“On Water” Sustainable Synthesis of 1,5‐Disubstituted Tetrazoles via Ugi‐Azide Reaction through Perturbation of Kosmotropes Using Nacl.

Abstract

“ON WATER” acceleration of Ugi‐Azide reaction has been devised as a novel synthetic route for the one‐pot synthesis of 1,5‐disubstituted tetrazoles using NaCl. Due to the formation of kosmotropes, reaction does not occur in aqueous media alone which explains the low extent of hydrophobic interaction of reactants with water. However, presence of NaCl agitates the water kosmotropes and enhances the hydrophobic interactions of reactants with aqueous phase and desired product was isolated in excellent yield. Thus, NaCl plays a decisive, indispensable and unprecedented role through the perturbation of kosmotropes of water on Ugi‐azide reaction in aqueous media. Among the various as synthesized tetrazoles, ferrocenyl 1,5‐disubstituted tetrazoles showed excellent β–hematin inhibitory activities (IC50<3.5 μg/ml) as compared to reference drug chloroquine. Further we have also showed the synthetic utility of these compounds by Pd mediated post reaction transformation through an example.

Chemical Waltz of Organic Molecules “On Water”: Saline-Assisted Sustainable Regioselective Synthesis of Fluorogenic Heterobioconjugates via Click Reaction

“…This may be due to the formation of water kosmotropes (hydrogen-bonded clathrate), which surround the hydrophobic organic reactants, decreasing the interaction between reactants (Figure ). A perusal of literature ,, revealed that when ionic species like NaCl, KCl, NaBr, CH 3 COONa, NH 4 Cl, Na 2 SO 4 , MgSO 4 , etc. are dissolved in water, they strongly interact with water molecules and perturb the kosmotropes, and hence breaking the water cage and creating more space for reaction to proceed via enforced hydrophobic interactions to furnish the desired product in almost quantitative yield.…”

“…Since water molecules have low magnitude of hydrophobhic interaction and cannot form hydrogen bonding with hydrocarbons, they form a cage- or clathrate-like structure around hydrocarbons called kosmotropes. These kosmotropes capture the hydrophobic reactant molecules inside the cavity and thus decrease the interaction of reactant molecules. − Therefore, the reaction cannot be carried out in water alone. Compounds like NaCl act as a “salting-out” agent, which increases the hydrophobic effect and thus disturbs the kosmotropes by increasing the cavity formation energy cost in aqueous solution. − When such salts are dissolved in water, molecules of water collapse around their ions to solvate them via a process known as ionic hydration.…”

Choline Azide: New Reagent and Ionic Liquid in Catalyst‐Free and Solvent‐Free Synthesis of 5‐Substituted‐1H‐Tetrazoles: A Triple Function Reagent

“…5‐substituted‐1 H ‐tetrazoles were synthesized in Continuous flow reactors and microreactors . Recently, synthesis of 1,5‐disubstituted tetrazoles via Ugi‐Azide reaction on water was reported …”

Rapid microwave promoted heterocyclization of primary amines with triethyl orthoformate and sodium azide using zinc sulfide nanoparticles as recyclable catalyst

“…The aforesaid protocol during decades has been developed by chemists and attempted to approach greener, faster and high performance procedure that leads rapidly and smoothly to 1-substituted tetrazoles. On the basis of Kamiya method and widespread utility of these compounds, some methods for the preparation of 1-substituted tetrazoles were recently developed and reported (10)(11)(12)(13)(14)(15)(16). Recently, using the ytterbium (III) triflate (10) (11), FeCl 3 (18), and Fe 3 O 4 @silica sulfonic acid (19) as catalyst for heterocyclization of primary amines and triethyl orthoformate with sodium azide has been reported.…”