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Nucleophilic Substitutions of Nitroarenes and Pyridines REVIEW 2111 Nucleophilic Substitutions of Nitroarenes and Pyridines: New Insight and New Applications NucleophilicManfred Substitutions of Nitroarenes and Pyridines Schlosser,*a Renzo Ruzziconi*b a Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale (EPFL – BCh), 1015 Lausanne, Switzerland E-mail: [email protected] b Chemistry Department, University of Perugia, Via Elce di Sotto 10, 06100 Perugia, Italy E-mail: [email protected] Received 29 March 2010 To a Teacher, Example and Friend lyzed by the hydrogen bromide that was evolved. Decades Abstract: At the beginning of this article an in-depth comparison of electrophilic and nucleophilic aromatic and heterocyclic substitu- later, other researchers came across the electronic coun- tion processes examines their scopes of applicability in a new light. terpart, namely the base catalysis of the bromination or io- 2,3 In the subsequent parts, recent progress in the area of halide and hy- dination of acetone. About that time, mechanistic dride displacement from pyridines is highlighted. Particular atten- investigations began to depart in many different direc- tion is paid to the leaving group aptitudes of fluoride and chloride, tions. They culminated in the systematization of reaction to the effect of ‘passive’ substituents on the reaction rates, and to the patterns by C. K. Ingold,4 the quantification of substituent control of the relative reactivity at halogen-bearing 4- versus 2-(or effects by L. P. Hammett 5 and H. C. Brown,6 the sophis- 6-)positions. ticated concept of non-classical resonance by S. 7,8 1 Introduction Winstein and R. Huisgen’s ground-breaking achieve- 2 Electrophilic as Opposed to Nucleophilic Substitutions ments featuring kinetics and selectivity.9 3 Nitroarenes as Substrates for Nucleophilic Substitutions The manifold contributions by the Huisgen school were 4 Nucleophilic Substitution at Resonance-Disabled Positions 5 Nucleofugality Contest between Fluorine and Chlorine unique in the sense that they invariably suggested practi- 6 Substituent Effects on the Reactivity of 2-Halopyridines cal applications and thus played a significant role in the 7 ‘Silyl Trick’: Discriminating between Two Potential revival experienced by organic synthesis since the 1970s. Exchange Sites Some highlights have since become textbook corner- 8 Hydride as the Nucleofugal Leaving Group stones, notably the 1,3-dipolar [3+2] cycloadditions 9 Summing Up (‘Huisgen reactions’), [2+2] cycloadditions, valence tau- Key words: fluorine, chlorine, lithium, nitroarenes, pyridines tomerizations, diazonium salt chemistry and 1,2-didehy- droarene (‘aryne’) chemistry. The latter subject is closely related to the ‘additive’ nucleophilic (het)aromatic substi- tution. This highly important topic was covered by J. Sauer 1 Introduction and R. Huisgen in their seminal 1960 review.10 Physical Organic Chemistry or, in the continental Europe- The present article takes this previous experience for an vocabulary, Reaction Mechanisms, may be conceived granted. It intends to focus on more specific features, in as the life science equivalent of the mind-setting current particular on the regioselectivity of nucleophilic displace- known as Enlightenment (Aufklärung, Illuminismo, ments at the 2- and 4-positions and on leaving group (nu- Lumières) that shaped the thinking, feeling and literature cleofuge) effects exerted on the reaction rates. of the 18th century. Cognition relieves man from his self- Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. imposed minority (I. Kant) and molds an emancipated, responsible and tolerant human being. This became a gen- 2 Electrophilic as Opposed to Nucleophilic eral belief. Substitutions In chemistry, the rational approach to cognition has well To bring the existing options into perspective, the electro- been triggered by the curiosity of a new generation of ex- philic and nucleophilic classes of aromatic substitutions perimenters. In 1904, A. Lapworth observed how identi- will be juxtaposed. Both categories of transformations can cal amounts of bromine consecutively added to acetone be accomplished in an addition/elimination or elimina- were decolorized, hence consumed, in progressively tion/addition mode (Scheme 1). Unlike carbocations, ‘na- shorter intervals.1 Endeavoring to understand this phe- ked’ carbanions hardly ever exist in the condensed phase. nomenon, he found the keto–enol equilibrium to be cata- Thus all negatively charged formulas shown below are an idealizing fiction. The real species are carbon–metal- SYNTHESIS 2010, No. 13, pp 2111–2123xx.xx.2010 bonded compounds as we shall see later. Advanced online publication: 02.06.2010 It crucially depends on its identity, whether or not an elec- DOI: 10.1055/s-0029-1218810; Art ID: C02410SS trophile can displace an arene-bound hydrogen atom. The © Georg Thieme Verlag Stuttgart · New York 2112 M. Schlosser, R. Ruzziconi REVIEW H El X Nu El – [H ] Nu –[X ] – [El ] H – [ Nu ] H El X Nu – [Bs ] X Nu H-Bs Bs El Bs Nu H-Bs H-Bs – []X Scheme 1 The principal modes available for executing electrophilic (left) and nucleophilic (right) aromatic substitutions: ‘electrophile or nu- cleophile addition first’ (in the upper lanes) versus ‘deprotonation first’ (in the lower lanes) [EI+ = electrophile; Nu– = nucleophile; Bs– = base] NMe NMe NMe 2 2 nitronium ion being a very powerful Lewis acid, it com- 2 Br – [HBr] bines with virtually all (het)aromatic substrates, be that 2 benzene, toluene, nitrobenzene or pyridine. Immediately Br 3 Br ensuing proton loss leads to the products, for example ni- H Br trobenzene, a mixture of 2- and 4-nitrotoluene, 1,3-dini- 1 trobenzene or 3-nitropyridine. Weaker electrophiles such as the bromonium ion require electron-rich substrates for Br Br Br 3 – [HBr] 11–13 Br 2 fast reaction. N,N-Dimethylaniline (1) or 2- H 14 N NH N NH NH aminopyridine (2) meet this condition. They form the N 2 2 corresponding ‘para isomers’ as the main, if not exclu- 2 sive, products (Scheme 2). 2 If the (het)aromatic substrate is electron-poor it is advis- Scheme 2 Reaction of an electron-rich arene and an electron-rich able to invert the sequence of the two individual steps. hetarene with bromine, a moderately strong electrophile Any electron-withdrawing substituent will acidify the ad- Biographical Sketches Manfred Schlosser, born in completed his Habilitation researcher (e.g., probing Ludwigshafen on Rhine, in 1966 before moving to metal effects in structure– was awarded a Ph.D. degree the newly founded German reactivity correlations), lec- (Dr. rer. nat.) under the su- Cancer Research Center (al- turer (e.g., at the University pervision of Georg Wittig at so in Heidelberg). In 1971 of Kyoto in 2009), author the University of Heidel- he was appointed to a chair and editor (e.g., Organome- berg in 1960. After one year for organic chemistry at the tallics in Synthesis, 2nd of freelance research with University of Lausanne. Manual, 2004, 3rd Manual the European Research As- Emeritus since 2004, he in preparation). Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. sociates in Brussels, he continues to be active as a Born in Sassoferrato (Anco- Pharmacy and later at the Basilicata University in na, Italy), Renzo Ruzziconi Chemistry Department of 1994. Since 1998 he holds studied chemistry at the the University of Perugia. a chair in Perugia. His re- University of Perugia where From 1980 until 1982 he search interests cover polar he accomplished his thesis stayed at the University of organometallic reagents, work under the guidance of Lausanne as a postdoctoral metal-oxidant-promoted ra- Professor Enrico Baciocchi. fellow with Professor dical reactions, fluoro- After the ‘Laurea’ diploma Manfred Schlosser. Associ- organic compounds and (1973), he was a research ate Professor at the Perugia transition metal-catalyzed fellow of the ‘Accademia Chemistry Department stereoselective reactions. Nazionale dei Lincei’ since 1987, he was appoint- (1975) at the Faculty of ed as full professor to the Synthesis 2010, No. 13, 2111–2123 © Thieme Stuttgart · New York REVIEW Nucleophilic Substitutions of Nitroarenes and Pyridines 2113 jacent ortho site15–17 and in that way facilitate its deproto- Numerous aromatic and heterocyclic substrates have been nation by strong bases such as butyllithium, successfully subjected to regiochemically exhaustive phenyllithium, lithium diisopropylamide or lithium functionalizations. For example, 3-fluorophenol,19 3- 2,2,6,6-tetramethylpiperidide. The resulting organometal- fluoropyridine19 and 2-fluoropyridine20 (Scheme 5, acids lic intermediate 3 readily combines with virtually any 7–9) were ornamented with a carboxy group at each va- electrophile El-X and thus secures utmost product flexi- cant position. In addition, 2-, 3- and 4-(trifluorometh- bility (Scheme 3). yl)pyridines gave the corresponding ten carboxylic acids21 and several chloro- and bromo(trifluoromethyl)pyridines Li 22–24 El were converted into a variety of new derivatives. X X X Li-R El -X Cl SiMe 3 Cl Cl Cl 3 e.g ., F, Cl, Br; OMe, OCH OMe, SPh; NMe X = 2 2 N F N F N F N F R = alkyl or aryl El e.g -X = ., FClO , FN(SO Ph) ; ClCF CFCl , Cl ; BrCH CH Br, Br ; I ; 3 2 2 2 2 2 2 2 2 2 1 1 1 1 1 2 B(OMe) /H O ; LiNHOMe, R OOC-N=N-COOR , R -N ; R -CH=O, R R C=O, CO 3 2 2 3 2 Cl SiMe Li Scheme 3 Structural elaboration of heterosubstituted arenes 3 Cl Cl Cl applying the ortho-metalation/electrophilic substitution sequence Li F N N F N F F The intermediacy
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