Determination of Succinic, Glutaric, and Adipic Acids as Quality Control of Cyclohexanone Production

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1 Appliction Note 85 Determintion of Succinic, Glutric, nd Adipic Acids s Qulity Control of Cyclohexnone Production INTRODUCTION Cyclohexnone is the key intermedite for the production of dipic cid, n importnt compound for the synthesis of nylon 66. Cyclohexne oxidtion is the norml method for the production of cyclohexnone; nd succinic, glutric, nd dipic cids (structures shown in Figure ), s well s their dehydrtion products, re the min y-products. The three liphtic dicroxylic cids re importnt chemicl rw mterils s well, nd their determintion is importnt for the qulity control of cyclohexnone production nd recycling of the y-products. O O O OH HO HO HO OH O O Succinic Acid Glutric Acid Adipic Acid Figure. Structures of succinic, glutric, nd dipic cids. O OH 8855 It is difficult to use potentiometric titrtion to determine succinic, glutric, nd dipic cids due to their similr ioniztion constnts. To determine these compounds y gs chromtogrphy (GC), precolumn derivtiztion esterifiction with lcohols is required ecuse of their strong polrity nd high oiling point. 4 This is time-consuming nd complicted opertion, resulting in poor reproduciility of the esterifiction rte. Therefore, the determintion of succinic, glutric, nd dipic cids is usully performed y ion chromtogrphy (IC) 5-7 nd reversed-phse high-performnce liquid chromtogrphy (RP-HPLC). 8,9 Becuse the three liphtic dicroxylic cids lck good ultrviolet (UV) chromophore, mss spectrometry (MS) is used to chieve sensitive detection., The work shown here descries n LC-MS method for the determintion of succinic, glutric, nd dipic cids in the y-products of cyclohexnone production. The seprtion is performed on Thermo Scientific Acclim Orgnic Acid (OA) column, which is designed for the seprtion of orgnic cids., Bseline seprtion of these three liphtic dicroxylic cids is oserved with resolutions (Rs).6 nd completed within min. Anlytes re detected y electrospry ioniztion (ESI) on Thermo Scientific MSQ Plus mss detector operted in the negtive ion mode y full scn MS. The mss spectr of the peks eluting t pproximtely.8,.5, nd 4.5 min revels the deprotonted moleculr ions [M-H]- t m/z 6.9, m/z.9, nd m/z 44.9 for succinic, glutric, nd dipic cids, respectively.

2 Ions with msses of m/z 7.9, m/z 86.9, nd m/z.9 re chrcteristic frgment ions cused y in-source collision induced dissocition (CID) nd correspond to the loss of one croxyl group using cone voltge setting of 6 V. Quntifiction is ccomplished vi selected ion monitoring (SIM) using ions corresponding to ech of the dicroxylic cids t m/z 7 for succinic cid, m/z for glutric cid, nd m/z 45 for dipic cid. Excellent linerity within. to 5 mg/l is oserved for ech dicroxylic cid, nd method detection limits (MDL) re ll.6 mg/l. EQUIPMENT Thermo Scientific Dionex UltiMte RSLC system including: SR- without Degsser LPG-4RS Pump WPS-TRS Autosmpler TCC-RS Thermosttted Column Comprtment DAD-RS UV-vis Detector MSQ Plus mss detector with ESI source Thermo Scientific Dionex AXP-MS Pump Thermo Scientific Dionex Chromeleon Chromtogrphy Dt System (CDS) softwre, Version 6.8, SR9 or higher REAGENTS AND STANDARDS Deionized (DI) wter, from Milli-Q Grdient A Acetonitrile (CH CN), HPLC grde (Ct.#AC64), Fisher Chemicl Formic cid (FA), HPLC grde, SCRC, Shnghi, Chin Succinic, glutric, nd dipic cids (nlyticl grde) were purchsed from SCRC, Shnghi, Chin. Prepre stock stndrd solutions with concentrtion of mg/l for ech liphtic dicroxylic cid y dissolving the pproprite mount of stndrds in DI wter. Prepre four working stndrd solutions rnging from. to 5. mg/l for the clirtion y dding the pproprite mount of the stock stndrd solution nd diluting with DI wter. SAMPLE PREPARATION Three smple solutions of mixed disic cids (#, #, nd #) generted from cyclohexne production were kindly donted y customer locted in Jingsu Province, Chin. Mke thousnd-fold dilutions with DI wter nd filter through.45 μm memrne (Millex -LH) prior to injection. CHROMATOGRAPHIC CONDITIONS Anlyticl Column: Acclim OA, μm,. 5 mm (P/N 787) Moile Phse: A:. FA queous (v/v) B: CH CN In grdient -5.. min, 5 B,. 5. min, 5 4 B Flow Rte:. ml/min Inj. Volume: μl Column Temp.: C MSQ-Plus Mss Detector Conditions Ioniztion Interfce: ESI Operting Mode: Negtive Scn Scn Events: Full scn for identifiction: 65 5 m/z SIM scn for quntittion: succinic cid: 7 m/z; glutric cid: m/z; dipic cid: 45 m/z Proe Temp.: 4 C Needle Voltge:.5 KV Cone Voltge: 6 V Neulizer Gs: Nitrogen t 75 psi Determintion of Succinic, Glutric, nd Adipic Acids s Qulity Control of Cyclohexnone Production

3 RESULTS AND DISCUSSION Seprtion of Succinic, Glutric, nd Adipic Acids on the Acclim OA Column Formic cid ws used in plce of sulfte or phosphte in order to develop n MS-comptile method with comprle performnce to typicl ionic moile phses. Figure shows the chromtogrms of mixed stndrds solution nd n undiluted smple solution seprted on the Acclim OA column under the specified chromtogrphic conditions with UV detection. Succinic, glutric, nd dipic cids were seprted with good resolution, nd two unknown peks with similr UV spectr to the three dicroxylic cids (Figure ) were found in the smple solution. The purity of these peks my e estimted using the pek purity mtch fctor, which cn e clculted y Chromeleon CDS softwre. The clculted vlues re 999 for succinic, for glutric, 998 for dipic cids, 994 for unknown pek, nd 997 for unknown pek (the corresponding vlue for purity is ). These results demonstrte tht the Acclim OA column provides good selectivity nd is suitle for the determintion of succinic, glutric, nd dipic cids in these smple solutions. Further experimenttion showed tht the two unknown compounds with UV sorption showed no MS response. Efforts to ionize nd detect the unknowns y MS (i.e., enlrgement of scn rnge from 5 to 8 mu, ppliction of different cone voltges etween nd V, use of tmospheric-pressure chemicl ioniztion [APCI] nd ESI sources in negtive nd positive ion modes, nd use of moile phses with different ph vlues) were unsuccessful. Becuse the unknowns were generted during cyclohexne oxidtion, they my e dehydrtion products of the three dicroxylic cids nd/or other degrdnts of cyclohexnone. mau Column: Acclim OA (. 5 mm, µm) Moile Phse: Acetonitrile/. formic cid (v/v), in grdient: cetonitrile, -5.. min, 5; 5. min, 4 Flow Rte:. ml/min Inj. Volume: µl Column Temp.: C Detection: UV, Chromtogrm: : An undiluted smple solution : A mixed stndrds solution ( mg/l for ech dicroxylic cid) 5 Pek:. Succinic cid. Glutric cid. Adipic cid 4. Unknown compound 5. Unknown compound Figure. Chromtogrms of () n undiluted smple solution nd () mixed stndrds solution ( mg/l for ech dicroxylic cid) A B 6. C D E Figure. UV spectr of (A) succinic cid, (B) glutric cid, (C) dipic cid, (D) unknown compound, nd (E) unknown compound. Appliction Note 85

4 Method Reproduciility, Linerity, nd Detection Limits Method reproduciility ws estimted y mking seven consecutive μl injections of mixed disic cids smple spiked with. mg/l of ech stndrd using MS detection. The retention time nd pek re reproduciilities re summrized in Tle nd show good precision. Tle. Reproduciility for Pek Retention Time nd Are Anlyte Retention Time RSD Pek Are RSD Stndrd Concentrtion (mg/l) Succinic cid..4. Glutric cid.7.. Adipic cid Clirtion linerity for MS detection of succinic, glutric, nd dipic cids ws investigted y mking three consecutive injections of mixed stndrds prepred t four different concentrtions. The externl stndrd method ws used to estlish the clirtion curve nd to quntify these liphtic dicroxylic cids in the mixed disic cids smples. Excellent linerity ws oserved from. to 5 mg/l when plotting the concentrtion versus the pek re (otined in SIM chnnels), nd the coefficient of determintion ws.998 for ech plot. The MDL of ech liphtic dicroxylic cid for MS detection ws clculted following the eqution: Detection limit = S t (n, - =.99) The symol S represents Stndrd Devition (SD) of replicte nlyses, n represents numer of replictes, nd t (n, - =.99) represents Student s t vlue for the 99 confidence level with n degrees of freedom. Seven replicte injections of mixed disic cids smple spiked with. mg/l of ech stndrd with MS detection were used to determine the MDLs. Tle summrizes the clirtion nd MDL dt, which show excellent method linerity nd sensitivity. Tle. Method Linerity Dt nd Method Detection Limits (MDL)* Regression Anlyte r MDL (mg/l) Equtions Succinic cid A = 667. c Glutric cid A = 44 c Adipic cid A = 787 c *The single-sided Student s t test method (t the 99 confidence limit) ws used for determining MDL, where the stndrd devition (SD) of the pek re of seven injections is multiplied y.7 to yield the MDL. The customer plnned to extrct the three liphtic dicroxylic cids from the y-product solutions nd use them s mterils to mke other chemicl products. Figure 4 shows the Totl Ion Current (TIC) chromtogrms of the originl nd spiked smples. 4, counts Column: Acclim OA (. 5 mm, µm) Moile Phse: Acetonitrile/. formic cid (v/v), in grdient: cetonitrile, -5.. min, 5; 5. min, 4 Flow Rte:. ml/min Inj. Volume: µl Column Temp.: C MS Detection: Ioniztion mode, ESI Opertion mode, negtive scn Proe temperture, 4 C Needle voltge, 5 V Cone voltge, 6 V Neulizer gs, nitrogen t 75 psi Chromtogrm: : Smple solution with -fold dilution : The sme smple spiked with.5 mg/l for ech dicroxylic cid Pek:. Succinic cid. Glutric cid. Adipic cid 4 5, A 4, counts 4 5 C B Smple Anlysis Three mixed disic cid smples generted during cyclohexne oxidtion for the production of cyclohexnone in different chemicl fctories were kindly supplied y customer. Assys were crried out to determine the contents of succinic, glutric, nd dipic cid in the smples. counts 4 5 Figure 4. TIC chromtogrms of smple solutions of mixed disic cids (A) #, (B) #, nd (C) # Determintion of Succinic, Glutric, nd Adipic Acids s Qulity Control of Cyclohexnone Production

5 Figure 5 shows the mss spectrum of ech individul cid in mixed disic cids smple. The deprotonted moleculr ions [M-H] - t m/z 6.9 for succinic cid, m/z.9 for glutric cid, nd m/z 45. for dipic cid were in good greement with their theoreticl moleculr weights of 8. mu,. mu, nd 46. mu, respectively. The ions detected t m/z 7.9, m/z 86.9, nd m/z.9 re chrcteristic frgment ions cused y in-source collision induced dissocition (CID) nd correspond to the loss of one croxyl group [M-44H] - using cone voltge setting of 6 V. Additionl frgment ions were detected t m/z 98.9, m/z.9, nd m/z 7. nd correspond to the loss of one wter molecule. The presence of moleculr ions nd chrcteristic frgment ions positively confirmed the identities of the three dicroxylic cids in the smple. Tle reports the dt for smple nlysis s utomticlly generted y the Chromeleon softwre. 9 Column: Acclim OA (. 5 mm, µm) Moile Phse: Acetonitrile/. formic cid (v/v) Grdient: Acetonitrile, -5.. min, 5; 5. min, 4 Flow Rte:. ml/min Inj. Volume: µl Column Temp.: C MS Detection: Ioniztion mode, ESI Opertion mode, negtive scn Proe temperture, 4 C Needle voltge, 5 V Cone voltge, 6 V Neulizer gs, nitrogen t 75 psi MS Spectr: (A) Succinic Acid; (B) Glutric Acid; (C) Adipic Acid Succinic Acid MW, m/z A 9 Glutric Acid MW,..9 B m/z Tle. Anlysis Results for Succinic, Glutric, nd Adipic Acids in the Cyclohexnone Production Smples* Smple** # # # Anlyte Amount Detected Added in Smple (mg/l) (mg/l) Succinic cid.*** Totl Amount Found in the Spiked Smple (mg/l) Recovery ().66 6 Glutric cid Adipic cid Succinic cid.7***.68 Glutric cid Adipic cid Succinic cid.5.6 Glutric cid Adipic cid *Averge of three determintions **-fold dilution ***Less thn or close to the MDL (.4 mg/l) CONCLUSION This work descries n effective method for the determintion of succinic, glutric, nd dipic cids in solutions of mixed disic cids generted during cyclohexne oxidtion. Using the Dionex UltiMte RSLC system with the Acclim OA column nd MS detection, fst seline seprtion of these three disic cids ws chieved with good resolution vlues (Rs.6), good method reproduciility, excellent linerity within. to 5 mg/l, nd ccurte results for industril smples C Adipic Acid MW, m/z Figure 5. Mss spectr of (A) succinic, (B) glutric, nd (C) dipic cids from the chromtogrphy of smple solution #. Appliction Note 85 5

6 REFERENCES. Zhng, M.; Wei, J.; Bi, Y.J.; Go, Y.; Wu, Y., Mio, Y.Q.; Shi, Z. Study of Cler Oxidtion of Cyclohexnone to Adipic Acid Using Hydrogen Peroxide. Chin. J. Org. Chem. 6, 6, 7.. Zhou, W.Y.; Hu, B.C.; Zho, L.R.; Liu, Z.L. Qulittive nd Quntittive Anlysis of the By-Products in the Course of Cyclohexnone Production y HPLC-MS/MS. J. Chin. Mss Spectr. Soc. 9,,.. Product Mnul for IonPc ICE-AS, Document No. 8-7, p 7, Dionex Corportion, Sunnyvle, CA, 6. wedocs/44-8-7_mnul_ice-as_ V.pdf (ccessed Jun, ). 4. Liu, J.; Chen, L.; Zhou, H. Determintion of Dicroxylic Acids in New Compound Liquid Fertilizer y Gs Chromtogrphy. Chin. J. Chromtogr. (Se Pu) 999, 7, Tnk, K.; Chikr, H.; Hu, W.Z., Hsee, K. Seprtion of Croxylic Acids on Wekly Acidic Ction-Exchnge Resin y Ion-Exclusion Chromtogrphy. J. Chromtogr., A 999, 85, Ng, K.L.; Pull, B.; Hddd, P.R.; Tnk, K. Retention Modeling of Electrosttic nd Adsorption Effects of Aliphtic nd Aromtic Croxylic Acids in Ion-Exclusion Chromtogrphy. J. Chromtogr., A 999, 85, IonPc ICE-AS Ion-Exclusion Column, LPN 84-, Dt Sheet for Dionex Corportion, Sunnyvle, CA, 8. wedocs/476-ds_ionpc_ice-as_apr7_ LPN84_.pdf (ccessed Jun, ). 8. Destndu, E.; Vil, J.; Jrdy, A.; Hennion, M.C.; Bonnet, D.; Lncelin, P. Roustness Study of Reversed-Phse Liquid Chromtogrphic Method for the Anlysis of Croxylic Acids in Industril Rection Mixtures. Anl. Chim. Act 6, 57,. 9. Destndu, E.; Vil, J.; Jrdy, A.; Hennion, M.C.; Bonnet, D.; Lncelin, P. Development nd Vlidtion of Reversed-Phse Liquid Chromtogrphy Method for the Quntittive Determintion of Croxylic Acids in Industril Rection Mixtures. J. Chromtogr., A 5, 88, 49.. Käkölä, J.; Alén, R. A Fst Method for Determining Low-Moleculr-Mss Aliphtic Croxylic Acids y High-Performnce Liquid Chromtogrphy Atmospheric Pressure Chemicl Ioniztion Mss Spectrometry. J. Sep. Sci. 6, 9, Käkölä, J.; Alén, R.; Pkknen, H.; Mtilinen, R.; Lhti, K. Quntittive Determintion of the Min Aliphtic Croxylic Acids in Wood Krft Blck Liquors y High-Performnce Liquid Chromtogrphy Mss Spectrometry. J. Chromtogr., A 7, 9, 6.. Product Mnul for Acclim Orgnic Acid (OA), Document No. 996-, Dionex Corportion, Sunnyvle, CA, 9. wedocs/4786-mn-996--acclim-oa- Jul9.pdf (ccessed Jun, ).. Acclim Orgnic Acid (OA) HPLC Column, LPN 6-, Dt Sheet for Dionex Corportion, Sunnyvle, CA, 4. wedocs/595-acclim_oa_v.pdf (ccessed Jun, ). Milli-Q nd Millex re registered trdemrks of Millipore Corportion. All other trdemrks re the property of Thermo Fisher Scientific Inc. nd its susidiries. Speed Simplicity Solutions Dionex Products 8 Titn Wy P.O. Box 6 Sunnyvle, CA (48) 77-7 North Americ U.S./Cnd (847) South Americ Brzil (55) 7 54 Europe Austri (4) Benelux () () Derk (45) Frnce () 9 Germny (49) Irelnd (5) Itly (9) Sweden (46) Switzerlnd (4) United Kingdom (44) Asi Pcific Austrli (6) 94 5 Chin (85) 48 8 Indi (9) Jpn (8) Kore (8) Singpore (65) Tiwn (886) LPN 89- PDF 8/ Thermo Fisher Scientific, Inc. 6 Determintion of Succinic, Glutric, nd Adipic Acids s Qulity Control of Cyclohexnone Production