Fischer Indole Synthesis in the Gas Phase, the Solution Phase, and at the Electrospray Droplet Interface

Abstract

Previous reports have shown that reactions occurring in the microdroplets formed during electrospray ionization can, under the right conditions, exhibit significantly greater rates than the corresponding bulk solution-phase reactions. The observed acceleration under electrospray ionization could result from a solution-phase, a gas-phase, or an interfacial reaction. This study shows that a gas-phase ion/molecule (or ion/ion) reaction is not responsible for the observed rate enhancement in the particular case of the Fischer indole synthesis. The results show that the accelerated reaction proceeds in the microdroplets, and evidence is provided that an interfacial process is involved. Graphical Abstract <!-- [INSERT GRAPHICAL ABSTRACT TEXT HERE] -->.

A microdroplet-accelerated Biginelli reaction: mechanisms and separation of isomers using IMS-MS

“…Recently, the groups of Cooks, [17][18][19][20][21][22][23][24][25][26] Zare, [27][28][29][30][31][32][33][34][35][36][37][38][39] and others [40][41][42][43][44][45][46] have reported the acceleration of reactions in microdroplet environments during the process of electrospraying reagents into a mass spectrometer. 32 Intrigued by the possibility of faster rates for multicomponent reactions, we explored the use of microdroplets as a means of enabling a rapid Biginelli reaction (Scheme 2).…”

“On‐Droplet” Chemistry: The Cycloaddition of Diethyl Azodicarboxylate and Quadricyclane

“…[4a] Work from our group, [10] as well as others, [11] has demonstrated that reactions in microdroplets generated through electrospray ionization (ESI) are often orders of magnitude faster than their counterparts in bulk solution. [18] New products,n ot observed in bulk, can be formed in microdroplet reactions as demonstrated by work from our group with an intramolecular Diels-Alder reaction of 3,5-hexadienyl acrylate which produced ah ydrolysis product in droplet rather than the typical bulkphase cycloadduct. In this work, Augusti et al argued that "polar acetal molecules are collected from the gas phase by the charged droplets and react with the acylium ions distributed at the liquid surface."…”

“…[11d] Additional studies have demonstrated that reactivity can also be enhanced at the surface of levitated droplets [13] and in microfluidic systems. [18] New products,n ot observed in bulk, can be formed in microdroplet reactions as demonstrated by work from our group with an intramolecular Diels-Alder reaction of 3,5-hexadienyl acrylate which produced ah ydrolysis product in droplet rather than the typical bulkphase cycloadduct. [16] These remarkable,c onfined-volume systems have been implemented to screen novel synthetic routes and optimize flow chemistry.…”

“…In this work, Augusti et al argued that "polar acetal molecules are collected from the gas phase by the charged droplets and react with the acylium ions distributed at the liquid surface." [18] New products,n ot observed in bulk, can be formed in microdroplet reactions as demonstrated by work from our group with an intramolecular Diels-Alder reaction of 3,5-hexadienyl acrylate which produced ah ydrolysis product in droplet rather than the typical bulkphase cycloadduct. [11d] Additional studies have demonstrated that reactivity can also be enhanced at the surface of levitated droplets [13] and in microfluidic systems.…”

“…[17] Interestingly,p revious reports have demonstrated that the microdroplet products are not simply gas-phase products from ion-molecule reactions. [18] New products,n ot observed in bulk, can be formed in microdroplet reactions as demonstrated by work from our group with an intramolecular Diels-Alder reaction of 3,5-hexadienyl acrylate which produced ah ydrolysis product in droplet rather than the typical bulkphase cycloadduct. [19] Intrigued by reports of dramatic acceleration "on water", we set out to investigate the same reactions to determine if they could be accelerated further in the microdroplet environment created by ESI, as the spray process would create an even larger surface-to-volume ratio than previously reported systems.W ec hose the [2s + 2s + 2p]c ycloaddition of diethyl azodicarboxylate (DEAD, 2)w ith quadricyclane (1)a samodel reaction (Scheme 1), first disclosed by Rieber et al [20] and later studied "on water" by Sharpless and coworkers.…”