NPTEL – Chemistry – Principles of Organic Synthesis Lecture 13 Electrophilic Aromatic Substitution I 5.1 Principles The reaction occurs in two stages: the electrophile adds to one carbon atom of the aromatic ring, yielding a carbocation in which the positive charge is delocalized, and a proton is then eliminated from the adduct. H E H E H E E -H E 5.2 Formation of Carbon-Carbon Bonds 5.2.1 Friedel-Crafts Acylation Acylation of aromatic rings is generally peroformed using acid chloride or acid anhydride as an acylating agent in the presence of Lewis acid. O Z RCOCl, AlCl Z 3 R H2O Mechanism AlCl3 RCOCl RC=O + AlCl4 H H RC=O COR Z Z COR Z Joint initiative of IITs and IISc – Funded by MHRD Page 1 of 26 NPTEL – Chemistry – Principles of Organic Synthesis In some circumstances, carboxylic acid is used as an acylating agent in the presence of a proton acid. HO OH O 2 PhOH, H2SO4 O O -H2O O O Phenolphthalein Indicator Intramolecular reactions are of particular value to construct cyclic systems. These reactions are usually carried out using dibasic acid anhydrides. For example, the synthesis -tetralone has been accomplished from benzene and succinic anhydride using AlCl3 in 80% yield. O O OH OH AlCl3 reduction + O O O O SOCl2 Cl AlCl3 O O Joint initiative of IITs and IISc – Funded by MHRD Page 2 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Examples: 5 mol% Tb(OTf)3 CO H 2 PhCl O D.-M. Cui, C. Zhang, M. Kawamura, S. Shimada, Tetrahedron Lett. 2004, 45, 1741. OMe OMe Ph-CO2H, TFAA AlPW12O40 COPh H. Firouzabadi, N. Iranpoor, F. Nowrouzi, Tetrahedron Lett. 2003, 44, 5343. 5.2.2 Friedel-Crafts Alkylation The reaction can be performed using alkyl halides, alcohols, esters, ethers, alkenes, aldehydes and ketones as alkylating agent. Reactions of the first four are accomplished using Lewis acid catalysis, while those of the last three by proton acids. Z Z Rr RCl, AlCl3 H2O Mechanism AlCl3 RCl R + AlCl4 H R H R Z Z R Z Joint initiative of IITs and IISc – Funded by MHRD Page 3 of 26 NPTEL – Chemistry – Principles of Organic Synthesis For examples, the industrial production of styrene involves the ethylation of benzene using AlCl3 followed by dehydrogenation. H2C CH2 ZnO AlCl3 heat Mechanism Z Z Z AlCl3 -H2O AlCl 3 AlCl -AlCl3 H 3 Examples: O Me N Me Bn N Me H + CHO Ph N CHO N TFA, THF, H2O Me Me Ph 87% yield 93% ee N. A. Paras, D. W. C. MacMillan, J. Am. Chem. Soc. 2001, 123, 4370. OH O OH O OH O AlCl3 AlCl3 NaCl Me OH OH OH 90% D. B. Bruce, A. J. S. Sorrie, R. H. Thomson, J. Chem. Soc. 1953, 2403. Joint initiative of IITs and IISc – Funded by MHRD Page 4 of 26 NPTEL – Chemistry – Principles of Organic Synthesis While the Bogert-Cook phenanthrene synthesis uses intramolecular alkylation as intermediate in the presence proton acid. -H Se H2SO4 oxidation Skraup Synthesis Skraup quinoline synthesis is an example for the reaction which involves aldehyde as alkylating agent. The process with aldehydes and ketones is useful when the reaction is intramolecular and stereochemically controlled. OH HO OH NH 2 H N Mechanism .. OH : 2 .. OH -H O .. HO H HO OH 2 HO OH H HO OH -H2O HO OH .. .. 2 H -H H OH OH O OH H H keto-enol proton .. transfer NH N N N .. 2 H H2 2 H H OH H H OH2 H H -H2O oxidation N N N N H H -H H Joint initiative of IITs and IISc – Funded by MHRD Page 5 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Aromatic compounds whose reactivity is comparable with or greater than that of benzene can be successfully alkylated. 5.2.3 Vilsmeier-Haack Reaction Reaction of secondary amines with formic acid gives N-formylamines which formylate aromatic compounds in the presence of phosphorus oxyhalide. H CHO POCl3 DMF Mechanism Cl O Cl O Cl Cl Cl P P P O O O Cl O O O -Cl Cl Cl .. Cl Me .. + P Me N H Cl Cl Me Me N H Cl N H N H Me Me Me Me :EDG : EDG NMe2 EDG :NMe2 EDG NMe2 Cl O H Cl Cl -Cl H Me P N H O Cl H H Me Cl Vilsmeier Reagent EDG NHMe2 EDG O EDG NMe2 O-H OH -NMe2H H H O 2 H 2 H Heterocycles are also common substrates. The reaction can also be performed on alkene. The reaction is more efficient with aromatic ring having electron donating group (EDG). Joint initiative of IITs and IISc – Funded by MHRD Page 6 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Examples: O Cl CHO POCl3 TIPS DMF OHC TIPS POCl3 95% N N S. Hesse, G. Kirsch, Tetrahedron Lett. 2002, 43, 1213. DMF CO2Ph CO2Ph OHC D. L. Comins, A. L. Williams, Org. Lett. 2001, 3, 3217. Me POBr3 Me TES Me TES O DMF O Me 64% R. A. Aungst, Jr., C. Chan, R. L. Funk, Org. Lett. 2001, 3, 2611. 5.2.4 Reimer-Tiemann Formylation The reaction involves formylation of phenol and analogues using chloroform in the presence of base. First, chloroform reacts with base to give electrophilic dichlorocarbene which in situ undergoes reaction with phenoxide ion. The resulting benzal chloride can be converted into salicylaldehyde by hydrolysis followed by acidification. OH OH CHO CHCl3 + H2O + 3 KCl KOH Joint initiative of IITs and IISc – Funded by MHRD Page 7 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Mechanism O H O O H Cl OH Cl Cl Cl OH :CCl2 H2O Cl : : Cl H Cl Cl Cl Cl O O O H O H H OH -Cl Cl -H Cl -Cl Cl OH + OH Cl H H Cl Cl H OH O O CHO H Pyrrole, which resembles phenol in reactivity towards electrophiles, undergoes reaction to give pyrrole 2-aldehyde along with 3-chloropyridine as by-product. Both products form from the same intermediates. H2O H H N N CHCl2 CHO :CCl2 H .. Cl N N CCl2 Cl -Cl .. Cl N N H .. Joint initiative of IITs and IISc – Funded by MHRD Page 8 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Example: OH OH CHO CHCl3, NaOH H2O CO2H CO2H NHBoc NHBoc M. E. Jung, T. I. Lazarova, J. Org. Chem. 1997, 62, 1553. 5.2.5 Kolbe-Schmidt Carboxylation o Phenoxide ions react with CO2 (weak electrophile) under pressure at about 100 C to give ortho substitution. OH OH CO H NaOH, CO2 2 H, H2O Mechanism The formation of ortho product predominates which may be due to the stabilizing influence of chelation on the transition state A. Na O-H O O O O OH O OH O C OH O O H OH O H A Joint initiative of IITs and IISc – Funded by MHRD Page 9 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Examples: Me Me HO Me HO Me CO2/KHCO3 OH OH 45% CF3 Me HO2C Me CF3 OH OH CO2, K2CO3 A. C. Regan, J. Chem. Soc., Chem. Commun. 1987, 520. 88% OH OH CO2H OH OH M. Hauptschein, E. A. Nodiff, A. J. Saggiomo, CO2, MeONa CO2H JACS, 1954, 76, 1051. MeO OMe MeOH MeO OMe 80% A. Fuerstner, N. Kindler, Tetrahedron Lett. 1996, 37, 7005. However, the Kolbe-Schmidt carboxylation is reversible at about 240 oC and the formation of more stable para-isomer predominates. The reaction conditions are also compatible with heterocyclic compounds. For example, pyrrole undergoes reactions at 120 oC to give pyrrole-2-carboxylic acid. 5.2.6 Gattermann-Koch Reaction The formylation of aromatic compound can be accomplished by treatment with CO and HCI in the presence of Lewis acid. The reaction is performed either under pressure or using copper(I) chloride whose role may be to aid the reaction between CO and HCl via the complex which it forms with CO. CHO CO, HCl, AlCl3 G G CuCl Joint initiative of IITs and IISc – Funded by MHRD Page 10 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Mechanism In this reaction, presumably the electrophile is the formyl cation A. AlCl O 3 AlCl3 Cl C O HC O AlCl3 H+ H Cl H G CHO CHO -AlCl4 HC O G -H G A Joint initiative of IITs and IISc – Funded by MHRD Page 11 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Problems: A. Outline synthetic routes to the following compounds. Ph O 1. 3. N O Ph CO2Me HO OH NO2 2. Me 4. O MeO N F B. What major products would you expect from the following reactions? SnCl4 1. N Cl H Cl O HO OH ZnCl 2. 2 AcOH NH2 Br2 3. o CS2, < 5 C O SO3/H2SO4 4. 160 oC O Me 5. Br2 NHAc Joint initiative of IITs and IISc – Funded by MHRD Page 12 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Text Books: R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New York, 2009. B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic Synthesis, Wiley Interscience, New Jersey, 2005. J. March, Advanced Organic Chemistry, 4th ed, Wiley Interscience, Yew York, 1992. Joint initiative of IITs and IISc – Funded by MHRD Page 13 of 26 NPTEL – Chemistry – Principles of Organic Synthesis Lecture 14 Electrophilic Aromatic Substitution II 5.2.7 Gattermann Formylation This is an alternative to the Gatterman-Koch reaction for formylation of aromatic compounds.