Editing Acridine

{{Short description|Organic compound used in dyes}}
{{cs1 config|name-list-style=vanc}}
{{chembox
| Watchedfields = changed
| verifiedrevid = 477241051
| ImageFile = Acridine_chemical_structure.png
| ImageSize = 250px
| ImageName = Acridine chemical structure
| PIN = Acridine<ref name=iupac2013>{{cite book | title =  Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book) | publisher = [[Royal Society of Chemistry|The Royal Society of Chemistry]] | date = 2014 | location = Cambridge | pages = 211, 214 | doi = 10.1039/9781849733069-FP001 | isbn = 978-0-85404-182-4}}</ref>
| OtherNames = Dibenzo[''b'',''e'']pyridine<ref name=crc>{{CRC90}}</ref><br />2,3-Benzoquinoline<ref name=fca />
|Section1={{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 8860
| InChI = 1/C13H9N/c1-3-7-12-10(5-1)9-11-6-2-4-8-13(11)14-12/h1-9H
| InChIKey = DZBUGLKDJFMEHC-UHFFFAOYAF
| SMILES1 = c1ccc2c(c1)cc3ccccc3n2
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 39677
| UNNumber = 2713
| Beilstein = 120200
| Gmelin = 143403
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H9N/c1-3-7-12-10(5-1)9-11-6-2-4-8-13(11)14-12/h1-9H
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DZBUGLKDJFMEHC-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 260-94-6
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 42NI1P5Q1X
| PubChem = 9215
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 36420
| SMILES = n1c3c(cc2c1cccc2)cccc3
| RTECS = AR7175000
| EINECS = 205-971-6
  }}
|Section2={{Chembox Properties
| C=13 | H=9 | N=1
| Appearance = White powder
| Odor = Irritating
| Density = 1.005&nbsp;g/cm<sup>3</sup> (20&nbsp;°C)<ref name=crc />
| MeltingPtC = 106–110
| MeltingPt_notes = <br> at [[standard pressure]]<ref name=crc />
| BoilingPtC = 344.86
| BoilingPt_notes = <br> at [[standard pressure]]<ref name=crc />
| MagSus = {{val|-123.3e-6|u=cm<sup>3</sup>/mol}}
| SolubleOther = Soluble in [[carbon tetrachloride|CCl<sub>4</sub>]], [[Alcohol (chemistry)|alcohol]]s, [[diethyl ether|(C<sub>2</sub>H<sub>5</sub>)<sub>2</sub>O]], [[benzene|C<sub>6</sub>H<sub>6</sub>]]<ref name=crc />
| Solubility = 46.5&nbsp;mg/L<ref name=crc />
| pKa = 5.58 (20&nbsp;°C)<ref name=crc />
| VaporPressure = 0.34&nbsp;kPa (150&nbsp;°C)<br> 2.39&nbsp;kPa (200&nbsp;°C)<br> 11.13&nbsp;kPa (250&nbsp;°C)<ref name=nist />
| LogP = 3.4<ref name=crc />
| LambdaMax = 392 nm<ref name="sigma" />
  }}
|Section4={{Chembox Thermochemistry
| DeltaHf = 179.4&nbsp;kJ/mol<ref name=crc />
| DeltaHc = 6581.3&nbsp;kJ/mol<ref name=nist>{{nist|name=Acridine|id=C260946|accessdate=2014-06-22|mask=FFFF|units=SI}}</ref>
| Entropy = 208.03&nbsp;J/mol·K<ref name=nist />
| HeatCapacity = 205.07&nbsp;J/mol·K<ref name=nist />
  }}
|Section7={{Chembox Hazards
| GHSPictograms = {{GHS07}}<ref name="sigma">{{Sigma-Aldrich|sial|id=a23609|name=Acridine|accessdate=2014-06-22}}</ref>
| GHSSignalWord = Danger
| HPhrases = {{H-phrases|302|312|315|319|332|335}}<ref name="sigma" />
| PPhrases = {{P-phrases|261|264|270|271|280|301+312|302+352|304+312|304+340|305+351+338|312|321|322|330|332+313|337+313|362|363|403+233|405|501}}
| NFPA-H = 2
| NFPA-F = 1
| NFPA-R = 0
| NFPA_ref = <ref name=fca>{{cite web|url = https://www.fishersci.ca/viewmsds.do?catNo=AC102761000|title = MSDS of Acridine|website = www.fishersci.ca|access-date = 2014-06-22|publisher = Fisher Scientific}}</ref>
| LD50 = 500&nbsp;mg/kg (mice, oral)<ref name=fca />
| PEL = TWA 0.2&nbsp;mg/m<sup>3</sup> (benzene-soluble fraction)<ref name=NIOSH>{{PGCH|0145}}</ref>
  }}
}}

'''Acridine''' is an [[organic compound]] and a [[heterocyclic compound|nitrogen heterocycle]] with the formula C<sub>13</sub>H<sub>9</sub>N. 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.

== Isolation and syntheses ==
[[Carl Gräbe]] and [[Heinrich Caro]] first isolated acridine in 1870 from [[coal tar]].<ref>{{cite journal |last1=Gräbe |first1=C. |last2=Caro |first2=H. |title=Ueber Acridin |journal=Berichte der Deutschen Chemischen Gesellschaft |date=July 1870 |volume=3 |issue=2 |pages=746–747 |doi=10.1002/cber.18700030223 |url=https://zenodo.org/record/1424998 |language=de}}</ref> Acridine is separated from coal tar by extracting with dilute [[sulfuric acid]]. Addition of [[potassium dichromate]] to this solution [[precipitate]]s acridine bichromate.  The bichromate is [[chemical decomposition|decomposed]] using [[ammonia]].

Acridine and its derivatives can be prepared by many synthetic processes.  In the [[Bernthsen acridine synthesis]], [[diphenylamine]] is condensed with [[carboxylic acid]]s in the presence of [[zinc chloride]]. When [[formic acid]] is the carboxylic acid, the reaction yields the parent acridine.  With the higher [[homologous series|larger carboxylic acids]], the derivatives substituted at the ''[[meso position|meso]]'' carbon atom are generated.
:[[Image:Bernthsen Acridine Synthesis Scheme.png|center|500px|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.<ref name ="Chisholm">{{EB1911|inline=1|wstitle=Acridine|volume=1|page=155}}</ref>  Another classic method for the synthesis of acridones is the [[Lehmstedt-Tanasescu reaction]].

In [[enzymology]], an [[acridone synthase]] ({{EC number|2.3.1.159}}) is an [[enzyme]] that [[catalysis|catalyzes]] the [[chemical reaction]]

:3 malonyl-CoA + ''N''-methylanthraniloyl-CoA {{eqm}} 4 CoA + 1,3-dihydroxy-''N''-methylacridone + 3 CO<sub>2</sub>

Thus, the two [[substrate (biochemistry)|substrates]] of this enzyme are [[malonyl-CoA]] and [[N-methylanthraniloyl-CoA|''N''-methylanthraniloyl-CoA]], whereas its three [[product (chemistry)|products]] are [[coenzyme A|CoA]], [[1,3-dihydroxy-N-methylacridone|1,3-dihydroxy-''N''-methylacridone]], and [[carbon dioxide|CO<sub>2</sub>]].<ref>{{cite journal|vauthors=Maier W, Baumert A, Schumann B, Furukawa H, Gröger D | date = 1993 | title = Synthesis of 1,3-dihydroxy-N-methylacridone and its conversion to rutacridone by cell-free extracts of Ruta-graveolens cell cultures | journal = [[Phytochemistry (journal)|Phytochemistry]]  | volume = 32 | issue = 3 | pages = 691&ndash;698 | doi = 10.1016/S0031-9422(00)95155-0 | bibcode = 1993PChem..32..691M }}</ref>

== Reactions==
Acridine displays the reactions expected of an unsaturated ''N''-heterocycle.  It undergoes ''N''-alkylation with  [[alkyl iodide]]s to form alkyl acridinium iodides, which are readily transformed by the action of alkaline [[potassium ferricyanide]] to ''N''-alkyl [[acridone]]s.

=== Basicity ===
Acridine and its homologues are weakly basic. Acridine is a photobase which has a ground state [[pKa|p''K''<sub>a</sub>]] of 5.1, similar to that of [[pyridine]], and an excited state p''K''<sub>a</sub> of 10.6.<ref>Joseph R. Lakowicz. [https://books.google.com/books?id=-PSybuLNxcAC Principles of Fluorescence Spectroscopy] 3rd edition. [[Springer Science+Business Media|Springer]] (2006). {{ISBN|978-0387-31278-1}}. Chapter 7. page 260.</ref> 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 (C<sub>9</sub>H<sub>5</sub>N(CO<sub>2</sub>H)<sub>2</sub>) otherwise known as [[quinoline]]-1,2-dicarboxylic acid.<ref name="Chisholm"/> Acridine is easily [[organic oxidation|oxidized]] by [[peroxymonosulfuric acid]] to the acridine [[amine oxide]]. The carbon 9-position of acridine is activated for [[addition reaction]]s.<ref>G. Collin, H. Höke,"Acridine" in [[Ullmann's Encyclopedia of Industrial Chemistry]] 2012, [[Wiley-VCH]], Weinheim.{{doi|10.1002/14356007.a01_147}}</ref>

==Applications==
Several [[dye]]s and drugs feature the acridine skeleton.<ref>{{cite journal |doi=10.2174/0929867023369277|title=Acridine Derivatives as Chemotherapeutic Agents|year=2002|last1=Denny|journal=Current Medicinal Chemistry|volume=9|issue=18|pages=1655–65|pmid=12171548}}</ref>  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 [[Intercalation (biochemistry)|intercalate]].  [[Acridine orange]] (3,6-dimethylaminoacridine) is a [[nucleic acid]]-selective metachromatic [[Staining (biology)|stain]] useful for cell cycle determination.

===Dyes===
At one time acridine dyes were commercially significant, but they are now uncommon because they are not [[Lightfastness|lightfast]]. Acridine dyes are prepared by condensation of [[m-Phenylenediamine|1,3-diaminobenzene]] derivatives.  Illustrative is the reaction of [[2,4-Diaminotoluene|2,4-diaminotoluene]] with acetaldehyde:<ref>{{Ullmann|first1=Thomas|last1=Gessner|first2=Udo|last2=Mayer|title=Triarylmethane and Diarylmethane Dyes|doi=10.1002/14356007.a27_179}}</ref>

[[File:SynthesisBasicYellow9.png|thumb|left|420px|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.<ref name="Chisholm"/>

=== Molecular biology ===
Acridine is known to induce small insertions or deletions in nucleotide sequences, resulting in [[Frameshift mutation|frameshift mutations]].<ref name=":0">{{cite book |last1=Krebs |first1=Jocelyn E. |url=https://books.google.com/books?id=pNdLDgAAQBAJ |title=Lewin's GENES XII |last2=Goldstein |first2=Elliott S. |last3=Kilpatrick |first3=Stephen T. |date=2017-03-02 |publisher=Jones & Bartlett Learning |isbn=978-1-284-10449-3 |pages=157, 2927 |language=en}}</ref> This compound was useful to identify the triplet nature of the [[Genetic code|genetic codes]].<ref name=":0" />

==Structure==
As established by [[X-ray crystallography]], acridine has been obtained in eight [[polymorphism (materials science)|polymorphs]].  All feature very similar planar molecules with nearly identical bond lengths and bond distances.<ref>{{cite journal |doi=10.1107/S2056989019003645|title=Acridine form IX|year=2019|last1=Stephens|first1=Peter W.|last2=Schur|first2=Einat|last3=Lapidus|first3=Saul H.|last4=Bernstein|first4=Joel|journal=Acta Crystallographica Section E|volume=75|issue=4|pages=489–491|pmid=31161062|pmc=6509685|s2cid=174807725|doi-access=free|bibcode=2019AcCrE..75..489S }}</ref><ref>{{cite journal |doi=10.1021/acs.cgd.9b00557 |title=The (Current) Acridine Solid Form Landscape: Eight Polymorphs and a Hydrate |year=2019 |last1=Schur |first1=Einat |last2=Bernstein |first2=Joel |last3=Price |first3=Louise S. |last4=Guo |first4=Rui |last5=Price |first5=Sarah L. |last6=Lapidus |first6=Saul H. |last7=Stephens |first7=Peter W. |journal=Crystal Growth & Design |volume=19 |issue=8 |pages=4884–4893 |s2cid=198349955 |url=https://discovery.ucl.ac.uk/id/eprint/10080967/1/Price%20AAM%20Acridine_Review_CGD_Rev.pdf }}</ref>

==Safety==
Acridine is a skin irritant.  Its {{LD50}} (rats, oral) is 2,000&nbsp;mg/kg and 500&nbsp;mg/kg (mice, oral).<ref name=fca>{{cite web|url = https://www.fishersci.ca/viewmsds.do?catNo=AC102761000|title = MSDS of Acridine|website = www.fishersci.ca|access-date = 2014-06-22|publisher = Fisher Scientific}}</ref>

==See also==
* [[Lucigenin]], a chemiluminescent compound derived from acridine
* [[Xanthene]]

== References ==
{{reflist|30em}}

== Literature ==
* {{cite journal|title=Synthesis of Acridine-based DNA Bis-intercalating Agents |first1=Gerard P. |last1=Moloney |first2=David P. |last2=Kelly |first3=P. |last3=Mack |journal=Molecules |date=2001 |volume=6 |issue=3 |pages=230–243 |url=http://www.mdpi.org/molecules/papers/60300230.pdf |doi=10.3390/60300230 |doi-access=free}}
* {{cite book|title=Recent Advances in the Chemistry of Acridines|first1=A. |last1=Schmidt |first2=M. |last2=Liu |series=Advances in Heterocyclic Chemistry |date=2015 |volume=15 |pages=287–353 |doi=10.1016/bs.aihch.2015.04.004|isbn=9780128021293 }} [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==
{{wikisourcepar|Harper%27s_New_Monthly_Magazine/Vol._XLIV/No._261/February_1872/Editor%27s_Scientific_Record/Acridine%2C_a_New_Anthracene_Derivative|A magazine account (1872) of the isolation of acridine.}}
*{{Commons category-inline}}
* Synthesis of acridone in ''Organic Syntheses'' '''19''':6; ''Coll. Vol.'' '''2''':15 [https://web.archive.org/web/20120716191017/http://www.orgsyn.org/orgsyn/prep.asp?prep=cv2p0015] from [[o-chlorobenzoic acid|''o''-chlorobenzoic acid]] and aniline in a [[Goldberg reaction]].
* Synthesis of 9-aminoacridine in ''[[Organic Syntheses]]'' '''22''':5; ''Coll. Vol.'' '''3''':53. [https://web.archive.org/web/20120716191036/http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0053] from ''N''-phenylanthranilic acid.

{{Tricyclics}}
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[[Category:Acridines| ]]
[[Category:Simple aromatic rings]]
[[Category:Substances discovered in the 19th century]]