Acridine

Last updated
Acridine
Acridine chemical structure.png
Names
Preferred IUPAC name
Acridine [1]
Other names
Dibenzo[b,e]pyridine [2]
2,3-Benzoquinoline [3]
Identifiers
3D model (JSmol)
120200
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.429 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 205-971-6
143403
PubChem CID
RTECS number
  • AR7175000
UNII
UN number 2713
  • InChI=1S/C13H9N/c1-3-7-12-10(5-1)9-11-6-2-4-8-13(11)14-12/h1-9H Yes check.svgY
    Key: DZBUGLKDJFMEHC-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C13H9N/c1-3-7-12-10(5-1)9-11-6-2-4-8-13(11)14-12/h1-9H
    Key: DZBUGLKDJFMEHC-UHFFFAOYAF
  • n1c3c(cc2c1cccc2)cccc3
  • c1ccc2c(c1)cc3ccccc3n2
Properties
C13H9N
Molar mass 179.222 g·mol−1
AppearanceWhite powder
Odor Irritating
Density 1.005 g/cm3 (20 °C) [2]
Melting point 106–110 °C (223–230 °F; 379–383 K)
at standard pressure [2]
Boiling point 344.86 °C (652.75 °F; 618.01 K)
at standard pressure [2]
46.5 mg/L [2]
Solubility Soluble in CCl4, alcohols, (C2H5)2O, C6H6 [2]
log P 3.4 [2]
Vapor pressure 0.34 kPa (150 °C)
2.39 kPa (200 °C)
11.13 kPa (250 °C) [4]
Acidity (pKa)5.58 (20 °C) [2]
UV-vis (λmax)392 nm [5]
−123.3×10−6 cm3/mol
Thermochemistry
205.07 J/mol·K [4]
Std molar
entropy (S⦵298)
208.03 J/mol·K [4]
179.4 kJ/mol [2]
6581.3 kJ/mol [4]
Hazards
GHS labelling:
GHS-pictogram-exclam.svg [5]
Danger
H302, H312, H315, H319, H332, H335 [5]
P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P312, P321, P322, P330, P332+P313, P337+P313, P362, P363, P403+P233, P405, P501
NFPA 704 (fire diamond)
[3]
NFPA 704.svgHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
1
0
Lethal dose or concentration (LD, LC):
500 mg/kg (mice, oral) [3]
NIOSH (US health exposure limits):
PEL (Permissible)
TWA 0.2 mg/m3 (benzene-soluble fraction) [6]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Acridine is an organic compound and a nitrogen heterocycle with the formula C13H9N. Acridines are substituted derivatives of the parent ring. It is a planar molecule that is structurally related to anthracene with one of the central CH groups replaced by nitrogen. Like the related molecules pyridine and quinoline, acridine is mildly basic. It is an almost colorless solid, which crystallizes in needles. There are few commercial applications of acridines; at one time acridine dyes were popular, but they are now relegated to niche applications, such as with acridine orange. The name is a reference to the acrid odour and acrid skin-irritating effect of the compound.

Contents

Isolation and syntheses

Carl Gräbe and Heinrich Caro first isolated acridine in 1870 from coal tar. [7] Acridine is separated from coal tar by extracting with dilute sulfuric acid. Addition of potassium dichromate to this solution precipitates acridine bichromate. The bichromate is decomposed using ammonia.

Acridine and its derivatives can be prepared by many synthetic processes. In the Bernthsen acridine synthesis, diphenylamine is condensed with carboxylic acids in the presence of zinc chloride. When formic acid is the carboxylic acid, the reaction yields the parent acridine. With the higher larger carboxylic acids, the derivatives substituted at the meso carbon atom are generated.

The Bernthsen acridine synthesis Bernthsen Acridine Synthesis Scheme.png
The Bernthsen acridine synthesis

Other older methods for the organic synthesis of acridines include condensing diphenylamine with chloroform in the presence of aluminium chloride, by passing the vapours of orthoaminodiphenylmethane over heated litharge, by heating salicylaldehyde with aniline and zinc chloride or by distilling acridone (9-position a carbonyl group) over zinc dust. [8] Another classic method for the synthesis of acridones is the Lehmstedt-Tanasescu reaction.

In enzymology, an acridone synthase (EC 2.3.1.159) is an enzyme that catalyzes the chemical reaction

3 malonyl-CoA + N-methylanthraniloyl-CoA ⇌ 4 CoA + 1,3-dihydroxy-N-methylacridone + 3 CO2

Thus, the two substrates of this enzyme are malonyl-CoA and N-methylanthraniloyl-CoA, whereas its three products are CoA, 1,3-dihydroxy-N-methylacridone, and CO2. [9]

Reactions

Acridine displays the reactions expected of an unsaturated N-heterocycle. It undergoes N-alkylation with alkyl iodides to form alkyl acridinium iodides, which are readily transformed by the action of alkaline potassium ferricyanide to N-alkyl acridones.

Basicity

Acridine and its homologues are weakly basic. Acridine is a photobase which has a ground state pKa of 5.1, similar to that of pyridine, and an excited state pKa of 10.6. [10] It also shares properties with quinoline.

Reduction and oxidation

Acridines can be reduced to the 9,10-dihydroacridines, sometimes called leucoacridines. Reaction with potassium cyanide gives the 9-cyano-9,10-dehydro derivative. On oxidation with potassium permanganate, it yields acridinic acid (C9H5N(CO2H)2) otherwise known as quinoline-1,2-dicarboxylic acid. [8] Acridine is easily oxidized by peroxymonosulfuric acid to the acridine amine oxide. The carbon 9-position of acridine is activated for addition reactions. [11]

Applications

Several dyes and drugs feature the acridine skeleton. [12] Many acridines, such as proflavine, also have antiseptic properties. Acridine and related derivatives (such as amsacrine) bind to DNA and RNA due to their abilities to intercalate. Acridine orange (3,6-dimethylaminoacridine) is a nucleic acid-selective metachromatic stain useful for cell cycle determination.

Dyes

At one time acridine dyes were commercially significant, but they are now uncommon because they are not lightfast. Acridine dyes are prepared by condensation of 1,3-diaminobenzene derivatives. Illustrative is the reaction of 2,4-diaminotoluene with acetaldehyde: [13]

Synthesis of C.I. Basic Yellow 9, an acridine dye. SynthesisBasicYellow9.png
Synthesis of C.I. Basic Yellow 9, an acridine dye.

9-Phenylacridine is the parent base of chrysaniline or 3,6-diamino-9-phenylacridine, which is the chief constituent of the dyestuff phosphine (not to be confused with phosphine gas), a byproduct in the manufacture of rosaniline. Chrysaniline forms red-coloured salts, which dye silk and wool in a fine yellow; and the solutions of the salts are characterized by their fine yellowish-green fluorescence. Chrysaniline was synthesized by O. Fischer and G. Koerner by condensing o-nitrobenzaldehyde with aniline, the resulting o-nitro-p-diaminotriphenylmethane being reduced to the corresponding o-amino compound, which on oxidation yields chrysaniline.

Benzoflavin, an isomer of chrysaniline, is also a dyestuff, and has been prepared by K. Oehler from m-phenylenediamine and benzaldehyde. These substances condense to form tetraaminotriphenylmethane, which, on heating with acids, loses ammonia and yields 3,6-diamino-9,10-dihydrophenylacridine, from which benzoflavin is obtained by oxidation. It is a yellow powder, soluble in hot water. [8]

Molecular biology

Acridine is known to induce small insertions or deletions in nucleotide sequences, resulting in frameshift mutations. [14] This compound was useful to identify the triplet nature of the genetic codes. [14]

Structure

As established by X-ray crystallography, acridine has been obtained in eight polymorphs. All feature very similar planar molecules with nearly identical bond lengths and bond distances. [15] [16]

Safety

Acridine is a skin irritant. Its LD50 (rats, oral) is 2,000 mg/kg and 500 mg/kg (mice, oral). [3]

See also

Related Research Articles

In chemistry, amines are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines, trimethylamine, and aniline. Inorganic derivatives of ammonia are also called amines, such as monochloramine.

The following outline is provided as an overview of and topical guide to organic chemistry:

<span class="mw-page-title-main">Aniline</span> Organic compound (C₆H₅NH₂); simplest aromatic amine

Aniline is an organic compound with the formula C6H5NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine. It is an industrially significant commodity chemical, as well as a versatile starting material for fine chemical synthesis. Its main use is in the manufacture of precursors to polyurethane, dyes, and other industrial chemicals. Like most volatile amines, it has the odor of rotten fish. It ignites readily, burning with a smoky flame characteristic of aromatic compounds. It is toxic to humans.

<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.

The Friedel–Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877 to attach substituents to an aromatic ring. Friedel–Crafts reactions are of two main types: alkylation reactions and acylation reactions. Both proceed by electrophilic aromatic substitution.

<span class="mw-page-title-main">Azo compound</span> Organic compounds with a diazenyl group (–N=N–)

Azo compounds are organic compounds bearing the functional group diazenyl.

In organic chemistry, ozonolysis is an organic reaction where the unsaturated bonds are cleaved with ozone. Multiple carbon–carbon bond are replaced by carbonyl groups, such as aldehydes, ketones, and carboxylic acids. The reaction is predominantly applied to alkenes, but alkynes and azo compounds are also susceptible to cleavage. The outcome of the reaction depends on the type of multiple bond being oxidized and the work-up conditions.

<i>N</i>,<i>N</i>-Dicyclohexylcarbodiimide Chemical compound

N,N′-Dicyclohexylcarbodiimide (DCC or DCCD) is an organic compound with the chemical formula (C6H11N)2C. It is a waxy white solid with a sweet odor. Its primary use is to couple amino acids during artificial peptide synthesis. The low melting point of this material allows it to be melted for easy handling. It is highly soluble in dichloromethane, tetrahydrofuran, acetonitrile and dimethylformamide, but insoluble in water.

<span class="mw-page-title-main">Martinet dioxindole synthesis</span>

The Martinet dioxindole synthesis was first reported in 1913 by J. Martinet. It is a chemical reaction in which a primary or secondary aniline or substituted aromatic amine is condensed with ethyl or methyl ester of mesoxalic acid to make a dioxindole in the absence of oxygen.

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

Potassium peroxymonosulfate is widely used as an oxidizing agent, for example, in pools and spas. It is the potassium salt of peroxymonosulfuric acid. Usually potassium peroxymonosulfate refers to the triple salt known as oxone.

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

Isatin, also known as tribulin, is an organic compound derived from indole with formula C8H5NO2. The compound was first obtained by Otto Linné Erdman and Auguste Laurent in 1840 as a product from the oxidation of indigo dye by nitric acid and chromic acids.

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

Phenazine is an organic compound with the formula (C6H4)2N2. It is a dibenzo annulated pyrazine, and the parent substance of many dyestuffs, such as the toluylene red, indulines, and safranines (and the closely related eurhodines). Phenazine crystallizes in yellow needles, which are only sparingly soluble in alcohol. Sulfuric acid dissolves it, forming a deep-red solution.

The Étard reaction is a chemical reaction that involves the direct oxidation of an aromatic or heterocyclic bound methyl group to an aldehyde using chromyl chloride. For example, toluene can be oxidized to benzaldehyde.

In organic chemistry, a homologation reaction, also known as homologization, is any chemical reaction that converts the reactant into the next member of the homologous series. A homologous series is a group of compounds that differ by a constant unit, generally a methylene group. The reactants undergo a homologation when the number of a repeated structural unit in the molecules is increased. The most common homologation reactions increase the number of methylene units in saturated chain within the molecule. For example, the reaction of aldehydes or ketones with diazomethane or methoxymethylenetriphenylphosphine to give the next homologue in the series.

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

The Doebner reaction is the chemical reaction of an aniline with an aldehyde and pyruvic acid to form quinoline-4-carboxylic acids.

In enzymology, an acridone synthase (EC 2.3.1.159) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Gould–Jacobs reaction</span> Gould-Jacobs reaction explained

The Gould–Jacobs reaction is an organic synthesis for the preparation of quinolines and 4‐hydroxyquinoline derivatives. The Gould–Jacobs reaction is a series of reactions. The series of reactions begins with the condensation/substitution of an aniline with alkoxy methylenemalonic ester or acyl malonic ester, producing anilidomethylenemalonic ester. Then through a 6 electron cyclization process, 4-hydroxy-3-carboalkoxyquinoline is formed, which exist mostly in the 4-oxo form. Saponification results in the formation of an acid. This step is followed by decarboxylation to give 4-hydroxyquinoline. The Gould–Jacobs reaction is effective for anilines with electron‐donating groups at the meta‐position.

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

Propionaldehyde or propanal is the organic compound with the formula CH3CH2CHO. It is the 3-carbon aldehyde. It is a colourless, flammable liquid with a pungent and fruity odour. It is produced on a large scale industrially.

<span class="mw-page-title-main">1,3-Diphenylisobenzofuran</span> Chemical compound

1,3-Diphenylisobenzofuran is a highly reactive diene that can scavenge unstable and short-lived dienophiles in a Diels-Alder reaction. It is furthermore used as a standard reagent for the determination of singlet oxygen, even in biological systems. Cycloadditions with 1,3-diphenylisobenzofuran and subsequent oxygen cleavage provide access to a variety of polyaromatics.

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

Naphtholactam is an organic compound derived from naphthalene. It is a tricyclic species consisting of a naphthalene core fused with a lactam (NH-CO-) at the 1,8-positions. The N-alkyl derivatives are commercially important.

References

  1. ↑ Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. pp. 211, 214. doi:10.1039/9781849733069-FP001. ISBN   978-0-85404-182-4.
  2. 1 2 3 4 5 6 7 8 9 Lide DR, ed. (2009). CRC Handbook of Chemistry and Physics (90th ed.). Boca Raton, Florida: CRC Press. ISBN   978-1-4200-9084-0.
  3. 1 2 3 4 "MSDS of Acridine". www.fishersci.ca. Fisher Scientific. Retrieved 2014-06-22.
  4. 1 2 3 4 Acridine in Linstrom, Peter J.; Mallard, William G. (eds.); NIST Chemistry WebBook, NIST Standard Reference Database Number 69, National Institute of Standards and Technology, Gaithersburg (MD) (retrieved 2014-06-22)
  5. 1 2 3 Sigma-Aldrich Co., Acridine. Retrieved on 2014-06-22.
  6. ↑ NIOSH Pocket Guide to Chemical Hazards. "#0145". National Institute for Occupational Safety and Health (NIOSH).
  7. ↑ Gräbe C, Caro H (July 1870). "Ueber Acridin". Berichte der Deutschen Chemischen Gesellschaft (in German). 3 (2): 746–747. doi:10.1002/cber.18700030223.
  8. 1 2 3 Wikisource-logo.svg One or more of the preceding sentences incorporates text from a publication now in the public domain :  Chisholm H, ed. (1911). "Acridine". Encyclopædia Britannica . Vol. 1 (11th ed.). Cambridge University Press. p. 155.
  9. ↑ Maier W, Baumert A, Schumann B, Furukawa H, Gröger D (1993). "Synthesis of 1,3-dihydroxy-N-methylacridone and its conversion to rutacridone by cell-free extracts of Ruta-graveolens cell cultures". Phytochemistry . 32 (3): 691–698. Bibcode:1993PChem..32..691M. doi:10.1016/S0031-9422(00)95155-0.
  10. ↑ Joseph R. Lakowicz. Principles of Fluorescence Spectroscopy 3rd edition. Springer (2006). ISBN   978-0387-31278-1. Chapter 7. page 260.
  11. ↑ G. Collin, H. Höke,"Acridine" in Ullmann's Encyclopedia of Industrial Chemistry 2012, Wiley-VCH, Weinheim. doi : 10.1002/14356007.a01_147
  12. ↑ Denny (2002). "Acridine Derivatives as Chemotherapeutic Agents". Current Medicinal Chemistry. 9 (18): 1655–65. doi:10.2174/0929867023369277. PMID   12171548.
  13. ↑ Gessner T, Mayer U. "Triarylmethane and Diarylmethane Dyes". Ullmann's Encyclopedia of Industrial Chemistry . Weinheim: Wiley-VCH. doi:10.1002/14356007.a27_179. ISBN   978-3527306732.
  14. 1 2 Krebs JE, Goldstein ES, Kilpatrick ST (2017-03-02). Lewin's GENES XII. Jones & Bartlett Learning. pp. 157, 2927. ISBN   978-1-284-10449-3.
  15. ↑ Stephens PW, Schur E, Lapidus SH, Bernstein J (2019). "Acridine form IX". Acta Crystallographica Section E. 75 (4): 489–491. Bibcode:2019AcCrE..75..489S. doi: 10.1107/S2056989019003645 . PMC   6509685 . PMID   31161062. S2CID   174807725.
  16. ↑ Schur E, Bernstein J, Price LS, Guo R, Price SL, Lapidus SH, Stephens PW (2019). "The (Current) Acridine Solid Form Landscape: Eight Polymorphs and a Hydrate" (PDF). Crystal Growth & Design. 19 (8): 4884–4893. doi:10.1021/acs.cgd.9b00557. S2CID   198349955.

Literature

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