Aromatic Substitution Reaction

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Aromatic Substitution Reaction

  1. 1. AMIT PANDITSchool Of Pharmacy DAVV, INDORE
  2. 2.  Nucleophilic aromatic substitution can follow two very different paths: the bimolecular displacement mechanism, for activated aryl halides; and the elimination-addition mechanism, which involves the remarkable intermediate called benzyne. AMIT PANDIT, SOP DAVV INDORE 2
  3. 3.  However, aryl halides do undergo nucleophilic substitution readily if the aromatic ring contains, in addition to halogen, certain other properly placed groups electron-withdrawing groups like NO2 , NO, or CN, located ortho or para to halogen. AMIT PANDIT, SOP DAVV INDORE 3
  4. 4. Addition–Elimination ReactionsIt is a two-step addition–eliminationmechanism,in which addition of the nucleophile to the arylhalide is followed by elimination of the halideleaving group. AMIT PANDIT, SOP DAVV INDORE 4
  5. 5. • Groups (such as NO2, CN, and halogen) which deactivate the ring toward electrophilic attack, encourage nucleophilic attack.• These groups are op-directors toward nucleophilic aromatic substitution. AMIT PANDIT, SOP DAVV INDORE 5
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  8. 8. the order of leaving-group reactivity in nucleophilic aromatic substitution is the opposite of that seen in aliphatic substitution. Fluoride is the most reactive leaving group in nucleophilic aromatic substitution, iodide theAMIT PANDIT, SOP DAVV INDORE least reactive. 8
  9. 9.  Kinetics: As the observation of second-order kinetics requires, the rate-determining step involves both the aryl halide and the nucleophile. Rate-enhancing effect of the nitro group. The high reactivity of aryl fluorides arises because fluorine is the most electronegative of the halogens, and its greater ability to attract electrons increases the rate of formation of the cyclohexadienyl anion intermediate in the first step of the mechanism. AMIT PANDIT, SOP DAVV INDORE 9
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  13. 13.  Halides derived from certain heterocyclic aromatic compounds are often quite reactive toward nucleophiles. 2-Chloropyridine, for example, reacts with sodium methoxide some 230 million times faster than chlorobenzene at 50°C.•In contrast to chlorobenzene, where the negative charge of theintermediatemust be borne by carbon, the anionic intermediate in the case of 2-chloropyridine has its negative charge on nitrogen.•Since nitrogen is more electronegative than carbon, the intermediate ismore stable and is formed faster than the one from chlorobenzene. AMIT PANDIT, SOP DAVV INDORE 13
  14. 14. Energy diagram AMIT PANDIT, SOP DAVV INDORE 14
  15. 15. THE ELIMINATION–ADDITION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION: BENZYNE Very strong bases such as sodium or potassium amide react readily with aryl halides, even those without electron-withdrawing substituents, to give products corresponding to nucleophilic substitution of halide by the base. AMIT PANDIT, SOP DAVV INDORE 15
  16. 16.  o-bromotoluene gave a mixture of o- methylaniline and m-methylaniline; p-bromotoluene gave m-methylaniline and p- methylaniline. AMIT PANDIT, SOP DAVV INDORE 16
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  18. 18. Step 1: Elimination stage. Amide ion is a very strongbase and brings about thedehydrohalogenation of chlorobenzene by abstracting aproton from the carbon adjacent to the one that bears theleaving group. The product of this step is an unstableintermediate called benzyne. AMIT PANDIT, SOP DAVV INDORE 18
  19. 19. Step 2: Beginning of addition phase.Amide ion acts as a nucleophile and adds to one of thecarbons of the triple bond. The product of this step is acarbanion.Step 3: Completion of addition phase.The aryl anion abstracts a proton from the ammonia used asthe solvent in the reaction. AMIT PANDIT, SOP DAVV INDORE 19
  20. 20.  The intermediate formed in this step contains a triple bond in an aromatic ring and is called benzyne. Aromatic compounds related to benzyne are known as arynes. The triple bond in benzyne is somewhat different from the usual triple bond of an alkyne, In benzyne one of the pi components of the triple bond is part of the delocalized pi system of the aromatic ring. The second pi component results from overlapping sp2-hybridized orbitals (not p-p overlap), lies in the plane of the ring, and does not interact with the aromatic pi system This pi bond is relatively weak AMIT PANDIT, SOP DAVV INDORE 20
  21. 21.  Because the ring prevents linearity of the C-C≡C-C unit and pi bonding in that unit is weak, benzyne is strained and highly reactive.The sp2 orbitals in theplane of the ring inbenzyne are not The electrostatic potentialproperly aligned for map shows a region ofgood overlap, and pi high electron densitybonding is weak. associated with the “triple bond.” AMIT PANDIT, SOP DAVV INDORE 21
  22. 22. Although benzyne is too unstable to be isolated, evidence that it is formedcan beobtained by a trapping experiment. When furan is added to a reaction thatforms a benzyne intermediate, furan traps the benzyne intermediate byreacting with it in aDiels–Alder reaction. The product of the Diels–Alder reaction can beisolated. AMIT PANDIT, SOP DAVV INDORE 22
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