![Author ORCID: We display the ORCID iD icon alongside authors names on our website to acknowledge that the ORCiD has been authenticated when entered by the user. To view the users ORCiD record click the icon. [opens in a new tab]](https://chemrxiv.org/engage/assets/public/chemrxiv/images/logos/orcid.png)
Abstract
Since its discovery in 1877, the Friedel-Crafts alkylation reaction has been the method of choice to prepare various aryl hydrocarbons. Recent developments for this reaction have resulted in the synthesis of these compounds in one pot process with various metal as well as metal free protocols. However, the alkylation of common feedstock aldehydes using electron-deficient arenes and also with two different arene nucleophiles are quite challenging and scantily explored. Herein, we provide a solution to these problems by a new concept, “catalyst activation” accomplished by increasing the Brønsted acidity of p-toluenesulfonic acid (pTSA) through strong hydrogen bonding with hexafluoroisopropanol (HFIP). The real-time NMR titration, as well as computational studies, reveal multiple roles of HFIP in increasing the Brønsted acidity of para-toluene sulphonic acid (pTSA) and stabilization of the transition states formed during the electrophilic aromatic substitution. The developed process has a great potential for industrial application reflected in the synthesis of various bio-active natural products like arundine, tartarinoid C, and several other bioactive molecules. Also, the used HFIP was recovered in a gram-scale synthesis making this protocol highly cost-effective and conducive to industrial production.
Supplementary materials
Title
Tandem Cooperative Friedel-Crafts Reaction of Aldehydes with Electron Deficient Arenes Through Catalyst-Activation via Hydrogen Bonding Network
Description
The alkylation of common feedstock aldehydes using electron-deficient arenes and also with two different arene nucleophiles are quite challenging and scantily explored. Herein, we provide a solution to these problems by a new concept, “catalyst activation” accomplished by increasing the Brønsted acidity of p-toluenesulfonic acid (pTSA) through strong hydrogen bonding with hexafluoroisopropanol (HFIP). The real-time NMR titration, as well as computational studies, reveal multiple roles of HFIP in increasing the Brønsted acidity of para-toluene sulphonic acid (pTSA) and stabilization of the transition states formed during the electrophilic aromatic substitution. The developed process has a great potential for industrial application reflected in the synthesis of various bio-active natural products like arundine, tartarinoid C, and several other bioactive molecules. Also, the used HFIP was recovered in a gram-scale synthesis making this protocol highly cost-effective and conducive to industrial production.
Actions
