In the Laboratory The Synthesis and Isolation of N tert Butyl 2 phenylsuccinamic Acid and N tert Butyl 3 phenylsuccinamic Acid W An Undergraduate Organic Chemistry Laboratory Experiment Victor Cesare Ishwar Sadarangani Janet Rollins and Dennis Costello Department of Chemistry St John s University Jamaica NY 11439 cesarev stjohns edu Carboxylic acids and their derivatives are fundamental topics of any undergraduate organic chemistry course and a number of laboratory experiments have been developed related to this subject The majority of these experiments 1 6 involve the synthesis of carboxylic acid esters i e Fischer esterification or using acetic anhydride a lachrymator as an acylating agent of an alcohol Less frequently amide syntheses 7 11 have also been employed Recently the facile high yielding synthesis of phenylsuccinamic acids 12 was described and one of these syntheses the reaction of phenylsuccinic anhydride with tert butylamine has been successfully modified and adapted for use in the second semester organic chemistry laboratory at St John s University Succinamic acids 4 amino 4oxobutanoic acids are compounds that contain both the amide and carboxylic acid functionalities see Figure 1 and are of interest because succinate based hydroxamic acids have been shown 13 to have anticancer activity Succinamic acids are easily synthesized by reacting succinic anhydride with an amine or ammonia 2 The reaction an example of nucleophilic acyl substitution demonstrates that the carbonyl carbons of unsymmetrical anhydride 1 are chemically nonequivalent and preferential attack by the bulky tert butylamine 2 occurs at the carbonyl carbon further away from the phenyl substituent Students can rationalize that attack is favored at this position as a result of steric factors O R1 N C O CH2 CH2 C OH R2 Figure 1 Structure of a succinamic acid R1 R2 H alkyl or aryl General Description of the Procedure The procedure is intended to be a traditional experiment Since phenylsuccinic anhydride 1 is an unsymmetrical anhydride one of the methylene hydrogens of succinic anhydride is replaced by the phenyl substituent two regioisomers are possible when it is reacted with an amine such as tertbutylamine 2 see Scheme I If the amine attacks the carbonyl carbon closest to the phenyl group in phenylsuccinic anhydride 1 labeled in the Scheme and ring opening occurs then phenylsuccinamic acid 3 will form If the amine attacks the carbonyl carbon further away from the phenyl group labeled in the Scheme then phenylsuccinamic acid 4 will form In fact in this experiment both compounds 3 and 4 are formed in a ratio of approximately 2 3 respectively Although the IUPAC names for these compounds are 4 tertbutylamino 4 oxo 3 phenylbutanoic acid 3 and 4 tertbutylamino 4 oxo 2 phenylbutanoic acid 4 they are commonly called phenylsuccinamic acids The experimental procedure for the synthesis and isolation compounds 3 and 4 is straightforward and is an attractive alternative to the experiments commonly used to demonstrate reactions involving carboxylic acid derivatives for the following reasons 1 The synthesis and isolation of the products which can easily be completed in approximately two hours introduces students to the carboxylic acid amide anhydride and amine functionalities in one lab period www JCE DivCHED org Unlike acetic anhydride phenylsuccinic anhydride 1 is not a lachrymator and is relatively unreactive with water O O C H3 3 C N C CH CH2 C OH H 4 tert butylamino 4 oxo 3 phenylbutanoic acid 3 1 ether HC O CH2 C C O 2 2 CH3 3CNH2 2 2 1 M HCl O 1 O CH3 3 C N C O CH2 CH C OH H 4 tert butylamino 4 oxo 2 phenylbutanoic acid 4 Scheme I Synthesis of the two isomeric phenylsuccinamic acids Vol 81 No 5 May 2004 Journal of Chemical Education 713 In the Laboratory 3 This is a highly visual experiment Students can see the reaction between anhydride 1 and amine 2 with the instantaneous precipitation of the tert butylamine salts of products 3 and 4 from the ether as soon as the amine is added Students also see that these salts are readily water soluble and that when these salts are converted to the phenylsuccinamic acids 3 and 4 these products easily precipitate from water 4 Students learn that acidity differences between two compounds can be employed to separate purify them The two isomeric products 3 and 4 which are very similar in structure are easily separated based on their difference in acidity This acidity difference is due to the electronic effects of the phenyl ring 5 Since each of the products 3 and 4 contains a chiral center the 1 H NMR demonstrates the diastereotopicity of the methylene protons and a doublet of doublets is observed The same is true of the starting reagent phenylsuccinic anhydride 1 Spectral data of 1 2 and 3 are included in the Supplemental Material W Hazards tert Butylamine is a toxic flammable liquid and preferably should be dispensed directly into an addition funnel from an automatic delivery pipet If this reagent is poured from the bottle the students should do so in an efficient fume hood while wearing gloves Diethyl ether is a flammable low boiling toxic liquid and should be dispensed in an efficient fume hood Also owing to the use of diethyl ether no flames should be used in the laboratory during this experiment Although the toxicological properties of phenylsuccinic anhydride have not been thoroughly investigated one should avoid inhalation and contact with skin The 1 M HCl solution is corrosive and should be handled with care Goggles lab coat and gloves should be worn throughout this experiment Evaluation of Student Results and Benefits of the Experiment Recently St John s University purchased a 400 MHz NMR spectrometer and this experiment has helped to incorporate the use of this instrument into the undergraduate organic laboratory Students gain practical experience in spectroscopy by making the peak assignments in all of their spectra data IR and NMR An additional benefit is that the diastereotopicity of the methylene protons in compounds 1 3 and 4 owing to the chiral carbon is clearly demonstrated in the 1H NMR spectra Although there are always some students that do not achieve complete separation of isomeric products this can advantageously be used to demonstrate that the NMR spectrometer can accurately determine the percent 714 Journal of Chemical Education age of each isomer by comparing the area of the methylene proton peaks of compounds 3 and 4 in the 1H NMR spectrum In addition