5/6/2020 Aromatic compounds chapter 1 Feb 2020 1 1 5/6/2020 Discovery of Benzene • Isolated in 1825 by Michael Faraday who determined C:H ratio to be 1:1. • Synthesized in 1834 by Eilhard Mitscherlich who determined molecular formula to be C6H6. He named it benzin. • Other related compounds with low C:H ratios had a pleasant smell, so they were classified as aromatic. chapter 1 Feb 2020 2 2 5/6/2020 Kekulé’s Structure • Proposed in 1872 by Friedrich Kekulé • Failed to explain existence of only one isomer of 1,2dichlorobenzene. • Proposed alternating single and double bonds – Irregular hexagonal • If that was a case, it would have been more reactive than alkenes……….but not!!! • Benzene is actually a resonance hybrid between the two Kekulé structures. chapter 1 Feb 2020 3 3 5/6/2020 Resonance Structures of Benzene • The C—C bond lengths in benzene – shorter than typical single-bond lengths – longer than typical double-bond lengths (bond order 1.5). • Benzene's resonance representation: – a circle inside the six-membered ring chapter 1 Feb 2020 4 4 5/6/2020 Structure of Benzene • Each sp2 hybridized C in the ring has an unhybridized p orbital perpendicular to the ring which overlaps around the ring. • The six pi electrons are delocalized over the six carbons. chapter 1 Feb 2020 5 5 5/6/2020 Unusual Stability of Benzene • Unlike alkenes and alkynes, benzene does not add Br2 to the double. chapter 1 Feb 2020 6 6 5/6/2020 Benzene - Resonance Energy • heats of hydrogenation for both cyclohexene and benzene are negative (heat is liberated) + H2 + 3H2 Ni 1-2 atm Ni 200-300 atm DH° = -28.6 kcal/mol (-120 kJ/mol) DH° = -49.8 kcal/mol (-208 kJ/mol) – these results are shown graphically on the next slide chapter 1 Feb 2020 7 7 5/6/2020 Molar Heats of Hydrogenation 36 Kca/mol -85.8 Kca/mol -49 Kca/mol -49.8 Kca/mol -28.6 Kca/mol the resonance energy of benzene, as determined by heats of hydrogenation, is approximately 36 kcal/mol chapter 1 Feb 2020 8 8 5/6/2020 The Thermodynamic Stability of Benzene  Since p bonds are formed from side-way overlap of p orbitals, p electron clouds are above & below the plane of the double bond p-electrons above and below ring 9 5/6/2020 Resonance Energy – resonance energies for several other aromatic hydrocarbons Res on ance en ergy Benzene N aphth alene [kcal/mol (kJ/mol)] 36 (151) 61 (255) chapter 1 A nthracen e 83 (347) Feb 2020 Ph enanth ren e 91 (381) 10 10 5/6/2020 Concept of Aromaticity • The underlying criteria for aromaticity were recognized in the early 1930s by Erich Hückel • To be aromatic, a ring must – have one 2p orbital on each atom of the ring – be planar or nearly planar, so that overlap of all 2p orbitals of the ring is continuous or nearly continuous – have 2, 6, 10, 14, 18, and so forth pi electrons in the cyclic arrangement of 2p orbitals – (4n + 2) pi system where n = 0, 1, 2, 3…….. chapter 1 Feb 2020 11 11 5/6/2020 Concept of Aromaticity • Benzene meets these criteria – it is cyclic, planar, has one 2p orbital on each atom of the ring, and has 6 pi electrons (the aromatic sextet) in the cyclic arrangement of its 2p orbitals • More examples chapter 1 Feb 2020 12 12 5/6/2020  All these (4n + 2) p, planar annulenes are aromatic (4n + 2) p planar annulenes: Benzene [6]Annulene [14]Annulene (aromatic) [18]Annulene (aromatic) 13 5/6/2020 Non-aromatic – may be cyclic, non-planar, chapter 1 Feb 2020 14 14 5/6/2020  Non-planar (4n + 2) p annulenes are non-aromatic 15 5/6/2020 chapter 1 Feb 2020 16 16 5/6/2020 Heterocyclic Aromatics • Heterocyclic compound: a compound that contains one or more atoms other than carbon in its ring • Heterocyclic aromatic compound: a heterocyclic compound whose ring is aromatic – pyridine and pyrimidine are heterocyclic analogs of benzene; each is aromatic N N Pyrid ine chapter 1 N Pyrimidin e Feb 2020 17 17 5/6/2020 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 sextet – pyridine has a resonance energy of 32 kcal (134 kJ)/mol, slightly less than that of benzene chapter 1 Feb 2020 18 18 5/6/2020 Concept of Aromaticity – the five-membered-ring compounds furan, pyrrole, and imidazole are also aromatic N O Furan chapter 1 N H Pyrrole N H Imidazole Feb 2020 19 19 5/6/2020 • Nature abounds in compounds with a heterocyclic aromatic ring fused to another aromatic ring HO N H In dole NH 2 N H Serotonin (a neurotran smitter) chapter 1 NH 2 N N N N H Pu rin e Feb 2020 N N N N H Aden ine 20 20 5/6/2020 chapter 1 Feb 2020 21 21 5/6/2020 SOME CHEMICAL CONSEQUENCES OF AROMATICITY • Acidity differences of the two sp3 hybridized carbon atoms. Why different? chapter 1 Feb 2020 22 22 5/6/2020 • Unlike other alkyl halides, cycloheptatrienyl bromide is polar and water soluble. Why? • Think of the nature of the stability of the ionic product! chapter 1 Feb 2020 23 23 5/6/2020 ANTIAROMATICITY An aromatic compound is more stable than an analogous cyclic compound with localized electrons. In contrast, an antiaromatic compound is less stable than an analogous cyclic compound with localized electrons. Aromaticity is characterized by stability, whereas antiaromaticity is characterized by instability. chapter 1 Feb 2020 24 24 5/6/2020 Anti aromatic – cyclic, planar, has one 2p orbital on each atom of the ring, satisfy 4n pi electron • Violate the Huckel • Very rare – Small rings 5,4,3 – Fused rings chapter 1 They have the flexibility to adopt Feb 2020 nonplanar conformation 25 25 5/6/2020 Identify aromatic, non-aromatic and anti-aromatic compounds chapter 1 Feb 2020 26 26 5/6/2020 Electrophilic Aromatic Substitution • Electrophilic aromatic substitution: a reaction in which an electrophile, E+, substitutes for an H on an aromatic ring H E + + E + + H • We study – several common types of electrophiles – how each is generated – the mechanism by which it replaces hydrogen chapter 1 Feb 2020 27 27 5/6/2020 chapter 1 Feb 2020 28 28 5/6/2020 chapter 1 Feb 2020 29 29 5/6/2020 • The following are the five most common electrophilic aromatic substitution reactions: 1. Halogenation: A bromine (Br), a chlorine (Cl), or an iodine (I) substitutes for a hydrogen. 2. Nitration: A nitro group (NO2) substitutes for a hydrogen. 3. Sulfonation: A sulfonic acid group (SO3H) substitutes for a hydrogen. 4. Friedel Crafts acylation: An acyl group (RC=O) substitutes for a hydrogen. 5. Friedel Crafts alkylation: An alkyl group (R) substitutes for a hydrogen. chapter 1 Feb 2020 30 30 5/6/2020 Electrophilic Aromatic Substitution • All occur by a common three-step mechanism – Step 1: generation of the electrophile + Reagent(s) E – Step 2: reaction of the electrophile with the ring H + + E H slow H E H E E Resonan ce-stab ilized cation intermed iate – Step 3: proton transfer to regenerate the aromatic ring H E E + Base chapter 1 fast + Base-H Feb 2020 31 31 5/6/2020 Chlorination and Bromination – Step 1: formation of a chloronium ion Cl Cl Cl + Fe Cl Cl Chlorine Ferric chlorid e (a Lew is bas e) (a Lew is acid) Cl Cl Cl Fe Cl Cl A molecular complex w ith a positive charge on chlorin e an d a negative charge on iron + chapter 1 Cl + Cl Cl Fe Cl Cl An ion p air contain ing a chloroniu m ion Feb 2020 32 32 5/6/2020 Chlorination and Bromination – Step 2: reaction of the chloronium ion with the aromatic ring + Cl + slow , rate d etermining + H Cl H + H + Cl Res on ance-s tabilized cation intermediate chapter 1 Cl Feb 2020 33 33 5/6/2020 Chlorination and Bromination – Step 3: proton transfer to FeCl4- forms HCl, regenerates the Lewis acid catalyst, and gives chlorobenzene + H Cl + Cl Cation intermediate Cl Fe Cl Cl fast Cl + H-Cl Chloroben zene chapter 1 Feb 2020 Cl + Fe Cl Cl 34 34 5/6/2020 Nitration • The electrophile is NO2+, generated in this way H O NO2 + H O SO3 H N itric acid H + H O NO2 H H O chapter 1 H H +O NO2 + HSO4 Conjugate acid of n itric acid + + NO2 The n itronium ion Feb 2020 35 35 5/6/2020 Nitration chapter 1 Feb 2020 36 36 5/6/2020 Sulfonation chapter 1 Feb 2020 37 37 5/6/2020 Sulfonation chapter 1 Feb 2020 38 38 5/6/2020 Friedel-Crafts Alkylation • Friedel-Crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group + Benzene Cl AlCl3 2-Ch loropropan e (Is op ropyl chloride) chapter 1 + HCl Isoprop ylb enzene (Cumen e) Feb 2020 39 39 5/6/2020 Friedel-Crafts Alkylation – Step 1: formation of an alkyl cation as an ion pair R R+ AlCl4 A n ion pair containing a carb ocation : : Cl : + Cl Cl Al Cl + : : R Cl Al-Cl Cl Cl – Step 2: reaction of the cation with the aromatic ring + + + R H R + H H R + R A resonance-stabilized cation – Step 3: proton transfer regenerates the aromatic ring + H R + Cl A lCl 3 chapter 1 R + A lCl 3 + HCl Feb 2020 40 40 5/6/2020 Friedel-Crafts Alkylations • There are two major limitations on F-C alkylations – it is practical only with stable carbocations, such as 2° and 3 carbocations – it fails on benzene rings bearing one or more strongly electron-withdrawing groups O CH O O O O CR COH COR CNH2 SO3 H C N NO2 NR3 CF3 CCl3 chapter 1 Feb 2020 + 41 41 5/6/2020 Friedel-Crafts Acylations • Treating an aromatic ring with an acid chloride in the presence of AlCl3 – acid (acyl) chloride: a derivative of a carboxylic acid in which the -OH is replaced by a chlorine O O + Benzene CH3 CCl Acetyl ch loride (an acyl halid e) chapter 1 CCH3 AlCl3 + HCl Acetop henone (a k eton e) Feb 2020 42 42 5/6/2020 Friedel-Crafts Acylations – the electrophile is an acylium ion generated by reaction of the acid chloride and the Lewis acid catalyst Cl + Al Cl Cl A n acyl A luminu m chlorid e chlorid e (a Lew is bas e) (a Lew is acid ) O R-C-Cl O + Cl R-C Cl Al-Cl Cl A molecular comp lex w ith a positive ch arge on ch lorine an d a negative ch arge on aluminu m chapter 1 Feb 2020 O R-C+ Cl Cl Al-Cl Cl A n ion p air contain ing an acylium ion 43 43 5/6/2020 Other Benzene Alkylations • Generation of carbocations – treating an alkene with a protic acid, most commonly H2SO4 or H3PO4 + CH3 CH=CH2 Benzene H3 PO4 Prop ene Isopropylbenzen e (Cumene) – treating an alcohol with H2SO4 or H3PO4 + HO Benzene chapter 1 H3 PO4 + H2 O 2-Methyl -2p henyl pro pane Feb 2020 (t ert -Bu ty lbenzene) 44 44 5/6/2020 Di- and Polysubstitution • Existing groups on a benzene ring influence further substitution in both orientation and rate • Orientation – certain substituents direct new substitution preferentially toward ortho-para positions, others direct preferentially toward meta positions • Rate – certain substituents are activating toward further substitution, others are deactivating toward further substitution chapter 1 Feb 2020 45 45 5/6/2020 Di- and Polysubstitution – -OCH3 is ortho-para directing OCH3 + Br2 CH3 COOH Anisole OCH3 Br OCH3 + o-Bromoanis ole (4%) chapter 1 Feb 2020 + HBr Br p-Bromo anisole (96%) 46 46 5/6/2020 Di- and Polysubstitution – -NO2 is meta directing NO2 + HNO3 NO2 NO2 H2 SO4 100o C NO2 N itroben zene m-D in itrobenzen e (93%) chapter 1 + NO2 o-D initrobenzen e NO2 + + H2 O NO2 p-D initrobenzen e Less than 7% combined Feb 2020 47 47 5/6/2020 Di- and Polysubstitution • Effects of substituents on further substitution strongly activating OrthoPara D irecting Meta D irecting mod erately activating NH2 NHR O NHCR O NHCAr w eakly activating R w eakly deactivating F mod erately deactivating O CH strongly deactivating NO2 chapter 1 Cl O CR OCR I Br NH3 + O OCAr O O COH O COR CF3 Feb 2020 OR OH NR2 O CNH2 O SOH O CCl3 48 48 5/6/2020 Di- and Polysubstitution • Generalizations 1. alkyl groups, phenyl groups, and substituents in which the atom bonded to the ring has an unshared pair of electrons are ortho-para directing; all other substituents are meta directing 2. all ortho-para directing groups are activating toward further substitution; the exception to this generalization are the halogens, which are weakly deactivating 3. all meta directing groups carry either a partial or full positive charge on the atom bonded to the ring chapter 1 Feb 2020 49 49 5/6/2020 Di- and Polysubstitution • The order of steps is important CH3 H2 CrO4 HNO3 CH3 Toluene COOH H 2 SO4 NO2 4-N itrotoluen e H2 CrO4 COOH NO2 4-Nitroben zoic acid HNO3 COOH H 2 SO4 Benzoic acid chapter 1 NO2 3-N itroben zoic acid Feb 2020 50 50 5/6/2020 Theory of Directing Effects • The rate of electrophilic aromatic substitution – the rate of EAS is determined by the slowest step in the reaction – for almost every EAS, the rate-determining step is attack of E+ on the aromatic ring to give a resonance-stabilized cation intermediate – the more stable this cation intermediate, the faster the rate-determining step and the faster the overall reaction chapter 1 Feb 2020 51 51 5/6/2020 Theory of Directing Effects • For ortho-para directors, ortho-para attack forms a more stable cation than meta attack – ortho-para products are formed faster than meta products • For meta directors, meta attack forms a more stable cation than ortho-para attack – meta products are formed faster than ortho-para products chapter 1 Feb 2020 52 52 5/6/2020 Theory of Directing Effects – -OCH3; assume meta attack OCH3 + N O2 + OCH3 + (a) H N O2 slow OCH3 + OCH3 fast H - H+ H (b) N O2 chapter 1 + N O2 OCH3 N O2 (c) Feb 2020 53 53 5/6/2020 Theory of Directing Effects – -OCH3; assume para (or ortho) attack OCH3 OCH 3 slow + N O2 + : : : : :OCH3 + OCH3 :OCH3 : OCH3 + + H (d) N O2 H (e) N O2 chapter 1 H (f) N O2 Feb 2020 + H N O2 fast - H+ N O2 (g) 54 54 5/6/2020 chapter 1 Feb 2020 55 55 5/6/2020 chapter 1 Feb 2020 56 56 5/6/2020 Theory of Directing Effects – -NO2; assume meta attack N O2 + N O2 + N O2 + (a) slow N O2 H N O2 + fast H - H+ H (b) N O2 N O2 N O2 chapter 1 + N O2 N O2 (c) Feb 2020 57 57 5/6/2020 Theory of Directing Effects – -NO2; assume para attack NO2 s low + NO2 + NO2 H (d) + NO2 NO2 NO2 + H NO2 (e) + H NO2 (f) NO2 fas t -H+ NO2 – contributor (e) places positive charge on adjacent atoms chapter 1 Feb 2020 58 58 5/6/2020 chapter 1 Feb 2020 59 59 5/6/2020 Activating-Deactivating • Any resonance effect, such as that of -NH2, OH, and -OR, which delocalizes the positive charge on the cation intermediate, lowers the activation energy for its formation and activates the ring toward further EAS chapter 1 Feb 2020 60 60 5/6/2020 chapter 1 Feb 2020 61 61 5/6/2020 chapter 1 Feb 2020 62 62 5/6/2020 Activating-Deactivating • Any resonance or inductive effect, such as that of -NO2, -C=O, -SO3H, -NR3+, -CCl3, and -CF3, which decreases electron density on the ring, deactivates the ring toward further EAS chapter 1 Feb 2020 63 63 5/6/2020 Activating-Deactivating chapter 1 Feb 2020 64 64 5/6/2020 Halogens • Halogens: the resonance and inductive effects operate in opposite directions – the inductive effect: the halogens are more electronegative than carbon and have an electronwithdrawing inductive effect; aryl halides, therefore, react more slowly in electrophilic aromatic substitution than benzene. – the resonance effect: a halogen ortho or para to the site of electrophilic attack stabilizes the cation intermediate by delocalizing the positive charge; halogen, therefore, is ortho-para directing + E chapter 1 + H E Feb 2020 + :Cl : :Cl : : : : :Cl + H E 65 65 5/6/2020 Problems chapter 1 Feb 2020 66 66 5/6/2020 Problems chapter 1 Feb 2020 67 67 5/6/2020 Problems chapter 1 Feb 2020 68 68 5/6/2020 THE EFFECT OF SUBSTITUENTS ON pKa • Electron-withdrawing groups stabilize a base and, therefore, increase the strength of its conjugate acid. Electron-donating groups estabilize a base, and this decreases the strength of its conjugate acid chapter 1 Feb 2020 69 69 5/6/2020 THE EFFECT OF SUBSTITUENTS ON pKa chapter 1 Feb 2020 70 70 5/6/2020 chapter 1 Feb 2020 71 71 5/6/2020 THE ORTHO-PARA RATIO • On substituted benzene with electron donating group, the para isomer will be formed preferentially if either the substituent on the ring or the incoming electrophile is large. chapter 1 Feb 2020 72 72 5/6/2020 chapter 1 Feb 2020 73 73 5/6/2020 DESIGNING A SYNTHESIS: SYNTHESIS OF MONOSUBSTITUTED AND DISUBSTITUTED BENZENES Grignard rxn chapter 1 Feb 2020 74 74 5/6/2020 chapter 1 Feb 2020 75 75 5/6/2020 If you start with nitration, acylation will not be occurring. Why? Alternative method chapter 1 Feb 2020 76 76 5/6/2020 THE SYNTHESIS OF TRISUBSTITUTED BENZENES • When a disubstituted benzene undergoes an electrophilic aromatic substitution reaction, the directing effects of both substituents have to be considered. Directing to the same positions chapter 1 Feb 2020 77 77 5/6/2020 chapter 1 Feb 2020 78 78 5/6/2020 Directing to different positions chapter 1 Feb 2020 79 79 5/6/2020 Nucleophilic Aromatic Substitution • Under standard reaction conditions aryl halides do not react with nucleophiles because the π electron cloud repels the approach of a nucleophile. • In the EAS reactions, a nucleophile replaces a leaving group on the aromatic ring for a ring bearing one or more strong electron wothdrawing group. • Electron-withdrawing substituents activate the ring for nucleophilic substitution. chapter 1 Feb 2020 80 80 5/6/2020 Examples of Nucleophilic Substitution chapter 1 Feb 2020 81 81 5/6/2020 Addition-Elimination Mechanism => chapter 1 Feb 2020 82 82 5/6/2020 Activated Positions • Nitro groups ortho and para to the halogen stabilize the intermediate (and the transition state leading to it). • The electron-withdrawing groups must be positioned ortho or para to the halogen. chapter 1 Feb 2020 83 83 5/6/2020 Number of substitients and the reaction conditions HCl HCl chapter 1 Feb 2020 84 84 5/6/2020 chapter 1 Feb 2020 85 85 5/6/2020 Benzyne Reaction: Elimination-Addition • Reactant is halobenzene with no electronwithdrawing groups on the ring. • Use a very strong base like NaNH2. chapter 1 Feb 2020 => 86 86 5/6/2020 Benzyne Intermediate • Sodium amide (-NH2) abstract a proton. • The benzyne intermediate forms when the bromide is expelled and the electrons on the sp2 orbital adjacent to it overlap with the empty sp2 orbital of the carbon that lost the bromide. • Benzynes are very reactive species due to the high strain of the triple bond. chapter 1 Feb 2020 87 87 5/6/2020 Benzyne Intermediate NH2 H H _ NH2 NH2 H NH2 H _ or H H CH3 H H CH3 H H CH3 H CH3 para-toluidine meta-toluidine chapter 1 H Feb 2020 => 88 88 5/6/2020 Nucleophilic Substitution on the Benzyne Intermediate chapter 1 Feb 2020 89 89 5/6/2020 Catalytic Hydrogenation CH 3 CH 3 3 H 2, 1000 psi CH 3 Ru, 100°C CH 3 • Elevated heat and pressure is required. • Possible catalysts: Pt, Pd, Ni, Ru, Rh. • Reduction cannot be stopped at an intermediate stage. chapter 1 Feb 2020 90 90 5/6/2020 Birch Reduction H H H H H H Na or Li NH3 (l), ROH H H H H H H H H • This reaction reduces the aromatic ring to a nonconjugated 1,4-cyclohexadiene. • The reducing agent is sodium or lithium in a mixture of liquid ammonia and alcohol. chapter 1 Feb 2020 91 91 5/6/2020 Mechanism of the Birch Reduction chapter 1 Feb 2020 92 92 5/6/2020 Limitations of the Birch Reduction chapter 1 Feb 2020 93 93 5/6/2020 Side-Chain Oxidation CH2CH3 CO2H KMnO4, NaOH H2O, 100oC (or Na2Cr2O7, H2SO4 , heat) • Alkylbenzenes are oxidized to benzoic acid by heating in basic KMnO4 or heating in Na2Cr2O7/H2SO4. • The benzylic carbon will be oxidized to the carboxylic acid. chapter 1 Feb 2020 94 94 5/6/2020 Side-Chain Halogenation Br CH2CH3 Br2 or NBS h CHCH3 • The benzylic position is the most reactive. • Br2 reacts only at the benzylic position. • Cl2 is not as selective as bromination, so results in mixtures. chapter 1 Feb 2020 95 95 5/6/2020 Reduction of Nitro Groups and Aryl Ketones O OH OH H2/ Pd O2N chapter 1 CH3 Feb 2020 H2N CH3 96 96 5/6/2020 Conversion of Halogens to Organometallic Reagents chapter 1 Feb 2020 97 97 5/6/2020 Hydrolysis of Sulfonic Acids Hydrolysis It helps to prepare substituted aromatic compounds chapter 1 Feb 2020 98 98 5/6/2020 Modifying the Influence of Strong Activating Groups CH3 OH O CH3 O NH2 Ac2O O Ac2O Pyrdine Activated HN Pyrdine Deactivated Activated Deactivated Diazotization of primary aromatic amines and their usefulness in synthesis NO2 NH2 Zn/ HCl N2 NaNO2 HCl chapter 1 Feb 2020 99 99