Isoquinoline

Isoquinoline, also known as benzo[c]pyridine or 2-benzanine, is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline derivatives. Isoquinoline is the structural backbone in naturally occurring alkaloids including papaverine and morphine. The isoquinoline ring in these natural compound derives from the aromatic amino acid tyrosine.

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Properties

Isoquinoline is a colorless hygroscopic liquid at room temperature with a penetrating, unpleasant odor. Impure samples can appear brownish, as is typical for nitrogen heterocycles. It crystallizes platelets that have a low solubility in water but dissolve well in ethanol, acetone, diethyl ether, carbon disulfide, and other common organic solvents. It is also soluble in dilute acids as the protonated derivative.

Being an analog of pyridine, isoquinoline is a weak base, with a pK_b of 8.6. It protonates to form salts upon treatment with strong acids, such as HCl. It forms adducts with Lewis acids, such as BF₃.

Production

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

Although isoquinoline derivatives can be synthesized by several methods, relatively few direct methods deliver the unsubstituted isoquinoline. The Pomeranz-Fritsch reaction provides an efficient method for the preparation of isoquinoline:

• The Pomeranz-Fritsch reaction uses a benzaldehyde and aminoacetoaldehyde diethyl acetal, which in an acid medium react to form isoquinoline. Alternatively, benzylamine and a glyoxal acetal can be used, to produce the same result.

The following methods are useful for the preparation of various isoquinoline derivatives:

• In the Bischler-Napieralski reaction an β-phenylethylamine is acylated and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or phosphorus pentoxide. The resulting 1-substituted-3,4-dihydroisoquinoline can then be dehydrogenated using palladium. The following Bischler-Napieralski reaction produces papaverine.

• The Pictet-Gams and Pictet-Spengler syntheses are both variations on the Bischler-Napieralski reaction. The differences are as follows:
• The Pictet-Gams reaction avoids the final dehydrogenation step of the Bischler-Napieralski reaction by constructing a β-phenylethylamine with a hydroxy group in the side chain. This reaction results in a 1-alkyl-isoquinoline.
• The Pictet-Spengler reaction combines a β-phenylethylamine and an aldehyde in an acid medium, which cyclizes the imine in a reaction of the Mannich type. This produces the tetrahydroisoquinoline instead of the dihydroisoquinoline.
• Intramolecular aza Wittig reactions also afford isoquinolines.

Applications of derivatives

Isoquinolines find many applicatons, including (but not limited to):

• anesthetics; dimethisoquin is one example (shown below).

• antihypertension agents, such as quinapril, quinapirilat, and debrisoquine (all derived from 1,2,3,4-tetrahydroisoquinoline).
• antifungal agents, such as 2,2'Hexadecamethylenediisoquinolinium dichloride, which is also used as a topical antiseptic. This derivative, shown below, is prepared by N-alkylation of isoquinoline with the appropriate dihalide.

• disinfectants, like N-laurylisoquinolinium bromide (shown below), which is prepared by simple N-alkylation of isoquinoline.

• vasodilators, a well-known example, papaverine, shown below.

Bisbenzylisoquinolinium compounds are compounds similar in structure to tubocurarine. They have two isoquinolinium structures, linked by a carbon chain, containing two ester linkages.

Isoquinolines and the human body

Parkinson's disease, a slowly progressing movement disorder, is thought to be caused by certain neurotoxins. A neurotoxin called MPTP (1[N]-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the precursor to MPP+, was found and linked to Parkinson's disease in the 1980's. The active neurotoxins destroy dopaminergic neurons, leading to parkinsonism and Parkinson's disease. Several tetrahydroisoquinoline derivatives have been found to have the same neurochemical properties as MPTP. These derivatives may act as neurotoxin precursors to active neurotoxins.

Other uses

Isoquinolines are used in the manufacture of dyes, paints, insecticides and antifungals. It is also used as a solvent for the extraction of resins an terpenes, and as a corrosion inhibitor.

See also

• Quinoline, an analog with the nitrogen atom in position 1.
• Pyridine, an analog without the fused benzene ring.
• Naphthalene, an analog without the nitrogen atom.
• Simple aromatic rings

References