research article determination of acid dissociation

Research ArticleDetermination of Acid Dissociation Constants(pK119886) of Bicyclic Thiohydantoin-Pyrrolidine Compounds in

20 Ethanol-Water Hydroorganic Solvent

Yahya Nural1 H Ali DoumlndaG12 Hayati SarJ3 Hasan Atabey3

Samet Belveren1 and Muumlge Gemili1

1 Department of Chemistry Faculty of Pharmacy Mersin University 33169 Mersin Turkey2 Advanced Technology Research amp Application Center Mersin University Yenisehir 33343 Mersin Turkey3 Department of Chemistry Faculty of Science and Arts Gaziosmanpasa University 60250 Tokat Turkey

Correspondence should be addressed to Yahya Nural ynural1805yahoocom

Received 17 January 2014 Revised 3 March 2014 Accepted 4 March 2014 Published 30 March 2014

Academic Editor Frantisek Foret

Copyright copy 2014 Yahya Nural et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The acid dissociation constants of potential bioactive fused ring thiohydantoin-pyrrolidine compounds were determined bypotentiometric titration in 20 (vv) ethanol-water mixed at 25 plusmn 01∘C at an ionic background of 01molL of NaCl using theHYPERQUAD computer program Proton affinities of potential donor atoms of the ligands were calculated by AM1 and PM3semiempiric methods We found potentiometrically three different acid dissociation constants for 1andashf We suggest that these aciddissociation constants are related to the carboxyl enol and amino groups

1 Introduction

Acid dissociation constants are important physicochemicalparameters which can provide critical information aboutdrug properties such as solubility lipophilicity acidity [1ndash3] transport behavior bonding to receptors [2ndash4] andpermeability [5] Hence the relationship between the aciddissociation constants and structure in drug design studiesis important [2 3 6] Acid dissociation constants are alsoimportant parameters for the selection of the optimumconditions in the development of analytical methods [57] and provide information about the stereochemical andconformational structures of active centers of enzymes [8]Acid dissociation constants are determined by various meth-ods such as potentiometric [5 9] spectroscopic [6] andelectrophoretic methods [2 10]

Thiohydantoins [11 12] are potential bioactive hete-rocyclic compounds with pharmaceutical and agriculturalapplications [13] due to their antimicrobial [14] antiviral [15]anti-inflammatory [13] antitumor [16 17] and antiandro-genic properties [18] In addition 2-thiohydantoins are useful

intermediates in the synthesis of natural products [19 20]Pyrrolidines and their derivatives are also present in manynatural products [21] and biologically important syntheticcompounds [22ndash24]

In the previous work [25] we have reported the synthesisand structural determination of a series polysubstitutedbicyclic thiohydantoins fused to pyrrolidines In this studypotentiometric and theoretical studies of some polysub-stituted thiohydantoin-pyrrolidine fused ring systems arereported

2 Experimental

21 Apparatus and Materials All reagents having analyti-cal grade were used without further purification Sodiumhydroxide (Merck) potassium hydrogen phthalate (Fluka)and sodium tetraborate (Fluka) were dried at 110∘C beforeuse and 005molkg potassium hydrogen phthalate and001molkg sodium tetraborate solutions were prepared forcalibration of the electrode systems Solution of ligands

Hindawi Publishing CorporationInternational Journal of Analytical ChemistryVolume 2014 Article ID 634194 6 pageshttpdxdoiorg1011552014634194

2 International Journal of Analytical Chemistry

1 2

N

O

S

O

NNH

O

S

O

HO

R1R1

R2R2

H3CO

(a) R1 = Me

(b) R1 = Ph

(c) R1 = Ph

(d) R1 = Ph

(e) R1 = PhCH2

(f) R1 = PhCH2

(g) R1 = PhCH2

R2= 2-naphthy1

R2= 4-chaoropheny1

R2= Ph

R2= 2-naphthy1

R2= Ph

R2= 4-methoxypheny1

R2= pyridin-3-y1

NH

Figure 1 Methyl ester of thiohydantoin-pyrrolidine compounds (1andashg) and their hydrolysis products in acidic media (2andashg)

110minus3molL in 20 (vv) ethanol-water 0025molL NaOHand 01molL HCl (J T Baker) and 10molL NaCl (Riedel-de Haen) stock solution were prepared Deionized water witha resistance of 182MΩsdotcm was obtained with an aquaMAX-Ultra water purification system (Young Lin Inst)

pH-Metric titrations were performed using the MolspinpH meter with an Orion 8102BNUWP ROSS ultracombi-nation pH electrode The temperature in the double-wallglass titration vessel was kept at 250 plusmn 01∘C and controlledusing a thermostat (DIGITERM 100 SELECTA) During thetitration the vessel solution was stirred The combinationpH electrode was calibrated by the buffer solutions of pH4005 (potassium hydrogen phthalate) and 9018 (sodiumtetraborate) at 250 (plusmn01)∘C according to the instructions ofthe Molspin Manual [26] An automatic microburette wasconnected to a Molspin pH-mV-meter

During the titration nitrogen (999) was purgedthrough the titration vessel Acidity and stability constantswere computed using the HYPERQUAD computer program[27]

22 Procedure The potentiometric titrations were carriedout using Molspin pH meter with an Orion 8102BNUWPROSS ultracombined electrode The titration temperaturewas adjusted at 250 plusmn 01∘C and controlled by a thermostat(DIGITERM 100 SELECTA) The double-wall glass titrationvessel was used and the titration solution was magneticallystirred Before and after each titration the double-wall glasstitration vessel was rinsed with distilled water and dried witha piece of tissue The titration vessel was capped by a lidwhich contained three holes for the electrode glass tubingfor nitrogen purging and plastic tubing for alkali from theburette Air bubbles were excludedwhile droppingwith alkalisolution The syringe was rinsed with deionized water and atleast three times with the alkali before filling with the alkalisolution The acid dissociation constants were determinedby titrating 5000mL of ligands with standardized NaOHsolution and three titrations were performed for each ligandHYPERQUAD computer program was used for the calcu-lation of acidity and stability constants Standard deviationsquoted only refer to random errors 130 of the titration datawere obtained for each experiment Volume increment of theNaOH solution was 003mL The pKw value as defined forthe aqueous systemwas obtained as 1398 at the ionic strengthemployed

3 Results and Discussion

Acid dissociation constants of the thiohydantoin-pyrrolidinecompounds containing methyl ester group as a substituent(1andashg) prepared according to the literature method [25]were determined potentiometrically at 250 (plusmn01)∘C in a20 (vv) ethanol-water mixture The solutions were pre-pared in acidic media and the ionic strength was keptconstant at 01 HYPERQUAD is one of latest developedcomputer programmes for calculating equilibrium constantsfrom potentiometric and spectrophotometric data [27] Inthis respect the programme is quite useful In this study itwas used for calculating acid dissociation constants of ligandsfrom potentiometric dataWe found potentiometrically threedifferent pK

119886

values for each compound except for 1g whichhad four acid dissociation constants due to the presence ofthe pyridine group For the thiohydantoin-pyrrolidine fusedring systems (1andashg) pK

1198861

pK1198862

and pK1198863

values were foundin a range of 321 plusmn 002ndash380 plusmn 005 813 plusmn 001ndash866 plusmn002 and 1087 plusmn 001ndash1270 plusmn 005 respectively pK

1198861

values(a range of 321 plusmn 002ndash380 plusmn 005) arise from hydrolysisof the methyl ester in acidic aqueous solution In acidicsolution the weak nucleophile water attacks carbonyl carbonatom having protonated oxygen atom then carboxylic acidderivatives and alcohol groups are formed [28] Similarlycarboxylic acid derivatives of the thiohydantoin-pyrrolidinecompounds (2andashg) are formed after hydrolysis of methylester groups of thiohydantoin-pyrrolidine compounds (1andashg) (Figure 1) Despite all this according to protonation ofthe thiohydantoin-pyrrolidine fused ring systems in acidicsolution the thiohydantoin-pyrrolidine fused ring systemscontaining carboxylic acid group (2andashf) may have four acidiccenters as carboxyl enthiol enol and amino group Asa result of theoretical and experimental calculations wesuggest that pK

1198861

value is related to the carboxyl grouppK1198862

and pK1198863

values are related to enol and amino grouprespectively

Acid dissociation constants were potentiometricallyobtained from several series of independent measurementsThree deprotonated species that formulated as LH

3 LH2

and LH were observed during titration processes Thedeprotonation equilibrium is as seen in the followingequations (charges are omitted for simplicity)

LH119899999445999468 LH

119899minus1+H (1)

International Journal of Analytical Chemistry 3

and the deprotonation constants (K119899) are given as

K119899=

[LH119899minus1] [H]

[LH119899]

(2)

All species have broad protonation space between pH2 and 12 When pH increases the protonated ligand lossesprotons and it is converted to the other forms The titrationcurves of the ligands (2andashg) and the distribution curves ofspecies H in 20 (vv) ethanol-water mixed are shown inFigure 2

Acid dissociation constants of ligands were computedfrom data which were obtained by potentiometric titrationsusing HYPERQUAD computer program These acid dissoci-ation constants are given in Table 1

Theoretical calculations were made in order to examinethe structure of the species and to determine protonationorder of nitrogen oxygen and sulphur atoms in the ligandsThe formation heats (119867

119891) and the total energies (TE) of

the ligands and monoprotonated species were calculatedby semiempirical AM1 and PM3 methods In addition theproton affinity of each nitrogen oxygen and sulphur atom(PA) in the ligands was found using formation heats in thefollowing equation and given in Table 2

PA = 3672 + Δ119867∘119891

(B) minus Δ119867∘119891

(BH+) (3)

where PA is the proton affinity of B types Δ119867∘119891

(B) is theformation heat of B molecule Δ119867∘

119891

(BH+) is the formationheat of BH+ molecule and 3672 is the formation heat of H+[29]

Proton affinity gives information about protonationorder Since the nitrogen oxygen and sulphur atoms havingthe highest PA are 2S in ligand in other ways 2S is morebasic than other nitrogen and oxygen groups Thus thefirst protonated atom is 2S in this ligand According to thecalculated results (TE 119867

119891 and PA) protonation orders of

atoms in the ligand are 3S 4N 1O and 5O but dissociationorders of atoms in the H are 5O 1O 4N and 3S There mightbe differences in these orders due to forming intermolecularhydrogen bonding and forming acid thiol and enol groupbecause of tautomerism in the ligand It is assumed thathigh affinity causes the protonation of the sulfur and oxygenatoms on ligand and increases the mobility of its 120587-electronsConsequently sulfur and oxygen atoms of thiohydantoinbegin to be hydrolyzed at appreciable rates in the solutionsmore alkaline than pH 9 [30 31]

According to the electronic delocalisation which isenhanced upon deprotonation the ligand is very versatilebecause thione and ketone formswere easily transformed intothiol and enol forms depending on pH [32 33] Thereforethe ligand (2H3+) has got four ionizable groups as thiolenol amino and carboxyl in ligands In other ways thepotential coordinating sites are sulphur atom of the thiolgroup nitrogen atoms of the amino group and oxygenatoms of the carboxyl group and hydroxyl group But due tointermolecular hydrogen bonding between the neighbouringnitrogen atoms and the basic nature of the sulphur atom thedissociation of the thiol group takes place at a very high pH

Table 1 Acid dissociation constants (pK119886

) of ligands (20 (vv)ethanol-water mixed 250 plusmn 01∘C 119868 = 01molL by NaCl) (log

10

120573

is cumulative acid dissociation constants)

Ligand Species log10

120573 pK119886

Values

2aLH3 1137 plusmn 002 322 plusmn 001

LH2 2003 plusmn 003 866 plusmn 002

LH 2325 plusmn 003 1137 plusmn 001

2bLH3 1116 plusmn 004 324 plusmn 001



2cLH3 1108 plusmn 002 321 plusmn 002



2dLH3 1095 plusmn 008 374 plusmn 004



2eLH3 1112 plusmn 004 340 plusmn 002



2fLH3 1087 plusmn 005 350 plusmn 003



2g





Table 2 The calculated 119867119891

TE and PA values with AM1 and PM3methods for ligand and its monoprotonated forms

Species AM1TE (kcalmol) 119867

119891

(kcalmol) PAH minus5940318 minus8783 mdash1 OndashH+

minus5954575 8441 194962 SndashH+

minus5956021 6995 209423 NndashH+

minus5954616 8399 195384 OndashH+

minus5951386 11630 16307

Species PM3TE (kcalmol) 119867

119891


minus5423882 8377 182232 SndashH+

minus5426561 5708 208923 NndashH+

minus5424216 8053 185474 OndashH+

minus5421939 10329 16771

level Thus acid dissociation constant of thiol group was notdetermined in our experimental conditions

4 Conclusion

In conclusion the acid dissociation constants of thiohydan-toin-pyrrolidine fused derivatives which constitute impor-tant information for future studies in this area were deter-mined potentiometrically and the results were interpreted


0 1 2 3 4 5 6 7 82

4

6

8

10

12

(2g)(2f)(2e)(2d)(2c)(2b)

pH

NaOH (mL)

(2a)

(a)

2 4 6 8 10 120

20

40

60

80

100 LH

()

pH

LLH3 LH2

(b)

()

2 4 6 8 10 120

20

40

60

80

100

pH

LH LLH3 LH2

(c)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3

LH2

(d)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3 LH2

(e)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LHL

LH3 LH2

(f)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3 LH2

(g)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH

L

LH3

LH4

LH2

(h)

Figure 2 Potentiometric titration curves (a) and distribution curves of ligands ((b) 2a (c) 2b (d) 2c (e) 2d (f) 2e (g) 2f (h) 2g) (20 (vv)ethanol-water mixed 250 plusmn 01∘C 119868 = 01molL by NaCl)


with the HYPERQUAD computer program The determi-nation of the acid dissociation constants was performedin 20 (vv) ethanol-water hydroorganic solvent at 25 plusmn01∘C at an ionic background of 01molL of NaCl Under

these conditions three different pK119886

values for 1andashf werecalculated In addition theoretical calculations were carriedout by AM1 and PM3 semiempiric methods

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

Some of this study is a part of Yahya Nural PhD thesis andthe authors thankMersin University (Project Grant BAP-SBEAKB 2009-3 DR for Yahya Nural) for the financial support

References

[1] M Meloun S Bordovska and A Vrana ldquoThe thermodynamicdissociation constants of the anticancer drugs camptothecine7-ethyl-10-hydroxycamptothecine 10-hydroxycamptothecineand 7-ethylcamptothecine by the least-squares nonlinearregression of multiwavelength spectrophotometric pH-titration datardquo Analytica Chimica Acta vol 584 no 2 pp419ndash432 2007

[2] G Roda C Dallanoce G Grazioso V Liberti andM deAmicildquoDetermination of acid dissociation constants of compoundsactive at neuronal nicotinic acetylcholine receptors by meansof electrophoretic and potentiometric techniquesrdquo AnalyticalSciences vol 26 no 1 pp 51ndash54 2010

[3] M Sanchooli ldquoEvaluation of acidity constants and evolutionof electronic features of phenol derivatives in different compo-sitions of methanolwater mixturerdquo Journal of Chemistry vol2013 Article ID 989362 8 pages 2013

[4] A E Putun G Bereket and E Keskin ldquoPotentiometric titra-tions of some 2-substituted 5-nitrobenzimidazole derivatives innonaqueous solventrdquo Journal of Chemical amp Engineering Datavol 40 no 1 pp 221ndash224 1995

[5] I Narin S Sarioglan B Anilanmert andH Sari ldquop119870a determi-nations for montelukast sodium and levodropropizinerdquo Journalof Solution Chemistry vol 39 no 10 pp 1582ndash1588 2010

[6] S Sanli Y Altun N Sanli G Alsancak and J L BeltranldquoSolvent effects on p119870a values of some substituted sulfonamidesin acetonitrile-water binary mixtures by the UV-spectroscopymethodrdquo Journal of Chemical amp Engineering Data vol 54 no11 pp 3014ndash3021 2009

[7] O Hakli K Ertekin M S Ozer and S Aycan ldquoDeterminationof p119870a values of clinically important perfluorochemicals innonaqueousmediardquo Journal of Analytical Chemistry vol 63 no11 pp 1051ndash1056 2008

[8] C Ogretir S Yarligan S Demirayak and T Arslan ldquoA theoret-ical approach to acidity-basicity behaviour of some biologicallyactive 6-phenyl-45-dihydro-3(2H)-pyridazinone derivativesrdquoJournal of Molecular Structure THEOCHEM vol 666-667 pp609ndash615 2003

[9] H Atabey and H Sari ldquoPotentiometric theoretical and ther-modynamic studies on equilibrium constants of aurintricar-boxylic acid and determination of stability constants of its

complexes with Cu2+ Ni2+ Zn2+ Co2+ Hg2+ and Pb2+ metalions in aqueous solutionrdquo Journal of Chemical amp EngineeringData vol 56 no 10 pp 3866ndash3872 2011

[10] S Ehala A A Grishina A E Sheshenev I M Lyapkalo andV Kasicka ldquoDetermination of acid-base dissociation constantsof very weak zwitterionic heterocyclic bases by capillary zoneelectrophoresisrdquo Journal of Chromatography A vol 1217 no 51pp 8048ndash8053 2010

[11] Z D Wang S O Sheikh and Y Zhang ldquoA simple synthesis of2-thiohydantoinsrdquoMolecules vol 11 no 10 pp 739ndash750 2006

[12] JThanusu V Kanagarajan andMGopalakrishnan ldquoSynthesisspectral analysis and in vitro microbiological evaluation of3-(3-alkyl-26-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones as a new class of antibacterial and antifungal agentsrdquoBioorganic amp Medicinal Chemistry Letters vol 20 no 2 pp713ndash717 2010

[13] S Cao L ZhuC Zhao et al ldquoSynthesis of thiohydantoins underone-pot three-component solvent-free conditionsrdquoMonatsheftefur Chemie vol 139 no 8 pp 923ndash926 2008

[14] J Marton J Enisz S Hosztafi and T Timar ldquoPreparation andfungicidal activity of 5-substituted hydantoins and their 2-thioanalogsrdquo Journal of Agricultural and Food Chemistry vol 41 no1 pp 148ndash152 1993

[15] A I Khodair A A El-Barbary Y A Abbas and D RImam ldquoSynthesis reactions and conformational analysis of 5-arylidene-2-thiohydantoins as potential antiviral agentsrdquo Phos-phorus Sulfur and Silicon and Related Elements vol 170 no 1pp 261ndash278 2001

[16] M BlancM Cussac A Boucherle andG Leclerc ldquoSynthesis of2-thiohydantoin derivatives with potential immunomodulatingand anticancer activitiesrdquo European Journal of Medicinal Chem-istry vol 27 no 3 pp 267ndash275 1992

[17] A M Al-Obaid H I El-Subbagh A Khodair and M MA Elmazar ldquo5-substituted-2-thiohydantoin analogs as a novelclass of antitumor agentsrdquo Anti-Cancer Drugs vol 7 no 8 pp873ndash880 1996

[18] K Tachibana I Imaoka T Shiraishi et al ldquoDiscovery ofan orally-active nonsteroidal androgen receptor pure antago-nist and the structure-activity relationships of its derivativesrdquoChemical amp Pharmaceutical Bulletin vol 56 no 11 pp 1555ndash1561 2008

[19] N Roue and J Bergman ldquoSynthesis of the marine alkaloidleucettamine Brdquo Tetrahedron vol 55 no 51 pp 14729ndash147381999

[20] R Jakse S Recnik J Svete A Golobic L Golicand B Stanovnik ldquoA simple synthesis of aplysinopsinanalogues by dimethylamine substitution in NN-(dimethylamino)methylidene derivatives of five-memberedheterocyclesrdquo Tetrahedron vol 57 no 39 pp 8395ndash8403 2001

[21] A L Harvey Advances in Drug Discovery Techniques JohnWiley amp Sons West Sussex England 1998

[22] C Najera and J M Sansano ldquo13-dipolar cycloadditionsapplications to the synthesis of antiviral agentsrdquo Organic ampBiomolecular Chemistry vol 7 no 22 pp 4567ndash4581 2009

[23] H A Dondas C W G Fishwick R Grigg and C Kilner ldquo13-dipolar cycloaddition of stabilised and non-stabilised azome-thine ylides derived from uracil polyoxin C (UPoC) access tonikkomycin analoguesrdquo Tetrahedron vol 60 no 15 pp 3473ndash3485 2004

[24] H A Dondas R Grigg and C Kilner ldquoX = Y = ZH systemsas potential 13-dipoles Part 58 cycloaddition route to chiral


conformationally constrained (R)-pro-(S)-pro peptidomimet-icsrdquo Tetrahedron vol 59 no 43 pp 8481ndash8487 2003

[25] Y Nural H A Dondas R Grigg and E Sahin ldquoPolysubsti-tuted fused ring bicyclic thiohydantoins from aminocarbo-N-thioylpyrrolidines derived from azomethine ylide 13-dipolarcycloadditionsrdquo Heterocycles vol 83 no 9 pp 2091ndash2114 2011

[26] L D Pettit ldquoAcademic Softwarerdquo Sourby Farm Timble OtleyUK 1992

[27] P Gans A Sabatini and A Vacca ldquoInvestigation of equilibriain solution Determination of equilibrium constants with theHYPERQUAD suite of programsrdquo Talanta vol 43 no 10 pp1739ndash1753 1996

[28] J Clayden N Greeves S Warren and P Wothers OrganicChemistry Oxford University Press Oxford UK 2007

[29] M J S Dewar and K M Dieter ldquoEvaluation of AM1 calculatedproton affinities and deprotonation enthalpiesrdquo Journal of theAmerican Chemical Society vol 108 no 25 pp 8075ndash80861986

[30] W I Congdon and J T Edward ldquoThiohydantoins X Kineticstudies of acid-hydrolysis of 1-acyl-2-thiohydantoinsrdquo Cana-dian Journal of Chemistry vol 50 no 23 pp 3767ndash3779 1972

[31] W I Congdon and J T Edward ldquoThiohydantoins XI Kineticstudies of alkaline-hydrolysis of 1-acyl-2-thiohydantoinsrdquoCanadian Journal of Chemistry vol 50 no 23 pp 3780ndash37881972

[32] Y Altun F Koseoglu H Demirelli I Yilmaz A Cukurovaliand N Kavak ldquoPotentiometric studies on nickel(II) copper(II)and zinc(II) metal complexes with new schiff bases containingcyclobutane and thiazole groups in 60 dioxane-water mix-turerdquo Journal of the Brazilian Chemical Society vol 20 no 2pp 299ndash308 2009

[33] M A Blanco E Lopez-Torres M A Mendiola E Brunet andM T Sevilla ldquoMacrocyclization of cyclic thiosemicarbazoneswith mercury saltsrdquo Tetrahedron vol 58 no 8 pp 1525ndash15312002

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Chemistry


Advances in

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Hindawi Publishing Corporationhttpwwwhindawicom

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Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


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Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


1 2

N

O

S

O

NNH

O

S

O

HO

R1R1

R2R2

H3CO

(a) R1 = Me

(b) R1 = Ph

(c) R1 = Ph

(d) R1 = Ph

(e) R1 = PhCH2

(f) R1 = PhCH2

(g) R1 = PhCH2

R2= 2-naphthy1

R2= 4-chaoropheny1

R2= Ph

R2= 2-naphthy1

R2= Ph

R2= 4-methoxypheny1

R2= pyridin-3-y1

NH

Figure 1 Methyl ester of thiohydantoin-pyrrolidine compounds (1andashg) and their hydrolysis products in acidic media (2andashg)

110minus3molL in 20 (vv) ethanol-water 0025molL NaOHand 01molL HCl (J T Baker) and 10molL NaCl (Riedel-de Haen) stock solution were prepared Deionized water witha resistance of 182MΩsdotcm was obtained with an aquaMAX-Ultra water purification system (Young Lin Inst)

pH-Metric titrations were performed using the MolspinpH meter with an Orion 8102BNUWP ROSS ultracombi-nation pH electrode The temperature in the double-wallglass titration vessel was kept at 250 plusmn 01∘C and controlledusing a thermostat (DIGITERM 100 SELECTA) During thetitration the vessel solution was stirred The combinationpH electrode was calibrated by the buffer solutions of pH4005 (potassium hydrogen phthalate) and 9018 (sodiumtetraborate) at 250 (plusmn01)∘C according to the instructions ofthe Molspin Manual [26] An automatic microburette wasconnected to a Molspin pH-mV-meter

During the titration nitrogen (999) was purgedthrough the titration vessel Acidity and stability constantswere computed using the HYPERQUAD computer program[27]

22 Procedure The potentiometric titrations were carriedout using Molspin pH meter with an Orion 8102BNUWPROSS ultracombined electrode The titration temperaturewas adjusted at 250 plusmn 01∘C and controlled by a thermostat(DIGITERM 100 SELECTA) The double-wall glass titrationvessel was used and the titration solution was magneticallystirred Before and after each titration the double-wall glasstitration vessel was rinsed with distilled water and dried witha piece of tissue The titration vessel was capped by a lidwhich contained three holes for the electrode glass tubingfor nitrogen purging and plastic tubing for alkali from theburette Air bubbles were excludedwhile droppingwith alkalisolution The syringe was rinsed with deionized water and atleast three times with the alkali before filling with the alkalisolution The acid dissociation constants were determinedby titrating 5000mL of ligands with standardized NaOHsolution and three titrations were performed for each ligandHYPERQUAD computer program was used for the calcu-lation of acidity and stability constants Standard deviationsquoted only refer to random errors 130 of the titration datawere obtained for each experiment Volume increment of theNaOH solution was 003mL The pKw value as defined forthe aqueous systemwas obtained as 1398 at the ionic strengthemployed

3 Results and Discussion

Acid dissociation constants of the thiohydantoin-pyrrolidinecompounds containing methyl ester group as a substituent(1andashg) prepared according to the literature method [25]were determined potentiometrically at 250 (plusmn01)∘C in a20 (vv) ethanol-water mixture The solutions were pre-pared in acidic media and the ionic strength was keptconstant at 01 HYPERQUAD is one of latest developedcomputer programmes for calculating equilibrium constantsfrom potentiometric and spectrophotometric data [27] Inthis respect the programme is quite useful In this study itwas used for calculating acid dissociation constants of ligandsfrom potentiometric dataWe found potentiometrically threedifferent pK

119886

values for each compound except for 1g whichhad four acid dissociation constants due to the presence ofthe pyridine group For the thiohydantoin-pyrrolidine fusedring systems (1andashg) pK

1198861

pK1198862

and pK1198863

values were foundin a range of 321 plusmn 002ndash380 plusmn 005 813 plusmn 001ndash866 plusmn002 and 1087 plusmn 001ndash1270 plusmn 005 respectively pK

1198861

values(a range of 321 plusmn 002ndash380 plusmn 005) arise from hydrolysisof the methyl ester in acidic aqueous solution In acidicsolution the weak nucleophile water attacks carbonyl carbonatom having protonated oxygen atom then carboxylic acidderivatives and alcohol groups are formed [28] Similarlycarboxylic acid derivatives of the thiohydantoin-pyrrolidinecompounds (2andashg) are formed after hydrolysis of methylester groups of thiohydantoin-pyrrolidine compounds (1andashg) (Figure 1) Despite all this according to protonation ofthe thiohydantoin-pyrrolidine fused ring systems in acidicsolution the thiohydantoin-pyrrolidine fused ring systemscontaining carboxylic acid group (2andashf) may have four acidiccenters as carboxyl enthiol enol and amino group Asa result of theoretical and experimental calculations wesuggest that pK

1198861

value is related to the carboxyl grouppK1198862

and pK1198863

values are related to enol and amino grouprespectively

Acid dissociation constants were potentiometricallyobtained from several series of independent measurementsThree deprotonated species that formulated as LH

3 LH2

and LH were observed during titration processes Thedeprotonation equilibrium is as seen in the followingequations (charges are omitted for simplicity)

LH119899999445999468 LH

119899minus1+H (1)



K119899=


[LH119899]

(2)






PA = 3672 + Δ119867∘119891

(B) minus Δ119867∘119891

(BH+) (3)



119891








10

120573



120573 pK119886

Values



















2g








119891


minus5954575 8441 194962 SndashH+

minus5956021 6995 209423 NndashH+

minus5954616 8399 195384 OndashH+

minus5951386 11630 16307


119891


minus5423882 8377 182232 SndashH+

minus5426561 5708 208923 NndashH+

minus5424216 8053 185474 OndashH+

minus5421939 10329 16771


4 Conclusion



0 1 2 3 4 5 6 7 82

4

6

8

10

12

(2g)(2f)(2e)(2d)(2c)(2b)

pH

NaOH (mL)

(2a)

(a)

2 4 6 8 10 120

20

40

60

80

100 LH

()

pH

LLH3 LH2

(b)

()

2 4 6 8 10 120

20

40

60

80

100

pH

LH LLH3 LH2

(c)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3

LH2

(d)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3 LH2

(e)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LHL

LH3 LH2

(f)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3 LH2

(g)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH

L

LH3

LH4

LH2

(h)








Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



K119899=


[LH119899]

(2)






PA = 3672 + Δ119867∘119891

(B) minus Δ119867∘119891

(BH+) (3)



119891








10

120573



120573 pK119886

Values



















2g








119891


minus5954575 8441 194962 SndashH+

minus5956021 6995 209423 NndashH+

minus5954616 8399 195384 OndashH+

minus5951386 11630 16307


119891


minus5423882 8377 182232 SndashH+

minus5426561 5708 208923 NndashH+

minus5424216 8053 185474 OndashH+

minus5421939 10329 16771


4 Conclusion



0 1 2 3 4 5 6 7 82

4

6

8

10

12

(2g)(2f)(2e)(2d)(2c)(2b)

pH

NaOH (mL)

(2a)

(a)

2 4 6 8 10 120

20

40

60

80

100 LH

()

pH

LLH3 LH2

(b)

()

2 4 6 8 10 120

20

40

60

80

100

pH

LH LLH3 LH2

(c)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3

LH2

(d)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3 LH2

(e)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LHL

LH3 LH2

(f)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3 LH2

(g)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH

L

LH3

LH4

LH2

(h)








Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


0 1 2 3 4 5 6 7 82

4

6

8

10

12

(2g)(2f)(2e)(2d)(2c)(2b)

pH

NaOH (mL)

(2a)

(a)

2 4 6 8 10 120

20

40

60

80

100 LH

()

pH

LLH3 LH2

(b)

()

2 4 6 8 10 120

20

40

60

80

100

pH

LH LLH3 LH2

(c)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3

LH2

(d)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3 LH2

(e)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LHL

LH3 LH2

(f)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH LLH3 LH2

(g)

2 4 6 8 10 120

20

40

60

80

100

()

pH

LH

L

LH3

LH4

LH2

(h)








Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of







Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

research article determination of acid dissociation

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