Electrophilic Aromatic Substitution in Benzene: Mechanisms and Reactions - Prof. Herman L., Study notes of Organic Chemistry

Download Electrophilic Aromatic Substitution in Benzene: Mechanisms and Reactions - Prof. Herman L. and more Study notes Organic Chemistry in PDF only on Docsity! Chapter 16 - Chemistry of Benzene – Electrophilic Aromatic Substitution Electrophilic aromatic substitution -> reaction in which a hydrogen atom is replaced by an electrophile + E+ EH + H+ SO3H NO, R Sulfonation Nitration Sy or Halogenation 4 Alkylation O | cr Acylation © 2004 Thomson/Brooks Cole Reaction profiles for addition & substitution reactions… Br Br Br + HBr Br2 Br2 Br2+ H Br Br Br Br e n e r g y reaction co-ordinate Br- + + HBr Typical substitution reaction… E+ H E H E H E arenium cation H + + + H E :B E loss of H+ "regenerates" benzene ring and lowers energy + Resonance stabilized arenium cation… CH3 H + 5. Friedel-Crafts acylation… R O R Cl O AlCl3 Mechanisms… 1. Halogenation (Cl2/Br2 and I2)… Br Br + FeBr3 Br Br Fe Br + FeBr3 + H-Br Br Br Br + - H Br + Fe BrBr Br Br - : : : electrophile = "Br+" iodination is a bit different… + I2 I + CuCl2 1/2 I2 + Cu ++ "I+" + Cu+ HI 2. Nitration… + HONO2 H2SO4 NO2 + H2O 3. Sulfonation… H2SO4/SO3 100o fuming sulfuric acid (oleum) = H2SO4 + SO3 SO3H benzenesulfonic acid Mechanism -> both SO3 and SO3H+ are possible electrophiles -> how to they work?… O S O O O S O O - + O S O O - ++ - OH S O O - ++& The reaction is reversible. Ar-SO3H + H2SO4, H2O, ∆ -> Ar-H. SO3H can be replaced with OH. SO3H OH 1. NaOH, 300o 2. H3O + CH3 CH3 strenuous conditions; usually only alkyl groups survive Question -> the pKa’s of an alcohol and phenol are ~ 16 and 10. Given this, why is the 2nd step necessary? Sulfonation of naphthalene provides an example of a kinetic vs thermodynamic control reaction… concd H2SO4 T = 0-40o -> 85% 15% SO3H + SO3H 160o 15% 85% 160o 2. no reaction if the aromatic ring contains strong electron withdrawing or amino substituents Y Y = -NO2, -SO3H, C N Z C O (Z = H, R, OH, OR) N (-NH2, -NHR, -NR2):N coordinateswith AlCl3 3. multiple substitution (alkyl groups activate the ring to EAS)… R more reactive than benzene to EAS + major minor + 1 t-BuCl AlCl3 t-Bu t-Bu t-Bu 1 4. carbocation rearrangements… + Cl AlCl3 + 2:1 + AlCl3 major minor Cl + mechanism… + R Cl C O AlCl3 R Cl C O AlCl3 -+ AlCl4 acyl/acylium cation - C OR + C OR + Anhydrides (and esters) also work… + O OO AlCl3 O + OH O O O + AlCl3 O O OH O *Reduction of aryl ketones… AlCl3Cl O + O reduction possible reduction methods: 1. H2, Pd/C (does not work for Ar-C(=O)-Ar) 2. Clemenson -> Zn-Hg/HCl 3. Wolff-Kishner -> NH2NH2, OH -, DMSO, ∆ A substituent can influence the electron density in an arene by both inductive and resonance effects. Generally, resonance more important than inductive effects in determining regiospecificity 1. inductive effects -> essentially caused by polarization of the Ar-Z bond… Cl δ−δ+ Ar O H Ar C N Ar C F F F CH3 δ− δ+ δ− δ+ δ−δ+ δ− δ− δ− ∆+ 2. resonance effects… O R O R etc... Z Z etc... **Common Substituents in EAS Reactions** N R1 R2 O H NH C R O O R O C O R R Ar CH CR2 H (R1, R2 = H or alkyl) Strongly activating... Activating... all have unshared e-pairs on the atom bonded to aromatic ring Standard.... o, p-directing net e donating Very strongly activating... Substituents effects -> explained… KEY FACTOR -> stabilization of the intermediate arenium cation case # 1: o, p-directing substituent and o-substitution… *resonance structures for arenium cation arising from o-addn; *p-addn also gives one 3° & two 2° H E CH3 H E CH3 H E CH3 CH3 E+ 3° 2°2° case # 2: o, p-directing substituent and m-substitution… CH3 CH3 H E CH3 HE CH3 HEE+ 2° 2° *resonance structures for arenium cation arising from m-addn; *all three structures are 2° 2° case # 3: m-directing substituent and o-substitution… H E NO2 H E NO2 H E N O O N O O E+ 3° *resonance structures for arenium cation arising from o-addn; *p-addn also gives one 3° & two 2°; *3° structure is very high energy (+ charges on adjacent atoms) & makes a very small contribution to resonance hydrid 2°2° bad news Substitution of disubstituted benzenes -> additivity of effects most powerful activator controls position of attack; steric factors are of secondary importance OH CH3 * CH3 NO2 * NH2 CO2H* * OCH3 * Br * Br Br * CH3 CH2CH3 OCH3 OCH3 * * CO2H * NO2 * * C(CH3)3 CH3 CO2H CO2H * no CH3 no Cl SO3H SO3H no An example of the utility of reversible sulfonation… C(CH3)3 HNO3 H2SO4 C(CH3)3 NO2 16% + m + p 11% 73% How can the yield of ortho be increased? Reductions -> arenes are resistant to reduction NO2 H2, Pt, high P OR H2, Rh/C OO NH2 O NH2 HOOH H2 Pd/C Some synthetic examples... CO,H ? —pP- NO, Cl ? —pP Nucleophilic aromatic substitution… Cl NO2 NO2 O2N OH NO2 NO2 O2N rate = k[ArX][Nuc] 1. OH- 2. H+ Benzyne… Cl 1.NaOH, H2O, 340 o, 2500 psi 2. H+ OH "normal" conditions chemical "hammer" OR ???? Not an example of aromatic nucleophilic substn Br * KNH2 liq. NH3 NH2* + * NH2 50% 50% NH2 - is str base than OH- Br * H NH2: : H N H H + Br + * benzyne * + NH2* H + other productNH2 : : 1.421 A 1.385 A 1.410 A 1.258 A  Benzylic bromination… C NBS, ROOR CCl4 Br + NH O O C H H H C H C H etc resonance hybrid C H H *Created by Prof. H. L. Ammon, Dept. of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742. Last update 8/13/04.