NPTEL – Chemistry – Principles of Organic Synthesis

Lecture 16 Aromatic Diazonium Salts

7.1.1 The Formation of Diazonium Salts

Addition of aqueous solution of NaNO2 to a solution of amine hydrochloride in presence of excess of HCl which is cooled by an ice-bath such that the temperature of the reaction remains below 5 ◦C diazotization of primary aromatic amine occurs.

NH 2 N2 Cl

NaNO2 HCl,< 5 oC

Mechanism

H -OH2 HO NO H2O NO NO

N HN NO HN NH2 H2N NO OH NO+ -H H

N N N N N N OH OH 2 -H O -H H 2

If electron withdrawing groups are attached to aromatic nucleus then the aromatic amines are difficult to diazotize because the nucleophilicity of the amino-nitrogen is reduced by the partial withdrawal of the unshared electron pair into the nucleus.

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NH2 NH2

N N O O O O

7.1.2 The Reaction of Diazonium Salts

7.1.2.1 Reactions of nucleophiles at nitrogen

Nucleophiles react with diazonium ions to give covalent diazo-compounds. For example, phenol via phenoxide ion couples with diazonium salt at pH 9-10 to afford para- azophenols in good yield.

N N Ar H tautomerizes O O HO N N N N Ar Ar

7.1.2.2 SN1 Reaction

Diazonium salts decompose on warming into nitrogen and aryl cation which is highly reactive and could be attacked by any nucleophile in its vicinity.

N2 OH -N OH2 2 H2O -H warm

7.1.2.3 One Electron Reductions

Diazonium ions could be reduced by single electron transfer to give an aryl radical and nitrogen. Copper(I) is frequently used for this purpose and the aryl radical is highly reactive capable of abstracting a ligand from the transition metal ion or a hydrogen atom from a covalent bond.

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N Cl Cl 2 CuCl . -CuCl + Cl Cu Cl -N2

7.2 Reactions in which Nitrogen Eliminated

7.2.1 Replacement by Hydroxyl

Diazonium salt on warming in water gives phenol via SN1 mechanism. The reaction is generally performed in acidic solution to preserve phenol in its unionized form.

N2 Cl OH H2O/H

warm

7.2.2 Replacement by Halogen

7.2.2.1 Schiemann Reaction

Treatment of an aqueous solution of diazonium salt with fluoroboric acid under cold conditions gives diazonium fluoroborate as precipitate, which could be dried and gently heated to afford the flurobenzene by decomposition. The reaction involves SN1 mechanism.

N N N Cl N BF4 F Aq. MBF4, cold dry ppt F -BF3 F B F heat M = Na, H, NH4 F - MCl salt precipitates BF4

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Examples:

F NH2 NaNO2, HCl

HPF6 S CO2Me CO2Me S 47%

A. Kiryanov, A. Seed, P. Sampson, Tetrahedron Lett. 2001, 42, 8797.

OH OH NaNO2 OH N NH2 F B N F OH F. Dolle, L. Dolei, H. Valette, F. Hinnen, F. Vaufrey, H. Guenther, C. Fuseasu, C. Coulon, M. Buttalender, C. Crouzel, J. Med. Chem. 1999, 42, 2251.

Me Me NH F 2 NaNO2, H HBF Me 4 Me Br Br H. Hart, J. F. Janssen, J. Org. Chem. 1970, 35, 3637.

7.2.2.2 Sandmeyer Reaction This method provides an effective route for the preparation of aromatic bromides and chlorides. Addition of cold aqueous solution of diazonium chloride to a solution of CuCl in HCl medium gives a sparingly soluble complex which is separated and heated to give aryl chloride or bromide by decomposition.

NH2 N2 X X HONO CuX . -N2 + X-Cu-X + N2 HX -CuX X = Br, Cl, CN

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Examples:

N N NaNO2, HCl NH2 Cl Me S CuSO4 Me S 53%

N. Zou, J.-F. Liu, B. Jiang, J. Combin. Chem. 2003, 5, 754.

CN NH2 HONO

Me CuCN Me

H. T. Clarke, R. R. Reed, Org. Synth. 1941, 1, 514.

F NH 2 F Br HNO2, CuBr N HBr N O O 65% B. Mallesham, B. M. Rajesh, P. R. Reddy, D. Srinivas, S. Trehan, Org. Lett. 2003, 5, 7963.

7.2.3 Replacement by Aromatic Carbon A number of methods lead to arylation of aromatic carbon by diazonium salts. 7.2.3.1 Pschorr Reaction This reaction describes the synthesis of phenanthrene and its derivatives via diazotation followed by intramoecular cyclization using copper powder.

G G HNO2, H Cu(0) NH2

G = CH=CH, CH2-CH2, CO, NH, CH2, others

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Mechanism The reactive intermediate depends on the reaction conditions. Under acidic conditions, the diazonium salt is believed to decompose into aryl cation and nitrogen. The aryl cation is highly reactive and attacked by the aryl ring that leads to cyclization. On the other hand, under neutral and basic conditions, the diazonium salt is reduced by single electron transfer to give aryl radical which proceeds reaction intramolecularly with benzene ring to give the cyclized product.

In acid solution:

G G G -N2

N2 H H -HH

G

Cu(0) + H In neutral or basic solution: . Cu(I) + H G G G . Cu(0) . N -N 2 2 + H Cu(I)

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Examples: O O

NaNO2, H2SO4

Cu-Sn, Na SO Me2N NMe2 2 4 65% Me2N NH2 NMe2

S. G. R. Guinot, J. D. Hepworth, M. Wainwright, J. Chem. Res. Synop. 1997, 183,. O O Bn Bn HNO2 N N N N

H2N

P. Tapolcsanyi, B. U. W. Maes, K. Monsieurs, G. L. F. Lemiere, Z. Riedl, G. Hajos, B. Van den Driessche, R. A. Dommisse, P. Maytyus, Tetrahedron 2003, 59, 5919.

7.2.3.2 Reduction by Copper(I) Ammonium Ion Diazotized anthranilic acid with copper(I) ammonium hydroxide gives diphenic acid in 90% yield.

CO2H CO2H CO2H N2 Cu(NH3)2OH 2

The process probably takes place via one-electron reduction of the diazonium ion followed by dimerization of the resulting aryl radicals. 7.3 Reactions in which Nitrogen is Retained The reaction of the terminal nitrogen of a diazonium salt with nucleophile affords a covalent azo-compound. 7.3.1 Reduction to Arylhyrazones The reduction of aromatic diazonium salts can be accomplished with sodium sulfite or

SnCl2 or electrolysis to provide arylhydrazines. In case of sodium sulfite based reduction, the diazonium ion with a sulfite anion may give a covalent azo-sulfite that, having a double bond conjugated to an electron-accepting group, may add to a second nucleophilic sulfite ion which on hydrolysis provides the hydrazine.

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O S N N O O O N O O O N S O O N S N S O N N O O O SO3 SO3 S O O

H H O 2H O N S NH2 N -2SO3 N O H SO3

7.3.2 Coupling Reactions Diazonium ions are weak electrophiles, however, they undergo coupling with activated aromatic nuclei such as aryl amines, phenols and aromatic heterocyclic compounds. For example, N,N-dimethylaniline reacts with diazonium ion almost at the para-position. However, the careful control of the pH of the reaction medium is necessary for the success of the process.

.. N N-Ar H -H Me N Me N N Me2N 2 N N 2 N Ar Ar

In case of primary and secondary aromatic amines, the reaction preferentially takes place at the nitrogen atoms of the diazonium ions. For example, aniline adds to the aromatic diazonium salt to give diazoaminobenzene.

.. N N-Ph NH2 NH N -H N

Diazoaminobenzene

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7.4 The Synthetic Value of Diazo-Coupling 7.4.1 Dye-stuffs

Aromatic azo-compounds are coloured. Several of those compounds synthesized by the diazo-coupling are employed as dye-stuffs. These compounds can be classified into three groups.

 First group of azo-compounds are neutral which are used as azoic combination (or ingrain) dyes. An example is para red which is prepared by coupling of 2-napthol with p-nitrobenzenediazonium salt.

NO2

N N O- OH + N N NO2

Para red

 The second group of azo-compounds posses either a sulfonic acid group or an amino group which are generally adsorbed directly on the fiber from aqueous solution. Examples are orange II (an acidic dye) and Bismarck brown R (a basic dye).

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SO3H

N N O- OH - + N N SO3 orange II (acidic dye)

H N Me 2 N N Me

Me Me NH2 + NH N 2 2 -2H N 2 + N

H2N NH2 NH2 N2 Me Bismarck brown R

 Azo-compounds that contain chelating groups to bind with a metal ions such as Al(III) are used a mordant dyes. An example is alizarin yellow R, which contains phenolic and carboxyl chelating groups.

Al OH O O CO2H O OH N2

CO2H Al(III) N + N N N

NO2

NO NO2 2 alizarin yellow R

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7.4.2 Indicators Azo-compounds that contain both an acidic and a basic group can be utilized as indicators since the colours of the conjugate acid and the conjugate base are different. Examples are methyl orange and methyl red which are prepared by coupling of dimethylaniline with diazotized sulfanilic acid and diazotized anthranilic acid, respectively.

HO3S CO2H N N N N

NMe2 Methyl red NMe2 Methyl orange

7.4.3 Synthesis of Amines Azo-compounds are susceptible to hydrogenolysis to give amines. For example, the coupling of 1-naphthol with benzenediazonium chloride gives azo-compound which could be reduced to 4-amino-1-naphthol in the presence of dithionite.

O- OH OH PhN2 Na2S2O4 + PhNH2 N N NH2 Ph

7.4.4 Synthesis of Quinones The ortho and para diamines and aminophenols readily oxidize to give quinones. Both classes of compounds can be readily prepared by diazo-coupling followed by reduction.

Ph N O N NH2 - + O O PhN2 OH OH FeCl /O Na2S2O4 3 2

Quinone

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Problems: A. How would you obtain the following compounds?

CO2H HO3S N N N N

NMe2 NMe2

O OH

N N O

B. Complete the following reactions.

O Me CuI 1.

N2 Cl

CHO Ac2O CO2H 2. +

O NaOAc 3. CO2Et

PhN2 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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