Substituent Effects in Electrophilic Substitutions Only one product can form when an electrophilic substitution occurs on benzene, but what would happen if we were to carry out a reaction on an aromatic ring that already has a substituent? The initial presence of a substituent on the ring has two effects. Substituents affect the reactivity of the aromatic ring. Some substituents activate the ring, making it more reactive than benzene, and some deactivate the ring, making it less reactive than benzene. In aromatic nitration, for instance, an –OH substituent makes the ring 1000 times more reactive than benzene, while an –NO 2 substituent makes the ring more than 10 million times less reactive. Substituents affect the orientation of the reaction. The three possible disubstituted products—ortho, meta, and para—are usually not formed in equal amounts. Instead, the nature of the substituent initially present on the benzene ring determines the position of the second substitution. An –OH group directs substitution toward the ortho and para positions, for instance, while a carbonyl group such as –CHO directs substitution primarily toward the meta position. lists experimental results for the nitration of some substituted benzenes. Orientation of Nitration in Substituted Benzenes Product (%) Ortho Meta Para Meta-directing deactivators – N + ( CH 3 ) 3 2 87 11 –NO 2 7 91 2 –CO 2 H 22 76 2 –CN 17 81 2 –CO 2 CH 3 28 66 6 –COCH 3 26 72 2 –CHO 19 72 9 Ortho- and para-directing deactivators –F 13 1 86 –Cl 35 1 64 –Br 43 1 56 –I 45 1 54 Ortho- and para-directing activators –CH 3 63 3 34 –OH 50 0 50 –NHCOCH 3 19 2 79 Substituents can be classified into three groups, as shown in : ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators. There are no meta-directing activators. Notice how the directing effect of a group correlates with its reactivity. All meta-directing groups are strongly deactivating, and most ortho- and para-directing groups are activating. The halogens are unique in being ortho- and para-directing but weakly deactivating. Classification of substituent effects in electrophilic aromatic substitution . All activating groups are ortho- and para-directing, and all deactivating groups other than halogen are meta-directing. Halogens are unique in being deactivating but ortho- and para-directing. Predicting the Product of an Electrophilic Aromatic Substitution Reaction Predict the major product of the sulfonation of toluene. Strategy Identify the substituent present on the ring, and decide whether it is ortho- and para-directing or meta-directing. According to , an alkyl substituent is ortho- and para-directing, so sulfonation of toluene will primarily give a mixture of o -toluenesulfonic acid and p -toluenesulfonic acid. Solution Problems Activating and Deactivating Effects What makes a group either activating or deactivating? The common characteristic of all activating groups is that they donate electrons to the ring, thereby making the ring more electron-rich, stabilizing the carbocation intermediate, and lowering the activation energy for its formation. Conversely, the common characteristic of all deactivating groups is that they withdraw electrons from the ring, thereby making the ring more electron-poor, destabilizing the carbocation intermediate, and raising the activation energy for its formation. Compare the electrostatic potential maps of benzaldehyde (deactivated), chlorobenzene (weakly deactivated), and phenol (activated) with that of benzene. As shown in , the ring is more positive (yellow-green) when an electron-withdrawing group such as –CHO or –Cl is present and more negative (red) when an electron-donating group such as –OH is present. Electrostatic potential maps of benzene and several substituted benzenes show that an electron-withdrawing group (–CHO or –Cl) makes the ring more electron-poor , while an electron-donating group (–OH) makes the ring more electron-rich . The withdrawal or donation of electrons by a substituent group is controlled by an interplay of inductive effects and resonance effects. As we saw in , an inductive effect is the withdrawal or donation of electrons through a σ bond due to electronegativity. Halogens, hydroxyl groups, carbonyl groups, cyano groups, and nitro groups inductively withdraw electrons through the σ bond linking the substituent to a benzene ring. This effect is most pronounced in halobenzenes and phenols, in which the electronegative atom is directly attached to the ring, but is also significant in carbonyl compounds, nitriles, and nitro compounds, in which the electronegative atom is farther removed. Alkyl groups, on the other hand, inductively donate electrons. This is the same hyperconjugative donating effect that causes alkyl substituents to stabilize alkenes ( ) and carbocations ( ). A resonance effect is the withdrawal or donation of electrons through a π bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring. Carbonyl, cyano, and nitro substituents, for example, withdraw electrons from the aromatic ring by resonance. The π electrons flow from the ring to the substituent, leaving a positive charge in the ring. Note that substituents with an electron-withdrawing resonance effect have the general structure –Y=Z, where the Z atom is more electronegative than Y. Conversely, halogen, hydroxyl, alkoxyl (–OR), and amino substituents donate electrons to the aromatic ring by resonance. Lone-pair electrons flow from the substituents to the ring, placing a negative charge on the ring. Substituents with an electron-donating resonance effect have the general structure –Ÿ , where the Y atom has a lone pair of electrons available for donation to the ring. One further point: inductive effects and resonance effects don’t necessarily act in the same direction. Halogen, hydroxyl, alkoxyl, and amino substituents, for instance, have electron-withdrawing inductive effects because of the electronegativity of the –X, –O, or –N atom bonded to the aromatic ring but have electron-donating resonance effects because of the lone-pair electrons on those –X, –O, or –N atoms. When the two effects act in opposite directions, the stronger effect dominates. Thus, hydroxyl, alkoxyl, and amino substituents are activators because their stronger electron-donating resonance effect outweighs their weaker electron-withdrawing inductive effect. Halogens, however, are deactivators because their stronger electron-withdrawing inductive effect outweighs their weaker electron-donating resonance effect. Problems Ortho- and Para-Directing Activators: Alkyl Groups Inductive and resonance effects account not only for reactivity but also for the orientation of electrophilic aromatic substitutions. Take alkyl groups, for instance, which have an electron-donating inductive effect and are ortho and para directors. The results of toluene nitration are shown in . Carbocation intermediates in the nitration of toluene . Ortho and para intermediates are more stable than the meta intermediate because the positive charge is on a tertiary carbon rather than a secondary carbon. Nitration of toluene might occur either ortho, meta, or para to the methyl group, giving the three carbocation intermediates shown in in . Although all three intermediates are resonance-stabilized, the ortho and para intermediates are more stabilized than the meta intermediate. For both the ortho and para reactions, but not for the meta reaction, a resonance form places the positive charge directly on the methyl-substituted carbon, where it is in a tertiary position and can be stabilized by the electron-donating inductive effect of the methyl group. The ortho and para intermediates are thus lower in energy than the meta intermediate and form faster. Ortho- and Para-Directing Activators: OH and NH 2 Hydroxyl, alkoxyl, and amino groups are also ortho–para activators, but for a different reason than for alkyl groups. As described earlier in this section, hydroxyl, alkoxyl, and amino groups have a strong, electron-donating resonance effect that outweighs a weaker electron-withdrawing inductive effect. When phenol is nitrated, for instance, reaction can occur either ortho, meta, or para to the –OH group, giving the carbocation intermediates shown in . The ortho and para intermediates are more stable than the meta intermediate because they have more resonance forms, including one particularly favorable form that allows the positive charge to be stabilized by electron donation from the substituent oxygen atom. The intermediate from the meta reaction has no such stabilization. Carbocation intermediates in the nitration of phenol . The ortho and para intermediates are more stable than the meta intermediate because they have more resonance forms, including one particularly favorable form that involves electron donation from the oxygen atom. Problems Ortho- and Para-Directing Deactivators: Halogens Halogens are deactivating because their stronger electron-withdrawing inductive effect outweighs their weaker electron-donating resonance effect. Although weak, that electron-donating resonance effect is nevertheless felt only at the ortho and para positions and not at the meta position ( ). Thus, a halogen substituent can stabilize the positive charge of the carbocation intermediates from ortho and para reaction in the same way that hydroxyl and amino substituents can. The meta intermediate, however, has no such stabilization and is therefore formed more slowly. Carbocation intermediates in the nitration of chlorobenzene . The ortho and para intermediates are more stable than the meta intermediate because of electron donation of the halogen lone-pair electrons. Note again that halogens, hydroxyl, alkoxyl, and amino groups all withdraw electrons inductively but donate electrons by resonance. Halogens have a stronger electron-withdrawing inductive effect but a weaker electron-donating resonance effect and are thus deactivators. Hydroxyl, alkoxyl, and amino groups have a weaker electron-withdrawing inductive effect but a stronger electron-donating resonance effect and are thus activators. All are ortho and para directors, however, because of the lone pair of electrons on the atom bonded to the aromatic ring. Meta-Directing Deactivators The influence of meta-directing substituents can be explained using the same kinds of arguments used for ortho and para directors. Look at the nitration of benzaldehyde, for instance ( ). Of the three possible carbocation intermediates, the meta intermediate has three favorable resonance forms, whereas the ortho and para intermediates have only two. In both ortho and para intermediates, the third resonance form is unfavorable because it places the positive charge directly on the carbon that bears the aldehyde group, where it is disfavored by a repulsive interaction with the positively polarized carbon atom of the C=O group. Hence, the meta intermediate is more favored and is formed faster than the ortho and para intermediates. Carbocation intermediates in the nitration of benzaldehyde . The ortho and para intermediates are less stable than the meta intermediate. The meta intermediate is more favorable than ortho and para intermediates because it has three favorable resonance forms rather than two. In general, any substituent that has a positively polarized atom ( δ + ) directly attached to the ring will make one of the resonance forms of the ortho and para intermediates unfavorable and will thus act as a meta director. Problems A Summary of Substituent Effects in Electrophilic Aromatic Substitution A summary of the activating and directing effects of substituents in electrophilic aromatic substitution is shown in . Substituent Effects in Electrophilic Aromatic Substitution Substituent Reactivity Orienting effect Inductive effect Resonance effect –CH 3 Activating Ortho, para Weak donating — –OH, –NH 2 Activating Ortho, para Weak withdrawing Strong donating –F, –Cl Deactivating Ortho, para Strong withdrawing Weak donating –Br, –I –NO 2 , –CN, Deactivating Meta Strong withdrawing Strong withdrawing –CHO, –CO 2 R –COR, –CO 2 H

Science


Trisubstituted Benzenes: Additivity of Effects Electrophilic substitution of a disubstituted benzene ring is governed by the same resonance and inductive effects that influence monosubstituted rings. The only difference is that it’s necessary to consider the additive effects of two different groups. In practice, this isn’t as difficult as it sounds; three rules are usually sufficient. RULE 1 If the directing effects of the two groups reinforce each other, the situation is straightforward. In p -nitrotoluene, for example, both the methyl and the nitro group direct further substitution to the same position (ortho to the methyl = meta to the nitro). A single product is thus formed on electrophilic substitution. RULE 2 If the directing effects of the two groups oppose each other, the more powerful activating group has the dominant influence, but mixtures of products are often formed. For example, bromination of p -methylphenol yields primarily 2-bromo-4-methylphenol because –OH is a more powerful activator than –CH 3 . RULE 3 Further substitution rarely occurs between the two groups in a meta-disubstituted compound because this site is too hindered. Aromatic rings with three adjacent substituents must therefore be prepared by some other route, such as by substitution of an ortho-disubstituted compound. Predicting the Product of Substitution on a Disubstituted Benzene What product would you expect from bromination of p -methylbenzoic acid? Strategy Identify the two substituents present on the ring, decide the directing effect of each and, if necessary, decide which substituent is the stronger activator. In the present case, the carboxyl group (–CO 2 H) is a meta director and the methyl group is an ortho and para director. Both groups direct bromination to the position next to the methyl group, yielding 3-bromo-4-methylbenzoic acid. Solution Problems

Science


Nucleophilic Aromatic Substitution Although aromatic substitution reactions usually occur by an electrophilic mechanism, aryl halides that have electron-withdrawing substituents can also undergo a nucleophilic substitution reaction. For example, 2,4,6-trinitrochlorobenzene reacts with aqueous NaOH at room temperature to give 2,4,6-trinitrophenol. Here, the nucleophile OH – substitutes for Cl – . Nucleophilic aromatic substitution is much less common than electrophilic substitution but nevertheless does have certain uses. One such use is the reaction of proteins with 2,4-dinitrofluorobenzene, known as Sanger’s reagent, to attach a “label” to the terminal NH 2 group of the amino acid at one end of the protein chain. Although the reaction appears superficially similar to the S N 1 and S N 2 nucleophilic substitutions of alkyl halides discussed in the chapter on Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations , it must be different because aryl halides are inert to both S N 1 and S N 2 conditions. S N 1 reactions don’t occur with aryl halides because dissociation of the halide is energetically unfavorable, due to the instability of the potential aryl cation product. S N 2 reactions don’t occur with aryl halides because the halo-substituted carbon of the aromatic ring is sterically shielded from a backside approach. For a nucleophile to react with an aryl halide, it would have to approach directly through the aromatic ring and invert the stereochemistry of the aromatic ring carbon—a geometric impossibility. Instead, nucleophilic substitutions on an aromatic ring proceed by the mechanism shown in . The nucleophile first adds to the electron-deficient aryl halide, forming a resonance-stabilized, negatively charged intermediate called a Meisenheimer complex after its discoverer. Halide ion is then eliminated. MECHANISM Mechanism of nucleophilic aromatic substitution . The reaction occurs in two steps and involves a resonance-stabilized carbanion intermediate. Nucleophilic aromatic substitution occurs only if the aromatic ring has an electron-withdrawing substituent in a position ortho or para to the leaving group to stabilize the anion intermediate through resonance ( ). A meta substituent offers no such resonance stabilization. Thus, p -chloronitrobenzene and o -chloronitrobenzene react with hydroxide ion at 130 °C to yield substitution products, but m -chloronitrobenzene is inert to OH – . Nucleophilic aromatic substitution on nitrochlorobenzenes . Only in the ortho and para intermediates is the negative charge stabilized by a resonance interaction with the nitro group, so only the ortho and para isomers undergo reaction. Note the differences between electrophilic and nucleophilic aromatic substitutions. Electrophilic substitutions are favored by electron-donating substituents, which stabilize a carbocation intermediate, while nucleophilic substitutions are favored by electron-withdrawing substituents, which stabilize a carbanion intermediate. Thus, the electron-withdrawing groups that deactivate rings for electrophilic substitution (nitro, carbonyl, cyano, and so forth) activate them for nucleophilic substitution. What’s more, these functional groups are meta directors in electrophilic substitution but are ortho–para directors in nucleophilic substitution. And finally, electrophilic substitutions replace hydrogen on the ring, while nucleophilic substitutions replace a leaving group, usually halide ion. Problems

Science


Benzyne Halobenzenes without electron-withdrawing substituents don’t react with nucleophiles under most conditions. At high temperature and pressure, however, even chlorobenzene can be forced to react. Chemists at the Dow Chemical Company discovered in 1928 that phenol could be prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340 °C under 170 atm pressure. A similar substitution reaction occurs with other strong bases. Treatment of bromobenzene with potassium amide (KNH 2 ) in liquid NH 3 solvent, for instance, gives aniline. Curiously, though, when using bromobenzene labeled with radioactive 14 C at the C1 position, the substitution product has equal amounts of the label at both C1 and C2, implying the presence of a symmetrical reaction intermediate in which C1 and C2 are equivalent. Further mechanistic evidence comes from trapping experiments. When bromobenzene is treated with KNH 2 in the presence of a conjugated diene, such as furan, a Diels–Alder reaction ( ) occurs, implying that the symmetrical intermediate is a benzyne , formed by elimination of HBr from bromobenzene. Benzyne is too reactive to be isolated as a pure compound but, in the presence of water, addition occurs to give phenol. In the presence of a diene, Diels–Alder cycloaddition takes place. The electronic structure of benzyne, shown in , is that of a highly distorted alkyne. Although a typical alkyne triple bond uses sp -hybridized carbon atoms, the benzyne triple bond uses sp 2 -hybridized carbons. Furthermore, a typical alkyne triple bond has two mutually perpendicular π bonds formed by p – p overlap, but the benzyne triple bond has one π bond formed by p – p overlap and one π bond formed by sp 2 – sp 2 overlap. The latter π bond is in the plane of the ring and is very weak. An orbital picture and electrostatic potential map of benzyne . The benzyne carbons are sp 2 -hybridized, and the “third” bond results from weak overlap of two adjacent sp 2 orbitals. Problems

Science


Oxidation of Aromatic Compounds Oxidation of Alkyl Side Chains Despite its unsaturation, the benzene ring is inert to strong oxidizing agents such as KMnO 4 , which will cleave alkene carbon–carbon bonds ( ). It turns out, however, that the presence of the aromatic ring has a dramatic effect on the reactivity of alkyl side chains. These side chains react rapidly with oxidizing agents and are converted into carboxyl groups, –CO 2 H.The net effect is conversion of an alkylbenzene into a benzoic acid, Ar–R → Ar – CO 2 H . Butylbenzene is oxidized by aqueous KMnO 4 to give benzoic acid, for instance. A similar oxidation is employed industrially for the preparation of the terephthalic acid used in the production of polyester fibers. Worldwide, approximately 118 million tons per year of terephthalic acid is produced by oxidation of p -xylene, using air as the oxidant and Co(III) salts as catalyst. The mechanism of side-chain oxidation is complex and involves reaction of C–H bonds at the position next to the aromatic ring to form intermediate benzylic radicals. tert -Butylbenzene has no benzylic hydrogens, however, and is therefore inert. Analogous side-chain oxidations occur in various biosynthetic pathways. The neurotransmitter norepinephrine, for instance, is biosynthesized from dopamine by a benzylic hydroxylation reaction. The process is catalyzed by the copper-containing enzyme dopamine β -monooxygenase and occurs by a radical mechanism. A copper–oxygen species in the enzyme first abstracts the pro-R benzylic hydrogen to give a radical, and a hydroxyl is then transferred from copper to carbon. Problems Bromination of Alkylbenzene Side Chains Side-chain bromination at the benzylic position occurs when an alkylbenzene is treated with N -bromosuccinimide (NBS). For example, propylbenzene gives (1-bromopropyl)benzene in 97% yield on reaction with NBS in the presence of benzoyl peroxide, (PhCO 2 ) 2 , as a radical initiator. Bromination occurs exclusively in the benzylic position next to the aromatic ring and does not give a mixture of products. The mechanism of benzylic bromination is similar to that discussed in for allylic bromination of alkenes. Abstraction of a benzylic hydrogen atom first generates an intermediate benzylic radical, which then reacts with Br 2 in step 2 to yield product and a Br · radical, which cycles back into the reaction to carry on the chain shown below as a summary. The Br 2 needed for reaction with the benzylic radical is produced in step 3 by a concurrent reaction of HBr with NBS. Reaction occurs exclusively at the benzylic position because the benzylic radical intermediate is stabilized by resonance. shows how the benzyl radical is stabilized by overlap of its p orbital with the ringed π electron system. A resonance-stabilized benzylic radical . The spin-density surface shows that the unpaired electron is shared by the ortho and para carbons of the ring. Problems

Science


Reduction of Aromatic Compounds Catalytic Hydrogenation of Aromatic Rings Just as aromatic rings are generally inert to oxidation, they’re also inert to catalytic hydrogenation under conditions that reduce typical alkene double bonds. As a result, it’s possible to reduce an alkene double bond selectively in the presence of an aromatic ring. For example, 4-phenyl-3-buten-2-one is reduced to 4-phenyl-2-butanone using a palladium catalyst at room temperature and atmospheric pressure. Neither the benzene ring nor the ketone carbonyl group is affected. To hydrogenate an aromatic ring, it’s necessary either to use a platinum catalyst with hydrogen gas at a pressure of several hundred atmospheres or to use a more effective catalyst such as rhodium on carbon. Under these conditions, aromatic rings are converted into cyclohexanes. For example, o -xylene yields 1,2-dimethylcyclohexane, and 4- tert -butylphenol gives 4- tert -butylcyclohexanol. Reduction of Aryl Alkyl Ketones In the same way that an aromatic ring activates a neighboring (benzylic) C–H toward oxidation, it also activates a benzylic carbonyl group toward reduction. Thus, an aryl alkyl ketone prepared by Friedel–Crafts acylation of an aromatic ring can be converted into an alkylbenzene by catalytic hydrogenation over a palladium catalyst. Propiophenone, for instance, is reduced to propylbenzene by catalytic hydrogenation. Because the net effect of Friedel–Crafts acylation followed by reduction is the preparation of a primary alkylbenzene, this two-step sequence of reactions makes it possible to circumvent the carbocation rearrangement problems associated with direct Friedel–Crafts alkylation using a primary alkyl halide ( ). The conversion of a carbonyl group into a methylene group ( C=O → CH 2 ) by catalytic hydrogenation is limited to aryl alkyl ketones; dialkyl ketones are not reduced under these conditions. Furthermore, the catalytic reduction of aryl alkyl ketones is not compatible with the presence of a nitro substituent on the aromatic ring because a nitro group is reduced to an amino group under reaction conditions. We’ll see a more general method for reducing ketone carbonyl groups to yield alkanes in Section 19.9 . Problems

Science


Synthesis of Polysubstituted Benzenes As discussed in the Introduction to Organic Synthesis in , one of the surest ways to learn organic chemistry is to work synthesis problems. The ability to plan a successful multistep synthesis of a complex molecule requires a working knowledge of the uses and limitations of a great many organic reactions. Not only must you know which reactions to use, you must also know when to use them because the order in which reactions are carried out is often critical to the success of the overall scheme. The ability to plan a sequence of reactions in the right order is particularly important in the synthesis of substituted aromatic rings, where the introduction of a new substituent is strongly affected by the directing effects of other substituents. Planning syntheses of substituted aromatic compounds is therefore a good way to gain confidence in using the many reactions discussed in the past few chapters. As we said in , it’s usually best to work a synthesis problem backward, or retrosynthetically. Look at the target molecule and ask yourself, “What is an immediate precursor of this compound?” Choose a likely answer and continue working backward, one step at a time, until you arrive at a simple starting material. Let’s try some examples. Synthesizing a Polysubstituted Benzene How would you synthesize 4-bromo-2-nitrotoluene from benzene? Strategy Draw the target molecule, identify the substituents, and recall how each group can be introduced separately. Then plan retrosynthetically. The three substituents on the ring are a bromine, a methyl group, and a nitro group. A bromine can be introduced by bromination with Br 2 /FeBr 3 , a methyl group can be introduced by Friedel–Crafts alkylation with CH 3 Cl/AlCl 3 , and a nitro group can be introduced by nitration with HNO 3 /H 2 SO 4 . Solution Ask yourself, “What is an immediate precursor of the target?” The final step will involve introduction of one of three groups—bromine, methyl, or nitro—so we have to consider three possibilities. Of the three, the bromination of o -nitrotoluene could be used because the activating methyl group would dominate the deactivating nitro group and direct bromination to the correct position. Unfortunately, a mixture of product isomers would be formed. A Friedel–Crafts reaction can’t be used as the final step because this reaction doesn’t work on a nitro-substituted (strongly deactivated) benzene. The best precursor of the desired product is probably p -bromotoluene, which can be nitrated ortho to the activating methyl group to give a single product. Next ask, “What is an immediate precursor of p -bromotoluene?” Perhaps toluene is an immediate precursor because the methyl group would direct bromination to the ortho and para positions. Alternatively, bromobenzene might be an immediate precursor because we could carry out a Friedel–Crafts methylation and obtain a mixture of ortho and para products. Both answers are satisfactory, although both would also lead unavoidably to a mixture of products that would have to be separated. “What is an immediate precursor of toluene?” Benzene, which could be methylated in a Friedel–Crafts reaction. Alternatively, “What is an immediate precursor of bromobenzene?” Benzene, which could be brominated. The retrosynthetic analysis has provided two valid routes from benzene to 4-bromo-2-nitrotoluene. Synthesizing a Polysubstituted Benzene Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene. Strategy Draw the target molecule, identify its substituents, and recall how each of the three can be introduced. Then plan retrosynthetically. The three substituents on the ring are a chlorine, a propyl group, and a sulfonic acid group. A chlorine can be introduced by chlorination with Cl 2 /FeCl 3 , a propyl group can be introduced by Friedel–Crafts acylation with CH 3 CH 2 COCl/AlCl 3 followed by reduction with H 2 /Pd, and a sulfonic acid group can be introduced by sulfonation with SO 3 /H 2 SO 4 . Solution “What is an immediate precursor of the target?” The final step will involve introduction of one of three groups—chlorine, propyl, or sulfonic acid—so we have to consider three possibilities. Of the three, the chlorination of o -propylbenzenesulfonic acid can’t be used because the reaction would occur at the wrong position. Similarly, a Friedel–Crafts reaction can’t be used as the final step because this reaction doesn’t work on sulfonic-acid-substituted (strongly deactivated) benzenes. Thus, the immediate precursor of the desired product is probably m -chloropropylbenzene, which can be sulfonated to give a mixture of product isomers that must then be separated. “What is an immediate precursor of m -chloropropylbenzene?” Because the two substituents have a meta relationship, the first substituent placed on the ring must be a meta director so that the second substitution will take place at the proper position. Furthermore, because primary alkyl groups such as propyl can’t be introduced directly by Friedel–Crafts alkylation, the precursor of m -chloropropylbenzene is probably m -chloropropiophenone, which could be catalytically reduced. “What is an immediate precursor of m -chloropropiophenone?” Propiophenone, which could be chlorinated in the meta position. “What is an immediate precursor of propiophenone?” Benzene, which could undergo Friedel–Crafts acylation with propanoyl chloride and AlCl 3 . The final synthesis is a four-step route from benzene: Planning an organic synthesis has been compared with playing chess. There are no tricks; all that’s required is a knowledge of the allowable moves (the organic reactions) and the discipline to plan ahead, carefully evaluating the consequences of each move. Practicing may not be easy, but it’s a great way to learn organic chemistry. Problems Combinatorial Chemistry Traditionally, organic compounds have been synthesized one at a time. This works well for preparing large amounts of a few substances, but it doesn’t work so well for preparing small amounts of a great many substances. This latter goal is particularly important in the pharmaceutical industry, where vast numbers of structurally similar compounds must be synthesized and screened to find an optimum drug candidate. To speed the process of drug discovery, combinatorial chemistry has been developed to prepare what are called combinatorial libraries, in which anywhere from a few dozen to several hundred thousand substances are prepared simultaneously. Among the early successes of combinatorial chemistry is the development of a benzodiazepine library, a class of aromatic compounds commonly used as antianxiety agents. Two main approaches to combinatorial chemistry are used— parallel synthesis and split synthesis. In parallel synthesis, each compound is prepared independently. Typically, a reactant is first linked to the surface of polymer beads, which are then placed into small wells on a 96-well glass plate. Programmable robotic instruments add different sequences of building blocks to the different wells, thereby making 96 different products. When the reaction sequences are complete, the polymer beads are washed and their products are released. In split synthesis, the initial reactant is again linked to the surface of polymer beads, which are then divided into several groups. A different building block is added to each group of beads, the different groups are combined, and the reassembled mix is again split to form new groups. Another building block is added to each group, the groups are again combined and redivided, and the process continues. If, for example, the beads are divided into four groups at each step, the number of compounds increases in the progression 4 → 16 → 64 → 256. After 10 steps, more than 1 million compounds have been prepared ( ). Of course, with so many different final products mixed together, the problem is to identify them. What structure is linked to what bead? Several approaches to this problem have been developed, all of which involve the attachment of encoding labels to each polymer bead to keep track of the chemistry each has undergone. Encoding labels used thus far have included proteins, nucleic acids, halogenated aromatic compounds, and even computer chips. Organic chemistry by robot means no spilled flasks! The results of split combinatorial synthesis . Assuming that 4 different building blocks are used at each step, 64 compounds result after 3 steps, and more than one million compounds result after 10 steps. acyl group acylation alkylation benzyne combinatorial chemistry electrophilic aromatic substitution Friedel–Crafts reaction inductive effect nucleophilic aromatic substitution resonance effect Summary We’ve continued the coverage of aromatic molecules in this chapter, shifting focus to concentrate on reactions. In particular, we’ve looked at the relationship between aromatic structure and reactivity, a relationship critical to understanding how numerous biological molecules and pharmaceutical agents are synthesized and why they behave as they do. An electrophilic aromatic substitution reaction takes place in two steps—initial reaction of an electrophile, E + , with the aromatic ring, followed by loss of H + from the resonance-stabilized carbocation intermediate to regenerate the aromatic ring. Many variations of the reaction can be carried out, including halogenation, nitration, and sulfonation. Friedel–Crafts alkylation and acylation reactions, which involve reaction of an aromatic ring with carbocation electrophiles, are particularly useful. They are limited, however, by the fact that the aromatic ring must be at least as reactive as a halobenzene. In addition, polyalkylation and carbocation rearrangements often occur in Friedel–Crafts alkylation. Substituents on the benzene ring affect both the reactivity of the ring toward further substitution and the orientation of that substitution. Groups can be classified as ortho- and para-directing activators, ortho- and para-directing deactivators, or meta-directing deactivators. Substituents influence aromatic rings by a combination of resonance and inductive effects. Resonance effects are transmitted through π bonds; inductive effects are transmitted through σ bonds. Halobenzenes undergo nucleophilic aromatic substitution through either of two mechanisms. If the halobenzene has a strongly electron-withdrawing substituent in the ortho or para position, substitution occurs by addition of a nucleophile to the ring, followed by elimination of halide from the intermediate anion. If the halobenzene is not activated by an electron-withdrawing substituent, substitution can occur by elimination of HX to give a benzyne , followed by addition of a nucleophile. The benzylic position of an alkylbenzene can be brominated by reaction with N -bromosuccinimide, and the entire side chain can be degraded to a carboxyl group by oxidation with aqueous KMnO 4 . Aromatic rings can also be reduced to cyclohexanes by hydrogenation over a platinum or rhodium catalyst, and aryl alkyl ketones are reduced to alkylbenzenes by hydrogenation over a platinum catalyst. Summary of Reactions Electrophilic aromatic substitution Fluorination ( ) Bromination ( ) Chlorination ( ) Iodination ( ) Nitration ( ) Sulfonation ( ) Friedel–Crafts alkylation ( ) Friedel–Crafts acylation ( ) Reduction of aromatic nitro groups ( ) Nucleophilic aromatic substitution By addition to activated aryl halides ( ) By formation of benzyne intermediate from unactivated aryl halide ( ) Oxidation of alkylbenzene side chain ( ) Benzylic bromination of alkylbenzene side chain ( ) Catalytic hydrogenation of aromatic ring ( ) Reduction of aryl alkyl ketones ( ) Additional Problems Visualizing Chemistry Mechanism Problems Mechanisms of Electrophilic Substitutions Additional Mechanism Practice Reactivity and Orientation of Electrophilic Substitutions Organic Synthesis General Problems

Science


Why This Chapter? The phenol resveratrol, found in the skin of red grapes, continues to be studied for its potential anti-cancer, antiarthritic, and hypoglycemic properties. (credit: modification of work “Weinreben-Ötlingen” by Pierre Likissas/Wikimedia Commons, CC BY 3.0) Up to this point, we’ve focused on developing some general ideas of organic reactivity, looking at the chemistry of hydrocarbons and alkyl halides, and examining some of the tools used in structural studies. With that background, it’s now time to begin a study of the oxygen-containing functional groups that lie at the heart of organic and biological chemistry. We’ll look at alcohols in this chapter and move on to carbonyl compounds in Chapters 19 through 23. Alcohols and phenols can be thought of as organic derivatives of water in which one of water’s hydrogens is replaced by an organic group: H–O–H versus R–O–H and Ar–O–H. In practice, the name alcohol is restricted to compounds that have their –OH group bonded to a saturated, sp 3 -hybridized carbon atom, while compounds with their –OH group bonded to a vinylic, sp 2 -hybridized carbon are called enols . We’ll look at enols in Chapter 22. Alcohols occur widely in nature and have many industrial and pharmaceutical applications. Methanol, for instance, is one of the most important of all industrial chemicals. Historically, methanol was prepared by heating wood in the absence of air and thus came to be called wood alcohol. Today, approximately 173 million tons (50 billion gallons) of methanol is manufactured worldwide each year, most of it by catalytic reduction of carbon monoxide with hydrogen gas. Methanol is toxic to humans, causing blindness in small doses (15 mL) and death in larger amounts (100–250 mL). Industrially, it is used both as a solvent and as a starting material for production of formaldehyde (CH 2 O) and acetic acid (CH 3 CO 2 H). Ethanol was one of the first organic chemicals to be prepared and purified. Its production by fermentation of grains and sugars has been carried out for perhaps 9000 years, and its purification by distillation goes back at least as far as the 12th century. Today, approximately 88 million tons (26 billion gallons) of ethanol are produced worldwide each year, most of it by fermentation of corn, barley, sorghum, and other plant sources. Almost all of this ethanol is used for bus and automobile fuel. Ethanol for industrial use as a solvent or chemical intermediate is largely obtained by acid-catalyzed hydration of ethylene at high temperature. Phenols occur widely throughout nature and also serve as intermediates in the industrial synthesis of products as diverse as adhesives and antiseptics. Phenol itself is a general disinfectant found in coal tar; methyl salicylate is a flavoring agent found in oil of wintergreen; and urushiols are the allergenic constituents of poison oak and poison ivy. Note that the word phenol is the name both of the specific compound (hydroxybenzene) and of the class of compounds.

Science


Naming Alcohols and Phenols Alcohols are classified as primary (1°), secondary (2°), or tertiary (3°), depending on the number of organic groups bonded to the hydroxyl-bearing carbon. Simple alcohols are named in the IUPAC system as derivatives of the parent alkane, using the suffix - ol. RULE 1 Select the longest carbon chain containing the hydroxyl group, and derive the parent name by replacing the - e ending of the corresponding alkane with - ol. The - e is deleted to prevent the occurrence of two adjacent vowels: propanol rather than propaneol, for example. RULE 2 Number the alkane chain beginning at the end nearer the hydroxyl group. RULE 3 Number the substituents according to their position on the chain, and write the name, listing the substituents in alphabetical order and identifying the position to which the –OH is bonded. Note that in naming cis -1,4-cyclohexanediol, the final -e of cyclohexane is not deleted because the next letter, d, is not a vowel; that is, cyclohexanediol rather than cyclohexandiol. Also, as with alkenes ( ), newer IUPAC naming recommendations place the locant immediately before the suffix rather than before the parent. Some simple and widely occurring alcohols have common names that are accepted by IUPAC. For example: Phenols are named as described previously for aromatic compounds according to the rules discussed in , with - phenol used as the parent name rather than - benzene. Problems

Science


Properties of Alcohols and Phenols Alcohols and phenols have nearly the same geometry around the oxygen atom as water. The R–O–H bond angle has an approximately tetrahedral value (108.5° in methanol, for instance), and the oxygen atom is sp 3 -hybridized. Also like water, alcohols and phenols have higher boiling points than might be expected, because of hydrogen-bonding ( ). A positively polarized –OH hydrogen atom from one molecule is attracted to a lone pair of electrons on the electronegative oxygen atom of another molecule, resulting in a weak force that holds the molecules together ( ). These intermolecular attractions must be overcome for a molecule to break free from the liquid and enter the vapor state, so the boiling temperature is raised. For example, 1-propanol (MW = 60), butane (MW = 58), and chloroethane (MW = 65) have similar molecular weights, yet 1-propanol boils at 97 °C, compared with –0.5 °C for the alkane and 12.5 °C for the chloroalkane. Hydrogen-bonding in alcohols and phenols . Attraction between a positively polarized –OH hydrogen and a negatively polarized oxygen holds molecules together. The electrostatic potential map of methanol shows the positively polarized –OH hydrogen and the negatively polarized oxygen. Another similarity with water is that alcohols and phenols are both weakly basic and weakly acidic. As weak bases, they are reversibly protonated by strong acids to yield oxonium ions, ROH 2 + . As weak acids, they dissociate slightly in dilute aqueous solution by donating a proton to water, generating H 3 O + and an alkoxide ion, RO – , or a phenoxide ion, ArO – . Recall from the earlier discussion of acidity in to that the strength of any acid HA in water can be expressed by an acidity constant, K a . K a = [ A − ] [ H 3 O + ] [ HA ] p K a = − log K a Compounds with a smaller K a and larger p K a are less acidic, whereas compounds with a larger K a and smaller p K a are more acidic. As shown in , simple alcohols like methanol and ethanol are about as acidic as water, but the more highly substituted tert -butyl alcohol is somewhat weaker. Substituent groups also have a significant effect: 2,2,2-trifluoroethanol is approximately 3700 times stronger than ethanol, for instance. Phenols and thiols, the sulfur analogs of alcohols, are substantially more acidic than water. Acidity Constants of Some Alcohols and Phenols Compound p K a (CH 3 ) 3 COH 18 CH 3 CH 2 OH 16 H 2 O 15.74 CH 3 OH 15.54 CF 3 CH 2 OH 12.43 p -Aminophenol 10.46 CH 3 SH 10.3 p -Methylphenol 10.17 Phenol 9.89 p -Chlorophenol 9.38 p -Nitrophenol 7.15 The effect of alkyl substitution on alcohol acidity is due primarily to solvation of the alkoxide ion formed on acid dissociation. The more readily the alkoxide ion is solvated by water, the more stable it is, the more its formation is energetically favored, and the greater the acidity of the parent alcohol. For example, the oxygen atom of an unhindered alkoxide ion, such as that from methanol, is sterically accessible and is easily solvated by water. The oxygen atom of a hindered alkoxide ion, however, such as that from tert -butyl alcohol, is less easily solvated and is therefore less stable. Inductive effects ( ) are also important in determining alcohol acidities. Electron-withdrawing halogen substituents, for instance, stabilize an alkoxide ion by spreading the charge over a larger volume, thus making the alcohol more acidic. Compare, for instance, the acidities of ethanol (p K a = 16) and 2,2,2-trifluoroethanol (p K a = 12.43), or of tert -butyl alcohol (p K a = 18) and nonafluoro- tert -butyl alcohol (p K a = 5.4). Because alcohols are weak acids, they don’t react with weak bases, such as amines or bicarbonate ion, and they only react to a limited extent with metal hydroxides such as NaOH. Alcohols do, however, react with alkali metals and with strong bases such as sodium hydride (NaH), sodium amide (NaNH 2 ), and Grignard reagents (RMgX). Alkoxides are themselves bases that are frequently used as reagents in organic chemistry. They are named systematically by adding the - ate suffix to the name of the alcohol. Methanol becomes methanolate, for instance. Phenols are about a million times more acidic than alcohols ( ). They are therefore soluble in dilute aqueous NaOH and can often be separated from a mixture simply by basic extraction into aqueous solution, followed by reacidification. Phenols are more acidic than alcohols because the phenoxide anion is resonance-stabilized. Delocalization of the negative charge over the ortho and para positions of the aromatic ring results in increased stability of the phenoxide anion relative to undissociated phenol and in a consequently lower ∆ G ° for dissociation. compares electrostatic potential maps of an alkoxide ion (CH 3 O – ) with phenoxide ion to show how the negative charge in phenoxide ion is delocalized from oxygen to the ring. The resonance-stabilized phenoxide ion is more stable than an alkoxide ion . Electrostatic potential maps show how the negative charge is concentrated on oxygen in the methoxide ion but is spread over the aromatic ring in the phenoxide ion. Substituted phenols can be either more acidic or less acidic than phenol itself, depending on whether the substituent is electron-withdrawing or electron-donating ( ). Phenols with an electron-withdrawing substituent are more acidic because these substituents delocalize the negative charge; phenols with an electron-donating substituent are less acidic because these substituents concentrate the charge. The acidifying effect of an electron-withdrawing substituent is particularly noticeable in phenols with a nitro group at the ortho or para position. Predicting the Relative Acidity of a Substituted Phenol Is p -hydroxybenzaldehyde more acidic or less acidic than phenol? Strategy Identify the substituent on the aromatic ring, and decide whether it is electron-donating or electron-withdrawing. Electron-withdrawing substituents make the phenol more acidic by stabilizing the phenoxide anion, and electron-donating substituents make the phenol less acidic by destabilizing the anion. Solution We saw in that a carbonyl group is electron-withdrawing. Thus, p -hydroxybenzaldehyde is more acidic (p K a = 7.9) than phenol (p K a = 9.89). Problems

Science


Preparation of Alcohols: A Review Alcohols occupy a central position in organic chemistry. They can be prepared from many other kinds of compounds (alkenes, alkyl halides, ketones, esters, and aldehydes, among others), and they can be transformed into an equally wide assortment of compounds ( ). The central position of alcohols in organic chemistry . Alcohols can be prepared from, and converted into, many other kinds of compounds. We’ve already seen several methods of alcohol synthesis: Alcohols can be prepared by hydration of alkenes. Because the direct hydration of alkenes with aqueous acid is generally a poor reaction in the laboratory, two indirect methods are commonly used. Hydroboration–oxidation yields the syn, non-Markovnikov hydration product ( ), whereas oxymercuration–demercuration yields the Markovnikov hydration product ( ). 1,2-Diols can be prepared either by direct hydroxylation of an alkene with OsO 4 followed by reduction with NaHSO 3 or by acid-catalyzed hydrolysis of an epoxide ( ). The OsO 4 reaction occurs with syn stereochemistry to give a cis diol, and epoxide opening occurs with anti stereochemistry to give a trans diol. Problems

Science


Alcohols from Carbonyl Compounds: Reduction The most general method for preparing alcohols, both in the laboratory and in living organisms, is by reduction of a carbonyl compound. Just as reduction of an alkene adds hydrogen to a C=C bond to give an alkane ( ), reduction of a carbonyl compound adds hydrogen to a C=O bond to give an alcohol. All kinds of carbonyl compounds can be reduced, including aldehydes, ketones, carboxylic acids, and esters. Reduction of Aldehydes and Ketones Aldehydes are easily reduced to give primary alcohols, and ketones are reduced to give secondary alcohols. Dozens of reagents are used in the laboratory to reduce aldehydes and ketones, depending on the circumstances, but sodium borohydride, NaBH 4 , is usually chosen because of its safety and ease of handling. Sodium borohydride is a white, crystalline solid that can be weighed in the open atmosphere and used in either water or alcohol solution. Lithium aluminum hydride, LiAlH 4 , is another reducing agent often used for reduction of aldehydes and ketones. A grayish powder that is soluble in ether and tetrahydrofuran, LiAlH 4 is much more reactive than NaBH 4 but also much more dangerous. It reacts violently with water and decomposes explosively when heated above 120 °C. We’ll defer a detailed discussion of these reductions until Chapter 19. For the moment, we’ll simply note that they involve the addition of a nucleophilic hydride ion ( : H – ) to the positively polarized, electrophilic carbon atom of the carbonyl group. The initial product is an alkoxide ion, which is protonated by addition of H 3 O + in a second step to yield the alcohol product. In living organisms, aldehyde and ketone reductions are carried out by either of the coenzymes NADH (reduced nicotinamide adenine dinucleotide) or NADPH (reduced nicotinamide adenine dinucleotide phosphate). Although these biological “reagents” are much more complex structurally than NaBH 4 or LiAlH 4 , the mechanisms of laboratory and biological reactions are similar. The coenzyme acts as a hydride-ion donor to give an alkoxide anion, and the intermediate anion is then protonated by acid. An example is the reduction of acetoacetyl ACP to β -hydroxybutyryl ACP, a step in the biological synthesis of fats ( ). Note that the pro- R hydrogen of NADPH is the one transferred in this example. Enzyme-catalyzed reactions usually occur with high specificity, although it’s not usually possible to predict the stereochemical result before the fact. The biological reduction of a ketone (acetoacetyl ACP) to an alcohol ( β -hydroxybutyryl ACP) by NADPH . Reduction of Carboxylic Acids and Esters Carboxylic acids and esters are reduced to give primary alcohols. These reactions aren’t as rapid as the reductions of aldehydes and ketones. NaBH 4 reduces esters very slowly and does not reduce carboxylic acids at all. Instead, carboxylic acid and ester reductions are usually carried out with the more reactive reducing agent LiAlH 4 . All carbonyl groups, including acids, esters, ketones, and aldehydes, are reduced by LiAlH 4 . Note that one hydrogen atom is delivered to the carbonyl carbon atom during aldehyde and ketone reductions but that two hydrogens become bonded to the former carbonyl carbon during carboxylic acid and ester reductions. We’ll defer a discussion of the mechanisms of these reactions until Chapter 21. Identifying a Reactant, Given the Product What carbonyl compounds would you reduce to obtain the following alcohols? Strategy Identify the target alcohol as primary, secondary, or tertiary. A primary alcohol can be prepared by reduction of an aldehyde, an ester, or a carboxylic acid; a secondary alcohol can be prepared by reduction of a ketone; and a tertiary alcohol can’t be prepared by reduction. Solution (a) The target molecule is a secondary alcohol, which can be prepared only by reduction of a ketone. Either NaBH 4 or LiAlH 4 can be used. (b) The target molecule is a primary alcohol, which can be prepared by reduction of an aldehyde, an ester, or a carboxylic acid. LiAlH 4 is needed for the ester and carboxylic acid reductions. Problems

Science


Alcohols from Carbonyl Compounds: Grignard Reaction Grignard reagents (RMgX), prepared by reaction of organohalides with magnesium ( ), react with carbonyl compounds to yield alcohols in much the same way that hydride reducing agents do. Just as carbonyl reduction involves addition of a hydride ion nucleophile to the C=O bond, Grignard reaction involves addition of a carbanion nucleophile (R: −+ MgX). The nucleophilic addition reaction of Grignard reagents to carbonyl compounds has no direct counterpart in biological chemistry because organomagnesium compounds are too strongly basic to exist in an aqueous medium. Nevertheless, the reaction is worth understanding for two reasons. First, the reaction is an unusually broad and useful method of alcohol synthesis and demonstrates again the relative freedom with which chemists can operate in the laboratory. Second, the reaction does have an indirect biological counterpart, for we’ll see in Chapter 23 that the addition of stabilized carbon nucleophiles to carbonyl compounds is used in almost all metabolic pathways as the major process for forming carbon–carbon bonds. As examples of their addition to carbonyl compounds, Grignard reagents react with formaldehyde, H 2 C =O , to give primary alcohols, with aldehydes to give secondary alcohols, and with ketones to give tertiary alcohols. Esters react with Grignard reagents to yield tertiary alcohols in which two of the substituents bonded to the hydroxyl-bearing carbon have come from the Grignard reagent, just as LiAlH 4 reduction of an ester adds two hydrogens. Carboxylic acids don’t give addition products when treated directly with Grignard reagents because the acidic carboxyl hydrogen reacts with the basic Grignard reagent to yield a hydrocarbon and the magnesium salt of the acid. Carboxylic acids do, however, react with Grignard reagents to give ketones if they are first treated with i -Pr 2 NMgCl-LiCl, called the turbo -Hauser base, to form a complex and increase the electrophilicity of the carboxylate anion toward nucleophilic addition with a Grignard reagent. The Grignard reaction, although useful, does have limitations. One major problem is that a Grignard reagent can’t be prepared from an organohalide if other reactive functional groups are present in the same molecule. For example, a compound that is both an alkyl halide and a ketone can’t form a Grignard reagent because it would react with itself. Similarly, a compound that is both an alkyl halide and a carboxylic acid, alcohol, or amine can’t form a Grignard reagent because the acidic RCO 2 H , RO H , or RN H 2 hydrogen present in the same molecule would react with the basic Grignard reagent as rapidly as it forms. In general, Grignard reagents can’t be prepared from alkyl halides that contain the following functional groups (FG): As with the reduction of carbonyl compounds discussed in the previous section, we’ll defer a detailed treatment of the Grignard reactions until Chapter 19. For the moment, it’s sufficient to note that Grignard reagents act as nucleophilic carbanions ( : R – ) and that their addition to a carbonyl compound is analogous to the addition of hydride ion. The intermediate is an alkoxide ion, which is protonated by addition of H 3 O + in a second step. Using a Grignard Reaction to Synthesize an Alcohol How could you use the addition of a Grignard reagent to a ketone to synthesize 2-phenyl-2-butanol? Strategy Draw the product, and identify the three groups bonded to the alcohol carbon atom. One of the three will have come from the Grignard reagent, and the remaining two will have come from the ketone. Solution 2-Phenyl-2-butanol has a methyl group, an ethyl group, and a phenyl group (–C 6 H 5 ) attached to the alcohol carbon atom. Thus, the possibilities are addition of ethylmagnesium bromide to acetophenone, addition of methylmagnesium bromide to propiophenone, and addition of phenylmagnesium bromide to 2-butanone. Using a Grignard Reaction to Synthesize an Alcohol How could you use the reaction of a Grignard reagent with a carbonyl compound to synthesize 2-methyl-2-pentanol? Strategy Draw the product, and identify the three groups bonded to the alcohol carbon atom. If the three groups are all different, the starting carbonyl compound must be a ketone. If two of the three groups are identical, the starting carbonyl compound could be either a ketone or an ester. Solution In the present instance, the product is a tertiary alcohol with two methyl groups and one propyl group. Starting from a ketone, the possibilities are addition of methylmagnesium bromide to 2-pentanone and addition of propylmagnesium bromide to acetone. Starting from an ester, the only possibility is addition of methylmagnesium bromide to an ester of butanoic acid, such as methyl butanoate. Problems

Science


Reactions of Alcohols We’ve already seen several reactions of alcohols—their conversion into alkyl halides and tosylates in and their dehydration to give alkenes in —albeit without mechanistic details. Let’s now look at those details. Conversion of Alcohols into Alkyl Halides Tertiary alcohols react with either HCl or HBr at 0 °C by an S N 1 mechanism through a carbocation intermediate. Primary and secondary alcohols are much more resistant to acid, however, and are best converted into halides by treatment with either SOCl 2 or PBr 3 through an S N 2 mechanism. The reaction of a tertiary alcohol with HX takes place by an S N 1 mechanism when acid protonates the hydroxyl oxygen atom. Water is expelled to generate a carbocation, and the cation reacts with nucleophilic halide ion to give the alkyl halide product. The reactions of primary and secondary alcohols with SOCl 2 and PBr 3 take place by S N 2 mechanisms. Hydroxide ion itself is too poor a leaving group to be displaced by nucleophiles in S N 2 reactions, but reaction of an alcohol with SOCl 2 or PBr 3 converts the –OH into a much better leaving group, either a chlorosulfite (–OSOCl) or a dibromophosphite (–OPBr 2 ), which is readily expelled by backside nucleophilic substitution. Conversion of Alcohols into Tosylates Alcohols react with p -toluenesulfonyl chloride (tosyl chloride, p -TosCl) in pyridine solution to yield alkyl tosylates, ROTos ( ). Only the O–H bond of the alcohol is broken in this reaction; the C–O bond remains intact, so no change of configuration occurs if the oxygen is attached to a chirality center. The resultant alkyl tosylates behave much like alkyl halides, undergoing both S N 1 and S N 2 substitution reactions. One of the most important reasons for using tosylates in S N 2 reactions is stereochemical. The S N 2 reaction of an alcohol with an alkyl halide proceeds with two inversions of configuration—one to make the halide from the alcohol and one to substitute the halide—and yields a product with the same stereochemistry as the starting alcohol. The S N 2 reaction of an alcohol with a tosylate, however, proceeds with only one inversion and yields a product of opposite stereochemistry to the starting alcohol. shows a series of reactions on the R enantiomer of 2-octanol that illustrates these stereochemical relationships. Stereochemical consequences of S N 2 reactions on derivatives of ( R )-2-octanol . Substitution through the halide gives a product with the same stereochemistry as the starting alcohol; substitution through the tosylate gives a product with opposite stereochemistry to the starting alcohol. Problems Dehydration of Alcohols to Yield Alkenes A third important reaction of alcohols, both in the laboratory and in biological pathways, is their dehydration to give alkenes. Because of the usefulness of the reaction, a number of methods have been devised for carrying out dehydrations. One method that works particularly well for tertiary alcohols is the acid-catalyzed reaction discussed in . For example, treatment of 1-methylcyclohexanol with warm, aqueous sulfuric acid in a solvent such as tetrahydrofuran results in loss of water and formation of 1-methylcyclohexene. Acid-catalyzed dehydrations usually follow Zaitsev’s rule ( ) and yield the more stable alkene as the major product. Thus, 2-methyl-2-butanol gives primarily 2-methyl-2-butene (trisubstituted double bond) rather than 2-methyl-1-butene (disubstituted double bond). This reaction is an E1 process ( ) and occurs by the three-step mechanism shown in on the next page. Protonation of the alcohol oxygen is followed by unimolecular loss of water to generate a carbocation intermediate and final loss of a proton from the neighboring carbon atom to complete the process. As with most E1 reactions, tertiary alcohols react fastest because they lead to stabilized, tertiary carbocation intermediates. Secondary alcohols can be made to react, but the conditions are severe (75% H 2 SO 4 , 100 °C) and sensitive molecules don’t survive. MECHANISM Mechanism for the acid-catalyzed dehydration of a tertiary alcohol to yield an alkene . The process is an E1 reaction and involves a carbocation intermediate. To circumvent the need for strong acid and allow the dehydration of secondary alcohols in a gentler way, reagents have been developed that are effective under mild, basic conditions. One such reagent, phosphorus oxychloride (POCl 3 ) in the basic amine solvent pyridine, is often able to effect the dehydration of secondary and tertiary alcohols at 0 °C. Alcohol dehydrations carried out with POCl 3 in pyridine take place by an E2 mechanism, as shown in . Because hydroxide ion is a poor leaving group ( ), direct E2 elimination of water from an alcohol does not occur. On reaction with POCl 3 , however, the –OH group is converted into a dichlorophosphate (–OPOCl 2 ), which is a good leaving group and is readily eliminated. Pyridine is both the reaction solvent and the base that removes a neighboring proton in the E2 elimination step. MECHANISM Mechanism for the dehydration of secondary and tertiary alcohols by reaction with POCl 3 in pyridine . The reaction is an E2 process. As noted in , biological dehydrations are also common and usually occur by an E1cB mechanism on a substrate in which the –OH group is two carbons away from a carbonyl group. One example occurs in the biosynthesis of the aromatic amino acid tyrosine. A base ( : B) first abstracts a proton from the carbon adjacent to the carbonyl group, and the anion intermediate then expels the –OH group with simultaneous protonation by an acid (HA) to form water. Problems Conversion of Alcohols into Esters Alcohols react with carboxylic acids to give esters, a reaction that is common in both the laboratory and living organisms. In the laboratory, the reaction can be carried out in a single step if a strong acid is used as catalyst. More frequently, though, the reactivity of the carboxylic acid is enhanced by first converting it into a carboxylic acid chloride, which then reacts with the alcohol. In living organisms, a similar process occurs, though a thioester or acyl adenosyl phosphate acts as substrate rather than a carboxylic acid chloride. We’ll look at the mechanisms of these reactions in Chapter 21.

Science


Oxidation of Alcohols Perhaps the most valuable reaction of alcohols is their oxidation to give carbonyl compounds—the opposite of the reduction of carbonyl compounds to give alcohols. Primary alcohols are oxidized either to aldehydes or carboxylic acids, and secondary alcohols are oxidized to ketones, but tertiary alcohols don’t normally react with most oxidizing agents. Primary and secondary alcohols can be oxidized by any of a number of reagents, including CrO 3 in aqueous acetic acid and KMnO 4 in aqueous NaOH, but chromium-based reagents are rarely used today because of their toxicity and fire danger. Today, primary and secondary alcohols are oxidized to aldehydes and ketones, respectively, using the iodine-containing Dess–Martin periodinane in dichloromethane solution. Primary alcohols are oxidized to carboxylic acids by heating with KMnO 4 in a basic aqueous solution. An aldehyde is involved as an intermediate in the KMnO 4 reaction but can’t usually be isolated because it is further oxidized too rapidly. All these oxidations occur by a mechanism that is closely related to the E2 reaction ( ). In the Dess–Martin oxidation, for instance, the first step involves a substitution reaction between the alcohol and the I(V) reagent to form a new periodinane intermediate, followed by expulsion of reduced I(III) as the leaving group. Similarly, when a Cr(VI) reagent, such as CrO 3 , is the oxidant, reaction with the alcohol gives a chromate intermediate followed by expulsion of a reduced Cr(VI) species. Biological alcohol oxidations are the opposite of biological carbonyl reductions and are facilitated by the coenzymes NAD + and NADP + . A base removes the –OH proton, and the alkoxide ion transfers a hydride ion to the coenzyme. An example is the oxidation of sn -glycerol 3-phosphate to dihydroxyacetone phosphate, a step in the biological metabolism of fats ( ). Note that addition occurs exclusively on the Re face of the NAD + ring, adding a hydrogen with pro- R stereochemistry. The biological oxidation of an alcohol ( sn -glycerol 3-phosphate) to give a ketone (dihydroxyacetone phosphate) . This mechanism is the exact opposite of the ketone reduction shown previously in . Problems

Science


Protection of Alcohols It often happens, particularly during the synthesis of complex molecules, that one functional group in a molecule interferes with an intended reaction on another functional group elsewhere in the same molecule. We saw earlier in this chapter, for instance, that a Grignard reagent can’t be prepared from an alcohol-containing halide because the C–Mg bond is not compatible with the presence of an acidic –OH group in the same molecule. When this kind of incompatibility arises, it’s sometimes possible to circumvent the problem by protecting the interfering functional group. Protection involves three steps: ( 1 ) introducing a protecting group to block the interfering function, ( 2 ) carrying out the desired reaction, and ( 3 ) removing the protecting group. One of the more common methods of alcohol protection involves reaction with a chlorotrialkylsilane, Cl–SiR 3 , to yield a trialkylsilyl ether, R′–O–SiR 3 . (Chloro -tert -butyldimethylsilane), usually abbreviated either TBS or TBDMS is often used, as is chlorotrimethylsilane (TMS), and the reaction is carried out in the presence of a base, such as triethylamine, to help form the alkoxide anion from the alcohol and to remove the HCl by-product from the reaction. The ether-forming step is an S N 2-like reaction of the alkoxide ion on the silicon atom, with concurrent loss of the leaving chloride anion. Unlike most S N 2 reactions, though, this reaction takes place at a tertiary center—a trialkyl-substituted silicon atom. The reaction occurs because silicon, a third-row atom, is larger than carbon and forms longer bonds. In addition, three alkyl substituents attached to silicon offer little steric hindrance to ether formation. Like most other ethers, which we’ll study in the next chapter, trialkylsilylethers are relatively unreactive. They have no acidic hydrogens and don’t react with oxidizing agents, reducing agents, or Grignard reagents. They do, however, react with aqueous acid or with fluoride ion to regenerate the alcohol. Tetrabutylammonium fluoride is often used. To solve the problem posed at the beginning of this section, note that it’s possible to use an alcohol-containing halide in a Grignard reaction by employing a protection sequence. For example, we can add 3-bromo-1-propanol to acetaldehyde by the route shown in . Use of a trialkylsilyl-protected alcohol during a Grignard reaction . Problems

Science


Phenols and Their Uses The outbreak of World War I provided a stimulus for the industrial preparation of large amounts of synthetic phenol, which was needed as a raw material to manufacture the explosive, picric acid (2,4,6-trinitrophenol). Today, approximately 132 million tons of phenol is manufactured worldwide each year for use in such products as Bakelite resin and adhesives for binding plywood. Phenol was manufactured for many years by the Dow process, in which chlorobenzene reacts with NaOH at high temperature and pressure ( ). Now, however, an alternative synthesis uses isopropylbenzene, commonly called cumene . Cumene reacts with air at high temperature by benzylic oxidation through a radical mechanism to form cumene hydroperoxide, which is converted into phenol and acetone by treatment with acid. This is a particularly efficient process because two valuable chemicals are prepared at the same time. As shown in , the reaction occurs by protonation of oxygen followed by shift of the phenyl group from carbon to oxygen with simultaneous loss of water. Replacement of the water then yields an intermediate called a hemiacetal —a compound that contains one –OR group and one –OH group bonded to the same carbon atom—which breaks down to phenol and acetone. MECHANISM Mechanism for the formation of phenol by acid-catalyzed rearrangement of cumene hydroperoxide . In addition to its use in making resins and adhesives, phenol is also the starting material for the synthesis of chlorinated phenols and the food preservatives BHT (butylated hydroxytoluene) and BHA (butylated hydroxyanisole). Pentachlorophenol, a widely used wood preservative, is prepared by reaction of phenol with excess Cl 2 . The herbicide 2,4-D (2,4-dichlorophenoxyacetic acid) is prepared from 2,4-dichlorophenol, and the hospital antiseptic agent hexachlorophene is prepared from 2,4,5-trichlorophenol. The food preservative BHT is prepared by Friedel–Crafts alkylation of p -methylphenol ( p -cresol) with 2-methylpropene in the presence of acid; BHA is prepared similarly by alkylation of p -methoxyphenol. Problems

Science


Reactions of Phenols Electrophilic Aromatic Substitution Reactions The hydroxyl group is a strongly activating, ortho- and para-directing substituent in electrophilic aromatic substitution reactions ( ). As a result, phenols are highly reactive substrates for electrophilic halogenation, nitration, sulfonation, and Friedel–Crafts reactions. Oxidation of Phenols: Quinones Phenols don’t undergo oxidation in the same way as alcohols because they don’t have a hydrogen atom on the hydroxyl-bearing carbon. Instead, oxidation of a phenol yields a 2,5-cyclohexadiene-1,4-dione, or quinone . Many different oxidizing agents will accomplish the transformation, with Na 2 Cr 2 O 7 as a common choice for simple phenols and potassium nitrosodisulfonate [(KSO 3 ) 2 NO], called Fremy’s salt, is often used. Quinones are a valuable class of compounds because of their oxidation–reduction, or redox, properties. They can be easily reduced to hydroquinones ( p -dihydroxybenzenes) by reagents such as NaBH 4 and SnCl 2 , and hydroquinones can be easily reoxidized back to quinones by Na 2 Cr 2 O 7 . The redox properties of quinones are crucial to the functioning of living cells, where compounds called ubiquinones act as biochemical oxidizing agents to mediate the electron-transfer processes involved in energy production. Ubiquinones, also called coenzymes Q, are components of the cells in all aerobic organisms, from the simplest bacterium to humans. They are so named because of their ubiquitous occurrence throughout nature. Ubiquinones function within the mitochondria of cells to mediate the respiration process in which electrons are transported from the biological reducing agent NADH to molecular oxygen. Through a complex series of steps, the ultimate result is a cycle whereby NADH is oxidized to NAD + , O 2 is reduced to water, and energy is produced. Ubiquinone acts only as an intermediary and is itself unchanged.

Science


Spectroscopy of Alcohols and Phenols Infrared Spectroscopy Alcohols have a strong C–O stretching absorption near 1050 cm –1 and a characteristic O–H stretching absorption at 3300 to 3600 cm –1 . The exact position of the O–H stretch depends on the extent of hydrogen-bonding in the molecule. Unassociated alcohols show a fairly sharp absorption near 3600 cm –1 , whereas hydrogen-bonded alcohols show a broader absorption in the 3300 to 3400 cm –1 range. The hydrogen-bonded hydroxyl absorption appears at 3350 cm –1 in the IR spectrum of cyclohexanol ( ). IR spectrum of cyclohexanol . Characteristic O–H and C–O stretching absorptions are indicated. Phenols also show a characteristic broad IR absorption at 3500 cm –1 due to the –OH group, as well as the usual 1500 and 1600 cm –1 aromatic bands ( ). In phenol itself, monosubstituted aromatic-ring peaks are visible at 690 and 760 cm –1 . IR spectrum of phenol . Problems Nuclear Magnetic Resonance Spectroscopy Carbon atoms bonded to electron-withdrawing –OH groups are deshielded and absorb at a lower field in the 13 C NMR spectrum than do typical alkane carbons. Most alcohol carbon absorptions fall in the range 50 to 80 δ, as shown in the following drawing for cyclohexanol: Alcohols also show characteristic absorptions in the 1 H NMR spectrum. Hydrogens on the oxygen-bearing carbon atom are deshielded by the electron-withdrawing effect of the nearby oxygen, and their absorptions occur in the range 3.4 to 4.5 δ. Spin–spin splitting, however, is not usually observed between the O–H proton of an alcohol and the neighboring protons on carbon. Most samples contain small amounts of acidic impurities, which catalyze an exchange of the O–H proton on a timescale so rapid that the effect of spin–spin splitting is removed. It’s often possible to take advantage of this rapid proton exchange to identify the position of the O–H absorption. If a small amount of deuterated water, D 2 O, is added to an NMR sample tube, the O–H proton is rapidly exchanged for deuterium and the hydroxyl absorption disappears from the spectrum. Typical spin–spin splitting is observed between protons on the oxygen-bearing carbon and other neighbors. For example, the signal of the two –CH 2 O– protons in 1-propanol is split into a triplet by coupling with the neighboring –CH 2 – protons ( ). 1 H NMR spectrum of 1-propanol . The protons on the oxygen-bearing carbon are split into a triplet at 3.58 δ. Phenols, like all aromatic compounds, show 1 H NMR absorptions near 7 to 8 δ, the expected position for aromatic-ring protons ( ). In addition, phenol O–H protons absorb at 3 to 8 δ. In neither case are these absorptions uniquely diagnostic for phenols, since other kinds of protons absorb in the same range. Problems Mass Spectrometry As noted in , alcohols undergo fragmentation in the mass spectrometer by two characteristic pathways, alpha cleavage and dehydration. In the alpha-cleavage pathway, a C–C bond nearest the hydroxyl group is broken, yielding a neutral radical plus a resonance-stabilized, oxygen-containing cation. In the dehydration pathway, water is eliminated, yielding an alkene radical cation. Both fragmentation modes are apparent in the mass spectrum of 1-butanol ( ). The peak at m / z = 56 is due to loss of water from the molecular ion, and the peak at m/z = 31 is due to an alpha cleavage. Mass spectrum of 1-butanol (M + = 74) . Dehydration gives a peak at m / z = 56, and fragmentation by alpha cleavage gives a peak at m / z = 31. Ethanol: Chemical, Drug, and Poison The production of ethanol by fermentation of grains and sugars is one of the oldest known organic reactions, going back at least 8000 years in the Middle East and perhaps as many as 9000 years in China. Fermentation is carried out by adding yeast to an aqueous sugar solution, where enzymes break down carbohydrates into ethanol and CO 2 . As noted in the chapter introduction, approximately 26 billion gallons of ethanol is produced each year by fermentation of corn and sugar, with essentially the entire amount used to make bus and automobile fuel. Ethanol is classified medically as a central nervous system (CNS) depressant. Its effects—that is, being drunk—resemble the human response to anesthetics. There is an initial excitability and increase in sociable behavior, but this results from depression of inhibition rather than from stimulation. At a blood alcohol concentration of 0.1% to 0.3%, motor coordination is affected, accompanied by loss of balance, slurred speech, and amnesia. When blood alcohol concentration rises to between 0.3% and 0.4%, nausea and loss of consciousness occur. Above 0.6%, spontaneous respiration and cardiovascular regulation are affected, ultimately leading to death. The LD 50 of ethanol is 10.6 g/kg ( Chapter 1 Chemistry Matters ). The passage of ethanol through the body begins with its absorption in the stomach and small intestine, followed by rapid distribution to all body fluids and organs. In the pituitary gland, ethanol inhibits the production of a hormone that regulates urine flow, causing increased urine production and dehydration. In the stomach, ethanol stimulates production of acid. Throughout the body, ethanol causes blood vessels to dilate, resulting in flushing of the skin and a sensation of warmth as blood moves into capillaries beneath the surface. The result is not a warming of the body, but an increased loss of heat at the surface. The Harger Drunkometer was the first breath analyzer, introduced in 1938 to help convict drunk drivers. (credit: “Unidentified police officer with a Harger “Drunkometer” breathalyzer” by Florida Memory, State Library and Archives of Florida/Wikimedia Commons, Public Doman) Ethanol metabolism occurs mainly in the liver and proceeds by oxidation in two steps, first to acetaldehyde (CH 3 CHO) and then to acetic acid (CH 3 CO 2 H). When continuously present in the body, ethanol and acetaldehyde are toxic, leading to the devastating physical and metabolic deterioration seen in people with chronic alcohol use disorder. The liver usually suffers the worst damage since it is the major site of alcohol metabolism. Approximately 17,000 people are killed each year in the United States in alcohol-related automobile accidents. Thus, all 50 states have made it illegal to drive with a blood alcohol concentration (BAC) above 0.08%. Fortunately, simple tests have been devised for measuring blood alcohol concentration. The original breath analyzer test measured alcohol concentration in expired air by the color change occurring when the bright-orange oxidizing agent potassium dichromate (K 2 Cr 2 O 7 ) reduced to blue-green chromium(III). Current consumer devices use a conductivity sensor, and tests used by law-enforcement agencies use IR spectroscopy to measure blood-alcohol levels in expired air. Just breathe into the machine, and let the spectrum tell the tale. alcohol alkoxide ion, RO – hydroquinone phenol phenoxide ion ArO – protecting group quinone Summary In previous chapters, we focused on developing general ideas of organic reactivity, looking at the chemistry of hydrocarbons and alkyl halides and seeing some of the tools used in structural studies. With that accomplished, we have now begun to study the oxygen-containing functional groups that lie at the heart of organic and biological chemistry. Alcohols are among the most versatile of all organic compounds. They occur widely in nature, are important industrially, and have an unusually rich chemistry. The most widely used methods of alcohol synthesis start with carbonyl compounds. Aldehydes, esters, and carboxylic acids are reduced by reaction with LiAlH 4 to give primary alcohols (RCH 2 OH); ketones are reduced to yield secondary alcohols (R 2 CHOH). Alcohols are also prepared by reaction of carbonyl compounds with Grignard reagents, RMgX. Addition of a Grignard reagent to formaldehyde yields a primary alcohol, addition to an aldehyde yields a secondary alcohol, and addition to a ketone or an ester yields a tertiary alcohol. The Grignard reaction is limited by the fact that Grignard reagents can’t be prepared from alkyl halides that contain reactive functional groups in the same molecule. This problem can sometimes be avoided by protecting the interfering functional group. Alcohols are often protected by formation of trialkylsilyl ethers. Alcohols undergo many reactions and can be converted into many other functional groups. They can be dehydrated to give alkenes by treatment with POCl 3 and can be transformed into alkyl halides by treatment with PBr 3 or SOCl 2 . Furthermore, alcohols are weakly acidic (p K a ≈ 16–18) and react with strong bases and with alkali metals to form alkoxide anions , which are used frequently in organic synthesis. Perhaps the most important reaction of alcohols is their oxidation to carbonyl compounds. Primary alcohols yield either aldehydes or carboxylic acids, secondary alcohols yield ketones, but tertiary alcohols are not normally oxidized. Phenols are aromatic counterparts of alcohols but are more acidic (p K a ≈ 10) because their corresponding phenoxide anions are resonance stabilized by delocalization of the negative charge into the aromatic ring. Substitution of the aromatic ring by an electron-withdrawing group increases phenol acidity, and substitution by an electron-donating group decreases acidity. Phenols can be oxidized to quinones , and quinones can be reduced back to hydroquinones . Summary of Reactions Synthesis of alcohols Reduction of carbonyl compounds ( ) (1) Aldehydes (2) Ketones (3) Esters (4) Carboxylic acids Grignard addition to carbonyl compounds ( ) (1) Formaldehyde (2) Aldehydes (3) Ketones (4) Esters Reactions of alcohols Dehydration ( ) (1) Tertiary alcohols (2) Secondary and tertiary alcohols Oxidation ( ) (1) Primary alcohols (2) Secondary alcohols Oxidation of phenols to quinones ( ) Additional Problems Visualizing Chemistry Mechanism Problems Naming Alcohols Synthesizing Alcohols Reactions of Alcohols Spectroscopy General Problems

Science


Why This Chapter? The appalling and unforgettable odor of skunks is due to a mixture of several simple thiols . (credit: modification of work “Striped Skunk” by Tom Friedel/Wikimedia Commons, CC BY 3.0) This chapter finishes the coverage of functional groups with C–O and C–S single bonds that was begun in the chapter on Alcohols and Phenols . We’ll focus primarily on ethers and take only a brief look at thiols and sulfides before going on to an extensive coverage of compounds with C=O double bonds in Chapters 19 through 23. Ethers (R–O–R′) , like the alcohols we saw in the preceding chapter, are organic derivatives of water, but they have two organic groups bonded to the same oxygen atom rather than one. The organic groups might be alkyl, aryl, or vinylic, and the oxygen atom might be in an open chain or a ring. Perhaps the most well-known ether is diethyl ether, which has a long history of medicinal use as an anesthetic and industrial use as a solvent. Other useful ethers include anisole, a pleasant-smelling aromatic ether used in perfumery, and tetrahydrofuran (THF), a cyclic ether often used as a solvent. Thiols (R–S–H) and sulfides (R–S–R′) are sulfur analogs of alcohols and ethers, respectively. Both functional groups are found in various biomolecules, although not as commonly as their oxygen-containing relatives.

Science


Names and Properties of Ethers Simple ethers with no other functional groups are named by identifying the two organic substituents and adding the word ether. If other functional groups are present, the ether part is considered an alkoxy substituent. For example: Like alcohols, ethers have nearly the same geometry as water. The R–O–R bonds have an approximately tetrahedral bond angle (112° in dimethyl ether), and the oxygen atom is sp 3 -hybridized. The electronegative oxygen atom gives ethers a slight dipole moment, and the boiling points of ethers are often slightly higher than the boiling points of comparable alkanes. compares the boiling points of some common ethers and their corresponding hydrocarbons. Comparison of Boiling Points of Ethers and Hydrocarbons Ether Boiling point °C Hydrocarbon Boiling point °C CH 3 OCH 3 –25 CH 3 CH 2 CH 3 –45 CH 3 CH 2 OCH 2 CH 3 34.6 CH 3 CH 2 CH 2 CH 2 CH 3 36 65 49 158 136 Ethers are relatively stable and unreactive in many respects, but some ethers react slowly with the oxygen in air to give peroxides, compounds that contain an O–O bond. The peroxides from low-molecular-weight ethers such as diisopropyl ether and tetrahydrofuran are explosive and extremely dangerous, even in small amounts. Ethers are very useful as solvents in the laboratory, but they must always be used cautiously and should not be stored for long periods of time. Problems

Science


Preparing Ethers Diethyl ether and other simple symmetrical ethers are prepared industrially by the sulfuric-acid-catalyzed reaction of alcohols. The reaction occurs by S N 2 displacement of water from a protonated ethanol molecule by the oxygen atom of a second ethanol. Unfortunately, this method is limited to use with primary alcohols because secondary and tertiary alcohols dehydrate by an E1 mechanism to yield alkenes ( ). The Williamson Ether Synthesis The most generally useful method of preparing ethers is the Williamson ether synthesis , in which an alkoxide ion reacts with a primary alkyl halide or tosylate in an S N 2 reaction. As we saw in , the alkoxide ion is normally prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH. A useful variation of the Williamson synthesis involves silver oxide, Ag 2 O, as a mild base rather than NaH. Under these conditions, the free alcohol reacts directly with the alkyl halide, so there is no need to preform the metal alkoxide intermediate. Sugars react particularly well; glucose, for example, reacts with excess iodomethane in the presence of Ag 2 O to generate a pentaether in 85% yield. Because the Williamson synthesis is an S N 2 reaction, it is subject to all the usual constraints, as discussed in . Primary halides and tosylates work best because competitive E2 elimination can occur with more hindered substrates. Unsymmetrical ethers should therefore be synthesized by reaction between the more hindered alkoxide partner and less hindered halide partner rather than vice versa. For example, tert -butyl methyl ether, a substance used in the 1990s as an octane booster in gasoline, is best prepared by reaction of tert -butoxide ion with iodomethane rather than by reaction of methoxide ion with 2-chloro-2-methylpropane. Problems Alkoxymercuration of Alkenes We saw in that alkenes react with water in the presence of mercuric acetate to yield a hydroxymercuration product. Subsequent treatment with NaBH 4 breaks the C–Hg bond and yields the alcohol. A similar alkoxymercuration reaction occurs when an alkene is treated with an alcohol in the presence of mercuric acetate or, even better, mercuric trifluoroacetate, (CF 3 CO 2 ) 2 Hg. Demercuration by reaction with NaBH 4 then yields an ether. The net result is Markovnikov addition of the alcohol to the alkene. The mechanism of the alkoxymercuration reaction is similar to that described in for hydroxymercuration. The reaction is initiated by electrophilic addition of Hg 2+ to the alkene, followed by reaction of the intermediate cation with alcohol and reduction of the C–Hg bond by NaBH 4 . A variety of alcohols and alkenes can be used in alkoxymercuration. Primary, secondary, and even tertiary alcohols react well, but ditertiary ethers can’t be prepared because of steric hindrance. Synthesizing an Ether How would you prepare ethyl phenyl ether? Use whichever method you think is more appropriate, Williamson synthesis or the alkoxymercuration reaction. Strategy Draw the target ether, identify the two groups attached to oxygen, and recall the limitations of the two methods for preparing ethers. Williamson synthesis uses an S N 2 reaction and requires that one of the two groups attached to oxygen be either secondary or (preferably) primary. The alkoxymercuration reaction requires that one of the two groups come from an alkene precursor. Ethyl phenyl ether could be made by either method. Solution Problems

Science


Reactions of Ethers: Acidic Cleavage Ethers are unreactive to many reagents used in organic chemistry, a property that accounts for their wide use as reaction solvents. Halogens, dilute acids, bases, and nucleophiles have no effect on most ethers. In fact, ethers undergo only one truly general reaction—they are cleaved by strong acids. Aqueous HBr and HI both work well, but HCl does not cleave ethers. Acidic ether cleavages are typical nucleophilic substitution reactions and take place by either S N 1 or S N 2 mechanisms, depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an S N 2 mechanism, in which I – or Br – reacts with the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide. For example, ethyl isopropyl ether exclusively yields isopropyl alcohol and iodoethane on cleavage by HI because nucleophilic attack by iodide ion occurs at the less hindered primary site rather than at the more hindered secondary site. Ethers with a tertiary, benzylic, or allylic group cleave by either an S N 1 or E1 mechanism because these substrates can produce stable intermediate carbocations. These reactions are often fast and take place at moderate temperatures. tert -Butyl ethers, for example, react by an E1 mechanism on treatment with trifluoroacetic acid at 0 °C. We’ll see in Section 26.7 that this reaction is often used in the laboratory synthesis of peptides. Predicting the Product of an Ether Cleavage Reaction Predict the products of the following reaction: Strategy Identify the substitution pattern of the two groups attached to oxygen—in this case a tertiary alkyl group and a primary alkyl group. Then recall the guidelines for ether cleavages. An ether with only primary and secondary alkyl groups usually undergoes cleavage by S N 2 attack of a nucleophile on the less hindered alkyl group, but an ether with a tertiary alkyl group usually undergoes cleavage by an S N 1 mechanism. In this case, an S N 1 cleavage of the tertiary C–O bond will occur, giving 1-propanol and a tertiary alkyl bromide. In addition, a competitive E1 reaction leading to alkene might occur. Solution Problems

Science


Cyclic Ethers: Epoxides For the most part, cyclic ethers behave like acyclic ethers. The chemistry of the ether functional group is the same, whether it’s in an open chain or in a ring. Common cyclic ethers such as tetrahydrofuran and dioxane are often used as solvents because of their inertness, yet they can be cleaved by strong acids. The one group of cyclic ethers that behaves differently from open-chain ethers are the three-membered-ring compounds called epoxides, or oxiranes, which we saw in . The strain of the three-membered ring gives epoxides unique chemical reactivity. Ethylene oxide, the simplest epoxide, is an intermediate in the manufacture of both ethylene glycol, used for automobile antifreeze, and polyester polymers. Approximately 37 million tons of ethylene oxide is produced worldwide each year, most of it by air oxidation of ethylene over a silver oxide catalyst at 300 °C. This process is not useful for other epoxides, however, and is of little value in the laboratory. Note that the name ethylene oxide is not a systematic one because the - ene ending implies the presence of a double bond in the molecule. The name is frequently used, however, because ethylene oxide is derived from ethylene by addition of an oxygen atom. Other simple epoxides are named similarly. The systematic name for ethylene oxide is 1,2-epoxyethane. In the laboratory, as we saw in , epoxides are usually prepared by treatment of an alkene with a peroxyacid (RCO 3 H), typically m -chloroperoxybenzoic acid. Epoxides can also be prepared from halohydrins, themselves produced by electrophilic addition of Cl 2 or Br2 to an alkene in the presence of water ( ). When a halohydrin is treated with base, HX is eliminated and an epoxide is produced by an intramolecular Williamson ether synthesis. That is, the nucleophilic alkoxide ion and the electrophilic alkyl halide are in the same molecule. Problems

Science


Reactions of Epoxides: Ring-Opening Acid-Catalyzed Epoxide Opening Epoxides are cleaved by treatment with acid just as other ethers are, but under much milder conditions because of ring strain. As we saw in , dilute aqueous acid at room temperature is sufficient for facilitating the hydrolysis of epoxides to give 1,2-diols, also called vicinal glycols. (The word vicinal means “adjacent,” and a glycol is a diol.) The epoxide cleavage takes place by S N 2-like backside attack of a nucleophile on the protonated epoxide, giving a trans-1,2-diol as product. Epoxides can also be opened by reaction with acids other than H 3 O + . If anhydrous HX is used, for instance, an epoxide is converted into a trans halohydrin. The regiochemistry of acid-catalyzed ring-opening depends on the epoxide’s structure, and a mixture of products is often formed. When both epoxide carbon atoms are either primary or secondary, attack of the nucleophile occurs primarily at the less highly substituted site: an S N 2-like result. When one of the epoxide carbon atoms is tertiary, however, nucleophilic attack occurs primarily at the more highly substituted site—an S N 1-like result. Thus, 1,2-epoxypropane reacts with HCl to give primarily 1-chloro-2-propanol, but 2-methyl-1,2-epoxypropane gives 2-chloro-2-methyl-1- propanol as the major product. The mechanisms of these acid-catalyzed epoxide openings are more complex than they initially appear. They seem to be neither purely S N 1 nor S N 2 but instead to be midway between the two extremes and to have characteristics of both. For instance, take the reaction of 1,2-epoxy-1-methylcyclohexane with HBr, shown in . The reaction yields only a single stereoisomer of 2-bromo-2-methylcyclohexanol in which the –Br and –OH groups are trans, an S N 2-like result caused by backside displacement of the epoxide oxygen. But the fact that Br – attacks the more hindered tertiary side of the epoxide rather than the less hindered secondary side is an S N 1-like result in which the more stable, tertiary carbocation is involved. Evidently, the transition state for acid-catalyzed epoxide opening has an S N 2-like geometry but also has a high degree of S N 1-like carbocationic character. Because the positive charge in the protonated epoxide is shared by the more highly substituted carbon atom, backside attack of Br – occurs at the more highly substituted site. Ring-opening of 1,2-epoxy-1-methylcyclohexane with HBr . There is a high degree of S N 1-like carbocation character in the transition state, which leads to backside attack of the nucleophile at the tertiary center and to formation of a product isomer that has –Br and –OH groups trans. Predicting the Product of Epoxide Ring-Opening Predict the major product of the following reaction: Strategy Identify the substitution pattern of the two epoxide carbon atoms. In this case, one carbon is secondary and one is primary. Then recall the guidelines for epoxide cleavages. An epoxide with only primary and secondary carbons usually undergoes cleavage by S N 2-like attack of a nucleophile on the less hindered carbon, but an epoxide with a tertiary carbon atom usually undergoes cleavage by backside attack on the more hindered carbon. In this case, an S N 2 cleavage of the primary C–O epoxide bond will occur. Solution Problems Base-Catalyzed Epoxide Opening Unlike other ethers, epoxide rings can be cleaved by bases and nucleophiles as well as by acid. Although an ether oxygen is normally a poor leaving group in an S N 2 reaction ( ), the strain of the three-membered ring causes epoxides to react with hydroxide ion at elevated temperatures. Base-catalyzed epoxide opening is a typical S N 2 reaction in which attack of the nucleophile takes place at the less hindered epoxide carbon. For example, 1,2-epoxypropane reacts with ethoxide ion exclusively at the less highly substituted, primary carbon to give 1-ethoxy-2-propanol. Many different nucleophiles can be used for epoxide opening, including amines (RNH 2 or R 2 NH) and Grignard reagents (RMgX). An example of an amine reacting with an epoxide occurs in the commercial synthesis of metoprolol, a so-called β -blocker that is used for treatment of cardiac arrhythmias, hypertension, and heart attacks. β -Blockers are among the most widely prescribed drugs in the world. A similar nucleophilic ring-opening occurs when epoxides are treated with Grignard reagents. Ethylene oxide is frequently used, thereby allowing the conversion of a Grignard reagent into a primary alcohol having two more carbons than the starting alkyl halide. 1-Bromobutane, for example, is converted into 1-hexanol by reaction of its Grignard reagent with ethylene oxide. Problems

Science


Crown Ethers Crown ethers , discovered in the early 1960s by Charles Pedersen at the DuPont Company, are a relatively recent addition to the ether family. They are named according to the general format x -crown- y, where x is the total number of atoms in the ring and y is the number of oxygen atoms. Thus, 18-crown-6 ether is an 18-membered ring containing 6 ether oxygen atoms. Note the size and negative (red) character of the crown ether cavity in the following electrostatic potential map. The importance of crown ethers stems from their ability to sequester specific metal cations in the center of the polyether cavity. 18-Crown-6, for example, binds strongly with potassium ion. As a result, a solution of 18-crown-6 in a nonpolar organic solvent will dissolve many potassium salts. Potassium permanganate, KMnO 4 , dissolves in toluene in the presence of 18-crown-6, for instance, and the resulting solution is a valuable reagent for oxidizing alkenes. The effect of using a crown ether to dissolve an inorganic salt in a hydrocarbon or ether solvent is similar to the effect of dissolving the salt in a polar aprotic solvent such as DMSO, DMF, or HMPA ( ). In both cases, the metal cation is strongly solvated, leaving the anion bare. Thus, the S N 2 reactivity of an anion is tremendously enhanced in the presence of a crown ether. Although crown ethers do not occur naturally, a group of compounds called ionophores have similar ion-binding properties. Produced by various microorganisms, ionophores are fat-soluble molecules that bind to specific ions and facilitate transport of the ions through biological membranes. The antibiotic valinomycin, for instance, binds specifically to K + ions with a ten-thousandfold selectivity over Na + . Problems

Science