Isoquinoline is an individual chemical specimenâÂÂa heterocyclic aromatic organic compoundâÂÂas well as the name of a family of many thousands of natural plant alkaloids, any one of which might be referred to as "an isoquinoline". 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. 1-Benzylisoquinoline is the structural backbone in many naturally occurring alkaloids such as papaverine. The isoquinoline ring in these natural compound derives from the aromatic amino acid tyrosine.
Isoquinoline is a colorless hygroscopic liquid at temperatures above its melting point with a penetrating, unpleasant odor. Impure samples can appear brownish, as is typical for nitrogen heterocycles. It crystallizes in form of platelets that have a low solubility in water but dissolve well in 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<sub>a</sub> of 5.14. It protonates to form salts upon treatment with strong acids, such as HCl. It forms adducts with Lewis acids, such as BF<sub>3</sub>.
Isoquinoline 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 sulfate.
Although isoquinoline derivatives can be synthesized by several methods, relatively few direct methods deliver the unsubstituted isoquinoline. The PomeranzâÂÂFritsch reaction provides an efficient method for the preparation of isoquinoline. This 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 using the Schlittler-Müller modification.
Several other methods are useful for the preparation of various isoquinoline derivatives.
In the BischlerâÂÂNapieralski reaction an ò-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 BischlerâÂÂNapieralski reaction produces papaverine.
The PictetâÂÂGams reaction and the PictetâÂÂSpengler reaction are both variations on the BischlerâÂÂNapieralski reaction. A PictetâÂÂGams reaction works similarly to the BischlerâÂÂNapieralski reaction; the only difference being that an additional hydroxy group in the reactant provides a site for dehydration under the same reaction conditions as the cyclization to give the isoquinoline rather than requiring a separate reaction to convert a dihydroisoquinoline intermediate.
In a PictetâÂÂSpengler reaction, a condensation of a ò-phenylethylamine and an aldehyde forms an imine, which undergoes a cyclization to form a tetrahydroisoquinoline instead of the dihydroisoquinoline. In enzymology, the (S)-norcoclaurine synthase () is an enzyme that catalyzes a biological Pictect-Spengler synthesis:
Intramolecular aza Wittig reactions also afford isoquinolines.
Isoquinolines find applications in medicinal chemistry.
Other:
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<sup>+</sup>, was found and linked to Parkinson's disease in the 1980s. 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 precursors to active neurotoxins.
Isoquinolines are used in the manufacture of dyes, paints, insecticides and fungicides. It is also used as a solvent for the liquidâÂÂliquid extraction of resins and terpenes, and as a corrosion inhibitor.