Aromatic Substitution Reaction

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NUCLEOPHILIC AROMATIC

SUBSTITUTION

AMIT PANDIT

School Of Pharmacy DAVV, INDORE

AMIT PANDIT, SOP DAVV INDORE 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.

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.

Addition–Elimination Reactions

It is a two-step addition–elimination mechanism,in which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group.

• 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.

the order of leaving-group reactivity in nucleophilic aromatic substitution is theopposite of that seen in aliphatic substitution. Fluoride is the most reactive leaving groupin nucleophilic aromatic substitution, iodide the least reactive.

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.

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 the intermediatemust 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 is more stable and is formed faster than the one from chlorobenzene.

Energy diagram

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.

o-bromotoluene gave a mixture of o-methylaniline and m-methylaniline;

p-bromotoluene gave m-methylaniline and p-methylaniline.

Step 1: Elimination stage. Amide ion is a very strong base and brings about thedehydrohalogenation of chlorobenzene by abstracting a proton from the carbon adjacent to the one that bears the leaving group. The product of this step is an unstable intermediate called benzyne.

Step 2: Beginning of addition phase. Amide ion acts as a nucleophile and adds to one of the carbons of the triple bond. The product of this step is a carbanion.

Step 3: Completion of addition phase. The aryl anion abstracts a proton from the ammonia used as the solvent in the reaction.

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

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 the plane of the ring in benzyne are not properly aligned for good overlap, and pi bonding is weak.

The electrostatic potential map shows a region of high electron density associated with the “triple bond.”

Although benzyne is too unstable to be isolated, evidence that it is formed can beobtained by a trapping experiment. When furan is added to a reaction that forms a benzyne intermediate, furan traps the benzyne intermediate by reacting with it in aDiels–Alder reaction. The product of the Diels–Alder reaction can beisolated.

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Aromatic Substitution Reaction

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