Accelerated generation of (protonated) imines and quinoxalines by formation of C=N bonds in the microdroplets of a nebuliser

Abstract

Ions corresponding to protonated imines appear in the positive ion electrospray mass spectra of mixtures of the parent aromatic aldehyde and arylamine. The formation of these imine products occurs readily in the electrospray source nebuliser, even without the application of a spray potential. This accelerated formation of C=N bonds in the nebuliser has been extended to encompass the preparation of quinoxalines from a range of substituted phenylenediamines and benzils. The condensation may be induced either under conventional positive ion electrospray conditions (to give the protonated quinoxalines) or when the nebuliser is disconnected from the mass spectrometer (to give the neutral quinoxaline). Ions corresponding to intermediate adducts formed by condensation of the phenylenediamine component with the protonated benzil are observed in many cases when the condensation occurs in the mass spectrometer. This finding supports an interpretation based on nucleophilic addition in droplets generated by the nebuliser.

Structure reactivity relationship in the accelerated formation of 2,3-diarylquinoxalines in the microdroplets of a nebuliser

“…If, as seems likely from previous qualitative data, 6 the reaction involves nucleophilic addition of the amino groups of the phenylenediamine to the (protonated) carbonyl groups of the benzil, substituents with a positive s value would be expected to favour the formation of the 2,3-diarylquinoxaline because the substituent would enhance the electrophilicity of the carbonyl groups. Conversely, substituents with a negative s value would be expected to have the opposite effect, leading to a greater proportion of 2,3-diphenylquinoxaline because they would reduce the electrophilicity of the carbonyl groups.…”

“…The formation of heterocycles in the nebuliser is particularly attractive, as illustrated by the Hantzsch synthesis of pyridine derivatives 4 and the facile formation of 2,3-diarylquinoxalines from 1,2-phenylenediamine, C 6 H 4 (NH 2 ) 2 , and a wide range of 3,3 0 -and 4,4 0 -disubstituted benzils, (XC 6 H 4 CO) 2 (X ¼ H, F, Cl, Br, CH 3 or CH 3 O). 6 The 2,3-diarylquinoxalines were formed when the nebuliser was not connected to the mass spectrometer (and was used merely to generate microdroplets). Protonated 2,3-diarylquinoxalines were formed when the nebuliser was connected to the mass spectrometer, which was operated in positive ion electrospray (ESIþ) mode.…”

“…All these reactions occurred far more rapidly than in conventional solution experiments. Moreover, evidence 6 was found under ESIþ conditions for the intermediacy of species that would have been expected to be formed in the acid-catalysed condensation of phenylenediamine with several benzils. In addition, the rate of formation of the protonated diarylquinoxalines in experiments in which the intermediate ions and products were detected in the mass spectrometer appeared to depend on the nature and position of the substituent, X, in the benzil.…”

“…In addition, the rate of formation of the protonated diarylquinoxalines in experiments in which the intermediate ions and products were detected in the mass spectrometer appeared to depend on the nature and position of the substituent, X, in the benzil. 6 It is desirable to set these qualitative observations about the influence of the substituent in the aromatic ring of the benzil on the rate of the condensation with phenylenediamine on a firmer and ideally quantitative foundation. One well-established method for correlating the influence of substituents with the rate of reaction is via a Hammett relationship, 7,8 in which each substituent is assigned a particular s value, which summarises the effects that it has on the electron density in the ring and the consequences of these effects on the chemistry of a reactive site elsewhere in the molecule.…”

Accelerated microdroplet synthesis of benzimidazoles by nucleophilic addition to protonated carboxylic acids

“…Examples of accelerated droplet chemistry involving somewhat related mechanisms are known, in particular the acid catalyzed reaction of ketones with amines to form imines. [5][6][7][8][9][10][11][12][13] It seems likely that the extraordinarily high acidity at the surface of aqueous droplets drives these rapid reactions, even in cases like this study where the solvent is nominally non-aqueous. We explore C-N coupling of amines using protonated carboxylic acids as reagents (clearly counter-intuitive entities, given that neutral carboxylic acids are normally proton donors not acceptors).…”