Solvent Screening Is Not Solvent Effect: A Review on the Most Neglected Aspect of Multicomponent Reactions

Abstract

In the current Perspective article, we critically review and discuss the importance of solvent effects on multicomponent reactions, likely the most neglected aspect in this research field. Although solvent-free reactions may be desirable sometimes, most multicomponent reactions still require a solvent to properly promote them. This requirement makes the knowledge of all drawbacks and advantages of each solvent a central issue when trying to optimize multicomponent reactions. Yet, only a few studies with actual evidence of solvent effects on these key reactions have been published. For the quantitative effects of solvents, studies are even scarcer. In this Perspective, we argue that greater efforts should be directed to such fundamental studies.

Revisiting Biginelli-like reactions: solvent effects, mechanisms, biological applications and correction of several literature reports

“…[18][19][20] The path toward greener catalyzed MCRs is illuminated by the elucidation of solvent effects, which also play a crucial role in considerations of selectivities (enantio-and diastereoselectivity), mechanistic route selection, and the recovery of catalytic systems. 1 Given that several solvents that were previously used are now subject to stricter regulations worldwide, [21][22][23][24][25] it is imperative to replace such solvents with environmentally friendly, bio-based, and non-toxic alternatives. [26][27][28][29][30][31][32] This replacement commences by utilizing solvents that possess these desirable features in basic research.…”

“…They may also align with green principles and the prospect of sustainable processes. As recently highlighted, 1 however, solvent effects have often been overlooked in the context of MCRs. The presence of multiple (at least three) active reagents, various mechanistic steps, and the possibility of multiple mechanistic pathways render MCRs particularly susceptible to the influence of solvent effects.…”

Multicomponent Reaction-Assisted Drug Discovery: A Time- and Cost-Effective Green Approach Speeding Up Identification and Optimization of Anticancer Drugs

“…For the generation of a diverse scaffold, other NIMCRs implemented are, namely, Pavarov-3CR, Dobener-3CR, Betti-3CR, and Petasis-3CR ( Figure 4 ). For further information on NIMCRs chemistry, the reader is directed toward comprehensive review articles and other very interesting recent publications [ 89 , 90 , 92 , 93 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 ].…”

Solvent Dependent Competitive Mechanisms for the Ugi Multicomponent Reaction: A Joint Theoretical and Experimental Study in the α-Acyl Aminocarboxamides vs α-Amino Amidines Formation

“…The Ugi MCR is among the most investigated MCRs, as recently reviewed . Despite its importance and the large number of available publications, several debates surrounding the Ugi MCR are noted. − One aspect still debated is the mechanism associated with this unique isocyanide MCR (Scheme ), especially considering the challenges associated with the investigation of multicomponent transformations. ,, For instance, established mechanistic views related to the Ugi four-components transformation have been challenged . Indeed, as will be discussed herein, fine details about the mechanism of this MCR have been emerging in less than one decade.…”