Synthesis and Reactions of Iso-quinolines, Chemistry tutorial


Isoquinoline is the heterocyclic aromatic organic compound. This is a structural isomer of quinoline. Isoquinoline and quinoline are Benzopyridines, which are composed of a benzene ring fused to the pyridine ring. The nitrogen in isoquinoline is on position 2 whereas the nitrogen is on position 1 in quinoline (Figure shown below). In a broader sense, the word isoquinoline is employed to make reference to the isoquinoline derivatives. 1-Benzylisoquinoline is the structural back bone in naturally taking place alkaloids comprising papaverine and morphine. The isoquinoline ring in this natural compound derives from the aromatic amino acid tyrosine.

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Fig: Structures of Quinoline and Isoquinoline

General Physical and Chemical Properties of Isoquinoline:

The Isoquinoline is a colourless hygroscopic liquid at room temperature having a penetrating, unpleasant odor. Impure samples can appear brownish, as is typical for the nitrogen heterocycles. It crystallizes to platelets and has a low solubility in water however dissolve well in ethanol, acetone, diethyl ether, carbon disulphide, and other common organic solvents. This is as well soluble in the dilute acids as the protonated derivative.

Being the analog of pyridine, isoquinoline is a weak base, having a pKb of 5.1. It protonates upon treatment by strong acids, like HCl to form salts. This form adducts with Lewis acids, such as BF3.

Isoquinoline is closely associated to quinoline in physical and chemical properties.  Modifications are merely as a result of the various position of the nitrogen atom relative to the carbocyclic ring.

Reactions with Electrophiles:

Isoquinoline such as quinoline is protonated and alkylated at the nitrogen atom and experiences electrophilic substitution in the benzene ring. Sulphonation by oleum provides mostly the 5-sulphonic acid, however fuming nitric acid and concentrated sulphuric acid at 0°C generate a 1:1 mixture of 5- and 8-nitroisoquinolines. Bromination in the presence of aluminium trichloride at 75°C provides a 78% result of 5-bromoisoquinoline (figure shown below).

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Fig: Reactions of Isoquinolines with Electrophiles

Reduction and Reactions with Nucleophiles:

Nucleophilic addition occurs at C-1 and this is considerably improved if the reaction is taken out on an isoquinolinium salt. Reduction by lithium aluminium hydride {tetrahydroaluminate(III)} in THF (tetrahydrofuran) for illustration provides a 1,2-dihydroisoquinoline. Such products behave as cyclic enamines and if isoquinolium salts are reacted by sodium borohydride [tetrahydroboronate(III)] in aqueous ethanol, further reduction to 1,2,3,4-tetrahydroisoquinolines is effected via protonation at C-4 and then hydride transfer from the reagent to the C-3 (figure shown below).

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Fig: Reduction of Isoquinoline

The cyanide anion adds to C-1 in 2-benzoylisoquinolinium salts in water/DCM (dichloromethane), making Reissert compounds; then, just similar to their quinoline counterparts, the adducts can be deprotonated through a base by the loss of the N-substituent and the formation of a 1-cyanoisoquinoline (figure shown below).

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Fig: Reaction of Isoquinoline with Nucleophiles

Synthesis of Isoquinolines:

Isoquinoline was first isolated from the coal tar in the year 1885 by Hoogewerf and van Dorp. They isolated it via fractional crystallization of the acid sulphate. Weissgerber developed a more rapid route in the year 1914 by selective extraction of coal tar; exploiting the fact that isoquinoline is more basic as compare to quinoline. Isoquinoline can then be isolated from the mixture via fractional crystallization of the acid sulphate.  

However isoquinoline derivatives can be synthesized by various methods, comparatively few direct methods deliver the unsubstituted isoquinoline. The Pomeranz-Fritsch reaction gives an efficient process for the preparation of isoquinoline.

The biological properties of numerous derivatives have ensured the growth of a number of syntheses providing access to all kinds of isoquinolines, both natural and man-made. Three significant routes are the Bischer-Napieralski, Picted-splenger and Pomeranz-Fritsch methods.

Bischler-Napieralski Synthesis:

This process is very helpful for the construction of 1-substituted 3,4-dihydroisoquinolines, which if essential can be oxidized to isoquinolines. A β-phenylethylamine (1-amino-2-phenylethane) is the starting material, and this is generally preformed via reaction of an aromatic aldehyde with nitromethane in the presence of sodium methoxide, and allowing adduct to remove methanol and provide a β-nitrosytrene (1-nitro-2-phenylethene). This product is then reduced to β-phenylethylamine generally by the action of lithium aluminium hydride. Once made, the β-phenylethylamine is reacted by an acyl chloride and a base to provide the corresponding amide (R1 = H) and then this is cyclised to a 3,4-dihydroisoquinoline by treatment with either phosphorus pentoxide or phosphorus oxychloride. Lastly, aromatization is accomplished through heating the 3,4-dihydroisoquinoline over palladium on charcoal (figure shown below).

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Fig: Synthesis of β-phenylethylamine

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Fig: Bischler-Napieralski Synthesis of Isoquinoline

On the other hand, a β-methoxy-β-phenylethylamine can be employed to circumvent the oxidation step after the conventional Bischler-Naperialski cyclisation. Here, whenever treated by the phosphorus reagent the amide (R1 = OMe) experiences both cyclisation and the removal of methanol to provide the isoquinoline (R=H) directly. This is termed as the Pictet-Gams modification of the Bischer-Napieralski synthesis.

Picket-Spengler Synthesis:

A β-phenylethylamine is treated by an aldehyde in the presence of dilute acid; ring closure takes place by a reaction of Mannish type reaction and the tetrahydroisoquinoline formed is dehydrogenated on the palladium (figure shown below).

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Fig: Picket-Spengler Synthesis

The Pomeranz-Fritsch Synthesis:

As both the two routes depend on a cyclisation of the benzene ring to what becomes C-1 of the heterocycle, the key step in the Pomeranz-Fritsch synthesis is the formation of a bond to C-4. A benzaldehyde is the starting material, and it is reacted by an amino-acetaldehyde dialkyl acetal to form an imine that is then cyclised directly under relatively severe acidic conditions (example: conc. H2SO4 at 100°C) to provide the isoquinoline. However the Pomeranz-Fritsch ring-closure conditions permit the cyclisation of unsubstituted imines, the reaction is accelerated greatly whenever electron-donating groups are present in the benzene ring (figure shown below).

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Fig: The Pomeranz-Fritsch Synthesis

Via slight modification, the Pomeranz-Fritsch synthesis can be made specifically helpful for the preparation of 1,2-dihydroisoquinolines. The imine is first reduced by sodium borohydride in 98% ethanol to the corresponding benzylamine, previous to cyclisation, by treatment by 6M hydrochloric acid. Whenever electron-donating groups (like a methoxyl) are present in the aromatic unit of the benzylamine, the ring closure step takes place at room temperature to give a 1,2-dihydroisoquinoline. As 1,2-dihydroisoquinolines are unstable in air, it is customary to carry out the reaction under the atmosphere of oxygen-free nitrogen.

The merit of the modified Pomeranz-Fritsch synthesis is that the 1,2-dihydroisoquinolinium salts can be reacted in situ by electrophiles, resulting 3,4-dihydroisoquinolinium salts that react by nucleophiles at C-3. Such a 'single pot' method can be employed to form complex 1,2,3,4-tetrahydroisoquinolines.

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