Organic Chemistry - City University of New York

Organic Chemistry - City University of New York

Heterocyclic Aromatics Heterocyclic compound: A compound that contains more than one kind of atom in a ring. In organic chemistry, the term refers to a ring with one or more atoms that differ from carbon. Pyridine and pyrimidine are heterocyclic analogs of benzene; each is aromatic. 4 3 5 2 6 N 1 Pyridine 3

4 N 2 5 N 6 1 Pyrimidine 21-1 Database for unknown compounds 21-2 Pyridine The nitrogen atom of pyridine is sp2 hybridized. The unshared pair of

electrons lies in an sp2 hybrid orbital and is not a part of the six pi electrons of the aromatic system (the aromatic sextet). Resonance energy of pyridine is134 kJ (32 kcal)/mol. 21-3 Furan and Pyrrole The oxygen atom of furan is sp2 hybridized. one unshared pairs of electrons on oxygen lies in an unhybridized 2p orbital and is a part of the aromatic sextet. The other unshared pair lies in an sp2 hybrid orbital and is not a part of the aromatic system. The resonance energy of furan is 67 kJ (16 kcal)/mol. O NH 21-4 Other Heterocyclics

CH2 CH2 NH2 HO N N H H Serotonin (a neurotransmitter) Indole N N N H3 C N O

H Purine O CH3 N N CH3 N N Caffeine 21-5 Aromatic Hydrocarbon Ions Any neutral, monocyclic, unsaturated hydrocarbon with an odd number of carbons must have at least one CH2 group and, therefore, cannot be aromatic.

CH2 Cyclopropene CH2 Cyclopentadiene CH2 Cycloheptatriene Cyclopropene, for example, has the correct number of pi electrons to be aromatic, 4(0) + 2 = 2, but does not have a closed loop of 2p orbitals. 21-6 Cyclopropenyl Cation If, however, the CH2 group of cyclopropene is transformed into a CH+ group in which carbon is sp2 hybridized and has a vacant 2p orbital, the overlap of orbitals is continuous and the cation is aromatic. H H +H H

H H + H + H H Cyclopropenyl cation represented as a hybrid of three equivalent contributing structures 21-7 Cyclopropenyl Cation When 3-chlorocyclopropene is treated with SbCl5, it forms a stable salt. H Cl + SbCl5 +

H SbCl6 - 3-ChloroAntimony(V) Cyclopropenyl cyclopropene chloride hexachloroantimonate (a Lewis acid) This chemical behavior is to be contrasted with that of 5-chloro-1,3-cyclopentadiene, which cannot be made to form a stable salt. 21-8 Cyclopentadienyl Cation H + AgBF4 Cl 5-Chloro-1,3cyclopentadiene + H BF 4

+ AgCl Cyclopentadienyl tetrafluoroborate If planar cyclopentadienyl cation were to exist, it would have 4 pi electrons and be antiaromatic. Note that we can draw five equivalent contributing structures for the cyclopentadienyl cation. Yet this cation is not aromatic because it has only 4 pi electrons. 21-9 Cyclopentadienyl Anion, C5H5 To convert cyclopentadiene to an aromatic ion, it is necessary to convert the CH2 group to a CH group in which carbon becomes sp2 hybridized and has 2 electrons in its unhybridized 2p orbital. H H H

H H the origin of the 6 pi electrons in the cyclopentadienyl anion H H : H H H H H H H H Cyclopentadienyl anion

(aromatic) n=1 21-10 Cyclopentadienyl Anion, C5H5 As seen in the Frost circle, the six pi electrons of cyclopentadienyl anion occupy the 1, 2, and 3 molecular orbitals, all of which are bonding. 21-11 Cyclopentadienyl Anion, C5H5 The pKa of cyclopentadiene is 16. In aqueous NaOH, it is in equilibrium with its sodium salt. H H CH2 + NaOH pKa16.0 : H H

H + Na + H2O pKa15.7 It is converted completely to its anion by very strong bases such as NaNH2 , NaH, and LDA. 21-12 Cycloheptatrienyl Cation, C7H7+ Cycloheptatriene forms an aromatic cation by conversion of its CH2 group to a CH+ group with its sp2 carbon having a vacant 2p orbital. H H + H

H H H H H H + H H H H H Cycloheptatrienyl cation (Tropylium ion) (aromatic) 21-13

Nomenclature Monosubstituted alkylbenzenes are named as derivatives of benzene. Many common names are retained. Toluene Ethylbenzene Cumene OH NH2 Phenol Aniline CHO COOH Styrene OCH3 BenzaldehydeBenzoic acid Anisole

21-14 Nomenclature Benzyl and phenyl groups CH3 Benzene Phenyl group, PhO Toluene CH2 Benzyl group, Bn O H3CO Ph 1-Phenyl-1-pentanone 4-(3-Methoxyphenyl)- (Z)-2-Phenyl2-butanone 2-butene 21-15

Disubstituted Benzenes Locate two groups by numbers or by the locators ortho (1,2-), meta (1,3-), and para (1,4-). Where one group imparts a special name, name the compound as a derivative of that molecule. CH3 NH2 COOH NO2 CH3 Cl CH3 Br 4-Bromotoluene 3-Chloroaniline 2-Nitrobenzoic acid m-Xylene (p-Bromotoluene) (m-Chloroaniline) (o-Nitrobenzoic acid) 21-16 Disubstituted Benzenes Where neither group imparts a special name, locate

the groups and list them in alphabetical order. CH2 CH3 4 3 NO2 2 Br 1 2 1 Cl 1-Chloro-4-ethylbenzene (p-Chloroethylbenzene) 1-Bromo-2-nitrobenzene (o-Bromonitrobenzene) 21-17 Polysubstituted Derivatives

If one group imparts a special name, name the molecule as a derivative of that compound. If no group imparts a special name, list them in alphabetical order, giving them the lowest set of numbers. 1 2 NO2 OH CH3 NO2 Br 6 1 2 4 Br 2

4 Cl 4 Br 1 Br CH2 CH3 4-Chloro-2-nitro- 2,4,6-Tribromo- 2-Bromo-1-ethyl-4phenol toluene nitrobenzene 21-18 Phenols The functional group of a phenol is an -OH group bonded to a benzene ring. OH

OH OH OH OH CH3 OH Phenol 3-Methylphenol1,2-Benzenediol 1,4-Benzenediol (m-Cresol) (Catechol) (Hydroquinone) 21-19 Acidity of Phenols Phenols are significantly more acidic than alcohols. OH + H2 O CH3CH2 OH + H2 O O- + H3 O+ +

CH3CH2 O + H3 O pKa = 9.95 pKa = 15.9 21-21 Acidity of Phenols Separation of waterinsoluble phenols from water-insoluble alcohols. 21-22 Acidity of Phenols (Resonance) The greater acidity of phenols compared with alcohols is due to the greater stability of the phenoxide ion relative to an alkoxide ion. O O O O

O H H These 2 Kekul structures are equivalent H These three contributing structures delocalize the negative charge onto carbon atoms of the ring 21-23 Phenol Subsitituents (Inductive Effect) Alkyl and halogen substituents effect acidities by inductive effects: Alkyl groups are electron-releasing. Halogens are electron-withdrawing. OH OH

OH CH3 Phenol m-Cresol pKa 9.95 pKa 10.01 OH OH Cl CH3 Cl p-Cresol m-Chlorophenol p-Chororophenol pKa 10.17 pKa 8.85 pKa 9.18 21-24 Phenol Subsitituents(Resonance, Inductiion) Nitro groups increase the acidity of phenols by both an electron-withdrawing inductive effect and a resonance effect. OH OH

OH NO2 Phenol pKa 9.95 NO2 m-Nitrophenol p-Nitrophenol pKa 8.28 pKa 7.15 21-25 Acidity of Phenols Part of the acid-strengthening effect of -NO2 is due to its electron-withdrawing inductive effect. In addition, -NO2 substituents in the ortho and para positions help to delocalize the negative charge. O O O N+

N+ O O delocalization of negative charge onto oxygen furthe increases the resonance stabilization of phenoxide O 21-26 Synthesis: Alkyl-Aryl Ethers Alkyl-aryl ethers can be prepared by the Williamson ether synthesis: but only using phenoxide salts and haloalkanes. haloarenes cannot be used because they are unreactive to SN2 reactions. X + RO- Na+ no reaction 21-29

Synthesis: Alkyl-Aryl Ethers OH + CH2 =CHCH2 Cl Phenol NaOH, H2 O, CH2 Cl2 3-Chloropropene (Allyl chloride) OCH2 CH=CH2 Phenyl 2-propenyl ethe (Allyl phenyl ether) O NaOH, H2 O, CH2 Cl2 OH + CH3 OSOCH3 Phenol O Dimethyl sulfate OCH3 + Na2 SO4 Methyl phenyl ether (Anisole)

21-30 Synthesis: Kolbe Carboxylation Phenoxide ions react with carbon dioxide to give a carboxylate salt. - OH NaOH H2 O Phenol + O Na CO2 OH O - + CO Na H2 O Sodium phenoxide

Sodium salicylate HCl H2 O OH O COH Salicylic acid 21-31 Mechanism: Kolbe Carboxylation The mechanism begins by nucleophilic addition of the phenoxide ion to a carbonyl group of CO2. O O O + C O Sodium phenoxide

O C (1) H O keto-enol tautomerism OH O C O (2) A cyclohexadienone intermediate Salicylate anion Go back to

aromatic structure 21-32 Synthesis: Quinones Because of the presence of the electron-donating -OH group, phenols are susceptible to oxidation by a variety of strong oxidizing agents. OH O H2 CrO4 Phenol O 1,4-Benzoquinone (p-Quinone) 21-33 Quinones O OH

O OH K2Cr2 O7 H2 SO4 1,2-Benzenediol (Catechol) 1,2-Benzoquinone (o-Quinone) OH O K2Cr2 O7 H2 SO4 OH 1,4-Benzenediol (Hydroquinone) O 1,4-Benzoquinone (p-Quinone) 21-34

Quinones Readily reduced to hydroquinones. O OH Na2 S2O4 , H2 O (reduction) O 1,4-Benzoquinone (p-Quinone) OH 1,4-Benzenediol (Hydroquinone) 21-35 Coenzyme Q Coenzyme Q is a carrier of electrons in the respiratory chain. O

OH MeO MeO O Coenzyme Q (oxidized form) reduction n H oxidation MeO MeO OH Coenzyme Q (reduced form) n H 21-36

Benzylic Oxidation Benzene is unaffected by strong oxidizing agents such as H2CrO4 and KMnO4 Halogen and nitro substituents are also unaffected by these reagents. An alkyl group with at least one hydrogen on its benzylic carbon is oxidized to a carboxyl group. CH3 O2N Cl COOH H2 CrO4 O2N Cl 2-Chloro-4-nitrotoluene2-Chloro-4-nitrobenzoic aci 21-38 Benzylic Oxidation

If there is more than one alkyl group on the benzene ring, each is oxidized to a -COOH group. H3 C CH3 K2 Cr2 O7 H2 SO4 1,4-Dimethylbenzene p-xylene) ( O HOC O COH 1,4-Benzenedicarboxylic acid (terephthalic acid) 21-39 Benzylic Chlorination

Chlorination and bromination occur by a radical chain mechanism. CH3 + Cl2 heat or light Toluene CH2 Cl + HCl Benzyl chloride Br NBS (PhCO2) 2 , CCl4 Ethylbenzene 1-Bromo-1-phenylethane (racemic) 21-40

Mechanism: Benzylic Reactions Benzylic radicals (and cations also) are easily formed because of the resonance stabilization of these intermediates. The benzyl radical is a hybrid of five contributing structures. C C C C C 21-41 Benzylic Halogenation Benzylic bromination is highly regioselective. Br NBS (PhCO2 )2 , CCl4 Ethylbenzene

1-Bromo-1-phenylethane (the only product formed) Benzylic chlorination is less regioselective. + Cl2 Ethylbenzene heat or light Cl Cl + 1-Chloro-1phenylethane (90%) 1-Chloro-2phenylethane (10%) 21-42 Hydrogenolysis Hydrogenolysis: Cleavage of a single bond by H2 Benzylic ethers are unique in that they are cleaved under conditions of catalytic hydrogenation.

this bond is cleaved O Benzyl butyl ether + H2 Pd/ C OH + 1-Butanol Me Toluene 21-43 Synthesis, Protecting Group: Benzyl Ethers The value of benzyl ethers is as protecting groups for the OH groups of alcohols and phenols. To carry out hydroboration/oxidation of this alkene, the phenolic -OH must first be protected; it is acidic enough to react with BH3 and destroy the reagent. 2. BH3 THF

1. ClCH2 Ph OH 2-(2-Propenyl)phenol (2-Allylphenol) Et3N O OH O Ph H2 Pd/ C Ph 3. H2 O2 / NaOH OH OH 2-(3-Hydroxypropyl)phenol 21-44

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