Editing Crown ether

{{Short description|Ring molecules with several ether (–O–) groups}}
[[Image:18-crown-6-potassium-3D-balls-A.png|thumb|right|200px|[[18-crown-6]] coordinating to a [[potassium]] ion]]

In [[organic chemistry]], '''crown ethers''' are cyclic [[chemical compound]]s that consist of a [[Ring (chemistry)|ring]] containing several [[ether]] groups ({{chem2|R\sO\sR’}}).  The most common crown ethers are cyclic [[oligomer]]s of [[ethylene oxide]], the repeating unit being ethyleneoxy, i.e., {{chem2|\sCH2CH2O\s}}.  Important members of this series are the tetramer (''n''&nbsp;=&nbsp;4), the pentamer (''n''&nbsp;=&nbsp;5), and the hexamer (''n''&nbsp;=&nbsp;6).  The term "crown" refers to the resemblance between the structure of a crown ether bound to a [[cation]], and a [[crown (headgear)|crown]] sitting on a person's head. The first number in a crown ether's name refers to the number of atoms in the cycle, and the second number refers to the number of those atoms that are [[oxygen]].  Crown ethers are much broader than the [[oligomer]]s of ethylene oxide; an important group are derived from [[catechol]].

Crown ethers strongly bind certain cations, forming [[complex (chemistry)|complexes]]. The oxygen atoms are well situated to coordinate with a cation located at the interior of the ring, whereas the exterior of the ring is hydrophobic. The resulting cations often form salts that are soluble in nonpolar solvents, and for this reason crown ethers are useful in [[phase transfer catalysis]]. The [[ligand|denticity]] of the polyether influences the affinity of the crown ether for various cations.  For example, 18-crown-6 has high affinity for potassium cation, 15-crown-5 for sodium cation, and 12-crown-4 for lithium cation. The high affinity of 18-crown-6 for potassium ions contributes to its toxicity.  The smallest crown ether still capable of binding cations is 8-crown-4,<ref>{{Cite journal|last1=van der Ham|first1=Alex|last2=Hansen|first2=Thomas|last3=Lodder|first3=Gerrit|last4=Codée|first4=Jeroen D. C.|last5=Hamlin|first5=Trevor A.|last6=Filippov|first6=Dmitri V.|date=2019|title=Computational and NMR Studies on the Complexation of Lithium Ion to 8-Crown-4|journal=ChemPhysChem|language=en|volume=20|issue=16|pages=2103–2109|doi=10.1002/cphc.201900496|issn=1439-7641|pmc=6772996|pmid=31282054}}</ref> with the largest experimentally confirmed crown ether being 81-crown-27.<ref>{{cite journal |last1=Yang |first1=Zhao |last2=Yu |first2=Ga-Er |last3=Cooke |first3=Jennifer |last4=Ali-Abid |first4=Ziad |last5=Viras |first5=Kyriakos |last6=Matsuura |first6=Hiroatsu |last7=Ryan |first7=Anthony J |last8=Booth |first8=Colin |title=Preparation and crystallinity of a large unsubstituted crown ether, cyclic heptacosa(oxyethy1ene) (cyc2o=E2, 81-crown-27), studied by Raman spectroscopy, X-ray scattering and differential scanning calorimetry |journal=J. Chem. Soc., Faraday Trans. |date=1996 |volume=92 |issue=17 |pages=3173–3182 |doi=10.1039/FT9969203173 |url=https://pubs.rsc.org/en/content/articlelanding/1996/FT/ft9969203173|url-access=subscription }}</ref> Crown ethers are not the only macrocyclic ligands that have affinity for the potassium cation. [[Ionophore]]s such as [[valinomycin]] also display a marked preference for the potassium cation over other cations.

Crown ethers have been shown to coordinate to [[Lewis acids]] through electrostatic, σ-hole (see [[halogen bond]]) interactions, between the Lewis basic oxygen atoms of the crown ether and the electrophilic Lewis acid center.<ref>{{cite journal |last1=Marczenko |first1=K. M. |last2=Mercier |first2=H. P. A. |last3=Schrobilgen |first3=G. J. |title=A Stable Crown-Ether Complex with a Noble-gas Compound |journal=Angew. Chem. Int. Ed. |volume=57 |issue=38 |pages=12448–12452 |doi=10.1002/anie.201806640|pmid=29953704 |year=2018 |s2cid=49589053 }}</ref><ref>{{cite journal |last1=Lipkowski |first1=J. |title=Antimony(III) fluoride: Inclusion complexes with crown ethers |last2=Fonari |first2=M. S. |last3=Kravtsov |first3=V. C. |last4=Simonov |first4=Y. A. |last5=Ganin |first5=E. V. |last6=Gemboldt |first6=V. O. |journal=J. Chem. Crystallogr. |date=1996 |volume=26 |issue=12 |page=823|doi=10.1007/BF01670315|bibcode=1996JCCry..26..823L |s2cid=93153773 }}</ref>

:[[Image:Various crown ethers (molecular diagrams).svg|thumb|center|700px|Structures of common crown ethers: [[12-crown-4]], [[15-crown-5]], [[18-crown-6]], [[dibenzo-18-crown-6]], and an [[aza-crown ether]]]]

==History==
In 1967, [[Charles Pedersen]], who was a [[chemist]] working at [[DuPont]], discovered a simple method of synthesizing a crown ether when he was trying to prepare a [[complexing agent]] for [[divalent cation]]s.<ref>{{Cite journal| last1 = Pedersen | first1 = C. J.| title = Cyclic polyethers and their complexes with metal salts| journal = Journal of the American Chemical Society| volume = 89| issue = 26| pages = 7017–7036| year = 1967 | doi = 10.1021/ja01002a035| bibcode = 1967JAChS..89.7017P}}</ref><ref>{{Cite journal| last1 = Pedersen | first1 = C. J.| title = Cyclic polyethers and their complexes with metal salts| journal = Journal of the American Chemical Society| volume = 89| issue = 10| pages = 2495–2496| year = 1967 | doi = 10.1021/ja00986a052| bibcode = 1967JAChS..89.2495P}}</ref> His strategy entailed linking two [[catechol]]ate groups through one [[hydroxyl]] on each molecule. This linking defines a polydentate ligand that could partially envelop the cation and, by [[ionization]] of the phenolic hydroxyls, neutralize the bound dication. He was surprised to isolate a [[by-product]] that strongly complexed [[potassium]] cations. Citing earlier work on the dissolution of [[potassium]] in 16-crown-4,<ref name="stewart">{{cite patent|inventor1-first=D. G.|inventor1-last=Stewart|inventor2-first= D. Y. |inventor2-last=Waddan |inventor3-first=E. T. |inventor3-last=Borrows |country-code=GB|patent-number=785229|issue-date= 1957-10-23}}</ref><ref name="down">{{cite journal|last1=Down|first1=J. L.|last2=Lewis|first2=J.|last3=Moore|first3=B.|last4=Wilkinson|first4=G.|title=761. The solubility of alkali metals in ethers|journal=Journal of the Chemical Society |year=1959|pages=3767 |doi=10.1039/jr9590003767}}</ref> he realized that the cyclic [[polyether]]s represented a new class of complexing agents that were capable of binding [[alkali metal]] cations. He proceeded to report systematic studies of the synthesis and binding properties of crown ethers in a seminal series of papers. The fields of [[organic synthesis]], [[phase transfer catalyst]]s, and other emerging disciplines benefited from the discovery of crown ethers.  Pedersen particularly popularized the dibenzo crown ethers.<ref>{{OrgSynth | first= Charles J.|last= Pedersen | title = Macrocyclic Polyethers: Dibenzo-18-Crown-6 Polyether and Dicyclohexyl-18-Crown-6 Polyether | collvol = 6 | collvolpages = 395 | year = 1988 | prep = CV6P0395}}</ref>

Pedersen shared the 1987 [[Nobel Prize in Chemistry]] for the discovery of the synthetic routes to, and binding properties of, crown ethers.

==Affinity for cations==
Due to the [[chelate effect]] and [[macrocyclic effect]], crown ethers exhibit stronger affinities for diverse cations than their divided or [[Open-chain compound|acyclic]] analogs. Hereby, the cation selectivity for alkali metal ions is mainly dependent on the size and charge density of the ion and the cavity size of the crown ether.<ref name=":0">{{Cite journal|last1=Liou|first1=Chien-Chung|last2=Brodbelt|first2=Jennifer S.|author-link1=Jennifer S. Brodbelt|date=July 1992|title=Determination of orders of relative alkali metal ion affinities of crown ethers and acyclic analogs by the kinetic method|journal=Journal of the American Society for Mass Spectrometry|volume=3|issue=5|pages=543–548|doi=10.1016/1044-0305(92)85031-e|pmid=24234497|s2cid=36106963 |issn=1044-0305|doi-access=|bibcode=1992JASMS...3..543L }}</ref> 
{| class="wikitable"
|+Comparison of Cavity Size with Effective Ion Radii of Alkali Metals
!Crown Ether
!Cavity Size/Å<ref>{{Citation|last1=Christensen|first1=J.J.|title=PREFACE|date=1978|work=Synthetic Multidentate Macrocyclic Compounds|pages=ix–x|publisher=Elsevier|isbn=978-0-12-377650-1|last2=Izatt|first2=R.M.|doi=10.1016/b978-0-12-377650-1.50005-8|doi-access=}}</ref>
!Favored Alkali Ion<ref>{{Cite journal|last=Frensdorff|first=Hans K.|date=February 1971|title=Stability constants of cyclic polyether complexes with univalent cations|journal=Journal of the American Chemical Society|language=en|volume=93|issue=3|pages=600–606|doi=10.1021/ja00732a007|bibcode=1971JAChS..93..600F |issn=0002-7863}}</ref>
!Effective Ion Radius/Å<ref>{{Cite journal|last=Shannon|first=R. D.|date=1976-09-01|title=Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides|journal=Acta Crystallographica Section A|volume=32|issue=5|pages=751–767|doi=10.1107/s0567739476001551|bibcode=1976AcCrA..32..751S|issn=0567-7394}}</ref>
|-
|12-crown-4
|0.6-0.75
|Li<sup>+</sup>
|0.76
|-
|15-crown-5
|0.86-0.92
|Na<sup>+</sup>
|1.02
|-
|18-crown-6
|1.34-1.55
|K<sup>+</sup>
|1.38
|-
|21-crown-7
|1.7-2.1
|Cs<sup>+</sup>
|1.67
|}
Affinities of a given crown ether towards the cations of [[lithium]], [[sodium]], and potassium can change by multiple magnitudes, which is attributed to the high differences in their charge density. Between the cations of potassium, [[rubidium]], and cesium changes in affinities are less notable, as their charge density varies less than the alkali metals in earlier periods.<ref name=":0" />

Apart from its high affinity for potassium cations, [[18-crown-6]] can also bind to protonated amines and form very stable complexes in both solution and the gas phase. Some [[amino acids]], such as [[lysine]], contain a primary [[amine]] on their side chains. Those protonated amino groups can bind to the cavity of 18-crown-6 and form stable complexes in the gas phase. Hydrogen-bonds are formed between the three hydrogen atoms of protonated amines and three oxygen atoms of 18-crown-6. These hydrogen-bonds make the complex a stable adduct. By incorporating luminescent substituents into their backbone, these compounds have proved to be sensitive ion probes, as changes in the absorption or fluorescence of the photoactive groups can be measured for very low concentrations of metal present.<ref>{{cite book|last1=Fabbrizzi|first1= L.|last2= Francese|first2= G.|last3= Licchelli|first3= M.|last4= Pallavicini|first4= P.|last5=Perotti |first5=A.|last6= Poggi|first6= A.|last7= Sacchi|first7= D.|last8= Taglietti|first8= A.|title= Chemosensors of Ion and Molecule Recognition|series= NATO ASI Series C |volume=492|editor1-last= Desvergne|editor1-first= J. P.|editor2-last= Czarnik|editor2-first= A. W.|publisher= Kluwer Academic Publishers|location= Dordrecht|date= 1997|page= 75}}</ref> Some attractive examples include macrocycles, incorporating oxygen and/or nitrogen donors, that are attached to polyaromatic species such as [[anthracenes]] (via the 9 and/or 10 positions)<ref>{{cite book|last1=Bouas-Laurent|first1= H.|last2= Desvergne|first2= J. P.|last3= Fages|first3= F.|last4= Marsau|first4= P. |title=Fluorescent Chemosensors for Ion and Molecule Recognition |url=https://archive.org/details/fluorescentchemo1992czar|url-access=limited|series=ACS Symposium Series 538|editor-first= Czarnik|editor-last= A. W. |publisher=American Chemical Society |location=Washington, DC|date= 1993| page= [https://archive.org/details/fluorescentchemo1992czar/page/n66 59]|isbn= 9780841227286}}</ref> or [[naphthalenes]] (via the 2 and 3 positions).<ref>{{cite journal|last1=Sharghi|first1=Hashem|last2=Ebrahimpourmoghaddam|first2=Sakineh|title=A Convenient and Efficient Method for the Preparation of Unique Fluorophores of Lariat Naphtho-Aza-Crown Ethers|journal=Helvetica Chimica Acta|volume=91|issue=7|year=2008|pages=1363–1373 |doi=10.1002/hlca.200890148}}</ref> Some modifications of dye ionophores by crown ethers exhibit [[Molar attenuation coefficient|extinction coefficients]] that are dependent on the chain lengths of chained cations.<ref>{{Cite journal|last1=Fuji|first1=Kaoru|last2=Tsubaki|first2=Kazunori|last3=Tanaka|first3=Kiyoshi|last4=Hayashi|first4=Noriyuki|last5=Otsubo|first5=Tadamune|last6=Kinoshita|first6=Takayoshi|date=April 1999|title=Visualization of Molecular Length of α,ω-Diamines and Temperature by a Receptor Based on Phenolphthalein and Crown Ether|journal=Journal of the American Chemical Society|volume=121|issue=15|pages=3807–3808|doi=10.1021/ja9836444|bibcode=1999JAChS.121.3807F |issn=0002-7863}}</ref> 

== Pharmaceutical applications ==
Crown ethers have been investigated as excipients in pharmaceutical applications,<ref>{{Cite journal |last1=Chehardoli |first1=Gholamabbas |last2=Bahmani |first2=Asrin |title=The role of crown ethers in drug delivery |journal=Supramolecular Chemistry |date=2019-04-03 |volume=31 |issue=4 |pages=221–238 |url=https://www.tandfonline.com/doi/abs/10.1080/10610278.2019.1568432 |doi=10.1080/10610278.2019.1568432 |issn=1061-0278|url-access=subscription }}</ref> demonstrating potential to improve the solubility of poorly soluble drugs and enhance their permeability across mucosal membranes.<ref>{{Cite journal |last1=Morrison |first1=Peter W. J. |last2=Porfiryeva |first2=Natalia N. |last3=Chahal |first3=Sukhmanpreet |last4=Salakhov |first4=Ilgiz A. |last5=Lacourt |first5=Charlène |last6=Semina |first6=Irina I. |last7=Moustafine |first7=Rouslan I. |last8=Khutoryanskiy |first8=Vitaliy V. |date=2017-10-02 |title=Crown Ethers: Novel Permeability Enhancers for Ocular Drug Delivery? |url=https://pubs.acs.org/doi/full/10.1021/acs.molpharmaceut.7b00556 |journal=Molecular Pharmaceutics |volume=14 |issue=10 |pages=3528–3538 |doi=10.1021/acs.molpharmaceut.7b00556 |pmid=28825493 |issn=1543-8384}}</ref> Evaluation of antibacterial activities of some thia crown ethers indicated that they can be considered as inhibitors for S. aureus methicillin resistance and P. aeruginosa.<ref>{{cite journal |author1=Seyedi |first=S. M. |author2=Sadeghian, A. |author3=Hazrathosseyni, A. |author4=Sadeghian, H. |author5=Sadeghian, M. |date=2007 |title=Synthesis and Biological Evaluation of Some New Thioether-Ester Crown Ethers |journal=Phosphorus, Sulfur, and Silicon and the Related Elements |volume=182 |issue=2 |pages=265–272|doi=10.1080/10426500600917060 }}</ref> In addition, some of these compounds were screened for their antibacterial and antifungal activity on ''Klebsiella pneumoniae, Staphilococcus aureus, Pseudomanas aeruginosa'' and ''Candida albicans''.<ref>{{Cite journal |last1=Sadeghian |first1=Ali |last2=Mohammad Seyedi |first2=Seyed |last3=Sadeghian |first3=Hamid |last4=Hazrathoseyni |first4=Ayla |last5=Sadeghian |first5=Mohammad |date=December 2007 |title=Synthesis, biological evaluation and QSAR studies of some new thioether–ester crown ethers |url=https://www.tandfonline.com/doi/full/10.1080/17415990701670718 |journal=Journal of Sulfur Chemistry |language=en |volume=28 |issue=6 |pages=597–605 |doi=10.1080/17415990701670718 |issn=1741-5993|url-access=subscription }}</ref> Despite these promising properties, their broader application remains limited due to concerns over the toxicity associated with crown ethers. 

==See also==
* [[Aza-crown ether]]
* [[Thia-crown ether]]
* [[Cryptand]]
* [[Metallacrown]]

==References==
{{Reflist}}

==External links ==
{{Commons category|Crown ethers}}
* {{cite web|url=http://nobelprize.org/chemistry/laureates/1987/pedersen-lecture.pdf |first=Charles |last=Pedersen |title=Nobel Lecture|date=1987|website=Nobel Prize}}
* [https://web.archive.org/web/20100206080936/http://www.org-chem.org/yuuki/crown/crown_en.html Molecular crown]

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[[Category:Crown ethers| ]]