Organic Chemistry I

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

Organic Chemistry, (9th edition) By John McMurry, Cengage Learning, 2016 1 and the Hückel 4n+2 Rule

For -like aromatic molecules:

• Benzene is cyclic and conjugated. • Benzene is unusually stable, having a heat of hydrogenation 150 kJ/mol less negative than the expected for a conjugated cyclic triene.

• Benzene is planar and has the shape of a regular hexagon. All bond angles are 120°, all carbon atoms are sp2-hybridized, and all carbon–carbon bond lengths are 139 pm.

• Benzene undergoes substitution reactions that retain the cyclic conjugation rather than electrophilic addition reactions that would destroy it.

• Benzene can be described as a resonance hybrid whose structure is intermediate between two line-bond structures.

Something else, called the Hückel 4n+2 rule, is needed to complete a description of aromaticity.

2 !"-# $%&'$()*)(+ $,- (./ .0*1/2 3n ϩ 4 %52/ !"#

P ROBL EM $"%! Pyridine is a flat, hexagonal molecule with bond angles of 120°. It undergoes substitution rather than addition and generally behaves like benzene. Draw a picture of the ␲ orbitals of pyridine to explain its properties. Check your answer by looking ahead to Section 15-5.

Pyridine !"-# $%&'$()*)(+ $,- (./ .0*1/2 3n ϩ 4 %52/ !"# N

P ROBL EM $"%! Pyridine is a flat, hexagonal molecule with bond angles of 120°. It undergoes substitution rather than addition and generally behaves like benzene. Draw a $"-& Aromaticitypicture of and the ␲ orbitalsthe Hückel of pyridine to! nexplain ϩ 'its Rule properties. Check your answer by looking ahead to Section 15-5. Let’s list what we’ve said thus far about benzene and, by extension, about other benzene-like aromatic molecules. Pyridine N Benzene is cyclic and conjugated. Benzene is unusually stable, having a heat of hydrogenation 150 kJ/mol less negative than $"-& we Aromaticity might expect and for the a conjugated Hückel !n cyclic ϩ ' Rule triene.

Benzene is planarLet’s listand what has we’ve the shape said thus of fara regular about benzene hexagon. and, by All extension, bond angles about 2 are 120°, all carbonother benzene-like atoms are aromatic sp -hybridized, molecules. and all carbon–carbon bond lengths are 139 pm. Benzene is cyclic and conjugated. Benzene undergoes Benzene substitution is unusually reactions stable, having that a heat retain of hydrogenation the cyclic 150 conjuga kJ/mol - tion rather than electrophilicless negative than addition we might expectreactions for a conjugated that would cyclic destroy triene. it. Benzene is planar and has the shape of a regular hexagon. All bond angles Benzene can be describedare 120°, all carbonas a resonance atoms are sp2 hybrid-hybridized, whose and all structure carbon–carbon is inter bond - mediate between lengthstwo line-bond are 139 pm. structures. Benzene undergoes substitution reactions that retain the cyclic conjuga- This list would tion seem rather to than be electrophilic a good description addition reactions of that benzene would destroy and otherit. aromatic molecules, Benzenebut it isn’tcan be enough.described as Something a resonance hybrid else, whose called structure the Hückel is inter- mediate between two line-bond structures. 4n ϩ 2 rule, is needed to complete a description of aromaticity. According to a theory devised in 1931This by list the would German seem to physicist be a good descriptionErich Hückel, of benzene a molecule and other is aromatic molecules, but it isn’t enough. Something else, called the Hückel aromatic only if it4 nhas ϩ 2 arule planar,, is needed monocyclic to complete asystem description of ofconjugation aromaticity. According and con to - tains a total of 4n ϩa theory 2 ␲ electrons, devised in 1931 where by the n German is an integerphysicist Erich(n ϭ Hückel, 0, 1, 2, a molecule3, . . .). isIn other words, only aromaticmolecules only ifwith it has 2, a planar,6, 10, monocyclic14, 18, . .system . ␲ electrons of conjugation can and be conaro-- According to a theory devised in 1931 by thetainsGerman a total ofphysicist 4n ϩ 2 ␲ electrons,Erich Hü whereckel, a n moleculeis an integeris (n ϭ 0, 1, 2, 3, . . .). In aromatic only if it hasmatic.a planar Molecules, monocyclic withothersystem words,4n ␲ ofelectronsonlyconjugation molecules (4, withand8, 12, 2,contains 6, 16, 10, . 14, . a.) 18, totalcan’t . . .of ␲ be electrons aromatic, can be even aro- 4n+2 � electrons, wherethoughn is theyan integer may( benmatic.= cyclic,0, 1Molecules, 2, 3planar,, . . with.). In and4othern ␲ electronsapparentlywords, (4,only 8, 12,conjugated.molecules 16, . . .) can’t Inbe aromatic,fact, planar, even with 2, 6, 10, 14, 18, .conjugated. . � electrons moleculescan bethougharomatic with they. 4mayn ␲ be electrons cyclic, planar, are and said apparently to be antiaromatic conjugated. In fact, because planar, conjugated molecules with 4n ␲ electrons are said to be antiaromatic because delocalization of their ␲ electrons would lead to their destabilization. If they are cyclic, planar, and apparently conjugateddelocalizationwith of4 theirn � electrons ␲ electrons( 4would, 8, 12 lead, 16 to, . their. .), itdestabilization. ϩ is said to be antiaromaticLet’sbecause look delocalizationat severalLet’s examples lookof theirat several� toelectrons examplessee how wouldto thesee how Hückellead theto Hückeltheir 4n ϩ 4 n2 rule 2 rule works. works. destabilization. has four ␲ electrons and is antiaromatic. The ␲ electrons Cyclobutadiene hasare localized four ␲ inelectrons two double and bonds is rather antiaromatic. than delocalized The around ␲ electrons the ring, are localized in twoas indicated double by bonds the electrostatic rather than potential delocalized map. around the ring, Cyclobutadiene has fouras� electronsindicatedand byis theantiaromatic electrostatic. The potential� electrons map.are localized in two double bonds rather than delocalized around the ring.

Cyclobutadiene is highly reactive and shows none of the properties associated with aromaticity. Even at -78 °C, it dimerizes by a Diels–Alder reaction. One molecule behaves as a and the other as a dienophile. Cyclobutadiene Two double bonds; four ␲ electrons

Cyclobutadiene 3

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Copyright 2016 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

80485_ch15_0451-0477l.indd 459 2/2/15 2:10 PM !"# !"#$%&' () *&+,&+& #+- #'./#%0!0%1 !"# !"#$%&' () *&+,&+& #+- #'./#%0!0%1 Cyclobutadiene is highly reactive and shows none of the properties Cyclobutadiene is highlyassociated reactive with and aromaticity. shows none In fact, of itthe was properties not even prepared until 1965, !"# !"#$%&' () *&+,&+&associated #+- #'./#%0!0%1 with aromaticity.when In Rowland fact, it wasPettit not of theeven University prepared of until Texas 1965, was able to make it at low when Rowland Pettit of temperature.the University Even of Texasat Ϫ78 was °C, ablehowever, to make cyclobutadiene it at low is so reactive that temperature.Cyclobutadiene Even at Ϫ78it dimerizes °isC, highly however, byreactive a cyclobutadiene Diels–Alder and shows reaction. noneis so reactiveofOne the molecule properties that behaves as a diene it dimerizesassociated by a Diels–Alder with aromaticity.and the reaction. other In as fact, aOne dienophile. it wasmolecule not even behaves prepared as auntil diene 1965, and the otherwhen asRowland a dienophile. Pettit of the University of Texas was able to make it at low temperature. Even at Ϫ78 °C, however,+ cyclobutadiene–78 °C is so reactive that it dimerizes by a Diels–Alder reaction. One moleculeDiels–Alder behaves as a diene + –78 °C and the other as a dienophile.Diels–Alder Benzene has six ␲ electrons (4n ϩ 2 ϭ 6 when n ϭ 1) and is aromatic. –78 °C Benzene has Benzenesix � electrons has six (␲4 nelectrons+2 = 6 when +(4n ϩn= 2 1ϭ) and6 whenis aromatic n ϭ 1) and. is Benzenearomatic. Diels–Alder Benzene Three double bonds; Benzene has six ␲ electrons (4n ϩ 2 ϭ 6 when n ϭ 1)six and ␲ electronsis aromatic. Three double bonds; Cyclooctatetraenesix ␲ electrons hasBenzene eight ␲ electrons and is not aromatic. The ␲ elec- trons are localized into four double bonds rather than delocalized around Cyclooctatetraene has eightthe ring, ␲ electrons and theThree andmolecule double is not bonds; isaromatic. tub-shaped The rather ␲ elec than- planar. It has no six ␲ electrons trons are localized into fourcyclic double conjugation bonds becauserather than neighboring delocalized p orbitals around don’t have the neces- Cyclooctatetraenethe ring,has Cyclooctatetraene andeight the� moleculeelectronssary has parallelis andeight tub-shapedis ␲ alignment notelectronsaromatic rather forand overlap, . thanisThe not planar.�aromatic. andelectrons it resemblesIt Thehasare ␲no eleclocalized an -open-chain poly- into four doublecyclicbonds conjugationtronsrather are localizedthan becauseenedelocalized into inneighboring fourits reactivity. doublearound p bonds orbitalsthe ratherring, don’t thanand have delocalizedthe themolecule neces around- is tub- shaped rathersarythan parallelplanarthe ring,. alignment and the for molecule overlap, is and tub-shaped it resembles rather an thanopen-chain planar. polyIt has- no ene in itscyclic reactivity. conjugation because neighboring p orbitals don’t have the neces- It has no cyclic conjugationsary parallelbecause alignmentneighboring for overlap,p orbitals and it don’tresembleshave anthe open-chainnecessary polyparallel- alignment for overlap,eneand init itsresembles reactivity.an open-chain polyene in its reactivity.

Cyclooctatetraene Four double bonds; eight ␲ electrons Cyclooctatetraene

Four doubleCyclooctatetraene bonds;Chemists in the early 1900s believed that the only requirement for eight ␲ electrons Four doublearomaticity bonds; was the presence of a cyclic . It4 was there- eight fore␲ electrons expected that cyclooctatetraene, as a close analog of benzene, would Chemists in the earlyalso 1900s prove believed to be unusually that the stable. only Therequirement facts, however, for proved otherwise. aromaticityChemists was the presencein theWhen early ofcyclooctatetraene a1900s cyclic believed conjugated was that first system.the preparedonly It requirement was in 1911there by- for the German chem- fore expectedaromaticity that cyclooctatetraene, was theist Richardpresence Willstätter, of as a acyclic close it conjugated analogwas found of benzene, system.not to be It particularlywouldwas there - stable. also provefore to expected be unusually that cyclooctatetraene, Sincestable. cyclooctatetraene The facts, as however, a close isn’t analog conjugated,proved of benzene, otherwise. with wouldits neighboring p orbit- When cyclooctatetraenealso prove to be unusuallyals was lacking first preparedstable. the necessary The in facts, 1911 parallel however, by the alignment German proved forotherwise.chem overlap,- the ␲ electrons ist RichardWhen Willstätter, cyclooctatetraene itare was localized found was first notin four preparedto be discrete particularly in 1911CϭC bybonds stable. the Germanrather than chem delocalized- around Sinceist cyclooctatetraene Richard Willstätter,the ring.isn’t it was conjugated,X-ray found studies not with toshow be its particularly that neighboring the C ᎐ stable. C single p orbit bonds- are 147 pm long als lacking Sincethe necessary cyclooctatetraeneand parallel the double isn’talignment bondsconjugated, are for 134 overlap, with pm itslong. theneighboring In ␲ addition, electrons p orbitthe 1-H NMR spectrum are localizedals lacking in four the discrete necessaryshows C aϭ singleparallelC bonds sharp alignment rather resonance than for delocalizedoverlap,line at 5.78 the ␦ around␲, a electrons value characteristic of an the ring.are X-ray localized studies in showfouralkene discrete that rather the C than ϭCC ᎐ Cbonds an single aromatic rather bonds molecule.than are delocalized 147 pm long around the ring. X-ray studies show that the C ᎐ C single bonds1 are 147 pm long and the double bonds areWhat’s 134 pm so speciallong. In about addition, 4n ϩ the2 ␲ electrons?H NMR spectrum Why do 2, 6, 10, 14 . . . ␲ elec- and the double bonds are 134 pm long. In addition, the 1H NMR spectrum shows a single sharptrons resonance lead to linearomatic at 5.78 stability, ␦, a value while characteristic other numbers of of an electrons do not? The shows a single sharp resonance line at 5.78 ␦, a value characteristic of an rather than ananswer aromatic comes molecule. from molecular orbital theory. When the energy levels of molec- alkene rather than an aromatic molecule. ular orbitals for cyclic conjugated molecules are calculated, it turns out that What’s so special about 4n ϩ 2 ␲ electrons? Why do 2, 6, 10, 14 . . . ␲ elec- What’s so specialthere about is always 4n ϩ 2 a ␲ single electrons? lowest-lying Why do 2, MO, 6, 10, above 14 . . which . ␲ elec the- MOs come in trons leadtrons to aromatic lead to aromatic stability, stability, while otherwhile numbersother numbers of electrons of electrons do not? do not? The The answer comesanswer from comes molecular from molecular orbital orbital theory. theory. When When the energy the energy levels levels of molec of molec- - ular orbitalsular orbitalsfor cyclic for conjugated cyclic conjugated molecules molecules are calculated, are calculated, it turns it turns out thatout that there is there always is alwaysa single a lowest-lying single lowest-lying MO, above MO, above which which the MOs the MOs come come in in

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80485_ch15_0451-0477l.indd80485_ch15_0451-0477l.indd 460 460 2/2/152/2/15 2:10 2:10 PM PM The number of � electrons must be the same as the number of atoms in the ring or that the !"# !"#$%&' () *&+,&+&substance #+- #must'./#%0!0%1be neutral. The numbers can differ and the substance can be an . Cyclopentadienyl anion and cycloheptatrienyl cation are aromatic and contains a six- membered ring. H H – HHC+ C H H C C CC HHC C CC C C HH HH

Cyclopentadienyl anion Cycloheptatrienyl cation

Six ␲ electrons; aromatic To see why the cyclopentadienyl anion and the cycloheptatrienyl cation In the relatedare aromatic,neutral , imagine starting1, 3 from- the related neutraland 1 hydrocarbons,,3,5-, 1,3- one hydrogen fromcyclopentadienethe saturated andCH 1,3,5-cycloheptatriene,2 carbon is removed. and removing one hydrogen from 3 the saturated CH2 carbon in each. If that carbon then rehybridizes from sp to The carbonspthen2, therehybridizes resultant productsfrom sp would3 to sp be2, thefullyresultant conjugated,products with awould p orbitalbe onfully everyconjugated, with a p orbitalcarbon.on every Therecarbon are three. ways in which the hydrogen might be removed. The hydrogen can be removed with both electrons (H:؊) from the 5 C ᎐ H bond, leaving a carbocation as product. The hydrogen can be removed with one electron (H·) from the C ᎐ H bond, leaving a carbon radical as product. ,The hydrogen can be removed with no electrons (H؉) from the C ᎐ H bond leaving a carbanion as product. All the potential products formed by removing a hydrogen from 1,3-cyclo- pentadiene and from 1,3,5-cycloheptatriene can be drawn with numerous resonance structures, but Hückel’s rule predicts that only the six-␲-electron cyclopenta dienyl anion and cycloheptatrienyl cation should be aromatic. The other products are predicted by the 4n ϩ 2 rule to be unstable and antiaro- matic $FIGURE %&'"(.

H H H H H + – H H H H H H H H –H – or or or H or H+ HH HH HH HH

1,3-Cyclopentadiene Cyclopentadienyl Cyclopentadienyl Cyclopentadienyl cation (four ␲ electrons) (!ve ␲ electrons) (six ␲ electrons)

H H H H H – H H H + H H H H H –H – or or H H or H H H H H H H or H+

HH HH HH HH

1,3,5-Cycloheptatriene Cycloheptatrienyl Cycloheptatrienyl Cycloheptatrienyl cation radical anion (six ␲ electrons) (seven ␲ electrons) (eight ␲ electrons) FIGURE %&'" The aromatic six-␲-electron cyclopentadienyl anion and the six-␲-electron cycloheptatrienyl cation. The anion can be formed by removing a hydrogen ion (H؉) from the CH! group of ",#-cyclopentadiene. The cation can be generated by removing a hydride ion ؊ (H: ) from the CH! group of ",#,$-cycloheptatriene.

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80485_ch15_0451-0477l.indd 462 2/2/15 2:10 PM !"# !"#$%&' () *&+,&+& #+- #'./#%0!0%1

!"# !"#$%&' () *&+,&+& #+- #'./#%0!0%1 H H HH+ – CH C H H H C C CC– HHC+ C HHCC CC H CC H CC C C HHC C CCHH C CHH HH Cyclopentadienyl anion CycloheptatrienylHH cation

CyclopentadienylSix ␲ electrons; anion aromaticCycloheptatrienyl ions cation To see why the cyclopentadienylSix ␲ electrons; anion aromatic and ions the cycloheptatrienyl cation are aromatic,To see why imagine the cyclopentadienyl starting from the anion related and the neutral cycloheptatrienyl hydrocarbons, cation 1,3- cyclopentadieneare aromatic, imagine and 1,3,5-cycloheptatriene, starting from the related and removing neutral hydrocarbons,one hydrogen from 1,3- 3 thecyclopentadiene saturated CH2 carbonand 1,3,5-cycloheptatriene, in each. If that carbon and then removing rehybridizes one hydrogen from sp from to 2 3 spthe, the saturated resultant CH products2 carbon wouldin each. be If fully that carbonconjugated, then rehybridizeswith a p orbital from on sp every to carbon.sp2, the There resultant are three products ways would in which be fully the conjugated,hydrogen might with abe p removed.orbital on every carbon. There are three ways in which the hydrogen might be removed. The hydrogen can be removed with both electrons (H:؊) from the ؊ C ᎐The H bond, hydrogen leaving can a carbocation be removed as withproduct. both electrons (H: ) from the TheC ᎐ hydrogen H bond, leaving can be a removed carbocation with as one product. electron (H·) from the C ᎐ H bond, leaving The hydrogen a carbon can radical be removed as product. with one electron (H·) from the C ᎐ H bond, ,Theleaving hydrogen a carbon can beradical removed as product. with no electrons (H؉) from the C ᎐ H bond ؉ leaving The hydrogen a carbanion can beas removedproduct. with no electrons (H ) from the C ᎐ H bond, leaving a carbanion as product. All the potential products formed by removing a hydrogen from 1,3-cyclo- All the potential products formed by removing a hydrogen from 1,3-cyclo- Among the potentialpentadieneproducts, and from 1,3,5-cycloheptatrieneonly the six-�-electron can be drawncyclopentadienyl with numerous anion and pentadiene and from 1,3,5-cycloheptatriene can be drawn with numerous resonance structures, but Hückel’s rule predicts that only the six-␲-electron cycloheptatrienyl cationresonanceshould structures,be aromatic but Hückel’saccording rule predictsto thethat onlyHückel’s the six-rule␲-electron. cyclopenta dienyl anion and cycloheptatrienyl cation should be aromatic. The cyclopenta dienyl anion and cycloheptatrienyl cation should be aromatic. The other products are predicted by the 4n ϩ 2 rule to be unstable and antiaro- other products are predicted by the 4n ϩ 2 rule to be unstable and antiaro- The other productsmaticare $FpredictedIGURE %&'"(. to be unstable and antiaromatic. matic $FIGURE %&'"(. H H H H HH H H H H + –– H H H + H H H H H H H –H – – H H H H H H –H or or or H or or or+ H or orH H+ HH HH HH HH HH HH HH HH

1,3-Cyclopentadiene1,3-Cyclopentadiene Cyclopentadienyl Cyclopentadienyl CyclopentadienylCyclopentadienyl Cyclopentadienyl cationcation radicalradical anionanion (four(four ␲ ␲electrons) electrons) (!(!veve ␲ ␲ electrons) electrons) (six ␲␲ electrons)electrons)

H HH H HH HH HH –– H H H H HH ++ HH HH HH H HH – –H–H– or or or H or or H H H H or H + H H HH HH HH H HH or orH+ H

HH HH HH HH HH HH HH HH

1,3,5-Cycloheptatriene1,3,5-Cycloheptatriene CycloheptatrienylCycloheptatrienyl CycloheptatrienylCycloheptatrienyl Cycloheptatrienyl cationcation radicalradical anionanion (six ␲ electrons) (seven ␲ electrons) (eight ␲ electrons) (six ␲ electrons) (seven ␲ electrons) (eight ␲ electrons) FIGURE %&'" The aromatic six-␲-electron cyclopentadienyl anion and the six-␲-electron FIGURE %&'" The aromatic six-␲-electron cyclopentadienyl anion and the six-␲-electron 6 cycloheptatrienyl cation. The anion can be formed by removing a hydrogen ion (H؉) from cycloheptatrienyl cation. The anion can be formed by removing a hydrogen ion (H؉) from the CH! group of ",#-cyclopentadiene. The cation can be generated by removing a hydride ion the CH؊! group of ",#-cyclopentadiene. The cation can be generated by removing a hydride ion .H؊ : ) from the CH! group of ",#,$-cycloheptatriene) (H: ) from the CH! group of ",#,$-cycloheptatriene.

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80485_ch15_0451-0477l.indd 462 2/2/15 2:10 PM 80485_ch15_0451-0477l.indd 462 2/2/15 2:10 PM !"-# $%&'$()* )&+, !"#

In practice, both the four-␲-electron cyclopentadienyl cation and the five- ␲-electron cyclopentadienyl radical are highly reactive and difficult to pre- pare. Neither shows any sign of the stability expected for an aromatic system. The six-␲-electron cyclopentadienyl anion, by contrast, is easily prepared and remarkably stable $FIGURE %&'(a). In fact, the anion is so stable and easily formed that 1,3-cyclopentadiene is one of the most acidic hydrocarbons known, with pKa ϭ 16, a value comparable to that of water! In the same way, the seven-␲-electron cycloheptatrienyl radical and eight- ␲-electron anion are reactive and difficult to prepare, while the six-␲-electron cycloheptatrienyl cation is extraordinarily stable (Figure 15-7b). In fact, the cyclo hepta trienyl cation was first prepared more than a century ago by reac- tion of 1,3,5-cycloheptatriene with Br2, although its structure was not recog- nized at the time.

(a) H H H HH + – Na NaOH H H + H2O H 1,3-Cyclo- Cyclopentadienyl pentadiene anion Aromatic cyclopentadienyl anion with six ␲ electrons

(b) H H HH H Br– ! H H

Br2 + HBr H H H 1,3,5-Cyclo- Cycloheptatrienyl heptatriene cation Cycloheptatrienyl cation six ␲ electrons FIGURE %&'( (a) The aromatic cyclopentadienyl anion, showing cyclic conjugation and six ␲ electrons in five p orbitals, and (b) the aromatic cycloheptatrienyl cation, showing cyclic conjugation and six ␲ electrons in seven p orbitals. Electrostatic potential maps indicate that both ions are symmetrical, with the charge equally shared among all atoms in each ring.

P ROBL EM %&'" Draw the five resonance structures of the cyclopentadienyl anion. Are all carbon–carbon bonds equivalent? How many absorption lines would you Problem 15-expect7 to see in the 1H NMR and 13C NMR spectra of the anion? CyclooctatetraeneP ROBLreadilyEM %&'(reacts with metal to form the stable cyclooctatetraene 2- dianion, C8HCyclooctatetraene8 . Why do you suppose readily reactsthis reaction with potassiumoccurs so metaleasily? to formWhat thegeometry stable do you 2؊ expect for thecyclooctatetracyclooctatetraene ene dianion,dianion? C8H8 . Why do you suppose this reaction occurs so easily? What geometry do you expect for the cyclooctatetraene dianion?

2–

2 K 2 K+

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7 !"! !"#$%&' () *&+,&+& #+- #'./#%0!0%1

P ROBL EM #$%& The relative energy levels of the five ␲ molecular orbitals of the cyclopenta- dienyl system are similar to those in benzene. That is, there is a single lowest- energy MO, above which the orbitals come in degenerate pairs. Draw a diagram like that in Figure 15-5, and tell which of the five orbitals are occupied in the cation, radical, and anion.

#$-$ Aromatic Heterocycles: Pyridine and Pyrrole

Look back once again at the definition of aromaticity in Section 15-3: . . . a cyclic, conjugated molecule containing 4n ϩ 2 ␲ electrons. Nothing in this definition says that the atoms in the ring must be carbon. In fact, heterocyclic compounds can also be aromatic. A heterocycle is a cyclic compound that contains atoms of two or more elements in its ring, usually carbon along with Heterocyclic compounds can alsonitrogen,be aromaticoxygen, or. Asulfur.heterocycle Pyridine isanda pyrimidine,cyclic compound for example,that are six- membered heterocycles with nitrogen in their rings 'FIGURE #$%&(. contains atoms of two or more elements in its ring, usually carbon along with nitrogen, oxygen,FIGUorRE #$%&sulfur Pyridine. Pyridine and and pyrimidine are six-membered heterocycles. pyrimidine are nitrogen-containing 4 H aromatic heterocycles with 3 H ␲ electron arrangements like that H H of benzene. Both have a lone pair 2 N of electrons on nitrogen in an sp! N H !"-" #$%&#'() *+'+$%),)-+.: /,$(0(1+ #10 /,$$%-+ !"# orbital in the plane of the ring. 1 Lone pair in 2 Pyridineof pyrrole that has(Six ␲two electrons) nitrogen spatoms orbital in a five-membered, unsaturated ring. Both nitrogens are sp2-hybridized, but one is in a double bond and Lonecontributes pair 2 2 (sp ) Pyrrole has two nitrogen atoms inonlya fiveone- electronmemberedH to theunsaturated aromatic ␲ systemLonering pair. each whereas in of the the otherfour sp is not- in a double 4 3 bond and contributes two from its2 lonesp2 orbital pair. hybridized carbons contributes5 oneN � electron and Nthe sp -hybridized nitrogen atom contributes the two from its lone pair, whichHoccupies a p orbital.H 6 2 N N H Lone pair in orbital 1 p Lone pair in 3 sp2 orbital Pyrimidine (SixHH ␲ electrons) Lone pair 2 (sp2) N1 H H N Pyridine is much like benzene in its ␲ electron structure. Each of the H H five sp2-hybridized carbons has a p orbital perpendicular to the planeDelocalized of the 8 lone pair ring, Pyrroleand each p orbital(Six ␲ electrons)contains one ␲ electron. The nitrogen atom is also (p) sp2-hybridized and has one electron in a p orbital, bringing the total to six Lone pair ␲ electrons. The nitrogen lone-pair electrons (red in an electrostatic poten- 3 in p orbital 2 Lone pair tial map)4 Nare in an sp orbital in the plane of the ring and are not part of the Lone pair in (sp2) aromatic ␲ system.H Pyrimidine, also shown2 in Figure 15-8, is a benzene 5 2 sp orbital analog that has two nitrogenN atoms in a six-membered, unsaturated ring. N1 H Both nitrogens areH sp2-hybridized,N and each contributes one electron to the H aromatic ␲ system. H Pyrrole (spelled with two r’s and one l) and imidazole are five-membered Imidazole (Six ␲ electrons) heterocycles, yet both have six ␲ electrons and are aromatic. In pyrrole,Delocalized each 2 2 of the four sp -hybridized carbons contributes one ␲ electron and lonethe sppair- hybridized nitrogen atom contributes the two from its lone pair, which(p) occu- piesFIG aU pRE orbital $#%& Pyrrole 'FIGU REand #$%)( imidazole. Imidazole, are five-membered, also shown nitrogen-containing in Figure 15-9, is heterocycles an analog but have six-␲-electron arrangements like that of the cyclopentadienyl anion. Both have a lone pair of electrons on nitrogen in a p orbital perpendicular to the ring.

Note that nitrogen atoms have different roles depending on the structure Copyright 2016 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed contentof does the not materially molecule. affect the overall learningThe experience. nitrogen Cengage Learning atoms reserves in the right pyridine to remove additional and content pyrimidine at any time if subsequent rights are restrictions both require in it. double bonds and contribute only one ␲ electron to the aromatic sextet, just as a carbon atom in benzene does. The nitrogen atom in pyrrole, however, is not 80485_ch15_0451-0477l.indd 464 in a double bond and contributes two ␲ electrons (its lone pair) to the aromatic 2/2/15 2:10 PM sextet. In imidazole, both kinds of nitrogen are present in the same molecule— a double-bonded “pyridine-like” nitrogen that contributes one ␲ electron and a “pyrrole-like” nitrogen that contributes two. Pyrimidine and imidazole rings are particularly important in biological chemistry. Pyrimidine, for instance, is the parent ring system in cytosine, thy- mine, and uracil, three of the five heterocyclic amine bases found in nucleic acids. An aromatic imidazole ring is present in histidine, one of the 20 amino acids found in proteins.

NH2 O O

H3C H H + N N N N H NH3

– N O N O N O N CO2 H H H H

Cytosine Thymine Uracil Histidine (in DNA and RNA) (in DNA) (in RNA) (an amino acid)

Copyright 2016 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

80485_ch15_0451-0477l.indd 465 2/2/15 2:10 PM !"" !"#$%&' () *&+,&+& #+- #'./#%0!0%1

Worked Example !"- ! Accounting for the Aromaticity of a Heterocycle Thiophene, a sulfur-containing heterocycle, undergoes typical aromatic substi- tution reactions rather than addition reactions. Why is thiophene aromatic?

S Thiophene

Strategy Recall the requirements for aromaticity—a planar, cyclic, conjugated mole- cule with 4n ϩ 2 ␲ electrons—and see how these requirements apply to thiophene.

Solution Thiophene is the sulfur analog of pyrrole. The sulfur atom is sp2-hybridized and has a lone pair of electrons in a p orbital perpendicular to the plane of the ring. Sulfur also has a second lone pair of electrons in the ring plane.

sp2-hybridized

S Thiophene !"" !"#$%&' () *&+,&+& #+- #'./#%0!0%1 !"-# $%&'('(&)( *+%,*-)( (%,$%./01 !"# Worked Example !"- ! Accounting for the Aromaticity of a Heterocycle

$%-" Thiophene,Polycyclic a sulfur-containing AromaticP ROB CompoundsL EM heterocycle, #$%& undergoes typical!"-# aromatic $%&'('(&)( substi *+%,*-)(- (%,$%./01 !"# Thiophene,The Hückeltutiona sulfurrule reactions is only-containing strictly ratherDraw applicablethanheterocycle, additionan orbital to monocyclic reactions. pictureundergoes ofcompounds, Why furan is thiophenetotypical show but the how aromatic?aromatic the moleculesubstitution is aromatic.reactions rathergeneralthan conceptaddition $%-" of aromaticityPolycyclicreactions can Aromatic. be extended Compounds to include polycyclic aromatic compounds. , with two benzene-likeS rings fused together;O anthra- cene, with Thethree Hückel rings; rule benzo[a], is only strictly with applicable five rings; Thiopheneto monocyclic and coronene, compounds, with six butFura then rings, are allgeneral well-known concept ofaromatic aromaticity hydrocarbons. can be extended Benzo[a]pyrene to include polycyclic is particu aromatic- larly interestingcompounds. because Naphthalene, it is one of with the two cancer-causing benzene-like ringssubstances fused together; found in anthra - cene, with three rings; benzo[a]pyrene, with five rings; and coronene, with six tobaccoStrategy smoke. The Hückel rings,rule areis allonly well-knownstrictlyP ROB aromaticL EMapplicable hydrocarbons. #$%#' to Benzo[a]pyrenemonocyclic is particucompounds- , but the general Recalllarly the interesting requirements because itfor is aromaticity—aone of the cancer-causing planar, substancescyclic, conjugated found in mole- concept of aromaticity can Thiamin,be extended or vitaminto Binclude1, containspolycyclic a positively aromaticcharged five-memberedcompounds nitrogen–. culetobacco with smoke. 4n ϩ 2 ␲ sulfur electrons—and heterocycle see called how a thesethiazolium requirements ring. Explain apply why to the thiazolium ring is thiophene. aromatic.

Solution H3C N NH2 S Thiophene is the sulfur analog of pyrrole. The sulfur atom is sp2-hybridized N +N Thiamin and has a lone pair of electrons in a p orbital perpendicular to the planeOH of the Naphthalenering. Sulfur alsoAnthracene has a second lone pairBenzo[a]pyrene of electrons in the ringCoronene plane. !"# !"#$%&' () *&+,&+& #+- #'./#%0!0%1 CH3 All polycyclicNaphthalene aromatic hydrocarbonsAnthracene can be representedBenzo[a]pyrene by a number of Coronene 2 different resonance forms. Naphthalene,FIGURE $%&$' for An instance,orbital sppicture-hybridized has three. All polycyclic aromaticand electrostatic hydrocarbons potential map can of be representedThiazolium by a number ring of different resonance forms.naphthalene, Naphthalene, showing that for the instance, ten has three. ␲ electrons are fully delocalizedS Thiophene throughout both rings.

Naphthalene Naphthalene 9 Naphthalene Naphthalene and other polycyclic aromatic hydrocarbons show many of P ROBL EM #$%& Just as there are heterocyclic analogs of benzene, there are also many het- the chemical propertiesNaphthalene associated and other with polycyclic aromaticity. aromatic Thus, hydrocarbons measurement show of itsmany of erocyclic analogs of naphthalene. Among the most common are quinoline, Drawthe an chemical orbital properties picture associatedof furan to with show aromaticity. how the Thus, molecule measurement is aromatic. of its heat of hydrogenation shows an aromatic stabilization isoquinoline, energy of approxi indole,- and purine. Quinoline, isoquinoline, and purine all con- Copyrightheat 2016 of Cengage hydrogenation Learning. All Rights Reserved. shows May not an be copied, aromatic scanned, or duplicated, stabilization in whole or in energypart. Due to electronic of approxi rights, some- third party content may be suppressed from the eBook and/or eChapter(s). mately 250 kJ/mol (60 kcal/mol). Furthermore, naphthalenetain pyridine-like reacts slowly nitrogens that are part of a double bond and contribute one Editorial reviewmately has deemed 250 that any kJ/mol suppressed (60 content kcal/mol). does not materially affectO Furthermore, the overall learning experience. naphthalene Cengage Learning reacts reserves the slowly right to remove additional content at any time if subsequent rights restrictions require it. with electrophiles such as Br2 to give substitution productselectron ratherto the aromatic than ␲ system. Indole and purine both contain pyrrole-like double-bondwith addition electrophiles products. such as Br2 to give substitutionFuran nitrogens products that contribute rather than two ␲ electrons. double-bond addition products. 80485_ch15_0451-0477l.indd 466 2/2/15 2:10 PM Br 54 54 4 3 6 Br 7 N 5 6 3 6 3 5 N 1 P ROBL EM #$%#' 2 8 Br2, Fe 7 2 7 N 2 6 2 Br2, Fe N N 1 9 N 4 Thiamin, or vitamin B1, contains a positively+ chargedHBr+ five-memberedHBr nitrogen– N Heat Heat 18 18 7 3 sulfur heterocycle called a thiazolium ring. Explain why the thiazolium ring is H H aromatic. NaphthaleneNaphthalene 1-Bromonaphthalene 1-Bromonaphthalene (75%) (75%)Quinoline Isoquinoline Indole Purine H C N NH The aromaticity3 of naphthalene2 is explained by Among the orbital the many picture biological in molecules that contain polycyclic aromatic The aromaticity of naphthalene is explainedS by the orbital picture in FIGURE $%&$'FIG. NaphthaleneURE $%&$'. Naphthalene has a cyclic, has a conjugatedcyclic, conjugated ␲ electronrings, ␲ electron thesystem, amino system, with acid tryptophanwith contains an indole ring and the antimalar- + p orbital overlapp orbital both overlap along both theN along ten-carbon the ten-carbonN periphery periphery ofial the drug ofmolecule quininetheThiamin molecule containsand and a quinoline ring. Adenine and guanine, two of the fiveOH heterocyclic amine bases found in nucleic acids, have rings based on across the acrosscentral the bond. central Since bond. ten Since ␲ electrons ten ␲ electrons is a Hückel is a Hückel number, number, there thereis is ␲ electron delocalization and consequent aromaticitypurine. in naphthalene. ␲ electron delocalization and consequent aromaticityCH3 in naphthalene. – CO2 NH O Thiazolium ring + 2 NH3 H N N H N N

N N N N N NH2 Copyright 2016 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some thirdH party content may be suppressed fromH the eBook and/or eChapter(s). H Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. Copyright 2016 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove Tryptophanadditional content at any time if subsequent rights restrictionsAdenine require it. Guanine (an amino acid) (in DNA and RNA) (in DNA and RNA) 80485_ch15_0451-0477l.indd 467 2/2/15 2:10 PM H 80485_ch15_0451-0477l.indd 467 CH CH2 2/2/15 2:10 PM HO Copyright 2016 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). H N Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.H Quinine CH3O (an antimalarial agent)

80485_ch15_0451-0477l.indd 466 N 2/2/15 2:10 PM

Copyright 2016 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

80485_ch15_0451-0477l.indd 468 2/2/15 2:10 PM !"# !"#$%&' () *&+,&+& #+- #'./#%0!0%1

!"# !"#$%&' () *&+,&+&FIGURE #+-$%&$' #An'./#%0!0%1 orbital picture and electrostatic potential map of naphthalene, showing that the ten FIGURE $%&$' An orbital␲ pictureelectrons are fully delocalized and electrostatic potentialthroughout map of both rings. naphthalene, showing that the ten ␲ electrons are fully delocalized throughout both rings. Naphthalene

Just as there are heterocyclic analogs of benzene, there are also many het- Naphthalene erocyclic analogs of naphthalene. Among the most common are quinoline, isoquinoline, indole, and purine. Quinoline, isoquinoline, and purine all con- Just as there aretain heterocyclic pyridine-like analogsnitrogens of that benzene, are part thereof a double are also bond many and contributehet- one ␲ erocyclic analogselectron of naphthalene. to the aromatic Among system. the Indolemost commonand purine are both quinoline, contain pyrrole-like nitrogens that contribute two ␲ electrons. isoquinoline, indole, and purine. Quinoline, isoquinoline, and purine all con- tain pyridine-like nitrogens that are part of a double bond and contribute one 54 54 4 3 6 7 N 5 electron to the aromatic6 ␲ system.3 Indole6 and purine3 both5 contain pyrrole-like N 1 nitrogens that contribute two ␲ electrons. 2 8 7 2 7 N 2 6 2 N N 1 9 N 4 N 18 18 7 3 54 54 4 3 H 6 H 7 N 5 6 3 6 3 5 N 1 Quinoline Isoquinoline 2 Indole8 Purine 7 2 7 N 2 6 2 N N 1 9 N 4 N 18 Among the many18 biological7 molecules that contain polycyclic3 aromatic rings, the amino acid tryptophan containsH an indoleH ring and the antimalar- ial drug quinine contains a quinoline ring. Adenine and guanine, two of the Quinoline Isoquinoline Indole Purine five heterocyclic amine bases found in nucleic acids, have rings based on purine. Biological moleculesAmongcontain the manypolycyclic biologicalaromatic moleculesrings that: contain polycyclic aromatic – rings, the amino acid tryptophan containsCO2 an indole ring and the antimalar- NH O ial drug quinine contains a quinoline+ ring. Adenine and2 guanine, two of the NH3 five heterocyclic amine bases foundH in nucleicN acids, have ringsN based on H purine. N N

N N N N N NH – 2 CO2 H H H NH O + 2 Tryptophan Adenine Guanine NH3 H (an amino acid)N (in DNA and NRNA) (inH DNA and RNA) N N

H N N CH NCH2 HO N N NH2 H H H N H H Quinine Tryptophan CH3O Adenine Guanine(an antimalarial agent) (an amino acid) (in DNA and RNA) (in DNA and RNA) 10 N H CH CH2 HO H N H Quinine CH3O (an antimalarial agent)

Copyright 2016 Cengage Learning. All Rights Reserved. May not beN copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it.

80485_ch15_0451-0477l.indd 468 2/2/15 2:10 PM

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