NPTEL – Chemistry – Principles of Organic Synthesis

Lecture 15 Aromatic Nucleophilic Substitution

6.1 Principles

There are four principal mechanisms for aromatic nucleophilic substitution which are similar to that of aliphatic nucleophilic substitution.

6.1.1 SNAr Mechanism The introduction of electron withdrawing group (EWG) on the aromatic nucleus makes the system susceptible to nucleophilic attack. The mechanism is similar to that of electrophilic substitution except that an anion rather than a cation intermediate is involved. The nucleophile adds to the aromatic ring to afford a delocalized anion from which the leaving group (LG) is eliminated.

LG Nu LG Nu LG Nu LG Nu Nu -LG slow fast EWG EWG EWG EWG EWG

The delocalization of the negative charge can occur only when the nucleophile adds to the ortho or para position with respect to the EWG. Addition to meta position gives an adduct stabilized by the inductive effect, but not the mesomeric effect. Therefore, towards nucleophiles, EWG are activating and ortho, para-orienting and, in contrast, electron donating group (EDG) deactivating and meta directing. These principles are opposite of those that apply to electrophilic substitution.

Nu LG

EWG

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6.1.2 SN1 Mechanism

This mechanism operates in the reaction of diazonium salts with nucleophiles. The driving force resides in the strength of the bonding in the nitrogen molecule that makes it a particularly good leaving group.

N N -N OH2 OH 2 H2O -H slow fast

6.1.3 Benzyne Mechanism

Aryl halides that have no activating groups proceed reactions with strong base to give benzyne intermediate which undergoes reaction with nucleophile to give a mixture of regioisomers.

14

NH2 14 Cl 14 NH2 NH3 H NH2 14

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6.1.4 SRN1 Mechanism

SRN1 reactions takes place via free-radical intermediate and have wide substrate scope. Besides initiation by solvated electrons, they are also initiated photochemically, electrochemically and even thermally.

Initiaiton

I I _. electron -I . donor

Termination I _. I _. . NH2 NH2 NH2 +

6.2 Displacement of Hydride Ion

Benzene having EWG such as nitro group reacts with the most reactive nucleophiles such as amide or amide ion by displacement of hydride ion.

O2N O2N O2N K Ph2N -KH NPh2 fast slow NPh2 H

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6.3 Displacement of Other Anions

6.3.1 Halides

The reactivity of halide increases with increase in number of electron withdrawing groups (Scheme 1). For examples, the reactivity of chlorobenzene having nitro groups towards aqueous NaHCO3 follows:

Cl OH NO2 aq NaHCO NO2 3 Cl OH 0 135 C O2N NO2 O2N NO2 aq NaHCO3

Cl 0 OH 35 C NO2 NO2 NO2 NO2 aq NaHCO3 100 0C NO2 NO2 However, m-nitrochlorobenzene does not undergo similar reaction:

Cl aq NaHCO3 No Reaction 135 0C NO2

Mechanism

Cl HO Cl HO Cl HO Cl OH OH -Cl

NO N N N NO 2 O O O O O O 2

Cl OH Cl HO Cl HO O HO Cl O2N O2N -Cl OH O2N N O

NO2

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6.3.2 Oxyanions

Aryl ethers bearing EWG in ortho and para positions proceed hydrolysis to afford phenols.

OMe HO OMe OH OH -OMe

NO2 N NO2 O O

6.3.3 Sulfite Ion

Aryl sulphonic acid can be converted, through their salts, to phenols, by alkali fusion. In spite of the extreme conditions, the reaction gives fairly good yields, except when the substrate contains other groups that are attacked by the alkali at the fusion temperature. Milder conditions can be used when the substrate contains activating groups, but the presence of deactivating groups hinders the reaction. The mechanism is obscured but the benzyne intermediate has been ruled out by the finding that the cine substitution does not occur. For example, sodium p-toluenesulfonate with fused sodium hydroxide gives p- cresol at 250-300 oC.

SO3Na OH

NaOH

-Na2SO3 Me Me p-cresol

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6.3.4 Nitrogen Anions

Nitrite ion could be displaced if other nitro groups are present to activate the aromatic nucleus.

OH o OH, 100 C NO2

NO2 NO2 OH

o NO2 NH3/EtOH, 100 C

6.4 Substitution via Benzynes

Halobenzenes (except fluorobenzene) directly react with strong base such as sodamide to give benzyne that can be reacted with any nucleophile present the reaction medium. For example, the addition of malonic ester to liquid ammonia having amide ion afford the corresponding enolate that reacts with benzyne as it is produced.

CH(CO Me) CH(CO2Me)2 Br 2 2

CH2(CO2Me) NH3 NH2

-HBr -NH2

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Furthermore, ortho substituted benzenes from which two stable molecules can be generated by elimination afford benzynes on thermolysis.

N N heat + N + CO O 2 2

O N N heat S + N2 + SO2 O O

If the nucleophile is not present in the reaction medium, benzyne dimerizes to give biphenylene.

2

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6.5.1 The SRN1 Reaction

Unactivated aryl halides proceed nucleophilic substitution with typically enolates, amide ion and thiol anion via a chain reaction involving anion radicals in that the initiation step is an electron transfer. The first two steps are similar to those in SN1 reaction which led to the designation SRNI (R for radical).

Initiaiton X X_. electron donor Propagation _. X . + X

_. . Nu Nu

_. X Nu _. Nu X +

The initiation of the reaction is generally either by solvated electron (sodium in liquid ammonia) or with photochemical excitation in that the nucleophile is the electron donar. For examples,

S I S + I light

I O + I light O

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OEt O NH OEt P OEt KNH2/NH3 2 KO P OEt O + O

6.5.2 Bucherer Reaction Some phenols proceed reaction with aqueous ammonium nitrite to give aromatic amines. The reactions are believed to take place via sulfite adduct of the keto-tautomer of phenol. Similarly, certain aromatic amines can be converted into phenols.

OH NH2 Na2SO3, NH3

H2O

NH2 OH Na2SO3, H2O

KOH

Proposed Mechanism

.. H H H O O.. -H H O 2- O SO3 H keto-enol tautomerism

SO3 SO3 H H O OH NH - NH :NH3 proton -H2O -HSO3 NH3 NH2 transfer H

SO3 SO3 SO3

NH2

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Examples:

OH (NH4)2SO3, H2O NH2 OH OH NH3

91% K. Korber, W. Tang, X. Hu, Tetrahedron Lett. 2002, 43, 7163.

Na2SO3 H2N HO NH3, H2O 65% L. F. Fieser, E. B. Hershberg, L. Long, Jr., M. S. Newman, J. Am. Chem. Soc.1937, 59, 475. ,

i. Na2SO3, EtOH, H2O ii. KOH

NH2 OH R. S. Coleman, M. A. Mortensen, Tetrahedron Lett. 2003, 44, 1215.

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Problems: Provide the major products with mechanistic rationale for the following reactions.

N 2 Heat 1.

CO2

heat 2. + O

OH

Na2SO3, H2O, NH3 3.

Me

Cl NaNH2/NH3 4.

NO2 OH 5.

F

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.

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