Quelet reaction
{{Short description|Chemical reaction}}
The Quelet reaction (also called the Blanc–Quelet reaction) is an organic coupling reaction in which a phenolic ether reacts with an aliphatic aldehyde to generate an α-chloroalkyl derivative.{{cite book|last1=Wang|first1=Zerong|title=Comprehensive organic name reactions and reagents|date=2009|publisher=John Wiley|location=Hoboken, N.J.|isbn=9780470638859|pages=2290–2292|chapter=517: Quelet Reaction}} The Quelet reaction is an example of a larger class of reaction, electrophilic aromatic substitution. The reaction is named after its creator R. Quelet, who first reported the reaction in 1932,{{cite journal | url=http://gallica.bnf.fr/ark:/12148/bpt6k73524/f155.image.r=Comptes%20rendus%201932%20195.langEN | title=preparation d'un derive chloro-methyl du para-bromo-anisol (methoxy-2 bromo-2 α-chlorotoluene). | author=R. Quelet | journal=Compt. Rend. | year=1932 | issue=T195 | page=155 | language=fr }} and is similar to the Blanc chloromethylation process.
The reaction proceeds under strong acid catalysis using HCl; zinc(II) chloride may be used as a catalyst in instances where the ether is deactivated.{{cite book|title=Organic reactions|last1=Denmark|first1=Scott E.|date=2006|publisher=Wiley|isbn=9780471264187|location=Hoboken, N.J.|pages=63–90|chapter=1:3 Chloromethylation of Aromatic Compounds}} The reaction primarily yields para-substituted products; however it can also produce ortho-substituted compounds if the para site is blocked.
Mechanism
The mechanism{{cite book | doi=10.1002/9780471739876 | title=Name Reactions and Reagents in Organic Synthesis | year=2005 | last1=Mundy | first1=Bradford P. | last2=Ellerd | first2=Michael G. | last3=Favaloro | first3=Frank G. | isbn=9780471739876 |pages=100–102}} of the Quelet reaction is primarily categorized as a reaction in polar acid. First, the carbonyl is protonated forming a highly reactive protonated aldehyde that acts as the electrophile to the nucleophilic pi-bond of the aromatic ring. Next, the aromatic ring is reformed via E1. Finally, the hydroxy group formed from the carbonyl oxygen is protonated a second time and leaves as a molecule of water, creating a carbocation that is attacked by the negatively charged chlorine ion.
Reaction conditions and limitations
File:Quelet mechanism with para-substituted reactant.jpg
The reaction requires a strong acid catalyst, but both Lewis acids and Brownsted-Lowry acids can be used in the Quelet reaction.{{Cite journal|last=Moulay|first=Saad|title=Towards Halomethylated Benzene-Bearing Monomeric and Polymeric Substrates|date=2011|journal=Designed Monomers and Polymers|volume=14|issue=3|pages=179–220|doi=10.1163/138577211X557495|doi-access=}} It has been noted that aqueous formaldehyde sometimes produces a better yield than paraformaldehyde. The reaction was first reported using zinc(II) chloride, however the reaction has been noted to proceed in the absence of this catalyst in highly activated aromatic compounds. If using an aromatic compound where the para-site is blocked, the reaction will add in the ortho-position (see example right).
Not all aromatic compounds can undergo Quelet reactions. For example, too highly halogenated aromatic compounds, aromatic compounds with nitro groups, and terphenyls cannot be used as reactants for Quelet reactions.{{cite book|last1=Fuson|first1=Reynold C.|last2=McKeever|first2=C. H.|title=Chloromethylation of Aromatic Compounds|date=2011|publisher=John Wiley|location=Hoboken, N.J.|pages=63–74}} Even for compounds that can undergo Quelet reactions, there sometimes exists other reactions that produce the same products in higher yields.{{Cite journal|last1=Sugawasa|first1=Shigehiko|last2=Fujisawa|first2=Toshiro|last3=Okada|first3=Kozo|date=1952|title=Synthesis of 2,2-Polymethylene-bis-(Py-tetrahydroisoquinoline) Derivatives|url=https://www.jstage.jst.go.jp/article/cpb1953/1/1/1_1_80/_pdf|journal=Pharmaceutical Bulletin|volume=1|pages=80–83|issn=1881-1345|via=JState}} The Quelet reaction can produce dangerous halomethyl ethers, gaseous and liquid compounds that are toxic to humans, and therefore is sometimes passed up for chloromethylations without these harmful byproducts.{{cite patent|country = US| number= EP0453993 A1| status = lapsed| title = Process for producing a halomethyl pivalate|pubdate = Oct 30, 1991|fdate= Apr 19, 1991|pridate= Apr 20, 1990
|inventor = Naoto Ihara Chemical Industry Co. Ltd. Yazawa, Keinosuke Ihara Chemical Ind. Co. Ltd. Ishikame|url=https://patents.google.com/patent/EP0453993A1}}
Usage
The Quelet reaction is an important step in the polymerization of aromatic monomers, such as styrene, PPO and PPEK. These chloromethylated aromatic polymers are used in a diverse set of industries, such as fuel cells and membranes for drug delivery.{{Cite journal|last=Zheng|first=Q. H.|display-authors=etal|date=2010|title=Water uptake profile in a model ion-exchange membrane: Conditions for water-rich channels|journal=The Journal of Chemical Physics|volume=142|issue=11|pages=237–240|doi=10.1063/1.4914512|pmid=25796265|osti=1176802|doi-access=free}}{{Cite journal|last=Shaikh|first=R.P.|display-authors=etal|date=2010|title=A review of multi-responsive membranous systems for rate-modulated drug delivery|journal=AAPS PharmSciTech|volume=11|issue=1|pages=441–459|doi=10.1208/s12249-010-9403-2|pmid=20300895|pmc=2850454}}