The Hammond Postulate Let’s summarize what we’ve learned of electrophilic addition reactions to this point: Electrophilic addition to an unsymmetrically substituted alkene gives the more substituted carbocation intermediate. A more substituted carbocation forms faster than a less substituted one and, once formed, rapidly goes on to give the final product. A more substituted carbocation is more stable than a less substituted one. That is, the stability order of carbocations is tertiary > secondary > primary > methyl. What we have not yet seen is how these two points are related. Why does the stability of the carbocation intermediate affect the rate at which it’s formed and thereby determine the structure of the final product? After all, carbocation stability is determined by the free-energy change Δ G °, but reaction rate is determined by the activation energy Δ G ‡ . The two quantities aren’t directly related. Although there is no simple quantitative relationship between the stability of a carbocation intermediate and the rate of its formation, there is an intuitive relationship. It’s generally true when comparing two similar reactions that the more stable intermediate forms faster than the less stable one. The situation is shown graphically in , where the energy profile in part (a) represents the typical situation, as opposed to the profile in part (b) . That is, the curves for two similar reactions don’t cross one another. Energy diagrams for two similar competing reactions . In (a) , the faster reaction yields the more stable intermediate. In (b) , the slower reaction yields the more stable intermediate. The curves shown in (a) represent the typical situation. Called the Hammond postulate , the explanation of the relationship between reaction rate and intermediate stability goes like this: Transition states represent energy maxima. They are high-energy activated complexes that occur transiently during the course of a reaction and immediately go on to a more stable species. Although we can’t actually observe transition states because they have no finite lifetime, the Hammond postulate says that we can get an idea of a particular transition state’s structure by looking at the structure of the nearest stable species. Imagine the two cases shown in , for example. The reaction profile in part (a) shows the energy curve for an endergonic reaction step, and the profile in part (b) shows the curve for an exergonic step. Energy diagrams for endergonic and exergonic steps . (a) In an endergonic step, the energy levels of transition state and product are closer. (b) In an exergonic step, the energy levels of transition state and reactant are closer. In an endergonic reaction ( a), the energy level of the transition state is closer to that of the product than that of the reactant. Since the transition state is closer energetically to the product, we make the natural assumption that it’s also closer structurally. In other words, the transition state for an endergonic reaction step structurally resembles the product of that step. Conversely, the transition state for an exergonic reaction ( b), is closer energetically, and thus structurally, to the reactant than to the product. We therefore say that the transition state for an exergonic reaction step structurally resembles the reactant for that step. Hammond postulate: The structure of a transition state resembles the structure of the nearest stable species. Transition states for endergonic steps structurally resemble products, and transition states for exergonic steps structurally resemble reactants. How does the Hammond postulate apply to electrophilic addition reactions? The formation of a carbocation by protonation of an alkene is an endergonic step. Thus, the transition state for alkene protonation structurally resembles the carbocation intermediate, and any factor that stabilizes the carbocation will also stabilize the nearby transition state. Since increasing alkyl substitution stabilizes carbocations, it also stabilizes the transition states leading to those ions, thus resulting in a faster reaction. In other words, more stable carbocations form faster because their greater stability is reflected in the lower-energy transition state leading to them ( ). Energy diagrams for carbocation formation . The more stable tertiary carbocation is formed faster (green curve) because its increased stability lowers the energy of the transition state leading to it. We can imagine the transition state for alkene protonation to be a structure in which one of the alkene carbon atoms has almost completely rehybridized from sp 2 to sp 3 and the remaining alkene carbon bears much of the positive charge ( ). This transition state is stabilized by hyperconjugation and inductive effects in the same way as the product carbocation. The more alkyl groups that are present, the greater the extent of stabilization and the faster the transition state forms. The hypothetical structure of a transition state for alkene protonation . The transition state is closer in both energy and structure to the carbocation than to the alkene. Thus, an increase in carbocation stability (lower Δ G °) also causes an increase in transition-state stability (lower Δ G ‡ ), thereby increasing the rate of its formation. Problems

Science


Evidence for the Mechanism of Electrophilic Additions: Carbocation Rearrangements How do we know that the carbocation mechanism for electrophilic addition reactions of alkenes is correct? The answer is that we don’t know it’s correct; at least we don’t know with complete certainty. Although an incorrect reaction mechanism can be disproved by demonstrating that it doesn’t account for observed data, a correct reaction mechanism can never be entirely proven. The best we can do is to show that a proposed mechanism is consistent with all known facts. If enough facts are accounted for, the mechanism is probably correct. One of the best pieces of evidence supporting the carbocation mechanism for the electrophilic addition reaction was discovered during the 1930s by F. C. Whitmore of Pennsylvania State University, who found that structural rearrangements often occur during the reaction of HX with an alkene. For example, reaction of HCl with 3-methyl-1-butene yields a substantial amount of 2-chloro-2-methylbutane in addition to the “expected” product, 2-chloro-3-methylbutane. If the reaction takes place in a single step, it would be difficult to account for rearrangement, but if the reaction takes place in several steps, rearrangement is more easily explained. Whitmore suggested that it is a carbocation intermediate that undergoes rearrangement. The secondary carbocation intermediate formed by protonation of 3-methyl-1-butene rearranges to a more stable tertiary carbocation by a hydride shift —the shift of a hydrogen atom and its electron pair (a hydride ion, : H − ) between neighboring carbons. Carbocation rearrangements can also occur by the shift of an alkyl group with its electron pair. For example, reaction of 3,3-dimethyl-1-butene with HCl leads to an equal mixture of unrearranged 3-chloro-2,2-dimethylbutane and rearranged 2-chloro-2,3-dimethylbutane. In this instance, a secondary carbocation rearranges to a more stable tertiary carbocation by the shift of a methyl group. Note the similarities between the two carbocation rearrangements: in both cases, a group (:H − or :CH 3 − ) moves to an adjacent positively charged carbon, taking its bonding electron pair with it. Also in both cases, a less stable carbocation rearranges to a more stable ion. Rearrangements of this kind are a common feature of carbocation chemistry and are particularly important in the biological pathways by which steroids and related substances are synthesized. An example is the following hydride shift that occurs during the biosynthesis of cholesterol. As always, when looking at any complex chemical transformation, whether biochemical or not, focus on the part of the molecule where the change is occurring and don’t worry about the rest. The tertiary carbocation just pictured looks complicated, but all the chemistry is taking place in the small part of the molecule inside the red circle. Problems Bioprospecting: Hunting for Natural Products Most people know the names of the common classes of biomolecules—proteins, carbohydrates, lipids, and nucleic acids—but there are many more kinds of compounds in living organisms than just those four. All living organisms also contain a vast diversity of substances usually grouped under the heading natural products . The term natural product really refers to any naturally occurring substance but is generally taken to mean a so-called secondary metabolite—a small molecule that is not essential to the growth and development of the producing organism and is not classified by structure. Rapamycin, an immunosuppressant natural product used during organ transplants, was originally isolated from a soil sample found on Rapa Nui (Easter Island), an island 2200 miles off the coast of Chile known for its giant Moai statues. (credit: modification of work “Moai facing inland at Ahu Tongariki” by Ian Sewell/Wikimedia Commons, CC BY 2.5) It has been estimated that well over 300,000 secondary metabolites exist, and it’s thought that their primary function is to increase the likelihood of an organism’s survival by repelling or attracting other organisms. Alkaloids, such as morphine; antibiotics, such as erythromycin and the penicillins; and immunosuppressive agents, such as rapamycin (sirolimus) prescribed for liver transplant recipients, are examples. Where do these natural products come from, and how are they found? Although most chemists and biologists spend their working time in the laboratory, a few spend their days scuba diving on South Pacific islands or trekking through the rainforests of South America and Southeast Asia at work as bioprospectors. Their job is to hunt for new and unusual natural products that might be useful as drugs. As noted in the Chapter 6 Chemistry Matters , more than half of all new drug candidates come either directly or indirectly from natural products. Morphine from the opium poppy, prostaglandin E 1 from sheep prostate glands, erythromycin A from a Streptomyces erythreus bacterium cultured from a Philippine soil sample, and benzylpenicillin from the mold Penicillium notatum are examples. The immunosuppressive agent rapamycin, whose structure is shown previously, was first isolated from a Streptomyces hygroscopicus bacterium found in a soil sample from Rapa Nui (Easter Island), located 2200 miles off the coast of Chile. With less than 1% of living organisms yet investigated, bioprospectors have a lot of work to do. But there is a race going on. Rainforests throughout the world are being destroyed at an alarming rate, causing many species of both plants and animals to become extinct before they can even be examined. The governments in many countries seem aware of the problem, but there is as yet no international treaty on biodiversity that could help preserve vanishing species. alkene ( R 2 C═ CR 2 ) allyl group degree of unsaturation E configuration E,Z system electrophilic addition reaction Hammond postulate hydride shift hyperconjugation Markovnikov’s rule methylene group regiospecific reaction unsaturated vinyl group Z configuration Summary Carbon–carbon double bonds are present in most organic and biological molecules, so a good understanding of their behavior is needed. In this chapter, we’ve looked at some consequences of alkene stereoisomerism and at the details of the broadest class of alkene reactions—the electrophilic addition reaction. An alkene is a hydrocarbon that contains a carbon–carbon double bond. Because they contain fewer hydrogens than alkanes with the same number of carbons, alkenes are said to be unsaturated . Because rotation around the double bond can’t occur, substituted alkenes can exist as cis–trans stereoisomers. The configuration of a double bond can be specified by applying the Cahn–Ingold–Prelog sequence rules, which rank the substituents on each double-bond carbon. If the higher-ranking groups on each carbon are on the same side of the double bond, the configuration is Z ( zusammen, “together”); if the higher-ranking groups on each carbon are on opposite sides of the double bond, the configuration is E ( entgegen, “apart”). Alkene chemistry is dominated by electrophilic addition reactions . When HX reacts with an unsymmetrically substituted alkene, Markovnikov’s rule predicts that the H will add to the carbon having fewer alkyl substituents and the X group will add to the carbon having more alkyl substituents. Electrophilic additions to alkenes take place through carbocation intermediates formed by reaction of the nucleophilic alkene π bond with electrophilic H + . Carbocation stability follows the order Tertiary (3°) > Secondary (2°) > Primary (1°) > Methyl R 3 C + > R 2 CH + > RCH 2 + > CH 3 + Markovnikov’s rule can be restated by saying that, in the addition of HX to an alkene, a more stable carbocation intermediate is formed. This result is explained by the Hammond postulate , which says that the transition state of an exergonic reaction step structurally resembles the reactant, whereas the transition state of an endergonic reaction step structurally resembles the product. Since an alkene protonation step is endergonic, the stability of the more highly substituted carbocation is reflected in the stability of the transition state leading to its formation. Evidence in support of a carbocation mechanism for electrophilic additions comes from the observation that structural rearrangements often take place during reaction. Rearrangements occur by shift of either a hydride ion, : H − (a hydride shift ), or an alkyl anion, : R − , from a carbon atom to the neighboring positively charged carbon. This results in isomerization of a less stable carbocation to a more stable one. Additional Problems Visualizing Chemistry Mechanism Problems Calculating a Degree of Unsaturation Naming Alkenes Alkene Isomers and Their Stability Carbocations and Electrophilic Addition Reactions General Problems

Science


Why This Chapter? The Spectra fiber used to make the bulletproof vests used by police and military is made of ultra-high-molecular-weight polyethylene, a simple alkene polymer. (credit: modification of work “US Navy 081028-N-3857R-007 Seabees participate in a chemical, biological and radiological warfare drill” by U.S. Navy photo by Mass Communication Specialist 1st Class Chad Runge/Wikimedia Commons, Public Domain) Much of the background needed to understand organic reactions has now been covered, and it’s time to begin a systematic description of the major functional groups. In this chapter on alkenes, and in future chapters on other functional groups, we’ll discuss a variety of reactions, but try to focus on the general principles and patterns of reactivity that tie organic chemistry together. There are no shortcuts; you have to know the reactions to understand organic and biological chemistry. Alkene addition reactions occur widely, both in the laboratory and in living organisms. Although we’ve studied only the addition of HX thus far, many closely related reactions also take place. In this chapter, we’ll see briefly how alkenes are prepared and we’ll discuss further examples of alkene addition reactions. Particularly important are the addition of a halogen (X 2 ) to give a 1,2-dihalide, addition of a hypohalous acid (HOX) to give a halohydrin, addition of water to give an alcohol, addition of hydrogen to give an alkane, addition of a single oxygen to give a three-membered cyclic ether called an epoxide , and addition of two hydroxyl groups to give a 1,2-diol. Some useful alkene reactions.

Science


Preparing Alkenes: A Preview of Elimination Reactions Before getting to the main subject of this chapter—the reactions of alkenes—let’s take a brief look at how alkenes are prepared. The subject is a bit complex, though, so we’ll return to it in Chapter 11 for a more detailed study. For the present, it’s enough to realize that alkenes are readily available from simple precursors—usually alcohols in biological systems and either alcohols or alkyl halides in the laboratory. Just as the chemistry of alkenes is dominated by addition reactions, the preparation of alkenes is dominated by elimination reactions. Additions and eliminations are, in many respects, two sides of the same coin. That is, an addition reaction might involve the addition of HBr or H 2 O to an alkene to form an alkyl halide or alcohol, whereas an elimination reaction might involve the loss of HBr or H 2 O from an alkyl halide or alcohol to form an alkene. The two most common elimination reactions are dehydrohalogenation—the loss of HX from an alkyl halide—and dehydration—the loss of water from an alcohol. Dehydrohalogenation usually occurs by reaction of an alkyl halide with strong base such as potassium hydroxide. For example, bromocyclohexane yields cyclohexene when treated with KOH in ethanol solution. Dehydration is often carried out in the laboratory by treatment of an alcohol with a strong acid. For example, when 1-methylcyclohexanol is warmed with aqueous sulfuric acid in tetrahydrofuran (THF) solvent, loss of water occurs and 1-methylcyclohexene is formed. In biological pathways, dehydrations rarely occur with isolated alcohols. Instead, they normally take place on substrates in which the −OH is positioned two carbons away from a C═O group. In the biosynthesis of fats, for instance, β -hydroxybutyryl ACP is converted by dehydration to trans -crotonyl ACP, where ACP is an abbreviation for acyl carrier protein. We’ll see the reason for this requirement in Section 11.10 . Problems

Science


Halogenation of Alkenes: Addition of X 2 Bromine and chlorine add rapidly to alkenes to yield 1,2-dihalides, a process called halogenation . For example, nearly 50 million tons of 1,2-dichloroethane (ethylene dichloride) are synthesized worldwide each year, much of it by addition of Cl 2 to ethylene. The product is used both as a solvent and as starting material for the manufacture of poly(vinyl chloride), PVC, the third most widely synthesized polymer in the world after polyethelyne and polypropolyne. Fluorine is too reactive and difficult to control for most laboratory applications, and iodine does not react with most alkenes. Based on what we’ve seen thus far, a possible mechanism for the reaction of bromine with alkenes might involve electrophilic addition of Br + to the alkene, giving a carbocation intermediate that could undergo further reaction with Br − to yield the dibromo addition product. Although this mechanism seems plausible, it’s not fully consistent with known facts. In particular, it doesn’t explain the stereochemistry of the addition reaction. That is, the mechanism doesn’t account for which product stereoisomer is formed. When the halogenation reaction is carried out on a cycloalkene, such as cyclopentene, only the trans stereoisomer of the dihalide addition product is formed, rather than the mixture of cis and trans isomers that might have been expected if a planar carbocation intermediate were involved. We say that the reaction occurs with anti stereochemistry , meaning that the two bromine atoms come from opposite faces of the double bond—one from the top face and one from the bottom face. An explanation for the observed stereochemistry of addition was suggested in 1937 by George Kimball and Irving Roberts, who proposed that the reaction intermediate is not a carbocation but is instead a bromonium ion , R 2 B r + , formed by electrophilic addition of Br + to the alkene. (Similarly, a chloronium ion contains a positively charged, divalent chlorine, R 2 Cl + .) The bromonium ion is formed in a single step by interaction of the alkene with Br 2 and the simultaneous loss of Br − . How does the formation of a bromonium ion account for the observed anti stereochemistry of addition to cyclopentene? If a bromonium ion is formed as an intermediate, we can imagine that the large bromine atom might “shield” one side of the molecule. Reaction with Br − ion in the second step could then occur only from the opposite, unshielded side to give the trans product. The bromonium ion postulate, made more than 85 years ago to explain the stereochemistry of halogen addition to alkenes, is a remarkable example of deductive logic in chemistry. Arguing from experimental results, chemists were able to make a hypothesis about the intimate mechanistic details of alkene electrophilic reactions. Subsequently, strong evidence supporting the mechanism came from the work of George Olah at the University of Southern California, who prepared and studied stable solutions of cyclic bromonium ions in liquid SO 2 . There’s no question that bromonium ions exist. Alkene halogenation reactions occur in nature just as they do in the laboratory but are limited primarily to marine organisms living in halide-rich environments. These biological halogenation reactions are carried out by enzymes called haloperoxidases , which use H 2 O 2 to oxidize Br − or Cl − ions to a biological equivalent of Br + or Cl + . Electrophilic addition to the double bond of a substrate molecule then yields a bromonium or chloronium ion intermediate just as in the laboratory, and reaction with another halide ion completes the process. Halomon, for example, an antitumor pentahalide isolated from red alga, is thought to arise by a route that involves twofold addition of BrCl through the corresponding bromonium ions. Problems

Science


Halohydrins from Alkenes: Addition of HO-X Another example of an electrophilic addition is the reaction an alkene with either Br 2 or Cl 2 in the presence of water to yield a 1,2-halo alcohol, called a halohydrin . We saw in the previous section that when Br 2 reacts with an alkene, the cyclic bromonium ion intermediate reacts with the only nucleophile present, Br − ion. If the reaction is carried out in the presence of an additional nucleophile, however, the intermediate bromonium ion can be intercepted by the added nucleophile and diverted to a different product. In the presence of a high concentration of water, for instance, water competes with Br − ion as a nucleophile and reacts with the bromonium ion intermediate to yield a bromohydrin . The net effect is addition of HO−Br to the alkene by the pathway shown in . MECHANISM Bromohydrin formation by reaction of an alkene with Br 2 in the presence of water . Water acts as a nucleophile in step 2 to react with the intermediate bromonium ion. In practice, few alkenes are soluble in water, and bromohydrin formation is often carried out in a solvent such as aqueous dimethyl sulfoxide, CH 3 SOCH 3 (DMSO), using a reagent called N -bromosuccinimide (NBS) as a source of Br 2 . NBS is a stable, easily handled compound that slowly decomposes in water to yield Br 2 at a controlled rate. Bromine itself can also be used in the addition reaction, but it is more dangerous and more difficult to handle than NBS. Notice that the aromatic ring in the above example does not react with Br 2 , even though it appears to have three carbon–carbon double bonds. As we’ll see in Section 15.2, aromatic rings are a good deal more stable and less reactive than might be expected. There are a number of biological examples of halohydrin formation, particularly in marine organisms. As with halogenation ( ), halohydrin formation is carried out by haloperoxidases . For example: Problems

Science


Hydration of Alkenes: Addition of H 2 O by Oxymercuration Water adds to alkenes to yield alcohols, a process called hydration. The reaction takes place on treatment of the alkene with water and a strong acid catalyst, such as H 2 SO 4 , by a mechanism similar to that of HX addition. Thus, as shown in , protonation of an alkene double bond yields a carbocation intermediate, which reacts with water to yield a protonated alcohol product, ROH 2 + . Loss of H + from this protonated alcohol gives the neutral alcohol and regenerates the acid catalyst. MECHANISM Mechanism of the acid-catalyzed hydration of an alkene to yield an alcohol. Protonation of the alkene gives a carbocation intermediate, which reacts with water. The initial product is then deprotonated. Most ethanol throughout the world is now made by fermentation of biological precursors, such as corn and sugar, but acid-catalyzed alkene hydration is particularly suited to large-scale industrial procedures, and approximately 90,000 tons of ethanol is manufactured each year in the United States by hydration of ethylene. The reaction is of little value in the laboratory, however, because it requires high temperatures—250 °C in the case of ethylene—and strongly acidic conditions. Acid-catalyzed hydration of double bonds is also uncommon in biological pathways. Instead, biological hydrations usually require that the double bond be adjacent to a carbonyl group for the reaction to proceed. Fumarate, for instance, is hydrated to give malate as one step in the citric acid cycle of food metabolism. Note that the requirement for an adjacent carbonyl group in the addition of water is the same as in for the elimination of water. We’ll see the reason for this requirement in Section 19.13 , but will note for now that the reaction is not an electrophilic addition but instead occurs through a mechanism that involves formation of an anion intermediate followed by protonation by an acid HA. When it comes to circumventing problems like those with acid-catalyzed alkene hydrations, laboratory chemists have a great advantage over the cellular “chemists” in living organisms. Laboratory chemists are not constrained to carry out their reactions in water solution; they can choose from any of a large number of solvents. Laboratory reactions don’t need to be carried out at a fixed temperature; they can take place over a wide range of temperatures. And laboratory reagents aren’t limited to containing carbon, oxygen, nitrogen, and a few other elements; they can contain any element in the periodic table. In the laboratory, alkenes are often hydrated by the oxymercuration–demercuration procedure, which involves electrophilic addition of Hg 2+ to the alkene on reaction with mercury(II) acetate [(CH 3 CO 2 ) 2 Hg. The intermediate organomercury compound is then treated with sodium borohydride, NaBH 4 , and demercuration occurs to produce an alcohol. For example: Alkene oxymercuration is closely analogous to halohydrin formation. The reaction is initiated by electrophilic addition of Hg 2+ (mercuric) ion to the alkene to give an intermediate mercurinium ion , whose structure resembles that of a bromonium ion ( ). Nucleophilic addition of water as in halohydrin formation, followed by the loss of a proton, then yields a stable organomercury product. The final step, demercuration of the organomercury compound by reaction with sodium borohydride, is complex and involves radicals. Note that the regiochemistry of the reaction corresponds to Markovnikov addition of water; that is, the −OH group attaches to the more highly substituted carbon atom, and the −H attaches to the less highly substituted carbon. The hydrogen that replaces mercury in the demercuration step can attach from either side of the molecule depending on the exact circumstances. Mechanism of the oxymercuration of an alkene to yield an alcohol. ( 1 ) Electrophilic addition of Hg 2+ gives a mercurinium ion, which ( 2 ) reacts with water as in halohydrin formation. Loss of a proton gives an organomercury product, and ( 3 ) reaction with NaBH 4 removes the mercury. The product of the reaction is a more highly substituted alcohol, corresponding to Markovnikov regiochemistry. Problems

Hydration of Alkenes: Addition of H2O by Oxymercuration

Science


Hydration of Alkenes: Addition of H 2 O by Hydroboration In addition to the oxymercuration–demercuration method, which yields the Markovnikov product, a complementary method that yields the non-Markovnikov product is also useful. Discovered in 1959 by H.C. Brown at Purdue University and called hydroboration , the reaction involves addition of a B−H bond of borane, BH 3 , to an alkene to yield an organoborane intermediate, RBH 2 . Oxidation of the organoborane by reaction with basic hydrogen peroxide, H 2 O 2 , then gives an alcohol. For example: Borane is very reactive as a Lewis acid because the boron atom has only six electrons in its valence shell rather than an octet. In tetrahydrofuran solution, BH 3 accepts an electron pair from a solvent molecule in a Lewis acid–base reaction to complete its octet and form a stable BH 3 –THF complex. When an alkene reacts with BH 3 in THF solution, rapid addition to the double bond occurs three times and a trialkylborane, R 3 B, is formed. For example, 1 molar equivalent of BH 3 adds to 3 molar equivalents of cyclohexene to yield tricyclohexylborane. When tricyclohexylborane is then treated with aqueous hydrogen H 2 O 2 in basic solution, an oxidation takes place. The three C−B bonds are broken, −OH groups bond to the three carbons, and 3 equivalents of cyclohexanol are produced. The net effect of the two-step hydroboration–oxidation sequence is hydration of the alkene double bond. One of the features that makes the hydroboration reaction so useful is the regiochemistry that results when an unsymmetrical alkene is hydroborated. For example, hydroboration–oxidation of 1-methylcyclopentene yields trans -2-methylcyclopentanol. In this process, boron and hydrogen add to the alkene from the same face of the double bond—that is, with syn stereochemistry , the opposite of anti—with boron attaching to the less highly substituted carbon. During the oxidation step, the boron is replaced by an −OH with the same stereochemistry, resulting in an overall syn non-Markovnikov addition of water. This stereochemical result is particularly useful because it is complementary to the Markovnikov regiochemistry observed for oxymercuration–demercuration. Why does alkene hydroboration take place with syn, non-Markovnikov regiochemistry to yield the less highly substituted alcohol? Hydroboration differs from many other alkene addition reactions in that it occurs in a single step without a carbocation intermediate ( ). Because the C−H and C−B bonds form at the same time and from the same face of the alkene, syn stereochemistry results. Non-Markovnikov regiochemistry occurs because attachment of boron is favored at the less sterically crowded carbon atom of the alkene. Mechanism of alkene hydroboration. The reaction occurs in a single step in which the C−H and C−B bonds form at the same time and on the same face of the double bond. The lower energy, more rapidly formed transition state is the one with less steric crowding, leading to non-Markovnikov regiochemistry. Predicting the Products of a Hydration Reaction What products would you obtain from reaction of 2-methyl-2-pentene with: (a) BH 3 , followed by H 2 O 2 , OH − (b) Hg(OAc) 2 , followed by NaBH 4 Strategy When predicting the product of a reaction, you have to recall what you know about the kind of reaction being carried out and apply that knowledge to the specific case you’re dealing with. In the present instance, recall that the two methods of hydration—hydroboration–oxidation and oxymercuration–demercuration—give complementary products. Hydroboration–oxidation occurs with syn stereochemistry and gives the non-Markovnikov addition product; oxymercuration–demercuration gives the Markovnikov product. Solution Synthesizing an Alcohol How might you prepare the following alcohol? Strategy Problems that require the synthesis of a specific target molecule should always be worked backward. Look at the target, identify its functional group(s), and ask yourself, “What are the methods for preparing that functional group?” In the present instance, the target molecule is a secondary alcohol (R 2 CHOH), and we’ve seen that alcohols can be prepared from alkenes by either hydroboration–oxidation or oxymercuration–demercuration. The −OH-bearing carbon in the product must have been a double-bond carbon in the alkene reactant, so there are two possibilities here: 4-methyl-2-hexene and 3-methyl-3-hexene. 4-Methyl-2-hexene has a disubstituted double bond, RCH═CHR ′ , and will probably give a mixture of two alcohols with either hydration method since Markovnikov’s rule does not apply to symmetrically substituted alkenes. 3-Methyl-3-hexene, however, has a trisubstituted double bond, and should give only the desired product on non-Markovnikov hydration using the hydroboration–oxidation method. Solution Problems

Hydration of Alkenes: Addition of H2O by Hydroboration

Science


Reduction of Alkenes: Hydrogenation Alkenes react with H 2 in the presence of a metal catalyst such as palladium or platinum to yield the corresponding saturated alkanes. We describe the result by saying that the double bond has been hydrogenated , or reduced . Note that the word reduction is used somewhat differently in organic chemistry from what you might have learned previously. In general chemistry, a reduction is defined as the gain of one or more electrons by an atom. In organic chemistry, however, a reduction is a reaction that results in a gain of electron density for carbon, caused either by bond formation between carbon and a less electronegative atom—usually hydrogen—or by bond-breaking between carbon and a more electronegative atom—usually oxygen, nitrogen, or a halogen. We’ll explore this topic in more detail in Section 10.8 . Reduction Increases electron density on carbon by: – forming this: C− H – or breaking one of these: C− O C− N C− X Platinum and palladium are the most common laboratory catalysts for alkene hydrogenations. Palladium is normally used as a very fine powder “supported” on an inert material such as charcoal (Pd/C) to maximize surface area. Platinum is normally used as PtO 2 , a reagent known as Adams’ catalyst after its discoverer, Roger Adams at the University of Illinois. Catalytic hydrogenation, unlike most other organic reactions, is a heterogeneous process rather than a homogeneous one. That is, the hydrogenation reaction does not occur in a homogeneous solution but instead takes place on the surface of solid catalyst particles. Hydrogenation usually occurs with syn stereochemistry: both hydrogens add to the double bond from the same face. As shown in , hydrogenation begins with adsorption of H 2 onto the catalyst surface. Complexation between catalyst and alkene then occurs as a vacant orbital on the metal interacts with the filled alkene π orbital on the alkene. In the final steps, hydrogen is inserted into the double bond and the saturated product diffuses away from the catalyst. The stereochemistry of hydrogenation is syn because both hydrogens add to the double bond from the same catalyst surface. MECHANISM Mechanism of alkene hydrogenation. The reaction takes place with syn stereochemistry on the surface of insoluble catalyst particles. An interesting feature of catalytic hydrogenation is that the reaction is extremely sensitive to the steric environment around the double bond. As a result, the catalyst usually approaches the more accessible face of an alkene, giving rise to a single product. In α -pinene, for example, one of the methyl groups attached to the four-membered ring hangs over the top face of the double bond and blocks approach of the hydrogenation catalyst from that side. Reduction therefore occurs exclusively from the bottom face to yield the product shown. Alkenes are much more reactive toward catalytic hydrogenation than most other unsaturated functional groups, and the reaction is therefore quite selective. Other functional groups, such as aldehydes, ketones, esters, and nitriles, often survive alkene hydrogenation conditions unchanged, although reaction with these groups does occur under more vigorous conditions. Note that, particularly in the hydrogenation of methyl 3-phenylpropenoate shown below, the aromatic ring is not reduced by hydrogen and palladium even though it contains apparent double bonds. In addition to its usefulness in the laboratory, catalytic hydrogenation is also important in the food industry, where unsaturated vegetable oils are reduced on a large scale to produce the saturated fats used in margarine and cooking products ( ). As we’ll see in Section 27.1 , vegetable oils are triesters of glycerol, HOCH 2 CH(OH)CH 2 OH, with three long-chain carboxylic acids called fatty acids . The fatty acids are generally polyunsaturated, and their double bonds have cis stereochemistry. Complete hydrogenation yields the corresponding saturated fatty acids, but incomplete hydrogenation often results in partial cis–trans isomerization of a remaining double bond. When eaten and digested, the free trans fatty acids are released, raising blood cholesterol levels and potentially contributing to coronary problems. Catalytic hydrogenation of polyunsaturated fats leads primarily to saturated products , along with a small amount of isomerized trans fats. Double-bond reductions are very common in biological pathways, although the mechanism is completely different from that of laboratory catalytic hydrogenation over palladium. As with biological hydrations ( ), biological reductions usually occur in two steps and require that the double bond be adjacent to a carbonyl group. In the first step, the biological reducing agent NADPH (reduced nicotinamide adenine dinucleotide phosphate), adds a hydride ion (H: − ) to the double bond to give an anion. In the second, the anion is protonated by acid HA, leading to overall addition of H 2 . An example is the reduction of trans -crotonyl ACP to yield butyryl ACP, a step involved in the biosynthesis of fatty acids ( ). Reduction of the carbon–carbon double bond in trans -crotonyl ACP, a step in the biosynthesis of fatty acids. One hydrogen is delivered from NADPH as a hydride ion, H: − ; the other hydrogen is delivered by protonation of the anion intermediate with an acid, HA. Problems

Science


Oxidation of Alkenes: Epoxidation and Hydroxylation Like the word reduction used in the previous section for the addition of hydrogen to a double bond, the word oxidation has a slightly different meaning in organic chemistry than what you might have previously learned. In general chemistry, an oxidation is defined as the loss of one or more electrons by an atom. In organic chemistry, however, an oxidation is a reaction that results in a loss of electron density for carbon, caused either by bond formation between carbon and a more electronegative atom—usually oxygen, nitrogen, or a halogen—or by bond-breaking between carbon and a less electronegative atom—usually hydrogen. Note that an oxidation often adds oxygen, while a reduction often adds hydrogen. Oxidation Decreases electron density on carbon by: – forming one of these: C− O C− N C− X – or breaking this: C− H In the laboratory, alkenes are oxidized to give epoxides on treatment with a peroxyacid , RCO 3 H, such as meta -chloroperoxybenzoic acid. An epoxide , also called an oxirane , is a cyclic ether with an oxygen atom in a three-membered ring. For example: Peroxyacids transfer an oxygen atom to the alkene with syn stereochemistry—both C−O bonds form on the same face of the double bond—through a one-step mechanism without intermediates. The oxygen atom farthest from the carbonyl group is the one transferred. Another method for the synthesis of epoxides involves the use of halohydrins, prepared by electrophilic addition of HO−X to alkenes ( ). When a halohydrin is treated with base, HX is eliminated and an epoxide is produced. Epoxides undergo an acid-catalyzed ring-opening reaction with water (a hydrolysis) to give the corresponding 1,2-dialcohol, or diol , also called a glycol . Thus, the net result of the two-step alkene epoxidation/hydrolysis is hydroxylation —the addition of an −OH group to each of the two double-bond carbons. In fact, approximately 204 million tons of ethylene glycol, HOCH 2 CH 2 OH, most of it used for automobile antifreeze, are produced worldwide each year by the epoxidation of ethylene and subsequent hydrolysis. Acid-catalyzed epoxide opening begins with protonation of the epoxide to increase its reactivity, followed by nucleophilic addition of water. This nucleophilic addition is analogous to the final step of alkene bromination, in which a cyclic bromonium ion is opened by a nucleophile ( ). That is, a trans -1,2-diol results when an epoxycycloalkane is opened by aqueous acid, just as a trans -1,2-dibromide results when a cycloalkene is brominated. We’ll look at epoxide chemistry in more detail in Section 18.6 . Hydroxylation can also be carried out directly (without going through an intermediate epoxide) by treating an alkene with osmium tetroxide, OsO 4 . The reaction occurs with syn stereochemistry and does not involve a carbocation intermediate. Instead, it takes place through an intermediate cyclic osmate , which is formed in a single step by addition of OsO 4 to the alkene. This cyclic osmate is then cleaved using aqueous sodium bisulfite, NaHSO 3 . Because OsO 4 is both very expensive and very toxic, the reaction is usually carried out using only a small, catalytic amount of OsO 4 in the presence of a stoichiometric amount of a safe and inexpensive co-oxidant such as N -methylmorpholine N -oxide, abbreviated NMO. The initially formed osmate intermediate reacts rapidly with NMO to yield the product diol plus N -methylmorpholine and reoxidized OsO 4 , which reacts with more alkene in a catalytic cycle. Problems

Science


Oxidation of Alkenes: Cleavage to Carbonyl Compounds In all the alkene addition reactions we’ve seen thus far, the carbon–carbon double bond has been converted into a single bond but the carbon skeleton has been unchanged. There are, however, powerful oxidizing reagents that will cleave C═C bonds and produce two carbonyl-containing fragments. Ozone (O 3 ) is perhaps the most useful double-bond cleavage reagent. Prepared by passing a stream of oxygen through a high-voltage electrical discharge, ozone adds rapidly to a C═C bond at low temperature to give a cyclic intermediate called a molozonide . Once formed, the molozonide spontaneously rearranges to form an ozonide . Although we won’t study the mechanism of this rearrangement in detail, it involves the molozonide coming apart into two fragments that then recombine in a different way. Low-molecular-weight ozonides are explosive and therefore not isolated. Instead, the ozonide is immediately treated with a reducing agent, such as zinc metal in acetic acid, to produce carbonyl compounds. The net result of the ozonolysis/reduction sequence is that the C═C bond is cleaved and an oxygen atom becomes doubly bonded to each of the original alkene carbons. If an alkene with a tetrasubstituted double bond is ozonized, two ketone fragments result; if an alkene with a trisubstituted double bond is ozonized, one ketone and one aldehyde result; and so on. Several oxidizing reagents other than ozone also cause double-bond cleavage, although such reactions are not often used. For example, potassium permanganate (KMnO 4 ) in neutral or acidic solution cleaves alkenes to give carbonyl-containing products. If hydrogens are present on the double bond, carboxylic acids are produced; if two hydrogens are present on one carbon, CO 2 is formed. In addition to direct cleavage with ozone or KMnO 4 , an alkene can also be cleaved in a two-step process by initial hydroxylation to a 1,2-diol, as discussed in the previous section, followed by treatment of the diol with periodic acid, HIO 4 . If the two −OH groups are in an open chain, two carbonyl compounds result. If the two −OH groups are on a ring, a single, open-chain dicarbonyl compound is formed. As indicated in the following examples, the cleavage reaction takes place through a cyclic periodate intermediate. Predicting the Reactant in an Ozonolysis Reaction What alkene would yield a mixture of cyclopentanone and propanal on treatment with ozone followed by reduction with zinc? Strategy Reaction of an alkene with ozone, followed by reduction with zinc, cleaves the C=C bond and becomes two C=O bonds. Working backward from the carbonyl-containing products, the alkene precursor can be found by removing the oxygen from each product and joining the two carbon atoms. Solution Problems

Science


Addition of Carbenes to Alkenes: Cyclopropane Synthesis Yet another kind of alkene addition is the reaction with a carbene to yield a cyclopropane. A carbene, R 2 C :, is a neutral molecule containing a divalent carbon with only six electrons in its valence shell. It is therefore highly reactive and generated only as a reaction intermediate, rather than as an isolable molecule. Because they’re electron-deficient, carbenes behave as electrophiles and react with nucleophilic C═C bonds. The reaction occurs in a single step without intermediates. One of the simplest methods for generating a substituted carbene is by treatment of chloroform, CHCl 3 , with a strong base such as KOH. As shown in , the loss of a proton from CHCl 3 gives trichloromethanide anion, − :CCl 3 , which spontaneously expels a Cl − ion to yield dichlorocarbene, :CCl 2 . MECHANISM Mechanism of the formation of dichlorocarbene by reaction of chloroform with strong base. Deprotonation of CHCl 3 gives the trichloromethanide anion, − :CCl 3 , which spontaneously expels a Cl – ion. The carbon atom in dichlorocarbene is sp 2 -hybridized, with a vacant p orbital extending above and below the plane of the three atoms and with an unshared pair of electrons occupying the third sp 2 lobe. Note that this electronic description of dichlorocarbene is similar to that of a carbocation ( ) with respect to both the sp 2 hybridization of carbon and the vacant p orbital. Electrostatic potential maps further illustrate the similarity ( ). The structure of dichlorocarbene. Electrostatic potential maps show how the positive region coincides with the empty p orbital in both dichlorocarbene and a carbocation (CH 3 + ). The negative region in the dichlorocarbene map coincides with the lone-pair electrons. If dichlorocarbene is generated in the presence of an alkene, addition to the double bond occurs and a dichlorocyclopropane is formed. As the reaction of dichlorocarbene with cis -2-pentene demonstrates, the addition is stereospecific , meaning that only a single stereoisomer is formed as product. Starting from a cis alkene, for instance, only cis-disubstituted cyclopropane is produced; starting from a trans alkene, only trans-disubstituted cyclopropane is produced. The best method for preparing nonhalogenated cyclopropanes is by a process called the Simmons–Smith reaction . First investigated at the DuPont company, this reaction does not involve a free carbene. Rather, it utilizes a carbenoid —a metal-complexed reagent with carbene-like reactivity. When diiodomethane is treated with a specially prepared zinc–copper mix, (iodomethyl)zinc iodide, ICH 2 ZnI, is formed. In the presence of an alkene, ICH 2 ZnI transfers a CH 2 group to the double bond to yield cyclopropane. For example, cyclohexene reacts cleanly and with good yield to give the corresponding cyclopropane. Although we won’t discuss the mechanistic details, carbene addition to an alkene is one of a general class of reactions called cycloadditions, which we’ll study more carefully in Chapter 30. Problems

Science


Radical Additions to Alkenes: Chain-Growth Polymers In our brief introduction to radical reactions in , we said that radicals can add to C═C bonds, taking one electron from the double bond and leaving one behind to yield a new radical. Let’s now look at the process in more detail, focusing on the industrial synthesis of alkene polymers. A polymer is a large—sometimes very large—molecule, built up by repetitive joining together of many smaller molecules, called monomers . Nature makes wide use of biological polymers. Cellulose, for instance, is a polymer built of repeating glucose monomer units; proteins are polymers built of repeating amino acid monomers; and nucleic acids are polymers built of repeating nucleotide monomers. Synthetic polymers, such as polyethylene, are much simpler chemically than biopolymers, but there is still a great diversity to their structures and properties, depending on the identity of the monomers and on the reaction conditions used for polymerization. The simplest synthetic polymers are those that result when an alkene is treated with a small amount of a suitable catalyst. Ethylene, for example, yields polyethylene, an enormous alkane that may have a molecular weight up to 6 million u and may contain as many as 200,000 monomer units. Worldwide production of polyethylene is approximately 88 million tons per year. Polyethylene and other simple alkene polymers are called chain-growth polymers because they are formed in a chain-reaction process in which an initiator adds to a carbon–carbon double bond to yield a reactive intermediate. The intermediate then reacts with a second molecule of monomer to yield a new intermediate, which reacts with a third monomer unit, and so on. Historically, ethylene polymerization was carried out at high pressure (1000–3000 atm) and high temperature (100–250 °C) in the presence of a radical initiator such as benzoyl peroxide. Like many radical reactions, the mechanism of ethylene polymerization occurs in three steps: initiation, propagation, and termination: Initiation The polymerization reaction is initiated when a few radicals are generated on heating a small amount of benzoyl peroxide catalyst to break the weak O−O bond. The initially formed benzoyloxy radical loses CO 2 and gives a phenyl radical (Ph · ), which adds to the C═C bond of ethylene to start the polymerization process. One electron from the ethylene double bond pairs up with the odd electron on the phenyl radical to form a new C−C bond, and the other electron remains on carbon. Propagation Polymerization occurs when the carbon radical formed in the initiation step adds to another ethylene molecule to yield another radical. Repetition of the process for hundreds or thousands of times builds the polymer chain. Termination The chain process is eventually ended by a reaction that consumes the radical. The combination of two growing chains is one possible chain-terminating reaction. 2 R – CH 2 CH 2 · ⟶ R – CH 2 CH 2 CH 2 CH 2 – R Ethylene is not unique in its ability to form a polymer. Many substituted ethylenes, called vinyl monomers, also undergo polymerization to yield polymers with substituent groups regularly spaced on alternating carbon atoms along the chain. Propylene, for example, yields polypropylene, and styrene yields polystyrene. When an unsymmetrically substituted vinyl monomer such as propylene or styrene is polymerized, the radical addition steps can take place at either end of the double bond to yield either a primary radical intermediate (RCH 2 · ) or a secondary radical (R 2 CH · ). Just as in electrophilic addition reactions, however, we find that only the more highly substituted, secondary radical is formed. shows some commercially important alkene polymers, their uses, and the monomers from which they are made. Some Alkene Polymers and Their Uses Monomer Formula Trade or common name of polymer Uses Ethylene H 2 C═ CH 2 Polyethylene Packaging, bottles Propene (propylene) H 2 C═ CHCH 3 Polypropylene Moldings, rope, carpets Chloroethylene (vinyl chloride) H 2 C═ CHCl Poly(vinyl chloride) Insulation, films, pipes Styrene H 2 C═ CHC 6 H 5 Polystyrene Foam, moldings Tetrafluoroethylene F 2 C═ CF 2 Teflon Gaskets, nonstick coatings Acrylonitrile H 2 C═ CHCN Orlon, Acrilan Fibers Methyl methacrylate Plexiglas, Lucite Paint, sheets, moldings Vinyl acetate H 2 C═ CHOCOCH 3 Poly(vinyl acetate) Paint, adhesives, foams Predicting the Structure of a Polymer Show the structure of poly(vinyl chloride), a polymer made from H 2 C═ CHCl , by drawing several repeating units. Strategy Mentally break the carbon–carbon double bond in the monomer unit, and form single bonds by connecting numerous units together. Solution The general structure of poly(vinyl chloride) is Problems

Science


Biological Additions of Radicals to Alkenes The same high reactivity of radicals that enables the alkene polymerization we saw in the previous section also makes it difficult to carry out controlled radical reactions on complex molecules. As a result, there are severe limitations on the usefulness of radical addition reactions in the laboratory. In contrast to an electrophilic addition, where reaction occurs once and the reactive cation intermediate is rapidly quenched by a nucleophile, the reactive intermediate in a radical reaction is not usually quenched. Instead, it reacts again and again in a largely uncontrollable way. In biological reactions, the situation is different from that in the laboratory. Only one substrate molecule at a time is present in the active site of an enzyme, and that molecule is held in a precise position, with other necessary reacting groups nearby. As a result, biological radical reactions are more controlled and more common than laboratory or industrial radical reactions. A particularly impressive example occurs in the biosynthesis of prostaglandins from arachidonic acid, where a sequence of four radical additions take place. Its reaction mechanism was discussed briefly in . As shown in , prostaglandin biosynthesis begins with abstraction of a hydrogen atom from C13 of arachidonic acid by an iron–oxy radical to give a carbon radical that reacts with O 2 at C11 through a resonance form. The oxygen radical that results adds to the C8–C9 double bond to give a carbon radical at C8, which adds to the C12–C13 double bond and gives a carbon radical at C13. A resonance form of this carbon radical adds at C15 to a second O 2 molecule, completing the prostaglandin skeleton. Reduction of the O−O bond then gives prostaglandin H 2 , called PGH 2 . The pathway looks complicated, but the entire process is catalyzed with exquisite control by a single enzyme. Pathway for the biosynthesis of prostaglandins from arachidonic acid. Steps 2 and 5 are radical addition reactions to O 2 ; steps 3 and 4 are radical additions to carbon–carbon double bonds.

Science


Reaction Stereochemistry: Addition of H 2 O to an Achiral Alkene Most of the biochemical reactions that take place in the body, as well as many organic reactions in the laboratory, yield products with chirality centers. For example, acid-catalyzed addition of H 2 O to 1-butene in the laboratory yields 2-butanol, a chiral alcohol. What is the stereochemistry of this chiral product? If a single enantiomer is formed, is it R or S ? If a mixture of enantiomers is formed, how much of each? In fact, the 2-butanol produced is a racemic mixture of R and S enantiomers. Let’s see why. To understand why a racemic product results from the reaction of H 2 O with 1-butene, think about the reaction mechanism. 1-Butene is first protonated to yield an intermediate secondary carbocation. Because the trivalent carbon is sp 2 -hybridized and planar, the cation has a plane of symmetry and is achiral. As a result, it can react with H 2 O equally well from either the top or the bottom. Reaction from the top leads to ( S )-2-butanol through transition state 1 (TS 1) in , and reaction from the bottom leads to ( R )-2-butanol through TS 2. But the two transition states are mirror images, so they have identical energies, form at identical rates, and are equally likely to occur. Reaction of H 2 O with the carbocation resulting from protonation of 1-butene. Reaction from the top leads to S product and is the mirror image of reaction from the bottom, which leads to R product. Because they are energetically identical, they are equally likely and lead to a racemic mixture of products. The dotted C···O bond in the transition state indicates partial bond formation. As a general rule, the formation of a new chirality center by achiral reactants always leads to a racemic mixture of enantiomeric products. Put another way, optical activity can’t appear from nowhere; an optically active product can only result by starting with an optically active reactant or chiral environment ( ). In contrast to laboratory reactions, enzyme-catalyzed biological reactions often give a single enantiomer of a chiral product, even when the substrate is achiral. One step in the citric acid cycle of food metabolism, for instance, is the aconitase-catalyzed addition of water to ( Z )-aconitate (usually called cis -aconitate) to give isocitrate. Even though cis -aconitate is achiral, only the (2 R ,3 S ) enantiomer of the product is formed. As discussed in and , cis -aconitate is a prochiral molecule, which is held in a chiral environment by the aconitase enzyme during the reaction. In this environment, the two faces of the double bond are chemically distinct, and addition occurs on only the Re face at C2.

Reaction Stereochemistry: Addition of H2O to an Achiral Alkene

Science


Reaction Stereochemistry: Addition of H 2 O to a Chiral Alkene The reaction discussed in the previous section involves an addition to an achiral reactant and forms an optically inactive, racemic mixture of two enantiomeric products. What would happen, though, if we were to carry out the reaction on a single enantiomer of a chiral reactant? For example, what stereochemical result would be obtained from addition of H 2 O to a chiral alkene, such as ( R )-4-methyl-1-hexene? The product of the reaction, 4-methyl-2-hexanol, has two chirality centers and so has four possible stereoisomers. Let’s think about the two chirality centers separately. What about the configuration at C4, the methyl-bearing carbon atom? Since C4 has the R configuration in the starting material and this chirality center is unaffected by the reaction, its configuration is unchanged. Thus, the configuration at C4 in the product remains R (assuming that the relative rankings of the four attached groups are not changed by the reaction). What about the configuration at C2, the newly formed chirality center? As shown in , the stereochemistry at C2 is established by reaction of H 2 O with a carbocation intermediate in the usual manner. But this carbocation doesn’t have a plane of symmetry; it is chiral because of the chirality center at C4. Because the carbocation is chiral and has no plane of symmetry, it doesn’t react equally well from the top and bottom faces. One of the two faces is likely, for steric reasons, to be a bit more accessible than the other, leading to a mixture of R and S products in some ratio other than 50 : 50. Thus, two diastereomeric products, (2 R ,4 R )-4-methyl-2-hexanol and (2 S ,4 R )-4-methyl-2-hexanol, are formed in unequal amounts, and the mixture is optically active. Stereochemistry of the acid-catalyzed addition of H 2 O to the chiral alkene, ( R )-4-methyl-1-hexene. A mixture of diastereomeric 2 R ,4 R and 2 S ,4 R products is formed in unequal amounts because reaction of the chiral carbocation intermediate is not equally likely from top and bottom. The product mixture is optically active. As a general rule, the formation of a new chirality center by a chiral reactant leads to unequal amounts of diastereomeric products. If the chiral reactant is optically active because only one enantiomer is used rather than a racemic mixture, then the products are also optically active. Problems Terpenes: Naturally Occurring Alkenes Ever since its discovery in Persia around 1000 A.D., it has been known that steam distillation , the distillation of plant materials together with water, produces a fragrant mixture of liquids called essential oils. The resulting oils have long been used as medicines, spices, and perfumes, and their investigation played a major role in the emergence of organic chemistry as a science during the 19th century. The wonderful fragrance of leaves from the California bay laurel is due primarily to myrcene, a simple terpene. (credit: “California Bay Umbellularia californica” by Don Loaire/Flickr, CC BY 2.0) Chemically, plant essential oils consist largely of mixtures of compounds called terpenoids—small organic molecules with an immense diversity of structure. More than 60,000 different terpenoids are known. Some are open-chain molecules, and others contain rings; some are hydrocarbons, and others contain oxygen. Hydrocarbon terpenoids, in particular, are known as terpenes, and all contain double bonds. For example: Regardless of their apparent structural differences, all terpenoids are related. According to a formalism called the isoprene rule, they can be thought of as arising from head-to-tail joining of 5-carbon isoprene units (2-methyl-1,3-butadiene). Carbon 1 is the head of the isoprene unit, and carbon 4 is the tail. For example, myrcene contains two isoprene units joined head to tail, forming an 8-carbon chain with two 1-carbon branches. α -Pinene similarly contains two isoprene units assembled into a more complex cyclic structure, and humulene contains three isoprene units. See if you can identify the isoprene units in α -pinene, humulene, and β -santalene. Terpenes (and terpenoids) are further classified according to the number of 5-carbon units they contain. Thus, monoterpenes are 10-carbon substances derived from two isoprene units, sesquiterpenes are 15-carbon molecules derived from three isoprene units, diterpenes are 20-carbon substances derived from four isoprene units, and so on. Monoterpenes and sesquiterpenes are found primarily in plants, but the higher terpenoids occur in both plants and animals, and many have important biological roles. The triterpenoid lanosterol, for instance, is the biological precursor from which all steroid hormones are made. Isoprene itself is not the true biological precursor of terpenoids. Nature instead uses two “isoprene equivalents”—isopentenyl diphosphate and dimethylallyl diphosphate—which are themselves made by two different routes depending on the organism. Lanosterol, in particular, is biosynthesized from acetic acid by a complex pathway that has been worked out in great detail. We’ll look at the subject more closely in Sections 27.5 and 27.7 . anti stereochemistry bromonium ion carbene, R 2 C chain-growth polymer epoxide glycol halohydrin hydroboration hydrogenated hydroxylation monomer oxidation oxirane oxymercuration–demercuration ozonide polymer reduction Simmons–Smith reaction stereospecific syn stereochemistry Summary With the background needed to understand organic reactions now covered, this chapter has begun the systematic description of major functional groups. Alkenes are generally prepared by an elimination reaction, such as dehydrohalogenation, the elimination of HX from an alkyl halide, or dehydration, the elimination of water from an alcohol. The converse of this elimination reaction is the addition of various substances to the alkene double bond to give saturated products. HCl, HBr, and HI add to alkenes by a two-step electrophilic addition mechanism. Initial reaction of the nucleophilic double bond with H + gives a carbocation intermediate, which then reacts with halide ion. Bromine and chlorine add to alkenes via three-membered-ring bromonium ion or chloronium ion intermediates to give addition products having anti stereochemistry . If water is present during the halogen addition reaction, a halohydrin is formed. Hydration of an alkene—the addition of water—is carried out by either of two procedures, depending on the product desired. Oxymercuration–demercuration involves electrophilic addition of Hg 2+ to an alkene, followed by trapping of the cation intermediate with water and subsequent treatment with NaBH 4 . Hydroboration involves addition of borane (BH 3 ) followed by oxidation of the intermediate organoborane with alkaline H 2 O 2 . The two hydration methods are complementary: oxymercuration–demercuration gives the product of Markovnikov addition, whereas hydroboration–oxidation gives the product with non-Markovnikov syn stereochemistry . Alkenes are reduced by addition of H 2 in the presence of a catalyst such as platinum or palladium to yield alkanes, a process called catalytic hydrogenation . Alkenes are also oxidized by reaction with a peroxyacid to give epoxides , which can be converted into trans-1,2-diols by acid-catalyzed hydrolysis. The corresponding cis-1,2-diols can be made directly from alkenes by hydroxylation with OsO 4 . Alkenes can also be cleaved to produce carbonyl compounds by reaction with ozone, followed by reduction with zinc metal. In addition, alkenes react with divalent substances called carbenes, R 2 C: , to give cyclopropanes. Nonhalogenated cyclopropanes are best prepared by treatment of the alkene with CH 2 I 2 and zinc–copper, a process called the Simmons–Smith reaction . Alkene polymers —large molecules resulting from repetitive bonding of many hundreds or thousands of small monomer units—are formed by chain-reaction polymerization of simple alkenes. Polyethylene, polypropylene, and polystyrene are examples. As a general rule, radical addition reactions are not common in the laboratory but occur frequently in biological pathways. Many reactions give chiral products. If the reactants are optically inactive, the products are also optically inactive. If one or both of the reactants is optically active, the products can also be optically active. Learning Reactions What’s seven times nine? Sixty-three, of course. You didn’t have to stop and figure it out; you knew the answer immediately because you long ago learned the multiplication tables. Learning the reactions of organic chemistry requires the same approach: reactions have to be learned for quick recall if they are to be useful. Different people take different approaches to learning reactions. Some people make flashcards; others find studying with friends to be helpful. To help guide your study, most chapters in this book end with a summary of the reactions just presented. In addition, the accompanying Study Guide and Student Solutions Manual has several appendixes that organize organic reactions from other perspectives. Fundamentally, though, there are no shortcuts. Learning organic chemistry does take effort. Summary of Reactions No stereochemistry is implied unless specifically indicated with wedged, solid, and dashed lines. Addition reactions of alkenes Addition of HCl, HBr, and HI ( and ) Markovnikov regiochemistry occurs, with H adding to the less highly substituted alkene carbon and halogen adding to the more highly substituted carbon. Addition of halogens Cl 2 and Br 2 ( ) Anti addition is observed through a halonium ion intermediate. Halohydrin formation ( ) Markovnikov regiochemistry and anti stereochemistry occur. Addition of water by oxymercuration–demercuration ( ) Markovnikov regiochemistry occurs. Addition of water by hydroboration–oxidation ( ) Non-Markovnikov syn addition occurs. Catalytic hydrogenation ( ) Syn addition occurs. Epoxidation with a peroxyacid ( ) Syn addition occurs. Hydroxylation with OsO 4 ( ) Syn addition occurs. Addition of carbenes to yield cyclopropanes ( ) (1) Dichlorocarbene addition (2) Simmons–Smith reaction Hydroxylation by acid-catalyzed epoxide hydrolysis ( ) Anti stereochemistry occurs. Oxidative cleavage of alkenes ( ) Reaction with ozone followed by zinc in acetic acid Reaction with KMnO 4 in acidic solution Cleavage of 1,2-diols ( ) Additional Problems Visualizing Chemistry Mechanism Problems Reactions of Alkenes Synthesis Using Alkenes Polymers General Problems

Reaction Stereochemistry: Addition of H2O to a Chiral Alkene

Science


Why This Chapter? Synthesizing organic compounds is like conducting a musical group. When in tune, chemists can create highly complex organic compounds. (credit: modification of work “Jazz great visits Navy” by U.S. Navy, Michael Worner/Wikimedia Commons, Public Domain) Alkynes are less common than alkenes, both in the laboratory and in living organisms, so we won’t cover them in great detail. The real importance of this chapter is that we’ll use alkyne chemistry as a vehicle to begin looking at some of the general strategies used in organic synthesis—the construction of complex molecules in the laboratory. Without the ability to design and synthesize new molecules in the laboratory, many of the medicines we take for granted would not exist and few new ones would be made. An alkyne is a hydrocarbon that contains a carbon–carbon triple bond. Acetylene, H–C≡C–H , the simplest alkyne, was once widely used in industry as a starting material for the preparation of acetaldehyde, acetic acid, vinyl chloride, and other high-volume chemicals, but more efficient routes to these substances using ethylene as starting material are now available. Acetylene is still used in the preparation of acrylic polymers, such as Plexiglas and Lucite, but is probably best known as the gas burned in high-temperature oxy–acetylene welding torches. In addition to simple alkynes with one triple bond, research is also being carried out on polyynes—linear carbon chains of alternating single and triple bonds. Polyynes with up to eight triple bonds are thought to be present in interstellar space, and evidence has been presented for the existence of carbyne , an allotrope of carbon consisting of alternating single and triple bonds in long chains of indefinite length. The electronic properties of polyynes are being explored for potential use in nanotechnology applications.

Science


Naming Alkynes Alkyne nomenclature follows the general rules for hydrocarbons discussed in and . The suffix -yne is used, and the position of the triple bond is indicated by giving the number of the first alkyne carbon in the chain. Numbering the main chain begins at the end nearer the triple bond so that the triple bond receives as low a number as possible. Compounds with more than one triple bond are called diynes, triynes, and so forth; compounds containing both double and triple bonds are called enynes (not ynenes). Numbering of an enyne chain starts from the end nearer the first multiple bond, whether double or triple. When there is a choice in numbering, double bonds receive lower numbers than triple bonds. For example: As with alkyl and alkenyl substituents derived from alkanes and alkenes, respectively, alkynyl groups are also possible. Problems

Science


Preparation of Alkynes: Elimination Reactions of Dihalides Alkynes can be prepared by the elimination of HX from alkyl halides in a similar manner as alkenes ( ). Treatment of a 1,2-dihaloalkane (called a vicinal dihalide) with an excess amount of a strong base such as KOH or NaNH 2 results in a twofold elimination of HX and formation of an alkyne. As with the elimination of HX to form an alkene, we’ll defer a full discussion of this topic and the relevant reaction mechanisms to Chapter 11. The starting vicinal dihalides are themselves readily available by addition of Br 2 or Cl 2 to alkenes. Thus, the overall halogenation/dehydrohalogenation sequence makes it possible to go from an alkene to an alkyne. For example, diphenylethylene is converted into diphenylacetylene by reaction with Br 2 and subsequent base treatment. The twofold dehydrohalogenation takes place through a vinylic halide intermediate, which suggests that vinylic halides themselves should give alkynes when treated with strong base. (A vinylic substituent is one that is attached to a double-bond.) This is indeed the case. For example:

Science


Reactions of Alkynes: Addition of HX and X 2 You might recall from that a carbon–carbon triple bond results from the interaction of two sp -hybridized carbon atoms. The two sp hybrid orbitals of carbon lie at an angle of 180° to each other along an axis perpendicular to the axes of the two unhybridized 2 p y and 2 p z orbitals. When two sp -hybridized carbons approach each other, one sp – sp σ bond and two p–p π bonds are formed. The two remaining sp orbitals form bonds to other atoms at an angle of 180° from the carbon–carbon bond. Thus, acetylene is a linear molecule with H–C≡C bond angles of 180° ( ). The length of the C≡C bond is 120 pm, and its strength is approximately 965 kJ/mol (231 kcal/mol), making it the shortest and strongest known carbon–carbon bond. The structure of acetylene, H–C≡C–H . The H–C≡C bond angles are 180°, and the C≡C bond length is 120 pm. The electrostatic potential map shows that the π bonds create a negative belt around the molecule. As a general rule, electrophiles undergo addition reactions with alkynes much as they do with alkenes. Take the reaction of alkynes with HX, for instance. The reaction often can be stopped with the addition of 1 equivalent of HX, but reaction with an excess of HX leads to a dihalide product. For example, reaction of 1-hexyne with 2 equivalents of HBr yields 2,2-dibromohexane. As the following examples indicate, the regiochemistry of addition follows Markovnikov’s rule, with halogen adding to the more highly substituted side of the alkyne bond and hydrogen adding to the less highly substituted side. Trans stereochemistry of H and X normally, although not always, occurs in the product. Bromine and chlorine also add to alkynes to give addition products, and trans stereochemistry again results. The mechanism of alkyne addition is similar but not identical to that of alkene addition. When an electrophile such as HBr adds to an alkene, the reaction takes place in two steps and involves an alkyl carbocation intermediate ( and ). If HBr were to add by the same mechanism to an alkyne, an analogous vinylic carbocation would be formed as the intermediate. A vinylic carbocation has an sp -hybridized carbon and generally forms less readily than an alkyl carbocation ( ). As a rule, a secondary vinylic carbocation forms about as readily as a primary alkyl carbocation, but a primary vinylic carbocation is so difficult to form that there is no clear evidence it even exists. Thus, many alkyne additions occur through more complex mechanistic pathways. The structure of a secondary vinylic carbocation. The cationic carbon atom is sp -hybridized and has a vacant p orbital perpendicular to the plane of the π bond orbitals. Only one R group is attached to the positively charged carbon rather than two, as in a secondary alkyl carbocation. The electrostatic potential map shows that the most positive regions coincide with lobes of the vacant p orbital and are perpendicular to the most negative regions associated with the π bond. Problems

Reactions of Alkynes: Addition of HX and X2

Science


Hydration of Alkynes Like alkenes ( and ), alkynes can be hydrated by either of two methods. Direct addition of water catalyzed by mercury(II) ion yields the Markovnikov product, and indirect addition of water by a hydroboration–oxidation sequence yields the non-Markovnikov product. Mercury(II)-Catalyzed Hydration of Alkynes Alkynes don’t react directly with aqueous acid but will undergo hydration readily in the presence of mercury(II) sulfate as a Lewis acid catalyst. The reaction occurs with Markovnikov regiochemistry, so the −OH group adds to the more highly substituted carbon and the −H attaches to the less highly substituted one. Interestingly, the actual product isolated from alkyne hydration is not a vinylic alcohol, or enol ( ene + ol ), but is instead a ketone. Although the enol is an intermediate in the reaction, it immediately rearranges into a ketone by a process called keto–enol tautomerism. The individual keto and enol forms are said to be tautomers , a word used to describe two isomers that undergo spontaneous interconversion accompanied by the change in position of a hydrogen. With few exceptions, the keto–enol tautomeric equilibrium lies on the side of the ketone; enols are almost never isolated. We’ll look more closely at this equilibrium in Section 22.1 . As shown in , the mechanism of the mercury(II)-catalyzed alkyne hydration reaction is analogous to the oxymercuration reaction of alkenes ( ). Electrophilic addition of mercury(II) ion to the alkyne gives a vinylic cation, which reacts with water and loses a proton to yield a mercury-containing enol intermediate. In contrast with alkene oxymercuration, however, no treatment with NaBH 4 is necessary to remove the mercury. The acidic reaction conditions alone are sufficient to effect replacement of mercury by hydrogen. Tautomerization then gives the ketone. MECHANISM Mechanism of the mercury(II)-catalyzed hydration of an alkyne to yield a ketone. The reaction occurs through initial formation of an intermediate enol, which tautomerizes to the ketone. A mixture of both possible ketones results when an unsymmetrically substituted internal alkyne ( RC≡CR′ ) is hydrated. The reaction is therefore most useful when applied to a terminal alkyne ( RC≡CH ) because only a methyl ketone is formed. Problems Hydroboration–Oxidation of Alkynes Borane adds rapidly to an alkyne just as it does to an alkene, and the resulting vinylic borane can be oxidized by H 2 O 2 to give an enol, which tautomerizes to either a ketone or an aldehyde, depending on the alkyne. Hydroboration–oxidation of an internal alkyne such as 3-hexyne is straightforward and gives a ketone, but hydroboration–oxidation of a terminal alkyne is more complex because two molecules of borane often add to the triple bond, complicating the situation. To prevent this double addition, a bulky, sterically encumbered borane such as bis(1,2-dimethylpropyl)borane, known commonly as disiamylborane is used in place of BH 3 . When a terminal alkyne such as 1-butene reacts with disiamylborane, addition to the triple bond occurs normally, but a second addition is hindered by the bulk of the dialkylborane. Oxidation with H 2 O 2 then gives an enol, which tautomerizes to the aldehyde. The hydroboration–oxidation sequence is complementary to the direct, mercury(II)-catalyzed hydration reaction of a terminal alkyne because different products result. Direct hydration with aqueous acid and mercury(II) sulfate leads to a methyl ketone, whereas hydroboration–oxidation of the same terminal alkyne leads to an aldehyde. Problems

Science


Reduction of Alkynes Alkynes are reduced to alkanes by addition of H 2 over a metal catalyst. The reaction occurs in two steps through an alkene intermediate, and measurements show that the first step in the reaction is more exothermic than the second. Complete reduction to the alkane occurs when palladium on carbon (Pd/C) is used as catalyst, but hydrogenation can be stopped at the alkene stage if the less active Lindlar catalyst is used. The Lindlar catalyst is a finely divided palladium metal that has been precipitated onto a calcium carbonate support and then deactivated by treatment with lead acetate and quinoline, an aromatic amine. The hydrogenation occurs with syn stereochemistry ( ), giving a cis alkene product. The alkyne hydrogenation reaction has been explored extensively by the Hoffmann–LaRoche pharmaceutical company, where it is used in the commercial synthesis of vitamin A. The cis isomer of vitamin A produced initially on hydrogenation is converted to the trans isomer by heating. An alternative method for the conversion of an alkyne to an alkene uses sodium or lithium metal as the reducing agent in liquid ammonia as solvent. This method is complementary to the Lindlar reduction because it produces trans rather than cis alkenes. For example, 5-decyne gives trans -5-decene on treatment with lithium in liquid ammonia. The mechanism is explained below. Alkali metals dissolve in liquid ammonia at −33 °C to produce a deep blue solution containing the metal cation and ammonia-solvated electrons. When an alkyne is then added to the solution, reduction occurs by the mechanism shown in . An electron first adds to the triple bond to yield an intermediate anion radical—a species that is both an anion (has a negative charge) and a radical (has an odd number of electrons). This anion radical is a strong base, able to remove H + from ammonia to give a vinylic radical. Addition of a second electron to the vinylic radical gives a vinylic anion, which abstracts a second H + from ammonia to give trans alkene product. MECHANISM Mechanism of the lithium/ammonia reduction of an alkyne to produce a trans alkene. Trans stereochemistry of the alkene product is established during the second reduction step ( 3 ) when the less-hindered trans vinylic anion is formed from the vinylic radical. Vinylic radicals undergo rapid cis–trans equilibration, but vinylic anions equilibrate much less rapidly. Thus, the more stable trans vinylic anion is formed rather than the less stable cis anion and is then protonated without equilibration. Problems

Science


Oxidative Cleavage of Alkynes Alkynes, like alkenes, can be cleaved by reaction with powerful oxidizing agents such as ozone or KMnO 4 , although the reaction is of little value and it is mentioned only for completeness. A triple bond is generally less reactive than a double bond, and yields of cleavage products can be low. The products obtained from cleavage of an internal alkyne are carboxylic acids; from a terminal alkyne, CO 2 is formed as one product.

Science


Alkyne Acidity: Formation of Acetylide Anions The most striking difference between alkenes and alkynes is that terminal alkynes are relatively acidic. When a terminal alkyne is treated with a strong base, such as sodium amide, Na + − NH 2 , the terminal hydrogen is removed and the corresponding acetylide anion is formed. According to the Brønsted–Lowry definition ( ), an acid is a substance that donates H + . Although we usually think of oxyacids (H 2 SO 4 , HNO 3 ) or halogen acids (HCl, HBr) in this context, any compound containing a hydrogen atom can be an acid under the right circumstances. By measuring dissociation constants of different acids and expressing the results as p K a values, an acidity order can be established. Recall from that a lower p K a corresponds to a stronger acid and a higher p K a corresponds to a weaker one. Where do hydrocarbons lie on the acidity scale? As the data in show, both methane (p K a ≈ 60) and ethylene (p K a = 44) are very weak acids and thus do not react with any of the common bases. Acetylene, however, has p K a = 25 and can be deprotonated by the conjugate base of any acid whose p K a is greater than 25. Amide ion (NH 2 − ), for example, the conjugate base of ammonia (p K a = 35), is often used to deprotonate terminal alkynes. Acidity of Simple Hydrocarbons Family Example K a p K a Alkyne HC≡CH 10 −25 25 Alkene H 2 C═ CH 2 10 −44 44 Alkane CH 4 10 −60 60 Why are terminal alkynes more acidic than alkenes or alkanes? In other words, why are acetylide anions more stable than vinylic or alkyl anions? The simplest explanation involves the hybridization of the negatively charged carbon atom. An acetylide anion has an sp -hybridized carbon, so the negative charge resides in an orbital that has 50% “ s character.” A vinylic anion has a sp 2 -hybridized carbon with 33% s character, and an alkyl anion ( sp 3 ) has only 25% s character. Because s orbitals are nearer the positive nucleus and lower in energy than p orbitals, the negative charge is stabilized to a greater extent in an orbital with higher s character ( ). A comparison of alkyl, vinylic, and acetylide anions. The acetylide anion, with sp hybridization, has more s character and is more stable. Electrostatic potential maps show that placing the negative charge closer to the carbon nucleus makes carbon appear less negative (red). Problems

Science


Alkylation of Acetylide Anions The negative charge and unshared electron pair on carbon make an acetylide anion strongly nucleophilic. As a result, an acetylide anion can react with electrophiles, such as alkyl halides, in a process that replaces the halide and yields a new alkyne product. We won’t study the details of this substitution reaction until Chapter 11, but for now you can picture it as happening by the pathway shown in . The nucleophilic acetylide ion uses an electron pair to form a bond to the positively polarized, electrophilic carbon atom of bromomethane. As the new C−C bond forms, Br − departs, taking with it the electron pair from the former C−Br bond and yielding propyne as product. We call such a reaction an alkylation because a new alkyl group has become attached to the starting alkyne. MECHANISM A mechanism for the alkylation reaction of acetylide anion with bromomethane to give propyne. Alkyne alkylation is not limited to acetylene itself. Any terminal alkyne can be converted into its corresponding anion and then allowed to react with an alkyl halide to give an internal alkyne product. Hex-1-yne, for instance, gives dec-5-yne when treated first with NaNH 2 and then with 1-bromobutane. Because of its generality, acetylide alkylation is a good method for preparing substituted alkynes from simpler precursors. A terminal alkyne can be prepared by alkylation of acetylene itself, and an internal alkyne can be prepared by further alkylation of a terminal alkyne. The only limit to the alkylation reaction is that it can only use primary alkyl bromides and alkyl iodides because acetylide ions are sufficiently strong bases to cause elimination instead of substitution when they react with secondary and tertiary alkyl halides. For example, reaction of bromocyclohexane with propyne anion yields the elimination product cyclohexene rather than the substitution product 1-propynylcyclohexane. Problems

Science


An Introduction to Organic Synthesis As mentioned in the introduction, one of the purposes of this chapter is to use alkyne chemistry as a vehicle to begin looking at some of the general strategies used in organic synthesis—the construction of complex molecules in the laboratory. There are many reasons for carrying out the laboratory synthesis of an organic compound. In the pharmaceutical industry, new molecules are designed and synthesized in the hope that some might be useful new drugs. In the chemical industry, syntheses are done to devise more economical routes to known compounds. In academic laboratories, the synthesis of extremely complex molecules is sometimes done just for the intellectual challenge involved in mastering so difficult a subject. The successful synthesis route is a highly creative work that is sometimes described by such subjective terms as elegant or beautiful . In this book, too, we will often devise syntheses of molecules from simpler precursors, but the purpose here is to learn. The ability to plan a successful multistep synthetic sequence requires a working knowledge of the uses and limitations of many different organic reactions. Furthermore, it requires the practical ability to piece together the steps in a sequence such that each reaction does only what is desired without causing changes elsewhere in the molecule. Planning a synthesis makes you approach a chemical problem in a logical way, draw on your knowledge of chemical reactions, and organize that knowledge into a workable plan—it helps you learn organic chemistry. There’s no secret to planning an organic synthesis: all it takes is a knowledge of the different reactions and some practice. The only real trick is to work backward in what is often called a retrosynthetic direction. Don’t look at a potential starting material and ask yourself what reactions it might undergo. Instead, look at the final product and ask, “What was the immediate precursor of that product?” For example, if the final product is an alkyl halide, the immediate precursor might be an alkene, to which you could add HX. If the final product is a cis alkene, the immediate precursor might be an alkyne, which you could hydrogenate using the Lindlar catalyst. Having found an immediate precursor, work backward again, one step at a time, until you get back to the starting material. You have to keep the starting material in mind, of course, so that you can work back to it, but you don’t want that starting material to be your main focus. Let’s work several examples of increasing complexity. Devising a Synthesis Route How would you synthesize cis -2-hexene from 1-pentyne and an alkyl halide? More than one step is needed. Strategy When undertaking any synthesis problem, you should look at the product, identify the functional groups it contains, and then ask yourself how those functional groups can be prepared. Always work retrosynthetically, one step at a time. The product in this case is a cis-disubstituted alkene, so the first question is, “What is an immediate precursor of a cis-disubstituted alkene?” We know that an alkene can be prepared from an alkyne by reduction and that the right choice of experimental conditions will allow us to prepare either a trans-disubstituted alkene (using lithium in liquid ammonia) or a cis-disubstituted alkene (using catalytic hydrogenation over the Lindlar catalyst). Thus, reduction of 2-hexyne by catalytic hydrogenation using the Lindlar catalyst should yield cis -2-hexene. Next ask, “What is an immediate precursor of 2-hexyne?” We’ve seen that an internal alkyne can be prepared by alkylation of a terminal alkyne anion. In the present instance, we’re told to start with 1-pentyne and an alkyl halide. Thus, alkylation of the anion of 1-pentyne with iodomethane should yield 2-hexyne. Solution cis -2-Hexene can be synthesized from the given starting materials in three steps. Devising a Synthesis Route How would you synthesize 2-bromopentane from acetylene and an alkyl halide? More than one step is needed. Strategy Identify the functional group in the product (an alkyl bromide) and work the problem retrosynthetically. What is an immediate precursor of an alkyl bromide? Perhaps an alkene plus HBr. Of the two possibilities, Markovnikov addition of HBr to 1-pentene looks like a better choice than addition to 2-pentene because the latter reaction would give a mixture of isomers. What is an immediate precursor of an alkene? Perhaps an alkyne, which could be reduced. What is an immediate precursor of a terminal alkyne? Perhaps sodium acetylide and an alkyl halide. Solution The desired product can be synthesized in four steps from acetylene and 1-bromopropane. Devising a Synthesis Route How would you synthesize 5-methyl-1-hexanol (5-methyl-1-hydroxyhexane) from acetylene and an alkyl halide? Strategy What is an immediate precursor of a primary alcohol? Perhaps a terminal alkene, which could be hydrated with non-Markovnikov regiochemistry by reaction with borane followed by oxidation with H 2 O 2 . What is an immediate precursor of a terminal alkene? Perhaps a terminal alkyne, which could be reduced. What is an immediate precursor of 5-methyl-1-hexyne? Perhaps acetylene and 1-bromo-3-methylbutane. Solution The synthesis can be completed in four steps from acetylene and 1-bromo-3-methylbutane: Problems The Art of Organic Synthesis Vitamin B 12 has been synthesized from scratch in the laboratory, but the bacteria growing on sludge from municipal sewage plants do a much better job. (credit: “Aeration and sludge-wasting” by U.S. Department of Agriculture/Flickr, Public Domain) If you think some of the synthesis problems at the end of this chapter are difficult, try devising a synthesis of vitamin B 12 starting only from simple substances you can buy in a chemical catalog. This extraordinary achievement was reported in 1973 as the culmination of a collaborative effort headed by Robert B. Woodward of Harvard University and Albert Eschenmoser of the Swiss Federal Institute of Technology in Zürich. More than 100 graduate students and postdoctoral associates contributed to the work, which took more than a decade to complete. Why put such extraordinary effort into the laboratory synthesis of a molecule so easily obtained from natural sources? There are many reasons. On a basic human level, a chemist might be motivated primarily by the challenge, much as a climber might be challenged by the ascent of a difficult peak. Beyond the pure challenge, the completion of a difficult synthesis is also valuable in that it establishes new standards and raises the field to a new level. If vitamin B 12 can be made, then why can’t any molecule found in nature be made? Indeed, the decades that have passed since the work of Woodward and Eschenmoser have seen the laboratory synthesis of many enormously complex and valuable substances. Sometimes these substances—for instance, the anticancer compound paclitaxel, trade named Taxol—are not easily available in nature, so laboratory synthesis is the only method for obtaining larger quantities. But perhaps the most important reason for undertaking a complex synthesis is that, in so doing, new reactions and new chemistry are discovered. It invariably happens in a complex synthesis that a point is reached at which the planned route fails. At such a time, the only alternatives are either to quit or to devise a way around the difficulty. New reactions and new principles come from such situations, and it is in this way that the science of organic chemistry grows richer. In the synthesis of vitamin B 12 , for example, unexpected findings emerged that led to the understanding of an entire new class of reactions—the pericyclic reactions that are the subject of Chapter 30 in this book. From synthesizing vitamin B 12 to understanding pericyclic reactions—no one could have possibly predicted such a link at the beginning of the synthesis, but that is the way of science. acetylide anion alkylation alkyne enol Lindlar Catalyst retrosynthetic tautomer Summary Alkynes are less common than alkenes, both in the laboratory and in living organisms, so we haven’t covered them in great detail. The real importance of this chapter is that alkyne chemistry is a useful vehicle for looking at the general strategies used in organic synthesis—the construction of complex molecules in the laboratory. An alkyne is a hydrocarbon that contains a carbon–carbon triple bond. Alkyne carbon atoms are sp -hybridized, and the triple bond consists of one sp – sp σ bond and two p–p π bonds. There are relatively few general methods of alkyne synthesis. Two favorable ones are the alkylation of an acetylide anion with a primary alkyl halide and the twofold elimination of HX from a vicinal dihalide. The chemistry of alkynes is dominated by electrophilic addition reactions, similar to those of alkenes. Alkynes react with HBr and HCl to yield vinylic halides and with Br 2 and Cl 2 to yield 1,2-dihalides (vicinal dihalides). Alkynes can be hydrated by reaction with aqueous sulfuric acid in the presence of mercury(II) catalyst. The reaction leads to an intermediate enol that immediately tautomerizes to yield a ketone. Because the addition reaction occurs with Markovnikov regiochemistry, a methyl ketone is produced from a terminal alkyne. Alternatively, hydroboration–oxidation of a terminal alkyne yields an aldehyde. Alkynes can be reduced to yield alkenes and alkanes. Complete reduction of the triple bond over a palladium hydrogenation catalyst yields an alkane; partial reduction by catalytic hydrogenation over a Lindlar catalyst yields a cis alkene. Reduction of the alkyne with lithium in ammonia yields a trans alkene. Terminal alkynes are weakly acidic. The alkyne hydrogen can be removed by a strong base such as Na + − NH 2 to yield an acetylide anion . An acetylide anion acts as a nucleophile and can displace a halide ion from a primary alkyl halide in an alkylation reaction. Acetylide anions are more stable than either alkyl anions or vinylic anions because their negative charge is in a hybrid orbital with 50% s character, allowing the charge to be closer to the nucleus. Summary of Reactions No stereochemistry is implied unless specifically indicated with wedged, solid, and dashed lines. Preparation of alkynes Dehydrohalogenation of vicinal dihalides ( ) Alkylation of acetylide anions ( ) Reactions of alkynes Addition of HCl and HBr ( ) Addition of Cl 2 and Br 2 ( ) Hydration ( ) (1) Mercuric sulfate catalyzed (2) Hydroboration–oxidation Reduction ( ) (1) Catalytic hydrogenation (2) Lithium in liquid ammonia Conversion into acetylide anions ( ) Additional Problems Visualizing Chemistry Mechanism Problems Naming Alkynes Reactions of Alkynes Organic Synthesis General Problems

Science


Why This Chapter? The gases released during volcanic eruptions contain large amounts of organohalides, including chloromethane, chloroform, dichlorodifluoromethane, and many others. (credit: modification of work “Tavurvur volcano” by Taro Taylor, Richard Bartz/Wikimedia Commons, CC BY 2.0) Alkyl halides are encountered less frequently than their oxygen-containing relatives and are not often involved in the biochemical pathways of terrestrial organisms, but some of the kinds of reactions they undergo—nucleophilic substitutions and eliminations—are encountered frequently. Thus, alkyl halide chemistry is a relatively simple model for many mechanistically similar but structurally more complex reactions found in biomolecules. We’ll begin this chapter with a look at how to name and prepare alkyl halides, and we’ll see several of their reactions. Then, in the next chapter, we’ll make a detailed study of the substitution and elimination reactions of alkyl halides—two of the most important and well-studied reaction types in organic chemistry. Now that we’ve covered the chemistry of hydrocarbons, it’s time to start looking at more complex substances that contain elements in addition to C and H. We’ll begin by discussing the chemistry of organohalides , compounds that contain one or more halogen atoms. Halogen-substituted organic compounds are widespread in nature, and more than 5000 organohalides have been found in algae and various other marine organisms. Chloromethane, for instance, is released in large amounts by ocean kelp, as well as by forest fires and volcanoes. Halogen-containing compounds also have an array of industrial applications, including their use as solvents, inhaled anesthetics in medicine, refrigerants, and pesticides. Still other halo-substituted compounds are used as medicines and food additives. The nonnutritive sweetener sucralose, marketed as Splenda, contains three chlorine atoms, for instance. Sucralose is about 600 times as sweet as sucrose, so only 1 mg is equivalent to an entire teaspoon of table sugar. A large variety of organohalides are known. The halogen might be bonded to an alkynyl group ( C≡C−X ), a vinylic group ( C═C–X ), an aromatic ring (Ar−X), or an alkyl group. In this chapter, however, we’ll be primarily concerned with alkyl halides , compounds with a halogen atom bonded to a saturated, sp 3 -hybridized carbon atom.

Science