy and are said to be degenerate, as are the antibonding orbitals ψ 4 * and ψ 5 *. The orbitals ψ 3 and ψ 4 * have no π electron density on two carbons because of a node passing through these atoms. Note that the two bonding orbitals ψ 2 and ψ 3 have the same energy, as do the two antibonding orbitals ψ 4 * and ψ 5 * . Such orbitals with the same energy are said to be degenerate . Note also that the two orbitals ψ 3 and ψ 4 * have nodes passing through ring carbon atoms, thereby leaving no π electron density on these carbons. The six p electrons of benzene occupy the three bonding molecular orbitals and are delocalized over the entire conjugated system, leading to the observed 150 kJ/mol stabilization of benzene. Problems

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Aromaticity and the Hückel 4 n + 2 Rule Let’s list what we’ve said thus far about benzene and, by extension, about other benzene-like aromatic molecules. Benzene is cyclic and conjugated. Benzene is unusually stable, having a heat of hydrogenation 150 kJ/mol less negative than we might expect for a conjugated cyclic triene. Benzene is planar and has the shape of a regular hexagon. All bond angles are 120°, all carbon atoms are sp 2 -hybridized, and all carbon–carbon bond lengths are 139 pm. Benzene undergoes substitution reactions that retain the cyclic conjugation rather than electrophilic addition reactions that would destroy it. Benzene can be described as a resonance hybrid whose structure is intermediate between two line-bond structures. This list might seem to be a good description of benzene and other aromatic molecules, but it isn’t enough. Something else, called the Hückel 4 n + 2 rule , is needed to complete a description of aromaticity. According to a theory devised in 1931 by the German physicist Erich Hückel, a molecule is aromatic only if it has a planar, monocyclic system of conjugation and contains a total of 4 n + 2 π electrons, where n is an integer ( n = 0, 1, 2, 3,). In other words, only molecules with 2, 6, 10, 14, 18, π electrons can be aromatic. Molecules with 4 n π electrons (4, 8, 12, 16,) can’t be aromatic, even though they may be cyclic, planar, and apparently conjugated. In fact, planar, conjugated molecules with 4 n π electrons are said to be antiaromatic because delocalization of their π electrons would lead to their destabilization. Let’s look at several examples to see how the Hückel 4 n + 2 rule works. Cyclobutadiene has four π electrons and is antiaromatic. As indicated by the electrostatic potential map, the π electrons are localized in two double bonds rather than delocalized around the ring. Cyclobutadiene is highly reactive and shows none of the properties associated with aromaticity. In fact, it was not even prepared until 1965, when Rowland Pettit at the University of Texas was able to make it at low temperature. Even at –78 °C, however, cyclobutadiene is so reactive that it dimerizes by a Diels–Alder reaction. One molecule behaves as a diene and the other as a dienophile. Benzene has six π electrons (4 n + 2 = 6 when n = 1) and is aromatic. Cyclooctatetraene has eight π electrons, but when it was first prepared in 1911 by the German chemist Richard Willstätter, it was found not to be particularly stable. In fact, its π electrons are localized into four double bonds rather than delocalized around the ring, and the molecule is tub-shaped rather than planar. It has no cyclic conjugation because neighboring p orbitals don’t have the necessary parallel alignment for overlap, and it resembles an open-chain polyene in its reactivity. X-ray studies show that the C–C single bonds in cyclooctatetraene are 147 pm long and the double bonds are 134 pm long. In addition, the 1 H NMR spectrum shows a single sharp resonance line at 5.78 δ, a value characteristic of an alkene rather than an aromatic molecule. What’s so special about 4 n + 2 π electrons? Why do 2, 6, 10, 14 π electrons lead to aromatic stability, while other numbers of electrons do not? The answer comes from molecular orbital theory. When the energy levels of molecular orbitals for cyclic conjugated molecules are calculated, it turns out that there is always a single lowest-lying MO, above which the MOs come in degenerate pairs. Thus, when electrons fill the various molecular orbitals, it takes two electrons, or one pair, to fill the lowest-lying orbital and four electrons, or two pairs, to fill each of n succeeding energy levels—a total of 4 n + 2. Any other number would leave an energy level partially filled. The six π molecular orbitals of benzene were shown previously in , and their relative energies are shown again in . The lowest-energy MO, ψ 1 , occurs singly and contains two electrons. The next two lowest-energy orbitals, ψ 2 and ψ 3 , are degenerate, and it therefore takes four electrons to fill both. The result is a stable six- π -electron aromatic molecule with filled bonding orbitals. Energy levels of the six benzene π molecular orbitals. There is a single, lowest-energy orbital, above which the orbitals come in degenerate pairs. Problems

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Aromatic Ions According to the Hückel criteria for aromaticity, a molecule must be cyclic, conjugated (nearly planar with a p orbital on each atom), and have 4 n + 2 π electrons. Nothing in this definition says that the number of π electrons must be the same as the number of atoms in the ring or that the substance must be neutral. In fact, the numbers can differ and the substance can be an ion. Thus, both the cyclopentadienyl anion and the cycloheptatrienyl cation are aromatic even though both are ions and neither contains a six-membered ring. To understand why the cyclopentadienyl anion and the cycloheptatrienyl cation are aromatic, imagine starting from the related neutral hydrocarbons, 1,3-cyclopentadiene and 1,3,5-cycloheptatriene, and removing one hydrogen from the saturated CH 2 carbon in each. If that carbon then rehybridizes from sp 3 to sp 2 , the resultant products would be fully conjugated, with a p orbital on every carbon. There are three ways in which the hydrogen might be removed. The hydrogen can be removed with both electrons (H : – ) from the C–H bond, leaving a carbocation as product. The hydrogen can be removed with one electron (H · ) from the C–H bond, leaving a carbon radical as product. The hydrogen can be removed with no electrons (H + ) from the C–H bond, leaving a carbanion as product. All the potential products formed by removing a hydrogen from 1,3-cyclopentadiene and from 1,3,5-cycloheptatriene can be drawn with numerous resonance structures, but Hückel’s rule predicts that only the six- π -electron cyclopentadienyl anion and cycloheptatrienyl cation can be aromatic. The other products are predicted by the 4 n + 2 rule to be unstable and antiaromatic ( ). The aromatic six- π -electron cyclopentadienyl anion and the six- π -electron cycloheptatrienyl cation. The anion can be formed by removing a hydrogen ion (H + ) from the CH 2 group of 1,3-cyclopentadiene. The cation can be generated by removing a hydride ion (H : – ) from the CH 2 group of 1,3,5-cycloheptatriene. In practice, both the four- π -electron cyclopentadienyl cation and the five- π -electron cyclopentadienyl radical are highly reactive and difficult to prepare. Neither shows any sign of the stability expected for an aromatic system. The six- π -electron cyclopentadienyl anion, by contrast, is easily prepared and remarkably stable ( a). In fact, the anion is so stable and easily formed that 1,3-cyclopentadiene is one of the most acidic hydrocarbons known, with p K a = 16, a value comparable to that of water! In the same way, the seven- π -electron cycloheptatrienyl radical and eight- π -electron anion are reactive and difficult to prepare, while the six- π -electron cycloheptatrienyl cation is extraordinarily stable ( b). In fact, the cycloheptatrienyl cation was first prepared more than a century ago by reaction of 1,3,5-cycloheptatriene with Br 2 , although its structure was not recognized at the time. (a) The aromatic cyclopentadienyl anion, showing cyclic conjugation and six π electrons in five p orbitals, and (b) the aromatic cycloheptatrienyl cation, showing cyclic conjugation and six π electrons in seven p orbitals. Electrostatic potential maps indicate that both ions are symmetrical, with the charge equally shared among all atoms in each ring. Problems

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Aromatic Heterocycles: Pyridine and Pyrrole Look back once again at the definition of aromaticity in : a cyclic, conjugated molecule containing 4 n + 2 π electrons. Nothing in this definition says that the atoms in the ring must be carbon. In fact, heterocyclic compounds can also be aromatic. A heterocycle is a cyclic compound that contains atoms of more than one element in its ring, usually carbon along with nitrogen, oxygen, or sulfur. Pyridine and pyrimidine, for example, are six-membered heterocycles with carbon and nitrogen in their rings ( ). Pyridine and pyrimidine are nitrogen-containing aromatic heterocycles with π electron arrangements like that of benzene. Both have a lone pair of electrons on nitrogen in an sp 2 orbital in the plane of the ring. Pyridine is much like benzene in its π electron structure. Each of the five sp 2 -hybridized carbons has a p orbital perpendicular to the plane of the ring, and each p orbital contains one π electron. The nitrogen atom is also sp 2 -hybridized and has one electron in a p orbital, bringing the total to six π electrons. The nitrogen lone-pair electrons (red in an electrostatic potential map) are in a sp 2 orbital in the plane of the ring and are not part of the aromatic π system. Pyrimidine, also shown in , is a benzene analog that has two nitrogen atoms in a six-membered, unsaturated ring. Both nitrogens are sp 2 -hybridized, and each contributes one electron to the aromatic π system. Pyrrole (spelled with two r ’s and one l ) and imidazole are five -membered heterocycles, yet both have six π electrons and are aromatic. In pyrrole, each of the four sp 2 -hybridized carbons contributes one π electron and the sp 2 -hybridized nitrogen atom contributes the two from its lone pair, which occupies a p orbital ( ). Imidazole, also shown in , is an analog of pyrrole that has two nitrogen atoms in a five-membered, unsaturated ring. Both nitrogens are sp 2 -hybridized, but one is in a double bond and contributes only one electron to the aromatic π system whereas the other is not in a double bond and contributes two from its lone pair. Pyrrole and imidazole are five-membered, nitrogen-containing heterocycles but have six- π -electron arrangements like that of the cyclopentadienyl anion. Both have a lone pair of electrons on nitrogen in a p orbital perpendicular to the ring. Note that nitrogen atoms have different roles depending on the structure of the molecule. The nitrogen atoms in pyridine and pyrimidine are both in double bonds and contribute only one π electron to the aromatic sextet, just as a carbon atom in benzene does. The nitrogen atom in pyrrole, however, is not in a double bond and contributes two π electrons (its lone pair) to the aromatic sextet. In imidazole, both kinds of nitrogen are present in the same molecule—a double-bonded “pyridine-like” nitrogen that contributes one π electron and a “pyrrole-like” nitrogen that contributes two. Pyrimidine and imidazole rings are particularly important in biological chemistry. Pyrimidine, for instance, is the parent ring system in cytosine, thymine, and uracil, three of the five heterocyclic amine bases found in nucleic acids. An aromatic imidazole ring is present in histidine, one of the 20 amino acids found in proteins. Accounting for the Aromaticity of a Heterocycle Thiophene, a sulfur-containing heterocycle, undergoes typical aromatic substitution reactions rather than addition reactions. Why is thiophene aromatic? Strategy Recall the requirements for aromaticity—a planar, cyclic, conjugated molecule with 4 n + 2 π electrons—and see how these requirements apply to thiophene. Solution Thiophene is the sulfur analog of pyrrole. The sulfur atom is sp 2 -hybridized and has a lone pair of electrons in a p orbital perpendicular to the plane of the ring. Sulfur also has a second lone pair of electrons in the ring plane. Problems

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Polycyclic Aromatic Compounds The Hückel rule is strictly applicable only to monocyclic compounds, but the general concept of aromaticity can be extended to include polycyclic aromatic compounds. Naphthalene, with two benzene-like rings fused together; anthracene, with three rings; benzo[a]pyrene, with five rings; and coronene, with six rings, are all well-known aromatic hydrocarbons. Benzo[a]pyrene is particularly interesting because it is one of the cancer-causing substances found in tobacco smoke. All polycyclic aromatic hydrocarbons can be represented by a number of different resonance forms. Naphthalene, for instance, has three. Naphthalene and other polycyclic aromatic hydrocarbons show many of the chemical properties associated with aromaticity. Thus, measurement of its heat of hydrogenation shows an aromatic stabilization energy of approximately 250 kJ/mol (60 kcal/mol). Furthermore, naphthalene reacts slowly with electrophiles such as Br 2 to give substitution products rather than double-bond addition products. The aromaticity of naphthalene is explained by the orbital picture in . Naphthalene has a cyclic, conjugated π electron system, with p orbital overlap both along the ten-carbon periphery of the molecule and across the central bond. Because ten π electrons is a Hückel number, there is π electron delocalization and consequent aromaticity in naphthalene. An orbital picture and electrostatic potential map of naphthalene, showing that the ten π electrons are fully delocalized throughout both rings. Just as there are heterocyclic analogs of benzene, there are also many heterocyclic analogs of naphthalene. Among the most common are quinoline, isoquinoline, indole, and purine. Quinoline, isoquinoline, and purine all contain pyridine-like nitrogens that are part of a double bond and contribute one electron to the aromatic π system. Indole and purine both contain pyrrole-like nitrogens that contribute two π electrons. Among the many biological molecules that contain polycyclic aromatic rings, the amino acid tryptophan contains an indole ring and the antimalarial drug quinine contains a quinoline ring. Adenine and guanine, two of the five heterocyclic amine bases found in nucleic acids, have rings based on purine. Problems

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Spectroscopy of Aromatic Compounds Infrared Spectroscopy As we saw in the brief introduction to infrared spectroscopy ( ), aromatic rings show a characteristic C–H stretching absorption at 3030 cm –1 and a series of peaks in the 1450 to 1600 cm –1 range of the infrared spectrum. The aromatic C–H band at 3030 cm –1 generally has low intensity and occurs just to the left of a typical saturated C–H band. As many as four absorptions are sometimes observed in the 1450 to 1600 cm –1 region because of the complex molecular motions of the ring itself. Two bands, one at 1500 cm –1 and one at 1600 cm –1 , are usually the most intense. In addition, aromatic compounds show weak absorptions in the 1660 to 2000 cm –1 region and strong absorptions in the 690 to 900 cm –1 range due to C–H out-of-plane bending. The exact position of both sets of absorptions is diagnostic of the substitution pattern of the aromatic ring ( in ). Substitution Absorption Substitution Absorption Monosubstituted: 690–710 cm –1 1,2,4-Trisubstituted: 780–830 cm –1 730–770 cm –1 870–900 cm –1 o -Disubstituted: 735–770 cm –1 1,2,3-Trisubstituted: 670–720 cm –1 m -Disubstituted: 690–710 cm –1 750–790 cm –1 810–850 cm –1 1,3,5-Trisubstituted: 660–700 cm –1 p -Disubstituted: 810–840 cm –1 830–900 cm –1 The IR spectrum of toluene in shows these characteristic absorptions. The infrared spectrum of toluene. Ultraviolet Spectroscopy Aromatic rings are detectable by ultraviolet spectroscopy because they contain a conjugated π electron system. In general, aromatic compounds show a series of bands, with a fairly intense absorption near 205 nm and a less intense absorption in the 255 to 275 nm range. The presence of these bands in the ultraviolet spectrum of a molecule is a sure indication of an aromatic ring. shows the ultraviolet spectrum of benzene. Ultraviolet spectrum of benzene. There are primary bands at 184 and 202 nm and secondary (fine-structure) bands at 255 nm. Nuclear Magnetic Resonance Spectroscopy Aromatic hydrogens are strongly deshielded by the ring and absorb between 6.5 and 8.0 δ. The spins of nonequivalent aromatic protons on substituted rings often couple with each other, giving rise to spin–spin splitting patterns that can identify the substitution of the ring. Much of the difference in chemical shift between aromatic protons (6.5–8.0 δ ) and vinylic protons (4.5–6.5 δ ) is due to a property of aromatic rings called ring-current . When an aromatic ring is oriented perpendicular to a strong magnetic field, the electrons circulate around the ring, producing a small local magnetic field. This induced field opposes the applied field in the middle of the ring but reinforces the applied field outside the ring ( ). Aromatic protons therefore experience an effective magnetic field greater than the applied field and come into resonance at a lower applied field. The origin of aromatic ring-current. Aromatic protons are deshielded by the induced magnetic field caused by delocalized π electrons circulating around the aromatic ring. Note that the aromatic ring-current produces different effects inside and outside the ring. If a ring were large enough to have both “inside” and “outside” protons, the protons on the outside would be deshielded and absorb at a field lower than normal but those on the inside would be shielded and absorb at a field higher than normal. This prediction has been strikingly confirmed by studies on [18]annulene, an 18- π -electron cyclic conjugated polyene that contains a Hückel number of electrons (4 n + 2 = 18 when n = 4). The six inside protons of [18]annulene are strongly shielded by the aromatic ring-current and absorb at –3.0 δ (that is, 3.0 ppm upfield from TMS, off the normal chart), while the 12 outside protons are strongly deshielded and absorb in the typical aromatic region at 9.3 ppm downfield from TMS. The presence of a ring-current is characteristic of all Hückel aromatic molecules and is a good test of aromaticity. For example, benzene, a six- π -electron aromatic molecule, absorbs at 7.37 δ because of its ring-current, but cyclooctatetraene, an eight- π -electron nonaromatic molecule, absorbs at 5.78 δ. Hydrogens on carbon next to aromatic rings— benzylic hydrogens—also show distinctive absorptions in the NMR spectrum. Benzylic protons normally absorb downfield from other alkane protons in the region from 2.3 to 3.0 δ. The 1 H NMR spectrum of p -bromotoluene, shown in , displays many of the features just discussed. The aromatic protons appear as two doublets at 7.04 and 7.37 δ, and the benzylic methyl protons absorb as a sharp singlet at 2.26 δ. Integration of the spectrum shows the expected 2 : 2 : 3 ratio of peak areas. The 1 H NMR spectrum of p -bromotoluene. The carbon atoms in an aromatic ring typically absorb in the range 110 to 140 δ in the 13 C NMR spectrum, as indicated by the examples in . These resonances are easily distinguished from those of alkane carbons but occur in the same range as alkene carbons. Thus, the presence of 13 C absorptions at 110 to 140 δ does not by itself establish the presence of an aromatic ring. Supporting evidence from infrared, ultraviolet, or 1 H NMR spectra is needed. Some 13 C NMR absorptions of aromatic compounds ( δ units). Aspirin, NSAIDs, and COX-2 Inhibitors Whatever the cause—whether tennis elbow, a sprained ankle, or a wrenched knee—pain and inflammation seem to go together. They are, however, different in their origin, and powerful drugs are available for treating each separately. Codeine, for example, is a powerful analgesic, or pain reliever, used in the management of debilitating pain, while cortisone and related steroids are potent anti-inflammatory agents, used for treating arthritis and other crippling inflammations. For minor pains and inflammation, both problems are often treated together by using a common over-the-counter medication called an NSAID, or nonsteroidal anti-inflammatory drug. One of the most common NSAIDs is aspirin, or acetylsalicylic acid, whose use goes back to the late 1800s. It had been known from before the time of Hippocrates in 400 BC that fevers could be lowered by chewing the bark of willow trees. The active agent in willow bark was found in 1827 to be an aromatic compound called salicin, which could be converted by reaction with water into salicyl alcohol and then oxidized to give salicylic acid. Salicylic acid turned out to be even more effective than salicin for reducing fevers and to have analgesic and anti-inflammatory action as well. Unfortunately, it also turned out to be too corrosive to the walls of the stomach for everyday use. Conversion of the phenol –OH group into an acetate ester, however, yielded acetylsalicylic acid, which proved just as potent as salicylic acid but less corrosive to the stomach. Many athletes rely on NSAIDs to help with pain and soreness. (credit: “Dillon Gee delivers a pitch” by Arturo Pardavila III/Wikimedia Commons, CC BY 2.0) Although extraordinary in its effect, aspirin is also more dangerous than commonly believed. 15 g of aspirin would be fatal to a child of 9–10 years, and 10 g would be lethal for a 6-year-old, and aspirin can cause stomach bleeding and allergic reactions in long-term users. Even more serious is a condition called Reye’s syndrome, a potentially fatal reaction to aspirin sometimes seen in children recovering from the flu. As a result of these problems, numerous other NSAIDs have been developed in the last several decades, most notably ibuprofen and naproxen. Like aspirin, both ibuprofen and naproxen are relatively simple aromatic compounds containing a side-chain carboxylic acid group. Ibuprofen, sold under the brand names Advil, Nuprin, Motrin, and others, has roughly the same potency as aspirin but is less prone to causing an upset stomach. Naproxen, sold under the names Aleve and Naprosyn, also has about the same potency as aspirin but remains active in the body six times longer. Aspirin and other NSAIDs function by blocking the cyclooxygenase (COX) enzymes that carry out the body’s synthesis of prostaglandins ( and Section 27.4 ). There are two forms of the enzyme: COX-1, which carries out the normal physiological production of prostaglandins, and COX-2, which mediates the body’s response to arthritis and other inflammatory conditions. Unfortunately, both COX-1 and COX-2 enzymes are blocked by aspirin, ibuprofen, and other NSAIDs, thereby shutting down not only the response to inflammation but also various protective functions, including the control mechanism for production of acid in the stomach. Medicinal chemists have therefore devised a number of drugs that act as selective inhibitors of only the COX-2 enzyme. Inflammation is thereby controlled without blocking protective functions. Originally heralded as a breakthrough in arthritis treatment, the first generation of COX-2 inhibitors, including rofecoxib, (marketed as Vioxx), celecoxib, (marketed as Celebrex), and Valdecoxib (marketed as Bextra), turned out to cause potentially serious heart problems, particularly in elderly or compromised patients. As a result, all three Cox-2 inhibitors were removed from the U.S. and other markets. Further studies, however, concluded that in proper doses the Cox-2 inhibitors were little different from other NSAIDs, and Vioxx returned to the market in 2017 for topical treatment of osteoarthritis. antiaromatic arene aromatic benzyl group degenerate orbitals heterocycle Hückel 4 n + 2 rule meta ( m ) ortho ( o ) para ( p ) phenyl group ring-current Summary Aromatic rings are a common part of many biological structures and are particularly important in nucleic acid chemistry and in the chemistry of several amino acids. In this chapter, we’ve seen how and why aromatic compounds are different from such apparently related compounds as cycloalkenes. The word aromatic is used for historical reasons to refer to the class of compounds related structurally to benzene. Aromatic compounds are systematically named according to IUPAC rules, but many common names are also used. Disubstituted benzenes are referred to as ortho (1,2 disubstituted), meta (1,3 disubstituted), or para (1,4 disubstituted) derivatives. The C 6 H 5 – unit itself is referred to as a phenyl group, and the C 6 H 5 CH 2 – unit is a benzyl group. Benzene is described by valence-bond theory as a resonance hybrid of two equivalent structures and is described by molecular orbital theory as a planar, cyclic, conjugated molecule with six π electrons. According to the Hückel rule , a molecule must have 4 n + 2 π electrons , where n = 0, 1, 2, 3, and so on, to be aromatic. Planar, cyclic, conjugated molecules with other numbers of π electrons are antiaromatic . Other substances besides benzene-like compounds are also aromatic. The cyclopentadienyl anion and the cycloheptatrienyl cation, for instance, are aromatic ions. Pyridine and pyrimidine are six-membered, nitrogen-containing, aromatic heterocycles . Pyrrole and imidazole are five-membered, nitrogen-containing heterocycles. Naphthalene, quinoline, indole, and many others are polycyclic aromatic compounds. Aromatic compounds have the following characteristics: Aromatic compounds are cyclic, planar, and conjugated. Aromatic compounds are unusually stable. Benzene, for instance, has a heat of hydrogenation 150 kJ/mol less than we might expect for a cyclic triene. Aromatic compounds react with electrophiles to give substitution products, in which cyclic conjugation is retained, rather than addition products, in which conjugation is destroyed. Aromatic compounds have 4 n + 2 π electrons, which are delocalized over the ring. Additional Problems Visualizing Chemistry Naming Aromatic Compounds Structure of Aromatic Compounds Aromaticity and Hückel’s Rule Spectroscopy General Problems

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Why This Chapter? In the 19th and early-20th centuries, benzene was used as an aftershave lotion because of its pleasant smell and as a solvent to decaffeinate coffee beans . Neither is a good idea. (credit: modification of work “ Ye Old Way ” by Geo. H. Walker & Co./Library of Congress) This chapter continues the coverage of aromatic molecules begun in the preceding chapter, but we’ll shift focus to concentrate on reactions, looking at the relationship between aromatic structure and reactivity. This relationship is critical in understanding how many biological molecules and pharmaceutical agents are synthesized and why they behave as they do. In the preceding chapter, we looked at aromaticity—the stability associated with benzene and related compounds that contain a cyclic conjugated system of 4 n + 2 π electrons. In this chapter, we’ll look at some of the unique reactions that aromatic molecules undergo. The most common reaction of aromatic compounds is electrophilic aromatic substitution , in which an electrophile (E + ) reacts with an aromatic ring and substitutes for one of the hydrogens. The reaction is characteristic of all aromatic rings, not just benzene and substituted benzenes. In fact, the ability of a compound to undergo electrophilic substitution is a good test of aromaticity. Many different substituents can be introduced onto an aromatic ring through electrophilic substitution. To list some possibilities, an aromatic ring can be substituted by a halogen (–Cl, –Br, –I), a nitro group (–NO 2 ), a sulfonic acid group (–SO 3 H), a hydroxyl group (–OH), an alkyl group (–R), or an acyl group (–COR). Starting from only a few simple materials, it’s possible to prepare many thousands of substituted aromatic compounds.

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Electrophilic Aromatic Substitution Reactions: Bromination Before seeing how electrophilic aromatic substitutions occur, let’s briefly recall what we said in the chapter on Alkenes: Structure and Reactivity about electrophilic alkene additions. When a reagent such as HCl adds to an alkene, the electrophilic hydrogen ion approaches the π electrons of the double bond and forms a bond to one carbon, leaving a positive charge at the other carbon. This carbocation intermediate then reacts with the nucleophilic Cl – ion to yield the addition product. An electrophilic aromatic substitution reaction begins in a similar way, but there are a number of differences. One difference is that aromatic rings are less reactive toward electrophiles than alkenes. For example, Br 2 in CH 2 Cl 2 solution reacts instantly with most alkenes but does not react with benzene at room temperature. For bromination of benzene to take place, a catalyst such as FeBr 3 is needed. The catalyst makes the Br 2 molecule more electrophilic by polarizing it to give a FeBr 4 – Br + species that reacts as if it were Br + . The polarized Br 2 molecule then reacts with the nucleophilic benzene ring to yield a nonaromatic carbocation intermediate that is doubly allylic ( ) and has three resonance forms. Although more stable than a typical alkyl carbocation because of resonance, the intermediate in electrophilic aromatic substitution is nevertheless much less stable than the starting benzene ring itself, with its 150 kJ/mol (36 kcal/mol) of aromatic stability. Thus, the reaction of an electrophile with a benzene ring is endergonic, has a substantial activation energy, and is rather slow. shows an energy diagram comparing the reaction of an electrophile with an alkene and with benzene. The benzene reaction is slower (higher ∆ G ‡ ) because the starting material is more stable. A comparison of the reactions of an electrophile (E + ) with an alkene and with benzene: Δ G ‡ alkene < Δ G ‡ benzene . The benzene reaction is slower than the alkene reaction because of the stability of the aromatic ring. Another difference between alkene addition and aromatic substitution occurs after the carbocation intermediate has formed. Instead of adding Br – to give an addition product, the carbocation intermediate loses H + from the bromine-bearing carbon to give a substitution product. Note that this loss of H + is similar to what occurs in the second step of an E1 reaction ( ). The net effect of reaction of Br 2 with benzene is the substitution of H + by Br + by the overall mechanism shown in . MECHANISM The mechanism for the electrophilic bromination of benzene . The reaction occurs in two steps and involves a resonance-stabilized carbocation intermediate. Why does the reaction of Br 2 with benzene take a different course than its reaction with an alkene? The answer is straightforward. If addition occurred, the 150 kJ/mol stabilization energy of the aromatic ring would be lost and the overall reaction would be endergonic. When substitution occurs, though, the stability of the aromatic ring is retained and the reaction is exergonic. An energy diagram for the overall process is shown in . An energy diagram for the electrophilic bromination of benzene . Because the stability of the aromatic ring is retained, the overall process is exergonic. Problems

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Other Aromatic Substitutions There are many other kinds of electrophilic aromatic substitutions besides bromination, and all occur by the same general mechanism. Let’s look at some of these other reactions briefly. Aromatic Halogenation Chlorine and iodine can be introduced into aromatic rings by electrophilic substitution reactions just as bromine can, but fluorine is too reactive and only poor yields of monofluoroaromatic products are obtained by direct fluorination. Instead, other sources of “F + ” are used, in which a fluorine atom is bonded to a positively charged nitrogen. One of the most common such reagents goes by the acronym F-TEDA-BF 4 in the presence of trifluoromethanesulfonic acid (TfOH). (You don’t need to know the full name of F-TEDA, which is sold under the name Selectfluor.) More than 20% of all pharmaceutical agents sold contain fluorine, including 30% of the top 100 drugs sold. Sitagliptin (Januvia), used to treat type 2 diabetes, fluoxetine (Prozac), an antidepressant, and atorvastatin (Lipitor), a statin used to lower cholesterol, are examples. Aromatic rings react with Cl 2 in the presence of FeCl 3 catalyst to yield chlorobenzenes, just as they react with Br 2 and FeBr 3 . This kind of reaction is used in the synthesis of numerous pharmaceutical agents, including the antiallergy medication loratadine, marketed as Claritin. Iodine itself is unreactive toward aromatic rings, so an oxidizing agent such as hydrogen peroxide or a copper salt such as CuCl 2 must be added to the reaction. These substances accelerate the iodination reaction by oxidizing I 2 to a more powerful electrophilic species that reacts as if it were I + . The aromatic ring then reacts with I + in the typical way, yielding a substitution product. Electrophilic aromatic halogenations also occur in the biosynthesis of many naturally occurring molecules, particularly those produced by marine organisms. In humans, the best-known example occurs in the thyroid gland during the biosynthesis of thyroxine, a hormone involved in regulating growth and metabolism. The amino acid tyrosine is first iodinated by thyroid peroxidase, and two of the iodinated tyrosine molecules then couple. The electrophilic iodinating agent is an I + species, perhaps hypoiodous acid (HIO), that is formed from iodide ion by oxidation with H 2 O 2 . Aromatic Nitration Aromatic rings are nitrated by reaction with a mixture of concentrated nitric and sulfuric acids. The electrophile is the nitronium ion, NO 2 + , which is formed from HNO 3 by protonation and loss of water. The nitronium ion reacts with benzene to yield a carbocation intermediate, and loss of H + from this intermediate gives the neutral substitution product, nitrobenzene ( ). The mechanism for electrophilic nitration of an aromatic ring . An electrostatic potential map of the reactive electrophile NO 2 + shows that the nitrogen atom is most positive. Electrophilic nitration of an aromatic ring does not occur in nature but is particularly important in the laboratory because the nitro-substituted product can be reduced by reagents such as iron, tin, or SnCl 2 to yield the corresponding arylamine, ArNH 2 . Attachment of an amino group (–NH 2 ) to an aromatic ring by the two-step nitration/reduction sequence is a key part of the industrial synthesis of many dyes and pharmaceutical agents. We’ll discuss this reduction and other reactions of aromatic nitrogen compounds in Chapter 24. Aromatic Sulfonation Aromatic rings can be sulfonated by reaction with so-called fuming sulfuric acid, a mixture of H 2 SO 4 and SO 3 . The reactive electrophile is either HSO 3 + or neutral SO 3 , depending on reaction conditions, and substitution occurs by the same two-step mechanism seen previously for bromination and nitration ( ). Note, however, that the sulfonation reaction is readily reversible. It can occur either forward or backward, depending on the reaction conditions. Sulfonation is favored in strong acid, but desulfonation is favored in hot, dilute aqueous acid. The mechanism for electrophilic sulfonation of an aromatic ring . An electrostatic potential map of the reactive electrophile HOSO 2 + shows that sulfur and hydrogen are the most positive atoms . Aromatic sulfonation does not occur naturally but is widely used in the preparation of dyes and pharmaceutical agents. For example, the sulfa drugs, such as sulfanilamide, were among the first clinically useful antibiotics. Although largely replaced today by more effective agents, sulfa drugs are still used in the treatment of meningitis and urinary tract infections. These drugs are prepared commercially by a process that involves aromatic sulfonation as its key step. Aromatic Hydroxylation Direct hydroxylation of an aromatic ring to yield a hydroxybenzene (a phenol ) is difficult and rarely done in the laboratory but occurs much more frequently in biological pathways. An example is the hydroxylation of p -hydroxyphenylacetate to give 3,4-dihydroxyphenylacetate. The reaction is catalyzed by p -hydroxyphenylacetate-3-hydroxylase and requires molecular oxygen plus the coenzyme reduced flavin adenine dinucleotide, abbreviated FADH 2 . By analogy with other electrophilic aromatic substitutions, you might expect that an electrophilic oxygen species acting as an “OH + equivalent” is needed for the hydroxylation reaction. That is just what happens, with the electrophilic oxygen arising by protonation of FAD hydroperoxide, RO–OH ( ); that is, RO–OH + H + → ROH + OH + . The FAD hydroperoxide itself is formed by reaction of FADH 2 with O 2 . MECHANISM Mechanism for the electrophilic hydroxylation of p -hydroxyphenylacetate, by reaction with FAD hydroperoxide . The hydroxylating species is an “OH + equivalent” that arises by protonation of FAD hydroperoxide, RO–OH + H + → ROH + OH + . The FAD hydroperoxide itself is formed by reaction of FADH 2 with O 2 . Problems

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Alkylation and Acylation of Aromatic Rings: The Friedel–Crafts Reaction Among the most useful electrophilic aromatic substitution reactions in the laboratory is alkylation —the introduction of an alkyl group onto the benzene ring. Called the Friedel–Crafts reaction after its founders in 1877, Charles Friedel and James Crafts, the reaction is carried out by treating an aromatic compound with an alkyl chloride, RCl, in the presence of AlCl 3 to generate a carbocation electrophile, R + . Aluminum chloride catalyzes the reaction by helping the alkyl halide to generate a carbocation in much the same way that FeBr 3 catalyzes aromatic brominations by polarizing Br 2 ( ). Loss of H + then completes the reaction ( ). MECHANISM Mechanism for the Friedel–Crafts alkylation reaction of benzene with 2-chloropropane to yield isopropylbenzene (cumene) . The electrophile is a carbocation, generated by AlCl 3 -assisted dissociation of an alkyl halide. Despite its utility, the Friedel–Crafts alkylation has several limitations. For one thing, only alkyl halides can be used. Aromatic (aryl) halides and vinylic halides don’t react because aryl and vinylic carbocations are too high in energy to form under Friedel–Crafts conditions. Another limitation is that Friedel–Crafts reactions don’t succeed on aromatic rings that are substituted either by a strongly electron-withdrawing group such as carbonyl (C=O) or by a basic amino group that can be protonated. We’ll see in the next section that the presence of a substituent group already on a ring can have a dramatic effect on that ring’s reactivity to further electrophilic substitution. Rings that contain any of the substituents listed in do not undergo Friedel–Crafts alkylation. Limitations on the aromatic substrate in Friedel–Crafts reactions . No reaction occurs if the substrate has either an electron-withdrawing substituent or a basic amino group. A third limitation to the Friedel–Crafts alkylation is that it’s often difficult to stop the reaction after a single substitution. Once the first alkyl group is on the ring, a second substitution reaction is facilitated for reasons we’ll discuss in the next section. Thus, we often observe polyalkylation. Reaction of benzene with 1 mol equivalent of 2-chloro-2-methylpropane, for example, yields p -di- tert -butylbenzene as the major product, along with small amounts of tert -butylbenzene and unreacted benzene. A high yield of mono-alkylation product is obtained only when a large excess of benzene is used. A final limitation to the Friedel–Crafts reaction is that a skeletal rearrangement of the alkyl carbocation electrophile sometimes occurs during reaction, particularly when a primary alkyl halide is used. Treatment of benzene with 1-chlorobutane at 0 °C, for instance, gives an approximately 2 : 1 ratio of rearranged ( sec -butyl) to unrearranged (butyl) products. The carbocation rearrangements that accompany Friedel–Crafts reactions are like those that accompany electrophilic additions to alkenes ( ) and occur either by hydride shift or alkyl shift. For example, the relatively unstable primary butyl carbocation produced by reaction of 1-chlorobutane with AlCl 3 rearranges to the more stable secondary butyl carbocation by the shift of a hydrogen atom and its electron pair (a hydride ion, H : – ) from C2 to C1. Similarly, alkylation of benzene with 1-chloro-2,2-dimethylpropane yields (1,1-dimethylpropyl)benzene. The initially formed primary carbocation rearranges to a tertiary carbocation by shift of a methyl group and its electron pair from C2 to C1. Just as an aromatic ring is alkylated by reaction with an alkyl chloride, it is acylated by reaction with a carboxylic acid chloride, RCOCl, in the presence of AlCl 3 . That is, an acyl group (–COR; pronounced a -sil) is substituted onto the aromatic ring. For example, reaction of benzene with acetyl chloride yields the ketone acetophenone. The mechanism of Friedel–Crafts acylation is similar to that of Friedel–Crafts alkylation, and the same limitations on the aromatic substrate noted previously in for alkylation also apply to acylation. The reactive electrophile is a resonance-stabilized acyl cation, generated by reaction between the acyl chloride and AlCl 3 ( ). As the resonance structures in the figure indicate, an acyl cation is stabilized by interaction of the vacant orbital on carbon with lone-pair electrons on the neighboring oxygen. Because of this stabilization, no carbocation rearrangement occurs during acylation. Mechanism of the Friedel–Crafts acylation reaction . The electrophile is a resonance-stabilized acyl cation, whose electrostatic potential map indicates that carbon is the most positive atom . Unlike the multiple substitutions that often occur in Friedel–Crafts alkylations, acylations never occur more than once on a ring because the product acylbenzene is less reactive than the nonacylated starting material. We’ll account for this reactivity difference in the next section. Aromatic alkylations occur in numerous biological pathways, although there is of course no AlCl 3 present in living systems to catalyze the reaction. Instead, the carbocation electrophile is typically formed by dissociation of an organodiphosphate, as we saw in . The dissociation is usually assisted by complexation to a divalent metal cation such as Mg 2+ , just as dissociation of an alkyl chloride is assisted by AlCl 3 . An example of a biological Friedel–Crafts reaction occurs during the biosynthesis of phylloquinone, or vitamin K 1 , the human blood-clotting factor. Phylloquinone is formed by reaction of 1,4-dihydroxynaphthoic acid with phytyl diphosphate. Phytyl diphosphate first dissociates to a resonance-stabilized allylic carbocation, which then substitutes onto the aromatic ring in the typical way. Several further transformations lead to phylloquinone ( ). Biosynthesis of phylloquinone (vitamin K 1 ) from 1,4-dihydroxynaphthoic acid . The key step that joins the 20-carbon phytyl side chain to the aromatic ring is a Friedel–Crafts-like electrophilic substitution reaction with a diphosphate ion as the leaving group. Predicting the Product of a Carbocation Rearrangement The Friedel–Crafts reaction of benzene with 2-chloro-3-methylbutane in the presence of AlCl 3 occurs with a carbocation rearrangement. What is the structure of the product? Strategy A Friedel–Crafts reaction involves initial formation of a carbocation, which can rearrange by either a hydride shift or an alkyl shift to give a more stable carbocation. Draw the initial carbocation, assess its stability, and see if the shift of a hydride ion or an alkyl group from a neighboring carbon will result in increased stability. In the present instance, the initial carbocation is a secondary one that can rearrange to a more stable tertiary one by a hydride shift. Use this more stable tertiary carbocation to complete the Friedel–Crafts reaction. Solution Problems

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