Acridine is an
organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...
and a
nitrogen heterocycle with the formula C
13H
9N. Acridines are substituted derivatives of the parent ring. It is a planar molecule that is structurally related to
anthracene
Anthracene is a solid polycyclic aromatic hydrocarbon (PAH) of formula C14H10, consisting of three fused benzene rings. It is a component of coal tar. Anthracene is used in the production of the red dye alizarin and other dyes. Anthracene is co ...
with one of the central CH groups replaced by nitrogen. Like the related molecules
pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid w ...
and
quinoline
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 sli ...
, 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
Acridine orange is an organic compound that serves as a nucleic acid-selective fluorescent dye with cationic properties useful for cell cycle determination. Acridine orange is cell-permeable, which allows the dye to interact with DNA by interca ...
. The name is a reference to the acrid odour and acrid skin-irritating effect of the compound.
Isolation and syntheses
Carl Gräbe
Carl Gräbe (; 24 February 1841 – 19 January 1927) was a German industrial and academic chemist from Frankfurt am Main who held professorships in his field at Leipzig, Königsberg, and Geneva. He is known for the first synthesis of the e ...
and
Heinrich Caro
Heinrich Caro (February 13, 1834 in Posen, Prussia Germany now Poznań, Poland – September 11, 1910 in Dresden), was a German chemist.
He was a Sephardic Jew. He started his study of chemistry at the Friedrich Wilhelms University and later ...
first isolated acridine in 1870 from
coal tar
Coal tar is a thick dark liquid which is a by-product of the production of coke and coal gas from coal. It is a type of creosote. It has both medical and industrial uses. Medicinally it is a topical medication applied to skin to treat pso ...
. Acridine is separated from coal tar by extracting with dilute
sulfuric acid
Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular fo ...
. Addition of
potassium dichromate
Potassium dichromate, , is a common inorganic chemical reagent, most commonly used as an oxidizing agent in various laboratory and industrial applications. As with all hexavalent chromium compounds, it is acutely and chronically harmful to health ...
to this solution
precipitate
In an aqueous solution, precipitation is the process of transforming a dissolved substance into an insoluble solid from a super-saturated solution. The solid formed is called the precipitate. In case of an inorganic chemical reaction leading ...
s acridine bichromate. The bichromate is
decomposed using
ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous ...
.
Acridine and its derivatives can be prepared by many synthetic processes. In the
Bernthsen acridine synthesis The Bernthsen acridine synthesis is the chemical reaction of a diarylamine heated with a carboxylic acid (or acid anhydride) and zinc chloride to form a 9-substituted acridine.
Using zinc chloride, one must heat the reaction to 200-270 °C f ...
,
diphenylamine
Diphenylamine is an organic compound with the formula (C6H5)2NH. The compound is a derivative of aniline, consisting of an amine bound to two phenyl groups. The compound is a colorless solid, but commercial samples are often yellow due to oxidiz ...
is condensed with
carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyli ...
s in the presence of
zinc chloride
Zinc chloride is the name of inorganic chemical compounds with the formula ZnCl2 and its hydrates. Zinc chlorides, of which nine crystalline forms are known, are colorless or white, and are highly soluble in water. This salt is hygroscopic ...
. When
formic acid
Formic acid (), systematically named methanoic acid, is the simplest carboxylic acid, and has the chemical formula HCOOH and structure . It is an important intermediate in chemical synthesis and occurs naturally, most notably in some ants. Est ...
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.
:
Other older methods for the
organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...
of acridines include condensing diphenylamine with
chloroform
Chloroform, or trichloromethane, is an organic compound with formula C H Cl3 and a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to PTFE. It is also a precursor to various ...
in the presence of
aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms hexahydrate with the formula , containing six water molecules of hydration. Both are colourless crystals, but samples are often contam ...
, by passing the vapours of orthoaminodiphenylmethane over heated
litharge
Litharge (from Greek lithargyros, lithos (stone) + argyros (silver) ''λιθάργυρος'') is one of the natural mineral forms of lead(II) oxide, PbO. Litharge is a secondary mineral which forms from the oxidation of galena ores. It forms as co ...
, by heating
salicylaldehyde
Salicylic aldehyde (2-hydroxybenzaldehyde) is the organic compound with the formula (C7 H6 O2) C6H4CHO-2-OH. Along with 3-hydroxybenzaldehyde and 4-hydroxybenzaldehyde, it is one of the three isomers of hydroxybenzaldehyde. This colorless oily ...
with
aniline
Aniline is an organic compound with the formula C6 H5 NH2. 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 starti ...
and
zinc chloride
Zinc chloride is the name of inorganic chemical compounds with the formula ZnCl2 and its hydrates. Zinc chlorides, of which nine crystalline forms are known, are colorless or white, and are highly soluble in water. This salt is hygroscopic ...
or by distilling
acridone
Acridone is an organic compound based on the acridine skeleton, with a carbonyl group at the ''9'' position. It is a yellow solid.
Synthesis and structure
The molecule is planar. Optical spectra reveal that the keto tautomer predominates in the ga ...
(9-position a
carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...
group) over
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
dust.
Another classic method for the synthesis of acridones is the
Lehmstedt-Tanasescu reaction.
In
enzymology
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
, an
acridone synthase () is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that
catalyzes the
chemical reaction
A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breaking ...
:3 malonyl-CoA + ''N''-methylanthraniloyl-CoA 4 CoA + 1,3-dihydroxy-''N''-methylacridone + 3 CO
2
Thus, the two
substrates of this enzyme are
malonyl-CoA
Malonyl-CoA is a coenzyme A derivative of malonic acid.
Functions
It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis.
Fatty acid biosynthesis
Malonyl-CoA provides 2-carbon units to fatty acids and com ...
and
''N''-methylanthraniloyl-CoA, whereas its three
products
Product may refer to:
Business
* Product (business), an item that serves as a solution to a specific consumer problem.
* Product (project management), a deliverable or set of deliverables that contribute to a business solution
Mathematics
* Produ ...
are
CoA
Coa may refer to:
Places
* Coa, County Fermanagh, a rural community in County Fermanagh, Northern Ireland
* Côa River, a tributary of the Douro, Portugal
** Battle of Coa, part of the Peninsular War period of the Napoleonic Wars
** Côa Valley ...
,
1,3-dihydroxy-''N''-methylacridone, and
CO2.
Reactions
Acridine displays the reactions expected of an unsaturated ''N''-heterocycle. It undergoes ''N''-alkylation with
alkyl iodide
Organoiodine compounds are organic compounds that contain one or more carbon–iodine bonds. They occur widely in organic chemistry, but are relatively rare in nature. The thyroxine hormones are organoiodine compounds that are required for he ...
s to form alkyl acridinium iodides, which are readily transformed by the action of alkaline
potassium ferricyanide
Potassium ferricyanide is the chemical compound with the formula K3 e(CN)6 This bright red salt contains the octahedrally coordinated 3−.html" ;"title="e(CN)6sup>3−">e(CN)6sup>3− ion. It is soluble in water and its solution shows some g ...
to ''N''-alkyl
acridone
Acridone is an organic compound based on the acridine skeleton, with a carbonyl group at the ''9'' position. It is a yellow solid.
Synthesis and structure
The molecule is planar. Optical spectra reveal that the keto tautomer predominates in the ga ...
s.
Basicity
Acridine and its homologues are weakly basic. Acridine is a photobase which has a ground state
p''K''a of 5.1, similar to that of
pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid w ...
, and an excited state p''K''
a of 10.6. It also shares properties with
quinoline
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 sli ...
.
Reduction and oxidation
Acridines can be reduced to the 9,10-dihydroacridines, sometimes called leucoacridines. Reaction with
potassium cyanide
Potassium cyanide is a compound with the formula KCN. This colorless crystalline salt, similar in appearance to sugar, is highly soluble in water. Most KCN is used in gold mining, organic synthesis, and electroplating. Smaller applications includ ...
gives the 9-cyano-9,10-dehydro derivative. On oxidation with
potassium permanganate
Potassium permanganate is an inorganic compound with the chemical formula KMnO4. It is a purplish-black crystalline salt, that dissolves in water as K+ and , an intensely pink to purple solution.
Potassium permanganate is widely used in the c ...
, it yields acridinic acid (C
9H
5N(CO
2H)
2) otherwise known as
quinoline
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 sli ...
-1,2-dicarboxylic acid.
Acridine is easily
oxidized
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
by
peroxymonosulfuric acid
Peroxymonosulfuric acid, , also known as persulfuric acid, peroxysulfuric acid, or Caro's acid. In this acid, the S(VI) center adopts its characteristic tetrahedral geometry; the connectivity is indicated by the formula HO–O–S(O)2–OH. It is ...
to the acridine
amine oxide
In chemistry, an amine oxide, also known as an amine ''N''-oxide or simply ''N''-oxide, is a chemical compound that contains the functional group , a nitrogen-oxygen coordinate covalent bond with three additional hydrogen and/or substituent-grou ...
. The carbon 9-position of acridine is activated for
addition reaction
In organic chemistry, an addition reaction is, in simplest terms, an organic reaction where two or more molecules combine to form a larger one (the adduct)..
Addition reactions are limited to chemical compounds that have multiple bonds, such as ...
s.
Applications
Several
dye
A dye is a colored substance that chemically bonds to the substrate to which it is being applied. This distinguishes dyes from pigments which do not chemically bind to the material they color. Dye is generally applied in an aqueous solution an ...
s and drugs feature the acridine skeleton. Many acridines, such as
proflavine
Proflavine, also called proflavin and diaminoacridine, is an acriflavine derivative, a disinfectant bacteriostatic against many gram-positive bacteria. It has been used in the form of the dihydrochloride and hemisulfate salts as a topical antisepti ...
, also have
antiseptic
An antiseptic (from Greek ἀντί ''anti'', "against" and σηπτικός ''sēptikos'', "putrefactive") is an antimicrobial substance or compound that is applied to living tissue/skin to reduce the possibility of infection, sepsis, or putre ...
properties. Acridine and related derivatives (such as
amsacrine) bind to
DNA and
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
due to their abilities to
intercalate
Intercalation may refer to:
*Intercalation (chemistry), insertion of a molecule (or ion) into layered solids such as graphite
* Intercalation (timekeeping), insertion of a leap day, week or month into some calendar years to make the calendar foll ...
.
Acridine orange
Acridine orange is an organic compound that serves as a nucleic acid-selective fluorescent dye with cationic properties useful for cell cycle determination. Acridine orange is cell-permeable, which allows the dye to interact with DNA by intercala ...
(3,6-dimethylaminoacridine) is a
nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
-selective metachromatic
stain
A stain is a discoloration that can be clearly distinguished from the surface, material, or medium it is found upon. They are caused by the chemical or physical interaction of two dissimilar materials. Accidental staining may make materials app ...
useful for cell cycle determination.
Dyes
At one time acridine dyes were commercially significant, but they are now uncommon because they are not
lightfast
Lightfastness is a property of a colourant such as dye or pigment that describes its resistance to fading when exposed to light. Dyes and pigments are used for example for dyeing of fabrics, plastics or other materials and manufacturing paints or ...
. Acridine dyes are prepared by condensation of
1,3-diaminobenzene derivatives. Illustrative is the reaction of
2,4-diaminotoluene
2,4-Diaminotoluene is an organic compound with the formula C6H3(NH2)2CH3. It is one isomer of six with this formula. It is a white solid although commercial samples are often yellow-tan.
Preparation
It is prepared by hydrogenation of 2,4-dinit ...
with acetaldehyde:
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
Phosphine (IUPAC name: phosphane) is a colorless, flammable, highly toxic compound with the chemical formula , classed as a pnictogen hydride. Pure phosphine is odorless, but technical grade samples have a highly unpleasant odor like rotting ...
gas), a byproduct in the manufacture of
rosaniline
Fuchsine (sometimes spelled fuchsin) or rosaniline hydrochloride is a magenta dye with chemical formula C20H19N3·HCl. . Chrysaniline forms red-coloured salts, which dye
silk
Silk is a natural protein fiber, some forms of which can be woven into textiles. The protein fiber of silk is composed mainly of fibroin and is produced by certain insect larvae to form cocoons. The best-known silk is obtained from the coc ...
and
wool
Wool is the textile fibre obtained from sheep and other mammals, especially goats, rabbits, and camelids. The term may also refer to inorganic materials, such as mineral wool and glass wool, that have properties similar to animal wool.
As ...
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
Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful.
It is a colorless liquid with a characteristic almond-like odor. ...
. 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.
Molecular biology
Acridine is known to induce small insertions or deletions in nucleotide sequences, resulting in
frameshift mutations
A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature ...
.
This compound was useful to identify the triplet nature of the
genetic codes.
Structure
As established by
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
, acridine has been obtained in eight
polymorphs. All feature very similar planar molecules with nearly identical bond lengths and bond distances.
Safety
Acridine is a skin irritant. Its (rats, oral) is 2,000 mg/kg and 500 mg/kg (mice, oral).
See also
*
Lucigenin, a chemiluminescent compound derived from acridine
References
Literature
*
* [review article dealing with physical properties of acridines, natural products possessing the acridine core, biologically active acridines, applications of acridines, new syntheses and reactions of acridines]
External links
*
* Synthesis of acridone in ''Organic Syntheses'' 19:6; ''Coll. Vol.'' 2:1
from
o-chlorobenzoic acid, ''o''-chlorobenzoic acid and aniline in a
Goldberg reaction Goldberg or Goldberger may refer to:
Arts and entertainment
* Goldberg Ensemble, a British string ensemble
* ''Goldberg Variations'', a set of 30 keyboard variations by Johann Sebastian Bach
* ''The Goldbergs (broadcast series)'', American radio ...
.
* Synthesis of 9-aminoacridine in ''
Organic Syntheses
''Organic Syntheses'' is a peer-reviewed scientific journal that was established in 1921. It publishes detailed and checked procedures for the synthesis of organic compounds. A unique feature of the review process is that all of the data and ex ...
'' 22:5; ''Coll. Vol.'' 3:53
from ''N''-phenylanthranilic acid.
{{Authority control
Acridines,
Simple aromatic rings