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Copy of Organic Chemistry Jonh Mc Murry16

Copy of Organic Chemistry Jonh Mc Murry16 - 270 CHAPTER 8...

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Unformatted text preview: 270 CHAPTER 8 Atkynes: An Introduction to Organic Synthesis Thomson lnteractiveto use a web-based palette to predict products for Problem 8.3 Click Organic the oxidative cleavage of alkynes. 3.7 Trans stereochemistry of the alkene product is established during the sec- ond reduction step 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. Using any alkyne needed, how would you prepare the following alkenes? (a) trans-Z—Octene (b) cis~3-Heptene (c) 3-Methyl»l~pentene Qxitlative Cleavage of Alkynes Alkymes, like alkenes, can be cleaved by reaction with powerful oxidizing agents such as ozone or KMnO4, although the reaction is of little value and we men- tion it only for completeness. A triple bond is generally less reactive than a dou- ble bond and yields of cleavage products are sometimes low. The products obtained from cleavage of an internal alkyne are carboxylic acids,- from a termi- nal alkyne, C02 is formed as one product. An internal alkyne O O R C—C R KMnO;OrO-q g Icl: _ = _’ —“_) + R/ \OH HO/ \R' A terminal alkyne O R—C=C~H l<imnl::uoroa_ II + O-C—O _ Fl/ \Ol-l mung Acidity: Formation of Acetyude Anions The most striking difference between alkenes and alkynes is that terminal alkynes are weakly acidic. When a terminal alkyne is treated with a strong base, such as sodium amide, Na+ ‘NHZ, the terminal hydrogen is removed and an acetylide anion is formed. Will—I3 Mt RHCECAH R—CEC:'i\ia+ + :m—I3 A terminal alkyne An acetylide anion According to the Bronsted—Lowry definition (Section 2.7), an acid is a sub- stance that donates I-i+. Although we usually think of oxyaclcls (£12804, HNO3) 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 Figure 8.5 A comparison of alkyl, vinylic, and acetylide anions. The acetylide anion, with sp hybridization, has more scharacter and is more stable. Electrostatic potential maps show that placing the negative charge closer to the carbon nucleus makes carbon appear less negative (red). 8.7 Alkyne Acidity: Formation of Acetylide Anions 271 constants of different acids and expressing the results as pKa values, an acidity order can be established. Recall from Section 2.8 that a low pKa corresponds to a strong acid and a high pKa corresponds to a weak acid. Where do hydrocarbons lie on the acidity scale? As the data in Table 8.1 show, both methane (pKa e: 60) and ethylene (ij, : 44) are very weak acids and thus do not react with any of the common bases. Acetylene, however, has pKa : 25 and can be deprotonated by the coniugate base of any acid whose pKa is greater than 25. Amide ion (NH2’), for example, the conjugate base ofammonia (pKa ——- 35), is often used to deprotonate terminal alkynes. Table 8.1 Acidity of Simple Hydrocarbons Family Example Ka pk'fl All-:ync HCECH 10‘25 25 Stronger acid A Allrene H2C:CH2 10—44 44 1ri='c.;"-'ei Alkane CH; 1043-0 60 acid 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 acetylicle anion has an sp-hybridizecl carbon, so the negative charge resides in an orbital that has 50% "5 character." A vinylic anion has an spZ-hybridized carbon with 33% 5 character, and an alkyl anion (sp3) has only 25% 5 character. Because 5 orbitals are nearer the positive nucleus and lower in energy than ,0 orbitals, the negative charge is stabilized to a greater extent in an orbital with higher 5 character (Figure 8.5). H -:.v / m7 51') H\ - ‘ H~c\\ ' ' H, c Q / fl HiCEC'fiQ H H A-zti‘iylir'te anion isn‘t/o s; 272 Problem 8.9 Thomson Click Organic Interactive to use a web-based palette to predict products for alkyne alkylation reactions. :~- :1 Figure 8.6 MECHANISM: A mechanism for the alkylation reaction of acetvlide anion with bromo— methane to give propyne. Sign in at www.thomsonedu.com to see a simulation based on this figure and to take a short quiz. CHAPTER 8 Alkynes: An Introduction to Organic Synthesis The presence of a negative charge and an unshared electron pair on carbon makes acetylide anions strongly nucleophilic. As a result, they react with many different kinds of electrophiles. The pKa of acetone, CH3COCH3, is 19.3. Which of the following bases is strong enough to deprotonate acetone? (3) 1<OH (pK£1 of H20 2 15.7) (c) NaHC03 (pKé‘. of £12603 = 6.4) (b) Na+ -C:CH (pic, of Czl-Iz : 25) ((l) Naocu3 (pKfl of CH301-l = 15.6) Alkylatinn of Acetylide Anions The negative charge and unshared electron pair on carbon make an acetylide anion strongly nucleophilic. As a result, an acetyiide anion can react with an alkyl halide such as bromomethane to substitute for the halogen and yield a new alkyne product. /' “‘2‘ H H {_ ‘\‘.l .- '1 i HiCEC: Na+ + H c‘ei- ~ H C:c—p H + Nam H H Acetylide anion Propyne We won’t study the details of this substitution reaction until Chapter 11 but for now can picture it as happening by the pathway shown in Figure 8.6. The nucleophilic acetylide ion uses an electron pair to form a bond to the positively polarized, electrophiiic carbon atom of bromomethane. As the new CwC 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 anew alkyl group has become attached to the starting alkyne. (“Hex H a l' r r N \‘\C air 0 The nucleophilic aoe’ryiide anion rises its I V "— fl H") electron lone pair to form a bond to the H positively polarized, eiectrophiiic carbon atom of bromomethane. As the new C-C 0 bond begins to form, the C—Br bond begins to break in the transition state. H <31 i". l he H *CTC-‘HCM-Br + Na'E' ,"\ H H Transition state 9 The new c—c bond is fully formed and the old C~Br bond is fully broken at the . 9 end of the reaction. ©Jnhn MrMuI'ry 8.8 Alkylalion of Acetyllde Anions 273 Alkyne alkyiation is not limited to acetylene itself. Any terminal alkyne can be converted into its corresponding anion and then alkylated by treatment with an alkyl halide, yielding an internal alkyne. For example, conversion of l-hexyne into its anion, followed by reaction with i-bromobutane, yields S-decyne. l. Mai-it? NH3 2. CI-I3CH2CH2CH25‘: 1-Hexyne S-Decyne (76%) CH3CH2CH2CH2CECH CH3CH2CH2CH2CECCH2CH2CH2CH3 Because of its generality, acetylide alkylation is an excellent method for preparing substituted alkynes from simpler precursors. /~\ terminal alkyne can be prepared by alkylation of acetylene itself, and an internal alkyne can be pre- pared by further alkylation of a terminal alkyne. “ii-Ni" — _ n RCH Fl: HiCEC— l-l —-~ _H—CECI :~'a"_| 2 H—CEC—CHZR Acetylene A terminal aikyne ital-€141 _ R'CH i3! R~C2c—n —' [R—CEC: aw] —2~ R—CEC—CHZR‘ A terminal alkyne An internal aikyne The alkylation reaction is limited to the use of primary alkyl bromides and alkyl iodides because acetylide ions are sufficiently strong bases to cause dehydrohalogenation 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 sub- stitution product i—propynylcyclohexane. ‘1 + CH3CECI-l + Nail-3t / V H H If / B, Cyclohexene + CH3CEC:_ NaJr H CH / 3 H CZC Bromocyclohexane [a secondary alkyl halide) NOT formed Problem 8.10 Show the terminal alkyne and alkyl halide from which the following products can be obtained. If two routes look feasible, list both. (a) CH3CH2CH2CECCH3 lb) (CH3)2CHCECCH2CH3 lci CECCH3 Problem 8.11 How would you prepare cis-Z-butene starting from propyne, an alkyl halide, and any other reagents needed? This problem can/r be worked in a single step. You’ll have to carry out more than one reaction. 274 CHAPTEFI 8 Alkvnes: An Introduction to Organic Synthesis 8.9 Strategy Solution An introduction in Organir: Synthesis There are many reasons for carrying out the laboratory synthesis of an organic compound. In the pharmaceutical industry, new organic molecules are designed and synthesized in the hope that some might be useful new drugs. In the chem: ical industry, syntheses are done to devise more economical routes to known compounds. In academic laboratories, the synthesis of complex molecules is sometimes done purely 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 beautifiii. In this book, too, we will often devise syntheses of molecules from simpler precursors. Our purpose, however, is pedagogical. The ability to plan a workable synthetic sequence requires knowledge of a variety of organic reactions. Further- more, it requires the practical ability to lit together the steps in a sequence such that each reaction does only what is desired without causing changes elsewhere in the molecule. Working synthesis problems is an excellent way to learn organic chemistry. Some of the syntheses we plan may seem trivial. Here‘s an example: Devising 3 Synthesis Route Prepare octane from 1-pentyne. CH3CH2CH2CECH fig CH3CH2CH2CHQCH2CH2CH2CH3 1»Pentyne Octane Compare the product with the starting material, and catalog the differences. in this case, we need to add three carbons to the chain and reduce the triple bond. Since the starting material is a terminal alkyne that can be alkylated, we might first pre- pare the acetylide anion of 1-pentyne, let it react with l-bromopropane, and then reduce the product using catalytic hydrogenation. 1. F\li,-ii\ll l_i, NH3 2, H‘CHchcha, THF 1-Pentyne 4-Oc1vne CH3CH2CHZCECH CH3CHZCHZCECCH2CH2CH3 le/Pd in ethanol H lei I I CH3CH2CHZC‘I*(IZCHZCH7_CH3 H H Octane The synthesis route just presented will work perfectly well but has little practical value because you can simply buy octane from any of several dozen Strategy 8.9 An Introduction to Organic Synthesis 275 chemical suppliers. The value of working the problem is that it 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: it takes a knowledge of the different reactions, some discipline, and a lot of practice. The only real trick is to work backward in what is often referred to as a retrosynthetic direction. Don’t look at the starting material and ask yourself what reactions it might I undergo. instead, look at the final product and ask, 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). lithe 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 more examples of increasing complexity. t‘AYInnL ...... LL‘A JM.-.—..\’I:ALA VVlldL VVd.) [11C lllllllCUldL': Devising 3 Synthesis Route Synthesize ci572~hexene from 1-pentyne and any alkyl halide needed. More than one step is required. CHCHCH CH 3 2\2 / 3 CH3CH2CH2CECH + RX —> /C:C\ 1-Pentyne Alkyl H H halide cis-Z-Hexene 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 in a retrosynthetic sense, 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-disubstiiuted alkene (using lithium in liquid ammonia) or a cisedisubstituted alkene [using catalytic hydrogenation over the Lindlar catalyst). Thus, reduction of Z—hexyne by catalytic hydrogenation using the Lindlar catalyst should yield cis-Z—hexene. CH3CH2c\H2 /CH3 CH3CH2CH2CZCCH3 Lindlarcatalvst /C_C\ l H J 2-Hexyne cisZ-Hexene Next ask, “What is an immediate precursor of 2—hexyne?” We’ve seen that an inter- nal alkyne can be prepared by alkylation of a terminal alkyne anion. In the present 276 CHAPTERS Alkynes: An Introduction to Organic Synthesis Solution instance, we’re told to start with 1-pentyne and an alkyl halide. Thus, alkylation of the anion of i-pentyne with iodomethane should yield 2-hex3me. I NH _ ” 3 CH3CH2CH2CEC13 CH3CH2CH2CECH + infirm, 1-Pentyne In THF CH3Cl-l2CI-I2CECI_ Nat + CH3i CH3CHQCH2CECCH3 2-Hexyne (is-Z-Hexene can be synthesized from the given starting materials in three steps. CH3CHZCH2 /CH3 1, "ilulk'l NH ii.) \ CHgCHZCHZCECH 7 #3 CH3CH2CHQCECCH3 _—l-—9 c=c 2. Cl—Igl, THF Lindlar catalyst / \ 1-Pentyne 2—Hexyne H H ,, WORKED'EXAMPLE 8.3 _ Strategy ciSvZ-Hexene Devising 3 Synthesis Route Synthesize 2-brom0pentane from acetylene and any aikyl halide needed More than one step is required, Br I HCECH + RX 1 CH3CH2CH2CHCH3 Acetylene Alkyl Z-Bromopentane halide identity the functional group in the product (an alkyl bromide) and work the prob- lem ret'tosynthetically. ”What is an immediate precursor of an alkyl bromide?” Per- haps an alkene plus HBt. Of the two possibilities, addition of HBr to t-pentene looks like a better choice than addition to 2-pentene because the latter reaction would give a mixture of isomers CH3CH2CH2CHZCH2 B] HBi l CH3CH2CH2CHCH3 Or Ether CH3CH2CH:CHCH3 ”What is an immediate precursor otan alkene?" Perhaps an alkyne, which could be reduced. l'l-. CH3CH2CH2CECH _—'- CH3CH2CH2CHZCH2 Ltridléircnlalytsi “What is an immediate precursor of a terminal alkyne?” Perhaps sodium acetylide and an alkyl halide. Na+ :EECH + nicuzcuzcu3 # cuacuzcuzczcn Soiution work-ICED EXAMPLE _s.4_ 7 Strategy Solution l-lCECH Acetylene 1-Hexyne 88 An Introduction to Organic Synthesis 277 The desired product can be synthesized in four steps from acetylene and 1-brom0- propane. 1. i‘-.‘:i\‘_l* _. NH3 l-lq HCECH —— —" CH3CH2CH2CECH —"> CH3CH2CH2CH:CH2 2. CH3CH2CHZBL THF Lindlar Acetylene 1-Pentyne catalyst 1-Pentene Jl lBr, ether CH3CH2CH2fi—3HCH3 Br Z—Bro mopentane Devising 3 Synthesis Route Synthesize l-hexanol (1-hydroxyhexane) from acetylene and an alkyl halide. HCECH + RX —, “_\ CI-I3CH2CHZCH2CHQCH2OH Acetylene Alkyl 1-Hexanol halide "What is an immediate precursor of a primary alcohol?” Perhaps a terminal alkene, which could be hydrated with non-Markovnikov regiochemistry by reaction with Dorane followed by oxidation with 1-1202. 1. l'il r-: : H _ CH3CH2CH2CH2CH C 2 2 i-i-:.03,NaOH CH3CH2CH2CH2CH2CHZOH “What is an immediate precursor of a terminal alkene?" Perhaps a terminal alkyne, which could be reduced. CH3CH2CHZCH2CECH ‘ ~ CH3CH2CH2CH2CH=CH2 Lindlar catalyst ”What is an immediate precursor of 1-hexyne?” Perhaps acetylene and 1-bromobutane. _ 2;: H __ _ __ CH3CH2CH2CH28r _ HC:CH —~~v l\-1: C:CH —~ CH3CH2CHQCHZC:CH The synthesis can be completed in four steps from acetylene and 1-bromobutane: 1. l'-..’-l‘~l‘*lw —7*_ —4 CH3CH2CH2CHZCECH i» 24 CH3CI-IZCHQCl-lglilr Lindlar catalyst CH3CH2CH2CH2CHZCHZ 1—Hexene CH3CHZCH2CH2CHZCHZOH 1-Hexanol 278 CHAPTER 8 Alkynes: An Introduction to Organic Synthesis Problem 8.12 Beginning with 4—octyne as your only source of carbon, and using any inorganic reagents necessary, how would you synthesize the following compounds? (a) t‘iv4-Octene (b) Butanal (c) 4-Brornooctane (cl) 4-Octanol (e) 4,5-Dichlorooctane (f) Butanoic acid Problem 8.13 Beginning with acetylene and any alkyl halides needed, how would you synthesize the following compounds? (3) Decane (b) 2,2—Dirnethylhexane (c) i-lexanai (cl) 2-Heptanone Focus On . . .. ' x, w - - . It you think some of the synthesis problems at the end of this chapter are hard, try devising a synthesis of vitamin B12 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 Univer- sity and Albert Eschenmoser of the Swiss Federal Institute ofTechnology in Ziirich. More than 100 graduate students and postdoctoral associates contributed to the work, which took more than a decade. CN CONH2 HZNOCrfi HQNOC CHsH Vitamin B12 has been synthe- sized from scratch in the |abo~ ratory, but bacteria growing HZNOC on sludge from municipal sewage plants do a much CONH2 better job. HN c0NH2 o 6 CH . 0\ HO N 3 H3C .‘ ‘//P\—0 0 0' CH3 0 CH20H Vitamin B12 {continued} aeetylide anion, 270 alkylation, 272 alkyne (RC i CR), 259 enoi, 264 retrosynthetlc, 275 tairtomer, 264 Summary and Key Words 279 Why put such extraordinary effort into the laboratory synthesis of a mol- ecule 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 for the way in which it establishes new standards and raises the Field to a new level. it vitamin 8,2 can be made, then why can’t any molecule found in nature be made? Indeed, the three and a half decades that have tory synthesis of many enormously complex and valuable substances. Some- times these substancesvthe anticancer compound Taxol, for instanceiare not easily available in nature, so iaboratory synthesis is the only method for obtaining larger quantities. But perhaps the most important reason for undertaking a complex syn- thesis is that, in so doing, new reactions and new chemistry are discovered. lt invariably happens in synthesis that a point is reached at which the planned route fails. At such a time, the only alternatives are to quit or to devise a way around the difficulty. New reactions and new principles come from such situ« ations, and it is in this way that the science of organic chemistry grows richer. In the synthesis of vitamin B12, for example, unexpected findings emerged that led to the understanding of an entire new class of reactions—the pericyciic reactions that are the subiect of Chapter 30 in this book. From synthesizing vitamin B12 to understanding, pericyclic reactions—n0 one could have possi- bly predicted such a link at the beginning of the synthesis, but that is the way of science. SUMMARY AND KEY WORDS 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 0‘ bond and two pep 7r bonds. There are relatively few general methods of alkyne syn- thesis. Two good 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 irlBr and HCl to yield vinylic halides and with Brz and C12 to yield 1,2-dihalides (vicinal dihalides), Alkynes can be hydrated by reaction with aqueous sulfuric acid in the presence of mercuryt‘ll) catalyst. The reaction leads to an intermediate enol that immediately isomerizes to yield a ketone tautomer. Since the addition reaction occurs with Markovnikov regiochemistry, a methyl ketone is p...
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