Phenolphthalein

{{Short description|pH indicator that turns pink in basic solution}}

{{About|Phenolphthalein|other related dyes in the phthalein family|Phthalein dye}}

{{chembox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 408953309

| ImageFile = Phenolphthalein.svg

| ImageClass = skin-invert

| ImageFile2 = Sample of solid phenolphthalein.jpg

| ImageSize2 = 250px

| PIN = 3,3-Bis(4-hydroxyphenyl)-2-benzofuran-1(3H)-one

| OtherNames = 3,3-Bis(4-hydroxyphenyl)isobenzofuran-1(3H)-one

| Section1 = {{Chembox Identifiers

|UNII_Ref = {{fdacite|changed|FDA}}

|UNII = 6QK969R2IF

|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

|ChemSpiderID = 4600

|InChI = 1/C20H14O4/c21-15-9-5-13(6-10-15)20(14-7-11-16(22)12-8-14)18-4-2-1-3-17(18)19(23)24-20/h1-12,21-22H

|InChIKey = KJFMBFZCATUALV-UHFFFAOYAH

|ChEMBL_Ref = {{ebicite|correct|EBI}}

|ChEMBL = 63857

|StdInChI_Ref = {{stdinchicite|correct|chemspider}}

|StdInChI = 1S/C20H14O4/c21-15-9-5-13(6-10-15)20(14-7-11-16(22)12-8-14)18-4-2-1-3-17(18)19(23)24-20/h1-12,21-22H

|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

|StdInChIKey = KJFMBFZCATUALV-UHFFFAOYSA-N

|CASNo=77-09-8

|CASNo_Ref = {{cascite|correct|CAS}}

|PubChem = 4764

|KEGG_Ref = {{keggcite|correct|kegg}}

|KEGG = D05456

|DrugBank_Ref = {{drugbankcite|changed|drugbank}}

|DrugBank = DB04824

|SMILES = O=C1OC(C2=C1C=CC=C2)(C3=CC=C(C=C3)O[H])C4=CC=C(C=C4)O[H]

}}

| Section2 = {{Chembox Properties

|C=20 | H=14 | O=4

|Appearance = White powder

|Density = 1.277 g/cm³ ({{convert|32|C}})

|MeltingPtC = 258-263

|MeltingPt_ref = {{cite web|url=https://www.sigmaaldrich.com/catalog/product/sial/105945|title=Phenolphthalein|access-date=7 October 2014|archive-date=8 November 2015|archive-url=https://web.archive.org/web/20151108081633/http://www.sigmaaldrich.com/catalog/product/sial/105945|url-status=live}}

|Solubility = 400 mg/l

|Solvent = other solvents

|SolubleOther = Insoluble in benzene and hexane; very soluble in ethanol and ether; slightly soluble in DMSO

|LambdaMax = 552 nm (1st)
374 nm (2nd)

}}

| Section6 = {{Chembox Pharmacology

|ATCCode_prefix = A06

|ATCCode_suffix = AB04

}}

| Section7 = {{Chembox Hazards

|GHSPictograms = {{GHS08}}

|GHSSignalWord = Danger

|HPhrases = {{H-phrases|341|350|361}}

|PPhrases = {{P-phrases|201|281|308+313}}

|NFPA-H = 2

|NFPA-F = 3

|NFPA-R = 0

}}

Phenolphthalein ({{IPAc-en|f|ɛ|ˈ|n|ɒ|l|(|f|)|θ|ə|l|iː|n}}{{cn|date=June 2022}} {{Respell|feh|NOL(F)|thə|leen}}) is a chemical compound with the formula C₂₀H₁₄O₄ and is often written as "HIn", "HPh", "phph" or simply "Ph" in shorthand notation. Phenolphthalein is often used as an indicator in acid–base titrations. For this application, it turns colorless in acidic solutions and pink in basic solutions. It belongs to the class of dyes known as phthalein dyes.

Phenolphthalein is slightly soluble in water and usually is dissolved in alcohols in experiments. It is a weak acid, which can lose H⁺ ions in solution. The nonionized phenolphthalein molecule is colorless and the double deprotonated phenolphthalein ion is fuchsia. Further proton loss in higher pH occurs slowly and leads to a colorless form. Phenolphthalein ion in concentrated sulfuric acid is orange red due to sulfonation.

Uses

=pH indicator=

{{pH_indicator|indicator_name=Phenolphthalein |low_pH=8.3 |high_pH=10.0|low_pH_color=white|low_pH_text=black|high_pH_color=magenta|high_pH_text=white}}

Phenolphthalein's common use is as an indicator in acid-base titrations. It also serves as a component of universal indicator, together with methyl red, bromothymol blue, and thymol blue.{{cite encyclopedia|url=https://www.iscid.org/encyclopedia/Universal_Indicator |title=Universal Indicator |encyclopedia=ISCID Encyclopedia of Science and Philosophy |url-status=dead |archive-url=https://web.archive.org/web/20060925035727/https://www.iscid.org/encyclopedia/Universal_Indicator |archive-date=September 25, 2006}}

Phenolphthalein adopts different forms in aqueous solution depending on the pH of the solution.{{cite journal |last1=Wittke |first1=Georg |title=Reactions of phenolphthalein at various pH values |journal=Journal of Chemical Education |date=1 March 1983 |volume=60 |issue=3 |pages=239 |doi=10.1021/ed060p239 |bibcode=1983JChEd..60..239W |issn=0021-9584}}{{cite journal |last1=Tamura |first1=Zenzo |title=Spectrophotometric Analysis of the Relationship between Dissociation and Coloration, and of the Structural Formulas of Phenolphthalein in Aqueous Solution |journal=Analytical Sciences |date= December 1996 |volume=12 |issue=6 |pages=927–930 |doi=10.2116/analsci.12.927|doi-access=free }}{{cite journal |last1=Abdel-Hamid |first1=Refat |title=The Adsorption Behavior of Phenolphthalein at a Mercury Electrode in Water-Ethanol Solutions |journal=Monatshefte für Chemie - Chemical Monthly |date=1 September 1998 |volume=129 |issue=8 |pages=817–826 |doi=10.1007/PL00013491|s2cid=92339258 }}{{cite journal |last1=Kunimoto |first1=Ko-Ki |title=Molecular structure and vibrational spectra of phenolphthalein and its dianion |journal=Spectrochimica Acta Part A |date= February 2001|volume=57 |issue=2 |pages=265–271 |doi=10.1016/S1386-1425(00)00371-1|pmid=11206560 |bibcode=2001AcSpA..57..265K }} Inconsistency exists in the literature about hydrated forms of the compounds and the color of sulfuric acid. Wittke reported in 1983 that it exists in protonated form (H₃In⁺) under strongly acidic conditions, providing an orange coloration. However, a later paper suggested that this color is due to sulfonation to phenolsulfonphthalein.

The lactone form (H₂In) is colorless between strongly acidic and slightly basic conditions. The doubly deprotonated (In^2-) phenolate form (the anion form of phenol) gives the familiar pink color. In strongly basic solutions, phenolphthalein is converted to its In(OH)³⁻ form, and its pink color undergoes a rather slow fading reaction and becomes completely colorless when pH is greater than 13.

The pK_a values of phenolphthalein were found to be 9.05, 9.50 and 12 while those of phenolsulfonphthalein are 1.2 and 7.70. The pK_a for the color change is 9.50.

class="wikitable" style="margin: 1em auto 1em auto; text-align: center;" ! Species \| H₃In⁺	H₂In	In²⁻	In(OH)³⁻
Structure \| File:Phenolphthalein-very-low-pH-2D-skeletal.svg \|\| File:Phenolphthalein-low-pH-2D-skeletal.svg \|\| File:Phenolphthalein-mid-pH-2D-skeletal.svg \|\| File:Phenolphthalein-high-pH-2D-skeletal.svg
Model \| 80px \|\| 80px \|\| 80px \|\| 80px
pH \| <−1 in H₂SO₄ \|\| 0–8.3 \|\| 8.3–10.0{{cite journal \|last1=Rathod \|first1=Balraj B. \|last2=Murthy \|first2=Sahana \|last3=Bandyopadhyay \|first3=Subhajit \|title=Is this Solution Pink Enough? A Smartphone Tutor to Resolve the Eternal Question in Phenolphthalein-Based Titration \|journal=Journal of Chemical Education \|date=20 February 2019 \|volume=96 \|issue=3 \|pages=486–494 \|doi=10.1021/acs.jchemed.8b00708\|bibcode=2019JChEd..96..486R \|s2cid=104475433 }} \|\| >12
Conditions \| strongly acidic \|\| acidic or near-neutral \|\| basic \|\| strongly basic
Color \| orange \|\| colorless \|\| pink to fuchsia \|\| colorless
Image \| 100px \|\| \|\| 100px \|\|

class="wikitable" style="margin: 1em auto 1em auto; text-align: center;"

! Species

| H₃In⁺

H₂In

In²⁻

In(OH)³⁻

Structure

| File:Phenolphthalein-very-low-pH-2D-skeletal.svg || File:Phenolphthalein-low-pH-2D-skeletal.svg || File:Phenolphthalein-mid-pH-2D-skeletal.svg || File:Phenolphthalein-high-pH-2D-skeletal.svg

Model

| 80px || 80px || 80px || 80px

| <−1 in H₂SO₄ || 0–8.3 || 8.3–10.0{{cite journal |last1=Rathod |first1=Balraj B. |last2=Murthy |first2=Sahana |last3=Bandyopadhyay |first3=Subhajit |title=Is this Solution Pink Enough? A Smartphone Tutor to Resolve the Eternal Question in Phenolphthalein-Based Titration |journal=Journal of Chemical Education |date=20 February 2019 |volume=96 |issue=3 |pages=486–494 |doi=10.1021/acs.jchemed.8b00708|bibcode=2019JChEd..96..486R |s2cid=104475433 }} || >12

Conditions

| strongly acidic || acidic or near-neutral || basic || strongly basic

Color

| orange || colorless || pink to fuchsia || colorless

Image

| 100px || || 100px ||

class="wikitable" style="margin: 1em auto 1em auto;"

PP startAnimGif

An animation of the pH-dependent reaction mechanism: H₃In⁺ → H₂In → In²⁻ → In(OH)³⁻

==Carbonation of concrete==

Phenolphthalein's pH sensitivity is exploited in other applications: concrete has naturally high pH due to the calcium hydroxide formed when Portland cement reacts with water. As the concrete reacts with carbon dioxide in the atmosphere, pH decreases to 8.5–9. When a 1% phenolphthalein solution is applied to normal concrete, it turns bright pink. However, if it remains colorless, it shows that the concrete has undergone carbonation. In a similar application, some spackling used to repair holes in drywall contains phenolphthalein. When applied, the basic spackling material retains a pink color; when the spackling has cured by reaction with atmospheric carbon dioxide, the pink color fades.{{cite patent | country = US | number = 6531528 | title = Ready to use spackle/repair product containing dryness indicator | pubdate = 2003-03-11 | inventor = Ronald D. Kurp | assign = Dap Products Inc.}}

==Education==

In a highly basic solution, phenolphthalein's slow change from pink to colorless as it is converted to its Ph(OH)³⁻ form is used in chemistry classes for the study of reaction kinetics.

==Entertainment==

Phenolphthalein is used in toys, for example as a component of disappearing inks, or disappearing dye on the "Hollywood Hair" Barbie hair. In the ink, it is mixed with sodium hydroxide, which reacts with carbon dioxide in the air. This reaction leads to the pH falling below the color change threshold as hydrogen ions are released by the reaction:

:OH⁻_(aq) + CO₂_(g) → carbonate_(aq) + H⁺_(aq).

To develop the hair and "magic" graphical patterns, the ink is sprayed with a solution of hydroxide, which leads to the appearance of the hidden graphics by the same mechanism described above for color change in alkaline solution. The pattern will eventually disappear again because of the reaction with carbon dioxide. Thymolphthalein is used for the same purpose and in the same way, when a blue color is desired.{{Cite web |url=https://www.chymist.com/Toystore%20part3.pdf |title=Toystore |access-date=2022-02-22 |archive-date=2021-07-02 |archive-url=https://web.archive.org/web/20210702182850/http://www.chymist.com/Toystore%20part3.pdf |url-status=live }}

== Detection of blood ==

A reduced form of phenolphthalein, phenolphthalin, which is colorless, is used in a test to identify substances thought to contain blood, commonly known as the Kastle–Meyer test. A dry sample is collected with a swab or filter paper. A few drops of alcohol, then a few drops of phenolphthalein, and finally a few drops of hydrogen peroxide are dripped onto the sample. If the sample contains hemoglobin, it will turn pink immediately upon addition of the peroxide, because of the generation of phenolphthalein. A positive test indicates the sample contains hemoglobin and, therefore, is likely blood. A false positive can result from the presence of substances with catalytic activity similar to hemoglobin. This test is not destructive to the sample; it can be kept and used in further tests. This test has the same reaction with blood from any animal whose blood contains hemoglobin, including almost all vertebrates; further testing would be required to determine whether it originated from a human.

=Laxative=

Phenolphthalein has been used for over a century as a laxative, but is now being removed from over-the-counter laxatives{{cite journal | pmid = 12708936 |date=May 2003 | author = Spiller, H. A. | author2 = Winter, M. L. | author3 = Weber, J. A. | author4 = Krenzelok, E. P. | author5 = Anderson, D. L. | author6 = Ryan, M. L. | title = Skin Breakdown and Blisters from Senna-Containing Laxatives in Young Children | volume = 37 | issue = 5 | pages = 636–639 | journal = The Annals of Pharmacotherapy | doi = 10.1345/aph.1C439 |s2cid=31837142 }} over concerns of carcinogenicity.{{cite journal | url = https://cancerres.aacrjournals.org/content/56/21/4922.full.pdf | journal = Cancer Research | volume = 56 | pages = 4922–4926 | date = 1996 | title = Phenolphthalein Exposure Causes Multiple Carcinogenic Effects in Experimental Model Systems | author = Dunnick, J. K. | author2 = Hailey, J. R. | pmid = 8895745 | issue = 21 | access-date = 2022-02-22 | archive-date = 2022-02-17 | archive-url = https://web.archive.org/web/20220217005030/https://cancerres.aacrjournals.org/content/56/21/4922.full.pdf | url-status = live }}{{cite journal | pmid = 9544189 | date = 1998 | author = Tice, R. R. | author2 = Furedi-Machacek, M. | author3 = Satterfield, D. | author4 = Udumudi, A. | author5 = Vasquez, M. | author6 = Dunnick, J. K. | title = Measurement of Micronucleated Erythrocytes and DNA Damage during Chronic Ingestion of Phenolphthalein in Transgenic Female Mice Heterozygous for the p53 Gene | volume = 31 | issue = 2 | pages = 113–124 | journal = Environmental and Molecular Mutagenesis | doi = 10.1002/(SICI)1098-2280(1998)31:2<113::AID-EM3>3.0.CO;2-N | s2cid = 36550267 }} Laxative products formerly containing phenolphthalein have often been reformulated with alternative active ingredients: Feen-a-Mint{{Cite web|url=https://www.drugbank.ca/drugs/DB04824|website=DrugBank|title=Phenolphthalein|access-date=2020-04-25|archive-date=2020-08-06|archive-url=https://web.archive.org/web/20200806152100/https://www.drugbank.ca/drugs/DB04824|url-status=live}} switched to bisacodyl, and Ex-Lax{{cite news |url= https://www.nytimes.com/1997/08/30/us/3-versions-of-ex-lax-are-recalled-after-fda-proposes-ban-on-ingredient.html |title= 3 Versions of Ex-Lax Are Recalled After F.D.A. Proposes Ban on Ingredient |first= Sheryl Gay |last= Stolberg |work= The New York Times |date= August 30, 1997 |access-date= April 25, 2020 |archive-date= May 7, 2021 |archive-url= https://web.archive.org/web/20210507041558/http://www.nytimes.com/1997/08/30/us/3-versions-of-ex-lax-are-recalled-after-fda-proposes-ban-on-ingredient.html |url-status= live }} was switched to a senna extract.

Thymolphthalein is a related laxative made from thymol.

Despite concerns regarding its carcinogenicity based on rodent studies, the use of phenolphthalein as a laxative is unlikely to cause ovarian cancer.{{cite journal | last = Cooper | first = G. S. | author2 = Longnecker, M. P. | author3 = Peters, R. K. | title = Ovarian Cancer Risk and Use of Phenolphthalein-Containing Laxatives | journal = Pharmacoepidemiology and Drug Safety | date = 2004 | volume = 13 | issue = 1 | pages = 35–39 | pmid = 14971121 | doi = 10.1002/pds.824 | s2cid = 24783082 | url = https://zenodo.org/record/1229318 | access-date = 2019-06-26 | archive-date = 2022-01-26 | archive-url = https://web.archive.org/web/20220126210628/https://zenodo.org/record/1229318 | url-status = live }} Some studies suggest a weak association with colon cancer, while others show none at all.{{cite book |chapter=Other pharmaceutical agents. |title=IARC monographs on the evaluation of carcinogenic risks to humans |date=2000 |volume=76 |pages=345–486 |publisher=International Agency for Research on Cancer |pmid=11000977 |pmc=7196975 |url=https://www.ncbi.nlm.nih.gov/books/NBK401424/}}

Phenolphthalein is described as a stimulant laxative. In addition, it has been found to inhibit human cellular calcium influx via store-operated calcium entry (SOCE, see {{link section|Calcium release activated channel|Structure}}) in vivo. This is effected by its inhibiting thrombin and thapsigargin, two activators of SOCE that increase intracellular free calcium.{{cite journal | last = Dobrydneva | first = Y. | author2 = Wilson, E. | author3 = Abelt, C. J. | author4 = Blackmore, P. F. | title = Phenolphthalein as a Prototype Drug for a Group of Structurally Related Calcium Channel Blockers in Human Platelets | journal = Journal of Cardiovascular Pharmacology | date = 2009 | volume = 53 | issue = 3 | pages = 231–240 | pmid = 19247192 | doi=10.1097/FJC.0b013e31819b5494| s2cid = 21833487 }}

Phenolphthalein has been added to the European Chemicals Agency's candidate list for substance of very high concern (SVHC).{{Cite web|url=https://echa.europa.eu/substance-information/-/substanceinfo/100.000.914|title=Phenolphthalein - Substance Information - ECHA|website=echa.europa.eu|language=en-GB|access-date=2017-11-06|archive-date=2018-06-12|archive-url=https://web.archive.org/web/20180612135929/https://echa.europa.eu/substance-information/-/substanceinfo/100.000.914|url-status=live}} It is on the IARC group 2B list for substances "possibly carcinogenic to humans".

The discovery of phenolphthalein's laxative effect was due to an attempt by the Hungarian government to label{{clarify|date=June 2023}} genuine local white wine with the substance in 1900. Phenolphthalein did not change the taste of the wine and would change color when a base is added, making it a good label in principle. However, it was found that ingestion of the substance led to diarrhea. Max Kiss, a Hungarian-born pharmacist residing in New York, heard about the news and launched Ex-Lax in 1906.{{cite web |last1=May |first1=Paul |title=Phenolphthalein - Molecule of the Month - March 2022 (HTML version) |url=https://www.chm.bris.ac.uk/motm/phenolphthalein/phphh.htm |website=www.chm.bris.ac.uk}}{{cite web |last1=Arney |first1=Kat |title=Phenolphthalein |url=https://www.chemistryworld.com/podcasts/phenolphthalein/3009674.article |website=Chemistry World |language=en |date=2018-10-25}}

Synthesis

Phenolphthalein can be synthesized by condensation of phthalic anhydride with two equivalents of phenol under acidic conditions. It was discovered in 1871 by Adolf von Baeyer.{{cite journal | author = Baeyer, A. | date = 1871 | title = Ueber eine neue Klasse von Farbstoffen | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 4 | issue = 2 | pages = 555–558 | doi = 10.1002/cber.18710040209 | url = https://zenodo.org/record/1425008 | access-date = 2020-09-02 | archive-date = 2021-02-14 | archive-url = https://web.archive.org/web/20210214061740/https://zenodo.org/record/1425008 | url-status = live }}{{cite journal | author = Baeyer, A. | date = 1871 | title = Ueber die Phenolfarbstoffe | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 4 | issue = 2 | pages = 658–665 | doi = 10.1002/cber.18710040247 | url = https://zenodo.org/record/1425010 | access-date = 2019-06-26 | archive-date = 2021-10-11 | archive-url = https://web.archive.org/web/20211011061658/https://zenodo.org/record/1425010 | url-status = live }}{{cite journal | author = Baeyer, A. | date = 1871 | title = Ueber die Phenolfarbstoffe | journal = Polytechnisches Journal | volume = 201 | issue = 89 | pages = 358–362 | url = https://dingler.culture.hu-berlin.de/article/pj201/ar201089 | access-date = 2022-02-22 | archive-date = 2021-10-11 | archive-url = https://web.archive.org/web/20211011061700/http://dingler.culture.hu-berlin.de/article/pj201/ar201089 | url-status = live }}

File:Phenolphthalein Synthesis.svg