Study On The Nucleophilic Ring-opening Reaction Of Cyclopropane Dihydropyrrolidones By Electrospray Mass Spectrometry

Succinimide is an important cyclic imide,and many compounds containing succinimide functional group have a wide range of functions in the fields of medicine and chemical industry.At present,the ring-opening phenomenon of these compounds has attracted people’s attention because the ring-opening hydrolysis of succinimide plays a key role in anticancer drugs.Electrospray tandem mass spectrometry（ESI-MSⁿ）combined with deuteration technology,directed synthesis technology,and quantum chemical density functional theory calculation was used to explore the nucleophilic ring-opening addition reaction which is occurs between the cyclopropane dihydropyrrolidones and the protic solvent.The main content is divided into the following two parts:In this paper,it was found that solvated ions produced by the addition of cyclopropane dihydropyrrolidone compounds and protic solvents could be observed in electrospray primary mass spectrometry when protonated solvents were used to dissolve these compounds.The solvated ion peak of cyclopropane dihydropyrrolidone compounds adducted methanol can be detected in ESI-MS when the solvent is methanol,and methods of ionization and instrument type have no effect on this phenomenon.The solvated ion peak of cyclopropane dihydropyrrolidinone compounds adducted deuterated methanol can be detected in ESI-MS when the solvent is deuterated methanol,it is proved that the methanol in the solvated ions really originates from the solvent.In addition,the solvated ion peak of these compounds addition water and ethanol can be detected in ESI-MS when the solvent is water or ethanol.However,for other commonly used solvents,such as isopropanol,acetonitrile,acetone,dichloromethane,ethyl acetate,etc.,and no similar phenomenon was observed in ESI-MS.In order to investigate the cause of this phenomenon,this work investigated the effects of reaction time,reaction concentration,and reaction temperature on the formation of solvated ions in cyclopropane dihydropyrrolidinone compounds.It was found that the cyclopropane dihydropyrrolidinone compound would react with a protic solvent in the solution state,so that the solvated ions generated by the compound addition solvent were observed in the mass spectrum.And the reaction rate is faster at lower concentration and higher temperature.In order to further confirm the structure of solvated ions,this paper directed the synthesis of2-（benzylcarbamoyl）cyclopropane-1-carboxylic acid.The mass spectrum fragment information observed in ESI-MSⁿis consistent with the hydrated ion of the compound,and it is inferred that the solvated ions observed in the mass spectrum of the cyclopropane dihydropyrrolidone compound are generated by the nucleophilic reaction between the compound and the solvent.This paper further studies the nucleophilic reaction mechanism of cyclopropane dihydropyrrolidinones with water,methanol and ethanol solvents using density functional theory 6-31G+（d）/B3LYP.It was found that water,methanol,ethanol,and cyclopropane dihydropyrrolidinones undergo a one-step synergetic ring-opening reaction.The reaction mechanism is that the oxygen atoms in water,methanol,and ethanol nucleophilically attack the carbon atoms on the succinimide group carbonyl group in the cyclopropane dihydropyrrolidone compound to form a transition state containing a four-membered ring.Synergistic reaction,and finally,ring opening generates the corresponding carboxylic acid.The nucleophilic ring-opening reactions of these 24 cyclopropane dihydropyrrolidones with water,methanol and ethanol have reaction energy barriers of 191.66～233.77 KJ?mol^-1,170.16～209.21 KJ?mol^-1 and 169.55～210.09 KJ?mol^-1.This paper confirms that these 24 succinimide-containing cyclopropane dihydropyrrolidones will undergo nucleophilic ring-opening reaction with solvents by electrospray mass spectrometry,which is provides a theoretical basis and method reference for the nucleophilic ring-opening reaction of succinimide compounds,as well as the sample preparation methods and quantitative research in its mass spectrometry detection.