Isoquinoline

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Isoquinoline
Isoquinoline numbered.svg
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Names
Preferred IUPAC name
Isoquinoline [1]
Other names
Benzo[c]pyridine
2-benzazine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.003.947 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 204-341-8
PubChem CID
UNII
  • InChI=1S/C9H7N/c1-2-4-9-7-10-6-5-8(9)3-1/h1-7H Yes check.svgY
    Key: AWJUIBRHMBBTKR-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C9H7N/c1-2-4-9-7-10-6-5-8(9)3-1/h1-7H
    Key: AWJUIBRHMBBTKR-UHFFFAOYAX
  • C1(C=NC=C2)=C2C=CC=C1
Properties
C9H7N
Molar mass 129.162 g·mol−1
AppearanceColorless oily liquid; hygroscopic platelets when solid
Density 1.099 g/cm3
Melting point 26–28 °C (79–82 °F; 299–301 K)
Boiling point 242 °C (468 °F; 515 K)
Acidity (pKa)pKBH+ = 5.14 [2]
−83.9·10−6 cm3/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Isoquinoline is an individual chemical specimen - a heterocyclic aromatic organic compound - as 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. [3] [4] [5] [6] [7] [8]

Contents

Properties

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 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 pKa of 5.14. [2] It protonates to form salts upon treatment with strong acids, such as HCl. It forms adducts with Lewis acids, such as BF3.

Production

Isoquinoline was first isolated from coal tar in 1885 by Hoogewerf and van Dorp. [9] 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 Pomeranz–Fritsch 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. [10] Alternatively, benzylamine and a glyoxal acetal can be used, to produce the same result using the Schlittler-Müller modification. [11]

Pomeranz-Fritsch einfach.svg

Several other 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.

Bischler-Naperialski reaction to papaverine.svg

The Pictet–Gams reaction and the Pictet–Spengler reaction are both variations on the Bischler–Napieralski reaction. A Pictet–Gams reaction works similarly to the Bischler–Napieralski 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.

Pictet-Gams reaction.svg

In a Pictet–Spengler reaction, a condensation of a β-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 (EC 4.2.1.78) is an enzyme that catalyzes a biological Pictect-Spengler synthesis:

1,2,3,4-Tetrahidroisoquinolines biosynthesis: in (S)-norcoclaurine synthase, the two substrates are 4-hydroxyphenylacetaldehyde and 4-(2-aminoethyl)benzene-1,2-diol, whereas its two products are (S)-norcoclaurine and H2O. (S)-norcoclaurine synthesis.svg
1,2,3,4-Tetrahidroisoquinolines biosynthesis: in (S)-norcoclaurine synthase, the two substrates are 4-hydroxyphenylacetaldehyde and 4-(2-aminoethyl)benzene-1,2-diol, whereas its two products are (S)-norcoclaurine and H2O.

Intramolecular aza Wittig reactions also afford isoquinolines.

Applications of derivatives

Isoquinolines find many applications, including:

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

In 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 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. [12]

Other uses

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

See also

Related Research Articles

<span class="mw-page-title-main">Heterocyclic compound</span> Molecule with one or more rings composed of different elements

A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and applications of organic heterocycles.

<span class="mw-page-title-main">Quinoline</span> Chemical compound

Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. It is a colorless hygroscopic liquid with a strong odor. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only slightly soluble in cold water but dissolves readily in hot water and most organic solvents. Quinoline itself has few applications, but many of its derivatives are useful in diverse applications. A prominent example is quinine, an alkaloid found in plants. Over 200 biologically active quinoline and quinazoline alkaloids are identified. 4-Hydroxy-2-alkylquinolines (HAQs) are involved in antibiotic resistance.

In retrosynthetic analysis, a synthon is a hypothetical unit within a target molecule that represents a potential starting reagent in the retroactive synthesis of that target molecule. The term was coined in 1967 by E. J. Corey. He noted in 1988 that the "word synthon has now come to be used to mean synthetic building block rather than retrosynthetic fragmentation structures". It was noted in 1998 that the phrase did not feature very prominently in Corey's 1981 book The Logic of Chemical Synthesis, as it was not included in the index. Because synthons are charged, when placed into a synthesis an uncharged form is found commercially instead of forming and using the potentially very unstable charged synthons.

The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine undergoes condensation with an aldehyde or ketone followed by ring closure. The reaction was first discovered in 1911 by Amé Pictet and Theodor Spengler. Traditionally an acidic catalyst in protic solvent was employed with heating, however the reaction has been shown to work in aprotic media in superior yields and sometimes without acid catalysis. The Pictet–Spengler reaction can be considered a special case of the Mannich reaction, which follows a similar reaction pathway. The driving force for this reaction is the electrophilicity of the iminium ion generated from the condensation of the aldehyde and amine under acid conditions. This explains the need for an acid catalyst in most cases, as the imine is not electrophilic enough for ring closure but the iminium ion is capable of undergoing the reaction.

The Skraup synthesis is a chemical reaction used to synthesize quinolines. It is named after the Czech chemist Zdenko Hans Skraup (1850-1910). In the archetypal Skraup reaction, aniline is heated with sulfuric acid, glycerol, and an oxidizing agent such as nitrobenzene to yield quinoline.

The Bischler–Napieralski reaction is an intramolecular electrophilic aromatic substitution reaction that allows for the cyclization of β-arylethylamides or β-arylethylcarbamates. It was first discovered in 1893 by August Bischler and Bernard Napieralski, in affiliation with Basle Chemical Works and the University of Zurich. The reaction is most notably used in the synthesis of dihydroisoquinolines, which can be subsequently oxidized to isoquinolines.

Pictet may refer to:

The Friedländer synthesis is a chemical reaction of 2-aminobenzaldehydes with ketones to form quinoline derivatives. It is named after German chemist Paul Friedländer (1857–1923).

<span class="mw-page-title-main">Doebner–Miller reaction</span>

The Doebner–Miller reaction is the organic reaction of an aniline with α,β-unsaturated carbonyl compounds to form quinolines.

<span class="mw-page-title-main">Benzylamine</span> Chemical compound

Benzylamine is an organic chemical compound with the condensed structural formula C6H5CH2NH2 (sometimes abbreviated as PhCH2NH2 or BnNH2). It consists of a benzyl group, C6H5CH2, attached to an amine functional group, NH2. This colorless water-soluble liquid is a common precursor in organic chemistry and used in the industrial production of many pharmaceuticals. The hydrochloride salt was used to treat motion sickness on the Mercury-Atlas 6 mission in which NASA astronaut John Glenn became the first American to orbit the Earth.

The Combes quinoline synthesis is a chemical reaction, which was first reported by Combes in 1888. Further studies and reviews of the Combes quinoline synthesis and its variations have been published by Alyamkina et al., Bergstrom and Franklin, Born, and Johnson and Mathews.

The Pomeranz–Fritsch reaction, also named Pomeranz–Fritsch cyclization, is a named reaction in organic chemistry. It is named after Paul Fritsch (1859–1913) and Cäsar Pomeranz (1860–1926). In general it is a synthesis of isoquinoline.

<span class="mw-page-title-main">Tetrahydroisoquinoline</span> Chemical compound

Tetrahydroisoquinoline (TIQ or THIQ) is an organic compound with the chemical formula C9H11N. Classified as a secondary amine, it is derived from isoquinoline by hydrogenation. It is a colorless viscous liquid that is miscible with most organic solvents. The tetrahydroisoquinoline skeleton is encountered in a number of bioactive compounds and drugs.

<span class="mw-page-title-main">Phenanthridine</span> Chemical compound

Phenanthridine is a nitrogen heterocyclic compound that is the basis of DNA-binding fluorescent dyes through intercalation. Examples of such dyes are ethidium bromide and propidium iodide. It is an isomer of acridine.

<span class="mw-page-title-main">Indole</span> Chemical compound

Indole is an aromatic, heterocyclic, organic compound with the formula C8H7N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environment and can be produced by a variety of bacteria. As an intercellular signal molecule, indole regulates various aspects of bacterial physiology, including spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence. The amino acid tryptophan is an indole derivative and the precursor of the neurotransmitter serotonin.

A ring forming reaction or ring-closing reaction in organic chemistry is a general term for a variety of reactions that introduce one or more rings into a molecule. A heterocycle forming reaction is such a reaction that introduces a new heterocycle. Important classes of ring forming reactions include annulations and cycloadditions.

<span class="mw-page-title-main">James M. Bobbitt</span> American chemist and professor (1930–2021)

James McCue Bobbitt was an American chemist and academic who taught chemistry at the University of Connecticut from 1956 to 1991 and developed the Bobbitt reaction.

The Bobbitt reaction is a name reaction in organic chemistry. It is named after the American chemist James M. Bobbitt. The reaction allows the synthesis of 1-, 4-, and N-substituted 1,2,3,4-tetrahydroisoquinolines and also 1-, and 4-substituted isoquinolines.

<span class="mw-page-title-main">Benzylisoquinoline alkaloids</span>

The benzylisoquinoline alkaloids are natural products that can be classified as isoquinoline alkaloids and are derived from benzylisoquinoline. They also include the benzyl(tetrahydro)isoquinoline alkaloids.

References

  1. ↑ Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 212. doi:10.1039/9781849733069-FP001. ISBN   978-0-85404-182-4.
  2. 1 2 Brown, H.C., et al., in Baude, E.A. and Nachod, F.C., Determination of Organic Structures by Physical Methods, Academic Press, New York, 1955.
  3. ↑ Gilchrist, T.L. (1997). Heterocyclic Chemistry (3rd ed.). Essex, UK: Addison Wesley Longman.
  4. ↑ Harris, J.; Pope, W.J. "isoQuinoline and the isoQuinoline-Reds" Journal of the Chemical Society (1922) volume 121, pp. 1029–1033.
  5. ↑ Katritsky, A.R.; Pozharskii, A.F. (2000). Handbook of Heterocyclic Chemistry (2nd ed.). Oxford, UK: Elsevier.
  6. ↑ Katritsky, A.R.; Rees, C.W.; Scriven, E.F. (Eds.). (1996). Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982–1995 (Vol. 5). Tarrytown, NY: Elsevier.
  7. ↑ Nagatsu, T. "Isoquinoline neurotoxins in the brain and Parkinson's disease" Neuroscience Research (1997) volume 29, pp. 99–111.
  8. ↑ O'Neil, Maryadele J. (Ed.). (2001). The Merck Index (13th ed.). Whitehouse Station, NJ: Merck.
  9. ↑ S. Hoogewerf and W.A. van Dorp (1885) "Sur un isomére de la quinoléine" (On an isomer of quinoline), Recueil des Travaux Chemiques des Pays-Bas (Collection of Work in Chemistry in the Netherlands), vol.4, no. 4, pages 125–129. See also: S. Hoogewerf and W.A. van Dorp (1886) "Sur quelques dérivés de l'isoquinoléine" (On some derivatives of isoquinoline), Recueil des Travaux Chemiques des Pays-Bas, vol.5, no. 9, pages 305–312.
  10. ↑ Li, J. J. (2014). "Pomeranz–Fritz reaction". Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (5th ed.). Springer. pp. 490–491. ISBN   9783319039794.
  11. ↑ Li, J. J. (2014). "Schlittler–Müller modification". Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (5th ed.). Springer. p. 492. ISBN   9783319039794.
  12. ↑ Niwa, Toshimitsu; Kajita, Mitsuharu; Nagatsu, Toshiharu (1998). "Isoquinoline Derivatives". Pharmacology of Endogenous Neurotoxins. pp. 3–23. doi:10.1007/978-1-4612-2000-8_1. ISBN   978-1-4612-7375-2.

"Quinoline"  . Encyclopædia Britannica . Vol. 22 (11th ed.). 1911. pp. 758–759.

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